JP4473698B2 - Pyridine compounds - Google Patents

Description

  The present invention relates to a pyridine compound having a peptidase inhibitory action and useful as a prophylactic / therapeutic agent for diabetes.

  Peptidases are known to be associated with various diseases. Dipeptidyl peptidase-IV (hereinafter sometimes abbreviated as DPP-IV), which is a kind of peptidase, specifically binds to a peptide containing proline (or alanine) second from the N-terminus, and the proline ( Alternatively, it is a serine protease that cleaves the C-terminal side of alanine) to produce a dipeptide. It has also been shown that DPP-IV is the same molecule as CD26 and has been reported to be related to the immune system. The role of DPP-IV in mammals has not been fully clarified, but it plays an important role in neuropeptide metabolism, T cell activation, cancer cell adhesion to endothelial cells, and HIV entry into cells. It is thought that he plays. Particularly in terms of sugar metabolism, DPP-IV plays a role in inactivation of GLP-1 (glucagon-like peptide-1) or GIP (Gastric inhibitory peptide / Glucose-dependent insulinotropic peptide), which are incretins. Regarding GLP-1, the plasma half-life is as short as 1-2 minutes, and GLP-1 (9-36) amide, a degradation product of DPP-IV, acts as an antagonist to the GLP-1 receptor. It is known that its physiological activity is significantly impaired by being decomposed into DPP-IV, such as working. It is also known that if the degradation of GLP-1 is inhibited by inhibiting DPP-IV activity, the physiological activity of GLP-1 is enhanced, such as promoting insulin secretion in a glucose concentration-dependent manner. Based on these facts, compounds having DPP-IV inhibitory activity are effective in impaired glucose tolerance, postprandial hyperglycemia, fasting hyperglycemia and associated obesity / diabetic complications observed in type I and type II diabetes It is expected.

On the other hand, the following compounds have been reported as pyridine compounds.
(1) a formula having an inhibitory action on cholesterol ester transfer protein (hereinafter abbreviated as CETP)

[Wherein R ₂ and R ₆ independently represent hydrogen, hydroxy, alkyl, etc .; R ₃ represents hydroxy, amide, etc .; R ₄ represents hydrogen, hydroxy, halogen, etc .; R ₅ represents hydrogen, hydroxy, halogen, etc. ] (Refer patent document 1).
(2) Formula having CETP inhibitory action or glucagon antagonistic action

[Wherein A represents C _6-10 aryl which may be substituted with halogen or the like; D represents linear or branched alkyl having 8 or less carbon atoms which may be substituted with hydroxy; and E and L are the same or differently, C _3-8 cycloalkyl are optionally may the number of 8 or less carbon atoms substituted by a straight-chain or branched alkyl or the like; T is R ⁷ -X- or ^{R 8 - (R 9) (} R 10) C -(R ⁷ and R ⁸ are the same or different and represent C _3-8 cycloalkyl, C _6-10 aryl, etc .; R ⁹ represents hydrogen, etc .; R ¹⁰ represents hydrogen, halogen, azide, etc.) A compound represented by the formula:
formula

[In the formula, A represents C _6-10 aryl optionally substituted with halogen or the like; D and E are the same or different and each represents a linear or branched alkyl having 8 or less carbon atoms which may be substituted with hydroxy. V represents O, S or NR ⁵ (R ⁵ represents hydrogen, linear or branched alkyl having 6 or less carbon atoms or phenyl); R ¹ represents C _3-6 cycloalkyl, C _6-10 aryl, etc. L and T are the same or different and each represents trifluoromethyl and the like] or a formula

Wherein Ar is an optionally substituted aromatic or heteroaromatic group; R ⁴ and R ⁵ are independently hydrogen, C _1-6 alkyl, etc .; R ^1a and R ^1b are independently tri Represents fluoromethyl, C _1-6 alkyl, etc.] (see Patent Documents 2 and 3).

(3) Formula with CETP inhibitory action

[Wherein, A and E are the same or different and each represents C _6-10 aryl which may be substituted with halogen or the like; D represents linear or branched alkyl having 8 or less carbon atoms which may be substituted with hydroxy] ; L is C _3-8 cycloalkyl, a straight-chain or branched alkyl, such as 8 carbon atoms; T is R ³ -X- and ^{R 4 - (R 5) (} R 6) C- (R 3 and R ⁴ is the same or different and represents C _3-8 cycloalkyl, C _6-10 aryl, etc .; R ⁵ represents hydrogen, etc .; R ⁶ represents hydrogen, halogen, azide, etc.) Compound or salt thereof (see Patent Document 4).
(4) Formula with herbicidal action

[Wherein R ₂ and R ₆ are independently bromoalkyl, chloroalkyl, etc .; R ₄ is alkyl, cycloalkylalkyl, alkylthioalkyl, cycloalkyl, alkoxyalkyl or dialkylaminoalkyl; R ₃ and R ₅ are , one CO-Y (Y represents an alkylthio, alkoxy or containing n heterocyclic group), the other ^{- (- C (R 9)} (R 10) -) integer of n-X (n is 1-3 R ⁹ and R ¹⁰ independently represent hydrogen, alkyl, etc .; X represents halogen, OH, etc.)] or a salt thereof (see Patent Document 5).

(5) Formula having DPP-IV inhibitory action

[Wherein R ¹ represents hydrogen or lower alkyl; R ² represents a heterocyclic group or aryl each optionally substituted by lower alkyl or the like; R ³ and R ⁴ together with the carbon atom to which they are bonded, halogen And the like, or a salt thereof (see Patent Document 6).
(6) Formula having DPP-IV inhibitory action

[Wherein X represents N or CR ⁵ (R ⁵ represents hydrogen or lower alkyl); R ¹ and R ² independently represent hydrogen or lower alkyl; R ³ is each substituted with lower alkyl or the like; A heterocyclic group or aryl; R ⁴ represents lower alkyl or the like] or a salt thereof (see Patent Document 7).
However, there are no reports on the compounds of the present invention.

International Publication No. WO99 / 41237 Pamphlet International Publication No. WO98 / 04528 Pamphlet U.S. Patent No. 6218431 US Pat. No. 5,925,645 International Publication No. WO92 / 20659 Pamphlet International Publication No. WO03 / 068748 Pamphlet International Publication No. WO03 / 068757 Pamphlet

  Development of a compound that has a peptidase inhibitory action, is useful as a preventive / therapeutic agent for diabetes, and has excellent properties such as drug efficacy, action time, specificity, and low toxicity is desired.

  The present inventors bonded an amino group which may be substituted via a divalent chain hydrocarbon group to the 3-position of the pyridine ring, and an aromatic group which may be substituted at the 4-position. Formulas with chemical structural characteristics

[Wherein, 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 is a divalent chain hydrocarbon group,
Q represents a bond or a divalent chain 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, or an optionally substituted group. A good amino group or a cyclic group which may be substituted is shown.
However, when X is an ethoxycarbonyl group, Q represents a divalent chain hydrocarbon group.]
Represented by the formula (however,
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 a salt thereof [hereinafter referred to as compound (I ) May have a superior peptidase inhibitory activity and is useful for the prevention and treatment of diabetes for the first time. Based on this knowledge, the present inventors have conducted intensive research and have completed the present invention.

That is, the present invention relates to 1) Compound (I);
2) R ¹ and R ² are the same or different and may be a hydrocarbon group which may be substituted, and X may be a cyano group, a nitro group, an acyl group, a substituted hydroxy group or a substituted group Compound (I) which is a thiol group or an optionally substituted cyclic group;
3) Compound (I) wherein the acyl group represented by X is a carboxyl group;
4) R ¹ and R ² are the same or different and are substituted with 1 to 3 substituents selected from a C _3-10 cycloalkyl group, a C _1-6 alkoxy-carbonyl group and a C _1-6 alkoxy group. Compound (I) which may be a C _1-10 alkyl group;
5) R ³ is a C _1-6 alkyl group _optionally substituted with 1 to 3 halogen atoms and a C _6-14 aryl _optionally substituted with 1 to 3 substituents selected from halogen atoms Compound (I) as a group;
6) Compound (I) wherein R ⁴ is an amino group;
7) Compound (I) wherein L is a C _1-10 alkylene group;
8) Compound (I) wherein Q is a bond;
9) Compound (I), wherein X is an acyl group, a substituted hydroxy group, an optionally substituted thiol group or an optionally substituted amino group;
10) Compound (I) wherein X is a carboxyl group;
11) 5- (Aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinic acid;
5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid;
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;
3-({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) methyl benzoate;
N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] isoxazole-4-carboxamide; or a salt thereof (I);
12) Prodrugs of compound (I);
13) A medicament comprising compound (I) or a prodrug thereof;
14) The medicament according to 13) above, which is a prophylactic / therapeutic agent for diabetes, diabetic complications, glucose intolerance or obesity;
15) A peptidase inhibitor comprising compound (I) or a prodrug thereof;
16) The inhibitor according to 15) above, wherein the peptidase is dipeptidyl peptidase-IV;
17) Use of compound (I) or a prodrug thereof for producing a prophylactic / therapeutic agent for diabetes, diabetic complications, glucose intolerance or obesity;
18) Use of compound (I) or a prodrug thereof for producing a peptidase inhibitor;
19) A method for preventing or treating diabetes, diabetic complications, glucose intolerance or obesity in a mammal, comprising administering the compound (I) or a prodrug thereof to the mammal;
20) A method for inhibiting peptidase in a mammal, comprising administering the compound (I) or a prodrug thereof to the mammal;
21) Formula

[Wherein R ¹ , R ² , R ³ and Q have the same meaning as in compound (I), La represents a bond or a divalent chain hydrocarbon group, and Xa represents a hydrogen atom, a nitro group or an acyl group. , A substituted hydroxy group, an optionally substituted thiol group, an optionally substituted amino group or an optionally substituted cyclic group; ]
A compound represented by the formula:

[The symbols in the formula are as defined above]
A method for producing a compound represented by the formula:
And so on.

  The compound of the present invention has an excellent peptidase inhibitory action and is useful as a prophylactic / therapeutic agent for diabetes.

Hereinafter, the definition of each symbol in formula (I) will be described in detail.
Examples of the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by R ¹ or R ² include a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _2-10 alkynyl group, 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, C _{3 -10} cycloalkyl-C _1-6 alkyl group and the like.

Here, examples of the C _1-10 alkyl group include 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.
Examples of the C _2-10 alkenyl group include 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 can be mentioned.
Examples of the C _2-10 alkynyl group include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1 -Hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, 1-octynyl and the like.

Examples of the C _3-10 cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, and 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 the like. .
Examples of the C _3-10 cycloalkenyl group include 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl and the like.
Examples of the C _4-10 cycloalkadienyl group include 2,4-cyclopentadiene-1-
Yl, 2,4-cyclohexadien-1-yl, 2,5-cyclohexadien-1-yl and the like.
Examples of the C _6-14 aryl group include phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, biphenylyl and the like. Of these, phenyl, 1-naphthyl, 2-naphthyl and the like are preferable.
Examples of the C _7-13 aralkyl group include benzyl, phenethyl, naphthylmethyl, biphenylylmethyl and the like.
Examples of the C _8-13 arylalkenyl group include styryl.
Examples of the C _3-10 cycloalkyl-C _1-6 alkyl group include cyclohexylmethyl and the like.

The aforementioned C _1-10 alkyl group, C _2-10 alkenyl group and C _2-10 alkynyl group may have 1 to 3 substituents at substitutable positions.
As such a substituent, for example,
(1) C _3-10 cycloalkyl group (eg, cyclopropyl, cyclohexyl);
(2) C _6-14 aryl group (eg, phenyl, naphthyl);
(3) substituted with 1 to 3 substituents selected from a carboxyl group, a carbamoyl group, a thiocarbamoyl group and a C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl) Aromatic heterocyclic groups which may be substituted (eg, thienyl, furyl, pyridyl, oxazolyl, thiazolyl, tetrazolyl, oxadiazolyl, pyrazinyl, quinolyl, indolyl);
(4) Non-aromatic heterocyclic group (eg, tetrahydrofuryl, morpholino, thiomorpholino, piperidino, pyrrolidinyl, piperazinyl, oxodioxolyl) optionally substituted by a C _1-6 alkyl group (eg, methyl, ethyl) , Oxodioxolanyl, oxo-2-benzofuranyl, oxooxadiazolyl);
(5) C _1-6 alkyl group (eg, methyl, ethyl), C _1-6 alkyl-carbonyl group (eg, acetyl, isobutanoyl, isopentanoyl) and C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl) Amino group optionally mono- or di-substituted with a substituent selected from ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl);
(6) C _1-6 alkylsulfonylamino group (eg, methylsulfonylamino);
(7) amidino group;
(8) C _1-6 alkyl-carbonyl group (eg, acetyl, isobutanoyl, isopentanoyl);
(9) C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl);
(10) a C _1-6 alkylsulfonyl group (eg, methylsulfonyl);
(11) Mono or disubstituted with a C _1-6 alkyl group (eg, methyl, ethyl) which may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine) A good carbamoyl group;
(12) Mono- or di-substituted with a C _1-6 alkyl group (eg, methyl, ethyl) which may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine) A good thiocarbamoyl group;
(13) Mono or disubstituted with a C _1-6 alkyl group (eg, methyl, ethyl) which may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine) A good sulfamoyl group;
(14) carboxyl group;
(15) hydroxy group;
(16) C _1-6 alkoxy group (eg, methoxy, ethoxy) optionally substituted by 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine);
(17) a C _2-6 alkenyloxy group (eg, ethenyloxy) optionally substituted by 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine);
(18) C _3-10 cycloalkyloxy group (eg, cyclohexyloxy);
(19) C _7-13 aralkyloxy group (eg, benzyloxy);
(20) C _6-14 aryloxy group (eg, phenyloxy, naphthyloxy);
(21) C _1-6 alkyl-carbonyloxy group (eg, acetyloxy, tert-butylcarbonyloxy);
(22) a thiol group;
(23) a C _1-6 alkylthio group (eg, methylthio, ethylthio) optionally substituted by 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine);
(24) C _7-13 aralkylthio group (eg, benzylthio);
(25) C _6-14 arylthio group (eg, phenylthio, naphthylthio);
(26) a sulfo group;
(27) a cyano group;
(28) an azido group;
(29) a nitro group;
(30) Nitroso group;
(31) a halogen atom (eg, fluorine, chlorine, bromine, iodine);
(32) C _1-6 alkylsulfinyl group (eg, methylsulfinyl);
Etc.

In addition, the C _3-10 cycloalkyl group, the C _3-10 cycloalkenyl group, the C _4-10 cycloalkadienyl group, the C _6-14 aryl group, the C _7-13 aralkyl exemplified as the “hydrocarbon group”. The group, C _8-13 arylalkenyl group and C _3-10 cycloalkyl-C _1-6 alkyl group may have 1 to 3 substituents at substitutable positions.
As such a substituent, for example,
Substituents exemplified as substituents in the aforementioned C _1-10 alkyl group and the like;
Substituted with 1 to 3 substituents selected from a halogen atom (eg, fluorine, chlorine, bromine, iodine), a carboxyl group, a C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl) and a carbamoyl group An _optionally substituted C _1-6 alkyl group (eg, methyl, ethyl);
Substituted with 1 to 3 substituents selected from a halogen atom (eg, fluorine, chlorine, bromine, iodine), a carboxyl group, a C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl) and a carbamoyl group An optionally substituted C _2-6 alkenyl group (eg, ethenyl, 1-propenyl);
A C _7-13 aralkyl group (eg, benzyl);
Etc.

The “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by R ¹ or R ² is preferably a C _1-10 alkyl group, a C _6-14 aryl group and a C _7-13 aralkyl group, More preferably, it is a C _1-10 alkyl group.
The “optionally substituted hydrocarbon group” represented by R ¹ or R ² is preferably (1) a C _3-10 cycloalkyl group, a C _1-6 alkoxy-carbonyl group, a C _1-6 alkoxy group, etc. A C _1-10 alkyl group _optionally substituted by 1 to 3 substituents selected from:
(2) a C _6-14 aryl group optionally substituted with 1 to 3 substituents selected from a halogen atom, a carboxyl group, a C _1-6 alkoxy-carbonyl group, a carbamoyl group, and the like; and (3) C _7-13 aralkyl groups;
It is. Among them, a C _1-10 alkyl group which may be substituted with 1 to 3 substituents selected from a C _3-10 cycloalkyl group, a C _1-6 alkoxy-carbonyl group, a C _1-6 alkoxy group, etc. Is preferred.

Of the “optionally substituted hydroxy groups” represented by R ¹ or R ² , as the “substituted hydroxy group”, those exemplified as X described later are used.
R ¹ and R ² are preferably selected from “optionally substituted hydrocarbon groups”, more preferably C _3-10 cycloalkyl groups, C _1-6 alkoxy-carbonyl groups, C _1-6 alkoxy groups, and the like. _{Or a} C _1-10 alkyl group which may be substituted with 1 to 3 substituents.

Examples of the “aromatic group” in the “optionally substituted aromatic group” represented by R ³ include an aromatic hydrocarbon group and an aromatic heterocyclic group.
Examples of the aromatic hydrocarbon group include the C _6-14 aryl group exemplified as the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by R ¹ or R ² .
Examples of the aromatic heterocyclic group include 5- to 7-membered monocyclic aromatic heterocycles containing 1 to 4 heteroatoms selected from oxygen atoms, sulfur atoms and nitrogen atoms in addition to carbon atoms as ring constituent atoms. Examples thereof include a cyclic group and a condensed aromatic heterocyclic group. Examples of the condensed aromatic heterocyclic group include a 5- to 7-membered monocyclic aromatic heterocyclic group, a 6-membered ring containing 1 to 2 nitrogen atoms, a benzene ring or one sulfur atom. And a group condensed with a 5-membered ring to be included.
As preferable examples of the aromatic heterocyclic group,
Furyl (eg, 2-furyl, 3-furyl), thienyl (eg, 2-thienyl, 3-thienyl), pyridyl (eg, 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (eg, 2-pyrimidinyl) 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyridazinyl (eg, 3-pyridazinyl, 4-pyridazinyl), pyrazinyl (eg, 2-pyrazinyl), pyrrolyl (eg, 1-pyrrolyl, 2-pyrrolyl, 3- Pyrrolyl), imidazolyl (eg, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), pyrazolyl (eg, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), thiazolyl (eg, 2-thiazolyl, 4 -Thiazolyl, 5-thiazolyl), isothiazolyl, oxazolyl (eg 2-oxazolyl, 4-oxa Lyl, 5-oxazolyl), isoxazolyl, oxadiazolyl (eg, 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl), thiadiazolyl (eg, 1,3, 4-thiadiazol-2-yl), triazolyl (eg, 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 (eg, tetrazol-1-yl, tetrazol-5-yl), etc. ;
Quinolyl (eg, 2-quinolyl, 3-quinolyl, 4-quinolyl), quinazolyl (eg, 2-quinazolyl, 4-quinazolyl), quinoxalyl (eg, 2-quinoxalyl), benzofuryl (eg, 2-benzofuryl, 3-benzofuryl) ), Benzothienyl (eg, 2-benzothienyl, 3-benzothienyl), benzoxazolyl (eg, 2-benzoxazolyl), benzothiazolyl (eg, 2-benzothiazolyl), benzimidazolyl (eg, benzimidazole- 1-yl, benzimidazol-2-yl), indolyl (eg, indol-1-yl, indol-3-yl), indazolyl (eg, 1H-indazol-3-yl), pyrrolopyrazinyl (eg, 1H-pyrrolo [ 2,3-b] pyrazin-2-yl, 1H-pyrrolo [2,3-b] pyrazin-6-yl), imidazopyridini (Eg, 1H-imidazo [4,5-b] pyridin-2-yl, 1H-imidazo [4,5-c] pyridin-2-yl), imidazopyrazinyl (eg, 1H-imidazo [4,5 -b] a condensed aromatic heterocyclic group such as pyrazin-2-yl).

The “aromatic group” in the “optionally substituted aromatic group” represented by R ³ is preferably an aromatic hydrocarbon group, more preferably a C _6-14 aryl group, still more preferably phenyl. It is.

The “aromatic group” in the “optionally substituted aromatic group” represented by R ³ may have 1 to 3 substituents at substitutable positions.
Examples of such a substituent include a substituent in the C _3-10 cycloalkyl group exemplified as the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by R ¹ or R ^2. What was illustrated is mentioned.
The substituent is preferably a C _1-6 alkyl group which may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine);
Halogen atoms (eg, fluorine, chlorine, bromine, iodine);
A C _1-6 alkoxy-carbonyl group;
Carboxyl group;
A hydroxy group;
A C _1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms;
And more preferably a C _1-6 alkyl group (eg, methyl, ethyl) optionally substituted by 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine);
Halogen atoms (eg, fluorine, chlorine, bromine, iodine);
Etc.
The “optionally substituted aromatic group” represented by R ³ is preferably C _1-6 optionally substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine). C _6-14 aryl group _optionally substituted with 1 to 3 substituents selected from alkyl group (eg, methyl, ethyl), halogen atom (eg, fluorine, chlorine, bromine, iodine), etc. _{The 6-14} aryl group is preferably phenyl).

Examples of the “optionally substituted amino group” represented by R ⁴ include a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _3-10 cycloalkyl group, which may be substituted, respectively. 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; optionally substituted by 1 or 2 substituents selected from an acyl group and the like An amino group is mentioned.
Here, 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 group and C _{8- As the 13} arylalkenyl group, those exemplified as the “hydrocarbon group” in the “optionally substituted hydrocarbon group” for R ¹ or R ² can be used.
These 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 group and C _8-13 aryl The alkenyl group may have 1 to 3 substituents at substitutable positions. As such a substituent, for example,
Halogen atoms (eg, fluorine, chlorine, bromine, iodine);
A C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl);
A C _1-6 alkyl-carbonyl group;
A cyano group;
A carbamoyl group optionally mono- or di-substituted with a C _1-10 alkyl group (eg, methyl, ethyl, propyl, isopropyl, neopentyl);
A hydroxy group;
Carboxyl group;
Etc.

As the acyl group exemplified as the substituent of the “optionally substituted amino group”, those exemplified as X described later can be used. Above all,
(1) C _1-6 alkyl-carbonyl group (eg, acetyl, isobutanoyl, isopentanoyl);
(2) a C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl) optionally substituted by a C _1-6 alkoxy-carbonyl group;
(3) C _3-10 cycloalkyl-carbonyl group (eg, cyclopentylcarbonyl, cyclohexylcarbonyl);
(4) 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 alkoxy-carbonyl group, an aromatic heterocyclic group (eg, Tetrazolyl, oxadiazolyl), a non-aromatic heterocyclic group (eg, oxooxadiazolyl) and a C _6-14 aryl-carbonyl group (eg, optionally substituted with 1 to 3 substituents selected from carbamoyl group) Benzoyl);
(5) C _7-13 aralkyloxy-carbonyl group (eg, benzyloxycarbonyl) optionally substituted by 1 to 3 substituents selected from a carboxyl group, a C _1-6 alkoxy-carbonyl group and a carbamoyl group ;
(6) a carbamoyl group;
(7) mono- or di-C _1-6 alkyl-carbamoyl group (eg, dimethylcarbamoyl);
(8) C _1-6 alkylsulfonyl group (eg, methylsulfonyl);
(9) a C _6-14 arylsulfonyl group (eg, phenylsulfonyl, methylsulfonylphenylsulfonyl) _optionally substituted with a C _1-6 alkylsulfonyl group;
(10) an aromatic heterocycle optionally substituted with 1 to 3 substituents selected from a C _1-6 alkyl group and a mono- or di- (C _1-6 alkyl-carbonyl) -amino group (eg, , Pyridyl, thiazolyl, oxazolyl, indolyl) -sulfonyl group (eg, 2-acetylamino-4-methyl-5-thiazolylsulfonyl);
(11) C _7-13 aralkyl-carbonyl group (eg, benzylcarbonyl, phenethylcarbonyl);
(12) C _8-13 arylalkenyl-carbonyl group (eg, styrylcarbonyl);
(13) 1 to 3 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, a C _1-6 alkoxy-carbonyl group and a carbamoyl group Aromatic heterocycles optionally substituted by three substituents (eg furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, pyrazinyl, benzofuryl, benzothienyl, quinoxalinyl) -carbonyl groups (eg, Furylcarbonyl, thienylcarbonyl, thiazolylcarbonyl, pyrazolylcarbonyl, pyridylcarbonyl, pyrazinylcarbonyl, benzofurylcarbonyl, benzothienylcarbonyl, quinoxalinylcarbonyl);
(14) C _1-6 alkyl group (the C _1-6 alkyl group may be substituted with 1 to 3 substituents selected from a carboxyl group, a C _1-6 alkoxy-carbonyl group, and a carbamoyl group) ), A nitrogen-containing heterocycle optionally substituted with 1 to 3 substituents selected from a carboxyl group, a C _1-6 alkoxy-carbonyl group and a carbamoyl group (eg, pyrrolidinyl, piperidinyl, piperazinyl, morpholino, oxopipe) Razinyl) -carbonyl group;
(15) C _6-14 aryl-nitrogen-containing heterocycle (eg, pyrrolidinyl, piperidinyl, piperazinyl, morpholino) -carbonyl group;
(16) 4-oxo-4,5,6,7-tetrahydro-1-benzofuranyl-carbonyl group;
(17) tetrahydropyranylcarbonyl group;
(18) a C _6-14 aryloxy-carbonyl group optionally substituted by 1 to 3 substituents selected from a carboxyl group, a C _1-6 alkoxy-carbonyl group and a carbamoyl group; (19) C _{7- 13} aralkyl-carbamoyl groups (eg, benzylcarbamoyl);
(20) Aromatic heterocycle optionally substituted with 1 to 3 substituents selected from a carboxyl group, a C _1-6 alkoxy-carbonyl group and a carbamoyl group (eg, pyridyl, thiazolyl, oxazolyl, indolyl)- A carbamoyl group (eg, thiazolylcarbamoyl, oxazolylcarbamoyl);
Etc. are preferable.
As preferable examples of the substituted amino group,
(1) mono- or di-C _1-10 alkylamino group (eg, methylamino, dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino);
(2) a mono- or di-C _2-10 alkenylamino group (eg diallylamino);
(3) a mono- or di-C _3-10 cycloalkylamino group (eg, cyclohexylamino);
(4) C _6-14 arylamino group (eg, phenylamino);
(5) mono- or di- (C _1-6 alkyl-carbonyl) -amino group (eg acetylamino, propionylamino, butanoylamino, isobutanoylamino, isopentanoylamino);
(6) a C _1-6 alkoxy-carbonylamino group (eg, methoxycarbonylamino) optionally substituted with a C _1-6 alkoxy-carbonyl group;
(7) Carbamoyl-C _1-10 alkylamino group (eg, carbamoylmethylamino);
(8) C _1-6 alkoxy-carbonyl-C _1-10 alkylamino group (eg, methoxycarbonylmethylamino, ethoxycarbonylmethylamino, tert-butoxycarbonylmethylamino);
(9) Carboxy-C _1-10 alkylamino group (eg, carboxymethylamino);
(10) C _3-10 cycloalkyl-carbonylamino group (eg, cyclopentylcarbonylamino, cyclohexylcarbonylamino);
(11) 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 alkoxy-carbonyl group, an aromatic heterocyclic group (eg, C _6-14 aryl-carbonylamino group (eg, optionally substituted by 1 to 3 substituents selected from tetrazolyl, oxadiazolyl), non-aromatic heterocyclic group (eg, oxooxadiazolyl) and carbamoyl group , Benzoylamino);
(12) a C _7-13 aralkyloxy-carbonylamino group (eg, benzyloxycarbonyl) optionally substituted by 1 to 3 substituents selected from a carboxyl group, a C _1-6 alkoxy-carbonyl group and a carbamoyl group amino);
(13) a carbamoylamino group;
(14) mono- or di-C _1-6 alkyl-carbamoylamino group (eg, dimethylcarbamoylamino);
(15) C _1-6 alkylsulfonylamino group (eg, methylsulfonylamino);
(16) C _1-6 alkylsulfonyl optionally substituted C _6-14 aryl-sulfonylamino group group (e.g., phenylsulfonyl amino, methylsulfonyl phenylsulfonylamino); (17) C _1-6 alkyl group and a mono- Aromatic heterocycle optionally substituted with 1 to 3 substituents selected from — or di- (C _1-6 alkyl-carbonyl) -amino group (eg, pyridyl, thiazolyl, oxazolyl, indolyl) -sulfonyl An amino group (eg, 2-acetylamino-4-methyl-5-thiazolylsulfonylamino);
(18) C _7-13 aralkyl-carbonylamino group (eg, benzylcarbonylamino, phenethylcarbonylamino);
(19) C _8-13 arylalkenyl-carbonylamino group (eg, styrylcarbonylamino);
(20) 1 to 3 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, a C _1-6 alkoxy-carbonyl group and a carbamoyl group An aromatic heterocycle optionally substituted by three substituents (eg furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, pyrazinyl, benzofuryl, benzothienyl, quinoxalinyl) -carbonylamino group;
(21) a C _1-6 alkyl group (the C _1-6 alkyl group may be substituted with 1 to 3 substituents selected from a carboxyl group, a C _1-6 alkoxy-carbonyl group, and a carbamoyl group) ), A nitrogen-containing heterocycle optionally substituted with 1 to 3 substituents selected from a carboxyl group, a C _1-6 alkoxy-carbonyl group and a carbamoyl group (eg, pyrrolidinyl, piperidinyl, piperazinyl, morpholino, oxopipe) Razinyl) -carbonylamino group; (22) C _6-14 aryl-nitrogen-containing heterocycle (eg, pyrrolidinyl, piperidinyl, piperazinyl, morpholino) -carbonylamino group;
(23) a tetrahydropyranylcarbonylamino group;
(24) 4-oxo-4,5,6,7-tetrahydro-1-benzofuranyl-carbonylamino group;
(25) a C _6-14 aryloxy-carbonylamino group optionally substituted with 1 to 3 substituents selected from a carboxyl group, a C _1-6 alkoxy-carbonyl group and a carbamoyl group;
(26) C _7-13 aralkyl-carbamoylamino group (eg, benzylcarbamoylamino);
(27) Aromatic heterocycle optionally substituted with 1 to 3 substituents selected from a carboxyl group, a C _1-6 alkoxy-carbonyl group and a carbamoyl group (eg, pyridyl, thiazolyl, oxazolyl, indolyl)- A carbamoylamino group;
Etc.
The “optionally substituted amino group” represented by R ⁴ is preferably an amino group which may be mono- or di-substituted with a C _1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl). . R ⁴ is particularly preferably an amino group.

Examples of the “divalent chain hydrocarbon group” represented by L or Q include divalent chain hydrocarbon groups having 1 to 10 carbon atoms, specifically,
(1) C _1-10 alkylene group (eg, —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) C _2-10 alkenylene group (eg, —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) C _2-10 alkynylene group (eg, —C≡C—, —CH ₂ —C≡C—, —CH ₂ —C≡C—CH ₂ —CH ₂ —);
Etc. are used.
The divalent chain 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. is there.

L is 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, and more preferably a bond, —CH ₂ —, — (CH ₂ ) ₂ —, —CH═CH— or the like. is there. Q is particularly preferably a bond.

As the “acyl group” represented by X, for example, 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 ^6a [wherein 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 ^5a and R ^6a are the same or different and each represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, or R ^5a and R ^6a together with an adjacent nitrogen atom , Which may form an optionally substituted nitrogen-containing heterocyclic ring].
As the “optionally substituted hydrocarbon group” for R ⁵ , R ⁶ , R ^5a or R ^6a , those exemplified as the aforementioned R ¹ or R ² can be used.

^Examples of the “heterocyclic group” in the “optionally substituted heterocyclic group” represented by R ⁵ , R ⁶ , R ^5a or R ^6a include aromatic heterocyclic groups and non-aromatic heterocyclic groups.
As the aromatic heterocyclic group, those exemplified as the “aromatic group” in the “optionally substituted aromatic group” represented by R ³ can be used.
Examples of the non-aromatic heterocyclic group include a 5- to 7-membered monocyclic non-aromatic group containing 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom as a ring constituent atom. Examples include heterocyclic groups and fused non-aromatic heterocyclic groups. Examples of the condensed non-aromatic heterocyclic group include these 5- to 7-membered monocyclic non-aromatic heterocyclic groups, 6-membered rings containing 1 to 2 nitrogen atoms, benzene rings, or 1 sulfur. And a group condensed with a 5-membered ring containing an atom.
Suitable examples of the non-aromatic heterocyclic group include pyrrolidinyl (eg, 1-pyrrolidinyl), piperidinyl (eg, piperidino), morpholinyl (eg, morpholino), thiomorpholinyl (eg, thiomorpholino), piperazinyl (eg, 1-pyrrolidinyl). Piperazinyl), hexamethyleneiminyl (eg, hexamethyleneimin-1-yl), oxazolidinyl (eg, oxazolidine-3-yl), thiazolidinyl (eg, thiazolidin-3-yl), imidazolidinyl (eg, imidazolidin-3- Yl), oxoimidazolidinyl (eg, 2-oxoimidazolidin-1-yl), dioxoimidazolidinyl (eg, 2,4-dioxoimidazolidin-3-yl), dioxooxazolidinyl ( Examples, 2,4-dioxooxazolidine-3-yl, 2,4-dioxooxazolidine 5-yl, 2,4-dioxooxazolidine-1-yl), dioxothiazolidinyl (eg, 2,4-dioxothiazolidin-3-yl, 2,4-dioxothiazolidin-5-yl) , Dioxoisoindolyl (eg, 1,3-dioxoisoindol-2-yl), oxooxadiazolyl (eg, 5-oxooxadiazol-3-yl), oxothiadiazolyl (eg, 5 -Oxothiadiazol-3-yl), oxopiperazinyl (eg, 3-oxopiperazin-1-yl), dioxopiperazinyl (eg, 2,3-dioxopiperazin-1-yl, 2,5- Dioxopiperazin-1-yl), oxodioxolyl (eg 2-oxo-1,3-dioxol-4-yl), oxodioxolanyl (eg 2-oxo-1,3-dioxolane-4- Il), Oki So-2-benzofuranyl (eg, 3-oxo-2-benzofuran-1-yl), oxodihydrooxadiazolyl (eg, 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3 -Yl), 4-oxo-2-thioxo-1,3-thiazolidin-5-yl, 4-oxo-2-thioxo-1,3-oxazolidine-5-yl, tetrahydropyranyl (eg, 4-tetrahydropyrani) ), 4-oxo-4,5,6,7-tetrahydro-1-benzofuranyl (eg, 4-oxo-4,5,6,7-tetrahydro-1-benzofuran-3-yl), 1,3 ( 2H, 5H) -dioxo-tetrahydroimidazo [1,5-a] pyridinyl, 1,3 (2H, 5H) -dioxo-10,10a-dihydroimidazo [1,5-b] isoquinolinyl and the like.

The “heterocyclic group” in the “optionally substituted heterocyclic group” represented by R ⁵ , R ⁶ , R ^5a or R ^6a has 1 to 3 substituents at substitutable positions. Also good.
Examples of such a substituent include a substituent in the C _3-10 cycloalkyl group exemplified as the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by R ¹ or R ^2. What was illustrated is mentioned.
The substituent is preferably a C _1-6 alkyl group (eg, methyl, ethyl) optionally substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine);
Halogen atoms (eg, fluorine, chlorine, bromine, iodine);
A C _6-14 aryl group;
A C _7-13 aralkyl group;
A hydroxy group;
A C _1-6 alkoxy group;
Carboxyl group;
A C _1-6 alkoxy-carbonyl group;
A carbamoyl group;
A C _1-6 alkyl group substituted with 1 to 3 substituents selected from a carboxyl group, a C _1-6 alkoxy-carbonyl group and a carbamoyl group;
Mono- or di- (C _1-6 alkyl-carbonyl) -amino groups;
Etc.

The “nitrogen-containing heterocycle” in the “optionally substituted nitrogen-containing heterocycle” formed by R ^5a and R ^6a together with the adjacent nitrogen atom is, for example, at least one nitrogen other than a carbon atom as a ring-constituting atom. Examples thereof include a 5- to 7-membered nitrogen-containing heterocyclic ring which contains an atom and may further contain 1 to 2 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom. Preferable examples of the nitrogen-containing heterocycle include pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, morpholine, thiomorpholine, oxopiperazine and the like.
The nitrogen-containing heterocycle may have 1 to 3 (preferably 1 or 2) substituents at substitutable positions. Such substituents include:
A hydroxy group;
A C _1-6 alkyl group optionally substituted by 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine);
A C _7-13 aralkyl group (eg, benzyl, diphenylmethyl) _optionally substituted by 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine);
A C _6-14 aryl group (eg, phenyl) _optionally substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine);
A C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl);
A C _1-6 alkyl group substituted with 1 to 3 substituents selected from a carboxyl group, a C _1-6 alkoxy-carbonyl group and a carbamoyl group;
Carboxyl group;
A carbamoyl group;
Etc.

As preferable examples of the “acyl group”,
(1) formyl group;
(2) carboxyl group;
(3) a carbamoyl group;
(4) C _1-6 alkyl-carbonyl group (eg, acetyl, isobutanoyl, isopentanoyl);
(5) C ₁ which may be substituted with 1 to 3 substituents selected from a carboxyl group, a carbamoyl group, a thiocarbamoyl group, a C _1-6 alkoxy-carbonyl group and a C _1-6 alkyl-carbonyloxy group. _-6 alkoxy-carbonyl groups (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl; carboxymethoxycarbonyl, carboxyethoxycarbonyl, carboxybutoxycarbonyl; carbamoylmethoxycarbonyl; thiocarbamoylmethoxycarbonyl; ethoxycarbonylmethoxycarbonyl, ethoxy Carbonylethoxycarbonyl, methoxycarbonylbutoxycarbonyl, ethoxycarbonylbutoxycarbonyl; tert-butylcarbonyloxymethoxycarbonyl);
(6) An aromatic heterocycle optionally substituted with 1 to 3 substituents selected from a carboxyl group, a carbamoyl group, a thiocarbamoyl group and a C _1-6 alkoxy-carbonyl group (eg, furyl, thienyl, pyridyl) , Thiazolyl, oxazolyl, pyrazinyl, indolyl) -C _1-6 alkoxy-carbonyl group (eg, pyridylmethoxycarbonyl; carboxythiazolylmethoxycarbonyl; carbamoylthiazolylmethoxycarbonyl; ethoxycarbonylthiazolylmethoxycarbonyl);
(7) a non-aromatic heterocycle optionally substituted with a C _1-6 alkyl group (eg, oxodioxolyl, oxodioxolanyl, oxo-2-benzofuranyl) -C _1-6 alkoxy-carbonyl group ( Examples, methyloxodioxolylmethoxycarbonyl, oxo-2-benzofuranylethoxycarbonyl);
(8) C _3-10 cycloalkyl-carbonyl group (eg, cyclopentylcarbonyl, cyclohexylcarbonyl);
(9) halogen atom, cyano group, optionally halogenated C _1-6 alkyl group (that is, optionally substituted by 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine) C _1-6 alkyl group), C _1-6 alkoxy group, carboxyl group, C _1-6 alkoxy-carbonyl group, aromatic heterocyclic group (eg, tetrazolyl, oxadiazolyl), non-aromatic heterocyclic group (eg, oxo oxadiazolyl) and one to three optionally substituted with a substituent C _6-14 aryl selected from carbamoyl - carbonyl group (e.g., benzoyl, 1-naphthoyl, 2-naphthoyl);
(10) a C _6-14 aryloxy-carbonyl group (eg, phenyloxycarbonyl, optionally substituted with 1 to 3 substituents selected from a carboxyl group, a C _1-6 alkoxy-carbonyl group and a carbamoyl group) Naphthyloxycarbonyl);
(11) Carboxyl group, carbamoyl group, thiocarbamoyl group, C _1-6 alkoxy-carbonyl group, halogen atom, cyano group, nitro group, C _1-6 alkoxy group, C _1-6 alkylsulfonyl group and C _1-6 An alkyl group (the C _1-6 alkyl group may be substituted with 1 to 3 substituents selected from a halogen atom, a carboxyl group, a C _1-6 alkoxy-carbonyl group and a carbamoyl group); C _7-13 aralkyloxy-carbonyl group optionally substituted by 1 to 3 substituents (eg, benzyloxycarbonyl, phenethyloxycarbonyl; carboxybenzyloxycarbonyl; methoxycarbonylbenzyloxycarbonyl; biphenylylmethoxycarbonyl) ;
(12) Mono or di-substituted with a C _1-6 alkyl group optionally substituted with 1 to 3 substituents selected from halogen atoms (eg, fluorine, chlorine, bromine, iodine) and C _1-6 alkoxy groups Substituted carbamoyl groups (eg, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, isobutylcarbamoyl, trifluoroethylcarbamoyl, N-methoxyethyl-N-methylcarbamoyl );
(13) Carbamoyl-C _1-6 optionally mono- or disubstituted with a C _1-6 alkyl group optionally substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine) Alkyl-carbamoyl groups (eg, carbamoylmethylcarbamoyl, carbamoylethylcarbamoyl, dimethylcarbamoylmethylcarbamoyl, dimethylcarbamoylethylcarbamoyl);
(14) C _1-6 alkyl C _1-6 alkoxy optionally substituted by a group - carbonyl -C _1-6 alkyl - carbamoyl group (e.g., methoxycarbonyl methylcarbamoyl, ethoxycarbonyl ethylcarbamoyl, N- ethoxycarbonylmethyl -N-methylcarbamoyl);
(15) Amino group, carboxyl group, C _1-6 alkoxy-carbonyl group, aromatic heterocyclic group (eg, tetrazolyl, oxadiazolyl) which may be mono- or di-substituted with a C _1-6 alkyl group, non-aromatic A C _6-14 aryl-carbamoyl group (eg, phenylcarbamoyl) _optionally substituted with 1 to 3 substituents selected from a heterocyclic group (eg, oxooxadiazolyl) and a carbamoyl group;
(16) C _1-6 alkyl optionally substituted with a group mono - or di -C _3-10 cycloalkyl - carbamoyl group (e.g., cyclopropylcarbamoyl, cyclopentylcarbamoyl, dicyclohexyl carbamoyl, N- cyclohexyl -N- methyl Carbamoyl);
(17) substituted with 1 to 3 substituents selected from halogen atoms (eg, fluorine, chlorine, bromine, iodine), hydroxy groups, carboxyl groups, C _1-6 alkoxy-carbonyl groups and C _1-6 alkyl groups An _optionally substituted C _7-13 aralkyl-carbamoyl group (eg, benzylcarbamoyl, phenethylcarbamoyl, phenylpropylcarbamoyl, hydroxyphenethylcarbamoyl, chlorobenzylcarbamoyl, methoxycarbonylbenzylcarbamoyl, N-benzyl-N-methylcarbamoyl);
(18) An aromatic heterocyclic ring optionally substituted with 1 to 3 substituents selected from a carboxyl group, a carbamoyl group and a C _1-6 alkoxy-carbonyl group (eg, pyridyl, thienyl, furyl, thiazolyl, oxazolyl) , Indolyl) -C _1-6 alkyl-carbamoyl group (eg, indolylethylcarbamoyl, pyridylmethylcarbamoyl, thienylmethylcarbamoyl, thiazolylmethylcarbamoyl);
(19) a C _1-6 alkylsulfonyl group (eg, methylsulfonyl, carboxymethylsulfonyl) optionally substituted with 1 to 3 substituents selected from a carboxyl group, a carbamoyl group, and a C _1-6 alkoxy-carbonyl group );
(20) substituted with 1 to 3 substituents selected from a C _1-6 alkyl group, a carboxyl group, a carbamoyl group, a thiocarbamoyl group, a C _1-6 alkoxy-carbonyl group and a C _1-6 alkylsulfonyl group An _{optionally substituted} C _6-14 arylsulfonyl group (eg, phenylsulfonyl; methylphenylsulfonyl; carboxyphenylsulfonyl; methoxycarbonylphenylsulfonyl; methylsulfonylphenylsulfonyl);
(21) a hydroxy group, a C _1-6 alkyl group (the C _1-6 alkyl group is substituted with 1 to 3 substituents selected from a carboxyl group, a C _1-6 alkoxy-carbonyl group and a carbamoyl group) A nitrogen-containing heterocycle optionally substituted with 1 to 3 substituents selected from a carboxyl group, a C _1-6 alkoxy-carbonyl group and a carbamoyl group (eg, pyrrolidinyl, piperidinyl, piperazinyl, morpholino) , Oxopiperazinyl) -carbonyl group (eg, pyrrolidinylcarbonyl, piperidinylcarbonyl, piperazinylcarbonyl, oxopiperazinylcarbonyl, morpholinocarbonyl, methoxycarbonylpyrrolidinylcarbonyl);
(22) 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine) optionally C _6-14 aryl optionally substituted with - nitrogen-containing heterocyclic ring (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholino) - A carbonyl group (eg, phenylpiperazinylcarbonyl, phenylpiperidinylcarbonyl);
(23) C _7-13 aralkyl optionally substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine) -nitrogen-containing heterocycle (eg, pyrrolidinyl, piperidinyl, piperazinyl, morpholino)- A carbonyl group (eg, benzylpiperazinylcarbonyl);
(24) Aromatic heterocycle optionally substituted with 1 to 3 substituents selected from a C _1-6 alkyl group and a mono- or di- (C _1-6 alkyl-carbonyl) -amino group (eg, , Pyridyl, thiazolyl, oxazolyl, indolyl) -sulfonyl group (eg, 2-acetylamino-4-methyl-5-thiazolylsulfonyl);
(25) Non-aromatic heterocycles (eg, oxodioxolyl, oxodioxolanyl, oxo-2-benzofuranyl) oxy-carbonyl groups (eg, oxodioxolanyloxycarbonyl, oxo-2-benzofuranyloxycarbonyl) );
(26) C _1-6 alkylsulfinyl group (eg, methylsulfinyl);
(27) a thiocarbamoyl group;
(28) a phosphono group which may be mono- or di-substituted with a C _1-6 alkyl group (eg, dimethylphosphono, diethylphosphono);
(29) C _7-13 aralkyl-carbonyl group (eg, benzylcarbonyl, phenethylcarbonyl);
(30) C _8-13 arylalkenyl-carbonyl group (eg, styrylcarbonyl);
(31) 1 to 3 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, a C _1-6 alkoxy-carbonyl group and a carbamoyl group Aromatic heterocycles optionally substituted by three substituents (eg, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, pyrazinyl, benzofuryl, benzothienyl, quinoxalinyl) -carbonyl groups (eg, Furylcarbonyl, thienylcarbonyl, thiazolylcarbonyl, pyrazolylcarbonyl, pyridylcarbonyl, pyrazinylcarbonyl, benzofurylcarbonyl, benzothienylcarbonyl, quinoxalinylcarbonyl);
(32) tetrahydropyranylcarbonyl group;
(33) 4-oxo-4,5,6,7-tetrahydro-1-benzofuranyl-carbonyl group;
(34) a C _3-10 cycloalkyl-C _1-6 alkoxy-carbonyl group optionally substituted with 1 to 3 substituents selected from a carboxyl group, a C _1-6 alkoxy-carbonyl group and a carbamoyl group ( Eg, cyclohexylmethoxycarbonyl);
(35) aromatic heterocycle (eg, thienyl, furyl, pyridyl, oxazolyl, thiazolyl, tetrazolyl, pyridyl, quinolyl, indolyl) -C _7-13 aralkyloxy-carbonyl group (eg, tetrazolylbenzyloxycarbonyl);
(36) a carboxyl group, C _1-6 alkoxy - 1 to 3 is an aromatic heterocyclic ring optionally (eg substituted with a substituent selected from carbonyl and a carbamoyl group, a thienyl, furyl, pyridyl, thiazolyl, oxazolyl , Indolyl) -carbamoyl group (eg, thienylcarbamoyl, furylcarbamoyl, thiazolylcarbamoyl, oxazolylcarbamoyl);
Etc.

The “acyl group” represented by X is preferably
(1) carboxyl group;
(2) a carbamoyl group;
(3) C ₁ which may be substituted with 1 to 3 substituents selected from a carboxyl group, a carbamoyl group, a thiocarbamoyl group, a C _1-6 alkoxy-carbonyl group and a C _1-6 alkyl-carbonyloxy group. _-6 alkoxy-carbonyl groups (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl; carboxymethoxycarbonyl, carboxyethoxycarbonyl, carboxybutoxycarbonyl; carbamoylmethoxycarbonyl; thiocarbamoylmethoxycarbonyl; ethoxycarbonylmethoxycarbonyl, ethoxy Carbonylethoxycarbonyl, methoxycarbonylbutoxycarbonyl, ethoxycarbonylbutoxycarbonyl; tert-butylcarbonyloxymethoxycarbonyl);
(4) A carbamoyl group mono- or di-substituted with a C _1-6 alkyl group which may be substituted with 1 to 3 substituents selected from a halogen atom and a C _1-6 alkoxy group (eg, methylcarbamoyl, Ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, isobutylcarbamoyl, trifluoroethylcarbamoyl, N-methoxyethyl-N-methylcarbamoyl);
(5) A carbamoyl-C _1-6 alkyl-carbamoyl group (eg, carbamoylmethylcarbamoyl, which may be mono- or di-substituted with a C _1-6 alkyl group _optionally substituted with 1 to 3 halogen atoms) Carbamoylethylcarbamoyl, dimethylcarbamoylmethylcarbamoyl, dimethylcarbamoylethylcarbamoyl);
Etc. Among these, a carboxyl group is preferable.

Examples of the “substituted hydroxy group” represented by X include, for example, a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _3-10 cycloalkyl group, a C _3-10 , which may be substituted. Cycloalkenyl group, C _6-14 aryl group, C _7-13 aralkyl group, C _8-13 arylalkenyl group, C _1-6 alkyl-carbonyl group (eg, acetyl, isobutanoyl, isopentanoyl), 5- or 6-membered A hydroxy group substituted with a substituent selected from aromatic heterocyclic groups (eg, furyl, thienyl, thiazolyl, oxazolyl, imidazolyl, triazolyl, pyrazolyl, pyrimidinyl), condensed aromatic heterocyclic groups (eg, indolyl), etc. It is done.
Here, 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 group and C _{8- As the 13} arylalkenyl group, those exemplified as the “hydrocarbon group” in the “optionally substituted hydrocarbon group” for R ¹ or R ² can be used.
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 group, C _8-13 The arylalkenyl group, C _1-6 alkyl-carbonyl group, 5- or 6-membered aromatic heterocyclic group and condensed aromatic heterocyclic group may each have 1 to 3 substituents at substitutable positions. Good. As such a substituent, for example,
Halogen atoms (eg, fluorine, chlorine, bromine, iodine);
A hydroxy group;
A cyano group;
1 or 2 substituents selected from a halogen atom (eg, fluorine, chlorine, bromine, iodine), a carboxyl group, a C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, tert-butoxycarbonyl) and a carbamoyl group An optionally substituted C _1-6 alkyl group;
It may be substituted with 1 or 2 substituents selected from a halogen atom (eg, fluorine, chlorine, bromine, iodine), a carboxyl group and a C _1-6 alkoxy-carbonyl group (eg, tert-butoxycarbonyl). A C _1-6 alkoxy group;
A C _1-6 alkylthio group (eg, methylthio, ethylthio);
A C _1-6 alkyl-carbonyl group;
Carboxyl group;
A C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl);
A carbamoyl group optionally mono- or di-substituted with a C _1-10 alkyl group (eg, methyl, ethyl, propyl, isopropyl, neopentyl);
An amino group optionally mono- or di-substituted with a C _1-10 alkyl group (eg, methyl, ethyl, propyl, isopropyl, neopentyl);
C _1-6 alkyl - carbonylamino group;
Substituted with 1 to 3 substituents selected from a C _1-6 alkyl group (eg, methyl, ethyl), a carboxyl group, a C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl) and a carbamoyl group. Optionally substituted aromatic heterocyclic group (eg, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridyl);
A C _1-6 alkylsulfinyl group (eg, methylsulfinyl);
A C _1-6 alkylsulfonyl group (eg, methylsulfonyl);
Etc.

As preferable examples of the “substituted hydroxy group”,
(1) a C _1-6 alkyl-carbonyloxy group;
(2) a C _1-10 alkoxy group optionally substituted by 1 to 3 substituents selected from a hydroxy group, a carboxyl group, a carbamoyl group and a C _1-6 alkoxy-carbonyl group;
(3) Halogen atom, carboxyl group, C _1-6 alkoxy-carbonyl group, C _1-6 alkylthio group, carbamoyl group, C _1-6 alkoxy group, C _1-6 alkylsulfonyl group, C _1-6 alkylsulfinyl group And a C _1-6 alkyl group (the C _1-6 alkyl group may be substituted with one or two substituents selected from a carboxyl group, a C _1-6 alkoxy-carbonyl group, and a carbamoyl group). A C _6-14 aryloxy group _optionally substituted by 1 to 3 selected substituents;
(4) C _1-6 alkyl group (the C _1-6 alkyl group may be substituted with one or two substituents selected from a carboxyl group, a C _1-6 alkoxy-carbonyl group, and a carbamoyl group) ), A 5- or 6-membered aromatic heterocyclic oxy group (preferably thienyloxy, thiazolyloxy) optionally substituted by 1 to 3 substituents selected from a carboxyl group, a C _1-6 alkoxy-carbonyl group and a carbamoyl group Oxazolyloxy, imidazolyloxy, triazolyloxy, pyrazolyloxy, pyridyloxy, pyrimidinyloxy);
(5) a condensed aromatic heterocyclic oxy group (preferably indolyloxy) optionally substituted by 1 to 3 substituents selected from a carboxyl group, a C _1-6 alkoxy-carbonyl group and a carbamoyl group;
(6) An aromatic heterocyclic ring (preferably pyridyl) -C _1-6 alkoxy group which may be substituted with 1 to 3 substituents selected from a carboxyl group, a C _1-6 alkoxy-carbonyl group and a carbamoyl group ;
(7) an aromatic heterocyclic ring (preferably tetrazolyl) -C _6-14 aryloxy group;
Etc.

Examples of the “optionally substituted thiol group” represented by X include, for example, a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _3-10 cycloalkyl group, C _3-10 cycloalkenyl group, C _6-14 aryl group, C _7-13 aralkyl group, C _8-13 arylalkenyl group, C _1-6 alkyl-carbonyl group (eg, acetyl, isobutanoyl, isopentanoyl), 5 Or substituted with a substituent selected from a 6-membered aromatic heterocyclic group (eg, furyl, thienyl, thiazolyl, oxazolyl, imidazolyl, triazolyl, pyrazolyl, pyrimidinyl), a condensed aromatic heterocyclic group (eg, indolyl), etc. A good thiol group is mentioned.
Here, 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 group and C _{8- As the 13} arylalkenyl group, those exemplified as the “hydrocarbon group” in the “optionally substituted hydrocarbon group” for R ¹ or R ² can be used.
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 group, C _8-13 The arylalkenyl group, C _1-6 alkyl-carbonyl group, 5- or 6-membered aromatic heterocyclic group and condensed aromatic heterocyclic group may each have 1 to 3 substituents at substitutable positions. Good. As such a substituent, those exemplified as the substituent in the C _1-10 alkyl group with respect to the “substituted hydroxy group” represented by X can be used.

Suitable examples of the “optionally substituted thiol group” include
(1) hydroxy group, a carboxyl group, a carbamoyl group and C _1-6 alkoxy - one to three optionally substituted with a substituent C _1-6 alkylthio group selected from a carbonyl group;
(2) a C _6-14 arylthio group optionally substituted by 1 to 3 substituents selected from a carboxyl group, a C _1-6 alkoxy-carbonyl group, a C _1-6 alkylthio group and a carbamoyl group;
(3) 5- or 6-membered aromatic heterocyclic thio optionally substituted with 1 to 3 substituents selected from a C _1-6 alkyl group, a carboxyl group, a C _1-6 alkoxy-carbonyl group and a carbamoyl group A group (preferably thienylthio, thiazolylthio, oxazolylthio, imidazolylthio, triazolylthio, pyrazolylthio, pyridylthio, pyrimidinylthio);
Etc.

As the “optionally substituted amino group” represented by X, those exemplified as the aforementioned R ⁴ can be used.

Examples of the “cyclic group” in the “optionally substituted cyclic group” represented by X include an aromatic hydrocarbon group, a non-aromatic cyclic hydrocarbon group, an aromatic heterocyclic group, a non-aromatic heterocyclic group and the like. Is mentioned.
As the aromatic hydrocarbon group and aromatic heterocyclic group, those exemplified as the “aromatic group” in the “optionally substituted aromatic group” represented by R ³ can be used.
Examples of the non-aromatic heterocyclic group include those exemplified as the “heterocyclic group” in the “optionally substituted heterocyclic group” represented by R ⁵ .
Examples of the non-aromatic cyclic hydrocarbon group include a C _3-10 cycloalkyl group, a C _3-10 cycloalkenyl group, and a C _4-10 cycloalkadienyl group, which may be condensed with a benzene ring, respectively. It is done.
Here, as the C _3-10 cycloalkyl group, the C _3-10 cycloalkenyl group and the C _4-10 cycloalkadienyl group, the “optionally substituted hydrocarbon group represented by the above R ¹ or R ² ” can be used. And those exemplified as the “hydrocarbon group” in FIG.
The “cyclic group” in the “optionally substituted cyclic group” represented by X may have 1 to 3 substituents at substitutable positions.
Examples of such a substituent include a substituent in the C _3-10 cycloalkyl group exemplified as the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by R ¹ or R ^2. What was illustrated is mentioned.
The substituent is preferably 1 to 3 selected from a halogen atom (eg, fluorine, chlorine, bromine, iodine), a carbamoyl group, a carboxyl group and a C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl). An optionally substituted C _1-6 alkyl group (eg, methyl, ethyl);
Halogen atoms (eg, fluorine, chlorine, bromine, iodine);
Carboxyl group;
A C _1-6 alkoxy-carbonyl group;
A carbamoyl group;
Etc.

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. Above all
(1) carboxyl group;
(2) a carbamoyl group;
(3) C ₁ which may be substituted with 1 to 3 substituents selected from a carboxyl group, a carbamoyl group, a thiocarbamoyl group, a C _1-6 alkoxy-carbonyl group and a C _1-6 alkyl-carbonyloxy group. _-6 alkoxy-carbonyl group;
(4) a carbamoyl group mono- or di-substituted with a C _1-6 alkyl group which may be substituted with 1 to 3 substituents selected from a halogen atom and a C _1-6 alkoxy group;
(5) a carbamoyl-C _1-6 alkyl-carbamoyl group optionally mono- or di-substituted with a C _1-6 alkyl group _optionally substituted with 1 to 3 halogen atoms;
Etc. are preferable, and a carboxyl group is particularly preferable.

In the compound (I), when X is an ethoxycarbonyl group, Q represents a divalent chain hydrocarbon group.
Compound (I) is
2,6-diisopropyl-3-methylaminomethyl-4- (4-fluorophenyl) -5-pentylpyridine [This compound is {[4- (4-fluorophenyl) -2,6-diisopropyl-5-pentyl Also called pyridin-3-yl] methyl} methylamine];
2,6-diisopropyl-3-aminomethyl-4- (4-fluorophenyl) -5-pentylpyridine [This compound is {[4- (4-fluorophenyl) -2,6-diisopropyl-5-pentylpyridine Also referred to as -3-yl] methyl} amine];
2,6-diisopropyl-3- (dimethylamino) methyl-4- (4-fluorophenyl) -5-pentylpyridine [This compound is 1- [4- (4-fluorophenyl) -2,6-diisopropyl- 5-pentylpyridin-3-yl] -N, N-dimethylmethanamine]];
2,6-diisopropyl-3- (ethylamino) methyl-4- (4-fluorophenyl) -5-pentylpyridine [This compound is N-{[4- (4-fluorophenyl) -2,6-diisopropyl -5-pentylpyridin-3-yl] methyl} ethanamine]; and
3- (tert-butyldimethylsilyloxymethyl) -2,6-diisopropyl-4- (4-fluorophenyl) -5- (indolyl-5-aminomethyl) pyridine [This compound is N-{[5- ( {[tert-butyl (dimethyl) silyl] oxy} methyl) -4- (4-fluorophenyl) -2,6-diisopropylpyridin-3-yl] methyl} -1H-indole-5-amine] Not included.

