SA05260027B1 - Pyridine compound - Google Patents

Abstract

A compound represented by the formula wherein R<1> and R<2> are the same or different and each is an optionally substituted hydrocarbon group or an optionally substituted hydroxy group; R<3> is an optionally substituted aromatic group; R<4> is an optionally substituted amino group; L is a divalent chain hydrocarbon group; Q is a bond or a divalent chain hydrocarbon group; and X is a hydrogen atom, a cyano group, a nitro group, an acyl group, a substituted hydroxy group, an optionally substituted thiol group, an optionally substituted amino group or an optionally substituted cyclic group; provided that when X is an ethoxycarbonyl group, then Q is a divalent chain hydrocarbon group. The compound has a peptidase inhibitory action, is useful as an agent for the prophylaxis or treatment of diabetes and the like, and is superior in efficacy, duration of action, specificity, lower toxicity and the like.

Description

¥ Pyridine Compound Full Description Background of the invention

The present invention relates to a pyridin compound having inhibitory activity for 0600286 useful as an agent

For the prevention or treatment of diabetes, etc. Peptidase is known to be associated with many diseases. The dipeptidyl dipeptidase-IV© (sometimes abbreviated here later as “DPP-IV”) is a type of peptidase, a serine protease that binds specifically to a peptide containing (alanine 4) proline. At the second place of Noi jbl and the terminal side-6 separates for proline (R) alanine to yield a dipeptide DPP-IV turns out to be the same molecule (ia 0026; it is registered as overlapping Also in the immune system Although the role of 007-17 in Aminobacteria is not yet fully understood, it is considered to play an important role in the metabolism of neuropeptides; activation of oT cells; adhesion of cancer cells to vascular endothelial cells blood, intracellular penetration of HIV, etc. Specifically, with regard to Sud metabolism, “DPP-IV is involved in the suppression of GLP-1 (glucagon-like peptide-1) glucagon.” peptide) GIP is a gastric inhibitory peptide/Glucose-dependent insulinotropic peptide 8 which are incretins with respect to GLP-1 in addition to Moreover, it is known that the physiological activity of GLP-1 is severely defective because it has a short plasma half-life of 1-? min. that GLP-1 amide (7-9”); which is a product of degradation by DPP-IV affecting the GLP-1 receptor as an antagonist; Thus, GLP-1 is hydrolyzed by 17-077. It is also known that stopping 0 degradation of GLP-1 by inhibiting DPP-IV activity leads to potentiation of the physiological activity exhibited by GLP-1 such as glucose concentration-dependent insulin efflux, etc. . of these facts; A compound with inhibitory activity of 007-17 would be expected to exhibit an effect on the impaired tolerance of 1060586p; High blood glucose after eating and high blood glucose with fasting v etc.; Obesity or complications of diabetes oY and type 1 observed in type 1 diabetes etc. associated ead The following compounds have been approved. Pyridine as a compound compound represented by the formula: (1)

R, =

RR NR ° is Ry etc.; “alkyl hydroxy hydrogen each separately is Res Ry where chydrogen st Rss etc? B E amido cihydroxy cholesterol ester transporter protein for Jays ia etc.; It has a “hydroxy” halogen effect (see CETP (abbreviated herein later as “cholesterol ester transfer protein”). (W099/41 237 00 0) in the form: Bde compound “”)

A

=

L N E alu Ls alkyl is D etc; chalogen optionally substituted by Copp aryl is A where is

E be ¢hydroxy or less optionally substituted by carbon atoms of straight or branched chain A straight or branched having an m alkyl chain and a same or different and each of which 0 is dl T etc ; “Cy cycloalkyl or less optionally substituted by carbon atoms and 85 isomers or dissimilars each with RT or 25-0807086 (where < halogen hydrogen etc.; “li is chydrogen is rR etc.; “Cg.10 aryl” Cig cycloalkyl tglucagon or resistance effect for CETP 0; etc.), which has an inhibitory effect to a compound represented by the formula: Ye

A

EEE

© Z L N T

£ where A is aryl mm optionally substituted 5 halogen da ul etc; EsD are the same or different and each is a straight or branched chain alkyl having A carbon atoms or fewer optionally substituted by 17 thydroxy is ©; 5 or 118 (where SARS is straight or branched chain alkyl hydrogen with at least 6 J carbon atoms R' ¢(phenyl is “Coo aryl” Ci cycloalkyl etc.; TL is the same or different and each of them is “trifluoromethyl etc.; and a compound represented by the formula: Ar Ar 4_5 “NO R NOR R ye rR” > mg 8 N 8 where Ar is an aromatic or hetero-aromatic group Optionally substituted; RY and 85 each Ve of each being “Cr alkyl hydrogen etc.” L and L 8 each separately being “Cig alkyl” trifluoromethyl etc. (see WO98/04528) American Invention No. (1) A compound represented by the formula: A = L N E Vo where A and 2 are the same or different and each has a Corp aryl optionally substituted by a halogen etc.; D is a straight or branched chain alkyl with A carbon atoms or less optionally inferred by L ¢hydroxy is a straight or branched chain alkyl Cag cycloalkyl with A carbon atoms or less “Jd etc; 7 is a conjugate or RERHROC- (where 83 and 87 are the same or different and each is “Ce.10 aryl” Cs.g cycloalkyl etc; R' is hydrogen etc; R® Y: is cazido < halogen hydrogen etc.); or salt thereof; It has an inhibitory effect to CETP (see US Patent No. (eaYego) (£) A compound represented by the formula:

° R, = RF NR where JS Res Rp of them separately is “chloroalkyl cbromoalkyl etc.; calkyl s—a Ry alkoxyalkyl «cycloalkyl calkylthioalkyl »cycloalkylalkyl or ¢dialkylaminoalkyl One of Rss Ry is CO-Y (where Y is alkoxy calkylthio or heterocyclic © group contain oN and the other is 6 <«( -("008708-- (where p is an integer of -1 ?; ROR each separately is "alkyl < hydrogen etc.; X is chalogen 011; etc.); etc.; or a salt thereof that has a herbicidal effect (see W092/2065 9 (©). Compound represented by the formula: NH, NHR NRX R “' 8 R 10 where R ! is hydrogen or R? teller alkyl is a heterocyclic group or aryl each optionally substituted by a dower alkyl etc; 183 Rs may form a phenyl ring etc.; each optionally substituted by a chalogen etc.; together with the carbon atoms bonded to them or a salt thereof; which has an inhibitory effect to DPP-IV (see 177003/068748). In the form: NHR soft 0 rR' adverb where X is mu CR' JN (where R® is hydrogen or lower alkyl 4 and 22 each separately is hydrogen or flower alkyl 183 is a heterocyclic or aryl group

0 JS of which optionally replaced by dower alkyl etc .; R* is dower alkyl etc; or salt thereof; which has an inhibitory effect on DPP-IV (see 068757/17003). However, the compound of the present invention is not mentioned. GENERAL DESCRIPTION OF THE INVENTION ° There is a need to develop a compound with an inhibitory effect for 0600056 that would be useful as an agent for the prevention or treatment of diabetes etc.; and excellent in effectiveness; selective duration of effect; low toxicity; etc. The present inventors first found that a compound of the formula: RA NR ! xq PLR 80 Rr? Ve where: RZ R! are the same or different and each is an optionally substituted hydrocarbon group or a hydroxy group optionally substituted; R? is an optionally substituted aromatic group; R* is an optionally substituted amino group; L Yo is a divalent chain hydrocarbon group;

Q is a double chain hydrocarbon bond or group (58 ¢ f).

X is a hydrogen atom “cyano group” (nitro group acyl group hydroxy group substituted; optionally substituted thiol group optionally substituted amino group or optionally substituted cyclic group;

7 Provided that: when X is a cethoxycarbonyl group, then © is a divalent chain hydrocarbon group and that compound is not: 2,6-diisopropyl-3-methylaminomethyl-4-(4-fluorophenyl)- 5-pentylpyridine;2,6-diisopropyl-3-aminomethyl-4-(4-fluorophenyl)-5-pentylpyridine;2,6-diisopropyl-3-(dimethylamino)methyl-4-(4-fluorophenyl) -5-pentylpyridine; Yo 2,6-diisopropyl-3-(ethylamino)methyl-4-(4-fluorophenyl)-5-pentylpyridine;

3-(tert-butyldimethylsilyloxymethyl)-2,6-diisopropyl-4-(4-fluorophenyl)-5-(indolyl- 5-aminomethyl)pyridine, or a salt thereof [sometimes abbreviated hereafter as compound () ]; Which is characterized by a chemical structure in which an optionally substituted amino group is attached to the ? From the pyridine ring via the hydrocarbon group © bivalent chain The aromatic group optionally substituted is attached to position 4 It has a superior inhibitory effect for peptidase and is useful as a compound for the prevention or treatment of og Sul disease etc. On the basis of this discovery; The current inventors have done extensive studies

They completed the present invention. accordingly; The present invention relates to: (1) Ve compound (I) (7) compound (); wherein 28 and 82 are the same or different and each optionally substituted hydrocarbon group Xs is a “cyano” group nitro group aro group substituted hydroxy group; optionally substituted thiol group or optionally substituted cyclic group; yo 9) Cua (I) compound The acyl group of X is a tcarboxyl group (£) oT compound) where RY and 82 are the same or different and each is an alkyl© group optionally substituted by 1 to “selected substituents from the cycloalkyl group and diene of the alkoxy-carbonyl group © and alkoxy ym; (0) compound (0); where 18 is a Cog aryl group optionally substituted by 1 to -*?selective substituents of a Crp alkyl group optionally substituted by 1 to ? atoms halogen atom ¢halogen (7) Cun compound (I) where RY is the amino group (V) compound (0), where L is the alkylene group Cun; (A) compound (0); where © is a bond; yo (9) compound (); where X is a cacyl group a substituted hydroxy group; an optionally substituted thiol group or a group amino optionally substituted; (01) compound ol) where X is the tcarboxyl group

A

compound (0; which is: (1) 5-(aminomethyl)-2-methyl-4-(4-methylphenyl)-6-neopentylnicotinic acid; 5-(aminomethyl)-6-isobutyl-2-methyl-4 -(4-methylphenyl)nicotinic acid; methyl 3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3- ylJmethoxy}-1-methyl-1H-pyrazole- 4-carboxylate;° {[2-isobutyl-6-methyl-4-(4-methylphenyl)-5-(2-morpholin-4-yl-2-oxoethyl)pyridin- 3-yl]methyl} amine; methyl 3 -({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3- yl]acetyl jamino)benzoate;

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-ylJisoxazole- 0 4-carboxamide, or a salt thereof; of compound ( ); ( prodrug ) a lie (VY) containing a compound (0) or a prodrug thereof; (pharmaceutical agent) a pharmaceutical agent (VY)

Sale which is wel (VY) of (pharmaceutical agent) (1 lb) Vo or glucose for the prevention or treatment of diabetes; Complications of diabetes mellitus carrying obesity; or a prodrug thereof; (D) comprising a peptidase inhibitor compound (10) “dipeptidy] dipeptidase-IV in the peptidase inhibitor (10) above; where it is (V1) use of a compound ( ) or a prodrug thereof to produce an agent for the prevention or treatment of (VV) 7 putrefactive or obesity; a prodrug thereof to produce a VA inhibitor for the prevention or treatment of diabetes; Complications of diabetes mellitus (method) method (V4) or drug (I) bad or obesity; in a mammal; Comprising administration of an initial glucose tolerance to the mammal; Yo in a mammal; It includes administering a compound ( ) or a peptidase drug, a method for inhibiting (01) a primer of it to the mammalian organism; q, a method for producing a compound represented by the formula: (71)

RL._N__R'

BU

Xa-Q 7 la CH; NH, (I-a) where: (I) njl 82 283 and 0 are as specified in a divalent chain compound; The hydrocarbon is a substituted La ° bond or group; hydroxy 4c sass acyl 4c gana nitro group chydrogen is an optionally substituted Xa atom or circular group (amino group (olla) group) substituted thiol group optionally substituted with, or a salt thereof; Which includes the subjugation of a compound represented by the formula: 1 Kheb and Hoor > “La-CN 3 0 vs,” where each symbol is as specified above; or a salt thereof for a reduction reaction; Jad The compound of the invention is useful as an agent for the prevention or treatment of diabetes, etc. Each symbol in formula (1) is described in detail below. 00 Replaced Optionally 'for a hydrocarbon of 'hydrocarbon group' the 'Cp.10 alkenyl group' and:.0; alkyl group may be stated as (JB) group eg RZ l or “Cs.19 cycloalkenyl group” C359 cycloalkyl group F:0; alkynyl group “Cy.3 aralkyl group” Cg pq aryl group “Cypo cycloalkadienyl dc sane etc. Cs. cycloalkyl Ci alkyl 4c sans arylalkenyl 00 ethyl methyl Led Hana, for example; on Cry alkyl, the group “<isopentyl” pentyl “tert-butyl” ¢sec-butyl “isobutyl” can be mentioned. «isopropyl»propyl

Ye «2,2-dimethylbutyl «<1,1-dimethylbutyl «isohexyl <hexyl ¢1-ethylpropyl ¢neopentyl etc. »decyl »nonyl myriads <heptyl «2-ethylbutyl «3,3-dimethylbutyl cethenyl Fryers As Ju and an alkenyl diene, the group “3-butenyl” 2-butenyl “¢I-butenyl <2-methyl-1-propenyl <2-propenyl “1-propenyl” 4-pentenyl “3- pentenyl «2-pentenyl «1-pentenyl «3-methyl-2-butenyl© ¢1-octenyl «1-heptenyl «5-hexenyl 3-hexenyl ¢l-hexenyl »4-methyl-3-pentenyl etc. ‎ “1-propynyl “ethynyl” (Jha) for example “Chg alkynyl” group 3-pentynyl «2-pentynyl «1-pentynyl «3-butynyl «2-butynyl <1-butynyl «2 -propynyl «1-heptynyl «5-hexynyl «4-hexynyl <3-hexynyl <2-hexynyl ¢1-hexynyl <«4-pentynyl 0 etc. <I-octynyl »cyclopropyl as (Jal on For the “Cio cycloalkyl” group the “cyclooctyl” cycloheptyl “cyclohexyl” cyclopentyl “cyclobutyl” bicyclo[3.2.2]nonyl <bicyclo[3.2.1]octyl <bicyclo[2.2.2]octyl ¢bicyclo[2.2.1] ]heptyl etc. “bicyclo[4.3.1]decyl <bicyclo[4.2.1]nonyl “bicyclo[3.3.1]nonyl 0

led example; On Sow on “Cao cycloalkenyl” group “3-cyclohexen-1-yl” 2-cyclohexen-1-yl “3-cyclopenten-1-yl “2-cyclopenten-1-yl etc. can be mentioned. LED light For example; On the cycloalkadienyl group, etc. “2,5-070101680160-1-71” 2,4-cyclohexadien-1-yl “2,4-cyclopentadien-1-yl 0 naphthyl phenyl” can be mentioned as (Jal For example “Copy aryl” the group “phenyl etc.) can be mentioned. Therefore cbiphenylyl “acenaphthylenyl” phenanthryl < anthryl etc. “2-naphthyl “<1-naphthyl” phenethyl “benzyl” is preferred over any “Jal” for example “Crys aralkyl de sane etc.” can be mentioned. “biphenylylmethyl ¢naphthylmethyl Yo etc. estyryl Led on dll” for example “Cars arylalkenyl group can be mentioned

11 0 and 0 for example; As 010801-06 alkyl group etc. can be mentioned. “cyclohexylmethy] 0 and 0 mentioned alkynyl and Copp alkenyl group M0 alkyl group If the group to ? Substitutions at the substitution position(s). eg” as: o ¢ (cyclohexyl “cyclopropyl” Jill cyclopropyl Ae) Cs cycloalkyl group (1) ¢ (naphthyl “phenyl eg; Je) pm aryl group 7) (example furyl; antagonist Jaws heterocyclic aromatic group (on)) (indolyl “quinolyl” ¢pyrazinyl ¢<oxadiazolyl “tetrazolyl < thiazolyl <oxazolyl” pyridyl carboxyl group to ? substituents selected from group 1 optionally substituted by 0 (eg cis alkoxy-carbonyl and a thiocarbamoyl group a ccarbamoyl group ¢(tert-butoxycarbonyl “propoxycarbonyl “ethoxycarbonyl” methoxycarbonyl) the exemplary ctetrahydrofuryl non-aromatic hetero-group (eg; (£) “oxodioxolyl” piperazinyl “pyrrolidinyl ¢piperidino ¢thiomorpholino” morpholino optionally substituted by (oxooxadiazolyl coxo-2-benzofuranyl coxodioxolanyl 0 ¢(ethyl “methyl eg Je) Cig alkyl group optionally substituted mono or binary by substituent(s) selected from amino group (©) of an alkyl-carbonyl group “(ethyl “methyl” (eg”); ©. alkyl dc sane from alkoxy-carbonyl and the isopentanoyl cisobutanoyl “acetyl” (eg) “propoxcarbonyl” ethoxycarbonyl “methoxycarbonyl” group Joos (although 00 ¢ (tert-butoxycarbonyl ¢)(methylsulfonylamino) (eg Cy alkylsulfonylamino de sane (1) ) tamidino (V) cisobutanoyl “acetyl” group (eg ? C1 alkyl-carbonyl group (A) ¢(isopentanoyl ~~ Ye “methoxycarbonyl) (eg ? Ci alkoxy-carbonyl group) (4): ¢ (tert-butoxycarbonyl “propoxycarbonyl” ethoxycarbonyl yyw

11 ¢(methylsulfonyl) (eg; ©: alkylsulfonyl group (V+) optionally substituted mono- or double-substituted by a carbamoyl group (11) to © 1 atoms optionally substituted by (ethyl “ methyl eg; Je) ©... alkyl ¢(iodine «bromine »chlorine »fluorine (eg halogen optionally substituted mono or double by a thiocarbamoyl group (VY) ° to ? atoms 1 optionally substituted by (ethyl amethyl (eg; ©...alkyl ¢ (iodine bromine «chlorine »fluorine eg Ae) halogen © alkyl optionally substituted mono or dimer by a sulfamoyl group (VV) halogen group to ¥ atoms of 1 optionally substituted by ethyl (eg; hydrate” ¢(iodine “bromine” chlorine “fluorine” (eg 0 ¢carboxyl group) 0) thydroxy group (10) optionally substituted ethoxy cmethoxy (eg; ©, alkoxy group) (01) <bromine “chlorine “fluorine” (eg halogen to ? atoms) 1 by ‘(iodine 0 optionally substituted (ethenyloxy eg’ Je) Cr alkenyloxy group (VV) <bromine “chlorine” fluorine (eg halogen to ? 1 atoms by ¢(iodine ¢(cyclohexyloxy «Ji mo (eg cycloalkyloxy de sans (YA) ¢)benzyloxy (eg; Cris aralkyloxy group (14) Y. ¢) naphthyloxy «phenyloxy e.g. Je) Coa aryloxy 4c sana (Y+) cacetyloxy of (on the methylated cilia; alkyl-carbonyloxy (YV) group (tert-butylcarbonyloxy (thiol) substituted (YY) group ethylthio cmethylthio (eg” ©: alkylthio group (YY) Yo “chlorine “fluorine” Jill (eg halogen) to ¥ atoms 1 optionally by ¢(iodine “bromine

YY

¢ (eg benzylthio” Je) and aralkylthio group (Y £) ¢ (naphthylthio “phenylthio) and (eg” arylthio group (Y0) tsulfo group (77) group Two sources; (YV) tazido group (YA) ° nitro group (Y4) 'nitroso group (01) ¢(iodine «bromine »chlorine »fluorine «Jill sabil Je) halogen atom ) 1) etc. ¢(methylsulfinyl (eg “© alkylsulfiny] group (YY) ic gana “Cao cycloalkenyl group” Cy cycloalkyl group 01 group “Cy; aralkyl group” “Cog aryl 0-; cycloalkadienyl group, for example, Jaw Wadih; those mentioned on cycloalkyl-Cig alkyl and Cg 13 arylalkenyl group to * substituents at position 1 of the aforementioned optionally have a “hydrocarbon for” aforementioned substitution group(s), etc; ©. alkyl group “bromine «chlorine »fluorine (eg Je) halogen to ¥ substituents selected from an atom (eg Cig alkoxy-carbonyl group ccarboxyl group (iodine tcarbamoyl) and an optionally substituted cthoxycarbonyl <methoxycarbonyl 0 group (1-propenyl sethenyl) (eg; Cr alkenyl group “chlorine »fluorine (eg; halogen) to ¥ substituents selected from an atom 1 by (eg Cig alkoxy-carbonyl group ccarboxyl group ¢(iodine bromine scarbamoyl) and (eg ethoxycarbonyl group “methoxycarbonyl”; etc. (eg benzyl” Je) Cruz aralkyl Yo

Optionally substituted Y¢ for “for © or hydrocarbon de sess’ of “hydrocarbon 4c sess” The “C7.13 aralkyl catabolite or the aryl group the Cj jg alkyl group is preferred as the Cj jg alkyl group R?

Cri alkyl Most preferably optionally substituted group for 8 or 182 would prefer to be: hydrocarbon de seas' to? Selected substituents from group 1 optionally substituted by Cy alkyl group (1) ° etc.; “C6 alkoxy ic sans “Cp alkoxy-carbonyl 4c sana” Cs.pg cycloalkyl to? Selected substituents of atom 1 optionally substituted by Cog aryl group (7) “carboamoyl group” Cp alkoxy-carbonyl carboxyl group :; group 0 etc.; or di. aralkyl group (7) Ye to ?1 optionally substituted by Copp alkyl group preferably from the above “Cy alkoxy-carbonyl group f.:; cycloalkyl group selected substituents from flexible group” etc. alkoxy optionally substituted “hydroxy Ae seas’ substituted” from hydroxy 4e sass’ can be used as those mentioned eg for l below. RE for ag or ve optionally substituted “” hydrocarbon preferably a and 82 each being “group to ¥ substituents selected from group 1 optionally substituted by Cryo alkyl group more etc. “Cig alkoxy group” Cy alkoxy-carbonyl group and cycloalkyl group “aromatic group” can be mentioned from “optionally substituted aromatic group” for aromatic; hydrocarbon heterocyclic group for example; as an aromatic RP Ye group; etc., aromatics; For example; as a hydrocarbon group The hydrocarbon group of the 'hydrocarbon group' mentioned eg for 'Cos aryl group etc. SA ex R? optionally substituted' for 1 or as a group can be stated (Jal) The aromatic heterocyclic group can be mentioned; for example Yo to; 1-membered atoms containing 1 monocyclic aromatic heterocyclic having from © to an atom consisting of a ring; (Jie nitrgen and atom Sulfur an oxygen atom selected from an atom

Vo and a fused aromatic heterocyclic group. Carbon can be negated in addition to atoms

Cun at the ends of the JB group (JB) fused aromatic heterocyclic group; eg one or two 1 monocyclic aromatic heterocyclic groups with © fused to one sulfur or benzene atom containing a ring have +7 members; nitrogen ring of atoms containing ring having © members etc. © Favorite examples of aromatic heterocyclic group can be cited as: eg (le)furyl heterocyclic cyclic monoaromatics such as 2-thienyl (on pyrimidine-3) (ex; thienyl “(3-furyl” 2-furyl (Jal) (ex pyrimidiny) “(4-pyridyl) «3-pyridyl «2-pyridyl eg; pyrazinyl “(4-pyridazinyl “3-pyridazinyl eg” (for imidazolyl “(3-pyrrolyl” 2-pyrrolyl ¢l-pyrrolyl “Jal” (for 01 pyrazolyl “(5-imidazolyl” 4- imidazolyl «2-imidazolyl «1-imidazolyl eg; 5-thiazolyl “4-thiazolyl” 2-thiazolyl eg Ju 0 (on oxadiazolyl “isoxazolyl”) 5-oxazolyl “4-oxazolyl 2-oxazolyl eg (on thiadiazolyl ¢(1) ,3,4-oxadiazol-2-yl «1 2,4-oxadiazol-5-yl exemplary Ju ¢1,2,4-triazol-1-yl eg Je)triazolyl «(1,3 ,4-thiadiazol-2-yl example” ¢(1,2,3-triazol-4-yl ~~ ¢1,2,3-triazol-2-yl ~~ ¢1,2,3-triazol -1-yl ~~ ¢1,2,4-triazol-3-yl etc; 0 (eg quinolyl Je fused aromatic heterocyclic groups “2-quinazolyl eg” Je) quinazolyl ¢(4-quinolyl “3-quinolyl” 2-quinolyl (eg benzofuryl “(2) -quinoxalyl eg “J) quinoxalyl “(4-quinazolyl “2-benzothienyl” (eg? eg; -yl <benzimidazol-1-yl

YYVY

indazolyl »)10001-3-1 (example pyrrolopyrazinyl ¢(1H-indazol-3-yl) (on Joo —example “(1H-pyrrolo[2,3-b]pyrazin-6- yl “1H-pyrrolo[2,3-b]pyrazin-2-yl (Jo lc) imidazopyridinyl chelate; “1H-imidazo[4,5-b]pyridin-2-yl imidazopyrazinyl” (1H- imidazo[4,5-c]pyridin-2-yl (on the unpaired Ja “(1H-imidazo[4,5-b]pyrazin-2-yl 0) etc. The ‘aromatic group’ of the ‘group optionally substituted aromatic" for 83 preferably aromatic hydrocarbon group; cons aryl group more preferred .phenyl "aromatic group" than "optionally substituted aromatic group" for 0 8 optionally has 1 To ?substitutes at the substitution position(s). Optionally" for RY or ALL R? substitutions are preferred: Vo optionally substituted Cr alkyl group by 1 to halogen atoms (eg ¢(iodine «bromine »chlorine «fluorine » Jil a halogen atom (eg ¢(iodine “bromine” chlorine “fluorine alkoxy-carbonyl 4c sense of ; tcarboxyl 4c sana thydroxy 4c seas 0 .© alkoxy group optionally substituted by 1 to ? chalogen atoms etc.”; More preferred: an alkyl group ...© (eg “(ethyl” methyl optionally substituted by 1 to ¥ Je atoms) halogen eg ¢(iodine “bromine” chlorine “fluorine” Yo atom Je) halogen eg ¢(iodine «bromine «chlorine «fluorine etc. The “optionally substituted aromatic group” for 87 would preferably be the 4m aryl group (where it would preferably be the aryl group LDM is (optionally substituted phenyl

by 1 to? Selected substituents from the Je) Cre alkyl group eg? (ethyl “methyl) optionally substituted by 1 to a halogen atom (eg “chlorine “fluorine”) iodine <bromine to a halogen atom (eg <bromine “chlorine “fluorine” Jill “(iodine etc. ° optionally substituted amino de seas'” for RY may be stated for example as an amino group optionally substituted by 1 or 1 of selected substituents from the alkyl group and 0; a modene alkenyl group; a di-cycloalkyl group; “Cig cycloalkenyl group” Cg py aryl group d-aralkyl group and a D-arylalkenyl group; each of them optionally substituted; a casyl group etc. The “Cryo alkyl group,” the “Copp alkenyl group,” the cycloalkyl group, and the “Cio cycloalkenyl group,” the aryl group “aralkyl group,” and the arylalkenyl group (La) can be used, for example. For “a hydrocarbon group of optionally substituted hydrocarbon Ac seas” for the aforementioned RY or 2. The “Cy jp alkyl group is an alkenyl group range of a cycloalkyl group and 0 is a “Cig cycloalkenyl group” The “Cg pq aryl group Crp; aralkyl group and the arylalkenyl group and “:©-”© optionally each have 1 to ¥ substituents at the substitution position(s). Those (Jad for example; can be stated as: halogen atom (eg ¢)iodine «bromine »chlorine »fluorine «Jill Cy alkoxy-carbonyl group (on Ju mal;” methoxycarbonyl (tert-butoxycarbonyl «ethoxycarbonyl | 01 ¢ an alkyl-carbonyl group and fcyano group a carbamoyl group optionally substituted mono- or double-substituted by an alkyl group and 0 (eg «methyl »Jill] ART ¢(neopentyl «isopropyl «propyl thydroxy 4c sess Yo ¢carboxyl de gana etc.

Ya

The amino Ae sens' substituent mentioned for example, in order to replace the acyl, the combination below can be used. Preferably: X optionally"; as it is mentioned, for example, for "isobutanoyl" acetyl "Jill bitter" (on the alkyl-carbonyl way of group (1) (isopentanoyl "methoxycarbonyl"), the exemplar; Jus (on Cy alkoxy -carbonyl group (7) ° optionally substituted by (tert-butoxycarbonyl «propoxycarbonyl «ethoxycarbonyl] of alkoxy-cabronyl group “cyclopentylcarbonyl” and (eg; cycloalkyl-carbonyl (?) ¢ (cyclohexylcarbonyl group inferred (eg benzoyl; Ju Bm) on aryl-carbonyl group (£) Ye. cyano group chalogen group to ? substituents selected from 1 atom optionally by the “carboxyl group” Cp alkoxy group optionally a halogenated group with an aromatic heterocyclic alkyl ctetrazolyl group (eg; “Cg alkoxy-carbonyl (oxooxadiazolyl” Jal tract Je) non-aromatic heterocyclic group (oxadiazolyl ¢carbamoyl) and group 10 (benzyloxycarbonyl) in (eg; aralkyloxy-carbonyl group (©) ccarboxyl group to ? selective substituents from group 1 optionally substituted By ¢tcarbamoyl and © Group. alkoxy-carbonyl ¢ carbamoyl group (1) Exemplary Jw (on mono- or di-Cis alkyl-carbamoyl group 07) Ye ¢ (dimethylcarbamoyl ¢ (methylsulfonyl eg Je) Cy alkylsulfonyl de gana (A) of alkylsulfonyl Bm optionally substituted by an arylsulfonyl de sane group (4) ¢ (methylsulfonylphenylsulfonyl “phenylsulfonyl eg; le) (indolyl coxazolyl “thiazolyl” pyridyl (eg sulfonyl de sana )0 ) Yo to * substituents selected from a group of aromatic heterocyclic 1 optionally substituted by

(eg mono- or (e)(alkyl-carbonyl)-amino and alkyl group ¢(2-acetylamino-4-methyl-5-thiazolylsulfonyl “benzylcarbonyl”) (eg; aralkyl- carbonyl group (V1) ¢ (phenethyl carbonyl ¢(styrylcarbonyl “Jill” and d) (eg arylalkenyl-carbonyl group (1 Y) ° “thiazolyl coxazolyl “thienyl” furyl eg; Je) carbonyl 4c sana 0 to?substitutes selected from Group 1 optionally substituted by (quinoxalinyl carbonyl ..©; alkoxy group “Cr; aralkyl group” Coy aryl group “Cig alkyl ¢tcarbamoyl group” and © group. alkoxy-carbonyl 4c sana carboxyl “piperazinyl” piperidinyl ¢pyrrolidinyl “Jal (eg carbonyl group (£1) optionally substituted) nitrogen heterocyclic containing (oxopiperazinyl “morpholino 0) (optionally substituted © group. alkyl to © substitutions selected from set 1 by ccarboxyl group to ? Alternatives selected from set 1 by ©. alkyl group ccarboxyl group (carbamoyl and © alkoxy-carbonyl-group and group 1 and its 2 ?; ©. alkoxy-carbonyl «piperazinyl «piperidinyl «pyrrolidinyl eg» le) carbonyl group (© ) Y. ¢Cg.14 aryl-nitrogen heterocyclic containing (morpholino ¢4-0x0-4,5,6,7-tetrahydro-1-benzofuranyl-carbonyl group 7 ) ttetrahydropyranylcarbonyl group (VV) to *1 substituents optionally substituted by Cog aryloxy-carbonyl group (VA) tcarbamoyl and Cig alkoxy-carbonyl group carboxyl group selected from Yo ¢(benzylcarbamoyl group) and d (eg; Aralkyl-carbamoyl Cluster (14)

: Y. coxazolyl “thiazolyl” pyridyl (eg; by (oxazolylcarbamoyl etc. ¢carbamoyl and C16 alkoxy-carbonyl group substituted ccarboxyl group; as: amino Preferred examples can be cited from ° «methylamino group (eg; mono- or and 0-nick alkylamino 4c sexs (V) ¢ (dibutylamino «propylamino «diethylamino ¢ethylamino < dimethylamino ¢ (diallylamino) (eg”; mono- or di-Cy.1o alkenylamino group ( Y ) ) For example mono- or di-Cs.o cycloalkylamino group (¥) ¢ (cyclohexylamino 1 ¢ (phenylamino) nm (eg arylamino) group (eg mono- or di-(Ci. alkyl-carbonyl)-amino group (©) < isobutanoylamino «butanoylamino »propionylamino cacetylamino ¢(isopentanoylamino (methoxycarbonylamino eg Je) Cp alkoxy-carbonylamino group (1) Vo bitter; alkoxy-carbonyl optionally substituted by a (V) Ci alkoxy-carbonyl-Cr.ip alkylamino group (V) ¢(carbamoylmethylamino cil le) Ci alkoxy-carbonyl-Cr.ip alkylamino group (A ) “ethoxycarbonylmethylamino ¢methoxycarbonylmethylamino alq_al” 0 ¢(tert-butoxycarbonylmethylamino ¢ (carboxymethylamino eg” Je) carboxy-Ci.io alkylamino group (4) Ex. Jou (on Ci cycloalkyl-carbonylamino group (1 +) ¢ (cyclohexylcarbonylamino «cyclopentylcarbonylamino substituted (benzoylamino eg; Je) md© aryl-carbonylamino group (V1) Yo group cyano group chalogen group to ? Substituents selected from 1 atom optionally by ccarboxyl group «Cig alkoxy group» by lial halogenated © alkyl group

AR stetrazolyl for example; aralkyloxy-carbonylamino group (1) to ? substituents selected from group 1 optionally substituted by benzyloxycarbonylamino © tcarbamoyl and Ci alkoxy-carbonyl group ccarboxyl tcarbamoylamino 4c sess (VV) (eg mono-r or di-C,. alkyl-carbamoylamino group ( \¢ ) ¢ (dimethylcarbamoylamino ¢(methylsulfonylamino) of (eg” alkylsulfonylamino group (Vo) 1 optionally by dain “Cg arylsulfonylamino (11) “phenylsulfonylamino” group eg duu (on Ci alkylsulfonyl group $ (methyl sulfonylphenylsulfonylamino “oxazolyl “thiazolyl” pyridyl) (eg; sulfonylamino (VV) group) to ¥ Selected substituents from 1 aromatic heterocyclic optionally substituted by indolyl 0 (eg mono- or di-(Cy.s alkyl-carbonyl)-amino and alkyl group s (2-acetylamino) -4-methyl-5 -thiazolylsulfonylamino The ideal (Jal) in the article (on the aralkyl-carbonylamino group (VA) ¢ (phenethylcarbonylamino “benzylcarbonylamino”) Jw (on the C3 arylalkenyl-carbonylamino group) (V4) Y. ¢(styrylcarbonylamino «oxazolyl «thienyl »furyl (eg? carbonylamino group (v4) <benzofuryl «pyrazinyl «pyridyl c¢pyrazolyl cisothiazolyl »isoxazolyl thiazolyl to ? 1 heterocyclic Aromatic optionally substituted by (quinoxalinyl <benzothienyl) or aralkyl group “C14 aryl group” Cig alkyl group “Cig alkoxy group” selected substituents from Yo group and 0. alkoxy-carbonyl group ccarboxyl group “Cig alkoxy group ¢carbamoyl yyw group

“p (YY) le) carbonylamino group eg” “piperidinyl” pyrrolidinyl (oxopiperazinyl morpholino “piperazinyl) a nitrogen-containing heterocyclic optionally substituted by 1 to “selected substituents of the Crp group alkyl (optionally substitute the .© alkyl group by 1 to ? substituents selected from the © ,dc gana carboxyl group , © alkoxy-carbonyl group and “(carbamoyl) ccarboxyl group , alkoxy-carbonyl group ...© and the ¢tcarbamoyl (YY) carbonylamino group (eg “piperidinyl” pyrrolidinyl (morpholino “piperazinyl) heterocyclic containing ¢Cs-14 aryl-nitrogen (YY ) ttetrahydropyranylcarbonylamino group 01 (£¥) ¢4-0x0-4,5,6,7-tetrahydro-1-benzofuranyl-carbonylamino group (Y© ) substituted Cog aryloxy-carbonylamino group Optionally by 1 to ?selected substituents of alkoxy-carbonyl 4c sana ccarboxyl dc sana er and tcarbamoyl group (Y1) alarkyl-carbamoylamino group role le)methoxylate ¢ (benzylcarbamoylamino ( YV) Yo carbamoylamino group (eg “oxazolyl” thiazolyl “pyridyl 01)) aromatic heterocyclic optionally substituted by 1 to ? Selected substituents of the carboxyl group C16 alkoxy-carbonyl group, tcarbamoyl group etc. The amino ie gana' is optionally substituted for *8 preferably the amino group is optionally substituted mono- or di- by a Cig alkyl group (eg; “methyl 0. (isopropyl “propyl ethyl 00) It is especially preferred if R* is an amino group. 'Divalent chain hydrocarbon group' may be stated for L or 'Q for example' as the divalent chain hydrocarbon group of which 1 to 10 .carbon atoms including special examples: (1) an alkylene group t (eg; ¢-(CHp)p- ¢-CHp- -:(012) -; ),C(CHs),-

Yy «-CH2-CH=CH- «-CH=CH- (eg 0.0 alkenylene group (Y) «-CHyp-CH=CH-CH,- ¢-C(CH3),-CH =CH- -tam-yes-tshm- ¢-CH=CH-CH,- ¢(-CH=CH-CH,-CH,-CH,- «-CH=CH-CH=CH- ¢-CH ,-CH,-CH=CH- ¢-CH-C=C- «-C=C- Fryers Jaws and Dine (on alkynylene group (¥) etc. ((-CH;-C =C-CH,-CHp- 0 Divalent chain "preferably a hydrocarbon group Ae send' The "-CH=CH- "-(CHp)s- are two merdenes; more preferably -mt-alkenylene or Cj alkylene group Etc. etc. “CH 0:©; more preferably alkylene is L group preferably Cc alkenylene or Cio alkylene group preferably © is bond; Ve group etc. It is especially preferred that © is -CH=CH- -(CHy)p- ¢-CHy- is most preferred bond; bond. As a complementary group (Jd For example oX for "acyl de sens' "-CO-NR¥R® "-PO;R'R® can be mentioned as ¢-SO,R' "-CO-OR'® in the will : symbiosis of hydrogen and 25 are the same or different, each being an RY atom [where -CS-NR*R® 10 is an optionally substituted or an optionally substituted heterocyclic group; the hydrocarbon is a hydrocarbon group a chydrogen group the same or different and each form an R® 4 RT atom

R%5 R™ is an optionally substituted or an optionally substituted heterocyclic group or may form the contiguous]; etc. Optionally substituted nitrogen together with a nitrogen atom containing the arcyl heterocycle (R® R® for 'Lidl substituted hydrocarbon de seas' aforementioned Y. can be used. 2 JR! Aromatics 'Ae sane' A hetero-aromatic circular group mentioned for example for Yo can be mentioned from the "optionally substituted aromatic group" for the aforementioned 83.

A

A non-aromatic heterocyclic group can be mentioned; For example; as a monocyclic non-aromatic heterocyclic group of © to 1 members containing 1 to ; Selected hetero-atoms of a coxygen atom a sulfur atom and a Jie nitrogen atom formed from a ring; In addition to carbon atoms and a cohesive non-aromatic heterocyclic group. The conjunctival non-aromatic heterochromatic group can be mentioned; For example (Jad on Led) Cua group monocyclic non-aromatic heterocyclic groups of 0 to 7 fuse and one or two nitrogen atoms containing a 1-membered ring; benzene ring or a single sulfur atom containing a ring with © members etc. Preferred examples of the non-aromatic heterocyclic group can be cited as 0 isostunasram (Je) for example; piperidinyl “(1-pyrrolidinyl (eg) morpholinyl “(piperidino) (eg) thiomorpholinyl “(morpholino) (eg piperazinyl” (thiomorpholino) (eg “(1-piperazinyl) hexamethyleniminyl (eg oxazolidinyl < (hexamethylenimin-1-yl Ju wu lc) eg thiazolidinyl «(oxazolidin-3-yl (eg Jars Ju Ic) imidazolidinyl ¢(thiazolidin) -3-yl 0 eg “(imidazolidin-3-yl oxoimidazolidinyl (eg dioxoimidazolidinyl ¢(2-oxoimidazolidin-1-yl” Jt Je) eg “dioxooxazolidinyl” (2, 4-dioxoimidazolidin-3-yl (eg ¢(2,4-dioxooxazolidin-1-yl «2,4-dioxooxazolidin-5-yl ~~ ¢2,4-dioxooxazolidin-3-yl Ju lc ) dioxothiazolidinyl recombinant “2,4-dioxothiazolidin-3-yl dioxoisoindolyl” (2,4-dioxothiazolidin-5-yl Ye. 2-yl for example; “(5-oxooxadiazol-3-yl le) oxothiadiazolyl for example; oxopiperazinyl” (5-oxothiadiazol-3-yl (for example Ja; dioxopiperazinyl ¢(3-oxopiperazin-1-yl (on “Jal Jw”) (2,5-dioxopiperazin-1-yl “2,3-dioxopiperazin-1-yl 01) (on Cyl Yo le) oxodioxolanyl ¢(2-0x0-1,3-dioxol-4-yl oxodihydrooxadiazolyl sealer) le} oxo-2-benzofuranyl ¢(2-oxo-1,3-dioxolan-4-yl oxodihydrooxadiazolyl sealer ¢(3-0x0-2-benzofuran-1 -yl (on J Ad Jn YY\VY

Yo ¢4-0x0-2-thioxo-1,3-thiazolidin-5-yl ¢ (5 -0x0-4,5-dihydro-1,2,4-oxadiazol-3-yl) closed Ju (on tetrahydropyranyl «4-oxo-2-thioxo-1,3-oxazolidin-5-yl (ex. 4-0x0-4,5,6,7-tetrahydro-1-benzofuranyl « (4-tetrahydropyranyl 1,3) 2H,5H)-dioxo- + (4-0x0-4,5 ,6,7-tetrahydro-1-benzofuran-3-yl «J— All 1,3(2H,5H)-dioxo-10,10a-dihydroimidazo [1,5- «tetrahydroimidazo[1,5-a]pyridinyl© etc. »blisoquinolinyl

Optionally substituted heterocyclic RS' for de pend' The heterocyclic group of * to * substituents at the substitution position(s). 1 optionally has an R® or RRS Jay group on For example; the aforementioned examples for Jal substituents can be mentioned from the “hydrocarbon group” and from the aforementioned examples for the aforementioned “cycloalkyl group 0 . 2 JR optionally substituted” as substituents for hydrocarbon preferably The substituents are: 1 optionally substituted by ethyl ©0601 (eg; Cr alkyl de gana ¢(iodine “bromine” “chlorine” fluorine) (eg halogen to ?) atoms (iodine cbromine) “chlorine” fluorine (eg halogen atom vo ¢Ce.14 aryl 4c sana ¢Cy.13 aralkyl 4c gene ¢thydroxy group ¢C1.6 alkoxy 4c sane scarboxyl group 1 n; alkoxy-carbonyl group ¢tcarbamoyl group “carboxyl group to ?selected substituents from group 1 substituted by ©. alkyl group ¢carbamoyl group and Cig alkoxy-carbonyl group dc gana etc. ¢mono- or di-(C).¢ alkyl-carbonyl)-amino group Yo containing heterocycle' of adjacent 'nitrogen containing heterocycle' can be mentioned; nitrogen substituted optionally" formed by 187 and 1867 together with atom 00

YYVY

For example Jha as a nitrogen-containing heterocycle having 1 to 1 members containing at least 1 nitrogen atom and optionally also containing 1 to 1 heterotoms selected from a coxygen atom a sulfur atom and a Jie nitrogen atom consisting of a ring; In addition to °.carbon atoms, preferred examples of a nitrogen-containing heterocycle can be cited as Led “morpholine “piperazine” piperidine “¢pyrazolidine < imidazolidine “pyrrolidine 2d” oxopiperazine <thiomorpholine heterocycle optionally containing nitrogen has 1 to ? (preferably 1 or “) substituents at the substituent position. Substituents may be stated as: Ve ¢thydroxy group Cre alkyl group optionally substituted by 1 to ?halogen atoms (eg ¢ (iodine “bromine” chlorine “fluorine” tl Crs aralkyl group Je) eg; (diphenylmethyl benzyl optionally substituted by 1 to ? halogen atoms (eg; “bromine” chlorine “fluorine (iodine Vo Je) Coq aryl group eg (phenyl optionally substituted by 1 to “?” halogen atoms (eg ¢(iodine “bromine” chlorine “fluorine” group Ci alkoxy-carbonyl (eg Ju; “methoxycarbonyl ¢ (ethoxycarbonyl) 2 Cg alkyl group substituted by 1 to © substituents selected from the “carboxyl group” alkoxy-carbonyl group ure and –carbamoyl group – carboxyl group – carbamoyl group etc. Preferred examples of 'acyl group' may be stated as: (1) Yo – formyl group (7) – tcarboxyl (¥) tcarbamoyl group

YY cisobutanoyl “acetyl” Jill (eg Ci alkyl-carbonyl dc gana (;) ¢(isopentanoyl) to ? 1 substituents optionally substituted by C6 alkoxy-carbonyl group (0) group cthiocarbamoyl group ccarbamoyl group ccarboxyl selected from the group of exemplary Ju bitter (alkyl-carbonyloxy) and group ©... alkoxy-carbonyl © stert-butoxycarbonyl ~~ «propoxycarbonyl ~~ »ethoxycarbonyl «methoxycarbony } ¢carboxybutoxycarbonyl «carboxyethoxycarbonyl »carboxymethoxycarbonyl ¢thiocarbamoylmethoxycarbonyl ¢carbamoylmethoxycarbonyl «ethoxycarbonylmethoxycarbonyl »ethoxycarbonylmethoxycarbonyl sethoxycarbonylbutoxycarbonyl «methoxycarbonylbutoxycarbonyl ~~ 0 ¢ (tert-butylcarbonyloxymethoxycarbonyl thienyl »furyl Jus (on C16 alkoxy-carbonyl group (7) heterocyclic indolyl “pyrazinyl coxazolyl” thiazolyl 1 ccarboxyl group to ? substituents selected from group 1 optionally by m (on) alkoxy-carbonyl and thiocarbamoyl group “carbamoyl group 0 scarboxythiazolylmethoxycarbonyl ¢pyridylmethoxycarbonyl 0 Joint Jn ¢ (ethoxycarbonylthiazolylmethoxycarbonyl ¢ carbamoylthiazolylmethoxycarbonyl coxodioxolyl eg Jou) on Ci alkoxy-carbonyl group (V) optionally substituted nonaromatic heterocyclic (0x0-2-benzofuranyl coxodioxolanyl “methyloxodioxolylmethoxycarbonyl”) example; Je) Cr alkyl by 0 ¢ (oxo0-2-benzofuranylethoxycarbonyl “cyclopentylcarbonyl” Jill and (eg) cycloalkyl-carbonyl group (A) ¢ (cyclohexylcarbonyl “1-naphthoyl” benzoyl) grown (eg Example; aryl-carbonyl group (3) chlaogen group to ¥ substituents selected from 1 atom optionally substituted by (2-naphthoyl "© inferred) Cig alkyl optionally substituted (i.e.; © group. alkyl cyano fluorine group; Ju ww (on halogen to ?1 atoms optionally by just

Ya

“carboxyl group” Cys alkoxy group “(iodine <bromine “chlorine tetrazolyl eg; Je) aromatic heterocyclic group “Cp alkoxy-carbonyl eg. le) 201” ); non-aromatic heterocyclic tcarbamoyl groups and the “0x00xadiazolyl” phenyloxycarbonyl group (e.g. the aryloxy-carbonyl group 2) to “selected substituents from group 1 optionally substituted by (naphthyloxycarbonyl ¢carbamoyl) yb and group an alkoxy-carbonyl group carboxyl group to ¥ substituents 1 yb optionally substituted by aralkyloxy-carbonyl group (VY) thiocarbamoyl group dc seas “carbamoyl group” carboxyl group selected from group nitro group “cyano group” chalogen group 3,3 “Ci alkoxy-carbonyl group 0 (Optionally replaces Cog alkyl and Ci alkylsulfonyl group “Cp alkoxy” carboxyl group chalogen group to ? Selected substituents from atom 1 by Cig alkyl group (alasil) carbamoyl group and Cis alkoxy-carbonyl group tcarboxybenzyloxycarbonyl group ¢penethyloxycarbonyl <benzyloxycarbonyl » preferred ¢ (diphenylylmethoxycarbonyl «methoxycarbonylbenzyloxycarbonyl 0) substituted Cg alkyl mono- or di-substituted by a carbamoyl group (VY) fluorine group (eg halogen to ? Substituents selected from 1 atoms optionally by M (eg. alkoxy and group (iodine <bromine cchlorine «diethylcarbamoyl ~~ «dimethylcarbamoyl ~~ cethylcarbamoyl 0» methylcarbamoyl «butylcarbamoyl »isopropylcarbamoyl <propylcarbamoyl «ethylmethylcarbamoyl | 0 ) N-methoxyethyl-N-methylcarbamoyl strifluoroethylcarbamoyl < isobutylcarbamoyl optionally substituted mono-carbamoyl-Ci6 alkyl-carbamoyl (\Y) group to ?1 optionally denoted by Cr alkyl or binary by (on) group iodine “bromine” chlorine “fluorine” (for example, halogen atoms) “carbamoylmethylcarbamoyl” article? Ju ww YO ¢ (dimethylcarbamoylethylcarbamoyl “dimethylcarbamoylmethylcarbamoyl”)

Yq optionally substituted by Cg alkoxy-carbonyl-Ce alkyl-carbamoyl group )( “methoxycarbonylmethylcarbamoyl” (eg; Cy alkyl group (N-ethoxycarbonylmethyl-N-methylcarbamoyl “ethoxycarbonylethylcarbamoyl”) substituted (phenylcarbamoyl (eg Ces aryl-carbamoyl group 0 ) optionally mono-substituted or amino to ?selected substituents from group 1 optionally by © Lybern alkoxy-carbonyl group carboxyl group “Cig alkyl bilaterally by a group ¢ (oxadiazolyl ctetrazolyl group) an aromatic heterocyclic group (eg”) carbamoyl and a non-aromatic heterocyclic (0x00xadiazolyl group (eg”) optionally substituted by mono- or mono- or mono- cycloalkyl-carbamoyl group ( 5 ) “cyclopentylcarbamoyl” cyclopropylcarbamoyl (eg Cre alkyl group 0 (N-cyclohexyl-N-methylcarbamoyl “dicyclohexylcarbamoyl”) to ¥ substituents 1 Optionally substituted by Crys aralkyl-carbamoyl (VV) group (iodine «bromine «chlorine «fluorine (eg”) a halogen selected from an atom and the © group. alkoxy-carbonyl carboxyl group chydroxy group “phenethylcarbamoyl <benzylcarbamoyl” exemplar; 0 to “selected substituents from group 1 optionally substituted by thiazolylmethylcarbamoyl of alkoxy-carbonyl and carbamoyl group +71 to ? selected substituents 1 optionally substituted by Co alkylsulfonyl group ( V9) (eg Cig alkoxy-carbonyl and carbamoyl group ccarboxyl group of ¢(carboxymethylsulfonyl “methylsulfonyl chelated Yo? substituents UY nm optionally substituted by arylsulfonyl group (Ye ) “carbamoyl ccarboxyl group “Cig alkyl group selected from v. b alkylsulfonyl group of alkoxy-carbonyl group cthiocarbamoyl group scarboxyphenylsulfonyl group ¢methylphenylsulfonyl ¢phenylsulfonyl 0 (eg ¢ (methylsulfonylphenylsulfonyl ¢methoxycarbonylphenylsulfonyl “piperazinyl” piperidinyl “pyrrolidinyl”) (eg; carbonyl (YY) group optionally substituted nitrogen heterocyclic containing (oxopiperazinyl “morpholino ©) (substituted Cr alkyl group) chydroxy to * substituents selected from group 1 by «carboxyl to * substituents selected from group 1 by ©. Optionally alkyl group “carboxyl group” carbamoyl group “m” and alkoxy-carbonyl group “pyrrolidinylcarbonyl” group “Jul” (e.g. carbamoyl and alkoxy-carbonyl group “oxopiperazinylcarbonyl” piperazinylcarbonyl “piperidinylcarbonyl | 0 (methoxycarbonylpyrrolidinylcarbonyl «morpholinocarbonyl «piperazinyl «piperidinyl «pyrrolidinyl eg» Je) carbonyl (YY) group (Jel) bm (eg aryl-nitrogen) heterocyclic containing morpholino 1 optionally substituted by ‎ (phenylpiperidinylcarbonyl «phenylpiperazinylcarbonyl ¢(iodine «bromine »chlorine «fluorine ‎(eg halogen to ¥ atoms ve «piperazinyl «piperidinyl «pyrrolidinyl eg» Je) carbonyl group (¥ ¥) and Lord (eg heterocyclic aralkyl-nitrogen containing a morpholino (on halogen) to ¥ atoms optionally substituted by benzylpiperazinylcarbonyl ¢ (iodine «bromine »chlorine «fluorine for example (indolyl « oxazolyl ¢thiazolyl «pyridyl (eg ?; sulfonyl group (Y£) Y. to © substituents selected from aromatic heterocyclic group 1 optionally substituted by (eg mono- or di -(Cy. alkyl-carbonyl)-amino .ren and alkyl group (2-acetylamino-4-methyl-5 -thiazolylsulfonyl coxodioxolanyl < oxodioxolyl) (eg; oxy-carbonyl group (YO) non-aromatic heterocyclic (on Ex. (oxo0-2-benzofuranyl 76 ¢ (ox0-2-benzofuranyloxycarbonyl «oxodioxolanyloxycarbonyl ¢ (methylsulfinyl eg; Je) Cig alkylsulfinyl group (Y1)

¢ thiocarbamoyl group (YV) optionally substituted mono or dimer by a phosphono group (YA) ¢(diethyl phosphono “dimethyl phosphono” (eg; Cy alkyl <benzylcarbonyl eg? Juv Liban) on aralkyl-carbonyl group Yq ) $) phenethylcarbonyl © ¢) styrylcarbonyl nm (eg aralkenyl-carbonyl dc sass (v4) “thiazolyl coxazolyl” thienyl furyl eg “le) carbonyl group ) VV) «benzothienyl <benzofuryl »pyrazinyl «pyridyl ¢pyrazolyl «isothiazolyl <isoxazolyl »furylcarbonyl heteroaromatic (eg quinoxalinyl 03771071081001 «pyrazolylcarbonyl «thiazolylcarbonyl sthienylcarbonyl | 0 «benzothienylcarbonyl «benzofurylcarbon] yl «pyrazinylcarbonyl to ?selected substitutes from a group 1 optionally substituted by (quinoxalinylcarbonyl dc gana “Cre alkoxy de sane” Cr3 aralkyl 4m; aryl group Cg alkyl tcarbamoyl group and C1 alkoxy-carbonyl group carboxyl 'tetrahydropyranylcarbonyl group ( VY) Vo ¢4-0x0-4,5,6,7-tetrahydro-1-benzofuranyl-carbonyl (YY) group (eg C39 cycloalyl-Ci¢ alkoxy-carbonyl group ) ) substitutions selected from 1 to 1 optionally substituted by cyclohexylmethoxycarbonyl ¢carbamoyl and C6 alkoxy-carbonyl group ccarboxyl group d furyl cthienyl group (example) aralkyloxy-carbonyl group ( Y©) 70 heterocyclic (indolyl “quinolyl” pyridyl ctetrazolyl rhododendron coxazolyl “pyridyl $ (tetrazolylbenzyloxycarbonyl) aromatic (eg thiazolyl “pyridyl” furyl cthienyl (eg; carbamoyl group) 37 aromatic heterocyclic “thienylcarbamoyl” Jal (eg indolyl < oxazolyl 1) optionally substituted by (oxazolylcarbamoyl “thiazolylcarbamoyl furylcarbamoyl ~~ Yo) and Crs alkoxy-carbonyl group carboxyl group to ¥ substituents selected from group etc. ¢carbamoyl

YyYvy vy preferably: X for “acyl de send tcarboxyl group (1) ¢carbamoyl group (7) to ? substituents 1 optionally substituted by ©. alkoxy- carbonyl group (7) cthiocarbamoyl group “carbamoyl group selected from group 08:50”(1; group © exemplary Jos M) on alkyl-carbonyloxy and group C16 alkoxy-carbonyl stert -butoxycarbonyl ~~ “propoxycarbonyl :ethxoxycarbonyl <methoxycarbonyl ¢carboxybutoxycarbonyl «carboxyethoxycarbonyl «carboxymethylcarbonyl ¢thiocarbamoylmethoxycarbonyl ¢carbamoylmethoxycarbonyl <ethoxycarbonylethoxycarbonyl «cthoxycarbonylmethoxycarbonyl | 0 ¢ethoxycarbonylbutoxycarbonyl »methoxycarbonylbutoxycarbonyl ¢ (tert-but) ylcarbonyloxymethoxycarbonyl from an alkyl mono- or double-substituted by a carbamoyl group (¢) and a halogen group to ?substituents selected from the 1 atom optionally substituted by cethylcarbamoyl «methylcarbamoyl eg; butylcarbamoyl ¢isopropylcarbamoyl (N-methoxyethyl-N-methylcarbamoyl optionally substituted mono or carbamoyl-Ci alkyl-carbamoyl group (©)

SHY to 1 optionally substituted by © an alkyl isotropic by group 0 «carbamoylethylcarbamoyl «carbamoylmethylcarbamoyl example» Ae) halogen etc. From (dimethylcarbamoylethylcarbamoyl «dimethylcarbamoylmethylcarbamoyl .carboxyl] that;. Prefer a group, for example; as a substituted X group "for hydroxy de seas'". "Cy.10 alkenyl group" Cj pg alkyl group can be mentioned substituted by a substituent chosen from the hydroxy group |©? dam aralkyl vy group + aromatic heterocyclic group having © or ¢ (isopentanoyl «isobutanoyl cacetyl eg; triazolyl «imidazolyl coxazolyl «thiazolyl » thienyl members (eg? ) a fused aromatic heterocyclic group “(pyrimidinyl 201 etc.) each of them is optionally substituted. “Cy cycloalkenyl group” C30 cycloalkyl ic gana and - p-hana as the special examples for the arylalkenyl edible and aralkyl group mentioned above. R? optionally substituted for “!1 or the hydrocarbon of the” group “hydrocarbon” Cyo alkenyl group©.; The alkyl group can be used as the “Coy aryl” group, the “Cp cycloalkenyl group” and the “Coy aryl” group; cycloalkyl group 0 “Cj alkyl-carbonyl group DR-M; The arylalkenyl de gana “C73 aralkyl aromatic heterocyclic group has a © or 7-membered aromatic heterocyclic group fused each to “substituents at the substitution site(s). Those alternatives can be mentioned; 1 of them is optional for him, for example; as: ¢(iodine <bromine «chlorine «fluorine «Jill (eg halogen Vo ¢thydroxy 4c sass ¢Cyano 4s sana) or ¥ of selected substituents from 1 optionally substituted by 0. alkyl group “(iodine bromine chlorine “fluorine” for example; Je) halogen atom “methoxycarbonyl bitter” (according to the article; alkoxy-carbonyl group “carboxyl group | ¥- ¢carbamoyl” and group (tert-butoxycarbonyl) or? of selected substituents of atom 1 optionally substituted by Crug alkoxy de sana carboxyl group “(iodine “bromine” chlorine “fluorine” Jbl (eg halogen ¢(tert-butoxycarbonyl) “Jia syl Je)©: alkoxy-carbonyl and ¢ group (ethylthio ¢methylthio eg” Je) Cy alkylthio group Yo bitter alkyl-carbonyl group ¢carboxyl group ve «methoxycarbonyl (eg pans? Ci alkoxy-carbonyl ¢ group) (ethoxycarbonyl and optionally d-alkyl substituted mono- or double-substituted by a carbamoyl group ¢ (neopentyl isopropyl «propyl cethyl »methyl ) eg; coxazolyl group «thienyl ¢furyl eg le) optionally substituted aromatic heterocyclic group (pyridyl «thiadiazolyl <oxadiazolyl «tetrazolyl ¢isoxazolyl» < thiazolyl cmethyl eg] Ju (on Cris alkyl to? Selected substituents from group 1 by 0 (Jal) (eg Ci alkoxy-carbonyl) carboxyl group de sana 0 (ethyl scarbamoyl 4c sana (ethoxycarbonyl “methoxycarbonyl ¢ (methylsulfinyl” “Jal” (eg Cpe alkylsulfinyl) etc. ¢(methylsulfonyl eg “J) Cig alkylsulfonyl group” substituent group”; as: hydroxy Preferred examples of “Vo ¢Cy. alkyl-carbonyloxy group ( 1) to? Selected substituents from group 1 optionally substituted by Cp alkoxy group (7) m alkoxy-carbonyl and carbamoyl group carboxyl group chydroxy group to “selected substituents from an atom 1 optionally substituted by Cg aryloxy group )( m alkylthio group Cj alkoxy-carbonyl group carboxyl group <halogen Y: Cp alkylsulfonyl group Cj alkOXy group “carbamoyl group 4c sana 1 by Cp alkyl (optionally replace the Ci alkyl group, Cig alkylsulfinyl group, and Cp alkoxy-carbonyl group with a ccarboxyl group or © from selected substituents of the ¢ (carbamoyl cthienyloxy) group aromatic © or > members (preferably heterocyclyloxy de sane (£) Yo «pyrazolyloxy «triazolyloxy «imidazolyloxy «oxazolyloxy» thiazolyloxy to ¥ substituents selected from 1 optionally substituted by (pyrimidinyloxy «pyridyloxy vo] or ? of 1 substitutions by Crp alkyl (optionally replace the Cr alkyl group with a carbamoyl group and a Cy alkoxy-carbonyl de gana ccarboxyl group selected from the ¢carbamoyl group of the alkoxy-carbonyl group of the optionally substituted ccarboxyl 4c sens (conjugated aromatic indolyloxy (preferably heterocyclyloxy group (©)

Cis alkoxy-carbonyl carboxyl group to ? Selected substituents from group 1 by means of ©¢carbamoyl and an optionally substituent group (heteroaromatic cyclic pyridyl (preferably Cre alkoxy) group (7)

Cis alkoxy-carbonyl carboxyl group to ? Selected substituents from group 1 by means of carbamoyl group, etc. (heteroaromatic circular tetrazolyl (preferably Cog aryloxy de sane (V) Ve

Led for example; On oX optionally substituted “for a thiol” a cryo alkyl group “group” optionally substituted by a substituent chosen from the thiol group “C39 cycloalkenyl group” Cig cycloalkyl group 0.0; alkenyl group “Cys arylalkenyl group” C73 aralkyl group “Cog aryl group” (isopentanoyl cisobutanoyl acetyl group (eg) ©... alkyl-carbonyl 0 “thiazolyl cthienyl “furyl” JB spel Je) 1 aromatic heterocyclic members of the © or hetero Ag il group «(pyrimidinyl «pyrazolyl»triazolyl «imidazolyl <oxazolyl etc.; each of them optionally substituted. o(indolyl) Conjunctival aromatics (eg Capo alkenyl group Cy alkyl group ic gana group Copy aryl group Cs cycloalkenyl group C39 cycloalkyl | 0 ic gana can be used Hana Ali They are the particular examples for the aforementioned Cg-Cy3 arylalkenyl dN and aralkyl group. R?SRY optionally substituted for hydrocarbon 4c sess' of hydrocarbon 00.0; alkenyl group 0-©; group alkyl group can be used; aryl group Cig cycloalkenyl group and di; cycloalkyl group Cg alkyl-carbonyl group Cs-Cy3 arylalkenyl group Coz aralkyl Y© group Aromatic heterotrophs with ©1 members and a circular group of aromatic heterotrophs fused each to * substituents at the substitution site(s). Those 1 of them can optionally be used for him

substituents” as substitutes for “Crip alkyl group etc.; for hydroxy Ae seas substituted” for the aforementioned X.

(Say male Aba is preferred from thiol Ae send' optionally substituted"; as:

(1) ©, alkylthio group optionally substituted by 1 to ? substituents

© selected from hydroxy de seme ccarboxyl group carbamoyl group and group

alkoxy-carbonyl bitter;

(7) The combination Cong arylthio optionally replaced by 1 to ? Selected substitutes of “Cj alkoxy-carbonyl 4c gana ccarboxyl Ac sana Cg alkylthio group and ¢carbamoyl group

aromatic thienylthio with © or + members (preferably heterocyclylthio group (¥) 01 “pyrazolylthio” triazolylthio “imidazolylthio” oxazolylthio “thiazolylthio to ? substituents selected from 1 optionally substituted by (pyrimidinylthio “pyridylthio) and group Cg alkoxy-carbonyl carboxyl group Cp alkyl dc sens etc. ¢carbamoyl

The 'optionally substituted amino group' for oX can be used as the special examples for the aforementioned RY.

Also mentions 'cyclic group' of 'optionally substituted cyclic group' for X for example (Jil) as ¢iglas hydrocarbon group cyclic hydrocarbon group non-aromatic; heterocyclic aromatic group; heterocyclic non-aromatic group etc.

(Say Y.) use an aromatic hydrocarbon group and a heteroaromatic cyclic group; as the particular examples for an 'aromatic group' from an optional substituted aromatic Ae send' for the aforementioned RP. In addition a group may be mentioned non-aromatic heterocyclic; as the particular examples for 'de send' heterocyclic" from "optionally substituted heterocyclic group" for

Ye 25 aforementioned.

rv round non-aromatic; For example; hydrocarbon mention group (Sa group “Cayo cycloalkenyl group and :; cycloalkyl group as Mn .benzene group” etc.; each of them optionally conjugated with a cycloalkadienyl ring and a C39 group cycloalkenyl 0:0-0; cycloalkyl group A group of 'hydrocarbon 4c send' Hana may be used as the particular examples for ©Cup cycloalkadienyl

Previous SA 82 JR optionally substituted 'for hydrocarbon' group to 1 optionally substituted X of 'cyclic group optionally substituted' for 'hi en 'group? substitutions at the substitution position(s) for eg ABI substituents; As oda, this can be mentioned from “hydrocarbon dc sens’ and the mentioned for example, for cycloalkyl term group 0

SA optionally substituted "for the preceding 8 or 2 ! hydrocarbon de saad! Preferably, the substitutions are: 1 optionally substituted by (ethyl emethyl «Joell spiel Je) Crip alkyl group «bromine »chlorine “fluorine (eg halogen) to ¥ substituents selected from an M© atom (on an alkoxy-carbonyl group and a carboxyl group carbamoyl group) iodine 0 ¢ (ethoxycarbonyl “methoxycarbonyl” Jal) ¢ (iodine «bromine »chlorine »fluorine eg Je) halogen atom tcarboxyl 4c sane ¢C).¢ alkoxy-carbonyl 4c sana etc. ¢carbamoyl XY group thiol substituted; hydroxy group cacyl group is X group preferably “ld of acyl group preferably more (optionally substituted amino-substituted bial or group preferably: tcarboxyl group) 1) ¢carbamoyl group (7) Yo

Ya

to ¥ substitutes 1 optionally replaced by ©. alkoxy-carbonyl group (1) de sans cthiocarbamoyl group ccarbamoyl group a ccarboxyl group selected from a flexible group; an M-alkyl-carbonyloxy and a M6-substituted alkoxy-carbonyl group an alkyl monosubstituted or doubled by carbamoyl group (£)¢Ci.6 alkoxy group and halogen group to “selected substituents of atom 1 optionally by oo m©-conductors optionally substituted mono- or di-ary alkyl-carbamoyl group 0 etc.; ¢halogen to ¥ atoms 1 e,© optionally substituted by an alkyl by a group: -carboxyl and preferably especially a group, then the © is cethoxycarbonyl is the X group when oI ) is a divalent chain compound. hydrocarbon group 0 moreover; Compound (1) does not contain: 2,6-diisopropyl-3 -methylaminomethyl-4-(4-fluorophenyl)-5-pentylpyridine; This compound is also referred to as: {[4-(4-fluorophenyl)-2, 6-diisopropyl-5-pentylpyridin-3-yl methyl }methylamine; 2,6-diisopropyl-3 -aminomethyl-4-(4-fluorophenyl)-5-pentylpyridine; Ve This compound is also referred to as: {[4-(4-fluorophenyl)-2,6-diisopropyl-5-pentylpyridin-3 -ylJmethyl} amine; 2,6-diisopropyl-3 -(dimethylamino)methyl-4-(4-fluorophenyl)-5-pentylpyridine; This compound is also referred to as: 1-[4-(4-fluorophenyl)-2,6-diisopropyl-5-pentylpyridin-3 -y1]-N,N- Ye dimethylmethaneamine; 2,6-diisopropyl-3 -(ethylamino)methyl-4-(4-fluorophenyl)-5-pentylpyridine; This compound is also referred to as:

N-{[4-(4-fluorophenyl)-2,6-diisopropyl-5-pentylpyridin-3-yljmethyl} ethaneamine; and Yo 3-(tert-butyldimethylsilyloxymethyl)-2, 6-diisopropyl-4-(4-fluorophenyl)-5 -(indolyl- 5-aminomethyl)pyridine,

Yyyvwy

Ya This compound is also referred to as:

N-{[5-({[tert-butyl(dimethyl)silylJoxy} methyl)-4-(4-fluorophenyl)-2,6- ditsopropylpyridin-3-yl)methyl}-1H-indol-5-amine. Preferred examples can be cited from compound (1); It is the following compounds. 8m is a compound where: an alkyl d and 82 are identical or different, each of which forms an RY group that is substituted (neopentyl «isobutyl <butyl <isopropyl «propyl «ethyl » methyl (preferably 0:60 cycloalkyl to ¥ substituents selected from group 1 optionally by etc. ') methoxycarbonyl of (preferably alkoxy-carbonyl group 0 (cyclopropyl Ye) substituent phenyl is Cots aryl 4m (preferably aryl group is group 3 eg; (le)©. alkyl Ae sane to ¥ substituents optionally selected from 1 by (on eg; bromine «chlorine 05

Optionally cis alkyl substituted mono or dimer by amino group is RY ¢ group (isopropyl «propyl «ethyl cmethyl » Jal (eg -0112-preferably); 0:0 alkylene is L group “ibd; (preferably Cy. alkenylene or C50 alkylene group is bond; Q group and ¢(-CH=CH- “(CHp),- “-CH,-0 ¢carboxyl group) sa X tcarbamoyl group of alkoxy-carbonyl 4c gana substituted Crp alkyl mono or double substituted by carbamoyl group or halogen to ?1 atoms optionally by © optionally substituted mono or binary by a carbamoyl-C;alkyl-carbamoyl group 'halogen to ?1 atoms optionally substituted by a Cg alkyl group ge

B is a compound compound where: 8 and 82 are the same or different and each has: (1) a Crp alkyl group optionally substituted by 1 to ? substituents selected from the ©Cio cycloalkyl group (preferably “(cyclopropyl) “Cy alkoxy-carbonyl group bitter alkoxy group etc.; (7) Cos aryl group (preferably (phenyl) optionally substituted by 1 to ? substituents selected from the chalogen atom carboxyl group “Cy alkoxy-carbonyl group” carbamoyl group etc.; or ¢ (benzyl rb (preferably aralkyl dc sana) 90 Ye substituted (phenyl 4 dd©) is aryl (preferably Cog group aryl is group BR?1 optionally substituted by © alkyl to “selected substituents from group 1 optionally by group “Cr alkoxy-carbonyl group chalogen atom halogen Y atoms to to ? 1 optionally substituted by Cr alkoxy group hydroxy group “carboxyl group etc.; (preferably an alkylene group); L is an alkylene group and:-:© (-012-preferably); Q is a bond; an alkylene group 0-0 or an alkenylene group 020 (preferably a -012 bond) ; ¢(-CH=CH- «(CHp)p- «-CH,- 0 and X is: ¢hydrogen atom (1) tcyano group (V) tcarboxyl 4c gana (iv ) (79 tcarbamoyl group (VF) Yo

2 1 Optionally substituted by Cog alkoxy-carbonyl substituent(s) (7c) a thiocarbamoyl group a carbamoyl group a carboxyl group selected from a bitter group; an alkyl-carbonyloxy and an alkoxy group -carbonyl heteroaromatic cyclic pyridyl group (preferably Cp alkoxy-carbonyl group (2%) optionally substituted by selected substituent(s) (indolyl coxazolyl < thiazolyl 5) and thiocarbamoyl group ( carbamoyl carboxyl group de sans from ¢C.¢ alkoxy-carbonyl heterocyclic non-aromatic (preferably Cp alkoxy-carbonyl (7e) group optionally substituted by (0x0-2-benzofuranyl coxodioxolanyl <oxodioxolyl (Cp.g alkyl group Ve and optionally substituted by substituent(s) aralkyloxy-carbonyl group (5Y) thiocarbamoyl group “carbamoyl group” ccarboxyl group selected from flexible group; alkoxy-carbonyl a ©.alkyl group mono- or di-substituted by a carbamoyl de gana group (g) and a halogen group to ?1 atoms optionally substituted by selected substituent(s) of Vo ¢Cy.¢ alkoxy optionally substituted mono or carbamoyl-C alkyl-carbamoyl group (Y) ¢thalogen to ¥ atoms 1 optionally substituted by Cog alkyl double-substituted by group: 1-0e0:<g«mmoleh:©substituted optionally alkyl-carbamoyl (LV) group (LV) ; alkyl dc sane by Y. optionally substituted mono- or Ur and 1-0L cycloalkyl-carbamoyl (LV) group (Cpe alkyl) by A group optionally replaced by substituent(s) Coy; aralkyl-carbamoyl group (IV) of an alkoxy-carbonyl chydroxy group chalogen group selected from a 0. alkyl atom; and an aromatic heterocyclic Yo “pyridyl group (preferably ©. alkyl) -carbamoyl group (J¥) ¢(indolyl <oxazolyl «thiazolyl ty] optionally substituted by selected substituent(s) Cr alkylsulfonyl 7m elastomer group ? alkoxy-carbonyl group and carbamoyl group of 8:0 group :<([1; group optionally substituted by selected substituent(s) Copy arylsulfonyl group (HV) ccarbamoyl group ccarboxyl dc sana “Cr alkyl group) of a flexible group? alkylsulfonyl bitter and an alkoxy-carbonyl group a cthiocarbamoyl ° (preferably a nitrogen heterocyclic containing carbonyl de sens (“S”) optionally substituted by a substituent (morpholino “piperazinyl” piperidino “pyrrolidinyl ¢Ci.¢ alkoxy- carbonyl and hydroxy group (substitutes) chosen from a group 4m (preferably aryl-nitrogen heterocyclic containing a carbonyl “p” group optionally substituted by an atom (morpholino “piperazinyl” piperidino “pyrrolidinyl Ye thalogen aralkyl-nitrogen heterocycles containing a carbonyl (“p”) group optionally substituted (morpholino «piperazinyl »piperidino «pyrrolidinyl] (preferably thalogen) by a non-aromatic hetero-atom (preferably oxy -carbonyl Ac gens (u=") Yo or ¢(ox0-2-benzofuranyl < oxodioxolanyl < oxodioxolyl optionally substituted mono- or double-substituted by a phosphono group (9 s) an alkyl alkyl group? -carbonyloxy group (£) optionally substituted by substituent(s) chosen from ©.” alkylthio group (ie) (5) 9 and elastic? alkoxy-carbonyl and carbamoyl group ccarboxyl group Optionally substituted by phenylthio rum (preferably arylthio (bear) group and group ©. alkoxy-carbonyl carboxyl group substituent(s) selected from bitter group; or an alkylthio (preferably an aromatic elm clo having a heterocyclylthio (−a0) Yo group optionally substituted by a (triazolylthio < oxazolylthio) group of ∼Cy.6 alkyl)

{amino group (iv) (1) (preferably C16 alkoxy-carbonyl-Cp.jp alkylamino group (1) “ethoxycarbonylmethylamino” methoxycarbonylmethylamino ¢ (tert-butoxycarbonylmethylamino tcarboxy-Ci.j alkylamino 4c seas) (7 c) ) ° «C713 aralkyloxy-carbonylamino (7d) group (7e) group 02702177071170; -11100? or di-Cy.¢ alkyl-carbamoylamino group (and 1) 'C1. alkylsulfonylamino group (57) optionally substituted by a Cg yy arylsulfonylamino group (VY group) Ve of ¢Cy.¢ alkylsulfonyl heteroaromatic (eg; sulfonylamino group) (41) optionally substituted by selected substituent(s) (indolyl «oxazolyl sthiazolyl »pyridyl or ¢émono- or di-(Cy.6 alkyl-carbonyl)-amino and the C6 alkyl de gana group of ¢(2-oxoimidazolidin-1-yl Ja <) oxoimidazolidinyl “tetrazolyl (V) Yo (preferably oxopiperazinyl ¢)(2,4-dioxoimidazolidin-3-yl) (preferably dioxoimidazolidinyl “2,3-dioxopiperazin-1-yl) (preferably dioxopiperazinyl”) 3-oxopiperazin-1 -yl 5-0x0-4,5-dihydro-1,2,4- (preferably oxodihydrooxadiazolyl) or (2,5-dioxopiperazin-1-yl -(oxadiazol-3-yl) 0 male GL (3(-(7)) is any of the Xs camino that is an RY group compound where the aforementioned B is in a compound

D Component Component where: is: X SA They are as specified for the preceding 3 compound QL RY (R? (RR! Yo hydrogen atom (1) ¢cyano group (V)

¢¢ (IV) (7) 'carboxyl group ('b) tcarbamoyl group (—aY) -alkoxy-carbonyl group© . optionally substituted by 1 to ? substituents selected from group ccarboxyl group “carbamoyl group” thiocarbamoyl group ° Cy alkoxy-carbonyl group and alkyl-carbonyloxy group bitter; (?d) alkoxy-carbonyl© group heterocyclic aromatic (preferably furyl (indolyl «pyrazinyl <oxazolyl «thiazolyl «pyridyl <thienyl] optionally inferred by 1 to ? substituents selected from the ccarboxyl group the carbamoyl group the thiocarbamoyl group and the alkoxy-carbonyl group Br; Ve (7e ) a non-aromatic heterocyclic Cp alkoxy-carbonyl group (preferably toward *“tagged” “oxodioxolanyl” optionally substituted by a bitter alkyl group; (5%) an aralkyloxy-carbonyl group and optionally substituted by 1 to 0 selected substitutes of ccarboxyl de sana carbamoyl group “thiocarbamoyl group Vo” group chalogen 53 “Cp alkoxy-carbonyl group” Cyano group “Nitro group” Cp alkoxy 4c sana Ci alkylsulfonyl group and Cre alkyl group (Optionally substitute the © alkyl group by 1 to selected substituents from the chalogen atom “carboxyl group C14 alkoxy-carbonyl group and ¢ group) carbamoyl (JV) a carbamoyl group mono- or di-substituted by a cis alkyl group XY. optionally substituted by a 1-selected substituent of the halogen atom and the tC alkoxy group Y) group carbamoyl-C™ alkyl-carbamoyl optionally substituted mono or dimer by an alkyl group©, optionally substituted by 1 to ¥ thalogen atoms (%&) of an alkoxy-carbonyl-Cyg alkyl-carbamoyl group. © optionally replaced by Yo by tC group. alkyl mono- or di-Cs pg cycloalkyl-carbamoyl 4c jana (sY) optionally inferred by a tC alkyl group go to 1 optionally substituted by a Cop aralkyl-carbamoyl group (LY) group carboxyl group <hydroxy group chalogen ? Substitutes selected from a bitter atom; ° and carbamoyl group carboxyl group selected substituents from VY group to ¢Cy.¢ alkoxy-carbonyl to ?1 substituent optionally substituted by ©.alkylsulfonyl (7m) group M0? alkoxy-carbonyl and carbamoyl group ccarboxyl group selected from group to ¥ substituents 1 ppm optionally substituted by arylsulfonyl de gana (Ann) 1 carbamoyl group carboxyl group Ae sana «Cig alkyl group selected from bitter; alkylsulfonyl 4c sass 3 Ci alkoxy-carbonyl group sthiocarbamoyl (preferably heterocyclic nitrogen containing carbonyl de gana (""o") 0 to 1 Optionally substituted by morpholino of a “piperidinyl” pyrrolidinyl conjugate bitter alkoxy-carbonyl and carboxy group 4c sana chydroxy substituents selected from group 1 (preferably 604 aryl-nitrogen heterocyclic containing carbonyl Group 1 (£7) optionally substituted by (morpholino «piperazinyl «piperidinyl »pyrrolidinyl thalogen to ? heterocyclic aralkyl-nitrogen idene atoms containing a carbonyl group (YF) optionally substituted with a morpholino «piperazinyl» piperidinyl «pyrrolidinyl (preferably 01 thalogen to ? 1 atoms) by a circular hetero-aromatic (preferably oxy-carbonyl group (p1!) a “oxodioxolanyl < oxodioxolyl optionally substituted mono- or double-substituted by a phosphono group (GY) group m; alkyl group b circular Aromatic heterotrophs (preferably Crs aralkyloxy-carbonyl group (LV): ¢(tetrazolyl)

a (“u) alkoxy-carbonyl group m:©-anomat m0a” Cy pg optionally substituted by 1 to ? selected substituents from the carboxyl group an alkoxy-carbonyl group of and tcarbamoyl group ( c) the aryl-carbamoyl group] nh optionally substituted by 1 to ?° selected substituents from the amino group optionally substituted mono- or double-substituted by a “Cy alkyl group” ccarboxyl group “Cg alkoxy-carbonyl group” aromatic heterocyclic group (preferably ¢) oxadiazolyl tetrazolyl non-aromatic heterocyclic group (preferably (0x00xadiazolyl) and tcarbamoyl group or (?!z) carbamoyl heteroaromatic group (preferably furyl “thienyl) Ye optionally substituted by 1 to ¥ substituents selected from the ccarboxyl group bitter alkoxy-carbonyl group and tcarbamoyl group (¢) ( )£ { ¢Cy.¢ alkyl-carbonyloxy group (cf) group Cry alkoxy optionally substituted by 1 to ¥ substituents selected from chydroxy group ccarboxyl group carbamoyl group and alkoxy-carbonyl group Vo pass; (1=—) Cog aryloxy group optionally substituted by 1 to * substituents selected from the chalogen atom “carboxyl group” Ci. alkoxy-carbonyl “Cg alkylthio 4c sana” carbamoyl group “Cg alkoxy group” C4 alkylsulfonyl group Cig alkylsulfinyl group and alkyl group of (90 optionally replace the Ci alkyl group by 1 or ¥ of selected substituents from the “carboxyl group Cy alkoxy-carbonyl group and the (carbamoyl ¢ (af) aromatic heterocyclyloxy group having Jo + members Jia dy) ¢triazolyloxy ~~ “imidazolyloxy” oxazolyloxy “thiazolyloxy” thienyloxy (pyrimidinyloxy “pyridyloxy” ¢pyrazolyloxy optionally substituted by 1 Elsie?Yo selected substituents from the © alkyl group (optionally substituted by the © . alkyl group by 1 or ¥ of selected substituents from the carboxyl group Ci. alkoxy-carbonyl group ty

Ci alkoxy-carbonyl ccarboxyl group ¢(carbamoyl group) and ¢tcarbamoyl group 4c sana (indolyloxy) conjugated aromatics (preferably heterocyclyloxy (e) group carboxyl group to ¥ substituents selected from group 1 optionally substituted by ¢tcarbamoyl and a ©...alkoxy-carbonyl group ° (heteroaromatic cyclic pyridyl) (preferably Cg alkoxy group (5%) ccarboxyl group to ? Substituents selected from group 1 optionally substituted by or ¢carbamoyl and a ©alkoxy-carbonyl group ¢(tetrazolyl) aromatic heterocyclic (preferably Coq aryloxy (;g) group to ? selected substituents 1 optionally substituted by Cu alkylthio (*a) Ve dc ganas carbamoyl group (©) carboxyl group hydroxy group of ¢C,.¢ alkoxy-carbonyl group to ?selected substituents 1 o optionally substituted by arylthio bear ) group ) of alkylthio group “C6 alkoxy-carbonyl group” carboxyl 4c gana group of or tcarbamoyl and Vo group members (preferably aromatic + Jo having heterocyclylthio dc sana ) h) striazolylthio ~~ “imidazolylthio <oxazolylthio sthiazolylthio” thienylthio to 1 optionally substituted by (pyrimidinylthio “pyridylthio” pyrazolylthio carboxyl group “Cig alkyl group ? Selected substituents from the tcarbamoyl-Br group and the alkoxy-carbonyl Ye group. 'amino 4c gana (i) (7) from alkoxy-carbonyl-C;.19 alkylamino group (1) ¢carboxy-Ci.1 alkylamino 4c gens c) to 1 optionally substituted by Cr aralkyloxy-carbonylamino group D) and Cg alkoxy-carbonyl group carboxyl group selected from Jia ¥ Yo ¢carbamoyl tcarbamoylamino group (7e) group

EA

¢mono- or di-C).¢ alkyl-carbamoylamino group (57) of; Jal Ju circular aromatic heterotrophs (on sulfonylamino (7i) group ° to ?1 substituents optionally substituted by indolyl «oxazolyl» thiazolyl «pyridyl ¢mono- or di-(C,.¢ alkyl-carbonyl) )-amino 4c sens s Cig alkyl 4c sana selected from ¢mono- or di-(Cy.¢ alkyl-carbonyl)-amino group (57) ¢C3.10 cycloalkyl-carbonylamino 4c see (1) to ? Cj alkoxy group “by Loa) circular group ¢(oxadiazolyl “tetrazolyl) heteroaromatic group (preferably ¢ carbamoyl) and a group (0x00xadiazolyl non-aromatic (preferably Rb?); aralkyl-carbonylamino group (a1) Vo ¢Cy.13 arylalkenyl-carbonylamino 4c sexe (1) cthiazolyl <oxazolyl “thienyl” furyl (preferably carbonylamino group (U1) sbenzofuryl ~~ “pyrazinyl” pyridyl “¢pyrazolyl” isothiazolyl 02071 to 1 aromatic heterocyclic optionally substituted by (quinoxalinyl <benzothienyl “Cr.13 aralkyl group” Cq.1q aryl group “Cig alkyl group” selected substituents from group * 0 and group ©. alkoxy-carbonyl group “carboxyl group” Cig alkoxy group ¢carbamoyl group <piperazinyl piperidinyl “pyrrolidinyl (preferably p-carbonylamino) group 7) to ?1 optionally substituted by nitrogen Heterocyclic containing (morpholino 1) by ©. alkyl (Optionally substituted by a Cig alkyl group with selected substituents from the Yo group and a Cy alkoxy-carbonyl group by a ccarboxyl group to ? Substituents selected from the group of

and Ci alkoxy-carbonyl group ccarboxyl group 0 (carbamoyl ¢carbamoyl <piperidinyl “pyrrolidinyl” (eg) carbonylamino group (a1) 4m; aryl-nitrogen heterocyclic containing (morpholino «piperazinyl ttetrahydropyranylcarbonylamion group (Ua) ° ¢4-0x0-4,5,6,7-tetrahydro-1-benzofuranyl-carbonylamino group (31) optionally substituted by a Cy alkoxy-carbonylamino de seas group (7t) rn?; alkoxy-carbonyl to 1 ppm optionally substituted by aryloxy-carbonylamino group (U5) and Cy alkoxy-carbonyl group ccarboxyl group Selected substituents from group ¥ 1 ¢carbamoyl or Cops aralkyl-carbamoylamino group (21) aromatic heterocyclic cthiazolyl (preferably carbamoylamion ic sess (=) “carboxyl to ? substituents selected from group 1 optionally substituted by (0xazolyl or m carbamoyl group and alkoxy-carbonyl group Vo ttetrazolyl (iv) (v) ¢(2-oxoimidazolidin-1-yl (preferably oxoimidazolidinyl (Lab)) «2,4-dioxoimidazolidin-3-yl (preferably dioxoimidazolidinyl (—aV) substituted ©. alkyl optionally substituted by (2,4-dioxoimidazolidin-1-yl) group and carboxyl group to ¥ substituents selected from group 1 optionally by Y. ¢Ci.¢ alkoxy-carbonyl ¢ (3-oxopiperazin- 1 -yl (preferably oxopiperazinyl (2) «2,3-dioxopiperazin-1-yl Ja 4) dioxopiperazinyl (——aV) ¢(2,5-dioxopiperazin-1-yl 5-0x0-4,5-dihydro- 1,2,4-oxadiazol-3- (preferably oxodihydrooxadiazolyl (sv) Yo ¢ (v1 tdioxoisoindolyl (JV)

(1h) oxazolyl optionally substituted by an alkoxy-carbonyl group mer; (2,4-dioxooxazolidin-5-yl Ja &) dioxooxazolidinyl (LY) or dioxothiazolidinyl (preferably ¢ (2,4-dioxothiazolidin-5-yl) each optionally substituted by an alkyl group©). Optionally substituted by 1 to ?selected substituents ° of a carboxyl group and an alkoxy-carbonyl group of (ly) 4-0x0-2-thioxo-1,3-thiazolidin-5-yl or 4- 0x0-2-thioxo-1,3- coxazolidin-5-yl each optionally substituted by a Cp alkyl group optionally substituted by 1 to ?substituents selected from a carboxyl group and an alkoxy-carbonyl group wren)?; dihydroimidazo[ 1,5-blisoquinolinyl ( Jv ) or (um) aryl group pm optionally substituted by an alkoxy-carbonyl group hemron.compound E DS all Vo aforementioned where: R*5R' Similar or different and each of them is Ja) Cp yg alkyl Ae sana The R' is isobutyl i.e. ¢ (neopentyl ¢methyl sa R® 3 is an aryl group with bm optionally substituted by Cr alkyl de gana (preferably 0 is 3 is ¢)(4-methylphenyl R* is famino group and X hr () cla) (5) (o)a (at (38) (h) (J) or (61) aforementioned [preferably (iv) (s) (at) (kd) or (os) compound F 5 -(aminomethyl)-2-methyl-4-(4-methylphenyl)-6-neopentylnicotinic acid Yo (example ¢(Y Y 5-(aminomethyl)-6-isobutyl-2-methyl-4-(4- methylphenyl)nicotinic acid

(Example 460); carboxylate (Veo (ex. {[2-isobutyl-6-methyl-4-(4-methylphenyl)-5-(2-morpholin-4-yl-2-oxoethyl)pyridin-°3-yllmethyl} amine; 311 (Example methyl 3-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3- yl]acetyl }amino)benzoate (YY) (Example ‎ 0

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl]isoxazole- 4-carboxamide (35);06 Jad).(fumarate :trifluoroacetate <hydrochloride or a salt thereof (preferably 0 preferably a salt of compound of) as a pharmacologically acceptable salt Examples of such a salt include salts with inorganic bases salts with organic bases salts with inorganic acids salts with organic acids salts with organic acids salts with basic or acidic amino acids, etc. Preferred examples of a salt with an inorganic base include alkali metal salts Jie sodium salt cpotassium salt etc. alkaline earth metal salts such as ccalcium salt 0 magnesium salt etc.; «cyclohexylamine ~~ «tert-butylamine ¢[tris(hydroxymethyl)methyl)methylamine] etc. ¢N,N-dibenzylethylenediamine < dicyclohexylamine «benzylamine <hydrochloric acid Preferred examples of salt with inorganic acid include salt with Yo etc “phosphoric acid” sulfuric acid “nitric acid < hydrobromic acid

Yyvy oY «acetic acid »formic acid Preferred examples of a salt with an organic acid include salt with «tartaric acid »oxalic acid «fumaric acid »phthalic acid »trifluoroacetic acid «methanesulfonic acid »malic acid »succinic acid «citric acid »maleic acid etc. “p-toluenesulfonic acid “benzenesulfonic acid lysin carginine base salt with amino include preferred examples of salt with acid ° etc.” ornithine caspartic acid acidic salt with amino include preferred examples of salt with acid etc. “glutamic acid is one of the salts mentioned above; Salt with inorganic acid is preferred, salt with acid, etc. “fumarate” trifluoroacetate “organic hydrochloride is more preferred 0 acid pl is a compound that turns into a compound () due to reaction (I) a prodrug of a compound ( ) infectious; etc.; under physiological conditions in the body; i.e. a compound transformed into a compound by hydrolysis (I) and a compound transformed into a compound ll by oxidation; reduction; enzymatic hydrolysis; by gastric acid etc. Examples of a prodrug for a compound () include an aqueous ill; (5-methyl-2-0x0-1,3- “pentylaminocarbonylated” alanylated “eicosanoylated” pyrrolidylmethylated <tetrahydrofuranylated “dioxolen-4-yl)methoxycarbonylated from hydroxy, etc.); A compound in which a group of dtert-butylated “pivaloyloxymethylated” Jil (for example, borated “phosphorylated < alkylated cacylated) process (I) compound Yo “palmitoylated cacetylated process (I) of a hydroxy compound a compound takes place It contains a group of 21807160 fumarylated succinylated pivaloylated propanoylated from carbxoyl etc.); A compound in which the “dimethylaminomethylcarbonylated” group is undergoing (for example; a compound in which the “phenyl esterified ethyl esterified” process (I) of the carbxoyl group is amidated or esterified (I) © «dimethylaminomethyl esterified «carboxymethyl esterified »ethoxycarbonyloxyethyl esterified «pivaloyloxymethyl esterified oY

«(5-methyl-2-0x0-1,3-dioxolen-4-yl)methyl esterified «phthalidyl esterified etc.]

etc. These compounds can be produced from compound (1) in a manner known by itself. A prodrug ( ) may be a compound that converts to compound (1) under physiological conditions depending on

© Description in: ‎Development of Pharmaceutical Products, vol. 7, Molecule Design, 163-198, Hirokawa Shoten (1990). Compound (1) may be labeled with an isotope (eg MC PH, JBL 35, etc.)