Preferable examples of compound (I) include the following compounds.
[Compound A]
R ¹ and R ² are the same or different, C _3-10 cycloalkyl group (preferably cyclopropyl), C _1-6 alkoxy - to 1 selected from carbonyl group (preferably methoxycarbonyl) three substituents An optionally substituted C _1-10 alkyl group (preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, neopentyl);
R ³ is a C _1-6 alkyl group (eg, methyl, ethyl) optionally substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine), a halogen atom (eg, fluorine, chlorine, bromine, iodine) is 1 to 3 substituents optionally substituted by a C _6-14 aryl group (the C _6-14 aryl group selected from such preferably phenyl);
R ⁴ is an amino group which may be mono- or di-substituted with a C _1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl);
L is 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 is a carboxyl Group;
A carbamoyl group;
A C _1-6 alkoxy-carbonyl group;
1-3 carbamoyl group is mono-or di-substituted at a C _1-6 alkyl group optionally substituted by halogen atoms; or 1-3 C _1-6 alkyl optionally substituted by a halogen atom A carbamoyl-C _1-6 alkyl-carbamoyl group optionally mono- or disubstituted with groups;
A compound that is

[Compound B]
R ¹ and R ² are the same or different,
(1) optionally substituted by 1 to 3 substituents selected from a C _3-10 cycloalkyl group (preferably cyclopropyl), a C _1-6 alkoxy-carbonyl group, a C _1-6 alkoxy group, etc. A C _1-10 alkyl group;
(2) a C _6-14 aryl group (preferably phenyl) optionally substituted with 1 to 3 substituents selected from a halogen atom, a carboxyl group, a C _1-6 alkoxy-carbonyl group, a carbamoyl group, and the like; Or (3) a C _7-13 aralkyl group (preferably benzyl);
R ³ is a C _1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, a halogen atom, a C _1-6 alkoxy-carbonyl group, a carboxyl group, a hydroxy group, and 1 to 3 halogen atoms. A C _6-14 aryl group which may be substituted with 1 to 3 substituents selected from a C _1-6 alkoxy group which may be substituted with (the C _6-14 aryl group is preferably phenyl) ;
R ⁴ is an amino group (preferably an amino group) optionally mono- or di-substituted with a C _1-6 alkyl group;
L is 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 is
(1) a hydrogen atom;
(2) a cyano group;
(3) (3a) carboxyl group;
(3b) a carbamoyl group;
(3c) a carboxyl group, a carbamoyl group, thiocarbamoyl group, C _1-6 alkoxy - carbonyl group and C _1-6 alkyl - substituted with a substituent selected from a carbonyl group C _1-6 alkoxy - carbonyl Group;
(3d) Aromatic heterocycle optionally substituted with a substituent selected from a carboxyl group, a carbamoyl group, a thiocarbamoyl group and a C _1-6 alkoxy-carbonyl group (preferably pyridyl, thiazolyl, oxazolyl, indolyl) -C _1-6 alkoxy-carbonyl groups;
(3e) a non-aromatic heterocyclic ring (preferably oxodioxolyl, oxodioxolanyl, oxo-2-benzofuranyl) -C _1-6 alkoxy-carbonyl group optionally substituted with a C _1-6 alkyl group;
(3f) a C _7-13 aralkyloxy-carbonyl group optionally substituted with a substituent selected from a carboxyl group, a carbamoyl group, a thiocarbamoyl group, and a C _1-6 alkoxy-carbonyl group;
(3g) a carbamoyl group mono- or di-substituted with a C _1-6 alkyl group which may be substituted with 1 to 3 halogen atoms and a substituent selected from a C _1-6 alkoxy group;
(3h) a carbamoyl-C _1-6 alkyl-carbamoyl group optionally mono- or disubstituted with a C _1-6 alkyl group _optionally substituted with 1 to 3 halogen atoms;
(3i) C _1-6 alkyl optionally substituted with C _1-6 alkoxy - carbonyl -C _1-6 alkyl - carbamoyl group;
(3j) a mono- or di-C _3-10 cycloalkyl-carbamoyl group optionally substituted by a C _1-6 alkyl group;
(3k) a C _7-13 aralkyl-carbamoyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, a C _1-6 alkoxy-carbonyl group and a C _1-6 alkyl group;
(3l) an aromatic heterocycle (preferably pyridyl, thiazolyl, oxazolyl, indolyl) -C _1-6 alkyl-carbamoyl group;
(3m) a carboxyl group, a carbamoyl group and C _1-6 alkoxy - optionally substituted with a substituent selected from the group C _1-6 alkylsulfonyl group;
(3n) C _1-6 alkyl group, a carboxyl group, a carbamoyl group, thiocarbamoyl group, C _1-6 alkoxy - optionally substituted with a substituent selected from carbonyl and C _1-6 alkylsulfonyl group C _{6 -14} arylsulfonyl group;
(3o) a nitrogen-containing heterocyclic ring (preferably pyrrolidinyl, piperidino, piperazinyl, morpholino) -carbonyl group which may be substituted with a substituent selected from a hydroxy group and a C _1-6 alkoxy-carbonyl group;
(3p) a C _6-14 aryl-nitrogen-containing heterocyclic ring (preferably pyrrolidinyl, piperidino, piperazinyl, morpholino) -carbonyl group optionally substituted with a halogen atom;
(3q) a C _7-13 aralkyl-nitrogen-containing heterocyclic ring (preferably pyrrolidinyl, piperidino, piperazinyl, morpholino) -carbonyl group optionally substituted with a halogen atom;
(3r) a non-aromatic heterocycle (preferably oxodioxolyl, oxodioxolanyl, oxo-2-benzofuranyl) oxy-carbonyl group; or
(3s) a phosphono group which may be mono- or di-substituted with a C _1-6 alkyl group;
(4) a C _1-6 alkyl-carbonyloxy group;
(5) (5a) a C _1-6 alkylthio group which may be substituted with a substituent selected from a carboxyl group, a carbamoyl group and a C _1-6 alkoxy-carbonyl group;
(5b) a C _6-14 arylthio group (preferably phenylthio) optionally substituted with a substituent selected from a carboxyl group, a C _1-6 alkoxy-carbonyl group and a C _1-6 alkylthio group; or
(5c) a 5-membered aromatic heterocyclic thio group (preferably thiazolylthio, oxazolylthio, triazolylthio) optionally substituted with a C _1-6 alkyl group;
(6) (6a) amino group;
(6b) a C _1-6 alkoxy-carbonyl-C _1-10 alkylamino group (preferably methoxycarbonylmethylamino, ethoxycarbonylmethylamino, tert-butoxycarbonylmethylamino);
(6c) a carboxy-C _1-10 alkylamino group;
(6d) a C _7-13 aralkyloxy-carbonylamino group;
(6e) a carbamoylamino group;
(6f) mono- or di-C _1-6 alkyl-carbamoylamino group;
(6g) 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 heterocycle optionally substituted with a substituent selected from a C _1-6 alkyl group and a mono- or di- (C _1-6 alkyl-carbonyl) -amino group (eg, pyridyl, thiazolyl, Oxazolyl, indolyl) -sulfonylamino group; or
(7) Tetrazolyl, oxoimidazolidinyl (preferably 2-oxoimidazolidin-1-yl), dioxoimidazolidinyl (preferably 2,4-dioxoimidazolidin-3-yl), oxopiperazinyl ( Preferably 3-oxopiperazin-1-yl), dioxopiperazinyl (preferably 2,3-dioxopiperazin-1-yl, 2,5-dioxopiperazin-1-yl) or oxodihydrooxadiazolyl (Preferably 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl);
A compound that is

[Compound C]
Of the compounds B, R ⁴ is an amino group, and X is any one of the above (3a) to (3s).

[Compound D]
R ¹ , R ² , R ³ , R ⁴ , L and Q are the same as the compound B, and X is
(1) a hydrogen atom;
(2) a cyano group;
(3) (3a) carboxyl group;
(3b) a carbamoyl group;
(3c) C ₁ which may be substituted with 1 to 3 substituents selected from a carboxyl group, a carbamoyl group, a thiocarbamoyl group, a C _1-6 alkoxy-carbonyl group and a C _1-6 alkyl-carbonyloxy group. _-6 alkoxy-carbonyl group;
(3d) An aromatic heterocyclic ring (preferably furyl, thienyl, pyridyl) optionally substituted by 1 to 3 substituents selected from a carboxyl group, a carbamoyl group, a thiocarbamoyl group and a C _1-6 alkoxy-carbonyl group , Thiazolyl, oxazolyl, pyrazinyl, indolyl) -C _1-6 alkoxy-carbonyl group;
(3e) a non-aromatic heterocyclic ring (preferably oxodioxolyl, oxodioxolanyl, oxo-2-benzofuranyl) -C _1-6 alkoxy-carbonyl group optionally substituted with a C _1-6 alkyl group;
(3f) carboxyl group, carbamoyl group, thiocarbamoyl group, C _1-6 alkoxy-carbonyl group, halogen atom, cyano group, nitro group, C _1-6 alkoxy group, C _1-6 alkylsulfonyl group and C _1-6 An alkyl group (the C _1-6 alkyl group may be substituted with 1 to 3 substituents selected from a halogen atom, a carboxyl group, a C _1-6 alkoxy-carbonyl group and a carbamoyl group); A C _7-13 aralkyloxy-carbonyl group _optionally substituted by 1 to 3 substituents;
(3g) a carbamoyl group mono- or di-substituted with a C _1-6 alkyl group which may be substituted with 1 to 3 substituents selected from a halogen atom and a C _1-6 alkoxy group;
(3h) a carbamoyl-C _1-6 alkyl-carbamoyl group optionally mono- or disubstituted with a C _1-6 alkyl group _optionally substituted with 1 to 3 halogen atoms;
(3i) C _1-6 alkyl optionally substituted with C _1-6 alkoxy - carbonyl -C _1-6 alkyl - carbamoyl group;
(3j) a mono- or di-C _3-10 cycloalkyl-carbamoyl group optionally substituted by a C _1-6 alkyl group;
(3k) C _7-13 aralkyl optionally substituted with 1 to 3 substituents selected from a halogen atom, hydroxy group, carboxyl group, C _1-6 alkoxy-carbonyl group and C _1-6 alkyl group A carbamoyl group;
(3l) an aromatic heterocycle optionally substituted with 1 to 3 substituents selected from a carboxyl group, a carbamoyl group and a C _1-6 alkoxy-carbonyl group (preferably pyridyl, thienyl, furyl, thiazolyl, oxazolyl) , Indolyl) -C _1-6 alkyl-carbamoyl group;
(3m) a C _1-6 alkylsulfonyl group which may be substituted with 1 to 3 substituents selected from a carboxyl group, a carbamoyl group and a C _1-6 alkoxy-carbonyl group;
(3n) substituted with 1 to 3 substituents selected from C _1-6 alkyl group, carboxyl group, carbamoyl group, thiocarbamoyl group, C _1-6 alkoxy-carbonyl group and C _1-6 alkylsulfonyl group An _{optionally substituted} C _6-14 arylsulfonyl group;
(3o) a nitrogen-containing heterocyclic ring (preferably pyrrolidinyl, piperidinyl, piperazinyl, morpholino) optionally substituted by 1 to 3 substituents selected from a hydroxy group, a carboxyl group and a C _1-6 alkoxy-carbonyl group A carbonyl group;
(3p) a C _6-14 aryl-nitrogen-containing heterocyclic ring (preferably pyrrolidinyl, piperidinyl, piperazinyl, morpholino) -carbonyl group optionally substituted with 1 to 3 halogen atoms;
(3q) a C _7-13 aralkyl-nitrogen-containing heterocyclic ring (preferably pyrrolidinyl, piperidinyl, piperazinyl, morpholino) -carbonyl group optionally substituted with 1 to 3 halogen atoms;
(3r) a non-aromatic heterocycle (preferably oxodioxolyl, oxodioxolanyl, oxo-2-benzofuranyl) oxy-carbonyl group;
(3s) a phosphono group which may be mono- or di-substituted with a C _1-6 alkyl group;
(3t) an aromatic heterocycle (preferably tetrazolyl) -C _7-13 aralkyloxy-carbonyl group;
(3u) a C _3-10 cycloalkyl-C _1-6 alkoxy-carbonyl group optionally substituted with 1 to 3 substituents selected from a carboxyl group, a C _1-6 alkoxy-carbonyl group and a carbamoyl group;
(3v) Amino group, carboxyl group, C _1-6 alkoxy-carbonyl group, aromatic heterocyclic group (preferably tetrazolyl, oxadiazolyl) which may be mono- or di-substituted with a C _1-6 alkyl group, non-aromatic A C _6-14 aryl-carbamoyl group optionally substituted by 1 to 3 substituents selected from a heterocyclic group (preferably oxooxadiazolyl) and a carbamoyl group; or
(3w) an aromatic heterocyclic ring (preferably thienyl, furyl) -carbamoyl group optionally substituted with 1 to 3 substituents selected from a carboxyl group, a C _1-6 alkoxy-carbonyl group and a carbamoyl group;
(4) (4a) a C _1-6 alkyl-carbonyloxy group;
(4b) a C _1-10 alkoxy group which may be substituted with 1 to 3 substituents selected from a hydroxy group, a carboxyl group, a carbamoyl group and a C _1-6 alkoxy-carbonyl group;
(4c) halogen atom, carboxyl group, C _1-6 alkoxy-carbonyl group, C _1-6 alkylthio group, carbamoyl group, C _1-6 alkoxy group, C _1-6 alkylsulfonyl group, C _1-6 alkylsulfinyl group And a C _1-6 alkyl group (the C _1-6 alkyl group may be substituted with one or two substituents selected from a carboxyl group, a C _1-6 alkoxy-carbonyl group, and a carbamoyl group). A C _6-14 aryloxy group _optionally substituted by 1 to 3 selected substituents;
(4d) C _1-6 alkyl group (the C _1-6 alkyl group may be substituted with 1 or 2 substituents selected from a carboxyl group, a C _1-6 alkoxy-carbonyl group, and a carbamoyl group) ), A 5- or 6-membered aromatic heterocyclic oxy group (preferably thienyloxy, thiazolyloxy) optionally substituted by 1 to 3 substituents selected from a carboxyl group, a C _1-6 alkoxy-carbonyl group and a carbamoyl group Oxazolyloxy, imidazolyloxy, triazolyloxy, pyrazolyloxy, pyridyloxy, pyrimidinyloxy);
(4e) a condensed aromatic heterocyclic oxy group (preferably indolyloxy) optionally substituted by 1 to 3 substituents selected from a carboxyl group, a C _1-6 alkoxy-carbonyl group and a carbamoyl group;
(4f) an aromatic heterocyclic ring (preferably pyridyl) -C _1-6 alkoxy group optionally substituted with 1 to 3 substituents selected from a carboxyl group, a C _1-6 alkoxy-carbonyl group and a carbamoyl group Or
(4g) an aromatic heterocyclic ring (preferably tetrazolyl) -C _6-14 aryloxy group;
(5) (5a) a C _1-6 alkylthio group optionally substituted by 1 to 3 substituents selected from a hydroxy group, a carboxyl group, a carbamoyl group and a C _1-6 alkoxy-carbonyl group;
(5b) a C _6-14 arylthio group optionally substituted by 1 to 3 substituents selected from a carboxyl group, a C _1-6 alkoxy-carbonyl group, a C _1-6 alkylthio group, and a carbamoyl group; or
(5c) 5- or 6-membered aromatic heterocyclic thio optionally substituted with 1 to 3 substituents selected from a C _1-6 alkyl group, a carboxyl group, a C _1-6 alkoxy-carbonyl group and a carbamoyl group A group (preferably thienylthio, thiazolylthio, oxazolylthio, imidazolylthio, triazolylthio, pyrazolylthio, pyridylthio, pyrimidinylthio);
(6) (6a) amino group;
(6b) a C _1-6 alkoxy-carbonyl-C _1-10 alkylamino group;
(6c) a carboxy-C _1-10 alkylamino group;
(6d) a C _7-13 aralkyloxy-carbonylamino group optionally substituted with 1 to 3 substituents selected from a carboxyl group, a C _1-6 alkoxy-carbonyl group, and a carbamoyl group;
(6e) a carbamoylamino group;
(6f) mono- or di-C _1-6 alkyl-carbamoylamino 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 heterocyclic ring optionally substituted with 1 to 3 substituents selected from a C _1-6 alkyl group and a mono- or di- (C _1-6 alkyl-carbonyl) -amino group (example: , Pyridyl, thiazolyl, oxazolyl, indolyl) -sulfonylamino group;
(6j) mono- or di- (C _1-6 alkyl-carbonyl) -amino group;
(6k) a C _3-10 cycloalkyl-carbonylamino group;
(6l) 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 alkoxy-carbonyl group, an aromatic heterocyclic group (preferably Tetrazolyl, oxadiazolyl), a non-aromatic heterocyclic group (preferably oxooxadiazolyl) and a C _6-14 aryl-carbonylamino group optionally substituted by 1 to 3 substituents selected from a carbamoyl group;
(6m) C _7-13 aralkyl-carbonylamino group;
(6n) a C _8-13 arylalkenyl-carbonylamino group;
(6o) 1 to 3 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, a C _1-6 alkoxy-carbonyl group and a carbamoyl group An aromatic heterocycle optionally substituted with three substituents (preferably furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, pyrazinyl, benzofuryl, benzothienyl, quinoxalinyl) -carbonylamino group;
(6p) C _1-6 alkyl group (the C _1-6 alkyl group may be substituted with 1 to 3 substituents selected from a carboxyl group, a C _1-6 alkoxy-carbonyl group, and a carbamoyl group) ), A nitrogen-containing heterocyclic ring (preferably pyrrolidinyl, piperidinyl, piperazinyl, morpholino) -carbonyl optionally substituted with 1 to 3 substituents selected from a carboxyl group, a C _1-6 alkoxy-carbonyl group and a carbamoyl group An amino group;
(6q) C _6-14 aryl-nitrogen-containing heterocycle (eg, pyrrolidinyl, piperidinyl, piperazinyl, morpholino) -carbonylamino group;
(6r) tetrahydropyranylcarbonylamino group;
(6s) 4-oxo-4,5,6,7-tetrahydro-1-benzofuranyl-carbonylamino group;
(6t) a C _1-6 alkoxy-carbonylamino group optionally substituted by a C _1-6 alkoxy-carbonyl group;
(6u) a C _6-14 aryloxy-carbonylamino group optionally substituted with 1 to 3 substituents selected from a carboxyl group, a C _1-6 alkoxy-carbonyl group, and a carbamoyl group;
(6v) a C _7-13 aralkyl-carbamoylamino group; or
(6w) an aromatic heterocyclic ring (preferably thiazolyl, oxazolyl) -carbamoylamino group which may be substituted with 1 to 3 substituents selected from a carboxyl group, a C _1-6 alkoxy-carbonyl group and a carbamoyl group; Or
(7) (7a) tetrazolyl;
(7b) oxoimidazolidinyl (preferably 2-oxoimidazolidin-1-yl);
(7c) dioxoimidazolidinyl (optionally substituted with a C _1-6 alkyl group optionally substituted with 1 to 3 substituents selected from a carboxyl group and a C _1-6 alkoxy-carbonyl group Preferably 2,4-dioxoimidazolidin-3-yl, 2,4-dioxoimidazolidin-1-yl);
(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) dioxoisoindolyl;
(7h) oxazolyl optionally substituted with a C _1-6 alkoxy-carbonyl group;
(7i) a dioxooxazolyl which may be substituted with a C _1-6 alkyl group which may be substituted with 1 to 3 substituents selected from a carboxyl group and a C _1-6 alkoxy-carbonyl group; Dinyl (preferably 2,4-dioxooxazolidine-5-yl) or dioxothiazolidinyl (preferably 2,4-dioxothiazolidine-5-yl);
(7j) 4-oxo-optionally substituted with a C _1-6 alkyl group which may be substituted with 1 to 3 substituents selected from a carboxyl group and a C _1-6 alkoxy-carbonyl group, 2-thioxo-1,3-thiazolidin-5-yl or 4-oxo-2-thioxo-1,3-oxazolidine-5-yl;
(7k) 1,3 (2H, 5H) -dioxo-tetrahydroimidazo [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 alkoxy-carbonyl group;
A compound that is

[Compound E]
Among the compounds D,
R ¹ and R ² are the same or different and are a C _1-10 alkyl group (preferably R ¹ is isobutyl or neopentyl, R ² is methyl);
R ³ is a C _6-14 aryl group _optionally substituted with a C _1-6 alkyl group (R ³ is preferably 4-methylphenyl);
R ⁴ is an amino group; and X is (3a), (3c), (3f), (3o), (3v), (4d), (5b), (6l) or (6o) [preferably Is (3a), (3o), (3v), (4d) or (6o)]
A compound that is

[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);
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);
3-({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) methyl 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 Is hydrochloride, trifluoroacetate, fumarate)

The salt of compound (I) is preferably a pharmacologically acceptable salt. Examples of such a salt include a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, and an organic acid. And salts with basic or acidic amino acids.
Preferable examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; aluminum salt; ammonium salt and the like.
Preferable examples of the salt with an organic base include trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris (hydroxymethyl) methylamine], tert-butylamine, cyclohexylamine, benzylamine, And salts with dicyclohexylamine, N, N-dibenzylethylenediamine and the like.
Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
Preferable examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, and benzenesulfonic acid , Salts with p-toluenesulfonic acid and the like.
Preferable examples of the salt with basic amino acid include salts with arginine, lysine, ornithine and the like.
Preferable examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like.
Among the above-mentioned salts, salts with inorganic acids and organic acids are preferable, and hydrochloride, trifluoroacetate, fumarate and the like are more preferable.

A prodrug of compound (I) is a compound that is converted into compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, that is, compound (I) that is enzymatically oxidized, reduced, hydrolyzed, etc. A compound that changes to compound (I) upon hydrolysis by gastric acid or the like. Compound (I) prodrugs include compounds in which the amino group of compound (I) is acylated, alkylated and phosphorylated (eg, the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated) , (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compounds, etc.); Compounds in which the hydroxyl group of compound (I) is acylated, alkylated, phosphorylated, borated (eg, hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanyl Compound, dimethylaminomethylcarbonylated compound, etc.); the carboxyl group of compound (I) is esterified, Mido compound (e.g., carboxyl group of compound (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, Phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamidated compounds, and the like). These compounds can be produced from compound (I) by a method known per se.
In addition, the prodrug of compound (I) is a compound that changes to compound (I) under physiological conditions as described in Hirokawa Shoten 1990, “Drug Development”, Volume 7, Molecular Design, pages 163 to 198. It may be.
Further, Compound (I), an isotope ^{(eg, 3 H, 14 C, 35} S, etc. ¹²⁵ I) may be labeled with a.
Furthermore, compound (I) may be an anhydride or a hydrate.

Compound (I) or a prodrug thereof (hereinafter sometimes simply referred to as the compound of the present invention) has low toxicity and should be used as it is or mixed with a pharmacologically acceptable carrier to form a pharmaceutical composition. Thus, it can be used as a preventive or therapeutic agent for various diseases described below for mammals (eg, humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs, monkeys, etc.).
Here, as the pharmacologically acceptable carrier, various organic or inorganic carrier substances commonly used as pharmaceutical materials are used, and excipients, lubricants, binders, disintegrants in solid preparations; solvents in liquid preparations , Solubilizing agents, suspending agents, isotonic agents, buffers, soothing agents and the like. If necessary, preparation additives such as preservatives, antioxidants, colorants, sweeteners and the like can also be used.
Preferable examples of the excipient include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light Anhydrous silicic acid, synthetic aluminum silicate, magnesium aluminate metasilicate and the like can be mentioned.
Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
Preferred examples of the binder include pregelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxy Examples thereof include propylmethylcellulose and polyvinylpyrrolidone.
Preferable examples of the disintegrant include lactose, sucrose, starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethylstarch sodium, light anhydrous silicic acid, low substituted hydroxypropylcellulose and the like.

Preferable 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.
Preferable examples of solubilizers include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate. Etc.
Suitable examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate; for example, polyvinyl alcohol, Examples include hydrophilic polymers such as polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose; polysorbates, polyoxyethylene hydrogenated castor oil, and the like.
Preferable examples of the tonicity agent include sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose and the like.
Preferable examples of the buffer include buffers such as phosphate, acetate, carbonate and citrate.
Preferable examples of the soothing agent include benzyl alcohol.
Preferable examples of the preservative include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
Preferable examples of the antioxidant include sulfite and ascorbate.
Suitable examples of the colorant include water-soluble edible tar dyes (eg, edible dyes such as edible red Nos. 2 and 3, edible yellows Nos. 4 and 5, and edible blue Nos. 1 and 2), water-insoluble lake dyes (E.g., an aluminum salt of the water-soluble edible tar dye), natural dyes (e.g., [beta] -carotene, chlorophyll, bengara, etc.).
Preferable examples of the sweetening agent include saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia and the like.

Examples of the dosage form of the pharmaceutical composition include tablets (including sublingual tablets and orally disintegrating tablets), capsules (including soft capsules and microcapsules), granules, powders, troches, syrups, emulsions, Oral preparations such as suspensions; and injections (eg, subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, infusions, etc.), external preparations (eg, transdermal preparations, ointments, etc.) ), Suppositories (eg, rectal suppositories, vaginal suppositories, etc.), pellets, nasal preparations, pulmonary preparations (inhalants), ophthalmic preparations and the like, and these are oral or parenteral, respectively. Safe administration.
These preparations may be controlled-release preparations such as immediate-release preparations or sustained-release preparations (eg, sustained-release microcapsules).
The pharmaceutical composition can be produced by a method commonly used in the field of pharmaceutical technology, for example, a method described in the Japanese Pharmacopoeia. Below, the specific manufacturing method of a formulation is explained in full detail.
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, etc., but is, for example, about 0.1 to 100% by weight.

For example, oral preparations include active ingredients, excipients (eg, lactose, sucrose, starch, D-mannitol, etc.), disintegrants (eg, carboxymethylcellulose calcium, etc.), binders (eg, pregelatinized starch, gum arabic) , Carboxymethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, etc.) or a lubricant (eg, talc, magnesium stearate, polyethylene glycol 6000, etc.) and the like, and then compression-molded, and if necessary, taste masking, enteric or For the purpose of durability, it is produced by coating with a coating base by a method known per se.
Examples of the coating base include sugar coating base, water-soluble film coating base, enteric film coating base, sustained-release film coating base and the like.
As the sugar coating base, sucrose is used, and one or more selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like may be used in combination.
Examples of the water-soluble film coating base include cellulose polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, and methylhydroxyethylcellulose; polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E [Eudragit E (trade name) Synthetic polymers such as polyvinyl pyrrolidone; polysaccharides such as pullulan.
Examples of enteric film coating bases include cellulose polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate; methacrylic acid copolymer L [Eudragit L (trade name) , Rohm Pharma Co., Ltd.], acrylic polymer such as methacrylic acid copolymer LD [Eudragit L-30D55 (trade name), Rohm Pharma Co., Ltd.], methacrylic acid copolymer S [Eudragit S (trade name), Rohm Pharma Co., Ltd.] A natural product such as shellac.
Examples of the sustained-release film coating base include cellulose polymers such as ethyl cellulose; aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name), Rohm Pharma Co., Ltd.], ethyl acrylate-methyl methacrylate copolymer suspension Acrylic polymers such as suspensions (Eudragit NE (trade name), Rohm Pharma) are listed.
Two or more of the coating bases described above may be mixed and used at an appropriate ratio. Moreover, you may use light-shielding agents, such as a titanium oxide, ferric oxide, etc. in the case of coating.

  For injection, the active ingredient is a dispersant (eg, polysorbate 80, polyoxyethylene hydrogenated castor oil 60, polyethylene glycol, carboxymethyl cellulose, sodium alginate, etc.), preservative (eg, methyl paraben, propyl paraben, benzyl alcohol, chlorobutanol, Phenol, etc.), isotonic agents (eg, sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose, etc.), etc. and aqueous solvents (eg, distilled water, physiological saline, Ringer's solution, etc.) or oily solvents (eg, , Olive oil, sesame oil, cottonseed oil, vegetable oils such as corn oil, propylene glycol, etc.) and the like. At this time, additives such as a solubilizing agent (eg, sodium salicylate, sodium acetate, etc.), a stabilizer (eg, human serum albumin, etc.), a soothing agent (eg, benzyl alcohol, etc.) may be used as desired.

The compound of the present invention has low toxicity (eg, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, carcinogenicity), few side effects, and mammals (eg, humans, cows, horses, dogs, cats, It can be used as a prophylactic or therapeutic agent for various diseases or a diagnostic agent for monkeys, mice, rats, etc. (especially humans).
The compound of the present invention has an excellent peptidase inhibitory action and can suppress degradation of physiologically active substances such as peptide hormones, cytokines, and neurotransmitters by peptidases.
Examples of the peptide hormone include glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2), GIP, growth hormone releasing hormone (GHRH) and the like.
Examples of cytokines include chemokines such as RANTES.
Examples of neurotransmitters include neuropeptide Y.

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 (Prolyl aminopeptidase), 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 leucyl aminopeptidase), EC 3.4.11.13 (Clostridial aminopeptidase), EC 3.4.11.14 (Cytosol alanyl aminopeptidase), EC 3.4.11.15 ( Lysyl aminopeptidase), EC 3.4.11.16 (Xaa-Trp aminopeptidase), EC 3.4.11.17 (Tryptophanyl aminopeptidase), EC 3.4.11.18 (Methionyl aminopeptidase), EC 3.4.11.19 (D-stereospecific aminopeptidase), EC 3.4.11.20 (Aminopeptidase) Ey), EC 3.4.11.21 (Aspartyl aminopeptidase), 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 (Cytosol 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- pepti dase 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-peptidase) and the like. Examples of peptidases include FAPα, DPP8, DPP9 and the like.
Among these, 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, EC 3.4.14.11 are preferable, especially EC 3.4. .14.5 (Dipeptidyl-peptidase IV) is preferred.
The compound of the present invention may have a glucagon antagonistic action or a CETP inhibitory action in addition to the peptidase inhibitory action. When the compound of the present invention has both of these actions, the compound of the present invention is diabetic (eg, type 1 diabetes, type 2 diabetes, gestational diabetes etc.) and hyperlipidemia (eg, hypertriglyceridemia, hypercholesterolemia) Symptom, hypoHDLemia, postprandial hyperlipidemia, etc.).

The compound of the present invention is a prophylactic / therapeutic agent for diabetes (eg, type 1 diabetes, type 2 diabetes, gestational diabetes, etc.); hyperlipidemia (eg, hypertriglyceridemia, hypercholesterolemia, hypoHDLemia, postprandial) Preventive / therapeutic agent for hyperlipidemia, etc .; preventive / therapeutic agent for arteriosclerosis; impaired glucose tolerance [IGT (Impaired
Glucose Tolerance)]; an insulin secretagogue; and an inhibitor of the transition from impaired glucose tolerance to diabetes.
Regarding the criteria for determining diabetes, a new criterion was reported in 1999 by the Japan Diabetes Society.
According to this report, diabetes is a fasting blood glucose level (glucose concentration in venous plasma) of 126 mg / dl or higher, and a 75 g oral glucose tolerance test (75 gOGTT) 2-hour value (glucose concentration in venous plasma) of 200 mg / dl or higher. This is a state in which the blood glucose level (glucose concentration in venous plasma) is at least 200 mg / dl as needed. In addition, the above-mentioned diabetes does not apply, and “fasting blood glucose level (glucose concentration in venous plasma) is less than 110 mg / dl or 75 g oral glucose tolerance test (75 gOGTT) 2 hour value (glucose concentration in venous plasma) is 140 mg / dl. A state that is not “a state indicating less than dl” (normal type) is referred to as a “boundary type”.
As for the criteria for determining diabetes, new criteria were reported from ADA (American Diabetes Association) in 1997 and from WHO in 1998.
According to these reports, diabetes is a fasting blood glucose level (glucose concentration in venous plasma) of 126 mg / dl or more, and a 2-hour value of 75 g oral glucose tolerance test (glucose concentration in venous plasma) is 200 mg / dl. This is a state showing dl or more.

According to the above report, glucose intolerance is a fasting blood glucose level (glucose concentration in venous plasma) of less than 126 mg / dl, and a 75-g oral glucose tolerance test 2 hour value (glucose concentration in venous plasma). Is a state showing 140 mg / dl or more and less than 200 mg / dl. Furthermore, according to the report of ADA, the state where the fasting blood glucose level (glucose concentration in venous plasma) is 110 mg / dl or more and less than 126 mg / dl is called IFG (Impaired Fasting Glucose). On the other hand, according to the report of WHO, the IFG (Impaired Fasting Glucose) is a state in which the 75 g oral glucose tolerance test 2 hour value (glucose concentration in venous plasma) is less than 140 mg / dl as IFG (Impaired Fasting Glycemia). Call.
The compound of the present invention is also used as a prophylactic / therapeutic agent for diabetes, borderline type, glucose intolerance, IFG (Impaired Fasting Glucose) and IFG (Impaired Fasting Glycemia) determined by the above-mentioned new criteria. Furthermore, the compound of the present invention can also prevent progression from borderline type, impaired glucose tolerance, IFG (Impaired Fasting Glucose) or IFG (Impaired Fasting Glycemia) to diabetes.

The compound of the present invention can be used, for example, for diabetic complications [eg, neuropathy, nephropathy, retinopathy, cataract, macrovascular disorder, osteopenia, diabetic hyperosmotic coma, infection (eg, respiratory infection, Urinary tract infection, digestive organ infection, skin soft tissue infection, lower limb infection, etc.), diabetic gangrene, xerostomia, hearing loss, cerebrovascular disorder, peripheral blood flow disorder, etc.], obesity, osteoporosis, evil Liquid (eg, cancer cachexia, tuberculosis cachex, diabetic cachexia, hematological cachexia, endocrine cachexia, infectious cachexia or acquired immunodeficiency syndrome), fat Liver, hypertension, polycystic ovary syndrome, kidney disease (eg, diabetic nephropathy, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal disease, etc.), muscular dystrophy, myocardial infarction, angina Disease, cerebrovascular disorder (eg, cerebral infarction, stroke), a Züheimer's disease, Parkinson's disease, anxiety, dementia, insulin resistance syndrome, syndrome X, metabolic syndrome, hyperinsulinemia, sensory disturbance in hyperinsulinemia, tumor (eg, leukemia, breast cancer, prostate cancer, skin cancer, etc.) ), Irritable bowel syndrome, acute or chronic diarrhea, inflammatory diseases (eg, rheumatoid arthritis, osteoarthritis, osteoarthritis, low back pain, gout, inflammation after surgery or trauma, swelling, neuralgia, sore throat, Cystitis, hepatitis (including non-alcoholic steatohepatitis), pneumonia, pancreatitis, enteritis, inflammatory bowel disease (including inflammatory bowel disease), ulcerative colitis, gastric mucosal damage (gastric mucosa caused by aspirin) Etc.), small intestinal mucosa damage, malabsorption, testicular dysfunction, visceral obesity syndrome and the like.
The compound of the present invention reduces visceral fat, suppresses visceral fat accumulation, improves glucose metabolism, improves lipid metabolism, suppresses oxidized LDL production, improves lipoprotein metabolism, improves coronary artery metabolism, prevents or treats cardiovascular complications, complications of heart failure Prevention or treatment, reduction of blood remnants, prevention or treatment of anovulation, prevention or treatment of hirsutism, prevention and treatment of hyperandrogenemia, improvement of pancreatic (β cell) function, pancreatic (β cell) regeneration, pancreas (Β cells) It is also used for promoting regeneration and regulating appetite.
The compound of the present invention is also used for secondary prevention and progression suppression of the various diseases described above (eg, cardiovascular events such as myocardial infarction).

  The compound of the present invention is selectively insulin secreted in hyperglycemic patients (for example, patients whose fasting blood glucose level is 126 mg / dl or higher or 75 g oral glucose tolerance test (75 gOGTT) 2 hour value is 140 mg / dl or higher). It is a glucose-dependent insulin secretagogue that exerts a promoting action. Therefore, the compound of the present invention is useful as a safe prophylactic / therapeutic agent for diabetes with low risk of vascular complications and hypoglycemia induction, which are harmful effects of insulin.

The compound of the present invention is also useful as a therapeutic agent for sulfonylurea secondary ineffective diabetes. Even in a diabetic patient who cannot obtain an insulin secretion effect with a sulfonylurea compound or a fast-acting insulin secretagogue, and therefore cannot obtain a sufficient blood glucose lowering effect. Excellent insulin secretion effect and blood glucose lowering effect.
Here, examples of the sulfonylurea compound include a compound having a sulfonylurea skeleton or a derivative thereof such as tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide, and glybazole.
In addition, as a fast-acting insulin secretagogue, a compound that does not have a sulfonylurea skeleton but promotes insulin secretion from pancreatic β cells in the same manner as the sulfonylurea compound, such as repaglinide, senaglinide, nateglinide, mitiglinide or a calcium salt hydrate thereof And the like.

  The dose of the compound of the present invention varies depending on the administration subject, administration route, target disease, symptom, and the like. For example, when administered orally to an adult diabetic patient, the dose is usually about 0.01 to 100 mg / kg body weight. It is preferably 0.05 to 30 mg / kg body weight, more preferably 0.1 to 10 mg / kg body weight, and it is desirable to administer this amount once to three times a day.

The compound of the present invention comprises a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, an antihyperlipidemic agent, an antihypertensive agent, an antiobesity agent, a diuretic, a chemotherapeutic agent, an immunotherapeutic agent, an antithrombotic agent, an osteoporosis therapeutic agent, It can be used in combination with a drug (hereinafter abbreviated as a concomitant drug) such as a dementia agent, an erectile dysfunction improving agent, a urinary incontinence / frequent urination therapeutic agent, or a dysuria therapeutic agent. In this case, the administration time of the compound of the present invention and the concomitant drug is not limited, and these may be administered to the administration subject at the same time or may be administered with a time difference. Furthermore, the compound of the present invention and the concomitant drug may be administered as two types of preparations containing each active ingredient, or may be administered as a single preparation containing both active ingredients.
The dose of the concomitant drug can be appropriately selected based on the clinically used dose. The compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, the concomitant drug may be used in an amount of 0.01 to 100 parts by weight per 1 part by weight of the compound of the present invention.

Examples of the therapeutic agent for diabetes include insulin preparations (eg, animal insulin preparations extracted from bovine and porcine pancreas; human insulin preparations genetically engineered using E. coli or yeast; insulin zinc; protamine insulin zinc; insulin Fragments or derivatives (eg, INS-1 etc.), oral insulin preparations, etc., insulin resistance improving agents (eg, pioglitazone or a salt thereof (preferably hydrochloride), rosiglitazone or a salt thereof (preferably maleate) , Reglixane (JTT-501), GI-262570, Netoglitazone (MCC-555), YM-440, DRF-2593, BM-13.1258, KRP-297, R-119702, Riboglitazone ) (CS-011), FK-614, compounds described in WO99 / 58510 (eg (E) -4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino]- 4-F Nylbutyric acid), compounds described in WO01 / 38325, Tesaglitazar (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 Antagonists, PPARγ / α dual agonists, α-glucosidase inhibitors (eg, voglibose, acarbose, miglitol, emiglitate, etc.), biguanides (eg, phenformin, metformin, buformin or salts thereof (eg, hydrochloride, fumarate) ), Insulin secretagogues [sulfonylureas (eg, tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetic acid) Hexamide, Glyclopyramide, Glimepiride, Glipizide, Glybsol, etc.), Repaglinide, Senaglinide, Nateglinide, Mitiglinide or its calcium salt hydrate], GPR40 agonist, GLP-1 receptor agonist [eg, GLP-1, GLP-1MR agent, NN-2211, AC-2993 (exendin-4), BIM-51077, Aib (8,35) hGLP-1 (7,37) NH ₂ , CJC-1131], amylin agonist (eg, pramlintide, etc.), phospho Tyrosine phosphatase inhibitors (eg, sodium vanadate), dipeptidyl peptidase IV inhibitors (eg, NVP-
DPP-278, PT-100, P32 / 98, LAF-237, P93 / 01, TS-021, MK-431, BMS-477118, etc.), β3 agonist (eg, CL-316243, SR-58611-A, UL) -TG-307, SB-226552, AJ-9677, BMS-196085, AZ40140, etc.), gluconeogenesis inhibitors (eg, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, glucagon antagonists, etc.), SGLT (sodium -glucose
cotransporter) inhibitors (eg, T-1095, etc.), 11β-hydroxysteroid dehydrogenase inhibitors (eg, BVT-3498, etc.), adiponectin or agonists thereof, IKK inhibitors (eg, AS-2868, etc.), leptin resistance Improvers, somatostatin receptor agonists (WO01 / 25228, WO03 / 42204, WO98 / 44921, WO98 / 45285, WO99 / 22735, etc.), glucokinase activators (eg, Ro-28-1675), etc. Can be mentioned.

As therapeutic agents for diabetic complications, aldose reductase inhibitors (eg, tolrestat, epalrestat, zenarestat, zopolrestat, minalrestat, fidarestat (SNK-860), CT-112, etc.), neurotrophic factor and its increase Drug (eg, NGF, NT-3, BDNF, neurotrophin production / secretion promoter described in WO01 / 14372 (for example, 4- (4-chlorophenyl) -2- (2-methyl-1-imidazolyl) -5 -[3- (2-methylphenoxy) propyl] oxazole, etc.), etc.), nerve regeneration promoters (eg, Y-128, etc.), PKC inhibitors (eg, ruboxistaurin mesylate; LY-333531) Etc.), AGE inhibitors (eg, ALT946, pimagedin, pyratoxatin, N-phenacylthiazoliu) Bromide (ALT766), ALT-711, EXO-226, pyridoline (Pyridorin), pyridoxamine), active oxygen scavengers (eg, thioctic acid, etc.), cerebral vasodilators (eg, thiopride, mexiletine, etc.), somatostatin receptor action Drug (BIM23190), apoptosis signal regulating kinase-1 (ASK-1) inhibitor.
Antihyperlipidemic agents include statins that are cholesterol synthesis inhibitors (eg, cerivastatin, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, itavastatin, rosuvastatin, pitavastatin or salts thereof (eg, sodium salt, Calcium salt)), squalene synthase inhibitors (eg, 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] piperidine-4-acetic acid) , Fibrate compounds (eg, bezafibrate, clofibrate, simfibrate, clinofibrate, etc.), ACAT inhibitors (eg, Avasimibe, F Emilucine), anion exchange resin (eg, cholestyramine), probucol, nicotinic acid drugs (eg, nicomol, niceritrol), icosapentate, plant sterols (eg, And soysterol, gamma-oryzanol, etc.).

Antihypertensive agents include angiotensin converting enzyme inhibitors (eg, captopril, enalapril, delapril, etc.), angiotensin II antagonists (eg, candesartan cilexetil, losartan, eprosartan, valsartan, telmisartan, irbesartan, tasosartan, 1-[[2 ' -(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 (eg, manidipine, nifedipine, amlodipine, efonidipine, nicardipine, etc.), potassium channel openers (eg, levcromakalim, L-27152, AL 0671, NIP-121, etc.), clonidine and the like.
Anti-obesity agents include, for example, central anti-obesity agents (eg, dexfenfluramine, fenfluramine, phentermine, sibutramine, ampepramon, dexamphetamine, mazindol, phenylpropanolamine, clobenzorex; MCH receptor antagonist (Eg, SB-568849; SNAP-7941; compounds included in WO01 / 82925 and WO01 / 87834, etc.); neuropeptide Y antagonists (eg, CP-422935, etc.); cannabinoid receptor antagonists (eg, SR-141716) SR-147778, etc.); Ghrelin antagonists; 11β-hydroxysteroid dehydrogenase inhibitors (eg, BVT-3498, etc.), pancreatic lipase inhibitors (eg, orlistat, ATL-962, etc.), β3 agonists (eg, CL) -316243, SR-58611-A, UL-TG-307, SB-226552, AJ-9677, BMS-196085, AZ40140, etc., peptidic appetite suppressants (eg, leptin, CNTF (ciliary neurotrophic factor)) Etc.) Cholecystokinin agonists (e.g., lintitript, FPL-15849), anorexigenic agents (e.g., P-57, etc.) and the like.

Examples of diuretics include xanthine derivatives (eg, sodium salicylate theobromine, calcium salicylate theobromine, etc.), thiazide preparations (eg, etiazide, cyclopentiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benchylhydrochlorothiazide, pentfurizide, Polythiazide, methycrothiazide, etc.), anti-aldosterone preparations (eg, spironolactone, triamterene, etc.), carbonic anhydrase inhibitors (eg, acetazolamide, etc.), chlorobenzenesulfonamide preparations (eg, chlorthalidone, mefluside, indapamide, etc.), azosemide, Examples include isosorbide, ethacrynic acid, piretanide, bumetanide, furosemide and the like.
Examples of chemotherapeutic agents include alkylating agents (eg, cyclophosphamide, ifosfamide, etc.), antimetabolites (eg, methotrexate, 5-fluorouracil or derivatives thereof), anticancer antibiotics (eg, mitomycin, Adriamycin, etc.), plant-derived anticancer agents (eg, vincristine, vindesine, taxol, etc.), cisplatin, carboplatin, etoposide and the like. Of these, 5-fluorouracil derivatives such as furuluron or neofluturon are preferable.
Examples of immunotherapeutic agents include microorganisms or bacterial components (eg, muramyl dipeptide derivatives, picibanil, etc.), polysaccharides having immunopotentiating activity (eg, lentinan, schizophyllan, krestin, etc.), cytokines obtained by genetic engineering techniques (Eg, interferon, interleukin (IL), etc.), colony stimulating factor (eg, granulocyte colony stimulating factor, erythropoietin, etc.), etc., among which interleukins such as IL-1, IL-2, IL-12, etc. Is preferred.

Examples of the antithrombotic agent include heparin (eg, heparin sodium, heparin calcium, dalteparin sodium), warfarin (eg, warfarin potassium), antithrombin drug (eg, aragatroban), Thrombolytic agents (eg, urokinase, tisokinase, alteplase, nateplase, monteplase, pamitepase), platelet aggregation inhibitors (eg, ticlopidine hydrochloride) ), Cilostazol, ethyl icosapentate, beraprost sodium, sarpogrelate hydrochloride, and the like.
Examples of osteoporosis treatment agents include alphacalcidol, calcitriol, elcatonin, salmon calcitonin.
salmon), estriol, ipriflavone, pamidronate disodium, alendronate sodium hydrate, incadronate disodium, and the like.
Examples of the anti-dementia agent include tacrine, donepezil, rivastigmine, galanthamine and the like.
Examples of the erectile dysfunction ameliorating agent include apomorphine, sildenafil citrate, and the like.
Examples of urinary incontinence / frequent urination treatments include flavoxate hydrochloride, oxybutynin hydrochloride, propiverine hydrochloride (propive)
rine hydrochloride).
Examples of the dysuria therapeutic agent include acetylcholinesterase inhibitors (eg, distigmine).

  In addition, drugs that have been shown to improve cachexia in animal models and clinically, ie, cyclooxygenase inhibitors (eg, indomethacin), progesterone derivatives (eg, megesterol acetate), carbohydrate steroids (eg, dexamethasone) , Metoclopramide drugs, tetrahydrocannabinol drugs, fat metabolism improvers (eg, eicosapentaenoic acid, etc.), growth hormone, IGF-1, or cachexia-inducing factors TNF-α, LIF, IL-6 An antibody against Oncostatin M can also be used in combination with the compound of the present invention.

The concomitant drug is preferably an insulin preparation, an insulin resistance improving agent, an α-glucosidase inhibitor, a biguanide agent, an insulin secretagogue (preferably a sulfonylurea agent) and the like.
Two or more of the above concomitant drugs may be used in combination at an appropriate ratio. As a preferable combination in the case of using two or more kinds of concomitant drugs, for example, the following combinations may be mentioned.
1) an insulin secretagogue (preferably a sulfonylurea) and an α-glucosidase inhibitor;
2) Insulin secretion promoter (preferably sulfonylurea) and biguanide agent;
3) Insulin secretion promoter (preferably sulfonylurea), biguanide and α-glucosidase inhibitor;
4) Insulin resistance improving agent and α-glucosidase inhibitor;
5) Insulin resistance improving agent and biguanide agent;
6) Insulin resistance improving agent, biguanide agent and α-glucosidase inhibitor.
When the compound of the present invention is used in combination with a concomitant drug, the amount of each agent can be reduced within a safe range in consideration of the opposite effect of these agents. In particular, the insulin resistance improving agent, insulin secretagogue (preferably sulfonylurea) and biguanide can be reduced from the usual dose. Thus, the adverse effects that would be caused by these agents can be safely prevented. In addition, the dosage of antidiabetic complications, antihyperlipidemic agents, and antihypertensive agents can be reduced, thereby effectively preventing the adverse effects that would be caused by these agents.

Hereafter, the manufacturing method of this invention compound is demonstrated.
The compound of the present invention can be produced according to a method known per se, for example, the method described in detail below or a method analogous thereto.
In the formula (I), L is La—CH ₂ — (La represents a bond or a divalent chain hydrocarbon group), X is Xa (Xa is a hydrogen atom, a nitro group, an acyl group, substituted A hydroxy group, an optionally substituted thiol group, an optionally substituted amino group or an optionally substituted cyclic group), and R ⁴ is an amino group (Ia) It can be produced by the following method A or a method analogous thereto.
Here, examples of the “divalent chain hydrocarbon group” represented by La include the same “divalent chain hydrocarbon groups” exemplified as L. La is preferably a bond or a C _1-9 alkylene group.
In addition, “acyl group”, “substituted hydroxy group”, “optionally substituted thiol group”, “optionally substituted amino group” and “optionally substituted cyclic group” represented by Xa "Are those exemplified as X above.
When Xa is an ethoxycarbonyl group, Q is preferably a divalent chain hydrocarbon group.
[Method A]

[The symbols in the formula are as defined above. ]

In this method, compound (Ia) is produced by subjecting compound (II) to a reduction reaction.
The reduction reaction is performed according to a conventional method in the presence of a reducing agent in a solvent that does not adversely influence the reaction.
Examples of the reducing agent include metal hydrogen compounds such as sodium bis (2-methoxyethoxy) aluminum hydride and diisobutylaluminum hydride; sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, sodium aluminum hydride, and the like. And metal hydride complex compounds.
The amount of the reducing agent to be used is generally 0.1 to 20 equivalents relative to compound (II).
Examples of the solvent that does not adversely affect the reaction include alcohols such as methanol, ethanol, propanol, 2-propanol, butanol, isobutanol and tert-butanol; aromatic hydrocarbons such as benzene, toluene and xylene; Aliphatic hydrocarbons such as hexane and heptane; ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane; methyl acetate, ethyl acetate, n-butyl acetate, tert-butyl acetate, etc. Esters such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone and the like are used. These solvents may be used by mixing two or more kinds at an appropriate ratio.
The reaction temperature is generally −70 to 150 ° C., preferably −20 to 100 ° C.
The reaction time is usually 0.1 to 100 hours, preferably 0.1 to 40 hours.

The reduction reaction is a solvent that does not adversely affect the reaction in the presence of a metal catalyst such as palladium-carbon, palladium black, palladium chloride, platinum oxide, platinum black, platinum-palladium, Raney nickel, Raney cobalt, and a hydrogen source. It can also be done inside.
The usage-amount of a metal catalyst is 0.001-1000 equivalent normally with respect to compound (II), Preferably it is 0.01-100 equivalent.
Examples of the hydrogen source include hydrogen gas, formic acid, amine formate, phosphinate, hydrazine and the like.
Examples of the solvent that does not adversely influence the reaction include those exemplified in the reduction reaction using the reducing agent.
The reaction temperature and reaction time are the same as in the reduction reaction using the reducing agent.
This reaction may be performed in the presence of ammonia (eg, aqueous ammonia, ammonia-ethanol, etc.) as necessary. By carrying out the reaction in the presence of ammonia, side reactions are suppressed and compound (Ia) can be produced in high yield.
The thus obtained compound (Ia) can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, etc. .

Compound (II) used as a raw material compound in Method A can be produced according to a method known per se.
For example, compound (II-a) in which Q and La are a bond and Xa is an acyl group in formula (II) can be produced by the following method B.
[Method B]

[The symbols in the formula are as defined above. ]

Compound (II-a) adversely affects the reaction of 1,4-dioxane, acetone or the like by a method known per se, such as compound (III) and an oxidizing agent such as dilute nitric acid or diammonium cerium nitrate. Can be prepared by reacting in a non-solvent.
The compound (III) can be obtained by a method known per se, for example, “New Experimental Chemistry Course (Edited by the Chemical Society of Japan)” published by Maruzen 1978, Vol. It can be produced, for example, from compound (IV) and compound (VII) by Hantzch's pyridine synthesis method described on page 2057 or a method analogous thereto.
Compound (IV) can be produced by a method known per se, for example, by subjecting compound (VI) and compound (V) to a known Knoevenagel method.
Compound (VII) is a method known per se, for example, the method described in Synthesis, (1999), 11, 1951-1960; Journal of Chemical Society Perkin Transactions 1, (2002), 1663-1671, Alternatively, it can be produced from compound (VIII) according to a method analogous thereto.
The aforementioned compound (V), compound (VI) and compound (VIII) can be produced according to a method known per se.

In the formula (I), the compound (Ib) in which R ⁴ is an amino group mono- or di-substituted with a C _1-10 alkyl group is a compound (Ib) in which R ⁴ is an amino group in the formula (I) -C) can be prepared by subjecting it to an alkylation reaction.
This reaction is carried out according to a conventional method, (1) in the presence of a base if necessary, in a solvent that does not adversely influence the reaction using an alkylating agent, or (2) in the presence of a reducing agent if necessary. The compound is used in a solvent that does not adversely influence the reaction.
Here, examples of the alkylating agent include C _1-10 alkyl halides, C _1-10 alkyl sulfonic acid esters, and the like.
Examples of carbonyl compounds include aldehydes and ketones.
The amount of the alkylating agent and the carbonyl compound to be used is preferably about 1 to about 5 equivalents relative to compound (Ic).
Examples of the base include alkali metal salts such as sodium hydroxide and potassium carbonate; amines such as pyridine and triethylamine; metal hydrides such as sodium hydride; alkali metal alkoxides such as sodium methoxide and potassium tert-butoxide. It is done.
The amount of the base to be used is preferably about 1 to about 5 equivalents relative to compound (Ic).
Examples of the reducing agent include metal hydrogen compounds such as diisobutylaluminum hydride; metal hydrogen complex compounds such as sodium cyanoborohydride; and the like.
The amount of the reducing agent to be used is generally 0.1 to 20 equivalents relative to compound (Ic).
The reaction using the carbonyl compound can also be carried out in the presence of a metal catalyst such as palladium-carbon and a hydrogen source in a solvent that does not adversely influence the reaction without using a reducing agent.
The amount of the metal catalyst to be used is preferably 0.01 to 100 equivalents relative to compound (Ic).
Examples of the hydrogen source include hydrogen gas, formic acid, formic acid amine salt and the like.
Examples of the “solvent that does not adversely influence the reaction” used in the alkylation reaction include aromatic hydrocarbons such as toluene; ethers such as tetrahydrofuran; halogenated hydrocarbons such as chloroform; N, N-dimethyl. Examples include amides such as formamide; sulfoxides such as dimethyl sulfoxide. These solvents may be mixed and used at an appropriate ratio.
In the alkylation reaction, the reaction temperature is preferably about −10 to about 100 ° C.
In the alkylation reaction, the reaction time is usually about 0.5 to about 20 hours.
The compound (Ib) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

When the compound of the present invention is produced, when the raw material compound has an amino group, carboxyl group, hydroxy group or carbonyl group as a substituent, a protecting group generally used in peptide chemistry or the like is introduced into these groups. The target compound can be obtained by removing the protecting group as necessary after the reaction.
Examples of protecting groups for amino groups include formyl group, C _1-6 alkyl-carbonyl group (eg, acetyl, propionyl, etc.), C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, tert-butoxy). Carbonyl), benzoyl group, C _7-13 aralkyl-carbonyl group (eg, benzylcarbonyl), C _7-13 aralkyloxy-carbonyl group (eg, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, etc.), trityl Group, phthaloyl group, N, N-dimethylaminomethylene group, silyl group (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl, etc.), C _2-6 alkenyl group (eg , 1-allyl, etc.). These groups are substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkoxy groups (eg, methoxy, ethoxy, propoxy, etc.) or nitro groups. Also good.
Examples of the protecting group for the carboxyl group include a C _1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), a C _7-13 aralkyl group (eg, benzyl, etc.), a phenyl group. , Trityl group, silyl group (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl, etc.), C _2-6 alkenyl group (eg, 1-allyl, etc.), etc. . These groups are substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkoxy groups (eg, methoxy, ethoxy, propoxy, etc.) or nitro groups. Also good.

Examples of the protecting group for the hydroxy group include a C _1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), a phenyl group, a trityl group, and a C _7-13 aralkyl group (eg, Benzyl etc.), formyl group, C _1-6 alkyl-carbonyl group (eg acetyl, propionyl etc.), benzoyl group, C _7-13 aralkyl-carbonyl group (eg benzylcarbonyl etc.), 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, silyl group (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl, etc.), C _2-6 alkenyl group (eg, 1-allyl, etc.), etc. Can be mentioned. These groups include 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkyl groups (eg, methyl, ethyl, propyl etc.), C _1-6 alkoxy groups (eg, , Methoxy, ethoxy, propoxy, etc.) or nitro or the like.
Examples of the protecting group for the carbonyl group include cyclic acetals (eg, 1,3-dioxane), acyclic acetals (eg, di-C _1-6 alkylacetal, etc.) and the like.
The introduction or removal of these protecting groups is carried out according to a method known per se, for example, the method described in Protective Groups in Organic Synthesis, published by John Wiley and Sons (1980). Just do it. For example, a method using acid, base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide (eg, trimethylsilyl iodide, trimethylsilyl bromide, etc.) A reduction method or the like is used.
In the production of the compound of the present invention, when the raw material compound can form a salt, the compound may be used as a salt. As such a salt, for example, those exemplified as the salt of compound (I) are used.

When compound (I) contains optical isomers, stereoisomers, positional isomers, and rotational isomers, these are also included as compound (I), and are synthesized by known synthesis methods and separation methods, respectively. Can be obtained as a single product. For example, when compound (I) has an optical isomer, the optical isomer resolved from the compound is also encompassed in compound (I).
The optical isomer can be produced by a method known per se. Specifically, an optical isomer is obtained by using an optically active synthetic intermediate or by optically resolving the final racemate according to a conventional method.
As the optical resolution method, a method known per se, for example, fractional recrystallization method, chiral column method, diastereomer method and the like are used.
1) Fractional recrystallization method Racemate and optically active compound (for example, (+)-mandelic acid, (−)-mandelic acid, (
+)-Tartaric acid, (−)-tartaric acid, (+)-1-phenethylamine, (−)-1-phenethylamine, cinchonine, (−)-cinchonidine, brucine, etc.) to form a salt, which is fractionally recrystallized. A method of separating by a method and obtaining a free optical isomer through a neutralization step if desired.
2) Chiral column method A method in which a racemate or a salt thereof is separated by applying to a column for optical isomer separation (chiral column). For example, in the case of liquid chromatography, a mixture of optical isomers is added to a chiral column such as ENANTIO-OVM (manufactured by Tosoh Corporation) or CHIRAL series (manufactured by Daicel Corporation), and water, various buffers (eg, phosphate buffer) The optical isomers are separated by developing an organic solvent (eg, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine, etc.) alone or as a mixed solution. In addition, for example, in the case of gas chromatography, separation is performed using a chiral column such as CP-Chirasil-DeX CB (manufactured by GL Sciences).

3) Diastereomer method A mixture of racemates is converted into a mixture of diastereomers by chemical reaction with an optically active reagent, and this is converted into a single substance through ordinary separation means (for example, fractional recrystallization, chromatography method, etc.). And then obtaining an optical isomer by cleaving the optically active reagent site by chemical treatment such as hydrolysis. For example, when the compound (I) has 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 ], (-)-Menthoxyacetic acid and the like) are subjected to a condensation reaction to obtain diastereomers of ester or amide, respectively. On the other hand, when the compound (I) has a carboxyl group, an amide or ester diastereomer is obtained by subjecting the compound and an optically active amine or alcohol reagent to a condensation reaction. The separated diastereomer is converted into the optical isomer of the original compound by subjecting it to an acid hydrolysis or basic hydrolysis reaction.

Compound (I) may be a crystal.
Crystals of compound (I) (hereinafter sometimes abbreviated as crystals of the present invention) can be produced by crystallization by applying a crystallization method known per se to compound (I).
Here, examples of the crystallization method include a crystallization method from a solution, a crystallization method from a vapor, and a crystallization method from a melt.
The “crystallization from solution” includes a state in which the compound is not saturated by changing factors related to the solubility of the compound (solvent composition, pH, temperature, ionic strength, redox state, etc.) or the amount of the solvent. In general, a method of shifting from a supersaturated state to a supersaturated state is typical, and specific examples include a concentration method, a cooling method, a reaction method (diffusion method, electrolytic method), a hydrothermal growth method, a flux method, and the like. Examples of the solvent used include aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, etc.), saturated hydrocarbons (eg, hexane, heptane, cyclohexane). Etc.), ethers (eg, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, etc.), nitriles (eg, acetonitrile, etc.), ketones (eg, acetone, etc.), sulfoxides (eg, dimethyl sulfoxide, etc.), acid amides (Eg, N, N-dimethylformamide, etc.), esters (eg, ethyl acetate, etc.), alcohols (eg, methanol, ethanol, isopropyl alcohol, etc.), water and the like are used. These solvents may be used alone or in admixture of two or more at an appropriate ratio (eg, 1: 1 to 1: 100 (volume ratio)).
Examples of the “crystallization method from vapor” include a vaporization method (sealed tube method, air flow method), a gas phase reaction method, a chemical transport method, and the like.
Examples of the “crystallization method from a melt” include normal freezing method (pulling method, temperature gradient method, Bridgman method), zone melting method (zone leveling method, float zone method),
Special growth methods (VLS method, liquid phase epitaxy method) and the like can be mentioned.
As a suitable example of the crystallization method, compound (I) is dissolved in a suitable solvent (eg, alcohols such as methanol, ethanol, etc.) at a temperature of 20 to 120 ° C., and the resulting solution is dissolved. The method of cooling to below temperature (for example, 0-50 degreeC, Preferably 0-20 degreeC) etc. are mentioned.
The crystals of the present invention thus obtained can be isolated by, for example, filtration.

In the present specification, the melting point is measured using, for example, a micro melting point measuring device (Yanako, MP-500D type or Buchi, B-545 type) or DSC (differential scanning calorimetry) apparatus (SEIKO, EXSTAR6000). Mean melting point.
In general, the melting point may vary depending on the measurement equipment, measurement conditions, and the like. The crystal in the present specification may be a crystal having a value different from the melting point described in the present specification as long as it is within a normal error range.
The crystal of the present invention is excellent in physicochemical properties (eg, melting point, solubility, stability, etc.) and biological properties (eg, pharmacokinetics (absorbability, distribution, metabolism, excretion), drug efficacy, etc.), and pharmaceuticals. As extremely useful.

The present invention will be described in more detail with reference to the following examples, experimental examples and formulation examples, which are not intended to limit the present invention, and may be changed without departing from the scope of the present invention.
In addition, the symbol in an Example has the following meaning.
s: singlet, d: doublet, t: triplet, q: quartet, m: multiplet, brs: wide singlet, J: coupling constant,
4-Me-Phenyl: 4-methylphenyl, 4-F-Phenyl: 4-fluorophenyl, 2,6-di-F-Phenyl: 2,6-difluorophenyl In the examples, room temperature is 1 to 30 It means ° C., and% indicates% by weight unless otherwise specified.

Example 1 Methyl 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate 1) Tetrahydrofuran (80 mL) of sodium hydride (60% oily, 8.0 g, 0.2 mol) The suspension was heated to reflux with vigorous stirring. To the resulting suspension, methyl isovalerate (11.6 g, 0.1
mol), acetonitrile (10.5 mL, 0.2 mol), and tetrahydrofuran (25 mL) were added dropwise over 30 minutes, and the mixture was heated to reflux for 5 hours. The reaction mixture was cooled to room temperature, 2-propanol (5 mL) was added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water (100 mL), and washed with hexane and then with a hexane-diethyl ether mixture. 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, and the solvent was evaporated under reduced pressure to give 5-methyl-3-oxohexanenitrile (12.6 g, yield 100%) as a pale yellow oil. . The resulting pale 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) 5-methyl-3-oxohexanenitrile (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 a mixture of toluene (200 mL) was heated to reflux for 12 hours using a Dean-Stark trap. The reaction mixture was cooled to room temperature, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (50 mL), methyl 3-aminocrotonate (4.6 g, 40 mmol) was added, and the mixture was heated to reflux for 6 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 5-cyano-6-isobutyl-2-methyl-4- (4-methylphenyl) -1,4-dihydropyridine-3-carboxylate. Methyl acid (7.45 g, yield 57%) was obtained 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, brs), 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 added to 1,4-dioxane (20 mL). 2N nitric acid (100
mL) was added and stirred at 70 ° C. for 1 hour. The reaction mixture was stirred in an ice bath, and ethyl acetate (100 mL) and 2N aqueous sodium hydroxide solution (100 mL) were added. The aqueous layer was separated and extracted with ethyl acetate. The organic layer and the extract were combined, washed with saturated brine, 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 5-cyano-6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (5.94 g, yield 82%) 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) 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 A mixture consisting of (15 mL) and methanol (45 mL) was stirred in a sealed tube under a 0.5 MPa hydrogen atmosphere at room temperature for 6 hours. The filtrate obtained by filtering the reaction solution was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and 10% aqueous potassium carbonate solution. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, and methyl 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (0.97 g, yield 95%) was obtained as pale yellow crystals. Got as.
¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.39 (2H, brs), 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) ).
Melting point 56-57 ℃

Example 2 5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid dihydrochloride 1) 5- (aminomethyl) -6-isobutyl-2-methyl-4- Di-tert-butyl dicarbonate (0.76 mL, 3.31 mmol) was added to a solution of methyl (4-methylphenyl) nicotinate (0.90 g, 2.76 mmol) in tetrahydrofuran (25 mL), 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 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl). ) Methyl nicotinate (1.16 g, 98% yield) was obtained 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) Methanol (30 mL) solution of methyl 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (1.0 g, 2.34 mmol) 1N aqueous sodium hydroxide solution (10 mL) was added to the mixture, and the mixture was heated to reflux for 3 days. The reaction solution was returned to room temperature, acidified with 0.5N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was crystallized from water-methanol to give 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (0.58 g, yield). 60%) was obtained 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) 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (0.20 g, 0.48 mmol) of 1,4-dioxane (4 4N Hydrogen chloride-1,4-dioxane solution (4 mL, 16 mmol) was added to the solution, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting white solid was washed with diisopropyl ether, and 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid dihydrochloride (0.18 g, yield 95%) was obtained 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, brs).
Example 3 5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinamide dihydrochloride 1) 5-{[(tert-butoxycarbonyl) amino] methyl} -6- Isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (0.11 g, 0.27 mmol) and 1-hydroxy-1H-benzotriazole ammonium salt (0.10 g, 0.65 mmol), 1-ethyl-3- ( A mixture consisting of 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 0.1M citric acid aqueous solution (50 mL). The organic layer and the extract extracted from the aqueous layer with ethyl acetate were combined, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. 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) was obtained 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, m), 5.22 (1H, brs), 5.41 (1H, brs), 7.11 (2H, d, J = 7.9 Hz), 7.23 (2H, d, J = 7.9 Hz).
2) Conducted from tert-butyl {[5- (aminocarbonyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (0.065 g, 0.16 mmol) In the same manner as in Example 2-3), 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinamide dihydrochloride (0.050 g, yield 82%) was converted to white. Obtained as a powder.
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, brs), 7.84 (1H, brs), 8.32 (3H, brs).

Example 4 5- (aminomethyl) -N- (3-amino-3-oxopropyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinamide dihydrochloride 1) 5-{[ (tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (0.12 g, 0.29 mmol) and 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 solution was partitioned between ethyl acetate-tetrahydrofuran (1: 1, 100 mL) and 0.1 M citric acid aqueous solution (100 mL). The organic layer and the extract extracted from the aqueous layer with ethyl acetate were combined, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, 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-[(3-amino-3-oxopropyl) amino] carbonyl-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridine-3. -Ill] methyl} tert-butyl carbamate (0.075 g, 54% yield) was obtained 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, brs), 5.23 (1H, brs), 5.38 (1H, brs), 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) 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) from the same method as in Example 2-3), 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.
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, brs), 3.09 (2H, q, J = 6.7 Hz), 3.82 (2H, d, J = 5.3 Hz), 6.82 (1H, brs), 7.21 (2H , d, J = 8.0 Hz), 7.27 (2H, d, J = 8.0 Hz), 7.28 (1H, brs), 8.24 (3H, brs), 8.36 (1H, brs).
Example 5 [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetonitrile 1) 5-{[(tert-butoxycarbonyl) amino] methyl} A suspension of 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 0.95 M diisobutylaluminum hydride Toluene solution (33 mL, 32 mmol) was added dropwise over 15 minutes. The mixture was stirred at -78 ° C for 1.5 hours, then warmed to 0 ° C and further stirred for 30 minutes. Methanol (1 mL) was added to the reaction mixture, sodium sulfate decahydrate (10.2 g, 32 mmol) was added, and the mixture was stirred at room temperature for 1 hr. The insoluble material was removed by filtration, 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, 60% yield) was obtained 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, brs), 4.36 (2H, d, J = 5.7 Hz), 7.05 (2H, d , J = 7.9 Hz), 7.24-7.26 (2H,
m).
2) tert-butyl {[5- (hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (0.50 g, 1.3 mmol) and triethylamine A mixture consisting of (0.35 mL, 2.5 mmol) and tetrahydrofuran (10 mL) was cooled to 0 ° C., and methanesulfonyl chloride (0.22 g, 1.9 mmol) was added dropwise. After stirring at room temperature for 30 minutes, the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in dimethyl sulfoxide (5 mL), potassium cyanide (0.41 g, 6.3 mmol) was added, and the mixture was stirred at 60 ° C. for 30 min. Ethyl acetate was added to the reaction mixture, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl {[5- (cyanomethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate ( 0.36 g, 72% yield) was obtained 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) {[5- (Cyanomethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (0.11 g, 0.27 mmol) in trifluoroacetic acid (5 mL) was added and stirred at room temperature for 15 minutes. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate-tetrahydrofuran. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off 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, yield 99). %) Was obtained 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, brs), 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) {[5- (cyanomethyl) -2 2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (0.90 g, 2.2 mmol) in ethanol (20 mL) and 2N aqueous sodium hydroxide solution (5.5 mL, 11 mmol) was added and heated to reflux for 2 hours. The reaction mixture was acidified with 6N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give {[5- (2-amino-2-oxoethyl) -2-isobutyl-6-methyl-4 -(4-Methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (0.25 g, yield 27%) was obtained as a colorless solid.
2) tert-butyl {[5- (2-amino-2-oxoethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (0.25 g, 0.59 To (mmol), trifluoroacetic acid (5 mL) was added, and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate-tetrahydrofuran. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. 4N hydrogen chloride-1,4-dioxane solution (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 give 2- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetamide dihydrochloride (0.19 g, Yield 81%) was obtained as a 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, brs), 7.15-7.22 (2H, m), 7.47 (2H, d, J = 8.1 Hz ).
Example 7 [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetic acid methyl dihydrochloride 1) {[5- (cyanomethyl) -2- To a solution of tert-butyl isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (0.90 g, 2.2 mmol) in ethanol (20 mL) was added 2N aqueous sodium hydroxide ( 5.5 mL, 11 mmol) was added and heated to reflux for 1.5 days. The reaction mixture was acidified with 6N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. 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).
mmol) and stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, washed with water and saturated brine, and 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-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] Methyl acetate (0.097 g, 10% yield) was obtained 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, brs), 6.98 (2H, d, J = 7.8 Hz), 7.23 (2H, d, J = 7.8 Hz).
2) 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 the same manner as in Example 2-3), methyl [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetate dihydrochloride (0.069 g, yield 76%) was obtained as a white powder.
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) {[5- (hydroxy To a solution of tert-butyl methyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (1.95 g, 4.9 mmol) in tetrahydrofuran (50 mL) was added manganese dioxide. (4.9 g, 56 mmol) was added, and the mixture was stirred at room temperature for 19 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 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, brs), 7.10 (2H, d, J = 8.1 Hz), 7.29 (2H, d , J = 8.1 Hz), 9.71 (1H, s).
2) Sodium hydride (60% oily, 0.060 g, 1.5 mmol) was added to a solution of triethyl phosphonoacetate (0.033 g, 1.5 mmol) in tetrahydrofuran (10 mL) at 0 ° C. and stirred for 20 minutes. To the reaction solution, 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) solution was added and the mixture was stirred at room temperature for 45 min. Ethyl acetate was added to the reaction mixture, and the mixture was washed successively with saturated brine, saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain (2E) -3- [5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) Pyridin-3-yl] ethyl acrylate (0.44 g, 96% yield) was obtained 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 , brs), 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) Ethyl (2E) -3- [5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acrylate ( A mixture of 0.12 g, 0.25 mmol) and 4N hydrogen chloride-1,4-dioxane solution (5 mL, 20 mmol) was stirred at room temperature for 10 minutes. The solvent was distilled off under reduced pressure, and the residue was partitioned between ethyl acetate-tetrahydrofuran and saturated aqueous sodium hydrogen carbonate. The organic layer and the extract extracted from the aqueous layer with ethyl acetate-tetrahydrofuran were combined and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain (2E) -3- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acrylic acid Ethyl (0.059 g, yield 64%) was obtained.
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,
brs), 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) (2E)- Ethyl 3- [5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acrylate (0.32 g, 0.69 mmol) 1N aqueous sodium hydroxide solution (3.4 mL, 3.4 mmol) was added to a tetrahydrofuran (10 mL) solution, and the mixture was stirred at 60 ° C. for 12 hours. The reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extracts were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain (2E) -3- [5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) Pyridin-3-yl] acrylic acid (0.28 g, 93% yield) was obtained 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,
brs), 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) (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) and (2E) -3- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine by the same method as in Example 2-3). -3-yl] acrylic acid dihydrochloride (0.077 g, 90% yield) was obtained as a white powder.
¹ H-NMR (CD ₃ OD) δ: 1.10 (6H, d, J = 6.6 Hz), 2.12-2.27 (1H, m), 2.46 (3H, brs), 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) (2E) -3 From-[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acrylic acid (0.19 g, 0.43 mmol), In the same manner as in Example 3-1), {[5-[(1E) -3-amino-3-oxoprop-1-en-1-yl] -2-isobutyl-6-methyl-4- (4 -Methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (0.19 g, yield 99%) was obtained.
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, brs), 6.00 (1H, d, J = 16.2 Hz), 7.06 (2H, d, J = 8.1 Hz), 7.22-7.28 (3H, m).
2) {[5-[(1E) -3-Amino-3-oxoprop-1-en-1-yl] -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] (2E) -3- [5- (aminomethyl) -6-isobutyl-2-methyl-methyl} carbamate (tert-butyl) (0.083 g, 0.19 mmol) by the same method as in Example 2-3). 4- (4-Methylphenyl) pyridin-3-yl] acrylamide dihydrochloride (0.078 g, yield 99%) was obtained.
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) 5-Methyl-3-oxohexanenitrile (5.0 g, 40 mmol) and benzaldehyde (4.2 g, 40 mmol), methyl 3-aminocrotonate (4.6 g, 40 mmol) and 5-cyano-6-isobutyl-2-methyl-4-phenyl-1,4 in the same manner as in Example 1-2). -Methyl -dihydropyridine-3-carboxylate (10.7 g, yield 86%) was obtained as a white powder.
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,
brs), 7.18-7.32 (5H, m).
2) From methyl 5-cyano-6-isobutyl-2-methyl-4-phenyl-1,4-dihydropyridine-3-carboxylate (10.7 g, 34 mmol) in the same manner as in Example 1-3) Methyl 5-cyano-6-isobutyl-2-methyl-4-phenylnicotinate (8.4 g, yield 80%) was obtained as a white powder.
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) 5- (Aminomethyl) -6- was prepared from methyl 5-cyano-6-isobutyl-2-methyl-4-phenylnicotinate (8.4 g, 27 mmol) in the same manner as in Example 1-4). Methyl isobutyl-2-methyl-4-phenylnicotinate (0.21 g, yield 2.5%) was obtained as a white powder.
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) Methyl 3-oxohexanoate (7.2 g, 50 mmol) and ammonium acetate (19.3 g, 250 mmol), acetic acid (3.0 g, 50 mmol), and toluene (500 mL) were heated to 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 saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain methyl 3-aminohex-2-enoate as a colorless oil.
From a colorless oil of 5-methyl-3-oxohexanenitrile (5.0 g, 40 mmol), p-tolualdehyde (4.8 g, 40 mmol), and methyl 3-aminohex-2-enoate as described above, In the same manner as in Example 1-2), methyl 5-cyano-6-isobutyl-4- (4-methylphenyl) -2-propyl-1,4-dihydropyridine-3-carboxylate (11.8 g, yield) 84%) was obtained as an oil.
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, brs), 7.09 (2H, d , J = 8.1 Hz), 7.13 (2H, d, J =
8.1 Hz).
2) Example 1-3) from methyl 5-cyano-6-isobutyl-4- (4-methylphenyl) -2-propyl-1,4-dihydropyridine-3-carboxylate (11.8 g, 33 mmol) In the same manner, methyl 5-cyano-6-isobutyl-4- (4-methylphenyl) -2-propylnicotinate (9.4 g, yield 80%) was obtained as an oil.
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) 5- (amino) methyl 5-cyano-6-isobutyl-4- (4-methylphenyl) -2-propylnicotinate (0.88 g, 2.6 mmol) was prepared in the same manner as in Example 1-4). Methyl) -6-isobutyl-4- (4-methylphenyl) -2-propylnicotinate (0.78 g, 88% yield) was obtained as an oil.
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) [5-{[(tert-butoxycarbonyl) Amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetic acid methyl (0.25 g, 0.56 mmol) in tetrahydrofuran (15 mL) and ethanol (10 mL) And 8N aqueous sodium hydroxide solution (3.0 mL, 24 mmol) were added, and the mixture was heated to reflux for 3 hours. The reaction mixture was acidified with 6N hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, 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-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] Acetic acid (0.16 g, yield 65%) was obtained as a white powder.
2) 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 the same manner as in Example 2-3), [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetic acid dihydrochloride (0.15 g, Yield 99%) was obtained as a white powder.
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) In the same manner as in Example 12-1) Dimethyl 3-aminopent-2-enedioate was obtained from dimethyl 1,3-acetonedicarboxylate (7.0 g, 40 mmol).
From the obtained dimethyl 3-aminopent-2-enedioate and 5-methyl-3-oxohexanenitrile (5.0 g, 40 mmol) and p-tolualdehyde (4.8 g, 40 mmol), -6-Isobutyl-2- (2-methoxy-2-oxoethyl) -4- (4-methylphenyl) -1,4-dihydropyridine-3-carboxylate (11.5 g, 75% yield) as a yellow oil Got as.
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, brs), 7.10 (2H, d, J = 8.1 Hz), 7.16 (2H, d, J
= 8.1 Hz).
2) 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 the same manner as in Example 1-3), methyl 5-cyano-6-isobutyl-2- (2-methoxy-2-oxoethyl) -4- (4-methylphenyl) nicotinate (3.2 g, yield) 28%) was obtained as a yellow-orange oil.
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) From methyl 5-cyano-6-isobutyl-2- (2-methoxy-2-oxoethyl) -4- (4-methylphenyl) nicotinate (3.2 g, 8.4 mmol) as in Example 1-4) In this way, methyl 5- (aminomethyl) -6-isobutyl-2- (2-methoxy-2-oxoethyl) -4- (4-methylphenyl) nicotinate (2.5 g, yield 77%) was pale yellow. Obtained as an oil.
¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.8 Hz), 1.39 (2H, brs), 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) 5-methyl-3-oxohexanenitrile (15.0 g, 120 mmol) , 2,6-difluorobenzaldehyde (17.0 g, 120 mmol) and methyl 3-aminocrotonate (13.8 g, 120 mmol) in the same manner as in Example 1-2), 5-cyano-4- Methyl (2,6-difluorophenyl) -6-isobutyl-2-methyl-1,4-dihydropyridine-3-carboxylate (14.8 g, yield 36%) was obtained as yellow crystals.
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, brs), 6.75-6.90 (2H, m), 7.05-7.25 (1H, m).
2) Example 1-3 from methyl 5-cyano-4- (2,6-difluorophenyl) -6-isobutyl-2-methyl-1,4-dihydropyridine-3-carboxylate (14.8 g, 43 mmol) ) To give methyl 5-cyano-4- (2,6-difluorophenyl) -6-isobutyl-2-methylnicotinate (11.7 g, yield 80%) as yellow crystals.
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) 5-methyl-4-cyano-4- (2,6-difluorophenyl) -6-isobutyl-2-methylnicotinate (11.7 g, 34 mmol) was prepared in the same manner as in Example 1-4) to give 5- Methyl (aminomethyl) -4- (2,6-difluorophenyl) -6-isobutyl-2-methylnicotinate (9.8 g, 83% yield) was obtained as a pale yellow solid.
¹ H-NMR (CDCl ₃ ) δ: 0.99 (6H, d, J = 6.6 Hz), 1.51 (2H, brs), 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).
Melting point 48-49 ℃

Example 16 Methyl 5- (aminomethyl) -4- (4-fluorophenyl) -6-isobutyl-2-methylnicotinate 1) 5-methyl-3-oxohexanenitrile (15.0 g, 120 mmol) and 4 5-Cyanobenz (14.9 g, 120 mmol) and methyl 3-aminocrotonate (13.8 g, 120 mmol) in the same manner as in Example 1-2), 5-cyano-4- (4-fluoro Phenyl) -6-isobutyl-2-methyl-1,4-dihydropyridine-3-carboxylate (27.4 g, 70% yield) was obtained as a yellow oil.
2) Example 1-3) from methyl 5-cyano-4- (4-fluorophenyl) -6-isobutyl-2-methyl-1,4-dihydropyridine-3-carboxylate (27 g, 82 mmol) In a similar manner, 5-cyano
Methyl-4- (4-fluorophenyl) -6-isobutyl-2-methylnicotinate (24.0 g, 61% yield) was obtained as a yellow oil.
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) 5- (amino) methyl 5-cyano-4- (4-fluorophenyl) -6-isobutyl-2-methylnicotinate (13.0 g, 40 mmol) was prepared in the same manner as in Example 1-4). Methyl) -4- (4-fluorophenyl) -6-isobutyl-2-methylnicotinate (11.2 g, 85% yield) was obtained as a pale yellow solid.
¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.26 (2H, brs), 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).
Melting point 55-57 ℃
Example 17 5- (aminomethyl) -6-isobutyl-4- (4-methylphenyl) -2-propylnicotinic acid dihydrochloride 1) 5- (aminomethyl) -6-isobutyl-4- (4-methyl) 5-([(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-4 from methyl phenyl) -2-propylnicotinate (0.78 g, 2.2 mmol) by the same method as in Example 2-1). Methyl-(4-methylphenyl) -2-propylnicotinate (0.71 g, 71% yield) was obtained as a white solid.
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, brs), 7.06 (2H, d, J = 7.9 Hz), 7.20 (2H,
d, J = 7.9 Hz).
2) From methyl 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-4- (4-methylphenyl) -2-propylnicotinate (0.71 g, 1.6 mmol), Example 2-2 ) To give 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-4- (4-methylphenyl) -2-propylnicotinic acid (0.59 g, yield 86%). Obtained.
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) Example 2-3) from 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-4- (4-methylphenyl) -2-propylnicotinic acid (0.59 g, 1.3 mmol) By the same method, 5- (aminomethyl) -6-isobutyl-4- (4-methylphenyl) -2-propylnicotinic acid dihydrochloride (0.50 g, yield 90%) was obtained as a white powder.
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, brs), 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- (aminomethyl) -6-isobutyl-2-methyl-4-phenylnicotinate ( 8.5 g, 27 mmol) and methyl 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4-phenylnicotinate (in the same manner as in Example 2-1) 9.4 g, 83% yield) was obtained as a white solid.
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, brs), 7.14-7.21 (2H, m), 7.37-7.44 (3H, m) .
2) The same method as in Example 2-2) from methyl 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4-phenylnicotinate (1.0 g, 2.4 mmol) Gave 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4-phenylnicotinic acid (0.39 g, 40% yield) as a white solid.
3) From 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4-phenylnicotinic acid (0.39 g, 0.98 mmol), in the same manner as in Example 2-3) 5- (aminomethyl) -6-isobutyl-2-methyl-4-phenylnicotinic acid dihydrochloride (0.25 g, yield 86%) was obtained as a white powder.
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
5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate methyl (0.50
g, 1.6 mmol), formic acid (5 mL), and formalin (5 mL) were stirred at 100 ° C. for 12 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain methyl 5-[(dimethylamino) methyl] -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (0.10 g, yield 19%) I got it.
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) 5-Methyl-3-oxohexanenitrile (15.0 g, 120 mmol) And isonicotinaldehyde (12.8 g, 120 mmol) and methyl 3-aminocrotonate (13.8 g, 120 mmol) in the same manner as in Example 1-2), 5-cyano-6-isobutyl- Methyl 2-methyl-1,4-dihydro-4,4′-bipyridine-3-carboxylate (26.4 g, 71% yield) was obtained as a yellow oil.
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), add nitric acid Ammonium cerium (45 g, 82 mmol) was added and stirred at room temperature for 1 hour. The reaction mixture was cooled to 0 ° C. and partitioned between ethyl acetate and 2N sodium hydroxide. The organic layer and the extract extracted from the aqueous layer with ethyl acetate were combined and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. 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 a yellow oil. Obtained.
3) Methyl 5-cyano-6-isobutyl-2-methyl-4,4′-bipyridine-3-carboxylate (15.0 g, 48
mmol), and methyl 5- (aminomethyl) -2-methyl-6-isobutyl- [4,4′-bipyridine] -3-carboxylate (10.9 g, yield) in the same manner as in Example 1-4). 72%) was obtained as a pale yellow solid.
¹ H-NMR (CDCl ₃ ) δ: 0.99 (6H, d, J = 6.6 Hz), 1.33 (2H, brs), 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).
Melting point 63-65 ℃

Example 21 Conducted from methyl 5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinate 1) methyl 3,3-dimethylbutanoate (86.0 g, 0.66 mol) In the same manner as in Example 1-1), 5,5-dimethyl-3-oxohexanenitrile (92.0 g, yield 99%) was obtained as an oil.
¹ H-NMR (CDCl ₃ ) δ: 1.05 (9H, s), 2.49 (2H, s), 3.43 (2H, s).
2) 5,5-dimethyl-3-oxohexanenitrile (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 to reflux for 12 hours using a Dean-Stark trap. The reaction mixture was cooled to room temperature, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (50 mL), methyl 3-aminocrotonate (18.2 g, 158 mmol) was added, and the mixture was heated to reflux for 6 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 5-cyano-2-methyl-4- (4-methylphenyl) -6-neopentyl-1,4-dihydropyridine-3-carboxylate. Methyl acid (23 g, 43% yield) was obtained 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, brs), 7.06-7.16 (4H, m).
3) From methyl 5-cyano-2-methyl-4- (4-methylphenyl) -6-neopentyl-1,4-dihydropyridine-3-carboxylate (20 g, 59.4 mmol) from Example 1-3) By the same method, methyl 5-cyano-2-methyl-4- (4-methylphenyl) -6-neopentylnicotinate (12 g, yield 60%) was obtained as colorless crystals.
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 ).
Melting point 139-140 ℃
4) From methyl 5-cyano-2-methyl-4- (4-methylphenyl) -6-neopentylnicotinate (4 g, 11.9 mmol) in the same manner as in Example 1-4), 5- ( Methyl aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinate (2.3 g, yield 56%) was obtained as colorless crystals.
¹ H-NMR (CDCl ₃ ) δ: 1.02 (9H, s), 1.44 (2H, brs), 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).
Melting point 119-120 ℃
Example 22 5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinic acid dihydrochloride 1) 5- (aminomethyl) -2-methyl-4- (4- To a solution of 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 stirred at room temperature for 1 hour. . To the reaction solution were added 8N aqueous sodium hydroxide solution (2 mL) and methanol (10 mL), and the mixture was heated to reflux for 3 days. The reaction mixture was returned to room temperature, acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. 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%) was obtained 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, brs ), 4.29 (1H, brs), 7.18 (2H, d, J = 8.3 Hz), 7.23 (2H, d, J = 8.3 Hz).
Melting point 216-217 ℃
2) 5-{[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinic acid (0.30 g, 0.7 mmol) and 4N hydrogen chloride-1 , 4-Dioxane solution (5 mL) was added, 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, and 5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinic acid dihydrochloride ( 0.2 g, 71% yield) was obtained 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, brs).

Example 23 5- (aminomethyl) -4- (4-chlorophenyl) -6-isobutyl-2-methylnicotinic acid tert-butyl 1) tert-butyl acetoacetate (580 mL, 3.5 mol), 25% aqueous ammonia ( A mixture of 1200 mL) and methanol (1000 mL) was stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure, and then partitioned between ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain tert-butyl 3-aminocrotonate (550 g, yield 99%) as a pale yellow powder.
¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.87 (3H, s), 4.46 (1H, s).
2) Performed from 5-methyl-3-oxohexanenitrile (4.0 g, 32 mmol), 4-chlorobenzaldehyde (4.5 g, 32 mmol), and tert-butyl 3-aminocrotonate (5.0 g, 32 mmol) In the same manner as in Example 1-2), 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.
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,
brs), 7.10-7.20 (2H, m), 7.25-7.30 (2H, m).
Melting point: 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) An aqueous solution (40 mL) of diammonium cerium nitrate (27 g, 49 mmol) was added at room temperature over 5 minutes. The reaction solution was partitioned between ethyl acetate and water. The organic layer and the extract extracted from the aqueous layer with ethyl acetate were combined and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. 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, yield 95%) as a white powder. It was.
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).
Melting point 70-72 ℃
4) 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) in a sealed tube at room temperature under a hydrogen atmosphere of 0.5 MPa. Stir for 5 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and 10% aqueous potassium carbonate solution. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, and tert-butyl 5- (aminomethyl) -4- (4-chlorophenyl) -6-isobutyl-2-methylnicotinate (0.98 g, yield 97%) was a white powder. Got as.
¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.8 Hz), 1.22 (9H, s), 1.42 (2H, brs), 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).
Melting point 81-83 ℃
Example 24 5- (aminomethyl) -4- (4-chlorophenyl) -6-isobutyl-2-methylnicotinic acid hydrochloride 1) 5- (aminomethyl) -4- (4-chlorophenyl) -6-isobutyl- A mixture of tert-butyl 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 Hydrogen chloride-1,4-dioxane solution (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, yield 99%) as a colorless oil. Got as.
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 (0.27
g, 4.6 mmol) was added and stirred at room temperature for 3 hours. The reaction solution 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 acid hydrochloride ( 0.43 g, 76%) was obtained 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, brs).

Example 25 5- (aminomethyl) -6-isobutyl-2-isopropyl-4- (4-methylphenyl) nicotinic acid tert-butyl 1) Meldrum acid (14.41 g, 0.1 mol) and pyridine (16.2 mL, 0.2 mol) ) In dichloromethane (100 mL) was added dropwise isobutyryl chloride (13.4 mL, 0.11 mol) at 0 ° C. over 30 minutes, and the mixture was stirred at 0 ° C. for 2 hours. The reaction mixture was poured into 0.5N hydrochloric acid and extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and 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 to reflux for 6 hours. The reaction mixture was cooled to room temperature, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give tert-butyl 4-methyl-3-oxopentanoate as a crude product (9.31). g). A mixture consisting 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 solution was concentrated under reduced pressure, and then partitioned between ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain tert-butyl 3-amino-4-methylpent-2-enoate as a crude product (9.26 g).
2) 5-Methyl-3-oxohexanenitrile (5.0 g, 40 mmol), p-tolualdehyde (4.8 g, 40 mmol), and 3-amino-4-methylpent-2-ene obtained in 1) above 5-Cyano-6-isobutyl-2-isopropyl-4- (4-methylphenyl) -1,4 was prepared from the crude product of acid tert-butyl (9.26 g) in the same manner as in Example 1-2). Tert-Butyl dihydropyridine-3-carboxylate (12.11 g, yield 76%) was obtained as colorless crystals.
3) Example 23-3 from tert-butyl 5-cyano-6-isobutyl-2-isopropyl-4- (4-methylphenyl) -1,4-dihydropyridine-3-carboxylate (3.94 g, 10 mmol) ) -Tert-butyl 5-cyano-6-isobutyl-2-isopropyl-4- (4-methylphenyl) nicotinate (2.88 g, yield 73%) was obtained as an oil.
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) 5-Cyano-6-isobutyl-2-isopropyl-4- (4-methylphenyl) nicotinic acid from tert-butyl (2.74 g, 7 mmol) in the same manner as in Example 1-4) Tert-butyl (aminomethyl) -6-isobutyl-2-isopropyl-4- (4-methylphenyl) nicotinate (2.15 g, yield 77%) was obtained as a white powder.
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, brs), 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 from tert-butyl (0.40 g, 1 mmol) in the same manner as in Example 24-1) (Aminomethyl) -6-isobutyl-2-isopropyl-4- (4-methylphenyl) nicotinic acid dihydrochloride (0.37 g, yield 90%) was obtained as a white powder.
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, brs).
Example 27 5- (aminomethyl) -4- (4-chlorophenyl) -2-methyl-6-neopentylnicotinic acid tert-butyl 1) 5,5-dimethyl-3-oxohexanenitrile (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 the same manner as in Example 1-2), 4- (4-chlorophenyl) Tert-Butyl-5-cyano-2-methyl-6-neopentyl-1,4-dihydropyridine-3-carboxylate (2.5 g, yield 38%) was obtained as a white powder.
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, brs), 7.10-7.35 (4H, m).
Melting point 208-210 ℃
2) Example 23-3) from tert-butyl 4- (4-chlorophenyl) -5-cyano-2-methyl-6-neopentyl-1,4-dihydropyridine-3-carboxylate (2.4 g, 5.9 mmol) In the same manner as above, tert-butyl 4- (4-chlorophenyl) -5-cyano-2-methyl-6-neopentylnicotinate (2.1
g, yield 90%) was obtained as a pale yellow powder.
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).
94-95 ℃
3) From tert-butyl 4- (4-chlorophenyl) -5-cyano-2-methyl-6-neopentylnicotinate (1.0 g, 2.5 mmol), in the same manner as in Example 23-4), 5- Tert-butyl (aminomethyl) -4- (4-chlorophenyl) -2-methyl-6-neopentylnicotinate (0.93 g, yield 92%) was obtained as a white powder.
¹ H-NMR (CDCl ₃ ) δ: 1.02 (9H, s), 1.22 (9H, s), 1.43 (2H, brs), 2.55 (3H, s), 2.86
(2H, s), 3.66 (2H, s), 7.15-7.25 (2H, m), 7.35-7.45 (2H, m).
Melting point 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 tert-butyl (0.95 g, 2.4 mmol) was prepared in the same manner as in Example 24-1). -(Aminomethyl) -4- (4-chlorophenyl) -2-methyl-6-neopentylnicotinic acid dihydrochloride (1.0 g, yield 98%) was obtained as a white powder.
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, brs).
Melting point 246-248 ℃
Example 29 5- (aminomethyl) -4- (4-chlorophenyl) -2,6-dineopentylnicotinic acid tert-butyl 1) of piperidine (0.94 g, 11 mmol) and acetic acid (0.66 g, 11 mmol) To an isopropanol solution (30 ml) is added an isopropanol solution (300 ml) of 5,5-dimethyl-3-oxohexanenitrile (17.0 g, 110 mmol) and p-chlorobenzaldehyde (15.5 g, 110 mmol) at room temperature for 30 minutes. The solution was added dropwise and stirred for 3 days. The solvent was distilled off under reduced pressure, and the residue was partitioned between ethyl acetate and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 3- (4-chlorophenyl) -2- (3,3-dimethylbutanoyl) acrylonitrile as a crude product (35.2 g). .
2) 3-Amino-5,5-dimethylhexa- from meldrum acid (8.65 g, 60 mmol) and tert-butylacetyl chloride (9.2 ml, 66 mmol) in the same manner as in Example 25-1) Tert-butyl 2-enoate was obtained as a crude product (13 g).
3) From the crude product (11.7 g) obtained in 1) above and the crude product (13.0 g) obtained in 2) above, in the same manner as in Example 1-2), 4- ( 4-tert-butyl 4-chlorophenyl) -5-cyano-2,6-dineopentyl-1,4-dihydropyridine-3-carboxylate (2.03 g, 15% yield) was obtained as a yellow oil. That is, the above-mentioned two kinds of crude products were dissolved in methanol (40 mL) and heated to reflux for 3.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 4- (4-chlorophenyl) -5-cyano-2,6-dineopentyl-1,4-dihydropyridine-3-carboxylic acid tert- Butyl was obtained.
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, brs), 5.37 (1H, brs ), 7.20-7.32 (4H, m).
4) From tert-butyl 4- (4-chlorophenyl) -5-cyano-2,6-dineopentyl-1,4-dihydropyridine-3-carboxylate (2.03 g, 4.44 mmol), as in Example 23-3) By the method of
There was obtained tert-butyl 4- (4-chlorophenyl) -5-cyano-2,6-dineopentylnicotinate (0.75 g, yield 38%).
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) From tert-butyl 4- (4-chlorophenyl) -5-cyano-2,6-dineopentylnicotinate (0.75 g, 1.65 mmol), in the same manner as in Example 23-4), 5- ( Aminomethyl) -4- (4-chlorophenyl) -2,6-dineopentylnicotinic acid tert-butyl (0.35 g, 46% yield) was obtained as a pale yellow solid.
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
From tert-butyl 5- (aminomethyl) -4- (4-chlorophenyl) -2,6-dineopentylnicotinate (0.30 g, 0.653 mmol), in the same manner as in Example 24-1), 5- (Aminomethyl) -4- (4-chlorophenyl) -2,6-dineopentylnicotinic acid dihydrochloride (0.21 g, 69% yield) was obtained as a white solid.
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, brs).

Example 31 5- (Aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinic acid hemifumarate (In this specification, bis [5- (aminomethyl) -2-methyl -4- (4-Methylphenyl) -6-neopentylnicotinic acid] sometimes referred to as fumarate
1) 5- (Aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinic acid dihydrochloride (5.99 g, 15.0 mmol), tetrahydrofuran (50 mL) and 1 M sodium hydroxide To a mixture of aqueous 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, 0.1 M hydrochloric acid (100 mL) was added, and the mixture was extracted with ethyl acetate-tetrahydrofuran (1: 1). The organic layer was washed with water and saturated 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 colorless powdery 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, brs).
2) 5-({[(Benzyloxy) carbonyl] amino} methyl) -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinic acid (5.5 g, 12 mmol), 5% palladium-carbon (11.0 g), tetrahydrofuran (100 mL) and ethanol (100 mL) were stirred overnight at room temperature under a hydrogen atmosphere. 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 powder crystals. It was.
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) Water while heating 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) (150 mL) and 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 Performed from tert-butyl 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate 1) tert-butyl 3-aminocrotonate (253 g, 1.60 mol) In the same manner as in Example 1-2), tert-butyl 5-cyano-6-isobutyl-2-methyl-4- (4-methylphenyl) -1,4-dihydropyridine-3-carboxylate (159 g, yield) 27%) was obtained as a white solid. Next, Example 23-3 from tert-butyl 5-cyano-6-isobutyl-2-methyl-4- (4-methylphenyl) -1,4-dihydropyridine-3-carboxylate (41.0 g, 112 mmol) ) -Tert-butyl 5-cyano-6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (40.8 g, 99% yield) was obtained as a yellow solid.
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) 5- (Amino) 5-tert-butyl 5-cyano-6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (515 g, 1.42 mmol) in the same manner as in Example 1-4) Methyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate tert-butyl (502 g, 96% yield) was obtained as a white solid.
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, brs), 7.13 (2H, d,
J = 7.9 Hz), 7.22 (2H, d, J = 7.9 Hz).
Example 33 ({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) acetic acid dihydrochloride 1) 5-{[( tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (510 mg, 1.24 mmol) in N, N-dimethylformamide solution (10 ml) in bromoacetic acid Benzyl (568 mg, 2.48 mmol) and potassium carbonate (343 mg, 2.48 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate (100 ml), washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography to obtain 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4- Methylphenyl) nicotinic acid 2- (benzyloxy) -2-oxoethyl (690 mg, 99% yield) was obtained 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,
brs), 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) 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 2- (benzyloxy) -2-oxoethyl (690 mg, 1.23 mmol), palladium-carbon (10%, dry) (132 mg, 0.124 mmol) and ethanol (10 ml) were stirred at room temperature for 30 minutes in a hydrogen atmosphere. After filtration, the solvent was distilled off under reduced pressure ({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl ] Carbonyl} oxy) acetic acid was obtained 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, brs), 4.36 (2H, s), 7.06 (2H, d, J = 7.7 Hz), 7.19 (2H, d, J = 7.7 Hz ).
3) From the crude product (580 mg) obtained in 2) above, ({[5- (aminomethyl) -6-isobutyl-2-methyl-4- ( 4-Methylphenyl) pyridin-3-yl] carbonyl} oxy) acetic acid dihydrochloride (517 mg, 94% yield) was obtained as a white powder.
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 5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 2-amino-2-oxoethyl 1) 5-{[(tert-butoxycarbonyl) amino] methyl } -6-Isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (500 mg, 1.22 mmol) in N, N-dimethylformamide solution (10 ml) and 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), washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography to obtain 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4- Methylphenyl) nicotinic acid 2-amino-2-oxoethyl (570 mg, 99% yield) was obtained 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,
brs), 4.40 (2H, s), 5.12 (2H, brs), 7.12 (2H, d, J = 7.7 Hz), 7.25 (2H, d, J = 7.9 Hz).
2) From 2-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 2-amino-2-oxoethyl (570 mg, 1.21 mmol) 2- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 2-amino-2-oxoethyl (370 mg, yield) in the same manner as in Example 8-3) 82%) was obtained as an oil.
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, brs), 7.19 (2H, d, J = 8.1 Hz), 7.27 (2H, d, J = 7.9 Hz ).
Example 35 4- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 4-ethoxy-4-oxobutyl dihydrochloride 1) 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 hour and the reaction was partitioned between ethyl acetate and water. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 4-ethoxy-4. -Oxobutyl (0.45 g, 85% yield) was obtained 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, brs ), 7.07 (2H, d, J = 8.0 Hz), 7.21 (2H, d, J = 8.0 Hz).
2) From 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate 4-ethoxy-4-oxobutyl (0.13 g, 0.25 mmol) In the same manner as in Example 2-3), 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 4-ethoxy-4-oxobutyl dihydrochloride (0.12 g , Yield 95%) was obtained as a white powder.
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,
brs), 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, brs).
Melting point 193-195 ° C
Example 36 4-({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) butanoic acid dihydrochloride 1) 5- {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate 4-ethoxy-4-oxobutyl (0.30 g, 0.57 mmol) was added to ethanol (20
1N aqueous sodium hydroxide solution (4.0 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 0.5N hydrochloric acid (20 mL) and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude crystals were recrystallized from diisopropyl ether-ethyl acetate to give 4-({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methyl Phenyl) pyridin-3-yl] carbonyl} oxy) butanoic acid (0.23 g, 82% yield) was obtained 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, brs), 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, brs), 7.10 (2H, d, J = 7.7 Hz), 7.26 (2H, d, J = 7.7 Hz).
2) 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) and 4-({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine- 3-yl] carbonyl} oxy) butanoic acid dihydrochloride (0.20 g, 99% yield) was obtained as a white powder.
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, brs), 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, brs).
Melting point 221-223 ° C

Example 37 5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid pyridin-2-ylmethyl trihydrochloride 1) 5-{[(tert-butoxycarbonyl) amino] Methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (1.00 g, 2.42 mmol) in N, N-dimethylformamide solution (15 ml) in 2- (bromomethyl) pyridine hydrogen bromide Acid salt (0.92 g, 3.64 mmol) and potassium carbonate (669 mg, 4.84 mmol) were added and stirred for 30 minutes. The reaction mixture was diluted with ethyl acetate (100 ml), washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography to obtain 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4- Methylphenyl) pyridin-2-ylmethyl nicotinate (1.20 g, 98% yield) was obtained 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, brs), 4.25 (1H, brs), 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) Example from 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid pyridin-2-ylmethyl (1.20 g, 2.38 mmol) 2-3) 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid pyridin-2-ylmethyl trihydrochloride (1.22 g, yield 99%) ) Was obtained as a pale pink solid.
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, brs), 7.62-7.66 (1H, m) , 8.06 (1H, t, J = 7.9 Hz), 8.39 (3H, brs), 8.68 (1H, d, J = 4.9 Hz).
Example 38 5- (Aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinic acid 2-ethoxy-1-methyl-2-oxoethyl dihydrochloride 1) 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) to 5-{[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinic acid 2- Ethoxy-1-methyl-2-oxoethyl (0.35 g, yield 56%) was obtained as a white powder.
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-{[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinic acid 2-ethoxy-1-methyl-2-oxoethyl (0.2 g , 0.38 mmol) in the same manner as in Example 22-2), 5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinic acid 2-ethoxy-1-methyl -2-Oxoethyl dihydrochloride (0.16 g, 85% yield) was obtained as a white powder.
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- (Aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinic acid (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl Hydrochloride 1) 5-{[(tert-Butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinic acid (1.0 g, 2.3 mmol) and 4-chloromethyl 5-{[(tert-butoxycarbonyl) amino] methyl} -2- by the same method as in Example 33-1) from 5-methyl-1,3-dioxol-2-one (0.42 g, 2.8 mmol) Methyl-4- (4-methylphenyl) -6-neopentylnicotinic acid (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl (0.9 g, yield 73%) as a white powder Obtained.
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) 5-{[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinic acid (5-methyl-2-oxo-1,3-dioxole) 4-Nyl) methyl (0.8 g, 1.5 mmol) in ethyl acetate (2 mL) was added 4N hydrogen chloride-ethyl acetate solution (8 mL), and the mixture was stirred at room temperature for 4 hr. The reaction solution was concentrated under reduced pressure, and the resulting white solid was recrystallized from methanol-ethyl acetate to give 5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinic acid. (5-Methyl-2-oxo-1,3-dioxol-4-yl) methyl dihydrochloride (0.6 g, yield 77%) was obtained 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 (In this specification, bis [5- (aminomethyl) -6-isobutyl- 2-methyl-4- (4-methylphenyl) nicotinic acid] sometimes called fumarate)
1) 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (53.7 g, 130 mmol) and 4N hydrogen chloride-1, A mixed solution of 4-dioxane solution (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 obtained white solid was dissolved in isopropanol (500 ml) and stirred at 50 ° C. for 30 minutes. The resulting mixture was cooled to room temperature and stirred at room temperature for 1 hour. The precipitated solid was collected by filtration, washed with isopropanol (50 ml), and 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid dihydrochloride, propane-2- All (1: 1) solvate (46.5 g, 80% yield) was obtained 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, brs).
2) 5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid dihydrochloride propan-2-ol (1: 1) solvate (35.6 g, 80 mmol ) Was suspended in water (80 ml), 1N aqueous sodium hydroxide solution (160 ml, 160 mmol) was added at room temperature, and the mixture was stirred for 1 hour. The precipitated solid was collected by filtration, washed with ethanol (10 ml), and 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (13.3 g, 53% yield) ) Was obtained 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) is suspended in water (400 ml) and heated for 30 minutes under reflux. Stir. Fumaric acid (3.43 g, 29.6 mmol) was added to the obtained suspension, and the mixture was stirred at room temperature for 1 hour. The precipitated solid was collected by filtration, washed with water (50 ml), and 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid hemifumarate (13.9 g, yield). 76%) was obtained 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
{[5-[(1E) -3-Amino-3-oxoprop-1-en-1-yl] -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} A mixture of tert-butyl carbamate (97.6 mg, 0.223 mmol), 10% palladium-carbon (24 mg, 0.0223 mmol) and ethanol (5 ml) was stirred at room temperature for 16 hours in a hydrogen atmosphere. After filtration, the solvent was distilled off under reduced pressure {[5- (3-amino-3-oxopropyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} Tert-butyl carbamate was obtained as a crude product. The crude product was dissolved in 4N hydrogen chloride-1,4-dioxane solution (10 ml) and stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the resulting white solid was washed with diisopropyl ether to give 3- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine-3- Iil] propionamide dihydrochloride (72.7 mg, 79% yield) was obtained 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 3- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] ethyl propionate dihydrochloride 1) (2E) -3- [ 5-{[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] ethyl acrylate (700 mg, 1.50 mmol), 10% A mixture of palladium-carbon (160 mg, 0.15 mmol) and ethanol (15 ml) was stirred at room temperature for 1 hour under a hydrogen atmosphere. After filtration, the solvent was distilled off under reduced pressure, and the resulting 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] Ethyl propionate (480 mg, 68% yield) was obtained 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, brs), 6.98 (2H, d, J = 7.91), 7.24
(2H, d, J = 7.9 Hz).
2) Ethyl 3- [5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] ethyl propionate (73.0 mg, 0.156 mmol) to ethyl 3- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] propionate in the same manner as in Example 2-3). The dihydrochloride (58.3 mg, 85% yield) was obtained as a white powder.
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) 3- [5-{[( tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] ethyl propionate (407 mg, 0.868 mmol) in tetrahydrofuran (10 ml) 1N aqueous sodium hydroxide solution (4.30 ml, 4.30 mmol) was added to and stirred at 50 ° C. for 5 hours. The reaction mixture was neutralized with 6N hydrochloric acid (0.8 ml), extracted with ethyl acetate, and the organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting 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, yield 60%) was obtained 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-{[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] propionic acid (100 mg, 0.234 mmol ) To 3- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] propionic acid dihydrochloride in the same manner as in Example 2-3) The salt (94.2 mg, 97% yield) was obtained as a white powder.
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) 5-{[(tert-butoxycarbonyl) amino] Methyl} -6-isobutyl-4- (4-methylphenyl) -2-propylnicotinate (2.50 g, 5.50 mmol) was used in the same manner as in Example 5-1) to give {[5- (hydroxymethyl ) -2-Isobutyl-4- (4-methylphenyl) -6-propylpyridin-3-yl] methyl} carbamate tert-butyl (1.40 g, 60% yield) was obtained as a pale pink powder.
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, brs), 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) Performed from tert-butyl {1.2-g, 2.81 mmol) {[5- (hydroxymethyl) -2-isobutyl-4- (4-methylphenyl) -6-propylpyridin-3-yl] methyl} carbamate In the same manner as in Example 5-2), 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.
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, brs), 7.05 (2H, d, 7.9 Hz), 7.30 (2H, d, J = 7.7 Hz),
3) Example from tert-butyl {0.85-g, 1.88 mmol) {[5- (cyanomethyl) -2-isobutyl-4- (4-methylphenyl) -6-propylpyridin-3-yl] methyl} carbamate 6-1) by the same method as that described in 6-1) {[5- (2-amino-2-oxoethyl) -2-isobutyl-4- (4-methylphenyl) -6-propylpyridin-3-yl] methyl} carbamic acid tert -Butyl (814 mg, 95% yield) was obtained as a white powder.
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, brs), 7.70 (2H, d , J = 8.1 Hz), 7.27 (2H, d, J = 7.7 Hz).
4) tert-butyl {[5- (2-amino-2-oxoethyl) -2-isobutyl-4- (4-methylphenyl) -6-propylpyridin-3-yl] methyl} carbamate (300 mg, 0.84 mmol) to 2- [5- (aminomethyl) -6-isobutyl-4- (4-methylphenyl) -2-propylpyridin-3-yl] acetamide (31) in the same manner as in Example 8-3). mg, yield 10%) was obtained as an oil.
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) Meldrum acid (14.41 g, 100 mmol) and isovaleryl chloride (11.5 ml, 110 mmol) Thus, tert-butyl 3-amino-5-methylhex-2-enoate was obtained as a crude product (10 g) by the same method as in Example 25-1).
2) Examples were prepared from 5-methyl-3-oxohexanenitrile (5.0 g, 40 mmol), p-tolualdehyde (4.8 g, 40 mmol), and the crude product (9.96 g) obtained in 1) above. In the same manner as in 1-2), tert-butyl 5-cyano-2,6-diisobutyl-4- (4-methylphenyl) -1,4-dihydropyridine-3-carboxylate (12.11 g, yield 74%) ) Was obtained as an oil.
3) Example 23-3) from tert-butyl 5-cyano-2,6-diisobutyl-4- (4-methylphenyl) -1,4-dihydropyridine-3-carboxylate (4.09 g, 10 mmol) In the same manner, tert-butyl 5-cyano-2,6-diisobutyl-4- (4-methylphenyl) nicotinate (3.39 g, yield 83%) was obtained.
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-cyano-2,6-diisobutyl-4- (4-methylphenyl) nicotinate (3.25 g,
8 mmol) and tert-butyl 5- (aminomethyl) -2,6-diisobutyl-4- (4-methylphenyl) nicotinate (2.85 g, yield 86) in the same manner as in Example 1-4). %) As an oil.
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, brs), 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
From tert-butyl 5- (aminomethyl) -2,6-diisobutyl-4- (4-methylphenyl) nicotinate (0.41 g, 1 mmol), in the same manner as in Example 24-1), 5- ( Aminomethyl) -2,6-diisobutyl-4- (4-methylphenyl) nicotinic acid dihydrochloride (0.39 g, 92% yield) was obtained as a white powder.
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, brs).
Example 47 ({2-Isobutyl-6-methyl-4- (4-methylphenyl) -5-[(4-methylphenyl) sulfonyl] pyridin-3-yl} methyl) amine p-toluenesulfonate 1) Bromoacetone (6.92 g, 50.5 mmol) was added dropwise to a suspension of sodium p-toluenesulfinate (9.0 g, 50.5 mmol) in ethanol (50 mL). The resulting mixture was heated to reflux for 30 minutes, cooled to room temperature, and partitioned between ethyl acetate and water. The organic layer is washed with saturated brine,
After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give 1-[(4-methylphenyl) sulfonyl] acetone (8.0 g, yield 75%) 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) 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 to reflux for 3 hours using a Dean-Stark trap. The reaction mixture was cooled to room temperature, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 4- (4-methylphenyl) -3-[(4-methylphenyl) sulfonyl]. But-3-en-2-one was obtained as a crude product (3.5 g).
3) A mixture of 5-methyl-3-oxohexanenitrile (14.3 g, 100 mmol) and acetic acid (6.0 g, 10 mmol), ammonium acetate (38.5 g, 500 mmol) and toluene (200 mL) was added to the Dean-Stark trap. And heated at reflux for 17 hours. The reaction mixture was cooled to room temperature, washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 3-amino-5-methylhex-2-enenitrile as a mixture (8.2 g). The mixture (0.65 g) and the crude product (1.7 g) obtained in 2) above were dissolved in ethanol (50 mL) and heated to reflux for 12 hours. The reaction solution was concentrated under reduced 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-dihydropyridine-3-carbonitrile (1.3 g, yield 64%) was obtained as a white powder.
EIMS (M + 1): 421
4) From 2-isobutyl-6-methyl-4- (4-methylphenyl) -5-[(4-methylphenyl) sulfonyl] -1,4-dihydropyridine-3-carbonitrile (1.13 g, 2.7 mmol), In the same manner as in Example 23-3), 2-isobutyl-6-methyl-4- (4-methylphenyl) -5-[(4-methylphenyl) sulfonyl] nicotinonitrile (0.77 g, yield 68) %) Was obtained as a white powder.
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).
Melting point 129-131 ℃
5) From 2-isobutyl-6-methyl-4- (4-methylphenyl) -5-[(4-methylphenyl) sulfonyl] nicotinonitrile (0.69 g, 1.6 mmol), as in Example 1-4) ({2-isobutyl-6-methyl-4- (4-methylphenyl) -5-[(4-methylphenyl) sulfonyl] pyridin-3-yl} methyl) amine (0.64 g, yield 93 %) As a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.6 Hz), 1.41 (2H, brs), 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) Ethanol of ({2-isobutyl-6-methyl-4- (4-methylphenyl) -5-[(4-methylphenyl) sulfonyl] pyridin-3-yl} methyl) amine (0.64 g, 1.5 mmol) A solution of p-toluenesulfonic acid monohydrate (0.29 g, 1.5 mmol) in ethanol (5 mL) was added dropwise to the (5 mL) solution at room temperature. The precipitated crystals are collected by filtration, washed with cold ethanol, and dried to give ({2-isobutyl-6-methyl-4- (4-methylphenyl) -5-[(4-methylphenyl) sulfonyl] Pyridin-3-yl} methyl) amine p-toluenesulfonate (0.57 g, 63% yield) was obtained 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, brs).
Melting point 234-235 ℃
Example 48 5- (Aminomethyl) -2-benzyl-6-isobutyl-4- (4-methylphenyl) nicotinic acid tert-butyl 1) Meldrum acid (14.41 g, 100 mmol) and phenylacetyl chloride (14.5 ml, 110 mmol), tert-butyl 3-amino-4-phenylbut-2-enoate was obtained as a crude product (16 g) in the same manner as in Example 25-1).
2) Examples were prepared from 5-methyl-3-oxohexanenitrile (5.0 g, 40 mmol), p-tolualdehyde (4.8 g, 40 mmol), and the crude product (16 g) obtained in 1) above. In the same manner as in 1-2), tert-butyl 2-benzyl-5-cyano-6-isobutyl-4- (4-methylphenyl) -1,4-dihydropyridine-3-carboxylate (14.1 g, yield) 79%) was obtained as an oil.
3) Example 23-3 from tert-butyl 2-benzyl-5-cyano-6-isobutyl-4- (4-methylphenyl) -1,4-dihydropyridine-3-carboxylate (4.43 g, 10 mmol) ) To give tert-butyl 2-benzyl-5-cyano-6-isobutyl-4- (4-methylphenyl) nicotinate (2.92 g, yield 66%).
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) From tert-butyl 2-benzyl-5-cyano-6-isobutyl-4- (4-methylphenyl) nicotinate (4.40 g, 10 mmol), in the same manner as in Example 1-4), 5- Tert-butyl (aminomethyl) -2-benzyl-6-isobutyl-4- (4-methylphenyl) nicotinate (2.45 g, yield 55%) was obtained as an oil.
¹ H-NMR (CDCl ₃ ) δ: 0.95 (6H, d, J = 6.6 Hz), 1.05 (9H, s), 1.26 (2H, brs), 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 tert-butyl (0.44 g, 1 mmol) was prepared in the same manner as in Example 24-1). -(Aminomethyl) -2-benzyl-6-isobutyl-4- (4-methylphenyl) nicotinic acid dihydrochloride (0.38 g, yield 82%) was obtained as a white powder.
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, brs).
Example 50 5- (Aminomethyl) -6-isobutyl-4- (4-methylphenyl) -2-phenylnicotinic acid dihydrochloride 1) Ethyl 3-oxo-3-phenylpropanoate (9.61 g, 50 mmol) From ethyl acetate and ammonium acetate (19.27 g, 250 mmol), ethyl 3-amino-3-phenylacrylate was obtained as a crude product (9.5 g) in the same manner as in Example 12-1).
2) Examples were prepared from 5-methyl-3-oxohexanenitrile (5.0 g, 40 mmol), p-tolualdehyde (4.8 g, 40 mmol), and the crude product (9.5 g) obtained in 1) above. In the same manner as in 1-2), ethyl 5-cyano-6-isobutyl-4- (4-methylphenyl) -2-phenyl-1,4-dihydropyridine-3-carboxylate (9.52 g, yield 59%) ) Was obtained as an oil.
3) Example 23-3) from ethyl 5-cyano-6-isobutyl-4- (4-methylphenyl) -2-phenyl-1,4-dihydropyridine-3-carboxylate (4.81 g, 12 mmol) By the same method, ethyl 5-cyano-6-isobutyl-4- (4-methylphenyl) -2-phenylnicotinate (4.11 g, yield 85%) was obtained as an oil.
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) 5- (Amino) ethyl 5-cyano-6-isobutyl-4- (4-methylphenyl) -2-phenylnicotinate (4.40 g, 10 mmol) by the same method as in Example 1-4) Methyl) -6-isobutyl-4- (4-methylphenyl) -2-phenylnicotinate (3.63 g, yield 90%) was obtained as an oil.
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, bs), 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) From 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) The resulting mixture was heated to reflux for 3 days. The reaction mixture was concentrated under reduced pressure, and tetrahydrofuran (20 mL) and 1N aqueous sodium hydroxide solution (30 mL) were added to the residue. Di-tert-butyl dicarbonate (0.55 mL, 2.4 mmol) was added to the resulting mixture, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-4- (4-methylphenyl) -2-phenylnicotinic acid (0.38 g, 0.8 mmol ) Was obtained as an oil. From the oil, 5- (aminomethyl) -6-isobutyl-4- (4-methylphenyl) -2-phenylnicotinic acid dihydrochloride (0.31 g, yield) was obtained in the same manner as in Example 2-3). 88%) was obtained as a white powder.
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, brs).
Example 51 Methyl 5- (aminomethyl) -2-ethyl-6-isobutyl-4- (4-methylphenyl) nicotinate 1) Methyl 3-oxopentanoate (6.50 g, 50 mmol) and ammonium acetate (19.27 g 250 mmol), methyl 3-aminopent-2-enoate was obtained as a crude product (6.4 g) in the same manner as in Example 12-1).
2) Examples were prepared from 5-methyl-3-oxohexanenitrile (5.0 g, 40 mmol), p-tolualdehyde (4.8 g, 40 mmol), and the crude product (3.2 g) obtained in 1) above. In the same manner as in 1-2), methyl 5-cyano-2-ethyl-6-isobutyl-4- (4-methylphenyl) -1,4-dihydropyridine-3-carboxylate (4.12 g, yield 48%) ) Was obtained as an oil.
3) Example 23-3) from methyl 5-cyano-2-ethyl-6-isobutyl-4- (4-methylphenyl) -1,4-dihydropyridine-3-carboxylate (4.06 g, 12 mmol) In the same manner, methyl 5-cyano-2-ethyl-6-isobutyl-4- (4-methylphenyl) nicotinate (3.41 g, yield 84%) was obtained.
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-cyano-2-ethyl-6-isobutyl-4- (4-methylphenyl) nicotinate (4.40 g,
10 mmol) and methyl 5- (aminomethyl) -2-ethyl-6-isobutyl-4- (4-methylphenyl) nicotinate (2.49 g, yield 73) in the same manner as in Example 1-4). %) As a white powder.
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
From methyl 5- (aminomethyl) -2-ethyl-6-isobutyl-4- (4-methylphenyl) nicotinate (0.34 g, 1 mmol) in the same manner as in Example 50-5), 5- (aminomethyl) -2-ethyl-6-isobutyl-4- (4-methylphenyl) nicotinate (0.34 g, 1 mmol) Aminomethyl) -2-ethyl-6-isobutyl-4- (4-methylphenyl) nicotinic acid dihydrochloride (0.30 g, 82% yield) was obtained as a white powder.
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, brs).
Example 53 5- (Aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinic acid maleate
5- (Aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinic acid (114 mg,
To a mixed solution of 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 further stirred at room temperature for 1 hour. The obtained solution was concentrated under reduced pressure, acetonitrile (10 mL) was added to the residue, and the mixture was stirred at room temperature for 1 hr. The precipitated crystals were collected by filtration to give 5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinic acid maleate (92.6 mg, 60%) as colorless powdery crystals. Got as.
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
5- (Aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinic acid (114 mg,
Tartaric acid (40.6 mg, 0.350 mmol) was added to a mixed solution of 0.350 mmol), acetonitrile (2 mL) and water (2 mL), and the mixture was stirred at room temperature. After tartaric acid was dissolved, acetonitrile (8 mL) was added, and the mixture was further stirred at room temperature for 1 hour. The obtained solution was concentrated under reduced pressure, acetonitrile (10 mL) was added to the residue, and the mixture was stirred at room temperature for 1 hr. The precipitated crystals were collected by filtration to give 5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinic acid tartrate (129 mg, 77%) as colorless powder crystals. Obtained.
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 5- (Aminomethyl) -2-isobutyl-4- (4-methylphenyl) -6-neopentylnicotinic acid tert-butyl 1) Meldrum acid (14.41 g, 100 mmol) and isovaleryl chloride (11.5 ml, 110 mmol), tert-butyl 3-amino-5-methylhex-2-enoate was obtained as a crude product (10 g) in the same manner as in Example 25-1).
2) From 5,5-dimethyl-3-oxohexanenitrile (5.57 g, 40 mmol), p-tolualdehyde (4.81 g, 40 mmol), and the crude product (10 g) obtained in 1) above, In the same manner as in Example 1-2), tert-butyl 5-cyano-2-isobutyl-4- (4-methylphenyl) -6-neopentyl-1,4-dihydropyridine-3-carboxylate (3.75 g, Yield 22%) was obtained as an oil.
3) Example 23-3 from tert-butyl 5-cyano-2-isobutyl-4- (4-methylphenyl) -6-neopentyl-1,4-dihydropyridine-3-carboxylate (3.38 g, 10 mmol) ) To obtain tert-butyl 5-cyano-2-isobutyl-4- (4-methylphenyl) -6-neopentylnicotinate (1.66 g, yield 49%).
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) From tert-butyl 5-cyano-2-isobutyl-4- (4-methylphenyl) -6-neopentylnicotinate (3.25 g, 8 mmol), in the same manner as in Example 1-4), 5 -(Aminomethyl) -2-isobutyl-4- (4-methylphenyl) -6-neopentylnicotinic acid tert-butyl (1.34 g, yield 89%) was obtained as white crystals.
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, brs), 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 5- (Aminomethyl) -2-benzyl-4- (4-methylphenyl) -6-neopentylnicotinic acid tert-butyl 1) Meldrum acid (14.41 g, 100 mmol) and phenylacetyl chloride (14.5 ml) , 110 mmol), tert-butyl 3-amino-4-phenylbut-2-enoate was obtained as a crude product (16 g) by the same method as in Example 25-1).
2) From 5,5-dimethyl-3-oxohexanenitrile (5.57 g, 40 mmol), p-tolualdehyde (4.81 g, 40 mmol), and the crude product (11.6 g) obtained in 1) above, In the same manner as in Example 1-2), tert-butyl 2-benzyl-5-cyano-4- (4-methylphenyl) -6-neopentyl-1,4-dihydropyridine-3-carboxylate (12.5 g, Yield 68%) was obtained as an oil.
3) Example 23-3 from tert-butyl 2-benzyl-5-cyano-4- (4-methylphenyl) -6-neopentyl-1,4-dihydropyridine-3-carboxylate (6.8 g, 10 mmol) ), Tert-butyl 2-benzyl-5-cyano-4- (4-methylphenyl) -6-neopentylnicotinate (6.8 g, yield 100%) was obtained.
4) From tert-butyl 2-benzyl-5-cyano-4- (4-methylphenyl) -6-neopentylnicotinate (3.18 g, 7 mmol), in the same manner as in Example 1-4), 5 -(Aminomethyl) -2-benzyl-4- (4-methylphenyl) -6-neopentylnicotinic acid tert-butyl (0.48 g, yield 15%) was obtained as white crystals.
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 5- (Aminomethyl) -2-ethyl-4- (4-methylphenyl) -6-neopentylnicotinic acid tert-butyl
1) Crude production of tert-butyl 3-aminopent-2-enoate from meldrum acid (14.41 g, 100 mmol) and propionyl chloride (9.6 ml, 110 mmol) in the same manner as in Example 25-1) As a product (8.5 g).
2) From 5,5-dimethyl-3-oxohexanenitrile (5.57 g, 40 mmol), p-tolualdehyde (4.81 g, 40 mmol), and the crude product (8.5 g) obtained in 1) above, In the same manner as in Example 1-2), tert-butyl 5-cyano-2-ethyl-4- (4-methylphenyl) -6-neopentyl-1,4-dihydropyridine-3-carboxylate (6.0 g, Yield 38%) was obtained as an oil.
3) Example 23-3 from tert-butyl 5-cyano-2-ethyl-4- (4-methylphenyl) -6-neopentyl-1,4-dihydropyridine-3-carboxylate (5.92 g, 15 mmol) ) To give tert-butyl 5-cyano-2-ethyl-4- (4-methylphenyl) -6-neopentylnicotinate (2.58 g, yield 43%) as a pale yellow solid.
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) From tert-butyl 5-cyano-2-ethyl-4- (4-methylphenyl) -6-neopentylnicotinate (2.36 g, 6 mmol), in the same manner as in Example 1-4), 5 -(Aminomethyl) -2-ethyl-4- (4-methylphenyl) -6-neopentylnicotinic acid tert-butyl (1.56 g, yield 65%) was obtained as an oil.
¹ H-NMR (CDCl ₃ ) δ: 1.03 (9H, s), 1.19 (9H, s), 1.28 (2H, brs), 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
From tert-butyl 5- (aminomethyl) -2-ethyl-4- (4-methylphenyl) -6-neopentylnicotinate (0.39 g, 1 mmol) in the same manner as in Example 24-1), 5- (Aminomethyl) -2-ethyl-4- (4-methylphenyl) -6-neopentylnicotinic acid dihydrochloride (0.37 g, yield 90%) was obtained as a white powder.
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, brs).