A hydrate of anhydride is (I) Compound 1. Compound ( ) and a prodrug thereof (sometimes hereafter referred to for simplicity as a compound of the present invention) exhibit little toxicity and can be used as an agent for the prevention or treatment of several diseases will be mentioned later for mammals (eg; human; mouse; rodent; dog; carrier etc.) as is or in combination with a carrier af cat; cattle; horse; pig;

10 pharmacology etc.; To give a drug composition. used; Hana Many organic or inorganic carriers traditionally used as materials for pharmaceutical preparations As a pharmacologically acceptable carrier that is added as an excipient ¢ (lubricant) binder disintegrant for solid preparations; and a solvent, a dissolution aid, a 0 suspension agent, an isotonicity agent, a pH stabilizer, a buffer, a softening agent soothing agent) etc.; for liquid formulations. when necessary; Pharmaceutical additive sale Jie preservative antioxidant coloring agent sweetening agent Yo Yo are preferred examples of excipients (excipient) include “D-mannito] “sucrose” lactose “D-sorbitol” dextrin “(pregelatinized starch) gelatin Gd WBA salad. hydroxypropyl cellulose “crystalline cellulose of silicic” pullulan “powdered dextrin” acacia “sodium carboxymethylcellulose etc. synthetic magnesium aluminate metasilicate light aluminum silicate anhydride talc calcium stearate magnesium stearate are preferred examples of a lubricant include colloidal; etc. silica “(pregelatinized starch) gelatin Preferred examples of a binder include pregelatinized starch ° “carboxymethylcellulose “methylcellulose powder” acacia “gelatin < saccharose “D-mannitol “sucrose” crystalline cellulose “sodium carboxymethylcellulose hydroxypropyl hydroxypropyl cellulose ¢ pullulan “dextrin” trehalose etc. “polyvinylpyrrolidone” methylcellulose “carboxymethylcellulose starch” sucrose lactose Examples of hydrolysate include 10 sodium carboxymethyl “sodium croscarmellose” slightly substituted calcium carboxymethylcellulose; etc. Hydroxypropyl cellulose is light “silicic ahydride” starch

Ringer Preferred examples of solvent include water for injection; physiological saline; Cu) olive oil; sesame oil; Corn oil; polyethylene glycol “propylene glycol” aspirated fodder cottonseed oil etc. 0 “propylene glycol” polyethylene glycol Preferred examples of dissolving aids include “cholesterol” “cholesterol” “cholesterol” “benzyl benzoate” “D-mannitol” “sodium salicylate <sodium citrate “sodium carbonate” triethanolamine etc. “sodium acetate” stearyltriethanolamine e.g. pela ww Preferred examples of a suspending agent include activators Y. “benzalkonium chloride” lecithin intel aminopropionate ¢sodium lauryl sulfate

Jie hydrophobic polymers etc.; cglycerol monostearate < benzethonium chloride “sodium carboxymethylcellulose ¢ < polyvinylpyrrolidone » polyvinyl alcohol hydroxypropyl < hydroxyethylcellulose < hydroxymethylcellulose » methylcellulose etc. ¢ tpolyoxyethylene hydrogenated castor Cu » polysorbates etc.; Yo “D-mannitol” glycerol “sodium chloride Frequency include Jalal Preferred examples etc.” Glucose “D-sorbitol”

YY\Y oo “phosphate Preferred examples of pH stabilizer include pH stabilizer carbonate pH stabilizer cacetate pH Cada etc. 6 etc. “benzyl alcohol preferred agent Softeners include A: “chlorobutanol” p-oxybenzoates (para. The preferred methylation for preservatives ° etc. “sorbic acid “dehydroacetic acid” phenethyl alcohol “benzyl alcohol” etc. “ascorbate” sulfite) Preferred examples of an antioxidant include soluble in ALE JOU Preferred examples of a coloring agent include dyes such as tar, ole and ?; , 3 etc.); lac dyes insoluble in 1 with number ; and ©; blue food color with number 0 for edible tar dye soluble in aluminum eg salt (J) water <chlorophil “beta carotene eg (J etc.); natural pigments (SA water is precipitated etc.); etc. cred iron oxide “dipotassium glycyrrhizinate < saccharin sodium Preferred examples of a sweetening agent include stevia caspartame 0

Je The aforementioned dosage form of the drug combination is; For example; Oral Agent Tablets (including sublingual tablets and orally dissolving tablets); capsules (including softgels and microcapsules); granules » powders; pinches; drink it; emulsions; suspensions; etc; or a non-gastrointestinal agent such as injection (e.g. “hypodermic injection; intravenous injection; intramuscular injection; intraperitoneal injection; drip infusion”; transdermal preparations; ointments; etc.); Suppositories (JU etc.) external agents (eg

Ail, for example; rectal suppositories; vaginal suppositories; etc); pills le preparations) pulmonary preparations (inhalations); eye preparations; etc. These may be given safely orally or via the gastrointestinal tract. These are controlled-release preparations such as Jal gall preparations These Yo may be rapid-release and extended-release preparations (eg; extended-release microcapsules) launch).

The medicinal composition may be produced according to a method traditionally used in the art of preparation; Like the method described in the Japanese Pharmaceutical Encyclopedia; etc. Specific production methods for pharmaceutical preparations are described in detail below. Although the content of the compound of the present invention in the medicinal composition varies depending 0 on de pall form the dose of the compound of the present invention; etc; it may be;. For example; About AY vem y of weight. For example; An oral agent is produced by adding; to the constituent Jail excipients (eg “<D-mannitol” Lis csucrose <actose etc.); decomposers (eg calcium carboxymethyicellulose etc.); binders (eg “acacia” (pregelatinized starch) powdered gelatin “carboxymethylcellulose polyvinylpyrrolidone <hydroxypropyl cellulose” etc.); Lubricants Je) eg; 0017071006 glycol 6000 “magnesium stearate” talc etc.) etc.; press molding of the resulting mixture; and when necessary; Encapsulation of the agent using an encapsulation base to mask (Fal) an enteric or extended-release property according to a known method. Examples of encapsulation base include “Su” encapsulation base; water soluble film encapsulation base; 32018 Enteric Film Packaging; extended release film wrapping base; etc. As a base for encapsulating sugar, sucrose may be used when necessary; In addition to one or more of the selected types of calcium carbonate “talc” deposited “acacia” gelatin powder “pullulan” carnauba ped etc. Y. as a water-soluble film encapsulation base; For example; Cellulose polymers use hydroxypropyl methylcellulose hydroxypropyl cellulose To “methylhydroxyethylcellulose <hydroxyethylcellulose 35 synthetics such as aminoalkyl methacrylate copolymer E “polyvinyl acetal dithylaminoacetate [trade name: 8” polyvinylpyrrolidone [Roehm Pharma “Eudragit” etc.; YO polysaccharides such as ¢pullulan etc. enteric membrane encapsulation base; For example; Cellulose polymers such as hydroxypropyl methylcellulose acetate <hydroxypropyl methylcellulose phthalate ov to “cellulose acetate phthalate” carboxymethylethylcellulose ¢succinate [trade name: methacrylic acid copolymer L J— acrylic acid polymers [trade name: methacrylic acid copolymer LD] Roehm Pharma <Eudragit L [labeled methacrylic acid copolymer 5 [Roehm Pharma «Eudragit 1-5] etc.; etc. cshellac Jie etc; Natural Products [Roehm Pharma «Eudragit 5 Trademark: ©] as cellulose polymers as extended-release film encapsulation base; For example; used as aminoalkyl methacrylate copolymer as acrylic acid polymers etc.; cethylcellulose ethyl acrylate-methyl suspension [Roehm Pharma ¢Eudragit RS [trade name: RS etc.]; Etc. [Roehm Pharma ¢ Eudragit NE [trade name: methacrylate copolymer] May mix two or more of the above encapsulation bases in proportions suitable for use. Ve cL etc. “ferric oxide” titanium oxide Jie A protective agent may be used Light (Lil) Packaging. Produces an injectable preparation by dissolving; suspend or emulsify the active ingredient in an aqueous solvent (eg) or an oily solvent eg Ringer; distilled water physiological salt solution; olive oil solution; Sesame oil; cottonseed oil die (eg vegetable oil 10 etc.) etc.; together with a dispersing agent (for example, propylene glycol corn oil, etc.; “polyoxyethylene 60 hydrogenated castor oil” cpolysorbate 80 “Jali” preservative “(A” sodium alginate “carboxymethylcellulose” polyethylene glycol “chlorobutanol” benzyl alcohol “ propylparaben “methylparaben (eg” “D-mannitol” “glycerol” sodium chloride etc.); a frequency agent (eg phenol 0

Jie etc) etc. in this step; When needed, glucose additives (D-sorbitol, etc.) may be used; Dissolving agents “sodium acetate” sodium salicylate (eg;

Jd human serum etc.); palliative agents (eg albumin stabilizing (eg; etc.) etc. “benzyl alcohol chronic toxicity; eg bala; Je toxicity) The compound of the present invention exhibits little toxicity Yo frontal toxicity ; reproductive toxicity vascular toxicity; breed to cancer); It causes fewer side effects and can be used as an agent for the prevention, treatment or diagnosis of several diseases of mammals (eg

OA

mouse rodent in particular ca dog; cat; lian for example; human; Cattle; (eo can stop hydrolysis peptidase Ja¥ has a superior inhibitory activity Jad) The compound of the invention Carriers ccytokines “peptide hormones Jia of a physiologically active substance peptidase due to neurotransmitter; etc. Peptide-2 “(GLP-1) glucagon Similar to peptide-1 Examples of peptide include peptide hormones Etc. (GHRH) Growth Hormone Releasing Hormone “GIP” (GLP-2) glucagon Similar to etc. (RANTES such as chemokine include cytokines Examples of neurotransmitter 7; etc. peptide Examples of neurotransmitters include “(Leucyl aminopeptidase) EC 3.4.11.1 include peptidases on td Ve

EC 3.4.11.3 «(Membrane alanine aminopeptidase) EC 3.4.11.2

EC 3.4.11.5 «(Tripeptide aminopeptidase) EC 3.4.11.4 «(Cystinyl aminopeptidase)

EC 3.4.11.7 «(Aminopeptidase =~ B) 60 3.4.11.6 « (Prolyl aminopeptidase)

EC 3.4.11.10 «(Xaa-Pro aminopeptidase) EC 3.4.11.9 «(Glutamyl aminopeptidase) ¢ (Clostridial aminopeptidase) EC 3.4.11.13 «(Bacterial leucyl aminopeptidase) '©

EC 3.4.11.15 «(Cytosol alanyl aminopeptidase) EC 34.11.14

EC 3.4.11.17 «(Xaa-Trp aminopeptidase) EC 3.4.11.16 «(Lysyl aminopeptidase) «(Methionyl aminopeptidase) 26 3.4.11.18 «(Tryptophanyl aminopeptidase)

EC 3.4.11.20 «(D-stereospecific aminopeptidase) EC 34.11.19

EC 3.4.11.22 «(Aspartyl aminopeptidase) EC 3.4.11.21 «(Aminopeptidase Ey) Y-

EC 3.4.13.4 «((Xaa-His dipeptidase) EC 3.4.13.3 «(Aminopeptidase I)

EC 3.4.13.7 ¢((Xaa-methyl-His dipeptidase) EC 3.4.13.5 «((Xaa-Arg dipeptidase)

EC 3.4.13.12 «(Xaa-Pro dipeptidase) 26 3.4.13.9 «(Glu-Glu dipeptidase) «(Non-stereospecific dipeptidase) EC 3.4.13.17 (Met-Xaa dipeptidase)

EC 3.4.13.19 «(Cytosol nonspecific dipeptidase) EC 3.4.13.18 Yo

EC 3.4.14.1 «(Beta-Ala-His dipeptidase) EC 3.4.13.20 «(Membrane dipeptidase)

EC 3.4.14.4 (Dipeptidyl-peptidase II) EC 3.4.14.2 « (Dipeptidyl-peptidase I) 2-11 oq

EC 3.4.14.6 «(Dipeptidyl-peptidase IV) EC 3.4.14.5 «((Dipeptidyl-peptidase ID)

EC 3.4.14.10 «(Tripeptidyl-peptidase I) EC 3.4.14.9 «(Dipeptidyl-dipeptidase) etc.; According to (Xaa-Pro dipeptidyl-peptidase) EC 3.4.14.11 «(Tripeptidyl-peptidase II) La J peptidase can be classified by the International Federation of Biochemistry and Molecular Biology. such as 0009 0:8 (FAPa Sui © EC 3.4.14.5 20 3.4144 (EC 3.4.14.2) of these 34.141 are preferred particularly EC and 3.4.14.11 EC 3.4.1410 “EC 3.4.149 EC 3.4.14.6 (Dipeptidyl-peptidase IV) EC 3.4.14.5 or effect of glucagon A compound of the present invention may concomitantly have an antagonistic effect for these all when the compound of the invention additionally has a peptidase The compound of the present invention is more effective as an agent for the prevention of diabetes than for Ng sl diabetes than oJ for the treatment of diabetes (for example; Elevation (He) etc.) Ve The compound of the present invention is useful as an agent for the prevention or treatment of diabetes mellitus (eg diabetes mellitus with pregnancy; oY eg type diabetes mellitus type diabetes mellitus etc.); as an agent for the prevention or treatment of hyperlipidemia (eg; elevated hyperlipidemia after pall in HDL blood; decreased cholesterol; elevated pall triglyceride food intake; etc.); as an agent for the prevention or treatment of atherosclerosis; A prophylactic agent for O-0 and an agent to prevent the build-up of tinsulin ¢ (IGT) glucose for the treatment of glucose intolerance and its conversion into diabetes. Diabetes Association

A999 Japanese new diagnostic hallmarks in fasting blood glucose according to this report; Diabetes is a condition that shows any of the YO level mg/dl; 2-hour level in 1776 intravenous plasma (intravenous plasma) glucose level (concentration in plasma in g glucose) (concentration VO OGTT) in oral glucose VO g tolerance test

YYVY

Te glucose of non-fasting blood (glucose concentration mg/dl; venous level 001) not less than mg/dl. A case that does not fall under the range of 001 in intravenous plasma (intravenous plasma) of at least fasting blood (glucose concentration) is the above-mentioned diabetes and is different from a case showing a mg/dl level or a 2-hour level in a stress test 011 Intravenous plasma) less than 0:06 intravenous plasma (less than glucose g) (concentration VO OGTT) by mouth glucose al a Yo © mg/dl (normal type) called “borderline type” 00 (American Diabetes Association) Distinctive Features ADA Additionally; it has approved

NAA SAWHO 1991 New Diagnostics of Diabetes in Fasting Blood (Glucose Concentration Showing Alla Level According to These Reports, Diabetes is mg/dL and the 2-hour Level in Test 171 Intravenous Plasma) is not less than glucose 0 mg/ Yoo (intravenous plasma) not less than oral glucose (glucose concentration g VO tolerated dl). glucose is a condition that shows glucose level according to the above reports; Impaired tolerance mg/dl and 2-hour level 177 fasting blood (concentration 06 in venous plasma) less than venous plasma) not less than oral glucose (concentration of glucose g VO in a tolerance test of 0 According to the report, the ADA condition shows 100 mg / dL and less than 0 mg / 100 mg / 100 in intravenous plasma (intravenous plasma) of no less than fasting blood glucose (glucose concentration level according to the report Like fasting. Glucose (TFG defect mg/dl called 1776 dl and less than fasting); A condition showing a 2-hour glucose test (TFG defect among “WHO 0140 mg/intravenous plasma”) is less than oral glucose (glucose concentration Vo g tolerance -0). The compound of the present invention can also be used as an agent for the prevention or treatment of diabetes mellitus (impaired fasting blood glucose 176) and IFG glucose) “impaired glucose tolerance”. (gull type as determined according to the new diagnostic features mentioned above. In addition to 0 abnormal) IFG “glucose” the compound of the present invention can prevent the development of borderline type; Impaired tolerance Cally Yo (impaired fasting blood) to diabetes mellitus (TFG) or impaired fasting glucose)

>

The compound of the present invention may also be used as a prophylactic or treatment agent for; (Jil) Complications of diabetes [Je] (Jal) neuropathy; renal impairment; Sudden cataract; macrovascular disease; osteopenia; hyperosmolar hypoglycaemia; infectious disease (eg (JO Respiratory infection; Urinary tract infection; Gastrointestinal infection; Soft cutaneous tissue infection; Lower extremity infection; etc.); gangrene of diabetes Mouth Cilia; Decreased hearing acuity; Cerebrovascular disorder; Circulatory disorder terminal; etc.]; obesity; osteoporosis; wasting (eg; cancerous wasting; tuberculosis wasting; diabetes wasting; blood disease wasting; endocrine disease wasting; infectious disease wasting or immunodeficiency wasting 0 acquired); fatty liver; high blood pressure; polycystic ovary disease. kidney disease (J) (J) path (Ja) diabetic nephropathy; glomerular nephritis; sclerosis ou renal disease; hypertensive nephrosclerosis. end stage renal disease; etc.); muscular malnutrition; myocardial infarction; angina pectoris; cerebrovascular injury (eg; cerebral infarction; stroke); ; cial insulin resistance disease; disease X metabolic disease; elevated blood insulin; sensory disturbance due to elevated blood insulin; tumor (eg leukemia; breast cancer; prostate cancer; skin cancer; etc.); irritable bowel disease; acute or chronic diarrhea; Inflammatory diseases (eg; chronic rheumatoid arthritis; deformity due to spondylitis; osteoarthritis of the lymph nodes; gout; post-operative or traumatic injury; edema; neuralgia; pharyngitis and laryngitis; cystitis; hepatitis (including pharyngitis) non-alcoholic fatty liver); rheumatoid arthritis; Cel; pancreatitis; gastroenteritis; inflammatory bowel diseases (including inflammatory bowel disease); ulcerative colitis; gastric mucosal injury (including aspirin-induced infection of the gastric mucosa) etc.); traumatic injury to the mucous membrane of the small intestine;

Yo malabsorption; testicular function disorder; visceral obesity; etc. The compound of the present invention may also be used to reduce visceral grease; stop visceral fat buildup 0 improve sugar metabolism; improved lipid metabolism; inhibition of oxidized LDL production; improve metabolism

Ty lipoprotein; improve artery metabolism delay prevention and treatment of cardiovascular complications reduce blood residue; prophylaxis and treatment of eB anemia; prevention and treatment of complications of androgen failure, ovulation prevention and treatment of excessive hair growth prevention and treatment of pancreatic hypertension (8); pancreatic (8-cell) regeneration; Induce regeneration (B cell) Improve pancreatic (cp cell) function; control appetite; etc. © The compounds of the present invention can also be used for secondary prevention and disease exacerbation Cardiovascular injury such as myocardial infarction (JB) The compound of the present invention is a substance that induces an insulin secretion flux based on patients with blood glucose (Jd path le) selectively induces glucose secretion 1080110 In patients with a elevation of 0 mg/dl or a 2-hour fasting blood glucose level of at least 1176 who show a level of 041 mg/dl (at least YO OGTT) oral glucose g Vo stress test etc.). So; The compound of the present invention is useful as a safe agent for the prevention or treatment of disease, etc.; pal glucose, a sugar with little potential for vascular complications; 1050110 Inducing a decrease in YO by-product Jail The compound of the present invention is also useful as a therapeutic agent for diabetes when the blood glucose Jay has a superior insulin-reducing effect and provides sulfonylurea secretion effect for insulin and substances Sulfonylurea led compounds that cause diabetes to fail, therefore; Fast-acting dnsulin fails to provide a sufficient lowering effect in providing an effect on blood glucose secretion. Term glucose 0 or derived from sulfonylurea We can mention a compound having a structure Lia sulfonylurea as a compound stolazamide ¢chlorpropamide «gliclazide glibenclamide tolbutamide adjuvant etc. glybuzole glipizide glimepiride glyclopyramide <acetohexamide fast acting; We can mention a compound that stimulates the secretion of insulin as a substance that causes a surge of secretion

AOU compound 501100710768; Although not Jie pancreatic M8 cell in the same way (insulin Yo crepaglinide for example; le) glinide such as compounds csulfonylurea skeleton of that etc.); Etc. Calcium salt hydrate to enjoy cnateglide «senaglinide

+1 Although the dose of the compound of the present invention varies depending on the person taking the remedy; method of administration; target disease; The condition to be treated ad the compound of the present invention as an active ingredient is generally given in a single dose of approximately ( = 0 mg/kg of body weight; Preferably 00 Teme, mg/kg body weight; More preferably 10-11 mg/kg body weight; In case; For example. Oral administration to adult diabetics. This dose is given as required 1 to ? times a day. The compound of the present invention can be used in combination with drugs Jia A therapeutic agent for Sul's disease A therapeutic agent for Sill complications (a je) Anti-hyperlipidemia agent Anti-hypertensive agent Anti-obesity agent Diuretic agent Diuretic agent chemotherapeutic; hereinafter as a combination drug). Each of them contains an active ingredient or may be given as a single preparation containing both active ingredients.de ja the combination drug may be determined as appropriate on the basis of the clinically used dose. the patient being treated; the method of administration; the target disease; the condition; the combination; etc. When 'Ye' is the patient to be administered; For example; human; Union drug is used in an amount of 00011 parts by weight for each part of the weight of the compound of the present invention. as a therapeutic agent for diabetes; We can mention insulin preparations (eg animal insulin preparations (JE) extracted from the pancreas of a cow and a pig; (a) insulin preparations genetically engineered using Escherichia Coli or yeast; ¢zinc insulin ¢protamine zinc insulin Y° part or derivative of insulin (eg; (INS-1 etc.); oral insulin preparation; etc.); insulin-sensitizing substances (eg pioglitazone or A salt thereof (preferably rosiglitazone (hydrochloride) or a salt thereof (preferably

“(MCC-555) Netoglitazone “GI-262570” “Reglixane (111-501) ¢(maleate 440-/see” FK-614 (Rivoglitazone (CS-011) “R-119702” “KRP-297” BM- 13.1258 “DRF-2593 Compounds described in WO99/58510 (eg” (E)-4-[4-(5-methyl-2-phenyl-

(4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyric acid » compounds described 8 in «Ragaglitazar ~~ (NN-622) «Tesaglitazar ~~ (AZ-242) <W001/38325 «MBX-102 ( LM-4156: BM-13-1258 < ONO-5816 < Muraglitazar (BMS-298585)

T-131 (Balaglitazone (NN-2344) (LY-510929) (MX-6054 «LY-519818] or its salt; (THR-0921 etc.); PPARY/QL o-glucosidase inhibitors (eg; 08115056 otuma; <emiglitate ¢miglitol etc.);

biguanides (eg buformin “metformin” phenformin or salts thereof (eg (succinate “fumarate chydrochloride” Jbl etc.); substances that cause sulfonylurea] insulin (eg Jaw); “glibenclamide tolbutamide” glyclopyramide ¢acetohexamide < tolazamide “chlorpropamide gliclazide” nateglide ¢senaglinide ¢ repaglinide (fm “glybuzole” glipizide “glimepiride mitiglinide Ye or calcium salt hydrate thereof]; modulator” GPR4A0 GLP-1 receptor antagonists [eg “AC-2993 (exendin-4) <NN-2211” GLP-IMR “GLP-1 ¢Aib(8,35)hGLP-1(7) 37)NH2 8114-7 010-1131] amylin antagonists (eg “Jal P0:8011080; etc.); phosphotyrosine phosphatase inhibitors (eg; sodium vanadate etc.); peptidase inhibitors IV 0106001 (eg

“MK-431 15-021 “P93/01 (LAF-237) “P32/98 PT-100 (NVP-DPP-278 | 0” SR-58611-A “CL-316243 Model”) Ju (on B3 etc.);

al lafie (eg) “AZ40140 BMS-196085 9677-lei” SB-226552 1)6-7hana glycogen Joris le) carbohydrate without glucose composition SGLT etc.) ¢ glucagon antagonist ¢glucose-6-phosphatase inhibitor 010501101856

Yo (cotransporter (le) (ex. sodium-glucose; “T-1095 transcript); 11B-hydroxysteroid dehydrogenase inhibitors (eg. 8171-3498 etc.) adiponectin

or supportive of it; (Je) IKK inhibitors (Jil 88-2868 etc.); Drugs that improve resistance

> cleptin somatostatin receptor antagonists (compounds described in “W001/25228” “W099/22735 “WO098/45285 01209844921 ....4 etc.); glucokinase activators (eg 1675-28-M82); etc. Examples of Jala therapeutics for diabetes complications include aldose reductase inhibitors (e.g.: Fidarestat < Minalrestat “Zopolrestat < Zenarestat” “Epalrestat” Tolrestat “CT-112” (SNK-860) etc.); Neurotrophic factors and neurotrophic drugs (eg BDNF (NT-3 (NGF) (Jill)) neurotrophin production-secretion inducers described in 2 (eg; 4-(4-chlorophenyl)-2-) 2-methyl-1-imidazolyl)-5-[3-«(2-methylphenoxy)propyl] oxazole etc) etc.); PKC inhibitors (eg (Jad (a) ¢LY-333531 ¢ruboxistaurin mesylate inhibitors LE) AGE inhibitors eg Jia (ALT766) N-phenacylthiazolium bromide pyratoxanthine pimagedine <ALT946 Pyridoxamine “Pyridorin EX0-226 (ALT-711 etc.)” active oxygen scavengers (eg; cthioctic acid etc.); cerebral vasodilators (eg “tiapride” Jul 0 Asnahan” 08; etc.); antagonists of the somatostatin (BIM23190) receptor and inhibitors of the early end of cell life cycle signal-regulatory kinase-1 (516-1M). cholesterol (eg “simvastatin” “pravastatin” “cerivastatin” pitavastatin “<rosuvastatin” “itavastatin” “fluvastatin” “atorvastatin” “lovastatin”) and any such (eg; sodium salt ¢ (calcium salt etc.) squalene synthase (eg; compounds described in (W097/10224) as N-[[(3R,55)-1-(3- acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5- ctetrahydro-4,1-benzoxazepin-3-yl]acetyl ]-piperidine-4-acetic acid; etc.); lc) fibrate compounds eg “(Jl” clinofibrate ¢simfibrate “clofibrate cbenzafibrate Yeo” Je) ACAT inhibitors eg “Eflucimibe ¢Avasimibe etc.) “resins” substituting anion (eg “colestyramine etc.) “probucol” drugs “Je) nicotinic acid”

example; sterols “ethyl icosapentate” (zl cniceritrol “nicomol”) are vegetable (eg;

ey-oryzanol “soysterol etc.); etc. Examples of Jalal anti-hypertensives include angiotensin converting enzyme inhibitors (eg “(z)” delapril cenalapril ccaptopril angiotensin II antagonists (eg “telmisartan” ¢valsartan <eprosartan <losartan » candesartan cilexetil 1-[[2'-(2,5-dihydro-5-0x0-4H-1,2,4-0xadiazol-3-yl)biphenyl- «tasosartan «irbesartan «4-yl]methyl ]-2-ethoxy-1H-benzimidazole-7-carboxylic acid etc.); calcium antagonists (eg nicardipine efonidipine amlodipine nifedipine manidipine etc.); potassium channel openers (eg “L-27152 <leveromakalim

¢<AL 0671 0 010-121 etc.) “Clonidine etc. Examples of an anti-obesity agent include anti-obesity agents that affect the central nervous system (eg phentermine fenfluramine Dexfenfluramine phenylpropanolamine Mazindol dexamphetamine Sibutramine clobenzorex MCH receptor antagonists (although 1 ¢SNAP-7941 ¢SB-568849 Compounds included in (WO01/87834 5 WO01/82925 etc.); Neuropeptide-7 antagonists (eg » 00-422935; etc.) Cannabis-like receptor antagonists (eg “Jor” SR-147778 “SR-141716 etc.) ¢ghrelin antagonist 11B-hydroxysteroid dehydrogenase inhibitors (eg (a BVT-3498 “Jal” etc.) ); pancreatic lipase inhibitors (eg “ATL-962 corlistat etc.”); B3 antigens (eg “AJ-9677” SB-226552 “UL-TG-307” SR-58611 -A «CL-316243 «J all 8148-5 240140 etc.); peptidic appetite suppressants (eg; deptin CNTF (Ciliary Neurotropic Factor ¢) antagonists (le) cholecystokinin via clintitript “Jill 01-15849; etc.); substance that reduces food intake

(eg P-57 (Jha etc.); etc. Yo. Examples of a diuretic agent include le xanthine derivatives eg sodium ctheobromine s calcium salicylate <theobromine s salicylate ell); Thiazide preparations (eg strichloromethyazide <cyclopenthiazide «ethiazide]

b “penflutizide < benzylhydrochlorothiazide < hydroflumethiazide < hydrochlorothiazide emethyclothiazide “polythiazide etc.); aldosterone antagonists (eg ctriamterene «spironolactone »Jbl etc.) carbonate dehydratase inhibitors (eg »acetazolamide etc.); chlorobenzenesulfonamide preparations (eg “indapamide” mefruside cchlortalidone etc.) <azosemide <bumetanide »furosemide <etacrynic acid etc. Examples of a chemotherapeutic agent include alkylation agents (eg “ifosfamide” cyclophosphamide = “anti-metabolites” (eg 5-fluorouracil “methotrexate or a derivative thereof; etc.); anticancer antibiotics 0 (eg “cadriamycin” mitomycin etc.); plant-derived anticancer agents (eg “taxol” vindesine ¢vincristin etc.) “carboplatin” cisplatin etoposide etc. Of these; furtulon and aeofurtulon which are derivatives of ¢5-fluorouracil etc. Examples of a therapeutic immunomodulatory agent include components from a microorganism or bacterial (eg Ve; derivative “picibanil” muramyl dipeptide etc.); polysaccharides have immune-enhancing activity (eg; krestin ¢sizofiran clentinan etc.) – cytokines produced by genetic engineering techniques (eg “(IL) interleukin interferon etc.); colony stimulating factors (eg granulocyte colony stimulating factor; cerythropoietin etc.); etc preferably interleukins such as IL-2 «IL-1 11-12 etc. 0 Examples include the Jalal anticoagulant heparin (eg Jur <heparin sodium «dalteparin sodium < heparin calcium etc.); warfarin (eg silyl; cwarfarin potassium etc.); anti-thrombin drugs le) thrombin eg caragatroban “Jal od) coagulation factors calteplase tisokinase “urokinase” Jil Ju wu le) cpamiteplase “monteplase ¢nateplase etc.); Platelet aggregation inhibitors (eg < beraprost sodium «ethyl icosapentate »cilostazol »ticlopidine hydrochloride «Jill©» sarpogrelate hydrochloride etc.); etc.

TA celcatonin “calcitriol alfacalcidol therapeutic for osteoporosis Jalal ahd include alendronate sodium “pamidronate disodium “ipriflavone “estriol ¢calcitonin salmon etc. <incadronate disodium “hydrate” galanthamine “rivastigmine” donepezil “tacrine anti dementia Jalal Examples include “sildenafil citrate” apomorphine Examples include an agent to improve erectile dysfunction etc. “flavoxate hydrochloride therapeutic for incontinence or urination Jalal ibd include . etc. “propiverine hydrochloride <oxybutynin hydrochloride (eg acetylcholine esterase therapeutic for dysuria Jalal Ah inhibitors include Ve etc.” (example distigmine) In addition, drugs that have a wasting-improving effect are proven In animal models and cases (eg 100000618610 etc.); Je) cyclooxygenase derivatives; medical Jue inhibitors; (eg; glucosteroid (Megesterol acetate) eg “Je) Progesterone agents” tetrahydrocannabinol agents “metoclopramide etc.” (dexamethason 0 agents etc.); Growth hormones ceicosapentaenoic acid Improve lipid metabolism (eg; Oncostatin 11 IL-6 “LIF 1217-6) Induce wasting such as Jalal or IGF-1 antibodies may be used in combination with a compound of the invention current cx)

Jal Allergen cinsulin Preferably combination drug is a preparation (preferably insulin cbiguanide ca-glucosidase inhibitor ¢insulin 0 etc. “(sulfonylurea or more of the combination drugs) 1 The above-mentioned combinations may be used in combination at appropriate proportions.1 The preferred combinations may be used if 7 or more drugs are used; the combination is eg ta-glucosidase and sulfonylurea (preferably insulin). (1) Yo sbiguanide 5 (sulfonylurea (preferably insulin) (7)

( ) Inducer of insulin secretion efflux (preferably biguanide “) sulfonylurea and inhibitor of β-glucosidase 8 sensitizer for insulin and inhibitor of ta-glucosidase (m) sensitizer for β-biguanide s insulin ° (7) a biguanide “insulin Jal” and an inhibitor of a-glucosidase. When the compound of the present invention is used in combination with a combination drug, its quantity can be reduced in a safe range, taking into account the antagonistic effect of these Specifically, the dose of a sensitizer for cinsulin, a substance that causes secretion flux (FDE 011): (biguanides (sulfonylurea) is preferred compared to the normal dose. Therefore, it is possible to safely prevent the effect of Gla that may be caused by these Agents In addition, the dosage of the therapeutic agent treating complications of diabetes mellitus, the anti-hyperlipidemia agent and the anti-hypertensive agent can be reduced, and thus an adverse effect that may be caused by these agents can be effectively prevented. The compound of the present invention may be produced according to a method known in itself as a method described in detail hereinafter; or a method similar thereto. compound (8-]) can be produced; It is a compound of formula (I) where L is La-CHp-Cus (La is a divalent chain hydrocarbon bond or group); X is Xa (where Xa is a chydrogen atom nitro group caceyl group substituted hydroxy group; optionally substituted thiol group optionally substituted amino group or 0 group optionally substituted circular); And 13 is the camino set according to the following method (a) or an equivalent method. 'As a divalent chain hydrocarbon group' for 'La' the analogous 'divalent chain hydrocarbon group' for the aforementioned 1 may be mentioned. Preferably La is the Cr alkylene bond or group Yo in addition; “as a group (“acyl” “hydroxy group”; “optionally substituted thiol group”” “optionally substituted amino group” and “optionally substituted cyclic group”; for “Xa” those Representatively mentioned for the aforementioned X.

Nor, when Xa is a cethoxycarbonyl group, © is preferably a divalent chain hydrocarbon group. Method (a) al won TT eae, rR’ R’ (IN) (I-a) 0 where the symbols are in the form as defined above. In this method; Compound (I) undergoes a reduction reaction to give compound (Fa) The reduction reaction takes place in the presence of a reducing agent; in a solvent that does not adversely affect the reaction; according to the traditional method. as a reducing agent can; Jal Jaw should mention metal hydrides such as “diisobutylaluminum hydride” sodium bis(2-methoxyethoxy)aluminum hydride | hydride “lithium aluminum hydride etc.; etc. The amount of reducing agent used is generally from 0.1 to 010 dl Sa for the compound (01. Vo as a solvent that does not adversely affect the reaction” can be used” for example Example; alcohols such as “tert-butanol” “isobutanol” butanol “2-propanol” propanol “ethanol” methanol etc.; aromatic hydrocarbons such as “xylene “toluene” benzene etc.; aliphatic hydrocarbons heptane <hexane J— methylated ethers “diisopropyl ether “diethyl ether” dimethoxyethane ¢dioxane “tetrahydrofuran stert-butylmethyl ether etc.; Jie esters tert-butyl acetate “n-butyl acetate” ethyl acetate methyl acetate 0 etc.; The reaction temperature is generally from dalton Ves preferably Ym to 0 Ves. Yo the reaction time is generally from 1.1 to dela 001 preferably 1.1 to te hours.

The reduction reaction cannot also be carried out in the presence of a metallurgical catalyst such as “palladium-carbon” “platinum black” platinum oxide “palladium chloride” palladium black “Raney-cobalt” Raney-nickel ¢platinum-palladium etc.; A source of hydrogen in a solvent does not affect the reaction badly. 0 The amount of metal catalyst used is generally from 0.000 to 001 equivalent.” Preferably 0 to 001 equivalent for the compound (ID) as a source of chydrogen. We can mention, for example, formic acid gas ¢ hydrogen salt “formic acid amine” salt “hydrazine” phosphinic acid etc. As a solvent that does not affect the reaction badly, we can mention those used in the aforementioned 0-reduction reaction that use the reducing agent. The reaction temperature and reaction time are similar to those of the aforementioned reduction reaction which uses a reducing agent. This reaction can take place in the presence of (le) ammonia for example; ammonia, aqueous cammonia-ethanol, etc.) when necessary. By reacting in the presence of cammonia: 10 side reactions can be stopped and the compound (Ira) can be produced with high yield. The compound (leg) thus obtained can be isolated and purified by known separation and purification methods; Jae concentration under reduced pressure; solvent extraction “peta sale] “eld case shift; chromatography; etc. The compound (ID) used as the starting compound in the aforementioned method (a) can be produced lids 0 by a method known by itself. For example; The compound (11-8); It is a compound of formula (ID) where © is a bond and 78 is a cacyl group. It can be produced according to the following method (b).

YY

Method (B) 1 1 0“ CHO OR § + LH 6 p.2

CN = "CN 3C (V1) (V) (IV)

RL_0O Wacom TT Xa Xa (VII) (VI)

RA_N_R a

R® R’ (il-a) (i) where the symbols are in the formula as defined above. Compound (8-]1) may be produced according to a method known by itself; For example; complex reaction etc.; In a diluted “diammonium cerium nitrate” solvent; nitric acid Ji and oxidant (I) © etc. cacetone ¢1,4-dioxane Jie badly affects the reaction (IV) according to a method known by itself ; For example, from compound (II) a compound can be produced by: 118020 according to the description in: pyridine according to the method of synthesis of (VII) and compound “Shin Jikken Kagaku Kouza (The Chemical Society of Japan ed. ), Vol. 14,

Synthesis and Reaction of Organic Compound IV, Maruzen (1978), page 2057, Ve or a method similar to it. According to a method known by itself, for example; By subjecting compound (IV) known compound. Knoevenagel can be produced to methods (V) and compound (VI) according to a method known by itself ¢ for example ¢ from compound (VID) a compound can be produced: According to the method described in (VID Yo yy

Synthesis (1999), vol. 11, pages 1951-1960; Journal of Chemical Society Perkin

Transactions 1, (2002), pages 1663-1671, etc.; or a method similar to it. The aforementioned according to the method of (VITD) and compound (VI) it is possible to produce compound (07; compound known by itself. © is the RY group that is Cun (I) which is A compound of formula (Ib) A compound can be produced by subjecting a compound (©-1), which is a single or double-substituted cryo alkyl by an amino “alkylation group” to a camino reaction that is an RY group that is Cua (I) a compound of formula alkylating in the presence of a base if necessary; using an agent (i) a solvent that does not adversely affect the reaction; or (vii) in the presence of a reducing agent if necessary; 0 in a solvent that does not adversely affect the reaction, according to the carbonyl method using a known compound. 10 alkyl sulfonate etc. “ketones” aldehydes for example; carbonyl can be mentioned as a compound Vo 1 used preferably of about carbonyl “S jy alkylating agent The amount of (1-0) oS yall Ally la 0 gm JY “sodium hydroxide as the base; for example; the salts of 318 alkali may be mentioned as metal hydrides etc.; “triethylamine” pyridine as amines etc.; “potassium carbonate “sodium methoxide J— metal alkali alkoxides etc.; sodium hydride such as Y: etc.; etc. “potassium t-butoxide to about © 1 equivalent. The amount of base used is preferably of about 0-© (for diisobutylaluminum (fie metal hydrides) compound (say) as an agent reduction” eg; etc.; etc. “sodium cyanoborohydride fie metal hydride etc; chydride Yo compounds equivalent with respect to 1,01 to 1, generally the amount of reducing agent used is of . (1-©) for the compound

p7: The reaction can also be carried out using the aforementioned carbonyl compound in the presence of a metal catalyst such as “palladium-carbon etc.; a source of chydrogen without the reducing agent; in a solvent that does not adversely affect the reaction. It is preferable that the amount of the metal catalyst used be from 02.01 to 001 equivalent in relation to the compound (le) as a source of chydrogen, for example 0 Gas 17010860 formic acid salt “formic acid amine” etc. can be mentioned. 'as a solvent that does not affect the reaction with a degree of Ris used for an alkylation reaction for example; Aromatic hydrocarbons such as “toluene etc.” may be mentioned; ethers such as “tetrahydrofuran 0 etc.; halogenated hydrocarbons such as “chloroform” etc.; amides such as “N,N-dimethylformamide etc.; x «dimethyl sulfoxide Jie sulfoxides etc. These solvents may be used in mixtures thereof mixed in appropriate proportions. In an alkylation reaction the reaction temperature is preferably around -01 to about (she) +m Vo in an alkylation reaction ; The reaction time is generally from about de about 01 ae la The compound (I-b) can be isolated and purified by known separation and purification methods; such as concentration; concentration under reduced pressure » solvent extraction; recrystallization recrystallization » Alla transformation chromatography; & when producing the compound of the present invention; And when the starting compound has a camino group, a carboxyl group, a hydroxy group, or a carbonyl de sane as an alternative; May be Jay Ae sane protection generally used in peptide chemistry etc.; in these groups. by removing the protect group as necessary after the reaction; The target compound can be obtained. The camino protecting group includes for example (Jha) the formyl group Ci alkyl-carbonyl Yo (eg Jp; “propionyl acetyl etc.); Ci alkoxy-carbonyl group (eg cethoxycarbonyl «methoxycarbonyl «Jill stert-butoxycarbonyl etc.); benzoyl group aralkyl-carbonyl group hand (on veo

eg cbenzylcarbonyl etc.); Aralkyloxy-carbonyl group dodec (on

for example;" 9-fluorenylmethoxycarbonyl ¢benzyloxycarbonyl chelate); group

ctrityl group “phthaloyl group” N,N-dimethylaminomethylene group

“dimethylphenylsilyl “triethylsilyl” Arletamanitas “Jal Silyl — le} silyl

ctert-butyldiethylsilyl «tert-butyldimethylsilyl ~~ © etc.); Cog alkenyl group (eg

eg » d-allyl etc.); etc. These combinations are optionally replaced by 1 to

le) halogen atoms e.g. bromine «chlorine «fluorine 00106 etc.); group

alkoxy:© (eg methoxy ““elastomer; not” 0:000; etc.); group «nitro» etc.

The protection group “a carboxy” for example; Cie alkyl group (at

0 emethyl “Jal retata ctert-butyl” butyl “isopropyl” propyl etc.); group

ctrityl phenyl group etc.); benzyl group eg; Je) yb aralkyl

«dimethylphenylsilyl «triethylsilyl» trimethylsilyl Example; Je) silyl group

stert-butyldiethylsilyl ctert-butyldimethylsilyl etc.); Je) Co alkenyl group syllable

Food) etc.); etc. These groups are optionally substituted by eI-allyl (Ji

Ve atoms (le) halogen for example ciodine bromine «chlorine «fluorine etc.]); group

(Nitro or group “(&)”propoxy “ethoxy”methoxy “Jal! way Je) Ci alkoxy

The hydroxy protection group is; For example; Cri alkyl group (eg

phenyl etc.); The “tert-butyl butyl ¢ isopropyl” propyl cethyl “methyl” group is an example

0 ctrityl group alarkyl group rrb (eg; benzyl etc.)

formyl group © .alkyl-carbonyl group (eg; “propionyl “acetyl

etc.); benzoyl group aralkyl-carbonyl group and d (eg (Jal

“2-tetrahydrofuranyl group “2-tetrahydropyranyl group etc.) cbenzylcarbonyl group

“dimethylphenylsily] “triethylsilyl” trimethylsilyl (eg; silyl group

ctert-butyldiethylsilyl ctert-butyldimethylsilyl ~~ Yo etc.); Je) Cos alkenyl de gana is a way

example; cl-allyl etc.); etc. These combinations are optionally replaced by 1 to ?

halogen atoms (eg ciodine bromine “chlorine” fluorine etc.); group

Cig alkyl (eg cpropyl cethyl “methyl” etc.); Ci alkoxy group (eg “propoxy” ethoxy “methoxy etc.) or nitro group etc. The carbonyl protecting group is; For example; Je) sa acetal eg ¢1,3-dioxane etc.); acetal is not circular (eg; “di-C alkyl acetal etc.); a The introduction and removal of these protective groups can follow a method known to be self-evident, for example, a method described in: Protectives in Organic Synthesis, John Wiley and Sons (1980), etc. For example; using a method that uses an acid; 3a cli light chydrazine (UV tetrabutylammonium “sodium N-methyldithiocarbamate” phenyl hydrazine | 0 Je) trialkylsilyl halide “palladium acetate” fluoride for example; trimethylsilyl ctrimethylsilyl bromide iodide etc.); etc; shorthand; etc. if the starting compound can form a salt when producing the compound of the present invention; A compound may be used in the form of a salt. so is salt; Those mentioned above can be used simulated for a salt (Sal)me when compound (I) contains an optical isomer a stereoisomer; An equivalent isomer or a circular isomer, these (Sey isomers may be included in the compound oD) can be obtained as a single product according to a synthesis method and separation method known by themselves. For example; When a compound has an optical isomer (I) the optical isomer separated from that compound is also intercalated into the compound (0). All racemate product is optically decomposed according to a conventional method to yield an optical isomer.The optical decomposition method may be a method known by itself as the YO fractional recrystallization method; the photoactive isotope column method; the “diastereomer” method etc.) 1) Method of partial recrystallization of vy “(+)-mandelic acid eg; Je) with an optically active racemate to form a salt of ¢“(+)-1-phenethylamine “(-)-tartaric acid” (+)-tartaric acid «(-)-mandelic acid etc.); <brucine «(-)-cinchonidine «cinchonine «(-)-1-phenethylamine dissociates optically free by a neutralization step on demand. Partial recrystallization isomer; It produces a photoactive chemical isotope column method (1) © optical (column isomer or salt thereof on a column to separate the racemate liquid chromatography is placed on a photoactive chemical Alls) to allow separation. Optical on column optically active chemical isomer isomer for example; a mixture of (manufactured by CHIRAL or Tosoh types (manufactured by ENANTIO-OVM such as etc.) is used; water is added; exponential stabilizers (Ltd. “Daicel Chemical Industries” by 0 and several pH solvents (for example; pH stabilizer “acetonitrile” isopropanol “methanol” ethanol “Jill” organic sil (le) isomer) etc.) alone or in a mixture to separate “diethylamine” trifluoroacetic acid optically. In the case of gas chromatography, for example, a column (manufactured by CP-Chirasil-DeX CB) uses a reduced optically active chemical isotope. 10 etc., to allow separation of the diastereomer method (GL Sciences Inc. Inc.) by chemical reaction with a diastereomeric reagent in a racemic mixture an optically active mixture prepared in one material by a typical separation method (eg ; partial recrystallization chromatographic method; etc); etc; It undergoes chemical treatment such as decomposition of the “0” optical aqueous isomer; etc; To separate an optically active reagent factor fraction; Thus, we get an amino or a hydroxy group on a group (I) The compound contains Laie (Joell, for example, primary or secondary in a molecule; the compound and an optically active organic acid (for example “(-) -menthoxyacetic acid “[a-methoxy-a-(trifluoromethyl)phenylacetic acid] MTPA in diastereomer or ester in the form of diastereomer undergo a condensation reaction to produce ol etc); Yo this is ccarboxyl Group (I), respectively.When the compound has an optically active form, the camide undergoes the reaction of an optically active alcohol or a reagent amine 5 of the compound.

Ya

An ester in the form of a diastereomer or an amide in the form of a diastereomer is condensed to produce the separated into optical 180006:1 of the parent compound by a hydrolysis reaction of the diastereomer arrangement. It undergoes acidic hydrolysis or basic hydrolysis. Compound (1) may be in crystal form. Here later sometimes referred to as the crystal of the invention Le) crystallization of compound () (© indicated by a self-recognized method of crystallization) can be produced (I) Current by compound crystallization Examples of crystallization methods include crystallization from a solution crystallization from vapor crystallization from a molten form; supersaturation by various factors involved in the solubility of compounds (0 redox composition etc.) Alla solvent; pH temperature; ionic strength; or the amount of solvent. To specify, for example; It is possible to mention a method of concentration, a hardening method; an electrolysis method); hydrothermal growth method; The “lin” method is a reaction method (aromatic method (on hydrocarbons as a bonding agent, etc.). Examples of solvents used (for example, halogenated hydrocarbons, etc.) include “xylene” toluene “benzene.” Jus Vo eg; Je) saturated hydrocarbons etc.); nitriles etc.) “dioxane” tetrahydrofuran “diisopropyl ether (on sulfoxides etc.) dimethyl sulfoxide eg Jou ¥- “(z= “ethyl acetate eg; Jum (on esters etc) – “N,N-dimethylformamide eg” el etc); “isopropyl alcohol ¢ethanol “methanol (eg; alcohols) These solvents are used alone or in combination with two or more in appropriate algebraic proportions (on (volume ratio)). 100:1 to 1:1 JB eg. “To crystallize from vapor” is, for example, evaporation method (sealed tube method; gas stream method); gas-state reaction method; chemical transfer method” etc. v4 Natural solidification method (JO method "Crystallization from a molten form" is, for example, the Bridgman zone melting method (a temperature gradient method; Czockralski method

VLS (Area Level Determination Method; Floating Area Method); Special growth method (liquid state epitaxial growth method); etc. 8 Preferred examples of the crystallization method include a method involving dissolving compound (1) in a suitable solvent (eg ethanol “methanol Ji alcohols” Jia etc.); at a temperature of 0 to LR YY and cooling the resulting solution to a temperature not exceeding the melting temperature (eg. 0 to 0*”C; preferably 0 to 10”C); etc. The crystals of the present invention thus produced may be dled ie (Jail). 0 by filtration, etc. In the present specification, melting point refers to the melting point measured using, for example, a small melting point instrument MP-500D “Yanako” or B-545 Buchi or a DSC instrument (PDF) “(SEIKO, EXSTAR6000) etc. Vo In general, melting points vary depending on the measuring device, measurement conditions etc. A crystal in the present specification may show a different melting point described in the present specification; As long as it is within the range of general error.The crystal of the present invention is superior in physico-chemical properties (eg (e.g. mal; melting point; solubility; stability; etc.) com) output); show effectiveness; etc.)” and is very useful as a pharmacological agent. The present invention is illustrated in more detail by examples; Empirical examples and formulation examples follow. These examples do not limit the present invention and the present invention may be modified to a extent not deviating from the scope of the invention. Yo The abbreviations in the examples have the following meanings: is single: d “(singlet) double” (triplet) AE it (doublet) and quadruple “(quartet) im brs” (multiplet) iT “(broad singlet) fixed pairing

Ae «4-fluorophenyl :4-F-Phenyl «4-methylphenyl :4-Me-Phenyl «(coupling constant) .2,6-difluorophenyl :2,6-di-F-Phenyl to EE in the examples; Room temperature means the temperature ranges from 7 and 7 means the percentage by weight; Unless otherwise indicated. dF + 1 ex. 0

Methyl 5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)nicotinate #7) sodium hydride heated with re-condensation and stirred vigorously; Suspension (1 ml). Added to (A+) tetrahydrofuran mol) in 17 aa A cy) acetonitrile mol) 1 g; 11.7 methyl isovalerate (mixture drops of 1 mL) to the resulting suspension YO) tetrahydrofuran 5 mol) 07 “alll 05) 0 min; The mixture is heated with re-condensation of the steam for ½ hours. Ye mixture left over milliliters). The mixture (©) 2-propanol is stirred and dé jal is added to the reaction to cool to a temperature and dissolve (patie min.) at room temperature. The reaction mixture is concentrated under pressure Ve for a period and a mixture of a solution of hexane milliliter) and washed successively with (100) remaining in concentrated water, hydrochloric acid. The aqueous layer was acidified by -hexane-diethyl ether Vo. The extracted substance was washed with water, dried over diethyl ether, and extracted with anhydrous. Vaporize The solvent under reduced pressure yields magnesium sulfate in the form of a yellow oil (Ver yield aa 1 ) 5-methyl-3-oxohexanenitrile which is used in the next step without additional precursor.” H-NMR (CDCl; ) 8 : 0.96 (6H, d, J = 6.6 Hz), 2.05-2.30 (1H, m), 2.50 (2H, d, J = 0 7.0 Hz), 3.43 (2H, 5).

S-methyl-3-oxohexanenitrile hr mixture of VY heated with vapor re-condensation for ½” mm; 50 mmol (p-tolualdehyde (A) / p-tolualdehyde) £1 can 0) mmol A can +, £4) acetic acid ¢ ool a g; £ 17 mmol 4) piperidine The reaction mixture was left to cool Dean-Stark lea using Alle 001 (Grammy) and Count OH: YO magnesium sulfate to room temperature; washed with saturated brine and dried over 8 M) anhydrous methanol. The solvent is evaporated under reduced pressure; the resulting residue is dissolved in

AY

g 40 milligrams (1) methyl 3-aminocrotonate (mL). Add to it and heat the mixture with re-condensation of steam for 7 hours. The reaction mixture was concentrated under pressure to produce reduced silica and the residue was purified by chromatography on a gel column methyl 5-cyano-6-isobutyl-2 -methyl-4-(4-methylphenyl)-1,4-dihydropyridine-3- Colorless crystals. (Fo g » by yield V, £0) carboxylate 0 "H-NMR (CDCl3) 8:0.93 (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, 5), 2.36 (3H, 5), 3.58 (3H, 5), 4.57 (1H, 5), 5.68 (1H, brs), 7.00-7.20 (4H, m).methyl 5 -Cyano-6-isobutyl-2-methyl-4-(4-methylphenyl)-1,4- yab ( Y 1,4- dioxane (mmol) in YY,0 g; dihydropyridine-3-carboxylate (v,Y) 0 ml) and the mixture was stirred for 1 hour (nitric acid 0 ml), and one (001 N) was added to it At 10 °C and while stirring continues in an ice bath; milliliters are added to the mixture. The aqueous layer was separated and extracted with magnesium sulfate extract; The mixture was washed with saturated saline and dried over anhydrous 10°. The solvent was evaporated under reduced pressure and the residue was purified by chromatography as methyl 5-cyano-6-isobutyl-2-methyl-4-(4- Fr-dsilica) on a gel column as a white powder. Yield 54 g (ZAY) ) methylphenyl)nicotinate "H-NMR (CDCl) 8: 1.01 (6H, d, J = 6.6 Hz), 2.20-2.35 (1H, m), 2.41 3H, 5), 2.63 (3H, s), 2.95 (2H , d, J = 7.4 Hz), 3.60 (3H, s), 7.20-7.30 (4H, m).0 methyl = 5-cyano-6-isobutyl-2-methyl-4-(4-methylphenyl)nicotinate; ) a mixture of aqueous ammonia in milliliters); (Raney-nickel mole); (wie 7.1 milliliters) can be stirred in methanol (0£) milliliters; Yo) tetrahydrofuran s mL); 1) yo 1 MPa and at room temperature for 1.0 hydrogen in a tightly closed tube under atmosphere hours. The reaction mixture was filtered and the leachate was concentrated under reduced pressure. The remaining Yo was divided and the layer was washed .701 aqueous as potassium carbonate and a solution of ethyl acetate between the organic solvent 0. anhydrous magnesium sulfate is evaporated with saturated brine and dried over

AY silica under reduced pressure and the residue was purified by gel column chromatography methyl 3-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)nicotinate yielding g; Yield 790 (Yellow crystals. +,4Y) “H-NMR (CDCl;) 8:0.98 (6H, d, J = 6.6 Hz), 1.39 (2H, brs), 2.15-2.30 (1H, m), 2.39 (3H, s), 2.53 (3H, 5), 2.80 (2H, d, J = 7.2 Hz), 3.50 (3H, s), 3.66 (2H, 5), 7.11© (2H, d, J = 8.0 Hz), 7.21 (2H, d, ] = 8.0 Hz). -methylphenyl)nicotinic acid dihydrochloride 0 mmol) to 7.71 mmol +, V1) di-tert-butyl dicarbonate (0 methyl ~~ 5-(aminomethyl)-6-isobutyl-2-) is added 4-methyl-(4-J las tetrahydrofuran g » 1.1 mmol) in »,9(methylphenyl)nicotinate h at room temperature. The reaction mixture was concentrated VY mL); the mixture was stirred for ¥ 5) the remaining by chromatography using a Buy Gadde column under pressure 0 methyl 5-{[(tert-butoxycarbonyl) amino] methyl }-6-isobutyl-2-methyl- yielding 8 White powder (794 daly g 1,11) 4-(4-methylphenyl) nicotinate white: “H-NMR (CDCl) 8:0.97 (6H, d, J = 6.8 Hz), 1.39 (9H, 5), 2.10-2.30 (1H, m), 2.39 (3H, 5), 2.54 (3H, 5), 2.78 (2H, d,] = 7.2 Hz), 3.50 (3H, 5), 4.15 ( 2H, d, 1 = 49 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). methyl 5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2- to a solution of (g; 4 7.7 mmol) in 1) methyl-4-(4- methylphenyl)nicotinate

(V+) aqueous sodium hydroxide (SOD) of a solution of 1 ml) add “01 methanol” (days). The mixture is left to cool to ad 1 ml and the mixture is heated with re-condensation of vo-ethyl acetate and extracted with hydrochloric acid at room temperature and acidified with 10+N anhydrous magnesium sulfate. The extracted material was washed with saturated brine and dried over microtome.

AY

Methanol is produced. The solvent evaporates under reduced pressure and the remaining water crystallizes - 5-{[(tert-butoxycarbonyl) amino] methyl }-6-isobutyl-2-methyl-4-(4-methylphenyl) total yield 7750) As a white powder. 5 A) nicotinic acid "H-NMR (CDCl) 8: 0.87 (6H, d, J = 6.4 Hz), 1.39 (9H, s), 1.95-2.10 (1H, m), 2.38 (3H) , 5), 2.67 (3H, 5), 2.75 (2H, d, J = 7.2 Hz), 4.13 2H, d, ] = 4.7 Hz), 4.30 (1H,t,] © =4.7Hz), 7.15 (2H , d, J = 7.9 Hz), 7.22 (2H, d, J = 7.9 Hz).5-{[(tert-butoxycarbonyl) amino] methyl }-6-isobutyl-2-methyl-4- to a solution of (1,4-dioxane mmol) in GEA g LY ) (4-methylphenyl) nicotinic acid

V1 mL; £) hydrogen chloride 1,4-dioxane mL) A titer of a solution of £ (mM) was added and the mixture was stirred for 2 hours at room temperature. The reaction mixture is concentrated under reduced pressure, so we get a white solid, which in turn is washed with 5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) to produce diisopropyl ether g » Productivity £90 (as a white powder. ); ), 8.45 (3H, brs). Example? 5-{[(tert-butoxycarbonyl) amino] methyl}-6-isobutyl-2-methyl-4-(4-methylphenyl) mmol) ; salt + YY gm; 51 ) nicotinic acid g 0.16 milligrams); 01 (N,N-dimethylformamide 5 mmol) Yo ml). Mathia with

Af saturated Sle sodium hydrogen carbonate and the mixture was washed successively with anhydrous cethyl acetate. The magnesium sulfate solvent and saturated brine were evaporated and dried over yielding silica under reduced pressure, and the residue was purified by chromatography using a tert-butyl 5 -(aminocarbonyl)-2-isobutyl-6-methyl-4-(4-) gel column. methylphenyl)pyridin-3 - yield 747) as a white powder. can +,+ 4) yllmethyl} carbamate © "H-NMR (CDCl; ) 8:0.97 (6H, d, J = 6.6 Hz), 1.39 (9H , 5), 2.10-2.30 (1H, m), 2.39 (3H, 5), 2.61 (3H, 5), 2.78 (2H, d, J = 7.4 Hz), 4.14 (2H, d, ] = 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). 5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) ?) 0 is obtained as a white powder (AY g yield +, +2) nicotinamide dihydrochloride tert-butyl { [5-(aminocarbonyl)-2-isobutyl-6-methyl-4-(4-methylphenyl)pyridin- from mmol) according to a similar method 116 can 0.0 15( 3-yl]methyl} carbamate

AY of the method followed in step number? From the example “H-NMR (DMSO-ds) 8:0.98 (6H, d, J = 6.6 Hz), 2.05-2.30 (1H, m), 2.37 (3H.s), Vo 2.66 (3H, 5), 3.02 (2H, 5), 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). 5-(aminomethyl)-N-(3-amino-3-oxopropyl )-6-isobutyl-2-methyl-4-(4- methylphenyl)nicotinamide dihydrochloride 00

S-{[(tert-butoxycarbonyl)) was stirred for 1 hour at room temperature a mixture of (1g; +,1Y) amino] methyl} -6-isobutyl-2-methyl-4-(4- methylphenyl) nicotinic acid g ;, ; 00 mL B-alaninamide hydrochloride (5 mmol); 4 g 44 mmol 0.0 89( I-hydroxy-1H-benzotriazole s mol); ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride s + gram) Yo mmol 44 lll +2 1Y) triethylamine 5 mmol) 1.44 can mL The reaction mixture is divided between © ) N,N-dimethylformamide Gram).

Ao

11 001 ( ethyl acetate-tetrahydrofuran milliliters) 5 (Suda) grams of solution

citric acid aqueous 01 (milliliter). The organic layer and the extracted material obtained from

Extraction of the All layer with ethyl acetate and the mixture was washed successively with

sodium hydrogen carbonate saturated aqueous and saturated brine and dried over anhydrous magnesium sulfate © . The solvent was evaporated under reduced pressure and the residue was purified by analyte

tert-butyl {[5-[(3-amino-3-oxopropyl)) produced silica gel J sac chromatography using

‎amino]carbonyl-2-isobutyl-6-methyl-4-(4-methylphenyl)pyridin-3-

0/8( yllmethyl } carbamate gm yield (Zot) as white powder.

H-NMR (CDCl) 8:0.97 (6H, d, J = 6.8 Hz), 1.38 (9H, 5), 1.98 (2H, t, J = 6.0 Hz), 2.10-2.25 (1H, m), 2.38 (3H, 5), 2.55 (3H, 5), 2.76 (2H, d, ] = 7.2 Hz), 3.36 (2H, q,] 00

=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). 5-(aminomethyl)-N-(3 -amino-3-oxopropyl)-6-isobutyl-2-methyl-4- (Y g; 799 (as powder +, +£A) (4 -methylphenyl)nicotinamide dihydrochloride tert- butyl {[5-[(3-amino-3-oxopropyl) amino]carbonyl-2-isobutyl-6- (a white Vo g; .+ m +, ©) methyl-4-(4-methylphenyl)pyridin-3-yljmethyl} carbamate

.” in Example 1 mol) according to a method similar to that in step “H-NMR (DMSO-d¢ ) 8:0.97 (6H, d, J = 6.6 Hz), 1.98 (2H, t ,J = 6.7 Hz), 2.10-2.25 (1H, m), 2.37 (3H, 5), 2.57 (3H, 5), 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=8.0Hz), 0 7.28 (1H, brs), 8.24 (3H, brs), 8.36 (1H, brs).0 Example [5-(aminomethyl)-6-isobutyl-2-methy]l-4-( 4-methylphenyl)pyridin-3-yl]acetonitrile methyl 5-{[(tert-butoxycarbonyl) cooled to -//a "C) suspended from (0 7,1 body, 4( amino]methyl }-6-isobutyl-2-methyl-4-( 4-methylphenyl) nicotinate 000 to which 0.95 mol of alll A) toluene (milligrams) in milligrams of YY) diisobutylaluminum hydride toluene per gram of solution is added to it

AT

Grammy) over a range of £58010 and after stirring the mixture for an hour and a half at -24°C to 0°C and stirred further for a min. Then add to the mixture find leaving g; Y+,Y ) sodium sulfate 10 hydrate (ml) 1 (methanol and respectively; Jeli mol); the mixture was stirred for 1 hour at room temperature. The insoluble matter was removed by filtration and the leachate was concentrated under reduced pressure. Purified 0-vintage silica purified by chromatography Avi using a tert-butyl Hallam column {[5-(hydroxymethyl)-2 -isobutyl-6-methyl-4-(4-methylphenyl)pyridin-3-) all yield 770) as an oil. 4 ) -tertyljmethyl} carbamate "H-NMR (CDCl3) 6:0.97 (6H, d, J = 6.6 Hz), 1.32 (9H, 5), 2.13-2.25 (1H, m), 2.42 (3H, 5), 2.68 (3H, 5), 2.75 (2H, d, J = 7.4 Hz), 4.05 (2H, d, J = 4.7 Hz), 4.19 (1H, 0 brs), 4.36 (2H, d ,J = 5.7 Hz), 7.05 (2H, with ] = 7.9 Hz), 7.24-7.26 (2H, m). tert-butyl {[5-(hydroxymethyl)-2-isobutyl-6-) cooled to zero degrees Celsius a mixture of 10 ml (01 g), 5( methyl-4-(4-methylphenyl)pyridin- 3-yljmethyl} carbamate mM) Y,0 «lila» 7 *( triethylamine mM) methanesulfonyl chloride mL); Added to it drops Ye. ) tetrahydrofuran 4 0 min at Ye g; 1.9 milligrams). After stirring the reaction mixture for (+, YY) saturated aqueous sodium hydrogen carbonate, the reaction mixture was poured into dd all magnesium sulfate heat, the extracted substance was dried over ethyl acetate, and the mixture was extracted with (*) dimethyl sulfoxide Anhydrous and the solvent evaporates under reduced pressure, the remainder is dissolved in milligrams). stir LY g, 41 ( potassium cyanide mL); 0 is added to the reaction mixture and ethyl acetate is washed in C. 0 min at Ve is added to the mixture for anhydrous time. magnesium sulfate is mixed with water and saturated brine respectively and dried over, the solvent is evaporated under reduced pressure and the residue is purified by chromatography using a tert-butyl column {[5- (cyanomethyl)-2-isobutyl-6-methyl-4-(4-(s—azd silica gel) iw on (% VY g; yield of 1 methylphenyl)pyridin-3-ylmethyl} carbamate ~~ Yo oil.

AY

H-NMR (CDCl;) 6: 0.97 (6H, d, J = 6.8 Hz), 1.38 (OH, 5), 2.16-2.25 (1H, m), 2.43 (3H, 5), 2.66 (3H, 5) ), 2.77 (2H, d, J = 7.2 Hz), 3.31 (2H, 5), 4.07 (2H, d, ] = 4.7 Hz), 7.04 2H, d, 1 = 8.0 Hz), 7.31 (2H, d, ] = 8.0 Hz). )pyridin-3-ylJmethyl } carbamate ~~ © min at room temperature. V0 mmol is poured in); the mixture is stirred for 71 ss; the mixture is extracted with sodium hydrogen carbonate reaction mixture in magnesium sulfate The extract was dried anhydrous acetate-tetrahydrofuran difference, the solvent was evaporated under reduced pressure, and the residue was purified by chromatography using [5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-) to give silica Hamlamam column 0 yield 14% (as oil. can +, + At) methylphenyl)pyridin-3-yl]acetonitrile "H-NMR (CDCl3) 8:0.99 (6H, d, J = 6.6 Hz), 2.11-2.22 (1H, m), 2.45 (3H, 5), 2.66 (3H, 5), 2.80 (2H, d, J = 7.2 Hz), 3.47 (2H, 5), 3.74 (2H, brs), 7.17 (2H, d, J = 7.8

Hz), 7.42 (2H, d, J = 7.8 Hz). 1 Ex 11 2-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-ylJacetamide dihydrochloride tert-butyl {[5-(cyanomethyl)-2-isobutyl- 6-methyl-4-(4-) to a solution of (9 mmol) in 7,7 can +, 4) methylphenyl)pyridin-3-yl]methyl} carbamate aqueous (0.0 mL) sodium hydroxide (mL) added ¥ N solution (Y + ethanol 00 mmol); The mixture is heated for two hours with the re-condensation of steam. added to 1 to acidify the reaction mixture.” The mixture is extracted with hydrochloric acid, the mixture is 1 standard magnesium, the extracted material is saturated with brine and dried over Juss cethyl acetate tert-butyl {[5-(2-amino-2- anhydride) and the solvent evaporates under reduced pressure to give oxoethyl sulfate -6-isobutyl-6-methyl-4-(4-methylphenyl)pyridin-3-ylJmethyl} carbamate Ye as a colorless solid. (IVY yield can 7 5)

AA tert-butyl {[5-(2-amino-2-oxoethyl)-2-mL) to ©) trifluoroacetic acid add (¥ (a—a 1°) isobutyl-6-methyl-4-( 4-methylphenyl)pyridin-3-yl methyl } carbamate min. at room temperature. Pour 01,4,000 mmol); The mixture is stirred for a saturated watery period; The mixture was extracted with sodium hydrogen carbonate (the reaction mixture in magnesium sulfate) the extract was dried -ethyl acetate-tetrahydrofuran© anhydrous; The solvent is evaporated under reduced pressure. added to the remainder; titer of milligram solution); The solvent 10 mL (£) hydrogen chloride 1,4-dioxane 2-[5-(aminomethyl)-6- is evaporated to diisopropyl ether under reduced pressure. Wash off the residue with isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3 -yl]acetamide dihydrochloride as a white powder. (FAY g; yield 08) 0" H-NMR (CD; OD) 8: 1.09-1.13 (6H, m), 2.09-2.22 (1H, m), 2.46 (3H, g 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 Ha).0” Example Methyl [5-(aminomethyl)-6-isobutyl - 2-methyl-4-(4-methylphenyl)pyridin-3- 00 yllacetate dihydrochloride tert-butyl {[5-(cyanomethyl)-2-isobutyl-6-methyl-4-(4-) to a solution of (/ g; 7.7 milligrams) in 4,4)methylphenyl)pyridin-3-yl [and 0 (1[aqueous carbamate]) 0.0 mL; sodium hydroxide N 1 mL solution) 0 (milligram ethanol) was added, and the mixture was heated for a day and a half with re-condensation of the vapor. ethyl acetate mixed with anhydrous solvent was evaporated under reduced pressure and the remainder was dissolved in magnesium sulfate over 5.4 mL (5.4 mL +,10 methyl iodide mL) and added (©) N,N-dimethylformamide g; 5.4 mmol) and 11 ) potassium carbonate (mol) and YO stirred the mixture for 1 hour at room temperature. It is added to the reaction mixture and saturated brine, dried over ela, and the mixture is washed, respectively, with cethyl acetate.

AQ

magnesium sulfate anhydrous. The solvent was evaporated under reduced pressure and the residue was purified by chromatography using an important column had silica methyl [5-{[(tert-butoxycarbonyl)amino]methyl }-6-isobutyl -2-methyl-4-(4- pa 4) V) methylphenyl)pyridin-3-yl]acetate yield (701) in the form of oil. H-NMR (CDCl3) 8:0.97 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.13-2.28 (1H, m), 2.40 © (3H, s), 2.49 ( 3H, 5), 2.75 (2H, d, J = 7.4 Hz), 3.36 (2H, s), 3.61 (3H, 5), 4.045 (2H, m), 4.27 (1H, brs), 6.98 (2H, d, J = 7.8 Hz), 7.23 (2H, d, J = 7.8 Hz).Methyl [5-(aminomethyl)-6-isobutyl-2-methyl-4-(4- on Jia a5 ?) an +, + 14) methylphenyl)pyridin-3-yl]acetate dihydrochloride (VT yield) as a white powder of methyl [5-{[(tert-butoxycarbonyl)amino]methyl}- 6- YY aa 00 41( isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl]acetate ,+ mmol) according to a method similar to that in step ¥ of the example.”H -NMR (CD; OD) 6: 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=7.7Hz), 7.48 2H,d,J=7.7Hz). 1° A eg Ethyl (2E)-3-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3- yl]acrylate tert-butyl { [5-(hydroxymethyl)-2-isobutyl-6-methyl-4-(4- to a solution of (1 mmol) 5,9 “ax ,328( methylphenyl)pyridin-3-yl]methyl]methyl } carbamate 00 in tetrahydrofuran (©1 milliliters) added manganese dioxide (£9.9 g); © Melsey (a gram-molecule); The mixture was stirred for 19 hours at room temperature. The reaction mixture was filtered and the leachate was concentrated under reduced pressure. The residue was purified by chromatography using an important silica column to produce tert-butyl {[5-formyl-2-isobutyl-6-methyl-4-(4- ),Y0) methylphenyl)pyridin-3-yljmethyl} carbamate Yo g; Yield 16%) as a yellow solid.

H-NMR (CDCl3) 8: 0.98 (6H, d, J = 6.6 Hz), 1.39 (9H, 5), 2.21-2.35 (1H, m), 2.43 (3H, 5), 2.79 (3H, 9( , 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).mmol) 0.9 can 0 ¥'Y) triethyl phosphonoacetate to a solution of (1) sodium hydride (mL) added at 0 °C 01 (tetrahydrofuran in min. add 01 mmol); and stir the mixture for 1,0 can 0,036 in oil; tert-butyl {[5-formyl-2-isobutyl-6-methyl- 4-(4-J cla) of a mixture of g; 48 mmol) +, VA) methylphenyl)pyridin-3-ylJmethyl } carbamate min at room temperature. £0 jad mL The mixture (©) is stirred in tetrahydrofuran and the mixture is washed successively with saturated brine ethyl acetate and 0 saturated aqueous and saturated brine are added to the reaction mixture and dried over ammonium chloride and an anhydrous solution The solvent is evaporated under reduced pressure The residue was purified by decomposition of magnesium sulfate ethyl (2E)-3-[5-{[(tert-) produced silica chromatography using a gel column butoxycarbonyl) amino]methyl}-6-i sobutyl-2-methyl-4- ( 4-methylphenyl)pyridine- yield 7270) as oil. can 4 ( 3-yllacrylate 06 "H-NMR (CDCl; ) : 0.98 (6H, d, L = 6.6 Hz), 1.23 (3H, 1, J = 7.2 Hz), 1.39 (9H, s), 2.16-2.27 (1H, m), 2.40 (3H, 5) , 2.64 (311, 9, 2.77 (211, 11-4 Hz), 4.08-4.17 (4H, m), 421 (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, ] = 16.4 Hz), ethyl (2E)-3-[5-{[(tert-butoxycarbonyl) Jax 1a 01 minutes stirred for (vx.amino]methyl} -6-isobutyl-2-methyl-4-(4-methylphenyl)pyridine-3 -yllacrylate hydrogen chloride 1,4-mmol) And the; Standard solution “Yo” g; 1 mmol). The solvent is evaporated under reduced pressure and divided into 10 mL; (©) saturated aqueous dioxane. sodium hydrogen carbonate ethyl acetate-tetrahydrofuran remaining between the extracted ethyl from the extraction of the aqueous layer with sald) The organic layer is combined with Yo anhydrous. The magnesium sulfate solvent was evaporated and the mixture was dried over acetate-tetrahydrofuran to produce silica under reduced pressure and the residue was purified by chromatography using a gel column ethyl (2E)-3-[5-(aminomethyl)-6-isobutyl-2- methyl-4-(4-methylphenyl)pyridine-3- (7 daly g; +, 04) yllacrylate "H-NMR (CDCl3) 8:0.99 (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, (4.13 (2H, 127.2 Hz), 5.76 (1H, d, J = 16.4 Hz), 7.01 2H,d,J=8.0Hz), © 7.24 (2H,d,1=8.0 Hz), 7.39 (1H, d, J = 16.4 Hz).1 Example (2E)-3-[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3- yl] acrylic acid dihydrochloride ethyl (2E)-3-[5-{[(tert-butoxycarbonyl) amino]methyl}-6-isobutyl- to a solution of (0 1 g; 0.19 mmol 0.77) 2-methyl-4-(4-methylphenyl)pyridine-3-yl]acrylate sodium 1 standard solution (1 milliliter) added 01 (tetrahydrofuran) in an hour 11 aqueous (©,4 milliliters 7) ,4 mmol), and the mixture was stirred for 10006 M (1) hydrochloric acid in Celsius. The reaction mixture was acidified with 0 at the combining temperature of the extracts; The mixture is washed with saline solution. cthyl acetate and extracted with Vo. The solvent was evaporated under reduced pressure and the remaining saturated magnesium sulfate was purified and dried over (2E)-3-{5-{[(tert-) to give silica by butoxycarbonyl gel column chromatography) amino]methyl} -6-isobutyl-2-methyl-4-(4-methylphenyl)pyridine-3 - g; yield 797) as a white solid. ), 2.39 Y. (3H, 5), 2.64 (3H, 5), 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).(2E)-3- [5-(aminomethyl)-6-isobutyl-2-methyl-4-(4- a Ja a (Y )7950 g; yield 0 VV) methylphenyl)pyridine-3-ylJacrylic acid dihydrochloride 0 (2E) -3-[5- {{(tert-butoxycarbonyl)amino methyl} -6-isobutyl- as a white powder of m ay +, YY aa 4 ¥) 2-methyl-4-(4-methylphenyl)pyridine -3-yljacrylic acid (FY mole) according to the method similar to that of the example "H-NMR (CD; OD) &: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, 5), 5.98 (IH, 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). © 01 Example (2E)-3-[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3- vlacrylamide dihydrochloride tert-butyl {[5-[(1E) )-3-amino-3-oxoprop-1-en-1-yl]-2-isobutyl-6- we get 1 ,; g; Yield 484 methyl-4-(4-methylphenyl)pyridine-3-ylJmethyl } carbamate (2E)-3-[5-{[(tert-butoxycarbonyl)amino]methyl} -6-isobutyl-2-methyl-4- of (% a4 mmol) 4 0 + g 4 (4-methylphenyl)pyridine-3-yl]acrylic acid (VT according to a method similar to that of example "H-NMR (CD; OD) ) 6:0.97 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.09-2.20 (1H, m), 2.37 (3H, s), 2.59 (3H, 5), 2.74 (2H, d , I = 7.2 Hz), 3.99 (2H, 5), 4.34 (1H, brs), 6.00 (1H, 0 d, J = 16.2 Hz), 7.06 (2H, d, J = 8.1 Hz), 7.22-7.28 ( 3H, m).(2E)-3-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-a-da (Y (% 14 g yield 0 YA) methylphenyl)pyridine -3-ylJacrylamide dihydrochloride tert-butyl {[5-[(1E)-3-amino-3-oxoprop-1 -en-1-yl]-2-isobutyl-6-methyl-4-(4- from) g « , ; mmol +, AY) methylphenyl)pyridine-3-yljmethyl} carbamate 0 (3-1 gram) according to the method similar to the example method "H-NMR (CD; OD) &:1.11 ( 6H, d, J = 6.6 Hz), 2.13-2.22 (1H, m), 2.45 (3H, 5), 2.87 (3H, 5),3.10 (2H, d, J = 7.5 Hz), 4.15 (2H, 5 ), 6.12 (1H, d, ] = 16.2 Hz), 7.11 (1H, d,

J=16.2Hz), 7.23 (2H,d, 1 = 7.9 Hz), 7.45 2H,d, J] = 7.9 Hz). 11 example ve

Methyl 5-(aminomethy] )-6-isobutyl-2-methyl-4-phenylnicotinate ay methyl S-cyano-6-isobutyl-2-methyl-4-phenyl- 1,4-dihydropyridine- ( 1 5 -methyl-3- as a white powder from (ZAR vol. yield 0 Y) 3-carboxylate g 50 mL £,Y) benzaldehyde g; 7450 mmol (©) oxohexanenitrile g; 50 mmol) according to £.7) methyl 3-aminocrotonate (mol) and YY (method similar to example oo "H-NMR (CDCl3) 8:0.93 (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, 5), 3.57 (3H, 5), 4.61 (1H, 5) ), 5.69 (1H, brs), 7.18-7.32 (5H, m.ca 84 ) methyl S-cyano-6-isobutyl-2-methyl-4-phenylnicotinate, we get (Y methyl 5-cyano-6- isobutyl-2-methyl-4-phenyl- as a white powder of ( Av yield 0 g ; ?? mmol) according to 1 +,V) 1,4-dihydropyridine-3-carboxylate ( FY Method similar to example method "H-NMR (CDCl3) 8: 1.01 (6H, d, J = 6.8 Hz), 2.21-2.35 (1H, m), 2.64 (3H, 5), 2.96 (2H, 2.17. 2 Hz), 3.57 3H, 5), 7.33-7.39 (2H, m), 7.44-7.50 (3H, m).

Methyl 5-(aminomethyl)-6-isobutyl-2-methyl-4-phenylnicotinate on Jaa (Ye methyl 5-cyano-6-isobutyl-2- yield 77.2) as white powder (ax +, TY) mmol) according to a method similar to YY g” /.4 (methyl-4-phenylnicotinate) 1.) of the method used in the step; - from the example “H-NMR (CDCl3) 8:1.02 (6H, d, J = 6.6 Hz), 2.17-2.33 (1H, m), 2.54 (3H, 5), 2.81 (2H, mh 1 - 7.4 Hz), 3.46 (3H, 5), 3.65 (2H, 5), -7.20 7.25 (2H, m), 7.38-7.46 3H, m).¥- 01 eg Methyl 5-(aminomethyl)-6-isobutyl-4-( 4-methylphenyl)-2-propylnicotinate 11 h mixture of and for Dean-Stark heated with vapor re-condensation using an apparatus (/ ammonium acetate mM; 0 g (V,Y) methyl 3-oxohexanoate mM) 0 g; ¥ ) acetic acid mmol); You g; vay (vo) mL). The reaction mixture is concentrated under reduced pressure and the residue is divided between 10001) toluene magnesium sulfate and saturated brine. The organic layer is dried over ethyl acetate

Anhydrous and the solvent evaporates under reduced pressure to produce methyl 3-aminohex-2-enoate as a colorless oil. Joa a; on methyl 5-cyano-6-isobutyl-4-(4-methylphenyl)-2-propyl-1,4- Y,A) dihydropyridine-3-carboxylate 1 g yield (TAS as oil of 5-methyl-3-oxohexanenitrile ~~ © )© g; 0;mmol) “a>£,A) p-tolaldehyde Ale 0 mol) and the aforementioned colorless oil of methyl 3-aminohex-2-6; By following the method used in Step No. From Example 1.) 1H, m), 2.23-2.47 (2H, m), 2.30 (3H, 5), 2.69-2.74 (2H, m), 3.57 (3H, s), 1.83-1.96 4.58 (1H, 5), 5.65 ( 1H, brs), 7.09 (2H, d, J = 8.1 Hz), 7.13 2H, d, = 8.1 Hz).00 methyl S-cyano-6-isobutyl-4-(4-methylphenyl)-2-propylnicotinate on (V methyl = 5-cyano-6-isobutyl-4-(4- g yield 780) in the form of oil from 4 ml VY cama VY, A) methylphenyl)-2-propyl-1,4- dihydropyridine-3-carboxylate.) 6.6 Hz), 1.73-1.85 m (2H, m), 2.22-2.35 (1H, m), 2.41 (3H, 5), 2.78 (2H, m), 2.96 (2H, d, J = 7.4 Hz ), 3.58 (3H, 5), 7.23-7.32 (4H, m). methyl S-(aminomethyl)-6-isobutyl-4-(4-methylphenyl)-2- on Joa a5 (v methyl 5-cyano-6-isobutyl-4-(4-) as oil from (ZAA) g Yield +, YA) propylnicotinate g 7 mmol) according to method +, AA) methylphenyl)-2-propylnicotinate 0

AE from Example 1 followed by step “H-NMR (CDCl3) 8: 0.94-0.99 (9H, m), 1.70-1.83 (2H, m), 2.18-2.31 (1H, m), 2.39 (3H, 5), 2.69-2.74 (2H, m), 2.81 (2H, d,J = 7.2 Hz), 3.48 GH, s), 3.65 (2H, s), 2 (2H, d,1=8.1Hz), 7.21 (2H, d,] = 8.1 Hz). {[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2- (— to solution 1) 68,01 mmol ) methyl-4-(4-methylphenyl)pyridine-3-yljacetate A titer of As (01 mL) ethanol (1 mL) added tetrahydrofuran (©) in mmol; the mixture was heated with aqueous YE (¥ mL) sodium hydroxide 1 hydrochloric solution acid Re-condensed for ? hours. The reaction mixture was acidified with 5 (0) H. The extract was washed with saturated brine, dried, standard acetate, and extracted with anhydrous. The solvent was evaporated under reduced pressure and the residue was purified by decomposing magnesium sulfate over ‎[5-{[(tert- finstig silica Dt) chromatography using a butoxycarbonyl)amino]methyl column }-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridine-3- throughput 16 %( as a white powder. can +, V1) ylJacetic acid 0 [5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3- we get (¥ [5- Yield 794) as a white powder of can v,00 ( ylJacetic acid dihydrochloride {[(tert-butoxycarbonyl)amino]methyl ( -6-isobutyl-2-methyl-4-(4- mmol) according to 1 7 can », 11 ( methylphenyl) pyridine-3-yl] acetic acid

IF for a method similar to that in Example 7-7 [Example 1 second step "H-NMR (CD; OD) 8: 1.10 (6H, d, J = 6.4 Hz), 2.09-2.25 (1H, m), 2.48 (3H, 5), 2.84 (3H, 5), 3.10 (2H, d, J = 7.4 Hz), 3.60 (2H, 5), 4.09 (2H, 5), 7.20 (2H, d, ] = 7.9 Hz) , 7.49 (2H, d, J = 7.9 Hz).

NE Example Methyl S-(aminomethyl)-6-isobutyl-2-(2-methoxy-2-oxoethyl)-4-(4- 00 methylphenyl)nicotinate dimethyl 1,3- from dimethyl 3-aminopent- 2-enedioate lc Joa a3 (“mmol) according to analogous method 50 can VY) acetonedicarboxylate (VY for example method)

Methyl 5-cyano-6-isobutyl-2-(2-methoxy-2-oxoethyl)-4-(4- on Joa a; Yo yield © 1/7) as oil «aa 118(methylphenyl)-1 ,4-dihydropyridine-3-carboxylate

S5-methyl-3- Product; dimethyl 3-aminopent-2-enedioate with an amber color of a g; 50 m€,A) p-tolualdehyde (m.m.) 0 can ©) oxohexanenitrile (m.m.)." H-NMR (CDCl3) 6:0.94 (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, 5), 3.58 (3H, 5), 3.77 (3H, 5), 3.85 -4.10 (2H, m), 4.59 (1H, 5), 7.01 (1H, brs), 7.10 (2H, d, ] = 8.1 Hz), 7.16 (2H, d, ] = 8.1 Hz).

Methyl = 5-cyano-6-isobutyl-2-(2-methoxy-2-oxoethyl)-4-(4-) we obtain “)” as an orange-yellow color from (% VA total yield ¥, Y ( methylphenyl)nicotinate

Methyl 5 ~Cyano-6-isobutyl-2-(2-methoxy-2-oxoethyl)-4-(4-methylphenyl)- 1,4-mM) according to method “0 can 11,5( dihydropyridine) -3-carboxylate

A(T) similar to the example method 0 "H-NMR (CDCl3) 8: 1.01 (6H, d, J = 6.6 Hz), 2.20-2.35 (1H, m), 2.41 GH, 5), 2.97 (2H, d,1=72Hz),3.54 3H, 5), 3.71 (3H, 5), 4.04 (2H, 5), 7.20-7.30 (4H, m),

Methyl 5-(aminomethyl)-6-isobutyl-2-(2-methoxy-2-oxoethyl)-4-(4- on Jans (v)

Methyl as a pale yellow oil of 7 daly aa Y,0 ( methylphenyl)nicotinate v.Y) >-cyano-6-isobutyl-2-(2-methoxy-2-oxoethyl)-4-(4-methylphenyl)nicotinate Yo . (4-1 mmol) according to the method similar to that of example AE aa "H-NMR (CDCl3) 8:0.98 (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, 5 ), 7.05-7.25 (4H, m).

Jo Example 0

Methyl 5-(aminomethyl)-4-(2,6-difluorophenyl)-6-isobutyl-2 -methylnicotinate methyl 3-(cyano)-4-(2,6-difluorophenyl)-6-isobutyl-2-methyl- 1 ,4 on Ja as ( 5-yellow crystals of (ZY yield aa YEA) dihydropyridine-3-carboxylate 2.65 momol) 111 g 11©) methyl-3-oxohexanenitrile methyl 3-aminocrotonate (mM) 0 g; 1 v) difluorobenzaldehyde 00.)

qv "H-NMR (CDCl) 8: 0.95-1.05 (6H, m), 1.80-2.05 (1H, m), 2.10-2.45 (2H, m), 2.31 (3H.5), 3.56 (3H, 5) , 5.21 (1H, 5), 5.87 (1H, brs), 6.75-6.90 (2H, m), 7.05-7.25 (1H,

m). methyl 5-cyano-4-(2,6-difluorophenyl)-6-isobutyl-2-methylnicotinate We obtain (¥ methyl 5-cyano-4-(2,6-) from ial as colored crystals (Fhe g Yield 11.7 (0 g; 4 A) difluorophenyl)-6-isobutyl-2-methyl-1 ,4-dihydropyridine-3-carboxylate

). (3H, 5), 2.97 (2H, d, J - 7.0 Hz), 3.65 (3H, s), 6.95-7.10 (2H, m), 7.35-7.55 (1H, m).methyl S-(aminomethyl)- 4-(2,6-difluorophenyl)-6-isobutyl-2- 7) 0 methyl 5- is obtained as a pale yellow solid from ( AY yield aa 9, A) methylnicotinate mM YE aa 1 V) cyano-4-(2,6-difluorophenyl)-6-isobutyl-2-methylnicotinate (£7 mol) according to a method similar to that of the example "H-NMR (CDCl) 8:0.99 (6H, d, J = 6.6 Hz), 1.51 (2H, brs), 2.15-2.35 (1H, m), 2.60 (3H), 2.83 (2H, , for J = 7.5 Hz), 3.56 (3H, 5), 3.62 (2H, 5), 6.95-7.05 2H, m), 1° 7.35-7.50 (1H, m). Melting point: 144-478 * 01 °C Ex. Methyl 5-(aminomethyl)-4-(4-fluorophenyl )-6-isobutyl-2-methylnicotinate methyl = 5-cyano-4-(4-fluorophenyl )-6-isobutyl-2-methyl-1,4- on da (VY. 5- as yellow oil from (AV g; yield of YV, 4) dihydropyridine-3-carboxylate 4 mmol grammes ); 011 can) ¥,A) methyl 5-cyano-4-(4-fluorophenyl)-6-isobutyl-2-methylnicotinate ()" 00 methyl 5-cyano-4-(4-fluorophenyl)-6- As a yellow oil of (7711 g; yield Vi)

aA mmol. AY aa ¥ Y) isobutyl-2-methyl-1 ,4-dihydropyridine-3-carboxylate (1-3 gram) according to the method similar to that of example “H-NMR (001) 1 (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).