Example 59 tert-Butyl 5- (aminomethyl) -4- (4-methylphenyl) -6-neopentyl-2-propylnicotinate
1) Crude production of tert-butyl 3-aminohex-2-enoate from meldrum acid (14.41 g, 100 mmol) and butyryl chloride (11.4 ml, 110 mmol) in the same manner as in Example 25-1) Obtained as a product (9.2 g).
2) From 5,5-dimethyl-3-oxohexanenitrile (5.57 g, 40 mmol), p-tolualdehyde (4.81 g, 40 mmol), and the crude product (16 g) obtained in 1) above, In the same manner as in Example 1-2), tert-butyl 5-cyano-4- (4-methylphenyl) -6-neopentyl-2-propyl-1,4-dihydropyridine-3-carboxylate (10.1 g, Yield 61%) was obtained as an oil.
3) Example 23-3 from tert-butyl 5-cyano-4- (4-methylphenyl) -6-neopentyl-2-propyl-1,4-dihydropyridine-3-carboxylate (9.8 g, 24 mmol) ) To give tert-butyl 5-cyano-4- (4-methylphenyl) -6-neopentyl-2-propylnicotinate (5.74 g, yield 58%) as an oil.
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) 5-tert-butyl 5-cyano-4- (4-methylphenyl) -6-neopentyl-2-propylnicotinate (4.47 g, 11 mmol) was prepared in the same manner as in Example 1-4) to give 5- Tert-butyl (aminomethyl) -4- (4-methylphenyl) -6-neopentyl-2-propylnicotinate (3.36 g, yield 74%) was obtained as white crystals.
¹ H-NMR (CDCl ₃ ) δ: 0.98 (3H, t, J = 7.3 Hz), 1.02 (9H, s), 1.14 (2H, brs), 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
From tert-butyl 5- (aminomethyl) -4- (4-methylphenyl) -6-neopentyl-2-propylnicotinate (0.41 g, 1 mmol), in the same manner as in Example 24-1), 5 -(Aminomethyl) -4- (4-methylphenyl) -6-neopentyl-2-propylnicotinic acid dihydrochloride (0.38 g, yield 90%) was obtained as a white powder.
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, brs), 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, brs).
Example 61 5- (Aminomethyl) -2-isopropyl-4- (4-methylphenyl) -6-neopentylnicotinic acid tert-butyl 1) Merdrum acid (14.41 g, 100 mmol) and isobutyryl chloride (11.4 ml, 110 mmol), tert-butyl 3-amino-4-methylpent-2-enoate was obtained as a crude product (9.2 g) in the same manner as in Example 25-1).
2) From 5,5-dimethyl-3-oxohexanenitrile (5.57 g, 40 mmol), p-tolualdehyde (4.81 g, 40 mmol), and the crude product (9.2 g) obtained in 1) above, In the same manner as in Example 1-2), tert-butyl 5-cyano-2-isopropyl-4- (4-methylphenyl) -6-neopentyl-1,4-dihydropyridine-3-carboxylate (4.91 g, Yield 30%) was obtained as an oil.
3) Example 23-3 from tert-butyl 5-4.9-2-isopropyl-4- (4-methylphenyl) -6-neopentyl-1,4-dihydropyridine-3-carboxylate (4.90 g, 12 mmol) ) To give tert-butyl 5-cyano-2-isopropyl-4- (4-methylphenyl) -6-neopentylnicotinate (2.48 g, yield 50%).
4) From tert-butyl 5-cyano-2-isopropyl-4- (4-methylphenyl) -6-neopentylnicotinate (3.25 g, 8 mmol), in the same manner as in Example 1-4), 5 -(Aminomethyl) -2-isopropyl-4- (4-methylphenyl) -6-neopentylnicotinic acid tert-butyl (1.26 g, yield 51%) was obtained as white crystals.
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, brs), 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
From tert-butyl 5- (aminomethyl) -2-isopropyl-4- (4-methylphenyl) -6-neopentylnicotinate (0.42 g, 1 mmol) in the same manner as in Example 24-1), 5- (Aminomethyl) -2-isopropyl-4- (4-methylphenyl) -6-neopentylnicotinic acid dihydrochloride (0.37 g, yield 88%) was obtained as a white powder.
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, brs).
Example 63 5- (Aminomethyl) -2-isobutyl-4- (4-methylphenyl) -6-neopentylnicotinic acid dihydrochloride
From tert-butyl 5- (aminomethyl) -2-isobutyl-4- (4-methylphenyl) -6-neopentylnicotinate (0.42 g, 1 mmol) in the same manner as in Example 24-1), 5- (Aminomethyl) -2-isobutyl-4- (4-methylphenyl) -6-neopentylnicotinic acid dihydrochloride (0.41 g, yield 93%) was obtained as a white powder.
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, brs).
Example 64 5- (Aminomethyl) -2-benzyl-4- (4-methylphenyl) -6-neopentylnicotinic acid dihydrochloride
From tert-butyl 5- (aminomethyl) -2-benzyl-4- (4-methylphenyl) -6-neopentylnicotinate (0.45 g, 1 mmol) in the same manner as in Example 24-1), 5- (Aminomethyl) -2-benzyl-4- (4-methylphenyl) -6-neopentylnicotinic acid dihydrochloride (0.43 g, 91% yield) was obtained as a white powder.
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, brs).
Example 65 Example 1 from methyl 5- (aminomethyl) -6-butyl-2-methyl-4- (4-methylphenyl) nicotinate dihydrochloride 1) 3-oxoheptanenitrile (64 g, 500 mmol) -2) in the same manner as in 6-butyl-5-cyano-2-methyl-4- (4-methylphenyl) -1,4-dihydropyridine-3-carboxylate (39 g, yield 24%) Was obtained as crystals.
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) Example 1-3) from methyl 6-butyl-5-cyano-2-methyl-4- (4-methylphenyl) -1,4-dihydropyridine-3-carboxylate (25 g, 77 mmol) By the same method, methyl 6-butyl-5-cyano-2-methyl-4- (4-methylphenyl) nicotinate (25 g, yield 65%) was obtained as crystals.
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) From methyl 6-butyl-5-cyano-2-methyl-4- (4-methylphenyl) nicotinate (4 g, 11.9 mmol) in the same manner as in Example 1-4), 5- (amino Methyl) -6-butyl-2-methyl-4- (4-methylphenyl) nicotinate (17 g, 68% yield) was obtained as an oil. The oil (3 g) was dissolved in ethyl acetate (10 mL), and 4N hydrogen chloride-ethyl acetate solution (10 mL) was added. The mixture was concentrated under reduced pressure to obtain methyl 5- (aminomethyl) -6-butyl-2-methyl-4- (4-methylphenyl) nicotinate dihydrochloride as a powder.
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) 5- (Aminomethyl) -6-butyl-2-methyl-4- 5-([(tert-Butoxycarbonyl) amino] methyl} -6-butyl-2-methyl 4-methylphenyl) nicotinate (14 g, 42.9 mmol) was prepared in the same manner as in Example 2-1). Methyl methyl-4- (4-methylphenyl) nicotinate (16.3 g, yield 89%) was obtained as crystals.
2) Example 2-2) from methyl 5-{[(tert-butoxycarbonyl) amino] methyl} -6-butyl-2-methyl-4- (4-methylphenyl) nicotinate (2.0 g, 4.7 mmol) In the same manner as above, 5-{[(tert-butoxycarbonyl) amino] methyl} -6-butyl-2-methyl-4- (4-methylphenyl) nicotinic acid (1.5 g, yield 77%) was crystallized. Got as.
3) Example 2-3) from 5-{[(tert-butoxycarbonyl) amino] methyl} -6-butyl-2-methyl-4- (4-methylphenyl) nicotinic acid (0.7 g, 1.7 mmol) By the same method, 5- (aminomethyl) -6-butyl-2-methyl-4- (4-methylphenyl) nicotinic acid dihydrochloride (0.56 g, yield 86%) was obtained as a white powder.
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) Example 1 from 3-oxohexanenitrile (60 g, 500 mmol) -2) in the same manner as in the above, methyl 5-cyano-2-methyl-4- (4-methylphenyl) -6-propyl-1,4-dihydropyridine-3-carboxylate (60 g, yield 39%) Was obtained as an oil.
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) Example 1-3) from methyl 5-cyano-2-methyl-4- (4-methylphenyl) -6-propyl-1,4-dihydropyridine-3-carboxylate (60 g, 193 mmol) By the same method, methyl 5-cyano-2-methyl-4- (4-methylphenyl) -6-propylnicotinate (34.8 g, yield 58%) was obtained as crystals.
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-cyano-2-methyl-4- (4-methylphenyl) -6-propylnicotinate (22 g, 71.3
mmol) and methyl 5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-propylnicotinate (15 g, 67% yield) in the same manner as in Example 1-4). ) Was obtained as an oil. The oil (2 g) was dissolved in ethyl acetate (10 mL), and 4N hydrogen chloride-ethyl acetate solution (10 mL) was added. The mixture was concentrated under reduced pressure to obtain methyl 5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-propylnicotinate dihydrochloride as a powder.
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) 5- (Aminomethyl) -2-methyl-4- (4-methyl) Methyl (phenyl) -6-propylnicotinate (13
g, 41.6 mmol) and 5-{[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-propylnicotine by the same method as in Example 2-1). Methyl acid (12 g, 70% yield) was obtained as crystals.
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) Example 2-2) from methyl 5-{[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-propylnicotinate (2 g, 4.8 mmol) In the same manner as above, 5-{[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-propylnicotinic acid (1.6 g, 83% yield) was crystallized. Got as.
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) Example 2-3) from 5-{[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-propylnicotinic acid (0.7 g, 2.1 mmol) In the same manner, 5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-propylnicotinic acid dihydrochloride (0.75 g, yield 96%) was obtained as a white powder.
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) 5- (aminomethyl) -4- (4-fluorophenyl) -6 5-{[(tert-butoxycarbonyl) amino] methyl} -4- (4-fluorophenyl) by the same method as in Example 2-1) from methyl isobutyl-2-methylnicotinate (2.00 g, 6.05 mmol) ) -6-isobutyl-2-methyl nicotinate (2.60 g, 99% yield) was obtained as a white solid.
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, brs), 7.07-7.20 (4H, m).
2) Example 2-2) from methyl 5-{[(tert-butoxycarbonyl) amino] methyl} -4- (4-fluorophenyl) -6-isobutyl-2-methylnicotinate (2.60 g, 6.24 mmol) 5-{[(tert-butoxycarbonyl) amino] methyl} -4- (4-fluorophenyl) -6-isobutyl-2-methylnicotinic acid (2.01 g, yield 79%) yellow Obtained as a solid.
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) Example 2-3) from 5-{[(tert-butoxycarbonyl) amino] methyl} -4- (4-fluorophenyl) -6-isobutyl-2-methylnicotinic acid (0.28 g, 0.673 mmol) In a similar manner, 5- (aminomethyl) -4- (4-fluorophenyl) -6-isobutyl-2-methylnicotinic acid dihydrochloride (0.20 g, yield 76%) was obtained as a white solid.
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) 5- (aminomethyl) -4- (2,6-difluoro Phenyl) -6-isobutyl-2-methylnicotinate (2.00 g, 6.38 mmol) was prepared in the same manner as in Example 2-1) by using 5-{[(tert-butoxycarbonyl) amino] methyl} -4- Methyl (2,6-difluorophenyl) -6-isobutyl-2-methylnicotinate (2.49 g, 87% yield) was obtained as a white solid.
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, brs), 6.97-7.02 (2H, m), 7.34-7.44 (1H, m) .
2) Example 2-from methyl 5-{[(tert-butoxycarbonyl) amino] methyl} -4- (2,6-difluorophenyl) -6-isobutyl-2-methylnicotinate (2.49 g, 5.55 mmol) 2-{[(tert-butoxycarbonyl) amino] methyl} -4- (2,6-difluorophenyl) -6-isobutyl-2-methylnicotinic acid (2.22 g, yield 92%) ) Was obtained as a yellow solid.
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, brs), 6.96-7.01 (2H, m), 7.34-7.43 (1H, m).
3) Example 2-3 from 5-{[(tert-butoxycarbonyl) amino] methyl} -4- (2,6-difluorophenyl) -6-isobutyl-2-methylnicotinic acid (0.28 g, 0.635 mmol) ) To give 5- (aminomethyl) -4- (2,6-difluorophenyl) -6-isobutyl-2-methylnicotinic acid dihydrochloride (185 mg, 70% yield) as a white solid It was.
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 5- (aminomethyl) -6-isobutyl-2-methyl-4- [4- (trifluoromethyl) phenyl] tert-butyl nicotinate 1) 5-methyl-3-oxohexanenitrile (4.0 g, 32 mmol) and 4- (trifluoromethyl) benzaldehyde (5.6 g, 32 mmol) by the same method as in Example 29-1), 2- (3-methylbutanoyl) -3- [4- (tri A crude product (9.8 g) of (fluoromethyl) phenyl] acrylonitrile was obtained.
2) From the crude product (9.8 g) obtained in 1) above and tert-butyl 3-aminocrotonate (5.47 g, 35 mmol), in the same manner as in Example 1-2), 5-cyano Tert-Butyl-6-isobutyl-2-methyl-4- [4- (trifluoromethyl) phenyl] -1,4-dihydropyridine-3-carboxylate (4.8 g, yield 36%) was obtained as a white powder. . That is, the aforementioned crude product and 3-aminocrotonic acid
tert-Butyl was dissolved in methanol (200 mL) and heated to reflux for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 5-cyano-6-isobutyl-2-methyl-4- [4- (trifluoromethyl) phenyl] -1,4-dihydropyridine. Tert-Butyl-3-carboxylate was obtained.
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,
brs), 7.36 (2H, d, J = 8.1 Hz), 7.56 (2H, d, J = 8.1 Hz).
Melting point 199-201 ℃
3) Performed from tert-butyl 5-cyano-6-isobutyl-2-methyl-4- [4- (trifluoromethyl) phenyl] -1,4-dihydropyridine-3-carboxylate (4.7 g, 11 mmol) In the same manner as in Example 23-3), tert-butyl 5-cyano-6-isobutyl-2-methyl-4- [4- (trifluoromethyl) phenyl] nicotinate (3.5 g, yield 76%) was obtained. Obtained as a white powder.
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).
Melting point 108-110 ℃
4) From tert-butyl 5-cyano-6-isobutyl-2-methyl-4- [4- (trifluoromethyl) phenyl] nicotinate (3.5 g, 8.2 mmol), the same method as in Example 1-4) Gave tert-butyl 5- (aminomethyl) -6-isobutyl-2-methyl-4- [4- (trifluoromethyl) phenyl] nicotinate (3.3 g, 96% yield) as a white powder.
¹ H-NMR (CDCl ₃ ) δ: 0.99 (6H, d, J = 6.6 Hz), 1.17 (9H, s), 1.38 (2H, brs), 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).
Melting point 88-90 ℃

Example 72 5- (Aminomethyl) -6-isobutyl-2-methyl-4- [4- (trifluoromethyl) phenyl] nicotinic acid hydrochloride
From tert-butyl 5- (aminomethyl) -6-isobutyl-2-methyl-4- [4- (trifluoromethyl) phenyl] nicotinate (1.0 g, 2.3 mmol), in the same manner as in Example 24, 5- (Aminomethyl) -6-isobutyl-2-methyl-4- [4- (trifluoromethyl) phenyl] nicotinic acid hydrochloride (0.51 g, yield 53%) was obtained as a white powder.
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, brs).
Example 73 tert-butyl 5- (aminomethyl) -6-isobutyl-4- [4- (methoxycarbonyl) phenyl] -2-methylnicotinate 1) 5-methyl-3-oxohexanenitrile (4.0 g, 32 mmol) and methyl 4-formylbenzoate (5.3 g, 32 mmol) in the same manner as in Example 29-1), 4- (2-cyano-5-methyl-3-oxohex-1-ene-1 -Yl) Methyl benzoate was obtained as crude product (10.1 g).
2) The crude product (10.1 g) obtained in 1) above and tert-butyl 3-aminocrotonate (5.25 g,
33 mmol) and 5-cyano-6-isobutyl-4- [4- (methoxycarbonyl) phenyl] -2-methyl-1,4-dihydropyridine-3-carboxylic acid in the same manner as in Example 1-2). Tert-butyl acid (5.9 g, yield 45%) was obtained as a white powder. That is, the above crude product and tert-butyl 3-aminocrotonate were dissolved in methanol (200 mL) and heated to reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 5-cyano-6-isobutyl-4- [4- (methoxycarbonyl) phenyl] -2-methyl-1,4-dihydropyridine- Tert-butyl 3-carboxylate was obtained.
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, brs), 7.32 (2H, d, J = 8.3 Hz), 7.99 (2H, d, J = 8.3 Hz).
Melting point 191-193 ° C
3) Examples from tert-butyl 5-cyano-6-isobutyl-4- [4- (methoxycarbonyl) phenyl] -2-methyl-1,4-dihydropyridine-3-carboxylate (5.7 g, 14 mmol) 23-3), tert-butyl 5-cyano-6-isobutyl-4- [4- (methoxycarbonyl) phenyl] -2-methylnicotinate (5.4 g, yield 95%) was obtained as a white powder. Got as.
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).
Melting point 108-109 ° C
4) From tert-butyl 5-cyano-6-isobutyl-4- [4- (methoxycarbonyl) phenyl] -2-methylnicotinate (5.3 g, 13 mmol), in the same manner as in Example 1-4) , Tert-butyl 5- (aminomethyl) -6-isobutyl-4- [4- (methoxycarbonyl) phenyl] -2-methylnicotinate (5.0 g, yield 94%) was obtained as a white powder.
¹ H-NMR (CDCl ₃ ) δ: 0.99 (6H, d, J = 6.6 Hz), 1.17 (9H, s), 1.49 (2H, brs), 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).
Melting point 77-81 ℃
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 tert-butyl (0.80 g, 1.9 mmol) was prepared in the same manner as in Example 24 to give 5 -(Aminomethyl) -6-isobutyl-4- [4- (methoxycarbonyl) phenyl] -2-methylnicotinic acid hydrochloride (0.50 g, yield 66%) was obtained as a white powder.
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 5- (aminomethyl) -4- (4-ethylphenyl) -6-isobutyl-2-methylnicotinic acid tert-butyl 1) 5-methyl-3-oxohexanenitrile (4.0 g, 32 mmol) and From 4-ethylbenzaldehyde (4.3 g, 32 mmol), a crude product of 3- (4-ethylphenyl) -2- (3-methylbutanoyl) acrylonitrile (8.8%) was obtained in the same manner as in Example 29-1). g) was obtained.
2) From the crude product (8.8 g) obtained in 1) above and tert-butyl 3-aminocrotonate (5.47 g, 35 mmol), in the same manner as in Example 1-2), 5-cyano Tert-Butyl-4- (4-ethylphenyl) -6-isobutyl-2-methyl-1,4-dihydropyridine-3-carboxylate (7.8 g, yield 64%) was obtained as a white powder. That is, the above crude product and tert-butyl 3-aminocrotonate were dissolved in methanol (200 mL) and heated to reflux for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 5-cyano-4- (4-ethylphenyl) -6-isobutyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid. The tert-butyl acid was obtained.
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, brs), 7.10 (2H, d, J = 8.3 Hz), 7.14 (2H, d, J = 8.3 Hz).
Melting point 165-166 ° C
3) Example 23-3 from tert-butyl 5-cyano-4- (4-ethylphenyl) -6-isobutyl-2-methyl-1,4-dihydropyridine-3-carboxylate (7.8 g, 21 mmol) ) To give tert-butyl 5-cyano-4- (4-ethylphenyl) -6-isobutyl-2-methylnicotinate (5.2 g, yield 67%) as a white powder.
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).
Melting point 85-86 ℃
4) tert-butyl 5-cyano-4- (4-ethylphenyl) -6-isobutyl-2-methylnicotinate (7.2
g, 19 mmol) and tert-butyl 5- (aminomethyl) -4- (4-ethylphenyl) -6-isobutyl-2-methylnicotinate (7.0 g) in the same manner as in Example 1-4). , Yield 97%) was obtained as a white powder.
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, brs), 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).
Melting point 50-52 ℃

Example 76 5- (Aminomethyl) -4- (4-ethylphenyl) -6-isobutyl-2-methylnicotinic acid hydrochloride
5- (Aminomethyl) -4- (4-ethylphenyl) -6-isobutyl-2-methylnicotinate tert-butyl (0.70 g, 1.8 mmol) was prepared in the same manner as in Example 24 by using 5- (amino Methyl) -4- (4-ethylphenyl) -6-isobutyl-2-methylnicotinic acid hydrochloride (0.52 g, yield 79%) was obtained as a white powder.
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, brs).
Example 77 Methyl 5- (aminomethyl) -4- (4-chlorophenyl) -2-ethyl-6-neopentylnicotinate 1) Methyl 3-oxopentanoate (13 g, 100 mmol) and ammonium acetate (38.5 g , 500 mmol), and methyl 3-aminopent-2-enoate was obtained as a crude product (20 g) in the same manner as in Example 12-1).
2) From 5,5-dimethyl-3-oxohexanenitrile (5.1 g, 32 mmol), 4-chlorobenzaldehyde (4.5 g, 32 mmol), and the crude product (3.2 g) obtained in 1) above, In the same manner as in Example 1-2), methyl 4- (4-chlorophenyl) -5-cyano-2-ethyl-6-neopentyl-1,4-dihydropyridine-3-carboxylate (1.4 g, yield 23) %) Was obtained as a yellow powder.
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, brs), 7.10-7.20 (2H, m), 7.25-7.30 (2H, m) .
3) Similar to Example 23-3) from methyl 4- (4-chlorophenyl) -5-cyano-2-ethyl-6-neopentyl-1,4-dihydropyridine-3-carboxylate (1.4 g, 3.7 mmol) By the above method, methyl 4- (4-chlorophenyl) -5-cyano-2-ethyl-6-neopentylnicotinate (0.58 g, yield 43%) was obtained as a pale yellow powder.
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).
Melting point 120-121 ℃
4) 5- (amino) methyl 4- (4-chlorophenyl) -5-cyano-2-ethyl-6-neopentylnicotinate (0.57 g, 1.5 mmol) in the same manner as in Example 23-4) Methyl) -4- (4-chlorophenyl) -2-ethyl-6-neopentylnicotinate (0.49 g, 85% yield) was obtained as a pale yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 1.03 (9H, s), 1.30 (3H, t, J = 7.5 Hz), 1.42 (2H, brs), 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) 5- (aminomethyl) -4- (4-chlorophenyl) -2- 5-([(tert-Butoxycarbonyl) amino] methyl} -4- (4-methyl 4-ethyl-6-neopentylnicotinate (0.42 g, 1.1 mmol) was prepared in the same manner as in Example 2-1). Methyl chlorophenyl) -2-ethyl-6-neopentylnicotinate (0.52 g, yield 97%) was obtained as a white powder.
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, brs), 7.10-7.20 (2H, m), 7.30-7.45 (2H, m).
2) From methyl 5-{[(tert-butoxycarbonyl) amino] methyl} -4- (4-chlorophenyl) -2-ethyl-6-neopentylnicotinate (0.47 g, 0.99 mmol), Example 2-2 ) To give 5-{[(tert-butoxycarbonyl) amino] methyl} -4- (4-chlorophenyl) -2-ethyl-6-neopentylnicotinic acid (0.37 g, 81% yield). Obtained as a white powder.
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, brs).
Melting point 71-72 ℃
3) Example 2-3) from 5-{[(tert-butoxycarbonyl) amino] methyl} -4- (4-chlorophenyl) -2-ethyl-6-neopentylnicotinic acid (0.30 g, 0.65 mmol) By the same method, 5- (aminomethyl) -4- (4-chlorophenyl) -2-ethyl-6-neopentylnicotinic acid dihydrochloride (0.24 g, yield 83%) was obtained as a white powder.
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, brs), 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, brs).
Melting point 230-235 ℃

Example 79 5- (aminomethyl) -4- (4-chlorophenyl) -2-isopropyl-6-neopentylnicotinic acid tert-butyl 1) 5,5-dimethyl-3-oxohexanenitrile (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 the same manner as in Example 1-2), 4- (4-Chlorophenyl) -5-cyano-2-isopropyl-6-neopentyl-1,4-dihydropyridine-3-carboxylate tert-butyl (2.00 g, yield 16%) was obtained as a white solid.
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) Example 23-3) from tert-butyl 4- (4-chlorophenyl) -5-cyano-2-isopropyl-6-neopentyl-1,4-dihydropyridine-3-carboxylate (2.00 g, 4.66 mmol) By the same method, tert-butyl 4- (4-chlorophenyl) -5-cyano-2-isopropyl-6-neopentylnicotinate (1.91 g, yield 96%) was obtained as a yellow solid.
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) 5- (4-Chlorophenyl) -5-cyano-2-isopropyl-6-neopentylnicotinic acid tert-butyl (1.80 g, 4.27 mmol) was prepared in the same manner as in Example 23-4) to give 5- ( Aminomethyl) -4- (4-chlorophenyl) -2-isopropyl-6-neopentylnicotinic acid tert-butyl (1.24)
g, 67% yield) was obtained as a white solid.
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 tert-butyl (406 mg, 0.941 mmol) was prepared in the same manner as in Example 24-1) to give 5- (Aminomethyl) -4- (4-chlorophenyl) -2-isopropyl-6-neopentylnicotinic acid dihydrochloride (393 mg, 93% yield) was obtained as a yellow solid.
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, brs).
Example 81 5- (aminomethyl) -4- (4-chlorophenyl) -6-isobutyl-2-isopropylnicotinic acid tert-butyl 1) 5-methyl-3-oxohexanenitrile (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 the same manner as in Example 1-2), 4- (4-chlorophenyl ) -5-cyano-6-isobutyl-2-isopropyl-1,4-dihydropyridine-3-carboxylate tert-butyl (6.18 g, yield 50%) was obtained as a yellow solid.
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, m), 4.55 (1H, s), 5.71 (1H, s), 7.15 (2H, d, J = 8.3 Hz), 7.25-7.27 (2H, m).
2) Example 23-3) 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 similar manner, tert-butyl 4- (4-chlorophenyl) -5-cyano-6-isobutyl-2-isopropylnicotinate (6.10 g, yield 99%) was obtained as a yellow oil.
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) 4- (4-Chlorophenyl) -5-cyano-6-isobutyl-2-isopropylnicotinic acid tert-butyl (6.10 g, 1.48 mmol) was prepared in the same manner as in Example 23-4) to give 5- (amino Methyl) -4- (4-chlorophenyl) -6-isobutyl-2-isopropylnicotinate tert-butyl (5.52 g, yield 89%) was obtained as a white solid.
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 tert-butyl (404 mg, 0.969 mmol) was prepared in the same manner as in Example 24-1) to give 5- ( Aminomethyl) -4- (4-chlorophenyl) -6-isobutyl-2-isopropylnicotinic acid dihydrochloride (263 mg, 62% yield) was obtained as a yellow solid.
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, brs).
Example 83 5- (aminomethyl) -4- (4-chlorophenyl) -2,6-diisobutylnicotinic acid tert-butyl 1) From merdramic acid (17.3 g, 120 mmol) and isovaleryl chloride (15.8 ml, 132 mmol) In the same manner as in Example 25-1), tert-butyl 3-amino-5-methylhex-2-enoate was obtained as a crude product (20.2 g).
2) Example 1 was prepared from 5-methyl-3-oxohexanenitrile (4.1 g, 33 mmol), 4-chlorobenzaldehyde (4.6 g, 33 mmol) and the crude product (10.1 g) obtained in 1) above. -2), tert-butyl 4- (4-chlorophenyl) -5-cyano-2,6-diisobutyl-1,4-dihydropyridine-3-carboxylate (10.2 g, yield 72%) was obtained. Obtained as a pale yellow powder.
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, brs), 7.15-7.25 (2H, m), 7.25-7.30 (2H, m).
Melting point 166-168 ℃
3) Same as Example 23-3) from tert-butyl 4- (4-chlorophenyl) -5-cyano-2,6-diisobutyl-1,4-dihydropyridine-3-carboxylate (9.8 g, 23 mmol) By this method, tert-butyl 4- (4-chlorophenyl) -5-cyano-2,6-diisobutylnicotinate (9.6 g, yield 99%) was obtained as a white powder.
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) 5- (Aminomethyl) was obtained from tert-butyl 4- (4-chlorophenyl) -5-cyano-2,6-diisobutylnicotinate (1.0 g, 2.3 mmol) in the same manner as in Example 23-4). ) -4- (4-Chlorophenyl) -2,6-diisobutylnicotinate tert-butyl (0.97 g, yield 96%) was obtained as a white powder.
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, brs), 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 tert-butyl (0.90
g, 2.1 mmol) and 5- (aminomethyl) -4- (4-chlorophenyl) -2,6-diisobutylnicotinic acid dihydrochloride (0.92 g, yield) by the same method as in Example 24-1). 98%) was obtained as a white powder.
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, brs).
Melting point 205 ° C (decomposition)
Example 85 5- (aminomethyl) -4- (4-chlorophenyl) -2-isobutyl-6-neopentylnicotinic acid tert-butyl 1) 5,5-dimethyl-3-oxohexanenitrile (4.6 g, 33 mmol) ), 4-chlorobenzaldehyde (4.6 g, 33 mmol) and the crude product of tert-butyl 3-amino-5-methylhex-2-enoate obtained in Example 83-1) (10.1 g) In the same manner as in Example 1-2), 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).
2) 4- (4-Chlorophenyl) -5-cyano-2-isobutyl-6-neopentyl was prepared from the crude product (7.9 g) obtained in 1) by the same method as in Example 23-3). Tert-butyl nicotinate (5.5 g, 37% yield) was obtained as a white powder.
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) From tert-butyl 4- (4-chlorophenyl) -5-cyano-2-isobutyl-6-neopentylnicotinate (5.2 g, 12 mmol), in the same manner as in Example 23-4), 5- Tert-butyl (aminomethyl) -4- (4-chlorophenyl) -2-isobutyl-6-neopentylnicotinate (4.5 g, yield 86%) was obtained as a yellow powder.
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, brs), 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 tert-butyl (0.50 g, 1.1 mmol) was prepared in the same manner as in Example 24-1). -(Aminomethyl) -4- (4-chlorophenyl) -2-isobutyl-6-neopentylnicotinic acid dihydrochloride (0.29 g, yield 56%) was obtained as a white powder.
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, brs).
Melting point 251 ° C (decomposition)
Example 87 [5- (Aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] acetonitrile dihydrochloride 1) 5-{[(tert-butoxycarbonyl) Amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinate methyl (10 g, 22.7 mmol) was prepared in the same manner as in Example 5-1) by {[5- ( Hydroxymethyl) -6-methyl-4- (4-methylphenyl) -2-neopentylpyridin-3-yl] methyl} carbamate tert-butyl (4.5 g, 48% yield) was obtained 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), 2.84 (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) tert-butyl {[5- (hydroxymethyl) -6-methyl-4- (4-methylphenyl) -2-neopentylpyridin-3-yl] methyl} carbamate (0.9 g, 2.2 mmol), triethylamine A mixture consisting of (0.4 g, 4.0 mmol) and tetrahydrofuran (30 mL) was 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 hydrogen carbonate and extracted with ethyl acetate. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and methanesulfonic acid [5-{[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-Neopentylpyridin-3-yl] methyl (0.85 g, 79% yield) was obtained 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) Methanesulfonic acid [5-{[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-
Methylphenyl) -6-neopentylpyridin-3-yl] methyl (0.84 g, 1.7 mmol) is dissolved in dimethyl sulfoxide (10 mL), potassium cyanide (0.14 g, 2.0 mmol) is added, and the mixture is heated at 60 ° C. for 1 hour. Stir. Ethyl acetate was added to the reaction mixture, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and 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%) was obtained as 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) Examples from tert-butyl {0.4-, 0.95 mmol) {[5- (cyanomethyl) -6-methyl-4- (4-methylphenyl) -2-neopentylpyridin-3-yl] methyl} carbamate In the same manner as in 2-3), [5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] acetonitrile dihydrochloride (0.28 g, 76 %) As a powder.
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) {[5- (cyanomethyl)- In the same manner as in Example 6-1) from tert-butyl 6-methyl-4- (4-methylphenyl) -2-neopentylpyridin-3-yl] methyl} carbamate (0.35 g, 0.83 mmol), {[5- (2-Amino-2-oxoethyl) -6-methyl-4- (4-methylphenyl) -2-neopentylpyridin-3-yl] methyl} tert-butyl carbamate (0.3 g, 82% ) Was obtained as a powder. 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) tert-Butyl {[5- (2-amino-2-oxoethyl) -6-methyl-4- (4-methylphenyl) -2-neopentylpyridin-3-yl] methyl} carbamate (0.22 g, 0.5 mmol) to 2- [5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] acetamide by the same method as in Example 6-2) Dihydrochloride (0.18 g, 85%) was obtained as a powder.
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 Acetic acid [5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methyl dihydrochloride 1) {[5- (hydroxymethyl)- 6-methyl-4- (4-methylphenyl) -2-neopentylpyridin-3-yl] methyl} carbamate tert-butyl (0.3 g, 0.73 mmol), triethylamine (0.1 g,
1.0 mmol) and a mixture of 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 hydrogen carbonate and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Acetic acid [5-{[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6 -Neopentylpyridin-3-yl] methyl (0.26 g, 76% yield) was obtained 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) Acetic acid [5-{[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methyl (0.12 g, 0.26 mmol) [5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methyl dihydrochloride by the same method as in Example 2-3). 99 mg, 90%) was obtained as a powder.
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) tert-butyl {[5- (hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (3.06 g, 7.68 mmol) and triethylamine A mixture consisting of (1.8 mL, 12.9 mmol) and tetrahydrofuran (30 mL) was 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 extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to remove methanesulfonic acid [5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4 -Methylphenyl) pyridin-3-yl] methyl was obtained as a crude product. The crude product was dissolved in N, N-dimethylformamide (30 ml), and potassium carbonate (1.77 g, 12.8 mmol) and 4- (methylthio) benzenethiol (1.00 g, 6.40 mmol) were added. Stir for hours. The reaction mixture was diluted with ethyl acetate (100 ml), washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography, and {[2-isobutyl-6-methyl-4- (4-methylphenyl) -5-({[4- (methylthio ) -Phenyl] thio} methyl) pyridin-3-yl] methyl} carbamate tert-butyl (3.43 g, 99% yield) was obtained 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, brs), 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) tert-butyl {[2-isobutyl-6-methyl-4- (4-methylphenyl) -5-({[4- (methylthio) phenyl] thio} methyl) pyridin-3-yl] methyl} carbamate (508 mg, 0.947 mmol) to {[2-isobutyl-6-methyl-4- (4-methylphenyl) -5-({[4- (methylthio) phenyl] by the same method as in Example 2-3). ] Thio} methyl) pyridin-3-yl] methyl} amine dihydrochloride (380 mg, 79% yield) was obtained as a yellow solid.
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, brs), 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, brs).
Example 91 {[2-Isobutyl-6-methyl-4- (4-methylphenyl) -5-({[4- (methylsulfonyl) phenyl] sulfonyl} methyl) pyridin-3-yl] methyl} amine dihydrochloride Salt 1) {[2-Isobutyl-6-methyl-4- (4-methylphenyl) -5-({[4- (methylthio) phenyl] thio} methyl) pyridin-3-yl] methyl} carbamic acid tert- Butyl (1.10 g, 2.05 mmol) in methanol (15 ml), water (1.5 ml), tetrahydrofuran (1.5 ml) mixed solution in sulfuric acid (121 mg, 1.23 mmol) and Oxone (registered trademark) (3.78 g, 6.15 mmol) And stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (100 ml), washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The white solid obtained by distilling off the solvent under reduced pressure was washed with diisopropyl ether, and {[2-isobutyl-6-methyl-4- (4-methylphenyl) -5-({[4- (methylsulfonyl)) Phenyl] sulfonyl} methyl) pyridin-3-yl] methyl} carbamate tert-butyl (1.06 g, 86% yield) was obtained 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, brs), 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} carbamic acid tert- Butyl (511 mg, 0.8
51 mmol) to {[2-isobutyl-6-methyl-4- (4-methylphenyl) -5-({[4- (methylsulfonyl) phenyl] sulfonyl}} in the same manner as in Example 2-3). Methyl) pyridin-3-yl] methyl} amine dihydrochloride (480 mg, 98% yield) was obtained as a white powder.
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, brs), 3.00 (2H , brs), 3.34 (3H, s), 3.68 (2H, brs), 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, brs).

Example 92 (6-Methyl-4- (4-methylphenyl) -5-{[(4-methyl-4H-1,2,4-triazol-3-yl) thio] methyl} -2-neopentylpyridine -3-yl) methylamine dihydrochloride 1) methanesulfonic acid [5-{[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridine- 3-yl] methyl (0.35 g, 0.71 mmol) and 4-methyl-4H-1,2,4-triazole-3-thiol (99 mg, 0.86 mmol) by a method similar to Example 33-1). [(6-Methyl-4- (4-methylphenyl) -5-{[(4-methyl-4H-1,2,4-triazol-3-yl) thio] methyl} -2-neopentylpyridine-3 -Il) methyl] tert-butyl carbamate (0.28 g, 77%) was obtained as a powder.
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) [(6-Methyl-4- (4-methylphenyl) -5-{[(4-methyl-4H-1,2,4-triazol-3-yl) thio] methyl} -2-neopentylpyridine 3- (yl) methyl] carbamate tert-butyl (0.18 g, 0.35 mmol) by a method similar to that in Example 2-3), (6-methyl-4- (4-methylphenyl) -5-{[ (4-Methyl-4H-1,2,4-triazol-3-yl) thio] methyl} -2-neopentylpyridin-3-yl) methylamine dihydrochloride (0.12 g, 72%) was obtained as a powder It was.
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) Methanesulfonic acid [5-{[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methyl (0.35 g, 0.71 mmol) And 2-mercaptothiazole (100 mg, 0.86 mmol) in the same manner as in Example 33-1) ({6-methyl-4- (4-methylphenyl) -2-neopentyl-5-[(1, 3-Thiazol-2-ylthio) methyl] pyridin-3-yl} methyl) carbamate tert-butyl (0.25 g, 69%) was obtained as a powder.
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) tert-Butyl ({6-methyl-4- (4-methylphenyl) -2-neopentyl-5-[(1,3-thiazol-2-ylthio) methyl] pyridin-3-yl} methyl) carbamate From (0.15 g, 0.29 mmol) in the same manner as in Example 2-3), {6-methyl-4- (4-methylphenyl) -2-neopentyl-5-[(1,3-thiazole-2- (Ilthio) methyl] pyridin-3-yl} methylamine dihydrochloride (0.11 g, 80%) was obtained as a powder.
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) {[5- (aminocarbonyl) -2-isobutyl-6-methyl -4- (4-Methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (1750 mg, 4.2 mmol) in dichloromethane (20 ml) was added triethylamine (1.2 ml, 8.4 mmol) and trifluoromethane Sulfonic anhydride (780 μL, 8.4 mmol) was added dropwise under ice cooling, and then stirred for 30 minutes. The reaction solution was washed successively with water and saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography {[5-cyano-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] Tert-butyl methyl} carbamate (1130 mg, yield 68%) was obtained as 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, brs), 7.13 (2H, d, J = 6.0 Hz), 7.31 (2H, d, J = 6.0 Hz) ).
2) From tert-butyl {[5-cyano-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (100 mg, 0.25 mmol), Example 2- In the same manner as in 3), 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinonitrile dihydrochloride (81 mg, 88% yield) was obtained as a white powder. Obtained.
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, brs).

Example 95 N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] urea dihydrochloride 1) 5-{[(tert-butoxycarbonyl ) Amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (412 mg, 1.0 mmol) in N, N-dimethylformamide solution (3 ml) and triethylamine (170 μL, 1.5 mmol) was added, and diphenylphosphoryl azide (260 μL, 1.5 mmol) was added dropwise under ice cooling, followed by stirring for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was dissolved in toluene (3 ml), and the mixture was stirred for 1 hour with heating under reflux. 25% aqueous ammonia (3 ml) was added to the reaction mixture, and the mixture was further stirred at 100 ° C. for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography, and {[5-[(aminocarbonyl) amino] -2-isobutyl-6-methyl-4- (4-methylphenyl) Pyridin-3-yl] methyl} carbamate tert-butyl (101 mg, yield 24%) was obtained 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, brs), 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) tert-butyl {[5-[(aminocarbonyl) amino] -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (100 mg, 0.23 mmol) To N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] urea dihydrochloride by the same method as in Example 2-3) (84 mg, 92% yield) was obtained as a white powder.
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, brs), 3.80 (2H, brs), 3.83 (1H, brs), 5.94 (1H, brs), 7.20 (2H, d, J = 7.8Hz), 7.36 (2H, d, J = 7.8 Hz), 8.28 (3H, brs).
Example 96 N '-[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -N, N-dimethylurea dihydrochloride 1) 5- {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (412 mg, 1.0 mmol) and 2M dimethylamine-tetrahydrofuran solution (0.6 mL, 1.2 mmol)) and {[5-{[(dimethylamino) carbonyl] amino} -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridine-3 by the same method as in Example 95-1). -Il] methyl} carbamate tert-butyl (158 mg, 35% yield) was obtained as a white powder.
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, brs), 5.32 (1H, s), 7.02 (2H, d, J = 7.8 Hz), 7.24 (2H, d, J = 7.8 Hz).
2) tert-butyl {[5-{[(dimethylamino) carbonyl] amino} -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (158 mg, 0.35 mmol) and N ′-[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] in the same manner as in Example 2-3). -N, N-dimethylurea dihydrochloride (108 mg, 73% yield) was obtained as a white powder.
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 , brs), 3.83 (2H, brs), 7.20 (2H, d, J = 7.8 Hz), 7.31 (2H,
d, J = 7.8 Hz), 7.86 (1H, brs), 8.39 (3H, brs).
Example 97 [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbamate benzyl dihydrochloride 1) 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) from Example 95-1) In a similar manner, [5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbamate benzyl (1600 mg, Yield 35%) was obtained as a white powder.
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, brs),
5.07 (2H, s), 5.70 (1H, brs), 6.95 (2H, brs), 7.17 (2H, d, J = 7.8 Hz), 7.20-7.26 (2H, m), 7.31-7.36 (3H, m) .
2) [5-{[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbamate benzyl (75 mg, 0.14 mmol) Then, in the same manner as in Example 2-3), [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbamate benzyl dihydrochloride (54 mg, 76% yield) was obtained as a white powder.
^{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, brs), 9.08 (1H, brs).

Example 98 5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) -3-pyridinamine trihydrochloride 1) [5-{[(tert-butoxycarbonyl) amino] methyl } -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbamate benzyl (1500 mg, 2.9 mmol) in ethanol solution (100 ml) with 5% palladium-carbon (150 mg ) And stirred at room temperature under a hydrogen atmosphere for 2 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained 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) was obtained as 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, brs), 4.22 (1H, brs), 7.06 (2H, d, J = 8.1 Hz), 7.29 (2H , d, J = 7.7 Hz).
2) From tert-butyl {[5-amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (50 mg, 0.13 mmol), Example 2- In the same manner as in 3), 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) -3-pyridinamine trihydrochloride (34 mg, 62% yield) was converted to white. Obtained as a powder.
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, brs), 7.26 (2H, d, J = 8.1Hz), 7.44 (2H, d, J = 8.1 Hz), 8.38 (3H, brs).
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, followed by stirring for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain an oil. To a solution of the oily substance in ethyl acetate (1 mL) was added 4N hydrogen chloride-ethyl acetate solution (1 mL), and the mixture was stirred at room temperature for 1 hr. The residue obtained by evaporating the solvent under reduced pressure was crystallized from hexane, and N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl Methanesulfonamide dihydrochloride (25 mg, 22% yield) was obtained 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, brs), 9.27 (1H, brs).
Example 100 N- [5-({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} sulfonyl) -4-methyl-1 , 3-Thiazol-2-yl] acetamide dihydrochloride
{[5-Amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (100 mg, 0.26 mmol) and 2- (acetylamino)- From 4-methyl-1,3-thiazole-5-sulfonyl chloride (76 mg, 0.3 mmol), N- [5-({[5- (aminomethyl) -6-isobutyl] was prepared in the same manner as in Example 99. -2-Methyl-4- (4-methylphenyl) pyridin-3-yl] amino} sulfonyl) -4-methyl-1,3-thiazol-2-yl] acetamide dihydrochloride (58 mg, 39% yield) ) Was obtained as a white powder.
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, brs), 3.69 (2H, brs), 6.92-6.97 (4H, m), 8.10 (3H, brs), 9.89 (1H, brs).

Example 101 {[5- (Aminomethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} amine trihydrochloride 1) {[5- (hydroxymethyl) -2-Isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (1.16 g, 2.91 mmol), triethylamine (0.8 mL,
After cooling a mixture consisting of 5.82 mmol) and tetrahydrofuran (15 mL) to 0 ° C., 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 extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to remove methanesulfonic acid [5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4 -Methylphenyl) pyridin-3-yl] methyl was obtained as a crude product. The crude product was dissolved in N, N-dimethylformamide (30 mL), sodium azide (379 mg, 5.82 mmol) was added, and the mixture was heated with stirring at 80 ° C. for 30 min. The reaction mixture was diluted with ethyl acetate (100 mL), washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was mixed with a mixture of 10% palladium-carbon (304 mg, 0.291 mmol) and ethanol (15 mL) at room temperature in a hydrogen atmosphere for 2 hours. After filtration, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography {[5- (aminomethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) Pyridin-3-yl] methyl} carbamate tert-butyl (690 mg, 60% yield) was obtained 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, brs), 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, brs), 7.02 (2H, d, J = 7.9 Hz), 7.25 (2H, d, J = 7.0 Hz) ).
2) Examples from tert-butyl {200-, 0.503 mmol) {[5- (aminomethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate In the same manner as in 2-3), {[5- (aminomethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} amine trihydrochloride (204 mg , Yield 99%) was obtained as a white powder.
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 , brs), 3.76 (4H, brs), 7.34-7.45 (4H, m), 8.51 (6H, brs).
Example 102 N-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} -4- (methylsulfonyl) benzenesulfonamide dihydrochloride Salt 1) tert-butyl {[5- (aminomethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (290 mg, 0.729 mmol), triethylamine 4- (Methylsulfonyl) benzenesulfonyl chloride (223 mg, 0.875 mmol) was added to a tetrahydrofuran solution (10 mL) of (0.15 mL, 1.09 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (100 mL), washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The yellow solid obtained by distilling off the solvent under reduced pressure was washed with diisopropyl ether to give ({2-isobutyl-6-methyl-4- (4-methylphenyl) -5-[({[4- (methyl Sulfonyl) phenyl] sulfonyl} amino) methyl] pyridin-3-yl} methyl) carbamate tert-butyl (391 mg, 87% yield) was obtained 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) ({2-Isobutyl-6-methyl-4- (4-methylphenyl) -5-[({[4- (methylsulfonyl) phenyl] sulfonyl} amino) methyl] pyridin-3-yl} methyl) carbamine N-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) was prepared from tert-butyl acid (391 mg, 0.635 mmol) in the same manner as in Example 2-3). ) Pyridin-3-yl] methyl} -4- (methylsulfonyl) benzenesulfonamide dihydrochloride (370 mg, 99% yield) was obtained as a yellow powder.
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, brs), 3.72 (2H, brs), 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, brs).
Example 103 ({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} amino) ethyl acetate trihydrochloride 1) methanesulfonic acid [ 5-{[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl (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 to the solution, 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 saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography ({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-Methylphenyl) pyridin-3-yl] methyl} amino) ethyl acetate (185 mg, 61% yield) was obtained 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, brs), 7.03 (2H, d, J = 7.8Hz) , 7.25 (2H, d, J = 7.8 Hz).
2) ({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} amino) ethyl acetate (60 mg, 0.12 mmol) and ({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] in the same manner as in Example 2-3). ] Methyl} amino) ethyl acetate trihydrochloride (57 mg, 95% yield) was obtained as a white powder.
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, brs), 3.03 (2H, brs), 3.61 (2H, s), 3.72 (2H,
brs), 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, brs).

Example 104 ({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} amino) acetic acid trihydrochloride 1) ({[5- {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} amino) ethyl acetate (100 mg, 0.2 mmol) in ethanol To the solution (3 mL) was added 8N aqueous sodium hydroxide solution (3 mL), and the mixture was stirred at 80 ° C. for 15 hr. The reaction mixture was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure ({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} Amino) acetic acid (92 mg, 99% yield) was obtained 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, brs), 7.18 (2H, d, J = 7.8Hz) , 7.22 (2H, d, J = 7.8 Hz).
2) ({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} amino) acetic acid (90 mg , 0.2 mmol) and ({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] by the same method as in Example 2-3). Methyl} amino) acetic acid trihydrochloride (75 mg, 80% yield) was obtained as a white powder.
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 , brs), 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, brs), 9.29 (1H, brs).
Example 105 4-{[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} -2-piperazinone Trihydrochloride 1) Methanesulfonic acid [5-{[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl (300 mg, 0.63 mmol) and 2-piperazinone (65 mg, 0.65 mmol) and ({2-isobutyl-6-methyl-4- (4-methylphenyl) -5-[(3-oxo-1- Piperazinyl) methyl] pyridin-3-yl} methyl) carbamate tert-butyl (78 mg, 77% yield) was obtained as a white powder.
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, brs),
3.28 (2H, s), 4.01 (2H, d, J = 5.1Hz), 4.20 (1H, brs), 5.69 (1H, brs), 6.96 (2H, d, J = 7.8 Hz), 7.21 (2H, d , J = 7.8 Hz).
2) tert-butyl ({2-isobutyl-6-methyl-4- (4-methylphenyl) -5-[(3-oxo-1-piperazinyl) methyl] pyridin-3-yl} methyl) carbamate mg, 0.15 mmol) by the same method as in Example 2-3), 4-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine-3- [Il] methyl} -2-piperazinone trihydrochloride (64 mg, 87% yield) was obtained as a white powder.
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 , brs), 3.18 (4H, brs), 3.75 (2H, brs), 7.30 (2H, d, J = 7.5 Hz), 7.41 (2H, d, J = 7.5 Hz), 7.41 (1H, brs), 8.52 (3H, brs).
Example 106 3-{[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} -2,4-imidazolidinedione dihydrochloride 1 ) {[5- (Hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (100 mg, 0.25 mmol) and hydantoin (38 mg, 0.38 mmol) and tributylphosphine (95 μL, 0.38 mmol) in tetrahydrofuran (3 ml) were added 1,1 '-(azodicarbonyl) dipiperidine (96 mg, 0.38 mmol) and stirred at room temperature for 4 hours. did. After concentrating the reaction solution, insoluble matters were removed by filtration, and the filtrate was purified by silica gel column chromatography to obtain {[5-[(2,5-dioxo-1-imidazolidinyl) methyl] -2-isobutyl-6- Methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (68
mg, yield 57%) was obtained 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, brs), 4.46 (2H, s), 5.10 (1H, brs), 7.07 (2H, d, J = 7.8 Hz), 7.23 (2H, d, J = 7.8 Hz).
2) {[5-[(2,5-Dioxo-1-imidazolidinyl) methyl] -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl To 3-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl}-by a method similar to that in Example 2-3). 2,4-imidazolidinedione dihydrochloride (54 mg, 95% yield) was obtained as a white powder.
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 , brs), 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, brs), 8.30 (1H, brs).

Example 107 1-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} -2,5-piperazinedione dihydrochloride 1) Oxalyl chloride (530 μL, 6 mmol) was added to a solution of Z-glycine (1.2 g, 6 mmol) and N, N-dimethylformamide (10 μL) in tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} amino) amino) ethyl acetate (1.4 g, 3 mmol), pyridine (970 μL, 12 mmol) and 4-dimethylaminopyridine (5 mg) in tetrahydrofuran (10 ml) were added dropwise under ice-cooling, followed by stirring for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting oil was dissolved in ethanol (10 mL). 5% Palladium-carbon (100 mg) was added and stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain {[5-[(2,5-dioxo-1-piperazinyl) methyl] -2-isobutyl-6-methyl-4- (4-methylphenyl) Pyridin-3-yl] methyl} carbamate tert-butyl (35 mg, 2.4% yield) was obtained 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, brs), 4.51 (2H , s), 5.88 (1H, brs), 6.98 (2H,
d, J = 7.5 Hz), 7.25 (2H, d, J = 7.5 Hz).
2) tert-Butyl {[5-[(2,5-dioxo-1-piperazinyl) methyl] -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate To 1-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl}-by the same method as in Example 2-3). 2,5-piperazinedione dihydrochloride (14 mg, 60% yield) was obtained as a white powder.
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, brs), 4.31 (2H, s), 7.18 (2H, d, J = 8.1 Hz), 7.37 (2H, d, J = 7.8 Hz), 8.06 (1H, brs), 8.24 (3H, brs).
Example 108 {[2-Isobutyl-4- (4-methylphenyl) -6-phenylpyridin-3-yl] methyl} amine dihydrochloride 1) Acetophenone (8.40 g, 70 mmol) and p-tolualdehyde (8.40 g, 70 mmol) in ethanol solution (140 mL) was added sodium hydroxide (7.0 g, 175 mmol) and stirred for 3 days. The reaction mixture was diluted with ethyl acetate (100 mL), washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The yellow solid obtained by distilling off the solvent under reduced pressure was washed with diisopropyl ether to give (2E) -3- (4-methylphenyl) -1-phenylprop-2-en-1-one (9.12
g, yield 59%) was obtained as a 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-oxohexanenitrile (5.0 g, 40 mmol) and acetic acid (2.3 mL, 40 mmol), ammonium acetate (15.4 g, 200 mmol) and toluene (250 mL) was added to the Dean-Stark trap. And heated at reflux for 12 hours. The reaction mixture was cooled to room temperature, washed with saturated brine, dried over anhydrous magnesium sulfate, and 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) and Sodium hydroxide (0.8 g, 20 mmol) was added and heated to reflux for 3 hours. The reaction mixture was diluted with ethyl acetate (100 mL), washed with saturated aqueous ammonium chloride, and the organic layer was dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography to give 2-isobutyl-4- (4-methylphenyl) -6-phenylnicotinonitrile (2.68 g, yield 49%). ) Was obtained 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) According to the same method as in Example 1-4) from 2-isobutyl-4- (4-methylphenyl) -6-phenylnicotinonitrile (2.65 g, 8.12 mmol), {[2-isobutyl-4- ( 4-Methylphenyl) -6-phenylpyridin-3-yl] methyl} amine (1.70 g, 63% yield) was obtained as a yellow oil. The oil was dissolved in 4N hydrogen chloride-1,4-dioxane solution (20 mL). The yellow solid obtained by distilling off the solvent under reduced pressure was washed with diisopropyl ether to give {[2-isobutyl-4- (4-methylphenyl) -6-phenylpyridin-3-yl] methyl} amine dihydrochloride The salt (1.99 g, 96% yield) was obtained 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, brs).
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) is heated to reflux in a mixed solvent of water (15 mL) and acetonitrile (15 mL). The mixture was stirred for 10 minutes to dissolve. After adding maleic acid (558 mg, 4.80 mmol) to the obtained solution, it 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 min. The precipitated solid was collected by filtration, washed with acetonitrile (30 mL), and 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid maleate (667 mg, yield). 32%) was obtained as a 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) Methyl 4-methoxyacetoacetate (5.85 g, 40 mmol), A solution of p-tolualdehyde (4.81 g, 40 mmol), piperidine (340 mg, 4 mmol) and acetic acid (240 mg, 4 mmol) in isopropanol (40 mL) was stirred at room temperature for 3 days. From the residue obtained by distilling off the solvent under reduced pressure and tert-butyl 3-aminocrotonate (4.71 g, 30.0 mol) in the same manner as in Example 1-2), 2- (methoxymethyl) -6 -Methyl-4- (4-methylphenyl) -1,4-dihydropyridine-3,5-dicarboxylate 3-methyl 5-tert-butyl (5.85 g, yield 50%) was obtained as a yellow oil. That is, the above residue and tert-butyl 3-aminocrotonate were dissolved in methanol (30 mL) and 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 to give 2- (methoxymethyl) -6-methyl-4- (4-methylphenyl) -1,4-dihydropyridine-3,5- 3-methyl 5-tert-butyl dicarboxylate was obtained.
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, brs), 7.01 (2H, d, J = 7.7 Hz), 7.15 (2H, d, J = 8.1 Hz).
2) From 3-methyl 5-tert-butyl (5.85 g, 15.1 mmol) 2- (methoxymethyl) -6-methyl-4- (4-methylphenyl) -1,4-dihydropyridine-3,5-dicarboxylate In the same manner as in Example 23-3), 2- (methoxymethyl) -6-methyl-4- (4-methylphenyl) pyridine-3,5-dicarboxylate 3-methyl 5-tert-butyl (3.78 g) Yield 65%) as a yellow oil.
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) 2- (methoxymethyl) -6-methyl-4- (4-methylphenyl) pyridine-3,5-dicarboxylate 3-methyl 5-tert-butyl (3.78 g, 9.81 mmol) in toluene (50 mL) The suspension was cooled to −78 ° C., and a 1.50 M diisobutylaluminum hydride-toluene solution (25 mL, 24.5 mmol) was added dropwise over 15 minutes. The mixture was stirred at -78 ° C for 30 minutes, then warmed to 0 ° C and further stirred for 10 minutes. Methanol (0.5 mL) was added to the reaction mixture, sodium sulfate decahydrate (8.1 g, 9.8 mmol) was added, and the mixture was stirred at room temperature for 1 hr. The insoluble material was removed by filtration, 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, yield 23). %) 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) tert-butyl 5- (hydroxymethyl) -6- (methoxymethyl) -2-methyl-4- (4-methylphenyl) nicotinate (810 mg, 2.27 mmol) and triethylamine (0.63 mL, 4.54 mmol) , And tetrahydrofuran (30 mL) was 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. After drying the organic layer with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was dissolved in N, N-dimethylformamide (20 mL), sodium azide (296 mg, 4.54 mmol) was added, and the mixture was stirred at 80 ° C. for 1 hr. Ethyl acetate was added to the reaction mixture, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. A mixture of the residue and 10% palladium-carbon (242 mg, 0.227 mmol) in ethanol (30 mL) was stirred at room temperature for 30 minutes in a hydrogen atmosphere. After filtration, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography to obtain 5- (aminomethyl) -6- (methoxymethyl) -2-methyl-4- (4-methyl Phenyl) nicotinic acid tert-butyl (600 mg, 74% yield) was obtained 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) Similar to Example 24-1) from tert-butyl 5- (aminomethyl) -6- (methoxymethyl) -2-methyl-4- (4-methylphenyl) nicotinate (600 mg, 1.69 mmol) According to the method, 5- (aminomethyl) -6- (methoxymethyl) -2-methyl-4- (4-methylphenyl) nicotinic acid dihydrochloride (533
mg, 84% yield) was obtained as a white powder.
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, brs).
Example 111 Ethyl 5,6-bis (aminomethyl) -2-methyl-4- (4-methylphenyl) nicotinic acid trihydrochloride 1) 4-[(tert-butoxycarbonyl) amino] -3-oxobutanoic acid ( 5.4 g, 22.0 mmol) to ethyl 3-amino-4-[(tert-butoxycarbonyl) amino] but-2-enoate (5.37 g, yield 99%) by the same method as in Example 108-2) Was obtained as a yellow oil.
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) tert-butyl acetoacetate (4.75 g, 30 mmol), p-tolualdehyde (4.51 g, 37.5 mmo)
l), a mixture of piperidine (0.30 ml, 3.00 mmol) and ethanol (0.2 ml) was stirred at room temperature for 1 day. The reaction mixture was diluted with ethyl acetate (100 mL), washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure and ethyl 3-amino-4-[(tert-butoxycarbonyl) amino] but-2-enoate (5.37 g, 22.0 mmol) were heated at 80 ° C. for 30 minutes. After stirring, the mixture was further heated and stirred at 130 ° C. for 3 hours. The resulting mixture was purified by silica gel column chromatography to give 2-{[(tert-butoxycarbonyl) amino] methyl} -6-methyl-4- (4-methylphenyl) -1,4-dihydropyridine-3, 3-ethyl 5-dicarboxylate 5-tert-butyl (1.95 g, 18% yield) was obtained 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, brs), 7.01 (2H, d, J = 7.9 Hz), 7.15 (2H, d, J = 8.1 Hz).
3) 2-{[(tert-butoxycarbonyl) amino] methyl} -6-methyl-4- (4-methylphenyl) -1,4-dihydropyridine-3,5-dicarboxylate 3-ethyl 5-tert-butyl (1.95 g, 4.01 mmol) to 2-{[(tert-butoxycarbonyl) amino] methyl} -6-methyl-4- (4-methylphenyl) pyridine-3 in the same manner as in Example 23-3) Thus, 3-ethyl 5-tert-butyl (1.94 g, yield 99%) was obtained as a yellow oil.
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, brs), 7.13 (2H, d, J = 8.3 Hz), 7.17 (2H, d, J = 8.3 Hz).
4) 2-{[(tert-butoxycarbonyl) amino] methyl} -6-methyl-4- (4-methylphenyl) pyridine-3,5-dicarboxylate 3-ethyl 5-tert-butyl (1.94 g, 4.00 mmol) to 6-{[(tert-butoxycarbonyl) amino] methyl} -5- (hydroxymethyl) -2-methyl-4- (4-methylphenyl) nicotine by a method similar to that in Example 110-3). Tert-butyl acid (1.45 g, yield 82%) was obtained as a yellow oil.
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, brs), 4.46 (2H, d , J = 6.0 Hz), 4.54 (2H, d, J = 5.8 Hz), 5.87 (1H, brs), 7.18 (2H, d, J = 8.3 Hz), 7.21 (2H, d, J = 8.3 Hz).
5) Conducted from tert-butyl 6-{[(tert-butoxycarbonyl) amino] methyl} -5- (hydroxymethyl) -2-methyl-4- (4-methylphenyl) nicotinate (1.45 g, 3.28 mmol) In a manner similar to Example 110-4), tert-butyl 5- (aminomethyl) -6-{[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) nicotinate (580 mg, 40% yield) was obtained as a white powder.
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, brs), 7.10 (2H, d, J = 8.1 Hz), 7.22 (2H, d, J = 7.9 Hz).
6) Conducted from tert-butyl 5- (aminomethyl) -6-{[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) nicotinate (580 mg, 1.31 mmol) In the same manner as in Example 24-1), 5,6-bis (aminomethyl) -2-methyl-4- (4-methylphenyl) nicotinic acid trihydrochloride (510 mg, 99% yield) was converted to a yellow solid. Got as.
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, brs), 8.54 (3H, brs).

Example 112 5- (aminomethyl) -6-hydroxy-2-methyl-4- (4-methylphenyl) nicotinic acid hydrochloride 1) tert-butyl acetoacetate (4.75 g, 30 mmol), p-tolualdehyde ( A mixture consisting of 4.51 g, 37.5 mmol), piperidine (0.30 mL, 3.00 mmol), and ethanol (0.2 mL) was stirred at room temperature for 1 day. The reaction mixture was diluted with ethyl acetate (100 mL), washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure, ethyl cyanoacetate (6.79 g, 60.0 mmol), ammonium acetate (11.6 g, 150 mmol)
Was stirred with heating at 140 ° C. for 3 hours. The reaction mixture was diluted with ethyl acetate (100 mL), washed with saturated aqueous sodium hydrogen carbonate, and the organic layer was dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography to obtain tert-butyl 5-cyano-6-hydroxy-2-methyl-4- (4-methylphenyl) nicotinate (0.87 g, yield 9%) was obtained 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) In the same manner as in Example 1-4) from tert-butyl 5-cyano-6-hydroxy-2-methyl-4- (4-methylphenyl) nicotinate (0.50 g, 1.54 mmol), 5- ( Aminomethyl) -6-hydroxy-2-methyl-4- (4-methylphenyl) nicotinate tert-butyl was obtained as a white solid. Subsequently, tert-butyl 5-{[(tert-butoxycarbonyl) amino] methyl} -6-hydroxy-2-methyl-4- (4-methylphenyl) nicotinate was prepared in the same manner as in Example 2-1). (210 mg, 32% yield) was obtained as a colorless oil.
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, brs).
3) Example 24- from tert-butyl 5-{[(tert-butoxycarbonyl) amino] methyl} -6-hydroxy-2-methyl-4- (4-methylphenyl) nicotinate (210 mg, 0.490 mmol) In the same manner as in 1), 5- (aminomethyl) -6-hydroxy-2-methyl-4- (4-methylphenyl) nicotinic acid hydrochloride (167 mg, 99% yield) was obtained as a white solid. .
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, brs), 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) with N, N-dimethylformamide (1.25 mL ) -Dichloromethane (0.4 mL) was dissolved in a mixed solvent and 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 (0.5 mL) and saturated brine (0.5 mL). Trifluoroacetic acid (2 mL) was added to the organic layer and stirred for 2 hours, and then the solvent was distilled off under reduced pressure. The residue was purified by preparative HPLC to give 5- (aminomethyl) -N, 6-diisobutyl-2-methyl-4- (4-methylphenyl) nicotinamide ditrifluoroacetate (22.4 mg, 63% yield) ) Was obtained as a yellow oil.
EIMS (M + 1): 368

The compounds of Examples 114 to 168 were synthesized in the same manner as in Example 113 from nicotinic acids and amines corresponding to Tables 1 to 4 below. However, the compounds of Examples 162 to 164 were obtained in a free form by neutralizing the obtained trifluoroacetates of nicotinamides with a saturated aqueous sodium bicarbonate solution.

Example 169 5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 4- (methoxycarbonyl) benzyl dihydrochloride 1) 5-{[(tert-butoxycarbonyl) Amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (2.00 g, 4.85 mmol) in N, N-dimethylformamide solution (20 mL) in 4- (bromomethyl) benzoic acid Methyl (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), washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography to obtain 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4- Methylphenyl) nicotinic acid 4- (methoxycarbonyl) benzyl (2.50 g, yield 92%) was obtained 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, brs), 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) From 4-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 4- (methoxycarbonyl) benzyl (0.50 g, 0.892 mmol) In the same manner as in Example 2-3), 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 4- (methoxycarbonyl) benzyl dihydrochloride (427 mg) , Yield 90%) was obtained as a white powder.
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, brs) .Example 170 4-[({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) Pyridin-3-yl] carbonyl} oxy) methyl] benzoic acid dihydrochloride 1) 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) 4-(({[5-{[(tert-butoxycarbonyl) amino] methyl}-) was prepared from 4- (methoxycarbonyl) benzyl nicotinate (1.10 g, 1.96 mmol) in the same manner as in Example 9-1). 6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] benzoic acid (340 mg, 32% yield) was obtained as a colorless oil.
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, brs), 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-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl ] Benzoic acid (370 mg, 0.677
mmol) to 4-[({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] in the same manner as in Example 2-3). Carbonyl} oxy) methyl] benzoic acid dihydrochloride (326 mg, 93% yield) was obtained as a white powder.
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, brs).
Example 171 5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 2-amino-2-thioxoethyl dihydrochloride 1) 5-{[(tert-butoxycarbonyl) Amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (3.00 g, 7.27 mmol) in N, N-dimethylformamide solution (50 ml) and 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 hour. The reaction mixture was diluted with ethyl acetate (100 mL), washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography to obtain 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4- Methylphenyl) cyanomethyl nicotinate (2.78 g, 85% yield) was obtained 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, brs), 4.50 (2H, s), 7.05 (2H, d, J = 8.1 Hz) ), 7.24 (2H, d, J = 7.9 Hz).
2) 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 (25 mL) was blown with hydrogen sulfide for 1 hour. After evaporating the solvent under reduced pressure, the residue was diluted with ethyl acetate (100 mL), washed with saturated brine, and dried over anhydrous magnesium sulfate. The yellow solid obtained by distilling off the solvent under reduced pressure was washed with diisopropyl ether to give 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) ) 2-amino-2-thioxoethyl nicotinate (2.81 g,
(94% yield) was obtained 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, brs), 4.80 (2H, s), 6.21 (1H, brs), 6.98 (1H , brs), 7.13 (2H, d, J = 7.9
Hz), 7.27 (2H, d, J = 7.5 Hz).
3) From 2-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 2-amino-2-thioxoethyl (200 mg, 0.412 mmol) In the same manner as in Example 2-3), 2- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 2-amino-2-thioxoethyl dihydrochloride (133 mg) Yield 70%) as a yellow solid.
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, brs), 8.98 (1H, brs), 9.85 (1H, brs).

Example 172 5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid [4- (ethoxycarbonyl) -1,3-thiazol-2-yl] methyl dihydrochloride 1) 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 2-amino-2-thioxoethyl dihydrochloride (2.02 g, 4.41 mmol) in tetrahydrofuran (30 mL) -Benzyl chloroformate (903 mg, 5.30 mmol) was added to the saturated sodium hydrogen carbonate solution (10 ml) mixed solution, and it stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (100 mL), washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography to obtain 5-({[(benzyloxy) carbonyl] amino} methyl) -6-isobutyl-2-methyl-4- ( 4-Aminophenyl) nicotinic acid 2-amino-2-thioxoethyl (2.00 g, yield 87%) was obtained 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, brs), 4.79 (2H, s), 5.04 (2H, s), 6.23 (1H, brs), 6.97 (1H , brs), 7.11 (2H, d, J = 8.1
Hz), 7.24 (2H, d, J = 7.9 Hz), 7.29-7.36 (5H, m).
2) 5-({[(Benzyloxy) carbonyl] amino} methyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 2-amino-2-thioxoethyl (2.00 g, 3.85 mmol) And an ethanol solution (70 mL) of ethyl bromopyruvate (1.08 g, 5.00 mmol) were refluxed for 1 hour. The reaction mixture was diluted with ethyl acetate (200 mL), washed with saturated aqueous sodium hydrogen carbonate, and the organic layer was dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography to obtain 5-({[(benzyloxy) carbonyl] amino} methyl) -6-isobutyl-2-methyl-4- ( 4-Methylphenyl) nicotinic acid [4- (ethoxycarbonyl) -1,3-thiazol-2-yl] methyl (2.37 g, yield 100%) was obtained 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) 5-({[(Benzyloxy) carbonyl] amino} methyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid [4- (ethoxycarbonyl) -1,3-thiazole- 2-yl] methyl (2.37 g, 3.85 mmol) was dissolved in 30% hydrogen bromide-acetic acid solution (30 mL) and stirred at room temperature for 30 minutes. The residue obtained by evaporating the solvent under reduced pressure was dissolved by adding saturated aqueous sodium bicarbonate (30 mL) and tetrahydrofuran (50 mL), and di-tert-butyl dicarbonate (1.02 g, 4.66 mmol) was added. And stirred at room temperature for 15 hours. The reaction mixture was diluted with ethyl acetate (200 mL), washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography to obtain 5-{[(tert-butoxycarbonyl) amino] methyl.
} -6-Isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid [4- (ethoxycarbonyl) -1,3-thiazol-2-yl] methyl (1.72 g, yield 78%) was colorless Obtained as an 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, brs), 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) 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid [4- (ethoxycarbonyl) -1,3-thiazole-2 -Il] methyl (373 mg, 0.643 mmol) in the same manner as in Example 2-3), 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid [ 4- (Ethoxycarbonyl) -1,3-thiazol-2-yl] methyl dihydrochloride (322 mg, 90% yield) was obtained as a white powder.
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, brs), 8.56 (1H, s).
Example 173 2-[({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] -1,3-thiazole -4-carboxylic acid dihydrochloride 1) 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid [4- (ethoxycarbonyl) 2-[({[5-{[(tert-butoxycarbonyl) amino]] from -1,3-thiazol-2-yl] methyl (1.34 g, 2.30 mmol) in the same manner as in Example 9-1) Methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] -1,3-thiazole-4-carboxylic acid (1.21 g, 95% yield) ) Was obtained as a colorless oil.
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, brs ), 2.85 (2H, brs), 4.11-4.19 (2H, m), 4.23 (1H, brs), 5.22 (2H, s), 7.02 (2H, d, J = 7.9 Hz), 7.10 (2H, d, J = 7.4 Hz), 8.24 (1H, s).
2) 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 (460 mg, 0.831 mmol) in the same manner as in Example 2-3), 2-[({[5- (aminomethyl) -6-isobutyl-2 -Methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] -1,3-thiazole-4-carboxylic acid dihydrochloride (362 mg, 83% yield) as a pale yellow powder Got as.
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, brs), 8.48 (1H, s).

Example 174 5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid [4- (aminocarbonyl) -1,3-thiazol-2-yl] methyl dihydrochloride 1) 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) by the same method as in Example 3-1), 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl -2-Methyl-4- (4-methylphenyl) nicotinic acid [4- (aminocarbonyl) -1,3-thiazol-2-yl] methyl (420 mg, yield 70%) was obtained as a colorless oil. .
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,
brs), 5.17 (2H, s), 5.64 (1H, brs), 7.01 (2H, d, J = 7.9 Hz), 7.09 (2H, d, J = 7.9 Hz), 8.13 (1H, s).
2) 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid [4- (aminocarbonyl) -1,3-thiazole-2 -Il] methyl (460 mg,
0.832 mmol) to 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid [4- (aminocarbonyl) -1 by the same method as in Example 2-3). , 3-Thiazol-2-yl] methyl dihydrochloride (208 mg, 48% yield) was obtained as a white powder.
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, brs), 7.66 (1H, brs), 8.22 (3H, brs), 8.48 (1H, s).
Example 175 5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid [(2,2-dimethylpropanoyl) oxy] methyl dihydrochloride 1) 5-{[ (tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (1.50 g, 3.37 mmol) in N, N-dimethylformamide solution (20 ml) Acid chloromethyl (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 hour. The reaction mixture was diluted with ethyl acetate (100 ml), washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography to give 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4 -(Methylphenyl) nicotinic acid [(2,2-dimethylpropanoyl) oxy] methyl (1.68 g, yield 95%) was obtained 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, brs), 5.57 (2H, s), 7.06 (2H, d, J = 8.1 Hz), 7.20 (2H, d,
J = 7.9 Hz).
2) 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid [(2,2-dimethylpropanoyl) oxy] methyl (1.68) g, 3.19 mmol) and in the same manner as in Example 2-3), 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid [(2,2-dimethyl) Propanoyl) oxy] methyl dihydrochloride (1.58 g, 99% yield) was obtained as a white solid.
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, brs). Example 176 5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (5-methyl-2 -Oxo-1,3-dioxol-4-yl) methyl dihydrochloride 1) 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) 4- (Chloromethyl) -5-methyl-1,3-dioxol-2-one (0.60 g, 4.04 mmol) was added to a solution of nicotinic acid (1.50 g, 3.37 mmol) in N, N-dimethylformamide (20 mL). Potassium carbonate (0.93 g, 6.72 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (100 mL), washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography to give 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4 -Methylphenyl) nicotinic acid (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl (1.50 g, yield 85%) was obtained 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-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (5-methyl-2-oxo-1,3-dioxole- 5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid from 4-yl) methyl (1.50 g, 2.86 mmol) in the same manner as in Example 2-3). (5-Methyl-2-oxo-1,3-dioxol-4-yl) methyl dihydrochloride (1.21 g, yield 85%) was obtained as a white powder.
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, brs).

Example 177 5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 3-oxo-1,3-dihydro-2-benzofuran-1-yl dihydrochloride 1) 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (1.50 g, 3.37 mmol) in N, N-dimethylformamide solution (30 3-Chloro-2-benzofuran-1 (3H) -one (0.86 g, 4.04 mmol) and potassium carbonate (0.93 g, 6.72 mmol) were added to mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (100 mL), washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography to give 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4 -Methylphenyl) nicotinic acid 3-oxo-1,3-dihydro-2-benzofuran-1-yl (1.83 g, 99% yield) was obtained 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) 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 3-oxo-1,3-dihydro-2-benzofuran-1 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 3-oxo was prepared by the same method as in Example 2-3) from 1-yl (1.83 g, 3.36 mmol). -1,3-Dihydro-2-benzofuran-1-yl dihydrochloride was obtained as a white powder.
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, brs).
Example 178 5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (2E) -2- (3-oxo-2-benzofuran-1 (3H) -ylidene) Ethyl dihydrochloride 1) N, N of 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (380 mg, 0.853 mmol) -Dimethylformamide solution (10 mL) with (3E) -3- (2-chloroethylidene) -2-benzofuran-1 (3H) -one (170 mg, 0.711 mmol) and potassium carbonate (147 mg, 1.07 mmol) The mixture was further stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (100 mL), washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography to give 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4 -Methylphenyl) nicotinic acid (2E) -2- (3-oxo-2-benzofuran-1 (3H) -ylidene) ethyl (270 mg, 55% yield) was obtained 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, brs), 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) 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (2E) -2- (3-oxo-2-benzofuran- 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) was prepared from 1 (3H) -ylidene) ethyl (270 mg, 0.473 mmol) in the same manner as in Example 2-3). Nicotinic acid (2E) -2- (3-oxo-2-benzofuran-1 (3H) -ylidene) ethyl dihydrochloride (204 mg, yield 79%) was obtained as a white powder.
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, brs).
Example 179 Benzyl 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate
5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (3.00 g, 6.73 mmol) in N, N-dimethylformamide solution (30 benzyl bromide (0.80 ml, 6.73 mmol) and potassium carbonate (1.85 g, 13.4 mmol) were added to mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (200 mL), washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was dissolved in trifluoroacetic acid (50 mL) and stirred at room temperature for 3 hours. After distilling off trifluoroacetic acid under reduced pressure, the residue was neutralized with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure 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) was obtained 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- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 2-oxo-1,3-dioxolan-4-yl dihydrochloride 1) 5-{[ (tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (1.50 g, 3.37 mmol) in N, N-dimethylformamide solution (30 mL) -Chloro-1,3-dioxolan-2-one (0.55 g, 4.04 mmol) and potassium carbonate (0.70 g,
5.05 mmol) was added and stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (100 mL), washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography to give 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4 -Methylphenyl) nicotinic acid 2-oxo-1,3-dioxolan-4-yl (1.39 g, yield 83%) was obtained 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, brs), 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) 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 2-oxo-1,3-dioxolan-4-yl (1.39) g, 2.79 mmol) and 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 2-oxo-1,3 in the same manner as in Example 2-3). -Dioxolan-4-yl dihydrochloride (1.31 g, 99% yield) was obtained as a white powder.
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, brs).
Example 181 Example from 5- (aminomethyl) -4- (4-hydroxyphenyl) -6-isobutyl-2-methylnicotinic acid dihydrochloride 1) 4- (benzyloxy) benzaldehyde (12.8 g, 60.4 mmol) In the same manner as in 1-2), tert-butyl 4- [4- (benzyloxy) phenyl] -5-cyano-6-isobutyl-2-methyl-1,4-dihydropyridine-3-carboxylate (21.4 g Yield 77%) as a pale pink solid.
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) Example 23 from tert-butyl 4- [4- (benzyloxy) phenyl] -5-cyano-6-isobutyl-2-methyl-1,4-dihydropyridine-3-carboxylate (2.33 g, 5.08 mmol) -3) in the same manner as tert-butyl 4- [4- (benzyloxy) phenyl] -5-cyano-6-isobutyl-2-methylnicotinate (2.18 g, 94% yield) as a yellow solid Obtained.
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) From tert-butyl 4- [4- (benzyloxy) phenyl] -5-cyano-6-isobutyl-2-methylnicotinate (2.13 g, 4.67 mmol) in the same manner as in Example 1-4), Tert-butyl 5- (aminomethyl) -4- (4-hydroxyphenyl) -6-isobutyl-2-methylnicotinate was obtained as a crude product. 5-{[(tert-butoxycarbonyl) amino] methyl} -4- (4-hydroxyphenyl) -6-isobutyl-2-methylnicotinic acid was prepared from the crude product in the same manner as in Example 2-1). Tert-butyl (1.35 g, 61% yield) was obtained as a pale yellow solid.
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, brs), 5.50 (1H, brs), 6.85 (2H, d, J = 8.5 Hz) ), 7.07 (2H, d, J = 8.5 Hz).
4) 5-{[(tert-butoxycarbonyl) amino] methyl} -4- (4-hydroxyphenyl) -6-isobutyl-2-methylnicotinate tert-butyl (316 mg, 0.671 mmol) and anisole (218 mg) , 2.01 mmol) was dissolved in trifluoroacetic acid (5 mL) and stirred at room temperature for 5 hours. After distilling off trifluoroacetic acid under reduced pressure, 4N hydrogen chloride-1,4-dioxane solution (20 mL) was added to the residue, and the mixture was stirred at room temperature for 30 minutes. After evaporating the solvent under reduced pressure, 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) was obtained 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, brs).
Example 182 5- (Aminomethyl) -6-isobutyl-4- (4-methoxyphenyl) -2-methylnicotinic acid dihydrochloride 1) 5-{[(tert-butoxycarbonyl) amino] methyl} -4- Tert-Butyl (4-hydroxyphenyl) -6-isobutyl-2-methylnicotinate (620 mg, 1.32 mmol) and potassium carbonate (365 mg,
2.64 mmol) N, N-dimethylformamide solution (20 mL) was added iodomethane (374 mg, 2.64 mmol), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate (100 mL), washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography to obtain 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-4- (4-methoxyphenyl) Tert-butyl-2-methylnicotinate (520 mg, 81% yield) was obtained 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, brs), 6.94 (2H, d, J = 8.7 Hz), 7.12 (2H , d, J = 8.7 Hz).
2) Example 181 from tert-butyl 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-4- (4-methoxyphenyl) -2-methylnicotinate (520 mg, 1.07 mmol) In the same manner as in 4), 5- (aminomethyl) -6-isobutyl-4- (4-methoxyphenyl) -2-methylnicotinic acid dihydrochloride (429 mg, 99% yield) was obtained as a yellow powder. It was.
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, brs).

Example 183 4-({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) methyl benzoate dihydrochloride 1) { [5- (hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridine-3-
Yl] methyl} carbamate tert-butyl (1.00 g, 2.51 mmol), triethylamine (0.7 mL,
5.02 mmol) and a mixture of 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 extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to remove methanesulfonic acid [5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4 -Methylphenyl) pyridin-3-yl] methyl was obtained as a crude product. The crude product was dissolved in N, N-dimethylformamide (15 ml), potassium carbonate (520 mg, 3.77 mmol) and methyl 4-mercaptobenzoate (422 mg, 2.51 mmol) were added, and the mixture was stirred at 50 ° C. for 1 hour. Stir with heating. The reaction mixture was diluted with ethyl acetate (100 mL), washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography to obtain 4-({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl. Methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) benzoate (1.01 g, 73% yield) was obtained 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, brs), 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) 4-({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) benzoic acid 4-({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine] was prepared from methyl (200 mg, 0.365 mmol) in the same manner as in Example 2-3). -3-yl] methyl} thio) methyl benzoate dihydrochloride (138 mg, 73% yield) was obtained as a pale yellow powder.
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, brs), 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, brs).
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) methyl benzoate (1.37 g , 2.51 mmol) to 4-({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4- Methylphenyl) pyridin-3-yl] methyl} thio) benzoic acid (0.97 g, 72% yield) was obtained as a white solid.
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, brs), 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-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) benzoic acid (0.27 g, 0.505 mmol) to 4-({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine- 3-yl] methyl} thio) benzoic acid dihydrochloride (198 mg, 77% yield) was obtained as a white powder.
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, brs), 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, brs).
Example 185 4-({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} sulfonyl) methyl benzoate dihydrochloride 1) 4 -({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) methyl benzoate (0.46 g, 0.838 mmol) and 4-({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4) by the same method as in Example 91-1). -Methylphenyl) pyridin-3-yl] methyl} sulfonyl) methyl benzoate (410 mg, 84% yield) was obtained as a colorless oil.
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, brs), 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) 4-({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} sulfonyl) benzoic acid 4-({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine] was prepared from methyl (410 mg, 0.706 mmol) in the same manner as in Example 2-3). -3-yl] methyl} sulfonyl) methyl benzoate dihydrochloride (352 mg, 90% yield) was obtained as a pale yellow powder.
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 , brs), 3.66-3.74 (2H, m), 3.93 (3H, s), 4.61 (2H, brs), 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, brs).

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) methyl benzoate (330 mg , 0.568 mmol) to 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.
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, brs), 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-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} sulfonyl) benzoic acid (300 mg, 0.530 mmol) in the same manner as in Example 2-3), 4-({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine- 3-yl] methyl} sulfonyl) benzoic acid dihydrochloride (279 mg, 97% yield) was obtained as a white powder.
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, brs), 2.95 (2H, brs), 3.70 (2H, brs), 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, brs).
Example 187 N-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} methanesulfonamide dihydrochloride 1) {[5- (Aminomethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (200 mg, 0.755 mmol) and triethylamine (0.14 mL, 1.00 mmol) Of methanesulfonyl chloride (86 mg,
0.875 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (100 mL), washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The yellow solid obtained by distilling off the solvent under reduced pressure was washed with diisopropyl ether to obtain [(2-isobutyl-6-methyl-4- (4-methylphenyl) -5-{[(methylsulfonyl) amino] Methyl} pyridin-3-yl) methyl] carbamate tert-butyl (210 mg, 87% yield) was obtained 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, brs),
4.01 (2H, d, J = 5.7 Hz), 4.03 (2H, d, J = 5.3 Hz), 4.18 (1H, brs), 7.03 (2H, d, J = 8.1 Hz), 7.29 (2H, d, J = 7.9 Hz).
2) tert-Butyl [(2-isobutyl-6-methyl-4- (4-methylphenyl) -5-{[(methylsulfonyl) amino] methyl} pyridin-3-yl) methyl] carbamate (210 mg, 0.441 mmol) to N-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl by a method similar to that in Example 2-3). } Methanesulfonamide dihydrochloride (126 mg, yield 64%) was obtained as a white powder.
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 , brs), 3.04 (2H, brs), 3.76 (2H, brs), 3.87 (2H, brs), 7.19 (1H, brs), 7.29 (2H, d, J = 7.5 Hz), 7.38 (2H, d, J = 7.7 Hz), 8.28 (3H, brs). Example 188 {[4- (2,4-dichlorophenyl) -6- (4-fluorophenyl) -2-isobutylpyridin-3-yl] methyl} amine (2E) -3- (2) Hydrochloride 1) 4-fluoroacetophenone (6.91 g, 50 mmol) and 2,6-dichlorobenzaldehyde (8.75 g, 59 mmol) were used in the same manner as in Example 108-1). , 4-dichlorophenyl) -1- (4-fluorophenyl) prop-2-en-1-one (10.3 g, 64% yield) was obtained as a pale yellow solid.
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) Similar to Example 108-2) from (2E) -3- (2,4-dichlorophenyl) -1- (4-fluorophenyl) prop-2-en-1-one (4.54 g, 15.4 mmol) By the method, 4- (2,4-dichlorophenyl) -6- (4-fluorophenyl) -2-isobutylnicotinonitrile (2.94 g, yield 48%) was obtained as a yellow oil.
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-isobutylnicotinonitrile (1.14 g, 2.85 mmol) was used in the same manner as in Example 23-4) to obtain {[4 -(2,4-Dichlorophenyl) -6- (4-fluorophenyl) -2-isobutylpyridin-3-yl] methyl} amine (780 mg, 68% yield) was obtained as a pale yellow oil. The oil was dissolved in 4N hydrogen chloride-1,4-dioxane solution (20 mL) and stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the resulting pale yellow solid was washed with diisopropyl ether, and {[4- (2,4-dichlorophenyl) -6- (4-fluorophenyl) -2-isobutylpyridin-3-yl ] Methyl} amine dihydrochloride (895 mg, 97% yield) was obtained 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 3- [5- (aminomethyl) -6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzoic acid methyl dihydrochloride 1) 3-bromoacetophenone (9.95 g, 50 mmol) (2E) -1- (3-bromophenyl) -3- (4-methylphenyl) prop-2-en-1-one (7.09) in the same manner as in Example 108-1).
g, yield 47%) was obtained as a pale yellow powder.
2) The same method as in Example 108-2) from (2E) -1- (3-bromophenyl) -3- (4-methylphenyl) prop-2-en-1-one (5.03 g, 16.7 mmol) Gave 6- (3-bromophenyl) -2-isobutyl-4- (4-methylphenyl) nicotinonitrile (2.20 g, 32% yield) as a pale yellow solid.
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) and triethylamine (0.70 mL, 10.0 mmol), [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride (410 mg, 0.500 mmol) in methanol (10 mL) -N, After dissolving in a mixed solvent of N-dimethylformamide (30 mL), the mixture was stirred for 15 hours in a carbon monoxide atmosphere. The reaction mixture was diluted with ethyl acetate (100 mL), washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography to obtain 3- [5-cyano-6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzoic acid. Methyl (1.39 g, 72% yield) was obtained as a colorless oil. 3- [5-Cyano-6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzoate methyl (1.30 g, 3.38 mmol) in the same manner as in Example 1-4) Methyl [5- (aminomethyl) -6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzoate (780 mg, yield 58%) was obtained as a colorless oil.
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) Similar to Example 2-1) from methyl 3- [5- (aminomethyl) -6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzoate (0.76 g, 1.96 mmol). According to the method, methyl 3- [5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzoate (730 mg, yield 76% ) Was obtained as a white powder.
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, brs), 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) Conducted from methyl 3- [5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzoate (200 mg, 0.409 mmol) In the same manner as in Example 2-3), methyl 3- [5- (aminomethyl) -6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzoate (188 mg, yield) 99%) was obtained as a white powder.
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, brs), 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] benzoate methyl (530 mg, 1.08 mmol) in the same manner as in Example 9-1) to give 3- [ 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzoic acid (500 mg, 98% yield) was obtained as a white solid. . 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, brs), 4.31-4.37 (2H, m), 4.42 (1H, brs), 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) Examples from 3- [5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzoic acid (200 mg, 0.421 mmol) In the same manner as in 2-3), 3- [5- (aminomethyl) -6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzoic acid dihydrochloride (188 mg, yield 99) %) As a white powder.
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, brs), 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) 3- [5-{[(tert-butoxycarbonyl) Amino] methyl} -6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzoic acid (300 mg, 0.632 mmol) was prepared in the same manner as in Example 3-1) by {[6- [ Obtained tert-butyl 3- (aminocarbonyl) phenyl] -2-isobutyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (160 mg, 53% yield) as a white solid.
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, brs), 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) Performed from tert-butyl {160- [3- (aminocarbonyl) phenyl] -2-isobutyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (160 mg, 0.338 mmol) In the same manner as in Example 2-3), 3- [5- (aminomethyl) -6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzamide dihydrochloride (127 mg, yield 84) %) As a white powder.
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, brs), 7.60 (1H, t, J = 7.8 Hz), 7.81 (1H, s), 7.96 (1H, d, J = 7.7 Hz), 8.14 (1H, brs), 8.33-8.44 (4H, m), 8.58 (1H, s).

Example 192 2- [5- (aminomethyl) -6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzoic acid methyl dihydrochloride 1) 2-bromoacetophenone (9.95 g, 50 mmol) (2E) -1- (2-bromophenyl) -3- (4-methylphenyl) prop-2-en-1-one (8.86) in the same manner as in Example 108-1).
g, yield 44%) was obtained as a pale yellow powder.
2) The same method as in Example 108-2) from (2E) -1- (2-bromophenyl) -3- (4-methylphenyl) prop-2-en-1-one (5.03 g, 16.7 mmol) Gave 6- (2-bromophenyl) -2-isobutyl-4- (4-methylphenyl) nicotinonitrile (3.58 g, 53% yield) as a pale yellow solid.
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) 6- (2-Bromophenyl) -2-isobutyl-4- (4-methylphenyl) nicotinonitrile (2.50
g, 6.14 mmol) to methyl 2- [5-cyano-6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzoate (1.80 g, (76% yield) was obtained as a colorless oil. That is, 6- (2-bromophenyl) -2-isobutyl-4- (4-methylphenyl) nicotinonitrile, and triethylamine (1.7 mL, 12.2 mmol), [1,1′-bis (diphenylphosphino) ferrocene ] Palladium (II) dichloride (501 mg, 0.614 mmol) was dissolved in methanol (7.5 mL) -N, N-dimethylformamide (15 mL), and then stirred under a carbon monoxide atmosphere for 13 hours. The reaction mixture was diluted with ethyl acetate (100 mL), washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography to give 2- [5-cyano-6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzoic acid. Methyl was obtained.
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) From methyl 2- [5-cyano-6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzoate (1.80 g, 4.68 mmol) in the same manner as in Example 1-4), Methyl 2- [5- (aminomethyl) -6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzoate was obtained as a crude product. 2- [5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-4- (4-methylphenyl) pyridine-2 was prepared from the crude product in the same manner as in Example 2-1). -Iyl] methyl benzoate (1.70 g, 74% yield) was obtained as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 0.99 (6H, d, J = 6.6 Hz), 1.43 (9H, s), 2.26-2.37 (1H, m), 2.4
1 (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, brs), 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) Conducted from methyl 2- [5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzoate (383 mg, 0.786 mmol) In the same manner as in Example 2-3), methyl 2- [5- (aminomethyl) -6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzoate (345 mg, yield) 95%) was obtained as a pale pink powder.
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, brs).
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] benzoate methyl (1.31 g, 2.69 mmol) in the same manner as in Example 9-1) to give 2- [ 5-{[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzoic acid (0.85 g, 67% yield) was obtained as a colorless oil. It was.
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, brs), 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) Examples from 2- [5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzoic acid (429 mg, 0.904 mmol) In the same manner as in 2-3), 2- [5- (aminomethyl) -6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzoic acid dihydrochloride (329 mg, yield 81) %) As a white powder.
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, brs).
Example 194 2- [5- (aminomethyl) -6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzamide dihydrochloride 1) 2- [5-{[(tert-butoxycarbonyl) Amino] methyl} -6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzoic acid (421 mg, 0.887 mmol) was prepared in the same manner as in Example 3-1) by {[6- [ Obtained tert-butyl 2- (aminocarbonyl) phenyl] -2-isobutyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (290 mg, 69% yield) as a colorless oil. .
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, brs), 5.54 (1H, brs), 6.42 (1H, brs), 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) Performed from tert-butyl {[6- [2- (aminocarbonyl) phenyl] -2-isobutyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (290 mg, 0.612 mmol) In the same manner as in Example 2-3), 2- [5- (aminomethyl) -6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzamide dihydrochloride (254 mg, yield 93) %) As a yellow powder.
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, brs).

Example 195 5- (Aminomethyl) -N, N-dicyclohexyl-6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinamide dihydrochloride 1) 5-cyano-6-isobutyl-2-methyl Tert-Butyl-4- (4-methylphenyl) nicotinate (3.
00 g, 8.23 mmol) to 5-cyano-6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (2.16 g, yield 85%) in the same manner as in Example 24-1). Was obtained as a white powder.
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, oxalyl chloride (0.68 mL, 7.78 mmol) and N, N- Dimethylformamide (0.05 mL) was added and stirred at room temperature for 30 minutes. After evaporating the solvent under reduced pressure, the residue was dissolved in tetrahydrofuran. Subsequently, 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), washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography to obtain 5-cyano-N, N-dicyclohexyl-6-isobutyl-2-methyl-4- (4-methylphenyl) nicotine. The amide (0.35 g, 11% yield) was obtained 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) From 5-cyano-N, N-dicyclohexyl-6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinamide (0.35 g, 0.742 mmol) in the same manner as in Example 108-3), 5- (Aminomethyl) -N, N-dicyclohexyl-6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinamide dihydrochloride (0.20 g, yield 49%) was obtained as a yellow powder.
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 1-{[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} piperidine-4-carboxylate methyl dihydrochloride 1) Similar to Example 195-2) 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) According to the method, methyl 1-{[5-cyano-6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} piperidine-4-carboxylate (3.20 g, yield 91% ) Was obtained as a colorless oil.
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) Performed 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 Example 108-3), 1-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} piperidine-4- Methyl carboxylate dihydrochloride (3.27 g, yield 87%) was obtained as a white powder.
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, brs).
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) is heated to reflux in a mixed solvent of water (1.5 mL) -acetonitrile (1.5 mL). The mixture was stirred for 10 minutes to dissolve. To the resulting solution was added tert-butylamine (23.4 mg, 0.320 mmol), and the mixture was stirred at the same temperature for 10 minutes. Then, acetonitrile (20 ml) was further added, the mixture was allowed to cool to room temperature, and stirred at 0 ° C. for 30 minutes. The precipitated solid was collected by filtration, washed with acetonitrile (10 mL), and 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid tert-butylamine salt (78.4 mg, Yield 63%) was obtained 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, brs), 3.37 (2H, s), 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) methanesulfonic acid [5- {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl (476 mg, 1 mmol) in tetrahydrofuran (5 mL) To the mixture was added 15% aqueous sodium methanethiolate solution (3 mL), and the mixture was stirred at 50 ° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained after evaporation of the solvent under reduced pressure was purified by silica gel column chromatography ({2-isobutyl-6-methyl-4- (4-methylphenyl) -5-[(methylthio) methyl] pyridine) Tert-Butyl-3-yl} methyl) carbamate (312 mg, 72% yield) was obtained 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, brs), 7.04 (2H , d, J = 8.1 Hz), 7.24 (2H, d,
J = 8.1 Hz).
2) From tert-butyl ({2-isobutyl-6-methyl-4- (4-methylphenyl) -5-[(methylthio) methyl] pyridin-3-yl} methyl) carbamate, Example 2-3) ({2-Isobutyl-6-methyl-4- (4-methylphenyl) -5-[(methylthio) methyl] pyridin-3-yl} methyl) amine dihydrochloride (36 mg, 96%) was obtained as a white powder.
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, brs), 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, brs).
Example 199 ({2-isobutyl-6-methyl-4- (4-methylphenyl) -5-[(methylsulfonyl) methyl] pyridin-3-yl} methyl) amine dihydrochloride 1) ({2-isobutyl -6-Methyl-4- (4-methylphenyl) -5-[(methylthio) methyl] pyridin-3-yl} methyl) carbamate tert-butyl (200 mg, 0.46 mmol) in methanol-water (10: 1 Oxone (registered trademark) (310 mg) was added to the solution, and sulfuric acid (50 μL) was added, followed by stirring at room temperature for 6 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained after evaporation of the solvent under reduced pressure was purified by silica gel column chromatography ({2-isobutyl-6-methyl-4- (4-methylphenyl) -5-[(methylsulfonyl) methyl] Pyridin-3-yl} methyl) carbamate tert-butyl (128 mg, 60% yield) was obtained 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, brs), 4.26 (2H, s), 7.71 (2H, d, J = 7.8 Hz), 7.26 (2H, d, J = 8.1 Hz).
2) Example 2-3 from tert-butyl ({2-isobutyl-6-methyl-4- (4-methylphenyl) -5-[(methylsulfonyl) methyl] pyridin-3-yl} methyl) carbamate ), And ({2-isobutyl-6-methyl-4- (4-methylphenyl) -5-[(methylsulfonyl) methyl] pyridin-3-yl} methyl) amine dihydrochloride (36 mg , Yield 96%) was obtained as a white powder.
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, brs), 3.68 (2H, brs), 4.40 (2H, s), 7.24 (2H, d, J = 8.1 Hz), 7.35 (2H, d, J = 7.8 Hz), 8.20 (3H, brs).
Example 200 ({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) acetic acid dihydrochloride 1) methanesulfonic acid [5 -{[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl (952 mg, 2 mmol) in N, N-dimethyl After potassium carbonate (415 mg, 3 mmol) was added to the formamide (5 mL) solution, ethyl mercaptoacetate (240 μL, 2.2 mmol) was added and stirred at 50 ° C. for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained after evaporation of the solvent under reduced pressure was dissolved in ethanol (5 mL), 1N aqueous sodium hydroxide solution (5 ml) was added, and the mixture was stirred at room temperature for 2 hr. 1N Hydrochloric acid (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained after evaporation of the solvent under reduced pressure 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) was obtained 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, brs), 7.18 (2H, d, J = 8.1 Hz), 7.24 (2H, d, J = 8.1 Hz), 12.49 (1H, brs).
2) Performed 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 Example 2-3), ({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) acetic acid dihydrochloride The salt (106 mg, yield 96%) was obtained as a white powder.
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, brs), 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, brs).

Example 201 ({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} sulfonyl) acetic acid dihydrochloride 1) ({[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 methanol- Oxone (registered trademark) (508 mg) was added to a water (10: 1, 5 mL) solution, sulfuric acid (50 μL) was added, and the mixture was stirred at room temperature for 6 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained after evaporation of the solvent under reduced pressure was purified by silica gel column chromatography to give an oil. From the obtained oil, ({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] was obtained in the same manner as in Example 2-3). ] Methyl} sulfonyl) acetic acid dihydrochloride (104
mg, yield 68%) was obtained as a white powder.
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, brs).
Example 202 {[2-Isobutyl-6-methyl-4- (4-methylphenyl) -5- (1H-tetrazol-5-ylmethyl) pyridin-3-yl] methyl} amine dihydrochloride 1) {[5 -(Cyanomethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (300 mg, 0.74 mmol) in toluene (5 mL) in dibutyl Tin oxide (37 mg, 0.15 mmol) and trimethylsilyl azide (292 μL, 2.2 mmol) were added, followed by stirring 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 saturated brine and dried over anhydrous magnesium sulfate. The residue obtained after evaporation of the solvent under reduced pressure was purified by silica gel column chromatography {[2-isobutyl-6-methyl-4- (4-methylphenyl) -5- (1H-tetrazole-5- Irmethyl) pyridin-3-yl] methyl} carbamate tert-butyl (229 mg, 69% yield) was obtained 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, brs), 4.79 (1H,
brs), 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} carbamate from tert-butyl Example 2 -3) by the same method as {[2-isobutyl-6-methyl-4- (4-methylphenyl) -5- (1H-tetrazol-5-ylmethyl) pyridin-3-yl] methyl} amine dihydrochloride The salt (181 mg, 87% yield) was obtained as a white powder.
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, brs).
Example 203 3-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} -1,2,4-oxadiazole-5 (4H) -one dihydrochloride 1) {[5- (cyanomethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (400 mg , 1.0 mmol) in ethanol (5 mL) was added sodium carbonate (420 mg, 4.0 mmol) and hydroxyammonium chloride (210 mg, 3.0 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 saturated brine and dried over anhydrous magnesium sulfate. The residue obtained after evaporation of the solvent under reduced pressure 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 hr. . The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography ({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 tert-butyl (120 mg, 26% yield) was obtained 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, brs), 7.02 (2H, d, J = 8.1 Hz) ), 7.26 (2H, d, J = 7.8 Hz). 2) ({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 from tert-butyl in the same manner as in Example 2-3), 3-{[5- (amino Methyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} -1,2,4-oxadiazol-5 (4H) -one dihydrochloride (181 mg Yield 87%) as a white powder.
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 , brs), 3.66 (2H, s), 3.76 (2H, brs), 7.16 (2H, d, J = 7.8
Hz), 7.36 (2H, d, J = 7.8 Hz), 8.26 (3H, brs).
Example 204 {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} phosphonic acid diethyl dihydrochloride 1) Methanesulfonic acid [5- {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl (692 mg, 1.45 mmol) to triethyl phosphite (772 (μL, 4.5 mmol) was added, followed by stirring at 150 ° C. for 3 hours. The reaction solution was cooled to room temperature and purified by silica gel column chromatography to obtain {[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine- Diethyl 3-yl] methyl} phosphonate (314 mg, 42% yield) was obtained 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, brs), 7.07 (2H, d, J = 8.1 Hz), 7.24 (2H, d , J = 8.1 Hz).
2) Example from diethyl {[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} phosphonate In the same manner as in 2-3), {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} diethyl phosphonate dihydrochloride ( 106 mg, yield 96%) was obtained as a white powder.
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, brs).

Example 205 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid pyridin-2-ylmethyl trihydrochloride 1) 5-{[(tert-butoxycarbonyl) amino] Methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (1.00 g, 2.42 mmol) and 2- (bromomethyl) pyridine hydrobromide (0.92 g, 3.64 mmol) and potassium carbonate (1.00 g, 7.27 mmol) to 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) by a method similar to that in Example 169-1). ) Pyridin-2-ylmethyl nicotinate (1.21 g, 99% yield) was obtained as a colorless oil.
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, brs), 4.25 (1H, brs), 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) Examples from 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid pyridin-2-ylmethyl (1.21 g, 2.40 mmol) In the same manner as in 2-3), 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid pyridin-2-ylmethyl trihydrochloride (1.23 g, yield 99) %) As a white solid.
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 = 6.9 Hz), 3.81 (2H, d, J = 4.9 Hz), 5.20 (2H, s), 7.19 (4H, s), 7.23 (1H, brs), 7.62-7.66 (1H, m) , 8.06 (1H, t, J = 7.9 Hz), 8.39 (3H, brs), 8.68 (1H, d, J = 4.9 Hz).
Example 206 [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetic acid benzyl dihydrochloride 1) [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). Example 169 -1) by the same method as in [5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetate benzyl ( 305 mg, 84% yield) was obtained as a white powder.
¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.8 Hz), 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, brs), 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) From [5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetate benzyl (240 mg, 0.464 mmol) In the same manner as in Example 2-3), [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetic acid benzyl dihydrochloride (214.5 mg , Yield 95%) as a white powder.
¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.6 Hz), 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 = 8.1 Hz), 7.20-7.45 (7H, m), 8.40 (3H, brs) .

Example 207 4-({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) benzamide dihydrochloride 1) 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) to {[5-({[4- (aminocarbonyl) phenyl] thio} methyl) in the same manner as in Example 3-1).
Tert-Butyl-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (360 mg, yield 72%) was obtained as a white solid.
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
= 5.1 Hz), 4.20 (1H, brs), 7.05 (2H, d, J = 7.4 Hz), 7.12 (2H, d, J = 8.5 Hz), 7.19 (2H, d, J = 7.9 Hz), 7.64 ( (2H, d, J = 8.5 Hz).
2) {[5-({[4- (Aminocarbonyl) phenyl] thio} methyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamic acid tert- 4-({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine] was prepared from butyl (360 mg, 0.674 mmol) in the same manner as in Example 2-3). -3-yl] methyl} thio) benzamide dihydrochloride (253 mg, 74% yield) was obtained as a white solid.
¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (6H, d, J = 6.5 Hz), 2.13-2.22 (1H, m), 2.37 (3H, s), 2.86 (3H, brs), 3.14 (2H , brs), 3.78 (2H, d, J = 4.7 Hz), 3.99 (2H, s), 7.22 (2H, d, J = 8.5 Hz), 7.26 (2H, d, J = 8.1 Hz), 7.33 (2H , d, J = 8.5 Hz), 7.37 (1H, brs) 7.98 (1H, brs), 8.39 (3H, brs).
Example 208 2-({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) methyl benzoate dihydrochloride 1) { [5- (Hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (1.00 g, 2.51 mmol) and 2-mercaptobenzoic acid 2-({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl --- methyl methyl ester (422 mg, 2.51 mmol) in the same manner as in Example 183-1). Methyl 4- (4-methylphenyl) pyridin-3-yl] methyl} thio) benzoate (1.19 g, 86% yield) was obtained as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.12-2.26 (1H, m), 2.35 (3H, s), 2.66 (3H, s ), 2.75 (2H, d, J = 7.4 Hz), 3.77 (2H, s), 3.89 (3H, s), 4.03 (2H, d, J = 4.9 Hz), 4.19 (1H, brs), 7.05 (1H , d, J = 8.1 Hz), 7.09-7.13 (3H, m), 7.17 (2H, d, J = 8.1 Hz), 7.32-7.38 (1H, m), 7.93 (1H, dd, J = 7.7, 1.5 Hz).
2) 2-({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) benzoic acid 2-({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine] was prepared from methyl (190 mg, 0.346 mmol) in the same manner as in Example 2-3). -3-yl] methyl} thio) methyl benzoate dihydrochloride (165 mg, 91% yield) was obtained as a white solid.
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, brs), 2.98 (2H , brs), 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 = 8.5 Hz), 7.47- 7.52 (1H, m), 7.87 (1H, dd, J =
7.7, 1.5 Hz), 8.18 (3H, brs).

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 methyl ester (1.00 g, 1.82 mmol ) To 2-({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl)) in the same manner as in Example 9-1). Pyridin-3-yl] methyl} thio) benzoic acid (0.86 g, 88% yield) was obtained as a white solid.
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, brs), 2.73 (3H, brs ), 2.90 (2H, d, J = 7.0 Hz), 3.77 (2H, s), 4.05 (2H, d, J = 4.5 Hz), 4.32 (1H, brs), 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-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-
2-({[5- (Aminomethyl) -6-isobutyl] from methylphenyl) pyridin-3-yl] methyl} thio) benzoic acid (0.29 g, 0.542 mmol) in the same manner as in Example 2-3). -2-Methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) benzoic acid (274 mg, 99% yield) was obtained as a white solid.
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, brs), 3.03 (2H , brs), 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, brs).
Example 210 2-({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) benzamide dihydrochloride 1) 2- ( {[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) benzoic acid (0.48 g, 0.898 mmol) to {[5-({[2- (aminocarbonyl) phenyl] thio} methyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) by the same method as in Example 3-1). ) -Pyridin-3-yl] methyl} carbamate tert-butyl (0.23 g, 48% yield) was obtained as a white solid.
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, brs), 5.39 (1H, brs), 6.68 (1H, brs), 6.99 (2H, d, J = 7.9
Hz), 7.19-7.34 (5H, m), 7.75-7.78 (1H, m).
2) {[5-({[2- (Aminocarbonyl) phenyl] thio} methyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamic acid tert- 2-({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine] was prepared from butyl (0.23 g, 0.431 mmol) in the same manner as in Example 2-3). -3-yl] methyl} thio) benzamide dihydrochloride (218 mg, 99% yield) was obtained as a white solid.
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 , brs), 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, brs) , 7.48 (1H, dd, J = 7.4, 1.4 Hz), 7.84 (1H, brs), 8.41 (3H, brs).

Example 211 3-({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) methyl benzoate dihydrochloride 1) { [5- (hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (1.20 g, 3.01 mmol) and 3-mercaptobenzoic acid 3-({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl --- methyl methyl ester (507 mg, 3.01 mmol) by a method similar to that in Example 183-1). Methyl 4- (4-methylphenyl) pyridin-3-yl] methyl} thio) benzoate (1.35 g, 82% yield) was obtained as a brown solid.
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, brs), 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) 3-({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) benzoic acid 3-({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine] was prepared from methyl (324 mg, 0.590 mmol) in the same manner as in Example 2-3). -3-yl] methyl} thio) methyl benzoate dihydrochloride (268 mg, 87% yield) was obtained as a white solid.
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 , brs), 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, brs).
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) methyl benzoate (0.90 g , 1.64 mmol) to 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.
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, brs), 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, brs ), 7.89 (1H, brs).
2) 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) to 3-({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine- 3-yl] methyl} thio) benzoic acid dihydrochloride (167 mg, 80% yield) was obtained as a white solid.
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, brs), 3.10 (2H , brs), 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, brs).

Example 213 3-({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) benzamide dihydrochloride 1) 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) to {[5-({[3- (aminocarbonyl) phenyl] thio} methyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) by the same method as in Example 3-1). ) -Pyridin-3-yl] methyl} carbamate tert-butyl (460 mg, 92% yield) was obtained as a white solid.
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, brs), 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) {[5-({[3- (Aminocarbonyl) phenyl] thio} methyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamic acid tert- 3-({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine] was prepared from butyl (460 mg, 0.862 mmol) in the same manner as in Example 2-3). -3-yl] methyl} thio) benzamide dihydrochloride (439 mg, quant.) Was obtained as a white solid.
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, brs), 7.70 (1H, brs), 7.75 (1H, d, J = 7.4 Hz), 8.04 (1H, brs), 8.46 (3H, brs).
Example 214 4-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} benzoic acid dihydrochloride 1) {[5- ( Hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (0.50 g, 1.05 mmol), methyl 4-hydroxybenzoate (0.16 g) , 1.05 mmol), and a solution of triphenylphosphine (0.36 g, 1.37 mmol) in tetrahydrofuran (10 mL) were added 40% diethyl azodicarboxylate in toluene (0.60 mL, 1.37 mmol) and stirred at room temperature for 30 minutes. . The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography to obtain 4-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl- Methyl 4- (4-methylphenyl) pyridin-3-yl] methoxy} benzoate (380 mg, 68% yield) was obtained 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, brs), 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) Methyl 4-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} benzoate (380 mg, 0.713 mmol) and 4-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4- Methylphenyl) pyridin-3-yl] methoxy} benzoic acid (300 mg, 81% yield) was obtained as a white solid.
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, brs ), 2.84 (2H, brs), 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-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} benzoic acid (0.30 g , 0.578 mmol) to 4-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] by a method similar to that in Example 2-3). Methoxy} benzoic acid dihydrochloride (267 mg, 94% yield) was obtained as a white solid.
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, brs), 3.11 (2H, brs ), 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, brs).

Example 215 4-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} methyl benzoate dihydrochloride
4-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} methyl benzoate (0.30 mg, 0.563 mmol) to 4-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy by the same method as in Example 2-3). } Methyl benzoate dihydrochloride (281 mg, 99% yield) was obtained as a white solid.
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, brs), 3.11 (2H , brs), 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, brs).
Example 216 {[2-Isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} amine dihydrochloride 1) 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 stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 4- (4-methylphenyl) but-3-en-2-one (9.2 g, yield 80%) as an oil. The oil (1.0 g, 6.24 mmol) was dissolved in ethanol (20 mL), and 3-amino-5-methylhex-2-enenitrile (0.93 g, 7.49 mmol) and sodium hydroxide (0.3 g, 7.49 mmol) were added. The mixture was added and heated to reflux for 2 hours. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous ammonium chloride and saturated brine, and dried over anhydrous magnesium sulfate. From the residue obtained by distilling off the solvent under reduced pressure, 2-isobutyl-6-methyl-4- (4-methylphenyl) nicotinonitrile (0.45 g, yield) was obtained in the same manner as in Example 23-3). 27%) was obtained as a yellow oil.
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) nicotinonitrile (0.45 g, 1.70 mmol) was used in the same manner as in Example 108-3) to obtain {[2-isobutyl-6-methyl -4- (4-Methylphenyl) pyridin-3-yl] methyl} amine dihydrochloride (456 mg, 78% yield) was obtained as a white solid.
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,
brs), 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 ) Bromoacetone (6.9 g, 50 mmol) was added to a solution of sodium 4-methylbenzenesulfinate (9.00 g, 50.5 mmol) in ethanol (50 mL), and the mixture was heated to reflux for 30 minutes. The reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give 1-[(4-methylphenyl) sulfonyl] acetone (8.0 g, yield 75%) 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) 1-[(4-Methylphenyl) sulfonyl] acetone (2.0 g, 9.4 mmol) and p-tolualdehyde (1.1 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 to reflux for 3 hours using a Dean-Stark trap. The reaction mixture was cooled to room temperature, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 4- (4-methylphenyl) -3-[(4-methylphenyl) sulfonyl] But-3-en-2-one was obtained as a crude product (3.5 g). A mixture of the crude product (1.73 g), 3-amino-5-methylhex-2-enenitrile (0.65 g, 5.23 mmol), and ethanol (50 mL) was heated to reflux for 12 hours. The reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography, and the obtained 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) was obtained as a white powder.
Melting point 135-137 ℃
3) From 2-isobutyl-6-methyl-4- (4-methylphenyl) -5-[(4-methylphenyl) sulfonyl] -1,4-dihydropyridine-3-carbonitrile (1.1 g, 2.7 mmol), In the same manner as in Example 23-3), 2-isobutyl-6-methyl-4- (4-methylphenyl) -5-[(4-methylphenyl) sulfonyl] nicotinonitrile (0.77 g, yield 68) %) Was obtained as a white powder.
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) From 2-isobutyl-6-methyl-4- (4-methylphenyl) -5-[(4-methylphenyl) sulfonyl] nicotinonitrile (0.69 g, 1.6 mmol), as in Example 1-4) ({2-isobutyl-6-methyl-4- (4-methylphenyl) -5-[(4-methylphenyl) sulfonyl] pyridin-3-yl} methyl) amine (0.64 g, yield 93 %) As a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.6 Hz), 1.41 (2H, brs), 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) in ethanol (5 mL) was dissolved in p-toluenesulfonic acid monohydrate (0.29 g, 1.5 mmol) in ethanol (5 mL) dropwise with stirring at room temperature. After the mixture was stirred at room temperature for 10 minutes, the precipitate was collected by filtration, washed with cooled ethanol, dried and ({2-isobutyl-6-methyl-4- (4-methylphenyl) -5-[( 4-Methylphenyl) sulfonyl] pyridin-3-yl} methyl) amine 4-methylbenzenesulfonate (0.57 g, 63% yield) was obtained 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, brs).
Example 218 {[2-isobutyl-6-methyl-4- (4-methylphenyl) -5- (methylsulfonyl) pyridin-3-yl] methyl} amine 1) 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) using a Dean-Stark trap And heated to reflux for 12 hours. The reaction mixture was cooled to room temperature, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (20 mL), 3-amino-5-methylhex-2-enenitrile (4.3 g, 35 mmol) was added, and the mixture was heated to reflux for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 2-isobutyl-6-methyl-4- (4-methylphenyl) -5- (methylsulfonyl) -1,4-dihydropyridine- 3-carbonitrile (6.38
g, 68% yield) was obtained 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) Example 23-3) from 2-isobutyl-6-methyl-4- (4-methylphenyl) -5- (methylsulfonyl) -1,4-dihydropyridine-3-carbonitrile (6.38 g, 18.6 mmol) In the same manner, 2-isobutyl-6-methyl-4- (4-methylphenyl) -5- (methylsulfonyl) nicotinonitrile (4.14 g, yield 65%) was obtained as a white solid.
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) In the same manner as in Example 1-4) from 2-isobutyl-6-methyl-4- (4-methylphenyl) -5- (methylsulfonyl) nicotinonitrile (1.06 g, 3.09 mmol), {[ 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.
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 3-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} methyl benzoate dihydrochloride 1) {[5- (Hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (0.75 g, 1.89 mmol), methyl 3-hydroxybenzoate (0.29) g, 1.90 mmol) by the same method as in Example 214-1), 3-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4- Methylphenyl) pyridin-3-yl] methoxy} methyl benzoate (730 mg, 72% yield) was obtained as a colorless oil.
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) 3-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} methyl benzoate (144 mg, 0.270 mmol) and 3-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (
4-methylphenyl) pyridin-3-yl] methoxy} methyl benzoate dihydrochloride (116 mg, 85% yield) was obtained as a white solid.
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, brs), 3.11 (2H , brs), 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, brs).
Example 220 3-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} benzoic acid dihydrochloride 1) 3-{[5 Conducted from-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} methyl benzoate (0.58 g, 1.10 mmol) In the same manner as in Example 9-1), 3-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine-3- [Il] methoxy} benzoic acid (460 mg, 80% yield) was obtained as a colorless oil.
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, brs), 4.28 (1H, brs), 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, brs), 7.64-7.70 (1H, m).
2) 3-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} benzoic acid (136 mg , 0.262 mmol) to 3-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] in the same manner as in Example 2-3). Methoxy} benzoic acid dihydrochloride (128 mg, 99% yield) was obtained as a white solid.
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), 3.04 (2H, brs), 3.81 (2H, brs), 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, brs).

Example 221 2-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} methyl benzoate dihydrochloride 1) {[5- (Hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (0.75 g, 1.89 mmol), methyl 2-hydroxybenzoate (0.29) g, 1.90 mmol) in the same manner as in Example 214-1), 2-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4- Methylphenyl) pyridin-3-yl] methoxy} methyl benzoate (700 mg, 70% yield) was obtained as a white solid.
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, brs), 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) 2-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} methyl benzoate (78.8 mg, 0.148 mmol) to 2-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl by the same method as in Example 2-3). ] Methoxy} methyl benzoate dihydrochloride (42.3 mg, 56% yield) was obtained as a white solid.
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, brs), 3.07 (2H , brs), 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, brs).
Example 222 2-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} benzoic acid dihydrochloride 1) 2-{[5 Performed from-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} methyl benzoate (0.62 g, 1.17 mmol) In the same manner as in Example 9-1), 2-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine-3- [Il] methoxy} benzoic acid (140 mg, 23% yield) was obtained as a white solid.
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) 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) to 2-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] by a method similar to that in Example 2-3). Methoxy} benzoic acid dihydrochloride (103 mg, 77% yield) was obtained as a white solid.
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, brs), 3.13 (2H , brs), 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, brs) .

Example 223 N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] benzamide dihydrochloride
{[5-Amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (192 mg, 0.5 mmol) in tetrahydrofuran (3 ml) solution After adding benzoyl chloride (88 μL, 0.75 mmol), triethylamine (140 μL, 1.0 mmol) was added and stirred for 30 minutes. A saturated aqueous sodium hydroxide solution (5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain an oil. To a solution of the obtained oil in ethyl acetate (1 ml), 4N hydrogen chloride-ethyl acetate solution (1 ml) was added and stirred at room temperature for 1 hour. The residue obtained by evaporating the solvent under reduced pressure was crystallized from hexane, and N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl Benzamide dihydrochloride (203 mg, yield 96%) was obtained 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, brs), 10.13 (1H, brs).
Example 224 N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -2-phenylacetamide dihydrochloride
{[5-Amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (192 mg, 0.5 mmol) and phenylacetyl chloride (100 μL, 0.75 mmol) and N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -2-phenyl in the same manner as in Example 223 Acetamide dihydrochloride (208 mg, yield 95%) was obtained as a white powder.
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, brs), 9.90 (1H, brs).

Example 225 N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -3-phenylpropanamide dihydrochloride
{[5-Amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (192 mg, 0.5 mmol) and hydrocinnamoyl chloride (111 μL , 0.75 mmol) by the same method as in Example 223, N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -3- Phenylpropanamide dihydrochloride (208 mg, yield 92%) was obtained as a white powder.
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, brs), 3.79 (2H, s), 7.10-7.29 (9H, m), 8.26 (3H , brs), 9.43 (1H, brs).
Example 226 (2E) -N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -3-phenylacrylamide dihydrochloride
{[5-Amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (192 mg, 0.5 mmol) and cinnamoyl chloride (125 mg, 0.75 mmol), (2E) -N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] was prepared in the same manner as in Example 223. -3-Phenylacrylamide dihydrochloride (208 mg, 92% yield) was obtained as a white powder.
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 , brs), 3.83 (2H, brs), 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, brs), 9.76 (1H, brs).