Methyl = 5-(aminomethyl)-4-(4-fluorophenyl)-6-isobutyl-2- the Joa a; (vo

Methyl 5- as a pale yellow solid of (7 AS yield can 01") methylnicotinate mM 0 g; 1 9 cyano-4-(4-fluorophenyl)-6-isobutyl-2-methylnicotinate (£7 gram) according to a method similar to the example method "H-NMR (CDCl; ) 6:0.98 (6H, d, J = 6.6 Hz), 1.26 (2H, brs), 2.15-2.35 (1H, m ), 2.54 (3H, 5), 2.81 (2H, d, J = 7.2 Hz), 3.51 (3H, 5), 3.65 (2H, 5), 7.00-7.30 (4H, m). 0 Melting point: 85 7-5*"C. Ex. No 3-(aminomethyl)-6-isobutyl-4-(4-methylphenyl )-2-propylnicotinic acid dihydrochloride methyl 5-{[(tert-butoxycarbonyl) )amino]methyl}-6-isobutyl-4-(4- on Jia a: )1 0 as a white solid (AVY g; yield 0,0) methylphenyl)-2-propylnicotinate methyl S- (aminomethyl)-6-isobutyl-4-(4-methylphenyl)-2-propylnicotinate from VY (7.7 mmol) according to a method similar to that of example 0 YA) "H-NMR (CDCl, ) 6:0.94-0.99 (9H, m), 1.39 (9H, 5), 1.70-1.83 (2H, m), 2.16-2.27 (1H, m), 2.38 (3H, 5), 2.70-2.75 (2H, m), 2.79 (2H, d, J = 7.2 Hz), 3.48 (3H, s), 4.14 0 00 (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). 5- {[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-4-(4- Anelmsa Joa a3 (Y methyl 5-{[(tert-) from (ZAT) total yield +,04 ) methylphenyl)-2-propylnicotinic acid butoxycarbonyl)amino]methyl} -6-isobutyl-4-(4-methylphenyl)-2-propylnicotinate (YY mmol) according to the method similar to that of the example 0,6 can 91 ) 00

H-NMR (CDCly) 8: 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, 5), 2.81-2.92 (4H, m), 4.40-4.09 (2H, m), 7.20 (2H, d, ] = 8.3

Hz), 7.26 (2H, d, J = 8.3 Hz). 5-(aminomethyl)-6-isobutyl-4-(4-methylphenyl)-2-propylnicotinic you get (v

S-{[(tert- total yield +49 (as white powder of +,0+) acid dihydrochloride 0 butoxycarbonyl)amino]methyl}-6-isobutyl-4-(4-methylphenyl)-2-propylnicotinic -1 mmol) according to the method similar to that of the example 017” g; +04) acid (¥ ' H-NMR (CD; OD) 8:1.04-1.13 (9H, m), 1.76-1.91 (2H, m), 2.13-2.25 (1H, m), 2.44 (3H, 5), 3.01-3.18 (4H, m), 4.20 (2H, brs), 7.28-7.36 (2H, m), 7.43 (2H, d, J = 00 7.9 Hz). - You obtain ("methyl yield 787) as a white solid from can 4 ) methyl-4-phenylnicotinate 0 mmol 771 g; A,0) 5-(aminomethyl)-6-isobutyl- 2-methyl-4-phenylnicotinate.) , 2.15-2.20 (1H, m), 2.55 (3H, s), 2.79 (2H, d, J = 7.2 Hz), 3.46 (3H, 5), 4.14 (2H, d, J = 4.9 Hz), 4.24 ( 1H, brs), 7.14-7.21 (2H, m), 7.37-7.44 (3H, m). 0 0 5-{[(tert-butoxycarbonyl)amino methyl } -6-isobutyl-2-methyl-4- means Joa a3 (Y methyl 5- yield 56) as a white solid of can +,¥ 4) phenylnicotinic acid 1 ) {[(tert-butoxycarbonyl)amino]methyl } -6-isobutyl-2-methyl-4-phenylnicotinate .(7-7 mmol) according to the method similar to that of the example 0,4 can

S-(aminomethyl)-6-isobutyl-2-methyl-4-phenylnicotinic acid (v 00 5-{[(tert-) is obtained as a white powder from TAT yield 0 g +,Ye ) dihydrochloride

Yuu +,¥'4) butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-phenylnicotinic acid (TY g; 0.94 mmol) according to a method similar to that of the example “H-NMR ( CD;OD) 6:1.04-1.15 (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).03 Example Methyl 5-[(dimethylamino)methyl]-6-isobutyl-2-methyl-4-(4- methylphenyl)nicotinate methyl 5-(aminomethyl)-6-isobutyl- hr mixture of 11 stirred at 100*C for formic mmol); 0,6 can +,0+) 2-methyl-4-(4 -methylphenyl)nicotinate sodium hydrogen mL The reaction mixture was poured into formalin (5 mL) © acid 00 The extract was dried over saturated ethyl acetate; the mixture was extracted with anhydrous Ala carbonate and the solvent was evaporated under pressure Reduced The residue is purified by magnesium sulfate

Methyl 5-[(dimethylamino)methyl]-6- to give silica gel column chromatography 719. Yield PERE PY isobutyl-2-methyl-4-(4-methylphenyl)nicotinate “H-NMR (CDCl3) ) 8: 0.98 (6H, d, J = 6.8 Hz), 1.97 (6H, 5), 2.14-2.28 (1H, m), 239 \o (3H, s), 2.53 (3H, 5), 2.89 (2H , d, J = 7.4 Hz), 3.23 (2H, s), 3.48 (3H, s), 7.04 (2H, d,

J=8.0Hz), 7.17 (2H, d, J=8.0 Hz). 01 Example Methyl 5-(aminomethyl)-2-methyl-6-isobutyl-[4,4'-bipyridine]-3 -carboxylate methyl 5-cyano-6-isobutyl-2-methyl-1,4-dihydro-4 ,4'-bipyridine-3-on Juan (1 p. 5-methyl-3- as yellow oil from (ZY) yield can 77.4 (carboxylate g; YA) isonicotinaldehyde m) 001 (aa V0) oxohexanenitrile mM 011 can V¥,A) methyl 3-aminocrotonate 5 mM) 0 (YY) according to a method similar to that in the example methyl 5-cyano-6-isobutyl-2-methyl-1,4-dihydro-4,4"-bipyridine- to a solution of (vy ve mL) add Vo.) acetone (mM); in TE (aa 01( 3-carboxylate mmol); the mixture was stirred for AY £0 g) diammonium cerium nitrate

YYVY

011 for one hour at room temperature. The reaction mixture is cooled to zero degrees Celsius and the organic layer is combined with the substance sodium hydroxide Y and ethyl acetate between, and the mixture is dried over the extracted ethyl acetate resulting from the extraction of the aqueous layer with anhydrous. The solvent was evaporated under reduced pressure and the residue was purified by a solution of magnesium sulfate methyl 5-cyano-6-isobutyl-2-methyl- silica chromatography using a 0 g gel column; Yield (©) in the form of a yellow oil. V as a pale yellow solid of (AVY yield can 14,4) carboxylate

EA g ) methyl 5-cyano-6-isobutyl-2-methyl-4,4'-bipyridine-3-carboxylate

JY [example; Step 1 - mM) according to a method similar to that used in the example; 1H, m), 2.57 (3H, 5), 2.82 (2H, d, J = 7.2 Hz), 3.49 (3H, 5), 3.61 (2H, 5), 7.15-7.25 (2H, m), 8.65-8.70 (2H, m). Melting point: 15-77"C. 71 as 0

Methyl 5-(aminomethyl)-2-methyl-4-(4-methylphenyl)-6-neopentylnicotinate g; Productivity of 14% (in the form of 4Y) 5,5-dimethyl-3-oxohexanenitrile (0 milligrams) obtained according to the 176 can AT method (methyl 3,3-dimethylbutanoate) oil from 1-. 1 Similar to that in example "H-NMR (CDCl3) 5: 1.05 (9H, s), 2.49 (2H, 5), 3.43 (2H, s). Y- 5,5-dimethyl-3-h mixture of 11 heated with re-condensation for a period of (19) mm (p-tolualdehyde) (19 mm); 098 mm (YY) oxohexanenitrile acetic (15.8 can 7) piperidine milligrams); The reaction mixture was allowed to cool to room temperature and washed with anhydrous saline solution. The solvent was evaporated under reduced pressure and saturated magnesium sulfate dissolved and dried over methyl 3-aminocrotonate (ml). And add to it (© +) the remaining methanol produced in

1 01 mmol) and the mixture is heated with vapor re-condensation for YOA (1 ALY) hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by lysis of methyl 5-cyano-2-methyl-4-(4-vintage silica on gel column chromatography; yield ¥) methylphenyl)-6-neopentyl-1 ,4-dihydropyridine-3-carboxylate as oil. ), 2.14- 2.41 (2H, m), 2.31 (3H, s), 2.37 (3H, 5), 3.58 (3H, 5), 4.57 (IH, s), 5.56 (1H, brs), 7.06-7.16 ( 4H, m).

Methyl 5-cyano-2-methyl-4-(4-methylphenyl)-6-neopentylnicotinate (¥ methyl 5-cyano-2-methyl-4-(4-yield £7) is obtained as colorless crystals of aa VY ) 0 mM 04.8 0 g Yo ) methylphenyl)-6-neopentyl-1,4-dihydropyridine-3-carboxylate .(-1 mol) according to a method similar to that in the example “H- NMR (CDCl) 8: 1.06 (9H, 5), 2.41 (3H, 5), 2.63 (3H, 5), 3.01 (2H, , 3.61 (3H, 5), 7.26 (4H, m).

ACY 40-19 Melting Point: 1

Methyl = 5-(aminomethyl)-2-methyl-4-(4-methylphenyl)-6- on Jom a; (¢

Methyl 5-g; Yield 0% % (as colorless crystals of V,Y) neopentylnicotinate gpm; 4 mM ¢ ) Cyano-2-methyl-4-(4-methylphenyl)-6-neopentylnicotinate (4-1 mol) according to a method similar to that of Example "H-NMR (CDCl3) 6:1.02 (9H , 5), 1.44 (2H, brs), 2.39 (3H, s), 2.53 (3H, 90, 2.88 | 0 (2H, 5), 3.50 (3H, 5), 3.72 (2H, 5), 7.12 (2H , m), 7.21 (2H, m).

A ALYY mV melting point

YY Example 3-(aminomethyl)-2-methyl-4-(4-methylphenyl )-6-neopentylnicotinic acid dihydrochloride +0

Methyl 5-(aminomethyl)-2-methyl-4-(4-methylphenyl)-6- to a solution of (0

Yo) tetrahydrofuran g 7.1 mmol) in 1) neopentylnicotinate

10 oz 41-6 (15 g; ? mmol) and stirred dicarbonate mL) sodium was added to the mixture at room temperature for 1 hour. A milliliter solution is added to the reaction mixture and the mixture is heated with 01 (5 N) methanol (7 milliliters) aqueous A hydroxide The reaction mixture is left to cool to room temperature GUY Re-condensing the steam for a period The substance is washed .60:1 acetate N) and extracted with 1) hydrochloric acid and acidified with anhydrous ©. The extracted magnesium sulfate solvent was evaporated with saturated brine and dried over 5-{[(tert-) yielding diisopropyl ether Under reduced pressure, the residue crystallizes from butoxycarbonyl)amino]methyl } -2-methyl-4-(4-methylphenyl)-6-neopentylnicotinic g; yield 47 7) in the form of crystals. ©) acid "H-NMR ( CDCl; ) 5:0.88 (9H, ,l 1.36 (9H, 5), 2.38 (3H, s), 2.72 (3H, 5), 2.88 (2H, 0 s), 4.21 (2H, brs), 4.29 (1H, brs), 7.18 2H, d, J = 8.3 Hz), 7.23 (2H, d, ] = 8.3 Hz). Melting point: 717-715"C. 5-{[(tert-milliliter) to ©) hydrogen chloride 1,4-dioxane is added; standard solution (¥ butoxycarbonyl)amino]methyl}-2-methyl-4-(4-methylphenyl)-6-neopentylnicotinic (¥) h at 117 mmol); The mixture was stirred for 1.1 g; oF) acid 0 room. The reaction mixture was concentrated under reduced pressure yielding a white solid which washed out the 5-(aminomethyl)-2-methyl-4-(4-methylphenyl)-6-diethyl ether phenestige as a powder in color (AVY yield). can 7 ( neopentylnicotinic acid dihydrochloride white. ,3.86 0 0 (2H, for - 5.5 112(, 7.23 2H, 0.1 8.1 Hz), 7.30 (2H, d, ] = 8.1 Hz), 8.24 (3H, brs).

IY Example tert-butyl 5-(aminomethyl)-4-(4-chlorophenyl)-6-isobutyl-2-methylnicotinate ©A+) tert-butyl acetoacetate Stir for 1 hour at room temperature a mixture of ( A

V+ + +) methanol mL) and 0 (aqueous ammonia 7 Yo mL 7.5 mol); Yo and water. ethyl acetate mL). and after concentrating the reaction mixture under reduced pressure; It is divided between and the solvent is evaporated under pressure “LY magnesium sulfate” The organic layer is dried over

0. g Yield of 14% (as powder, color 00+) tert-butyl 3-aminocrotonate reduced to yield: pale yellow.” H-NMR (CDCl; ) 8:1.47 (9H, s), 1.87 (3H, 5), 4.46 (1H, 5).tert-butyl 4-(4-chlorophenyl)-5-cyano-6-isobutyl-2-methyl-1,4- on Joa a3 (Y-5 g; yield 17%) As a white powder of V,1) dihydropyridine-3-carboxylate 0 4-chlorobenzaldehyde 4 mmol; TY; g; methyl-3-oxohexanenitrile (mM YY) tert-butyl (©) 3- aminocrotonate 5 mM) VY aa gf °) (T=) mol) according to a method similar to that in the example “H-NMR (J000) 8:0.93 (3H, d, J = 6.6 Hz), 0.99 (3H, d, 1 = 6.6 Hz), 1.29 (9H, 9, 1.80-1.95 (1H, m), 2.10-2.30 (2H, m), 2.34 (3H, 5), 4.54 (1H, 5), 5.56 (1H, brs), + 7.10-7.20 (2H, m), 7.25-7.30 (2H, m). -5-cyano-6-isobutyl-2-methyl-1,4- to a solution of (001 mmol acetone) in Yo g V, 1) dihydropyridine-3-carboxylate £4 ( a> YV) diammonium cerium nitrate (mL) of 0 (mL) aqueous solution (1 mmol) was added at room temperature over 0 minutes. The reaction mixture is divided between water and water. The organic layer is combined with the extracted material resulting from anhydrous ethyl acetate extraction. The magnesium sulfate was evaporated and the mixture was dried over cethyl acetate aqueous bed with the solvent under reduced pressure and the residue was purified by chromatography on a tert-butyl 4-(4-chlorophenyl)-5-cyano-6-isobutyl-2 gel column. -methylnicotinate produced silica Yo yield 790 (as white powder. cas V,Y) “H-NMR (CDCl; ) 8:1.01 (6H, d, J = 6.8 Hz), 1.27 (9H, 5), "77" -1106 Melting point: tert-butyl 4-(4-chlorophenyl)-5-cyano-6-isobutyl-2-methylnicotinate;) The mixture of ve

Y) ammonia 776 (sll ¢) Rany-cobalt g; 7.6 mmol);

m sealed under 0.0 MPa hydrogen atmosphere at room temperature for a period of 2 hours. The reaction mixture was filtered and the leachate was concentrated under reduced pressure. The residue was divided between ethyl acetate and 701 aqueous potassium carbonate solution and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by chromatography using a silica pt column to yield -5 tert-butyl A) (aminomethyl)-4-(4-chlorophenyl)-6-isobutyl-2-methylnicotinate 4 g; Yield (74Y as a white powder. “H-NMR (CDCl3) 5: 0.98 (6H, d, J = 6.8 Hz), 1.22 (9H, 5), 1.42 (2H, brs), 2.15-2.30 (1H, m), 2.55 (3H, 5), 2.79 (2H, d, J = 7.2 Hz), 3.61 (2H, 5), 7.21 (2H, d, ] = 8.3 Hz), 7.41 2H, d , 1- 8.3 Hz). 0 Stir for ; hours and at 0 *"C mixture of tert-butyl 5-(aminomethyl)-4-(4- chlorophenyl)-6-isobutyl-2-methylnicotinate ) 1 g 0.9 millimol) trifluoroacetic acid (£ milliliter). The reaction mixture was concentrated under reduced pressure and the remaining solute in 1,4-dioxane (£ 0 mL) to the resulting solution was added; A titer of hydrogen chloride 1,4-dioxane solution (?; VT « lille mmol); The mixture was concentrated under reduced Ye pressure and the residue was washed with diisopropyyl ether to give 5-(aminomethyl)-4-(4- +,1Y) chlorophenyl)-6-isobutyl-2-methylnicotinic acid dihydrochloride g; Yield 4) As a colorless oil. (Y 5-(aminomethyl)-4-(4-chlorophenyl)-6-isobutyl-2-methylnicotinic acid can +,1Y) dihydrochloride 1.0 mmol) is dissolved in isopropanol )+ 1 milliliter); Yo to which is added Y) propylene oxide 7 gm 6.7 mmol). Stir the mixture for how long? hours at room temperature. The reaction mixture is concentrated under reduced pressure.” The resulting zyrite crystallizes from isopropanol—diisopropyl ether, producing 5-(aminomethyl)-4-(4-chlorophenyl)-

10 g No (as powder in color 0,47) 6-isobutyl-2-methylnicotinic acid hydrochloride white. H-NMR (DMSO-ds ) 8:0.96 (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, 5), 7.34 (2H, d, J = 7.5 Hz), 7.54 2H, d , J = 7.5

Hz), 8.43 (1H, brs). ©

Yo as tert-butyl S-(aminomethyl)-6-isobutyl-2-isopropyl-4-(4-methylphenyl) nicotinate pyridine s (mmol) 1.1 g; (VEE) Meldrum acid To a solution of (1 milliliter) added to 001 (gram dichloromethane) in esa 0.7 «slike 17

Vo mol) over a period of 111 “alle 1,4) isobutyryl chloride drops; 0 minutes and at 0”C; the mixture was stirred at 0C for two hours. The reaction mixture was poured, the substance was washed, standard dichloromethane, and extracted mixture with 0.58 hydrochloric 8610 solvent evaporated in 0. anhydrous magnesium sulfate extracted with saturated brine and dried over under reduced pressure heated with re-condensation for 7 hours mixture of resulting residue; After letting 001 (toluene s mol) Ale 1051 g; VY,Y) tert-butanol 06 and adie dry the mixture to cool to room temperature; wash the reaction mixture with tert-butyl saline 4- Anhydrous The solvent evaporates under reduced pressure to give magnesium sulfate over an hour at VY temperature stirred for (9.71 aa) as a crude product methyl-3-oxopentanoate (778) 001 (mL) Aqueous ammonia s mixture of crude product (4.71 g) dd al) ethyl mL). The reaction mixture is concentrated under reduced pressure; split between (001 and 1 mL) anhydrous Y+; the solvent magnesium sulfate is evaporated and water. The organic layer was dried over acetate 9,77 (as a crude product tert-butyl 3-amino-4-methylpent-2-enoate under reduced pressure to yield 5 gm). 6-isobutyl-2-isopropyl-4-(4-methylphenyl)-1,4- (¥ 5-) is obtained as colorless crystals of (ZV g; Yield (VY, Y) dihydropyridine-3-carboxylate Ye ¢,A) p-tolualdehyde g +£ mmol); ©) methyl-3-oxohexanenitrile tert-butyl 3-amino-4- g) of 3,Y1) milligrams) and crude product 400 g;

0 methylpent-2-enoate produced in the previous step 1); according to the method similar to that of the example.) 7-1 tert-butyl ~~ S-cyano-6-isobutyl-2-isopropyl-4-(4- — le 0 tert-butyl 5-cyano-6- from Coy XK (7177 g) yield Y,AA) methylphenyl)nicotinate v,a¢ ) 1sobutyl-2-isopropyl-4-(4- methylphenyl)-1,4-dihydropyridine-3-carboxylate 0 g; 01 milligram) according to the method similar to that of Example ?7-?). “H-NMR (J000) 8:1.01 (6H, d, 1 = 6.6 Hz), 1.25 (9H, 5), 1.32 (6H, d, J = 6.6 Hz), 2.26-2.35 (1H, m), 2.40 (3H, 5), 2.94 2H, 1, = 7.2 Hz), 3.14-3.23 (1H, m), 7.26- 7.35 (4H, m).tert-butyl 5-(aminomethyl)-6- isobutyl-2-isopropyl-4-(4-on Joa a3 (¢ tert-butyl g yield 7977) as a white powder of Y,1©) methylphenyl)nicotinate mV g; Y, VE ) 5-cyano-6-isobutyl-2-isopropyl-4-(4-methylphenyl)nicotinate (£7) mol) according to a method similar to that of the example "H-NMR (CDCl3) 8:0.99 (6H, d, ] = 6.6 Hz), 1.18 (9H, , 1.30 GH (6H, d, J = 6.6 Hz), 1.39 (2H, brs), 2.26-2.35 (1H, m), 2.39 (3H, 5) , 2.78 (2H, d,J=6.9 Hz), 3.04-3.14 0 : (1H, m), 3.60 (2H, s), 7.13 (2H, d, J = 8.2 Hz), 7.20 (2H, d, J = 8.2 Hz). (4-methylphenyl)nicotinic on Juans Y. tert-butyl 5- yield +14 (as white powder of 0 g +,YV) acid dihydrochloride

Vas 6 ) (aminomethyl)-6-isobutyl-2-isopropyl-4-(4-methylphenyl)nicotinate). 8: 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=5.4Hz), 722 Yo (2H, d, J =8.1 Hz), 7.28 (2H, d, J = 8.1 Hz), 8.21 (3H, brs).

Vv is an example

1 0 A tert-butyl 5-(aminomethyl)-4-(4-chlorophenyl )-2-methyl-6-neopentylnicotinate tert-butyl 4-(4-chlorophenyl)-5-cyano-2-methyl-6-neopentyl- 1,4- a a i (0 5,5-cd yield 774) as a white powder of Y,0 ) dihydropyridine-3-carboxylate 4-mM); YA 7 g ( dimethyl- 3-oxohexanenitrile tert-butyl 3- mmol) 0100816 mcb 01 g; Y,¥) chlorobenzaldehyde 0

AY) gram-molecule) according to the method similar to that of the example lle VT g; (7.5 "H-NMR )0001:( 8:1.01 (9H, 5), 1.29 (9H, 5), 2.17 (1H) , d, J = 13.9 Hz), 2.34 (3H, s), 2.35 (1H, d,J = 13.9 Hz), 4.55 (1H, 5), 5.46 (1H, brs), 7.10-7.35 (4H, m) .

ASOT 01-71 Melting point: tert-butyl ~~ 4-(4-chlorophenyl)-5-cyano-2-methyl-6- on Joao; (xv 0 tert-butyl g; yield 7960) as a pale yellow powder of 11( neopentylnicotinate 4-(4-chlorophenyl)-5-cyano-2-methyl-6-neopentyl- 1,4-dihydropyridine-3- c; 0.9 milligrams) according to the method similar to that of Example 4) carboxylate. -?) yy "H-NMR (CDCl; ) 8:1.06 (9H, 5), 1.28 (9H, 5), 2.65 (3H, , 3.00 (2H, 5), 7.30-7.35 m (2H, m), 7.45-7.50 (2H, m).Melting point: 4 55-4*C. tert-butyl = 5-(aminomethyl)-4-(4-chlorophenyl)-2-methyl -6- Joa (v tert-butyl 4-(4- g yield 797) as a white powder of +,Y) neopentylnictinate g; ,5,?mmol 1 ) chlorophenyl)-5-cyano- 2-methyl-6-neopentylnictinate Ye.) 4-77 gram) according to the method similar to the example method "H-NMR (CDCl) 8:1.02 (9H, 5), 1.22 (9H, 5), 1.43(2H, brs), 2.55 (3H, 6 (2H, 5), 3.66 (2H, 5), 7.15-7.25 (2H, m), 7.35-7.45 (2H, m). :,

YA Example Yo 3-(aminomethyl)-4-(4-chlorophenyl )-2-methyl-6-neopentylnicotinic acid dihydrochloride

0 5-(aminomethyl)-4-(4-chlorophenyl)-2-methyl-6-neopentylnicotinic We obtain tert-butyl 5- yield 744) as a white powder from aa 1( acid dihydrochloride body, a v4 5( (aminomethyl)-4-(4-chlorophenyl)-2-methyl-6-neopentylnictinate

mmol) according to a method similar to that of Example 4 1-7.) “H-NMR 0180-4 ( 5:1.02 (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: AAT EA-Y ET Ex. g; 11 mmol) and acetic Ale 11 can ,17 (40 mol) in 50000801 added to drops of a solution (+ ¥ milliliters) of VV) 5,5-dimethyl-3-oxohexanenitrile g; The solvent is under reduced pressure; the residue is partitioned between ethyl acetate and a saturated brine.The organic layer is dried over anhydrous magnesium sulfate and the solvent evaporates under reduced pressure to yield 3-(4-chlorophenyl)-2-(3,3-dimethylbutanoyl)acrylonitrile As crude product Yo.) g) ¥ (we get tert-butyl 3-amino-5,5-dimethylhex-2-enoat as crude product VY) g) from Meldrum acid Y: (1250 / g; 01 milligrams) tert-butylacetyl chlorides (4.7 milliliters 17 milligrams) according to a method similar to that of Example 1710 (") step_up to tert-butyl 4(4-chlorophenyl)-5-cyano- 2,6-dineopentyl-1,4- can 0.0 ( dihydropyridine-3-caroxylate yield (Ye) as yellow oil from the crude product produced in the previous step (11,7) 1 g) and the resulting crude product In the previous step (VF) (YF (Yo g) according to the method similar to the example method (Y =) where these two types of crude products are dissolved in methanol (+£ mL) and the mixture is heated with (sale) steam condensation for COG 1½ hours.The reaction mixture was concentrated under reduced pressure and the residue was purified by chromatography

YY. tert-butyl 4-(4-chlorophenyl)-5-cyano-2,6-dineopentyl-1,4-vintage silica gel column .dihydropyridine-3-carboxylate "H-NMR (CDCl;) 8:1.00 (9H, s), 1.03 (9H, s), 1.29 (9H, s), 2.24 (4H, 5), 4.58 (1H, brs), 5.37 (1H, brs), 7.20-7.32 (4H, m). tert-butyl 4-(4-chlorophenyl)-5-cyano-2,6-dineopentylnicotinate obtains (¢ © tert-butyl 4-(4-chlorophenyl)-5-cyano-2,6-dineopentyl-) yield 777) from can “, V0) total 4.44 mmol) according to 00 ¥) 1,4-dihydropyridine-3-carboxylate

ATTY Method similar to example H-NMR (CDCl3) 8: 1.04 (9H, s), 1.07 (SH, 5), 1.24 (9H, s), 2.84 (2H, s), 3.00 (2H, s) , 7.31 2H, d,] = 8.67 Hz), 7.45 (2H, d, ] = 8.67 Hz).00 tert-butyl 5-(aminomethyl)-4-(4-chlorophenyl)-2,6- ansi daa (© Yield 47 7) as a pale-yellow solid of can +,Y0) dineopentylnicotinate 0,19 g; 6 ) tert-butyl 4-(4-chlorophenyl)-5-cyano-2,6- dineopentylnicotinate mM) according to the method similar to that of Example 4-7). “H-NMR (CDCl3) 8: 1.02 (9H, s), 1.04 (9H, s), 1.18 (9H, 5), 2.74 (2H, 5), 2.86 (2H, 0 s), 3.64 (2H, s), 7.21 (2H, d, J = 8.48 Hz), 7.40 (2H, d, J = 8.48 Hz). 1 Example 5-(aminomethyl)-4-(4-chlorophenyl)-2,6-dineopentylnicotinic acid dihydrochloride 5-(aminomethyl)-4-(4-chlorophenyl)-2,6-dineopentylnicotinic acid you get tert- butyl 5-g; Yield 19 lbs (as a white solid of +,YY) dihydrochloride Y:

IOV (pa 0 ) (aminomethyl)-4-(4-chlorophenyl)-2,6-dineopentylnicotinate (1-74 mmol) .(1-74 mmol) according to a method similar to that of example “H-NMR (I00-)8 : 0.99 (9H, s), 1.03 (9H, 5), 2.77 (2H, 5), 2.91 (2H, s), 3.83 (2H, d, J = 5.65Hz), 7.35 (2H, with J = 8.48 Hz), 7.54 (2H, d, J = 8.29 Hz), 8.12 (2H, brs).1 as Ye 5-(aminomethyl)-2-methyl-4-(4-methylphenyl)-6-neopentylnicotinic acid hemifumarate

d (sometimes referred to as bis[5-(aminomethyl)-2-methyl-4-(4-methylphenyl)-6-neopentylnicotinic acid] fumarate in this specification) 1 °) to a mixture of 5-(aminomethyl)-2-methyl-4-(4-methylphenyl)-6-

(en lla molecule #1 g; 4 ( neopentylnicotinic acid dihydrochloride aqueous sodium hydroxide mL) and 1 mole of a solution of © + tetrahydrofuran benzyl chloroformate at room temperature dic 5 mL); It is added in drops (01 gram molecule). The resulting mixture is stirred for two hours (le 17,0 ml 1,44 40)

0 and 1 mol of hydrochloric acid (a milliliter) is added to it. The mixture was extracted with (1:0) tetrahydrofuran —ethyl acetate. The organic layer was washed with water and saturated brine; dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The remainder of tetrahydrofuran recrystallized to give (5-([() benzyloxy)carbonyl]amino } methyl)-2- Y) methyl-4-(4-methylphenyl)-6-neopentylnicotinic acid 0.0 g AY %) as crystals

10 colorless powder. H-NMR (DMSO-d) 8: 0.98 (9H, s), 2.33 (3H, s), 2.44 (3H, 5), 2.70 (2H, 5), 3.97 (2H, d, J = 4.1 Hz), 4.98 (2H, 5), 7.15-7.20 (4H, m), 7.27-7.42 (6H, m), 12.96 (1H, brs).") stirred overnight at room temperature under atmosphere Hydrogen is a mixture of -5

(({[(benzyloxy)carbonyl]amino ( methyl)-2-methyl-4-(4-methylphenyl)-6- | 01 palladium-carbon /© « mmol) 11 g; 8 ) neopentylnicotinic acid (milliliter). The reaction mixture was filtered off; 0 (5 mL ethanol) 001( tetrahydrofuran (ax VY)

5- To produce methanol and concentrate the leachate under reduced pressure. The remaining g; 17 ) (aminomethyl)-2-methyl-4-(4-methylphenyl)-6-neopentylnicotinic acid recrystallized as colorless powdered crystals. (ZY YO "H-NMR (DMSO-dg ) 6:0.96 (9H, s), 2.33 (3H, 5), 2.36 (3H, s), 2.76 )211 3.56 (2H, 5), 7.12-7.18 (4H, m).

1 5-(aminomethyl)-2-methyl-4-(4-methylphenyl)-6-neopentylnicotinic acid ha (7 mmol V,Y0 g; YY) fumaric acids mmol) ¥,0 can V1 £) with heating. The resulting aqueous solution was concentrated under pressure (V0) in grams) in 5-(aminomethyl)-2- water and recrystallized with water to give reduced ethanol. The residue was washed with ca +, Y ) methyl-4-(4-methylphenyl)-6-neopentylnicotinic acid hemifumarate © oll as powderless crystals 777 ' H-NMR (DMSO-ds) 8:0.97 (9H, 5) , 2.34 (3H, 5), 2.40 (3H, 5), 2.77 (2H, 5), 3.65 (2H, 5), 6.45 (1H, 5), 7.14-7.21 (4H, m).

AAS tert-butyl 5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)nicotinate Ve tert-butyl 5-cyano-6-isobutyl-2-methyl-4-(4-methylphenyl)- 1,4- We obtain ( \ as a white solid from) 771 mass yield (Y 09) dihydropyridine-3-carboxylate mol) according to the similar method 0,10 pa YOY) tert-butyl 3 -aminocrotonate tert-butyl 5-cyano-6-isobutyl-2-methyl-4- on Juan cll after (Y=) for example method tert- yield £49 (as yellow solid cpa € +,A) (4-methylphenyl)nicotinate 0 butyl 5-cyano-6-isobutyl-2-methyl-4-(4-methylphenyl)-1,4-dihydropyridine-3-mM) according to a method similar to that of Example 111 g; £1) carboxylate . )- vy ' H-NMR (CDCl; ) 6:1.01 (6H, d, J = 6.9 Hz), 1.26 (9H, 5), 2.21-2.32 (1H, m), 2.41 (3H, s), 2.64 ( 3H, 5), 2.93 (2H, d, J = 7.5 Hz), 7.18-7.32 (4H, m). 0 tert-butyl 5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) gives Y tert-butyl 5-cyano-6-yield 47 (as a white solid of can 0+ Y) nicotinate millimol 1, £Y g; ©) 0) isobutyl-2-methyl-4-(4-methylphenyl) nicotinate (4-1 Jad) according to the analogous method For method 1 H-NMR (CDCl; ) 8:0.98 (6H, d, J = 6.6 Hz), 1.19 (9H, 5), 2.13-231 (1H, (2.39 0 (3H, 5), 2.56 (3H, 5), 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).

101

TY Example (([5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenylpyridin-3- yllcarbonyl}oxy)acetic acid dihydrochloride 5-{[(tert-butoxycarbonyl)amino] -methyl}-6-isobutyl- (ml) from 01 (to a solution (1 mmol) 4 01 mg 0 ) 2-methyl-4-(4-methylphenyl) nicotinate acid 0 ml Y,€A mg; 071A) benzyl bromoacetate (N,N-dimethylformamide added in mmol); and stir 0.44 cans YET) potassium carbonate 5 mol) ethyl acetate min at room temperature. The reaction mixture was diluted with 0 magnesium (ml) and washed with saturated saline. The organic layer was dried over 0) anhydrous. The solvent was evaporated under reduced pressure, and the resulting residue was purified by analyzing sulfate 0 2-(benzyloxy)-2-oxoethyl 5-{[(tert-) producing silica, butoxycarbonyl)amino]methyl }-6-isobutyl-2 column chromatography. -methyl-4-(4-methylphenyl) nicotinate mg; Yield 799 (Ol. 144) “H-NMR (CDCl3) 8:0.97 (6H, d, ] = 6.6 Hz), 1.39 (9H, 5), 2.14-2.26 (1H, m), 2.36 (3H, s) ),2.59 (3H, 5), 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 (SH, m). min at 0 °C stirred for ( (benzyloxy)-2-oxoethyl 5-{[(tert-butoxycarbonyl)amino }methyl ( -6-isobutyl-2- mmol); 1, YY stereo 19+) methyl-4-(4-methylphenyl) nicotinate 00 ethanol 5 mmol) +) VE cane VTY) dry) 7) palladium-carbon {[5-{[(tert- After filtering, the solvent evaporates under reduced pressure to produce 01 (butoxycarbonyl)amino]methyl ( -6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3- mg). 0A +) As a crude product ylcarbonyl}oxy) acetic acid "H-NMR (CDCl; ) 8:0.96 (6H, d, J = 6.6 Hz), 1.39 (9H, 5), 2.37 (3H, 5), 2.62 (3H, Ye 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=7.7Hz) , 7.19 2H, d,] = 7.7 Hz).

YY\Y

YY ¢ ( {{5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin- you get (v mg yield 798) (as powder ©1V) 3-yl]carbonyl} oxy)acetic acid dihydrochloride (mg) according to method 0A) (Y) white from the crude product produced in the previous step (FY) similar to the example method "H-NMR (CD; 0D) 6:1.11 (6H, d, J = 6.6 Hz), 2.15-2.27 (IH, m), 2.45 (3H, s), 2.94 © (3H, 5), 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, I = 7.9 Hz).

Te eg 2-amino-2-oxoethyl 5-(aminomethyl )-6-isobutyl-2-methyl-4-(4- methylphenyDnicotinate 0 ({[5-(tert-butoxycarbonyl)amino]-methyl }-6 -isobutyl- (mL) of 0 ( to solution (/mmol) 77 tase © + +) 2-methyl-4-(4-methylphenyl) nicotinic acid 7,64 mMol (aaa YY) 23000 acetamide N,N-dimethylformamide added in mmol) and the mixture was stirred 0.44 mg ¥¥V) potassium carbonate 001 (grams) ethyl acetate min at room temperature The reaction mixture was diluted with 0 sad Vo magnesium sulfate (mL) and washed with saturated saline. The organic layer was dried over anhydrous and the solvent was evaporated under reduced pressure. As for the resulting residue, it was purified by chromatography 2-amino-2-oxoethyl 5- {[(tert-butoxycarbonyl)amino [011], producing a silica gel column with a yield of 799 mg (as oil. OV.) 6-isobutyl-2 -methyl-4-(4-methylphenyl)nicotinate "H-NMR (CDCl; ) 8: 0.98 (6H, d, J = 6.8 Hz), 1.39 (9H, 5), 2.17-2.31 (1H, m), 2.39 00 (3H, s),2.57 (3H, 9(), 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=7.7Hz), 7.25 (2H,d,J=7.9 Hz).2-amino-2-oxoethyl 5-(aminomethyl)-6-isobutyl-2-methyl -4-(4- We obtain (¥ 2-amino-2-oxoethyl 5-) as an oil from (ZA V, yield 70) methylphenyl)nicotinate {[(tert-butoxycarbonyl)amino]methyl}-6 -isobutyl-2-methyl-4-(4- Yo mmol) according to method 071 mg V+)methylphenyl)nicotinate

AFA similar to the example method

Ye "H-NMR (CDCl; ) §: 0.99 (6H, d, J] = 6.6 Hz), 2.17-2.32 (1H, m), 2.40 (3H, s), 2.57 (3H, 5), 2.82 (2H , d, J = 7.2 Hz), 3.70 (2H, 5), 4.39 (2H, 5), 5.20 (2H, brs), 7.19 (2H, d,J=8.1Hz), 7.27 (2H, d, J = 7.9 Hz).

To Ju. 4-ethoxy-4-oxobutyl 5-(aminomethyl )-6-isobutyl-2-methyl-4-(4- © methylphenyl)nicotinate dihydrochloride 5-{[(tert-Gme) Stir for one hour and at room temperature mixture (0 butoxycarbonyl)amino]-methyl } -6-isobutyl-2-methyl-4-(4-methylphenyl)nicotinate 011 mm; YY) ethyl 4-bromobutyrate mmol); 1 g .41( 41

NN-5 mmol) 1 g +, 2) potassium carbonate mol); 0 and water. washed ethyl acetate (ml); The reaction mixture was divided between (10) dimethylformamide magnesium sulfate organic layer respectively; with water and saturated brine and dried over anhydrous. The solvent was evaporated under reduced pressure and the residue was purified by gel column chromatography {4-ethoxy-4-oxobutyl 5-{[( tert-butoxycarbonyl)aminnojmethyl} -6- 48 is produced as powder (% Ao yield 0, g 58 ) isobutyl-2-methyl-4-(4-methylphenyl)nicotinate Vo in white color. H-NMR (CDCl, )8: 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, 5), 2.54 (3H, 9), 2.78 (2H, d, J = 7.3 Hz), 3.95 2H, t, 1 = 6.2 Hz), 4.11 (2H, gq, J = 7.2 Hz), 4.53 (2H, d, J = 5.3 Hz), 4.23 (1H, brs), 7.07 (2H, d,J=80Hz), 7.21 2H ,d,J=8.0 0

Hz). 4-ethoxy-4-oxobutyl S-(aminomethyl)-6-isobutyl-2-methyl-4-(4-) (Y g; yield 10%) (as powder in color 7) methylphenyl) nicotinate dihydrochloride 4- ethoxy-4-oxobutyl 5- {[(tert-butoxycarbonyl)amino]methyl} -6-isobutyl- white from g; 0 mmol) according to 4,1) 2-methyl-4-(4- methylphenyl)nicotinate ~~ Yo (FY) to the method similar to that of the example

1 "H-NMR (DMSO-ds) 6:0.96 (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,] = 7.9 Hz), 7.28 (2H, d, J = 7.9 Hz ), 8.21 (3H, brs).

Ase) 45-1497 Fusion: Akio

Je 4-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3- yl]carbonyl }oxy)butanoic acid dihydrochloride 4-ethoxy-4-oxobutyl 5-{ [(tert-butoxycarbonyl)amino]methyl }-6-isobutyl-2- (1 mmol) dissolved in 0.217 g +,¥) methyl-4-(4-methylphenyl)nicotinate 0 ¢) aqueous sodium hydroxide N from a solution of 1 mL) to which 01 (ethanol) is added. The mixture was stirred for one hour at room temperature. The reaction mixture was poured into -ethyl acetate (mL) and the mixture was extracted with 0.0 + 1 N hydrochloric acid anhydrous. The magnesium sulfate was evaporated The organic layer was washed with saturated brine and dried over ~diisopropyl ether solvent under pressure Reduced and recrystallized the resulting raw crystals of Ve 4-({[5- {{(tert-butoxycarbonyl)amino]methyl }-6-isobutyl-2- to produce ethyl acetate tama, ¥ ¥) methyl-4-(4 -methylphenyl)pyridin-3-yl]carbonyl } oxy)butanoic acid White powder (JAY) H-NMR yield (CDCl, ( 5:1.02 (6H, d, J = 6.4 Hz), 1.39 (9H, 5), 1.55-1.70 (2H, m), 2.12 (2H, 617.1 Hz), 2.15-2.30 (1H, m), 2.39 (3H, 5), 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 = 7.7Hz), 7.26 (2H, d, J = 7.7 Hz). methylphenyl)pyridin-3-yljcarbonyl ( oxy) butanoic acid dihydrochloride 4-({[5- {[(tert-butoxycarbonyl)amino]methy} - yield 19 0” as a white powder of Yo 6-1 sobutyl-2- methyl-4-(4-methylphenyl)pyridin-3 -yl]carbonyl }oxy)butanoic acid .)-7 mmol) according to the method similar to the example method + Ee can 0 )

H-NMR (DMSO-dg) 6:0.97 (6H, d, J = 6.6 Hz), 1.40-1.55 (2H, m), 2.00 (2H, t, J = Hz), -2.15 2.30 (1H, m), 2.36 (3H, s), 2.52 (3H, brs), 2.80-2.95 (2H, m), 3.83 7.4 J in Hz), 7.20 2H, d, J = 7.7 Hz ), 7.29 (2H, 6.2 = ] Ba (2H, d,J = 4.3 Hz), 3.92 (2H, Hz), 8.29 (3H, brs). 7.7 - © Melting Point: 77-771 ?” milliliters) of 5-{[(tert-butoxycarbonyl)amino]-methyl } -6-isobutyl- 1 ) 2-methyl-4-(4-methylphenyl) nicotinate acid 0 g; 0.7 mmol) in N,N-dimethylformamide added +,4Y) 2-(bromomethyl)pyridine hydrobromide g 84 mmol) potassium carbonate y )17.4 mg; 4.84 mmol); The mixture is stirred for 70 minutes. The reaction mixture was diluted with 100 (ethyl acetate) and washed with saturated saline. The organic layer was dried over anhydrous magnesium sulfate 1 and the solvent was evaporated under reduced pressure. As for the resulting residue, it was purified by silica column chromatography to produce pyridin-2-ylmethyl 5-{[(tert-butoxycarbonyl)amino]methyl}-6- can V,Y) isobutyl-2-methyl-4-( 4-methylphenyl)nicotinate yield AA %) as a pale pink solid. (6H, d, J = 6.6 Hz), 1.39 (9H, 5), 2.14-2.25 (1H, m), 2.35 8: 0.97 (J00) “H-NMR (BH, 5), 2.56 (3H, 5), 2.78 (2H, d, J = 7.2 Hz), 4.14 (2H, brs), 4.25 (1H, brs), 5.06 | 0 (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), ( 1H, m), 7.57 (1H, t, J = 7.7 Hz), 8.52 (1H, d, J = 4.7 Hz). 7.17-7.22 ¥ (you get pyridin-2-ylmethyl 5-(aminomethyl)-6 -isobutyl-2-methyl-4-(4- V, YY) methylphenyl)nicotinate trihydrochloride g yield 749) as a pale pink yo solid of pyridin-2-ylmethyl 5-{[(tert-butoxycarbonyl) )amino]methyl}-6- 0 ) isobutyl-2-methyl-4-(4-methylphenyl)nicotinate g VYA milligram) according to the method similar to that of example (1-3).

No (6H, d, J = 6.4 Hz), 2.17-2.28 (1H, m), 2.34 3H, 5), 5:0.97 (y-01480 H-NMR a 3H, s), 2.94 ( 2H, d, J = 6.8 Hz), 3.81 (2H, d, J = 4.9 Hz), 5.20 (2H, 5), 7.19 2.61 (4H, s), 7.23 (1H, brs), 7.62-7.66 ( 1H, m), 8.06 (1H, t, J = 7.9 Hz), 8.39 (3H, brs), (1H, d, J = 4.9 Hz). 8.68 © Example 8? 2-ethoxy-1-methyl-2-oxoethyl 5-(aminomethy!)-2-methyi-4-(4-methylphenyl)-6- neopentylnicotinate dihydrochloride 1 ( we get 2-ethoxy-1 -methyl-2-oxoethyl 5-{[(tert-butoxycarbonyl)amino] methyl} -2-methyl-4-(4-methylphenyl)-6-neopentylnicotinate ( 58 ?, g; yield 550,000 ( As a white powder of 5-{[(tert-butoxycarbonyl)amino] methyl}-2-methyl-4- (4-methylphenyl)-6-neopentylnicotinic acid ) 8,” g; 0.1 mL mol (£Y) ethyl 2-bromopropionate , + g; 0.4 mmol) according to the method similar to that of Example ?7?-1). H-NMR (CDCl; ) 58:1.02 (9H, 5), 1.11 3H, d, J = 7.0 Hz) , 1.25 (3H, t, ] = 7.1 Hz), 0 1, .f (9H, s), 2.38 (3H, 5), 2.62 (3H, d, 1 = 4.9 Hz), 2.83-2.93 (2H, m), 4.17 2H, 1.37 Hz), 4.21 (3H, 5), 4.82 (1H, q, J = 7.1 Hz), 7.04-7.12 (2H, m), 7.19-7.21 (2H, 7.0 = m). -neopentylnicotinate dihydrochloride yield Ao %( 00 | as Osh white powder of 2-ethoxy-1-methyl-2-oxoethyl 5-{[(tert-butoxycarbonyl) oY ) amino]methyl} - 2-methyl-4-(4-methylphenyl)-6-neopentylnicotinate g SYA mmol) according to a method similar to that of the example (Y=YY H-NMR (DMSO-dg) 6:1.02 ( 9H, 5), 1.06 (3H, d, J = 7.0 Hz), 1.16 3H, t,] = 1 Hz), 2.37 (3H, 5), 2.58 (3H, 5), 2.95 (2H, 5) , 3.88 (2H, 5), 4.11 (2H, g, J = 7.0 Hz), J = 7.1 Hz) 7.13-7.16 (1H, m), 7.23-7.32 (3H, m), 8.24 (3H, s) ). Y° .and (1H, 4.77) Example TA

1 (5-methyl-2-0x0-1,3-dioxol-4-ylmethyl 5-(aminomethyl)-2-methyl-4-(4- methylphenyl)-6-neopentylnicotinate dihydrochloride (5-methyl-2-0x0- 1,3-dioxol-4-ylymethyl 5-{[(tert-butoxycarbonyl) on Juan )1 pa 4 ) amino jmethyl}-2-methyl-4-(4-methylphenyl)-6-neopentylnicotinate 5-{[ (tert-butoxycarbonyl)amino] methyl}-2- yield of 77 (as white powder of © mmol VY oa) methyl-4-(4-methylphenyl)-6-neopentylnicotinic acid mmol Y, A g; 7 ( 4-chloromethyl-5-methyl-1,3-dioxol-2-one 5 g) FY g) according to the method similar to that of example "H-NMR (CDCl3) 8: 1.01 (9H, s) 1.36 (9H, 9(), 1.97 (3H, s), 2.39 (3H, 5), 2.53 (3H, s), 2.88 (2H, s), 4.16 (3H, s), 4.74 2H , 5), 7.02 2H, d, J = 7.8 Hz), 7.17 2H, d,J= 0 0 7.8 Hz).(5-methyl-2-0x0-1,3-dioxol-4-yl)methyl 5- {[(tert-) to a solution (7? milliliters) of (¥ butoxycarbonyl)amino]methyl}-2-methyl-4-(4-methylphenyl)-6-neopentylnicotinate § titer is added from a solution of ethyl acetate mL gram molecule) in 1.0 aa + A) milliliters) and the mixture was stirred for a period of hours at A) hydrogen chloride ethyl acetate 08 room temperature. The reaction mixture was concentrated under reduced pressure and the solid was recrystallized as (5-methyl-2-0x0-1,3-dioxol-4-yl)methyl 5- to yield white ethyl acetate —methanol from (aminomethyl)-2. -methyl-4-(4-methylphenyl)-6-neopentylnicotinate dihydrochloride as a white powder. (IVY g; yield 4.7) “H-NMR (B01150-4) 8:1.00 (9H, : (, 1.99 (3H, 5), 2.34 (3H, 5), 2.52 )311, 90,293 0 (2H, s), 3.83 (2H, d, J = 5.5 Hz), 4.93 (2H, 5), 7.13 (2H , d, J = 7.9 Hz), 7.20 2H, d, J - 7.9 Hz), 8.18 (3H, (0 fe) ex. 5-(aminomethyl)-6-isobutyl-2-methyl-4-(4- methylphenyl)nicotinic acid hemifumarate +5 bis[ 5-(aminomethyl)-6-isobutyl-2-methyl-4-(4- sometimes as a) methylphenyl)nicotinic (sal) is indicated in this standard acid] fumarate yyw

VY. 5-{[(tert-) Stir for ? hours at room temperature a mixed solution of (0 butoxycarbonyl)amino]-methyl}-6-isobutyl-2-methyl-4-(4-methylphenyl) nicotinate hydrogen chloride mL mole) and; A standard solution of 100 g; © ¥,V) acid (mL). The precipitated solid was collected by filtration and washed with 5001 (1,4-dioxane in mL Ail). Dissolve the white solid Ye +) diisopropyl ether © min at 0*"C. Leave the mixture Ve mL) and stir for 1 hour The resulting mixture is left isopropanol © +) to cool to room temperature; stir for 1 hour at Room temperature (ble © +) isopropanol The precipitated solid was collected by filtration and washed with 5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)nicotinic acid to produce a colored solid (ZA g; yield £7.0) (1:1) dissolved dihydrochloride propan-2-ol 0 white. ' H-NMR (DMSO-dg) 8:0.97 (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, 5), 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). 6-isobutyl-2-methyl-4-(4-methylphenyl)nicotinic acid ( Vo mmol) is suspended in Ar aa 17 ( (1:0) dihydrochloride propan-2-ol 001) Aqueous sodium hydroxide N from a solution of 1 water (80 milliliters) to which a gram molecule is added) at room temperature The mixture was stirred for an hour (Ale 001 “lille 5- milliliters) to produce 01 (ethanol) one. The precipitated solid was collected by filtration and washed with ¥ 00 g) (aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)nicotinic acid XY. As a white solid. (Zo Yield H-NMR (DMSO-d) 8:0.93 (6H, d, J = 6.8 Hz), 2.14-2.25 (1H, m), 2.34 (3H, 5) ,

2.38 (3H, 5), 2.70 (2H, d, J = 7.2 Hz), 3.49 (2H, 5), 7.14-7.20 (4H, m). 5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)nicotinic acid (v c; £.9 mmol) is suspended in water (£00 mL) and the mixture is heated with reconstitution 104 ) ve milliliters 79,6 can 4 ¥) fumaric acid min. 0 vapor condensation is added and stirred for 1 gram) to the resulting suspension and the mixture is stirred for one hour at room temperature.

YY

5- milliliter (0) The precipitated solid was collected by filtration and the leachate was washed with water (aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenylnicotinic acid hemifumarate) as white crystals. (VT) (a 1.5)

I H-NMR (DMSO-ds ) 8: 0.93 (6H, d, J = 6.6 Hz), 2.26-2.28 (1H, m), 2.35 3H, 5), 2.42 (3H, s), 2.72 (2H, 4) ,1 = 7.2 Hz), 3.55 (2H, 5), 6.49 (1H, s), 7.17 2H, d,J=83 °

Hz), 7.21 (2H, d, J = 8.3 Hz). 4) Example 3-[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3- yl]propionamide dihydrochloride tert- mixture of hydrogen h at a temperature room and under VT atmosphere stirred for 10 butyl {[5-[(1E)-3-amino-3-oxoprop-1-en-1 -yl]-2-isobutyl-6-methyl-4-(4- mmol 771 mg AY, 1 ) methylphenyl)pyridin-3-yl] methyl } carbamate 0) ethanol s mmol) 7 Y mg Y¢) palladium-carbon AREY gram) tert-butyl {[5-3-] After filtering the mixture, the solvent evaporates under reduced pressure to yield 0 mL) amino-3-oxopropyl)-2-isobutyl-6-methyl-4-(4-methylphenyl)pyridin- 3-yl] methyl} | 0 hydrogen chloride 1,4- as a raw product. The raw product is dissolved in; titrate of a carbamate solution at room temperature. The solvent (ad 0 mL) was evaporated and the mixture was stirred (01) dioxane 3-]5- diisopropyl ether was produced under reduced pressure and the resulting solid was washed with (4-(aminomethyl)-6-isobutyl-2-methyl-4-(4) -methylphenyl)pyridin-3 -yl]propionamide As a white powder. (VA summed yield VY,V) dihydrochloride 00 "H-NMR (CD; OD) 6:1.09 (6H, d,] = 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, 5), 7.29 (2H, d, J = 7.9 Hz), 7.50 (2H, d, J = 7.7 Hz).£Y Joe ethyl 3-[5-(aminomethyl)-6 -i sobutyl-2-methyl-4-(4-methylphenyl)pyridin-3- Ye yl]propionate dihydrochloride

YY\V

1 ethyl (2E)-3-[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2- a mixture of (1 mg; 1.00 mmol 0) methyl-4- (4-methylphenyl)pyridin-3-yl]acrylate ethanol mg; 10+ milligrams) and 1 1+) palladium-carbon 701 gram) at room temperature for 1 hour. After hydrogen (mL) is stirred under an atmosphere of Yo) filtration.; The solvent was evaporated under reduced pressure and the resulting residue was purified by decomposing © ethyl 3-[5-{[(tert-) to give an important column chromatographic silica butoxycarbonyl(amino]methyl} -6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3- coagulant; Yield 774) as a white powder.‎ £A+) yl]propionate

H-NMR (J00) 8: 0.96 (6H, d, J = 6.6 Hz), 1.18 (3H, t, J = 7.2 Hz), 1.38 (9H, 8), 2.11-2.30 (3H, m), 2.40 (3H, 5), 2.57 (3H, 8), 2.62-2.68 (2H, m), 2.72 (2H, d, J = 74

Hz), 3.96-4.07 (4H, m), 4.18 (1H, brs), 6.98 (2H, d, J = 7.91), 7.24 (2H, d,J=179

Hz). ethyl 3-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4- can Jaa (Y (% Ao mg yield OAY) methylphenyl)pyridin-3-yl]propionate dihydrochloride ethyl 3 -[5-{[(tert-butoxycarbonyl)amino]methyl}-6- as a white powder of 5

I probe YY) isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl]propionate .(3-7 mmol) according to the method similar to that of the example

I H-NMR (CD; OD) 8: 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, 5), 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 = 79 Hz). 0

EY Joa 3-[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3-yl]propionic acid dihydrochloride ethyl 3-[5-{[(tert-mL) mNG 0 ( to a solution of pickled_o) 1 butoxycarbonyl)amino]methyl} -6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3- Yo 1 tetrahydrofuran (no £0 mg; 4804) is added mmol) in yllpropionate (mM) 00 « milliliters 5.70 le sodium hydroxide (NM) solution

1*“Live for © hours. The reaction mixture was neutralized with +0 N and the mixture was stirred when the organic layer was washed with ethyl acetate (mL) and extracted with (1,8) anhydrous hydrochloric acid. The solvent was evaporated under pressure with magnesium sulfate saturated brine and dried over 3-]5- to give reduced silica and the resulting residue was purified by gel column chromatography {[(tert-butoxycarbonyl)amino]methyl ( -6-isobutyl-2-methyl-4-(4- ° mg; yield +771 (as powder with color YOO) methylphenyl)pyridin-3-yljpropionic acid yellow.” H-NMR (CD; OD) 6:1.04 (6H, d, J = 6.6 Hz), 2.05-2.17 (1H, m), 2.26-2.36 (2H, m), 2.44 (3H, 5), 2.75-2.87 (SH, m), 2.97 (2H, d, J = 7.5 Hz), 4.05 (2H, 5), 7.17 (2H , d,]=8.1Hz),7.40 2H,d,J=7.7Hz).00 3-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3- Yield (Y as a white powder from 0 mg AV yield 7 ) yl]propionic acid dihydrochloride 3-[5- [(tert-butoxycarbonyl)aminolmethyl} -6-isobutyl-2-methyl-4-(4- (— mmol 177 4 vol 0 ) methylphenyl)pyridin-3-yl]Jpropionic acid according to the method similar to that of Example 7-?).

I H-NMR (CD; OD) 8: 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, 5), 3.05 (2H, d, J = 7.5 Hz), 4.05 (2H, 5), 7.26 (2H, d, J = 7.9 Hz), 7.51 (2H, d , 1 = 8.1 Hz). £8 Jha 2-[5-(aminomethyl)-6-isobutyl-4-( 4-methylphenyl)-2-propylpyridin-3-yljacetamide 0 tert-butyl {[5-(hydroxymethyl)-2-isobutyl-4-( 4-methylphenyl)-6- we obtain (1 c yield +71 (as a pink powder 0, +) propylpyridin-3-yljmethyl} carbamate methyl S- {[(tert-butoxycarbonyl)amino methyl } -6- isobutyl-4-(4- from coals mmol) according to 5.00 g; Y,© +) methylphenyl)-2-propylnicotinate (Y-o similar to example 45 yall YO {.NMR) (CDCl; ) 5:0.96 (6H, with J = 6.6 Hz), 1.02 (3H, d, J = 7.4 Hz), 1.38 (9H, 5), 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, 0.17 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). tert-butyl {[5-(cyanomethyl)-2-isobutyl-4-(4-methylpheny1)-6- we obtain tert-butyl as oil from (% TV g; yield + AY ) propylpyridin-3 -ylJmethyl} carbamate {[5-(hydroxymethyl)-2-isobutyl-4-(4-methylphenyl)-6-propylpyridin-3-°mM) according to similar method TAY C 0 Y +) yllmethyl } carbamate (Y—o for the example method

H-NMR (CDCl3) 8: 0.97 (6H, d, J = 6.6 Hz), 1.05 3H, t, I = 4 Hz), 1.38 (9H, s), 1.78-1.90 (2H, m), 2.18-2.27 (1H, m), 2.43 (3H, 5), 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), | 0 7.30 (2H, d, J = 7.7 Hz), tert-butyl {[5-(2-amino-2-oxoethyl)-2-isobutyl-4-(4-methylphenyl)-6- yielding 0 mg ; Yield of 40 # (as white powder A "6 ) propylpyridin-3-ylJmethyl} carbamate tert-butyl {[5-(cyanomethyl)-2-isobutyl-4-(4-methylphenyl)-6-propylpyridin-3- from milligrams) according to the similar method VAM cum vy AY) yllmethyl }carbamate 0 (V1 for the example method

H-NMR (CD; OD) 6: 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, 5 ), 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). 2-[5-(aminomethyl)-6-isobutyl-4-(4-methylphenyl)-2-propylpyridin-3- produces ( 1 tert-butyl {[5-(2-amino-2-oxoethyl)- as oil of 1 0 0 mg; yield (YY) yllacetamide (0 mg) 2-isobutyl-4-(4-methylphenyl)-6-propylpyridin-3-yljmethyl} carbamate (FA mmol) according to the analogous method For example method 4

H-NMR (CD; OD) 8: 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, 5), 2.71-2.76 (2H, m), 2.79 2H, d,J=74 Y°

Hz), 3.33 (2H, 5), 3.53 2H, 5), 7.11 (2H, 01 7.9 Hz), 7.30 (2H, d, J = 7.9 Hz). fo like

05 tert-butyl 5-(aminomethyl)-2,6-diisobutyl-4-( 4-methylphenyl)nicotinate g) from V+ as crude product tert-butyl 3.amino-5-methylhex-2-enoate on Juans (1 112) isovaleryl chloride s mmol) 001 g; V¢,81) Meldrum acid (V-Yo mM) according to method similar to that of example 101 mM tert-butyl 5-cyano-2,6-diisobutyl-4-(4-methylphenyl)-1 A on aa (¥ ° 5-methyl-3- as an oil from AVE) with a yield of 1,11 (dihydropyridine-3) -carboxylate g; 50 mL £,A) p-tolualdehyde mM); 56 an ©) oxohexanenitrile aforementioned according to method (1 mol); and the crude product (2.87 g) produced in 1-7 (similar to the example method) tert-butyl 5-cyano-2,6-diisobutyl-4-(4-methylphenyl)nicotinate) we get tert-0 butyl 5-cyano-2,6-diisobutyl-4-(4-methylphenyl)- from 0 AY g; Yield 1) mmol) according to 10g; 14) 1,4-dihydropyridine-3-carboxylate (method similar to example method ?2-7?). 111-1111 (F0020) 5 :0.95 (6H, d, J = 6.6 Hz), 1.00 (6H, d, J = 6.6 Hz), 1.23 (9H, 5), 2.19233 (1H, m), 2.41 (3H, 5), 2.76 (2H, d, J = 7.5 Hz), 2.94 2H, 4.1 = 72 Hz), 0 7.20-7.35 (4H, m). tert-butyl ~~ 5-(aminomethyl)-2,6-diisobutyl-4-(4- on Ja aS (¢ tert-butyl 5-cyano-2,6- as ZAT oil) caa yield Y,A0 ) methylphenyl)nicotinate mM) according to A g; 58 ( diisobutyl-4-(4-methylphenyl)nicotinate 4-1). Method similar to that of Example 0

H-NMR (J00) 8: 0.93 (6H, d, J = 6.6 Hz), 0.97 (6H, d, 1 = 6.6 Hz), 1.17 (9H, 3), 1.38 (2H, brs), -2.16 2.30 (2H, m), 2.39 (3H, f) 2.67 (2H, d, J = 7.5 Hz), 2.79 (2H, d,

J = 7.2 Hz), 3.62 (2H, 5), 7.13 (2H, d, J = 8.1 Hz), 7.21 (2H, d, J = 8.1 Hz). £1 Example 5-(aminomethyl)-2,6-diisobutyl-4-(4-methylphenyl )nicotinic acid dihydrochloride ~~ Y° 5-(aminomethyl)-2,6-diisobutyl-4-(4-methylphenyl)nicotinic acid we obtain tert-butyl 5- with a yield of 797) as a white powder from (cpa, 79) dihydrochloride

(aminomethyl)-2,6-diisobutyl-4-(4-methylphenyl)nicotinate ) 41 g 1 mmol) according to the method similar to that of Example 4 (H-NMR 1-7). DMSO-d ) 5:0.90 (6H, d, J = 6.6 Hz), 0.96 (6H, d,J = 6.6 Hz), 2.16-2.29 (2H, m), 2.37 (3H, 5), 2.68 ( 2H, d, J =7.2 Hz), 2.88 (2H, d, J = 7.2 Hz), 3.79 (2H, 4, J=5.1Hz), 7.22 (2H,d,J=8.1 Hz), 7.29 ( 2H, d, J = 8.1 Hz), 8.12 (3H, brs).° Ex. 1 sobutyl-6-methyl-4- 4-methylphenyl)-5-[(4-methylphenyl)sulfonyl]pyridin-3- 2-1 { yl}methyl)amine p-toluenesulfonate ) ( to a suspension of pa 1 ) sodium p-toluenesulfinate 04.0 mmol) in ethanol (0 ml) add bromoacetone dropwise ) 1.47g; anhydrous magnesium sulfate.The solvent is evaporated under reduced pressure.an residue by silica gel column chromatography to give -4)]-1 can A)methylphenyl)sulfonyljacetone 0 yielding Yo 0 as a colorless oil. H-NMR (CDCl; ) 5: 2.41 (3H, 5), 2.46 (3H, 5), 4.14 (2H, 5), 7.37 (2H, d, J = 8.2 Hz), 7.77 (2H, d , J = 8.2 Hz).(Y A mixture of 1-[(4-methylphenyl)-sulfonyljacetone ) is heated ¥ g; 5.4 mmol); p-tolualdehyde ) 4 g VE mmol) piperidine (4% +,+ Yee 6.94 mmol); acetic acid (3+ milliliters); 0.9 mmol (Yoo) toluene s milliliters) with re-vapor condensation using a Dean-Stark trap for ?* hours. Leave the reaction mixture to cool to room temperature; Washed with saturated brine and dried on anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 4-(4-methylphenyl)-3-[(4-methylphenyl)sulfonylbut-3-en-2-one Ye as crude product (5, g). ?) a mixture of 7,04 (5-methyl-3-oxohexanenitrile g 001 mmol) is heated; acetic acid )7 g; 01 milligrams); YA,0) ammonium acetate g

t (0 mmol) 7001 (toluene s mL) with vapor re-condensation using a Dean-Stark trap for VV 1 hour. The reaction mixture was left to cool to a temperature cd zl), washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by column chromatography © silica wrecker to give 3-amino-S-methylhex-2-enenitrile as mixture AY (g). The mixture (59 g) and the crude product (VV) g) obtained in step (Y mentioned Wl) were dissolved in ethanol (04 milliliters) and the mixture was heated with steam re-condensation for a period of VY hour. The reaction mixture is concentrated under reduced pressure; The resulting residue was purified by column chromatography with a silica base of 2-isobutyl-6-methyl-4-(4-methylphenyl)-5-[(4- 0 |) with a cohesion of 3-butyrate. -0, V,Y) methylphenyl)sulfonyl]-1 g yield of 5) as white powder. LEXY (M+) 5 a a3 (¢ on 2-isobutyl-6-methyl-4-(4) -methylphenyl)-5-[(4- 0 VV) methylphenyl)sulfonyl]nicotinonitrile colum(AA) yield as white powder 4-sen 1,4 2-isobutyl-6-methyl-4-(4-) methylphenyl)-5-[(4-methylphenyl)sulfonyl] 1 ¥) dihydropyridine-3-carbonitrile g; VY mmol) according to a method similar to that of the example AY-YY H-NMR (CDCl3) ) 8:0.99 (6H, d, J = 6.6 Hz), 2.20-2.35 (1H, m), 2.38 (3H, 5), 2.39 (3H, s), 2.91 (2H, d, ] = 7.2 Hz ), 3.07 3H, 5), 6.86 (2H, d, J = 8.1 Hz), 7.08 (4H, d, J QH,d,J=81Hz). XY: 7.23 ,8.1112 - AAR point FYI YA: lead! pyridin-3-yl }methyl)amine ( 4 gm yield AY %) as Opless oil of 2-isobutyl-6-methyl-4-(4-methylphenyl)-5-[(4- methylphenyl)sulfonyl]nicotinotrile 8 )4 1 g; 0.6 mmol) according to the method similar to that of Example (6)

YYA

I H-NMR (CDCl3 ) 8: 0.96 (6H, with J = 6.6 Hz), 1.41 (2H, brs), 2.20-2.35 (1H, m), 2.38 (6H, 5), 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). ({2-isobutyl-6-methyl-4-(4-methylphenyl)-5-[(4- ethylphenyl) dissolved from) 1 g; 1.0 mmol +E ) methylphenyl)sulfonyl]pyridin-3 -yljmethyl)amine ~~ © p-toluenesulfonic acid (ml) add dropwise a solution of (©) ethanol (gram) in milliliters) at p-ethanol (©) milligram) in 0.9 pa 4 ( monohydrate Cool and dry ethanol, room temperature. Precipitated crystals were collected by filtration; washed with ({2-isobutyl-6-methyl-4-(4-methylphenyl)-5-[(4- — tard) g; +,0 Y) methylphenyl)sulfonyl)pyridin-3-yl}methyl)amine p-toluenesulfonate Ye (yield 777) as a white powder.

I H-NMR (F-01150) 8:0.94 (6H, d, J = 6.6 Hz), 2.15-2.30 (1H, m), 2.29 (3H, s), 2.37 (6H, s), 2.78 ( 2H, 4, J = 7.0 Hz), 2.84 (3H, s), 3.57 (2H, s), 6.87 (2H, d,J=79

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). 1°

A ARTYO-YYE Melting point:

EA eg tert-butyl 5-(aminomethyl)-2-benzyl-6-isobutyl-4-(4-methylphenylnicotinate g) from V1) as crude product tert-butyl 3-amino-4-phenylbut- 2-enoat We get (1 1 £,0) phenylacetyl chlorides mM) 001 cpa 1 ) Meldrum acid 0 00 (V-Yo mM) according to the method similar to that of the example 011 mL; tert-butyl 2-benzyl-5-cyano-6-isobutyl-4-(4-methylphenyl)-1,4- ?) we get 5-methyl-3- as oil from (* V4 g Yield of 1,4 (dihydropyridine-3-carboxylate mL 500 cpa £,A) p-tolualdehyde g; 560 mmol) oxohexanenitrile (©) mentioned above according to (1 g) produced in step ‎ V7) mol.); And the raw product TO (YY) the method similar to the example method

YYw

13 tert-butyl 2-benzyl-5-cyano-6-isobutyl-4-(4-methylphenyl)nicotinate We get 0 tert-butyl 2-benzyl-5-cyano-6-isobutyl-4-(4- g Yield of 771 (of 7) mmol 10 g; £,£Y) methylphenyl)-1,4-dihydropyridine-3-carboxylate (FY in grams) according to method similar to that of the example

I H-NMR (CDCl; ) 8:0.98 (6H, d, J = 6.6 Hz), 1.10 (9H, s), 2.19-2.35 (1H, m), 2.40© (3H, 5), 2.94 (2H, d,] = 7.2 Hz), 4.28 (2H, 5), 7. 16-7.32 (9H, m). tert-butyl 5-(aminomethyl)-2-benzyl-6-isobutyl-4-(4- nh_pg) ( ¢ tert-butyl 2-benzyl-5-g; yield 00% (as oil of 20) methylphenyl nicotinate (mmol) 10 g; £.6+) cyano-6-isobutyl-4-(4-methylphenyl)nicotinate (£7) Ja yl Glad dll J lV

I H-NMR (CDCl ) 8: 0.95 (6H, d, J = 6.6 Hz), 1.05 (9H, 5), 1 26 (2H, brs), 2.21-2.30 (1H, m), 2.38 3H, 5) , 2.79 (2H, 4, I = 7.5 Hz), 3.62 (2H, 5), 4.20 (2H, 5), 7.11-7.31 (9H, m). £3 Example 5-(aminomethyl)-2-benzyl-6-isobutyl-4-( 4-methylphenyl)nicotinic acid 0 dihydrochloride 5-(aminomethyl)-2-benzyl-6-isobutyl-4-(4- methylphenyl)nicotinic tert-butyl 5- is obtained as a white powder from (AY yield cpa 7 A) acid dihydrochloride 1 mM; ¢ ) (aminomethyl)-2-benzyl-6- isobutyl-4-(4-methylphenylnicotinate .)1-7 4 mol) according to the method similar to that of Example 0

H-NMR (DMSO-dg) 8: 0.93 (6H, d, J = 6.3 Hz), 2.16-2.29 (1H, m), 2.37 (3H, 9), 2.82 (2H, d, J = 6.6 Hz), 3.77 (2H, d, ] = 4.8 Hz), 4.13 (2H, s), 7.15-7.31 (9H, m), 8.16 (3H, brs). or Jo 5-(aminomethyl)-6-isobutyl-4-(4-methylphenyl )-2-phenylnicotinic acid 8 dihydrochloride

YY\WV

YY. ethyl 3-0x0- from (an 9,0) as a crude product ethyl 3-amino-3-phenylacrylate obtains (1) ammonium acetate s) of (1,4 g) 3-phenylpropanoate

IVY mmol) according to the method similar to that of the example YOu g; VAY ( ) ethyl 5-cyano-6-isobutyl-4-(4-methylphenyl)-2-phenyl-1,4- on Jia a3 (Y© 5-methyl-3-g; yield £09 (as oil of 7 ( dihydropyridine-3-carboxylate; g; 56 mM A) p-tolualdehyde g; 56 mmol)©) oxohexanenitrile The aforementioned according to (1 mol) and the crude product (4.0 g) produced in step (Y=) the method similar to the example method ethyl 5-cyano-6-isobutyl-4-(4-methylphenyl) -2-phenylnicotinate 0 yo ethyl 5-cyano-6-isobutyl-4-(4-methylphenyl)-2- is obtained as oil from (FAS g; yield £1 mmol) according to 11 g;

H-NMR (CDCl;) 8: 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, 127.2 Hz) , 3.91 (2H, q, J = 7.2 Hz), 7.26733 (4H, m), 7.43 )° 7.48 (3H, m), 7.624-7.69 (2H, m). ethyl 5-(aminomethyl)-6-isobutyl-4-(4-methylphenyl)-2- ;) we obtain ethyl 5-cyano-6-isobutyl-4-(4- yield +42) as oil from ( pa 1 ¥) phenylnicotinate mole) according to lle 01 px 6 ( methylphenyl)-2-phenylnicotinate 4-1 . Method similar to that of the example Ye

H-NMR (CDCl;) 6: 0.80 (3H,t,J] = 7.2 Hz), 1 .03 (6H, d, J = 6.6 Hz), 1.36 (ZH, bs), 2.29-2.42 (4H, m ), 2.90 2H, d,J = 7.2 Hz), 3.70 (2H, 5), 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). ethyl 5-(aminomethyl)-6-isobutyl-4-(4-methylphenyl)-2- A mixture of ( 6 Yo 01 ( 1 N hydrochloric acid « g; ? mmol) oA ( phenylnicotinate) is heated milliliter) with re-condensation of the vapor for a period of 2 days. The reaction mixture is concentrated in 0 acetic acid s (milliliter)

11 sodium hydroxide mL) and a solution of 10) tetrahydrofuran under reduced pressure. 61:4 N (1?mL) was added to the residue. 1 aqueous mmol (1 aqueous mmol) was added to the resulting mixture and the resulting mixture was stirred at Vod 00 milliliter (00) dicarbonate 1 standard hydrochloric acid at room temperature for two hours. The reaction mixture is acidified by ar. The extracted material was washed with saturated brine, dried acetate, and extracted with anhydrous ©. The solvent was evaporated under reduced pressure and the residue, magnesium sulfate, was purified on 5-{[(tert-) to give silica by column chromatography important butoxycarbonyl)amino]methyl} -6-isobutyl-4-(4- methylphenyl)-2-phenylnicotinic 5-(aminomethyl)- (Yams mM) is obtained as oil. 1.8 g; 0 YA) acid g; 1,0 g) 6-isobutyl-4 -(4-methylphenyl)-2-phenylnicotinic acid dihydrochloride 0 as a white powder of oil according to the method similar to the example method (IA yield). (v- ¥

H-NMR (DMSO-dg) 8: 1.01 (6H, with J = 6.6 Hz), 2.24-2.35 (1H, m), 2.38 (3H, 9), 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). ° 2) Example methyl 5-(aminomethyl)-2-ethyl-6-isobutyl-4-( 4-methylphenyl)nicotinate methyl 3- as crude product (£71g) of methyl 3-aminopent-2- enoate We get (1 g 14,YY) ammonium acetate s mol) Gor pa t,0n ) oxopentanoate (1-117 mmol) according to the method similar to that of the example YOu “0 methyl 5-cyano-2-ethyl-6-isobutyl-4-(4-methylphenyl)-1,4- ?) 5-methyl-3- is obtained as oil from 0 EA g; Yield 7 ( dihydropyridine-3-carboxylate mL 500 cas €,A) p-tolualdehyde g; 46 milligrams); 2-ethyl-6-isobutyl-4-(4-methylphenyl)-nicotinate ?) we get methyl 5-cyano-2-ethyl-6-isobutyl-4-(4-methylphenyl)- from (% At Yield aa ¥, 8))

milligrams) according to VY pa 1) 1,4-dihydropyridine-3-carboxylate the method similar to that of Example 77-?).

I H-NMR (J00) 58:1.01 (6H, d,J = 6.6 Hz), 1.32 GH, t,J = 7.5 Hz), 2.24-2.36 (1H, m), 2.41 (3H, 5), 2.85 (2H, q, J=7.5Hz), 2.96 2H, d,J = 6.9 Hz), 3.59 3H, Ss), 7.24-7.30 (4H, m). ° methyl 5-(aminomethyl)-2-ethyl-6-isobutyl-4-(4-methylphenyl) ¢ methyl 5-cyano-2-ethyl- is obtained as a white powder from (VY CYF 4) ) nicotinate milligrams) according to 10 g;

I H-NMR (CDCl3) 8: 0.98 (6H, d, J = 6.6 Hz), 1.29 (3H, 32 7.5 Hz), 218-231 00 (1H, m), 2.34 (3H, 5), 2.77 (2H , g, J = 7.5 Hz), 2.81 (2H, d,J=7.2 Hz), 3.49 (3H, s), 3.65 (2H, 5), 7.11 (2H, d, J = 8.0 Hz), 7.21 2H, d, ] = 8.0 Hz). ov Example 5-(aminomethyl)-2-ethyl-6-isobutyl-4-(4-methylphenyl Jnicotinic acid dihydrochloride '© 5-(aminomethyl)-2-ethyl-6-isobutyl-4-(4-methylphenylnicotinic We obtain 5-methyl as a white powder from (LAY yield cpa 1.7 1) (1 mM acid dihydrochloride 1 g; 0 Yt) (aminomethyl)-2-ethyl-6-isobutyl-4 -(4-methylphenyl) nicotinate (0-0 + mol) according to the method similar to that of the example

H-NMR (J01480-4 5:0.97 (6H, d, J = 6.6 Hz), 1.26 3H, t, J =7.5 Hz), 2.17-2.26 Ye (1H, m), 2.37 (3H, s) , 2.89 (2H, g, J = 7.3 Hz), 3.00 2H, d, J = 6.9 Hz), 3.81 (2H, d, 1 6.0112, 7.25 (2H, d, J = 8.2 Hz), 7.30 (2H, d , J = 8.2 Hz), 8.38 (3H, brs).ov Example 5-(aminomethyl)-2-methyl-4-(4-methylphenyl )-6-neopentylnicotinic acid maleate 5-(aminomethyl)-2- methyl-4-(4-methylphenyl)-6- to a mixed solution of Yo (mL) Y) acetonitrile mmol); 1.75 mg 184 (neopentylnictinic acid mmol) and stirred 1.7500 mg; 1 ( maleic acid mL) add Y)eles

mixture at room temperature. After the dissolution of “maleic acid”, A) acetonitrile (mL) was added and the mixture was stirred at room temperature for one hour. The resulting solution is concentrated under reduced pressure; 0 (acetonitrile mL) is added to the residue. The mixture was stirred at room temperature for one hour. The precipitated crystals were collected by filtration to give 5-(aminomethyl)-2-methyl-4-(4-methylphenyl)-6-neopentylnicotinic acid maleate ° ) 41 mg “+ 0 as colorless powdery crystals. H-NMR (DMSO-d) 8: 1.00 (9H, s), 2.36 (3H, s), 2.49 (3H, 5), 2.81 (2H, s), 3.84 (2H, 5), 6.01 ( 2H, 8), 7.17-7.21 (2H, m), 7.27-7.31 (2H, m). Example ot 5-(aminomethyl)-2-methyl-4-( 4-methylphenyl)-6-neopentylnicotinic acid tartarate 0 to a mixed solution of 5-(aminomethyl)-2-methyl-4-(4-methylphenyl)-6- neopentylnicotinic acid ) 4 mg A mol); Y) acetonitrile (mL) and water (Y) mL) add 1.7560 pe ¢+,1) tartaric acid mmol); The mixture was stirred at room temperature. After dissolution of the tartaric acid, A) acetonitrile (ml) was added; the mixture was stirred at room temperature for one hour. The solution was concentrated zal Cand under reduced pressure and 0 (acetonitrile ml) was added to the residue. The mixture was stirred at room temperature for one hour The precipitated crystals were collected by filtration to give 5-(aminomethyl)-2-methyl-4-(4-methylphenyl)-6-neopentylnicotinic acid tartarate (74 mg « YY %) as crystals Colorless powder. 5), 3.96 (2H, 8), 7.15-7.19 (2H, m), 7.21-7.25 (2H, m).oo Ja tert-butyl 5-(aminomethyl)-2-isobutyl-4-( 4-methylphenyl)-6-neopentylnicotinate (1) gets tert-butyl 3-amino-5-methylhex-2-enoate as crude product (V+g) from £1,£1) Meldrum acid ~ ~ ¥° g; isobutyl-4-(4-methylphenyl)-6-neopentyl-1 ,4- we obtain (° 5,5-dimethyl-3- as oil from 0 YY yield ea 5,?) dihydropyridine- 3-carboxylate 0 g; £,AY) p-tolualdehyde (No. 8 g; 50 mmol); isobutyl-4-(4-methylphenyl)-6- on Jaa (¥ tert-butyl 5-cyano-2-isobutyl-4-(4- yield 49 7) from 17 aa (neopentylnicotinate 10 mM) g; 7 ( methylphenyl)-6-neopentyl-1 ,4-dihydropyridine-3-carboxylate (©2-77 mol) according to the method similar to that of the example

H-NMR (CDCl; ) 8: 0.95 (6H, d, J = 6.6 Hz), 1.06 (9H, 5), 1.24 (9H, 5), 222-235 00 (1H, m), 2.40 (3H, 5) ), 2.76 (2H, d, J = 7.2 Hz), 3.00 (2H, 5), 7.19-7.35 (4H, m). tert-butyl 5-(aminomethyl)-2-isobutyl-4-(4-methylphenyl)-6- we obtain ( ¢ tert-butyl 5- with a yield of 84 *) as white crystals of can 04 ( mM neopentylnicotinate A g; ¥,Y0) cyano-2-isobutyl-4-(4-methylphenyl)-6-neopentylnicotinate (4-1 mol) according to the method similar to that of Example 1°

H-NMR (CDCl; ) 8: 0.93 (6H, d, J = 6.6 Hz), 1.02 (9H, 5), 1.17 9H, 5), 1.24 (2H, brs), 2.22-2.31 (1H, m), 2.39 (3H, 5), 2.66 (2H, d, J = 7.5 Hz), 2.87 (2H, 5), 3.68 (2H, s), 7.13 (2H, d, ] = 8.0 Hz), 7.21 (2H, d , J = 8.0 Hz). 502 Example tert-butyl 5-(aminomethyl)-2-benzyl-4-(4-methylphenyl )-6-neopentylnicotinate | 0 g) VT) as a crude product from tert-butyl 3-amino-4-phenylbut-2-enoat we get (1 {£,0) phenylacetyl chlorides mmol) 001 g; Y¢,¢)) Meldrum acid (1-75 mmol) .) according to the method similar to that of example 100 mL tert-butyl 2-benzyl-5-cyano-4-(4-methylphenyl)- 6-neopentyl-1 ,4- (¥ 5,5-dimethyl-3- as oil is obtained from (ZA g; yield VY,0) dihydropyridine-3-carboxylate yo 60 g £,AY ) p-tolualdehyde (mM); 50 p20, oY)oxohexanenitrile

in milligram molecule) and the crude product (10.7 g) produced in (1) aforementioned according to the method similar to that of example (7-1) 0. We connect on tert-butyl 2-benzyl-5-cyano- 4-(4-methylphenyl)-6- 1,A) neopentylnicotinate g; Yield ++ (%) of tert-butyl 2-benzyl-5-cyano-4-(4-A) methylphenyl)-6-neopentyl-1,4-dihydropyridine-3-carboxylate ~~ © CAM 01 mmol) according to the method similar to the example method (FT ¢) (we obtain tert-butyl 5-(aminomethyl)-2-benzyl-4-(4-methylphenyl)-6-A) neopentylnicotinate 4 g yield of Vo0 as white crystals of -2-tert-butyl (YA) benzyl-5-cyano-4-(4-methylphenyl)-6-neopentylnicotinate g; 1 mmol 0 gram) according to the method similar to that of the example.) 4-1 (9H, s), 1.07 (9H, :(, 2.39 (3H, 5), 2.85 (2H, s) , 3.67 (2H, 8:0.96 (J020) H-NMR s), 4.18 (2H, s), 7.11-7.32 (9H, m). Example ov tert-butyl 5-(aminomethyl) )-2-ethyl-4-(4-methylphenyl )-6-neopentylnicotinate 1 0 We obtain tert-butyl 3-aminopent-2-enoate as a crude product (p>A,©) from Meldrum 1451 ) acid g; 001 milligrams (propionyl chloride s) (4.7 milligrams, read 011 milligrams) according to the method similar to that of Example 17 (Y) we obtain -4, tert-butyl 5-cyano- 2-ethyl-4-(4-methylphenyl)-6-neopentyl-1 «aa 1] dihydropyridine-3-carboxylate yield (AYA) as oil from 5,5-dimethyl-3-oxohexanenitrile ~~ Y+ (Not 5 g te mmol); (§,A)) p-tolualdehyde (g 560 mmol) and the crude product (A) g) produced in 1) aforementioned according to the similar method For the example method (AY) we obtain tert-butyl 5-cyano-2-ethyl-4-(4-methylphenyl)-6-neopentylnicotinate aa Y,0 A (yield 47%) as a color solid Cab yellow of tert-butyl 5-cyano-2-ethyl- Vo (aa 7 ) 4-(4-methylphenyl)-6-neopentyl-1 ,4-dihydropyridine-3-carboxylate ~~ Y° milligrams) according to a method similar to the example method (PTY

H-NMR (CDCl) 5: 1.07 (9H, 5), 1.26 (9H, 5), 1.34 (3H, t, J = 7.5 Hz), 2.41 (3H, 5), 2.89 (2H, q, J = 7.5 Hz), 3.01 (2H, 5), 7.20-7.29 (4H, m). tert-butyl 5-(aminomethyl)-2-ethyl-4-(4-methylphenyl)-6- (¢ tert-butyl 5-cyano-2-ethyl-4-g; yield £70) as oil of 15 ( mmol neopentylnicotinate) according to 1 g; “AY (4-methylphenyl)-6-neopentylnicotinate > 4-1).

H-NMR (CDCl) 8: 1.03 (9H, s), 1.19 (9H, s), 1.28 (2H, brs), 1.32 BH, A 1 5

Hz), 2.39 (3H, 5), 2.80 2H, 0.1 7.5 Hz), 2.87 (2H, 5), 3.68 (2H, 5), 7.1 3(2H,d,] = 8.1 Hz), 7.21 (2H, d , ] = 8.1 Hz).

OA 0 5-(aminomethyl)-2-ethyl-4-(4-methylphenyl)- 6-neopentylnicotinic acid dihydrochloride 5-(aminomethyl)-2-ethyl-4-(4-methylphenyl)-6-neopentylnicotinic We get tert-butyl 5-c; Yield 2 pounds (as a white powder of 0 yv, mL) acid dihydrochloride 1 g; vy v4) (aminomethyl)-2-ethyl-4-(4-methylphenyl)-6-neopentylnicotinate Vo .) 7 4 mol) according to the method similar to that of the example

H-NMR (DMSO-ds) 8: 1.02 (9H, s), 1.26 (3H, t,J=7.5Hz), 2.37 3H, s), 2.78 (2H, q, J = 7.5 Hz), 2.92 (2H , 5), 3.83 (2H, d, J = 5.4 Hz), 7.21 (2H, 4, J = 8.0 Ha), 7.29 (2H, d, J = 8.0 Hz), 8.13 (3H, brs). 45m Joa Y. tert-butyl 5-(aminomethyl)-4-( 4-methylphenyl)-6-neopentyi-2-propylnicotinate

Meldrum (p > 7 ) as crude product tert-butyl 3-aminohex-2-enoate on Juan (1,011 mL (11,2) butyryl chlorides) 100 g; 1 ) acid (Y-Ye mM) According to the method similar to that of the example tert-butyl 5-cyano-4-(4-methylphenyl)-6-neopentyl-2-propyl-1,4- ?) we get on YO 5,5-dimethyl-3- yield (£1) as oil of aa 01 ( dihydropyridine-3-carboxylate 60 g £,AY) p-tolualdehyde (No. 8 g 50 mmol); oxohexanenitrile

a mmol) and the crude product (VT) g) obtained in (1) aforementioned according to the method similar to that of the example (AY) ¥) we obtain tert-butyl 5-cyano-4-(4-methylphenyl )-6-neopentyl-2- (pa OVE ) propylnicotinate (LOA) yield as oil of tert-butyl 5-cyano-4-(4-A) methylphenyl)-6-neopentyl-2-propyl -1 ,4-dihydropyridine-3-carboxylate ~~ © 4 collage VE mmol) according to a method similar to that of the example (¥-YY H-NMR (CDCl; ) 8:1.00 (3H, 1 = 7.5 Hz), 1.06 (9H, 5), 1.26 (9H, 1 .75-1.88 !(2H, m), 2.41 (3H, s), 2.81-2.86 (2H, m), 3.00 (2H , 5), 7.1 8-7.30 (4H, m). ¢ ( we get tert-butyl 5-(aminomethyl)-4-(4-methylphenyl)-6-neopentyl-2- propylnicotinate 0 ) 7 Total yield of AVE as white crystals of tert-butyl 5-cyano- 4-(4-methylphenyl)-6-neopentyl-2-propylnicotinate (for 4 C 11 mmol) according to the method Similar to the example method (4-1). (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), ( 2H, d, J = 8.1 Hz), 7.21 2H, d, J = 8.1 Hz). 0 7.13 ex 11 5-(aminomethyl)-4-(4-methylphenyl)-6-neopentyl-2-propyini cotinic acid dihydrochloride you get 5-(aminomethyl)-4-(4- methylphenyl)-6-neopentyl-2-propylnicotinic (cpa +, YA) dihydrochloride 00 yield + £9) as a white powder of -5-tert-butyl (aminomethyl)-4-(4-methylphenyl)- 6-neopentyl-2-propylnicotinate ) 651 gp; 1 lle mol) according to the method similar to that of the example ;"-1). H-NMR (DMSO-dg) 8:0.93 (3H, t, J = 7.3 Hz), 1.02 (9H, 5 ), 1.69-1.81 (2H, m), (3H, 5), 2.74-2.79 (2H, m), 2.94 (2H, brs), 3.84 (2H, 0.11 Hz), 7.22 (2H, d , 2.37 J=8.0Hz), 7.29 (2H, d, J] =8.0 Hz), 8.14 (3H, brs).¥° 11 Joe tert-butyl 5-(aminomethyl)-2-isopropyl -4-(4-methylphenyl )-6-neopentylnicotinate YY\V

As a crude product (9.7 g) of tert-butyl 3-amino-4-methylpent-2-enoate we obtain (1 116(isobutyryl chloride) mmol) 001 g; )) Meldrum acid (V-Yo mM) according to a method similar to that of example 110 mL; tert-butyl 5-cyano-2-isopropyl-4-(4-methylphenyl)-6-neopentyl-1 ,4- ?) we obtain 5,5-dimethyl-3- as oil from (7 0 yield aa £,2Y) dihydropyridine-3-carboxylate ~~ © g £,A)) petolualdehyde g; 50 mmol); ©,0V) oxohexanenitrile aforementioned according to the method (1 mmol) and the crude product (9.7 g) produced in (Y=) similar to the example method tert-butyl 5 -cyano-2-isopropyl-4-(4-methylphenyl)-6-neopentyl- we get 0 tert-butyl 5-cyano-2-isopropyl -4-(4- from (for ;, g; Yield of A) nicotinate 0 mL VY £90 g ( methylphenyl)-6-neopentyl-1, A-dihydropyridine-3-carboxylate mol) according to the method similar to that of Example 3-7? tert -butyl 5-(aminomethyl)-2-isopropyl-4-(4-methylphenyl)-6- ;) you get tert-butyl-5-g; Yield (0%) as white crystals of 1) neopentylnicotinate mM A g 2) cyano-2-isopropyl-4-(4-methylphenyl)-6-neopentyl-nicotinate 0 (£7) Jad 3 al dial Zl JY ihe (dom ss

H-NMR (CDCl; ) 5: 1.04 (9H, 5), 1.18 (9H, 5), 1.30 (6H, d, J = 6.9 Hz), 1.32 (2H, brs), 2.39 (3H, 5), 2.85 (2H, 5), 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). 7 Joe Y. 5-(aminomethyl)-2-isopropyl-4-(4-methylphenyl )-6-neopentylnicotinic acid dihydrochloride 5-(aminomethyl)-2-isopropyl-4-(4-methylphenyl)-6- on Jaa as powder in color (%AN g; yield YY) neopentylnicotinic acid dihydrochloride tert-butyl 5-(aminomethyl)-2-isopropyl-4-(4-methylphenyl)-6-white from Yo ms. ) according to the analogous method 1 g; 7 ) neopentylnicotinate) 1-7 4 for the example method

ARI

H-NMR (DMSO-dg) 8: 1.04 (9H, 5), 1.25 (6H, d, J = 6.6 Hz), 2.36 (3H, 5), 2.90 (2H, s), 3.03-3.13 (1H, m ), 3.81 (2H, d,J=5.4Hz), 7.22 (2H, d, J=82 Hz), 7.28 (2H, d, J=8.2 Hz), 8.18 (3H, brs). 17 Example 5-(aminomethyl)-2-isobutyl-4-( 4-methylphenyl)-6-neopentylnicotinic acid © dihydrochloride 5-(aminomethyl)-2-isobutyl-4-(4-methylphenyl)-6- on Ja a3 as powder in color (AY g; yield +, £1) neopentylnicotinic acid dihydrochloride tert-butyl 5-(aminomethyl)-2-isobutyl-4-(4-methylphenyl)-6- white from mmol) according to the analogous method 1 g; 7 (neopentylnicotinate 0). 1-4 for the example method

H-NMR (DMSO-ds ) 5: 0.89 (6H, d, J = 6.6 Hz), 1.02 (9H, s), 2.18-2.31 (1H, m), 2.37 3H, 5), 2.66 (2H, d, J = 7.2 Hz), 2.91 (2H, 5), 3.84 (2H, d,J =5.1 Hz), 7.21 (2H, 4, ] = 8.1 Hz), 7.29 (2H, d, J = 8.1 Hz), 8.08 (3H, brs).