Example 227 [({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) oxy] acetic acid ethyl dihydrochloride 1) 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) To [({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine) in the same manner as in Example 95-1). -3-yl] amino} carbonyl) oxy] ethyl acetate was obtained as an oil.
EIMS (M + 1): 514
2) [({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methyl)] was obtained from the oily substance obtained in 1) by the same method as in Example 2-3). Phenyl) pyridin-3-yl] amino} carbonyl) oxy] ethyl acetate dihydrochloride (202 mg, 45% yield) was obtained as a white powder.
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, brs), 3.91 (2H, brs), 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, brs), 9.12 (1H, brs).
Example 228 N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -N'-benzylurea dihydrochloride 1) 5-{[ From (tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (412 mg, 1.0 mmol) and benzylamine (218 μL, 2.0 mmol), examples 95-1) According to the same method, {[5-{[(benzylamino) carbonyl] amino} -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamine The tert-butyl acid was obtained as an oil.
EIMS (M + 1): 517
2) N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) was obtained from the oily substance obtained in 1) by the same method as in Example 2-3). ) Pyridin-3-yl] -N'-benzylurea dihydrochloride (181 mg, 40% yield) was obtained as a white powder.
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 , brs), 3.81 (2H, brs), 4.19 (2H, brs), 7.11-7.35 (9H, m), 8.43 (3H, brs).

Example 229 4-{[({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl)
Pyridin-3-yl] amino} carbonyl) oxy] methyl} benzoic acid methyl dihydrochloride 1) 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) and 4-{[({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4 by the same method as in Example 95-1). -(4-Methylphenyl) pyridin-3-yl] amino} carbonyl) oxy] methyl} methyl benzoate was obtained as an oil.
EIMS (M + 1): 576
2) From the oily substance obtained in the above 1), 4-{[({[5- (aminomethyl) -6-isobutyl-2-methyl-4- ( 4-methylphenyl) pyridin-3-yl] amino} carbonyl) oxy] methyl} methyl benzoate dihydrochloride (195 mg, 38% yield) was obtained as a white powder.
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 , brs), 3.78 (2H, brs), 3.87 (3H, s), 5.09 (2H, brs), 7.14-7.29 (6H, m), 7.92 (2H, d, J = 8.4 Hz), 8.30 (3H, brs), 9.19 (1H, brs).
Example 230 3-[({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] benzoic acid dihydrochloride 1 ) 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 To the solution 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 hour. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained after evaporation of the solvent under reduced pressure was purified by silica gel column chromatography to give 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4- Methylphenyl) nicotinic acid 3- (methoxycarbonyl) benzyl (1.80 g, 94% yield) was obtained 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, brs), 4.20 (1H, brs), 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) From 3-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 3- (methoxycarbonyl) benzyl (1.69 g, 3.01 mmol) In the same manner as in Example 9-1), 3-[({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine was obtained. -3-yl] carbonyl} oxy) methyl] benzoic acid (1.43 g, 87% yield) was obtained as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.13-2.25 (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,
brs), 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-{[(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) to 3-[({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] in the same manner as in Example 2-3). Carbonyl} oxy) methyl] benzoic acid dihydrochloride (293 mg, 60% yield) was obtained as a white solid.
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, brs).

Example 231 2-[({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] benzoic acid dihydrochloride 1 ) 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 2-Bromobenzyl bromide (0.61 g, 2.43 mmol) and potassium carbonate (0.51 g, 3.65 mmol) were added to the solution, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained after evaporation of the solvent under reduced pressure was purified by silica gel column chromatography to give 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4 -Methylphenyl) nicotinic acid 2-bromobenzyl (1.23 g, yield 87%) was obtained 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,
brs), 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) 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 2-bromobenzyl (1.23 g, 2.12 mmol) and triethylamine (0.59) mL, 4.24 mmol), [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride (174 mg, 0.212 mmol) in methanol (5 mL) -N, N-dimethylformamide (15 mL) After dissolution, the mixture was stirred for 14 hours under a carbon monoxide atmosphere. The reaction mixture was diluted with ethyl acetate (100 mL), washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography to give 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4 -(Methylphenyl) nicotinic acid 2- (methoxycarbonyl) benzyl (0.88 g, yield 74%) was obtained 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, brs), 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) From 2-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 2- (methoxycarbonyl) benzyl (0.88 g, 1.54 mmol) In the same manner as in Example 9-1), 2-[({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine was obtained. -3-yl] carbonyl} oxy) methyl] benzoic acid (0.75 g, 89% yield) was obtained as a colorless oil.
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,
brs), 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) 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) to 2-[({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] in the same manner as in Example 2-3). Carbonyl} oxy) methyl] benzoic acid dihydrochloride (278 mg, 65% yield) was obtained as a white solid.
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, brs ).
Example 232 4-({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) benzoic acid methyl dihydrochloride
{[5-Amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (192 mg, 0.5 mmol) and terephthalic acid monomethyl chloride (149 mg , 0.75 mmol) by the same method as in Example 223, 4-({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino } Carbonyl) methyl benzoate dihydrochloride (230 mg, 89% yield) was obtained as a white powder.
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 , brs), 3.85 (2H, brs), 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, brs), 10.13 (1H, brs).

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) methyl benzoate (260 mg , 0.48 mmol) and 4-({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4) by the same method as in Example 36-1). -Methylphenyl) pyridin-3-yl] amino} carbonyl) benzoic acid (248 mg, 98% yield) was obtained as a white powder.
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, brs), 3.99 (2H, brs), 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, brs).
2) 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) and 4-({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine] in the same manner as in Example 2-3). -3-yl] amino} carbonyl) benzoic acid dihydrochloride (230
mg, yield 99%) was obtained as a white powder.
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 , brs), 3.83 (2H, brs), 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, brs) , 10.11 (1H, brs).
Example 234 (4-{[5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methoxy} phenyl) acetic acid methyl dihydrochloride 1) { [5- (Hydroxymethyl) -6-methyl-4- (4-methylphenyl) -2-neopentylpyridin-3-yl] methyl} carbamate tert-butyl (0.44 g, 1.1 mmol) and 4-hydroxyphenyl (4-{[5-{[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- () was prepared from methyl acetate (0.18 g, 1.1 mmol) in the same manner as in Example 214-1). Methyl 4-methylphenyl) -6-neopentylpyridin-3-yl] methoxy} phenyl) acetate (0.36 g, 61% yield) was obtained as a white powder.
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) (4-{[5-{[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methoxy} phenyl) acetic acid (4-{[5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neo] from methyl (0.13 g, 0.22 mmol) by the same method as in Example 2-3). Methyl pentylpyridin-3-yl] methoxy} phenyl) acetic acid dihydrochloride (0.088 g, 74% yield) was obtained as a white powder.
¹ H-NMR (DMSO-d ₆ ) δ: 1.04 (9H, s), 2.35 (3H, s), 2.77 (3H, brs), 3.14 (2H, brs),
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, brs).

Example 235 2- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -1,3-oxazole-4-carboxylic acid methyl dihydrochloride 1) Example 195-2 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) ) Methyl N-{[5-cyano-6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} selinate (5.37 g, yield 87%) Was obtained as a colorless oil. 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) 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., diethylaminosulfur trifluoride (1.72 mL, 11.8 mmol) was added, and the mixture was stirred at the same temperature for 1 hr. After potassium carbonate (1.36 g, 14.7 mmol) was added, the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate, washed with saturated multistory water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give 2- [5-cyano-6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -4,5-dihydro-1, Methyl 3-oxazol-4-carboxylate (3.59 g, 69% yield) was obtained 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) 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 then bromotrichloromethane (0.73 mL, 7.42 mmol) was added and stirred at the same temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give 2- [5-cyano-6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -1,3-oxazole-4- Methyl carboxylate (520 mg, 63% yield) was obtained 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-cyano-6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -1,3-oxazole-4-carboxylate (0.52 g, 1.34 mmol) To 2- (5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -1,3- Methyl oxazole-4-carboxylate dihydrochloride (456 mg, 73% yield) was obtained as a white solid.
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) {[5- (Hydroxymethyl) -6-methyl-4- (4-methylphenyl) -2-neopentylpyridin-3-yl] methyl} carbamate tert-butyl (0.22 g, 0.53 mmol) and 4-hydroxy {[5-{[4- (2-Amino-2-oxoethyl) phenoxy] methyl} -6-methyl- was prepared from phenylacetamide (0.081 g, 0.53 mmol) in the same manner as in Example 214-1). 4- (4-Methylphenyl) -2-neopentylpyridin-3-yl] methyl} carbamate tert-butyl (0.14 g, 47% yield) was obtained as a white powder.
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, brs), 6.75-6.8
0 (2H, m), 7.05 (2H, d, J = 7.9 Hz), 7.10-7.20 (4H, m).
2) {[5-{[4- (2-Amino-2-oxoethyl) phenoxy] methyl} -6-methyl-4- (4-methylphenyl) -2-neopentylpyridin-3-yl] methyl} carbamine 2- (4-{[5- (aminomethyl) -2-methyl-4- (4-methylphenyl) was obtained from tert-butyl acid (0.11 g, 0.20 mmol) by the same method as in Example 2-3). ) -6-Neopentylpyridin-3-yl] methoxy} phenyl) acetamide dihydrochloride (0.098 g, 92% yield) was obtained as a pale yellow powder.
¹ H-NMR (DMSO-d ₆ ) δ: 1.05 (9H, s), 2.36 (3H, s), 2.79 (3H, brs), 3.05-3.25 (2H, m), 3.28 (2H, s), 3.88 (2H, brs), 4.66 (2H, s), 6.79 (2H, d, J = 8.5 Hz), 6.83 (1H, brs), 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, brs), 8.19 (3H, brs).

Example 237 (4-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} phenyl) acetic acid methyl 1) {[5- ( Hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (500 mg, 1.25 mmol) and methyl (4-hydroxyphenyl) acetate ( 250 mg, 1.51 mmol) and (4-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- ( Methyl 4-methylphenyl) pyridin-3-yl] methoxy} phenyl) acetate (570 mg, 83% yield) was obtained as a colorless oil.
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 stirred for 1 hour. The reaction solution 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 distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give (4-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} phenyl) Methyl acetate (300 mg, yield 65%) was obtained 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
{[5-Amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (192 mg, 0.5 mmol) and isophthalic acid monomethyl chloride (149 mg , 0.75 mmol) by the same method as in Example 223, 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 a white powder.
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 , brs), 3.85 (2H, brs), 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, brs), 10.19 (1H, brs).

Example 239 3-{[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1H-indole-2-carboxylate methyl 1) {[5- (Hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} tert-butyl carbamate (0.60 g, 1.49 mmol) and 3-hydroxyindole -2
3-Carboxylic acid methyl ester (0.26 g, 1.36 mmol) was prepared in the same manner as in Example 214-1) by using 3-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2- Methyl methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1H-indole-2-carboxylate (0.41 g, 52% yield) was obtained as a pale yellow solid.
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, brs), 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, brs).
2) 3-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1H-indole- Methyl 2-carboxylate (0.26 g, 1.36 mmol) was dissolved in 4N hydrogen chloride-ethyl acetate solution (10 mL) and stirred at room temperature for 30 minutes. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate, extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. The yellow solid obtained after evaporation of the solvent under reduced pressure was recrystallized from ethyl acetate-hexane to give 3-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) Pyridin-3-yl] methoxy} -1H-indole-2-carboxylate methyl ester (256 mg, yield 75%) was obtained 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, brs).
Example 240 5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 4-cyanobenzyl 1) 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 the same manner as in Example 169-1), 5-{[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 4-cyanobenzyl (2.32 g, 86% yield) as a yellow oil Got as.
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,
brs), 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) 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate 4-cyanobenzyl (0.52 g, 0.985 mmol) in trifluoroacetic acid (10 mL) and stirred at room temperature for 1 hour. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate, extracted twice with ethyl acetate, the extract was dried over anhydrous magnesium sulfate, and 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4 4-Cyanobenzyl (methylphenyl) nicotinate (0.42 g, 99% yield) was obtained 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
{[5-Amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (192 mg, 0.5 mmol) and quinoxaline-2-carbonyl chloride ( 144
mg, 0.75 mmol), and 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.
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 , brs), 3.86 (2H, brs), 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, brs), 9.34 (1H
, s), 10.50 (1H, brs).
Example 242 N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -2,5-dimethylfuran-3-carboxamide dihydrochloride
{[5-Amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (192 mg, 0.5 mmol) and 2,5-dimethylfuran- N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine- was prepared from 3-carbonyl chloride (119 mg, 0.75 mmol) in the same manner as in Example 223. 3-yl] -2,5-dimethylfuran-3-carboxamide dihydrochloride (215 mg, 90% yield) was obtained as a white powder.
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, brs), 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, brs), 9.32 (1H, brs).

Example 243 N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -3-methylthiophene-2-carboxamide dihydrochloride
{[5-Amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (192 mg, 0.5 mmol) and 3-methylthiophene-2- From carbonyl chloride (120 mg, 0.75 mmol), in the same manner as in Example 223, N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine-3- [Il] -3-Methylthiophene-2-carboxamide dihydrochloride (215 mg, 90% yield) was obtained as a white powder.
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, brs), 3.82 (2H, brs), 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, brs), 9.37 (1H, brs).
Example 244 N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -1-benzothiophene-2-carboxamide dihydrochloride
{[5-Amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (192 mg, 0.5 mmol) and 1-benzothiophene-2- From carbonyl chloride (150 mg, 0.75 mmol), in the same manner as in Example 223, N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine-3- [Il] -1-benzothiophene-2-carboxamide dihydrochloride (215 mg, 90% yield) was obtained as a white powder.
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 , brs), 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, brs), 10.34 (1H, brs).

Example 245 N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -3-methyl-1-benzofuran-2-carboxamide dihydrochloride
{[5-Amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (192 mg, 0.5 mmol) and 3-methyl-1-benzofuran N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine from 2-carbonyl chloride (150 mg, 0.75 mmol) in the same manner as in Example 223 -3-yl] -3-methyl-1-benzofuran-2-carboxamide dihydrochloride (213 mg, 90% yield) was obtained as a white powder.
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, brs), 3.83 (2H, brs), 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, brs), 10.08 (1H, brs).
Example 246 [4-({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) -2-oxopiperazine-1- Yl] acetic acid methyl dihydrochloride 1) with 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (412 mg, 1.0 mmol) [4-({[5-{[(tert-butoxycarbonyl) amino] was prepared from methyl (2-oxopiperazin-1-yl) acetate (344 mg, 2.0 mmol) in the same manner as in Example 95-1). ] Methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) -2-oxopiperazin-1-yl] methyl acetate was obtained as an oil.
EIMS (M + 1): 582
2) [4-({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4)] was obtained from the oily substance obtained in 1) by the same method as in Example 2-3). -Methylphenyl) pyridin-3-yl] amino} carbonyl) -2-oxopiperazin-1-yl] acetic acid methyl dihydrochloride (271 mg, 49% yield) was obtained as a white powder.
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 , brs), 3.14 (2H, t, J = 5.1 Hz), 3.46 (2H, t, J = 5.1 Hz),
3.66 (3H, s), 3.81 (4H, brs), 4.08 (2H, s), 7.17 (2H, d, J = 7.8 Hz), 7.29 (2H,
d, J = 7.8 Hz), 8.43 (3H, brs).

Example 247 5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid [5- (methoxycarbonyl) pyridin-2-yl] methyl 1) 5-{[(tert -Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (1.85 g, 4.48 mmol) and methyl 6- (hydroxymethyl) nicotinate (0.68 g, 4.07 mmol), triphenylphosphine (1.39 g, 5.29 mmol) in tetrahydrofuran (20 mL) and 40% diethyl azodicarboxylate in toluene (2.3 mL, 5.29).
mmol) was added and stirred at room temperature for 30 minutes. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography to give 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4 -Methylphenyl) nicotinic acid [5- (methoxycarbonyl) pyridin-2-yl] methyl (2.29 g, 99% yield) was obtained 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, brs), 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-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid [5- (methoxycarbonyl) pyridin-2-yl] methyl ( 0.37 g, 0.659 mmol) was dissolved in 4N hydrogen chloride-ethyl acetate solution (10 mL) and stirred at room temperature for 30 minutes. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate, extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid [5- (methoxycarbonyl) pyridin-2-yl] methyl (142 mg, yield 46%) was obtained 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 ) 5-{[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid [5- (methoxycarbonyl) pyridin-2-yl] methyl (1.90) g, 3.38
mmol) to 6-[({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methyl) in the same manner as in Example 9-1). Phenyl) pyridin-3-yl] carbonyl} oxy) methyl] nicotinic acid (1.08 g, 58% yield) was obtained as a colorless oil.
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, brs), 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-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl ] 6-[({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methyl) was prepared from nicotinic acid (0.50 g, 0.913 mmol) in the same manner as in Example 2-3). Phenyl) pyridin-3-yl] carbonyl} oxy) methyl] nicotinic acid trihydrochloride (413 mg, 81% yield) was obtained as a white solid.
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, brs), 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, brs), 8.98 (1H, d, J = 1.5 Hz).

Example 249 5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid [5- (aminocarbonyl) pyridin-2-yl] methyl 1) 6-[({[ 5-{[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] nicotinic acid (0.58 g, 1.06 mmol) to 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid [5] by the same method as in Example 3-1). -(Aminocarbonyl) pyridin-2-yl] methyl (222 mg, 38% yield) was obtained as a colorless oil.
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,
brs), 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-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid [5- (aminocarbonyl) pyridin-2-yl] methyl ( 0.22 g, 0.406 mmol) to 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid [5- (aminocarbonyl) by the same method as in Example 247-2). ) Pyridin-2-yl] methyl (159 mg, 87% yield) was obtained as a colorless oil.
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 Hydrochloride 1) {[5- (hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (0.53 g, 1.33 mmol) and According to a method similar to that in Example 214-1) from ethyl 2-ethyl-4-hydroxypyrimidine-5-carboxylate (0.26 g, 1.33 mmol), 4-{[5-{[(tert-butoxycarbonyl) amino] Methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -2-ethylpyrimidine-5-carboxylate (308 mg, 40% yield) as a white solid Got as.
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) 4-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -2-ethylpyrimidine 4-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4- Methylphenyl) pyridin-3-yl] methoxy} -2-ethylpyrimidine-5-carboxylate ethyl tetrahydrochloride (269 mg, 80% yield) was obtained as a white solid.
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, brs), 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, brs), 8.46 (1H, s).

Example 251 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 4- (1H-tetrazol-5-yl) benzyl dihydrochloride 1) 5-{[( of tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate 4-cyanobenzyl (1.28 g, 2.43 mmol) and tributyltin azide (2.3 mL, 8.49 mmol) The toluene (7.5 mL) solution was heated to reflux for 3 hours under an argon atmosphere. The residue obtained after evaporation of the solvent under reduced pressure was purified by silica gel column chromatography to give 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4 -Methylphenyl) nicotinic acid 4- (1H-tetrazol-5-yl) benzyl (1.23 g, yield 88%) was obtained 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, brs), 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) 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 4- (1H-tetrazol-5-yl) benzyl (0.75 g) , 1.33 mmol) in the same manner as in Example 2-3), 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 4- (1H-tetrazole-5 -Yl) benzyl dihydrochloride (688 mg, 95% yield) was obtained as a white solid.
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, brs).
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-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (2.00 g, 4.85 mmol) and 5- (chloro Methyl) furan-2-carboxylate (0.85 g, 4.85 mmol) in the same manner as in Example 169-1), 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2- Methyl-4- (4-methylphenyl) nicotinic acid [5- (methoxycarbonyl) -2-furyl] methyl (2.37 g, yield 88%) was obtained as a yellow oil.
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, brs), 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-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid [5- (methoxycarbonyl) -2-furyl] methyl (2.11) g, 3.83 mmol), and 5-[({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- ( 4-Methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] furan-2-carboxylic acid (1.95 g, 95% yield) was obtained as a white solid.
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,
brs), 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-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl ] From the furan-2-carboxylic acid (0.61 g, 1.14 mmol) in the same manner as in Example 2-3), 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 .
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, brs), 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, brs).

Example 253 5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid [5- (aminocarbonyl) -2-furyl] methyl dihydrochloride 1) 5-[( {[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] -furan-2- In the same manner as in Example 3-1) from carboxylic acid (0.75 g, 1.40 mmol), 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4- Methylphenyl) nicotinic acid [5- (aminocarbonyl) -2-furyl] methyl (520 mg, 69% yield) was obtained as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.14-2.27 (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,
brs), 4.94 (2H, s), 5.45 (1H, brs), 6.16 (1H, brs), 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-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid [5- (aminocarbonyl) -2-furyl] methyl (0.52 g, 0.971 mmol) to 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid [5- (aminocarbonyl) by the same method as in Example 2-3). -2-furyl] methyl dihydrochloride (471 mg, 95% yield) was obtained as a white solid.
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, brs), 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, brs), 7.73 (1H, brs), 8.28 (3H, brs).
Example 254 3-{[[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] (methyl) amino] carbonyl} methyl benzoate dihydrochloride
3-({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) benzoic acid (212 Methyl iodide (282 mg, 2.0 mmol) was added to a mixture of mg, 0.4 mmol), potassium carbonate (138 mg, 1.0 mmol), and N, N-dimethylformamide (5 mL), 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 saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain an oil. To a solution of the obtained oil in ethyl acetate (1 ml), 4N hydrogen chloride-ethyl acetate solution (1 ml) was added and stirred at room temperature for 1 hour. The residue obtained by distilling off the solvent under reduced pressure was crystallized from hexane to give 3-{[[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine-3. -Il] (methyl) amino] carbonyl} methyl benzoate dihydrochloride (203 mg, 95% yield) was obtained as a white powder.
EIMS (M + 1): 460

Example 255 N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] isophthalamide dihydrochloride 1) 3-({[5- { Conducted from [(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) benzoic acid (260 mg, 0.48 mmol) In the same manner as in Example 3-1), {[5-{[3- (aminocarbonyl) benzoyl] amino} -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] Tert-butyl methyl} carbamate (248 mg, 98% yield) was obtained as a white powder.
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, brs), 4.13 (2H, brs), 4.40 (1H, brs), 5.79 (
1H, brs), 6.38 (1H, brs), 7.03 (2H, d, J = 8.1 Hz), 7.18 (2H, d, J = 8.1 Hz), 7.39-7.45 (1H, brs), 7.60-7.63 (1H , m), 7.88-7.92 (2H, m).
2) {[5-{[3- (Aminocarbonyl) benzoyl] amino} -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (248 mg, 0.47 mmol) and N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl by the same method as in Example 2-3). ] Isophthalamide dihydrochloride (233 mg, yield 99%) was obtained as a white powder.
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 , brs), 3.84 (2H, brs), 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, brs), 10.04 (1H, brs).
Example 256 5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 4- [2-oxo-2- (2-oxo-2-phenylethoxy) ethyl] benzyl Dihydrochloride 1) 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (2.00 g, 4.85 mmol) and 4- (bromomethyl ) Phenylacetic acid phenacyl ester (1.69 g, 4.85 mmol) was prepared in the same manner as in Example 169-1) by using 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- 4- [2-oxo-2- (2-oxo-2-phenylethoxy) ethyl] benzyl (2.85 g, 4-methylphenyl) nicotinic acid
Yield 86%) was obtained as a colorless oil.
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, brs), 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) 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 4- [2-oxo-2- (2-oxo-2) -Phenylethoxy) ethyl] benzyl (0.27 g, 0.398 mmol) in the same manner as in Example 2-3), 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) 4- [2-oxo-2- (2-oxo-2-phenylethoxy) ethyl] benzyl nicotinate dihydrochloride (117 mg, 45% yield) was obtained as a white solid.
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, brs), 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 Hz), 7.56 (2H, d, J = 7.9 Hz), 7.67-7.72 (1H, m), 7.92-7.98 (2H, m), 8.17 (3H, brs).

Example 257 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 4- (2-methoxy-2-oxoethyl) benzyl dihydrochloride 1) 5-{[( tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 4- [2-oxo-2- (2-oxo-2-phenylethoxy) ethyl] benzyl (2.58 g, 3.80 mmol) to {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, 77% yield) was obtained as a colorless oil.
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, brs), 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) {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) and potassium carbonate (0.32 g, 2.32 mmol) and N, N-dimethylformamide (15 mL) were added with methyl iodide (197 mg, 1.39 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained after evaporation of the solvent under reduced pressure was purified by silica gel column chromatography to give 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4 4- (2-Methoxy-2-oxoethyl) benzyl (methylphenyl) nicotinate (0.56 g, 84% yield) was obtained 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, brs), 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) 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 4- (2-methoxy-2-oxoethyl) benzyl (0.56 g , 0.974 mmol) in the same manner as in Example 2-3), 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 4- (2-methoxy-2 -Oxoethyl) benzyl dihydrochloride (483 mg, 90% yield) was obtained as a white solid.
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, brs).
Example 258 {4-[({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] phenyl} acetic acid dihydrochloride salt
{4-[({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] In the same manner as in Example 2-3), from phenyl} acetic acid (0.50 g, 0.892 mmol), {4-[({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4- Methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] phenyl} acetic acid dihydrochloride (348 mg, 73% yield) was obtained as a white solid.
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, brs).

Example 259 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 4- (2-amino-2-oxoethyl) benzyl dihydrochloride 1) {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) to 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 4 by the same method as in Example 3-1). -(2-Amino-2-oxoethyl) benzyl (360 mg, 72% yield) was obtained as a colorless oil.
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, brs), 4.91 (2H, s), 5.31 (2H, brs), 7.04-7.06 (4H, m), 7.16 (2H, d, J = 7.9 Hz), 7.20 (2H, d , J = 8.1 Hz).
2) 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 4- (2-amino-2-oxoethyl) benzyl (0.36 g , 0.643 mmol) and 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 4- (2-amino-2) in the same manner as in Example 2-3). -Oxoethyl) benzyl dihydrochloride (231 mg, 67% yield) was obtained as a white solid.
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, brs), 3.37 (2H , s), 3.81 (2H, d, J = 5.5 Hz), 4.93 (2H, s), 6.88 (1H, brs), 6.98 (2H, d, J = 8.1 Hz), 7.13-7.25 (6H, m) , 7.49 (1H, brs), 8.21 (3H, brs).
Example 260 5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 4- (methylsulfonyl) benzyl dihydrochloride 1) 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) ) To Example 169-1) in the same manner as in Example 169-1), 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 4- ( Methylsulfonyl) benzyl (530 mg, 73% yield) was obtained as a colorless oil.
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, brs), 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) From 4-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 4- (methylsulfonyl) benzyl (0.53 g, 0.913 mmol) In the same manner as in Example 2-3), 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 4- (methylsulfonyl) benzyl dihydrochloride (466 mg , Yield 92%) was obtained as a white solid.
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 3- [4-({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) -2-oxopiperazine- 1-yl] ethyl propionate dihydrochloride 1) 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 the same manner as in Example 95-1), 3- [4-({[5-{[( tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) -2-oxopiperazin-1-yl] ethyl propionate Obtained as an oil.
EIMS (M + 1): 610
2) From the oily substance obtained in 1) above, 3- [4-({[5- (aminomethyl) -6-isobutyl-2-methyl-4 Ethyl (4-methylphenyl) pyridin-3-yl] amino} carbonyl) -2-oxopiperazin-1-yl] propionate dihydrochloride (278 mg, 49% yield) was obtained as a white powder.
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, brs), 3.37-3.47 (4H, m), 3.74 (2H, s), 3.83 (2H, brs), 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, brs).
Example 262 N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -2-methoxybenzamide dihydrochloride
{[5-Amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (192 mg, 0.5 mmol) and 2-methoxybenzoyl chloride (128 mg, 0.75 mmol) and N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -2 by the same method as in Example 223 -Methoxybenzamide dihydrochloride (209 mg, 95% yield) was obtained as a white powder.
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, brs), 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, brs), 9.55 (1H, brs).

Example 263 N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -2-fluorobenzamide dihydrochloride
{[5-Amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (192 mg, 0.5 mmol) and 2-fluorobenzoyl chloride (122 mg, 0.75 mmol) and N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -2 by the same method as in Example 223 -Fluorobenzamide dihydrochloride (204 mg, yield 95%) was obtained as a white powder.
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, brs), 9.86 (1H, brs).
Example 264 N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -3-methoxybenzamide dihydrochloride
{[5-Amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (192 mg, 0.5 mmol) and 3-methoxybenzoyl chloride (128 mg, 0.75 mmol) and N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -3 in the same manner as in Example 223. -Methoxybenzamide dihydrochloride (196 mg, yield 80%) was obtained as a white powder.
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, brs), 7.08-7.10 (2H, m), 7.18-7.36 (6H, m), 8.33 (3H, brs), 9.96 (1H, brs).

Example 265 N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -3-fluorobenzamide dihydrochloride
{[5-Amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (192 mg, 0.5 mmol) and 3-fluorobenzoyl chloride (122 mg, 0.75 mmol) and N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -3 by the same method as in Example 223. -Fluorobenzamide dihydrochloride (186 mg, 78% yield) was obtained as a white powder.
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, brs), 10.22 (1H, brs).
Example 266 N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -4-methoxybenzamide dihydrochloride
{[5-Amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (192 mg, 0.5 mmol) and 4-methoxybenzoyl chloride (128 mg, 0.75 mmol) and N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -4 in the same manner as in Example 223. -Methoxybenzamide dihydrochloride (209 mg, 95% yield) was obtained as a white powder.
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, brs), 6.96 (1H, t, J = 9.0 Hz), 7.25 (4H, s), 7.67 (2H, d, J = 9.0 Hz), 8.43 (3H, brs), 9.92 (1H, brs).

Example 267 N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -4-fluorobenzamide dihydrochloride
{[5-Amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (192 mg, 0.5 mmol) and 4-fluorobenzoyl chloride (122 mg, 0.75 mmol) and N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -4 in the same manner as in Example 223. -Fluorobenzamide dihydrochloride (204 mg, yield 95%) was obtained as a white powder.
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, brs), 10.14 (1H, brs).
Example 268 5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetic acid (5-methyl-2-oxo-1,3-dioxol-4- Yl) methyl 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 4- (chloromethyl) -5-methyl-1,3-dioxol-2-one (209 mg, 1.41 mmol) in the same manner as in Example 176-1) [5-{[ (tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetic acid (5-methyl-2-oxo-1,3-dioxol-4 -Il) methyl
(540 mg, 86% yield) was obtained as a white powder.
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, brs), 4.76 (2H , s), 6.93 (2H, d, J = 7.9 Hz), 7.21 (2H, d, J = 7.9 Hz).
2) [5-{[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetic acid (5-methyl-2-oxo- 5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4) from 1,3-dioxol-4-yl) methyl (530 mg, 0.984 mmol) in the same manner as in Example 2-3). -Methylphenyl) pyridin-3-yl] acetic acid (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl dihydrochloride (500 mg, yield 99%) was obtained as a white powder.
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, brs).

Example 269 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 2- [4- (methoxycarbonyl) phenyl] ethyl dihydrochloride 1) 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) to 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 2 in the same manner as in Example 169-1). -[4- (Methoxycarbonyl) phenyl] ethyl (1.77 g, 70% yield) was obtained as a colorless oil.
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, brs), 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) 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 2- [4- (methoxycarbonyl) phenyl] ethyl (0.37 g , 0.644 mmol) and 2- (4- (methoxycarbonyl) 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid in the same manner as in Example 2-3). ) Phenyl] ethyl dihydrochloride (291 mg, 82% yield) was obtained as a white solid.
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, brs), 2.73 (2H , d, J = 6.4 Hz), 2.91 (2H, brs), 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, brs ).
Example 270 4- [2-({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) ethyl] benzoic acid dihydrochloride Salt 1) 5-{[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 2- [4- (methoxycarbonyl) phenyl] ethyl (1.40 g, 2.44 mmol) to 4- [2-({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4 by the same method as in Example 9-1). -(4-Methylphenyl) pyridin-3-yl] carbonyl} oxy) ethyl] benzoic acid (1.30 g, 95% yield) was obtained as a colorless oil.
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, brs), 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-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy ) Ethyl] benzoic acid (0.40 g, 0.713 mmol) and 4- [2-({[5- (aminomethyl) -6-isobutyl-2-methyl-4-methyl] (4-Methylphenyl) pyridin-3-yl] carbonyl} oxy) ethyl] benzoic acid dihydrochloride (359 mg, 94% yield) was obtained as a white solid.
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, brs).

Example 271 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 2- [4- (aminocarbonyl) phenyl] ethyl dihydrochloride 1) 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) and 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotine by the same method as in Example 3-1). The acid 2- [4- (aminocarbonyl) phenyl] ethyl (598 mg, 99% yield) was obtained as a colorless oil.
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), 4.24 (1H, brs), 5.67 (1H, brs), 6.06 (1H, brs), 7.02 (2H, d, J = 7.9 Hz), 7.15-7.19 (4H, m), 7.73 (2H, d, J = 8.1 Hz).
2) 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 2- [4- (aminocarbonyl) phenyl] ethyl (598 mg , 1.06 mmol) and 2- (4- (aminocarbonyl) 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid in the same manner as in Example 2-3). ) Phenyl] ethyl dihydrochloride (508 mg, 90% yield) was obtained as a white solid.
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, brs), 2.67 (2H , t, J = 6.4 Hz), 2.87 (2H, brs), 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, brs), 7.81 (2H, d, J = 8.3 Hz), 7.95 (1H, brs), 8.27 (3H, brs).
Example 272 3-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} benzamide 1) 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) to Example 3-1) In the same manner, {[5-{[3- (aminocarbonyl) phenoxy] methyl} -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamic acid tert -Butyl (240 mg, 80% yield) was obtained as a white solid.
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,
brs), 4.68 (2H, s), 5.55 (1H, brs), 6.01 (1H, brs), 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, s).
2) tert-butyl {[5-{[3- (aminocarbonyl) phenoxy] methyl} -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (240 mg, 0.463 mmol) and 3-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] in the same manner as in Example 239-2). ] Methoxy} benzamide (166 mg, 85% yield) was obtained as a white solid.
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, brs), 6.06 (1H, brs), 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 2-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -5-methylbenzoic acid methyl dihydrochloride 1) {[5- (hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} tert-butyl carbamate (1.0 g, 2.51 mmol) and 2-hydroxy- 2-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2 was prepared from methyl 5-methylbenzoate (500 mg, 3.01 mmol) in the same manner as in Example 214-1). -Methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -5-methylbenzoate (720 mg, 52% yield) was obtained as a white powder.
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, brs), 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) 2-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -5-methylbenzoic acid 2-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine from methyl acid (150 mg, 0.274 mmol) in the same manner as in Example 2-3) Methyl-3-yl] methoxy} -5-methylbenzoate dihydrochloride (100 mg, 70% yield) was obtained as a white powder.
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, brs). Example 274 2-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine-3 -Yl] methoxy} -5-chlorobenzoic acid methyl dihydrochloride 1) {[5- (hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} 2-{[5-{[(tert-butoxy) was prepared from tert-butyl carbamate (0.80 g, 2.0 mmol) and methyl 5-chlorosalicylate (0.56 g, 3.0 mmol) in the same manner as in Example 106-1). Carbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -5-chlorobenzoate (0.80 g, 71% yield) in white powder Got as.
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) 2-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -5-chlorobenzoate A mixture of methyl acid (0.19 g, 0.33 mmol) and hydrogen chloride-methanol solution (4 mL) was 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 give 2-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine-3. -Iyl] methoxy} -5-chlorobenzoic acid methyl dihydrochloride (0.17 g, 96% yield) was obtained 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, brs), 3.08 (2H , brs), 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, brs).

Example 275 2-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -5-methoxymethyl benzoate dihydrochloride 1) {[5- (Hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (0.80 g, 2.0 mmol) and 5-methoxysalicylic acid 2-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4-methyl (0.55 g, 3.0 mmol) was prepared in the same manner as in Example 106-1). Methyl (4-methylphenyl) pyridin-3-yl] methoxy} -5-methoxybenzoate (0.70 g, 62% yield) was obtained as a white powder.
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) 2-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -5-methoxybenzoate 2-([5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine] from methyl acid (0.23 g, 0.40 mmol) in the same manner as in Example 274-2) Methyl-3-yl] methoxy} -5-methoxybenzoate dihydrochloride (0.20 g, 96% yield) was obtained as a white powder.
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, brs), 2.93 (2H , brs), 3.72 (3H, s), 3.73 (3H, s), 3.79 (2H, d, J = 4.9
Hz), 4.69 (2H, brs), 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, brs).
Example 276 2-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -4-methoxybenzoic acid dihydrochloride 1) { [5- (Hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (0.80 g, 2.0 mmol) and methyl 4-methoxysalicylate (0.55 g, 3.0 mmol) to 2-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- ( Methyl 4-methylphenyl) pyridin-3-yl] methoxy} -4-methoxybenzoate (0.81 g, 72% yield) was obtained as a white powder.
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-methoxybenzoate 2-([5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4 was prepared from methyl acid (0.51 g, 0.91 mmol) in the same manner as in Example 36-1). -(4-Methylphenyl) pyridin-3-yl] methoxy} -4-methoxybenzoic acid (0.19 g, 37% yield) was obtained as a white powder.
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, brs).
3) 2-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -4-methoxybenzoate A mixture of 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 give 2-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine-3- [Il] methoxy} -4-methoxybenzoic acid dihydrochloride (0.12 g, 81% yield) was obtained 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, brs), 3.06 (2H , brs), 3.73 (3H, s), 3.82 (2H, brs), 4.76 (2H, brs), 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, brs).

Example 277 6-({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} methyl) methyl nicotinate trihydrochloride 1) { [5- (Hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (1.50 g, 3.76 mmol) and 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 saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to remove methanesulfonic acid [5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4 -Methylphenyl) pyridin-3-yl] methyl was obtained 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% oily, 226 mg, 5.65 mmol) in tetrahydrofuran (50 mL) at 60 ° C. And stirred for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained after evaporation of the solvent under reduced pressure was purified by silica gel column chromatography to obtain {[5-{[(5-bromopyridin-2-yl) methoxy] methyl} -2-isobutyl-6- Obtained tert-butyl methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (1.35 g, yield 63%) 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) {[5-{[(5-Bromopyridin-2-yl) methoxy] methyl} -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamic acid tert 6-({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl ---- by the same method as in Example 231-2) from -butyl (1.35 g, 2.37 mmol). Methyl 4- (4-methylphenyl) pyridin-3-yl] methoxy} methyl) nicotinate (1.15 g, 88% yield) was obtained 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), 2.40 (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, brs), 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) 6-({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} methyl) nicotinic acid 6-({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine] was prepared from methyl (0.19 g, 0.347 mmol) in the same manner as in Example 2-3). -3-yl] methoxy} methyl) methyl nicotinate trihydrochloride (114 mg, 58% yield) was obtained as a white solid.
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, brs), 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, brs), 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) methyl nicotinate (0.96 g , 1.75 mmol) and 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.
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,
brs), 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-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} methyl) nicotinic acid (0.28 g, 0.525 mmol) to 6-({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine- 3-Iyl] methoxy} methyl) nicotinic acid trihydrochloride (259 mg, 90% yield) was obtained as a white solid.
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, brs), 3.13-3.22 (2H, m), 3.81 (2H, brs), 4.29 (2H, brs), 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, brs), 8.93-8.96 (1H, m).

Example 279 2- {2- [5- [aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] ethyl} methyl benzoate dihydrochloride 1) {[ 5-formyl-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (0.36 g, 0.908 mmol) and diethyl (2-bromobenzyl) phosphonate Sodium methoxide (165 mg, 4.08 mmol) was added to a solution of (363 mg, 1.18 mmol) in N, N-dimethylformamide (10 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained after evaporation of the solvent under reduced pressure was purified by silica gel column chromatography to obtain {[5-[(E) -2- (2-bromophenyl) vinyl] -2-isobutyl-6-methyl. Tert-Butyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (390 mg, yield 78%) was obtained 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, brs), 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) {[5-[(E) -2- (2-Bromophenyl) vinyl] -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamic acid tert- 2-{(E) -2- [5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl- Methyl 2-methyl-4- (4-methylphenyl) pyridin-3-yl] vinyl} benzoate (280 mg, 74% yield) was obtained as a yellow oil.
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, brs), 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) 2-{(E) -2- [5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] vinyl } A mixture of methyl benzoate (0.28 g, 0.53 mmol), 10% palladium-carbon (57 mg, 0.053 mmol), and methanol (10 mL) was placed in a sealed tube at room temperature under a hydrogen atmosphere of 0.5 MPa at room temperature. Stir for hours. The filtrate obtained by filtering the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 2- {2- [5-{[(tert-butoxycarbonyl) amino] methyl} -6- Methyl isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] ethyl} benzoate (250 mg, 88% yield) was obtained 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, brs), 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) 2- {2- [5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] ethyl} methyl benzoate (0.25 g, 0.471 mmol) to 2- {2- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine by the same method as in Example 2-3) -3-yl] ethyl} methyl benzoate dihydrochloride (201 mg, 84% yield) was obtained as a white solid.
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, brs), 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, brs).
Example 280 4-[({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} oxy) methyl] benzoic acid methyl dihydrochloride 1) [5-{[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetic acid (300 mg, 0.703 mmol) and 4 4-[({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-- by the same method as in Example 169-1) from methyl (bromomethyl) benzoate (209 mg, 0.914 mmol). Methyl isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} oxy) methyl] benzoate (258 mg, 64% yield) was obtained as a white powder.
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) 4-[({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} oxy) methyl ] In the same manner as in Example 2-3) from methyl benzoate (68.6 mg, 0.119 mmol), 4-[({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4- Methylphenyl) pyridin-3-yl] acetyl} oxy) methyl] benzoic acid methyl dihydrochloride (60 mg, 92% yield) was obtained as a white powder.
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, brs).

Example 281 2-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -5-methylbenzoic acid dihydrochloride 1) 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 the same manner as in Example 9-1), 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.
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-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -5-methylbenzoic acid 2-{[5- (aminomethyl) -6-isobutyl-2-methyl-4] from the acid (168 mg, 0.316 mmol) in the same manner as in Example 2-3).
-(4-Methylphenyl) pyridin-3-yl] methoxy} -5-methylbenzoic acid dihydrochloride (150 mg, 94% yield) was obtained as a white powder.
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, brs).
Example 282 Methyl 3-[({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} oxy) methyl] benzoate dihydrochloride 1) [5-{[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetic acid (466 mg, 1.09 mmol) and 3 3-[({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-- by the method similar to Example 169-1) from methyl- (bromomethyl) benzoate (325 mg, 1.42 mmol). Methyl isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} oxy) methyl] benzoate (401 mg, 64% yield) was obtained as a white powder.
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, brs), 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) 3-[({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} oxy) methyl ] In the same manner as in Example 2-3) from methyl benzoate (84.6 mg, 0.147 mmol), 3-[({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4- Methylphenyl) pyridin-3-yl] acetyl} oxy) methyl] benzoic acid methyl dihydrochloride (80 mg, 99% yield) was obtained as a white powder.
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, brs).

Example 283 2-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -4-methoxybenzamide dihydrochloride 1) 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) by the same method as in Example 3-1), {[5-{[2- (aminocarbonyl) -5-methoxyphenoxy] methyl} -2-isobutyl-6-methyl-4- ( 4-Methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (0.31 g, yield 82%) was obtained as a white powder.
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 (1H, brs), 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, brs), 8.18 (1H, d, J = 8.9 Hz).
2) {[5-{[2- (Aminocarbonyl) -5-methoxyphenoxy] methyl} -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamic acid tert 2-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine from 2-butyl (0.25 g, 0.46 mmol) in the same manner as in Example 2-3) -3-yl] methoxy} -4-methoxybenzamide dihydrochloride (0.22 g, 91% yield) was obtained 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), 2.35 (3H, s), 2.78 (3H, brs), 3.01 (2H , brs), 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, brs), 7.15-7.35 (4H, m), 7.74 (1H, d, J = 8.7 Hz), 8.28 (3H, brs).
Example 284 3-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -2-naphthoic acid methyl dihydrochloride 1) { [5- (Hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (1.0 g, 2.51 mmol) and 3-hydroxy-2 3-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl from methyl naphthoate (609 mg, 3.01 mmol) in the same manner as in Example 214-1) Methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -2-naphthoate (1.07 g, yield 73%) was obtained as a white powder.
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, brs), 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) 3-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -2-naphthoic acid 3-([5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine-] was prepared from methyl (220 mg, 0.378 mmol) in the same manner as in Example 2-3). Methyl 3-yl] methoxy} -2-naphthoate dihydrochloride (178 mg, 84% yield) was obtained as a white powder.
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, brs).

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 methyl ester (817 mg , 1.40 mmol) to 3-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methyl) by a method similar to that in Example 9-1). Phenyl) pyridin-3-yl] methoxy} -2-naphthoic acid (860 mg, 100% yield) was obtained as a white powder.
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, brs), 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-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -2-naphthoic acid (320 mg, 0.563 mmol) to 3-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine-3] in the same manner as in Example 2-3). -Il] methoxy} -2-naphthoic acid dihydrochloride (300 mg, 98% yield) was obtained as a white powder.
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, brs).
Example 286 2-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -5-methylbenzamide dihydrochloride 1) 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) and {[5-{[2- (aminocarbonyl) -4-methylphenoxy] methyl} -2-isobutyl-6-methyl-4- (4) by the same method as in Example 3-1). -Methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (250 mg, 91% yield) was obtained as a white powder.
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) {[5-{[2- (Aminocarbonyl) -4-methylphenoxy] methyl} -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamic acid tert 2-([5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine] from 2-butyl (230 mg, 0.433 mmol) in the same manner as in Example 2-3) -3-yl] methoxy} -5-methylbenzamide dihydrochloride (200 mg, 92% yield) was obtained as a white powder.
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, brs).

Example 287 N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetamide dihydrochloride
{[5-Amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (192 mg, 0.5 mmol) and acetyl chloride (53 μL, 0.75 mmol) in the same manner as in Example 223, 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.
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, brs), 3.82 (2H, s), 7.17 (2H, d, J = 7.5 Hz), 7.33 (2H, d, J = 7.5 Hz), 8.31 (3H, brs), 9.50 (1H, brs).
Example 288 N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] propanamide dihydrochloride
{[5-Amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (192 mg, 0.5 mmol) and propionyl chloride (65 μL, 0.75 mmol) to N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] propanamide dihydrochloride in the same manner as in Example 223 (195 mg, 93% yield) was obtained as a white powder.
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, brs), 3.83 (2H, s), 7.17 (2H, d, J = 7.8 Hz), 7.32 (2H , d, J = 7.8 Hz), 8.37 (3H, brs), 9.49 (1H, brs).

Example 289 N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -2,2-dimethylpropanamide dihydrochloride
{[5-Amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (192 mg, 0.5 mmol) and pivaloyl chloride (92 μL , 0.75 mmol) by the same method as in Example 223, N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -2, 2-Dimethylpropanamide dihydrochloride (184 mg, yield 72%) was obtained as a white powder.
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, brs), 3.81 (2H, s), 7.14 (2H, d, J = 8.1 Hz), 7.28 (2H, d, J = 8.1 Hz), 8.28 (3H, brs), 8.95 (1H, brs).
Example 290 N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] cyclopropanecarboxamide dihydrochloride
{[5-Amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (192 mg, 0.5 mmol) and cyclopropanecarbonyl chloride (68 μL , 0.75 mmol) and N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] cyclopropanecarboxamide by a method similar to that in Example 223. Dihydrochloride (170 mg, 85% yield) was obtained as a white powder.
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, brs), 3.81 (2H, s), 7.16 (2H, d, J = 7.5 Hz ), 7.32 (2H, d, J = 7.5 Hz), 8.32 (3H, brs), 9.70 (1H, brs).

Example 291 N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] cyclopentanecarboxamide dihydrochloride
{[5-Amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (192 mg, 0.5 mmol) and cyclopentanecarbonyl chloride (68 μL , 0.75 mmol) by the same method as in Example 223, 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.
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, brs), 3.81 (2H, s), 7.15 (2H, d, J =
7.8 Hz), 7.30 (2H, d, J = 7.8 Hz), 8.32 (3H, brs), 9.39 (1H, brs).
Example 292 N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] pyridine-2-carboxamide trihydrochloride
{[5-Amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (192 mg, 0.5 mmol) and pyridine-2-carbonyl chloride ( 106 mg,
0.75 mmol) and 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.
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, brs), 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, brs), 8.61 (1H, d, J = 4.8 Hz), 10.33 (1H, s).

Example 293 N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] nicotinamide trihydrochloride
{[5-Amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (192 mg, 0.5 mmol) and nicotinoyl chloride (106 mg, 0.75 mmol) and N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] nicotinamide trihydrochloride in the same manner as in Example 223 The salt (225 mg, 94% yield) was obtained as a white powder.
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, brs), 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, brs), 8.85 (1H, d, J = 3.6 Hz), 8.94 (1H, s),
10.90 (1H, brs).
Example 294 N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] isonicotinamide trihydrochloride
{[5-Amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (192 mg, 0.5 mmol) and isonicotinoyl chloride (106 mg , 0.75
mmol) and N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] isonicotinamide trihydrochloride in the same manner as in Example 223 Salt (215 mg,
Yield 91%) was obtained as a white powder.
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, brs), 3.88 (2H, s), 7.28 (4H, s), 7.87 (2H, d, J = 6.0
Hz), 8.51 (3H, brs), 8.88 (2H, d, J = 6.0 Hz), 11.20 (1H, brs).

Example 295 {[2-Isobutyl-6-methyl-4- (4-methylphenyl) -5- (phenoxymethyl) pyridin-3-yl] methyl} amine dihydrochloride 1) {[5- (hydroxymethyl) Example 214 from tert-butyl-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) -1), and tert-butyl {[2-isobutyl-6-methyl-4- (4-methylphenyl) -5- (phenoxymethyl) pyridin-3-yl] methyl} carbamate (270 mg Yield 56%) as a colorless oil.
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, brs), 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) Examples from tert-butyl {[2-isobutyl-6-methyl-4- (4-methylphenyl) -5- (phenoxymethyl) pyridin-3-yl] methyl} carbamate (0.27 g, 0.569 mmol) In the same manner as in 2-3), {[2-isobutyl-6-methyl-4- (4-methylphenyl) -5- (phenoxymethyl) pyridin-3-yl] methyl} amine dihydrochloride (132 mg Yield 51%) as a colorless oil.
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, brs), 3.12 (2H , brs), 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, brs).
Example 296 6-({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} methyl) nicotinamide trihydrochloride 1) 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) to {[5-({[5- (aminocarbonyl) pyridin-2-yl] methoxy} methyl) -2-isobutyl-6-methyl-4- Obtained tert-butyl (4-methylphenyl) pyridin-3-yl] methyl} carbamate (370 mg, 77% yield) as a white solid.
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, brs), 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) {[5-({[5- (Aminocarbonyl) pyridin-2-yl] methoxy} methyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} In the same manner as in Example 2-3), from tert-butyl carbamate (0.37 g, 0.695 mmol), 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.
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, brs), 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, brs), 8.99 (1H, brs).

Example 297 4-{[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} isophthalic acid dihydrochloride 1) {[5- ( Hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (1.00 g, 2.51 mmol) and dimethyl 4-hydroxyisophthalate (528 mg , 2.51 mmol) to 4-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methyl) by a method similar to that in Example 214-1). Phenyl) pyridin-3-yl] methoxy} isophthalate dimethyl (1.12 g, 75% yield) was obtained as a white solid.
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, brs), 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) 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) and 4-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4- Methylphenyl) pyridin-3-yl] methoxy} isophthalic acid (310 mg, 90% yield) was obtained as a white solid.
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, brs), 3.13 (2H, brs), 4.16 (2H, brs), 4.94 (2H, brs), 6.76 (1H, brs), 7.07 (2H, brs), 7.22 (2H, d, J = 7.7 Hz), 8.01 (1H, brs), 8.53 (1H , brs).
3) 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) and 4-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] in the same manner as in Example 2-3). Methoxy} isophthalic acid dihydrochloride (256 mg, 86% yield) was obtained as a white solid.
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, brs), 3.08 (2H , brs), 3.83 (2H, brs), 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, brs).
Example 298 2-{(E) -2- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] vinyl} methyl benzoate dihydrochloride
2-{(E) -2- [5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] vinyl} benzoate 2-((E) -2- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (2) by the same method as in Example 2-3) from methyl acid (0.10 g, 0.189 mmol). 4-Methylphenyl) pyridin-3-yl] vinyl} methyl benzoate dihydrochloride (31.4 mg, 33% yield) was obtained as a white solid.
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, brs), 3.06 (2H , brs), 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, brs).

Example 299 4- [1-({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) ethyl] benzoic acid dihydrochloride Salt 1) 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (1.00 g, 2.42 mmol) and 4- (1-hydroxy 5-([((tert-butoxycarbonyl) amino] methyl) -6-isobutyl-2-methyl-4- (ethyl) benzoic acid methyl (486 mg, 2.42 mmol) by a method similar to that in Example 247-1). 1- [4- (methoxycarbonyl) phenyl] ethyl (1.02 g, yield 73%) of (4-methylphenyl) nicotinic acid was obtained as a colorless oil.
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, brs), 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) 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 1- [4- (methoxycarbonyl) phenyl] ethyl (1.02 g , 1.77 mmol
) To 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.
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 , brs), 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-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy ) Ethyl] benzoic acid (0.30 g, 0.522 mmol) in the same manner as in Example 2-3), 4- [1-({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-Methylphenyl) pyridin-3-yl] carbonyl} oxy) ethyl] benzoic acid dihydrochloride (259 mg, 93% yield) was obtained as a white solid.
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, brs), 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, brs).
Example 300 [(2-Isobutyl-6-methyl-4- (4-methylphenyl) -5-{[2- (methylthio) phenoxy] methyl} pyridin-3-yl) methyl] amine dihydrochloride 1) { [5- (Hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (1.50 g, 3.76 mmol) and 2- (methylthio) [(2-Isobutyl-6-methyl-4- (4-methylphenyl) -5-{[2- (methylthio) phenoxy] was prepared from phenol (573 mg, 3.76 mmol) in the same manner as in Example 214-1). [Methyl} pyridin-3-yl) methyl] carbamate tert-butyl (1.37 g, 70% yield) was obtained as a colorless oil.
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, brs), 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) 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) to [(2-isobutyl-6-methyl-4- (4-methylphenyl) -5-{[2- (methylthio) phenoxy] methyl} pyridine by the same method as in Example 2-3). -3-yl) methyl] amine dihydrochloride (112 mg,
(69% yield) was obtained as a white solid.
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 , brs), 3.15 (2H, brs), 3.83 (2H, brs), 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, brs).

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- (methylthio) phenoxy] methyl} pyridin-3-yl) methyl] carbamate (0.38 g, 0.730 mmol) to [(2-isobutyl-6-methyl-4- (4-methylphenyl) -5-{[2- (methylsulfonyl) phenoxy] methyl} pyridine- Obtained tert-butyl 3-yl) methyl] carbamate (330 mg, 81% yield) as a white solid.
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, brs), 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) 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)
To (2-3) in the same manner as in Example 2-3) [(2-isobutyl-6-methyl-4- (4-methylphenyl) -5-{[2- (methylsulfonyl) phenoxy] methyl} pyridine-3- (Il) methyl] amine dihydrochloride (227 mg, 59% yield) was obtained as a white solid.
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, brs), 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, brs).
Example 302 [(2-Isobutyl-6-methyl-4- (4-methylphenyl) -5-{[2- (methylsulfinyl) phenoxy] methyl} pyridin-3-yl) methyl] amine dihydrochloride 1) [(2-Isobutyl-6-methyl-4- (4-methylphenyl) -5-{[2- (methylthio) phenoxy] methyl} pyridin-3-yl) methyl] carbamate tert-butyl (0.47 g, 0.902 mmol) in a mixed solution of methanol (10 mL) and water (10 mL) was added sodium periodate (377 mg, 1.76 mmol), and the mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained after evaporation of the solvent under reduced pressure was purified by silica gel column chromatography to obtain [(2-isobutyl-6-methyl-4- (4-methylphenyl) -5-{[2- (methyl Sulfinyl) phenoxy] methyl} pyridin-3-yl) methyl] carbamate tert-butyl (164 mg, 33% yield) was obtained 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, brs), 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) tert-Butyl [(2-isobutyl-6-methyl-4- (4-methylphenyl) -5-{[2- (methylsulfinyl) phenoxy] methyl} pyridin-3-yl) methyl] carbamate (164 mg, 0.306 mmol) and [(2-isobutyl-6-methyl-4- (4-methylphenyl) -5-{[2- (methylsulfinyl) phenoxy] methyl] in the same manner as in Example 2-3). } Pyridin-3-yl) methyl] amine dihydrochloride (97.4 mg, 62% yield) was obtained as a white solid.
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 , brs), 3.06 (2H, brs), 3.82 (2H, brs), 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, brs).

Example 303 3-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -2-naphthamide dihydrochloride 1) 3- { [5-{[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -2-naphthoic acid (500 mg, 0.879 mmol) to {[5-({[3- (aminocarbonyl) -2-naphthyl] oxy} methyl) -2-isobutyl-6-methyl-4- (4) in the same manner as in Example 3-1). -Methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (230 mg, yield 46%) was obtained as a white powder.
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) {[5-({[3- (Aminocarbonyl) -2-naphthyl] oxy} methyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamine 3-{[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) was prepared from tert-butyl acid (230 mg, 0.405 mmol) in the same manner as in Example 2-3). ) Pyridin-3-yl] methoxy} -2-naphthamide dihydrochloride (200 mg, 91% yield) was obtained as a white powder.
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, brs).
Example 304 5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) -N-phenylnicotinamide
5-({[(Benzyloxy) carbonyl] amino} methyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (523 mg, 1.17 mmol) in tetrahydrofuran (5 ml) in oxalyl Chloride (120 μL, 1.4 mmol) was added and 1 drop of N, N-dimethylformamide was added. The reaction solution was stirred for 3 hours, the reaction solution was concentrated, and the residue was dissolved in tetrahydrofuran (5 ml). Aniline (91 μL, 1.0 mmol) and triethylamine (210 μL, 1.5 mmol) were added and 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 saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain an oil. To a solution of the oily substance in ethanol (5 ml) was added 10% palladium-carbon (50 mg), and the mixture was stirred at room temperature for 3 hours in a hydrogen atmosphere. The reaction solution was filtered and the filtrate was concentrated, and the resulting oil was crystallized from hexane and diethyl ether to give 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) -N-phenylnicotinamide (320 mg, 83% yield) was obtained 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, brs), 7.04-7.26 (9H, m).

Example 305 3-{[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1-methyl-1H-pyrazole-4-carboxylic acid Methyl acid dihydrochloride 1) {[5- (hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (3.00 g, 7.52 mmol) and ethyl 3-hydroxy-1-methyl-1H-pyrazole-4-carboxylate (1.28 g, 7.52 mmol) in the same manner as in Example 183-1), 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%) as a colorless oil.
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- In the same manner as in Example 9-1), ethyl 1H-pyrazole-4-carboxylate (3.23 g, 5.86 mmol) was used as 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 .
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, brs), 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 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine-3. -Iyl] methoxy} -1-methyl-1H-pyrazole-4-carboxylate methyl ester (470 mg, 91% yield) was obtained 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, brs), 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) 3-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1-methyl- In the same manner as in Example 2-3), methyl 1H-pyrazole-4-carboxylate (0.47 g, 0.876 mmol) was used to produce 3-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- Methyl (4-methylphenyl) pyridin-3-yl] methoxy} -1-methyl-1H-pyrazole-4-carboxylate dihydrochloride (382 mg, 85% yield) was obtained as a white solid.
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, brs), 3.16 (2H , brs), 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, brs).
Example 306 3-{[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1-methyl-1H-pyrazole-4-carboxylic acid Acid dihydrochloride
3-{[5-{[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1-methyl-1H- In the same manner as in Example 2-3), pyrazole-4-carboxylic acid (0.30 g, 0.574 mmol) was subjected to 3-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4- Methylphenyl) pyridin-3-yl] methoxy} -1-methyl-1H-pyrazole-4-carboxylic acid dihydrochloride (268 mg, 94% yield) was obtained as a white solid.
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, brs), 3.14 (2H , brs), 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, brs).

Example 307 3-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1-methyl-1H-pyrazole-4-carboxamide Dihydrochloride 1) 3-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1 {-(5-({[4- (aminocarbonyl) -1-methyl-1H] by the same method as in Example 3-1) from 1-methyl-1H-pyrazole-4-carboxylic acid (0.50 g, 0.957 mmol). -Pyrazol-3-yl] oxy} methyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (307 mg, 61% yield) Was obtained as a colorless oil.
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, brs), 4.98 (2H, s), 5.30 (1H, brs), 6.43 (1H, brs), 7.01 (2H, d, J = 8.1 Hz), 7.20 (2H, d , J = 7.7 Hz), 7.69 (1H, s).
2) {[5-({[4- (Aminocarbonyl) -1-methyl-1H-pyrazol-3-yl] oxy} methyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridine 3-{[5- (Aminomethyl) -6-isobutyl-2-methyl] from tert-butyl-3-methyl] carbamate (307 mg, 0.588 mmol) in the same manner as in Example 2-3) -4- (4-Methylphenyl) pyridin-3-yl] methoxy} -1-methyl-1H-pyrazole-4-carboxamide dihydrochloride (253 mg, yield 87%) was obtained as a white solid.
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, brs), 3.17 (2H , brs), 3.63 (3H, s), 3.82 (2H, d, J = 4.7 Hz), 4.93 (2H, s), 6.37 (1H, brs), 7.08 (1H, brs), 7.29 (2H, d, J = 7.9 Hz), 7.35 (2H, d, J =
8.1 Hz), 7.91 (1H, s), 8.42 (3H, brs).
Example 308 (3-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1-methyl-1H-pyrazole-4- Yl) acetic acid dihydrochloride 1) {[5- (hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (1.00 g, 2.51 mmol), (3-hydroxy-1-methyl-1H-pyrazol-4-yl) methyl acetate (0.43 g, 2.51 mmol), tributylphosphine (0.61 g, 3.01 mmol) in tetrahydrofuran (20 mL) , 1 ′-(Azodicarbonyl) dipiperidine (0.76 g, 3.01 mmol) was added and stirred at room temperature for 30 minutes. After filtering the reaction solution, the residue obtained by distilling off the solvent of the filtrate under reduced pressure 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] methoxy} -1-methyl-1H-pyrazol-4-yl) acetate methyl (1.20 g, 86% yield) Obtained as a colorless oil. Next, (3-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1- (3-{[5-{[(tert-butoxycarbonyl) amino] methyl) was prepared from methyl-1H-pyrazol-4-yl) acetate methyl (1.20 g, 2.18 mmol) in the same manner as in Example 9-1). } -6-Isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1-methyl-1H-pyrazol-4-yl) acetic acid (173 mg, 15% yield) Obtained as a white solid.
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, brs), 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) (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) and (3-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine-3-] in the same manner as in Example 2-3). [Il] methoxy} -1-methyl-1H-pyrazol-4-yl) acetic acid dihydrochloride (84.2 mg, 51% yield) was obtained as a white solid.
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, brs), 3.00 (2H , brs), 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, brs).

Example 309 N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -3- (1H-tetrazol-5-yl) benzamide dihydrochloride salt
{[5-Amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (383 mg, 1.0 mmol) in tetrahydrofuran (5 ml) solution After adding 3-cyanobenzoyl chloride (245 mg, 1.5 mmol), triethylamine (280 μL,
2.0 mmol) was added and stirred for 18 hours. A saturated aqueous sodium carbonate solution (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel 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 dimethyl sulfoxide (3 mL) solution of the oil, and the mixture was stirred at 100 ° C. for 3 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain an oil. To a solution of the oily substance in ethyl acetate (2 mL) was added 4N hydrogen chloride-ethyl acetate solution (2 mL), and the mixture was stirred at room temperature for 3 hr. The residue obtained by evaporating the solvent under reduced pressure was crystallized from hexane, and N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl ] -3- (1H-tetrazol-5-yl) benzamide dihydrochloride (86 mg, 16% yield) was obtained as a white powder.
¹ H-NMR (DOSO-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, brs), 8.34 (1H, brs), 10.10 (1H, brs).
Example 310 2-{[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -3-methylbenzoic acid methyl dihydrochloride 1) {[5- (hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} tert-butyl carbamate (1.0 g, 2.51 mmol) and 2-hydroxy- 2-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2 was prepared from methyl 3-methylbenzoate (500 mg, 3.01 mmol) in the same manner as in Example 214-1). -Methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -3-methylbenzoate (600 mg, 44% yield) was obtained as a white powder.
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, brs), 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-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -3-methylbenzoate 2-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine from methyl acid (240 mg, 0.439 mmol) in the same manner as in Example 2-3) Methyl-3-yl] methoxy} -3-methylbenzoate dihydrochloride (215 mg, 94% yield) was obtained as a white powder.
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, brs).

Example 311 2- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -N-cyclopropylacetamide dihydrochloride 1) [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-dimethyl A mixture of formamide (5 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain {[5- [2- (cyclopropylamino) -2-oxoethyl] -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridine-3- [Il] methyl} carbamate tert-butyl (150 mg, 69% yield) was obtained 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, brs), 6.94 (2H, d,
J = 7.9 Hz), 7.23 (2H, d, J = 7.9 Hz).
2) tert-Butyl {[5- [2- (cyclopropylamino) -2-oxoethyl] -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate ( 120 mg, 0.258 mmol) to 2- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl by the same method as in Example 2-3). ] -N-cyclopropylacetamide dihydrochloride (100 mg, 89% yield) was obtained as a white powder.
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, brs).
Example 312 {[2-Isobutyl-6-methyl-4- (4-methylphenyl) -5- (2-morpholin-4-yl-2-oxoethyl) pyridin-3-yl] methyl} amine dihydrochloride 1 ) [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) by the same method as in Example 311-1), {[2-isobutyl-6-methyl-4- (4-methylphenyl) -5- (2-morpholin-4-yl- 2-Oxoethyl) pyridin-3-yl] methyl} carbamate tert-butyl (50 mg, 22% yield) was obtained as a white powder.
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, brs), 6.98 (2H, d, J = 7.9 Hz), 7.22 (2H, d, J = 7.9 Hz ).
2) 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) and {[2-isobutyl-6-methyl-4- (4-methylphenyl) -5- (2-morpholin-4-yl-2] by the same method as in Example 2-3). -Oxoethyl) pyridin-3-yl] methyl} amine dihydrochloride (40 mg, 94% yield) was obtained as a white powder.
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, brs).

Example 313 2- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -N-benzylacetamide dihydrochloride 1) [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 ) To {[5- [2- (benzylamino) -2-oxoethyl] -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridine-) in the same manner as in Example 311-1). Obtained tert-butyl 3-yl] methyl} carbamate (150 mg, 62% yield) as a white powder.
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, brs), 4.34 (2H, d, J = 5.8 Hz) ), 5.45 (1H, brs), 6.88 (2H,
d, J = 7.9 Hz), 7.10-7.20 (4H, m), 7.25-7.35 (3H, m).
2) {[5- [2- (Benzylamino) -2-oxoethyl] -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} tert-butyl carbamate (130 mg, 0.252 mmol) to 2- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] by the same method as in Example 2-3). -N-benzylacetamide dihydrochloride (125 mg, 100% yield) was obtained as a white powder.
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, brs).
Example 314 [(2-Isobutyl-6-methyl-4- (4-methylphenyl) -5-{[2- (1H-tetrazol-5-yl) phenoxy] methyl} pyridin-3-yl) methyl] amine Dihydrochloride 1) {[5- (hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (0.67 g, 1.68 mmol) And 2-hydroxybenzonitrile (221 mg, 1.85 mmol) in the same manner as in Example 214-1), {[5-[(2-cyanophenoxy) methyl] -2-isobutyl-6-methyl-4- There was obtained tert-butyl (4-methylphenyl) pyridin-3-yl] methyl} carbamate (586 mg, yield 70%) as a colorless oil.
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,
brs), 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) {[5-[(2-Cyanophenoxy) methyl] -2-isobutyl-6-methyl-4- (4-methylphenyl)
[(2-Isobutyl-6-methyl-4- (4-methylphenyl)] by a method similar to that in Example 251-1) from tert-butyl pyridin-3-yl] methyl} carbamate (586 mg, 1.17 mmol). ) -5-{[2- (1H-tetrazol-5-yl) phenoxy] methyl} pyridin-3-yl) methyl] carbamate tert-butyl (400 mg, 63% yield) was obtained as a white solid.
¹ H-NMR (CDCl ₃ ) δ: 0.99 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.17-2.28 (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,
brs), 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] carbamic acid [(2-Isobutyl-6-methyl-4- (4-methylphenyl) -5-{[2- (1H]] was prepared in the same manner as in Example 2-3) from tert-butyl (400 mg, 0.737 mmol). -Tetrazol-5-yl) phenoxy] methyl} pyridin-3-yl) methyl] amine dihydrochloride (327 mg, 86% yield) was obtained as a white solid.
¹ H-NMR (DMSO-d ₆ ) δ: 1.01 (6H, d, J = 6.6 Hz), 2.17-2.29 (4H, m), 2.88 (3H, brs), 3.16 (2H, brs), 3.80 (2H , brs), 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, brs).

Example 315 5-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methylene} -1,3-thiazolidine-2,4-dione Dihydrochloride 1) {[5-formyl-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (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 heated and stirred at 80 ° C. for 3.5 days. After cooling to room temperature, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain {[5-[(2,4-dioxo-1,3-thiazolidine-5-ylidene) methyl]. Tert-Butyl-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (400 mg, 53% yield) was obtained 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, brs), 6.96 (2H, d, J = 8.1 Hz), 7.19 (2H, d , J = 8.1 Hz), 7.51 (1H, s) .2) {[5-[(2,4-Dioxo-1,3-thiazolidine-5-ylidene) methyl] -2-isobutyl-6-methyl-4 -(4-Methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (157 mg, 0.316 mmol) in a similar manner to Example 2-3) -6-Isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methylene} -1,3-thiazolidine-2,4-dione dihydrochloride (155 mg, 100% yield) Obtained as a white powder.
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, brs).
Example 316 2-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -3-methylbenzoic acid dihydrochloride 1) 2 -{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -3-methylbenzoate ( 300 mg, 0.563 mmol) to 2-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4) by the same method as in Example 9-1). -Methylphenyl) pyridin-3-yl] methoxy} -3-methylbenzoic acid (280 mg, 93% yield) was obtained as a white powder.
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, brs), 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-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -3-methylbenzoate Acid (58.4 mg, 0.110 mmol)
To 2-([5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -3 by a method similar to that in Example 2-3). -Methylbenzoic acid dihydrochloride (55 mg, 100% yield) was obtained as a white powder.
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, brs).

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-chlorobenzoate methyl (0.57 g, 1.0 mmol) in the same manner as in Example 43-1), 2-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4- Methylphenyl) pyridin-3-yl] methoxy} -5-chlorobenzoic acid (0.54 g, 97% yield) was obtained as a white powder.
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) 2-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -5-chlorobenzoate {[5-{[2- (aminocarbonyl) -4-chlorophenoxy] methyl} -2-isobutyl-6-methyl from the acid (0.28 g, 0.51 mmol) by the same method as in Example 3-1). Tert-Butyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (0.20 g, 71% yield) was obtained as a white powder.
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, brs), 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, brs), 8.18 (1H, d, J = 2.8 Hz).
3) {[5-{[2- (Aminocarbonyl) -4-chlorophenoxy] methyl} -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamic acid tert 2-([5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl)] from 2-butyl (0.17 g, 0.31 mmol) in the same manner as in Example 2-3). Pyridin-3-yl] methoxy} -5-chlorobenzamide dihydrochloride (0.16 g, 99% yield) was obtained as a white powder.
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, brs), 3.08 (2H , brs), 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, brs), 7.55 (1H, d, J = 2.7 Hz), 8.36 (3H, brs).
Example 318 2-{[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -5-chlorobenzoic acid dihydrochloride
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) and 2-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine-3] in the same manner as in Example 276-3). -Il] methoxy} -5-chlorobenzoic acid dihydrochloride (0.16 g, 85% yield) was obtained 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), 2.36 (3H, s), 2.83 (3H, brs), 3.05 (2H , brs), 3.75-3.90 (2H, m), 4.77 (2H, brs), 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, brs).

Example 319 4 '-[({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] biphenyl-4-carboxyl Acid dihydrochloride 1) 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (1.82 g, 4.41 mmol) and 4-bromo In the same manner as in Example 169-1), from benzyl bromide (1.10 g, 4.41 mmol), 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4- Methylphenyl) nicotinic acid 4-bromobenzyl (1.92 g, yield 75%) was obtained as a colorless oil.
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, brs), 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) 4-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 4-bromobenzyl (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 a mixed solution of water (2.5 mL) was stirred under an argon atmosphere for 12 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained after evaporation of the solvent under reduced pressure was purified by silica gel column chromatography to give 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4 -Methylphenyl) nicotinic acid [4 '-(methoxycarbonyl) biphenyl-4-yl] methyl (570 mg, 48% yield) was obtained 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, brs), 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) 5-{[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid [4 '-(methoxycarbonyl) biphenyl-4-yl] methyl (570 mg, 0.895 mmol) and 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.
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,
brs), 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-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) 4 '-[({[5- (aminomethyl) -6-isobutyl-2-methyl-] was prepared from methyl] biphenyl-4-carboxylic acid (380 mg, 0.610 mmol) in the same manner as in Example 2-3). 4- (4-Methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] biphenyl-4-carboxylic acid dihydrochloride (255 mg, 70% yield) was obtained as a white solid.
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, brs), 2.92 (2H , brs), 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, brs).
Example 320 5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid pyridin-4-ylmethyl trihydrochloride 1) 5-{[(tert-butoxycarbonyl) amino] Methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (0.50 g, 1.21 mmol) and 4- (chloromethyl) pyridine hydrochloride (0.20 g, 1.21 mmol) and potassium carbonate (0.42 g, 3.0 mmol) in the same manner as in Example 169-1), 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotine Acid pyridin-4-ylmethyl (322 mg, 53% yield) was obtained as a colorless oil.
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, brs), 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) Examples from 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid pyridin-4-ylmethyl (322 mg, 0.639 mmol) In the same manner as in 2-3), 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid pyridin-4-ylmethyl trihydrochloride (260 mg, yield 79 %) As a white solid.
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, brs), 2.89 (2H , brs), 3.81 (2H, d, J = 5.5 Hz), 5.29 (2H, s), 7.17-7.24 (4H, m), 7.60 (2H, brs), 8.35 (3H, brs), 8.83-8.84 ( 2H, brs).

Example 321 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid pyridin-3-ylmethyl trihydrochloride 1) 5-{[(tert-butoxycarbonyl) amino] Methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (0.50 g, 1.21 mmol) and 3- (bromomethyl) pyridine hydrobromide (0.46 g, 1.81 mmol) and potassium carbonate (0.50 g, 3.6 mmol) to 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) by a method similar to that of Example 169-1) ) Pyridin-3-ylmethyl nicotinate (454 mg, 74% yield) was obtained as a colorless oil.
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, brs), 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) Examples from 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid pyridin-3-ylmethyl (454 mg, 0.903 mmol) In the same manner as in 2-3), 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid pyridin-3-ylmethyl trihydrochloride (183 mg, yield 39) %) As a white solid.
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, brs), 8.67 (1H, s), 8.90 (1H, d, J = 5.5 Hz).
Example 322 2-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -3-methoxybenzoic acid methyl dihydrochloride 1) {[5- (Hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (0.80 g, 2.0 mmol) and 3-methoxysalicylic acid 2-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4-methyl (0.55 g, 3.0 mmol) was prepared in the same manner as in Example 106-1). Methyl (4-methylphenyl) pyridin-3-yl] methoxy} -3-methoxybenzoate (0.62 g, 55% yield) was obtained as a white powder.
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) 2-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -3-methoxybenzoate 2-([5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine] from methyl acid (0.19 g, 0.34 mmol) in the same manner as in Example 274-2) Methyl-3-yl] methoxy} -3-methoxybenzoate dihydrochloride (0.12 g, 66% yield) was obtained 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), 2.94 (3H, brs), 3.00-3.20 (2H, m), 3.51 (3H, s), 3.63 (3H, s), 3.72 (2H, brs), 4.88 (2H, brs), 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, brs).

Example 323 2-({[5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methyl} thio) methyl benzoate dihydrochloride 1) Methanesulfonic acid [5-{[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methyl (2.0 g, 4.7 mmol) And methyl thiosalicylate (757 mg, 45 mmol) in the same manner as in Example 33-1), 2-({[5-{[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- Methyl (4-methylphenyl) -6-neopentylpyridin-3-yl] methyl} thio) benzoate (1.46 g, 63% yield) was obtained as a powder.
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, brs), 7.04-7.18 (6H, m), 7.32-7.38 (1H, m), 7.91-7.95 (1H, m).
2) 2-({[5-{[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methyl} thio) benzoic acid 2-({[5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neo] from methyl acid (300 mg, 0.533 mmol) in the same manner as in Example 2-3). Pentylpyridin-3-yl] methyl} thio) methyl benzoate dihydrochloride (254
mg, yield 89%) was obtained as a powder.
¹ H-NMR (DMSO-d ₆ ) δ: 1.03 (9H, s), 2.34 (3H, s), 2.83 (3H, s), 3.18 (2H, brs), 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, brs).
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) methyl benzoate ( 1.0 g, 1.78 mmol) to 4-({[5-{[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) by a method similar to that in Example 9-1). ) -6-Neopentylpyridin-3-yl] methyl} thio) benzoic acid (897 mg, 92% yield) was obtained as a white solid.
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, brs), 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) 4-({[5-{[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methyl} thio) benzoic acid 2-({[5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentyl] from the acid (200 mg, 0.364 mmol) in the same manner as in Example 2-3). Pyridin-3-yl] methyl} thio) benzoic acid dihydrochloride (158 mg, 83% yield) was obtained as a white powder.
¹ H-NMR (DMSO-d ₆ ) δ: 1.03 (9H, s), 2.34 (3H, s), 2.81 (3H, s), 3.15 (2H, brs), 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, brs).

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) benzoic acid (500 mg , 0.911 mmol) and 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.
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, brs), 5.45 (1H, brs), 6.68 (1H, brs), 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) 4-({[5-{[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methyl} thio) benzamide (200 mg, 0.365 mmol) to 2-({[5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylpyridine] in the same manner as in Example 2-3). -3-yl] methyl} thio) benzamide dihydrochloride (160 mg, 84% yield) was obtained as a white powder.
¹ H-NMR (DMSO-d ₆ ) δ: 1.03 (9H, s), 2.37 (3H, s), 2.76 (3H, s), 3.17 (2H, brs), 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, brs).
Example 326 2-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -3-methylbenzamide dihydrochloride 1) 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) and {[5-{[2- (aminocarbonyl) -6-methylphenoxy] methyl} -2-isobutyl-6-methyl-4- (4) in the same manner as in Example 3-1). -Methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (190 mg, yield 95%) was obtained as a white powder.
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, brs), 4.81 (2H, s), 5.80 (1H, brs), 6.40 (1H, brs), 6.65 (2H, s), 7.02-7.23 (4H, m), 7.56 (1H, s).
2) {[5-{[2- (aminocarbonyl) -6-methylphenoxy] methyl} -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamic acid tert 2-([5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine] from 2-butyl (150 mg, 0.282 mmol) in the same manner as in Example 2-3) -3-yl] methoxy} -3-methylbenzamide dihydrochloride (100 mg, 70% yield) was obtained as a white powder.
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, brs), 7.53 (1H, brs), 8.52 (3H, brs).

Example 327 2- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -N-phenylacetamide dihydrochloride 1) [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) To [{5- (2-anilino-2-oxoethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] in the same manner as in Example 311-1). Obtained tert-butyl methyl} carbamate (220 mg, 94% yield) as a white powder.
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, brs), 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) tert-butyl {[5- (2-anilino-2-oxoethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (210 mg, 0.419 mmol) to 2- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -N— in the same manner as in Example 2-3). Phenylacetamide dihydrochloride (200 mg, 100% yield) was obtained as a white powder.
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, brs), 10.20 (1H, s).
Example 328 N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] cyclohexanecarboxamide dihydrochloride
{[5-Amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (192 mg, 0.5 mmol) and cyclohexanecarbonyl chloride (100 μL, 0.75 mmol), and N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] cyclohexanecarboxamide dihydrochloride in the same manner as in Example 223 (230 mg, 98% yield) was obtained as a white powder.
¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.00-1.25 (6H, m), 1.41 (2H, brs), 1.59 (2H, brs), 2.08-2.22 (2H, m), 2.37 (3H, s), 2.53 (3H, s), 3.03 (2H, brs), 3.81 (2H, s), 7.14 (2H, d, J = 7.8 Hz), 7.30 (2H, d, J = 7.8 Hz), 8.33 (3H, brs), 9.37 (1H, brs).

Example 329 N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] piperidine-1-carboxamide dihydrochloride 1) 5-{[( tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (412 mg, 1.0 mmol) and piperidine (150 μL, 1.5 mmol), Example 95- In the same manner as in 1), ({2-isobutyl-6-methyl-4- (4-methylphenyl) -5-[(piperidin-1-ylcarbonyl) amino] pyridin-3-yl} methyl) carbamic acid tert-Butyl was obtained as an oil.
EIMS (M + 1): 495
2) N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) was obtained from the oil obtained in 1) by the same method as in Example 2-3). ) Pyridin-3-yl] piperidine-1-carboxamide dihydrochloride (218 mg, 47% yield) was obtained as a white powder.
¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.3 Hz), 1.07-1.19 (4H, m), 1.44 (2H, brs),
2.12-2.27 (1H, m), 2.37 (3H, s), 2.60 (3H, s), 3.05 (2H, brs), 3.15 (4H, brs), 3.83 (2H, s), 7.19 (2H, d, J = 7.8 Hz), 7.31 (2H, d, J = 7.8 Hz), 7.96 (1H, brs), 8.27 (3H, brs).
Example 330 N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] tetrahydro-2H-pyran-4-carboxamide dihydrochloride
{[5-Amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (192 mg, 0.5 mmol) and tetrahydro-2H-pyran-4 N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine-3 from carbonyl chloride (111 mg, 0.75 mmol) in the same manner as in Example 223 -Il] tetrahydro-2H-pyran-4-carboxamide dihydrochloride (232 mg, 98% yield) was obtained as a white powder.
¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.00-1.25 (6H, m), 1.41 (2H, brs), 1.59 (2H, brs), 2.08-2.22 (2H, m), 2.37 (3H, s), 2.53 (3H, s), 3.03 (2H, brs), 3.81 (2H, s), 7.14 (2H, d, J = 7.5 Hz), 7.30 (2H, d, J = 7.8 Hz), 8.27 (3H, brs), 9.43 (1H, brs).

Example 331 N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] morpholine-4-carboxamide dihydrochloride 1) 5-{[( tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (412 mg, 1.0 mmol) and morpholine (130 μL, 1.5 mmol) to give Example 95- In the same manner as in 1), ({2-isobutyl-6-methyl-4- (4-methylphenyl) -5-[(morpholin-4-ylcarbonyl) amino] pyridin-3-yl} methyl) carbamic acid tert-Butyl was obtained as an oil.
EIMS (M + 1): 497
2) N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) was obtained from the oil obtained in 1) by the same method as in Example 2-3). ) Pyridin-3-yl] morpholine-4-carboxamide dihydrochloride (278 mg, 59% yield) was obtained as a white powder.
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 , brs), 3.19 (4H, brs), 3.86 (2H, brs), 7.21 (2H, d, J = 7.8 Hz), 7.34 (2H, d, J = 7.8 Hz), 8.44 (4H, brs).
Example 332 N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] piperidine-4-carboxamide trihydrochloride
{[5-Amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (192 mg, 0.5 mmol) and 4- (chlorocarbonyl) piperidine N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) was prepared from benzyl-1-carboxylate (210 mg, 0.75 mmol) in the same manner as in Example 223. Pyridin-3-yl] piperidine-4-carboxamide trihydrochloride (246 mg, 98% yield) was obtained as a white powder.
¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.44 (4H, brs), 2.15-2.26 (1H, m), 2.38 (3H, s), 2.38-2.57 (1H, m), 2.57 (3H, s), 2.76 (2H, brs), 3.07 (4H, brs), 3.81 (2H, brs), 7.17 (2H, d, J = 8.1 Hz), 7.30 (2H, d, J = 8.1 Hz), 8.41 (3H, brs), 8.80 (1H, brs), 9.09 (1H, brs), 9.84 (1H, brs).

Example 333 N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] piperazine-1-carboxamide trihydrochloride 1) 5-{[( tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (412 mg, 1.0 mmol) and piperazine-1-carboxylic acid tert-butyl (140 mg, 1.5 mmol) to 4-({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methyl) by a method similar to that in Example 95-1). Phenyl) pyridin-3-yl] amino} carbonyl) piperazine-1-carboxylate tert-butyl was obtained as an oil.
EIMS (M + 1): 596
2) N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) was obtained from the oily substance obtained in 1) by the same method as in Example 2-3). ) Pyridin-3-yl] piperazine-1-carboxamide trihydrochloride (250 mg, 97% yield) was obtained as a white powder.
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, brs), 3.42 (4H, brs), 3.82 (2H, brs), 7.19 (2H, d, J = 7.5 Hz), 7.31 (2H, d, J = 7.5 Hz), 8.37 (3H, brs), 8.60 (1H, brs), 9.41 (2H, brs).
Example 334 (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 dihydrochloride 1) {[5-formyl-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl ( 500 mg, 1.26 mmol), (4-oxo-2-thioxo-1,3-thiazolidin-3-yl) acetic acid (241 mg, 1.26 mmol) in the same manner as in Example 315-1), (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, yield 50%) was obtained as a yellow powder.
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,
brs), 6.96 (2H, d, J = 7.9 Hz), 7.20 (2H, d, J = 7.9 Hz), 7.38 (1H, s).
2) (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) was prepared in the same manner as in Example 2-3) by the same procedure as (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 dihydrochloride (198 mg, yield 100%) was obtained as a yellow powder.
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, brs).

Example 335 5-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methylene} -2-thioxo-1,3-thiazolidine-4 -One dihydrochloride 1) {[5-formyl-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (500 mg, 1.26 mmol), 2- (Thioxo-1,3-thiazolidin-4-one (168 mg, 1.26 mmol) was used in the same manner as in Example 315-1) to give ({2-isobutyl-6-methyl-4- (4-methylphenyl) ) -5-[(4-Oxo-2-thioxo-1,3-thiazolidine-5-ylidene) methyl] pyridin-3-yl} methyl) carbamate tert-butyl (310 mg, 48% yield) yellow Obtained as a powder.
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, brs), 6.95 (2H, d, J = 7.7 Hz), 7.20 (2H, d , J = 7.7 Hz), 7.34 (1H, s) .2) ({2-isobutyl-6-methyl-4- (4-methylphenyl) -5-[(4-oxo-2-thioxo-1,3 5-Thiazolidine-5-ylidene) methyl] pyridin-3-yl} methyl) carbamate tert-butyl (200 mg, 0.390 mmol) in the same manner as in Example 2-3), 5-{[5- (amino Methyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methylene} -2-thioxo-1,3-thiazolidin-4-one dihydrochloride (173 mg, yield 100%) was obtained as a yellow powder.
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, brs).
Example 336 3-({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) methyl benzoate 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 3-aminobenzoic acid Methyl acid (532
mg, 3.52 mmol) by the same method as in Example 311-1), 3-({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- ( 4-Methylphenyl) pyridin-3-yl] acetyl} amino) methyl benzoate (230 mg, 35% yield) was obtained as a white powder.
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, brs), 5.50 (1H, brs), 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) 3-({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) benzoic acid 3-({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine] was prepared from methyl (75.2 mg, 0.134 mmol) in the same manner as in Example 2-3). -3-yl] acetyl} amino) methyl benzoate dihydrochloride (65 mg, 91% yield) was obtained as a white powder.
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, brs), 8.20 (1H , s), 10.6 (1H, brs).

Example 337 3-({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) pyridine-2-carboxylic acid methyl trihydrochloride Salt 1) {[5- (hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (2.08 g, 5.22 mmol); 3-({[5-{[(tert-butoxycarbonyl) amino] methyl}-) was prepared from methyl 3-mercaptopyridine-2-carboxylate (883 mg, 5.22 mmol) in the same manner as in Example 183-1). 6-Isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) pyridine-2-carboxylate methyl (1.43 g, 2.60
mmol) was obtained as a yellow oil.
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, brs), 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) 3-({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) pyridine- In the same manner as in Example 2-3), from methyl 2-carboxylate (197 mg, 0.359 mmol), 3-({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4- Methylphenyl) pyridin-3-yl] methyl} thio) pyridine-2-carboxylate methyl trihydrochloride (161 mg, 80% yield) was obtained as a pale yellow solid.
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, brs), 3.18 (2H , brs), 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) pyridine- 3-({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2 was prepared from methyl 2-carboxylate (1.23 g, 2.24 mmol) in the same manner as in Example 9-1). -Methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) pyridine-2-carboxylic acid (1.19 g, 99% yield) was obtained as a colorless oil.
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, brs ), 3.17 (2H, brs), 3.81 (2H, s), 4.08-4.13 (2H, m), 4.31 (1H, brs), 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-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) pyridine- 3-({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methyl) was prepared from 2-carboxylic acid (0.38 g, 0.709 mmol) in the same manner as in Example 2-3). Phenyl) pyridin-3-yl] methyl} thio) pyridine-2-carboxylic acid trihydrochloride (265 mg, 69% yield) was obtained as a pale yellow solid.
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, m), 3.05 (2H, brs), 3.75 (2H, brs), 3.89 (2H, brs), 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 ) 3-({[5-{[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) pyridine-2 -Carboxylic acid (0.82 g, 1.53 m
mol) to {[5-({[2- (aminocarbonyl) pyridin-3-yl] thio} methyl) -2-isobutyl-6-methyl-4- ( 4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (720 mg, yield 88%) was obtained as a colorless oil.
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, brs), 5.44 (1H, brs), 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, brs), 8.24 (1H, dd, J = 4.3, 1.3 Hz).
2) {[5-({[2- (Aminocarbonyl) pyridin-3-yl] thio} methyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} In the same manner as in Example 2-3), from tert-butyl carbamate (720 mg, 1.35 mmol), 3-({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4- Methylphenyl) pyridin-3-yl] methyl} thio) pyridine-2-carboxamide trihydrochloride (546 mg, 74% yield) was obtained as a pale yellow solid.
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 , brs), 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, brs), 7.69 (1H, d, J = 7.5 Hz), 8.09 (1H, brs), 8.36 (1H, dd, J = 4.5, 1.2 Hz), 8.51 (3H, brs).
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 methanesulfonyl chloride ( 0.27 mL, 3.48 mmol) was added dropwise. After stirring at room temperature for 30 minutes, the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and then the solvent was distilled off 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), potassium carbonate (480 mg, 3.48 mmol) and 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2- Methyl-4- (4-methylphenyl) nicotinic acid (0.95 g, 2.32 mmol) was added, and the mixture was heated with stirring at 70 ° C. for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained after evaporation of the solvent under reduced pressure was purified by silica gel column chromatography to give 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4 -Methylphenyl) nicotinic acid [4- (methoxycarbonyl) cyclohexyl] methyl (750 mg, 57% yield) was obtained 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, brs), 7.07 (2H, d, J = 7.9 Hz), 7.20 (2H, d, J = 7.7 Hz).
2) 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid [4- (methoxycarbonyl) cyclohexyl] methyl (750 mg, 1.32 mmol) to 4-[({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methyl) by a method similar to that in Example 9-1). Phenyl) pyridin-3-yl] carbonyl} oxy) methyl] cyclohexanecarboxylic acid (550 mg, 75% yield) was obtained as a white solid.
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, brs), 3.78 (2H, d, J = 6.6 Hz), 4.12-4.16 (2H, m ), 4.24 (1H, brs), 7.07 (2H, d, J = 7.9 Hz), 7.20 (2H, d, J = 7.7 Hz).
3) 4-[({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl ] By the method similar to Example 2-3) from cyclohexanecarboxylic acid (320 mg, 0.579 mmol), 4-[({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4- Methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] cyclohexanecarboxylic acid dihydrochloride (254 mg, 83% yield) was obtained as a white solid.
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, brs).

Example 341 N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] thiophene-2-carboxamide dihydrochloride
{[5-Amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (192 mg, 0.5 mmol) and thiophene-2-carbonyl chloride ( 110 mg, 0.75 mmol) and N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] thiophene in the same manner as in Example 223 -2-Carboxamide dihydrochloride (171 mg, 75% yield) was obtained as a white powder.
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, brs), 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, brs), 10.18 (1H, brs).
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) methyl benzoate (130 mg , 0.232 mmol) and 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.
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, brs), 4.90 (1H, brs), 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-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) benzoic acid (105 mg, 0.192 mmol) in the same manner as in Example 2-3), 3-({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine- 3-yl] acetyl} amino) benzoic acid dihydrochloride (95 mg, 95% yield) was obtained as a white powder.
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, brs).

Example 343 4-[({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) methyl] benzoic acid methyl dihydrochloride 1) [5-{[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetic acid (390 mg, 0.914 mmol) and 4 4-[({[5-{[(tert-butoxycarbonyl) amino] methyl} -6 from the methyl-(aminomethyl) benzoate (553 mg, 2.74 mmol) in the same manner as in Example 311-1. -Isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) methyl] methyl benzoate (350 mg, 67% yield) was obtained as a white powder.
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, brs), 4.39 (2H, d, J = 5.8 Hz), 5.49 (1H, brs), 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) 4-[({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) methyl ] In the same manner as in Example 2-3) from methyl benzoate (60 mg, 0.105 mmol), 4-[({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4- Methylphenyl) pyridin-3-yl] acetyl} amino) methyl] benzoic acid methyl dihydrochloride (51 mg, 89% yield) was obtained 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), 2.40 (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, brs).
Example 344 5-[({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] pyrazine-2-carboxylic acid Dihydrochloride 1) 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (1.00 g, 2.43 mmol) and 5- (bromomethyl ) 5-[({[5-{[(tert-butoxycarbonyl) amino] methyl} -6] from methyl pyrazine-2-carboxylate (0.51 g, 2.21 mmol) in the same manner as in Example 169-1) -Isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] pyrazine-2-carboxylate methyl (1.35 g,
Yield 98%) as a colorless oil.
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, brs), 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} oxy) methyl ] 5-[({[5-{[(tert-butoxycarbonyl) amino] methyl} -6] from methyl pyrazine-2-carboxylate (1.35 g, 2.40 mmol) in the same manner as in Example 9-1) -Isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] pyrazine-2-carboxylic acid (600 mg, 45% yield) was obtained as a colorless oil.
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,
brs), 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-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl ] 5-[({[5- (aminomethyl) -6-isobutyl-2-methyl-4-] pyrazine-2-carboxylic acid (600 mg, 1.09 mmol) by the same method as in Example 2-3). (4-Methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] pyrazine-2-carboxylic acid dihydrochloride (497 mg, yield 76%) was obtained as a yellow solid.
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, brs), 2.94 (2H , brs), 3.80 (2H, d, J = 4.7 Hz), 5.23 (2H, s), 7.08-7.18 (4H, m), 8.38 (3H, brs), 8.43 (1H, d, J = 1.3 Hz) , 9.10 (1H, d, J = 1.3 Hz).

Example 345 4- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 4-bromobenzyl dihydrochloride
Example 2-3 from 4-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate 4-bromobenzyl (0.73 g, 1.26 mmol) ) In the same manner as 4-bromobenzyl dihydrochloride (628 mg, 90% yield) 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate Obtained as a solid.
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, brs), 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, brs).
Example 346 {[5-[(2-Bromophenoxy) methyl] -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} amine dihydrochloride 1) {[5 -(Hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (1.00 g, 2.51 mmol) and 2-bromophenol (478 mg , 2.76 mmol) and {[5-[(2-bromophenoxy) methyl] -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridine-3 by the same method as in Example 214-1). -Il] methyl} tert-butyl carbamate (640 mg, 46% yield) was obtained as a white solid.
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,
brs), 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) tert-Butyl {[5-[(2-bromophenoxy) methyl] -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (640 mg, 1.16 mmol) to {[5-[(2-bromophenoxy) methyl] -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl by the same method as in Example 2-3). ] Methyl} amine dihydrochloride (458 mg, 75% yield) was obtained as a white solid.
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, brs), 3.20 (2H , brs), 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, brs).

Example 347 4-[({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] -3-methoxybenzoic acid Dihydrochloride 1) 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (0.80 g, 1.94 mmol) and 4- (bromomethyl ) -3-{[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl from methyl 3-methoxybenzoate (503 mg, 1.94 mmol) in the same manner as in Example 169-1) 4-Methoxy-4- (methoxycarbonyl) benzyl-4- (4-methylphenyl) nicotinate (1.15 g, yield 100%) was obtained as a colorless oil.
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, brs), 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) 2-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 2-methoxy-4- (methoxycarbonyl) benzyl (1.15 g, 1.94 mmol) to 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.
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, brs), 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) 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) by the same method as in Example 2-3), 4-[({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-Methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] -3-methoxybenzoic acid dihydrochloride (247 mg, 74% yield) was obtained as a white solid.
¹ H-NMR (DMSO-d ₆ ) δ: 0.96 (6H, d, J = 6.6 Hz), 2.17-2.26 (1H, m), 2.32 (3H, s),
2.84 (2H, brs), 3.79 (2H, d, J = 5.7 Hz), 3.83 (3H, s), 5.03 (2H, s), 6.96 (1H, d, J = 7.7 Hz), 7.13 (2H, d , J = 8.1 Hz), 7.18 (2H, d, J = 8.1 Hz), 7.42-7.45 (1H, m), 7.46 (1H, s), 8.19 (3H, brs).
Example 348 4-[({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] -2-methoxybenzoic acid Dihydrochloride 1) 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (0.50 g, 1.22 mmol) and 4- (bromomethyl ) -2-Methoxy-2-methoxybenzoate (315 mg, 1.22 mmol) in the same manner as in Example 169-1), 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl 4-Methoxy-4- (methoxycarbonyl) benzyl-4- (4-methylphenyl) nicotinate (680 mg, 94% yield) was obtained 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), 2.54 (3H, s ), 2.78 (2H, d, J = 7.4 Hz), 3.86 (3H, s), 3.90 (3H, s), 4.11-4.13 (2H, m), 4.21 (1H, brs), 4.94 (2H, s) , 6.65 (1H, dd, J = 8.0, 1.4 Hz),
6.75 (1H, d, J = 1.1 Hz), 6.99 (2H, d, J = 8.1 Hz), 7.08 (2H, d, J = 7.7 Hz), 7.70 (1H, d, J = 7.9 Hz).
2) 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 3-methoxy-4- (methoxycarbonyl) benzyl (680 mg, In the same manner as in Example 9-1), 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.
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, brs), 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) 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) by the same method as in Example 2-3), 4-[({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-Methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] -2-methoxybenzoic acid dihydrochloride (240 mg, 85% yield) was obtained as a white solid.
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, brs), 2.93 (2H , brs), 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, brs).

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] In the same manner as in Example 9-1) from methyl benzoate (200 mg, 0.349 mmol), 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.
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, brs), 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-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) methyl ] 4-[({[5- (aminomethyl) -6-isobutyl-2-l] benzoic acid (150 mg, 0.268 mmol) in the same manner as in Example 2-3).
Methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) methyl] benzoic acid dihydrochloride (135 mg, 95% yield) was obtained as a white powder.
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, brs), 8.45 (1H, brs).
Example 350 N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] isoxazole-4-carboxamide dihydrochloride
{[5-Amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamic acid tert-butyl (192 mg, 0.5 mmol) and isoxazole-4-carbonyl chloride (100 mg, 0.75 mmol) and N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] by the same method as in Example 223 Isoxazole-4-carboxamide dihydrochloride (173 mg, yield 76%) was obtained as a white powder.
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, brs), 7.09 (1H, s), 7.20 (2H, d, J = 8.1 Hz), 7.25 (2H,
d, J = 8.1 Hz), 8.28 (3H, brs), 8.73 (1H, brs), 10.59 (1H, brs).

Example 351 N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] furan-2-carboxamide dihydrochloride
{[5-Amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (192 mg, 0.5 mmol) and furan-2-carbonyl chloride ( 100 mg, 0.75 mmol) and N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] furan in the same manner as in Example 223. -2-carboxamide dihydrochloride (190 mg, 85% yield) was obtained as a white powder.
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, brs), 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, brs), 9.98 (1H, brs).
Example 352 N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -4-methylbenzamide dihydrochloride
{[5-Amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (192 mg, 0.5 mmol) and 4-methylbenzoyl chloride (116 mg, 0.75 mmol) and N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -4 in the same manner as in Example 223. -Methylbenzamide dihydrochloride (211 mg, yield 87%) was obtained as a white powder.
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, brs), 3.84 (2H, s), 7.21-7.27 (6H, m), 7.55 (2H, d, J = 8.1 Hz), 8.32 (3H, brs), 9.88 (1H, brs).

Example 353 N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -4-tert-butylbenzamide dihydrochloride
{[5-Amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamic acid tert-butyl (192 mg, 0.5 mmol) and 4-tert-butylbenzoyl chloride (147 mg, 0.75 mmol) and N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] by a method similar to that in Example 223 -4-tert-Butylbenzamide dihydrochloride (211 mg, 83% yield) was obtained as a white powder.
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, brs), 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, brs), 9.91 (1H, brs).
Example 354 N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -4-chlorobenzamide dihydrochloride
{[5-Amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (192 mg, 0.5 mmol) and 4-chlorobenzoyl chloride (131 mg, 0.75 mmol) and N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -4 in the same manner as in Example 223. -Chlorobenzamide dihydrochloride (203 mg, 82% yield) was obtained as a white powder.
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, brs), 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, brs), 10.20 (1H, brs).

Example 355 N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -4-cyanobenzamide dihydrochloride
{[5-Amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (192 mg, 0.5 mmol) and 4-cyanobenzoyl chloride (126 mg , 0.75 mmol) by the same method as in Example 223, 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.
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 , brs), 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, brs), 10.36 (1H, brs).
Example 356 N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -4-trifluoromethylbenzamide dihydrochloride
{[5-Amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamic acid tert-butyl (192 mg, 0.5 mmol) and 4-trifluoromethylbenzoyl chloride (156 mg, 0.75 mmol) and N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] by a method similar to that in Example 223. -4-Trifluoromethylbenzamide dihydrochloride (209 mg, yield 86%) was obtained as a white powder.
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, brs), 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, brs), 10.21 (1H, brs).

Example 357 N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] furan-3-carboxamide dihydrochloride
{[5-Amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (192 mg, 0.5 mmol) and furan-3-carbonyl chloride ( 100 mg, 0.75 mmol) and N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] furan in the same manner as in Example 223. -3-Carboxamide dihydrochloride (190 mg, 85% yield) was obtained as a white powder.
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, brs), 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, brs), 9.74 (1H, brs).
Example 358 N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] thiophene-3-carboxamide dihydrochloride
{[5-Amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (192 mg, 0.5 mmol) and thiophene-3-carbonyl chloride ( 110 mg, 0.75 mmol) and N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] thiophene in the same manner as in Example 223 -3-Carboxamide dihydrochloride (233 mg, 99% yield) was obtained as a white powder.
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, brs), 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, brs), 9.91 (1H, brs).

Example 359 4-[({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] -3-fluorobenzoic acid Dihydrochloride 1) 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (0.50 g, 1.21 mmol) and 4- (bromomethyl ) -3-{[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl from methyl 3-fluorobenzoate (299 mg, 1.21 mmol) in the same manner as in Example 169-1) 4-Fluoro-4- (methoxycarbonyl) benzyl-4- (4-methylphenyl) nicotinate (650 mg, yield 92%) was obtained as a colorless oil.
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, brs), 5.05 (2H, s), 6.98-7.09 (5H, m), 7.64-7.71 (2H, m).
2) 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 2-fluoro-4- (methoxycarbonyl) benzyl (650 mg, 1.12 mmol) to 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.
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,
brs), 5.07 (2H, s), 7.00-7.12 (5H, m), 7.70-7.76 (2H, m).
3) 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) by the same method as in Example 2-3), 4-[({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-Methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] -3-fluorobenzoic acid dihydrochloride (329 mg, 76% yield) was obtained as a white solid.
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, brs), 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, brs).
Example 360 4-[({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] -3-chlorobenzoic acid Dihydrochloride 1) 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (0.36 g, 0.873 mmol) and 4- (bromomethyl ) -3-{[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl from methyl 3-chlorobenzoate (230 mg, 0.873 mmol) in the same manner as in Example 169-1) 4-Chloro-4- (methoxycarbonyl) benzyl-4- (4-methylphenyl) nicotinate (518 mg, yield 99%) was obtained as a colorless oil.
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, brs), 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) 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 2-chloro-4- (methoxycarbonyl) benzyl (518 mg, 0.870 mmol) to 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.
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, brs), 2.82 (2H, brs), 4.09-4.17 (2H, m), 4.25 (1H, brs), 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) 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) by the same method as in Example 2-3), 4-[({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-Methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] -3-chlorobenzoic acid dihydrochloride (265 mg, 66% yield) was obtained as a white solid.
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 , brs), 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, brs).

Example 361 4-[({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] isophthalic acid dihydrochloride 1 ) 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) to 4-[({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4 by the same method as in Example 169-1). -(4-Methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] isophthalate (1.12 g, 99% yield) was obtained as a colorless oil.
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, brs), 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} oxy) methyl ] 4-[({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2] from dimethyl isophthalate (1.12 g, 1.81 mmol) in the same manner as in Example 9-1) -Methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] isophthalic acid (750 mg, 68% yield) was obtained as a colorless oil.
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, brs), 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-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl ] 4-[({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methyl) is synthesized from isophthalic acid (420 mg, 0.711 mmol) in the same manner as in Example 2-3). Phenyl) pyridin-3-yl] carbonyl} oxy) methyl] isophthalic acid dihydrochloride (362 mg, 90% yield) was obtained as a white solid.
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, brs), 2.90 (2H , brs), 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, brs), 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 Salt 1) With [5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetic acid (500 mg, 1.17 mmol) From 4- (dimethylamino) aniline (500 mg, 3.67 mmol), in the same manner as in Example 311-1), {[5- (2-{[4- (dimethylamino) phenyl] amino} -2- Oxoethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (450 mg, 71% yield) was obtained as a white powder.
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, brs), 6.58 (1H, brs), 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) {[5- (2-{[4- (Dimethylamino) phenyl] amino} -2-oxoethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl } 2- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methyl) was prepared from tert-butyl carbamate (100 mg, 0.268 mmol) in the same manner as in Example 2-3). Phenyl) pyridin-3-yl] -N- [4- (dimethylamino) phenyl] acetamide trihydrochloride (62 mg, 42% yield) was obtained as a purple powder.
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, brs).

Example 363 Ethyl 5- (aminomethyl) -4- (4-methylphenyl) -2,6-dineopentylnicotinate 1) Potassium 3-ethoxy-3-oxopropionate (7.6 g, 45 mmol); A mixture of magnesium chloride (2.8 g, 30 mmol) and tetrahydrofuran (75 mL) was stirred at 50 ° C. for 4 hours. The resulting suspension was cooled to room temperature and a mixture consisting of tert-butylacetic acid (3.5 g, 30 mmol), N, N′-carbonyldiimidazole (5.8 g, 36 mmol), and tetrahydrofuran (50 mL). The reaction solution stirred at room temperature for 1 hour was added dropwise. The resulting mixture was stirred at room temperature for 3 days. The reaction mixture was partitioned between ethyl acetate and 0.5N hydrochloric acid, and the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 5,5 -Ethyl dimethyl-3-oxohexanoate was obtained as a crude product (5.9 g). A mixture of the crude product (5.9 g) and ammonium acetate (9.8 g, 127 mmol), acetic acid (1.45 mL, 25 mmol), and toluene (200 mL) was heated using a Dean-Stark trap for 17 hours. Refluxed. The reaction mixture was cooled to room temperature, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. 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, brs), 8.05 (1H, s).
2) 5,5-dimethyl-3-oxohexanenitrile (2.4 g, 13 mmol), p-tolualdehyde (1.6 g, 13 mol), and 3-amino-5,5-dimethylhex-2-enoic acid 5-Cyano-4- (4-methylphenyl) -2,6-dineopentyl-1,4-dihydropyridine-3-carboxyl from ethyl (2.5 g, 13 mmol) in the same manner as in Example 1-2) Ethyl acid (3.5 g, yield 65%) was obtained as a white powder.
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, brs), 7.09 (2H, d, J = 8.0 Hz), 7.17 (2H, d, J = 8.0 Hz).
3) From ethyl 5-cyano-4- (4-methylphenyl) -2,6-dineopentyl-1,4-dihydropyridine-3-carboxylate (3.4 g, 8.2 mmol), the same as in Example 23-3) By the method, ethyl 5-cyano-4- (4-methylphenyl) -2,6-dineopentylnicotinate (3.2 g, yield 96%) was obtained as a white powder.
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) From 5-ethyl-4-cyano-4- (4-methylphenyl) -2,6-dineopentylnicotinate (1.0 g, 2.5 mmol) in the same manner as in Example 1-4), 5- (amino Methyl) -4- (4-methylphenyl) -2,6-dineopentylnicotinate (0.91 g, yield 90%) was obtained as a colorless oil.
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, brs), 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) Methanesulfone Acid [5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl (1.91 g, 4.01 mmol), 1, A mixture of 3-propanediol (3.05 g, 40.1 mmol), sodium hydride (60% oily, 1.60 g, 40.1 mmol), and tetrahydrofuran (5 mL) was stirred at 55 ° C. for 16 hours. The reaction mixture was cooled to room temperature and quenched with 1N hydrochloric acid. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and the organic layer was dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography to obtain {[5-[(3-hydroxypropoxy) methyl] -2-isobutyl-6-methyl-4- (4-methyl Phenyl) pyridin-3-yl] methyl} carbamate tert-butyl (840 mg, 46% yield) was obtained 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, brs), 7.03 (2H, d, J = 7.9 Hz), 7.24 (2H, d, J = 7.9 Hz).
2) tert-butyl {[5-[(3-hydroxypropoxy) methyl] -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (18 mg, 0.0394 mmol) to 3-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} in the same manner as in Example 2-3). Propan-1-ol dihydrochloride (15 mg, 100% yield) was obtained as a white powder.
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, brs).

Example 365 4-[({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] phthalic acid dihydrochloride 1 ) 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) to 4-[({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4 by the same method as in Example 169-1) -(4-Methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] phthalate dimethyl (1.68 g, yield 95%) was obtained as a colorless oil.
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, brs), 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} oxy) methyl ] 4-[({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2] from dimethyl phthalate (1.68 g, 2.72 mmol) in the same manner as in Example 9-1) -Methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] phthalic acid (1.60 g, 99% yield) was obtained as a colorless oil.
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, brs ), 3.10 (2H, d, J = 7.0 Hz), 4.23 (2H, d, J = 4.9 Hz), 4.51 (1H, brs), 5.01 (2H, s), 7.07 (2H, s), 7.21-7.24 (3H, m), 8.03 (1H, s), 8.1
3 (1H, d, J = 7.9 Hz).
3) 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) to 4-[({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] in the same manner as in Example 2-3). Carbonyl} oxy) methyl] phthalic acid dihydrochloride (396 mg, 84% yield) was obtained as a white solid.
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, brs), 2.91 (2H , brs), 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, brs).
Example 366 4-[({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] -2-fluorobenzoic acid Dihydrochloride 1) 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 the same manner as in Example 247-1), 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl- 4-Bromo-3-fluorobenzyl 4- (4-methylphenyl) nicotinate (1.36 g, 78% yield) was obtained as a colorless oil.
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,
brs), 4.86 (2H, s), 6.61-6.65 (1H, m), 7.00-7.06 (3H, m), 7.12-7.19 (3H, m).
2) 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 4-bromo-3-fluorobenzyl (1.36 g, 2.27 mmol) From the same manner as in Example 231-2), 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 3-fluoro- 4- (Methoxycarbonyl) benzyl (520 mg, 39% yield) was obtained as a yellow oil.
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, brs), 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) 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 3-fluoro-4- (methoxycarbonyl) benzyl (520 mg, 0.899 mmol) to 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.
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,
brs), 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) 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) by the same method as in Example 2-3), 4-[({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-Methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] -2-fluorobenzoic acid dihydrochloride (192 mg, 42% yield) was obtained as a white solid.
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, brs).

Example 367 N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -4-oxo-4,5,6,7-tetrahydro- 1-benzofuran-3-carboxamide dihydrochloride
{[5-Amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (192 mg, 0.5 mmol) and 4-oxo-4,5 , 6,7-Tetrahydro-1-benzofuran-3-carbonyl chloride (150 mg, 0.75 mmol) in the same manner as in Example 223, N- [5- (aminomethyl) -6-isobutyl-2-methyl -4- (4-Methylphenyl) pyridin-3-yl] -4-oxo-4,5,6,7-tetrahydro-1-benzofuran-3-carboxamide dihydrochloride (172 mg, 66% yield) Obtained as a white powder.
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, brs), 11.42 (1H, brs).
Example 368 N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -2-phenyl-1,3-thiazole-4-carboxamide Hydrochloride
{[5-Amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (192 mg, 0.5 mmol) and 2-phenyl-1,3 N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) was prepared from 2-thiazole-4-carbonyl chloride (167 mg, 0.75 mmol) in the same manner as in Example 223. ) Pyridin-3-yl] -2-phenyl-1,3-thiazole-4-carboxamide dihydrochloride (155 mg, 57% yield) was obtained as a white powder. 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, brs), 9.85 (1H, brs).

Example 369 N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] pyrazine-2-carboxamide dihydrochloride
{[5-Amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (192 mg, 0.5 mmol) and pyrazine-2-carbonyl chloride ( 107 mg,
0.75 mmol) and N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] pyrazin-2- Carboxamide dihydrochloride (157 mg, 63% yield) was obtained as a white powder.
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, brs ), 8.70 (1H, s), 8.88 (1H, s), 9.08 (1H, s), 10.48 (1H, brs).
Example 370 4-[({[5- (Aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] acetyl} oxy) methyl] benzoic acid dihydrochloride 1) 6N in tert-butyl (16 g, 37 mmol) {[5- (cyanomethyl) -6-methyl-4- (4-methylphenyl) -2-neopentylpyridin-3-yl] methyl} carbamate Hydrochloric acid (200 mL) was added, and the mixture was stirred at 90 ° C. for 24 hr. The reaction mixture was washed with a tetrahydrofuran-toluene (1: 2) mixed solvent, and then concentrated under reduced pressure. The residue was dissolved in water and made alkaline with 4N aqueous sodium hydroxide solution. The obtained alkaline solution was washed with ethyl acetate and then concentrated under reduced pressure. Tetrahydrofuran (100 mL) and water (50 mL) were added to the residue and stirred vigorously, di-tert-butyl dicarbonate (8.5 mL, 37 mmol) was added dropwise, and the mixture was stirred at room temperature for 17 hours. 1N Hydrochloric acid was added to the reaction mixture to acidify the aqueous layer, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was crystallized from hexane-ethyl acetate to give [5-{[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridine-3- Il] acetic acid (13 g, 80% yield) was obtained 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, brs), 3.43 (2H, brs), 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) [5-{[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6
-Neopentylpyridin-3-yl] acetic acid (0.50 g, 1.1 mmol) and triethylamine (0.17 mL,
1.3 mmol) and tetrahydrofuran (20 mL) were ice-cooled, and a solution of 2,4,6-trichlorobenzoic acid chloride (0.31 g, 1.3 mmol) in tetrahydrofuran (2 mL) was added dropwise thereto. . The resulting mixture was stirred at room temperature for 14 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), and the resulting solution was added 2-oxo-2-phenylethyl 4- (hydroxymethyl) benzoate (0.37 g, 1.4 mmol) and 4-dimethylaminopyridine (0.17 g, 1.4 mmol) was added and stirred at room temperature for 30 minutes. The reaction solution was partitioned between ethyl acetate and water. The organic layer was washed successively with 0.1 M aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and 4-[({[5-{[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridine. -3-yl] acetyl} oxy) methyl] benzoic acid 2-oxo-2-phenylethyl (0.63 g, 80% yield) was obtained 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) 4-[({[5-{[(tert-Butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] acetyl} oxy) Methyl] benzoic acid 2-oxo-2-phenylethyl (0.61 g, 0.88 mmol) was dissolved in ethyl acetate (2 mL), and the resulting solution was mixed with water (2 mL), acetic acid (5 mL), and zinc Powder (0.42 g, 6.4 mmol) was added sequentially. The resulting mixture was stirred at 55 ° C. for 24 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. 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} oxy) methyl] benzoic acid (0.29 g, 48% yield) was obtained 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-{[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] acetyl} oxy) 4-[({[5- (aminomethyl) -2-methyl-4- (4-methylphenyl)] from methyl] benzoic acid (0.25 g, 0.44 mmol) by a method similar to Example 276-3). -6-Neopentylpyridin-3-yl] acetyl} oxy) methyl] benzoic acid dihydrochloride (0.22 g, 92.4% yield) was obtained as a pale yellow powder.
¹ H-NMR (DMSO-d ₆ ) δ: 1.01 (9H, s), 2.37 (3H, s), 2.73 (3H, brs), 3.00-3.30 (2H, m), 3.57 (2H, brs), 3.82 (2H, brs), 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, brs).

Example 371 2-[({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] furan-3-carboxylic acid Dihydrochloride 1) 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (0.50 g, 1.22 mmol) and 2- (bromomethyl ) 5-{[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl from methyl furan-3-carboxylate (266 mg, 1.22 mmol) in the same manner as in Example 169-1) 4- (4-Methylphenyl) nicotinic acid [3- (methoxycarbonyl) -2-furyl] methyl (320 mg, 47% yield) was obtained as a colorless oil.
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, brs), 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) 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid [3- (methoxycarbonyl) -2-furyl] methyl (320 mg, 0.581 mmol) to 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, 99% yield) was obtained as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.13-2.22 (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,
brs), 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) 2-[({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl ] In the same manner as in Example 2-3) from furan-3-carboxylic acid (310 mg, 0.577 mmol), 2-[({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-Methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] furan-3-carboxylic acid dihydrochloride (241 mg, 81% yield) was obtained as a pale yellow solid.
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, brs), 2.90 (2H , brs), 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, brs) .
Example 372 4-[({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] -3-nitrobenzoic acid Dihydrochloride 1) 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (1.91 g, 4.63 mmol) and 4- (hydroxy Methyl) -3-nitrobenzoate (978 mg, 4.63 mmol) was prepared in the same manner as in Example 247-1) by using 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2- Methyl-4- (4-methylphenyl) nicotinic acid 4- (methoxycarbonyl) -2-nitrobenzyl (1.91 g, yield 63%) was obtained as a colorless oil.
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, brs), 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) 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 4- (methoxycarbonyl) -2-nitrobenzyl (0.33 g, In the same manner as in Example 9-1), 4-[({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4- Methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] -3-nitrobenzoic acid (300 mg, 93% yield) was obtained as a colorless oil.
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, brs), 5.42 (2H, s), 7.02-7.20 (5H, m), 8.12-8.16 (1H, m), 8.73 ( 1H, s).
3) 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) by the same method as in Example 2-3), 4-[({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-Methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] -3-nitrobenzoic acid dihydrochloride (247 mg, 86% yield) was obtained as a white solid.
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, brs), 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, brs), 8.48 (1H, d, J = 1.7 Hz).

Example 373 3-{[5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methoxy} -1-methyl-1H-pyrazole-4- Methyl carboxylate dihydrochloride 1) {[5- (hydroxymethyl) -6-methyl-4- (4-methylphenyl) -2-neopentylpyridin-3-yl] methyl} carbamate tert-butyl (2.09 g , 5.07 mmol) and ethyl 3-hydroxy-1-methyl-1H-pyrazole-4-carboxylate (863 mg, 5.07 mmol) in the same manner as in Example 183-1), 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.
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, brs), 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, s).
2) 3-{[5-{[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methoxy} -1-methyl 3-{[5-{[(tert-butoxycarbonyl) amino] methyl} -2 from ethyl -1H-pyrazole-4-carboxylate (2.34 g, 4.14 mmol) in the same manner as in Example 9-1) -Methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methoxy} -1-methyl-1H-pyrazole-4-carboxylic acid (2.22 g, yield 99%) as a colorless oil Got as.
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, brs), 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) 3-{[5-{[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methoxy} -1-methyl 1-H-pyrazole-4-carboxylic acid (0.51 g, 0.950 mmol) in the same manner as in Example 305-3), 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) as a colorless oil Got as.
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, brs), 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) 3-{[5-{[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methoxy} -1-methyl 1-H-pyrazole-4-carboxylate (480 mg, 0.872 mmol) in the same manner as in Example 2-3), 3-{[5- (aminomethyl) -2-methyl-4- (4- Methylphenyl) -6-neopentylpyridin-3-yl] methoxy} -1-methyl-1H-pyrazole-4-carboxylate methyl dihydrochloride (349 mg, 76% yield) was obtained as a white solid.
¹ H-NMR (DMSO-d ₆ ) δ: 1.05 (9H, s), 2.38 (3H, s), 2.91 (3H, brs), 3.28 (2H, brs), 3.65 (3H, s), 3.66 (3H , s), 3.89 (2H, brs), 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, brs).
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-{[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methoxy} -1-methyl-1H 3-pyrazole-4-carboxylic acid (0.29 g, 0.540 mmol) in the same manner as in Example 2-3), 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.
¹ H-NMR (DMSO-d ₆ ) δ: 1.04 (9H, s), 2.38 (3H, s), 2.87 (3H, brs), 3.23 (2H, brs), 3.64 (3H, s), 3.89 (2H , brs), 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, brs).

Example 375 3-{[5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methoxy} -1-methyl-1H-pyrazole-4- Carboxamide dihydrochloride 1) 3-{[5-{[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methoxy} In the same manner as in Example 3-1), from the -1-methyl-1H-pyrazole-4-carboxylic acid (0.60 g, 1.12 mmol), {[5-({[4- (aminocarbonyl) -1-methyl -1H-pyrazol-3-yl] oxy} methyl) -6-methyl-4- (4-methylphenyl) -2-neopentylpyridin-3-yl] methyl} carbamate tert-butyl (110 mg, yield) 18%) was obtained as a colorless oil.
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, brs), 6.43 (1H, brs), 7.01 (2H, d, J = 7.7 Hz), 7.20 (2H, d, J = 8.3 Hz), 7.69 (1H, s).
2) {[5-({[4- (Aminocarbonyl) -1-methyl-1H-pyrazol-3-yl] oxy} methyl) -6-methyl-4- (4-methylphenyl) -2-neopentyl Pyridin-3-yl] methyl} carbamate tert-butyl (110 mg, 0.205 mmol) was prepared in the same manner as in Example 2-3) by using 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.
¹ H-NMR (DMSO-d ₆ ) δ: 1.04 (9H, s), 2.38 (3H, s), 2.91 (3H, brs), 3.25 (2H, brs), 3.63 (3H, s), 3.88 (2H , brs), 4.92 (2H, s), 6.35 (1H, brs), 7.09 (1H, brs), 7.27
(2H, d, J = 7.0 Hz), 7.34 (2H, d, J = 7.5 Hz), 7.91 (1H, s), 8.29 (3H, brs).
Example 376 {2-[({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] phenyl} acetic acid dihydrochloride Salt 1) 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (1.00 g, 2.42 mmol) and [2- (bromomethyl) Phenyl] ethyl acetate (624 mg, 2.42 mmol) was prepared in the same manner as in Example 169-1) by using 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- ( 2- (2-Ethoxy-2-oxoethyl) benzyl 4-methylphenyl) nicotinate (980 mg, 70% yield) was obtained as a colorless oil. 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, brs), 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) 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 2- (2-ethoxy-2-oxoethyl) benzyl (980 mg , 1.71 mmol) to {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.
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, brs), 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) {2-[({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) Methyl] phenyl} acetic acid (210 mg,
0.374 mmol) to {2-[({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine-3-] by the same method as in Example 2-3). [Il] carbonyl} oxy) methyl] phenyl} acetic acid dihydrochloride (125 mg, 62% yield) was obtained as a white solid.
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, brs), 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, brs) .