Te example Vo 5-(aminomethyl)-2-benzyl-4-(4-methylphenyl )-6-neopentylnicotinic acid dihydrochloride 5-(aminomethyl)-2-benzyl-4-(4-methylphenyl)-6-neopentylnicotinic We get tert-butyl 5-g; Yield of 7/91 as a white powder of 5 9 acid dihydrochloride 1 g +, 8 ) (aminomethyl)-2-benzyl-4-(4-methylphenyl)-6-neopentylnicotinate Ye (VY 4 mmol) according To the method similar to the example method ' H-NMR (DMSO-d) 8:0.95 (9H, 5), 2.37 (3H, 5), 2.89 (2H, 5), 3.82 (2H,d,J=54

Hz), 4.14 (2H, s), 7.18-7.31 (9H, m), 8.17 (3H, brs). 0 Jha methyl 5-(aminomethyl)-6-butyl-2-methyl-4-( 4-methylphenyDnicotinate ~~ Y° dihydrochloride methyl 6-butyl-5-cyano-2-methyl-4-(4-methylphenyl)-1 A de nh_l ( \ 3- cv 4 17) as crystals of 7) dihydropyridine-3-carboxylate c ; 060 mmol) according to a method similar to that of 4 ( oxoheptanenetrile . (Y -1 Ex. 11-1111117 (CDCl) 8:0.92 )311, 127.3 Hz), | 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, 5), 5.77 (1H, s), 7.07-7.14 (4H, m)

Yo) methyl 6-butyl-5-cyano-2-methyl-4-(4-methylphenyl)nicotinate We get (¥ methyl 6-butyl-5-cyano-2-methyl-4-(4-methylphenyl)- g; yield of 10 (mM crystals) according to the VY method ?g;1,4-dihydropyridine-3-carboxylate (0) ?-1 similar to the example method

H-NMR (CDCl3) 6:0.97 (3H, t,] = 7.3 1 40-1.52 (2H, m), 1.74-1.84(2H, m), 2.41 (3H, 5), 2.62 (3H, 5), 3.04-3.09 (2H, m), 3.60 (3H, 5), 7.23-7.29 (4H, m).methyl 5-(aminomethyl)-6-butyl-2-methyl-4-(4- on Jaa ( v methyl 6-butyl-5-cyano-2- as oil from (XA yield aa VV) methylphenyl)nicotinate Vo mmol) according to 1,4 pn) methyl-4-(4-methylphenyl) Dissolve the oil (¥ g) in nicotinate (101 ml) ethyl acetate in (1-4) method similar to the example method (ml). The mixture was concentrated 10( hydrogen chloride ethyl acetate) and a standard solution of methyl 5-(aminomethyl)-6-butyl-2-methyl-4-(4-) was added under reduced pressure to give as a powder. methylphenyl)nicotinate dihydrochloride ~ ~ 0 "H-NMR (DMSO-d¢) 6:0.95 (3H,t,J =7.3 Hz), 1.38-1.51 (2H, m), 1.65-1.75 (2H, m), 2.37 (3H, 5) , 2.53 (3H, 5), 2.98-3.03 (2H, m), 3.47 (3H, 5), 3.82 (2H, d, 1 = 5.5

Hz), 7.19 (2H, d, J = 8.1 Hz), 7.30 (2H, d, J = 8.1 Hz), 8.38 3H, 5). 11 Example 5-(aminomethyl)-6-butyl-2-methyl-4-(4-methylphenyl )nicotinic acid ~~ ¥° dihydrochloride

VEN methyl 5- {[(tert-butoxycarbonyl)amino]methyl } -6-butyl-2-methyl-4- ( 1 methyl 5- as crystals of 0 A yield (aa VT, ¥) (4-methylphenyl)nicotinate

Sle 57,9 pa ) ¢) (aminomethyl)-6-butyl-2-methyl-4-(4-methylphenyl)nicotinate .(1-7 mol) according to the method similar to that of Example 5- {[(tert) -butoxycarbonyl)amino]methyl} -6-butyl-2-methyl-4-(4-?) We obtain methyl 5-{[(tert-) as crystals from (AVY) g yield 8 ( methylphenyl)nicotinic acid

Y ) butoxycarbonyl)amino]methyl} -6-butyl-2-methyl-4-(4-methylphenyl)nicotinate (YY mmol) according to method similar to example 4,7 aa 5-(aminomethyl)-6 -butyl-2-methyl-4-(4-methylphenyl)nicotinic acid )* 5-{[(tert- yield 787) is obtained as a white powder from aa +,07) dihydrochloride 0 butoxycarbonyl)amino]methyl } -6-butyl-2-methyl-4-(4-methylphenyl)nicotinic acid mmol) according to the method similar to that of Example 7-?).VY g; 0 V)

I H-NMR (DMSO-dg ) 8:0.95 (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,] = 8.1 Hz), 8.40 3H, 5). 0

IV Example methyl 5-(aminomethyl)-2-methyl-4-(4-methylphenyl)- 6-propylnicotinate dihydrochloride methyl 5-cyano-2-methyl-4-(4-methylphenyl)-6-propyl-1 ,4- We obtain 1) 3-oxohexanenitrile with a yield of 779) as oil from can +) dihydropyridine-3-carboxylate Y. (T=) mmol) according to the method similar to that of the example 0001 g; 1)

H-NMR (CDCl) 8: 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, 5 ), 3.58 (3H, 5), 4.56 (1H, s), 5.80 (1H, 5), 7.09 2H, d,J = 8.1 Hz), 7.13 (2H, d, J = 8.1 Hz). methyl 5-cyano-2-methyl-4-(4-methylphenyl)-6-propylnicotinate 7? We get YO methyl 5-cyano-2-methyl-4-(4-methylphenyl)- as crystals from ( oA? g; yield A)

VY EY

milligram) according to VAT incl; 1) 6-propyl-1,4-dihydropyridine-3-carboxylate (©-1) to the method similar to that of the example.

HNMR (CDCl) 5: 1.05 (3H, t, J = 7.4 Hz), 1.79-1.91 (2H, m), 2.41 (3H, 5), 2.62 (3H, 5), 3.02-3.07 (2H, m), 3.60 (3H, 5), 7.23-7.29 (4H, m). methyl 5-(aminomethyl)-2-methyl-4-(4-methylphenyl)-6- 0 methyl 5-cyano-2-methyl-4-(4- as oil from (AV) Yield of 0 ( milligrams propylnicotinate) according to VY can YY ( methylphenyl)-6-propylnicotinate (ml) 10 (ml) ethyl acetate (¥ g) oil is dissolved in 1-4) 0 method similar to that of the example The mixture is concentrated 10( hydrogen chloride ethyl acetate) and a standard solution of methyl 5-(aminomethyl)-2-methyl-4-(4-methylphenyl)-6- is added under reduced pressure to give 0 0 As a powder. Propylnicotinate dihydrochloride

H-NMR (DMSO-d¢ ) 8: 1.02 (3H, t, J = 7.4 Hz), 1.69-1.82 (2H, m), 2.37 (3H, 5), 2.53 (3H, s), 2.96-3.02 ( 2H, m), 3.47 (3H, s), 3.82 (2H, d,J = 5.5 Hz), 1 9(2H,d,] - 8.1 Hz), 7.31 (2H, 4, = 8.1 Hz), 8.38 ( 3H, 5).

IA Example 0 5-(aminomethyl)-2-methyl-4-(4-methylphenyl)-6-propylni cotinic acid dihydrochloride methyl 5- {[(tert-butoxycarbonyl)amino methyl} 2-methyl-4-(4) - on our plate!) 1 methyl 5- as crystals of (* 701 yield cas)Y)methylphenyl)-6-propylnicotinate g; 41.6 mM VY) (aminomethyl)-2-methyl-4-(4-methylphenyl)-6-propylnicotinate A (VY mol) according to a method similar to that of the example

H-NMR (CDCl: ) 8: 1.03 (3H, t, J = 7.4 Hz), 1.39 (9H, 5), 1.72-1.79 (2H, m), 2.38 (3H, s), 2.53 (3H, 5) , 2.84-2.90 (2H, m), 3.49 (3H, s), 4.15 (2H, d, J = 5.1 Hz), 4.25 (1H, 5), 7.05 (2H, d, ] = 8.1 Hz), 7.20 ( 2H, d, J = 8.1 Hz). 5-{[(tert-butoxycarbonyl)amino]methyl } 2-methyl-4-(4- we obtain (Y Yo methyl 5-) as crystals of (LAY aggregate; yield V1) methylphenyl)-6- propylnicotinic acid {[(tert-butoxycarbonyl)amino]methyl} 2-methyl-4-(4-methylphenyl)-6-

1 g; 4.8 milligrams) according to the method similar to that of Y) propylnicotinate. (Y -Y example | H-NMR (DMSO-dg ) 8:0.96 (3H, t, J = 7.4 Hz), 1.35 (9H, 5), 1.64-1.76 (2H, m), 2.33 (3H , s), 2.44 (3H, 5) 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). 5-(aminomethyl)-2-methyl-4-(4-methylpheny!)-6-propylnicotinic)" [5-[0] yield 797) is obtained as a white powder of 4, VO ) dihydrochloride butoxycarbonyl acid )amino]methyl } 2-methyl-4-(4-methylphenyl)-6-propylnicotinic acid mmol) according to the method similar to that of Example 7-?).

H-NMR (DMSO-d) 8:1.02 (3H, Ba ] = 7.4 Hz), 1.69-1.82 (2H, m), 2.37 3H, 5), 0 2.62 (3H, s), 3.01-3.07 ( 2H, m), 3.82 (2H, d, J = 5.3 Hz), 7.24 (2H, d, ] =8.1 Hz), 7.31 (2H, d, J = 8.1 Hz), 8.41 (3H, 5). 18 Example 5-(aminomethyl)-4-(4-fluorophenyl )-6-isobutyl-2-methylnicotinic acid dihydrochloride 0 methyl 5- {[(tert-butoxycarbonyl)amino]methyl } -4-(4-fluorophenyl) )- we obtain 1) total yield of 949% (as a white solid from 0) 6-isobutyl-2-methylnicotinate g; ) methyl 5-(aminomethyl)-4-(4-fluorophenyl)-6 -isobutyl-2-methylnicotinate (1-7 mmol) according to the method similar to that of the example.

I H-NMR (CDCl; ) 58: 0.97 (6H, d, J = 6.8 Hz), 1.39 (9H, 5), 2.16-2.26 (1H, m), 2.54 000 (3H, s), 2.78 (2H, d, J = 7.2 Hz), 3.5 1 (3H, s), 4.08-4.17 (2H, m), 4.22 (1H, brs), 7.07-7.20 (4H, m). 5-{[(tert-butoxycarbonyl)amino]methyl } -4-(4-fluorophenyl)-6- you get ((

Ca ial (yield 779 g) as a solid in color ,0 ) isobutyl-2-methylnicotinic acid methyl ~~ 5-{[ (tert-butoxycarbonyl)amino methyl} -4-(4-fluorophenyl)-6-isobutyl-2- ~~ Y° Cma; 6.74 milligrams) according to the method similar to 0) methylnicotinate of method Example 7-?).

YYVY

H-NMR (CD; OD) 6: 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, ] = 7.4 Hz), 4.13 (2H, 5), 7.1 7-7.25 (2H, m), 7.32-7.39 (2H, m).5-(aminomethyl)-4-(4-fluorophenyl)-6- isobutyl-2-methylnicotinic ()" 5-{[(tert-) is obtained as a white solid from (ZY g; yield 70) acid dihydrochloride butoxycarbonyl)amino]methyl}-4-(4- fluorophenyl) -6-isobutyl-2-methylnicotinic ~~ © ?. total 197 mmol) according to the method similar to that of the article A) acid (FY)

H-NMR (CD; OD) 8: 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). 1 Example Yo 5-(aminomethyl)-4-(2,6-difluorophenyl )-6-isobutyl-2-methylnicotinic acid dihydrochloride methyl 5-{[(tert-butoxycarbonyl)amino methyl }-4-(2,6- ) on Jai) 1 as a solid (% AY g; yield of 4 ) difluorophenyl)-6-isobutyl-2-methylnicotinate methyl 5-(aminomethyl)-4-(2,6-difluorophenyl)-6-isobutyl- 2- White of 1 mmol) according to the method similar to that of BTA g; Y) methylnicotinate (VY Jad

I H-NMR (CDCl; ) 8: 0.97 (6H, d, J = 6.8 Hz), 1.39 (9H, 5), 2.16-2.27 (1H, m), 2.61 (3H,s),2.79 (2H,d) ,J = 7.4 Hz), 3.57 (3H, 5), 4.13 (2H, d, J = 5.3 Hz), 4.36 (1H, brs), 6.97-7.02 (2H, m), 7.34-7.44 (1H, m) . Ye. 5- {[(tert-butoxycarbonyl)amino]methyl }-4-(2,6-difluorophenyl)-6- we obtain ( ¥ c. yield 797) as a yellow solid of 7” ) isobutyl-2-methylnicotinic acid methyl 5-{ [(tert-butoxycarbonyl)amino]methyl } -4-(2 ,6-difluorophenyl)-6-isobutyl- co.; 0.00 mmol) according to analogous method 4 ( 2-methylnicotinate .)0-" for the example method Yo

Veo “H-NMR (CDCl3) 8: 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). 2,6-difluorophenyl)-6-isobutyl-2-n(v) as a solid in color (AV mg; yield VAC ( methylnicotinic acid dihydrochloride ~~ ° 5-{ [(tert-butoxycarbonyl)amino] methyl }-4-(2,6-difluorophenyl)-6- white mM) according to the 1.178 c ny YA) isobutyl-2-methylnicotinic time method similar to that of Example 7 -?).

H-NMR (CD; OD) 6: 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). 0 of 1 Example tert-butyl 5-(aminomethyl )-6-isobutyl-2-methyl-4-[4-(trifluoromethyl) phenyl]nicotinate 2-(3-methylbutanoyl)-3-[4-(trifluroromethyl) phenyl acrylonitrile we get (1 milligram) VY ; c) 5-methyl-3-oxohexanenitrile from (p>VA) as crude product 0 mmol) according to method TY cpa 0,7) and 31(060208706i4-0222010:0061 VY Similar to the example method tert-butyl 5-cyano-6-isobutyl-2-methyl-4-[4-(trifluoromethyl) ?) is obtained as a powder in color 0 YU yield cas © A) phenyl]- 1 ,4-dihydropyridine-3-carboxylate tert-butyl 3- 5 Lal mentioned (1 g) yielded in VA (white of the crude product 00 mmol) according to the method similar to that of YO can 4 (No, aminocrotonate tert-butyl 3- and their compounds from Lal. The aforementioned crude product, daa, is melted. Example: 1-1 milliliters) and the mixture is heated with steam re-condensation for one hour. 0 (methanol In the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography tert-butyl 5.cyano-6-isobutyl-2-methyl-4-[4-(trifluoromethyl) to give silica gel Yo .phenyl] -1,4-dihydropyridine-3-carboxylate

YY\vv

YET:

H-NMR (CDC}3) 8: 0.93 (3H, d, J = 6.6 Hz), 0.99 (3H, d, J = 6.5 Hz), 1.28 (94, 5), 1.75-2.00 (1H, m), 2.10-2.35 (2H, m), 2.36 (3H, s), 4.64 (1H, 5), 5.60 (1H, brs), 7.36 (2H, d, J = 8.1 Hz), 7.56 (2H, d, J = 8.1 Hz). ?” 11-195 C. Melting point: tert-butyl 5-cyano-6-isobutyl-2-methyl-4-[4-(trifluoromethyl) on das (YY © tert-butyl 5-cyano - Yield 7177) as a white powder of pa Y,0)phenyl]nicotinate 6-isobutyl-2-methyl-4-[4-(trifluoromethyl) phenyl]-1,4-dihydropyridine-3- mmol) According to the method similar to that of example 11 pn f ,V) carboxylate .)- yy

I H-NMR (CDCl; ) 5: 1.02 (6H, d, J = 6.6 Hz), 1.23 (9H, 5), 2.20-2.40 (1H, m), 2.67 0 (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).

Agi) Yom) eA Melting point: tert-butyl 5-(aminomethyl)-6-isobutyl-2-methyl-4-[4- on Jaan; total yield 97%) as white powder from ‎ ¥,¥) (trifluoromethyl) phenyl]nicotinate tert-butyl ~~ 5-cyano-6-isobutyl-2-methyl-4- [4-(trifluoromethyl) ~~ phenyl]nicotinate 1-4 .) Grammy) according to the method similar to that of the example AY g; VL 0)

H-NMR (CDCl3) 8: 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, 5), 2.80 (2H, with J = 7.4 Hz), 3.60 (2H, 5), 7.42 (2H, d, J = 8.0 Ho), 7.70 2H, d, J = 8.0 Hz).

Aggie em AA Melting point: 0

YY as 5-(aminomethyl)-6-isobutyl-2-methyl-4-[4-(trifluoromethyl )phenyl]nicotinic acid hydrochloride 5-(aminomethyl)-6-isobutyl-2-methyl-4-[4 - We deliver (Lov gm yield 51) (trifluoromethyl)phenyl]nicotinic acid hydrochloride Yo tert-butyl 5-(aminomethyl)-6-isobutyl-2-methyl-4-[4- as a white powder from

0 mmol) according to the method VT g; 1 ( (trifluoromethyl) phenyl]nicotinate 7 .6 similar to the example method

H-NMR (0150-0) 6:0.97 (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? No tert-butyl 5-(aminomethyl)-6-isobutyl-4-[4-( methoxycarbonyl)phenyl]-2- methylnicotinate as raw product methyl 4-(2-cyano-5-methyl-3) -oxohex-1-en-1 -yDbenzoate We get (1 mmol) YY oa ?; (5-methyl-3-oxohexanenitrile g) from 10 (0 mmol) according to To the method TY ma © 1, ( methyl 4-formylbenzoate 5 1-749 ). similar to the example method tert-butyl 5-cyano-6-isobutyl-4-[4-(methoxycarbonyl)phenyl]-2- we get V (yield 46 0 as powder in color cas 5,9( methyl-1 ,4-dihydropyridine-3-carboxylate tert-butyl 3- 5 Lill masculine) (1 g) yielded in V0)) white of the crude product 0 milligrams) according to the method similar to that of YY cpa 5, Ye) aminocrotonate tert-butyl 3- aminocrotonate s The aforementioned crude product is dissolved daa L(Y) example is milliliters The mixture is heated with re-condensation of steam for two hours. Y + +) methanol is concentrated in the remaining by gel column chromatography Any reaction mixture under reduced pressure tert-butyl 5-cyano-6-isobutyl-4-[4-(methoxycarbonyl) phenyl]-2- To give silica 0 0 .methyl-1,4-dihydropyridine-3-carboxylate "H-NMR (CDCl; ) 8:0.91 (3H, d, J] = 6.6 Hz), 0.98 (3H, d, J = 6.6 Hz), 1.26 (9H, 5), 1.75-2.00 (1H, m), 2.15-2.35 (2H, m), 2.36 (3H, s), 3.90 (3H, s), 4.63 (1H, 3), 5.69 (1H, brs), 7.32 (2H, d, ] = 8.3 Hz), 7.99 (2H, d, J = 8.3 Hz).

Auge) AFA) Melting Point: Yo tert-butyl 5-cyano-6-isobutyl-4-[4-(methoxycarbonyl) phenyl]-2- you get (¥ tert-butyl S-cyano-yield £ 90) as a white powder of CPA 4 (methylnicotinate

YY\WW

YEA

6-isobutyl-4-[4-(methoxycarbonyl)phenyl] -2-methyl-1,4-dihydropyridine-3- to the method similar to that of the example Wb mmol) VE can 0, Y) carboxylate. (v-YY

H-NMR (CDCl; ) 8: 1.01 (6H, d, J = 6.6 Hz), 1.23 (9H, 5), 2.20-2.35 (1H, m), 2.67 (3H, 5), 2.94 (2H, d, J = 7.4 Hz), 3.96 (3H, 5), 7.40-7.50 (2H, m), 8.10-8.20 2H, m). 1°.Yutham" Melting point: r tert-butyl 5-(aminomethyl)-6-isobutyl-4-[4-(methoxycarbonyl) ;) we obtain tert-butyl g; yield 744) as a colored powder white from © ) phenyl]-2-methylnicotinate c ©, 3 5-cyano-6-isobutyl-4-[4-(methoxycarbonyl) phenyl]-2-methylnicotinate (£) mmol) according to the method Similar to the example method 1?0

H-NMR (CDCl; ) 8: 0.99 (6H, d, J = 6.6 Hz), 1.17 (9H, (, 1.49 (2H, brs), 2.15-2.35 (1H, m), 2.57 (3H, 5), 2.79 (2H, d, J = 7.2 Hz), 3.59 (2H, s), 3.96 (3H, 5), 7.30-7.40 (2H, m), 8.05-8.15 (2H, m). Melting point: 7/ 0 5-(aminomethyl)-6-isobutyl-4-[4-(methoxycarbonyl )phenyl]-2-methylnicotinic acid hydrochloride 5-(aminomethyl)-6-isobutyl-4- [4-(methoxycarbonyl)phenyl]-2- we obtain a yield of 176 # (as a white powder from aa 6 ) methylnicotinic acid hydrochloride tert-butyl 5-(aminomethyl)-6-isobutyl-4-[4-( methoxycarbonyl) phenyl]-2- 0 mmol) according to analogous method 0.5 g; 0 ) methylnicotinate

JE for the example method

I H-NMR (Y-01180) 5:0.93 (6H, d, J = 6.6 Hz), 2.05-2.25 (1H, m), 2.41 (3H, 5), 2.70 (2H, d, J = 7.0 Hz), 3.54 (2H, 5), 3.88 (3H, 5), 7.41 (2H, d,J=8.1Hz), 7.95 (2H,d,J=8.1Hz). Ye veo Example: tert-butyl 5-(aminomethyl)-4-(4-ethylphenyl )-6-isobutyl-2-methylnicotinate

<4

AA) as a crude product 3-(4-ethylphenyl)-2-(3-methylbutanoyl) acrylonitrile we obtain (1 mol) and -4 La VY; g (5-methyl-3-oxohexanenitrile g) in milligrams) according to the analogous method TY; g; 749-(ethylbenzaldehyde). Yield 774) as a white powder of the product aa V, A) dihydropyridine-3-carboxylate

Yo can 0,8 V) tert-butyl 3-aminocrotonate lal mentioned 1) resulting in crude (p > AA) this is dissolved (1-7 mmol) according to the similar method For the example method, milliliters (001) of methanol in tert-butyl 3-aminocrotonate s, the aforementioned crude product, and the mixture is heated with steam re-condensation for a period of hours. The reaction mixture is concentrated under 0 pressure of tert-butyl to give silica reduced and the remaining purified by gel column chromatography .5-cyano-4-(4-ethylphenyl)-6-isobutyl-2 -methyl-1,4-dihydropyridine-3-carboxylate

H-NMR (CDCl; ) 8:0.94 (3H, d, J = 6.5 Hz), 0.99 (3H, d, J = 6.5 Hz), 1 20 (3H, d, J = 6.6 Hz), 1.28 ( 9H, 5), 1.80-2.00 (1H, m), 2.10-2.30 (2H, m), 2.32 3H, 5), 2.61 (2H, q, J = 7.6 Hz), 4.52 (1H, 5), 5.55 ( 1H, brs), 7.10 (2H, d, J=83Hz), 7.14 (2H, 0 d, J=8.3 Hz). 1 11-10 Melting point: tert-butyl 5-cyano-4-(4-ethylphenyl)-6-isobutyl-2-methylnicotinate ?) we get tert-butyl 5-cyano-4- (4-ethylphenyl)- g; Yield £7 (as a white powder of 7 ) milligrams YY aa V, A) 6-isobutyl-2-methyl-1 ,4-dihydropyridine-3-carboxylate 0 (YY gram) according to a method similar to that of the example ,

I H-NMR (CDCl; ) 8: 1.01 (6H, d, J = 6.6 Hz), 1.23 (9H, 5), 1.26 3H, t, J = 7.6 Hz), 2.20-2.35 (1H, m), 2.64 (3H, 5), 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/-81 "C. Ye tert-butyl 5-(aminomethyl)-4-(4-ethylphenyl)-6-isobutyl-2- we get ( ¢ tert-butyl 5-cyano-4 - As a white powder of (% AV (no g; yield of methylnicotinate you mmol) 11 g 7 ) (4-ethylphenyl)-6-isobutyl-2-methylnicotinate 4-1 . According to the method similar to the example method

I H-NMR (CDCl; ) 8: 0.98 (6H, d, J = 6.6 Hz), 1.17 (9H, 5), 1.25 (3H, 1b = 7.5 Hz), 1.38 (2H, brs), -2.15 2.30 (1H, m), 2.55 (3H, s), 2.69 (2H, gq, J = 7.5 Hz), 2.78 (2H, d, 1-74 Hz), 3.63 (2H, sg), 7.15 2H, d , = 7.9 Hz), 724 @H, d, I = 79 Ha). © #"Celsius 7-80 Melting Point: ‎

YA Example 5-(aminomethyl)-4-(4-ethylphenyl )-6-isobutyl-2-methylnicotinic acid hydrochloride 5-(aminomethyl)-4-(4-ethylphenyl)-6-isobutyl-2-methylnicotinic You get tert-butyl-5 as a white powder from (£Y4 yield cpa +,0Y) acid hydrochloride 0

VA C 0"1) (aminomethyl)-4-(4-ethylphenyl)-6-isobutyl-2-methylnicotinate

YE millimol) according to the method similar to that of the example

H-NMR (DMSO-dg ) 8: 0.95 (6H, d, J = 7.5 Hz), 1.23 (3H, pa J = 7.5 Hz), 2.10-2.30 (1H, m), 2.47 (3H, 5) , 2.67 (2H, q, J = 7.5 Hz), 2.77 (2H, d, J = 7.0 Hz), 3.74 (2H, 5), 7.22 (2H, d, J = 8.0 Hz), 7.30 (2H, d, J = 8.0 Hz), 8.81 (1H, brs). '° Example no methyl 5-(aminomethyl)-4-(4-chlorophenyl )-2-ethyl-6-neopentylnicotinate methyl 3-g) from Y+) as raw product methyl 3-aminopent-2-enoate We obtain (1 g) T'A,0) ammonium acetate s (mmol) 001 g; 1 ¥) oxopentanoate (1-17 mmol) according to the method similar to that of the example <>» methyl 4-(4-chlorophenyl)-5-cyano-2-ethyl-6-neopentyl-1,4- ?) we get 5.5- g yield 777) as a yellow powder from V, £) dihydropyridine-3-carboxylate 4- « mM) YY aa 1 ( dimethyl-3-oxohexanenitrile g) product YY) mmol) and crude product ¥Y g £,0) chlorobenzaldehyde .).

Vo

H-NMR (CDCl) 8: 0.95-1.05 (3H, m), 1.01 (9H, s), 2.20 (1H, d,J=13.8 Hz), 2.37 (1H, d,J =13.8Hz), 2.77 2H , 6.17 7.5 Hz), 3.58 (3H, s), 4.60 (1H, 5), 5.63 (1H, brs), 7.10-7.20 (2H, m), 7.25-7.30 (2H, m). methyl 4-(4-chlorophenyl)-5-cyano-2-ethyl-6-neopentylnicotinate We obtain ( methyl 4-(4-chlorophenyl)- as a pale yellow powder- from (% £Y yield) can 4,00) © 7.17 mL (6 ag; 5-cyano-2-ethyl-6-neopentyl-1 .4-dihydropyridine-3-carboxylate mol) according to the method similar to that of the example? 32-7).

H-NMR (CDCl3) 8: 1.07 (9H, 5), 1.33 BH, t, l - 5 Hz), 2.87 (2H, q, J = 7.5 Hz), 3.03 (2H, 5), 3.61 (3H , s), 7.25-7.35 (2H, m), 7.45-7.50 (2H, m).

Gaal 71-1171 Melting point: 0 methyl 5-(aminomethyl)-4-(4-chlorophenyl)-2-ethyl-6- ng (¢ methyl 4-) as a pale-yellow-colored oil of (FAS) yield +, 88 (0.9 mmol) neopentylnicotinate (for 8 g (4-chlorophenyl)-5-cyano-2-ethyl-6-neopentylnicotinate.) 17 g) according to the method similar to that of Example “H-NMR (CDCl3) 8: 1.03 (9H, 5), 1.30 3H, t, J = 5 Hz), 1.42 (2H, brs), 2.77 2H, 0 gq, J = 7.5 Hz), 2.89 ( 2H, 5), 3.51 (3H, 5), 3.69 (2H, s), 7.15-7.25 (2H, m), 7.35-7.45 (2H, m).

YA Example 5-(aminomethyl)-4-(4-chlorophenyl )-2-ethyl-6-neopentylnicotinic acid dihydrochloride 0 methyl 5- ({[(tert-butoxycarbonyl)amino]}methyl}-4-(4 -chlorophenyl)- we obtain ( 1 ) as a white powder from (£aV) total yield 5" ( 2-ethyl-6-neopentylnicotinate 7 ) methyl 5-(aminomethyl)-4-(4-chlorophenyl)- 2-ethyl-6-neopentylnicotinate (1-17 mmol) according to the method similar to that of the example 1,1 pa "H-NMR (CDCl; ) 8:1.02 (9H, 0.1.30 3H, t, 1 = 7.5 Hz), 1.38 (9H, s), 2.78 2H, q, ¥°

J = 7.5 Hz), 2.87 (2H, 5), 3.51 (3H, 5), 4.18 (3H, brs), 7.10-7.20 (2H, m), 7.30-7.45 (2H, m).

YoY 5- {[(tert-butoxycarbonyl)amino]methyl }-4-[4-(chlorophenyl)-2- ?) we obtain a yield of 741) as a white powder from cpa +, YY) ethyl-6- neopentylnicotinic acid methyl 5-1 [(tert-butoxycarbonyl)amino}methyl ( -4- [4-(chlorophenyl)-2-ethyl-6- mmol) according to similar method 1.94 (not 4 g neopentylnicotinate Method Example 7-?).©

I H-NMR (CDCl; ) 8: 1.01 (9H, s), 1.24 (3H, t,J = 7.4 Hz), 1.33 (9H, 5), 2.73 (2H, q,

J=17.4 Hz), 2.73 (2H, 5), 3.92 (2H, d, ] = 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).

J YY VY Melting point: 5-(aminomethyl)-4-(4-chlorophenyl)-2-ethyl-6-neopentylnicotinic We get ye 5-{[(tert-) as a white powder from ( LAY total yield +, VE ( acid dihydrochloride butoxycarbonyl)amino methyl }-4- [4-(chlorophenyl)-2-ethyl-6-neopentylnicotinic —v mmol) according to a method similar to that of the example 1.66 cpa 0 V+) acid (¥

H-NMR (DMSO-ds) 8: 1.03 (9H, 5), 1.26 (3H, t,J = 7.4 Hz), 2.79 2H, q, J = 74 0

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). ?#C. 5-771 Melting point: va Example tert-butyl 5-(aminomethyl)-4-(4-chlorophenyl )-2-isopropyl-6-neopentylnicotinate | 0 tert-butyl 4-(4-chlorophenyl)-5-cyano-2-isopropyl-6-neopentyl-1,4- ( 5,5-1) is obtained as a white solid from (* 01g Yield of Y) dihydropyridine-3-carboxylate 4- mM) YY g 151 Y) dimethyl-3-oxohexanenitrile tert-butyl 3-amino-4- 5 7,7? mmol) aa 717 ) chlorobenzaldehyde mmol) according to similar method Yoox 048 A) methylpent-2-enoate ~~ ¥°

AY) for the example method

lah (9H, 5), 1.04 (3H, d, J = 6.8 Hz), 1.21 3H, d, J = 7.0 Hz), 8:1.02 (J00) I H-NMR (9H, s) , 2.20 (1H, d, J = 13.9 Hz), 2.33 (1H, d, J = 14.1 Hz), 4.07-4.30 (1H, m), 1.28 4.55 (1H, s), 5.65 (1H, s), 7.16 2H, d, J = 8.3 Hz), 7.22-7.35 (2H, m). tert-butyl 4-(4-chlorophenyl)-5-cyano-2-isopropyl-6- ( tert-butyl 4- g; yield of 0 976 as a yellow solid of 0 9511 0 ) neopentylnicotinate (4) -chlorophenyl)-5 -cyano-2-isopropyl-6-neopentyl-1 ,4-dihydropyridine-3- ? g; £10 mmol) according to a method similar to that of the example carboxylate (*- vy

H-NMR (CDCl3) 8:1.06 (9H, 5), 1.27 (9H, 5), 1.32 (6H, d, J = 6.6 Hz), 3.00 (2H, ),3.13-3.25 (1H, m), 7.32 (2H, les = 8.5 Hz), 7.45 (2H, d, J = 8.5 Hz). 0 tert-butyl 5-(aminomethyl)-4-(4-chlorophenyl)-2-isopropyl-6- yields 0 tert-butyl 4-(4- a white colored poultice of TY ( g; yield 85 ( neopentylnicotinate mM 71 g 0 ) chlorophenyl)-5-cyano-2-isopropyl-6-neopentylnicotinate (17 mol) according to the method similar to that of the example

H-NMR (J00) 8:1.04 (9H, 5), 1.21 (9H, 5), 1.30 (6H, d, J = 6.6 Hz), 2.85 (2H, 0 s), 3.01-3.16 (1H, m), 3.64 (2H, 5), 7.22 (2H, d, J = 8.5 Hz), 7.40 (2H, d, J = 8.5 Hz).

Ar Joe 5-(aminomethyl)-4-(4-chlorophenyl )-2-isopropyl-6-neopentylnicotinic acid dihydrochloride 5-(aminomethyl)-4-(4-chlorophenyl)-2-isopropyl-6-neopentylnicotinic Ye tert-butyl (yield 797 mg) as a yellow solid of 4 ¥) acid dihydrochloride volume £07 ) 5-(aminomethyl)-4-(4-chlorophenyl)-2-isopropyl-6-neopentylnicotinate .)1 -7?4 mmol) according to the method similar to that of Example 941

H-NMR (F01/50-4) 8:1.04 (9H, 5), 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,] = 8.5 Hz), 7.55(2H, d,J=8.5 Y°

Hz), 8.11 (3H, brs). 41 examples

Uh tert-butyl 5-(aminomethyl)-4-( 4-chlorophenyl )-6-isobutyl-2-isopropylnicotinate 1 we get tert-butyl 4-(4-chlorophenyl)-5-cyano-6- isoputyl-2-isopropyl-1 A 1 A) dihydropyridine-3-carboxylate total yield 0 725) as a yellow solid of -5-methyl-3-oxohexanenitrile) 4 g; ?? mM) 4 chlorobenzaldehyde © ) £1 g YY mmol) tert-butyl 3-amino-4-s 4A) methylpent-2-enoate ,5 g 51 mmol ) according to the method similar to that of Example 1-?). (3H, d,J = 7.0 Hz), 1.28 (9H, s), 1.81-1.98 (1H, m), 2.25 (ZH, d, J = 7.4 Hz), -4.09 (1H, 5) , 7.15 (2H, 4, J = 8.3 Hz), 7.25-7.27 @H, m). 0 5.71 H (1H, m), 4.55 (1H, 426 Jo (Y) on tert-butyl 4-(4-chlorophenyl)-5-cyano-6-isobutyl-2- 0 ( isopropylnicotinate total yield of 949 0 as yellow oil of -4)-4 (tert-butyl (chlorophenyl)-5 -cyano-6-isoputyl-2-isopropyl-1 .4-dihydropyridine-3-carboxylate YEA aa 1 1 mmol) according to a method similar to that of Example FY H-NMR (CDCl3 ) 5: 1.01 (6H, d, J = 6.6 Hz), 1.26 (9H, 5), 1.32 (6H, d, J = 6.8 Hz), 6 ' (1H, m), 2.95 (2H, d, J =7.2 Hz), 3.19-3.25 (1H, m), 7.33 (2H, d,J=87 2.22-2.39 Hz), 7.46 (2H, d, J = 8.7 Hz).(V we get tert-butyl 5-(aminomethyl)-4-(4-chlorophenyl)-6-isobutyl-2- isopropylnicotinate ) 57 g; Yield of 84 ( as a white solid of -4 tert-butyl VL EA aa 0 ) (4-chlorophenyl)-5-cyano-6-isobutyl-2-isopropylnicotinate 0 mmol) according to a method similar to that of the example (EY H-NMR (CDCls ) 5:0.99 (6H, d, J = 6.8 Hz), 1.21 (9H, 5), 1.30 (6H, d, J = 6.8 Hz), (1H, m ), 2.78 (2H, d, J = 7.2 Hz), 3.01-3.16 (1H, m), 3.59 (1H, s), 7.22 2.23-2.39 (2H, d, J = 8.5 Hz), 7.39 (2H , d, J = 8.5 Hz). -4-(4-chlorophenyl)-6-isobutyl-2-isopropylnicotinic yield tert-butyl (777) is obtained as a yellow solid from 1 Y) acid dihydrochloride mg 6 ) 5-(aminomethyl)- 4-(4-chlorophenyl)-6-isobutyl-2-isopropylnicotinate (1-7 4 mmol) according to the method similar to that of Example 14

HNMR (DMSO-dg ) 5:0.99 (6H, d, J = 6.6 Hz), 1.25 (6H, d,J = 6.8 Hz), 220239 © (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 ).

AY eg tert-butyl 5-(aminomethyl)-4-( 4-chlorophenyl)-2,6-diisobutylnicotinate g) from YY) as crude product tert-butyl 3-amino-5-methylhex-2-enoate We get 1) 0

Vo,A) isovaleryl chloride (mmol) 11 g; -(4-chlorophenyl)-5-cyano-2,6-diisobutyl-1,4- on Jaa (¥ as a pale yellow powder (VY yield aa) +,Y) dihydropyridine-3-carboxylate 4 (an molecule Le gm?? 1 ) 5-methyl-3-oxohexanenitrile from the product 05 (pa 01 (mM) and the crude product YY gm 1 ) chlorobenzaldehyde .)?- 1 aforementioned according to a method similar to that of Example 1) in “H-NMR (CDCl3) 8:0.95-1.05 (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, 5), 5.51 (1H, brs), 7.15-7.25 (2H, m), 7.25- 730 (2H, m) 0 05°) 18-135 Melting point: 4,1) tert-butyl 4-(4-chlorophenyl)-5-cyano-2,6-diisobutylnicotinate ?) we get tert-butyl 4-( 4-chlorophenyl)-5-cyano-2,6-g; yield 49% (as white powder of mmol) according to YV pa 8 A) diisobutyl-1,4-dihydropyridine-3-carboxylate to Method similar to that of Example 3-7). Ye

You

I H-NMR (CDCls ) 8: 0.95 (6H, d, J = 6.8 Hz), 1.00 (6H, d, J = 6.6 Hz), 1.25 (9H, 5), 2.15-2.40 (2H, m), 2.76 (2H, d,] = 7.2 Hz), 2.95 (2H, d, J = 4 Hz), 7.30-7.35 (2H, m), 7.40-7.50 (2H, m). tert-butyl 5-(aminomethyl)-4-(4-chlorophenyl)-2,6- nm tert-butyl 4-(4-cg; yield 97 7) as a white powder of 0A (No diisobutylnicotinate © 7,?mM (cpa) chlorophenyl)-5-cyano-2,6-diisobutylnicotinate according to a method similar to that of Example 7?-?). H-NMR (CDCl3) 8: 0.94 (6H, d, J = 6.6 Hz), 0.98 (6H, 0.17 6.6 Hz), 1 20 (9H, s), (2H, brs), -2.15 2.35 (2H, m), 2.67 (2H, d, J = 7.4 Hz), 2.80 (2H, d,J=17.4 Hz), 1.48 (2H, 5), 7.20-7.25 (2H, m), 7.35 -7.45 2H, m). 00 3.61 Example At 5-(aminomethyl)-4-(4-chlorophenyl)-2,6-diisobutylnicotinic acid dihydrochloride you get 5-(aminomethyl)-4-(4-chlorophenyl)-2,6-diisobutylnicotinic acid (+,4Y) dihydrochloride g Yield 7948) as a white powder of 5 tert-butyl v, iv) (aminomethyl)-4-(4-chlorophenyl)-2,6-diisobutlnicotinate Vo g; 1,?mmol) according to the method similar to that of Example 4 1-7. H-NMR (DMSO-ds ) 6:0.90 (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 =5.5Hz), (2H, d, 1 = 8.5 Hz), 7.50-7.60 (2H, m), 8.17 (3H, brs). 7.36 T - Melting point: ©00" decomposition Ae Jus tert-butyl 5-(aminomethyl)-4-(4-chlorophenyl)-2-isobutyl-6 -neopentylnicotinate \ ( we get -4, tert-butyl 4-(4-chlorophenyl) -5-cyano-2-isobutyl-6-neopentyl-1 dihydropyridine-3-carboxylate as crude product (V,4 g) aged 5,5-dimethyl-3-oxohexanenitrile ~~ Ye ( 1 g YY mmol); 4-chlorobenzaldehyde (£1,VY a mmol) and the crude product (V+) g) of tert-butyl 3-amino-5- Yyw yov

Jud According to the method similar to that of (YAY obtained in the example of methylhex-2-enoate .)-1 tert-butyl 4-(4-chlorophenyl)-5-cyano-2-isobutyl-6- we obtain ( Y

V,4) as a white powder from the crude product (% YY g; yield ©,0) neopentylnicotinate (¥-YY according to the method similar to that of example al above 1) yielded in (> ©

H-NMR (CDCl; ) 6: 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, 0, 1 2 Hz), 3.01 (2H, s), 7.30-7.35 (2H, m), 7.40-7.50 (2H, m). tert-butyl 5-(aminomethyl)-4-(4-chlorophenyl)-2-isobutyl-6- (¥ tert-butyl 4-(4-) is obtained as a yellow powder from (% AT) yield aa 8 ( neopentylnicotinate 10 mmol VY g; 0, Y) chlorophenyl)-5-cyano-2-isobutyl-6-neopentylnicotinate (Gramic ETF) according to a method similar to that of the example

I H-NMR (CDCl3) 8: 0.93 (6H, d, J = 6.8 Hz), 1.02 (9H, 1 20 (9H, s), 1.86 (2H, brs), 2.15-2.35 (1H, m), 2.67 (2H, d, ] = 7.4 Hz), 2.87 (2H, 5), 3.71 (2H, 5), 7.20- 7.25 (2H, m), 7.35-7.45 2H, m). 08

AN Example 5-(aminomethyl)-4-(4-chlorophenyl )-2-isobutyl-6-neopentylnicotinic acid dihydrochloride 5-(aminomethyl)-4-(4-chlorophenyl)-2-isobutyl-6-neopentylnicotinic We obtain tert-butyl 5- vol (yield 757) as a white powder from 0.1 0.1 00 ¥ (+,¥4) acid dihydrochloride 6 ) (aminomethyl)-4-(4-chlorophenyl)-2-isobutyl- 6-neopentylnicotinate (1-74 mmol) according to the method similar to that of the example.

H-NMR (DMSO-dg) 5: 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, 5), 3.84 (2H, d, J =5.5Hz), 7.30-7.40 (2H, m), 7.50-7.60 (2H, m), 8.12 (3H, brs). ¥°?” Celsius (decomposition). ©1 Melting point: ‎

AY like ticks

16 [5-(aminomethyl)-2-methyl-4-(4-methylphenyl)-6-neopentylpyridin-3-vl]acetonitrile dihydrochloride tert-butyl {[5-(hydroxymethyl)-6-methyl-4-(4- methylphenyl)-2- we get )1 g; Yield 446 7) As a powder in color 8) neopentylpyridin-3-yljmethyl} carbamate methyl 5- {[(tert-butoxycarbonyl)amino]methyl} -2-methyl-4-(4- white) of 77.7 °C mmol) according to \ +) methylphenyl)-6-neopentylnicotinate (Yo) method similar to the example method "H-NMR (CDCl3) 8: 1.01 (9H, 5), 1.37 (9H, 5), 2.41 (3H) , 5), 2.67 (3H, 5), 2.84 (2H, 9).4.10 (2H, 4, J = 4.9 Hz), 4.16 (1H, 5), 4.36 (2H, d, J = 5.7 Hz), 7.05 (2H, d, J = 8.1 Hz), 7.26 2H, d, J = 8.1 Hz).00 tert-butyl {[5-(hydroxymethyl)-6-methyl-4-(4-methylphenyl)-2- mixture from (Y mmol); VY g; vy 1) neopentylpyridin-3-yljmethyl carbamate } mL) cooled to +) tetrahydrofuran g; ; mmol) 4) triethylamine 1 g millimol vy ¥) methanesulfonyl chloride (0 * C) and added dropwise, the reaction mixture was poured into Ga Ye, after stirring at room temperature for 0, and the substance was dried by aqueous ethyl acetate. The mixture was extracted with Anhydrous sodium hydrogen carbonate. The solvent is evaporated under reduced pressure to give 0 sulfate extracted over [5-{ [(tert-butoxycarbonyl)amino]methyl} -2-methyl-4-(4-methylphenyl)-6- productivity? 0 as powder cpa + AC ) neopentylpyridin-3-yljmethyl methanesulfonate white. Te "H-NMR (CDCl) 6:1.01 911 1.37 (9H, s), 2.41 (3H, 8), 2.67 3H, 8), 2.75 (3H, 9), 2.86 (2H, 5), 4.11 (2H, with J = 4.9 Hz), 4.17 (1H, 5), 491 (2H, 5), 7.04 (2H, d, J = 8.1 Hz), 7.27 (2H, d, ] = 8.1 Hz).[5- {[(tert-butoxycarbonyl)amino]methyl} -2-methyl-4-(4-methylphenyl)-6- dissolves (¥ milligram (117 cpa ey At ) neopentylpyridin-3-yljmethyl methanesulfonate Yo milliliter ¥ can 014 ) potassium cyanide milliliter) and add 10) dimethyl sulfoxide to ethyl acetate for one hour. Aggie Grams.) Stir the mixture when

1008 reaction mixture; The mixture was washed sequentially with water and saturated brine and dried on anhydrous. The solvent is evaporated under reduced pressure. The residue magnesium sulfate tert-butyl {[5-(cyanomethyl)-6-) was purified to give silica by gel column chromatography as 5( methyl-4-(4-chlorophenyl)-2-neopentylpyridin-3 -yl methyl} carbamate Yield 17 (as powder. © ' H-NMR (CDCl3) 8: 1.01 (9H, 5), 1.37 (9H, 5), 2.43 (3H, 5), 2.65 (3H, 5), 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). 7 A) 3-yl]acetonitrile dihydrochloride Ve (cyanomethyl)-6-methyl-4-(4-methylphenyl)-2 -neopentylpyridin-3- g; 030 mmol) according to similar method 4 ( yllmethyl} carbamate (TY) for the example method

H-NMR (DMSO-ds) 8: 1.01 (9H, s), 2.42 (3H, 5), 2.76 (3H, s), 3.06 (2H, s), 3.59 (2H, 5), 3.80 (2H, d , J = 5.3 Hz), 7.24 (2H, d, J = 7.9 Hz), 7.42 (2H, d, J = 79 Hz), 0 8.20 (3H, s).

A Example 2-[5-(aminomethyl)-2-methyl-4-(4-methylphenyl )-6-neopentylpyridin-3- yl]acetamide dihydrochloride tert-butyl {[5-(2-amino-2-) oxoethyl)-6-methyl-4-(4-methylphenyl)-2- (1"0 tert-butyl) is obtained as a powder from 0 AY g +,Y) neopentylpyridin-3-yljmethyl} carbamate {[ 5-(cyanomethyl)-6-methyl-4-(4-methylphenyl)-2 -neopentylpyridin-3-mM) according to the similar method AY Cm 0 ,¥'0) yllmethyl} carbamate 1.) 7. For example method H-NMR (YL000) 6: 1.02 (9H, 5), 1.37 (9H, 5), 2.40 (3H, 5), 2.56 (3H, s), 2.84 (2H, Yo s), 3.30 (2H, s), 4.10 2H, d, J = 4.9 Hz), 4.19 (1H, 5), 5.15 (1H, 5), 5.20 (1H, s), 7.00 (2H, d, J = 7.9 Hz), 7.24 (2H, d, ] = 7.9 Hz).

0 2-[5-(aminomethyl)-2-methyl-4-(4-methylphenyl-6-) on Jai (Y as powder (% AG pa 1 A) neopentylpyridin-3-yljmethyl} acitamide dihydrochloride tert-butyl ~~ { [5-(2-amino-2-oxoethyl)-6-methyl-4-(4-methylphenyl)-2-mN) according to 1.8 g; YY) neopentylpyridin -3-yl]methyl} carbamate (7-7) to the method similar to the example method ©

H-NMR (DMSO-dg ) 8: 1.03 (9H, 5), 2.41 (3H, 8), 2.77 (2H, 5), 3.29 (3H, 7 (2H, 5), 4.28 (2H, 5), 7.03 (1H, 5), 7.20 (2H, d, J = 7.8 Hz), 7.38 (2H, d, J = 7.8 Hz), 7.39 (1H, 5), 8.24 (3H, 5). Example [5 -(aminomethyl)-2-methyl-4-( 4-methylphenyl)-6-neopentylpyridin-3-yljmethyl 01 tert-butyl dihydrochloride acetate {[5-(hydroxymethyl)-6-methyl-4-(4-methylphenyl)- 2- Cool down a mixture of (1 g (2 mmol) 0, (nepentylpyridin-3-yl]methyl carbamate) to Y + (tetrahydrofuran) 1 g; +) triethylamine (mM). After 1.8 g; mixture with anhydrous 5-hydrogen carbonate The solvent evaporates under reduced pressure to give 170 sulfate extracted on {[(tert-butoxycarbonyl)amino]methy!} -2-methyl-4-(4-methylphenyl-6-) Yield 7776) as a white powder. ca» +,Y) neopentylpyridin-3-yljmethyl acetate 0

H-NMR (J2i) 8: 1.02 (9H, 5), 1.37 (9H, 5), 2.00 (3H, 5), 2.40 (3H, 5), 2.57 (3H, s), 2.85 (2H, s) ), 4.11 (2H, d, J=4.9 Hz), 4.17 (1H, 5), 4.76 (2H, s), 7.00 2H, d,J= 8.1 Hz), 7.22 (2H, d, ] = 8.1 Hz) . [5-(aminomethyl)-2-methyl-4-(4-methylphenyl)-6-neopentylpyridin- (Y [5-{[(tert- 750 mg)) is obtained as a powder from 34) 3-yl] methyl acetate dihydrochloride ~~ Y° butoxycarbonyl)amino]methyl} -2-methyl-4-(4-methylphenyl-6-neopentylpyridin-3-

O (ty VY) ylimethyl acetate total 1.771 milligrams) according to the method similar to that of Example 7-?). H-NMR (DMSO-dg ) 8: 1.02 (9H, 5), 1.96 (3H, 5), 2.40 (3H, 5), 2.78 (3H, 5), 3.14 (2H, s), 3.82 ( 2H, 5), 4.72 (2H, 3), 7.21 (2H, d, J =7.8 Hz), 7.36 (2H, d,J=7.8 Hz), 3H,s). © 8.23 Ex 31 {[2-isobutyl-6-methyl-4-(4-methylphenyl)-5-({[4-( methylthio)phenyl]thio} methyl)pyridin-3-yl] methyl}amine dihydrochloride 1) cooled mixture of tert-butyl {[5-(hydroxymethyl)-2-isobutyl-6-methyl-4-(4- methylphenyl)pyridin-3-yl]-methyl} 01 carbamate (17 g VIA mmol) 0.8( triethylamine mL lle 0.0 mol) tetrahydrofuran s 0 mmol) to 0C; Add dropwise (+,A4) methanesulfonyl chloride (1065 milligrams per milliliter). after stirring at room temperature for 900 minutes; The reaction mixture is poured into an aqueous sodium hydrogen carbonate solution; The mixture was extracted with ethyl acetate 05. The extracted material was dried on SY magnesium sulfate, and the solvent was evaporated under aida pressure to give -6-isobutyl-2- (NgA 110 mtg) (ANH 1010:07/670i-5-1] ))1] methyl-4-(4-methylphenyl)pyridin-3-ylmethyl methanesulfonate as a crude product. The crude product was dissolved in (Y'+) N,N-dimethylformamide milliliters). Potassium carbonate (17.8 aa), VY) mMol) and aa 1 (4-(methylthio)benzenethiol - 0 mMol) were added and the mixture was stirred under heating at 0 *"C for 1 hour One. Caddy the reaction mixture by 01 (ethyl acetate) and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography silica to give ___ tert-butyl {[2-isobutyl-6-methyl-4-(4-methylphenyl)-5-({[4- (methylthio)phenyljthio}methyl) pyridin-3-yl]-methyl}carbamate Yo 9 ;, a yield 4) as a yellow solid.

VY

H-NMR (CDCls ) 6: 0.97 (6H, with J = 6.6 Hz), 1.38 (9H, 5), 2.15-2.24 (1H, m), 2.40 (3H, s), 2.45 (3H, 5) , 2.63 (3H, 5), 2.75 (2H, d, T= 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-isobutyl-6-methyl-4-(4-methylphenyl)-5-({[4- i.e. nh__pg) (Y ©

Ya. ) (methylthio)phenyl]thio } methyl)pyridin-3-yl]-methyl}amine dihydrochloride tert-butyl {[2-isobutyl-6-methyl-d-(4- yield 7974) as a yellow solid from ( pre methylphenyl)-5-( {[4-(methylthio)phenyl]thio}methyl) pyridin-3-yl}- milligram) according to the similar method 1949 compiled On A) methyl} carbamate .)? 1- For the example method Ye

I H-NMR (DMSO-d) 8: 0.98 (6H, d, J = 6.6 Hz), 2.13-2.22 (1H, m), 2.40 (3H, s), 2.46 (3H, 5), 2.78 (3H, 5), 3.11 (2H, brs), 3.76 (2H, d, J = 4.5 Hz), 3.87 (2H, 5), 7.12 (2H, d, J =8.7 Hz), 7.16 (2H, d, J = 8.7 Hz), 7.22 (2H, d, 1 = 7.9 Hz), 7.33 (2H, 1 - 7.9 Hz), 8.38 (3H, brs). 11 Ex 0 {[2-isobutyl-6-methyl-4-(4-methylphenyl)-5-({[4-(methylsulfonyl) phenyl]sulfonyl}methyl)pyridin-3-yljmethyl} amine dihydrochloride tert-butyl {[2-isobutyl-6-methyl-4-(4-methylphenyl)-5-({[4- that is a solution of )1

Y.00 g 0 ) (methylthio)phenyl]thio}methyl) pyridin-3-yl}-methyl} carbamate tetrahydrofuran s mL); Water (1.0 milliliters) (©) methanol mmol) in -

Oxone 5 mmol) 0.77 mg; 171 ( sulfuric acid mL) add 0 © (g 1.10 mmol) and stir the mixture at temperature TVA (trademark; milliliters) and 100 (100) ethyl acetate washed the chamber for 2 hours. The reaction mixture was diluted with saturated aqueous and saturated brine. sodium hydrogen carbonate successively with an anhydrous solution and the solvent evaporated under pressure magnesium sulfate The organic layer was dried over YO to give reduced diisopropyyl ether. The resulting white solid was washed off with tert-butyl {[2-isobutyl-6-methyl-4-(4-methylphenyl)-5-( {[4-

YY\V

(L) (methylsulfonyt)phenyl[sulfonyl }methyl) pyridin-3-yl]-methyl} carbamate as white powder. (IAT g; yield

H-NMR (CDCl3) 6: 0.98 (6H, d, J = 6.8 Hz), 1.38 (9H, 5), 2.1 7-2.27 (1H, m), 2.42 (3H, s), 2.70 (3H, 5) , 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=79Hz), 7.69 ° (2H, d, J = 8.3 Hz), 8.00 (2H, d, J = 8.5 Hz). {[2-isobutyl-6-methyl-4-(4-methylphenyl)-5-({[4-on-Jaa (¥ (methylsulfonyl)phenyl]sulfonyl} methyl)pyridin-3-yl}-methyl } amine tert-butyl {[2-mg; yield 794] as a white powder of £44) dihydrochloride isobutyl-6-methyl-4-(4-methylphenyl)-5-({[4-0 oy)) (methylsulfonyl) phenyl]sulfonyl } methyl) pyridin-3-yl}-methyl ( carbamate .(3-1 mmol) according to method similar to example method 1801 mg; I H-NMR (DMSO-dg) 8: 0.97 (6H, d, J = 6.6 Hz), 2.17-2.27 (1H, m), 2.38 (3H, 5), 2.81 (3H, brs), 3.00 (2H, brs), 3.34 (3H, s), 3.68 (2H, brs), 7.03 (2H, d,J=7.4Hz), 722 (2H, d,]1=7.9 Hz), 7.77 (2H, d, J = 7.0 Hz), 8.11 (2H, d, J = 8.5Hz), 8.26 BH, 0 brs). 17 Ex. (6-methyl-4-(4-methylphenyl)-5-{[(4-methyl-4H-1 .2,4-triazol-3-yl)thiojmethyl } -2- neopentylpyridin-3-yl) methylamine dihydrochloride tert-butyl [(6-methyl-4-(4-methylphenyl)-5- {{(4-methyl-4H-1,2,4-) you get ( \ Y. g 5 A) triazol-3-yl)thio]methyl }-2-neopentylpyridin-3-yl}-methyl } carbamate [5- {[(tert-butoxycarbonyl)amino methyl} -2-methyl-4-(4-) as a powder of A vv

VY mM 0, Yo ) methylphenyl)-6-neopentylpyridin-3-yl methyl methanesulfonate +, AN mM 49) 4-methyl-4H-1,2,4-traiazole-3-thiol s millimole). ( 1-+???? a gram-molecule) according to the method similar to that of the example YO

YY\Ww

H-NMR (CDCl3 ) 8: 1.02 (9H, s), 1.37 (9H, 5), 2.39 (3H, 5), 2.65 3H, 5), 2.84 (2H, s), 3.41 (3H, s), 4.07 (2H, d, J = 5.3 Hz), 4.17 3H, 5), 7.02 (2H, 127.9 Hz), 7.22 (2H, d, J = 7.9 Hz), 8.08 (1H, s). (6-methyl-4-(4-methylphenyl)-5- {[(4-methyl-4H-1,2 4-triazol-3- ?) we get g; +, VY ) yl)thioJmethyl }-2-neopentylpyridin-3-yl)-methylamine dihydrochloride 0 tert-butyl [(6-methyl-4-(4-methylphenyl)-5-{[(4-methyl-4H-) as powder from (AVY)

YA ) 1,2,4-triazol-3-yl)thio]methyl}-2-neopentylpyridin-3 -yl]-methyl} carbamate (TY mmol) according to method similar to example method 178 g; I H-NMR (DMSO-dg ) 5:1.02 (9H, s), 2.39 (3H, s), 2.80 (3H, 5), 3.19 (2H, 5), 3.41 (3H, 5), 3.79 (2H , 5), 4.05 (2H, 5), 7.13 (2H, d, J = 8.1 Hz), 7.35 (2H, d, J = 8.1 Hz), 0 8.25 (3H, s), 8.74 (1H, s). av Example {6-methyl-4-(4-methylphenyl)-2-neopentyl-5-[(1,3 -thiazol-2-ylthio)methyl]pyridin- 3-yl} methylamine dihydrochloride tert-butyl ({6 -methyl-4-(4-methylphenyl)-2-neopentyl-5-[(1,3- on plate)1 1 15 0 as powder 8 ) thiazol-2-ylthio)methyl}pyridin-3 -yl} -methyl)carbamate [5-{[(tert-butoxycarbonyl)amino}methyl } -2-methyl-4-(4-methylphenyl)-6- from 2-3 mmol) YY c 0 vo)neopentylpyridin-3-yl}-methanesulfonate mM) according to analogous method 187 mg; 001) mercaptothiazole (TY) for example method Ye

I H-NMR (J00) 6: 1.02 (9H, s), 1.37 (9H, 5), 2.38 (3H, 5), 2.64 (3H, 5), 2.84 (2H, s), 4.08 (2H, d, J = 5.1 Hz), 4.17 (3H, 5), 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). {6-methyl-4-(4-methylphenyl)-2-neopentyl-5-[(1 ,3-thiazol-2- ( Y (% Av .g ) ylthio)methyl]pyridin-3-yl}- methylamine dihydrochloride 8 tert-butyl ({6-methyl-4-(4-methylphenyl)-2-neopentyl-5-[(1,3-thiazol-) as powder from

06 mmol +, TA aa 1©) 2-ylthio)methyl]pyridin-3-yl}-methyl)carbamate (2-7 gram) according to a method similar to that of Example 111-111 (DMSO-ds). ) 8:1.01 (9H, 5), 2.38 (3H, 5), 2.78 (3H, 5), 3.10 (2H, 5), 3.78 (2H, s), 4.20 (2H, 5), 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) . © af Example 5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)nicotinotrile dihydrochloride tert-butyl ({5-(aminocarbonyl)-2-isobutyl-6-methyl-4- mL) of Y+) to a solution of (0 mg ,.7; mmol 175 6( (4-methylphenyl)pyridin-3-yl]-methyl} carbamate | 0 mMol AE «lille 1] ) triethylamine dichloromethane (g) added in 8.4 μl; YA) trifluoromethanesulfonic anhydride (g); A minute drip is added. The reaction mixture was washed off to Ye (mm) with ice cooling. The mixture was stirred for magnesium sulfate, respectively, with water and brine. The organic layer is dried over and the solvent is evaporated under reduced pressure. The resulting residue was purified by SY 0 tert-butyl ({5-cyano-2-isobutyl-6-methyl-4-“Lacy silica) gel column chromatography (0%” mg; yield 0) (4-methylphenyl )pyridin-3-yl]-methyl} carbamate As white crystals.

I H-NMR (CDCl3 ) :0.97 (6H, d, J = 6.6 Hz), 1.40 (9H, 5), 2.20-2.29 (1H, m), 2.43 (3H, 5), 2.77 (3H, 5), 2.83 (2H, d, J = 9.0 Hz), 4.18 (2H, 5), 4.20 (1H, brs), 7.13 2H, 0 d, J = 6.0 Hz), 7.31 (2H, d, J = 6.0 Hz). aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) )- 0 de nh_sal (Y tert- as a white powder of (% AA yield cane AY ) nicotinonitrile dihydrochloride butyl {5- cyano-2-isobutyl-6-methyl-4-(4-methylphenyl)pyridin-3 -yl]-mM) according to similar method 1.75 mg 0 ( methyl}carbamate 5 for example method 7 -?).

111-1010 (DMSO-de ) 8:0.95 (6H, d, J = 6.6 Hz), 2.21-2.27(1H, m), 2.42 (3H, 5), (3H, 5), 2.89 (2H , d, J = 6.9 Hz), 3.82 (2H, d, J = 5.4 Hz), 7.33-7.40 (4H, m), 2.71 (3H, brs). 8.50 as 46 N-[5-( aminomethyl)-6-i sobutyl-2-methyl-4-(4-methylphenyl)pyridin-3 -yljurea © dihydrochloride 0) to a solution (¥ milliliters) of {[(tert-butoxycarbonyl)amino]- methyl } -6-isobutyl- -5 (£VY) 2-methyl-4-(4-methylphenyl) nicotinate acid mg; 1 mmol) in N,N-dimethylformamide added (0 μl triethylamine 1.0 mmol 0); YT (diphenylphosphoryl azide 1.0 mmol) was added dropwise under cooling with ice. The mixture was stirred for Ve min and ele was added to the reaction mixture. The mixture was extracted with cethyl acetate and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was dissolved in toluene (? milliliters). The mixture is heated with re-condensation of steam and stirring 0 A for one hour. Aqueous ammonia solution 772 (?mL) was added to the reaction mixture and the mixture was stirred at 100*C for 1 hour. ele is added to the reaction mixture; The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried on anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by silica column chromatography to give -5{( tert-butyl (aminocarbonyl) amino]-2-isobutyl-6-methyl-4-(4-methylphenyl)pyridin -3-yl]- Ye elmcdtam (Obta (01 mg; yield; 77) as white crystals. (6H, d, J = 6.6 Hz), 1.39 (9H, 5), 2.15-2.26 (1H, m), 2.39 8:0.98 (J02) 111-114 (3H, s), 2.56 (3H, 5), 2.76 (2H, d, J =7.2Hz), 4.10 (2H, d, J = 5.1 Hz), 4.24 (1H, (1H, s), 7.01 (2H, d, J = 7.5 Hz), 4 (2H, d, J = 17.5 Hz). 5.50 (brs), 4.38 ( 2H, (Y Yo get N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin- cane 4 ) 3-yl] urea dihydrochloride yield 797 (as a white powder of tert-butyl ({5-(aminocarbonyl) amino]-2-isobutyl-6-methyl-4-(4-methylphenyl)pyridin-3-yl}- YYVY

AY

Jal in milliliters) according to a method similar to that of “YY cana 0 ( methyl } carbamate (¥-Y

I H-NMR (DMSO-d ) 8: 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). © 11 Example N'-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl )pyridin-3-y1]-N,N- dimethylurea dihydrochloride tert-butyl {[5 - {[(dimethylamino)carbonylJamino }-2-isobutyl-6- we get ( 1 (# Vo mg; yield 0 A) methyl-4-(4-methylphenyl)pyridin-3-yl]-methyl } carbamate 01 {[(tert-butoxycarbonyl)amino]-methyl} -6-isobutyl-2- as a white powder of 1 mg; 1 Y) methyl-4-(4-methylphenyl) nicotinate acid 0.7 milliliters » 1) dimethylamine tetrahydrofuran and a solution? Grammolecular (1-945 gram molecule) according to the method similar to the example method.

H-NMR (CDCl; ) 8: 0.97 (6H, d, J = 6.6 Hz), 1.38 (9H, 5), 2.15-2.25 (1H, m), 2.41 0 (3H, 5), 2.51 (3H, 5) ), 2.71 (6H, 5), 2.75 (2H, d, I = 9.0 Hz), 4.08 (2H, d, J = 5.1 Hz), 423 (1H, brs), 5.32 (1H, 5), 7.02 (2H , d, J = 78 Hz), 7.24 (2H, d, J = 7.8 Hz).

N'-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-a ha aS (Y mg; yield 0 A)methylphenyl)pyridin-3-yl]-N,N -dimethylurea dihydrochloride tert-butyl {[5-{[(dimethylamino)carbonyl]amino}-2- as a white powder of ( YY oY. cpa 8 A) isobutyl-6-methyl-4-(4-methylphenyl)pyridin -3 -yl}-methyl} carbamate (P= mmol) according to the method similar to that of the example +70 ! H-NMR (WL-0150) 6:0.98 (6H, d, J = 6.3 Hz), 2.1 7-2.20 (1H, m), 2.39 (3H, s), 2.64 (9H, s), 3.09 ( 2H, brs), 3.83 (2H, brs), 7.20 (2H, d, ] =7.8 Hz), 7.31 2H, d, J = 7.8 Hz), 7.86 (1H, brs), 8.39 (3H, brs). ¥° 19 is an example

benzyl [5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyDpyridin-3- yl]carbamate dihydrochloride Juans (0) substituted on benzyl [5-{[(tert- butoxycarbonyl) amino] methyl}-6-isobutyl-2- 0 ) methyl-4-(4-methylphenyl)pyridin-3-yl] carbamate mg Yield of Yo 0© as Osh white powder of {[ (tert-butoxycarbonyl)amino]-methy! }-6-isobutyl-2- -5 Ad cpa 0 ) methyl-4-(4-methylphenyl) nicotinic acid mmol) benzyl alcohol s )¥, ¥ milliliters 01” mmol) according to the method similar to that of the example (Ve H-NMR (CDCl ) 8: 0.97 (6H, d, J 6.6 Hz), 1.38 (9H, 5), 2.13-2.16 (1H, m), 2.39 (GH, 5), 2.51 (3H, 5), 2.75 (2H, d, J = 7.2 Hz), 4.08 (2H, 5), 4.22 (1H, brs), 5.07 @ H, 0 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- (3H, m).7.36?) benzyl [5-(aminomethyl)-6-isobutyl-2-methyl-4-(4- ——1= Jaa methylphenyl)pyridin-3-yl] carbamate dihydrochloride ( 4 mg Yield (V1 as a white powder of benzyl [5-{[(tert-butoxycarbonyl) amino] methyl}-6- isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl) ] carbamate (5 mg; 1.04 mmol) according to the method similar to that of the example (FY H-NMR (DMSO-dg ) 58:0.97 (6H, d, J = 6.3 Hz), 2.15-2.22 (1H, m) , 2.39 3H, 5), (3H, 5), 2.99 (2H, 5), 3.79 (2H, 5), 5.00 (2H, 5), 7.14-7.18 (4H, m), 7.29-7.35 2.56 (5H, m), 8.29 (3H, brs), 9.08 (1H, brs). AR Example AA 5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)-3 -pyridinamine trihydrochloride (0) to a solution (0 mL) of benzyl [5-{[(tert-butoxycarbonyl) amino] methyl}- 00 ) 6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl] carbamate Yo mg 0, m gram molecule) in ethanol, palladium-carbon Jo (+ ©) mg) was added and the mixture was stirred under hydrogen atmosphere at da room temperature for two hours. The reaction mixture is filtered

The filtrate is concentrated under reduced pressure. The residue was purified by column chromatography viscous silica to give tert-butyl {[5-amino-2-isobutyl-6-methyl-4-(4-0 ( methylphenyl)pyridin-3-yl]-methyl} carbamate mg; yield 8 lb (as white powder.” H-NMR (CDCl) 8:0.94 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.09-2.16 (1H, m), 2.41 ° (3H, s), 2.42 (3H, 5), 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, I = 7.7 Hz). -methylphenyl)-3-pyridinamine trihydrochloride (; 7 mg; yield 777) as a white tert-butyl ([5-amino-2-isobutyl-6-methyl-4-(4-methylphenyl)) pyridin-3-yl}-01 0 ) methyl } carbamate totaled 1.17 mmol) according to a method similar to that of Example 7-?). H-NMR (DMSO-d¢) 5:0.94 (6H, d, J = 6.6 Hz), 1.97-2.08 (1H, m), 2.42 3H, 5), (3H, s), 2.99 (2H, 5), 3.69 (2H, 5), 5.40 ( 3H, brs), 7.26 (2H, d, J = 8.1Hz), 7.44 2.65 (2H, d, J] = 8.1 Hz), 8.38 (3H, brs).° Example 23 N-[5- (aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3- yl]methanesulfonamide dihydrochloride to Jona from tert-butyl ~ {[5-amino-2-isobutyl- 6-methyl-4-(4-0 ( methylphenyl)pyridin-3-yl]-methyl} carbamate Y. stereo; YT, + milligrams) in tetrahydrofuran? mL) YA aly Sia (0) triethylamine mM) was added and V4 5S ¥+ (methanesulfonyl chloride, + mMol) was added at room temperature. Then stir the mixture for? hours. Water is added to the reaction mixture; The mixture was extracted with ethyl acetate. The organic layer was washed with TO saturated brine and dried on anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by silica column chromatography to give oil. To a solution of oil in 1 ( ethyl acetate mL) hydrogen solution is added

YY. milliliters) and stir the mixture at room temperature for an hour. 1 (chioride ethyl acetate

N-[5- to give one hexane. The solvent evaporates under reduced pressure and the resulting substance (aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3 -y1] crystallizes as a white powder. 0 YY Yield cane YO) methanesulfonamide dihydrochloride

I H-NMR (DMSO-d¢) 8:0.97 (6H, d, J = 6.6 Hz), 2.1 8-2.24 (1H, m), 2.20 (3H, s), © 2.39 (3H, 5), 2.71 (3H, 5), 2.96 (2H, 5), 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). 001 Example N-[5-({[5-(aminomethyl )-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3- yl]amino} sulfonyl)-4-methyl-1.3 -thiazol-2-vl]acetamide dihydrochloride 0

N-[5-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-on-Ja ad methylphenyl)pyridin-3-yljamino} sulfonyl)-4-methyl-1,3 -thiazol-2-yl] tert-butyl acetamide {[5-mg; Yield 7749) as a white powder of oA) dihydrochloride amino-2-isobutyl-6-methyl-4-(4-methylphenyl)pyridin-3 -yl}-methyl} carbamate 2-(acetylamino)-4-methyl-1, 3-thiazole-5- 5 mg 7 mmol) 0 ( 0 mmol) according to a method similar to that of 1.7 mg; V1) sulfonyl chloride 44 Example I H-NMR ( DMSO-ds) 8:0.94 (6H, d, J = 6.6 Hz), 2.02 (3H, (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). [5-(aminomethyl)-2-isobutyl-6-methyl-4-( 4-methylphenyl)pyridin-3- ylimethyl} amine trihydrochloride tert-butyl {[5-(hydroxymethyl)-2-isobutyl-6-methyl-4) -(4- Cool down a mixture of (1 mmol) VA) g; sie AY 0 Ablle «,A) triethylamine ml 4,77 (ane 0+ +) methanesulfonyl chloride to zero “ghosting” and added by drip

aphd mol). After stirring at room temperature for a period (Ada Yo), the reaction mixture was poured into an aqueous sodium hydrogen carbonate solution (cassia), and the mixture was extracted with ethyl acetate. The extracted substance was dried on anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give [ 5-{[(tert-butoxycarbonyl)amino]methyl} -6-isobutyl-2-methyl-4-(4- methylphenyl)pyridin-3-yljmethyl methanesulfonate© as crude product 0 Crude product is lysed in N ,N-dimethylformamide (+¥ ml) and cana TVA (sodium azide 8.87 mmol) was added. The mixture was stirred at Ayah for Te min. The reaction mixture was diluted with 100 (ethyl acetate) and washed with saturated saline. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to give a residue. 0 A mixture of the resulting residue, palladium-carbon 701 (4 mg YY, + milligrams mole) Yo) ethanol, milliliters) was stirred under a hydrogen atmosphere at room temperature for two hours. after filtering; The solvent was evaporated under reduced pressure and the residue was purified by column chromatography significant silica to give tert-butyl {[5-(aminomethyl)-2- 0 ) isobutyl-6-methyl-4-(4-methylphenyl)pyridine- 3-yljmethyl } carbamate aggregate 0 yield 10) as yellow oil. BRS), 2.14- (1H, M), 2.41 (3H, 5), 2.64 (3H, 8S), 4.02 (2H, d, J =5.1 Hz), 4.18 (1H, brs), 2.23 (2H, d, J = 7.9 Hz), 7.25 (2H, d, J = 7.0 Hz). 7.02?) We get {[5-(Aminomethyl)-2-isobutyl-6-methyl-4-(4) -methylphenyl)pyridin- 01 lb) 3-ylmethyl}amine trihydrochloride 0 mg; yielding £99 (as a ard-colored powder of tert-butyl {[5-(aminomethyl)-2-isobutyl-6-methyl-4-(4-methylphenyl)pyridin-3-0 ( yllmethyl } carbamate c.507 mmol) according to the method similar to that of the example (FY H-NMR (DMSO-dg ) 8:0.97 (6H, d, J = 6.6 Hz), 2.13-2.24 (1H, m), 2.43 (3H, 5), (3H, s), 2.98 (2H, brs), 3.76 (4H, brs), 7.34-7.45 (4H, m), 8.51 (6H, brs).Yo 2.50 Example 011 ‏

l N-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyDpyridin-3-ylimethyl}- 4-(methylsulfonyl)benzenesulfonamide dihydrochloride 0) into solution ( 0 milliliters) of tert-butyl {[5-(aminomethy!)-2-isobutyl-6-methyl-4- YA ) (4-methylphenyl)pyridin-3-yljmethyl} carbamate mg 95 no mmol © Grammy ) triethylamine s (0,000 milligrams) in tetrahydrofuran

add (YYY) 4-(methylsulfonyl)benzenesulfonyl chloride mg; 1,895 mmol) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with 100 (ethyl acetate mL) and washed alternately with saturated sodium hydrogen carbonate evening solution and saturated saline. The organic layer was dried over anhydrous magnesium sulfate 0. The solvent was evaporated under reduced pressure and the resulting yellow solid was washed with diisopropyl ether to give tert-butyl ({2-isobutyl-6- methyl-4-(4-methylphenyl)-5-[({ [4- (methylsulfonyl)phenyl] sulfonyl } amino) (aaa 1 ) methyl]pyridin-3-yl}methyl)carbamate Yield (LAY) Yellow powder. (6H, d, J 6.6 Hz), 1.36 (9H) , 5), 2.13-2.22 (1H, m), 2.41 veo 8:0.95 (J020) I H-NMR (3H, s), 2.61 (3H, 5), 2.73 (2H, d, J = 7.4 Hz), 3.08 (3H, s), 3.83 (2H, d, J = 5.8 Hz), (2H, d, J = 4.9 Hz), 4.11-4.20 (2H, m), 6.84 (2H, d ,J=8.1Hz), 7.13 (2H,d,] 3.97 =7.7Hz), 7.77 2H, d, J = 8.7 Hz), 7.98 (2H, d, J = 5 Hz). You get N-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pVY)pyridin-3-yljmethyl} -4-(methylsulfonyl)benzenesulfonamide dihydrochloride mg; yield £99 (as an amber powder of tert-butyl ({2-isobutyl-6-methyl-4-(4- methylphenyl)-5-{( {[4-(methylsulfonyl)phenyl] sulfonyl }amino)methyl ]pyridin-3-Yo (axe 91( yl}methyl)carbamate 1 mmol) according to the method similar to that of Example 7-?). d, J = 6.6 Hz), 2.11-2.19 (1H, m), 2.35 (3H, s), Yo (3H, 5), 2.70-2.82 (2H, m), 3.31 (3H, s), 3.66 (2H, brs), 3.72 (2H, brs), 7.11- 2.50 (4H, m), 7.83 (2H, dd, J =8.3,1.3 Hz), 8.08 2H, d, J = 8.1 Hz), 8.31 (3H, brs). 7.21 Yyw

For example 0101 ethyl ({[5-(aminomethyl )-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3- yl]methyl}amino)acetate trihydro chloride 1 ( to a solution of {[(tert-butoxycarbonyl)amino]methyl} -6-isobutyl-2-methyl-4- -5[ Yoo) (4-methylphenyl)pyridin-3-yljmethyl methanesulfonate ~~ ° mg ; 6.15 mmol (tetrahydrofuran) © milliliters) add (ils Sse YYY) triethylamine « 1 mmol) 0 5 ( glycine ethyl ester hydrochloride mg ,1 mmol) and stir the mixture at AiR For UV duration, ele is added to the deli mixture and the filament is extracted with acetate to cook. The organic layer was washed with 0 saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by silica column chromatography to give -5]) ethyl methyl - 6-isobutyl-2-methyl-4-(4-methylphenyl) dilute It needs -)) 1 YAO ( pyridin-3-yljmethyl}amino)acetate +1 mg yield ( as a white powder. (6H, d, J = 6.6 Hz), 1.22 GH, t,J = 6.9 Hz), 1.38 (OH, s), 8:0.95 (J020) I H-NMR (1H, m), 2.41 (3H, 5), 2.67 (3H, 5), 2.73 (2H, d, J =7.2Hz),3.18 (2H, 5), Vo 2.15-2.22 (2H, 5), 4.02 (2H, 5), 4.09 (2H, gq, J = 6.9Hz), 4.18 (1H, brs) , 7.03 (2H, d,J 3.43 =7.8Hz), 7.25 (2H, d, J = 7.8 Hz). Joa al (Y) on ethyl ({[5-(aminomethyl)-6-isobutyl) -2-methyl-4-(4-Y) methylphenyl)pyridin-3-yljmethyl }amino)acetate trihydrochloride© mg; Yield of ae 08 7 (as a Lad-colored powder of -6-ethyl ({[5-{[(tert-butoxycarbonyl)amino methyl} 0 ) isobutyl-2-methyl-4-(4-methylphenyl)) pyridin-3-yl]methyl }amino)acetate mg; 0 mmol) according to the method similar to that of the example (FY J = 6.6 Hz), 1.18 (3H, t, I = 6.9 Hz), 2.11-2.24 with H-NMR (DMSO-dg ) 5:0.97 (6H, (1H, m), 2.42 (3H, s), 2.92 (3H, brs), 3.03 (2H, brs), 3.61 (2H, s), 3.72 (2H, brs), (2H, s), 4.08 (2H, q, J = 6.9 Hz), 7.35 (2H, d, J =8.1Hz), 7.40 2H, d, J = 8.1 Yo 4.06 Hz), 8.43 (3H, brs). Example Vet

No ({[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenylpyridin-3- yl)methyl}amino)acetic acid trihydrochloride 0) into a solution of ethyl ({[ 5-{[(tert-butoxycarbonyl)amino]methyl }-6-isobutyl-2- 0.1 cana 0 ) methyl-4-(4-methylphenyl)pyridin-3-ylimethyl}amino)acetate m© molecule Gram) in ethanol (¥ milliliters) added aqueous sodium hydroxide solution A (? milliliters) and the mixture was stirred at fA (4) for 10 hours. 1 N hydrochloric acid was added to equalize the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried on anhydrous magnesium sulfate. Cad solvent evaporates under reduced pressure to give -6-}({[5-{[(tert-butoxycarbonyl)amino]methyl isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-ylJmethyl ( amino (0 acetic acid) (57 mg yield £99) as a white powder. “H-NMR (DMSO-dg) 8:0.91 (6H, d, J = 6.3 Hz), 1.35 (9H, 5), 2.11-2.24 (1H, m), (3H, s), 2.54 (2H, 5), 2.57 (3H, 5), 2.97 (2H, 5), 3.39 (2H, 5), 3.76 (2H, 5), 6.78 2.36 (1H, brs), 7.18 (2H, d, J = 7.8Hz), 7.22 (2H, d, J = 7.8 Hz). Y 0 ( we get {[5-(aminomethyl)- 6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin- ( VO) 3-yl]methyl}aminoacetic acid trihydrochloride mg; yield (LA) as a white powder of {[(tert-butoxycarbonyl) )amino]methyl}-6-isobutyl-2-methyl-4- -5[{( qe ) (4-methylphenyl)pyridin-3-yljmethyl }amino)acetic acid mg; 0.7 mL ss gram) according to the method similar to that of Example 3-1.) , 2.42 (3H, s), Ye (3H, s), 3.01 (2H, brs), 3.52 (2H, 5), 3.72 (2H, 5), 4.04 (2H, 5), 7.35 (2H, d , J 2.89 Hz), 7.39 (2H, d, J = 8.1 Hz), 8.37 (3H, brs), 9.29 (1H, brs).=8.1

Yeo Example 4-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3 -yllmethyl}- 2-piperazinone trihydrochloride Yo tert-butyl ({2-isobutyl) -6-methyl-4-(4-methylphenyl)-5-[(3-oxo-1-) is obtained ( \ as powder AVY ( mg; yield 1 A)piperazinyl)methyl]pyridin-3- yl} methyl)carbamate stop

It is white from [(tert-butoxycarbonyl)amino]methyl} -6-isobutyl-2-methyl-4-(4-{-5[ lle 1,17 cpa Yoo)methylphenyl)pyridin-3-ylJmethyl } methanesulfonate (molecule) 5 1©) 2-piperazinone aggregate; 0710+ mmol) according to the method similar to that of Example YY (6H, d, J = 6.6 Hz), 1.39 (9H, 5), 2.14-3 (1H, m), 2.49° 8:0.96 ( j00) H-NMR (5H, 5), 2.64 (3H, 5), 2.73 (2H, d, J] = 7.2Hz), 2.89 (2H, 5), 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), (2H , d, J = 7.8 Hz). pyridin-3-ylJmethyl}-2-piperazinone trihydrochloride |0 yield 74897) as a white powder of tert-butyl ({2-isobutyl-6-methyl-4-(4-ye ) methylphenyl)-5-[ (3-0x0-1 -piperazinyl)methyl]pyridin-3-yl} methyl)carbamate mg; 1.01 mmol) according to the method similar to that of the example (FY I H-NMR (DMSO-dg ) 8:0.98 (6H, d, J = 6.6 Hz), 1.91 (2H, 5), 2.09-2.14 (1H, m), (3H, 5), 3.00 (3H, brs), 3.18 (4H, brs), 3.75 (2H, brs), 7.30 (2H, d, J = 7.5 Hz), Yo 2.42 (2H, d, J = 7.5 Hz), 7.41 (1H, brs), 8.52 (3H, brs). 7.41

Example 0101 3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3-yl]methyl }- 2,4-imidazolidinedione dihydrochloride (VY: A solution of tert-butyl {[5-(hydroxymethyl)-2-isobutyl-6-methyl-4-(4-0 ) methylphenyl)pyridin-3-ylJmethyl ( carbamate mg “YO” mmol ) VA cans ¥A) hydantoin + mmol) tributylphosphine s (40 μmol, mmol) in tetrahydrofuran (¥ml) add 1,1 1,74 aaa 1) (azodicarbonyl)dipeperidine mmol) and the mixture was stirred at YO room temperature for ; hours. The reaction mixture was concentrated and the undissolved substances were removed by filtration. The leachate was purified by silica gel column chromatography to give tert-butyl {[5-[(2,5-dioxo-1-imidazolidinyl)methyl] -2-isobutyl-6-methyl-4-(4-yvi). mg; yield £0 (as powder in color 1 A) methylphenyl)pyridin-3-yljmethyl} carbamate white. | H-NMR (CDCl; ) 8: 0.95 (6H, d, J = 6.6 Hz), 1.38 (9H, 5), 2.11-2.26 (1H, m), 2.39 (3H, 5), 2.55 (3H, 8) , 2.73 (2H, d, = 7.5 Hz), 3.77 (2H, 5), 3.99 (2H, d, J = 5.1 Ho), 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). 3- {[5-(Aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) we get (¥ mg; yield of 4 ( pyridin-3-yljmethyl} -2,4-imidazolidinedione tert-butyl dihydrochloride {[5-[(2,5-dioxo-1 -imidazolidinyl)methyl]-2- as a white powder of ( 5 according to isobutyl-6-methyl-4-(4-methylphenyl) pyridin-3-yl] methyl} carbamate 0 (YY method similar to example method 111-1148 0143 (J0-4 8:0.96 (6H, d, J = 6.6 Hz), 2.14-2.19 (1H, m) , 2.37 (3H, 9), 2.84 (3H.5), 3.11 (2H, brs), 3.71 (4H, 5), 4.35 (2H, 5), 7.18 (2H, d, J = 8.1 Hz), 7.33 ( 2H, d,J = 7.8 Hz), 8.00 (1H, brs), 8.30 (1H, brs). 4-methylphenyl)pyridin-3-ylimethyl}- 2,5-piperazinedione dihydrochloride

NN- 5 mmol) 1 g; 1 (Z-glycine) to a solution of 1) oxalyl tetrahydrofuran (μl) added in 10) dimethylformamide + mmol ); The mixture was stirred at a temperature of OF ) chloride and ethyl ({[5-{[(tert--) min. The reaction mixture was added dropwise to a solution of 0 room for butoxycarbonyl)amino]methyl ( -6-isobutyl -2-methyl-4-(4-methylphenyl)pyridin-3- μmol AV)pyridine g;?mM)0¢) yllmethyl}amino)acetate \ +) tetrahydrofuran g) in 0) 4-dimethylaminopyridine s (mmol) 0 ml) under refrigeration with ice and the mixture was stirred for ¥ hours. Water is added to the reaction mixture © The organic layer is washed with saturated brine ethyl acetate and the mixture is extracted with anhydrous. The solvent was evaporated under reduced pressure and the magnesium sulfate oil was dissolved and dried

VY

mg) and stir the mixture 001 (palladium-carbon 76 milliliters). The resulting ethanol was added at room temperature for two hours. The reaction mixture was filtered and the hydrogen was concentrated under a leachate atmosphere under reduced pressure. The resulting residue was purified by tert-butyl analysis {[5-[( 2,5-dioxo-1 -piperazinyl)methyl]-2- column chromatography to give mg VO) isobutyl-6-methyl-4-(4-methylphenyl)pyridin-3-yl] methyl} carbamate © 0 Yield: 1.8) As a white powder

I H-NMR (CDCl3 ) 8: 0.97 (6H, with J = 6.6 Hz), 1.39 (9H, 5), 2.18-2.24 (1H, m), 2.40 (3H, 5), 2.51 (3H, 5) ), 2.76 (2H, d, J =17.5Hz), 3.47 (2H, 5), 3.93 (2H, s), 4.03 (2H, d, 1- 5.1 Hz), 4.24 (1H, brs), 4.51 (ZH , s), 5.88 (1H, brs), 6.98 (2H, d, J = 7.5 Hz), 7.25 (2H, d, J = 7.5 Hz). Ve 1-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) we get (¥ (% Te collected; VE yield) pyridin-3-ylJmethyl}-2 ,5-piperazinedione dihydrochloride tert-butyl {[5-[(2,5-dioxo-1-piperazinylymethyl]-2-isobutyl-) as a white powder according to method 6-methyl-4-(4-methylphenyl )pyridin-3-yl] methyl} carbamate similar to that of Example 7-?).

H-NMR (DMSO-ds ) 8: 0.97 (6H, with J = 6.6 Hz), 2.15-2.19 (1H, m), 2.39 3H, 5), 2.69 (3H, s), 3.25 (2H, 5) ), 3.67 (2H, s), 3.73 (2H, brs), 4.31 (2H, 5), 7.1 8(2H,d,J= 8.1 Hz), 7.37 (2H, with ] = 7.8 Hz), 8.06 (1H, brs), 8.24 (3H, brs). 0118 J {[2-isobutyl-4-(4-methylphenyl )-6-phenylpyridin-3-yljmethyl amine dihydrochloride mmol) 001 g; A (acetophenone) mL of 05 ( To a solution (1 mM ethanol) was added in 10 g; A, ¢ + (p-tolualdehyde s mM) and the mixture was stirred for ½ days. Diluted 1,775 g; V) sodium hydroxide mL) and washed with saturated brine. 001) ethyl acetate Reaction mixture by Ye Solvent is evaporated under reduced pressure 0 anhydrous magnesium sulfate The organic layer is dried on To give diisopropyl ether and wash the resulting yellowish-colored solid by

Y) (2E)-3-(4-methylphenyl)-1 -phenylprop-2-en-1-one 4,1 gm (fodial) appears as a yellow powder. HNMR (CDCls) 6:2.40 ( 3H, 5), 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). (Y©Lis heated from 5-methyl-3-oxohexanenitrile (6 g; 56 mmol); acetic acid )¥, " milliliters; 0 mmol) ¢ (aa )©,{) ammonium acetate 00 milliliters) 5 YOu ( toluene milliliters) with sale) condensation Steam using a Dean-Stark trap for VY h. The reaction mixture is allowed to cool to temperature (Ad al), washed with saturated brine, and dried over anhydrous magnesium sulfate. 0 solvent is evaporated under reduced pressure to give Residue (£.0 g). The residue (0 (a > YY) is dissolved in (001 milliliters) ethanol (2E)-3-(4-methylphenyl)-1-phenylprop-2-en-1 - cilia yg one (14,¥ g; 1.6 mmol) 0,/( sodium hydroxide s g; 01 mmol). The mixture is heated with re-condensation (lad) The reaction mixture was diluted with 100 (ethyl acetate mL) and washed with saturated Sle ammonium chloride 1 The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure The resulting residue was purified by chromatography Important columnar silica to give aly es 1 A) 2-isobutyl-4-(4-methylphenyl)-6-phenylnicotinonitrile 4 ) as a yellow oil. H-NMR (CDCl ) 5:1.07 (6H, d, J = 6.8 Hz), 2.35-2.48 (4H, m), 3.06 (2H, d, J = Hz), 7.35 (2H, d,J = 7.9 Hz), 7.49-7.56 (SH, m), 7.67 (1H, s), 8.07-8.13 (1H, Ve 7.2 m).0 you get {[2-Tsobutyl-4-(4-methylphenyl)-6-phenylpyridin-3-yljmethyl} amine VV) C; Yield (TY as yellowish-colored oil of 2-isobutyl-4-(4-methylphenyl)-6- ANY pa 686 ) phenylnicotinonitrile mmol) according to the method analogous © to the example method 4-1 (0) The oil is dissolved in a standard ¢ hydrogen chloride 1,4-dioxane yo solution (mL) and the solvent is evaporated under reduced pressure. The resulting yellowish-brown solid was washed with diisopropyl ether to give {[2-Isobutyl-4-(4-methylphenyl)-6-

phenylpyridin-3-yllmethyl} amine dihydrochloride ( 4 g; yield of 16 ) as yellow powder. (6H, d, J = 6.6 Hz), 2.34-2.41 (4H, m), 2.94 (2H, 1 8: 1.03 (F01480-4 H-NMR Hz), 4.00 (2H, d, J = 5.5 Hz), 7.36 (2H, d, J = 8.2 Hz), 7.41 (2H, d,J=283 = 7.0 Hz), 7.47-7.54 (3H, m), 7.70 (1H, 5), 8.15 (2H, dd, 1 = 7.9, 1.5 Hz), 8.43 (3H, brs).° Example 011-5 (aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl )nicotinic acid maleate we get 5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)nicotinic acid ) 00, aggregate 5.80 mmol) in a mixed solvent of water (10 (lle 1©) acetonitrile s 0 milliliters) and the mixture is heated with sale) by condensing the vapor for 10 minutes. pa 8 A) malic acid 5.80 mmol) was added to the resulting solution and the mixture was stirred at the same temperature for 10 minutes. Yo + (acetonitrile in milliliters) is added to the resulting solution and the mixture is left to cool to room temperature and stirred at 0 “C for .? min. The precipitated solid is collected by filtration and washed with (1) acetonitrile (7 milliliters) B to give -5 (aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)nicotinic acid ‎TTY) maleate (yield 777) as a white powder. “H-NMR (DMSO-d) 8:0.96 (6H) , d, J = 6.6 Hz), 2.18-2.27 (1H, m), 2.37 (3H, S), (2H, d, J = 7.0 Hz), 3.79 (2H, 5), 6.01 (2H, 5 ), 7.19 (2H, d, J = 7.9 Hz), 7.29 2.74 (2H, d,J=17.5 Hz). 90 Ex. 001 5-(aminomethyl)-6-(methoxymethyl)- 2-methyl-4-(4-methylphenyl)nicotinic acid : dihydrochloride (1) stirred (£4 milliliter) solution of “an 0,A0) methyl 4-methoxycetoacetate 46 mmol) cpa 4 ,71 ( p-tolualdehyde 460 mmol) piperidine TO (740 mg ; ; mmol) Yi) acetic acids mg; ; milligrams) in isopropanol at room temperature for ? days. The solvent evaporates under adda dor a to give a residue. You get 3-methyl 5-tert-butyl 2-(methoxymethyl)-6-methyl-4-

Ya

8 or g; Product 0, Ao) (4-methylphenyl)-1,4-dihydropyridine-3,5-dhcarboxylate (g £,YV) tert-butyl 3-aminocrotonate s as yellow oil from the resulting residue This substance is dissolved (1-7 mol) according to the method similar to that of the example “0 milliliters) ¥' +) methanol in the aforementioned retarded tert-butyl 3-aminocrotonate and the mixture is heated with re-condensation of steam for 1 hour and a half The reaction mixture was concentrated under silica under reduced pressure and the residue was purified by gel column chromatography: 3-methyl 5-tert-butyl 2-(methoxymethyl)-6-methyl-4-(4-methylphenyl)-1, 4- to give .dihydropyridine-3,5-dicarboxylate H-NMR (CDCl ) &: 1.40 (9H, 5), 2.28 (3H, 5), 2.32 (3H, 5), 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, Ye 4,177 112, 7.15 (2H, d) ,] = 8.1 Hz). ) pyridine-3,5-dicarboxylate 3-methyl 5-tert-butyl 2-(methoxymethyl)-6-methyl-4-(4-methylphenyl)-1,4- mmol) according to 15 ,1 g; , 2.61 (3H, 5), 3.36 (3H, 5), 3.54 (3H, 5), 4.66 (2H, 5), 7.13-7.15 (2H, m), 7.17-7.19 (2H, m). 3-methyl 5-tert-butyl 2-(methoxymethyl)-6-methyl-4-(4-) cooled suspension of (¥ mmol) in BAY combination VT VA)methylphenyl)pyridine-3, 5-dicarboxylate 0 mole solution (1.90 mL) to -78"C and add dropwise (©+) toluene mL; 4.5 mMol (©) diisobutylaluminum hydride toluene to dry under dd 90 min. The mixture was stirred at -7/8"C for 11 minutes to the reaction mixture and methanol added. Add 01 0C and stirred also for 1 g; 9.8 mmol). The mixture was stirred at room temperature (AY) sodium sulfate 10 hydrate 8 for one hour. The insoluble matter is removed by filtration and the silica is concentrated under reduced pressure. The residue was purified by gel column chromatography

YAN tert-butyl ~~ 5-(hydroxymethyl)-6-(methoxymethyl)-2-methyl-4-(4- to give_ci) mg yield 777) as yellow oil. AY +) methylphenyl) nicotinate

H-NMR (CDCl; ) 8: 1.21 (9H, 5), 2.39 (3H, 5), 2.59 (3H, 5), 3.50 (3H, 5), 4.39 (2H, d,] = 6.8 Hz), 4.76 (2H, 5), 7.21 (4H, 5). tert-butyl 5-(hydroxymethyl)-6-(methoxymethyl)-2-methyl-4-(4-) cooled mixture of ( ¢ oo triethylamine ¢ mmol) 11 mg 0 ) methylphenyl) nicotinate milliliters) to ¥ +) tetrahydrofuran s in milligrams) £08 “lille +7 9 milliliters; 7,460 mL +, ¥ (methanesulfonyl chloreide “C” and add joa dropwise. Dilute the reaction mixture (Aids “0 mol). After stirring at room temperature for a period of 100 mL) and washed with 001 (ethyl acetate) solution with 0 saturated aqueous. The organic layer was dried over sodium hydrogen carbonate lamate; the solvent was evaporated under reduced pressure. The residue was dissolved in magnesium sulfate (4.54 mg; sodium azide (197 mL) and 01) was added. N,N-dimethylfirmamide to ethyl acetate mol). The mixture was stirred at 00 “”C for 1 hour. The reaction mixture was added; the mixture was washed sequentially by water and saturated brine and dried over anhydrous Vo. The solvent was evaporated under reduced pressure stirred residue mixture; magnesium sulfate 01 (ethanol 5 mmol) + TTY mg; mL) under the solvent atmosphere under reduced pressure and the resulting residue was purified by chromatography tert-butyl 5-(aminomethyl)-6-(methoxymethyl)-2-methyl- to give columnar silica gel 0 cane V+ +) 4-(4-methylphenyl)nicotinate productivity; No %) as yellow oil. I H-NMR (CDCl; ) 8:1.19 (9H, 5), 2.40 (3H, 5), 2.57 (3H, 5), 3.48 (3H, 5), 3.63 (2H, (2H, 5), 7.12 (2H, d, J = 8.1 Hz), 7.23 (2H, d, J = 7.7 Hz). 5, 4.69 m) you get 5-(aminomethyl)-6- (methoxymethyl)-2-methyl-4-(4-methylphenyl) cane OY) nicotinic acid dihydrochloride Yo (LAE) yield as a white powder of tert-butyl 5-(aminomethyl)-6-(methoxymethyl)- 2-methyl-4-(4-methylphenyl) YY\W

YAY

mmol) according to the method similar to that of 0.14 cana 001(nicotinate) 1-7 4 Example H-NMR (DMSO-ds) 8:2.37 (3H, 5), 2.53 (3H, s) ), 3.41 (3H, 5), 3.86 (2H, 01-7)

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). 111 as oe 5,6-bis(aminomethyl)-2-methyl-4-(4-methylphenyl)nicotinic acid trihydrochloride ©,¥V) ethyl 3-amino-4-[(tert-butoxycarbonyl) amino] but- 2-enoate We obtain 1) ethyl 4-[(tert-butoxycarbonyl) amino]-3- yielding £99 (as yellowish oil of oa mmol) according to the method similar to that of YY pa 0,€ ) oxobutanoate.”-0118 Example Ye

H-NMR (CDCl3) 5: 1.26 3H, t, J = 7.2 Hz), 1.46 (9H, 5), 3.77 (2H, d, J] = 6.6 Hz, 4.12 (2H, q, J = 7.1 Hz) , 4.55 (1H, 5). mmol); ) p-tolualdehyde in milliliters) at room temperature for one day. +, Y) ethanol (milligrams) N° milliliter) and washed with brine 001) ethyl acetate The reaction mixture was diluted with anhydrous and evaporated The solvent under pressure magnesium sulfate saturated The organic layer was dried on ethyl 3-amino-4-[(tert-butoxycarbonyl) amino] but-2- 5 reduced The residue stirred min and also stirred Ye mmol gram) at #01 “C for a period of YY g 0,YV) enoate for a period of 2 hours. The resulting mixture was purified by column chromatography Like Te at Yo 3-ethyl 5-tert-butyl 2-{[([( tert-butoxycarbonyl) amino] methyl }-6- to give silica gel pa, 40 ) methyl-4-(4-methylphenyl)-1,4-dihydropyridine-3,5-dicarboxylate as a yellow oil. (TVA Yield 111-1118 (CDCl; ) 58: 1.22-1.28 (3H, m), 1.40 (9H, 5), 1.46 (9H, 5), 2.27 (6H, 5), 4.04-4.18 (3H , m), 4.37-4.44 (1H, m), 4.87 (1H, 5), 5.35 (1H, brs), 7.01 @H,d,J= Yo 7.9 Hz), 7.15 (2H, d, ] = 8.1 Hz ).

VAY

3-ethyl 5-tert-butyl 2-{[(tert-butoxycarbonyl) amino] methyl}-6- we get )" (799 cf yield 84 ) methyl-4-(4-methylphenyl)pyridine-3 ,5-dicarboxylate 3-ethyl 5-tert-butyl 2-{[(tert-butoxycarbonyl) amino] methyl}- as yellow oil of 58 g ) 6-methyl-4-(4-methylphenyl)-1 ,4-dihydropyridine-3,5-dicarboxylate (molecule) according to the method similar to that of Example 3-7). Ae 4,00 0 ' H-NMR (CDCl3) 8:0.93 (3H, t, J = 7.2 Hz), 1.23 (9H, 1 47 (9H, 5), 2.37 (3H, 3), 2.61 (3H, 5), 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).tert-butyl 6-{[(tert-butoxycarbonyl)amino] methyl} -5- on Jaa;) (FAY Cm; Yield 08 ( (hydroxymethyl)-2-methyl-4-(4-methylphenyl)nicotinate Ve 3-ethyl 5-tert-butyl 2-{[ (tert-butoxycarbonyl)amino] methyl}- as a yellow oil of g ; mmol 1,1) 6-methyl-4-(4-methylphenyl)pyridin-3,5-dicarboxylate (FY + g ) according to the method similar to the example method ' H-NMR (J00) 8: 1.20 (9H, 5), 1.46 (9H, 5), 2.39 (3H, 5), 2.57 (3H, s), 3.38 (1H , brs), 4.46 (2H, with 1 = 6.0 Hz), 4.54 (2H, d, J = 5.8 Hz), 5.87 (1H, brs), 7.18 2H, d,J 1° - 8.3 Hz), 7.21 (2H, d, J = 8.3 Hz). tert-butyl 5-(aminomethyl)-6-{[(tert-butoxycarbonyl)amino]methyl}- (0 mg; yield 0 74) is obtained as a powder in color ©80( 2-methyl-4-(4) -methylphenyl)nicotinate tert-butyl 6-{[(tert-butoxycarbonyl)amino] methyl}-5-(hydroxymethyl)-2- white mmol) according to VIVA C 058 ( methyl-4 -(4-methylphenyl)nicotinate 0.4-0111.) Similar method to example 111-1111 (CDCls ) 58: 1.18 (9H, 5), 1.49 (9H, 5), 2.39 (3H, 5), 2.56 ( 3H, 5), 3.62 (2H, s), 4.58 (2H, 1L = 4.7 Hz), 6.22 (1H, brs), 7.10 (2H, d,J=8.1Hz), 7.22 2H, d, J = 7.9 Hz). 5,6-bis(aminomethyl)-2-methyl-4-(4-methylphenyl)nicotinic acid on Ja a3 (1 Yo total yield £99) as a yellow solid of (0 +) tert-butyl trihydrochloride 5-(aminomethyl)-6- {[(tert-butoxycarbonyl)amino]methyl }-2-methyl-4-(4-

p 0.71 (pas 08 0( methylphenyl)nicotinate mmol) according to the method similar to that of Example 4 1-7 (3H, s), 2.57 (3H, 5), 3.84-3.89 ( 2H, m), 4.51 -4.61 8:2.37 (Y-01150) 111-1111 (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). © Ex 111 5-(aminomethyl)-6-hydroxy-2-methyl-4-(4-methylphenyl)nicotinic acid hydrochloride (1) stir mixture of tert-butyl acetoacetate ) 5 g 1 milligram); can £,0)) p-tolualdehyde ~~ V: 7.5 mmol); “alle 1,7 1( piperidine ¥ mmol) 5 Y) ethanol, + milliliters) at room temperature for one day. The reaction mixture was diluted with 100 (ethyl acetate) and washed with saturated saline. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. volatility of the resulting residue; T+ can 6.9( ethyl cyanoacetate mmol 0) 5 11.1 ( ammonium acetate g; 10051 mmol) at Ase Ee for ? hours. The reaction mixture was diluted with 100 (ethyl acetate mL) and washed with a saturated Al “sodium hydrogen carbonate” solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on a silica gel to give (AY) tert-butyl 5-cyano-6-hydroxy-2-methyl-4-(4-methylphenyl)nicotinate | 0 g; Yield 74) as a white solid. H-NMR (CDCl; ) 8:1.19 (9H, s), 2.41 (3H, 5), 2.57 (3H, 5), 7.24-7.31 (4H, m). Joa ai (Y on tert) -butyl 5-(aminomethyl)-6-hydroxy-2-methyl-4-(4- methylphenyl)nicotinate as a white solid of tert-butyl 5-cyano-6-hydroxy-2- methyl- 4-(4-methylphenyl)nicotinate 8 ( 4 »; g 1.08 mmol) according to the method similar to that of Example 1- ;). Jaan then on tert-butyl 5-{[(tert-butoxy carbonyl) amino] methyl} -6-hydroxy-2-methyi-4-(4-)

Yield Ae 777) as a colorless oil according to method 0? (methylphenyl)nicotinate

VY similar to the example method

H-NMR (CDCl3) 6: 1.13 (9H, s), 1.39 (9H, 5), 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). 5-(aminomethyl)-6-hydroxy-2-methyl-4-(4-methylphenyl)nicotinic (yield 749 ¥ °) is obtained as a white solid of cane VV) acid hydrochloride tert-butyl 5-{ [(tert-butoxy carbonyl) amino] methyl} -6-hydroxy-2-methyl-4-(4-mM) according to method 4960 aaa 0 ( methylphenyl) nicotinate 1-7 4 .) similar to method example

I H-NMR (DMSO-ds) 5:2.33 (3H, 5), 2.35 (3H, 8), 3.51 (2H, 5), 7.15 2H, d,J=79

Hz), 7.26 (2H, d, J = 7.9 Hz), 7.94 (3H, brs), 12.42 (1H, 1 2.74 (1H, s).01“ J 5-(aminomethyl)-N.6-diisobutyl-2 -methyl-4-(4-methylphenylnicotinamide ditrifluoroacetate 5-{[(tert-butoxycarbonyl)amino]methyl} -6-isobutyl-2-methyl-4-(4-Vo isobutylamine molecule; 0.00 mmol) 4 ( methylphenyl)nicotinic acid mg ; V1) 1-hydroxy-1H-benzotriazole mmol 1097 mg 0,7) 1-ethyl-3-(3-dimethylaminopropyl)cardiimide mmol) and +, 0 VY comprising 097 mmol) in a solvent mixture of 1 ¥,A) hydrochloride (mL); The mixture was stirred +, ¢) dichloromethane (ml) 017 *(N,N-dimethylformamide 0 ml) ¥) dichloromethane for two days. The reaction mixture was diluted by 1 4500 at saturated aqueous (+0,0 mL) sodium hydrogen carbonate and washed sequentially with solution (mL) to layer Y) trifluoroacetic acid and saturated saline (+0,0 mL). Add the organic and stir the mixture for two hours. The solvent was evaporated under reduced pressure and the 5-(aminomethyl)-N,6-diisobutyl-2- primer was purified to give the residue HPLC by Ye analysis g 27% (as YY oil, €) methyl-4-(4 -methylphenyl)nicotinamide ditrifluoroacetate in yellow.

YYvww

YAR

A ((M+1) EIMS According to the following tables, amines s nicotinic acids from 114-168 make the compounds of the examples

VY we obtain the compounds of the examples. © 1 Table (M+1) 2CF;COOH FIA 4-Me-Phenyl Fl yyw

H,C 2CF;COOH FA 4-Me-Phenyl H VY

HC ~N- 2CF;COOH YA. 4-Me-Phenyl A Vio a 2CF;COOH ‘Ly 4-Me-Phenyl H 117

QA N— 2CF;COOH $41 4-Me-Phenyl i YAY

Sh H 2CF;COOH YAS 4-Me-Phenyl 0 H YA

H NON 0 J 2026001 sold 4-Me-Pheny! H 115 or

HO

2CF;COOH ‘vn 4-F-Phenyl H \Y. og"

HO

2CF;COOH so 2,6-di-F-Phenyl H 1171 6

HO

2CF;COOH £7. 4-Me-Phenyl 0 No H.C. 0 text( N —_

YAY

2CF3COOH 8 4-F-Phenyl 0 CL H, Cw OL H 0

N— 2CF;COOH M 2,6-di-F-Phenyl 0 77

H ye( nu H 0

N— 2CF,COOH ov. 4-Me-Phenyl H vo

Oo H 200001 ve 4-F-Phenyl 0 Tr © N— 2CF;COOH oY 2,6-di-F-Phenyl H B © N— 1 Table CSA (M+1 ) 2CF,COOH coy 4-Me-Phenyl 0 1 A has N - 2CF;COOH $6. 4-F-Phenyl Cl H 1759 An N— 2CF;COOH 67 2,6-di-F-Phenyl Cl Hi and An An N - 2CF;COOH TY 4-Me-Phenyl H \ YY

Qk

Cl 2CF;COOH M0 4-F-Phenyl H Ps 7 0

Cl 2CF;COOH 6 2,6-di-F-Phenyl H yey ol

Cl 2CF;COOH $y 4-Me-Phenyl H + 0 J N= 2CF;COOH £4. 4-F-Phenyl H and cl” J N= 2CF;COOH OA 2,6-di-F-Phenyl H yy 07 J N=

YAA

2CF;COOH 7 4-Me-Phenyl H VY

HyCu On N= 0 2CF;COOH iVY 4-Me-Phenyl J TVA

H,C NO N- 2CF;COOH $Y 2,6-di-F-Phenyl {i 4

He 0 N— 2CF;COOH vos 4-Me-Phenyl H 4

HEN

CH, oe oe

Vids

HA EIMS -R -NR>*R" Example (M+1) 2CF;COOH YA 4-Me-Phenyl HC "4

H.C.N—

N— 0 | 1 ' 0 1 b l

N—

N— 2CF;COOH YAS 4-Me-Phenyl CH, YEA Grinding Mill M 2CF,COOH | 2,6-di-F-PhenylCH, | 4

H.C. grinding N— oo 0 a"

2CF;COOH ¢ y 0 2,6-di-F-Phenyl CH, 1 0 1 a" 2CF3;COOH £11 4-Me-Phenyl CH, Voy QL N—g 0 2CF;COOH 7 4-Me-Phenyl N= 3 and H,C—0 2CF;COOH $Y A 4-F-Phenyl 0 Voi N— 3 n H.C—0 2CF ;COOH 'en 2,6-di-F-Phenyl a yoo N- - H.C—0 Ng 3CF;COOH 'ov 4-Me-Phenyl 0 6 la halash 1 4-F-Phenyl Ql \oV 1C30 NY N= 3CF;COOH 7/1 4-Me-Phenyl NN \ oA OO Jen § Example HA EIMS -NR'*R™ (M+ 1) 14 Te( 3CF;COOH savy 4-Me-Phenyl NY KN- 3CF;COOH Te 4-F-Phenyl Cl "2 4 lahash 2CF;COOH vos 4 Me-Phenyl 0 H 11 H,C AN—

Va. $00 4-Me-Phenyl H YY

Co

N

H

{04 4-F-Phenyl H 1S

N--

N

H

Fa 2,6-di-F-Phenyl H Vv ¢

Co

N

H

2CF;COOH VAL 4-F-Phenyl Vio no z 2CF;COOH ‘ox 2,6-di-F-Phenyl 111 © 2CF;COOH vis 4-F-Phenyl CH, VY

H .C ~N— 2CF;COOH vy 2,6-di-F-Phenyl CH, VA

H 3 H N— Ex. 10195 4-(methoxycarbonyl)benzyl 5-(aminomethyl)-6-isobutyl-2-methyl-4-(4- methylphenyl)nicotinate dihydrochloride 0) to a solution of Yo ) milliliters) of 5-{[(tert-butoxycarbonyl)amino methyl }-6-isobutyl- 2-methyl-4-(4-methylphenyl)nicotinic acid ~~ ° )? g; 4.05 mmol) in N,N-dimethylformamide added 17 ( methyl 4-(bromomethyl)benzoat g 5.77 mmol) 1 5 ) potassium carbonate g; 1.77 mmol ) and the mixture was stirred at room temperature for VE 1 hour. The reaction mixture was diluted with ethyl 001 (mL acetate) and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate 0 and the solvent was evaporated under reduced pressure. The resulting residue was purified by Jan chromatogram in a silica column to give 4-(methoxycarbonyl)benzyl 5- {[ (tert-butoxycarbonyl)amino]methyl ( -6-isobutyl-2- 1,0 ) methyl-4-(4-methylphenyl)nicotinic g; Yield 97 *( as a colorless oil.

I H-NMR (CDCl): 8:0.96 (6H, d, J = 6.6 Hz), 1.38 (9H, 1 4-2.25 (1H, m), 2.35 (3H, 5), 2.54 (3H) , 5), 2.78 (2H, d, ] = 7.2 Hz), 3.93 (3H, 5), 412 (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, 1- 8.3 Ha).4-(methoxycarbonyl)benzyl 5-(aminomethyl)-6-isobutyl-2- 4-methyl-4-(Y©, yield £9) is obtained as a cane-colored powder; 71( (4-methylphenyl)nicotinate dihydrochloride 4-(methoxycarbonyl)benzyl 5- {[(tert-butoxycarbonyl)amino }methyl ( -6- of a mMol AY G5) isobutyl-2-methyl-4-(4-methylphenyl)nicotinate (TY gram) according to a method similar to that of Example 111-1111 (DMSO-dg ) 8: 0.96 (6H, d, J = 6.8 Hz), 2.20 (1H, m), 2.34 (3H, 5), 2.85 01 (2H, d, J = 6.6 Hz), 3.80 (2H, d, J = 5.3 Hz), 3.87 (3H, 5), 5.07 (2H, 5), 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).1 Example 4-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3- yl]carbonyl } oxy)methyl benzoic acid dihydrochloride Yo 4-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl- we get ( \ (aaa 6 ) 4-(4 -methylphenyl) pyridin-3-yl]carbonyl}oxy)methyl]benzoic acid 4-(methoxycarbonyl)benzyl 5-{[(tert- yield 777) as a colorless oil of butoxycarbonyl)amino]methyl}-6-isobutyl- 2-methyl-4-(4-methyiphenyl)nicotinate (1-49 mmol) .) according to the method similar to the example method 1,976 c VY ( 0

H-NMR (J000) 5:0.97 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.16-2.27 (1H, m), 2.35 (3H, 5), 2.55 (3H, 5) ), 2.79 (2H, d, J = 7.4 Hz), 4.12 (2H, s), 4.22 (1H, brs), 5.00 (2H, 5), 7.02 (2H, d, J] = 7.7 Hz), -7.06 7.14 (4H, m), 7.99 (2H, d, J = 8.3 Hz). 4-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) ?) we get the yield of cane YYT)pyridin-3-yl]carbonyl}oxy)methyl benzoic acid dihydrochloride 8 4-[({[5-{[(tert-butoxycarbonyl)amino]methyl]-6-b) as a white powder of isobutyl-2-methyl-4-(4-methylphenyl)pyridin- 3-yljcarbonyl ( oxy)methyl]benzoic

<7 According to the method similar to that of (ala mmol +, TYY pane YY) acid (FY "H-NMR (DMSO-dg) 8:0.95 (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).°

IVY Example 2-amino-2-thioxoethyl S-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) nicotinate dihydrochloride 5-{[(tert-butoxycarbonyl)amino]methyl}-6 -isobutyl- to a solution (+0 mL) of (1 mmol) in Vi YY aa ¥) 2-methyl-4-(4-methylphenyl)nicotinic acid 0 mL 4.80 mmol 7 ) bromoacetonitrile added N,N-dimethylformamide mmol) and the mixture was stirred 01.9 g; 0Y), potassium carbonate (ool > ethyl acetate) at room temperature for 1 h. The reaction mixture was diluted by milliliters) and washed with saturated saline. The organic layer was dried on anhydrous 100 and the solvent was evaporated under reduced pressure. The residue magnesium sulfate 0 cyanomethyl 5-{[(tert-) was purified to give the resulting silica by gel column chromatography butoxycarbonyl) amino]methyl }-6-isobutyl-2-methyl-4-(4-methylphenyl)nicotinate Yellow solid. (HAG yield cpa Y,VA) “H-NMR (J00) 6:0.98 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.19-2.28 (1H, m), 2.39 (3H, 5), 2.56 (3H, 5), 2.80 (2H, d, J = 7.2 Hz), 4.17 (2H, d, 1 = 4.9 Hz), 4.24 (1H, Ye brs ), 4.50 (2H, s), 7.05 (2H, d, J = 8.1 Hz), 7.24 (2H, d, J = 7.9 Hz).cyanomethyl 5-{[(tert-mL) of YO) in hydrogen sulfide inflate solution (¥ butoxycarbonyl) amino]methyl }-6-isobutyl-2-methyl-4-(4-methylphenyl)nicotinate mL; 1.107 mL +4) triethylamine 5 mmol) 1 ,11 g; Y,VA) for one hour. The solvent was evaporated under N (N-dimethylformamide) in µl. The solution was washed with ethyl acetate (001) under reduced pressure and the residue was diluted by anhydrous. The solvent under magnesium sulfate was evaporated by saturated brine and dried over yyw

Vay diisopropyl ether under reduced pressure and the resulting yellow solid was washed by 2-amino-2-thioxoethyl 5-{[(tert-butoxycarbonyl)amino}methyl}-6-isobutyl-2- to give a yield of 744) as a substance brown solid (cpa YAY) methyl-4-(4-methylphenylnicotinate yellowish. 111-1114 (CDCl; ) 5:0.98 (6H, d, J = 6.6 Hz), 1.39 (9H, 5), 2.19- 2.28 (IH, m), 2.40 © (3H, s), 2.56 3H, 5), 2.79 (2H, with ] = 7.4 Hz), 4.14 (2H, d, J = 4.5 Hz), 4.22 (1H, brs), 4.80 (2H, 5), 6.21 (1H, brs), 6.98 (1H, brs), 7.13 (2H, d, J = 7.9 Hz), 7.27 (2H, d, J = 7.5 Hz). 2-amino-2-thioxoethyl 5-(aminomethyl)-6-isobutyl-2-methyl-4-(4- obtain (V as solid color (% V+ yield cane Y YY) methylphenylnicotinate dihydrochloride 0 2-amino-2-thioxoethyl 5-{[(tert-butoxycarbonyl)amino]methyl}-6- fluorine of mM 417 cana 001( isobutyl-2-methyl-4-(4-methylphenyhnicotinate (YY) Grammy) according to the method similar to the example method

H-NMR (01150-0) 8:0.97 (6H, d, J = 6.6 Hz), 2.16-2.27 (1H, m), 2.37 (3H, 5), 2.58 (3H, 5), 2.83 (2H , with J = 6.2 Hz), 3.83 (2H, d, ] = 5.7 Hz), 4.45 (2H, 5), 7.21 yo (2H, d,] = 7.7 Hz), 7.29 (2H, d, J = 7.9 Hz), 8.16 (3H, brs), 8.98 (1H, brs), 9.85 (1H, brs). Example A [4-(ethoxycarbonyl)-1,3-thiazol-2-yljmethyl 5-(aminomethyl)-6-isobutyl-2-methyl- 4-(4-methylphenylnicotinate dihydrochloride Ye. 2-amino-2-thioxoethyl) 5-(aminomethyl)-6-isobutyl-2- (js to mixed solution) 1 molecule lle,1 aa 7 ) methyl-4-(4-methylphenyl)nicotinate saturated aqueous dihydrochloride sodium hydrogen carbonate mL (- +) tetrahydrofuran (mL) in mmol (5.01 mg; 447 benzyl chloroformate) mL (10) was added and the mixture was stirred at room temperature for one hour. reaction by VO mL) and washed with saturated saline. The organic layer (001) ethyl acetate was dried and the solvent was evaporated under reduced pressure. The residue SY magnesium sulfate was purified over

2-amino-2-thioxoethyl 5- to give the silica obtained by gel column chromatography ({[benzyloxy)carbonyl]amino} methyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) as a substance Pale yellow solid. (ZAY g; Y yield) nicotinate

I H-NMR (CDCl; ) 8: 0.97 (6H, d, J = 6.6 Hz), 2.16-2.25 (1H, m), 2.39 (3H, 5), 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=17.9Hz), 7.29-7.36 (5H, m). 2-amino-2-thioxoethyl 5-({[benzyloxy)carbonyl] mL) of V+) heated to a solution of )" CGDM) amino }methyl)-6-isobutyl-2-methyl-4- (4-methylphenyl)nicotinate with ethanol reconstituted (g; © milliliters) in 0.1 A) ethyl bromopyruvate (5 milligrams) (0 milliliters) (001) ethyl acetate Steam condensation for 1 hour. Dilute Reaction mixture with saturated aqueous. The organic layer was dried over sodium hydrogen carbonate and washed with anhydrous. The solvent was evaporated under reduced pressure and the residue [4-(ethoxycarbonyl)-1,3-magnesium sulfate was purified to give silica produced by gel column chromatography thiazol-2-yljmethyl 5-({[(benzyloxy)carbonyl]amino ymethyl)-6-isobutyl-2-methyl- 0 as colorless oil. ) 700 cpa yield Y,TV ) 4-(4-methylphenyl)nicotinate

H-NMR (CDCl; ) 8: 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, 5), 2.56 (3H, 5), 2.82 (2H, d, J = 7.2 Hz), 421 (2H, d, J = 5.3 Ha), 4.44 (2H, q, J = 7.0 Hz), 5.03 (3H, 5), 5.22 (2H, 5), 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). Ye. [4-(ethoxycarbonyl)-1,3-thiazol-2-ylJmethyl 5-({[(benzyloxy)carbonyl] ?) di-soluble an VY, vv) amino ymethyl)-6-isobutyl-2-methyl -4-(4-methylphenyl)nicotinate milliliter) and stir 1 (771 hydrogen bromide acetic acid milligram) in a solution one minute. The solvent was evaporated under reduced pressure and Ye melted the mixture at room temperature for

Y+) saturated aqueous sodium hydrogen carbonate residue produced by adding a solution of Yo 0.07 g ( di-tert-butyl dicarbonate mL). Add (© +) tetrahydrofuran 5 milliliters) h. dilute 11 mmol) and stir the mixture at room temperature for 1

105 ml) and washed with saturated brine. Yeo) ethyl acetate The reaction mixture was anhydrous. The solvent was evaporated under reduced pressure, magnesium sulfate, the organic layer was dried on [4-] to give silica, and the resulting residue was purified by gel column chromatography (ethoxycarbonyl)-1,3-thiazol-2-ylJmethyl 5-{[( tert-butoxycarbonyl)amino]methyl}- as oil (% VA gm yield ,VY) 6-isobutyl-2-methyl-4-(4-methylphenyl)nicotinate 0 . Colorless "H-NMR (CDCl3) 6:0.97 (6H, d, J = 6.6 Hz), 1.38 (9H, 5), 1.42 (3H, t, ] = 7.2 Hz), 2.17-2.27 (1H, m), 2.33 (3H, s), 2.56 (3H, 8), 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). Ye [4-(ethoxycarbonyl)-1,3-thiazol-2-ylJmethyl 5-(aminomethyl)-6- ;) you get a yield of cane ¥YY) isobutyl-2-methyl-4-(4-methylphenyl )nicotinate dihydrochloride [4-(ethoxycarbonyl)-1,3-thiazol-2-yllmethyl 5-{[(tert- as a white powder of “0 4 butoxycarbonyl)amino]jmethyl }-6-isobutyl-2-methyl- 4-(4-methylphenyl)nicotinate. )-" to" milligrams) according to a method similar to example cane ¥VY) yo "H-NMR (DMSO0-d¢) 8:0.96 (6H, has J = 6.6 Hz), 1.32 (3H, t, ] = 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). [({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3- Ye yl]carbonyl } oxy)methyl]-1,3-thiazole-4-carboxylic acid dihydrochloride 2-[({[5-{[(tert-butoxycarbonyl)amino methyl }-6-isobutyl-2-methyl- we get () 4-(4-methylphenyl)pyridin-3-yl]carbonyl } oxy) methyl]-1,3-thiazol-4-carboxlic acid [4-(ethoxycarbonyl)-1,3-thiazol-2-collective; yield £90 (as colorless oil of V, YY) ylmethyl 5-{[( tert-butoxycarbonyl)amino]methyl } -6-isobutyl-2-methyl-4-(4- +0 mmol) according to method 0.01 g; 7 4(methylphenyl)nicotinate i 1-4 Similar to the yan example method

H-NMR (CDCl3) 6: 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-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) you get ( Y pyridin-3-yl]carbonyl} oxy)methyl]-1,3- thiazole-4-carboxylic acid dihydrochloride © 2[(L[5-{[(tert-) as pale yellow powder of (LAY mg; yield FY) butoxycarbonyl)amino]methyl ( -6-isobutyl-2-methyl) -4-(4-methylphenyl)pyridin-3- mM 81 mg 0 ) yl]carbonyl }oxy)methyl}-1,3-thiazol-4-carboxlic acid (FY molecule) according to the analogous method For example method ' H-NMR (DMSO-ds ) 5:0.96 (6H, d, J = 6.6 Hz), 2.16-2.27 (1H, m), 2.30 (3H, s), Ve 2.53 (3H, s), 2.85 (2H, d, J = 7.0 Hz), 3.80 (2H, d, J = 5.1 Hz), 5.29 (2H, 5), 7.12 (4H, s), 8.21 (3H, brs), 8.48 (1H, s) 1174 Example [4-(aminocarbonyl)-1,3-thiazol-2-ylJmethyl 5-(aminomethyl)-6-isobutyl-2-methyl- 4-(4-methylphenyl)nicotinate dihydrochloride 1 [4-(aminocarbonyl) )-1,3-thiazol-2-ylJmethyl 5-{[(tert-butoxy you get (1 01 ) carbonyl) amino] methyl}-6- isobutyl-2-methyl-4-(4-methylphenyl)nicotinate 2-[({[5-{[(tert-butoxycarbonyl)amino] as a colorless oil of (XV yield) cane methyl }-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3) -yl]carbonyl } oxy)methyl] mmol) according to 019 mg"; 10 Y) -1,3-thiazole-4-carboxylic acid 00 (VY) method similar to the example "H-NMR (J020) 8:0.97 (6H, d, J = 6.6 Hz), 1.38 (9H, 5), 2.18-2.27 (1H, m), 2.33 (3H, s), 2.57 (3H, 8), 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, ] = 7.9 Hz), 8.13 (1H, s). Yo[4-(aminocarbonyl)-1,3-thiazol-2-ylmethyl 5-(aminomethyl)-6- you get (V aggregate; yield 0 A) isobutyl-2-methyl-4-(4- methylphenyl)nicotinate dihydrochloride

Qa 44 7) as a white powder of [4-(aminocarbonyl)-1,3-thiazol-2-yl methyl 5-{[(tert- butoxycarbonyl)amino methyl} -6-isobutyl-2-methyl-4 -(4-methyiphenyl)nicotinate 0 ) total 877 mmol) according to the method similar to that of Example 7-?). H-NMR (DMSO-d) §:0.96 (6H, d, J = 6.6 Hz), 2.18-2.27 (1H, m), 2.30 (3H, s), (3H, s), 2.79-2.89 (2H, m), 3.79 (2H, d, J = 5.5 Hz), 5.28 (2H, s), 7.12 (4H, s), 2.53° (1H, brs), 7.66 (1H, brs), 8.22 (3H, brs), 8.48 (1H, s). 7.62 Ave Joe [(2,2-dimethylpropanoyl)oxy]methyl 5-(aminomethyl)-6-isobutyl-2-methyl-4-(4- methylphenyl)nicotinate dihydrochloride (1 0) to a solution (00 milliliters) of 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl- V0 ) 2-methyl-4-(4 -methylphenyl)nicotinic acid total Sle 7.71 mol) in N,N-dimethylformamide add chloromethyl pivalate (09, + milliliters 4.04 milligrams) 5 cpa +,4Y) potassium carbonate 2 ,77 mmol) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl 001 (0 mL acetate) and washed with saturated brine. The organic layer was dried on anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by silica gel column chromatography to give -2,2)] dimethylpropanoyl)oxy]methyl 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl- cpa 1,1 A) 2-methyl-4-(4-methylphenyl)nicotinate (yield £90) as yellow oil. H-NMR (CDCl; ) 8:0.97 (6H, d, J] = 6.6 Hz), 1.16 (9H, s), 1.39 (9H, s), 2.14-2.29 Ye (1H, m), 2.38 (3H, s), 2.54 (3H, 5), 2.78 (2H, d, J = 7.4 Hz ), 4.13 (2H, d, J] = 4.9 Hz), (1H, brs), 5.57 (2H, s), 7.06 (2H, d, J = 8.1 Hz), 7.20 (2H, d, J = 7.9 Hz). methylphenyl)nicotinate dihydrochloride g; yield 14%) as a white Yo-solid of [(2,2-dimethylpropanoyl)oxy]methyl 5-{[(tert-butoxycarbonyl) ea 1 A) amino]methyl} -6-isobutyl-2-methyl-4-(4-methylphenyl)nicotinate 5.19 mmol) according to a method similar to that of the example (PY?

YEA

H-NMR (DMSO-d ) 8: 0.96 (6H, d, J = 6.6 Hz), 1.09 (9H, 5), 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).

IVA Example (5-methyl-2-0x0-1,3-dioxol-4-yl)methyl 5-(aminomethyl)-6-isobutyl-2-methyl-4-(4- methylphenylnicotinate dihydrochloride 5-{[ (tert-butoxycarbonyl)amino]methyl }-6-isobutyl- mL) of Y.) to solution (1 mmol) in 7.71 g; 1,9 (1) 2-methyl -4-(4-methylphenyDnicotinic acid m ) 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one added N,N-dimethylformamide g 1.17mmol +, YF ) potassium carbonate s total; 4.04 milligrams (0 gram) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted (mL) and the mixture was washed with saturated saline. 001(ethyl acetate) was dried by anhydrous solution. The solvent was evaporated under reduced pressure and the organic layer magnesium sulfate was purified on (5-methyl-) to give silica as the residue obtained by gel column chromatography 2-0x0-1 ,3-dioxol-4-y)methyl 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-0 as colorless oil. (% Ao g » yield 6 ) methyl-4 -(4-methylphenyl)nicotinate

H-NMR (CDCls ) 8: 0.97 (6H, with J = 6.8 Hz), 1.38 (9H, 5), 1.97 (3H, 5), 2.16-2.26 (1H, m), 2.40 (3H, s) , 2.54 (3H, 5), 2.79 (2H, d, ] = 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). (5-methyl-2-oxo0-1,3-dioxol-4-yl)methyl 5-(aminomethyl)-6-isobutyl- (Y | 00) (785 g) yield 1,711) 2- methyl-4-(4-methylphenylnicotinate dihydrochloride (5-methyl-2-o0x0-1,3-dioxol-4-yhmethyl 5-{[(tert-) as a white powder of butoxycarbonyl)amino Jmethyl ( -6-isobutyl- 2-methyl-4-(4-methylphenyl)nicotinate mM) according to the method similar to that of Example 7-?). J = 6.6 Hz), 1.97 (3H, 5), 2.17-2.28 (1H, m), Yo 2.35(3H, s), 2.82 (2H, d, J = 7.0 Hz), 3.79 (2H, d, J = 5.5 Hz), 4.93 (2H, 5), 7.12 (2H, d, J = 8.1 Hz), 7.20 (2H, d, ] = 7.9 Hz), 8.15 (3H, brs).

1

IVY Example 3-0x0-1.3-dihydro-2-benzofuran-1-yl 5-(aminomethyl)-6-isobutyl-2-methyl-4-(4- methylphenyl)nicotinate dihydrochloride 5-{[(tert- butoxycarbonyl)amino|methyl}-6-isobutyl- (mL) of 0 " (to a 1-mol) solution in TTY Von ) 2-methyl-4-(4-methylphenyl)nicotinic acid © £08 aa 0 yA ) 3-chloro-2-benzofuran-1(3H)-one added N,N-dimethylformamide (mmol) LYY g 008 ¥) potassium carbonate 5 mmol) The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted by (mL) and the mixture was washed with saturated brine. The layer 100 (ethyl acetate anhydrous) was dried. The solvent was evaporated under reduced pressure and the organic magnesium sulfate was evaporated on 0 3-0x0-1,3- to give the residue silica produced by gel column chromatography dihydro-2-benzofuran-1-yl ~~ 5-{ [(tert-butoxycarbonyl)amino }methyl }-6- isobutyl-2-yield 799 (as colorless oil. aa), AY) methyl-4-(4-methylphenyl)nicotinate

H-NMR (CDCl3) 8: 0.96 (6H, d, J = 6.6 Hz), 1.38 (9H, 5), 2.16-2.25 (1H, m), 2.42 (3H, 5), 2.63 (3H, 5), 2.78 (2H, d, ] = 7.4 Hz), 4.12 (2H, 5), 6.98-7.08 (3H, m), 7.17 Yo (2H, d, J = 7.9 Hz), 7.24 (1H, 5), -7.59 7.64 (2H, m), 7.83-7.88 (1H, m). 3-0x0-1,3-dihydro-2-benzofuran-1-yl 5-(aminomethyl)-6-isobutyl-2-on Juans (¥3-) as a white powder of methyl-4-(4-) methylphenyl)nicotinate dihydrochloride oxo-1,3-dihydro-2-benzofuran-1-yl 5-{[(tert-butoxycarbonyl)amino}methyl} -6- lla molecule 7,776 g; VAY) isobutyl-2- methyl-4-(4-methylphenyl)nicotinate | 0. (3-7 grams) according to the method similar to the example method

H-NMR (DMSO-ds ) 5: 0.95 (6H, d, J = 6.6 Hz), 2.15-2.28 (1H, m), 2.38 (3H, 5), 2.59 3H, 5), 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). Yo 117/8 Example

You (2E)-2-(3-0x0-2-benzofuran-1(3H)-ylidene)ethyl 5-(aminomethyl)-6-isobutyl-2- methyl-4-(4-methylphenyDnicotinate dihydrochloride 5-{[( tert-butoxycarbonyl)amino}methyl }-6-isobutyl- mL) from 0 ( to solution ( ) mmol) +, AGT mg YA. ) 2-methyl-4-(4-methylphenyl)nicotinic acid (3E)-3-(2-chloroethylidene)-2-benzofuran- N,N-dimethylformamide added in © 1 £V) potassium carbonate m mol) 69211 mg (VV) 1(3H)-one mmol) and the mixture was stirred at room temperature for one hour. 0.10 mg; mL) and the mixture was washed with ethyl (001) acetate The reaction mixture was diluted by anhydrous The solvent was evaporated under magnesium sulfate saturated brine The organic layer was dried on a silica press and the resulting residue was purified by gel column chromatography 00 (2E)-2-(3 -0x0-2-benzofuran-1(3H)-ylidene)ethyl 5-4 [(tert-butoxycarbonyl)amino] ( 755 _volume; yield 0 ) methyl} -6-isobutyl-2-methyl-4-(4 -methylphenyl)nicotinate as a colorless oil

H-NMR (J00) 8: 0.97 (6H, d, J = 6.6 Hz), 1.38 (9H, 5), 2.16-2.26 (4H, m), 2.58 (3H, 5), 2.78 (2H, d , J = 7.4 Hz), 4.12 (2H, 5), 4.21 (1H, brs), 4.85 (2H, d, J = 7.4 Vo

Hz), 5.25 (1H, t,J = 7.4 Hz), 7.07 (2H, d, J = 8.3 Hz), 7.12 (2H, d, ] = 8.1 Hz), 7.55- 7.64 (2H, m), -7.72 7.78 (1H, m), 7.92-7.95 (1H, m). (2E)-2-(3-ox0-2-benzofuran-1(3H)-ylidene)ethyl 5-(aminomethyl)-6- we get (Y mg yield 10 lb) isobutyl-2-methyl- 4-(4-methylphenyl)nicotinate dihydrochloride (2E)-2-(3-0x0-2-benzofuran-1(3H)-ylidene)ethyl 5- as a white powder of (ZV 9 ¥. {[(tert- butoxycarbonyl) amino] methyl }-6-isobutyl-2-methyl-4-(4-methylphenyl) mg 7/59 mmol) according to a method similar to that of 10) nicotinate (YY) example “H-NMR (DMSO-ds ) 8:0.95 (6H, d, J = 6.6 Hz), 2.07 (3H, s), 2.18-2.29 (1H, m), 2.79 (2H, d, ] = 6.6 Hz), 3.78 2H, d,] = 7.4 Hz), 4.81 2H, d, J = 7.5 Hz), 5.68 (1H, Y° 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).

IVA example

11 benzyl 5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)nicotinate 5-{[(tert-butoxycarbonyl)amino}methyl ( -6-isobutyl-mL) from Yo) to a solution

2-methyl-4-(4-methylphenyl)nicotinic acid )¥ C LVY mmol) in N,N-dimethylformamide add +A) benzyl bromide 1.77 mmol © VA©) potassium carbonates g; 17.4 mmol) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate

Yo) milliliters) and wash the mixture with saturated saline. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in trifluoroacetic acid (+ © milliliters) and the mixture was stirred at room temperature for

0? hours. The trifluoroacetic acid was evaporated under reduced pressure and the residue was neutralized by a saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate

The organic layer was washed with brine and dried on anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by silica gel column chromatography to give benzyl 5-(aminomethyl)-6-isobutyl-2-methyl-

aa 7,701 (4-(4-methylphenyDnicotinate) 0 yield £99) as a yellow solid.

H-NMR (J00) 6:0.91 (6H, d, J = 6.6 Hz), 2.07-2.18 (1H, m), 2.34 (3H, s), 2.51

‎(3H, 5), 2.72 (2H, d, J = 7.4 Hz), 3.84 (2H, 5), 4.94 (2H, 5), 7.02-7.12 (6H, m), -7.24

7.31 (3H, m).

2-0x0-1,3-dioxolan-4-yl 5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) Ye nicotinate dihydrochloride 5-{[(tert-butoxycarbonyl)amino]methyl }-6-isobutyl- in mL) from 0 ) to solution (1).

V0 ( 2-methyl-4-(4-methylphenyl)nicotinic acid 7.71 mmol) in N,N-dimethylformamide added pa 0.0 5 (4-chloro-1,3 -dioxolan-2-one 5.06 mL 0 mol) 0 ( potassium carbonates g; 0.00 mmol) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with 100 ethyl (acetate) and the mixture was washed with saturated brine. The organic layer is dried

D

YoY Anhydrous. The solvent was evaporated under reduced pressure and the residue magnesium sulfate was purified as 2-0x0-1,3-dioxolan-4-yl to give the resulting silica by gel column chromatography 5-{[(tert-butoxycarbonyl)amino methyl} -6-isobutyl-2-methyl-4-(4-methylphenyl) as colorless oil. (FAY g; yield 1,4) nicotinate 1 H-NMR (CDCl; ) 8:0.98 (6H, d, J = 6.8 Hz), 1.39 (9H, 5), 2.19-2.28 (1H, m), 2.41 © (3H, s), 2.60 (3H, 5), 2.81 (2H, d, J = 7.4 Hz) , 3.67 (1H, dd, 1 = 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). 2-0x0-1,3-dioxolan-4-yl 5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-Y) yield (yield £29 (as powder in color pa ),Y )) methylphenylnicotinate dihydrochloride 0 2-0x0-1,3-dioxolan-4-yl 5-{[(tert-butoxycarbonyl)amino]methyl}-6- white from 74 g? mmol 14 ( isobutyl-2-methyl-4-(4-methylphenyl) nicotinate (FY gram) according to the method similar to that of the example "H-NMR (DMSO-d¢) 8:0.96 (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 = Vo 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).

JAY Joe 5-(aminomethyl)-4-( 4-hydroxyphenyl )-6-isobutyl-2-methylnicotinic acid dihydrochloride Ye tert-butyl 4-[4-(benzyloxy)phenyl]-5-cyano-6-isobutyl-2- methyl- you get ( ) as a pink solid (AVY daly) (g YY, £) 1,4-dihydropyridin-3-carboxylate mM) according to 01.4 can VY,A) 4-(benzyloxy)-benzaldehyde dimers from 1-7). J = 6.6 Hz), 1.28 91, 5), Y° 1.80-1.96 (1H, m), 2.14-2.29 (2H, m), 2.32 (3H, 5), 4.51 (1H, 5), 5.03 (2H, 5), 5.49 (1H, s), 6.90 (2H, d, J = 8.7 Hz), 7.15 (2H, d, ] = 8.7 Hz), 7.29-7.46 (SH, m).

The (Y) tert-butyl 4-[4-(benzyloxy)phenyl]-5-cyano-6-isobutyl-2- can 7,1 (methylnicotinate yield 4 749) as a yellow solid of -4[-4 tert-butyl (benzyloxy)phenyl]-5-cyano-6-isobutyl-2-methyl- 1,4-dihydropyridin-3-carboxylate aa ¥ TY) 5.08 mmol Grammy) according to a method similar to that of the example (Y-YY “H-NMR (CDCl;) 8:1.01 (6H, d, J = 6.6 Hz), 1.25 (9H, 5), 2.17-2.33 (1H, m), 2.63 ° (3H, 5), 2.93 (2H, d, J] = 7.4 Hz), 5.12 (2H, 5), 7.06 (2H, d, J = 8.9 Hz), 7.31 (2H, d ,J Hz), 7.39-7.49 (5H, m). as a crude product of tert-butyl 4-[4-(benzyloxy)phenyl]-5-cyano-6- aa 1 ¥) isobutyl-2-methylnicotinate 0 £7 mmol) according to a method similar to that of the example .)4-1 yields tert-butyl 5-{[(tert-butoxycarbonyl)amino] cas 0, *( methyl}-4-(4-hydroxyphenyl)-6-isobutyl-2-methylnicotinate yield (77) as a pale yellow solid from the crude product according to the method similar to that of the example (1-7). H-NMR (CDCl3) 8:0.97 (6H, d, J = 6.6 Hz), 1.22 (9H, 5). ), 1.40 (9H, 5), 2.12-2.27 1 (1H, m), 2.55 (3H, 5), 2.76 (2H, d, ] = 7.2 Hz), 4.14 (2H, d, J = 4.9 Hz ), 4.25 (1H, brs), 5.50 (1H, brs), 6.85 (2H, d, ] = 8.5 Hz), 7.07 (2H, d, J = 8.5 Hz). ;) tert-butyl dissolves 5-{[(tert-butoxycarbonyl)amino]methyl}-4-(4-hydroxyphenyl)-6- YT) isobutyl-2-methylnicotinate mg 0.191 mmol) YY A)anisole s YX 7.10 milligrams) were collected in trifluoroacetic acid (© milliliters) and the mixture was stirred at room temperature for © hours. trifluoroacetic acid evaporates under aide pressure and hydrogen chloride 1,4-dioxane solution is added to the remainder; N (Yo) milliliters). The mixture was stirred at room temperature for 1 min. The solvent was evaporated under reduced pressure and the resulting yellow solid was washed with diisopropyl ether to give 5-(aminomethyl)- 4-(4-hydroxyphenyl)-6-isobutyl-2-methylnicotinic acid dihydrochloride ~~ Ye ( 4 mg; yield 749) as a yellow powder.

Yet

H-NMR (DMSO-d ) 8: 0.97 (6H, d, J = 6.6 Hz), 2.14-2.27 (1H, m), 2.59 (3H, 5), 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).

JAY Joe 5-(aminomethyl)-6-isobutyl-4-(4-methoxyphenyl)-2-methylnicotinic acid ° dihydrochloride tert-butyl 5-{[(tert-butoxycarbonyl)amino]methyl}-4-mL) of 0 ( to a solution of ) 1 mM 0.77 mg; 0 ) (4-hydroxyphenyl)-6-isobutyl-2-methylnicotinate

NN- mg 7.14 milligrams) in 58 ) potassium carbonate 5 milligrams) milligram) 7.14 cane 4 ) iodomethane Add dimethylformamide 0 ethyl min. The reaction mixture was diluted with 0 and the mixture was stirred at room temperature for 0 mL) and the mixture was washed with saturated saline. The organic layer was dried over anhydrous acetate 100. The solvent was evaporated under reduced pressure and the resulting residue was purified by decomposition of magnesium sulfate tert-butyl 5-{[(tert-butoxycarbonyl)amino] to give a mg yield silica gel column chromatography. 0 ) methyl} -6-isobutyl-4-(4-methoxyphenyl)-2-methylnicotinate 0 as colorless oil. (ZA

H-NMR (CDCl3) 8: 0.97 (6H, d, J = 6.8 Hz), 1.21 (9H, s), 1.39 (9H, 5), 2.13-2.26 (1H, m), 2.55 (3H, s), 2.76 (2H, d, J = 7.4 Hz), 3.84 (3H, 5), 4.12 (2H, 5), 4.22 (1H, brs), 6.94 (2H, d, J = 8.7 Hz), 7.12 (2H, d , J = 8.7 Hz). 5-(aminomethyl)-6-isobutyl-4-(4-methoxyphenyl)-2-methylnicotinic acid L ( yields tert-butyl 5- (79; mg; yield 74949) as a yellow powder from dihydrochloride {[( tert-butoxycarbonyl) amino] methyl} -6-isobutyl-4-(4-methoxyphenyl)-2-mM) according to similar method 0.11 mg; ©Y +) methylnicotinate (EVA) for example method "H-NMR (Y-01180) 6:0.97 (6H, d, J = 6.6 Hz), 2.16-2.27 (1H, m), 2.54 (3H, 5), Yo 2.85 (2H, d, J = 6.6 Hz), 3.57(3H, s), 3.84 (2H, 5), 7.05 (2H, d, J = 8.7 Hz), 7.26 (2H, d, J = 8.7 Hz), 8.17 (3H, brs).

Y.o

YAY Example methyl 4-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3- yljmethyl}thio)benzoat dihydrochloride tert-butyl {[5-( hydroxymethyl)-2-isobutyl-6- from by WA AC cooled to zero ( 1 mmol 7.51 cpa 1 ) methyl-4-(4-methylphenyl)pyridin-3-yl methyl } carbamate ~ ~ © tetrahydrofuran 5 mmol) 8.07 mmol (V, 0) triethylamine mmol; mmol Vi VY mg; 7 (methanesulfonyl chloride ml) and add dropwise (701 pour Reaction mixture in AEB (Ve gram). After stirring at room temperature for a period, saturated aqueous ethyl acetate was dried; The mixture was extracted with anhydrous sodium hydrogen carbonate adie and the solvent was evaporated under pressure with magnesium sulfate. - Litalassi as a crude product The crude product is dissolved in methylphenyl)pyridin-3-ylJmethyl methanesulfonate mg; ©Y +) potassium carbonate iba; 0; mL) Y©) N,N-dimethylformamide mMOL 7.21 cane £YY) methyl 4-mercaptobenzoat s mM (¥,VYV mM). The mixture was stirred and heated at 4360 for one hour. Dilute the reaction mixture (V) in milliliters) and wash the mixture with saturated saline. The layer 0) ethyl acetate was dried with anhydrous. The solvent was evaporated under reduced pressure and the organic magnesium sulfate was purified over methyl 4-({[5-{[(tert-) to give the remaining silica obtained by floating column chromatography butoxycarbonyl)amino Jmethyl} -6-isobutyl-2- methyl-4-(4-methylphenyl)pyridin-3- as colorless oil. (VY g; yield 1,0) yllmethyl}thio)benzoat 0

H-NMR (CDCl; ) 8: 0.97 (6H, d, J = 6.6 Hz), 1.38 (9H, 5), 2.16-2.25 (1H, m), 2.37 (3H, 5), 2.65 (3H, 5) , 2.75 (2H, d, J = 7.4 Hz), 3.86 (2H, 5), 3.89 (3H, 5), 4.04 (2H, 4,

J=5.1 Hz), 4.20 (1H, brs), 7.04 (2H, d, = 7.9 Hz), 7.09 (2H, d, J = 8.7 Hz), 7.19 (2H, d,] - 7.7 Hz), 7.85 ( 2H, d, J = 8.7 Hz). methyl 4-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-on Jaa (Y Ye mg; yield 1 ¥A) methylphenyl)pyridin-3-yl]methyl }thio)benzoat dihydrochloride methyl 4-({[5-{[(tert-butoxycarbonyl) amino] as a pale yellow powder from (Avy)

thio) benzoat } thio-d] 1 and 3- thi- tamum ( luminal dam [nabta--4)-4- slow (- 2-ab6-1901- methyl} You) total 7715 milligrams ) according to the method similar to that of the example (FY “H-NMR (DMSO-d ) 5:0.98 (6H, d, ] = 6.6 Hz), 2.12-2.23 (1H, m), 2.35 (3H, s) , (3H, 5), 3.64 (2H, brs), 3.75 (2H, d, J = 5.7 Hz), 3.83 (3H, 5), 4.01 (2H, 0 2.81 (6H, m), 7.82 (2H, d, J = 8.7 Hz), 8.30 (3H, brs).° 7.24-7.33 JAE Joe 4-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3-yl methyl} thio)benzoic acid dihydrochloride )( we get 4-({[5-{[(tert-butoxycarbonyl)amino]methyl }-6-isobutyl-2-methyl -4- (+,4Y) (4-methylphenyl)pyridin-3-yljmethyl}thio)benzoic acid 0 g yield (AVY) as a white solid of methyl 4-({[5-{[( tert-butoxycarbonyl)amino]methyl}-6- 11/( isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yljmethyl ( thio)benzoat Y,0 body) milligram) According to the method similar to (VJB "H-NMR (CDCl3) 6: 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, 5), 3.30-3.40 (2H, m), 3.90 (2H, s), 4.12-4.18 (2H, m), 4.30 (1H, Vo 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). ¥ (You get 4-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) 4A) pyridin-3-yl]methyl}thio)benzoic acid dihydrochloride mg yield (Zvy 0 as a white powder of 4-({[5-{[(tert-butoxycarbonyl)amino]methyl }-6-isobutyl-2- methyl-4-(4-methylphenyl)pyridin-3-ylJmethyl ( thio)benzoic acid (for 0 7 g 8 mmol) according to a method similar to that of Example 7-?). H-NMR (DMSO-ds ) 8:0.98 (6H, d, J = 6.6 Hz), 2.13-2.23 (1H, m), 2.36 (3H, 5), ' (3H, s), 3.05 ( 2H, brs), 3.71-3.80 (2H, m), 4.01 (2H, s), 7.23-7.27 (4H, m), 7.32 2.81 (2H, d, J =8.1 Hz), 7.80 (2H, d , J = 8.3 Hz), 8.32 (3H, brs). Yo Example d81

1 methyl 4-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3- ylimethyl }sulfonyl)benzoat dihydrochloride methyl 4-({[5-{[(tert) -butoxycarbonyl)amino]methyl}-6- you get isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-ylJmethyl } sulfonyl )benzoat methyl 4-({[5-{ [(tert- as a colorless oil of (IA. cg. yield 0 butoxycarbonyl)amino methyl} -6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3- mmol) according to Method + AYA g +, £7) yl]methyl thio)benzoat

VY similar to the example method "H-NMR (CDCl; ) 6:0.98 (6H, d, J = 6.7 Hz), 1.38 (9H, s), 2.17-2.26 (1H, m), 2.41 (3H, 5) , 2.64 (3H, 5), 2.77 (2H, d, ] = 7.4 Hz), 3.98 (3H, 5), 4.00 (2H, d, = 5.3 Hz), 00 4.18 (1H, brs), 4.32 (2H, 5), 6.87 (2H, d, ] = 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) . methyl 4-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4- — lc nhp (Y mg; YOY) methylphenyl)pyridin-3-yl]methyl} sulfonyl (benzoat dihydrochloride methyl 4-({[5-{[(tert-) yield 140) as a pale yellow powder of 0 butoxycarbonyl)amino]methyl } -6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin -3- mol) according to the method ile 706 cane £34) ylimethyl}sulfonyl)benzoat 7-7 similar to the example method "H-NMR (DMSO-ds) 5:0.98 (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 Ye. (2H, d, J = 79 Hz), 7.23 (2H, d,] = 7.9 Hz), 7.66 (2H, d, J = 8.3 Hz), 8.09 (2H, d, J = 8.7 Hz), 8.30 (3H , brs).

IAT Example 4-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3 -yllmethyl} sulfonyl)benzoic acid dihydrochloride Yo 4-({[5- {[(tert-butoxycarbonyl)amino methyl} -6-isobutyl-2-methyl-4- we get (1 mg yield Ve) (4-methylphenyl)pyridin-3-yl methyl} sulfonyl)benzoic acid

1 methyl 4-({[5-{[(tert-butoxycarbonyl)amino methyl }-6- colorless Cy (%8)

YY”) isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-ylJmethyl ( sulfonyl )benzoat (078 mmol) according to method similar to example method 1,914 mg; “H- NMR (CDCl; ) 58: 0.98 (6H, d, J = 6.6 Hz), 1.39 (9H, 5), 2.14-2.22 (1H, m), 2.34 (3H, s), 2.43 (3H, 5), 2.86 (2H, d, J = 7.4 Hz), 4.06 (2H, d, ] = 4.5 Hz), 4.28 (1H, ° brs), 4.35 (2H, 5), 6.97 (2H, d, I = 7.9 Hz), 7.23 (2H, d, J = 7.7 Hz), 7.60 (2H, d, ] = 8.1 Hz), 8.17 (2H, d, J = 8.1 Hz). -2-methyl-4-(4-methylphenyl) on Jaa (Y (# 197 mg; yield of 4 pyridin-3-ylJmethyl }sulfonyl)benzoic acid dihydrochloride 4-({[5-{[(tert-) butoxycarbonyl)amino]methyl } -6-isobutyl-2- as a white powder from 0 mg Yoo) methyl-4-(4-methylphenyl)pyridin-3-ylJmethyl} sulfonyl)benzoic acid .) 1-3 mmol) according to a method similar to that of the example 0 "H-NMR (CDCl; ) 5:0.98 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.14-2.22 (1H, m), 2.34 (3H, 5), 2.43 (3H, 5), 2.86 (2H, d, ] = 7.4 Hz), 4.06 (2H, d, ] = 4.5 Hz), 4.28 (1H, brs), 4.35 (2H, 5 ), 6.97 (2H, d, J = 7.9 Hz), 7.23 2H, d, = 7.7 Hz), 7.60 QH, d, J = 1o 8.1 Hz), 8.17 (2H, d, J = 8.1 Hz).

YAY mal N- {[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-ylJmethyl } methanesulfonamide dihydrochloride tert-butyl {[5-(aminomethyl)-2) -isobutyl-6-methyl-4- mL) from V+) to a solution of (re 266 no mmol (ana 00 ) (4-methylphenyl)pyridin-3-yljmethyl} carbamate tetrahydrofuran mmol) in 1 mL 4 (triethylamine gram) mole) and the mixture was stirred (Ae 1,875 (ana AT) methanesulfonyl chloride 01( ethyl acetate) was added at room temperature for 1 hour. The reaction mixture was diluted with saturated aqueous and sodium hydrogen carbonate brine (mL) and washed successively with anhydrous Yo. The solvent was evaporated under pressure saturated magnesium sulfate. The organic layer was dried over tert- to give diisopropyl ether a yellow solid obtained with sald) reducer and washed butyl [(2-isobutyl-6-methyl-4-(4-methylphenyl)-5-{[methylsulfonyl)amino]methyl} as a white solid. (ZAY yield) ?0 ( pyridin-3-yl)methyl]carbamate "H-NMR (CDCl; ) 6:0.96 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.16-2.25 (1H, m ), 2.42 (3H, s), 2.61 (3H, 5), 2.68 (3H, 5), 2.76 (2H, d, J = 7.4 Hz), 3.87 (1H, brs), 4.01 (2H, d,J= 5.7Hz),4.03 (2H, d, J = 5.3 Hz), 4.18 (1H, brs), 7.03 (2H, d, J = 8.1 Hz), 7.29 5 (2H, d, T = 7.9 Hz).

N-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4- on Ju 5 (Y)

YR ) methylphenyl)pyridin-3-yljmethyl }methanesulfonamide dihydrochloride tert-butyl [(2-isobutyl-6-methyl-4-(4- white from Osh) yield 14% (as powder aa methylphenyl)-5-{{ methylsulfonyl)amino methyl} pyridin-3-yl)methyl]carbamate | 0 (YY in milligrams) according to method similar to that of the example 0.441 cana YY ) "H-NMR (DMSO-ds) 8:0.96 (6H, d, J = 6.6 Hz), 2.12-2.23 (1H, m) , 2.41 (3H, 5), 2.71 (3H, 5), 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).

JAA as 0 L )-2-isobutylpyridin-3-yljmethyl }amine dihydrochloride (2E)-3-(2,4-dichlorophenyl)-1-(4-fluorophenyl)prop-2-en-1-one We obtain (0 0 9 g; yield 14%) as a solid in Coals ji al of 4-fluoroacetophenone Y. ) 1.9 g; 0 mmol (AY©) 2,6-dichlorobenzamide g; 09 mmol) according to a method similar to that of example AVY A “H-NMR (CDCl3) 6: 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).¥ (we get 4-(2,4-dichlorophenyl)-6-(4-flucrophenyl) -2-isobutylnicotinonitrile (2E)-3-(2,4-dichlorophenyl)-1-(4- (4 ji al) as color oil ( EA g; yield 684 ) Yo 19.4 can £, 0¢)fluorophenyl(prop-2-en-1-one mmol) according to the method (YY A) similar to the example method

YY. H-NMR (CDCl3) 8:1.06 (6H, with J = 6.6 Hz), 2.32-2.45 (1H, m), 3.04 (2H, d, ] = 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) {[4-(2,4-dichlorophenyl)-6-(4-fluorophenyl)-2-isobutylpyridin-3- (0,4-4-) is obtained from ral as yellow-colored oil (TA). Yield cane VAL) p(1[06091 © mM YAS AH ) dichlorophenyl)-6-(4-fluorophenyl)-2-isobutylnicotinotrile mol) according to the method similar to that of Example 4-77) The oil is dissolved in a solution (mL) and the mixture is stirred at a temperature of yo) NH hydrogen chloride 1,4-dioxane min. The solvent is evaporated under reduced pressure and the resulting solid is washed with 0 chamber for {[4] -(2,4-dichlorophenyl)-6-(4- to give diisopropyl ether with cull yellow color 0 mg 58 ) fluorophenyl)-2-isobutylpyridin-3-ylJmethyl }amine dihydrochloride as yellow powder baht. (£4Y Yield “H-NMR (DMSO-dg) 6:0.97 (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, Yo m). Example: methyl 3-[5-(aminomethyl)-6-isobutyl-4-(4-methylphenyl)pyridin-2-yl]benzoat dihydrochloride

Vv, 4 ) (2E)-1-(3-bromophenyl)-3-(4-methylphenyl)prop-2-en-1-one we get ( 0 g; 1,40) 3-bromoacetophenone g; Yield 497 7) As a pale yellow powder of (1-0168-mM). contains (¥ (2E)-1-(3-bromophenyl)-3-coll; yield 777) as a pale yellow solid of 7.701 (mmol) according to 1.7 can 5.07 ( (4-methylphenyl)prop-2-en-1-one 00 (YY A) Method similar to example method

ARR

H-NMR (CDCls) 8: 1.06 (6H, with J = 6.6 Hz), 2.35-2.42 (1H, m), 2.45 (3H, 5), 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, 5).6-(3-bromophenyl)-2-isobutyl-4-(4 -methylphenyl)nicotinonitrile (* 10 mmol; +,V) triethylamine g; 5.40 mmol) YY) 0 mg; (501) [1,1bis(diphenylphosphino) )ferrocene]palladium(Il) dichloride 5 grams) N,N- 5 milliliters) V+) methanol millimeters) dissolved in a mixed solvent of 8

Vo for carbon monoxide (ml) and stirred the mixture under atmosphere (Yo) dimethylformamide (ml) and washed the mixture with ethyl acetate solution (100) h. The reaction mixture was diluted with anhydrous and the solvent was evaporated under magnesium sulfate saturated brine. Drying The organic layer was placed on 0 methyl 3-[3-]5- to give silica a reduced pressure.The resulting residue was purified by gel chromatography (ZY Y yield can V,¥4) cyano-6-isobutyl-4-(4-methylphenyl) )pyridin-2-yl|benzoat methyl 3-[5-(aminomethyl)-6-isobutyl-4-(4-) colorless. & 4K produced as colorless oil from (Z0A mg yield VA) methylphenyl )pyridin-2-ylJbenzoat g ¥) methyl 3-[5-cyano-6-isobutyl-4-(4-methylphenyl)pyridin-2-yl]benzoat 05 (1-4 mmol) according to To the method similar to the example method TFA "H-NMR (CDCl3) 8:1.05 (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, 5), 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).methyl 3-[5-{[(tert-butoxycarbonyl)amino methyl} -6-isobutyl-4-(4-)4 Y : mg; Yield 79776) as a white powder of VY ( methylphenyl)pyridin-2-yl]benzoat methyl 3-[5-(aminomethyl)-6-isobutyl-4-(4-methylphenyl)pyridin-2-yl]benzoat 1.) -1 mmol) according to the method similar to that of the example 0.57 can +, VT) "H-NMR (CDCl; ) 5:1.04 (6H, d, ] = 6.6 Hz), 1.43 (9H, 5), 2.37-2.46 (4H, m), 2.87 (2H, d, J =7.2 Hz), 3.94 (3H, 5), 4.29-4.35 (2H, m), 4.38 (1H, brs), 7.23 QH, d, J = Yo 8.3 Hz), 7.28 (2H, d, ] = 8.1 Hz), 7.50 (1H, 5), 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).

methyl 3-[5-(aminomethyl)-6-isobutyl-4-(4-methylphenyl)pyridin-2-yl Jbenzoat ( methyl 3-[5- yield £29 (as white powder from cane V AA) dihydrochloride { [(tert-butoxycarbonyl)amino methyl } -6-isobutyl -4-(4-methylphenyl)pyridin-2- mmol) according to the method similar to that of 409 (ana 0 ( yllbenzoat (FY) example 0 "H -NMR (DMSO-de ) 8: 1.04 (6H, d, J = 6.4 Hz), 2.33-2.44 (4H, m), 2.93 (2H, l - 7.0 Hz), 3.90 (3H, 5 ), 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).036 Example Ve 3-[5 -(aminomethyl)-6-isobutyl-4-(4-methylphenyl)pyridin-2-ylJbenzoic acid dihydrochloride 3-[5-{[(tert-butoxycarbonyl)amino methyl} -6-isobutyl-4-(4- le ‏ t_sell (\ as a solid in color (714A yield cane © +) methylphenyl)pyridin-2-ylJbenzoic acid methyl 3-[5-{[(tert-butoxycarbonyl)amino]methyl} -6-isobutyl-4- (4-yo m white) according to 0.08 mg OF ( methylphenyl)pyridin-2-yl]benzoat (V9) method similar to example “H-NMR (0001) 5 ( 6H, d, J = 6.6 Hz), 1.43 (9H, 5), 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, 5), 7.58 (1H,t,J=7.5Hz), 8.12 (1H, d, J = 7.9 Hz), 8.36 (1H,d, J = 7.4 Hz), 8.67 (1H, s). v. 3-[5-(aminomethyl)-6-isobutyl-4-(4-methylphenyl)pyridin-2- on Joa aj (¥ mg yield 799 (as white powder of YAA) yllbenzoic acid dihydrochloride 3-[5] -{[(tert-butoxycarbonyl)amino methyl} -6-isobutyl-4-(4-methylphenyl)pyridin- mmol) by analogous method 1.471 mg; 001(2-71[502016 acid] 7-7 of the example method ve "H-NMR (DMSO-d ( 3 (6H, d, J 2 7.4 Hz), 2.32-2.43 (4H, m), 2.92 (2H, d, J = 7.0Hz) ),4.02 (2H, d, J = 5.3 Hz), 7.36 (2H, d, ] = 8.1 Hz), 7.41 (2H, d, J = 8.3

YYVY

11

Hz), 7.63 (1H, 1b 7.8 Hz), 7.74 (1H, 5), 8.01-8.04 (1H, m), 8.35 (3H, brs), 8.37- 8.41 (1H, m), 8.71-8.72 ( 1H, m). 1 Joe 3-[5-(aminomethyl)-6-isobutyl-4-(4-methylphenyl)pyridin-2-yl Jbenzamide dihydrochloride ° tert-butyl {[6-[3-(aminocarbonyl)phenyl]-2-isobutyl- 4-(4- — le Ja 3 6 as a solid (% oF yield cane V+) methylphenyl)pyridin-3-yljmethyl} carbamate 3-[5-{[(tert-butoxycarbonyl)aminoJmethyl } -6-isobutyl -4-(4- white mmol) according to 1.177 mg Po ( methylphenyl)pyridin-2-yl]benzoic acid

VY to the method similar to that of the example 0 "H-NMR (CDCl; ) 6:1.04 (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) 3-[ 5-(aminomethyl)-6-isobutyl-4-(4-methylphenyl)pyridin-2- on Joa as (Y 0 tert-) as a white powder of ( Af mg; yield VY Y) yl]benzamide dihydrochloride butyl {[6-[3-(aminocarbonyl)phenyl]-2-isobutyl -4-(4-methylphenyl)pyridin-3- mol) according to the method le +, YYA mg 11+) ylimethyl} carbamate method similar to that of Example 7-?).” H-NMR (DMSO-d¢) 8:1.03 (6H, d, J = 6.6 Hz), 2.34-2.44 (4H, m), 2.93 (2H, l.l.) ‎ XY.=7.0Hz),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, ] = 7.8 Hz), 7.81 (1H, 5), 7.96 (1H, d, J = 7.7 Haz), 8.14 (1H, brs), -8.33 8.44 (4H, m), 8.58 (1H, s).

Yay Example methyl 2-[5-(aminomethyl)-6-isobutyl-4-(4-methylphenyl )pyridin-2-yl]benzoat Yo dihydrochloride

"0

A,A%) (2E)-1-(2-bromophenyl)-3-(4-methylphenyl)prop-2-en-1-one gives (1 gm 4,40) 2-bromoacetophenone Yield 44 7) as a pale yellow powder of cpa (07) +A mM) according to a method similar to that of Example 0 6-(2-bromophenyl)-2-isobutyl-4-(4-methylphenyl)nicotinotrile You get ( Y (2E)-1-(2-bromophenyl)-3- as a pale yellow solid of 0 oF yield aa (58 µmol ©) according to 11.7 aa 0 ,4 YY) (4-methylphenyl)prop-2-en-1-one 1-0178 .) Similar method to example 111-1118 (CDCl3) 5:1.06 (6H, d, J = 6.6 Hz), 2.34 -2.44 (4H, m), 3.07 (2H, d, ] = 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). 0 methyl 2-[5-cyano-6-isobutyl-4-(4-methylphenyl)pyridin-2- on Joa ai (¥ 6-(2-bromophenyl)-2- as colorless oil of (ZY) g; yield of V,A) yljbenzoat mM) according to 6.04 g (Y,0) isobutyl-4-(4-methylphenyl)nicotinonitrile 6-(2-bromophenyl)-2- soluble cad i.e. (1849-3) to the method similar to the example method 17.7 mL VV) triethylamine ctisobutyl-4-(4-methylphenyl)nicotinotrile 0 [1,1'-bis(diphenylphosphino) )ferrocene]palladium(ll) dichloride s gram molecule).

N,N- 5 mL (V,0) methanol mM (in +, IVE mg; 50)

VY for carbon monoxide (ml) and the mixture was stirred under dimethylformamide (V0 ml) atmosphere and the mixture was washed with ethyl acetate solution (100 hr). The reaction mixture was diluted with anhydrous and the solvent was evaporated under magnesium sulfate saturated brine. Drying The organic layer on Ye methyl to give the silica a reduced pressure. The resulting residue was purified by gel column chromatography .2-[5-cyano-6-isobutyl-4-(4-methylphenyl)pyridin-2-ylJbenzoat "H-NMR". (CDCl3) &: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).Yo methyl 2-[5-(aminomethyl)-6-isobutyl-4-(4-methylphenyl)pyridin-2- you get (¢ methyl 2-[5-cyano-6-isobutyl-4-(4-methylphenyl)pyridin - From ala as a product 1

101 mmol) according to the method similar to that of 2,14 can 1A); “with [0[a/-2]4-1). Jaa methyl 2-[5-{[(tert-butoxycarbonyl)amino methyl) }-6-isobutyl-4-(4-) obtained as a colorless oil from (AVE of all yields V,V+) methylphenyl)pyridin-2-yljbenzoat

VY raw product according to method similar to example method © 111-111 (CDCl; ) 8:0.99 (6H, d, J = 6.6 Hz), 1.43 (9H, s), 2.26-2.37 (1H, m), 2.41 (3H, s), 2.80 (2H, d, J = 7.4 Hz), 3.75 (3H, 5), 4.32 (2H, with 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). methyl 2-[5-(aminomethyl)-6-isobutyl-4-(4-methylphenyl)pyridin-2- (yield 2 0 £90) is obtained as a pale pink powder from cane (©; ? yl]benzoat dihydrochloride methyl 2-[5-{[(tert-butoxycarbonyl) amino] methyl}-6-isobutyl-4-(4-methylphenyl) mmol) according to method VAT cass YAY) pyridin-2- ylJbenzoat similar to example method 7-?). (2H, d, J = 6.6 Hz), 3.69 (3H, 5), 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, 5), 7.57-7.70 (2H, m), 7.76 (2H, d, J = 7.5 Hz), 8.51 (3H, brs). aminomethyl)-6-isobutyl-4-(4-methylphenyl)pyridin-2-ylJbenzoic acid Y. dihydrochloride 2-[5- {[(tert-butoxycarbonyl)amino]methyl }-6-isobutyl-4-(4- On Joa 3 (1 yield 779) as colorless oil can + ,A0) methylphenyl)pyridin-2-yl]benzoic acid methyl ~~ 2-[5-{[(tert-butoxycarbonyl)amino]methyl}-6 -isobutyl-4-(4-mN g; 7.14 mmol) according to V, YY) methylphenyl)pyridin-2-ylbenzoat 0 (V3 method similar to that of example)

A (CDCl3) 8: 1.02 (6H, d, J = 6.6 Hz), 1.42 (9H, s), 2.21-2.33 (1H, m), 2.44 Ra (3H, 5), 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). Joa a5 (¥ on 2-[5-(aminomethyl)-6-isobutyl-4-(4-methylphenyl)pyridin-2- cans ¥ Y4) yl]benzoic acid dihydrochloride© yields (AA) as a white powder of 2-[5-{[(tert-butoxycarbonyl)amino]methyl } -6-isobutyl-4-(4-methylphenyl)pyridin- 1.904 cane £14) 2-yl]benzoic acid milligram) according to a method similar to that of Example 7-?). H-NMR (DMSO-d ) 8:0.99 (6H, d, J = 6.6 Hz), 2.27-2.36 (1H, m), 2.41 (3H, s), (2H, d, ] = 6.6 Hz), 4.04 (2H, d, 1 = 5.1 Hz), 7.36 (2H, d, ] = 8.3 Hz), 7.40-7.49 0 2.90 (3H, m), 7.54-7.70 (3H, m), 7.76 -7.84 (1H, m), 8.44 (3H, brs). Ex 138 2-[5-(aminomethyl)-6-isobutyl-4-(4-methylphenyl)pyridin-2-yl]benzamide dihydrochloride tert-butyl {[6-[2-(aminocarbonyl)phenyl}-2-isobutyl-4-(4- ole Jia = ( 1 Yo Y4+) methylphenyl)pyridin-3-yl]methyl} carbamate mg yield 19 # ( as Hs-free oil from 2-[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-4-(4- AAY cans € YY) methylphenyl)pyridin-2-yl benzoic acid, + mmol) according to the method similar to that of Example 0-7 ("H-NMR (CDCl) 8:1.01 (6H, d, J = 6.6 Hz), 1.43 (9H, s), -2.30 2.37 (1H, m), 2.41 Ye. Hz), 4.42 (1H, brs), 5.54 (1H, = 4.7 ] by (3H, 5), 2.83 (2H, d, J = 7.4 Hz), 4.34 (2H, 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), (1H , m).7.70-7.75 Jaa (¥ on 2-[5-(aminomethyl)-6-isobutyl-4-(4-methylphenyl)pyridin-2- cane YO £) ylbenzamide dihydrochloride Yo yield 797) as a yellow powder of tert-butyl {[6-[3-(aminocarbonyl)phenyl]-2-isobutyl-4-(4-methylphenyl)pyridin-3-only

ARR

mmol) according to method 1.117 vol 0 ( 1110 (Frame 6 carbamate similar to method example 7-?). = 6.6 Hz), 2.27-2.37 (1H, m), 2.40 3H, 5), 2.90-2.99 (2H, m), 4.04 (2H, m), 7.36 (2H, d, ] = 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). 8 140 Jos 5-(aminomethyl)-N,N-dicyclohexyl-6-isobutyl-2-methyl-4-(4-methylphenyl) nicotinamide dihydrochloride 5-cyano-6-isobutyl-2-methyl-4-(4-methylphenyl) )nicotinic acid ( \ tert-butyl 5-cyano-6-isobutyl-2-) is obtained as a white powder from (% AS yield can?,11) (00 g 8.77 mmol) According to ¥) methyl-4-(4-methylphenyl)nicotinate

VY 4 Method similar to example H-NMR (CDCl3) 8: 1.00 (6H, d, J = 6.6 Hz), 2.17-2.32 (1H, m), 2.42 (3H, s), 2.67 (3H, 5) ), 2.95 (2H, d, ] = 7.4 Hz), 7.27-7.34 (4H, m).

Y) 5-cyano-6-isobutyl-2-methyl-4-(4-methylphenyl)nicotinic acid To a solution of (Y 0 +,"A) oxalyl chloride add dichloromethane g; 1.49 mmol gram) in milliliters) and stir (+,0) N,N-dimethylformamide (mg) and V,VA «ill min. The solvent is evaporated under reduced pressure and Te mixture is dissolved at room temperature for 10 mL read 8 (triethylamine next; add remaining tetrahydrofuran in mM) and stir 7.78"ill 0,©( dicyclohexylamine s mol) V° ethyl acetate min. The reaction mixture was diluted with 70 mL of mixture at room temperature at room temperature and washed with saturated brine. The organic layer was dried on 01 (the solvent was evaporated under reduced pressure and the resulting residue was purified by SLY sulfate 5-cyano-N, N-dicyclohexyl-6-isobutyl-2- to give a silica gel column chromatography as a colorless oil. (711) yield aa +, YO) methyl-4-(4-methylphenyl)nicotinamide 8

H-NMR (CDCl; ) 8: 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,

no = l 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, Hz), 7.46 (2H, d, J = 8.1 Hz). 8.5 Joa a3 (V on 5-(aminomethyl)-N,N-dicyclohexyl-6-isobutyl-2-methyl-4-(4- can +,Y) methylphenyl)nicotinamide dihydrochloride (yield 49 7) as a yellowish-yellow powder of 5-cyano-N,N-dicyclohexyl-6-isobutyl-2-methyl-4-(4-methylphenyl) nicotinamide )¥ 0,+ g; VEY + mmol) according to the method similar to that of the example (YY eA "H-NMR (DMSO-dg ) 6:0.73-0.88 (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).Ye Ex. 33 methyl 1-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3- yl]carbonyl} piperidine-4-carboxylate dihydrochloride 1 ( you get methyl 1-{[5-cyano-6-isobutyl-2-methyl-4-(4- methylphenyl)pyridin- YY) 3-yl]carbonyl}piperidine-4-carboxylate 0g yield (£9) as colorless oil of 5-cyano-6-isobutyl-2-methyl-4-(4-methylphenyl )nicotinic acid ) 8 g AY mmol) VY) methyl isonipecotate s mL 5.77 mmol) according to the method similar to that of example 695-1?). (6H, dd, J = 12.1, 6.6 Hz), 1.42-1.85 (4H, m), 2.19-7 6:1.01 (J00) “H-NMR (3H, m), 2.40 (3H, s), 2.55-2.60 (3H , m), 2.61-3.20 (SH, m), 3.63-3.66 (3H, m), Ye. (1H, m), 7.25-7.42 (4H, m).4.23-4.45 methyl 1-{ [5-(aminomethyl)-6-isobutyl-2-methyl-4-(4- le Jia a3 (Y methylphenyl)pyridin-3-yl}carbonyl } piperidine-4-carboxylate dihydrochloride (not aa YY Yield (AY) as a white powder of methyl 1-{[5-cyano-6-isobutyl-2- Ve. ) methyl-4-(4-methylphenyl)pyridin-3-yl]carbonyl} piperidine-4-carboxylate 0 g; 2.78 mmol) according to the method similar to that of example YY oA only

H-NMR (DMSO-dg) 8: 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).

AV as oe 5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)nicotinic acid tert- butylamine salt 5-(aminomethyl)-6-isobutyl-2-methyl-4-(4 -methylphenyDnicotinic acid acetonitrile (mmol) is dissolved in a mixed solvent of water (1.0 milliliters) 1.77 cu tert-butylamine (0) minutes. Add 01 steam condensation for [sale] milliliters) with heating with *,0 (Ye mol) to the resulting solution and stir the mixture at the same temperature as lle + TY (mg; YY (mL)); And leave the mixture to cool to the degree Ye) acetonitrile minutes. Add 01 heat for a minute. The precipitated solid Yo was collected at room temperature and stirred at 0C for 5-(aminomethyl)-6-isobutyl-2-mL to give 10 acetonitrile by filtration and washed with 1 mg of VAS yield (4-methyl) 4-methylphenyl)nicotinic acid tert-butylamine salt 0 As a white powder.‎ (+7)

H-NMR (DMSO-d ) 5: 0.91 (6H, d, J = 6.6 Hz), 1.12 (9H, 5), 2.06-2.25 (1H, m), 2.31 (3H, 5), 2.34 (3H, 5) ), 2.66 (2H, d, J = 7.0 Hz), 3.31 (2H, brs), 3.37 (2H, 5), 7.10 (2H, d, J=8.1 Hz), 7.16 (2H, d, J = 8.1 Hz ).

NAA Example Y. ({2-isobutyl-6-methyl-4-(4-methylphenyl)-5-[(methylthio)methyl Jpyridin-3-yl} methyl)amine dihydrochloride [5-{[(tert-butoxycarbonyl) )amino]methyl }-6-isobutyl-2-methyl-4- to a solution of 1) mMol 1 mg; 7 ) (4-methylphenyl)pyridin-3-methyl methanesulfonate aqueous sodium methanethiolate mL) tetrahydrofuran © (grams) solution in YO**C for 2 hours is added. Water is added to the reaction mixture (0 ml) and the mixture is stirred at (0 ¥). The organic layer is washed with saturated brine and dried with acetate 60071. The mixture is extracted with

YYvw

YY. anhydrous. The solvent was evaporated under reduced pressure and the resulting residue, magnesium sulfate, was purified on tert-butyl ({2-isobutyl-6-methyl-4-(4- to give silica) by gel column chromatography mg YY ( methylphenyl) -5-[(methylthio)methyl]pyridin-3-yl } methyl)carbamate as a white powder. (VY yield H-NMR (CDCl3) 6:0.96 (6H, d, J = 6.6 Hz), 1.38 (9H, 5), 1.94 (3H, 5), 2.12-2.23° (1H, m), 2.42 (3H, 5), 2.67 (3H, 5), 2.75 (2H, d, ] = 6.9 Hz), 3.39 (2H, 5), 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-isobutyl-6-methyl-4-(4-methylphenyl)-5-[(methylthio)methyl] we obtain (Y yield 97%) (as powder with color cana ¥1) pyridin-3-yl}methyl )amine dihydrochloride tert-butyl ~~ ({2-isobutyl-6-methyl-4-(4-methylphenyl)-5- ad Ye according to a method similar to that of [(methylthio)methyl]pyridin-3- yl}methyl)carbamate (YY Example “H-NMR (DMSO-dg )8: 0.97 (6H, d, J = 6.6 Hz), 1.93 (3H, s), 2.12-2.19(1H, m), 2.42 (3H, 8), 2.89 (3H, 5), 3.08 (2H, brs), 3.48 (2H, s), 3.75 (2H, 5), 7.28 2H, d, J = 7.8 Hz), 7.39 (2H, d, J = 7.8 Hz), 8.36 (3H, brs). 10 149 Jo. ({2-isobutyl-6-methyl-4-(4-methylphenyl)-5-[ (methylsulfonyl)methyl]pyridin-3- yl}methyl)amine dihydrochloride tert-butyl ({2-isobutyl-6-methyl-4) -(4-methylphenyl)-5- to a solution of 1 mM ET (ane 0 ( [(methylthio)methyl]pyridin-3-yl}methyl)carbamate | 0 1 (trademark; oxone) milliliter) add (Vi) + (gram) in 001 E0”- μl water). The mixture was stirred at room temperature (© + sulfuric acid mg) and then saturated aqueous sodium hydrogen carbonate was added to the reaction mixture for a period of 7 hours. The organic layer was washed with saturated brine and dried.” Acetate 01 was added and the mixture was extracted with anhydrous. The solvent was evaporated under reduced pressure and the resulting residue magnesium sulfate was purified over YO tert-butyl {[2-isobutyl-6-methyl-4-(4-) to give silica by gel column chromatography.

VY A) methyl phenyl)-5-[(methylsulfonyl)methyl]pyridin-3-ylJmethyl} carbamate cv 17 (as white powder. (6H, d, J = 6.6 Hz), 1.38 (9H, 5), 2.19 -2.28 (1H, m), 2.41 5:0.97 (J00290) I H-NMR (3H, s), 2.61 (3H, 5), 2.74 (3H, 5), 2.75 (2H, d, J = 7.2 Hz), 4.25 (2H, d, J = 5.1 Hz), (1H, brs), 4.26 (2H, s), 7.71 (2H, d, ] =7.8 Hz), 7.26 (2H, d, J = 8.1 Hz).° 4.24") you get ({2-isobutyl-6-methyl-4-(4-methylphenyl)-5-[(methylsulfonyl) methyl]pyridin-3-yl}methyl) amine dihydrochloride (¥1 mg; yield 27 lb) as a white powder of tert-butyl {[2-isobutyl-6-methyl-4-(4-methylphenyl)-5-[(methylsulfonyl)methyl]pyridin- 3-yljmethyl} carbamate according to a similar method (¥- Y of the example method 0 "H-NMR (F01450-0) 5:0.97 (6H, d, J = 6.6 Hz), 2.17-2.24 (1H) , m), 2.40 (3H, s), 2.81 (3H, 5), 2.87 (3H, 5), 2.89 (2H, brs), 3.68 (2H, brs), 4.40 (2H, 5), 7.24 (2H, d, J - 8.1 Hz), 7.35 (2H, d, J = 7.8 Hz), 8.20 (3H, brs).({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) )pyridin-3-yl methyl } Vo thio)acetic acid dihydrochloride [5-{[(tert-butoxycarbonyl)amino]methyl} -6-isobutyl-2-methyl-4- to a solution of ) 1 mg; ? mmol 7 ) (4-methylphenyl)pyridin-3-yljmethyl methanesulfonate £10) potassium carbonate (mL) added (©) N,N-dimethylformamide (g) per µL (1 +) ethyl mercaptoacetate mg; ¥ millimole) and then add To (mmol). The mixture was stirred at 00*"C for 1 hour. Water was added to 7.7 71:e. The organic layer was washed with acetate brine. The reaction mixture was extracted and the mixture extracted with anhydrous. The solvent was evaporated under reduced pressure and saturated magnesium sulfate dissolved And dried on 1 N aqueous sodium hydroxide, add a solution of 0.0 milliliters (©) ethanol resulting in hydrochloric milliliters (ml) and stir the mixture at room temperature for two hours. Add *( Yo

Jui 1 g:0 N acetate (0 mL) was added to the reaction mixture and the mixture was extracted with 1 4 anhydrous. The magnesium sulfate organic layer was evaporated with saturated brine and dried over

YYZ

To give silica the solvent under reduced pressure and purify the resulting residue by gel chromatography {[5-{[(tert-butoxycarbonyl)amino methyl }-6-isobutyl-2-methyl-4-(4- 0 YV) yield 0 mg 658 ) methylphenyl)pyridin-3-ylJmethyl } thio)acetic acid as a white powder. , 5), 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).({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) pyridin-yielding (Y cv 175 (as powder color 001) 3-ylJmethyl} thio)acetic acid dihydrochloride 0 ({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-white) according to the method similar to that of methylphenyl)pyridin -3-yljmethyl} thio)acetic acid (YY) Example H-NMR (DMSO-d ) 6:0.96 (6H, d, J = 6.6 Hz), 2.14-2.25 (1H, m), 2.42 (3H) , 5), 2.85 (3H, brs), 3.01 (2H, s), 3.20 (2H, s), 3.59 (2H, s), 3.70 (2H, 5), 7.26 (2H, d, J = yo 8.1 Hz ), 7.37 (2H, d, J = 8.1 Hz), 8.23 (3H, brs). 0110 Joe (([5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenylpyridin-3-yl methyl} sulfonylacetic acid dihydrochloride ({{5-{[(tert-butoxycarbonyl)aminojmethyl))-6 -isobutyl-2-methyl- to a solution of (1|0 mg; +00 mM YT +) 4-(4-methylphenyl)pyridin-3-yl methyl} thio)acetic acid commercial; Ade ) oxone water (0:15; © mL) add ~methanol mol (in µL). The mixture was stirred at room temperature (© + sulfuric acid mg) and then saturated A 040 A was added to the reaction mixture Sle sodium hydrogen carbonate for 7 hours. To be added. The organic layer was washed with saturated brine, the acetate was dried, and the mixture was extracted with anhydrous Yo. The solvent was evaporated under reduced pressure and the remaining magnesium sulfate was purified on (([5-(aminomethyl)-) to give oil. Silica was obtained by gel column chromatography yyy 6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3-yl methyl } sulfonyl)acetic acid as a white powder from the oil produced according to (4A total yield V+£) dihydrochloride (PY) to a method similar to the example method “H-NMR (DMSO- ds ) 8: 0.95 (6H, d, J = 6.6 Hz), 2.21-2.28 (1H, m), 2.39 3H, 5), 2.65 (3H, s), 2.74 (2H, s), 3.61(2H, 5) ), 4.13 (2H, s), 4.55 (2H, 5), 7.18 2H, d, J = 8.1 e

Hz), 7.29 (2H, d, J = 7.8 Hz), 8.01 (3H, brs). {[2-isobutyl-6-methyl-4-(4-methylphenyl)-5-(1H-tetrazo]-5-ylmethyl)pyridin-3- yllmethyl } amine dihydrochloride tert-butyl {[5-(cyanomethyl)-2 -isobutyl-6-methyl-4-(4-methyl to a solution of 1) 0 mmol) in +, VE cana 001( phenyl)pyridin-3-yljmethyl} carbamate) 0 0 mg (TV) dibutyltin oxide (mL) add (©) toluene .. μL 7.7 mmol) and stir the mixture at (YAY) trimethylsilyl azide .ethyl acetate C for ? days. Water is added to the reaction mixture; The mixture was extracted with anhydrous 0. magnesium sulfate. The organic layer was washed with saturated brine and dried over 1 silica. The solvent was evaporated under reduced pressure and the resulting residue was purified by tert-butyl {[2-isobutyl-6-methyl-] gel chromatography. 4-(4-methyl phenyl)-5-(1H-tetrazol-5-to) has a total yield of £79 (as a powder in 4 (ylmethyl)pyridin-3-yl]methyl} carbamate white. -NMR (CDCl; ) 0:0.90 (6H, d, J = 6.6 Hz), 1.36 (9H, s), 2.08-2.11 (1H, m), 2.35 Ye (3H, s), 2.42 (3H, s), 2.83 (2H, 5), 4.03(2H, s), 4.09 (2H, brs), 4.79 (1H, brs), 7.01 (2H, d,] = 8.1 Hz), 7.18 (2H, d, J = 7.8 Hz). pyridin-3-yljmethyl} amine dihydrochloride tert-butyl {[2-isobutyl-6-methyl-4-(4-methyl phenyl)-5-(1H-) as a white powder of Yo according to a method similar to that of tetrazol -5-ylmethyl)pyridin-3-yljmethyl} carbamate (Example 7-?).