Example 377 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 2- (2-amino-2-oxoethyl) benzyl dihydrochloride 1) {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) to 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 2 in the same manner as in Example 3-1). -(2-Amino-2-oxoethyl) benzyl (323 mg, 83% yield) was obtained 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), 2.35 (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, brs), 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) 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 2- (2-amino-2-oxoethyl) benzyl (323 mg , 0.577 mmol) to 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid 2- (2-amino-2) in the same manner as in Example 2-3). -Oxoethyl) benzyl dihydrochloride (209 mg, 68% yield) was obtained as a white solid.
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 , brs), 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, brs), 8.35 (3H, brs).
Example 378 3-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} thiophene-2-carboxylate methyl dihydrochloride 1) {[5- (Hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} tert-butyl carbamate (0.50 g, 1.25 mmol) and 3-hydroxythiophene 2-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2 from methyl-2-carboxylate (0.20 g, 1.25 mmol) in the same manner as in Example 214-1) -Methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} thiophene-2-carboxylate (460 mg, yield 68%) was obtained as a colorless oil.
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, brs), 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) 3-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} thiophene-2-carbon 3-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine from methyl acid (158 mg, 0.293 mmol) in the same manner as in Example 2-3) Methyl -3-yl] methoxy} thiophene-2-carboxylate dihydrochloride (126 mg, 84% yield) was obtained as a white solid.
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 , brs), 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, brs).

Example 379 4-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -2-methyl-1,3-thiazole-5 -Methyl carboxylate dihydrochloride 1) {[5- (hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} tert-butyl 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 the same manner as in Example 214-1), 4-{[5- {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -2-methyl-1,3-thiazole-5- Ethyl carboxylate (910 mg, yield 96%) was obtained as a colorless oil.
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- 4-{[5-{[(tert-butoxycarbonyl) amino] methyl}-is prepared from ethyl 1,3-thiazole-5-carboxylate (910 mg, 1.60 mmol) in the same manner as in Example 9-1). 6-Isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -2-methyl-1,3-thiazole-5-carboxylic acid (750 mg, 87% yield) colorless Obtained as an oil.
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, brs), 2.95 (2H, d, J = 7.0 Hz), 4.09-4.15 (2H, m), 4.31 (1H, brs), 5.22 (2H, s), 7.05 (2H, d, J = 7.9 Hz), 7.22 (2H, d, J = 7.9 Hz).
3) 4-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -2-methyl- 4-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6 from 1,3-thiazole-5-carboxylic acid (530 mg, 0.982 mmol) in the same manner as in Example 305-3) -Isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -2-methyl-1,3-thiazole-5-carboxylate (420 mg, 77% yield) Obtained as a yellow solid.
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, brs), 5.14 (2H , s), 7.09 (2H, d, J = 8.1 Hz), 7.16 (2H, d, J = 7.9 Hz).
4) 4-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -2-methyl- 4-([5- (Aminomethyl) -6-isobutyl-2-methyl-methyl-1,3-thiazole-5-carboxylate (420 mg, 0.759 mmol) was prepared in the same manner as in Example 2-3). 4- (4-Methylphenyl) pyridin-3-yl] methoxy} -2-methyl-1,3-thiazole-5-carboxylate methyl dihydrochloride (342 mg, 85% yield) was obtained as a pale yellow solid It was.
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 , brs), 3.13 (2H, brs), 3.70 (3H, s), 3.80 (2H, brs), 5.17 (2H, s), 7.20-7.26 (2H, m), 7.31 (2H, d, J = 7.4 Hz), 8.38 (3H, brs).
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-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -2-methyl-1, 4-Thrazole-5-carboxylic acid (220 mg, 0.408 mmol) was subjected to 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, 69% yield) was obtained as a white solid.
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 , brs), 3.10 (2H, brs), 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) {[5- (hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} tert-butyl carbamate (1.00 g , 2.51 mmol) and ethyl 1-acetyl-3-hydroxy-1H-pyrazole-4-carboxylate (597 mg, 3.01 mmol) in the same manner as in Example 214-1), 1-acetyl-3-{[ 5-{[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1H-pyrazole-4-
Ethyl carboxylate (1.12 g, 77% yield) was obtained as a white solid.
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, brs), 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) 1-acetyl-3-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy}- Saturated multistory water (10 mL) was added to a solution of ethyl 1H-pyrazole-4-carboxylate (0.86 g, 1.49 mmol) in tetrahydrofuran (10 mL) -methanol (5 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 3-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) Pyridin-3-yl] methoxy} -1H-pyrazole-4-carboxylate (798 mg, 99% yield) was obtained 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, brs), 2.65-2.78 (5H, m), 3.87-4.04 (2H, m), 4.08 -4.35 (5H, m), 4.87 (1H, brs), 6.91-7.01 (2H, m), 7.07-7.15 (2H, m), 7.84 (1H, s).
3) 3-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1H-pyrazole- Sodium hydride (60% oily, 98 mg, 2.44 mmol) was added to a solution of ethyl 4-carboxylate (1.09 g, 2.03 mmol) in N, N-dimethylformamide (20 mL), and the mixture was stirred at room temperature for 30 min. After adding tert-butyl bromoacetate (0.36 mL, 2.44 mmol) to the reaction solution, the mixture was stirred with heating at 60 ° C. for 30 minutes. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 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, yield 72%) was obtained 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) 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 tetrahydrofuran (15 mL) -methanol (10 mL) mixed solution with 1N aqueous sodium hydroxide (10 mL) ) Was added and heated to reflux for 1 hour. The reaction solution was returned to room temperature, acidified with 0.5N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 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, yield 99%) was obtained as an oil. . 3-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl)] was prepared from the oil (107 mg, 0.189 mmol) in the same manner as in Example 2-3). Pyridin-3-yl] methoxy} -1- (carboxymethyl) -1H-pyrazole-4-carboxylic acid dihydrochloride (58.2 mg, 59% yield) was obtained as a white solid.
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, brs), 3.04 (2H , brs), 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, brs).
Example 382 3-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1- (2-methoxy-2-oxoethyl) -1H-pyrazole-4-carboxylate methyl dihydrochloride 1) 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) was prepared by a method similar to that in Example 305-3) to give 3-{[5- {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1- (2-methoxy-2-oxoethyl)- Methyl 1H-pyrazole-4-carboxylate (560 mg, 0.636 mmol) was obtained as a colorless oil.
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, brs), 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) 3-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1- (2 3-Methyl-2-oxoethyl) -1H-pyrazole-4-carboxylate (98.7 mg, 0.166 mmol) in the same manner as in Example 2-3), 3-{[5- (aminomethyl) -6- Isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1- (2-methoxy-2-oxoethyl) -1H-pyrazole-4-carboxylate methyl dihydrochloride (59.8 mg , Yield 63%) was obtained as a white solid.
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, brs), 2.94 (2H , brs), 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 [3-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -4- (methoxycarbonyl) -1H-pyrazole -1-yl] acetic acid dihydrochloride 1) 3-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine-3- [Il] methoxy} -1- (2-methoxy-2-oxoethyl) -1H-pyrazole-4-carboxylate (0.46 g, 0.775 mmol) in 1N aqueous sodium hydroxide solution (1 mL) was added to a tetrahydrofuran solution. Stir at room temperature for 30 minutes. The reaction mixture was acidified with 0.5N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give [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) was colorless oil Obtained as a thing.
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) [3-{[5-{[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -4- ( [3-{[5- (aminomethyl) -6-isobutyl-2] was prepared from methoxycarbonyl) -1H-pyrazol-1-yl] acetic acid (100 mg, 0.172 mmol) in the same manner as in Example 2-3). -Methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -4- (methoxycarbonyl) -1H-pyrazol-1-yl] acetic acid dihydrochloride (42.4 mg, 44% yield) white Obtained as a solid.
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, brs), 3.07 (2H , brs), 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, brs).
Example 384 3-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1- (2-amino-2-oxoethyl) -1H-pyrazole-4-carboxylate methyl dihydrochloride 1) [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) was prepared in the same manner as in Example 3-1). (2-Amino-2-oxoethyl) -3-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl Methyl} methoxy} -1H-pyrazole-4-carboxylate (150 mg, 37% yield) was obtained as a white solid.
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, brs), 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) 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, 0.259 mmol) in the same manner as in Example 2-3), 3-{[5- (aminomethyl) -6- Isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1- (2-amino-2-oxoethyl) -1H-pyrazole-4-carboxylate methyl dihydrochloride (141 mg Yield 98%) as a white solid.
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, brs), 3.09 (2H , brs), 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, brs).

Example 385 N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] terephthalamide dihydrochloride 1) 4-({[5- { Conducted from [(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) benzoic acid (260 mg, 0.48 mmol) In the same manner as in Example 3-1), {[5-{[4- (aminocarbonyl) benzoyl] amino} -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] Tert-butyl methyl} carbamate (248 mg, 98% yield) was obtained as a white powder.
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, brs), 4.13 (2H, brs), 4.37 (1H, brs), 5.84 (1H, brs), 6.33 (1H, brs), 7.05 (2H, d, J = 8.1 Hz), 7.19 (2H, d, J = 8.1 Hz), 7.37 (1H, brs), 7.47 (2H, d, J = 8.1 Hz), 7.73 (2H, d, J = 8.1 Hz).
2) tert-butyl {[5-{[4- (aminocarbonyl) benzoyl] amino} -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (248 mg, 0.47 mmol) and N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl by the same method as in Example 2-3). ] Terephthalamide dihydrochloride (233 mg, yield 99%) was obtained as a white powder.
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 , brs), 3.85 (2H, brs), 7.25 (4H, s), 7.51 (1H, brs), 7.68
(2H, d, J = 8.1 Hz), 7.89 (2H, d, J = 8.1 Hz), 8.09 (1H, brs), 8.37 (3H, brs), 10.16 (1H, brs).
Example 386 1-({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) piperidine-4-carboxylate dihydrochloride Salt 1) 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 the same manner as in Example 95-1), 1-({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4 -Methylphenyl) pyridin-3-yl] amino} carbonyl) piperidine-4-carboxylate was obtained as an oil.
EIMS (M + 1): 567
2) From the oily substance obtained in the above 1), 1-({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4- Methylphenyl) pyridin-3-yl] amino} carbonyl) ethyl piperidine-4-carboxylate dihydrochloride (324 mg, 69% yield) was obtained as a white powder.
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, brs), 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, brs), 8.45 (3H, brs).

Example 387 2-[({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) amino] -1,3-oxazole Ethyl-4-carboxylate dihydrochloride 1) 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 the same manner as in Example 95-1), 2-[({[5-{[(tert -Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) amino] -1,3-oxazole-4-carboxylate Obtained as an oil.
EIMS (M + 1): 566
2) 2-[({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4) was obtained from the oily substance obtained in 1) by the same method as in Example 2-3). -Methylphenyl) pyridin-3-yl] amino} carbonyl) amino] -1,3-oxazole-4-carboxylate ethyl dihydrochloride (224 mg, 48% yield) was obtained as a white powder.
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, brs), 3.82 (2H, s), 4.27 (2H, q, J = 7.2 Hz), 7.15-7.29 (4H, m), 8.44 (3H, brs) , 8.45 (1H, s), 9.32 (1H, brs), 11.14 (1H, brs).
Example 388 2-[({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) amino] -1,3-thiazole Ethyl-4-carboxylate dihydrochloride 1) 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 the same manner as in Example 95-1), 2-[({[5-{[(tert -Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) amino] -1,3-thiazole-4-carboxylate Obtained as an oil.
EIMS (M + 1): 582
2) 2-[({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4) was obtained from the oily substance obtained in 1) by the same method as in Example 2-3). -Methylphenyl) pyridin-3-yl] amino} carbonyl) amino] -1,3-thiazole-4-carboxylate ethyl dihydrochloride (282 mg, 51% yield) was obtained as a white powder.
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, brs), 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, brs), 11.21 (1H, brs).

Example 389 N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -4-phenylpiperidine-1-carboxamide dihydrochloride 1) 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) ) To [(2-isobutyl-6-methyl-4- (4-methylphenyl) -5-{[(4-phenylpiperidin-1-yl) carbonyl]] in the same manner as in Example 95-1). Amino} pyridin-3-yl) methyl] carbamate tert-butyl was obtained as an oil.
EIMS (M + 1): 571
2) N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) was obtained from the oily substance obtained in 1) by the same method as in Example 2-3). ) Pyridin-3-yl] -4-phenylpiperidine-1-carboxamide dihydrochloride (240 mg, 44% yield) was obtained as a white powder.
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, brs), 3.82 (2H, brs), 3.95-3.99 (2H, m), 7.11-7.37 (9H, m), 8.19 (1H , brs), 8.44 (1H, brs).
Example 390 methyl 1-({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) pyrrolidine-2-carboxylate dihydrochloride Salt 1) 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (412 mg, 1.0 mmol) and DL-proline methyl ester ( 286 mg, 2.0 mmol) from the same method as in Example 95-1), 1-({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- Methyl (4-methylphenyl) pyridin-3-yl] amino} carbonyl) pyrrolidine-2-carboxylate was obtained as an oil.
EIMS (M + 1): 539
2) From the oily substance obtained in the above 1), 1-({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4- Methylphenyl) pyridin-3-yl] amino} carbonyl) pyrrolidine-2-carboxylate methyl dihydrochloride (400 mg, 78% yield) was obtained as a white powder.
¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.80 (3H, brs), 2.04-2.09 (1H, m),
2.11-2.23 (1H, m), 2.39 (3H, s), 2.63 (2H, s), 3.07 (4H, brs), 3.59 (3H, s), 3.86 (2H, brs), 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, brs), 8.39 (3H, brs).

Example 391 1-({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) piperidine-3-carboxylate dihydrochloride Salt 1) 5-{[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (412 mg, 1.0 mmol) and ethyl 3-piperidinecarboxylate From the ester (314 mg, 2.0 mmol), in the same manner as in Example 95-1), 1-({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl- Ethyl 4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) piperidine-3-carboxylate was obtained as an oil.
EIMS (M + 1): 567
2) From the oily substance obtained in the above 1), 1-({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4- Methylphenyl) pyridin-3-yl] amino} carbonyl) piperidine-3-carboxylate dihydrochloride (256 mg, 48% yield) was obtained as a white powder.
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, brs ), 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, brs), 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, brs), 8.29 (3H, brs).
Example 392 2- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] tetrahydroimidazo [1,5-a] pyridine-1,3 ( 2H, 5H) -Dione dihydrochloride 1) 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (412 mg, 1.0 mmol ) And 2-piperidinecarboxylic acid ethyl ester (314 mg, 2.0 mmol) in the same manner as in Example 95-1), {[5- (1,3-dioxohexahydroimidazo [1,5-a ] Pyridin-2 (3H) -yl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl was obtained as an oil.
EIMS (M + 1): 553
2) 2- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) was obtained from the oily substance obtained in 1) by the same method as in Example 2-3). ) Pyridin-3-yl] tetrahydroimidazo [1,5-a] pyridine-1,3 (2H, 5H) -dione dihydrochloride (282 mg, 57% yield) was obtained as a white powder.
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, brs), 1.99 (1H, brs), 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, brs).

Example 393 2- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -10,10a-dihydroimidazo [1,5-b] isoquinoline -1,3 (2H, 5H) -dione dihydrochloride 1) 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 the same manner as in Example 95-1), {[5- (1 , 3-Dioxo-1,5,10,10a-tetrahydroimidazo [1,5-b] isoquinolin-2 (3H) -yl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridine Obtained tert-butyl 3-yl] methyl} carbamate as an oil.
EIMS (M + 1): 569
2) 2- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) was obtained from the oily substance obtained in 1) by the same method as in Example 2-3). ) Pyridin-3-yl] -10,10a-dihydroimidazo [1,5-b] isoquinoline-1,3 (2H, 5H) -dione dihydrochloride (368 mg, 68% yield) as a white powder It was.
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, brs).
Example 394 2-({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) methyl benzoate dihydrochloride
{[5-Amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (192 mg, 0.5 mmol) and 2- (chlorocarbonyl) benzoic acid 2-({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine-] from methyl acid (149 mg, 0.75 mmol) in the same manner as in Example 223 Methyl 3-yl] amino} carbonyl) benzoate dihydrochloride (230 mg, 89% yield) was obtained as a white powder.
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 , brs), 3.77 (3H, s), 3.79 (2H, brs), 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, brs), 10.03 (1H, brs).

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) methyl benzoate (260 mg , 0.48 mmol) in the same manner as in Example 36-1), 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.
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, brs), 4.09 (3H, brs), 6.17 (1H, brs), 6.91 (1H, brs), 7.09 (2H, brs), 7.25-7.27 (3H, m), 7.37 (1H, brs), 7.88 (1H, brs).
2) 2-({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-
2-({[5- (aminomethyl) -6-] from methylphenyl) pyridin-3-yl] amino} carbonyl) benzoic acid (247 mg, 0.47 mmol) in the same manner as in Example 2-3). Isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) benzoic acid dihydrochloride (220
mg, 94% yield) was obtained as a white powder.
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 , brs), 3.86 (2H, brs), 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, brs), 10.02 (1H, brs).
Example 396 2- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -1H-isoindole-1,3 (2H) -dione Hydrochloride 1) 2-({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) From benzoic acid (260 mg, 0.48 mmol), in the same manner as in Example 3-1, {[5- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)- Tert-butyl 2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (221 mg, 94% yield) was obtained as a white powder.
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, brs), 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) {[5- (1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl ] Methyl} carbamate tert-butyl (221 mg, 0.45 mmol) from 2- [5- (aminomethyl) -6-isobutyl-2-methyl-4- ( 4-Methylphenyl) pyridin-3-yl] -1H-isoindole-1,3 (2H) -dione dihydrochloride (213 mg, 99% yield) was obtained as a white powder.
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, brs), 7.05 (2H, d, J = 7.8 Hz), 7.13 (2H, d, J = 7.8 Hz), 7.85 (4H, brs), 8.03 (3H , brs).

Example 397 3-[({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) oxy] benzoic acid methyl dihydrochloride 1) 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) and 3-[({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4 by the same method as in Example 95-1). Methyl-(4-methylphenyl) pyridin-3-yl] amino} carbonyl) oxy] benzoate was obtained as an oil.
EIMS (M + 1): 562
2) 3-[({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4) was obtained from the oily substance obtained in 1) by the same method as in Example 2-3). -Methylphenyl) pyridin-3-yl] amino} carbonyl) oxy] methyl benzoate dihydrochloride (172 mg, 32% yield) was obtained as a white powder.
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, brs), 9.75 (1H, brs).
Example 398 4-[({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) oxy] benzoic acid methyl dihydrochloride 1) 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) and 4-[({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4 by the same method as in Example 95-1). -(4-Methylphenyl) pyridin-3-yl]
Amino} carbonyl) oxy] methyl benzoate was obtained as an oil.
EIMS (M + 1): 562
2) 4-[({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4) was obtained from the oily substance obtained in 1) by the same method as in Example 2-3). -Methylphenyl) pyridin-3-yl] amino} carbonyl) oxy] methyl benzoate dihydrochloride (182 mg, 34% yield) was obtained as a white powder.
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 , brs), 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, brs), 9.71 (1H, brs).

Example 399 Methyl 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbamate dihydrochloride 1) 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) as in Example 95-1) By the method, methyl 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbamate was obtained as an oil.
EIMS (M + 1): 443
2) 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine- was obtained from the oily substance obtained in 1) by the same method as in Example 2-3). Methyl 3-yl] carbamate dihydrochloride (330 mg, 80% yield) was obtained as a white powder.
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, brs), 9.03 (1H, brs).
Example 400 {3- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -2,4-dioxoimidazolidin-1-yl} Ethyl acetate dihydrochloride 1) 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (412 mg, 1.0 mmol) and 2, 2,2 ′-[({[5-{[(tert-butoxycarbonyl) amino] methyl] was prepared from diethyl 2′-iminodiacetate (380 mg, 2.0 mmol) in the same manner as in Example 95-1). } -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) imino] diethyl acetate was obtained as white crystals (260 mg, 43% yield).
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, brs ), 6.33 (1H, brs), 7.04 (2H, d, J = 7.8 Hz), 7.25 (2H, d, J = 7.8 Hz).
2) 2,2 '-[({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} [3- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4 -Methylphenyl) pyridin-3-yl] -2,4-dioxoimidazolidin-1-yl} ethyl acetate dihydrochloride (240 mg, 98% yield) was obtained as a white powder.
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, brs).

Example 401 6-({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) pyridine-2-carboxylate ethyl dihydrochloride salt
{[5-Amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (192 mg, 0.5 mmol) and 6- (chlorocarbonyl) pyridine 2-({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methyl) was prepared from ethyl-2-carboxylate (149 mg, 0.75 mmol) in the same manner as in Example 223. Phenyl) pyridin-3-yl] amino} carbonyl) ethyl pyridine-2-carboxylate dihydrochloride (230 mg, 89% yield) was obtained as a white powder.
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, brs), 3.84 (2H, brs), 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, brs), 9.90 (1H, brs).
Example 402 6-({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) pyridine-2-carboxylic acid dihydrochloride 1) 6-({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) pyridine- From ethyl 2-carboxylate (260 mg, 0.48 mmol), in the same manner as in Example 36-1), 6-({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl- 2-Methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) pyridine-2-carboxylic acid (247 mg, 98% yield) was obtained as a white powder.
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, brs), 4.15 (2H, s), 4.42 (1H, brs), 7.01 (2H, d, J = 7.8 Hz), 7.10 (2H, d, J = 7.8 Hz), 7.99 (1H , brs), 8.21-8.31 (2H, m), 9.36 (1H, brs).
2) 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) was used in the same manner as in Example 2-3) to give 6-({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4- Methylphenyl) pyridin-3-yl] amino} carbonyl) pyridine-2-carboxylic acid dihydrochloride (221 mg, 94% yield) was obtained as a white powder.
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 , brs), 3.85 (2H, brs), 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, brs) , 10.67 (1H, brs).

Example 403 N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] pyridine-2,6-dicarboxamide dihydrochloride 1) 6- ({[5-{[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) pyridine-2-carboxylic acid (260 mg, 0.48 mmol) from the same manner as in Example 3-1), {[5-({[6- (aminocarbonyl) pyridin-2-yl] carbonyl} amino) -2-isobutyl-6 -Methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (221 mg, 94% yield) was obtained as a white powder.
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, brs), 4.29 (1H, brs), 5.53 (1H, brs), 6.75 (1H, brs), 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) {[5-({[6- (Aminocarbonyl) pyridin-2-yl] carbonyl} amino) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} Tert-Butyl carbamate (221
mg, 0.45 mmol) and N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl by the same method as in Example 2-3). ] Pyridine-2,6-dicarboxamide dihydrochloride (206 mg, 94% yield) was obtained as a white powder.
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 , brs), 3.86 (2H, brs), 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, brs), 8.80 (1H, s),
10.77 (1H, brs).
Example 404 N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -1-benzyl-4-methoxy-1H-pyrazole-3- Carboxamide dihydrochloride
{[5-Amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (192 mg, 0.5 mmol) and 1-benzyl-4-methoxy -1H-pyrazole-3-carbonyl chloride (188 mg, 0.75 mmol) was prepared in the same manner as in Example 223 by N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4- Methylphenyl) pyridin-3-yl] -1-benzyl-4-methoxy-1H-pyrazole-3-carboxamide dihydrochloride (230 mg, 81% yield) was obtained as a white powder.
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 , brs), 3.67 (3H, s), 3.81 (2H, brs), 5.15 (2H, s), 7.16-7.39 (9H, m), 8.11 (1H, s), 8.21 (3H, brs).

Example 405 N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -1,5-dimethyl-1H-pyrazole-3-carboxamide Hydrochloride
{[5-Amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (192 mg, 0.5 mmol) and 1,5-dimethyl-1H N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) was prepared from 2-pyrazole-3-carbonyl chloride (118 mg, 0.75 mmol) in the same manner as in Example 223. ) Pyridin-3-yl] -1,5-dimethyl-1H-pyrazole-3-carboxamide dihydrochloride (235 mg, 97% yield) was obtained as a white powder.
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 , brs), 3.73 (3H, s), 3.82 (2H, brs), 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, brs).
Example 406 [5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] acetic acid dihydrochloride
Performed from [5-{[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] acetic acid (0.63 g, 1.43 mmol) In the same manner as in Example 2-3), [5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] acetic acid dihydrochloride (0.56 g, Yield 94%) was obtained as a white powder.
¹ H-NMR (DMSO-d ₆ ) δ: 1.03 (9H, s), 2.41 (3H, s), 2.73 (3H, brs), 3.19 (2H, brs),
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, brs).

Example 407 [5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] acetic acid (5-methyl-2-oxo-1,3-dioxole- 4-yl) methyl dihydrochloride 1) [5-{[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] acetic acid (0.63 g, 1.43 mmol), and [5-{[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl)- 6-Neopentylpyridin-3-yl] acetic acid (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl (0.091 g, 28% yield) was obtained as a white powder.
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-{[(tert-Butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] acetic acid (5-methyl-2-oxo From -1,3-dioxol-4-yl) methyl (0.090 g, 0.16 mmol), in the same manner as in Example 2-3), [5- (aminomethyl) -2-methyl-4- (4- Methylphenyl) -6-neopentylpyridin-3-yl] acetic acid (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl dihydrochloride (0.085 g, 99% yield) pale yellow Obtained as a powder.
¹ H-NMR (DMSO-d ₆ ) δ: 1.01 (9H, s), 2.14 (3H, s), 2.38 (3H, s), 2.71 (3H, brs), 3.13 (2H, brs), 3.52 (2H , brs), 3.73 (2H, brs), 4.92 (2H, s), 7.10 (2H, d, J = 7.5 Hz), 7.31 (2H, d, J = 7.5 Hz), 8.15 (3H, brs).
Example 408 Methyl 5- (aminomethyl) -6-isobutyl-2- (methoxymethyl) -4- (4-methylphenyl) nicotinate 1) Methyl 4-methoxyacetate (5.85 g, 40 mmol) and ammonium acetate A mixture consisting of (15.4 g, 200 mmol), acetic acid (2.3 mL, 40 mmol), and toluene (100 mL) was heated to reflux for 10 hours using a Dean-Stark trap. The reaction mixture was cooled to room temperature, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give methyl 3-amino-4-methoxybut-2-enoate as a crude product (5.8 g ). From the crude product (5.8 g), 5-methyl-3-oxohexanenitrile (5.7 g, purity 87.5%, 40 mmol), and p-tolualdehyde (4.8 g, 40 mmol), Example 1-2 ), Methyl 5-cyano-6-isobutyl-2- (methoxymethyl) -4- (4-methylphenyl) -1,4-dihydropyridine-3-carboxylate (7.8 g, yield 55% ) Was obtained as a pale yellow powder.
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) From methyl 5-cyano-6-isobutyl-2- (methoxymethyl) -4- (4-methylphenyl) -1,4-dihydropyridine-3-carboxylate (7.7 g, 22 mmol), Example 23- In the same manner as in 3), methyl 5-cyano-6-isobutyl-2- (methoxymethyl) -4- (4-methylphenyl) nicotinate (7.5 g, yield 99%) was obtained as a white powder.
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) From methyl 5-cyano-6-isobutyl-2- (methoxymethyl) -4- (4-methylphenyl) nicotinate (7.4 g, 21 mmol) in the same manner as in Example 1-4), 5 -(Aminomethyl) -6-isobutyl-2- (methoxymethyl) -4- (4-methylphenyl) nicotinic acid methyl ester (7.1 g, yield 93%) was obtained as a pale yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.8 Hz), 1.22 (2H, brs), 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) Methanesulfonic acid [ 5-{[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methyl (600 mg, 1.2 mmol) and 2-mercapto ({6-Methyl-4- (4-methylphenyl) -2-neopentyl-5-[(pyridin-2-ylthio)) from pyridine (145 mg, 1.3 mmol) in the same manner as in Example 33-1) Methyl] pyridin-3-yl} methyl) carbamate tert-butyl (480 mg, 78% yield) was obtained as a powder.
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) tert-butyl ({6-methyl-4- (4-methylphenyl) -2-neopentyl-5-[(pyridin-2-ylthio) methyl] pyridin-3-yl} methyl) carbamate (200 mg, 0.395 mmol) by the same method as in Example 2-3), and {6-methyl-4- (4-methylphenyl) -2-neopentyl-5-[(pyridin-2-ylthio) methyl] pyridine-3- Ir} methylamine trihydrochloride (167 mg, 82% yield) was obtained as a powder.
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, brs), 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 Hydrochloride 1) Methanesulfonic acid [5-{[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methyl (600 mg , 1.2 mmol) and 3-mercapto-1,2,4-triazole (131 mg, 1.3 mmol) in the same manner as in Example 33-1) ({6-methyl-4- (4-methylphenyl) Tert-Butyl-2-neopentyl-5-[(4H-1,2,4-triazol-3-ylthio) methyl] pyridin-3-yl} methyl) carbamate (455 mg, 2% yield) as a powder Obtained.
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-[(4H-1,2,4-triazol-3-ylthio) methyl] pyridin-3-yl} methyl) carbamine In the same manner as in Example 2-3) from tert-butyl acid (200 mg, 0.403 mmol), {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 as a powder.
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, brs), 8.45 (1H, s).

Example 411 [5-[(1H-imidazol-2-ylthio) methyl] -6-methyl-4- (4-methylphenyl) -2-neopentylpyridin-3-yl] methylamine trihydrochloride 1) Methane Sulfonic acid [5-{[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methyl (500 mg, 1.0 mmol) and From 2-mercaptoimidazole (110 mg, 1.1 mmol) in the same manner as in Example 33-1), {[5-[(1H-imidazol-2-ylthio) methyl] -6-methyl-4- (4- Methylphenyl) -2-neopentylpyridin-3-yl] methyl} carbamate tert-butyl (373 mg, yield 75%) was obtained as a powder.
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, brs), 7.01 (2H, d, J = 7.9 Hz), 7.06 (1H, brs), 7.23 (2H , d, J = 7.9 Hz).
2) tert-butyl {[5-[(1H-imidazol-2-ylthio) methyl] -6-methyl-4- (4-methylphenyl) -2-neopentylpyridin-3-yl] methyl} carbamate ( 200 mg, 0.404 mmol), and in the same manner as in Example 2-3), [5-[(1H-imidazol-2-ylthio) methyl] -6-methyl-4- (4-methylphenyl) -2- Neopentylpyridin-3-yl] methylamine trihydrochloride (160
mg, yield 79%) was obtained as a powder.
¹ H-NMR (DMSO-d ₆ ) δ: 1.01 (9H, s), 2.40 (3H, s), 2.67 (3H, s), 3.07 (2H, brs), 3.74 (2H, brs), 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, brs).
Example 412 {6-Methyl-4- (4-methylphenyl) -2-neopentyl-5-[(pyrimidin-2-ylthio) methyl] pyridin-3-yl} methylamine trihydrochloride 1) Methanesulfonic acid [ 5-{[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methyl (500 mg, 1.0 mmol) and 2-mercapto ({6-Methyl-4- (4-methylphenyl) -2-neopentyl-5-[(pyrimidin-2-ylthio)) was prepared from pyrimidine (123 mg, 1.1 mmol) in the same manner as in Example 33-1. Methyl] pyridin-3-yl} methyl) carbamate tert-butyl (380 mg, 77% yield) was obtained as a powder.
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, brs), 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) tert-butyl ({6-methyl-4- (4-methylphenyl) -2-neopentyl-5-[(pyrimidin-2-ylthio) methyl] pyridin-3-yl} methyl) carbamate (200 mg, 0.395 mmol) to {6-methyl-4- (4-methylphenyl) -2-neopentyl-5-[(pyrimidin-2-ylthio) methyl] pyridine-3- Ir} methylamine trihydrochloride (180 mg, 88% yield) was obtained as a powder.
¹ H-NMR (DMSO-d ₆ ) δ: 1.02 (9H, s), 2.35 (3H, s), 2.85 (3H, s), 3.17 (2H, brs), 3.80 (2H, s), 4.18 (2H , s), 7.21-7.13 (5H, m), 8.22 (3H, brs), 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) Methanesulfonic acid [5-{[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methyl (500 mg, 1.0 mmol) and 5-methoxy-2-benzimidazolethiol (198 mg, 1.1 mmol) in the same manner as in Example 33-1), {[5-{[(5-methoxy-1H- Benzimidazol-2-yl) thio] methyl} -6-methyl-4- (4-methylphenyl) -2-neopentylpyridin-3-yl] methyl} carbamate tert-butyl (530 mg, 92% yield) ) Was obtained as a powder.
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] methyl} carbamate tert-butyl (200 mg, 0.365 mmol) by a method similar to that in Example 2-3) [5- {[(5-Methoxy-1H-benzimidazol-2-yl) thio] methyl} -6-methyl-4- (4-methylphenyl) -2-neopentylpyridin-3-yl] methylamine trihydrochloride ( 194 mg, 91% yield) was obtained as a powder.
¹ H-NMR (DMSO-d ₆ ) δ: 1.02 (9H, s), 2.30 (3H, s), 2.83 (3H, s), 3.12 (2H, brs), 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, brs).
Example 414 methyl 3-{[5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methoxy} -1H-pyrazole-5-carboxylate Hydrochloride 1) Methanesulfonic acid [5-{[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methyl (1.4 g , 2.85 mmol) and methyl 3-hydroxy-1H-pyrazole-5-carboxylate (426 mg, 3.0 mmol) in the same manner as in Example 33-1), 3-{[5-{[(tert-butoxy Carbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methoxy} -1H-pyrazole-5-carboxylate methyl ester (800 mg, 52% yield) ) Was obtained as a powder.
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, brs), 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, brs).
2) 3-{[5-{[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methoxy} -1H-pyrazole 3-([5- (Aminomethyl) -2-methyl-4- (4-methylphenyl)-] from methyl 5-carboxylate (200 mg, 0.373 mmol) in the same manner as in Example 2-3). 6-Neopentylpyridin-3-yl] methoxy} -1H-pyrazole-5-carboxylate methyl dihydrochloride (142 mg, yield 75%) was obtained as a powder.
¹ H-NMR (DMSO-d ₆ ) δ: 1.03 (9H, s), 2.37 (3H, s), 2.84 (3H, s), 3.23 (2H, brs), 3.81 (3H, s), 3.87 (2H , brs), 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, brs).

Example 415 3-{[5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methoxy} -1H-pyrazole-5-carboxylic acid dihydrochloride Salt 1) 3-{[5-{[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methoxy} -1H- Methyl pyrazole-5-carboxylate (1.16
g, 2.16 mmol), and 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. 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-{[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methoxy} -1H-pyrazole 3-5-[[5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6] from -5-carboxylic acid (200 mg, 0.383 mmol) in the same manner as in Example 2-3). -Neopentylpyridin-3-yl] methoxy} -1H-pyrazole-5-carboxylic acid dihydrochloride (180 mg, 95% yield) was obtained as a white powder.
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, brs).
Example 416 5- (Aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinic acid 4- (methoxycarbonyl) benzyl dihydrochloride 1) 5-{[(tert-butoxycarbonyl ) Amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinic acid (7.8 g, 18.3 mmol) in the same manner as in Example 169-1), 5-{[( tert-Butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinic acid 4- (methoxycarbonyl) benzyl (7.36 g, 70% yield) was obtained as a white solid. It was.
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) 5-{[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinic acid 4- (methoxycarbonyl) benzyl (200 mg, 0.348 mmol) To 5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinic acid 4- (methoxycarbonyl) benzyl dihydrochloride by the same method as in Example 2-3). 181 mg, 95% yield) was obtained as a white powder.
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, brs).

Example 417 4-[({[5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] carbonyl} oxy) methyl] benzoic acid dihydrochloride 1) 5-{[(tert-Butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinic acid 4- (methoxycarbonyl) benzyl (2.0 g, 3.48 mmol) To 4-(({[5-{[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neo in the same manner as in Example 9-1). Pentylpyridin-3-yl] carbonyl} oxy) methyl] benzoic acid (1.68 g, 86% yield) was obtained as a white solid.
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-{[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] carbonyl} oxy) 4-[({[5- (aminomethyl) -2-methyl-4- (4-methylphenyl)-] from methyl] benzoic acid (200 mg, 0.357 mmol) in the same manner as in Example 2-3). 6-Neopentylpyridin-3-yl] carbonyl} oxy) methyl] benzoic acid dihydrochloride (150 mg, 79% yield) was obtained as a white powder.
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, brs).
Example 418 [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetic acid 4- (trifluoromethyl) benzyl dihydrochloride 1) [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)- In the same manner as in Example 169-1), 4- (trifluoromethyl) benzene (250 mg, 1.05 mmol), [5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2- Methyl-4- (4-methylphenyl) pyridin-3-yl] acetic acid 4- (trifluoromethyl) benzyl (350 mg, 85% yield) was obtained as a white powder.
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, brs), 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) [5-{[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetic acid 4- (trifluoromethyl) benzyl ( [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetic acid by the same method as in Example 2-3) from 330 mg, 0.564 mmol). 4- (Trifluoromethyl) benzyl dihydrochloride (283 mg, 66% yield) was obtained as a white powder.
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, brs).

Example 419 [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetic acid 4-fluorobenzyl dihydrochloride 1) [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) to [5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methyl) in the same manner as in Example 169-1). Phenyl) pyridin-3-yl] acetic acid 4-fluorobenzyl (325 mg, 86% yield) was obtained as a white powder.
¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.11-2.26 (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, brs), 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) [5-{[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetic acid 4-fluorobenzyl (300 mg, 0.561 mmol) to 4-fluorobenzyl [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetate by the same method as in Example 2-3). Dihydrochloride (234 mg, 82% yield) was obtained as a white powder.
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, brs).
Example 420 {[2-Isobutyl-6-methyl-4- (4-methylphenyl) -5- (2-oxo-2-pyrrolidin-1-ylethyl) pyridin-3-yl] methyl} amine dihydrochloride 1 ) [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) by the same method as in Example 311-1), {[2-isobutyl-6-methyl-4- (4-methylphenyl) -5- (2-oxo-2-pyrrolidine-1 -Ilethyl) pyridin-3-yl] methyl} carbamate tert-butyl (120 mg, 36% yield) was obtained as a white powder.
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, brs), 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-ylethyl) pyridin-3-yl] methyl} tert-butyl carbamate ( 100 mg, 0.208 mmol) from the same manner as in Example 2-3), {[2-isobutyl-6-methyl-4- (4-methylphenyl) -5- (2-oxo-2-pyrrolidine-1 -Iylethyl) pyridin-3-yl] methyl} amine dihydrochloride (62.4 mg, 66% yield) was obtained as a white powder.
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, brs).

Example 421 1-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} ethyl ethyl piperidine-4-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) and piperidine-4 1-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl was prepared from ethyl-carboxylate (553 mg, 3.52 mmol) in the same manner as in Example 311-1). Ethyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} piperidine-4-carboxylate (330 mg, yield 50%) was obtained as a white powder.
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, brs), 6.98 (2H, d, J = 8.1 Hz), 7.21 (2H, d, J = 8.1 Hz).
2) 1-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} piperidine-4-carboxyl 1-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine from ethyl acetate (20 mg, 0.0354 mmol) in the same manner as in Example 2-3) -3-yl] acetyl} ethyl piperidine-4-carboxylate dihydrochloride (8.2 mg, 43% yield) was obtained as a white powder.
EIMS (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} ethyl piperidine-4-carboxylate ( 290 mg, 0.513 mmol) to 1-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4) by the same method as in Example 9-1). -Methylphenyl) pyridin-3-yl] acetyl} piperidine-4-carboxylic acid (240 mg, 87% yield) was obtained as a white powder.
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, brs), 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-{[(tert- Example 2 from butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} piperidine-4-carboxylic acid (230 mg, 0.428 mmol) 3) 1-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} piperidine-4-carboxylic acid The hydrochloride (220 mg, 100% yield) was obtained as a white powder.
EIMS (M + 1): 438

Example 423 N-2-adamantyl-2- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetamide dihydrochloride 1) [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) by the same method as in Example 311-1), {[5- [2- (2-adamantylamino) -2-oxoethyl] -2-isobutyl-6-methyl-4- (4- Methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (50 mg, 13% yield) was obtained as a white powder.
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, brs), 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) 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) to N-2-adamantyl-2- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methyl) by a method similar to that in Example 2-3). Phenyl) pyridin-3-yl] acetamide dihydrochloride (45.1 mg, 100% yield) was obtained as a white powder.
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, brs).
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 solution was stirred at room temperature for 16 hours. The reaction solution was poured into saturated brine and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain [(2-isobutyl-6-methyl-4- (4-methylphenyl) -5- {2-oxo-2-[(2-thienylmethyl) amino] ethyl} Pyridin-3-yl) methyl] carbamate tert-butyl (493 mg, 81% yield) was obtained 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, brs), 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-Isobutyl-6-methyl-4- (4-methylphenyl) -5- {2-oxo-2-[(2-thienylmethyl) amino] ethyl} pyridin-3-yl) methyl] carbamine 2- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) was obtained from tert-butyl acid (480 mg, 0.92 mmol) in the same manner as in Example 2-3). Pyridin-3-yl] -N- (2-thienylmethyl) acetamide dihydrochloride (300 mg, 66% yield) was obtained as a white powder.
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, brs).

Example 425 2- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -N- (pyridin-3-ylmethyl) acetamide Trihydrochloride 1 ) [5-{[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetic acid (500 mg, 1.17 mmol) and 3- [(2-Isobutyl-6-methyl-4- (4-methylphenyl) -5- {2-oxo] was prepared from (aminomethyl) pyridine (133 mg, 1.17 mmol) in the same manner as in Example 424-1). Tert-Butyl-2-[(pyridin-3-ylmethyl) amino] ethyl} pyridin-3-yl) methyl] carbamate (394 mg, yield 65%) was obtained as a white powder.
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, brs), 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-Isobutyl-6-methyl-4- (4-methylphenyl) -5- {2-oxo-2-[(pyridin-3-ylmethyl) amino] ethyl} pyridin-3-yl) methyl] 2- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) was prepared from tert-butyl carbamate (380 mg, 0.74 mmol) in the same manner as in Example 2-3). ) Pyridin-3-yl] -N- (pyridin-3-ylmethyl) acetamide trihydrochloride (380 mg, 98% yield) was obtained as a white powder.
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, brs), 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 Salt 1) With [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), 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 stirred at room temperature for 24 hours. The reaction solution was poured into saturated brine and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give 4-({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine-3. Methyl -yl] acetyl} amino) thiophene-3-carboxylate (440 mg, 66% yield) was obtained 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, brs), 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) 4-({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) thiophene- In the same manner as in Example 2-3), methyl 3-carboxylate (262 mg, 0.46 mmol) was used to prepare 4-({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4- Methylphenyl) pyridin-3-yl] acetyl} amino) thiophene-3-carboxylic acid methyl dihydrochloride (161 mg, 65% yield) was obtained as a white powder.
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 brs), 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-
4-({[5-{[(methylphenyl) pyridin-3-yl] acetyl} amino) thiophene-3-carboxylate (280 mg, 0.495 mmol) by a method similar to that in Example 9-1). tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) thiophene-3-carboxylic acid (183 mg, 67% yield) ) Was obtained as a white powder.
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, brs), 6.98-7.25 (4H, m), 7.85-8.05 (2H, m).
2) 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) to 4-({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] by the same method as in Example 2-3). Acetyl} amino) thiophene-3-carboxylic acid dihydrochloride (143 mg, 64% yield) was obtained 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), 2.35 (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 4-({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) methyl benzoate 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 4-aminobenzoic acid Methyl acid (177
mg, 1.17 mmol) to 4-({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4) by the same method as in Example 426-1). -Methylphenyl) pyridin-3-yl] acetyl} amino) methyl benzoate (442 mg, 67% yield) was obtained as a white powder.
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, brs), 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) 4-({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) benzoic acid 4-({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine] was prepared from methyl (154 mg, 0.275 mmol) in the same manner as in Example 2-3). -3-yl] acetyl} amino) methyl benzoate dihydrochloride (142 mg, 97% yield) was obtained 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), 2.36 (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, brs).

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) methyl benzoate (280 mg , 0.500 mmol) by the same method as in Example 9-1), 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.
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, brs), 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-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-
4-({[5- (aminomethyl) -6-isobutyl] from methylphenyl) pyridin-3-yl] acetyl} amino) benzoic acid (270 mg, 0.495 mmol) in the same manner as in Example 2-3) -2-Methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) benzoic acid dihydrochloride (235 mg, 92% yield) was obtained as a white powder.
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, brs).
Example 430 2-[({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) methyl] -1,3-thiazole Ethyl 4-carboxylate dihydrochloride 1) ethyl 2-({[(benzyloxy) carbonyl] amino} methyl) -1,3-thiazole-4-carboxylate (3.5 g, 10.9 mmol) brominated in 30% Dissolved in hydrogen-acetic acid solution (50 mL) and stirred at room temperature for 2 hours. The white precipitate was collected by filtration and dissolved in saturated aqueous sodium hydrogen carbonate. The obtained solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give ethyl 2- (aminomethyl) -1,3-thiazole-4-carboxylate (793 mg, yield 40%) as an oil. . The 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) by the same method as in Example 424-1), 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, yield 100%) was obtained as a white powder.
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, brs), 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) 2-[({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) methyl 2-[({[5- (aminomethyl) -6-isobutyl-] from ethyl] -1,3-thiazole-4-carboxylate (178 mg, 0.299 mmol) in the same manner as in Example 2-3). 2-Methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) methyl] -1,3-thiazole-4-carboxylate dihydrochloride (138 mg, 81% yield) in white Obtained as a powder.
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, brs), 8.91 (1H, s).

Example 431 2-[({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) methyl] -1,3-thiazole -4-carboxylic acid dihydrochloride 1) 2-[({[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine-3 -Yl] acetyl} amino) methyl] -1,3-thiazole-4-carboxylate (460 mg, 0.773 mmol) was prepared in the same manner as in Example 9-1) by 2-[({[5- { [(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) methyl] -1,3-thiazole-4-carboxylic The acid (438 mg, 100% yield) was obtained as a white powder.
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, brs), 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) 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) by the same method as in Example 2-3), 2-[({[5- (aminomethyl) -6-isobutyl-2 -Methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) methyl] -1,3-thiazole-4-carboxylic acid dihydrochloride (235 mg, 91% yield) as a white powder Obtained.
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, brs).
Example 432 Methyl 1-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} prolinate 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 methylproline hydrochloride (194 mg, 1.17 mmol) to methyl 1-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methyl) by a method similar to that in Example 426-1). Phenyl) pyridin-3-yl] acetyl} prolinate (456 mg, 72% yield) was obtained as a white powder.
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-{[5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} prolinate (456 mg , 0.848 mmol) and methyl 1-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] in the same manner as in Example 2-3). ] Acetyl} prolinate dihydrochloride (277.5
mg, yield 64%) was obtained as a white powder.
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-Oxadiazol-3-yl) benzamide dihydrochloride
{[5-Amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (383 mg, 1.0 mmol) in tetrahydrofuran (5 mL) solution After adding 3-cyanobenzoyl chloride (245 mg, 1.5 mmol), triethylamine (280 μL,
2.0 mmol) was added and stirred for 18 hours. A saturated aqueous sodium carbonate solution (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain an oil. To a solution of the oil in ethanol (5 mL) was added sodium carbonate (420 mg,
4.0 mmol) and hydroxylamine hydrochloride (192 mg, 3.0 mmol) were added and stirred at 80 ° C. for 15 hours. Distilled water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain an oily substance. N, N′-carbonyldiimidazole (324 mg, 2.0 mmol) was added to a tetrahydrofuran (3 ml) solution of the oil, and the mixture was stirred at 65 ° C. for 2 hours. A saturated aqueous sodium carbonate solution (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain an oil. To a solution of the obtained oil in ethyl acetate (2 mL) was added 4N hydrogen chloride-ethyl acetate solution (2 mL), and the mixture was stirred at room temperature for 3 hr. The residue obtained by evaporating the solvent under reduced pressure was crystallized from hexane, and N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl ] -3- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) benzamide dihydrochloride (115 mg, yield 21%) was obtained as a white powder.
¹ H-NMR (DOSO-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, brs), 10.13 (1H, brs), 13.12 (1H, brs).

Experimental example 1
Measurement of dipeptidyl peptidase IV inhibitory activity in rat plasma The reaction was carried out using a 96-well flat bottom plate according to the method of Raymond et al. (Diabetes, 47, 1253-1258, 1998). Performed at 30 ° C. 69 μL of water, 10 μL of 1M Tris-HCl buffer (pH 7.5), 1 μL of a test compound N, N-dimethylformamide solution was added to 100 μL of a 1 mM Gly-Pro-p-NA aqueous solution to prepare a mixed solution. Subsequently, 20 μL of plasma prepared from SD rat blood by a conventional method was added to the above mixed solution, and an enzyme reaction was started at 30 ° C. The absorbance after 0 hour and 1 hour was measured at a wavelength of 405 nm using a microplate reader, and the increase (ΔODs) was determined. At the same time, the increase in absorbance (ΔODc) in the reaction solution not containing the test compound and the increase in absorbance (ΔODb) in the reaction solution not containing the test compound and enzyme were determined, and the inhibition rate of the dipeptidyl peptidase IV enzyme activity was calculated. :
{1-[(ΔODs−ΔODb) / (ΔODc−ΔODb)]} × 100
Determined by
The dipeptidyl peptidase IV inhibitory activity of the test compound group was expressed as an IC ₅₀ value (nM) and is shown in [Table 5].

  Thus, since the compound of the present invention has excellent dipeptidyl peptidase IV inhibitory activity, it is useful as a prophylactic / therapeutic agent for diabetes.

Experimental example 2
Measurement of dipeptidyl peptidase IV inhibitory activity in rat plasma In the same manner as in Experimental Example 1, the dipeptidyl peptidase IV inhibitory activity of the test compound was measured. The results are shown in [Table 6].

  Thus, since the compound of the present invention has excellent dipeptidyl peptidase IV inhibitory activity, it is useful as a prophylactic / therapeutic agent for diabetes.

Formulation Example 1 (Manufacture of capsules)
1) Compound of Example 1 30 mg
2) Fine powder cellulose 10 mg
3) Lactose 19 mg
4) Magnesium stearate 1 mg
60 mg total
1), 2), 3) and 4) are mixed and filled into gelatin capsules.
Formulation Example 2 (Manufacture of tablets)
1) 30 g of the compound of Example 1
2) Lactose 50 g
3) Corn starch 15 g
4) Carboxymethylcellulose calcium 44 g
5) Magnesium stearate 1 g
1000 tablets total 140 g
The total amount of 1), 2), and 3) and 30 g of 4) are kneaded with water, dried in vacuum, and then sized. 14 g of 4) and 1 g of 5) are mixed with the sized powder, and tableted with a tableting machine. In this way, 1000 tablets containing 30 mg of the compound of Example 1 per tablet are obtained.

  The compound of the present invention has an excellent peptidase inhibitory action and is useful as a prophylactic / therapeutic agent for diabetes.

Claims (12)

formula

[Where:
R ¹ and R ² are the same or different,
(1) a C _1-10 alkyl group which may be substituted with 1 to 3 substituents selected from a C _3-10 cycloalkyl group, a C _1-6 alkoxy-carbonyl group and a C _1-6 alkoxy group;
(2) a C _6-14 aryl group optionally substituted with 1 to 3 substituents selected from a halogen atom, a carboxyl group, a C _1-6 alkoxy-carbonyl group and a carbamoyl group; or (3) C _{7 -13} aralkyl groups;
R ³ is a C _1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, a halogen atom, a C _1-6 alkoxy-carbonyl group, a carboxyl group, a hydroxy group, and 1 to 3 halogen atoms. Phenyl optionally substituted with 1 to 3 substituents selected from C _1-6 alkoxy groups optionally substituted with
R ⁴ represents an amino group,
L is methylene,
Q is a bond, —CH ₂ —, — (CH ₂ ) ₂ — or —CH═CH—, and X is
(3) (3a) carboxyl group;
(3b) a carbamoyl group;
(3c) C ₁ which may be substituted with 1 to 3 substituents selected from a carboxyl group, a carbamoyl group, a thiocarbamoyl group, a C _1-6 alkoxy-carbonyl group and a C _1-6 alkyl-carbonyloxy group. _-6 alkoxy-carbonyl group;
(3d) an aromatic heterocyclic ring-C _1-6 alkoxy-carbonyl optionally substituted with 1 to 3 substituents selected from a carboxyl group, a carbamoyl group, a thiocarbamoyl group and a C _1-6 alkoxy-carbonyl group Group;
(3e) a non-aromatic heterocyclic ring optionally substituted with a C _1-6 alkyl group-C _1-6 alkoxy-carbonyl group;
(3f) carboxyl group, carbamoyl group, thiocarbamoyl group, C _1-6 alkoxy-carbonyl group, halogen atom, cyano group, nitro group, C _1-6 alkoxy group, C _1-6 alkylsulfonyl group and C _1-6 An alkyl group (the C _1-6 alkyl group may be substituted with 1 to 3 substituents selected from a halogen atom, a carboxyl group, a C _1-6 alkoxy-carbonyl group and a carbamoyl group); A C _7-13 aralkyloxy-carbonyl group _optionally substituted by 1 to 3 substituents;
(3g) a carbamoyl group mono- or di-substituted with a C _1-6 alkyl group which may be substituted with 1 to 3 substituents selected from a halogen atom and a C _1-6 alkoxy group;
(3h) a carbamoyl-C _1-6 alkyl-carbamoyl group optionally mono- or disubstituted with a C _1-6 alkyl group _optionally substituted with 1 to 3 halogen atoms;
(3i) C _1-6 alkyl optionally substituted with C _1-6 alkoxy - carbonyl -C _1-6 alkyl - carbamoyl group;
(3j) a mono- or di-C _3-10 cycloalkyl-carbamoyl group optionally substituted by a C _1-6 alkyl group;
(3k) C _7-13 aralkyl optionally substituted with 1 to 3 substituents selected from a halogen atom, hydroxy group, carboxyl group, C _1-6 alkoxy-carbonyl group and C _1-6 alkyl group A carbamoyl group;
(3l) an aromatic heterocyclic ring-C _1-6 alkyl-carbamoyl group optionally substituted with 1 to 3 substituents selected from a carboxyl group, a carbamoyl group and a C _1-6 alkoxy-carbonyl group;
(3m) a C _1-6 alkylsulfonyl group which may be substituted with 1 to 3 substituents selected from a carboxyl group, a carbamoyl group and a C _1-6 alkoxy-carbonyl group;
(3n) substituted with 1 to 3 substituents selected from C _1-6 alkyl group, carboxyl group, carbamoyl group, thiocarbamoyl group, C _1-6 alkoxy-carbonyl group and C _1-6 alkylsulfonyl group An _{optionally substituted} C _6-14 arylsulfonyl group;
(3o) a nitrogen-containing heterocyclic-carbonyl group which may be substituted with 1 to 3 substituents selected from a hydroxy group, a carboxyl group and a C _1-6 alkoxy-carbonyl group;
(3p) a C _6-14 aryl-nitrogen-containing heterocyclic-carbonyl group optionally substituted with 1 to 3 halogen atoms;
(3q) a C _7-13 aralkyl-nitrogen-containing heterocyclic-carbonyl group optionally substituted with 1 to 3 halogen atoms;
(3r) a non-aromatic heterocyclic oxy-carbonyl group;
(3s) a phosphono group which may be mono- or di-substituted with a C _1-6 alkyl group;
(3t) aromatic heterocycle-C _7-13 aralkyloxy-carbonyl group;
(3u) a C _3-10 cycloalkyl-C _1-6 alkoxy-carbonyl group optionally substituted with 1 to 3 substituents selected from a carboxyl group, a C _1-6 alkoxy-carbonyl group and a carbamoyl group;
(3v) From an amino group, a carboxyl group, a C _1-6 alkoxy-carbonyl group, an aromatic heterocyclic group, a non-aromatic heterocyclic group and a carbamoyl group which may be mono- or di-substituted with a C _1-6 alkyl group A C _6-14 aryl-carbamoyl group _optionally substituted with 1 to 3 selected substituents;
(3w) an aromatic heterocyclic-carbamoyl group optionally substituted by 1 to 3 substituents selected from a carboxyl group, a C _1-6 alkoxy-carbonyl group and a carbamoyl group;
(4) (4a) a C _1-6 alkyl-carbonyloxy group;
(4b) a C _1-10 alkoxy group which may be substituted with 1 to 3 substituents selected from a hydroxy group, a carboxyl group, a carbamoyl group and a C _1-6 alkoxy-carbonyl group;
(4c) halogen atom, carboxyl group, C _1-6 alkoxy-carbonyl group, C _1-6 alkylthio group, carbamoyl group, C _1-6 alkoxy group, C _1-6 alkylsulfonyl group, C _1-6 alkylsulfinyl group And a C _1-6 alkyl group (the C _1-6 alkyl group may be substituted with one or two substituents selected from a carboxyl group, a C _1-6 alkoxy-carbonyl group, and a carbamoyl group). A C _6-14 aryloxy group _optionally substituted by 1 to 3 selected substituents;
(4d) C _1-6 alkyl group (the C _1-6 alkyl group may be substituted with 1 or 2 substituents selected from a carboxyl group, a C _1-6 alkoxy-carbonyl group, and a carbamoyl group) ), A 5- or 6-membered aromatic heterocyclic oxy group optionally substituted with 1 to 3 substituents selected from a carboxyl group, a C _1-6 alkoxy-carbonyl group and a carbamoyl group;
(4e) a condensed aromatic heterocyclic oxy group optionally substituted with 1 to 3 substituents selected from a carboxyl group, a C _1-6 alkoxy-carbonyl group, and a carbamoyl group;
(4f) an aromatic heterocyclic ring -C _1-6 alkoxy group optionally substituted with 1 to 3 substituents selected from a carboxyl group, a C _1-6 alkoxy-carbonyl group and a carbamoyl group;
(4g) Aromatic heterocycle-C _6-14 aryloxy group;
(5) (5a) a C _1-6 alkylthio group optionally substituted by 1 to 3 substituents selected from a hydroxy group, a carboxyl group, a carbamoyl group and a C _1-6 alkoxy-carbonyl group;
(5b) a C _6-14 arylthio group optionally substituted by 1 to 3 substituents selected from a carboxyl group, a C _1-6 alkoxy-carbonyl group, a C _1-6 alkylthio group, and a carbamoyl group;
(5c) 5- or 6-membered aromatic heterocyclic thio optionally substituted with 1 to 3 substituents selected from a C _1-6 alkyl group, a carboxyl group, a C _1-6 alkoxy-carbonyl group and a carbamoyl group Group;
(6) (6a) amino group;
(6b) a C _1-6 alkoxy-carbonyl-C _1-10 alkylamino group;
(6c) a carboxy-C _1-10 alkylamino group;
(6d) a C _7-13 aralkyloxy-carbonylamino group optionally substituted with 1 to 3 substituents selected from a carboxyl group, a C _1-6 alkoxy-carbonyl group, and a carbamoyl group;
(6e) a carbamoylamino group;
(6f) mono- or di-C _1-6 alkyl-carbamoylamino group;
(6g) C _1-6 alkylsulfonylamino group;
(6h) a C _6-14 arylsulfonylamino group _optionally substituted with a C _1-6 alkylsulfonyl group;
(6i) Aromatic heterocyclyl-sulfonyl optionally substituted with 1 to 3 substituents selected from a C _1-6 alkyl group and a mono- or di- (C _1-6 alkyl-carbonyl) -amino group An amino group;
(6j) mono- or di- (C _1-6 alkyl-carbonyl) -amino group;
(6k) a C _3-10 cycloalkyl-carbonylamino group;
(6l) halogen atom, cyano group, optionally halogenated C _1-6 alkyl group, C _1-6 alkoxy group, carboxyl group, C _1-6 alkoxy-carbonyl group, aromatic heterocyclic group, non-aromatic A C _6-14 aryl-carbonylamino group _optionally substituted with 1 to 3 substituents selected from a heterocyclic group and a carbamoyl group;
(6m) C _7-13 aralkyl-carbonylamino group;
(6n) a C _8-13 arylalkenyl-carbonylamino group;
(6o) 1 to 3 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, a C _1-6 alkoxy-carbonyl group and a carbamoyl group An aromatic heterocyclic-carbonylamino group optionally substituted with three substituents;
(6p) C _1-6 alkyl group (the C _1-6 alkyl group may be substituted with 1 to 3 substituents selected from a carboxyl group, a C _1-6 alkoxy-carbonyl group, and a carbamoyl group) ), A nitrogen-containing heterocyclic-carbonylamino group optionally substituted with 1 to 3 substituents selected from a carboxyl group, a C _1-6 alkoxy-carbonyl group and a carbamoyl group;
(6q) C _6-14 aryl-nitrogen-containing heterocyclic-carbonylamino group;
(6r) tetrahydropyranylcarbonylamino group;
(6s) 4-oxo-4,5,6,7-tetrahydro-1-benzofuranyl-carbonylamino group;
(6t) a C _1-6 alkoxy-carbonylamino group optionally substituted by a C _1-6 alkoxy-carbonyl group;
(6u) a C _6-14 aryloxy-carbonylamino group optionally substituted with 1 to 3 substituents selected from a carboxyl group, a C _1-6 alkoxy-carbonyl group, and a carbamoyl group;
(6v) a C _7-13 aralkyl-carbamoylamino group; or
(6w) an aromatic heterocyclic-carbamoylamino group optionally substituted with 1 to 3 substituents selected from a carboxyl group, a C _1-6 alkoxy-carbonyl group and a carbamoyl group;
Indicates.
However, when X is an ethoxycarbonyl group, Q represents —CH ₂ —, — (CH ₂ ) ₂ — or —CH═CH—] or a salt thereof. R ¹ and R ² may be the same or different and may be substituted with 1 to 3 substituents selected from a C _3-10 cycloalkyl group, a C _1-6 alkoxy-carbonyl group and a C _1-6 alkoxy group. 2. A compound according to claim 1 which is a good _C1-10 alkyl group. 2. R ³ is phenyl optionally substituted by 1 to 3 substituents selected from a C _1-6 alkyl group _optionally substituted with 1 to 3 halogen atoms and a halogen atom. Compound.   The compound according to claim 1, wherein Q is a bond.   The compound according to claim 1, wherein X is a carboxyl group. 5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinic acid;
5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid;
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;
3-({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) methyl benzoate;
The N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] isoxazole-4-carboxamide, or a salt thereof. Compound.   A medicament comprising the compound according to claim 1 or a salt thereof.   The medicament according to claim 7, which is a prophylactic / therapeutic agent for diabetes, diabetic complications, glucose intolerance or obesity.   A dipeptidyl peptidase-IV inhibitor comprising the compound according to claim 1 or a salt thereof.   Use of the compound according to claim 1 or a salt thereof for producing a prophylactic / therapeutic agent for diabetes, diabetic complications, glucose intolerance or obesity.   Use of the compound according to claim 1 or a salt thereof for producing a dipeptidyl peptidase-IV inhibitor. formula

[Wherein R ¹ , R ² , R ³ , X and Q are as defined in claim 1,
La is shows the bond. Or a salt thereof is subjected to a reduction reaction,

[The symbols in the formula are as defined above] or a method for producing a salt thereof.