YY¢ "H-NMR (DMSO-d ) 8: 1.00 (6H, d, J = 6.6 Hz), 2.15-2.23 (1H, m), 2.36 (3H, 5), 2.74 (3H, s), 3.14 ( 2H, s), 3.78 (2H, s), 4.04 (2H, 5), 7.06 (2H, d, J = 8.1 Hz), 7.28 (2H, d, J = 8.1 Hz), 8.35 (3H, brs). 3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl methyl} - °1,2.4-oxadiazol-5(4H)-one dihydrochloride tert-butyl {[5-(cyanomethyl)-2-isobutyl-6-methyl-4-(4-methyl) to a solution of (1 mmol) in 1 mg; £0 (phenyl)pyridin-3- yljmethyl } carbamate mg; § mmol (£Y+) sodium carbonate mml) add (©) ethanol (mg; ¥ mmol) and stir the mixture at (YY +) hydroxy ammonium chlorides 0 .ethyl acetate days. Water is added to the reaction mixture and the mixture is extracted with 1 C for anhydrous time. magnesium sulfate The organic layer is washed with saturated brine and dried to tetrahydrofuran (©) The solvent is evaporated under reduced pressure and the resulting residue is dissolved in mg; -6-methyl-4-(4-methylphenyl gel column chromatography silica)-5-[(5-0x0-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl] pyridin-3- mg; Yield 777) as a white powder. , m), 2.40 (3H, s), 2.51 (3H, 5), 2.73 (2H, d, J = 7.2 Hz), 3.62 (2H, s), 4.02 (2H, d, J = 4.5 Hz), Y 4.45 (1H, brs), 7.02 (2H, d, J = 8.1 Hz), 7.26 (2H, d, ] = 7.8 Hz). 4-(4-methylphenyl) you get (¥ YAY yield) pyridin-3-ylJmethyl}-1,2,4-oxadiazol-5(4H)-one dihydrochloride tert-butyl ({2-isobutyl- 6-methyl-4-(4-methylphenyl)- as a white powder of 0 AVY 5-[(5-0x0-4,5-dihydro-1,2,4-0xadiazol-3-yl)methyl]pyridin- 3-yl }methyl)carbamate ~~ Yo (FY) according to the method similar to that of the example

YYo

H-NMR (DMSO-d) 8: 0.98 (6H, d, J = 6.6 Hz), 2.13-2.21 (1H, m), 2.39 (3H, 5), 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).

Yet example diethyl {[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3- o yl]methyl} phosphonate dihydrochloride [5-{[(tert-m) momol) to £.0 ¢ alg Sua VVY ) triethyl phosphite add ( \butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3- mmol ) and stir the mixture at 1,80 cana 14Y) yl]methyl methanesulfonate reaction to cool to room temperature and purify dads for ? hours. Leaves 400 0 diethyl {[5-{[(tert-) to give silica by gel column chromatography butoxycarbonyl)amino Jmethyl ( -6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3- Yield 47 7) As a white powder. cane 710 lb) yl]methyl phosphonate "H-NMR (J020)) 8:0.95 (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, 5), 2.73 (2H, d, J = 5.1 Hz), 2.96 (1H , s), Yo 3.04 (1H, s), 3.86 (4H, q, J = 7.2 Hz), 4.00 (2H, d, ] = 4.8 Hz), 4.17 (1H, brs), 7.07 (2H, d, J = 8.1 Hz), 7.24 (2H, d, J = 8.1 Hz).diethyl ~ {[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4- (mle Joa a (¥) total productivity 001 ) methylphenyl)pyridin-3-ylJmethyl ( phosphonate dihydrochloride diethyl {[5-{[(tert-butoxycarbonyl)amino]methyl}-6- as a white powder of (% anv.) according to isobutyl-2-methyl -4-(4-methylphenyl)pyridin-3-ylJmethyl } phosphonate .)7-7 Similar to the example method "H-NMR (DMSO-d¢) 6:0.97 (6H, d, ] = 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, 5), 3.17 (2H, 5s), 3.78 (2H, 5), 3.82 (4H, q,J = 7.2 Hz), 7.26 (2H, d, J = 7.8 Hz), 7.39 (2H, d, ] = 7.8 Hz), 8.43 (3H, brs). Yo

Y.o Example YYvw pyridin-2-yimethyl 5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) nicotinate trihydrochloride pyridin-2-ylmethyl 5-{[(tert-butoxycarbonyl)amino] methyl}-6- on Joa ai (1 c. yield £29 (as non-oil V,Y)Y) isobutyl-2-methyl-4-(4-methylphenyl)nicotinate 5-{[(tert-butoxycarbonyl) amino]methyl} -6-isobutyl-2-methyl-4-(4-MnHs—1A© grammic molecule); a 1,17 (+s 1) methylphenyl)nicotinic 40 mmol) 7,14 .; g , 7 ) 2-(bromomethyl)pyridin hydrobromide mmol) according to the analogous method VL YY g; 1( potassium carbonate .)1-19 for the example method

'H-NMR (CDC13)8: 0.97 (6H, d, J = 6.6 Hz), 1.39 (9H, 5), 2.14-2.25 (1H, m), 2.35 0 (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, 12 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, ] = 4.7 Hz). pyridin-2-ylmethyl 5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-) obtained (¥ yield 14%) as aa solid color V,YY) methylphenyl)nicotinate trihydrochloride 0 pyridin -2-ylmethyl 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2- white (mm) according to 0.460 cma), YY) methyl-4-(4 -methylphenyl)nicotinate

7-7.) Method similar to example 1-1111 (DMS0-dg)8:0.97 (6H, d, J = 6.4Hz), 2.17-2.28 (1H, m), 2.34 (3H, 5), 2.61 (3H, s), 2.94 (2H, with 1 = 6.9 Hz), 3.81 2H, d, J = 4.9 Hz), 5.20 (2H, 5), 7.19 (4H, 0 s, 7.23 (1H, brs), 7.62-7.66 (1H, m), 8.06 (1H, t, J = 7.9Hz), 8.39 (3H, brs), 8.68 (1H, d, J = 4.9Hz).benzyl[5-(aminomethyl) -6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3- yl]acetate dihydrochloride Yo benzyl [5- {[(tert-butoxycarbonyl)amino]methyl} -6-isobutyl-2- on Ja a3 )1 as powder (AE yield ase +0) methyl-4-(4-methylphenyl)pyridin-3-yl]acetate

As a white color from {[(tert-butoxycarbonyl)amino]methyl }-6-isobutyl-2-methyl-4-(4- -5[ YY cana 05 ) methylphenyl)pyridin-3-yl]acetic acid mmol (015 cane YAY) benzyl bromides mmol) according to the method similar to that of Example 1-179” H-NMR (CDCl) 8:0.97 (6H, d, J = 6.8Hz) , 1.38 (9H, 5), 2.12-2.28 (1H, m), 2.38 ° (3H, s), 2.49 (3H, 5), 2.76 (2H, d, J = 6.6 Hz), 3.39 (2H, 5), 4.03 (2H, d, ] = 5.1 Hz), (1H, brs), 5.05 (2H, s), 6.90 (2H, d, J = 7.9Hz), 7.14 (2H, d, J = 7.9 Hz), 7.19- 4.20 (2H, m), 7.31-7.40 (3H, m). 7.25 ?) benzyl [5-(aminomethyl)-6-isobutyl-2-methyl-4-(4- oto Joa a5 YY £,0) methylphenyl)pyridin-3-yl]acetate dihydrochloride 0 mg; yield £90) as a white powder of benzyl [5-{[(tert-butoxycarbonyl)amino]methyl}-6 -isobutyl- (aan 1 +) 2-methyl-4-(4-methylphenyl)pyridin-3-yljacetate 4714 mmol) according to a method similar to that of the example (PY “H-NMR (DMS0- d¢)8:0.98 (6H, d, J = 6.6Hz), 2.11-2.27 (1H, m), 2.38 (3H, 5), 2.78 (3H, s), 3.15 (2H, 5), 3.78 (2H, d, J = 5.1 Hz), 5.04 (2H, 5), 7.10 (2H, d, J = 8.1Hz), Vo (7H, m), 8.40 (3H, brs). 7.20-7.45 Example No } Al-Jataa’ D [1B 3 Hastal Gm (Naj’ Dam [Nabata’a 0-4)-4- | Strictly 7--6-1501171-2-(30110010617[1)-1]5)-4 thio)benzamide dihydrochloride Ye \ get tert-butyl {[5-({[4-(aminocarbonyl) (phenyl]thio}methyl)-2-isobutyl- YT. ) 6-methyl-4-(4-methyl phenyl)pyridin-3-yljmethyl}carbamate mg VY yield %) as a white solid of - 6-} 4-({[5-{[(tert-butoxycarbonyl)amino]methyl isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-ylJmethyl } thio)benzoic acid ) 00, « +,AV0 (aa mmol) according to the method similar to that of the example (VY “H-NMR (CDCl;) 6:0.97 (6H, d, J = 6.6 Hz), 1.38 (9H, s) ), 2.13-2.25 (1H, m), 2.38 Yo (3H, s), 2.65 (3H, 5), 2.76 (2H, d, J = 7.4 Hz), 3.85 (2H, 5), 4.04 (2H , d, J = 5.1Hz), incl

YYA

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 = 7.9Hz), 7.64 (2H, d, J = 8.5Hz ). 4-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4- lo Joa ai (¥ mg; YO 9 methylphenyl)pyridin-3-yljmethyl ( thio)benzamide dihydrochloride tert-butyl {[5-({[4- Yield 774) as an aged white elderberry solid 0 (aminocarbonyl)phenyl]thio } methyl)-2-i sobutyl -6-methyl-4-(4-methylphenyl) mmol ) according to 1,174 vol. 0 ) pyridin-3-yl} methyl} carbamate method similar to that of Example 7-?). H-NMR (DMSO0-dg) 8:0.99 (6H, d, J = 6.5Hz), 2.13-2.22 (1H, m), 2.37 (3H, s), 2.86 (3H, brs), 3.14 (2H, brs), 3.78 (2H, d, J = 4.7Hz), 3.99 (2H, 5), 7.22 2H, d, J = 01 8.5Hz), 7.26 (2H, d, J = 8.1Hz), 7.33 (2H, d, J = 8.5Hz), 7.37 (1H, brs), 7.98 (1H, brs), 8.39 (3H, brs).

Yo A Example methyl 2-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3- yl]methyl}thio)benzoat dihydrochloride Vo methyl 2-( {[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2- you get (9 yields (aa V,) 9) methyl-4-(4-methylphenyl)pyridin-3 -yljmethyl} thio)benzoat tert-butyl {[5-(hydroxymethyl)-2-isobutyl-6-methyl-4-(4- as colorless oil from (% A g; 0,¥) mmol) 1( methylphenyl) pyridin-3-yl} methyl } carbamate to method Wiha (mmol) (Y,0 mg; £YY) methyl 2-mercaptobenzoats 0

VAY similar to example H-NMR (J20s) 58: 0.98 (6H, d, J = 6.6Hz), 1.39 (9H, s), 2.12-2.26 (1H, m), 2.35 (3H, s) ), 2.66 (3H, s), 2.75 (2H, d, J = 7.4Hz), 3.77 (2H, s), 3.89 (3H, s), 4.03 (2H, d,

J = 4.9Hz), 4.19 (1H, brs), 7.05 (1H, d, J = 8.1Hz), 7.09-7.13 (3H, m), 7.17 2H, d, J =8.1Hz), 7.32-7.38 (1H , m), 7.93 (1H, dd, J = 7.7, 1.5 Hz). Yo methyl 2-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-on Jia a5 (¥ yield caw) 10)methylphenyl)pyridin-3-ylJmethyl} thio) benzoate dihydrochloride

751) as a solid white elderberry methyl 2-({[5-{[(tert- 0111077108170 0101) ]-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3 - millimole) according to the method 1,717 ane V4 +) yl]methyl}thio)benzoat similar to the method of Example 7-?). H-NMR (DMSO-dg) 5:0.98 (6H, d, J = 6.6 Hz), 2.13-2.25 (1H, m), 2.34 (311), (, 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 = 8.5Hz), 7.47-7.52 (1H, m), 7.87 (1H, dd, 1 = 7.7, 1.5

Hz), 8.18 (3H, brs). 10 Example 2-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yiJmethyl} Ye thio)benzoic acid methyl 2-({[5] -{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2- (1 g yield 3 ) methyl-4-(4-methylphenyl)pyridin-3-ylJmethyl } thio) benzoic acid methyl 2-({[5-{[(tert- solid white elderberry)))/4 butoxycarbonyl)amino]methyl } -6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin- 3- d mmol) according to the analogous method V,AY g; (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, I = 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- Y. 7.97 (1H, m). 2-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) get (Y yield 799) pyridin-3-ylJmethyl}thio) )benzoic acid ({[5-{[(tert-butoxycarbonyl)amino]methyl }-6-isobutyl-2-methyl-4-(4-white from 1,8 mmol 47 can +,Y4) methylphenyl)pyridin-3-yl methyl} thio)benzoic acid Ye (1-3 gram) according to the method similar to the example method

Yr. H-NMR (DMSO-de) 8: 0.99 (6H, d, J = 6.4 Hz), 2.15-2.24 (1H, m), 2.34 3H, 5), 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 2-(1)15-(2001010 60771 Ngtaa 0 [1/- 32 Ht Dam) [Lajs Dam 1 Gata 00--4)-4- [BJTAH-6-1801011/1-2-0-( 8 thio)benzamide dihydrochloride tert-butyl {[5-({[4-(aminocarbonyl)phenyl]thio}methyl)-2-isobutyl- (1 g; yield 7 ¥) 6-methyl-4 -(4-methylphenyl)pyridin-3-yl}methyl}carbamate 2-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6- as a white solid from ( IN A) isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-ylJmethyl } thio)benzoic acid 0

LVF mmol) according to the method similar to that of the example AA aa "H-NMR (CDCl;) 6:0.97 (6H, d, J = 6.8 Hz), 1.39 (9H, s), 2.14-2.26 (1H, m), 2.40 (3H, 5), 2.64 (3H, 5), 2.75 (2H, d, J = 7.4 Hz), 3.82 (2H, s), 4.00 (2H, d, J = 5.3 Hz), 4.27 ( Yo 2-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4- ou lo Jn(Y;mg71 A) methylphenyl)pyridin-3-yljmethyl} thio)benzamide dihydrochloride tert -butyl {[S-({[2- yield) 749 (as a white solid of (aminocarbonyl)phenyl]thio } methyl)-2-isobutyl-6-methyl -4-(4-methylphenyl) mmol ) according to 0.471 c. , 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, 5), 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). Yo 711 is an example

YY methyl 3-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3- yllmethyl}thio)benzoat dihydrochloride methyl 3-({[5-{[(tert) -butoxycarbonyl)amino]methyl}-6-isobutyl-2- (1 g; yield Ve) methyl-4-(4-methylphenyl)pyridin-3-ylJmethyl } thio)benzoat tert-butyl {[ 5-(hydroxymethyl)-2-isobutyl-6-methyl- as a brown solid of 0 AY © mMol (V0) g; 0 ) 4-(4-methylphenyl) pyridin-3-yl]methyl } carbamate milligrams (according to Yoo) aggregate; ©0V) methyl 3-mercaptobenzoat 5 gram) 1-178? Method similar to example method "H-NMR (CDCl3) 6:0.97 (6H, d, J = 6.6 Hz), 1.39 (9H, ,l(2.15-2.24 (1H, m), 2.38 (3H, s) ), 2.64 (3H, 5), 2.75 (2H, d, J = 7.4 Hz), 3.83 (2H, 5), 3.90 (3H, s), 4.02 (2H, d, Ve

J=5.1Hz), 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). methyl 3-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-on Joa a3 (¥ mg; yield 1 A)methylphenyl)pyridin-3-ylJmethyl}thio) benzoat dihydrochloride methyl 3-({[5-{[(tert-) solid white elderberry (JAY 0 butoxycarbonyl)amino]methyl }-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3 – mg; 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 Ye (2H, d,J=7.4Hz),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).11 Example 3-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3-yljmethyl } thio)benzoic acid dihydrochloride Yo 3-({[5-{[(tert-butoxycarbonyl)amino]methyl } -6-isobutyl-2-methyl-4- you get ( ) (% VY g; yield 1," ¥) (4-methylphenyl)pyridin-3-yljmethyl } thio)benzoic acid only methyl 3-({[5-{[(tert-butoxycarbonyl)aminoJmethyl}- 6- A white solid compress of cp +, ) isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-ylJmethyl } thio)benzoat (1-49 mmol) according to the method similar to that of Example 84 'H-NMR (CDCl) 8:0.97 (6H, d, ] = 6.6 Hz), 1.39 (9H, 5), 2.13-2.26 (1H, m), 2.38 (3H, s), 2.68 (3H , 5), 2.79 (2H, d, J = 7.0 Hz), 3.85 (2H, 5), 4.04 (2H, d, J = 4.9 Hz), 4.24 ° (1H, brs), 7.00 (2H, d,J = 7.2 Hz), 7.19 (2H, d, I = 7.9 Hz), 7.30-7.35 (2H, m), 7.84 (1H, brs), 7.89 (1H, brs). 3-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) ?) we get TA yield 0' (not 1 mg pyridin-3-ylJmethyl) }thio)benzoic acid dihydrochloride 3-({[5-{[(tert-butoxycarbonyl)amino }methyl }-6-isobutyl- as a white solid of 0 body +, YY ) 2-methyl-4- (4-methylphenyl)pyridin-3-yl]methyl}thio)benzoic acid (mM) according to the method similar to that of Example 7-?). 441 "H-NMR & 01150-0) 5:0.98 (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, ] = 5.1 Hz) , 3.97 (2H, 5), 7.21 2H, d,] = 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).

ARAN

3-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yljmethyl } thio)benzamide dihydrochloride tert-butyl {[5-({[3-(aminocarbonyl) )phenyl]thio}methyl)-2-isobutyl- (\mg; yield 0 ) 6-methyl-4-(4-methylphenyl)pyridin-3-ylJmethyl}carbamate | 0 3-({[5-{[(tert-butoxycarbonyl)amino]Jmethyl }-6- as a white solid of ( ay *,00 ) isobutyl-2-methyl-4-(4-methylphenyl)pyridin- 3-ylimethyl thio)benzoic acid

VY milligrams) according to the method similar to that of the example 0,975 can

H-NMR (CDCl3) 8: 0.97 (6H, d, 1 = 6.6 Hz), 1.39 (9H, s), 2.16-2.27 (1H, m), 2.38 (3H, s), 2.65 (3H, 5), 2.75 (2H, d, J = 7.2 Hz), 3.84 (2H, 5), 4.02 (2H, d, J = 5.1 Hz), Yo 4.24 (1H, brs), 6.99 (2H, d, J = 7.9 Hz) , 7.19 (2H, d, ] = 7.7 Hz), 7.25-7.31 (2H, m), 7.49-7.53 (1H, m), 7.56-7.59 (1H, m).

yyy 3-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4- — le Joa 3 (Y stereo; 4 ) methylphenyl)pyridin-3-yljmethyl } thio)benzamide dihydrochloride tert -butyl {[5-({[3- quantitative) as a white elderberry solid (aminocarbonyl)phenyl]thio } methyl)-2-isobutyl-6-methyl-4-(4-methylphenyl) mmol) According to +, ATY comprising £74) pyridin-3-yljmethyl} carbamate ©

APY Method similar to example method 11-1117 (DMSO-de) 5:0.99 (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, 5s), 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). Ye 16 Example 4-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-y1] methoxy}benzoic acid dihydrochloride tert-butyl {[5- (hydroxymethyl)-2-isobutyl-6-methyl-4-(4-) to a solution of 1 mM 01# (oa +,0+) methylphenyl)pyridin-3-ylJmethyl}carbamate Vo mMol gram) #01 g; methyl 4-hydroxybenzoate (+,37) ; V+) tetrahydrofuran mmol) in 0.717 gg 7 (triphenylphosphine diethyl mmol) of 0.77 lll ,10 (740 ml) Ve. min solution was added and the mixture was stirred at room temperature for 1 toluene in azodicarboxylate The solvent was evaporated under reduced pressure and the resulting residue was purified by 0 methyl column chromatography 4-{[5-{[(tert-butoxycarbonyl)aminoJmethyl}-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl methoxy) to give silica gel mg TAL yield } benzoat as a colorless oil. (707A "H-NMR (CDCl;) 8:0.99 (6H, in ] = 6.6 Hz), 1.39 (9H, 5), 2.16-2.27 (1H, m), 2.34 (3H, 5), 2.62 (3H, 5), 2.80 (2H, d, J = 7.4 Hz), 3.87 (3H, 5), 4.08-4.13 (2H, m), 430 Yo (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=7.7Hz), 7.93 (2H, d, J = 8.9 Hz).

YY\Y

Y ( we get 4-{[5-{[(tert-butoxycarbonyl)amino methyl }-6-isobutyl-2-methyl-4- 00 ) (4-methylphenyl)pyridin-3-ylJmethoxy} benzoic acid total AY yield %( as a white solid of methyl 4-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl- YA ) 2-methyl-4-(4 -methylphenyl)pyridin-3-yljmethoxy} benzoat mg 11 no mM °) according to method similar to example 1% ("H-NMR (CDCl3) 8:1.00 (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). yljmethoxy}benzoic acid dihydrochloride 4-{[5-{[(tert- yield 7954) as a white elderberry solid of butoxycarbonyl)amino Jmethyl }-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3 - milligrams) according to the method 1,274 aa +, Y) ylimethoxy} benzoic acid 1 similar to the method of Example 7-?). H-NMR (CDCl) 8: 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, 5), 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). Yio Jha Yo. methyl 4-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3- ylmethoxy}benzoat dihydrochloride methyl 4- {[5-(aminomethyl)-6-isobutyl-2) -methyl-4-(4- on Ja a yield cana YAN ) methylphenyl)pyridin-3-ylJmethoxy}benzoat dihydrochloride methyl 4-{[5-{[(tert-white aged) os LAL asi (444) Yo ‎butoxycarbonyl)amino]methyl } -6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-

mmol) according to method 1.577 vol +, Ye) 7111160741 (FY similar to example method "H-NMR (DMSO-dg) 6:1.00 (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 (SH, 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). 16 Example {[2-isobutyl-6-methyl-4-(4-methylphenyl)pyridin-3-yl]methyl } amine dihydrochloride

V+) acetone s (mM) YAY can A,0) p-tolualdehyde to a solution of 1 (0) mM YAY can add (17( sodium hydroxide ,17) You (mL) in water ethyl Gram) and the mixture was stirred at room temperature for ? days. The reaction mixture was diluted with magnesium sulfate and saturated brine and dried on ela, washed successively with anhydrous 4-(4-methylphenyl)but-3-en-2-one cacetate. The solvent evaporates under reduced pressure to give (1) as oil. Dissolve the remaining oil (ZA g; yield 9,Y)methylphenyl)but-3-en-2-one 0 3-amino-5-ml) and add 01 (ethanol µmol) in Ae 1.74 g; sodium hydroxide 5 mol) Abe V,€4 g” +,4Y) methylhex-2-enenitrile µmol). The mixture is heated with steam re-condensation for 2 hours.‎ 7,49 daa (0,7) ammonium chloride Wash successively with cethyl acetate solution Dilute the reaction mixture with anhydrous. The solvent saturated aqueous magnesium sulfate and saturated brine is evaporated and dried On Ye 2-isobutyl-6-methyl-4-(4-) under reduced pressure to give a residue. We get a yellow oil from the substance (VY yield cpa 8 (methylphenyl)nicotinotrile .)-77 Residue generated according to a method similar to the example method 'H-NMR (CDCl) 5: 1.01 (6H, d, J = 6.6 Hz), 2.20-2.33 (1H, m), 2.43 (3H, 3 (3H,s), 2.96 (2H,d,J = 7.4 Hz), 7.11 (1H, 5), 7.31 (2H, d, J = 7.9 Hz), 7.47 2H, d,] Y° = 8.3 Hz).

yy {[2-isobutyl-6-methyl-4-(4-methylphenyl)pyridin-3-ylmethyl }amine) (¥ 2-isobutyl-6-) is obtained as a white solid from AT aggregate; yield £07 dihydrochloride (mmol) according to 117 can +, £0) methyl-4-(4-methylphenyl)nicotinotrile (T=) SA to a method similar to that of the example "H-NMR (DMSO-dg) 6 :0.98 (6H, Bl 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).

NY Example ((2-1sobutyl-6-methyl-4-(4-methylphenyl)-5-[(4-methylphenyl)sulfonyl]pyridin-3- ylimethyl)amine 4-methylbenzenesulfonate 01 mol) Ale ©0,# g; 4) sodium 4-methylbenzenesulfinate To a solution of (1 mmol) 50 can 1,3) bromoacetone (mL) add (© +) ethanol in ethyl min. . The reaction mixture is divided between Vo vapor condensation (for sale) and the mixture is heated with magnesium and water. The organic layer was washed with saturated brine and dried at 186°C. The solvent was evaporated under reduced pressure and the remainder was purified by chromatography. Sulfate 0 (Ave g yield A) 1-[(4-methylphenyl)sulfonyl]acetone gives a silica gel column as a colorless oil.” H-NMR ( CDClz)o: 2.41 (3H, 5), 2.46 (3H, 5), 4.14 (2H, 5s), 7.37 (2H, 4, ] = 8.2 Hz), 7.77 (2H, d, J = 8.2 Hz). mmol 9.4 «aa Y) I-[(4-methylphenyl)sulfonyl]acetone Heated mixture of (xv 0 0 AY) piperidine g 5.4 mmol ),V) p-tolualdehyde grams); gram) for ¥ hours. The reaction mixture is cooled to room temperature; washed with anhydrous Stark's brine. The solvent is evaporated under reduced pressure to give saturated magnesium sulfate and dried over Yo as a crude product (M9-4) 4-methylphenyl)-3-[(4-methylphenyl)sulfonyl Jbut-3-en-2-one 3-amino-5-methylhex-2-enenitrile g).

Reduce aa ,15 (5.77 mmol) ethanol s (+ © milliliters) and re-evaporate for 11 hours. The reaction mixture is cooled to room temperature; The solvent is evaporated under reduced pressure. The remainder was purified by silica gel column chromatography and the resulting solid was recrystallized from diisopropyl ether-ethyl acetate to give 2-isobutyl-6-methyl-4-(4- methylphenyl)-5-[(4-methylphenyl) sulfonyl-1,4-dihydropyridin-3-carbonitrile ~~ © ) ,7/g; Yield 774) as a white powder. Melting point: 0 (Asie) YY=1 ?) you get 2-isobutyl-6-methyl-4-(4-methylphenyl)-5-[(4-methylphenyl) VV) sulfonyl]nicotinotrile ,+ g; Yield of TA # (as a white powder of 2-isobutyl- 6-methyl-4-(4-methylphenyl)-5-[(4-methylphenyl)sulfonyl- 1,4-dihydropyridin-3- V ,Y) carbonitrile 0 g; 7.7 mmol) according to the method similar to that of example Y-yYy ( . 'H-NMR (CDCl3)3: 0.99 (6H, d, J = 6.6 Hz), 2.20-2.35 (1H, m) , 2.38 (3H, 5), 2.39 GH, 5), 2.91 (2H, d, J = 7.2 Hz), 3.07 (3H, 5), 6.86 (2H, d, J = 8.1 Hz), 7.08 (4H , d, J Hz), 7.23 (2H, d, ] = 8.1 Hz). 8.1 = Vo 4) you get ({2-isobutyl-6-methyl-4-(4-methylphenyl)- 5-[(4-methylphenyl) 1,14( sulfonyl]pyridin-3-yl }methyl)amine colum; yield 797) as a colorless oil of -2,isobutyl-6-methyl-4-(4-methylphenyl (-5-[ (4-methylphenyl)sulfonyl [010011001116 0.6 can 1.14 mmol) according to a method similar to that of Example 4-1.) H-NMR (CDCl3)d : 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, 5), 6.76 2H, d, J = 8.1 Hz), 0 J = 8.1 Hz), 7.27 (2H, d, J = 8.3 Hz). , d, J = 8.3 Hz), 7.09 (2H, 7.03 ( {2-isobutyl-6-methyl-4-(4-methylphenyl)-5-[ (4-methylphenyl)sulfonyl] 0, 8 can +, ¢) pyridin-3-yl}methyl)amine mmol) in ethanol (© milliliters) and add a solution of “aa +,Y4) p-toluenesulfonic acid hydrate 1.0 mL YO mol) in ethanol (© milliliters) with stirring at room temperature. The mixture was stirred at room temperature for 10 minutes. The precipitate was collected by filtration; Wash with cold ethanol and dry to sneeze ({2-isobutyl-6-methyl-4-(4-methylphenyl)-5-[(4-)

YYA

.,0 V) methylphenyl)sulfonyl]pyridin-3-yl }methyl)amine 4-methylbenzenesulfonate (yield 777 g) as a white powder. 'H-NMR (DMSO0-de)8: 0.94 (6H, d, J = 6.6 Hz), 2.15-2.30 (1H, m), 2.29 (3H, s), 2.37 (6H, 5), 2.78 (2H, d, 1 7.0 Hz), 2.84 (3H, 5), 3.57 (2H, 5) ), 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, e brs). Example huh? {[2-isobutyl-6-methyl-4-(4-methylphenyl)-5-(methylsulfonyl)pyridin-3-yl methyl} amine mmol); YV can ,14( 1- (methylsulfonyl)acetone Heated mixture of 1 00 7.7 mL; piperidine (Y1) +, mM) YV aa ¥,Y£) p-tolualdehyde toluene 5 mL 8.4 mMol ) +, ¥1) acetic acid milligram); h. VY was cooled for Dean-Stark mL (with vapor re-condensation using a Yoo trap) washed with saturated brine and dried over Adal reaction mixture to anhydrous temperature. The solvent was evaporated under reduced pressure and the resulting residue was dissolved in magnesium sulfate Ve mL YO «an £,Y) 3-amino-5-methylhex-2-enenitrile mL). Add 10 (mol methanol) and heat the mixture with re-condensation of steam for 7 hours. The reaction mixture was concentrated to give silica under reduced pressure and the remainder was purified by gel column chromatography 2-isobutyl-6-methyl-4-(4-methylphenyl)-5-(methylsulfonyl)-1,4-dihydropyridin-3- As a yellow oil. (ZA g; yield 1,YA) carbonitrile 0 "H-NMR (CDCl) 6:0.95 (3H, d, J = 6.6 Hz), 1.01 (3H, d, J = 6.6 Hz) , 2.18-2.25 (1H, m), 2.32 (3H, 5), 2.35 (3H, 5), 2.40 (3H, 5), 2.44 (1H, 5), 3.04 (1H, 5), 4.69 (1H, s) ), 5.80 (1H, 5), 7.14 (2H, d, J = 8.1 Hz), 7.21 (2H, d, J = 8.3 Hz). -(methylsulfonyl) obtained (Y 2-isobutyl-6- (ms total yield £70) as a white solid 4 ) nicotinonitrile Yo methyl-4-(4-methylphenyl)-5-(methylsulfonyl)-1 ,4-dihydropyridin-3-carbonitrile in milligrams) according to the method similar to that of Example ?7-?).

YYw

H-NMR (CDCl5) 8: 1.02 (6H, d, ] = 6.8 Hz), 2.23-2.37 (1H, m), 2.44 (3H, 5), 5 (2H, d, J = 7.2 Hz), 3.05 (3H, s), 7.24 (2H, d, ] = 8.1 Hz), 7.33 (2H, d, ] = 7.9 Hz).{[2-isobutyl-6-methyl-4-(4-methylphenyl)-5- (methylsulfonyl) Ie Joa a3 (¥ Total yield © 70/7 as a white solid of pyridin-3-yl[methyl-amine }amine +,AY) 2-isobutyl-6-methyl-4-(4) - methylphenyl)-5-(methylsulfonyl)nicotinotrile©

.) 1-4 g; 7.09 mmol) according to the method similar to the example method "H-NMR (CDCl) 6:0.99 (6H, d, J = 6.8 Hz), 2.22-2.36 (1H, m), 2.43 (3H, 5) , 0 (3H, 5), 2.82 (2H, d, J = 7.4 Hz), 2.96 (3H, s), 3.50 (2H, 5), 7.12 (2H, d, J = 7.9 Hz), 7.26 (2H, d, J = 7.7 Hz).

13 Ex. (tert-butoxycarbonyl)amino]methyl }-6-isobutyl-2- you get ( 1 (VY yield) cana YY ( methyl-4-(4-methylphenyl)pyridin-3-yljmethoxy}benzoat tert-butyl { [5-(hydroxymethyl)-2-isobutyl-6-methyl-4-(4- as a colorless oil of Vo) Al 0.85 aa 0 V0 ( methylphenyl)pyridin-3-ylJmethyl} carbamate mmol) according to method 0.60 aa +, YS) methyl 3-hydroxybenzoat s

similar to the example method.) 1-714

H-NMR (CDCl5) 6: 0.99 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.19-2.28 (1H, m), 2.35 (3H, 8), 2.62 (3H, 5) , 2.79 (2H, d, J = 7.2 Hz), 3.89 (3H, 5), 4.07-4.11 (2H, m), 4.67 Y. (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), methyl 3- {[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methyl on Joa a3 (Y (Aho mg » yield 111) phenyl)pyridin-3-ylJmethoxy}benzoat dihydrochloride methyl 3 -{[5-{[(tert-butoxycarbonyl)amino]methyl }-6- a white solid of Ye mg VEE) isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl methoxy} benzoate

(YY millimol) according to the method similar to that of Example #0

m “H-NMR (DMSO0-dg) 8:1.00 (6H, d, J = 6.6 Hz), 2.17-2.26 (1H, m), 2.34 (3H, s), (3H, brs), 3.11 (2H, brs), 3.83 (5H, 5), 4.79 (2H, s), 7.15 (1H, dd, J = 7.8,2.2 2.83 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). 001 Jie 0 3- {[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methvlphenyl)pyridin-3-vyl] ‎methoxy}benzoic acid dihydrochloride )( you get {[(tert-butoxycarbonyl)amino ]methyl } -6-isobutyl-2-methyl-4- -5[{-3 (4-methylphenyl)pyridin-3-ylJmethoxy} benzoic acid (£74 mg; yield of AAs as Ve oil) Colorless methyl 3-{[5-{[(tert-butoxycarbonyl)amino]methyl }-6-isobutyl-2- +,0A) methyl-4-(4-methylphenyl)pyridin-3-yljmethoxy} benzate g; 0.01 mmol) according to a method similar to that of the example.) 1-49 “H-NMR (CDCl;) 8:0.99 (6H, d, J = 6.6 Hz), 1.39 (9H, 5), 2.17-2.28 (1H, m), 2.34 (3H, 5), 2.65 (3H, 5), 2.82 (2H, d, J = 7.2 Hz), 4.11 (2H, brs), 4.28 (1H, brs), 4.68 (2H, 8), 7.03-7.07 (3H, m), 7.16 (2H, d, J = 7.9 Hz), 7.33 (1H, t,J = 8.0 Hz), 7.47 0 (1H, brs), 7.64-7.70 (1H, m). ?) you get 3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) Y YA) pyridin-3-ylJmethoxy} benzoic acid dihydrochloride 99 mg yield (£99) as a white solid of 3-{[5-{[(tert-butoxycarbonyl)amino]methyl } -6-isobutyl-2- 1 ( methyl-4-(4-methylphenyl)pyridin-3-ylJmethoxy} benzoic acid 00 mg 777 mmol) according to the method similar to the example method (TY "H-NMR (DMSO-dg) 8: 1.00 (6H, d, J = 6.2 Hz), 2.18-2.27 (1H, m), 2.34 (3H, (, (3H, m), 3.04 (2H, brs), 3.81 (2H, brs), 4.76 (2H, 5), 7.11 (2H, d, J = 8.1 2.73-2.79 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). Ye Example 771 Horizon

p methyl 2-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3- ylJmethoxy}benzoat dihydrochloride 1 ( you get methyl 2-{ [5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2- Ve +) methyl-4-(4-methylphenyl)pyridin-3-ylJmethoxy} benzoat mg; Yield to (©) as a white solid of tert-butyl {[5-(hydroxymethyl)-2-isobutyl-6-methyl-4-(4-0,1#( methylphenyl)pyridin-3-yl]methyl } carbamate g (0.84 mmol) 1.79 (methyl 2-hydroxybenzoat g; 0.60 mmol) according to the method

VY YE Similar to example method "H-NMR (U00) 8:0.99 (6H, d, J = 6.6 Hz), 1.39 (9H, 5), 2.19-2.28 (1H, m), 2.36 (3H, s), 2.67 (3H, 5), 2.78 (2H, d, J = 7.4 Hz), 3.81 (3H, s), 4.09 (2H, d, J] = 4.0 Hz), Ve 4.23 (1H, brs), 4.71 (2H, 5), 6.66 (1H, d, J = 8.3 Hz), 6.93-6.98 (1H, m), 7.04 (2H, d,

J=8.1Hz), 7.16 (2H, d, J = 7.7 Hz), 7.29-7.35 (1H, m), 7.72 (1H, dd, J = 7.6, 1.8

Hz). methyl 2-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methyl) yields (¥ (Fo yield 0 mg £Y,¥) phenyl)pyridin-3 -ylJmethoxy}benzoat dihydrochloride © methyl 2-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6- as a white solid of stereo; YA,A) isobutyl-2-methyl-4- (4-methylphenyl)pyridin-3-yljmethoxy}benzoat (.7-7 mmol) according to the method similar to that of Example +, YEA "H-NMR (DMSO-dg) 8:1.00 (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), Ye 6.91 (1H, d, J = 8.5 Hz), 7.03 (2H, t, J = 7.4 Hz), 7.25 (2H, d, ] = 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).

YVY Joe 2- {[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-y1] methoxy} benzoic acid dihydrochloride Yo 2-{[5-{[(tert-) butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4- you get (1 as a substance (% YY mg; yield) 001 ( (4-methylphenyl)pyridin-3-yljmethoxy} benzoic acid yey methyl 2-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl- white solid of mm VAY aa 5 ) 2-methyl-4-(4-methylphenyl)pyridin-3 -yl methoxy} benzoate (V8 molecular) according to a method similar to that of the example "H-NMR (CDCl3) 8:0.99 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.21-2.30 ( 1H, m), 2.34 (3H, 5), 2.65 (3H, 5), 2.81 (2H, d, J = 7.4 Hz), 4.10 2H, d, J = 5.3 Hz), 4.92 (2H, s), 2 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). As a substance (VV productivity cana 0 ¥) pyridin-3-ylmethoxy} benzoic acid dihydrochloride 2-{[5-{[(tert-butoxycarbonyl)amino]methyl }-6-isobutyl-2- white solid of Ye t1 aa 1 ((b<mtd[ 3-tmO)-4-abt benzoic acid (FY gram molecule) according to the method similar to that of the example le "H-NMR (DMSO- dg) 5: 1.00 (6H, d, J = 6.6 Hz), 2.18-2.27 (1H, m), 2.37 (3H, 5), 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 = 8.5Hz), 7.02 (1H,t,J=7.4 Hz), 7.27 2H, d, J] = 7.9 Hz) , 7.32 (2H, d, J = 8.1 Hz), Yo 7.38-7.44 (1H, m), 7.61 (1H, dd, J = 7.5, 1.7 Hz), 8.39 (3H, brs).

YY Joe

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl] benzamide dihydrochloride tert-butyl {[5-amino-2-isobutyl-6-methyl-4 -(4-methylphenyl) a solution of J ve mg; +0.0 mmol) in VAY) pyridin-3-yljmethyl carbamate mMOL 01.5 μl AA) benzoyl chloride mL) add Y) tetrahydrofuran 31 mmol). The mixture was stirred for 1 μl 01 (5 g triethylamine) saturated aqueous (0 mL) into the reaction mixture sodium hydroxide 1 min. A solution was added, the organic layer was washed with saturated brine, ethyl acetate was dried, and the mixture was extracted with anhydrous Ye. The solvent is evaporated under reduced pressure and the resulting residue, magnesium sulfate, is thickened to give an oil. to a solution of the resulting oil in silica gel column chromatography

YYVY

1 liter (ethyl acetate) solution add hydrogen chloride ethyl acetate; 1 standard (mL) and the mixture was stirred at room temperature for one hour. The solvent evaporates under reduced pressure and the remaining hexane crystallizes to give N-[5-(aminomethyl)-6-isobutyl- 0 9 2-methyl-4-(4-methylphenyl)pyridin-3-yl]Jbenzamide dihydrochloride Yield 0#147 mg (as a white powder. “H-NMR) 0080-45: 1.00 (6H, d, J = 6.6 Hz), 2.20-2.32 (1H, m), 2.31 (3H, s) , (3H, s), 3.11 (2H, s), 3.87 (2H, 5), 7.17-7.66 (9H, m), 8.49 (3H, brs), 10.13 (1H, 2.64 brs). Example 5" N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3 -yl]-2- Ye phenylacetamide dihydrochloride we get N-[5 -(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3- 01 A) y1]-2-phenylacetamide dihydrochloride mg; Yield 740 (as white powder of tert-butyl {[5-amino-2-isobutyl-6-methyl-4-(4-methylphenyl) pyridin-3- AY) yl]methyl} carbamate 0 mg ,+ mmol) phenylacetyl chlorides 01 μl (01.75 mmol) according to a method similar to that of Example YY 'H-NMR (DMSO-dg) 5:0.97 (6H, d, 1 = 6.6 Hz), 1.98-2.26 (1H, m), 2.40 3H, 5), (3H, s), 3.04 (2H, 5), 3.40 (2H, 5), 3.78 (2H, 5), 6.94 -6.97 (2H, m), 7.12-7.53 2.50 (7H, m), 8.44 (3H, brs), 9.90 (1H, brs). Ye YYo Jue N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl]-3- phenylpropanamide dihydrochloride we get N- [5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) ‎Y + A)pyridin-3-yl]-3-phenylpropanamide dihydrochloride ~~ Yo mg. yield of 57) as a white powder of tert-butyl {[5-amino-2-isobutyl-6-methyl-4-(4- VAY ) methylphenyl)pyridin-3-ylmethyl} carbamate mg; 1.5 milligrams)

1.5 m “sly Sie 111 ( hydrocinnamoyl chloride s mmol) according to the method similar to that of Example YY “H-NMR (DMSO-d) 8:0.97 (6H, d, J = 6.6 Hz) , 2.15-2.23 (1H, m), 2.33 (2H, t, J = 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 7.2 (9H, m), 8.26 (3H, brs), 9.43 (1H, brs).° Example TY (2E)-N-[5-(aminomethyl) )-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-y1]-3- phenylacrylamide dihydrochloride Juans on (2E)-N-[5-(aminomethyl)-6 -isobutyl-2-methyl-4-(4-methylphenyl) 0 A)pyridin-3-yl]-3-phenylacrylamide dihydrochloride 0 total yield AY 0 as a white powder of tert-butyl {[5-] amino-2-isobutyl-6-methyl-4-(4-methylphenyl) pyridin- ‎VAY) 3-21[0601( carbamate mg©,+ (Ale)5 cinnamoyl chloride ) 5 mg ; ), 2.34 (3H, 5), (3H, s), 3.02 (2H, brs), 3.83 (2H, brs), 6.63 (1H, d, J = 15.6 Hz), 7.16-7.23 2H, 0 2.55 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). YY ethyl [({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) pyridin-3- yl]amino } carbonyl)oxylacetate dihydrochloride Ye )) you get ethyl [({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2- methyl-4-(4-methylphenyl) pyridin-3-yl]amino}carbonyl)oxylacetate) 5-{[(tert- butoxycarbonyl) amino]methyl}-6-isobutyl-2-methyl-4-(4-methylphenyl) £1Y) nicotinic acid mg; 1 mmol (cana V+£) ethyl hydroxyacetate s Y Yo mmol) according to a method similar to that of Example 1-465 (.0Y¢:(M+1) EIMS YY\vww

Yéo ethyl [({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) le yield ( Y )7 45 can yield YY)pyridin-3-ylJamino}carbonyl) oxylacetate dihydrochloride aforementioned according to analogous method 1) as a white powder from the oil obtained in Example 7-?). 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, ] = 7.8 Hz), 8.21 (3H , brs), 9.12 (1H, brs).

YYA J

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-y1]-N'- 01 benzylurea dihydrochloride tert-butyl {[5-{[(benzylamino)carbonyl ]amino }-2-isobutyl-6-methyl- ( 1 5-{[(tert- tert-) quist of 4-(4-methylphenyl) pyridin-3-yl)methyl} carbamate butoxycarbonyl) amino]methyl }-6-isobutyl-2-methyl-4-(4-methylphenyl)nicotinic μl; ? mM benzylamine s (YVA) mmol (1 mg; £1Y) acid 0 gram) according to the method similar to that of Example (1-95). ¥ on N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin- ‎YAY) 3-yl]-N'-benzylurea dihydrochloride mg; yield (160 As a white Osh powder PE 0 the oil produced in (1) the aforementioned according to the method similar to that of Example 7-7). 11-111 (DMSO-dg) 8:0.96 (6H, d, J = 6.3 Hz), 2.09-2.22 (1H, m), 2.41 (3H, 5), 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). 3 J methyl 4- {[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3- Yo yl]amino}carbonyl)oxy]methyl }benzoat dihydrochloride

Juans) 1 on -051-2n6-180010- ( sq. 10 [Musabsa (Nuss Taq-No «Manat-1H1)])-4-1]))]5 methyl methyl-4-(4- methylphenyl ) pyridin-3-ylJamino} carbonyl)oxy]methyl}benzoat as an oil of 5-{[(tert- butoxycarbonyl) amino]methyl}-6-isobutyl-2-methyl-4-(4- methylphenyl) nicotinic acid ( 7 mg; 1 mmol) 4-5 methyl cpa YO ( hydroxymethylbenzoat ~~ © 1.0 mmol) according to method similar to example method (V0 EIMS (agay) : oY Jaa (Y on methyl 4-{[( {[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4- methylphenyl)pyridin-3-ylJamino } carbonyl) oxyjmethyl }benzoat | dihydro chloride (0) 155 mg; yield (KFA) as a white powder from the oil obtained in above-mentioned 1 according to the similar method according to the example method (PY “H-NMR (DMS0) -dg)8:0.97 (6H, d, J = 6.3 Hz), 2.14-2.23 (1H, m), 2.39 (3H, s), (3H, 5), 2.97 (2H, brs), 3.78 ( 2H, brs), 3.87 (3H, 5), 5.09 (2H, brs), 7.14-7.29 2.55 (6H, m), 7.92 (2H, d, J = 8.4 Hz), 8.30 (3H, brs), 9.19 (1H, brs).00 ex 10? 3-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3- yl]carbonyl }oxy)methyl]benzoic acid dihydrochloride )1) into a solution of 5-{[(tert-butoxycarbonyl)amino]methyl } -6-isobutyl-2-methyl-4- EY can). Ve ) (4-methylphenyl)nicotinic acid mmol) in NN- dimethylformamide | 0 (© ) mL) add +,V4) methyl 3-(bromomethyl)benzoat g 7 mmol) potassium carbonate s (1 a, g; 8.10 mmol) and stir the mixture at room temperature room for one hour. The reaction mixture was diluted with cethyl acetate, washed with pada-brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by YO silica gel column chromatography to give 3-(methoxycarbonyl)benzyl 5-{[(tert- butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl -4-(4-methylphenyl)nicotinate (VAY) g; Yield 796) as a colorless oil.

Yev’ H-NMR (CDCl3) 8: 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, 5 ), 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, 0,12 7.9 Hz), 7.22 (1H, d,] = 7.7 Hz), 7.35 (1H, t.J = 7.7 Hz), 7.83 (1H, s), 7.98 (1H, d, ] = 7.7 Hz. (4-methylphenyl)pyridin-3-yl]carbonyl ( oxy)methyl benzoic acid 3-(methoxycarbonyl)benzyl 5-{[(tert- as colorless oil of (LAV) yield butoxycarbonyl)amino methyl} -6 -isobutyl-2-methyl-4-(4-methylphenyl)nicotinate (1-49 to the method similar to the example Wik mmol) Vie) g; : 0.96 (6H, with J = 6.6 Hz), 1.38 (9H, 5), 2.13-2.25 (1H, m), 2.34 Ve (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, 5), 8.04 (1H, d, J = 7.5 Hz). 3-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) you get (¥ mg; YAY yield) pyridin-3-ylJcarbonyl}oxy)methyl] benzoic acid dihydrochloride 00 3-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6- and “0) as a white solid of isobutyl-2-methyl-4-(4-methylphenyl)pyridin -3-yl]carbonyl } oxy)methyl Jbenzoic milligram) according to the method similar to the example method, 9717 g. 8) acid. -?) Y "H-NMR (DMSO-dg) 8:0.96 (6H, d, J = 6.6 Hz), 2.16-2.25 (1H, m), 2.32 (3H, s), Ye 2.54 (3H, 5), 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 = 17.6

Hz), 7.73-7.74 (1H, m), 7.89-7.92 (1H, m), 8.30 (3H, brs). 71 Example 2-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3- Yo yi]carbonyl}oxy)methyl]benzoic acid dihydrochloride only

YEA

5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4- to a solution of )1

NN- mmol) in 1,117 g 101 ((4-methylphenyl)nicotinic acid 0.7 G +,7)) 2-bromobenzyl bromide (mL) add (101) dimethylformamide mmol gram) 7.15 aa +,01) potassium carbonate 5 mol) (Ale ethyl) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with anhydrous ©. Evaporated magnesium sulfate Washed with solution Saline was saturated and dried over solvent cacetate under reduced pressure and the resulting residue was purified by gel column chromatography 2-bromobenzyl 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2- to give silica as an oilless Colour. (FAY total yield V, YY) methyl-4-(4-methylphenyl)nicotinate 11-1111 (CDCl3) 8:0.97 (6H, d, J = 6.8 Hz), 1.38 (9H, 5), 2.14-2.25 (1H, m), 2.35 01 (3H, s), 2.56 (3H, 5), 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). bromobenzyl 5-{[(tert-butoxycarbonyl)amino]methyl }-6-isobutyl-2- dissolved (¥ mmol); 1.11 g; V,YY) methyl-4-(4 -methylphenyl)nicotinate 0 mM)(1,1-!] 4,74 « , lille +,04) triethylamine mM 0.717 mg 4 ) bis(diphenylphosphino)ferrocene]palladium(II) dichloride mL) and stir (Y©) N,N-dimethylformamide mL)© (methanol mol) in ethyl h. The reaction mixture was diluted with 14 carbon monoxide for the resulting mixture under atmosphere (mL) and the mixture was washed with saturated brine. The organic layer was dried over anhydrous Ye 001 acetate and the solvent was evaporated under reduced pressure. The resulting residue magnesium sulfate 2-(methoxycarbonyl)benzyl 5- was purified to give silica by gel column chromatography {[(tert-butoxycarbonyl)amino] ]methyl}-6-isobutyl-2-methyl-4-(4- yield 774) as a yellow oil. aa +, AA) methylphenyl)nicotinate "H-NMR (CDCl) 8:0.97 (6H, d, J = 6.6 Hz), 1.38 (9H, 5), 2.16-2.25 (1H, m), 2.35 Yo (3H, 5), 2.56 (3H, 5), 2.78 (2H, d, J = 7.2 Hz), 3.87 ( 3H, 5), 4.11-4.16 (2H, m), 4.21

Yea (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). 2-[({[5-{[(tert-butoxycarbonyl)amino]methyl }-6-isobutyl-2-methyl- you get (* (pa +,V0 ) 4-(4-methylphenyl)pyridin-3 -yl]carbonyl } oxy)methyl]benzoic acid 2-(methoxycarbonyl)benzyl 5-{[(tert-) as untouched oil from (% Ad productivity © butoxycarbonyl)amino]methyl }-6-isobutyl-2- methyl-4-(4-methylphenyl)nicotinate .(1-4 mmol) according to the method similar to that of the example 0.94 g; AN) 'H-NMR (CDCl;) 8:0.96 (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- 0 8.09 (1H, m). 2-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4- to Jn a3 ( ¢ methylphenyl)pyridin-3-yljcarbonyl }oxy)methyl benzoic acid dihydrochloride 2-[({[ 5-{[(tert- mg; yield 110 (as white solid of YVA) butoxycarbonyl)amino]methyl} -6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-0 mM mol) according to + AYY can +, £0) yl]carbonyl}oxy)methyl benzoic acid (FY) to the method similar to that of the example "H-NMR (DMSO-d) 8:0.96 (6H, d, J = 6.6 Hz), 2.18-2.27 (1H, m), 2.35 (3H, s), 2.84 (2H, d, J=17.2 Hz), 3.82 (2H, d, J = 5.3 Hz), 5.32 (2H, 5) , 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, and m), 8.19 (3H, brs).

YY Joe methyl 4-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3- yl]amino}carbonyl)benzoate dihydrochloride methyl 4-({[5-( aminomethyl)-6-isobutyl-2-methyl-4-(4-methyl you get Yo mg; yield YY'+) phenyl)pyridin-3-yljamino}carbonyl)benzoate dihydrochloride tert-butyl {[5- amino-2-isobutyl-6-methyl-4-(4-methyl) as a white powder from (% A]

Yo. Gather 3-21 [10 servings of growth (feed (7 mg; +0 + mmol) ( carbamate mmol) 1.75 pane) £4) terephthalic acid monomethyl ester chloride 5

YY according to the method similar to the example method

H-NMR (DMSO-dg) 8: 1.00 (6H, d, J = 6.6 Hz), 2.22-2.31 (1H, m), 2.31 (3H, f) 2.54 (3H, 5), 2.95 (2H , brs), 3.85 (2H, brs), 3.87 (3H, 5), 7.20-7.27 (4H, m), 7.72 ° (2H, d, ] = 8.4 Hz), 7.99 (2H, d, J = 8.4 Hz ), 8.26 (3H, brs), 10.13 (1H, brs).vy Joe 4-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3-yl] amino } carbonyl)benzoic acid dihydrochloride 4-({[5- {[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4- we get 10 mg yield VE A) (4-methylphenyl)pyridin-3-yl]Jamino } carbonyl)benzoic acid methyl 4-({[5-{[(tert-butoxycarbonyl)amino]methyl}- as a white powder of (LA 6-isobutyl-2) -methyl-4-(4-methylphenyl)pyridin-3 -ylJamino} carbonyl)benzoate .(1-?7 mmol) according to the method similar to that of the example 1.44 mg; Yi.)

H-NMR (DMSO-dg) 5: 0.98 (6H, d, J = 6.6 Hz), 1.35 (9H, 5), 2.18-2.29 (1H, m), Vo 2.29 (3H, 5), 2.59 (3H , 5), 2.88 (2H, brs), 3.99 (2H, brs), 7.14 (1H, 5), 7.20 (4H, 5), 7.70 (2H, d, J = 8.4 Hz), 7.97 2H, d, J = 8.4 Hz), 10.13 (1H, brs). 4-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl))) we get (4 94 vol. YY yield ( pyridin-3-ylJamino ( carbonyl) benzoic acid dihydrochloride 4-({[5-{[(tert-butoxycarbonyl)aminojmethyl } -6-isobutyl-2- white from Osh as powder | 0 mg; Y¢ A) methyl-4-(4 -methylphenyl)pyridin-3-ylJamino } carbonyl)benzoic acid (YY mM) according to the method similar to that of the example 0.4 111-1111 (DMSO-dg) 5:1.00 (6H, d, J = 6.6 Hz ), 2.22-2.32 (1H, m), 2.31 3H, 5), 2.55 (3H, 5), 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). Yo

I'm jo

Yo methyl (4-{[5-(aminomethyl)-2-methyl-4-(4-methylphenyl)-6-neopentylpyridin-3- ylJmethoxy}phenyl)acetate dihydrochloride methyl (4-{[5-{[(tert-) butoxycarbonyl)amino]methyl}-2-methyl-4-(4- you get () productivity es ,1 ) methylphenyl)-6-neopentylpyridin-3-yljmethoxy} phenyl)acetate tert-butyl {[5- (hydroxymethyl)-6-methyl-4-(4-methyl as a white powder of 8 oe mmol 1.1 g; 4 ) phenyl)-2-neopentylpyridin-3-ylJmethyl } carbamate mmol Gram) according to 111 g; ), 1.37 (9H, s), 2.36 (3H, 5), 2.61 (3H, 5), 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, ] = 8.5 Ve

Hz), 7.05 (2H, d, J = 8.5 Hz), 7.14 (2H, d, ] = 8.5 Hz), 7.17 (2H, d, J = 8.5 Hz). methyl (4-{[5-(aminomethyl)-2-methyl-4-(4-methylphenyl)-6- you get (¥ g; yield +, + AA) neopentylpyridin-3-ylJmethoxy}phenyl) methyl acetate dihydrochloride (4-{[5-{[(tert-butoxycarbonyl)aminojmethyl}- as a white powder of (ZY£2-methyl-4-(4-methylphenyl)-6-neopentylpyridin-3-yljmethoxy} phenyl )acetate 0 (TY mM) according to the method similar to that of the example 177 g; +N)' H-NMR :5 (01/80-0) 1.04 (9H, s), 2.35 (3H , 5), 2.77 (3H, brs), 3.14 (2H, brs), 3.58 (2H, d, J =7.0 Hz), 3.59 (3H, s), 3.87 (2H, 5), 4.66 (2H, 5) , 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). Yo

Y¥o Example methyl 2-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-y1]- 1,3-oxazole-4-carboxylate dihydrochloride methyl N- {[5-cyano-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin- you get ( 1

S-cyano-6- as colorless oil from (LAY yield aa 0,YV) 3-yljcarbonyl}serinate Yo mmol 11.1 g °) isobutyl-2-methyl-4-(4 -methylphenyl)nicotinic acid yw

1

gram) serine methyl ester hydrochloride s ( 4 g 1.4 mmol)

According to the method similar to that of example .) 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), (2H , m), 4.43-4.52 (2H, m), 5.03 (2H, 5), 6.21 (1H, d, J = 7.0 Hz), 7.12- e 4.19-4.29 (2H, m), 7.17-7.22 ( 2H, m), 7.29-7.38 (5H, m). 7.17 ¥) cooled to -7//8*C solution of methyl N-{[5-cyano-6-isobutyl-2-methyl-4-( 4- ¥V) methylphenyl)pyridin-3-yl]carbonyl}serinate, 5 g; LAY mmol) in dichloromethane (© .mL) and add {,VY)dithylaminosulfur trifluoride 0 mL 11.8 mmol). The mixture was stirred at the same temperature for one hour. Potassium carbonate (17 g VEY mmol) was added and the mixture was stirred at room temperature for 0 min. The reaction mixture was diluted with cethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the remainder was purified by silica gel column chromatography 0 to give methyl 2-[5-cyano-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3- y11-4, 5-dihydro-1,3-oxazole-4-carboxylate (4g yield £79) as non-oil

the color. H-NMR (CDCl) 6: 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, 5), 4.11-4.16 (1H, m), 4.23 2H, d, J = Hz), 4.33 (1H, dd, J = 8.8, 7.4 Hz), 4.59 -4.65 (1H, m), 5.03 (2H, s), 7.05 (2H, 4, Ye. 5.5 J=8.5 Hz), 7.13-7.21 (2H, m), 7.29-7.38 (5H, m). (Y cooled to joa 53° 40 a solution of methyl 2-[5-cyano-6-isobutyl-2-methyl-4-(4- oA ¥) methylphenyl)pyridin-3-y1] -4,5-dihydro-1,3-0xazole-4-carboxylate g YAY mmol (5,111) 1,8-diazabicyclo[5.4.0]-7-undecene mL 7.47 mL °¥ mol) in 01 (dichloromethane mL) and add bromotrichloromethane VEY plik +, VY (mmol). The mixture was stirred at the same temperature for one hour. The reaction mixture was diluted with cethyl acetate, washed with ammonium solution

No, Ale chloride is saturated and dried on anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the remainder was purified by silica gel column chromatography to give methyl 2-[5-cyano- 6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3 -yl]-1, 3-oxazole-4-carboxylate cane OY + (yield 757) as a colorless oil. 'H-NMR (CDCl) 8:1.03 (6H, d, J = 6.8 Hz), 2.24-2.34 (4H, m), 2.59 (3H, 5), 3.00 ° (2H, d, J = 7.4 Hz), 3.92 (3H, 5), 7.11 (2H, d,J=8.5Hz), 7.16 (2H, d, J = 8.3 Hz), 0 8.08 (1H, 5). €(we get methyl 2-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) ‎pyridin-3-yl]-1 ,3-oxazole-4-carboxylate dihydrochloride ( 1 mg; yield 7977) 0 as a white solid of methyl 2-[5-cyano-6-isobutyl-2-methyl-4-(4-methyl phenyl)pyridin-3-yl]-1,3-0xazole- 4-carboxylate (7 074 mmol body) according to a method similar to that of the example (P= +A “H-NMR (DMSO-d) 5:1.00 (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, 5), 3 85 (2H, d, J = 4.7Hz), 7.11 (2H, d, J = 8.1, Hz), 7.20 (2H, d, J = 8.1 Hz), 8.30-8.47 (3H, m), 8.77 (1H, d, J = 1.5 Hz). 2.1 Example Ir 2-(4-{[5-(aminomethyl)-2-methyl-4-(4-methylphenyl )-6-neopentylpyridin-3-yl] methoxy } phenyl)acetamide dihydrochloride ) 1 We get tert-butyl {[5-{[4~(2-amino-2-oxoethyl)phenoxy]methyl}-6-methyl- aa 64 ) 4-(4-methylphenyl)-2-neopentylpyridin -3-yljmethyl } carbamate Ye yield ey %( as a white powder of tert-butyl {[5-(hydroxymethyl)-6-methyl-4-(4-YY ) methylphenyl)-2-neopentylpyridin- 3-ylJmethyl } carbamate; g 87 mmol (AY) 4-hydroxyphenylacetamide s 5 g 1.07 mmol) according to method similar to (VY) EJB (CDCl3)8: 1.04 (9H, s), 1.37 (9H, 5), 2.36 (3H, s), 2.62 3H, 5), 2.88 (2H, Yo 111-111 (2H, s), 4.10-4.25 (3H, m), 4.61 (2H, 5) , 5.35 (2H, brs), 6.75-6.80 (2H, m), 3.51, 5 (2H, d, J = 7.9 Hz), 7.10-7.20 (4H, m).

Yot 2-(4-{[5-(aminomethyl)-2-methyl-4-(4-methylphenyl)-6-neopentyl) on Juans (¥ (4 AY ,; total yield of A) pyridin-3- ylJmethoxy}phenyl)acetamide dihydrochloride tert-butyl {[5-{[4-(2-amino-2-oxoethyl)phenoxy] as a pale yellow powder of methyl }-6-methyl-4-(4-methylphenyl)- 2-neopentylpyridin-3-yljmethyl ( carbamate (YY mmol) according to the method similar to that of the example 1.00 c 11 0 'H-NMR :5(J01150-4) 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, ] = 7.4 Hz), 7.42 (1H, brs), 8.19 (3H, brs). yllmethoxy}phenyl)acetate methyl (4-{[5-{[(tert-butoxycarbonyl)amino }methyl}-6-isobutyl-2- you get (1 yield aaa ©V+) methyl-4-(4 -methylphenyl)pyridin-3-ylJmethoxy} phenyl)acetate tert-butyl {[5-(hydroxymethyl)-2-isobutyl-6-methyl-4-(4- as colorless oil of ( AY 0 mmol) V,YO cana © +) methylphenyl)pyridin-3-yljmethyl} carbamate mM) according to V,0) cane You) methyl (4-hydroxyphenyl)acetate and AVY E method similar to that of the example H-NMR (CDCl) 8: 0.99 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.17-2.30 (1H, m), 2.36 (3H, 5), 2.62 (3H, 5) ), 2.78 (2H, d, ] = 7.4 Hz), 3.51 (2H, 5), 3.56 (3H, 5), 4.10 2H, d, 00

J=4.7Hz), 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). methyl (4- {[5-{[(tert-butoxycarbonyl)amino]methyl }-6-isobutyl-2-methyl- dissolved ( Y 0.0 mM 4 sc; OV ( 4-(4) -methylphenyl)pyridin-3-ylJmethoxy} phenyl)acetate in milliliters) and the mixture was stirred for one hour. 01 (trifluoroacetic acid mole) in YO sodium ethyl acetate at reduced pressure and the residue was divided between Gan and the reaction mixture was concentrated Anhydrous saturated magnesium sulfate The organic layer was dried over Ale hydrogen carbonate

Yoo and the solvent is evaporated under reduced pressure. The residue was purified by gel column chromatography methyl (4-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methyl ¢ L— tac silica Yoo (phenyl)pyridin-3-yljmethoxy) }phenyl)acetate total yield +5%) as colorless oil. (6H, d, J = 6.6 Hz), 2.18-2.25 (1H, m), 2.34 (3H, s), ° 5:0.98, -01150 0) “H-NMR (3H, s), 2.88 (2H, d, J = 7.4 Hz), 3.30 (2H, d, J = 5.3 Hz), 3.61 (3H, s), 4.20 2.60 (2H, d, J = 4.7 Hz), 4.60 (2H, 5),6.70 (2H, d, ] = 8.5 Hz), 6.79 (2H, 4, J = 8.5 Hz), (2H, d, J = 8.3 Hz), 7.15 (2H, d, J = 8.3 Hz).

IVA Jo 3-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yljamino} Ye carbonyl)benzoic acid dihydrochloride 3-({[5-(aminomethyl) -6-isobutyl-2-methyl-4-(4-methylphenyl) you get (789 mg yield) YY) pyridin-3-ylJamino}carbonyl)benzoic acid dihydrochloride tert-butyl {[5-amino-2- isobutyl-6-methyl-4-(4- as white powder of mm) 1,8 cane 7 ) methylphenyl)pyridin-3-yljmethyl}carbamate © mmol) +,V0 mg 1 £9) isophthalic acid monomethy! ester chloride s

YY According to the method similar to the example method "H-NMR and 01150-0) 6:1.01 (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, with J = 7.8 Hz ), 8.07 (1H, d, J = 7.8 Hz), 8.16 (1H, 5), 8.36 (3H, brs), 10.19 0 0 (1H, brs).0 Example methyl 3-{[5-( aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3- ylmethoxy}-1H-indole-2-carboxylate methyl 3-{[5-{[(tert-butoxycarbonyl)amino]methyl } -6-isobutyl-2- you get ( 1 Ye 61 ) methyl-4-(4-methylphenyl)pyridin-3-yljmethoxy}-1H-indole-2-carboxylate tert-butyl {[5-(hydroxymethyl)- 2- A pale yellow solid of (OF yield) can

0 g ) isobutyl-6-methyl-4-(4-methylphenyl)pyridin-3-yljmethyl} carbamate 1,1 g 1 ( methyl 3-hydroxyindole-2-carboxylate mmol) and 4 . (0-0 mmol) according to a method similar to that of Example 117-1114 (CDCl3) 8:0.97 (6H, d, J = 6.8 Hz), 1.37 (9H, 5), 2.17-2.26 (1H, m ), 2.37 (3H, 5), 2.77 (2H, d,] = 7.2 Hz), 2.86 (3H, s), 3.82 (3H, 5), 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). methyl 3-{[5-{[(tert-butoxycarbonyl)amino]methyl} -6-isobutyl-2-methyl-4- soluble (Y 0.77 vol 1 ) (4-methylphenyl)pyridin-3 -yljmethoxy}-1 H-indole-2-carboxylate mL) 01( hydrogen chloride ethyl acetate mMol) in ; standard solution 0 min. The reaction mixture was neutralized with Ve and the mixture was stirred at room temperature for a period. The saturated ethyl acetate was dried and extracted with anhydrous Sle sodium hydrogen carbonate and the solvent was evaporated under reduced pressure. The magnesium sulfate was re-extracted over methyl to give hexane —ethyl acetate. The resulting yellow solid crystallized from 3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) )pyridin-3 yl] 0 mg; Yield © 0 (yellow crystals Ye) methoxy}-1H-indole-2-carboxylate dim. 'H-NMR (J) 5:0.98 (6H, d, J = 6.6 Hz), 2.17- 2.30 (1H, m), 2.38 (3H, 5), 2.79 (2H, d, J = 7.4 Hz), 2.86 (3H, 5), 3.51 (2H, 5), 3.83 (3H, 5), 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). Ye

Ye. Example 4-cyanobenzyl 5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)nicotinate 4-cyanobenzyl 5- {[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl- We get 1 yellow oil (7 AT yield can 7 ) 2-methyl-4-(4-methylphenyl)nicotinate 5-{[(tert-butoxycarbonyl)amino }methyl } -6-isobutyl-2 -methyl-4-(4-methyl of 8 4-cyanobenzyl mM) and 58.01 g 0 (phenyl)nicotinic acid

Yov milligram) according to the method similar to that of the example (5.01 cpa) bromide. ( 0-48 11-1111 (CDCl) 8:0.97 (6H, d, J = 6.8 Hz), 1.38 (9H, s), 2.17-2.26 (1H, m), 2.37 (3H, s), 2.54 (3H , 5), 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=8.1Hz),7.54 2H, d, J = 8.3 5

Hz). 4-cyanobenzyl 5-{[(tert-butoxycarbonyl)amino]methyl} -6-isobutyl-2- (¥ mol) dissolves in Ale 1,985 (aa 7 ) methyl-4-(4-methylphenyl (nicotinate in milliliters) and the mixture was stirred at room temperature for 10 hours (10 hours) saturated aqueous trifluoroacetic acid and one sodium hydrogen carbonate was extracted. The reaction mixture was neutralized with 0 anhydrous magnesium sulfate. The extracted substance was dried over Lethyl acetate with (ih ye 4-cyanobenzyl 5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) el lacty) yield 44 g (as yellow oil. +, £Y) nicotinate

H-NMR (CDCl) 8: 0.90 (6H, with J = 6.6 Hz), 2.08-2.17 (1H, m), 2.32 (3H, 5), 2.54 (3H, 5), 2.70 (2H, d, J = 7.0 Hz), 3.97 (2H, 5), 4.99 (2H, 5), 7.00 (2H, d, J = 8.1 Hz), Ye 7.08-7.14 (4H, m), 7.54 (2H, d, ] = 8.3 Hz).

Ye) Jo.

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3 -y1]quinoxaline-2-carboxamide dihydrochloride

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) we get A 0 ov mg; Yield 1 ¥V) pyridin-3-yl]quinoxaline-2-carboxamide dihydrochloride tert-butyl {[5-amino-2-isobutyl-6-methyl-4-(4-methyl) as a white powder of 1 mmol gram) 0.5 mg 7 ) phenyl)pyridin-3-yljmethyl} carbamate mmol) according to 1.75 mg; VEE) quinoxaline-2-carbonyl chloride s

YY Method similar to example method Ye "H-NMR (DMSO-d) 8: 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 =

YoA 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).

YEY Joe

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-y1]-2,5-dimethylfuran-3-carboxamide dihydrochloride °

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) yields a yield of YY 0)pyridin-3-yl}-2,5-dimethylfuran-3- tert-butyl carboxamide dihydrochloride {[5-amino-2-isobutyl-6-methyl-4-(4-methyl as a white powder of ( q. stereo; 0,+ mmol) VAY) phenyl)pyridin -3-yl]methyl} carbamate ‎VY 4) 2,5-dimethylfuran-3-carbonyl chlorides 0 mg; 1.75 mmol) according to the method similar to the example method IVY J = 6.6 Hz), 2.17 (3H, 5), 2.17-2.29 (1H, m), has 'H-NMR (DMSO -d) 8:0.99 (6H, (3H, s), 2.34 (3H, 5), 2.54 (3H, 5), 2.99 (2H, brs), 3.82 (2H, d, ] = 5.1 Hz), 6.25 2.29 J = 8.1 Hz), 8.28 (3H, brs), 9.32 (1H, by (1H, s), 7.20 2H, d, J = 8.1 Hz), 7.26 (2H, brs). Vo YEV Example N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-y1]-3- methylthiophene-2-carboxamide dihydrochloride

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) yield cana 71 5( pyridin-3-yl]-3-methylthiophene-2-carboxamide dihydrochloride |00 tert-butyl {[5-amino-2-isobutyl-6-methyl-4-(4-methyl) as a white powder of (0 sc; +0,0 mmol) 097(phenyl)pyridin- 3-ylJmethyl} carbamate mM) according to 1,705 mg; 0.98 (6H, d, J = 6.6 Hz), 2.08 (3H, s), 2.09-2.33 (1H, m), Yo 2.34 (3H, s), 2.51 (3H, 5), 2.91 (2H, brs), 3.82 (2H, brs), 6.89 (1H, d, J = 5.1 Hz),

7:49 7.19 (2H, d, J = 7.8 Hz), 7.27 2H, 0.1 = 7.8 Hz, 7.55 (1H, d, J = 5.1 Hz), 8.17 (3H, brs), 9.37 (1H, brs ).

Yet Jo

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3-y1}-1-benzothiophene-2-carboxamide dihydrochloride©

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) we get mg; Yield YY 0) pyridin-3-yl]-1 -benzothiophene-2-carboxamide dihydrochloride tert-butyl {[5-amino-2-isobutyl-6-methyl-4-(4-methyl as white powder from ) 0 mg; 10+ mmol) 7 ) phenyl)pyridin-3-yljmethyl } carbamate mmol) according to 1.20 mg; 0 ) 1-benzothiophene-2-carbonyl chlorides 0

NYY to the method similar to the example method. 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). vo

Yeo Jo

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3 -yl}-3- methyl-1-benzofuran-2-carboxamide dihydrochloride

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) we get 171 mg ¥) pyridin-3-yl]-3-methyl-1 “benzofuran-2 -carboxamide dihydrochloride | 0 tert-butyl {[5-amino-2-isobutyl-6-methyl-4-(4-yield .4%) (as white powder of mmol) 10 cana 7 (methylphenyl)pyridin-3- ylJmethyl ( carbamate mmol) 1.25 mg; 8:1.00 (6H, d, 1 6.6 Hz), 2.16-2.29 (1H, m), 2.29 (3H, s), Yo 2.41 (3H, 5), 2.60 (3H, 5), 3.03 (2H, brs) , 3.83 (2H, brs), 7.25 (4H, 5), 7.35 (1H, 1, J 1 a

- 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).

Yih Example methyl [4-({[5-(aminomethyl )-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3- yl]amino }carbonyl)-2-oxopiperazin-1- yl]acetate dihydrochloride ° methyl [4-({[5-{[(tert-butoxycarbonyl)amino methyl} -6-isobutyl-2- we get, ( 1 methyl-4-(4-methylphenyl)pyridin-3- yl] amino } carbonyl)-2-oxopiperazin-1-yl] 5-{[(tert-butoxycarbonyl)amino]methyl} -6-isobutyl-2-methyl-4- from ZnS acetate methyl (2-3 millimol) 1 mg; 41 Y) (4-methylphenyl)nicotinic acid mg; ? mmol) according to the method 4 ( oxopiperazin-1-yl)acetate 0 (Ye) similar to the example method for DV (M+1) EIMS methyl [4-({ [5-(aminomethyl)-6-isobutyl The aforementioned -2-methyl-4-(4-methyl (Y phenyl)pyridin-3-ylJamino} carbonyl)-2-oxopiperazin-1 -ylJacetate dihydrochloride (1 mg; yield 49 7) as powder in a white color from the oil produced in (YYY) TY according to a method similar to that of the example “H-NMR (01150-1(5:0.98 (6H, d, J = 6.3 Hz), 1.99-2.28 (1H, m) ), 2.37 (3H, s), 2.50 (3H, 5), 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, 5), 7.17 (2H, d, J = 7.8 Hz), 7.29 2H,d,J=17.8

Hz), 8.43 (3H, brs). 01 / 59? ]methyl } -6-isobutyl-2-methyl-4- to a solution of ( 1 methyl 6- + m mmol) can 5 ) (4-methylphenyl)nicotinic acid 8 mmol) £ 0 cpa 1 A) (hydroxymethyl)nicotinate 01( tetrahydrofuran mol) in lle 5.79 g; 1,7 45) triphenylphosphine and ?

mL, 9 mL ¥,Y) diethyl azodicarboxylate toluene / + mL) solution is added min. The solvent was evaporated under 90 pg) and the mixture was stirred at room temperature for a period to give silica at reduced pressure and the resulting residue was purified by gel column chromatography [5-(methoxycarbonyl)pyridin-2-ylJmethyl 5-{[(tert) -butoxycarbonyl)amino] methyl }- g yield 49 (as Article 4 ) 6-isobutyl-2-methyl-4-(4-methylphenyl)nicotinate ° white solid. 'H-NMR (CDCl;) 8: 0.97 (6H, d, J = 6.6 Hz), 1.39 (9H, 5), 2.17-2.26 (1H, m), 2.35 (3H, 5), 2.58 (3H, 5), 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=7.9Hz), 8.14 (1H, dd, J =8.2,2.2 Hz), 9.10 (1H, dd, J = 2.1, 0.75 Hz). 01 [5-(methoxycarbonyl)pyridin-2-yljmethyl 5- {[(tert-butoxycarbonyl)amino] dissolved (Y g 199 m¥V) methyl} -6-isobutyl-2-methyl-4-( 4-methylphenyl)nicotinate (mL) 10 (hydrogen chloride ethyl acetate mol) in a standard solution § 1 min. The reaction mixture was neutralized with Vo and the mixture was stirred at room temperature for 2. The extract was dried over aqueous ethyl acetate saturated with sodium hydrogen carbonate 05[5-(methoxy) and the solvent was evaporated under reduced pressure to give SY magnesium sulfate carbonyl )pyridin-2-yljmethyl 5-(aminomethyl)-6-isobutyl -2-methyl-4-(4-methyl cv. 47 7) as colorless oil. V €Y) phenylnicotinate

IH.NMR (CDCl3) 5: 0.98 (6H, d, J = 6.6 Hz), 2.17-2.29 (1H, m), 2.35 (3H, 5), 2.57 (3H, 5), 2.81 (2H, d, J = 7.4 Hz), 3.65 2H, 5), 3.96 (3H, 5), 5.11 (2H, 5), 6.89 (1H, 0. ¥-

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).

YEA Joe 6-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3-yl] carbonyl }oxy)methyl]nicotinic acid trihydrochloride Ye 6-[({ [5- {[(tert-butoxycarbonyl)amino]methyl} -6-isobutyl-2-methyl- we get (1 g “0 A) 4-(4-methylphenyl)pyridin-3-yl]carbonyl } oxy)methyl]nicotinic acid y [5-(methoxy carbonyl)pyridin-2-ylJmethyl 5- as a colorless oil of (Fo) yielding {[(tert-butoxycarbonyl)amino]methyl } -6-isobutyl- 2-methyl-4-(4-methylphenyl) total “7.78 mmol) according to the method similar to that of (4 + nicotinate) 1-4. Example H-NMR (CDCl) 8: 0.98 (6H, with J = 6.8 Hz), 1.39 (9H, 5), 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, 5), 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, 5). 6-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) you get (Y mg; yield €1Y) pyridin-3-yl]carbonyl}oxy )methylnicotinic acid trihydrochloride 6-[({[5- {[(tert-butoxycarbonyl)amino]methyl }-6- as a white solid of 0 AY 0 isobutyl-2-methyl-4-(4-methylphenyl)pyridin -3-yljcarbonyl }oxy)methyl]ni cotinic milligram) according to the method similar to that of SAVY acid 6). ( b' H-NMR (DMSO-dg) 5:0.97 (6H, d, J = 6.6 Hz), 2.18-2.28 (1H, m), 2.33 (3H, 5), 2.63 (3H, brs) , 2.90-2.97 (2H, m), 3.82 (2H, d, J = 5.1 Hz), 5.15 (2H, 5), 7.03 (1H, d, 0

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). 54? Joe [5-(aminocarbonyl)pyridin-2-ylJmethyl 5-(aminomethyl)-6-isobutyl-2-methyl-4-(4- methylphenylnicotinate XY). - {[(tert-butoxycarbonyl) on a plate!) 1 mg YYY ) amino]methyl}-6-isobutyl-2-methyl-4-(4-methylphenylnicotinate 6-[({[5-{[ (tert-butoxycarbonyl)aminoJmethyl}-6- as a colorless oil of (AFA) yield isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl]carbonyl ( oxy)methyl]nicotinic =r g mmol) according to the method similar to that of the example .,0 A) acid Ye . ) 1 yy 'H.NMR (CDCl;) 8:0.97 (6H, d, J = 6.6 Hz), 1.39 (9H , 5), 2.17-2.26 (1H, m), 2.36 (3H, 5), 2.58 (3H, 5), 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, } = 8.1 Hz), 7.14 2H, d,1=7.9

Hz), 8.03 (1H, d, J = 8.3, 2.3 Hz), 8.89 (1H, d, J = 23 Hz). [5-(aminocarbonyl)pyridin-2-ylJmethyl 5-(aminomethyl)-6-isobutyl- on Juans (Yo) as a colorless oil (FAY total yield 4) ( 2-methyl-4-(4-) methylphenylnicotinate [5-(aminocarbonyl)pyridin-2-ylJmethyl 5-{[(tert-butoxycarbonyl)amino] from 146006 mM YY) methyl }-6-isobutyl-2-methyl-4-( 4-methylphenyl)nicotinate (YY 497 mol) according to the method similar to that of the example

H-NMR (CDCl) 8: 0.98 (6H, d, J = 6.6 Hz), 2.15-2.31 (1H, m), 2.36 (3H, 5), 2.57 Ve (3H, 5), 2.81 (2H, d, J = 7.4 Hz), 3.65 (2H, 5), 5.10 (2H, 5), 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).

Yor example ethyl 4- {[5-(aminomethyl)-6-isobutyl-2 -methyl-4-(4-methylphenyl)pyridin-3-yl] methoxy} -2-ethylpyrimidine-5-carboxylate tetrahydrochloride Vo ethyl 4-{[5- {[(tert-butoxycarbonyl)amino methyl} -6-isobutyl-2- we get ( \ methyl-4-(4-methylphenyl)pyridin-3 -ylJmethoxy}-2-ethylpyrimidine-5 -tert-butyl carboxylate {[5-(hydroxymethyl)- as a white solid of (74 0 vg yield 0 A) (pa +0 ¥) 2-isobutyl-6-methyl-4-(4-methylphenyl) (pyridin-3 -yllmethyl} carbamate +,Y1) ethyl 2-ethyl-4-hydroxypyrimidine-5-carboxylate mM) and 1.77 Ye (1-711 46 mmol) according to the similar method For the example method, 0.77 can

H-NMR (J020) 8:0.99 (6H, d, J = 6.8 Hz), 1.20-1.29 (6H, m), 1.39 (9H, 5), 2.19- 2.28 (1H, m), 2.34 (3H , 5), 2.67 (3H, 5), 2.75-2.83 (4H, m), 4.10 (2H, d, J = 4.9 Hz), 427-434 (3H, m), 5.22 (2H, s), 7.06 ( 2H, d, J = 8.1 Hz), 7.14 (2H, 1l 7.9 Hz), 8.86 (1H, s). Yo ethyl 4-{ [5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) we get ( Y 1113 ) pyridin-3-ylJmethoxy} -2-ethylpyrimidine-5-carboxylate tetrahydrochloride aq

mg; Av yield ( as a white solid of ethyl 4-{[5-{[(tert-butoxycarbonyl) amino]methyl }-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3- yl methoxy ( -2- mmol) according to the 1.07 vol 0 A) ethylpyrimidine-5-carboxylate method similar to that of Example 7-?). “H-NMR (DMSO-d) 5: 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, 5), 7.25-7.31 (2H, m), 7.38-7.43 (2H, m), 8.43 (3H, brs), 8.46 (1H, s).

Yo Jus 4-(1H-tetrazol-5-yl)benzyl 5-(aminomethyl)-6-isobutyi-2-methyl-4-(4-methyl Ve phenyl)nicotinate dihydrochloride 4-cyanobenzyl 5-{[(tert-butoxycarbonyl) )amino]methyl}-6-isobutyl-2- solution of (1 mmol) VEY g; 1 A) methyl-4-(4-methylphenyl)nicotinate mL) V0) toulene ? Milliliters (8.49 milligrams) in 1, (tributyltin azide 0) heated under an argon atmosphere with sale) vapor condensation for ? hours. The solvent was evaporated under reduced pressure and the resulting residue was purified by silica gel column chromatography to give 4-(1H-tetrazol-5-yl)benzyl ~~ 5-{[(tert-butoxycarbonyl)amino]}methyl}-6-isobutyl -2- aa), YY) methyl-4-(4-methylphenyl)nicotinate (ZAA) yield as colorless oil.” H-NMR (CDCls) 6:0.96 (6H, d, J = 6.6 Hz ), 1.39 (9H, s), 2.15-2.24 (1H, m), 2.25 (3H, 5), 2.54 (3H, 5), 2.83 (2H, d, J = 7.2 Hz), 4.18 (2H, d, 1 = 4.9 Hz), 4.32 (1H, Y.J = bl brs), 5.00 (2H, s), 7.01 2H, d,J = 7.9 Hz), 7.07 2H, d, J = 7.9 Hz), 7.18 2H, Hz), 8.03 (2H, d, J = 8.1 Hz). isobutyl-2-methyl-4-cane TAA) (4-methylphenyl)nicotinate dihydrochloride (yield £40) as a white Yo solid of 4-(1H-tetrazol-5-yl)benzyl 5-{[ (tert-butoxycarbonyl)amino]methyl}- avo ) 6-isobutyl-2-methyl-4-(4-methylphenyl)nicotinate g V,YY mmol) according to the method similar to that of the example ( Y=

Ye

H-NMR (DMSO-dg) 5: 0.96 (6H, d, J = 6.6 Hz), 2.1 7-2.26 (1H, m), 2.30 (3H, s), 2.54 (3H, 5), 2.87 (2H, d, ] = 6.8 Hz), 3.81 (2H, d, J =5.5Hz), 5.08 (2H, 5), 7.14- 7.25 (6H, m), 8.02 (2H, d, J = 8.1 Hz), 8.22 ( 3H, brs).

Yeo¥ Example 5-[({[5-(aminomethyl )-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3-yl] © carbonyl }oxy)methyl |furan-2- carboxylic acid dihydrochloride [5-(methoxycarbonyl)-2-furyl]methyl 5- {[(tert-butoxycarbonyl) get (\full yield of VY, ¥V) amino]methyl} -6-isobutyl-2- methyl-4-(4-methylphenyl)nicotinate 5-{[(tert-butoxycarbonyl) amino methyl }-6-isobutyl-2- as yellow oil of 0 AA g; 4,868 milligrams (Y) methyl-4-(4-methylphenyl)nicotinic acid 00 milligrams) 5,85 aa vy Ae) methyl 5-(chloromethyl)furan-2-carboxylate s . ( 1714-11 according to the method similar to the example method

H-NMR (CDCl;) 8: 0.96 (6H, d, J = 6.6 Hz), 1.38 (9H, 5), 2.1 3-2.24 (1H, m), 2.35 (3H, 5), 2.52 (3H, 5) ), 2.77 (2H, d, J = 7.2 Hz), 3.91 (3H, 5), 4.11 (2H, d, J = 5.1 Ha), 4.19 (1H, brs), 4.94 (2H, 5), 6.24 (1H , d, J = 3.6 Hz), 7.00 (2H, d, J = 8.1 Hz), 7.06 vo (1H, d, J = 3.6 Hz), 7.11 2H, d, J = 7.9 Hz). 5-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl- we get (¥ 4-(4-methylphenyl)pyridin-3-yl] carbonyl} oxy )methyl]furan-2-carboxylic acid [5-(methoxycarbonyl)-2-furyl] yield 180 ) as a white solid of ax 58 ) methyl 5-4 [(tert-butoxycarbonyl)amino]methyl }-6- isobutyl-2-methyl-4-(4-methyl Ye mmol) according to the similar method (TAY (YO) phenyl)nicotinate (V9) for the example method

H-NMR (CDCl;) 8: 0.96 (6H, d, J = 6.6 Hz), 1.38 911 2.1 4-225 (1H, m), 2.36 (3H, s), 2.53 (3H, 5), 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). Yo 5-[({ [5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) ?) we get 16 ) pyridin-3-yl]carbonyl ( oxy)methyl]furan- 2-carboxylic acid dihydrochloride

YY\WV

5-[({[5-{[(tert-butoxycarbonyl)amino] as a white solid of (Va yield) cana methyl }-6-isobutyl-2 -methyl-4-(4-methylphenyl)pyridin -3-y1} carbonyl} oxy)methyl] mmol) according to the method 006 g; 1 ) furan-2-carboxylic acid similar to the method of Example 7-?).

H-NMR (DMSO-dg) 5: 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, 5), 6.46 (1H, d,J=3.4 Hz), 7.11- 7.14 (3H, m), 7.17 (2H, d, ] = 8.1 Hz), 8.29 ( 3H, brs).

Yor example [5-(aminocarbonyl)-2-furyl methyl 5=( aminomethyl)-6-isobutyl-2-methyl-4-(4- methylphenyl)nicotinate dihydrochloride Ve [5-(aminocarbonyl)-2-furyljmethyl 5- {[(tert-butoxycarbonyol)amino] we get (1) 779 yield aa 0 ) methyl}-6-isobutyl-2-methyl-4-(4-methylphenyl)nicotinate 5-[({[ 5- {[(tert-butoxycarbonyl amino]methyl }-6-isobutyl-2- as a colorless oil of methyl-4-(4-methylphenyl)pyridin-3-yl] carbonyl } oxy)methyl]-furan-2 -carboxylic —v mmol) according to a method similar to that of the example VE can VO ) acid 5 ( ) 'H-NMR (CDCl) 8:0.96 (6H, d, J = 6.6 Hz), 1.38 (9H, 5 ), 2.14-2.27 (1H, m), 2.35 (3H, 5), 2.52 (3H, 5), 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 4 112(, 6.98 2H,d, J = 8.1 Hz), 7.04 ( 1H, d, J = 3.6 Hz), 7.09 (2H, d,J = 7.9 Hz).Ye [5-(aminocarbonyl)-2-furyljmethyl 5-(aminomethyl)-6-isobutyl-2- we get ( Y mg; yield £90 (as EV)) methyl-4-(4-methylphenyl)nicotinate dihydrochloride [5-(aminocarbonyl)-2-furylJmethyl 5-{ [(tert-butoxycarbonyol) white solid of g 8 Y ) amino methyl} -6-isobutyl-2-methyl-4-(4-methylphenyl)nicotinate .)-1 mmol) according to the method similar to that of the example AVY Ye

H-NMR (DMSO-dg) 8: 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

Yay (1H, d, 12 3.4 Hz), 7.12 (2H, d, 1 = 7.9 Hz), 7.18 (2H, d, I = 8.3 H2), 7.43 (1 H, brs), 7.73 (1H, brs), 8.28 (3H, brs). Example Yot methyl 3- {[[5-(aminomethyl)-6-i sobutyl-2-methyl-4-(4-methylphenyl )pyridin-3- yll(methyl)amino]carbonyl benzoate dihydrochloride ° to a mixture of {[(tert-butoxycarbonyl)amino]methyl} -6-isobutyl-2-methyl- -5[{(-3 YY) 4-(4-methylphenyl)pyridin-3-ylJamino} carbonyl) benzoic acid mg; 1.5 millimol (1 cpa) YA) potassium carbonate millimol) and N,N-dimethylformamide (© milliliters) added methyl iodide (7 mg; ? 0 millimol ) and stirred the mixture at room temperature for hours A. Water is added to the reaction mixture and the mixture is extracted with 2061816_Atah. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and purified. The remainder obtained by silica gel column chromatography to give oil. To a solution of the resulting oil in ethyl acetate (1 mL) a solution of hydrogen chloride ethyl acetate ¢ VO (1 mL) was added and the mixture was stirred at room temperature for one hour. Cant solvent evaporates under reduced pressure and the remaining hexane crystallizes to give methyl 3-{[[5-(amino methyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl) ] (methyl)amino] mg; Yield £90 (as white powder.‎ 0 Y) carbonyl }benzoate dihydrochloride

LET (M+) EIMS

Yoo Example TY:

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenylpyridin-3-yl]isophthalamide dihydrochloride tert-butyl {[5-{[3-(aminocarbonyl)benzoyl]amino-2- isobutyl-6- we get ( ) 7948 mg; VE yield A) methyl-4-(4-methylphenyl)pyridin-3-yl methyl} carbamate 3-({[5- {[tert-butoxycarbonyl)amino]methyl } -6-isobutyl-2- white from Osh ©? As a powder in mg; ) methyl-4-(4-methylphenyl)pyridin-3-ylJamino} carbonyl)benzoic acid (VF mmol) according to the method similar to that of Example 44

m (6H, d, J = 6.6 Hz), 1.38 (9H, 5), 2.20-2.31 (1H, m), 2.33 8:0.99 (J00b) '{-NMR (3H, s), 2.49 (3H, 5), 2.78 (2H, brs), 4.13 (2H, brs), 4.40 (1H, brs), 5.79 (1H, brs), (1H, brs), 7.03 (2H, d, J = 8.1 Hz), 7.18 (2H, d, J = 8.1 Hz), 7.7.39-7.45 (1H, 6.38 brs), 7.60-7.63 (1H, m), 7.88-7.92 (2H, m). Jans ( 7 0 on N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin- YYY) 3-yllisophthalamide dihydrochloride mg; yield of £49 (as a white powder of tert-butyl {[5- {[3-(aminocarbonyl)benzoyl]amino-2-isobutyl-6-methyl-4-(4-YE A) methylphenyl)pyridin-3 -yljmethyl}carbamate mg; Ale 1.497 mol) according to the method similar to that of the example (FY (6H, d, J = 6.3 Hz), 2.22-2.30 (1H, m), 2.30 (3H, 5), Ve 8 H-NMR: 1.00 (and 01480-0) (3H, s), 2.89 (2H, brs), 3.84 (2H, brs), 7.23 (4H, 5), 7.56 (1H, t, J = 7.8 Hz ), 2.51 (2H, d, J = 7.8 Hz), 8.06 (2H, d, J = 7.8 Hz), 8.14 (1H, 5), 8.16 GH, brs), 10.04 7.83 (1H, brs) ..

You Example 4-[2-0x0-2-(2-0x0-2-phenylethoxy)ethyl]benzyl 5-(aminomethyl )-6-isobutyl-2- Yo methyl-4-(4-methylphenyl)nicotinate dihydrochloride 4-[2-0x0-2-(2-0x0-2-phenylethoxy)ethyl]benzyl 5- {[(tert-butoxy on Ja a3 ( 1 carbonyl)amino]methyl}-6-isobutyl-2- methyl-4-(4-methylphenyl)nicotinate ) mar gm; Yield 7785) as a colorless oil of 5-{[(tert-butoxycarbonyl)amino]methyl}-6- isobutyl-2-methyl-4-(4-methylphenyl)nicotinic acid 0 ) ¥ g blood mmol ) phenacyl 4-(bromomethyl)phenylacetate s ( 4 g £,A0 mmol) according to a method similar to that of Example 1-4). H-NMR (CDCls) 8: 0.96 (6H, d, J = 6.6 Hz), 1.38 (9H, 5), 2.15-2.24 (1H, m), 2.38 (3H, s), 2.52 (3H) , 5), 2.77 (2H, d, J = 7.4 Hz), 3.82 (2H, 5), 4.11-4.16 (2H, m), 4.21 (1H, brs), 4.91 2H, s), 5.36 (2H , 5), 7.02-7.05 (4H, m), 7.15 (2H, d, I = 7.7 Hz), Yo (2H, m), 7.46-7.51 (2H, m), 7.58-7.64 (1H, m ), 7.88-7.91 (2H, m). 7.26-7.29 only

4-[2-0x0-2-(2-0x0-2-phenylethoxy)ethyl]benzyl = 5-(aminomethyl)-6- (Y mg; yield of 11 (no-isobutyl-2-) methyl-4-(4-methylphenyl)nicotinate dihydrochloride 4-[2-0x0-2-(2-0x0-2-phenylethoxy)ethyl]benzyl 5- as a white solid of (% ¢o {[(tert-) butoxycarbonyl)amino |methyl}-6-isobutyl-2 -methyl-4-(4-methylphenyl) to the method similar to that of Lala (g. ms. mole) 6 Y V) nicotinate 5. (v- 1 Example H-NMR (DMSO0-de) 6:0.96 (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, 5), 4.95 (2H, 5), 5.53 (2H, 5), 7.02 (2H, d,) =8.1 Hz), 7.15 (2H, d, J = 7.5 Hz), 7.26 (4H, t, 1 = 7.72), 7.56 (2H, d,J= 7.9 Hz), 7.67-7.72 (1H, m), 7.92-7.98 (2H, m), 8.17 (3H, brs).

Yov Example 4-(2-methoxy-2-oxoethyl)benzyl 5-(aminomethyl)-6-isobutyl-2-methyl-4-(4- methylphenyl)nicotinate dihydrochloride {4-[({[5-{ [(tert-butoxycarbonyl)amino]methyl } -6-isobutyl-2-methyl- you get ( \ aa V0 ) 4-(4-methylphenyl)pyridin-3-ylJcarbonyl }oxy)methyl]phenyl } acetic acid 0 4-[2-0x%0-2-(2-0x0-2-phenylethoxy)ethylJbenzyl 5- as a colorless oil of (AVY) yield {[(tert-butoxycarbonyl)amino]methyl } -6-isobutyl -2-methyl-4-(4-methylphenyl) to the method analogous to that of ah a mmol (ca d A) nicotinate (V4) ex. 'H-NMR (CDCl3) 8:0.95 ( 6H, has J = 6.6 Hz), 1.38 (9H, 5), 2.14-2.23 (1H, m), 2.37 Ye (3H, s), 2.52 (3H, 5), 2.77 (2H, d, J = 7.2 Hz), 3.65 (2H, 5), 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). {4-[({[5-{[(tert-butoxycarbonyl)amino]methyl }-6-isobutyl-2- ?) to a mixture of methyl-4-(4-methylphenyl)pyridin-3-yl]carbonyl ( oxy)methyl]phenyl }acetic acid Y° g » 7.77 mL +,¥Y) potassium carbonate mmol) 0.176 g; (7 5)

V4Y) methyl iodide (mL) add 01 (N,N-dimethylformamide 5 mol)

YY\V

a mg 0.9 mmol) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with cethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give 5-4-(2-methoxy-2-oxoethyl)benzyl {[(tert-butoxycarbonyl)amino jmethyl}-6-isobutyl-2- methyl-4-(4-methylphenyl) ~~ © nicotinate ) 01+ g; Yield 7484) as a colorless oil. H-NMR (CDCl) 8: 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 , 5), 2.77 (2H, d, J = 7.4 Hz), 3.62 (2H, 5s), 3.70 (3H, 5), 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), (2H, d, J = 8.1 Hz). 4-(2-methoxy-2-oxoethyl)benzyl 5-(aminomethyl)-6-isobutyl-2- ‎cane £AY) methyl-4-(4-methylphenyl)nicotinate dihydrochloride yield +9 (as a white solid) from 4-(2-methoxy-2-oxoethyl)benzyl 5-{[(tert-butoxy ‎carbonyl)amino Jmethyl } -6-isobutyl-2-methyl-4-(4-methylphenyl)nicotinate ) ma" 0 c; 1.994 milligrams) according to the method similar to that of Example 7-?). H-NMR (DMSO-d) 5:0.95 (6H, d, J = 6.6 Hz), 2.14-2.26 (1H, m), 2.37 (3H, s), (2H, m), 3.62 ( 3H, s), 3.69 (2H, s), 3.81 (2H, d, J = 5.3 Hz), 4.94 (2H, 5), 2.79-2.88 (2H, d, J = 8.1 Hz), 7.13-7.24 (6H, m), 8.21 (3H, brs). 7.00

Yoh Example {4-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl] p1 carbonyl} oxy)methyl]phenyl} 266116 acid dihydrochloride {4-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) to obtain mg VE A)pyridin-3-yl]carbonyl } oxy) methyl}phenyl} acetic acid dihydrochloride {4-[({[5-{[(tert-butoxycarbonyl)amino] as a white solid of (AVY) yielding methyl }-6-isobutyl-2-methyl-4- (4-methylphenyl)pyridin-3-yl]carbonyl }oxy)methyl] 0 mmol) according to the similar method +, AY Cm 19 0 (phenyl}acetic 40 for example method 7-?).

11 "H-NMR (DMSO-dg) 8:0.96 (6H, d, J = 6.6 Hz), 2.1 6-2.27 (1H, m), 2.37 (3H, s), 2.53 (3H, s), 2.90 ( 2H, d, J = 5.8 Hz), 3.57 (2H, 5), 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, 1l = 8.1 Hz), 7.23 (2H, d, J = 8.1 Hz), 8.30 (3H, brs).

Yo Ju. oe 4-(2-amino-2-oxoethyl)benzyl 5-(aminomethyl)-6-i sobutyl-2-methyl-4-(4- methylphenylnicotinate dihydrochloride 4-(2-amino-2-oxoethyl)benzyl 5-{ [(tert-butoxycarbonyl)amino] We get (1) AVY yield cane 01( methyl} -6-isobutyl-2-methyl-4-(4-methylphenyl)nicotinate {4-[({[5- {[(tert-butoxycarbonyl)amino methyl} -6-isobutyl-2- as a colorless oil of 0 methyl-4-(4-methylphenyl)pyridin-3-yl]carbonyl} oxy)methyl]phenyl}acetic acid 8 Collect ALY mmol) according to the method similar to that of the example - L(V "H-NMR (CDCL) 8:0.95 (6H, d, J = 6.6 Hz), 1.38 (9H, 5), 2.13- 2.26 (1H, m), 2.39 (3H, s), 2.52 (3H, 8), 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), Yo 7.20 (2H, d, J = 8.1 Hz). Yield 771) as a white solid of 4-(2-amino-2-oxoethyl)benzyl 5-{[(tert-butoxycarbonyl)amino] methyl} -6-isobutyl-2-methyl-4-(4 -methylphenyl)nicotinate Ye ) 0.15 mSUEY mmol) according to the method similar to that of the example (FY “H-NMR (DMSO-de) 8:0.95 (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, 5), 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). Yh. Jo. Ye 4-(methylsulfonyl)benzyl 5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)nicotinate dihydrochloride

YVY

4-(methylsulfonyl)benzyl 5- {[(tert-butoxycarbonyl)amino]methyl}- we get ( \ as oil (AVY mg; yield 0 ) 6-isobutyl-2-methyl-4-(4 -methylphenyl)nicotinate 5-{[(tert-butoxycarbonyl)amino]methyl} -6-isobutyl-2-methyl-4-(4- colorless maleomeric molecule) 0.01 mg; 5 ( methylphenyl)nicotinic acid mmol) 0.01 aaa 0 ) 1-(bromomethyl)-4-(methylsulfonyl)benzene s ©

NARA RR according to the method similar to the example method

H-NMR (CDCl) 8: 0.97 (6H, d, J = 6.6 Hz), 1.39 (9H, 5), 2.19-2.28 (1H, m), 2.38 (3H, s), 2.55 (3H, 5), 2.78 (2H, d, J = 7.4 Hz), 3.04 GH, 5), 4.1 2-4.13 (2H, m), 4.21 (1H, brs), 5.01 (2H, s), 7.04 (2H, d, J] = 8.1 Hz), 7.14 (2H, d, J =7.9Hz), 7.19 (2H, d,J=8.3 Hz), 7.83 (2H, d, J = 8.5 Hz). Ve 4-(methylsulfonyl)benzyl 5-(aminomethyl)-6-isobutyl-2-methyl-4- we obtain (Y as solid material (% AY total yield £77) (4-methylphenyl)nicotinate dihydrochloride 4-(methylsulfonyl)benzyl 5- {[(tert-butoxycarbonyl)amino]methyl }-6- white from g; 6,917 mmol 8 9 isobutyl-2-methyl-4-(4-methylphenyl)nicotinate Grammy) according to the method similar to that of Example 7-?). VO

H-NMR (DMSO-dg) 8: 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, 5), 3.81 (2H, d, J = 5.1 Hz), 5.11 (2H, 5), 7.15-7.28 (6H, m), 7.84 (2H, d, J = 8.3 Hz), 8.23-8.40 (3H, m). ?11 Example ethyl 3-[4-({[5-(aminomethyl )-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3- XY.yl]amino } carbonyl)-2 -oxopiperazin-1-yl]propionate dihydrochloride ethyl 3-[4-({[5- {[(tert-butoxycarbonyl)amino]methy!} -6-isobutyl-2- we get: ( \ methyl-4- (4-methylphenyl)pyridin-3-yl Jamino } carbonyl)-2-oxopiperazin-1- 5-{[(tert-butoxycarbonyl)amino]methyl } -6-isobutyl-2- as a list of yl]propionate (— mmol 1 mg;1 ) methyl-4-(4-methylphenyl)nicotinic acid ~~ Y° mg; ¥ mmol) according to YOu ( ethyl (2-oxopiperazin-1-yl) propionate 5 (Ye) Similar to the example method

YYzw

Ye yield 744) amino ( carbonyl)-2-oxopiperazin-1 -yl]propionate (1) as a white powder from oil produced in dihydrochloride (YVA)-7 according to a method similar to that of the aforementioned dal example ©" H-NMR (DMS0-d¢)8: 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 , 5), 2.64 (2H, 5), 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, ] = 7.8 Hz), 7.29 (2H, d,J=7.8

Hz), 8.40 (3H, brs). 17 Example 1

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl}-2- methoxybenzamide dihydrochloride

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) we get (£40 mg. yield 400) pyridin-3-yl]-2-methoxybenzamide dihydrochloride tert-butyl {[5-amino-2-isobutyl-6-methyl-4-(4- as a white powder of 5 mg; 0.8 mmol) 7 ( methylphenyl)pyridin-3-ylJmethyl} carbamate mol) according to method lle 175 mg; 1 A) 2-methoxybenzoyl chloride

YY Similar to example method 'H-NMR (DMSO-dg) 8:1.00 (6H, d, J = 6.6 Hz), 2.18-2.29 (1H, m), 2.36 (3H, 5), 2.61 (3H, s) ), 3.03 (2H, s), 3.69 (3H, s), 3.84 (2H, brs), 6.98 (1H, t, J = 5 Hz), 7.08 Ye. (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).

YAY Example N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl}-2- fluorobenzamide dihydrochloride Yo

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) has a yield of £90 (as powder cans 01 (; pyridin-3-yl]-2- fluorobenzamide dihydrochloride applauded

A white fluoride of tert-butyl {[5-amino-2-isobutyl-6-methyl-4-(4-methylphenyl)pyridin- cara) 4Y) 3-ylJmethyl} carbamate 0.8 mmol 2-fluorobenzoyl s 1,75 cana 7 ) chloride mmol) according to the method similar to that of example NYY IH.NMR (DMSO-dg) 5:0.99 (6H, d, J = 6.6 Hz) , 2.21-2.28 (1H, m), 2.37 3H, 5), ° (3H, s), 2.92 (2H, s), 3.84 (2H, 5), 7.1 3.732 (7H, m), 7.49-7.54 (1H, m), 8.20 2.55 (3H, brs), 9.86 (1H, brs). Ye Jha N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4 -methylphenyl)pyridin-3-yl}-3- methoxybenzamide dihydrochloride Ye we get N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) pyridin-3 -y1]-3-methoxybenzamide dihydrochloride ( 1 mg yield Av#) as a white powder of tert-butyl {[5-amino-2-isobutyl-6-methyl-4-(4-methyl Y) phenyl)pyridin-3-yljmethyl ( carbamate 4 mg; 1.8 mmol) VTA) 3-methoxybenzoyl chlorides 0 mg; 175 mmol) according to a method similar to that of Example YY (DMSO-dg) 3:1.00 (6H, d, J = 6.6 Hz), 2.19-2.31 (1H, m), 2.32 (3H, 5) ), 111-1118 (3H, 5), 3.02 (2H, 5), 3.75 (3H, 5), 3.85 (2H, brs), 7.08-7.10 (2H, m), 7.18-7.36 2.58 ( 6H, m), 8.33 (3H, brs), 9.96 (1H, brs). Yio Jo. 0 N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyri din-3-yl]-3- fluorobenzamide dihydrochloride we get N-[5- (aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) pyridin-3-yl]-3-fluorobenzamide dihydrochloride ( 1 mg yield VA %) as a white powder of Ye tert-butyl {[5-amino-2-isobutyl-6-methyl-4-(4-methyl phenyl)pyridin- carbamate ( Box 3-7110 ( 7 mg 0,+ mmol) 3-fluorobenzoyl s

Yve mmol) according to the method similar to that of the example 1.75 mg; 1 YY) chloride

YY

H-NMR (DMSO-d) 8: 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, 5), 7.26 (4H, 5), 7.38-7.42 (2H, m), 7.50 (2H, s), 8.41 (3H, brs), 10.22 (1H, brs).

Yan Example N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl]-4- methoxybenzamide dihydrochloride

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) on Joa a3 (£96 yield casa Y + 4)pyridin-3-yl)-4-methoxybenzamide dihydrochloride 0 tert-butyl {[5-amino-2-isobutyl-6-methyl-4-(4-methyl as a white powder of 1.5 mmol; 7 ) phenyl)pyridin-3 -yljmethyl} carbamate mM) according to method +, VO mg; V YA) 4-methoxybenzoyl chloride 5

YY similar to the example method "H-NMR (DMSO-d) 5:1.00 (6H, d, J = 6.6 Hz), 2.19-2.26 (1H, m), 2.31 (3H, s), Yo 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, 5), 7.67 (2H, d, J = 9.0 Hz), 8.43 (3H, brs), 9.92 (1H, brs).

YJ

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-y1}-4-fluorobenzamide dihydrochloride XY.

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) yields a yield of £90 mg (as £10 powder) pyridin-3-yl]-4-fluorobenzamide dihydrochloride tert-butyl {[S-amino-2-isobutyl-6-methyl-4-(4-methyl phenyl)pyridin- in white from 4-fluorobenzoyl mg; +0.0 mmol) and VY) 3-yl]methyl carbamate) according to the method similar to that of the example lle 1.75 mg; VYY) chloride TO

YY

A

H-NMR (DMSO-d) 8: 1.00 (6H, d, J = 6.6 Hz), 2.14-2.31 (1H, m), 2.31 (3H, 5), 2.62 (3H, s), 3.08 (2H, s), 3.85 (2H, 5), 7.25-7.30 (6H, m), 7.70-7.75 (2H, m), 8.41 (3H, brs), 10.14 (1H, brs).

YA Example (5-methyl-2-0x0-1,3-dioxol-4-yl)methyl 5-(aminomethyl )-6-isobutyl-2-methyl-4-(4-© methylphenyl)pyridin-3 -yl]acetate dihydrochloride (5-methyl-2-0x0-1,3-dioxol-4-yl)methyl [5- {[(tert-butoxycarbonyl) we get 1 of. ) amino Jmethyl} -6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-ylJacetate [5-{[(tert-butoxycarbonyl)amino] as a white powder of (% AT mg; yield ‎ (aaa 5 ) methyl}-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl]acetic acid 0 can Y +4) 4-(chloromethyl)-5-methyl-1,3 -dioxol-2-one 5 mM) 1 (VV mM) according to method similar to example 61 "H-NMR (CDCl) 6:0.97 (6H, d, J = 6.8 Hz), 1.38 (9H, 5), 2.14 (3H, 5), 2.16-2.28 (1H, m), 2.40 (3H, 5), 2.49 (3H, 5), 2.75 (2H, d, J = 7.4 Hz), 3.40 (2H, 5), 4.04 (2H, d, J = 5.1Hz), 4.21 (1H, brs), 4.76 (2H, s), 6.93 (2H, d, J = 79 Hz), 7.21 2H, d, J = Vo 7.9 Hz.(5-methyl-2-0x0-1,3-dioxol-4-yl)methyl 5-(aminomethyl)-6-isobutyl- (Y mg; yield 0 ) 2 -methyl-4-(4-methylphenyl)pyridin-3-yl]acetate dihydrochloride (5-methyl-2-0x0-1,3-dioxol-4-yl)methyl 5-{[(tert-) as a white powder from )4 butoxycarbonyl)amino]methyl} -6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3- | 0 mmol) according to the method similar to that of 1,944 aggregate OT) yl]acetate Example 7 -?). 5), 2.88 (3H, 5), 3.29 (2H, d, J = 7.2 Hz), 3.54-3.64 (4H, m), 4.94 (2H, 5), 7.16 (2H, d, J = 7.9 Hz), 7.33 (2H, d, ] = 7.9 Hz), 8.63 (3H, brs). Yo Example 13?

YY\Y

No 2-[4-(methoxycarbonyl)phenyljethyl 5-( aminomethyl)-6-isobutyl-2-methyl-4-(4- methylphenyl)nicotinate dihydrochloride 1 ( you get 2-[4-( methoxycarbonyl)phenyl]ethyl 5-{ [(tert-butoxycarbonyl) ‎ea VV Y) amino]methyl} -6-isobutyl-2-methyl-4-(4-methylphenyl)nicotinate Ye © yield %) as oil Colorless from 5-{[(tert-butoxycarbonyl)amino }methyl}-6-isobutyl-2- 0 ) methyl-4-(4-methylphenyl) nicotinic acid g FV milligram) methyl 4-(2-bromoethyl)benzoate 5 ) 1 g; 8.7 mmol) according to method similar to example method 1179 Hz), 1.39 (9H, 5), 2.16-2.28 (1H, m), 2.37 = 6.6 for “H-NMR (CDCl;) 8: 0.97 (6H, d, Hz), 2.77 (2H, d, ] = 7.4 Hz), 3.91 (3H, s), 1 7.0 12 Pa (3H, 5), 2.46 (3H, 5), 2.66 (2H, (4H, m), 4.22 (1H, brs), 7.02 (2H, d, J = 8.1 Hz), 7.15 (4H, d, J = 8.3 Hz), 4.11-4.15 (2H, d, J = 8.5 Hz). 4-methylphenyDnicotinate dihydrochloride yielding AY ( as a white Vee solid of 2-[4-(methoxycarbonyl)phenylJethyl 5-{[(tert-butoxycarbonyl) TY) amino]methyl }-6-isobutyl- 2-methyl-4-(4-methylphenyl)nicotinate 6 g TEE mmol) according to the method similar to that of Example 7-?). H-NMR (DMSO-dg) 5:0.96 (6H, d, J = 6.8 Hz), 2.14-2.27 (1H, m), 2.35 (3H, s), (3H, brs), 2.73 (2H, d, J = 6.4 Hz), 2.91 (2H, brs), 3.81 (2H, d, J = 5.3 Hz), 3.85 2.42 Hz), 7.22 (2H, d, J = 7.9 Hz), Ye = 6.8 Hz), 7.12 (2H, 6.5 = ] Ba ( 3H, s), 4.17 2H, (2H, d, J = 8.3 Hz), 7.89 (2H, d, J = 8.3 Hz), 8.34 (3H, brs). 7.29

For example, 4-[2-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl )pyridin-3- yl]carbonyl}oxy)ethylbenzoic acid dihydrochloride 4-[ 2-({[5- {[(tert-butoxycarbonyl)amino methyl} -6-isobuty}-2- we get ( \ Yo g; 00 ) methyl-4-(4-methylphenyl)pyridin-3 -ylJcarbonyl} oxy)ethyl]benzoic acid 2-[4-(methoxycarbonyl)phenyl]ethyl 5-{[(tert-) yield 40 (as colorless oil of

Butoxycarbonyl)amino]methyl ( -6-isobutyl-2-methyl-4-(4-methyiphenyl)nicotinate ) total 7.44 mmol) according to the method similar to that of Example (1-49). H-NMR (CDCl) 8: 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, 5 ), 2.70 (2H, d, J = 6.9 Hz), 2.79 (2H, d, ] = 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=© Hz.8.3 Jas (¥ on 4-[2-({[5-(aminomethyl)) -6-isobutyl-2-methyl-4-(4-methylphenyl) Yo 4) pyridin-3-yl]carbonyl }oxy)ethyl]benzoic acid dihydrochloride mg; yield q¢ 0 as a white solid of -6-} ‎{[(tert-butoxycarbonyl)amino methyl -5[{(-2[-4 ‎isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yljcarbonyl }oxy)ethyl [benzoic] acid 0 (60 g; 1717 mmol) according to the method similar to that of Example 7-?).(6H, d, J = 6.6 Hz), 2.14-2.25 (1H, m), 2.35 (3H , s), 8:0.96, 01450-0) “H-NMR (3H, 5), 2.71 (2H, t,J = 6.5 Hz), 2.87 (2H, d, J = 7.0 Hz), 3.80 (2H, d, J = 5.3 2.42 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). | Vo Example 1 for 2-[4-(aminocarbonyl)phenyl]ethyl 5-(aminomethyl)-6-isobutyl-2-methyl-4-(4- methylphenylnicotinate dihydrochloride 1) ( you get - 2 [4-aminocarbonyl)phenyl]ethyl 5-{[(tert-butoxycarbonyl)amino] 049A) methyl}-6-isobutyl-2-methyl-4-(4-methylphenyl)nicotinate 0 mg; Yield of 19 ( colorless Cy of {[(tert-butoxycarbonyl)amino]methyl } -6-isobutyl-2- -5[{(-2[-4 AA 08 ) methyl-4-(4- methylphenyl)pyridin-3-yl]carbonyl } oxy)ethyl|benzoic acid 01 mmol) according to a method similar to that of the example (VY “H-NMR (CDCls) 8:0.97 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.16-2.27 (1H, m), 2.37 (3H, s), 2.47 (3H, 5), 2.66 (2H, t, J = 7.1 Hz), 2.78 (2H, d, J = 7.2 Hz), 4.09-4.15 Yo (4H, m), 4.24 (1H, brs), 5.67 (1H, brs), 6.06 (1H, brs), 7.02 (2H, d , J = 7.9 Hz), (4H, m), 7.73 (2H, d, J = 8.1 Hz).

>75 2-[4-(aminocarbonyl)phenyl]ethyl 5-(aminomethyl)-6-isobutyl-2- on Ja a3 (Y mg yield +44 (as material © A) methyl-4-(4-) methylphenyl)nicotinate dihydrochloride 2-[4-(aminocarbonyl)phenyl]ethyl 5-{[(tert-butoxycarbonyl) 04 A) amino]methyl }-6-isobutyl-2-methyl- white solid 4-(4-methylphenyl)nicotinate (YY molecule) according to a method similar to that of the example de © 11-1111 (DMSO-dg) 5:0.96 (6H, with J = 6.6 Hz), 2.16-2.25 ( 1H, m), 2.36 (3H, 5), 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).

IVY Example Ye 3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-vi] methoxy}benzamide tert-butyl {[5-{[3- (aminocarbonyl)phenoxy]methyl}-2-isobutyl-6- 1 (ZA+ yield case YE +) methyl-4-(4-methylphenyl)pyridin-3-yljmethyl} carbamate 3-{[5] -{[(tert-butoxycarbonyl)amino]methyl } -6-isobutyl- as a white solid of 0 aa 0 ) 2-methyl-4-(4-methylphenyl)pyridin-3-ylJmethoxy}benzoic acid (0-1 mmol) according to the method similar to the example method "H-NMR (CDCl) 8:0.99 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.21-2.28 (1H, m), 2.35 (3H, 5), 2.62 (3H, 5), 2.79 (2H, 4, J = 7.2 Hz), 4.09-4.11 (2H, m), 4.22 (1H, brs), 4.68 (2H, 5) ), 5.55 (1H, brs), 6.01 (1H, brs), 6.96-7.01 (1H, m), 7.04 (2H, d, J = 7.9 Ye

Hz), 7.17 (CH, d, J = 7.7 Hz), 7.29-7.32 (2H, m), 8.02 (1H, s). 3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) obtained (¥ mg yield 75) as a white solid 17( pyridin-3-ylmethoxy}benzamide tert-butyl {[5-{[3-(aminocarbonyl)phenoxy]methyl}-2-isobutyl-6-methyl-4-(4-mM +, FY stereo; 0 ) methylphenyl) pyridin-3-yl methyl } carbamate ~~ Y¢ Grammy) according to the method similar to that of Example 4?7-?).

Ya.

H-NMR (CDCls) 8: 1.00 (6H, d, J = 6.8 Hz), 2.21-2.30 (1H, m), 2.36 (3H, s), 2.61 (3H, 5), 2.81 (2H, d, J = 7.2 Hz), 3.60 (2H, 5), 4.68 (2H, 5), 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).

IVY Joe © methyl 2-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3- ylmethoxy}-5-methylbenzoate dihydrochloride methyl 2-{[5-{[( tert-butoxycarbonyl)amino methyl }-6-isobutyl-2- we get ( 1 pa VY ) methyl-4-(4-methylphenyl)pyridin-3-yljmethoxy}-5-methylbenzoate tert-butyl {[5-( hydroxymethyl)-2-isobutyl-6- as a white powder of (% oy daly 0 mmol Y.00 g; 1) methyl-4-(4-methylphenyl)pyridin-3-yl]methyl ( carbamate mM) 7.10 mg (0) methyl 2-hydroxy-5-methylbenzoate 5 gram) according to the method similar to that of Example 4 (1-71) "H-NMR (CDCl;) 8: 0.98 (6H, d, J = 6.6 Hz), 1.39 (9H, 5), 2.17-2.26 (1H, m), 2.27 (3H, s), 2.37 3H, 5), 2.67 (3H, 5), 2.78 (2H, d, J = 7.2 Hz), 3.80 (3H, 5), 4.09 2H, d, 0

J=4.9 Hz), 4.20 (1H, brs), 4.68 (2H, 5), 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). methyl 2-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methyl) ( Y mg; yield 0 ) phenyl)pyridin-3-ylJmethoxy}-5-methylbenzoate dihydrochloride methyl 2-{[5-{[(tert-butoxycarbonyl)amino}methyl}- nor (as a white powder of Yo 6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yljmethoxy} -5-methylbenzoate mM) according to the method similar to that of Example 7-?). 6.2 Hz), 2.18-2.24 (1H, m), 2.24 (3H, s), 2.37 (3H, s), 2.99 (3H, 5), 3.29 (2H, d, J = 7.2 Hz), 3.70-3.76 ( SH, 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). Yo 7174 Jha

YY\Y

YAN methyl 2- {[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3- yljmethoxy}-5-chlorobenzoate dihydrochloride methyl 2-{[5-{[(tert- butoxycarbonyl)amino}methyl}-6-isobutyl-2- we get (1 g 0, As ) methyl-4-(4-methylphenyl)pyridin-3-ylJmethoxy}-5-chlorobenzoate tert-butyl {[ 5-(hydroxymethyl)-2-isobutyl-6- as a white powder from 0 VY daly) oe mM Yop ty Ar ) methyl-4-(4-methylphenyl)pyridin-3-yl jmethyl } carbamate col. ¥ mmol) according to 7 ) methyl 5-chlorosalicylate 5 gram) {V1 Method similar to example method "H-NMR (CDCl3)3: 0.98 (6H, d, J = 6.6 Hz), 1.39 (9H, 5), 2.15-2.30 (1H, m), 2.37 (3H, s), 2.66 (3H, 5), 2.78 (2H, d, J = 7.2 Hz), 3.81 (3H, 5), 4.09 ( 2H, d, J = 4.9 Hz), Ve 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 QH, d, J = 8.0 Hz), 7.26 (1H, dd, J = 2.7, 8.9 Hz), 7.69 (1H, d, J] = 2.7 Hz).methyl 2-{[5-{[(tert) -butoxy ?) was stirred at room temperature for ¥ hours a mixture of carbonyl)amino[methyl} -6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-y1] hydrogen ms. and a solution of 1,77 aa 4 ) methoxy} -5-chlorobenzoate 05 ml). The reaction mixture was concentrated under reduced pressure and the substance was washed with £) chloride methanol methyl 2-{[5-(aminomethyl)-6-isobutyl-) to give diisopropyl ether the resulting solid with 2-methyl-4-(4-methylphenyl)pyridin -3-yljmethoxy} -5-chlorobenzoate g; Yield 797 (As a white powder.‎ +,VY) dihydrochloride

H-NMR (DMSO-dg)3: 0.99 (6H, d, J = 6.6 Hz), 2.15-2.30 (1H, m), 2.35 (3H, ), 0 3.08 (3H, brs), 3.08 (2H, brs ), 3.75 (3H, 5), 3.82 (2H, d, J = 4.5 Hz), 4.79 (2H, 5), 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).

Yve example methyl 2- {[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3- Yo ylmethoxy}-5-methoxybenzoate dihydrochloride

YAY methyl 2-{[5-{[(tert-butoxycarbonyl)amino]methyl} -6-isobutyl-2- we get (1 rg) methyl-4-(4-methylphenyl)pyridin-3- ylJmethoxy}-5-methoxybenzoate tert-butyl {[5-(hydroxymethyl)-2-isobutyl-6- as a white powder of ( TY yield mM Yop AL) methyl-4-(4-methylphenyl) pyridin-3-ylJmethyl} carbamate g; ? millimol) according to , .,9 ) methyl 5-methoxysalicylate s gram) ©

LY Method similar to that of example (CDCl3)s: 0.98 (6H, d, J = 6.6 Hz), 1.39 (9H, 5), 2.15-2.30 (1H, m), 2.38 (3H, s), 2.69 3H, s), 2.78 (2H, d, ] = 7.2 Hz), 3.77 (3H, 5), 3.81 (3H, 5), 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, 9.0112, 7.01 2H, d , J = 7.9 Hz), 7.17 2H, d, J = 79 Hz), 7.24 (1H, d,) = 32 0

Hz). methyl 2-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methyl a daa (¥ g 0 ) phenyl)pyridin-3-yljmethoxy}-5-methoxybenzoate dihydrochloride methyl 2-{[5-{[(tert-butoxycarbonyl)amino] yield of 7% (as a white powder of methyl }-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3 -ylJmethoxy}- 5- 0 mmol) according to the analogous method 1.460 c 7 ¥) methoxybenzoate (?-71) 4 for the example method “H-NMR (01/50-0)5: 0.98 (6H) , d, J = 6.6 Hz), 2.15-2.30 (1H, m), 2.37 (3H, 5), 2.73 (3H, brs), 2.93 (2H, brs), 3.72 (3H, 5), 3.73 (3H, 5), 3.79 (2H, d, } = 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 Ye = 3.2 Hz), 7.20 (2H, d, J = 7.8 Hz), 7.29 (2H, d, J = 7.8 Hz), 8.11 (3H, brs).

TV Example 2-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3- yllmethoxy}-4-methoxybenzoic acid dihydrochloride methyl 2-{[5- {[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2- we get ( 10 Ye g; 6,1 ) methyl-4-(4-methylphenyl)pyridin-3-ylJmethoxy}-4 -methoxybenzoate tert-butyl {[5-(hydroxymethyl)-2-isobutyl-6- yield 7977) as a white powder from

YAY

mM Yoana oA ) methyl-4-(4-methylphenyl)pyridin-3-yljmethyl} carbamate combination; ? mmol) according to 0.00 (methyl 4-methoxysalicylate 5 g) (VY eT method similar to example method "H-NMR (CDCl5)8: 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, 5), 2.78 (2H, d, J = 7.2 Hz), 3.75 3H, 5), 3.77 ( 3H, 5), 4.09 2H, d, °

J =4.7Hz),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-{[5-{[(tert-butoxycarbonyl)amino]methyl }-6-isobutyl-2-methyl-4- we obtain (¥; g; yield of 8 ) (4-methylphenyl)pyridin-3 -ylJmethoxy} -4-methoxybenzoic acid methyl 2-{[5-{[(tert-butoxycarbonyl)amino]methyl}- as a white powder of (7 00 6-isobutyl-2-methyl-4-(4-methylphenyl) )pyridin-3-ylJmethoxy} -4-methoxybenzoate

V7 mmol) according to the method similar to that of the example 1.91 aa 51 ) 'H-NMR (CDCl5)8: 0.99 (6H, d, J = 6.8 Hz), 1.39 (9H, 5), 2.15-2.35 (1H, m), 2.35 (3H, 5), 2.64 (3H, 5), 2.81 (2H, d, J = 7.2 Hz), 3.82 (3H, 5), 4.09 (2H, d, J = 4.9 Hz) , 4.15-4.30 (1H, m), 4.87 (2H, 5), 6.30 (1H, d, J = 2.3 Hz), 6.63 (1H, dd, J = 2.3, 8.9 Yo

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). 2-{[5-{[(tert-butoxy) Stir at room temperature for +7 hours a mixture of 0 carbonyl)amino]methyl ( -6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin- 3-yl] mM) and 6 N + YA aa +.) ©) methoxy} -4-methoxybenzoic acid 00 mL). The reaction mixture was concentrated under reduced pressure and the substance was washed €) hydrochloric acid 2-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-) to give acetonitrile the resulting solid with methylphenyl)pyridin-3 -ylJmethoxy}-4-methoxybenzoic | acid dihydrochloride as a white powder. (TAY g; yield +) Y) "H-NMR (DMSO-de)3: 0.99 (6H, d, J = 6.6 Hz), 2.10-2.30 (1H, m) , 2.37 (3H, s), Ye 2.86 (3H, brs), 3.06 (2H, brs), 3.73 (3H, s), 3.82 (2H, brs), 4.76 (2H, brs), 6.31 (1H,

d d,J=2.1Hz), 6.60 (1H, dd, J = 2.1, 8.7 Hz), 7.26 (2H, d, ] = 7.2 Hz), 7.32 (2H, d, J Hz), 7.68 ( 1H, d, J = 8.7 Hz), 8.28 (3H, brs). 7.2 -

Example IVY methyl 6-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3- ylmethoxy}methyl)nicotinate trihydrochloride ° 0 cooled to zero 563° 4 18 dar of tert-butyl {[5-(hydroxymethyl)-2-isobutyl-6- methyl-4-(4-methylphenyl)pyridin-3-ylJmethyl ( carbamate (1.9 g) 7.11 mmol) 01 0) triethylamine milliliter; 11.57 mmol) 0 ( tetrahydrofuran mL) and add dropwise (1£V) methanesulfonyl chloride mg 0 50.15 mmol). After stirring at room temperature for 0 AE) the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate; The mixture was extracted with ethyl acetate. The extracted material was dried on anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure to give {[(tert-butoxycarbonyl)amino]methyl ( -6-isobutyl-2-methyl- -5] methanesulfonate 1i[a4-2160910116071(0171010-3-2)-4 as crude product. Crude product Ve is added to a solution of (axa AEA) (5-bromopyridin-2-yhmethanol 4.51 mmol) sodium hydrides (1/ in oil; 776 (aaa 9.16 mmol) in tetrahydrofuran (+0 mL) and the mixture was stirred at 44007 for 1 hour. The reaction mixture was diluted with cethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the remainder was evaporated by silica gel column chromatography 0 0 to give tert-butyl {[5-{[(5-bromopyridin-2-yl)methoxy]Jmethyl}-2-isobutyl-6- 01 *( methyl-4-(4-methyl phenyl)pyridin-3-yljmethyl} carbamate in total (ZY) productivity

As a white solid. H-NMR (CDCly) 8: 0.97 (6H, d, J = 6.6 Hz), 1.38 (9H, 5), 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, ] = 4.9 Hz), 4.23 (2H, 5), (2H, 5), 7.01 2H, d, 12 7.9 Hz), 7.16-7.20 (3H, m), 7.73 (1H, dd, J = 8.4,2.4 Yo 439 Hz), 8.54 (1H, d, J = 2.1 Hz).

YAC methyl 6-({[5- {[(tert-butoxycarbonyl)amino]methyl } -6-isobutyl-2- we get (Y g 8 ) methyl-4-(4-methylphenyl)pyridin-3 -yljmethoxy}methyl)nicotinate tert-butyl {[5-{[(5-bromopyridin-2-yl)methoxy] as a yellow oil of (AAA) yielding methyl} -2-isobutyl-6-methyl-4 -(4-methylphenyl)pyridin-3 -yl]methyl } carbamate -??#1 mM) according to a weight-like method (LTV can Yo) ° (¥ "H-NMR (CDCls) 8:0.97 (6H, d, J = 6.6 Hz), 1.38 (9H, 5), 2.16-2.25 (1H, m), 2.40 (3H, 5), 2.67 (3H, 5), 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, 5), 7.02 (2H, 4,1 = 7.9 Hz), 7.1 9(211, 0,1 = 7.7 112), 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 01

Hz). methyl 6-( {[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methyl at Jaa 0 mg; yield 106 ) phenyl)pyridin-3-yljmethoxy}methyl)nicotinate trihydrochloride methyl 6-({[5-{[(tert-butoxycarbonyl)amino] as a white solid of 0 oA methyl }-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-ylJmethoxy} methyl) 1 mmol) according to the method analogous to that of TEV aa 4 ( nicotinate . ) - 1 Example H-NMR (DMSO-dg) 6:0.98 (6H, d, J = 6.6 Hz), 2.11 -2.22 (1H, m), 2.38 (311 5), 3.14 (2H, brs), 3.81 (2H, d, J = 5.3 Hz), 3.90 3H, 5), 4.29 (2H, 5), 4.51 (2H, s), 7.23 (2H, d, T= 7.9 Hz), 7.32 (2H, d, ] = 7.9 Hz), 7.38 (1H, d, ] = 8.1 Hz), 8.25 (1H,dd,J 0 = 8.1, 2.2 Hz), 8.38 3H, brs), 8.98 (1H, d, J = 1.5 Hz).

YVA Example 6-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl )pyridin-3-yl methoxy} methyl)nicotinic acid trihydrochloride 6-( {[5- {[(tert-butoxycarbonyl)amino methyl }-6-isobutyl-2-methyl-4- ( 10 Ye mg; yield 0 ) (4-methylphenyl)pyridin-3-ylJmethoxy}methylnicotinic acid methyl 6 -({[5-{[(tert-butoxycarbonyl)amino]methyl}-6- as colorless oil of ( AY

YAR

g 5 ) isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-ylJmethoxy}nicotinate .(1-9 mmol) according to the method similar to that of Example 5 'H.NMR (CDCl) 5:0.97 (6H, d, J = 6.6 Hz), 1.38 (9H, 5), 2.14-2.26 (1H, m), 2.39 (3H, s), 2.71 (3H, 5), 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, d, J = 8.2, 6 1.8 Hz), 9.15 (1H, d, J = 1.5 Hz). 6-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) you get (¥ mg; yield of 4 ) pyridin-3-ylJmethoxy}methyl)nicotinic acid trihydrochloride 6-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6- as a white solid of ( 84 isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-ylJmethoxy}methyl) )nicotinic acid 00 c.075,.mmol) according to the method similar to that of Example 7-?). , 2.11-2.22 (1H, m), 2.39 (3H, 5), 2.94 (3H, brs), 3.13-3.22 (2H, m), 3.81 (2H, brs), 4.29 (2H, brs), 4.51 (2H , 5), 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). yo

Yva Example methyl 2- {2-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl )pyridin-3- yllethyl}benzoate dihydrochloride tert-butyl {[5-formyl- 2-isobutyl-6-methyl-4-(4-methylphenyl) to a solution of ( 1 diethyl (2-5 mmol) ++ A g »,71( pyridin-3-yljmethyl} carbamate- 11.37-0 mmol) in VA mg 1 ¥) bromobenzyl)phosphonate mg 4.048 ml 110) sodium methoxide ml) 01 (dimethylformamide) was added and the mixture was stirred at room temperature for one hour. The mixture of magnesium sulfate was diluted over Chingy washed with saturated brine with cethyl acetate reacted under reduced pressure and the resulting residue was purified by anhydrous DDL analysis. Ye tert-butyl {[5-[(E)-2-(2-bromophenyl)vinyl]- evaporates to give a silica gel column chromatography

0 ) 2-isobutyl-6-methyl-4-(4-methylphenyl)pyridin-3-yljmethyl} carbamate mg; Yield (VA as a white solid. H-NMR (CDCl) 58: 1.00 (6H, d, J = 6.6 Hz), 1.39 (9H, 5), 2.18-2.30 (1H, m), 2.39 (3H, 5), 2.72 (3H, 5), 2.78 (2H, d, 1 = 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, ] = 7.9 Hz), © (1H, m), 7.15-7.18 (2H, m), 7.22 (2H, d, J = 7.7 Hz), 7.50 (1H, d, I = 7.5 7.05-7.08 Hz).Jaa (¥ on methyl 2-{(E)-2-[5-{) [(tert-butoxycarbonyl)amino]methyl}-6- isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl]vinyl benzoate ) m mgm 0 VE yield %) as oil with a yellow color of tert-butyl {[5-[(E)-2-(2-bromophenyl) vinyl]-2- 0 ) isobutyl-6-methyl-4-(4-methylphenyl)pyridin-3-yl methyl } carbamate mg 1.50 mmol) according to a method similar to that of Example 71-771 'H-NMR (CDCl;) 8:0.99 (6H, d, J = 6.6 Hz), 1.39 (9H, 5), 2.18-2.27 (1H, m), 2.39 (3H, 5), 2.74 (3H, 5), 2.78 (2H, d, J = 7.4 Hz), 3.89 (3H, 5) , 4.11 (2H, d, J = 5.3 Hz), (1H, brs), 6.47 (1H, d, J = 16.8 Hz), 7.02 (2H, d,J = 7.9 Hz), 7.13 (1H, d , J = Yo 4.24 Hz), 7.20-7.29 (4H, m), 7.35-7.40 (1H, m), 7.86 (1H, dd, J = 7.8, 1.4 Hz). 2-{(E)-2-[5- {[(tert-butoxycarbonyl)amino methyl }-6-isobutyl-2- A) methyl-4-(4-methylphenyl)pyridin-3-yl]vinyl } benzoate 57 g; 6.87 mmol); palladium-carbon 701 (collected 0.057 milligrams) —( 0 no cut-out) 01 (milliliter) stirred in a sealed tube under 0.5 millibar hydrogen at room temperature for ? hours The reaction mixture was filtered and the filtrate was concentrated under reduced pressure The resulting residue was purified by silica gel column chromatography to give methyl 2-{2-[5-{[(tert-butoxycarbonyl)amino]methyl } -6-isobutyl- 2-methyl-4-(4- YO ) methylphenyl)pyridin-3-yl]ethyl } benzoate mg; yield AA %) as Osh Yo white solid.” H-NMR (CDCl3) ) 8: 0.97 (6H, d, J = 6.6 Hz), 1.39 (9H, 5), 2.14-2.23 (1H, m), 2.43 (3H, s), 2.60 (3H, 5), 2.62-2.68 (2H, m), 2.73 (2H, d, J = 7.4 Hz), 2.91-2.96 (2H, m),

YAA

3.82 (3H, 5), 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). methyl 2-{2-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methyl;) yield 744) as cane 010(phenyl)pyridin-3-yljethyl} methyl benzoate dihydrochloride is a white solid of -6- (the epithelium (it needs to be stained <H01i-5-1])61]-2-12 0 ©?,” body (isobutyl-2-methyl-4-) 4-methylphenyl)pyridin-3-yl]ethyl }benzoate 0.491 mmol) according to the method similar to that of Example 7-?). H-NMR (DMSO-d) 8:0.99 (6H, d, J = 6.6 Hz), 2.11-2.20 (1H, m), 2.45 (3H, 5), (2H, m), 2.83-2.90 (5H, m), 2.91-2.96 (2H, m), 3.18 (2H, brs), 3.73-3.84 2.63-2.72 (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 Ve Hz), 7.35 (1H, dd, J = 7.4, 1.8 Hz), 7.42 (2H, d, J = 7.9 Hz ), 7.75 (1H, dd, J=17.5, Hz), 8.46 (3H, brs).1.5 YA: Example: methyl 4-[({[5-(aminomethyl)-6-isobutyl- 2-methyl-4-(4-methylphenyl)pyridin-3- yllacetyl} oxy)methyl]benzoate dihydrochloride Vo methyl 4-[({[5- {[(tert-butoxycarbonyl)amino]methyl }-6-isobutyl-2 - You get (0 mg; Yo A) methyl-4-(4-methylphenyl)pyridin-3-yl] acetyl }oxy)methyljbenzoate [5-{[(tert-butoxycarbonyl)amino}methyl}-6 - Yield of 4 +% (as white powder of 17 aaa 01 (isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl]acetic acid m AVE mg Y +4) methyl 4-(bromomethyl)benzoate s mM) T VY mol) according to method similar to example 111-1117 (J0) 6:0.97 (6H, d, J = 6.8 Hz), 1.39 (9H, s), 2.17-2.26 (1H, m), 2.38 (3H, 5), 2.49 (3H, 5), 2.77 (2H, d, J = 7.0 Hz), 3.42 (3H, 5), 3.93 ( 3H, 5), 4.03 (2H, d,

J=5.1Hz), 5.09 (2H, 5), 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). Yo methyl 4-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methyl) yields Y cane 0 ) phenyl)pyridin-3-yl]acetyl }oxy )methyl]benzoate dihydrochloride ‎YyYw

YAAQ methyl 4-[({[5-{[(tert-butoxycarbonyl)amino] as a white powder of (% av methyl } -6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3- yl] acetyl } oxy)methyl] to a method similar to the lab method totaling 4 mmol (TA) benzoate Ex. 7-7). 11-1111 )01/50-405:0.98 (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, 5), 3.79 (2H, d, J = 4.5 Hz), 3.87 (3H, s), 5.13 (2H, 5), 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, 4, J = 8.3 Hz), 8.63 (3H, brs).

YAY Example 2-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl] Ye methoxy}-5-methylbenzoic acid dihydrochloride 2-{[5 - {[(tert-butoxycarbonyl)Jamino]methyl } -6-isobutyl-2-methyl-4- we get 1 mg; Yield 0 ) (4-methylphenyl)pyridin-3-ylJmethoxy}-5-methylbenzoic 40 methyl 2-{[5-{[(tert-butoxycarbonyl)amino]methyl}- 0 as a white powder of 6-isobutyl -2-methyl-4-(4-methylphenyl)pyridin-3-ylJmethoxy}-5-methylbenzoate Vo . (1-4 mmol) according to a method similar to that of the example 1,947 vol. © vv) “H-NMR (CDCl) 8:0.99 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.18-2.30 (1H, m), 2.32 (3H, 5), 2.34 (3H, 5), 2.64 (3H, 5), 2.80 (2H, d, J = 7.4 Hz), 4.10 (2H, d , ] =4.9 Hz), 420 (1H, s), 4.88 (2H, 5), 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).Ye 2-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl) we get (¥ mg yield 10 ) pyridin-3-yllmethoxy}-5-methylbenzoic acid dihydrochloride 2-{[5-{[(tert-butoxycarbonyl)amino]methyl }-6- as a powder with a white color of (#q¢ isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-ylJmethoxy}-5-methylbenzoic acid . (¥- Y mmol) according to a method similar to that of Example 0701 Combined 1 A) Yo "H-NMR (DMS0-d¢)3:1.02 (6H, with J = 6.6 Hz), 2.18-2.30 (1H, m), 2.24 (3H, s), 2.38 ( 3H, 5), 3.00 (3H, 5), 3.30 (2H, d, J = 6.8 Hz), 3.87 (2H, d, J = 2.6 Hz), 4.78

Ya. (2H, 5), 6.72 (1H, d, J = 8.5 Hz), 7.20-7.22 (1H, m), 7.30-7.34 (4H, m), 7.43 (1H, d, 1- 1.5 Hz), 8.63 ( 3H, brs).

YAY Example methyl 3-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3- yl]acetyl }oxy)methyl]benzoate dihydrochloride ° methyl 3 -[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2- (1 mg £0)) methyl-4-(4-methylphenyl)pyridin-3 -yl]acetyl ( oxy)methyl]benzoate [5-{[(tert-butoxycarbonyl)amino]methyl }-6- from and yield 4 + % (as powder in color 0.15 mg 7 ) isobutyl- 2-methyl-4-(4-methylphenyl)pyridin-3-yl]acetic acid mM 0.17 mg; TYO ) methyl 3-(bromomethyl)benzoate 5 mol) eV 1164-1.) mol) according to a method similar to that of Example 11-1111 (CDCl;) 8:0.96 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.17-2.26 (1H, m), 2.36 ( 3H, s), 2.48 (3H, 5), 2.74 (2H, d, J = 7.4 Hz), 3.41 (2H, 5), 3.93 (3H, 5), 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). | Ye methyl 3-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methyl) you get (¥ mg; yield 0 ) phenyl)pyridin-3-ylJacetyl}oxy )methyl]benzoate dihydrochloride methyl 3-[({[5-{[(tert-butoxycarbonyl)amino] as a white powder of ( 945 methyl }-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin -3-yl]acetyl } oxy)methyl] mM) according to a method similar to that of 1,497 mol AE,T) benzoate 0 (FY Example 111-1111 (DMS0-ds)8: 0.98 (6H, d, J = 6.6 Hz), 2.17-2.26 (1H, m), 2.36 (3H, 5), 2.88 (3H, 5), 3.30 (2H, d, ] = 6.8 Hz), 3.60 (2H , 5), 3.80 (2H, d, J = 3.8 Hz), 3.88 (3H, ), 5.13 (2H, 5), 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). Yo

YAY is an example

Ya 2-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3-vl]methoxy}-4-methoxybenzamide dihydrochloride tert-butyl {[5-{[2- (aminocarbonyl)-5-methoxyphenoxy[methyl}-2- we get ( 1 Gb; 0 J ) isobutyl-6-methyl-4-(4-methylphenyl)pyridin-3-ylJmethyl} carbamate 2-{[ 5- {[(tert-butoxycarbonyl)amino|methyl} - as a white powder from (% AY yield © 6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-ylJmethoxy} -4 -methoxybenzoic —v mM) according to the method similar to that of the example TA cpa 0 ,7 (0 1) . H-NMR (CDCl5)8: 0.99 (6H, d, J = 6.6 Hz), 1.39 (9H) , 5), 2.15-2.30 (1H, m), 2.36 (3H, 5), 2.63 (3H, 5), 2.80 (2H, d, J = 7.2 Hz), 3.80 (3H, 5), 4.10 (2H, d, J = 5.1 Hz), 01 4.20-4.25 (1H, m), 4.75 (2H, s), 5.51 81H, 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-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) ?) we get g yield YY)pyridin-3-yl]methoxy}-4-methoxybenzamide dihydrochloride 0 tert-butyl {[5-{[2-(aminocarbonyl)-5-methoxy) as a white powder of (74) phenoxylmethyl}-2-isobutyl-6-methyl-4-(4-methylphenyl)pyridin-3 -ylimethyl } mmol) according to the method similar to that of 147 g; +, YO) carbamate (YY eg 'H-NMR :05,01450-0 0.99 (6H, d, J = 6.6 Hz ), 2.10-2.30 (1H, m), 2.35 (3H, 5), Ye 2.78 (3H, brs), 3.01 (2H, brs), 3.74 (3H, 5), 3.80 (2H, d, J = 5.1 Hz ), 4.82 (2H, 5), 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). Z YA as methyl 3- {[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3- Yo yllmethoxy}-2-naphthoate dihydrochloride dance

Yay methyl 3-{[5- {{(tert-butoxycarbonyl)amino methyl} -6-isobutyl-2- you get (/g; yield of 0) (no methyl-4-(4-methylphenyl) pyridin-3-yljmethoxy}-2-naphthoate tert-butyl {[5-(hydroxymethyl)-2-isobutyl-6-methyl- 0 as white powder of 7.01 mmol; 1) 4-(4-methylphenyl)pyridin-3-ylJmethyl} carbamate mM) according to (Vor) mg; For example method H-NMR (CDCl) 8: 1.00 (6H, d, J = 6.6 Hz), 1.38 (9H, 5), 2.18-2.31 (1H, m), 2.34 (3H, s), 2.70 (3H , 8), 2.79 (2H, d, I = 7.4 Hz), 3.87 (3H, 5), 4.1 1 (2H, d, J = 4.7 Hz), 4.20 (1H, brs), 4.81 (2H, 5), 6.91 (1H, 5), 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 = Ve 8.1 Hz), 8.22 (1H, s).methyl 3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4- methyl (Y mg; yield 117 A)phenyl)pyridin-3-yljmethoxy}-2-naphthoate dihydrochloride methyl 3-{[5-{[(tert-butoxycarbonyl)amino]methyl}- as a colored powder white from 4

YY.) 6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-ylJmethoxy}-2-naphthoate 0 (YY mol) according to a method similar to that of the example (Ale 1,78 (aaa " H-NMR )01/150-05: 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, 5), 3.91 (2H, s), 4.96 (2H, 8), 7.35- 7.45 (6H, m), 7.58 (1H, t, J = 7.35 Hz), 7.79 (1H, d, ] = 8.1 Hz), 7.98 (1H, d, J = 7.9

Hz), 8.32 (1H, s), 8.63 (3H, brs). Ye

YAo Jos 3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-v1} methoxy} -2-naphthoic acid dihydrochloride 3-{[5-{[( tert-butoxycarbonyl)amino]methyl } -6-isobutyl-2-methyl-4- we obtain ( 1 (001% mg; yield of 0 ( (4-methylphenyl)pyridin-3-ylJmethoxy-2-naphthoic acid) Yo methyl 3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6- as a white powder from

Yay

AVY) isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3 -yljmethoxy}-2-naphthoate (1-9 mmol). -1111 (CDCl) 6: 1.02 (6H, d, J = 6.6 Hz), 1.38 (9H, 5), 2.20-2.30 (1H, m), 2.32 (3H, s), 2.81 (3H, 5), 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). 3. {[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) you get (¥ (4A mg; yield Yo +)pyridin-3-yljmethoxy}-2- naphthoic acid dihydrochloride 3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2- as a white powder of 0 mg methyl-4-(4-methylphenyl)pyridin-3 -ylJmethoxy}-2-naphthoic acid 0 (FF mmol) according to the method similar to that of the example +07 "H-NMR (DMS0-dg)5:1.00 (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, ] = 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).Yo

YAN Example 2-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl] methoxy}-5-methylbenzamide dihydrochloride tert-butyl {[5] -{[2-(aminocarbonyl)-4-methylphenoxy]methyl}-2- you get () mg; YO ) isobutyl-6-methyl-4-(4-methylphenyl)pyridin-3-yljmethyl } carbamate | 0 2-{[5-{[(tert-butoxycarbonyl)amino]methyl}- as a white powder of ( 711 yield 6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-) ylJmethoxy}-5-methylbenzoic mM) according to the method similar to that of the ballast +0 VA mg; YVT) acid (VY "H-NMR (CDCl) 8:0.99 (6H, d, J = 6.6 Hz) , 1.39 (9H, s), 2.17-2.28 (1H, m), 2.31 Yo (3H, s), 2.35 (3H, s), 2.64 (3H, 5), 2.81 (2H, 5), 4.11 (2H, 5), 4.20 (1H, 5), 4.76 (2H,

s), 6.66 (1H, d, J = 8.5 Hz), 7.00 (2H, d, J = 8.1 Hz), 7.17 (2H, 1H 8.1 Hz), 7.55 (2H, s), 8.00 (2H, s) ). 2-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) ?) we get mg; Yield 0 ) pyridin-3-yljmethoxy} -5-methylbenzamide dihydrochloride tert-butyl {[5-{[2-(aminocarbonyl)-4-methylphenoxy] as a white powder from (% ay 0 methyl} -2-isobutyl) -6-methyl-4-(4-methylphenyl)pyridin-3-ylJmethyl } carbamate (FY mM) according to method similar to example 1,477 (aaa TY )

H-NMR (DMSO-dg)8: 1.01 (6H, d, J = 6.4 Hz), 2.10-2.30 (4H, m), 2.36 (3H, 5), 2.96 (3H, 5), 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, with J = 8.5 Hz), 7.15 (1H, dd, J = 8.5 , 1.9 Hz), 7.25-7.38 (4H, m), 7.42 (1H, 0 d,J = 1.9 Hz), 8.64 (3H, brs).

YAY Example N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl] acetamide dihydrochloride

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) Vo yields £40 (as powder in cans VA) pyridin-3-ylJacetamide dihydrochloride tert-butyl { [5-amino-2-isobutyl-6-methyl-4-(4-methylphenyl)pyridin-3- white from oY) acetyl chlorides ms) 1,5 cane 7 ( yllmethyl } carbamate

YY mmol) according to method similar to example method 175 μl; H-NMR (DMSO-d) 5:0.98 (6H, d, J = 6.6 Hz), 1.76 (3H, s), -2.13 2.22 (1H, m), Ye 2.39 (3H, 5), 2.55 3H, s), 3.02 (2H, brs), 3.82 (2H, 5), 7.17 (2H, d, J = 7.5 Hz), 7.33 (2H , d, J = 7.5 Hz), 8.31 (3H, brs), 9.50 (1H, brs).

YAN Example N-[5-(aminomethyl)-6-isobutyl-2-methyi-4-(4-methylphenyl)pyridin-3-yl] propanamide dihydrochloride Yo

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) you get mg; Yield 7497 (as powder in color 19©) pyridin-3-yl]propanamide dihydrochloride

YYVY tert-butyl {[5-amino-2-isobutyl-6-methyl-4-(4-methylphenyl)pyridin-3- white of 0) propionyl chloride ms) 1,5 ana 7 ) yl )methyl} carbamate .177 mmol) according to the method similar to that of the example 0.78 μmol "H-NMR (DMSO-de) 8:0.82 3H, t, J = 6.9 Hz), 0.98 (6H) , night = 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).

YA Example, N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-y1]-2.2- dimethylpropanamide dihydrochloride

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) you get (% VY mg; yield V AE) pyridin-3-yl]-2,2- tert-butyl dimethylpropanamide dihydrochloride {[5-amino-2-isobutyl-6-methyl-4-(4-methyl as a white powder of mg; 8 mmol) 7 (phenyl)pyridin-3-yl] methyl} carbamate 4Y) pivaloyl chlorides 0 μl; VO, + mmol) according to a method similar to that of Example YY 111-1118 (DMSO-dg) 8:0.89 (9H, s), 0.98 (6H, d, J = 6.6 Hz), -2.12 2.24 (1H, m), 2.36 (3H, 5), 2.51 (3H, s), 2.97 (2H, brs), 3.81 (2H, 5), 7.14 (2H, d, ] = 8.1 Hz), 7.28 (2H, d, J = 8.1 Hz), 8.28 (3H, brs), 8.95 (1H, brs). v4. Example 0

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

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) is obtained (Zhe mg yield VV) pyridin-3-yl]cyclopropanecarboxamide dihydrochloride tert-butyl {[5 -amino-2-isobutyl-6-methyl-4-(4-methyl as a white powder of Yo mg, + mmol) 1 4Y)phenyl)pyridin-3-yljmethyl }carbamate ?

Yan mmol) according to +, VO μl; TA) cyclopropanecarbonyl chloride

NYY (method similar to example method "H-NMR, 0180-0) 8:0.58-0.67 (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, 5), 3.02 (2H, brs), 3.81 (2H, 5), 7.16 (2H, d, J = 7.5 Hz), 7.32 ( 2H, d, J = 7.5 Hz), 8.32 (3H, brs), 9.70 (1H, brs).®

TH Example N-[5-(aminomethy!)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl] cyclopentanecarboxamide dihydrochloride

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) we get (1% mg; YTV yield) pyridin-3-yl]cyclopentanecarboxamide dihydrochloride 0 tert-butyl {[5-amino-2-isobutyl-6-methyl-4-(4-methyl as white powder of 0 mg; + 0.0 mmol) 7 ( phenyl)pyridin-3-yl]methyl} carbamate =) milligrams) according to 1.75 µL 1 A) cyclopentanecarbonyl chloride

YY Method similar to example method 'H-NMR (DMSO-dg) : 0.98 (6H, d, J = 6.6 Hz), 1.30-1.62 (9H, m), 2.15-2.24 (1H, vo 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).

Yay J

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenypyridin-3-yl]pyridine- 2-carboxamide trihydrochloride AK

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) we get ) 791 mg; Yield YY A) pyridin-3-yl]pyridine-2-carboxamide 00106 tert-butyl {[5-amino-2-isobutyl-6-methyl-4-(4-methyl) as a white powder of mg ,+ mmol) 1 Y) phenyl)pyridin-3-yl]methyl carbamate mmol) according to the method 1.75 mg; 011) pyridine-2-carbonyl chlorides Ye similar to the example method YY dispersed

Yay "H-NMR (DMSO-d) 8: 1.01 (6H, with J = 6.6 Hz), 2.20-2.28 (1H, m), 2.28 (3H, 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, 5)

Yar Jo.

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl] °nicotinamide trihydrochioride

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) yielding £98 (as powder in color ana YYO ( pyridin-3-yl] nicotinamide trihydrochloride tert-butyl) {[5-amino-2-isobutyl-6-methyl-4-(4-methyl phenyl)pyridin-3-white nicotinoyl chloride s mg;+0,0 mmol) 7 ( yllmethyl}carbamate 0

YY mmol) according to the method similar to that of the example 1.25 cama 0 ) "H-NMR (DMSO-dg) 6: 1.02 (6H, d, J = 6.6 Hz), 2.23-2.31 (1H, m) , 2.31 (3H, 5), 2.73 (3H, 5), 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, 5), 10.90 (1H, brs).

Ya like 0

N-[5-(aminomethyl)-6-isobutyl-2-methyi-4-(4-methylphenyl)pyridin-3-yl] isonicotinamide trihydrochloride N-[5-(aminomethyl)-6-isobutyl-2 -methyl-4-(4-methylphenyl) yields 791) as powder (cana Y) 0) pyridin-3-yl] isonicotinamide trihydrochloride tert-butyl {[5-amino-2-isobutyl-6-methyl- 4-(4-methyl phenyl)pyridin- white Ye isonicotinoyl chloride 3 mmol) 1.8 mg VAY ( 3-yllmethyl} carbamate

YY mM) according to the method similar to that of the example + VO compiled 0) "H-NMR (DMSO-d) 8: 1.01 (6H, d, ] = 6.6 Hz), 2.22-2.31 (1H, m ), 2.31 (3H, 5), 2.70 (3H, s), 3.51 (2H, brs), 3.88 (2H, 5), 7.28 (4H, 5), 7.87 (2H, d, J = 6.0 Hz), 8.51 (3H, brs), 8.88 (2H, d, J = 6.0 Hz), 11.20 (1H, brs).Yo

Yiu Ju.

Y4A {[2-isobutyl-6-methyl-4-(4-methylphenyl)-5-(phenoxymethyl)pyridin-3 -yl} methyl} amine dihydrochloride tert-butyl {[2-isobutyl-6-methyl-4-( 4-methyl phenyl)-5-(phenoxy) we obtain (1) color ane yield 701 (as case YY) methyDpyridin-3-yljmethyl} carbamate tert-butyl { [5-(hydroxymethyl)-2-isobutyl -6-methyi-4-(4-methylphenyl)pyridin- from © 1 (pase 4£,0) phenols ms) 1c;6 ( 3-yllmethyl} carbamate

VY E in mmol) according to the method similar to that of the example "H-NMR (CDCl) 8:0.99 (6H, d, J = 6.6 Hz), 1.39 (9H, 5), 2.18-2.27 (1H, m) , 2.36 (3H, 5), 2.63 (3H, 5), 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 Ve

Hz), 7.17 2H, d, ] = 7.7 Hz), 7.21-7.24 (2H, m). {[2-isobutyl-6-methyl-4-(4-methylphenyl)-5-(phenoxymethyl) ?) we get a yield of (0) mg as an oilless 117(pyridin-3-yl] methyl}amine dihydrochloride tert-butyl {[2-isobutyl-6-methyl-4-(4-methyl phenyl)-5-(phenoxymethyl) color in mm) according to 9095 aa oY V) pyridin-3-yljmethyl} carbamate 0 method similar to that of Example 7-?). H-NMR (DMSO0-dg) 8: 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, ] = 4.9 Hz), 4.70 (2H, 5), 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).113 as 0 6-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl] methoxy }methyl)nicotinamide trihydrochloride tert-butyl {[5-({[5-(aminocarbonyl)pyridin-2-ylJmethoxy}methyl)-2- you get () (aaa TV ) isobutyl-6-methyl-4-( 4-methylphenyl)pyridin-3-ylJmethyl } carbamate 6-({[5-{[(tert-butoxycarbonyl)amino] as a white solid of (% YY yielding Ye methyl }-6-isobutyl-2- only methyl-4-(4-methylphenyl)pyridin-3-ylJmethoxy} methyl)

mmol) according to analogous method 1.894 pa +, £A) nicotinic acid (VY for example method 'H-NMR (CDCls) 8:0.96 (6H, d, J = 6.6 Hz), 1.38 ( 9H, s), 2.13-2.23 (1H, m), 2.40 (3H, s), 2.67 (3H, 5), 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), 6 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). 6-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) you get ( mg; YAY yield ) pyridin-3-yl] methoxy}methyl)nicotinamide trihydrochloride tert-butyl {[5-({[5-(aminocarbonyl)pyridin-2-yl] as a white solid of (% vo methoxy} methyl)-2-isobutyl-6-methyl-4-(4-methylphenyl) )pyridin-3-yljmethyl} | 0 g; 0.190 mmol) according to a method similar to that of the carbamate (+, YY) carbamate Example 7-?)." H-NMR (01/50-0) 8 :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, 5), 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- Vo 7.69 (1H, m), 8.27-8.30 (1H, m), 8.50 (3H, brs), 8.99 (1H, brs).

YAY Example 4- {[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl] methoxy }isophthalic acid dihydrochloride dimethyl 4-{[5-{[ (5-tert-butoxycarbonyl)amino]methyl}-6-isobutyl- (VY: g; yield of 17 2-methyl-4-(4-methylphenyl)pyridin-3-ylJmethoxy}isophthalate tert-butyl {[5-(hydroxymethyl)-2-isobutyl-6- as a white solid of (% ve mmol 7.51 p1) methyl-4-(4-methylphenyl)pyridin-3-ylimethyl) } carbamate milligrams) 7.01 cana 0YA) dimethyl 4-hydroxyisophthalate 5 gram) o 1-1714 according to method similar to example Yo (E020) ra 6:0.99 (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, 5), 4.06-4.11 only

Yeo (2H, m), 4.23 (1H, brs), 4.77 (2H, 5), 6.71 (1H, d, J = 8.9 Hz), 7.05 (2H, d, = 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). 4-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4- you get (Y ( 7/90 cane yield ?0 ) (4-methylphenyl (pyridin-3-yljmethoxy}isophthalic acid 0 dimethyl 4-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6- as a white solid of can 7 ( isobutyl-2-methyl-4-) 4-methylphenyl)pyridin-3-ylJmethoxy}isophthalate .(1-4 mmol) according to a method similar to that of Example 4 "H-NMR (CDCl) 8:1.03 (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), Ve 7.22 (2H, d,J = 7.7 Hz), 8.01 (1H, brs), 8.53 (1H, brs).4-{[5-(aminomethyl)-6-isobutyl-2-methyl -4-(4-methylphenyl) yields (¥)7857 yield (aaa YO) pyridin-3-yl]methoxy} isophthalic acid dihydrochloride 4-{[5-{[(tert-butoxycarbonyl)amino]methyl }-6-isobutyl- as a white solid of JBM; +,¥) ) 2-methyl-4-(4-methylphenyl)pyridin-3-ylJmethoxy}isophthalic acid 0 (FY mM) according to to the method similar to that of Example 100) “H-NMR (DMSO-d) 5:1.00 (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, 5), 7.01 (1H, d, J = 8.9 Hz), 7.27 (2H, d, J = 8.1 Hz), 7.31 (2H, d, ] = 7.7 Hz), 7.97 (1H, dd, ] = 8.7, 2.3 Hz), 8.18 (1H, d, J = 2.1 Hz), 8.34 (3H, brs). Y.

Yah J methyl 2-{(E)-2-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin- 3-yl]vinyl}benzoate dihydrochloride methyl 2-{(E) )-2-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methyl) obtained as a material (1 yield) case 701 4(phenyl)pyridin-3-yl]vinyl } benzoate dihydrochloride Yo methyl 2-{(E)-2-[5-{[(tert-butoxycarbonyl)amino]methyl ( -6- from ad) colored solid

AER

Body 0 ) isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl]vinyl } benzoate milligram) according to the method similar to that of Example 7-?). 4 111-111 ( f 01/50-0) 6:1.01 (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,] ° =7.9 Hz), 7.40 (1H, t,J = 7.5 Hz), 7.53 (1H, t, J = 7.5 Hz), 7.79 (1H, dd, } = 7.8, 1.2

Hz), 8.32 (3H, brs).

Yad Example 4-[1-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl] carbonyl }oxy)ethyl]benzoic acid dihydrochloride Ve 1-[4-(methoxycarbonyl)phenyl]ethyl 5-{[(tert-butoxycarbonyl) we get 1 mass yield 17 ) amino]methyl} -6-isobutyl-2-methyl-4-(4- methylphenyl)nicotinate 5-{[(tert-butoxycarbonyl)amino }methyl }-6-isobutyl-2- l% (as colorless oil of mmol) YAY G1) methyl-4-(4) -methylphenyl)nicotinic acid milligrams) according to 7.47 cane £AT) methyl 4-(1-hydroxyethyl)benzoates 0

AVY 497 Method similar to example method 'H-NMR (CDCl3) 8:0.97 (6H, d, J = 6.6 Hz), 1.25 (3H, d, J = 7.0 Hz), 1.39 (9H, 5), -2.16 2.24 (1H, m), 2.33 (3H, s), 2.48 (3H, 5), 2.78 (2H, d, ] = 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). Y. 4-[1-({[5-{[(tert-butoxycarbonyl)aminoJmethyl ( -6-isobutyl-2-) you get ( 7 qc. ) methyl-4-(4-methylphenyl)pyridin-3- yl]carbonyl } oxy)ethyl Jbenzoic acid 1-[4-(methoxycarbonyl)phenyl]ethyl 5- as a colorless oil of (% qo mg; yield {[(tert-butoxycarbonyl)amino]methyl }-6- isobutyl-2-methyl-4-(4-methylphenyl) mmol) according to the method similar to that of 1.77 g; nicotinate (V0 Y) © 1-4 (Example vey "H") -NMR (CDCl3) 8: 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, 5), 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). isobutyl-2-methyl-4-(4-methylphenyl) 0 mg; yield 4 ) pyridin-3-yl] carbonyl } oxy)ethyl]benzoic acid dihydrochloride 4-[1-({[5] -{[(tert-butoxycarbonyl)amino]methyl }-6- as a white solid of ( 97 isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl]carbonyl ( oxy)ethylJbenzoic acid

YY mmol) according to the method similar to that of the example 1.577 c,0) 'H-NMR (DMSO-dg) 8:0.97 (6H, d, J = 6.8 Hz), 1.22 (3H, d , J = 6.6 Hz), 2.17-2.26 Ye (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). ?00 Jha [(2-isobutyl-6-methyl-4-(4-methylphenyl)-5- {{2-(methylthio)phenoxyjmethyl } pyridin-3-yl)methyl]amine dihydrochloride Ve tert-butyl [( 2-isobutyl-6-methyl-4-(4-methylphenyl)-5-{[2-on Joa ai)1 yield (aa),T'Y) (methylthio)phenoxy]methyl}pyridin-3 -yl)methyl]carbamate tert-butyl {[5-(hydroxymethyl)-2-isobutyl-6-methyl-4-(4- as colorless oil of (ZV mmol) VY aa N00 ) methylphenyl) pyridin-3-ylJmethyl } carbamate mM) according to the method 7,77 cane 0VY) 2-(methylthio)phenol s 0

AVY) EJB method similar to

H-NMR (CDCl) 6: 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, 5), 2.69 (3H, 5), 2.78 (2H, d, ] = 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). Yo [(2-isobutyl-6-methyl-4-(4-methylphenyl)-5- {[2-(methylthio) you get (¥ yield » mg 11 ) phenoxy]methyl} pyridin-3-yl )methyljamine dihydrochloride voy tert-butyl [(2-isobutyl-6-methyl-4-(4-methyl) as a white solid of 8 14 0 2) Y)phenyl)-5-{[2-(methylthio)phenoxy [methyl} pyridin-3-yl)methyl]carbamate (TY mM) according to method similar to example method 1,777 mg; “H-NMR (01/50-0) 5:1.00 (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, 5), 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). 10 Example [(2-isobutyl-6-methyl-4-(4-methylphenyl)-5- {[2-(methylsulfonyl)phenoxy]methyl} pyridin-3-yl)methyl]amine dihydrochloride 01 tert- butyl [(2-isobutyl-6-methyl-4-(4-methylphenyl)-5-{[2- on Jaa] (1 yield aaa YY) (methylsulfonyl)phenoxy}methyl} pyridin-3-yl )methylJcarbamate tert-butyl [(2-isobutyl-6-methyl-4-(4-methyl) as a white solid from (ZA)

OYA ) phenyl)-5- {[2-(methylthio)phenoxy]methyl} pyridin-3-yl)methyl}carbamate (1-9) mmol) according to the method similar to that of the example 1,770 p.m. 0 "H-NMR (CDCl) 6: 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, 5) ), 2.79 (2H, d, J = 7.4 Hz), 3.08 (3H, 5), 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=17.9 Hz), 7.45-7.50 (1H, m), 7.97 (1H, dd, J = 7.7, 1.7 Hz). [(2-isobutyl-6-methyl-4-(4-methylphenyl)-5- {[2-(methylsulfonyl) we get ( Yy 0 mg yield YYV) phenoxy]methyl}pyridin-3-y) )methyl]Jamine dihydrochloride tert-butyl [(2-isobutyl-6-methyl-4-(4-methyl) as a white solid of ) 4 phenyl)-5-{[2-(methylsulfonyl)phenoxy]methyl} pyridin -3-yl)methyl]carbamate mM) according to the method similar to that of Example 7-?). 1,599 g; (6H, d, J = 6.4 Hz), 2.17-2.28 (1H, m), 2.35 (3H, s), Yo 2.84 (3H, brs), 3.05-3.17 (5H, m), 3.84 (2H, d, = 4.7 Hz), 4.87 (2H, s), 7.11 (1H, 4,

YY\V

Yet 1- 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).

Yor Jue [(2-isobutyl-6-methyl-4-(4-methylphenyl)-5-{[2-(methylsulfinyl)phenoxy]methyl } pyridin-3-yl)methyl]amine dihydrochloride ° tert-butyl [(2) -isobutyl-6-methyl-4-(4-methylphenyl)-5-{[2-] to a mixed solution of (0

GAY body (Y) (methylthio)phenoxy]methyl}pyridin-3-yl)methyl]carbamate sodium (10 mL) add (10 mL) water and 0 (methanol) in le mM The mixture was stirred at room temperature, 1776 mg (YVY) periodate, and washed successively with water and a solution of cethyl acetate A for two days. The reaction mixture was diluted with anhydrous 0. The solvent was evaporated under reduced pressure magnesium sulfate to saturated brine and dried over tert-butyl to give silica and the resulting residue was purified by gel column chromatography [(2-isobutyl-6-methyl-4-(4-methylphenyl)-3) -{[2-(methylsulfinyl)phenoxy]methyl } yield of 1 as yellow oil. cana VE)pyridin-3-yl)methyl]carbamate "H-NMR (CDCl) 6:1.00 (6H, d, J = 6.6 Hz), 1.39 (9H, 5), 2.21-2.29 (1H, m), 2.35 Ye (3H, s), 2.61 (3H, 5), 2.69 (3H, 5), 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-isobutyl-6-methyl-4-(4-methylphenyl)-5- {[2-(methylsulfinyl)) obtaining (Y 10 mg; yield 4 ) phenoxy]methyl ( pyridin-3-yl )methyl]amine dihydrochloride tert-butyl [(2-isobutyl-6-methyl-4-(4-methyl) as a white solid of (% TY phenyl)-5-{[2-(methylsulfinyl)phenoxy]methyl} pyridin-3-yl)methyljcarbamate ms) according to the method similar to that of Example 7-?). 1,705 mg; 4) 'H-NMR (DMSO-d) 8:1.00 (6H, d, J = 6.6 Hz), 2.17-2.27 (1H, m), 2.34 (3H, s), Yo 2.63 (3H, s), 2.77 (3H, brs), 3.06 (2H, brs), 3.82 (2H, brs) , 4.70 (1H, d, J = 10.6 Hz), s

mm 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). rev Example 3- {[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-y1] methoxy} -2-naphthamide dihydrochloride ° tert-butyl {[5] -({[3-(aminocarbonyl)-2-naphthyl]oxy}methyl)-2- (1 mg) yields 771( isobutyl-6-methyl-4-(4-methylphenyl)pyridin-3-yljmethyl } carbamate 3-{[5-{[(tert-butoxycarbonyl)amino]methyl}- yield 46 7 as a white powder of 6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yljmethoxy} -2-naphthoic acid (VF mmol) according to method similar to example method + AVA uaa 01): “H-NMR (CDCl) 8:0.89 (6H, d, J = 6.6 Hz), 1.35 (9H, s), 2.07-2.22 (1H, m), 2.28 (3H, s), 2.79 (3H, 5), 2.87 (2H, d, ] = 7.2 Hz), 4.14-4.21 (3H, m), 4.95 (2H , 5), 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=7.5Hz), 7.81 (1H, d, J = 8.1 Hz), 8.67 (1H, 5), 11.73 (2H, s). 3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) ?) gets 00 (141 mg yield 001( pyridin-3-yl] methoxy}-2 -naphthamide dihydrochloride tert-butyl {[5-({[3-(aminocarbonyl)-2-naphthyljoxy} as a white powder of methyl)-2-isobutyl-6-methyl-4-(4-methylphenyl)pyridin-3 -ylJmethyl } carbamate

YY mmol) according to a method similar to that of example 14605 (aaa 0 'H-NMR )01180-005:1.00 (6H, d, J = 6.4 Hz), 2.17-2.30 (1H, m), 2.32 (3H , 3(, Ye 2.51 (3H, s), 2.81 (2H, s), 3.83 (2H, s), 4.88 (2H, 5), 7.25-7.33 (4H, m), 7.40 (1H, t,

J=75Hz), 7.50 (1H, t,J=7.5Hz), 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 4.? 5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)-N-phenylnicotinamide 5 to a solution of 5-({[(benzyloxy)carbonyl}amino } methyl)-6-isobutyl -2-methyl-4- OY ¥) (4-methylphenyl)nicotinic acid mg; 0.117 milligrams) in YYVY

Ye mmol 1.4 μl; VY +) oxalyl chloride mL) add ©) tetrahydrofuran ?saad reaction solution stirred LN N-dimethylformamide gram) and add one drop of ml). Add (©) tetrahydrofuran hours and the reaction mixture is concentrated. Dissolve the remainder in 1.0 μL; YY + triethylamine (5 mmol) 1 “ily Sue (90 mmol) aniline. Water is added to the reaction mixture 0 mmol and the mixture is stirred for © 071 AH. The organic layer was washed with saturated brine, the acetate was dried, and the mixture was extracted with anhydrous. The solvent is evaporated under reduced pressure and the resulting residue, magnesium sulfate, is purified over ethanol to give oil. to a solution of oil in silica by hydrogen gel column chromatography (mg) and the mixture was stirred under atmosphere (© + palladium-carbon 701 ml) added (©) at room temperature for ? hours. The reaction mixture was filtered, and the filtrate was concentrated. 4-methylphenyl)-N-phenylnicotinamide as a white powder

H-NMR (CDCl) 8: 1.00 (6H, d, J = 6.6 Hz), 2.17-2.31 (1H, m), 2.34 (3H, s), 2.65 (3H, 5), 2.82 (2H, d, J = 7.5 Hz), 3.69 (2H, 5), 6.93 (1H, brs), 7.04-7.26 (9H, m). 10

Teo example methyl 3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl]methoxy}-1-methyl-1H-pyrazole-4- carboxylate dihydrochloride ethyl 3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2- you get ( 1 methyl-4-(4-methylphenyl)pyridin-3-ylJmethoxy}-1 -methyl-1H-pyrazole-4-0 tert-butyl {[5-(hydroxy yield 797/9) as colorless oil of oa ¥,YY) carboxylate 9) methyl)-2-isobutyl-6-methyl-4 -(4-methylphenyl)pyridin-3-yl|methyl } carbamate ethyl 3-hydroxy-1-methyl-1H-pyrazole-4- 5 mmol) V,0F mg;g; 7,507 mmol) according to a method similar to that of 1, YA) carboxylate

VAY Jade Ye

H-NMR (CDCl) 8: 0.98 (6H, with J = 6.8 Hz), 1.28 (3H, 1, J = 7.1 Hz), 1.39 (9H, s), 2.17-2.26 (1H, m), 2.36 (3H, 5), 2.66 (3H, 5), 2.77 (2H, d, J = 7.4 Hz), 3.67 (3H, s),

1 4.08 (2H, d, J = 4.7 Hz), 4.19-4.26 (3H, m), 4.90 (2H, 5), 7.10 (2H, d, J = 8.1 Hz), 7.16 (2H, d, J = 8.1 Hz), 7.61 (1H, s). 3-{[5-{[(tert-butoxycarbonyl)amino]methyl ( -6-isobutyl-2-methyl-4-) you get (¥ (4-methylphenyl)pyridin-3-ylJmethoxy}-1-methyl- 1H-pyrazole-4-carboxylic acid ethyl 3-{[5-{[(tert-butoxy) yield 1h0 as a white solid of aa V,04) © carbonyl)amino]methyl }-6-isobutyl-2- methyl-4-(4-methylphenyl)pyridin-3-yl] mM 8.87 (aa T,X ¥) methoxy}-1-methyl-1H-pyrazole-4-carboxylate 1-4 gram ) according to the method similar to the example method "H-NMR (recommended) 6:0.99 (6H, d, J = 6.8 Hz), 1.38 (9H, s), 2.15-2.28 (1H, m), 2.36 (3H , s), 2.66 (3H, 5), 2.79 (2H, d, J = 7.4 Hz), 3.71 (3H, 5), 4.04-4.09 (2H, m), 4.23 Ve (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-{[5-{[(tert-butoxycarbonyl)amino] methyl} -6-isobutyl-2-methyl-4-(4- dissolves ( methylphenyl)pyridin-3-yljmethoxy}-1-methyl-1H-pyrazole-4-carboxylic acid mL) ©) N, N-dimethylformamide (mmol) in 1,587 (con v.00 (0 mmol) potassium carbonate) and add 0.74 mg; (VV) methyl iodides (mmol). The mixture was stirred at room temperature for 1 hour VEE C 0, ) to the reaction mixture; The mixture was washed with one ethyl acetate saturated saline solution. Anhydrous is added. The solvent was evaporated under reduced pressure and the remaining magnesium sulfate was purified and dried over methyl 3-{[5-{[(tert-butoxycarbonyl) to give silica by gel column chromatography 00 amino]methyl }-6-isobutyl-2- methyl-4-(4-methylphenyl)pyridin-3-yljmethoxy}-1- Yield (£9) as a white solid. cane 470) methyl-1H-pyrazole-4-carboxylate "H-NMR (J020) ‎ 6:0.99 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.17-2.26 (1H, m), 2.36 (3H, 8), 2.66 (3H, 8), 2.77 (2H, d , J = 7.4 Hz), 3.68 (3H, s), 3.76 (3H, 5), 4.08 (2H, d,

J = 4.7 Hz), 4.23 (1H, brs), 4.90 (2H, s), 7.10 2H, d,J = 79 Hz), 7.16 2H, d, J = Yo 7.9 Hz), 7.62 (1H, s). Just

YA methyl 3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methyl) you get (£phenyl)pyridin-3-ylJmethoxy}-1-methyl-1H-pyrazole-4 -carboxylate dihydrochloride methyl 3-{[5-{[(tert- as a white solid of 0 Ao yield cana VAY ) butoxycarbonyl)amino jmethyl } -6-isobutyl-2-methyl-4-(4-methylphenyl )pyridin-3- mM HAY (aa +, £Y) ylimethoxy}-1-methyl-1H-pyrazole-4-carboxylate 0 . 9 grams) according to a method similar to that of the example?: “H-NMR (DMSO-d) 6:1.00 (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, 5), 3.82 (2H, d, I = 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, 5), 8.41 (3H, brs).Ve 10 as 3-{[5-(aminomethyl) -6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl] ‎methoxy} -1-methyl-1H-pyrazole-4-carboxylic acid dihydrochloride 3-{[5-(aminomethyl)-6 -isobutyl-2-methyl-4-(4-methylphenyl) you get pyridin-3-yl] methoxy} attanrotamate-4-m1-h-111-pt1-20- acid dihydrochloride 0 3-{[5- {[(tert-yield 744) as a white solid of (aaa YTA) butoxycarbonyl)amino jmethyl } -6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-mM +,0V § (aa +,¥+) yljmethoxy}-1-methyl-1H-pyrazole-4-carboxylic acid (*- 1 mol) according to the method similar to that of example "H-NMR (DMSO-de) 5: 0.99 (6H, d, J = 6.4 Hz), 2.14-2.25 (1H, m), 2.39 (3H, 5), Ye 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).

TV Example 3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenvl)pyridin-3-yi] methoxy} -1-methyl-1H-pyrazole-4- carboxamide dihydrochloride Yo tert-butyl {[5-({[4-(aminocarbonyl)-1-methyl-1H-pyrazole-3- on Jans (1 ylJoxy}methyl)-2-isobutyl-6-methyl-4- (4-methylphenyl)pyridin-3-yl jmethyl }

6.4 3-{[5-{[(tert-butoxy) as a colorless oil of (7711 mg yield YY) carbamate carbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-methylphenyl) pyridin-3-yl] mM +,40V can » ,8 ( methoxy}-1-methyl-1H-pyrazole-4-carboxylic acid

AVF Gram) according to the method similar to that of the example "H-NMR (CDCl) 6:0.99 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.19-2.28 (1H, m), 2.37 ° (3H, 8), 2.65 (3H, 5), 2.79 (2H, d, J = 7.4 Hz), 3.69 (3H, 5), 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).3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) you get (¥

Yo 9 pyridin-3-ylJmethoxy}-1-methyl-1H-pyrazole-4-carboxamide dihydrochloride 0 tert-butyl {[5-({[4-(aminocarbonyl)-1-) as a white solid from (LAY ) Productivity of cane methyl-1H-pyrazole-3-yl]oxy}methyl)-2-isobutyl-6-methyl-4-(4-methylphenyl) mmol) according to 0A aggregate 00 (no pyridin-3-yljmethyl} carbamate method similar to that of Example 7-?). 2.38 (3H, s), vo 2.93 (3H, brs), 3.17 (2H, brs), 3.63 (3H, s), 3.82 (2H, d, ] = 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).

Yoh Example (3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl] Ye. methoxy} -1-methyl-1H-pyrazol- 4-yl)acetic acid dihydrochloride tert-butyl {[5-(hydroxymethyl)-2-isobutyl-6-methyl-4-(4- to a solution of 6 mmol); 1,7 «pa 1 ( methylphenyl)pyridin-3-yljmethyl} carbamate mmol 7.21 g vt ¥) methyl (3-hydroxy-1-methyl-1H-pyrazol-4-yi)acetate mmol) in ? ,10 pn 1 ( tributylphosphine 5 gram) Y© g +,¥1) 1,1'(azodicarbonyl)dipiperidine mL) add 0) tetrahydrofuran min. Filter 10 mmol) and stir the mixture at room temperature for 7.01 minutes.

The reaction mixture and the solvent in the filter material are evaporated under reduced pressure. The resulting residue, methyl (3-{[5-{[(tert-)) was purified to give silica by butoxycarbonyl)amino gel column chromatography [10 sub]-6-isobutyl-2-methyl-4-(4-). methylphenyl)pyridin-3- as a non-oil (AT VV yield) ylJmethoxy}-1-methyl-1H-pyrazol-4-yl)acetate (3-{[5-{[(tert-butoxycarbonyl)amino) methyl }-6-isobutyl-2- you get dae the color. © methyl-4-(4-methylphenyl)pyridin-3-yl methoxy} -1-methyl-1H-pyrazol-4-yl)acetic methyl (3-{[5-{[(tert- as a white solid of 0 Vo mg; yield 1 YY) acid butoxycarbonyl)amino]methyl } -6-isobutyl-2-methyl-4-(4- methylphenyl)pyridin-3-mM) TAA can 1 ( ylimethoxy}-1-methyl-1H-pyrazol-4-yl)acetate 1-4 .) according to the method similar to that of example 0 'H-NMR (CDCls) 8: 0.95 (6H, d, J = 6.6 Hz), 1.38 (9H, 5), 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, 5), 3.66 (3H, s), 4.05-4.09 (2H, m), 4.27 (1H, brs), 4.84 (2H, 5), 7.03 (2H, d, J = 7.9 Hz), 7.12 (1H, 5), 7.18 (2H, d,] = 7.7 Hz). (3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) you get (Y 0

A¢,Y) pyridin-3-yljmethoxy}-1-methyl-1H-pyrazol-4-ylacetic acid dihydrochloride (3-{[5-{[(tert-butoxycarbonyl)) as a white solid from ( 51 yield cane amino]methyl }-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yljmethoxy}-1-mM) according to TTY compiled 1 Y¥) methyl-1H -pyrazol-4-yl)acetic acid (FY) Method similar to example Ye 1-1116 (DMSO-dg) 0.98:0 (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, ] = 7.5 Hz), 7.37 (1H, s), 8.18 (3H, brs)."15 Examples Ye

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl}-3-(1H-tetrazol-5-yl)benzamide dihydrochloride

11

to a solution of tert-butyl {[5-amino-2-isobutyl-6-methyl-4-(4-methylphenyl) AY) pyridin-3-yljmethyl} carbamate ¥ mg; 1 milligram (mmol) in tetrahydrofuran (© milliliter) add YE ©) 3-cyanobenzoyl chloride mg; 0.5 mmol) and add (YAW) triethylamine μl ¥ mmol). The mixture is stirred for YA hours. A saturated aqueous sodium hydrogen carbonate solution (© milliliters) 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 evaporated under reduced pressure and the resulting residue was purified by silica gel column chromatography to give oil. To a solution of the resulting oil in dimethyl sulfoxide (¥ mL) add 4V) sodium azide 0 mg; 1.0 mmol) 5 ¥\Y) ammonium chloride mg; 1 mmol) and the mixture was stirred at 100”C for ¥ hours. Add distilled (01 milliliters) to the reaction mixture and extract the mixture with ethyl acetate. The organic layer was washed with saturated brine and dried on anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by silica gel column chromatography to give oil. To a solution of oil 0 produced in Y (ethyl acetate milliliters) add a NM solution of hydrogen chloride ethyl acetate ¢ (? milliliters) and stir the resulting mixture at room temperature for ?* hours. The cual evaporates under reduced pressure and the resulting residue crystallizes from hexane to give N-[5-(aminomethyl)- 6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-y1]-3- (1H-tetrazol-5-yl)benzamide

cane AT) dihydrochloride (yield 717) as a white powder. H-NMR )0080-05:0.99 (6H, d, J = 6.6 Hz), 2.11-2.27 (1H, m), 2.27 3H, 5), X. (3H, s), 2.93 (2H, s), 3.83 (2H, 5), 7.22 (4H, 5), 7.64 (1H, t,J = 7.8 Hz), 7.76 2.52 (1H, d, J = 7.8 Hz), 8.16 (4H, brs) , 8.34 (1H, brs), 10.10 (1H, brs).

01 Je z methyl 2- {[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3- ylmethoxy}-3-methylbenzoate dihydrochloride Yo )( you get On methyl 2-{[5-{[(tert-butoxycarbonyl)amino]}methyl}-6-isobutyl-2- (pa 0 ) methyl-4-(4-methylphenyl)pyridin-3-ylJmethoxy}- 3-methylbenzoate

yield of £4% (as a white powder of tert-butyl {[5-(hydroxymethyl)-2-isobutyl-6- 7,51 can)) methyl-4-(4-methylphenyl)pyridin-3-yljmethyl} carbamate mmol) 5 7.10 cps ©) methyl 2-hydroxy-3-methylbenzoate mmol) according to a method similar to that of the example VY E "H-NMR (CDCl) 6:0.98 (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, 9, 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, 1 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). methyl 2-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methyl on Joa ai ( 00 ?5 mg; yield ) phenyl)pyridin-3-ylJmethoxy}-3 -methylbenzoate dihydrochloride methyl 2-{[5-{[(tert-butoxycarbonyl) amino]methyl}- as a white powder of (£94 6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3- yljmethoxy}-3-methylbenzoate (FY mM) according to method similar to example 1.479 aaa 745("H-NMR)01450-05:1.01 (6H, d, J = 6.4 Hz), 1.82 (3H) , s), 2.14-2.29 (1H, m), Vo 2.36 (3H, s), 3.02 (3H, 5), 3.31 (2H, d, J = 6.8 Hz), 3.67 (3H, 5), 3.78 2H, d, J = 2.45 Hz), 4.81 (2H, 5), 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 711 pz 2-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin -3-y1]-N- cyclopropylacetamide dihydrochloride 1) Stir at room temperature for V7 hours a mixture of [5-{[(tert-butoxycarbonyl) amino Jmethyl }-6-isobutyl- 2-methyl-4-(4-methylphenyl)pyridin-3-yl]acetic acid 001 (mg; gram molecule); YY 0) 1-hydroxy-1H-benzotriazole mg; 0.41 milligrams); TV ) 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride mg 15 mmol) N N-dimethylformamide s (© milliliters). Dilute the reaction mixture with

ethyl acetate and washed with saturated brine. The organic layer was dried over magnesium 6 and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl {[5-[2-(cyclopropylamino)-2-oxoethyl]-2- isobutyl-6-methyl-4-(4-methylphenyl)pyridin- 3-ylJmethyl } carbamate (0 mg yield 118) as a white powder. 9H, ,L(0 (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). -yI]-N-cyclopropylacetamide dihydrochloride tert-butyl {[5-[2-(cyclopropylamino)-2-oxoethyl]-2-isobutyl-6- in white from a volume of 158 mL 0 methyl-4-(4) -methylphenyl)pyridin-3-yl methyl } carbamate (PY molecule) according to a method similar to that of the example "H-NMR )01/150-05:0.34 (2H, 5), 0.57 (2H, d, J = 5.5 Hz), 0.99 (6H, d, J = 6.2 Yo

Hz), 2.11-2.25 (1H, m), 2.41 (3H, 5), 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). 11 Example {[2-isobutyl-6-methyl-4-(4-methylphenyl)-5-(2-morpholin-4-yl-2-oxoethyl)pyridin- A 3-yllmethyl} amine dihydrochloride tert-butyl {[2-isobutyl-6-methyl-4-(4-methylphenyl)-5-(2-morpholin-) we obtain (9 as powder (AVY mg; yield 0+) 4-yl-2- oxoethyl)pyridin-3-yl]methyl} carbamate [5-{[(tert-butoxycarbonyl)amino]methyl } -6-isobutyl-2-methyl-4-(4-) white from mg 479 mmol ) 001( methylphenyl)-pyridin-3-yljacetic acid Yo (mM) according to the method similar to that of 0.41 cane V YY) morpholine (VY) example YYVY

r98' H-NMR (CDCl3) 8: 0.97 (6H, d, 1 = 6.6 Hz), 1.37 (9H, 5), 2.09-2.27 (1H, m), 2.41 (3H, 8), 2.50 (3H, s) ), 2.73 (2H, d, J = 7.4 Hz), 3.17 (2H, d, J = 4.1 Hz), 3.30 (2H, 5), 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-isobutyl-6-methyl-4-(4-methylphenyl)-5-(2-morpholin-4-yl-2- ?) you get ©)794 yield cosa 01(oxoethyl)pyridin- 3-yljmethyl}amine dihydrochloride tert-butyl {[2-isobutyl-6-methyl-4-(4-methylphenyl)-5-(2- as a white powder of 107 mg 8 mg) morpholin-4-yl -2-oxoethyl)pyridin-3-ylJmethyl } carbamate (TYM) according to a method similar to that of the example “H-NMR (01/50-0(15:0.99 (6H, d, J = 6.4 Hz)),” 2.09-2.30 (1H, m), 2.41 (3H, s), Ye 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, 1=7.7Hz), 7.39 (2H, d, J = 7.7 Hz), 8.52 (3H, brs).

ARAN

2-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl]-N- benzylacetamide dihydrochloride 1 tert-butyl {[5-[2-(benzylamino)- 2-oxoethyl]-2-isobutyl-6-methyl-4- we get (1) yield 17%) as powder case YO +) (4-methylphenyl)pyridin-3-yl]methyl} carbamate [5- { [(tert-butoxycarbonyl)amino}methyl}-6-isobutyl-2-methyl-4-(4-milligram white) 419 cana 001( methylphenyl)pyridin-3-yl]acetic acid ‏ milligrams) according to the method similar to that of 0.41 mg V0) benzylamine 00

VY Example 'H-NMR (CDCl) 8: 0.96 (6H, d, J = 6.6 Hz), 1.37 (9H, 5), 2.12-2.27 (1H, m), 7 (3H, s), 2.56 (3H, 5), 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). Yo 2-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin- yield (¥ + + (4) as cana Yo color powder) 3-y1] -N-benzylacetamide dihydrochloride

1 tert-butyl {[5-[2-(benzylamino)-2-oxoethyl]-2-isobutyl-6-methyl-4-(4-mM white +, YOY (aaa 0 ( methylphenyl)) pyridin-3-yllmethyl} carbamate (P = gram) according to a method similar to that of the example 'H-NMR 01150-415:0.99 (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 5), 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).

ME Example [(2-isobutyl-6-methyl-4-(4-methylphenyl)-5-{[2-(1H-tetrazol-5-yl)phenoxy] methyl} pyridin-3-yl)methyl ]amine dihydrochloride tert-butyl {[5-[(2-cyanophenoxy)methyl]-2-isobutyl-6-methyl-4-(4-) you get 1 Ye as ZV (ZV) throughput © A1) methylphenyl)pyridin-3-yljmethyl} carbamate tert-butyl {[5-(hydroxymethyl)-2-isobutyl-6-methyl-4-(4-methylphenyl) color from 1,148 mM) ca +,1V) pyridin-3-ylJmethyl} carbamate mmol) according to the method 0.85 mg (YY) 2-hydroxybenzonitrile s

AVY VE similar to example 10' H-NMR (CDCl) 8: 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, b J = 7.9 Hz), 7.40-7.46 (1H, m), 7.50 -7.56 (1H, m). tert-butyl [(2-isobutyl-6-methyl-4-(4-methylphenyl)-5-{[2-(1H-) get (Y | 00 mg; yield 0 ) tetrazol-5-yl )phenoxy]methyl } pyridin-3-yl)methyl]carbamate tert-butyl {[5-[(2-cyanophenoxy)methyl]-2- as a white solid of 0 + mg; 7 ) isobutyl-6 -methyl-4-(4-methylphenyl)pyridin-3-ylJmethyl } carbamate (V=Ye mM) according to a method similar to that of Example 111 "H-NMR (J02) 8:0.99 (6H, d , J = 6.6 Hz), 1.39 (9H, s), 2.17-2.28 (1H, m), 2.32 Yo (3H, s), 2.59 (3H, s), 2.82 (2H, d, J = 7.4 Hz), 4.09-4.13 (2H, m), 4.31 (1H, brs),

YYZ

s (2H, s), 6.91-6.95 (3H, m), 7.12 2H, d, J = 7.7 Hz), 7.18 (1H, t, J = 7.6 Hz), 4.92 (1H, m), 8.42 (2H, dd, 1 = 7.9, 1.7 Hz). -5-yl) (aaa YYV) phenoxy]methyl}pyridin-3-yl)methylJamine dihydrochloride yield oe 0 as a ard color solid of tert-butyl [(2-isobutyl-6-methyl) -4-(4-methyl phenyl)-5- {[2-(1H-tetrazol-5-yl)phenoxy]methyl} pyridin-3-yl)methyl]carbamate 1,779 cana £0 ) mmol) according to a method similar to the example method (FY "H-NMR (DMSO-d) 8:1.01 (6H, d, ] = 6.6 Hz), 2.17-2.29 (4H, m), 2.88 (3H , brs), (2H, brs), 3.80 (2H, brs), 4.89 (2H, s), 7.03-7.10 (3H, m), 7.13-7.17 (3H, m), 3.16 (1H, m), 7.87 (1H, d, J = 7.7 Hz), 8.41 (3H, brs).A 7.46-7.52 Me Jo 5-{[5-(aminomethyl)-6-isobutyl-2-methyl- 4-(4-methylphenyl)pyridin-3-yl] methylene}-1,3-thiazolidine-2,4-dione dihydrochloride 0) was stirred with heating at 0 “#” for three and a half days with a mixture of -5[{ tert-butyl formyl-2-isobutyl-6-methyl-4-(4-methylphenyl)pyridin-3-ylJmethyl ( carbamate | 0 cana 101( )1.0 mmol VY) 1,3-thiazolidine-2,4-dione «(cal a mg 1.51 mmol) V0) piperidine + , +” milliliters) 5,01 (ethanol milliliters). After al & to cool to room temperature; The solvent evaporates under reduced pressure. The residue was purified by silica gel chromatography to give tert-butyl {[5-[(2,4-dioxo-1,3-thiazolidin-5- ylidene)methyl]-2-isobutyl-6-methyl-4 -(4-methylphenyl)pyridin-3-ylJmethyl} | 0 carbamate (+ + lb mg yield 757) as a white powder. H-NMR (CDCl) 8: 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). Y Yo ( we get 5-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4- methylphenyl)pyridin-3-yljmethylene}-1,3-thiazolidine-2,4-dione dihydrochloride (1 00 mg yield 001) as a white powder of tert-butyl {[5-[(2,4) -dioxo-1,3-thiazolidin-5-

ilidene)methyl]-2-isobutyl-6-methyl-4-(4-methylphenyl)pyridin-3-yl methyl } carbamate (for 11 mg mmol) according to the method similar to that of the example Y -*( . J = 6.4 Hz), 2.14-2.29 (1H, m), 2.37 (3H, s), has “H-NMR (DMSO0-d¢)8:0.99 (6H, (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 ° 2.51 Hz), 7.28-7.40 ( 3H, m), 8.49 (3H, brs). Ex. 76 2-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl methoxy} -3-methylbenzoic acid dihydrochloride) 1 0 you get 2-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4- acid -3- (J «Matt 3-71[0-Sun0 Term (1NrDm 4-6:1) ‎cana YA) yield 4%) as a white powder of methyl 2-{[5-{[(tert-butoxycarbonyl)amino) ]methyl}- -3-methylbenzoate ( b«d 6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl 0.077 aaa 0 ) mMg ) according to the method similar to that of Example 1-4.) , 2.24-2.32 Yo (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 ), (1H, brs), 4.83 (2H, s), 6.60 (2H, d, J = 7.5 Hz), 7.02-7.13 (3H, m), 7.19-7.24 4.20 (1H, m), 7.45-7.54 (1H, m). -methylbenzoic acid dihydrochloride 0 (©5 mg; Yoo yield (as a white powder of -6-} 2-{[5-{[(tert-butoxycarbonyl)amino methyl isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl) methoxy }-3-methylbenzoic acid 101 cana OAS (mmol) according to the method similar to that of Example =Y ¥ ( . J = 6.4 Hz), 1.79 (3H, s), 2.14-2.28 ( 1H, m), Yo has “H-NMR (DMSO0-de)8:1.00 (6H, (3H, 5), 2.97 (3H, s), 3.26 (2H, d, J = 6.8 Hz) , 3.77 (2H, d, ] = 4.0 Hz), 4.81 2.36

YYA

(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). 1 Example 2-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl] methoxy}-5-chlorobenzamide dihydrochloride 5 2-{[5] -{[(tert-butoxycarbonyl)amino]methyl ( -6-isobutyl-2-methyl-4- you get ( 1 ,4 g yield ) (4-methylphenyl)pyridin-3-yljmethoxy}-5 -chlorobenzoic acid methyl 2-{[5-{[(tert-butoxycarbonyl)amino]methyl}- as a white powder of ( ay 6-1sobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl methoxy} -5-chlorobenzoate (1- 49 mmol) according to the method similar to that of the example 1 g; 1,090) 0' H-NMR (CDCl3)8: 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, 5), 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, d, J = 2.6, 8.9 Hz), 7.90 (1H, d, J = 8.9 Hz). tert-butyl {[5-{[2-(aminocarbonyl)-4-chlorophenoxyjmethyl}-2- on Joa ai ?) Vo g; 0 isobutyl-6-methyl-4-(4-methylphenyl) pyridin-3-yljmethyl ( carbamate 2-{[5-{[(tert-butoxycarbonyl)amino|methyl }- as a white powder of 11% (yield) 6-1sobutyl-2-methyl-4-(4) -methylphenyl)pyridin-3-ylJmethoxy}-5-chlorobenzoic 7 mM) according to the method similar to that of example 1,81 can +, YA) acid 1 0 "H-NMR:5(YL020) ‎ 0.99 (6H, d, J = 6.6 Hz), 1.39 (9H, 5), 2.15-2.35 (1H, m), 2.36 (3H, s), 2.63 (3H, 5), 2.80 (2H, d, ] = 7.4 Hz), 4.10 (2H, d, ] = 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, 41-9).

Hz), 7.18 (2H, d, ] = 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). Yo 2-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) you get (¥ (799 yield can +11 ) pyridin-3-ylJmethoxy}-5- chlorobenzamide dihydrochloride tert-butyl {[5-{[2-(aminocarbonyl)-4-chlorophenoxy] as a white powder of methyl} -2-isobutyl-6-methyl-4-(4-methylphenyl)pyridin-3-yl ] methyl } carbamate (FY mM) according to a method similar to that of Example 171c 1 v) “H-NMR (DMS0-d)8:0.99 (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, 5), 6.83 (1H , d, J = © 9.0 Hz), 7.25 (2H, 4, ] = 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).

IA Joe 2-{[5-(aminomethy!)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3 -yl] methoxy} -5-chlorobenzoic acid dihydrochloride Ve 2-{[5-( aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) oN ) pyridin-3-yljmethoxy}-5-chlorobenzoic acid dihydrochloride 2-{[5-{[(tert) -butoxycarbonyl)amino]methyl}-6- as a white powder of (LAO isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-ylJmethoxy}-5-chlorobenzoic acid -71706 mmol) according to To the method similar to the example method 1,77 Cm 0 ( Ye i

H-NMR (DMS0-dg) 5:0.99 (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, ] = 2.8, 8.9

Hz), 7.61 (1H, d, J = 2.8 Hz), 8.30 (3H, brs). Ye

AARNE

4'-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl] carbonyl }oxy)methyl]biphenyl-4-carboxylic acid dihydrochloride 4-bromobenzyl 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl- (0 yield © 097 as colorless oil from can V,4Y) 2-methyl-4-(4-methylphenyl)nicotinate 8 5-{[(tert-butoxycarbonyl)amino]methyl } -6-isobutyl-2-methyl-4-(4- 4-bromobenzyl 3 mmol) 4.41 pm 7 ( methylphenyl)nicotinic acid

YYW

YY. gram-molecule) according to the method similar to that of the example lle £8) c 1 ) bromide . ( a-10 8 'H-NMR (CDCl) 8: 0.96 (6H, d, J = 6.6 Hz), 1.38 (9H, 5), 2.15-2.26 (1H, m), 2.38 (3H, 5), 2.53 (3H, 5), 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). [(tert-butoxy) a solution of 11 hours argon stirred under an atmosphere of (Y 3 ) carbonyl)amino methyl } -6-isobutyl-2-methyl-4-(4-methylphenyl)nicotinate y 0) [4-(methoxycarbonyl)phenyl boronic acid mmol); LAV g mmol 7.80 cana YAA) potassium carbonate mg; 7.75 mmol); 0 mmol +, YAY (711 mg) tetrakis(triphenylphosphine)palladium(0) mL) and water (0.¥ mL). The reaction mixture was diluted with V0 (grams dioxane) in anhydrous magnesium sulfate. Washed with saturated brine and dried over cethyl acetate. The solvent was evaporated under reduced pressure and the resulting residue was purified by gel column chromatography [4'-(methoxycarbonyl )biphenyl-4-yljmethyl 5-4 [(tert-butoxycarbonyl) to give silica 0 (pa OV ) amino]methyl }-6-isobutyl-2-methyl-4-(4-methylphenyl)nicotinate yield 48 7) As a colorless oil. 2.55 (3H, 5), 2.78 2H, d, J = 7.4 Hz), 3.91 (3H, 5), 4.16 (2H, d, } = 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, 0

J=8.3 Hz), 7.64 2H, d, J = 8.7 Hz), 8.10 (2H, d, J = 8.5 Hz).

A-[({[5-{[(tert-butoxycarbonyl)amino]methyl} -6-isobutyl-2-methyl-4-(4-methyl ( 1 mg; ) phenyl)pyridin-3-yl] carbonyl } oxy)methyl]biphenyl-4-carboxylic acid [4'-(methoxycarbonyl)biphenyl-4-yljmethyl as a white solid of 0 TA yielding 5-{[(tert-butoxycarbonyl) amino ]methyl} -6-isobutyl-2-methyl-4-(4- Ye mmol) according to the method 1,895 mg; OV ( methylphenyl)nicotinate 1-49 .) similar to the example method

YY

H-NMR (CDCl;) 6: 0.96 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.15-2.26 (1H, m), 2.34 (3H, 5), 2.56 (3H, 5) ), 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). 5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) we get ( ¢ © pyridin-3-yl]carbonyl }oxy)methyl|biphenyl-4-carboxylic acid dihydrochloride

A({[5-{[(tert-) yield +1) as a white solid of (ana YOO) butoxycarbonyl)amino]methyl ( -6-isobutyl-2-methyl-4- (4-methylphenyl)pyridin- 3- mmol 0.101 b mg; ) yl]carbonyl} oxy)methylJbiphenyl-4-carboxylic acid (YY gram) according to the method similar to that of Example 0

H-NMR (DMSO-dg) 8: 0.96 (6H, d, J = 6.6 Hz), 2.15-2.26 (1H, m), 2.33 (3H, 5), 2.57 (3H, brs), 2.92 (2H, brs) ), 3.82 (2H, d, J = 4.3 Hz), 5.04 (2H, 5), 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, with J = 8.5 Hz), 8.34 (3H, brs).

TY as Ne pyridin-4-ylmethyl 5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl) nicotinate trihydrochloride pyridin-4-ylmethyl 5- {[(tert-butoxycarbonyl)amino]methyl }-6- We obtain ( 1 "?? mg; yield £07 (as non-oil) isobutyl-2-methyl-4-(4-methylphenyl)nicotinate 5- {[(tert-butoxycarbonyl)amino]methyl } -6-isobutyl-2-methyl-4-(4-methyl color of Ye 4-(chloromethyl) mmol) 0.71 g; 4 ) phenyl)nicotinic acid potassium carbonate s mmol) 0.71 can 0 ( pyridine hydrochloride (V1 g; ? mmol) according to the method similar to that of Example 7) “H-NMR (CDCl3)8:0.97 (6H, d, J = 6.6 Hz), 1.39 (9H, 5), 2.17-2.27 (1H, m), 2.36 (3H, s), 2.56 (3H, 5), 2.78 (2H, d, 12 7.4 Hz), 4.14 (2H, d, ] = 4.9 Hz), 4.42 (1H, Yo 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).

YYy pyridin-4-ylmethyl 5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-) we obtain (Y as a solid in color (ZV from the yield of YT +) methylphenyl)nicotinate trihydrochloride pyridin -4-ylmethyl 5- {[(tert-butoxycarbonyl)amino]methyl }-6-isobutyl-2- white from milligram) according to 1174 "? colloquium ( methyl-4-(4-methylphenyl) )nicotinate to the method similar to that of Example 3-7.” H-NMR (DMSO-de) 8:0.97 (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, 5), 7.1 7-7.24 (4H, m), 7.60 (2H, brs), 8.35 (3H, brs), 8.83-8.84 (2H, brs).

J pyridin-3-ylmethyl 5-(aminomethyl )-6-isobutyl-2-methyl-4-(4-methylphenyl) Ve nicotinate trihydrochloride pyridin-3-ylmethyl 5- {[(tert-butoxycarbonyl)amino}methyl}-6 - We obtain ( 1 as nonoil 0 VE mg yield £0€) isobutyl-2-methyl-4-(4-methylphenyl)nicotinate 5-{[(tert-butoxycarbonyl)amino methyl} -6- isobutyl-2-methyl-4-(4-methyl 3-molecule color); le 1,71 (pa; 4 ( phenyl)nicotinic acid 08 mmol) VA) g 1 ( ( (bromomethyl)pyridine hydrobromide 0 ) potassium carbonate s gm; 7.6 mmol) according to method similar to that of example (V4 111-111 (CDCl3)5:0.96 (6H, d, J = 6.6 Hz), 1.38 (9H, 5), 2.15-2.24 (1H , m), 2.36 (3H, s), 2.54 (3H, 5), 2.77 (2H, d, ] = 7.4 Hz), 4.12 (2H, d, J = 4.1 Hz), 4.20 (1H, Ye brs), 4.94 (2H, 5), 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, ] = 4.8, 1.6 Hz).pyridin-3-ylmethyl 5-(aminomethyl)-6-isobutyl-2-methyl-4-(4- We obtain (Y as a solid in color (% va mg; yield 1 AY) methylphenyl)nicotinate 06 pyridin-3-ylmethyl 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2- white of Yo mM) according to 1.507 mg; tO) methyl-4-(4-methylphenyl)nicotinate to the method similar to that of the example (PY

79 H-NMR (DMSO-d) 8:0.96 (6H, d, J = 6.8 Hz), 2.17-2.26 (1H, m), 2.31 (3H, s), 2.59 (3H, 5), 2.93 (2H, d, J = 6.0 Hz), 3.78 (2H, d, J = 5.5 Hz), 5.22 (2H, 5), 7.12 (4H, 5), 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).

YY as oe methyl 2-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl )pyridin-3- ylJmethoxy}-3-methoxybenzoate dihydrochloride methyl 2-{[5-{ [(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2- we get (1 g) 1 Y ) methyl-4-(4-methylphenyl)pyridin-3-yljmethoxy}-3-methoxybenzoate tert- butyl {[5-(hydroxymethyl)-2-isobutyl-6-00% yield (as white powder of 0 mmol Y g) methyl-4-(4-methylphenyl)pyridin-3-yljmethyl } carbamate g; ? milligram) according to 1500 ( methyl 3-methoxysalicylate 5 grams)

VY 1 similar to ds hall

H-NMR (CDCl3)3: 0.98 (6H, d, J = 6.6 Hz), 1.38 (9H, 5), 2.15-2.30 (1H, m), 2.34 (3H, s), 2.73 (3H, 5), 2.75 (2H, d, ] = 7.4 Hz), 3.54 (3H, 5), 3.64 (3H, 5), 3.97 (2H, d, Vo

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, ] = 8.1 Hz), 7.14 (1H, dd, J = 1.5, 8.1 Hz). methyl 2-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methyl ?) we get 17 g) phenyl)pyridin-3-ylmethoxy}-3-methoxybenzoate dihydrochloride 0 methyl 2-{[5-{[(tert-butoxycarbonyl)amino] yield 17) as a white powder of methyl}-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-ylJmethoxy} -3-methoxy mmol) according to a method similar to that of 174 aa + (4) benzoate .) ?-717 4 Ex. "H-NMR :5(J01150-1) 0.99 (6H, d, J = 6.6 Hz), 2.10-2.30 (1H, m), 2.37 (3H, s), Yo 2.94 (3H, brs), 3.00-3.20 (2H, m), 3.51 (3H, 5), 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), 7 (3H, brs).

Example YY methyl 2-({[5-(aminomethyl)-2-methyl-4-( 4-methylphenyl)-6-neopentylpyridin-3- yllmethyl } thio)benzoate dihydrochloride °)1 we get On methyl 2-({[5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4- methylphenyl)-6-neopentylpyridin-3-yljmethyl} thio)benzoate (1.57 gm yield of {[(tert-butoxycarbonyl Jamino }methyl }-2-methyl-4-(4-methyl -5] methanesulfonate [0] 1no-3-mate mate tum [Njam Durham 0-6] as a powder -(1 stump ctm 7 g; 0.7 mmol) cana VO VY) methyl thiosalicylate s £0 mmol) according to the method

.) 1-?? Similar to example method 111-1111 (CDCl) 8: 1.02 (9H, 5), 1.37 (9H, 5), 2.34 (3H, 5), 2.65 (3H, 5), 2.83 (2H, 5), 3.89 ( 3H, 5), 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) . methyl 2-( {[5-(aminomethyl)-2-methyl-4-(4-methylphenyl)-6- we get (V yield pane 4 ) neopentylpyridin-3-yljmethyljthio)benzoate dihydrochloride methyl 2- (([5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-qom ( as powder from MGBBM; Yeo ) 4-(4-methylphenyl)-6-neopentylpyridin-3-ylJmethyl } thio ) benzoate (FY in mM) according to the method similar to that of Example 7 ' {-NMR (DMSO-d) 5: 1.03 (9H, 5), 2.34 (3H, 5), 2.83 (3H, 5), 3.18 (2H, brs), 3.80 000 (3H, s), 3.88 (2H, 5), 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). yye Example 2-({[5-(aminomethyl)-2-methyl-4-(4-methylphenyl)-6-neopentylpyri din-3-y1] methyl} thio)benzoic acid dihydrochloride Yo 4-({[ 5-{[(tert-butoxycarbonyl)amino}methyl } -2-methyl-4-(4- we get ( 1 mg; yield AQ) (no methylphenyl)-6-neopentylpyridin-3-yljmethyl} thio)benzoic acid

YYyo methyl 4-({[5-{ [(tert-butoxycarbonyl)amino] as a white solid of (ay methyl }-2-methyl-4-(4-methylphenyl)-6 -neopentylpyridin-3-yljmethyl) } thio) milligrams) according to the method similar to that of the article (VIVA aa) benzoate 0-4.

H-NMR (CDCl) 8: 1.12 (9H, 5), 1.38 (9H, 5), 2.38 (3H, 5), 3.09 (3H, s), 3.47 (2H, 2 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- {[5-(aminomethyl)-2-methyl-4-(4-methylphenyl)-6-neopentyl (Y 0 AY mg; yield VO A)pyridin-3-ylJmethyl} thio)benzoic acid dihydrochloride | 0 4-({[5-{[(tert-butoxycarbonyl)amino]methyl} -2-methyl-4- as a white powder of stereoisomer; Yoo ) (4-methylphenyl)-6-neopentylpyridin-3- yl]methyl} thio)benzoic acid ?,; mmol) according to the method similar to that of Example 7-?). (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 Vo ( 3H, brs).

YYo Jo 2-({[5-(aminomethyl)-2-methyl-4-(4-methylphenyl )-6-neopentylpyridin-3-vl] methyl} thio)benzamide dihydrochloride 4-({[5-{[(tert) -butoxycarbonyl)amino]methyl } -2-methyl-4-(4- according to correct) 10 mg; yield of ) methylphenyl)-6-neopentylpyridin-3-yljmethyl} thio)benzamide 4-({[ 5-{[(5-tert-butoxycarbonyl)amino] A white solid is obtained from (ZY 0 methyl}-2 -methyl-4-(4-methylphenyl)-6-neopentylpyridin-3 -ylJmethyl} thio) benzoic milligram) according to the method similar to that of the example 1.911 vol. (Ov) acid 10-? Ye

H-NMR (J020) 6:1.02 (9H, s), 1.37 (9H, 5), 2.39 (3H, 5), 2.63 (3H, s), 2.83 (2H, s), 3.81 (2H, 5), 4.04 (2H, with 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-({[5-(aminomethyl)-2-methyl-4-(4-methylphenyl)-6-neopentyl ‏ ?) You get (784 mg yield) 0 ) pyridin-3-ylJmethyl}thio)benzamide dihydrochloride © 4-({[5-{[(tert-butoxycarbonyl amino]methyl} -2-methyl-4-) as powder in a white color of 0 mg) (4-methylphenyl)-6-neopentylpyridin-3-ylmethyl} thio)benzamide, mM) according to a method similar to that of Example 7-?). 5 "H-NMR (DMSO-dg) 8:1.03 (9H, 5), 2.37 (3H, 5), 2.76 (3H, 5), 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, 5), 8.20 01 (3H, brs).

ANU

2- {[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-vl]methoxy} -3-methylbenzamide dihydrochloride tert-butyl {[5-{[2-( aminocarbonyl)-6-methylphenoxy]methyl}-2- we get ( 1 1 mg 0 ) isobutyl-6-methyl-4-(4-methylphenyl)pyridin-3-yl methyl } carbamate 2-{[5 -{[(tert-butoxycarbonyl)amino]methyl}- yield of 95 0 as a white powder of 6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-ylJmethoxy} -3-methyl benzoic aggregate ; 77/5 mmol) according to the method similar to that of example 0) acid

nara

H-NMR (CDCl) 8: 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, 5), 3.16 (2H, d, J = 6.8 Hz), 4.04 (2H, 5), 4.20 (1H, brs), 4.81 (2H, 5),5.80 (1H, brs), 6.40 ( 1H, brs), 6.65 (2H, s), 7.02-7.23 (4H, m), 7.56 (1H, s).2-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4) -methylphenyl) to obtain (Y Yo mg; yield 0 ( pyridin-3-yljmethoxy}-3-methylbenzamide dihydrochloride tert-butyl {[5-{[2-(aminocarbonyl)-6-methylphenoxy] as a colored powder white from (70

A methyl } -2-isobutyl-6-methyl-4-(4-methylphenyl)pyridin-3 -ylJmethyl } carbamate YAY cane 0 , + mmol) according to a method similar to that of Example 1-?) H-NMR (DMSO-dg) 8:1.00 (6H, d, J = 6.4 Hz), 1.76 (3H, 5), 2.13-2.29 (1 H, m), (3H, 5), 2.96 (3H, 5), 3.21 (2H, d, J = 6.6 Hz), 3.76 (2H, d, J = 4.9 Hz), 4.78 2.37 (2H, 5), 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).

TYY Example 2-[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3-yl]-N- phenylacetamide dihydrochloride tert-butyl {[5-(2- anilino-2-oxoethyl)-2-isobutyl-6-methyl-4-(4-on-Jaa ( 1 Ye as powder) (Af mg; YY yield) methylphenyl)pyridin-3-yljmethyl} carbamate [ 5-{[(tert-butoxycarbonyl)amino methyl} -6-isobutyl-2-methyl-4-(4- from sand in milligram) E79 mg 0 ( methylphenyl)pyridin-3 -ylJacetic acid (mM) according to the method similar to that of the example 0.41 mg; 0) aniline 4 (0-11 0).

H-NMR (CDCl;) 8: 0.98 (6H, d, J = 6.6 Hz), 1.38 (9H, 5), 2.15-2.29 (1H, m), 2.40 (3H, s), 2.63 (3H, 5) , 2.77 (2H, d, J = 7.2 Hz), 3.66 (3H, 5), 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-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin- (YY mg yield + + (7) is obtained as a powder in color 001 (3-yl]- N-phenylacetamide dihydrochloride tert-butyl {[5-(2-anilino-2-oxoethyl)-2-isobutyl-6-methyl-4-(4-methyl white mmol) according to 1419 ref. 0 ) phenyl)pyridin-3-yljmethyl} carbamate (32-7). 1H, m), 2.38 (3H, s), Yo 2.85 (3H, 5), 3.25 (2H, 5), 3.62 (2H, 5), 3.83 (2H, 5), 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 48??

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyri din-3-yl]cyclohexanecarboxamide dihydrochloride

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) we obtain (% aA) in the total yield of YY ( pyridin-3-yl]cyclohexanecarboxamide dihydrochloride ~~ © tert- butyl {[5-amino-2-isobutyl-6-methyl-4-(4- as white powder, mmol) 1.5 mg; Y)methylphenyl)pyridin-3-ylJmethyl} carbamate mmol) according to VO + μl; 0 ( cyclohexanecarbonyl chloride

YY The method similar to the example method

H-NMR (DMSO-de) 8: 0.98 (6H, d, J = 6.6 Hz), 1.00-1.25 (6H, m), 1.41 (2H, brs), 01 1.59 (2H, brs), 2.08-2.22 ( 2H, m), 2.37 (3H, 5), 2.53 (3H, 5), 3.03 (2H, brs), 3.81 (2H, 5), 7.14 (2H, d, J = 7.8 Hz), 7.30 (2H, d , J = 7.8 Hz), 8.33 (3H, brs), 9.37 (1H, brs). 79 Example N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyri din-3-vi] Vo piperidine-1-carboxamide dihydrochloride tert-butyl ( {2- isobutyl-6-methyl-4-(4-methylphenyl)-5-[(piperidin-1-) we get ( 1 5-{[(tert-butoxy from SS ylcarbonyl)amino]pyridin-3-yl} methyl)carbamate carbonyl)amino methyl} -6-isobutyl-2-methyl-4-(4-methylphenyl)nicotinic acid µl 1.0 mmol 0 ( piperidine s mmol) 1 mg; ENVY (0) 1-45 grams) according to the method similar to the example method. £40 (gram: 5)

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin- you get (Y yield 49 7) as powder cane YY A) 3-yl]piperidine-1 -carboxamide dihydrochloride mentioned above according to the method similar to that of Example 1) in a white color from the oil produced in YO (FX)

YY\vww

H-NMR 01180-005: 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,] = 7.8 Hz), 7.31 (2H, d, J = 7.8 Hz), 7.96 (1H, brs), 8.27 (3H, brs). ve example oe

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3-yl] tetrahydro-2H-pyran-4-carboxamide dihydrochloride

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) yields cane "7 ) pyridin-3-yl]tetrahydro-2H-pyran-4-carboxamide tert-butyl dihydrochloride {[5-amino-2-isobutyl-6-methyl-4-(4-methyl as white powder of) 00 798 mg; 0.8 mmol) 7 ) phenyl)pyridin- 3-ylJmethyl} carbamate ms) + VO mg; 11( tetrahydro-2H-pyran-4-carbonyl chloride

YY according to the method similar to the example method

H-NMR (DMSO-dg) 8: 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, 5), 2.53 (3H, 5), 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). 71 Example N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3-yl] morpholine-4-carboxamide dihydrochloride Ye. tert-butyl ({2-isobutyl-6-methyl-4-(4-methylphenyl)-5-[(morpholin-) we get ( \ 5-{[(tert- 4-ylcarbonyl)amino] pyridin-3-yl}methyl)carbamate butoxycarbonyl)amino}methyl}-6-isobutyl-2-methyl -4-(4-methylphenyl)nicotinic *0,0 μl; morpholine (00 mmol) 1 mg; 11 ) acid . (1-906 GM) according to the method similar to that of the example Ye b (Latham: Ah 5 silver)

2,9 ¥ (we get N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin- cane YV A) 3-ylmorpholine-4-carboxamide dihydrochloride yield 759) as a white powder from the oil produced in (1) aforementioned according to a method similar to that of the example

-?). , 5), 3.14 (6H, brs), 3.19 (4H, brs), 3.86 (2H, brs), 7.21 (2H, d, J = 7.8 Hz), 2.70 (2H, d, J = 7.8 Hz) , 8.44 (4H, brs). 7.34 Try Jo N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3-yi] piperidine-4 -carboxamide trihydrochloride 01 N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) YET ( pyridin-3-yl]piperidine-4-carboxamide trihydrochloride mg Yield 798) as a white powder of tert-butyl {[5-amino-2-isobutyl-6-methyl-4-(4-methyl phenyl)pyridin-3-yljmethy!} carbamate ) 7 mg; 1 0.5 mmol) and benzyl 0.75 cana Y/ +) 4-(chlorocarbonyl)piperidine-1 -carboxylate 05 mmol —( according to the method similar to that of the example NYY 'H-NMR (DMSO-dg) 3: 0.98 (6H, d, J = 6.6 Hz), 1.44 (4H, brs), 2.1 5-2.26 (1H, m), (3H, 5), 2.38-2.57 (1H, m), 2.57 (3H, s), 2.76 (2H, brs), 3.07 (4H, brs), 3.81 2.38 (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). Ye Example yy N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3-yl] piperazine-1-carboxamide trihydrochloride \ ( we get tert-butyl 4-({[5-{[(tert-butoxycarbonyl)amino Jmethyl}-6-isobutyl-2- methyl-4-(4-methylphenyl)pyridin-3-yl]amino} carbonyl)piperazine -1-carboxylate ~~ Y° as aged oil 5-{[(tert-butoxycarbonyl)amino Jmethyl } -6-isobutyl-2-methyl-4-(4- ENT ( methylphenyl)nicotinic acid mg; 1 male (mol) tert-butyl

YY

Total 1.0 mmol) according to method 1 ¢ +) piperazine-1-carboxylate

A) 9 - 5 Similar to the example method EIMS: (M+1) .04%

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylpheny}pyridin-) is obtained as a powder (LAY from the yield of YO ( 3-yl]piperazine-1 carboxamide trihydrochloride aforementioned according to the method similar to that of example 1) in a white color from the oil produced in . ), 2.15-2.26 (1H, m), 2.42 BH, 5), 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=17.5Hz), 7.31 (2H, d,] = 7.5 Hz), 8.37 (3H, brs), 8.60 (1H, brs), 9.41 (2H, brs). Ve 74 Example (5-{[5-(aminomethyl )-6-isobutyl-2-methyl-4-(4-methylphenyl )pyridin-3-yl] methylene} -4-0x0-2-thioxo-1.3 -thiazolidin-3-yl)acetic acid dihydrochloride (5-{[5-¢ [(tert-butoxycarbonyl)amino]methyl} -6-isobutyl-2-methyl-4- you get ( ( 4-methylphenyl) pyridin-3 -yl]methylene}-4-oxo0-2-thioxo-1,3 -thiazolidin-3-yl)acetic 0 tert-butyl {[5-formyl-2-] as a yellow powder of (75 0) Productivity of cana YOO ) acid mg O40 ) isobutyl-6-methyl-4-(4-methylphenyl)pyridin-3-yljmethyl} carbamate

Y£)) (4-0xo0-2-thioxo-1,3-thiazolidin-3-yl)acetic acid 5 mmol) 1 .)0-? mmol) according to the method similar to that of the example 0.71 mg; 2.27 (1H, m), 236 00

GH, 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). ) 5- {[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) ?) we get pyridin-3-yljmethylene} -4-ox0-2-thioxo-1,3 -thiazolidin-3-yl)acetic acid (S-{[5-{[(tert-) as a yellow powder of (ZV++ YA yield pool) dihydrochloride Ye butoxycarbonyl)amino]methyl} -6-isobutyl- 2-methyl-4-(4-methylphenyl)pyridin-3 -

YY ) yl]methylene}-4-oxo0-2-thioxo-1 ,3-thiazolidin-3-yl)acetic acid Mg 7872 mmol) according to the method similar to that of the example (TY 'H- NMR )01450-05: 0.98 (6H, d, J = 6.4 Hz), 2.17-2.31 (1H, m), 2.36 (3H, s), (3H, s), 2.95 (2H, d, J = 6.6 Hz), 3.80 (2H, d, J = 7.4 Hz), 4.63 (2H, s), 7.22 2.55 (2H, d, J = 8.1 Hz), 7.30 (2H, d, J = 8.1 Hz), 7.55 (1H, s), 8.35 (3H, brs). © Example Yre 5-{[5-(aminomethy!)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3-yl] methylene} -2-thioxo-1, 3-thiazolidin-4-one dihydrochloride ) we get tert-butyl ({2-isobutyl-6-methyl-4-(4-methylphenyl)-5-[(4-0x0-2-)

YY. ) thioxo-1,3-thiazolidine-5-ylidene)methyl]pyridin-3-yl }methyl)carbamate Ve tert-butyl {[5-formyl-2-isobutyl-6-] as a yellow powder of (LEA) mg yield 0.71 mM On ) methyl-4-(4-methylphenyl)pyridin-3-yljmethyl } carbamate 0.76 mg mmol 10 A) 2-thioxo-1, 3-thiazolidin-4-one 5 mol) (1-6 gram) according to the method similar to that of the example

H-NMR (00pi) 8: 0.98 (6H, d, J = 6.8 Hz), 1.39 (9H, 5), 2.15-2.31 (1H, m), 2.37 Yo (3H, 5), 2.50 (3H, 5) ), 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, 5).5- {[5-(aminomethy!)-6-isobutyl-2-methyl-4-(4-methylphenyl) we get (¥ mg; 1 (L-pyridin-3-ylJmethylene}-2-thioxo-1,3-thiazolidin-4-one dihydrochloride tert-butyl ({2-isobutyl-6-methyl-4-(4-methyl) as a yellow powder from )7000 yield 00 phenyl)-5-[(4-0x0-2-thioxo-1,3-thiazolidine-5-ylidene)methyl]pyridin-3-yl } methyl) mmol) according to the method Similar to 17950 aaa 0) carbamate method. ) Y Example 'H-NMR (DMSO-d) 8:0.97 (6H, d, J = 6.6 Hz), 2.11-2.31 (1H, m), 2.36 (3H, 5), 2.52 (2H, s) ), 2.90 (3H, 5), 3.79 (2H, 5), 7.19 (2H, d, J = 8.1 Hz), 7.26-7.37 (3H, m), Ye 8.27 (3H, brs).

Fy is an example

Nose : methyl 3-({[5-(aminomethyl )-6-isobutyl-2-methyl-4-(4-methylphenyl)pyri din-3- yllacetyl }amino)benzoate dihydrochloride methyl 3-({[5] - {[(tert-butoxycarbonyl)amino]methyl} -6-isobutyl-2- we get ( \? mg; yield Ye ) methyl-4-(4-methylphenyl)pyridin-3-yljacetyl } amino) benzoate [5-{[(tert-butoxycarbonyl)amino]methyl} -6-isobutyl- from ad as powder in color ( #5 mMol VY aggregate One ) 2-methyl-4-(4 -methylphenyl)pyridin-3-ylJacetic acid mg; 2.07 milligrams) according to OFY (methyl 3-aminobenzoate s) 1-?311. The method is similar to that of the example.

H-NMR (J020) 8: 0.98 (6H, d, J = 6.6 Hz), 1.38 (9H, 5), 2.16-2.31 (1H, m), 2.41 (3H, s), 2.64 3H, 5) , 2.77 (2H, d,] = 7.4 Hz), 3.47 (2H, 5), 3.91 3H, 5), 4.07 2H,d, 00

J = 4.5 Hz), 4.20 (1H, brs), 5.50 (1H, brs), 7.02 (2H,d,J=7.9Hz), 7.24 2H, d, J = 7.9 Hz), 7.38 (1H, t, J = 7.9 Hz), 7.72-7.86 3H, m). methyl 3-( {[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methyl ?) we get ) 791 mg; Yield +5( phenyl)pyridin-3-yl]acetyl }amino)benzoate dihydrochloride methyl 3-({{5- {[(tert-butoxycarbonyl)amino]methyl}-6- as white powder from Baala 0 ) isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3 -yl]acetyl }amino)benzoate mmol) according to the method similar to that of Example 7-?).‎ 1.17 4 ana

H-NMR )01150-015: 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, 5), 2.98 (2H, 5), 3.78 (2H, 3 84 (3H, 5), 7.19 2H, d, J = 8.1 Hz), 7.32 (2H, d, J = 8.1 Hz), 7.44 (1H, , J = 7.9 Hz), 7.61-7.71 (2H, m), 8.10 Y (3H, brs), 8.20 (1H, s), 10.6 (1H, brs). Example for methyl 3-({[5-(aminomethyl )-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3- yllmethyl} thio)pyridine-2-carboxylate trihydrochloride methyl 3-({ [5- {[(tert-butoxycarbonyl)amino])methyl}-6-isobutyl-2- we get (V YO Ra 3 methyl-4-(4-methylphenyl)pyridin-3-yl]methyl} thio)pyridine-2-carboxylate tert-butyl {[5-(hydroxymethyl)- mmol) as a yellow oil of 0.01 g; YYw cp “0 A) 2-isobutyl-6-methyl- 4-(4-methylphenyl)pyridin-3-yl methyl} carbamate (mg AAT) methyl 3-mercaptopyridine-2-carboxylate 5 mmol) 7 . ( Y=YAY to the method similar to the example method suds mmol) 77 (l0) yra 8:0.98 (6H, d, J = 6.6 Hz), 1.39 (9H, 5), 2.14-2.26 (1H, m), 2.35 (3H, s), 2.66 (3H, 5), 2.76 (2H, d, J=7.2Hz),3.76 (2H, s), 3.99 (3H, 5), 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). methyl 3-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methyl) we get (¥ 01 ) phenyl)pyridin-3-yljmethyl } thio)pyridine-2-carboxylate trihydrochloride methyl 3-({[5-{[(tert-butoxy) as a pale yellow solid of 0 Av mg yield 0 carbonyl)amino methyl }-6-isobutyl-2 -methyl-4-(4-methylphenyl) pyridin-3-yl] mmol) according to 1,759 mg; 1 4V) methyl} thio)pyridine-2-carboxylate . ) - method similar to the example method? 3H, brs), 3.18 (2H, brs), 3.77 (2H, d, J = 5.1 Hz), 3.83 (3H, 5), 3.94 (2H, s), Vo 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).

FYA Example 3-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3-yl] methyl} thio)pyridine-2-carboxylic acid trihydrochloride XY. 3-({[5-{[(tert-butoxycarbonyl)amino]methyl} -6-isobutyl-2-methyl-4- we get (1 object 414) (4-methylphenyl)pyridin-3-ylJmethyl) } thio)pyridine-2-carboxylic acid methyl 3-({[5-{[(tert-butoxycarbonyl)amino] yield 44%) as colorless oil of methyl }-6-isobutyl-2-methyl -4-( 4-methylphenyl)pyridin-3-ylJmethyl} thio)pyridine- 7.74 mmol) according to the method similar to that of 0 Y ¥) 2-carboxylate 8 . (Example 9-10).

mB (6H, d, J = 6.6 Hz), 1.38 (9H, 5), 2.21-2.32 (1H, m), 2.37 5:1.06 (WL020) 'H.NMR (3H, 5), 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) ( Y ° we get {[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylpheny) 3 Yio ) pyridin-3-yljmethyl }thio)pyridine-2-carboxylic acid trihydrochloride mg; Yield 14 0 as a pale yellow solid of {[(tert-butoxycarbonyl)amino] -5[{(-3 methyl }-6-isobutyl-2-methyl-4- (4-methylphenyl)pyridin-3- yljmethyl} thio)pyridine- 0 YA) 2-carboxylic acid total 709 mmol) according to the method similar to 0 A method for example 7-7). 'H-NMR (DMSO-dg) 5:0.99 (6H, d, J = 6.6 Hz), 2.13-2.24 (1H, m), 2.34 3H, 5), (3H, m), 3.05 (2H , brs), 3.75 (2H, brs), 3.89 (2H, brs), 7.26 2H, d, J = 6.4 2.79-2.82 Hz), 7.31 (2H, d, J = 8.3 Hz), 7.48 (1H, dd, J = 8.3, 4.5 Hz), 7.72 (1H,d,J=38.3 Hz), 8.19-8.36 (3H, m), 8.43 (1H, d, J = 4.5 Hz). ra 3-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenylpyridin-3-yl] methyl } thio)pyridine-2-carboxamide trihydrochloride \ ( we get on tert-butyl {[5-({[2-(aminocarbonyl)pyridin-3-yl]thio} methyl)-2- (p20 VY. ) isobutyl-6-methyl-4-(4-methylphenyl) pyridin-3-yl methyl} carbamate 0 yield (AAA) as a colorless oil of 3-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6- isobutyl-2-methyl -4-(4-methylphenyl)pyridin-3 -ylJmethyl} thio)pyridin-2-carboxylic 0.97 can 7 ) acid mmol) according to the method similar to that of the example? +- A) ' H-NMR (CDCl;) 8:0.98 (6H, d, J = 6.6 Hz), 1.38 (9H, 5), 2.1 4-2.26 (1H, m), 2.33 (3H, s), 2.67 3H, 5), 2.75 (2H, d, ] = 7.2 Hz), 3.71 (2H, s), 4.03 (2H, d, 1 = 4.9 Hz), Yo (1H, brs), 5.44 (1H, brs), 7.12-7.18 (4H, m), 7.25-7.29 (1H, m), 7.42 (1H, dd, J 4.18 Hz), 7.82 (1H, brs), 8.24 (1H, dd, J = 4.3, 1.3 Hz 1.3 , 8.3 -

vi 3-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) ?) you get 1 mg pyridin-3-yljmethyl }thio)pyridine-2- tert-butyl carboxamide trihydrochloride {[5-({[2-(aminocarbonyl)) as a pale yellow solid of 0 Ve yield

pyridin-3-yljthio} methy!)-2-isobutyl-6-methyl-4-(4-methylphenyl)pyridin-3 -71[ 0.75 cpa VY +) methyl}carbamate ~~ ° mmol Grammy) according to the method similar to that of Example 7-?). 111-1111 (DMSO-dq) 8:1.01 (6H, d, J = 6.6 Hz), 2.13-2.26 (1H, m), 2.34 (3H, 5), (3H, s), 3.25 (2H , brs), 3.79 (2H, d,J=5.1 Hz), 3.86 (2H, s), 7.29-7.40 (4H, 2.96 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). 01 example vie 4-[({[5-(aminomethyl )-6-isobutyl-2-methyl-4-(4-methylphenyl)pyri din-3-yl] carbonyl }oxy)methyl]cyclohexanecarboxylic acid dihydrochloride 1) cooled to zero ie 4 a mixture of methyl 4-(hydroxymethyl)cyclohexanecarboxylate 0 (; ca vy" 7.7 mmol); lille 1©) triethylamine 4.74 mmol) tetrahydrofuran (5.01 mL) and add dropwise methanesulfonyl chloride (YY), + mL; YEA mmol) after stirring at room temperature for VO Adds The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate; the mixture was extracted with ethyl acetate The extract was dried over anhydrous magnesium sulfate Ye and the solvent was evaporated under reduced pressure to give methyl 4-{[(methylsulfonyl)oxy]methyl} cyclohexanecarboxylate as crude product. Crude product dissolved in N,N-dimethylformamide (Vo) mL); aa d (A+) potassium carbonate 7.44 mmol) added [(tert-butoxycarbonyl)amino ]methyl } -6-isobutyl-2-methyl-4-(4-methylphenyl) 5-1 nicotinic acid (46 gm 7.77 mmol). The mixture was stirred and heated at YO 1°C for one hour. The reaction mixture was diluted with cethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under aida pressure and the resulting residue was purified by silica column chromatography to give [4-(methoxy)

Barb carbonyl)cyclohexyljmethyl 5- {[(tert-butoxycarbonyl)amino]methyl }-6-isobutyl-2- VO ) methyl-4-(4-methylphenyl)nicotinate total yield 757) as colorless oil. H-NMR (CDCl;) 8:0.97 (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=7.4Hz),3.67 (3H, s), 3.78 CH, d,] = 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). 3-y1] carbonyl } oxy)methyl] cyclohexanecarboxylic acid 0 ) yield 9705) as a white solid of [4-(methoxycarbonyl) cyclohexyljmethyl 5- {[(tert-butoxycarbonyl)amino]methyl} - 6-isobutyl-2-methyl-4- 0 0.17 cana YOu ) (4-methylphenyl)nicotinate mmol) according to the method similar to that of Example 9- A) 'H-NMR (CDCl; ) 8: 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, 5), 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, 0.1 9 Vo Hz), 7.20 (2H, d, J = 7.7 Hz).(v we get [5-(aminomethyl)-6-isobutyl- 2-methyl-4-(4-methylphenyl) {([-4 pyridin-3-yl]carbonyl } oxy)methyl]cyclohexanecarboxylic acid dihydrochloride cane YO (FAY) yield as a white solid of {[(tert-butoxycarbonyl) -5[{([-4 amino]methyl} -6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yljcarbonyl} oxy) Y- 01 ( methyl]cyclohexanecarboxylic acid ¥ aggregate; 1.0979 mmol) according to the method similar to the example method (T-Y H-NMR (DMSO-d) 5:0.97 (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 Yo (2H, d, J = 8.1 Hz), 8.34 (3H, brs). Example vey YY\Y

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3-vl]thiophene-2-carboxamide dihydrochloride

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) we get (Ave mg; yield VV)) pyridin-3-ylJthiophene-2-carboxamide dihydrochloride tert- butyl { [5-amino-2-isobutyl-6-methyl-4-(4-methyl —e as white powder © mg; 10+ mmol) 14 Y)phenyl)pyridin-3-yl] methyl } carbamate mM) according to +5 VO mg; 1 01) thiophene-2-carbonyl chloride 5

YY Method similar to example method 'H.NMR (DMSO-dg) 8: 1.00 (6H, d, J = 6.6 Hz), 2.20-2.31 (1H, m), 2.31 3H, 3), 2.63 (3H, 5 ), 3.07 (2H, brs), 3.86 (2H, s), 7.12 (1H, dd, J = 3.3, 4.8 Hz), 7.25 (4H, s), Ye 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 7; {[(tert-butoxycarbonyl)amino]methyl }-6-isobutyl-2-methyl-4- d \ ( AY mg; yield 0 ) (4-methylphenyl)pyridin-3-yl]acetyl } amino)benzoic acid methyl 3-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6- as a white powder of 0 ) isobutyl-2-methyl-4-(4-methylphenyl)pyridin- 3 -yl]acetyl }amino)benzoate (1-9 mmol) according to a method similar to that of the example ITY cana "H-NMR (CDCl) 8: 0.94 (6H, d, J = 6.6 Hz), 1.38 ( 9H, s), 2.10-2.27 (1H, m), 2.36 A (3H, s), 2.89-3.10 (5H, m), 3.90 (2H, d,J=5.7Hz), 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,] = 8.0 Hz), 7.65 (1H, d J = 7.7 Hz), 7.89 (1H, s), 8.17 (1H, s).3-({[5-(aminomethyl)-6-isobutyl-2-methyl-4- (4-methylphenyl) ?) we get (#90 mg yield 8 ( pyridin-3-yl]acetyl }amino)benzoic acid dihydrochloride | Y° 3-({[5-{[(tert-butoxycarbonyl) amino]methyl}-6-isobutyl-2- as a white powder

YY\Ww

Veo ) methyl-4-(4-methylphenyl)pyridin-3-yljacetyl} amino)benzoic acid packed in mg; +N AY mmol) la to the method similar to the example method (FY H-NMR (DMSO-d)3:1.00 (6H, d, J = 6.8 Hz), 2.08-2.25 (1H, m), 2.37 (3H, 5), (3H, s), 2.83 (2H, 5), 3.20 (2H, 5), 3.82 (2H, 5), 7.09-7.51 (5H, m), -7.54 7.79 2.51 (2H, m), 8.14 (1H, s), 8.44 (3H, 5), 10.34 (1H, brs).° Example 48? 6-isobutyl-2-methyl-4-(4-methylphenyl )pyridin-3- yl]acetyl}amino)methyl]benzoate dihydrochloride 1 ( we get methyl 4-[({[5- {[ (tert-butoxycarbonyl)amino]methy! }-6-isobutyl-2- Yo. ) methyl-4-(4-methylphenyl)pyridin-3-yljacetyl} amino)methyl]benzoate 0 mg; yield TY %( as a white powder of -6-} {[(tert-butoxycarbonyl)amino]methyl -5[ YA) isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-ylJacetic acid mg $A) E mmol) methyl 4-(aminomethyl)benzoate s ) ¥ 8 mg; Y,VE mmol) according to the method similar to that of Example 11?-1). (6H, d, J = 6.6 Hz), 1.37 (9H, s), 2.11-2.29 (1H, m), 2.39 Ye 8 : 0.96 ) 'H-NMR (3H, s), 2.55 (3H, 5), 2.74 (2H, d, ] = 7.2 Hz), 3.35 (2H, 5), 3.93 (3H , 5), 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 = Hz), 7.16 (2H, d, J = 7.9 Hz), 7.23 (2H, d,] = 8.1 Hz), 7.99 (2H, d, J = 8.1 Hz). on methyl 4-[( {[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methyl ‎(aa©)) ) phenyl)pyridin-3-yl]acetyl} amino)methyl] benzoate dihydrochloride 0 yield AQ % (as a white powder of methyl 4-[({[5- {[(tert-butoxycarbonyl)amino] methyl }-6-isobutyl-2-methyl-4- (4) -methylphenyl)pyridin-3-yl]acetyl} amino)methyl] T+) benzoate aggregate; #1001 mmol) according to the method similar to that of the example (FY 'H-NMR (DMSO-dg) 8:0.99 (6H, d, J = 6.6 Hz), 2.11-2.27 (1H, m) , 2.40 (3H, s), Yo (3H, s), 3.24 (2H, d, J = 6.0 Hz), 3.44 (2H, 3 .78-3.89 (5H, m), 4.28 (2H, d, J 2.81 bug

=5.5 Hz), 7.20 (2H, d, J = 7.9 Hz), 7.27-7.38 (5H, m), 7.94 (2H, d, J = -9 Hz), 8.54 (3H, brs). ret Joe 5-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4~( 4-methylphenyl)pyridin-3-yl] carbonyl }oxy)methyl]pyrazine-2-carboxylic acid dihydrochloride © methyl 5-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2- we get 1 methyl-4-(4-methylphenyl)pyridin-3-yl]carboinyl} oxy )methyl]pyrazine-2-[5-{[(tert-butoxycarbonyl) as a colorless oil of (FAA © yield) carboxylate 7 can)) amino]methyl }-6-isobutyl-2-methyl-4 -(4-methylphenyl)nicotinic acid gm +,01) methyl 5-(bromomethyl)pyrazine-2-carboxylate 5 mmol) (0.1-48 mmol) according to the method similar to that of the example 5.1 "H-NMR (J00) 8:0.97 (6H, d, J = 6.6 Hz), 1.39 (9H, 5), 2.17-2.27 (1H, m), 2.31 (3H, s), 2.58 (3H, 5), 2.79 (2H, d, J = 7.2 Hz), 4.06 (3H, 5), 4.12-4.16 (2H, m), 4.22 (1H, brs), 5.13 (2H, 5), 7.02 2H, d, J = 8.1 Hz), 7.10 2H, d, J = 9 Hz), 8.36 (1H, d,J=1.3Hz), 9.19 (1H, d, ] = 1.3 Hz).Ve 5-[( {[5-{[(tert-butoxycarbonyl)amino]methyl} -6-isobutyl-2-methyl- we get (Y 4-(4-methylphenyl)pyridin-3-yl]carbonyl } oxy)methyl]pyrazine -2- carboxylic acid methyl 5-[({[5-{[(tert-butoxycarbonyl) yield £0 %) (as colorless oil of cane 0 ) amino]methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl)pyridin-3-yl]carbonyl } oxy) milligram) according to Vote C 58 ) methyl]pyrazine-2-carboxylate 0 . ( 1-4 Method similar to example method 'H-NMR (CDCl) 8: 0.97 (6H, d, J = 6.8 Hz), 1.39 (9H, s), 2.16-2.28 (1H, m), 2.33 (3H , 5), 2.59 (3H, 5), 2.82 (2H, d, ] = 7.4 Hz), 4.11-4.19 (2H, m), 4.24 (1H, brs), 5.18 (2H, 5), 7.04 (2H, d, J = 7.9 Hz), 7.12 (2H, d, J = 7.2 Hz), 8.20 (1H, 5), 9.30 (1H, s).Yo 5-[({[5-(aminomethyl)-6-isobutyl -2-methyl-4-(4-methylphenyl) on Jaa (*pyridin-3-yl]carbonyl} oxy)methyl|pyrazine-2-carboxylic acid dihydrochloride

YY\V

5-[({[5-{[(tert-butoxycarbonyl) as a yellow solid of (ZV yield cane £4Y) amino]methyl} -6-isobutyl-2-methyl-4-(4-methylphenyl) )pyridin-3 -yl]carbonyl} oxy) mmol) according to 0084 vol 0) methyl]pyrazine-2-carboxylic acid (¥-Y) method similar to that of the example

H-NMR (DMSO-dg) 8: 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).

Yio Example 4-bromobenzyl 5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)nicotinate dihydrochloride ye 4-bromobenzyl 5-(aminomethyl)-6-isobutyl-2-methyl-4 -(4-methyl obtained in mg; yield 79550) as a white solid TY A) phenyl)nicotinate dihydrochloride 4-bromobenzyl 5-{ [(tert-butoxycarbonyl)amino]methyl} -6-isobutyl-2- methyl-4- of mmol) according to the method 0.776 g; Y¥) (4-methylphenyl)nicotinate Ve similar to the method for Example 7-?). H-NMR (DMSO-dg) 5:0.96 (6H, d, J = 6.8 Hz), 2.14-2.27 (1H, m), 2.36 (3H, s), (2H, brs), 3.80 (2H , d, J = 5.3 Hz), 4.97 (2H, 5), 7.00 (2H, d,] = 8.5 Hz), 2 2.87 (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 YET {[5-[(2-bromophenoxy)methyl] -2-isobutyl-6-methyl -4-(4-methylphenyl)pyridin-3- Ye. yllmethyl }amine dihydrochloride Juans ( \ on tert-butyl {[5-[(2-bromophenoxy)methyl]-2-isobutyl-6- methyl-4-(4- NE ) methylphenyl)pyridin-3-ylJmethyl} carbamate aggregate; Yield of 43 0 as a white solid of tert-butyl { [5-(hydroxymethyl)-2-isobutyl-6-methyl-4-(4-methyl 1 ) phenyl)pyridin-3-yljmethyl} carbamate Yeo g ; (Y,0) milligrams (A) 2-bromophenol 5 no. 126 A, ? milligrams) according to the method similar to that of Example 1-714?

vey’ H.NMR (CDCl) 8: 0.99 (6H, d, J = 6.6 Hz), 1.39 (9H, 5), 2.19-2.28 (1H, m), 2.37 (3H, 5), 2.69 (3H, 5) ), 2.79 (2H, d, 1 = 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). { [5-[(2-bromophenoxy)methyl]-2-isobutyl-6-methyl-4-(4-methyl) we obtain ( Y ° as (% Vo volume; yield £0 A) phenyl )pyridin-3-yljmethyl} amine dihydrochloride : tert-butyl { [5-[(2-bromophenoxy)methyl]-2-isobutyl-6-methyl- from and 0.11 mmol color solid Combine (NE) 4-(4-methylphenyl)pyridin-3-yl methyl} carbamate .(32-7 grams) according to the method similar to that of the example

H-NMR (DMSO-de) 8: 1.01 (6H, d, J = 6.6 Hz), 2.1 6-2.30 (1H, m), 2.36 (3H, s), Ye 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 (SH, m), 7.58 (1H, dd, J = 7.7, 1.5 Hz ), 8.48 (3H, brs). ? 59 Joe 4-[({[5-(aminomethyl )-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3-v] carbonyl }oxy)methyl]-3 -methoxybenzoic acid dihydrochloride Vo 2-methoxy-4-(methoxycarbonyl)benzyl 5-{[(tert-butoxycarbonyl) we get ( \ g; yield 8 ) amino]methyl } _6-isobutyl-2-methyl-4-(4- methylphenyl)nicotinate 5- {[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2- as colorless oil of (Yoo mmol) 0.94 g Av) methyl-4- (4-methylphenyl)nicotinic acid 0.54 mmol (pa 0 7( methyl 4-(bromomethyl)-3-methoxybenzoates 0.1-4 gram) according to the method similar to that of the example

H-NMR (CDCls) 8: 0.96 (6H, d, J = 6.6 Hz), 1.38 (9H, 5), 2.1 5-2.24 (1H, m), 2.34 (3H, s), 2.54 (3H, 5) , 2.77 (2H, d, J - 7.2 Hz), 3.85 (3H, 5), 3.93 (3H, 5), 4.10-4.16 (2H, m), 4.20 (1H, brs), 5.06 (2H, s), 6.96(1H,d,J=79Hz),7.03(2H,d,J=8.1

Hz), 7.10 (2H, d, J = 7.9 Hz), 7.48-7.53 (2H, m). Yo 4-[({[5- {[(tert-butoxycarbonyl)amino]methyl} -6-isobutyl-2-methyl- we get (Y 4-(4-methylphenyl)pyridin-3-y1] carbonyl } oxy)methyl]-3-methoxybenzoic acid vey 2-methoxy-4-(methoxycarbonyl) as a colorless oil of (LAY yield) cpa 0 benzyl 5- {[(tert-butoxycarbonyl) amino Jmethyl} -6-isobutyl- 2-methyl-4-(4-methyl mmol) according to the similar method 0.94 g; 1-4 (phenyl)nicotinate (©) for the example method.

H-NMR (lumen) 8:0.97 (6H, d, ] = 6.6 Hz), 1.39 (9H, 5), 2.16-2.26 (1H, m), 2.35 ° (3H, 5), 2.56 ( 3H, 5), 2.80 (2H, d, ] = 7.2 Hz), 3 86 (3H, 5), 4.11-4.16 (2H, m), 4.23 (1H, brs), 5.08 (2H, 5), 6.97 ( 1H, d, J =7.9 Hz), 7.04 (2H, d,J = 7.7 Hz), 7.11 (2H, d,J=7.7Hz), 7.53 (1H, 5), 7.58 (1H, d, J = 7.9 Hz). 4-[({[5-(aminomethy1)-6-isobutyl-2-methyl-4-(4-methylphenyl) we get (¥ 9 (not pyridin-3-yl]carbonyl } oxy)methyl] -3-methoxybenzoic acid dihydrochloride 0 4-[({[5-{[(tert-butoxycarbonyl)amino] as a white solid of (0 VE daly) mg; methyl }-6-isobutyl-2- methyl -4-(4-methylphenyl)pyridin-3-yl]carbonyl} oxy) mmol) according to 1.10 g 0 ," *( methyl]-3-methoxybenzoic acid method similar to that of the example 7-?).

H-NMR (DMSO-de) 5: 0.96 (6H, d, J = 6.6Hz), 2.17-2.26 (1H, m), 2.32 (3H, s), Vo 2.84 (2H, brs), 3.79 (2H, d, J = 5.7Hz), 3.83 (GH, 5), 5.03 (2H, s), 6.96 (1H, d, J = 7.7Hz), 7.13 (2H, d, J = 8.1Hz), 7.18 (2H, d, J = 8.1Hz), 7.42-7.45 (1H, m), 7.46 (1H, s), 8.19 (3H, brs).

YEA Joe 4-[({[5-(aminomethyl )-6-isobutyl-2-methyl-4-(4-methylphenyl)pyri din-3-yl1] 1 carbonyl} oxy)methyl]-2-methoxybenzoic acid dihydrochloride 3 -methoxy-4-(methoxycarbonyl)benzyl 5-1 [(tert-butoxycarbonyl) you get ( \ mgpsm 6 ) amino methyl } -6-isobutyl-2-methyl-4-(4-methylphenyDnicotinate 5-{ [(tert-butoxycarbonyl )amino methyl }-6- yield 744) as colorless oil of 0.11 mmol aa 80 ) isobutyl-2-methyl-4-(4-methylphenyl)nicotinic acid Ye ml 1,YY mg; ) 5: 0.96 (6H, with J = 6.6Hz), 1.38 (9H, 5), 2.16-2.25 (1H, m), 2.33 (3H, s), 2.54 (3H, 5), 2.78 (2H, d, J = 7.4Hz), 3.86 (3H, 5), 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 = 1.1Hz), 6.99 (2H, d, J = 8.1Hz), 7.08 (2H, d, J = 7.7Hz), 7.70 (1H, d , J = 7.9 Hz). 4-[({[5-{[(tert-butoxycarbonyl Jamino]methyl } -6-isobutyl-2-methyl- we get (Y © 4-(4-methylphenyl)pyridin-3-yl]carbonyl } oxy )methyl]-2 -methoxybenzoic acid 3-methoxy-4-(methoxycarbonyl) as a colorless oil of (AY yield 0 ) benzyl 5-{[(tert-butoxycarbonyl) amino]methyl }-6-isobutyl- 2-methyl-4-(4-methyl mmol) according to analogous method 016 mg; (6H, d, J = 6.6 Hz), 1.38 (9H, 5), 2.16-2.25 (1H, m), 2.33 (3H, 5), 2.54 (3H, 5), 2.78 (2H, d, J = 7.4 Hz), 4.04 3H, 5), 4.11-4.13 (2H, m), 4.20 (1H, brs), 4.98 (2H, 5), 6.77 (1H, d, J = 9.4 Hz), 6.84 (1H, 5) , 6.99 (2H, d, J=8.1

Hz), 7.07 2H, d, J = 7.9 Hz), 8.08 (1H, d, J = 7.9 Hz). 4-[( {[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) we get ( y yo

YE ) pyridin-3-yl]carbonyl}oxy)methyl]-2-methoxybenzoic acid dihydrochloride 4-[({[5-{[(tert-butoxycarbonyl)amino] as a white solid of (% AC mg; Productivity of methyl }-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3 -yl]carbonyl } oxy) mmol) according to 1,509 aaa Ya ¥) methyl]-2- methoxybenzoic acid

AFF Method similar to example method 0 "H-NMR (DMSO-dg) 8:0.96 (6H, d, J = 6.6 Hz), 2.14-2.26 (1H, m), 2.33 (3H, 5), 2.58 (3H) , brs), 2.93 (2H, brs), 3.78 (3H, 5), 3.81 (2H, d, J = 4.5 Hz), 5.01 (2H, s), 6.62 (1H, d, 127.9 Hz), 6.92 (1H , d, } = 0.9 Hz), 7.12-7.22 (4H, m), 7.55 (1H, d, J - 7.7 Hz), 8.37 (3H, brs).rel da ve 4-[({[5-(aminomethyl) )-6-isobutyl-2-methyl-4-(4-methylphenyl)pyri din-3-yl] acetyl }amino)methyl]benzoic acid dihydrochloride

Yio 4-[({[5- {[(tert-butoxycarbonyl)amino]methyl} -6-isobutyl-2-methyl- we get (0 mg VAY ) 4-(4-methylphenyl)pyridin-3 -yl]acetyl} amino)methyl]benzoic acid methyl 4-[({[5-{[(tert-butoxycarbonyl)amino] yield 4 9 %) as a white powder of methyl } -6-isobutyl-2-methyl -4-(4-methylphenyl)pyridin-3 -yl]acetyl }amino)methyl] mmol) according to the method similar to that of 1749 vol 0 ) benzoate © (V-4 Example 'H- NMR (Ylp): 0.92 (6H, d, J = 6.6 Hz), 1.34 (9H, 5), 2.1 0-2.24 (1H, m), 2.35 (3H, 5), 2.38 (3H, 5) , 2.58 (2H, 5), 3.22 (2H, 8), 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=8.1Hz), 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). Ye 4-[( {[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) we get (mg; yield VY ¢) pyridin-3-yl]acetyl} amino)methylJbenzoic acid dihydrochloride 4-[({[5-{ [(tert-butoxycarbonyl)amino]methyl}-6- as a white powder of ( q0 isobutyl-2-methyl-4-(4-methylphenyl)pyridin- 3 -yl]acetyl }amino)methyl]benzoic

Jal) milligram) according to the method similar to that of 1.774 (aaa You) acid 0 . ( b H-NMR (DMSO0-dg)5:0.98 (6H, d, J = 6.6 Hz), 2.07-2.24 (1H, m), 2.40 3H, 5), 2.78 (3H, 5), 3.10 (2H, 5), 3.41 (2H, 5), 3.78 (2H, 5), 4.27 (2H, d,J=5.7Hz), 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). Ye. voo Jha

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

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) we get (Lv “>mg yield 1 YY)pyridin-3-yl]isoxazole-4-carboxamide Yo tert-butyl dihydrochloride {[S-amino-2-isobutyl-6-methyl-4-(4- of ard as color powder, mmol) 0,8 cana 7 ) methylphenyl)pyridin-3- yl}methyl} carbamate ve mmol) according to +5 VO mg; \ + +) isoxazole-4-carbonyl chloride 5

YY The method similar to the example method

H-NMR (DMSO-dg) 8: 0.99 (6H, d, J = 6.6 Hz), 2.20-2.31 (1H, m), 2.53 (3H, s), 2.94 (2H, 5), 3.82 (2H, brs ), 7.09 (1H, 5), 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). ° veo) Example N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3-yl]furan-2- carboxamide dihydrochloride

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) we get 0 mg; VA blood yield) pyridin-3-yljfuran-2-carboxamide dihydrochloride 1 tert-butyl {[5-amino-2-isobutyl-6-methyl-4-(4-ar) as colored powder, mMol ) 55 pan) 4Y) methylphenyl)pyridin-3-yljmethyl} carbamate mmol) according to the method + VO incl. 0 ) furan-2-carbonyl chloride s

YY similar to the example method

H-NMR (DMSO-dg) 8: 1.00 (6H, d, J = 6.6 Hz), 2.09-2.30 (1H, m), 2.32 (3H, s), Yo 2.58 (3H, s), 3.04 (2H, brs), 3.83 (2H, 5), 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). your J

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3-yl]-4- AK methylbenzamide dihydrochloride

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) obtained as powder (#81 mg; yield RR ) pyridin-3-y1]-4- methylbenzamide dihydrochloride tert-butyl {[5-amino-2-isobutyl-6-methyl-4-(4-methylphenyl)pyridin- in white from 4-methylbenzoyl mg; 5 mmol) and 1 AY) 3-ylmethyl}carbamate 5 mmol) according to method similar to example method 1.75 mg; 117) chloride

YY vey “H-NMR (DMSO-dg) 8: 1.00 (6H, d, J = 6.6 Hz), 2.22-2.32 (1H, m), 2.31 (3H, 5), 2.32 (3H, 5), 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).

Yor Jo.

N-[5-(aminomethy!)-6-isobutyl-2-methyl-4-(4-methylphenyl )pyridin-3-yl]-4-tert- ° butylbenzamide dihydrochloride

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) we get) 787 mg. Yield 1111( pyridin-3-yl]-4-tert-butylbenzamide dihydrochloride tert-butyl {[5-amino-2-isobutyl-6-methyl-4-(4-methyl) as a white powder of 4tert-5 mmol) 1.5 mg; 7 ( phenyl)pyridin-3-yljmethyl} carbamate 0 mmol) according to method 1.75 mg; 04 V) butylbenzoyl chloride

YY similar to example method 111-111 (DMSO-dg) 5: 1.00 (6H, d, J = 6.6 Hz), 1.27 (9H, 5), 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, ] = 8.4 Hz), 8.32 (3H, brs), 9.91 (1H, brs). Yo

Tot Example N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3 -yl]-4- chlorobenzamide dihydrochloride

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) obtained as powder 0 AY total yield YoY)pyridin-3-yl]-4-chlorobenzamide dihydrochloride AR tert-butyl {[5-amino-2-isobutyl-6-methyl-4-(4-methyl phenyl)pyridin- in white from 4-chlorobenzoyl mg; 0.8 mmol) and 7 3-ylJmethyl ( carbamate mmol) according to the method similar to that of the example 1.75 mg 111 ( chloride

NYY

H-NMR (DMSO-d¢) 8: 1.00 (6H, d, J = 6.6 Hz), 2.20-2.30 (1H, m), 2.31 (3H, 5), Yo 2.62 (3H, s), 3.08 ( 2H, brs), 3.86 (2H, 5), 7.25 (4H, 5), 7.52 (2H, d, J = 8.4 Hz), 7.67 (2H, d, J = 8.4 Hz), 8.41 (3H, brs), 10.20 (1h, brs).

YEA

Yoo Example N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3-yi]-4- cyanobenzamide dihydrochloride

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) yield 85% (cane Yo 4) pyridin-3-yl]-4-cyanobenzamide dihydrochloride © tert-butyl {[5-amino-2-isobutyl-6-methyl-4-(4-methyl phenyl)pyridin- white from 4-cyanobenzoyl 5 mmol) 1.8 mg V4 Y) 3-yl]methyl} carbamate mM) according to a method similar to the example method 1729 vol; YT) chloride

YY

'H.NMR (DMSO-dg) 8: 1.00 (6H, d, J = 6.6 Hz), 2.10-2.31(1H, m), 2.31 (3H, 5), ye 2.59 (3H, 5), 3.02 (2H , brs), 3.85 (2H, 5), 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).

Yor example N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3-yl]-4- trifluoromethylbenzamide dihydrochloride Vo

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) we obtain (% AT total yield) 8 pyridin-3-yl]-4-trifluoromethylbenzamide dihydrochloride tert-butyl {[5-amino-2-isobutyl-6-methyl-4-(4-methyl as white powder of mg; 6.5 mmol) 9 Y)phenyl)pyridin-3-yljmethyl} carbamate mmol) according to +, VO cb 1 01) detrifluoromethylbenzoyl chloride s 9

NYY Method similar to example 117-1118 (DMSO-dg) 5: 1.00 (6H, d, J = 6.6 Hz), 2.21-2.32 (1H, m), 2.31 (3H, 5), 2.55 (3H, s) ), 2.96 (2H, brs), 3.83 (2H, 5), 7.22 (2H, d,J=7.8Hz),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). Yo

Yov Example YY\vv

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

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) we get (% blood yield aaa 0 ) pyridin-3-yl]furan-3-carboxamide dihydrochloride tert -butyl {[5-amino-2-isobutyl-6-methyl-4-(4-methyl as white powder from © furan- 5 mmol) 5 pe 18 Y)phenyl)pyridin-3-yljmethyl } Tamima absorbed milligram) according to the similar method + VO aaa 0 ( 3-carbonyl chloride

YY of the example method “H-NMR (DMSO-dg) : 0.99 (6H, d, J = 6.6 Hz), 2.21 -2.32 (1H, m), 2.55 (3H, 5), 2.98 (3H, s), 3.82 (2H, brs), 6.74 (1H, 5), 7.20 (2H, d,J=7.8Hz), 7.25 2H, d,J = Ye 7.8 Hz), 7.69 (1H, s), 8.15 ( 1H, s), 8.30 (3H, brs), 9.74 (1H, brs): Yoh Jha

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

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) we get Vo (749 cana yield ¥ YY) pyridin-3-yl]thiophene-3-carboxamide dihydrochloride tert-butyl {[5-amino-2-isobutyl-6-methyl-4-(4-methyl as a white powder of 10 mg + mmol) 1 Y)phenyl)pyridin-3-yljmethyl} carbamate mmol) according to VO + mg; 0 ) thiophene-3-carbonyl chloride 5

YY Method similar to example method Ye "H-NMR (DMSO-de) 5: 0.99 (6H, d, J = 6.6 Hz), 2.20-2.31 (1H, m), 2.31 (3H, 5), 2.59 (3H) , s), 3.05 (2H, brs), 3.84 (2H, 5), 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).voq Jia Yo 4-[({[5-(aminomethyl)-6-isobutyl-2- methyl-4-(4-methylphenyl )pyridin-3-yl]carbonyl }oxy)methyl]-3-fluorobenzoic acid dihydrochloride

Yo. 2-fluoro-4-(methoxycarbonyl)benzyl 5-{[(tert-butoxycarbonyl) on Jaa ( ) mg 10 ) amino]methyl} -6-isobutyl-2-methyl-4-(4-methylphenyl) nicotinate 5-{[(tert-butoxycarbonyl)amino]methyl}-6- yield 797) as colorless oil of Ale 0,71 can 4 ( isobutyl-2-methyl-4-(4-methylphenylnicotinic acid) Molecule lle 0171 mg; 6H, has J = 6.8 Hz), 1.38 (9H, 5), 2.16-2.25 (1H, m), 2.33 (3H, s), 2.54 3H, 5), 2.77 (2H, d, J = 7.4 Hz ), 3.94 3H, 5), 4.09-4.1 3 (2H, m), 4.20 (1H, brs), 5.05 (2H, s), 6.98-7.09 (5H, m), 7.64-7.71 (2H, m). 4-[({[5-{[(tert-butoxycarbonyl)amino]methyl} -6-isobutyl-2-methyl- we get (01 84 ) 4-(4-methyl-phenyl)pyridin-3- yljcarbonyl} oxy)methyl]-3-fluorobenzoic acid 2-fluoro-4-(methoxycarbonyl)benzyl 5- as colorless oil of (AVY yield) cana {[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl -2-methyl-4-(4-methylphenyl) milligram) according to the method similar to that of 0.11 mg) nicotinate. ( 0-9 Ex. 0' H-NMR (CDCl) 8:0.97 (6H, d, J = 6.8 Hz), 1.38 (9H, 5), 2.13-2.25 (1H, m), 2.33 (3H, 5 ), 2.56 (3H, 5), 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).4-[( {[5-(aminomethy!)-6-isobutyl-2-methyl-4-(4-methylphenyl) we get 0 ¥ya ) pyridin 3-yl]carbonyl} oxy)methyl]-3-fluorobenzoic acid dihydrochloride | 00 4-[({[5-{[(tert-butoxycarbonyl)amino] as a white solid of (% V1 yield) cana methyl }-6-isobutyl-2-methyl-4-(4-methyl-) phenyl)pyridin-3 -yl]carbonyl} oxy) mmol) according to +, VAY comp. 0 ( methyl]-3-fluorobenzoic acid . Method similar to that of the example? -?) "H-NMR (DMSO-de) 8:0.95 (6H, d, J = 6.6 Hz), 2.16-2.23 (1H, m), 2.29 (3H, 5 Yo 2.86 (2H, brs), 3.78 (2H, d, J = 5.5) Hz), 5.11 (2H, 5), 7.07-7.13 (4H, m), 7.18 (1H, 1,

J = 17.6 Hz), 7.60-7.69 (2H, m), 8.23 (3H, brs).

YY\V

1 1 0. Example 4-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3-vy1] carbonyl }oxy)methyl]-3-chlorobenzoic acid dihydrochloride 2 -chloro-4-(methoxycarbonyl)benzyl 5-{ [(tert-butoxycarbonyl) we get 1 (pa 1 A) amino]methyl} -6-isobutyl-2-methyl-4-(4-methylphenyl)nicotinate ° 5-{[(tert-butoxycarbonyl)amino]methyl}-6- yield £29 (as colorless oil of mmol AVY 0 g ARY isobutyl-2-methyl-4-(4-methylphenyl)nicotinic) acid mM +, AYY mg; YY) methyl 4-(bromomethyl)-3-chlorobenzoate 5 g) LY g) according to a method similar to that of example 'H-NMR (CDCl;) 8 :0.97 (6H, d, J = 6.8 Hz), 1.38 (9H, 5), 2.17-2.26 (1H, m), 2.32 Ve (3H, s), 2.56 (3H, 5), 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, 5), 7.02-7.04 (3H, m), 7.09 (2H, d, J = 8.1 Hz), 7.78 (1H, d, J = 8.0, 1.6 Hz), 7.99 (1H, d, J = 1.5 Hz). 4-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl- we get ( Y 0 ) 4-(4-methylphenyl)pyridin-3-yl]carbonyl } oxy)methyl}-3-chlorobenzoic acid 0 2-chloro-4-(methoxycarbonyl)benzyl as a white solid of (% AY mg; yield 5-{[(tert-butoxycarbonyl)amino]methyl}- 6-isobutyl-2 -methyl-4-(4-methylphenyl) mmol) according to the method similar to that of 1,870 vol. 51 A) nicotinate 1-9) Example “H-NMR ( CDCls) 5: 0.98 (6H, d, J = 6.6 Hz), 1.39 (9H, 5), 2.22-2.33 (4H, m), 2.59 Ye. (3H, brs), 2.82 (2H, brs), -4.09 4.17 (2H, m), 4.25 (1H, brs), 5.13 (2H, 5), 7.01-7.14 (5H, m), 7.83 (1H, dd, J = 8.0, 1.6 Hz), 8.04 (1H, d, J = 1.5 Hz).

Yio ) pyridin-3-yl]carbonyl} oxy)methyl]-3-chlorobenzoic acid dihydrochloride 4-[({[5-{[(tert-butoxycarbonyl)amino] mg; yield 767%) as a white solid of Yo methyl }-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl] carbonyl } oxy)

OCA (£Y +) methyl]-3-chlorobenzoic acid (VY) is a millimole) according to a method similar to that of Example 7-?). H-NMR (DMSO-dg) 8:0.96 (6H, d, J = 6.6 Hz), 2.15-2.24 (1H, m), 2.29 (3H, s), J = 5.3 Hz), 5.14 (2H , 5), 7.13 (4H, 5), 7.16 bl (3H, 5), 2.86 (2H, brs), 3.79 (2H, 2.54 (1H, d, J = 7.9 Hz), 7.78 (1H, dd, J = 7.9, 1.5 Hz), 7.90 (1H, d,J=1.5Hz), 8.25 ° (3H, brs). Ex. 11 4-[({[5-(aminomethy]) -6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3-y1] carbonyl }oxy)methyllisophthalic acid dihydrochloride 1 Ye ( we get dimethyl 4-[({[5- { [(tert-butoxycarbonyl)amino]methyl}-6-isobutyl- 2-methyl-4-(4-methylphenyl)pyridin-3-yl]carbonyl} oxy)methyl]isophthalate (g; yield £99) As a colorless oil of 5-{[(tert-butoxycarbonyl)amino]methyl}-6- VAY can .,8 ( isobutyl-2-methyl-4-(4-methylphenylnicotinic acid mmol) 5 VAY gama 77 ( dimethyl 4-(bromomethyl)isophthalate mmol 0 gram) according to the method similar to that of the example HARARE 'H-NMR (J0M) 5:0.98 (6H, d, J = 6.6 Hz), 1.39 (9H, 5), 2.15-2.26 (1H, m), 2.35 (3H, 5), 2.57 3H, 5), 2.79 (2H, d, J = 7.4 Hz), 3.91 (3H, 5), 3.96 3H, 5), 4.116 (2H, m), 4.23 (1H, brs), 5.45 (2H, 5), 6.99 (1H, d, J = 8.1 Hz), 7.06 (2H, 0141-3 Hz), 7.13 (2H, d, J = 7.9 Hz), 7.99 (1H, dd, J = 8.1, 1.9 Hz), 8.59 (1H, d,J=19 Hz). 79 ¥ We get {[(tert-butoxycarbonyl)amino]methyl} -6-isobutyl-2-methyl- -5]))]-4 Yo. ) 4-(4-methylphenyl)pyridin-3-yljcarbonyl} oxy)methyl}isophthalic acid mg; Yield (ZA) as a colorless oil of dimethyl 4-[({[5-{[(tert-butoxycarbonyl)amino] methyl }-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin- 3 -yl]carbonyl } oxy)methyl] 1.80 pa V,1Y) isophthalate "8 mmol) according to the method similar to that of Example 1-9 ( .

Yor “H-NMR (CDCl) 6: 0.97 (6H, d, J = 6.4 Hz), 1.38 (9H, 5), 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, 5), z 7.01-7.17 (5H, m), 7.96-8.08 (1H, m) ), 8.64-8.75 (1H, m).4-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) we get (¥ mg YOY ) pyridin -3-yl]carbonyl ( oxy)methyl Jisophthalic acid dihydrochloride © 4-[({[5-{[(tert-butoxycarbonyl)amino] yield 960 (as a white solid of methyl }-6-isobutyl-2-methyl) -4-(4-methylphenyl)pyridin-3-yl]carb onyl }oxy)methyl] mmol) according to the analogous method 17211 vol £11) isophthalic acid (FY) for the example method "H-NMR (DMSO-d) 8:0.97 (6H, d, J = 6.6 Hz), 2.16-2.27 (1H, m), 2.33 (3H, 5), 01 2.57 (3H, brs), 2.90 (2H, brs), 3.82 (2H, d, J = 5.1 Hz), 5.42 (2H, 5), 7.01 (111), J = 8.1 Hz), 7.19 (2H, d, = 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).

AY Example 2-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl]-N-[4- Vo (dimethylamino)phenyl]acetamide trihydrochloride tert -butyl {[5-(2- {[4-(dimethylamino)phenyljamino }-2-oxoethyl)-2- we get ( 1 mg; £0 ) isobutyl-6-methyl-4-(4- methylphenyl)pyridin-3-yl methyl } carbamate [5-{[(tert-butoxycarbonyl)amino]methyl }-6- as a white powder from AVY Productivity

VAY Advent 5060( isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl]acetic acid 00 mmol) Ove ( 4-(dimethylamino)aniline 7111 mg, ? mmol ) according to the method similar to that of the example OF 'H-NMR (CDCl): 0.98 (6H, with J = 6.6 Hz), 1.38 (9H, 5), 2.16-2.27 (1H, m), 2.40 (3H , 8), 2.63 (3H, 5), 2.77 (2H, d, J = 7.4 Hz), 2.90 (6H, 5), 3.42 (2H, 5), 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 = Yo 7.7 Hz), 7.18 2H, d, J = 8.1 Hz), 7.24 (2H, d,J = 7.7 Hz).

Yot¢ 2-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin- you get (Y yield aaa NY ) 3-y1}-N-[4- (dimethylamino)phenyl]acetamide trihydrochloride tert-butyl {[5-(2-{[4-(dimethylamino)phenyl] l% (as a violet powder of amino} -2-oxoethyl)-2-isobutyl-6-methyl -4-(4-methylphenyl)pyridin-3 -yllmethyl} milligram) according to the method similar to that of 1774 vol. 0) carbamate © . (v=1 Example 'H-NMR (DMSO-de)5:0.99 (6H, d, J = 6.4 Hz), 2.13-2.28 (1H, m), 2.38 (3H, 5), 2.76 (3H , 5), 3.01 (6H, 5), 3.13 (2H, 5), 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). Ye 17 eg ethyl 5-(aminomethyl)-4-(4-methylphenyl)-2,6-dineopentylnicotinate £0 mmol); 17 ) potassium 3-ethoxy-3-oxopropionate mixture of ( \ (milliliter) Yo) tetrahydrofuran mmol) and 0 g; Y,A) magnesium chloride for; hours. The resulting suspension is cooled to room temperature; Add A500 flips at Ve

Yo g ¥,0) tert-butylacetic acid drip into suspension reaction mixture produced by stirring a mixture of milligrams (V1 cpa©,A) N,N'-carbonyldiimidazole «(ls milliliter milliliter) ) at room temperature for one hour. The resulting mixture (0+) tetrahydrofuran s ethyl acetate was stirred at room temperature for ¥ days. The reaction mixture is divided among titres. The organic layer was washed successively with 1,8 hydrochloric acids in saturated aqueous B and saturated brine and dried over anhydrous sodium hydrogen carbonate ethyl 5,5-. The solvent was evaporated under reduced pressure to give magnesium sulfate (a > 0.9) as the crude product (0.9 g). A mixture of the crude product dimethyl-3-oxohexanoate «alla 045( acetic acid «(ool o> mM VY g 4, A) ammonium acetate mL) is heated with vapor re-condensation using a Yo +) toluene trap ; millimole) YO TO h. The reaction mixture is cooled to room temperature; Wash with 11 minutes solution of Dean-Stark solvent under reduced pressure anhydrous Ady. magnesium sulfate saturated brine and dry on

Yoo ethyl 3-amino-5,5- to give silica and the rest was purified by column chromatography Important yield 757 g) as white powder. ¥,0) dimethylhex-2-enoate 'H-NMR :5 (J0201) ) 1.00 (9H, 5), 1.27 (3H, t, J = 7.2 Hz), 1.98 (2H, 5), 4.11 (2H, b J = 7.2 Hz), 4.45 (2H, brs), 8.05 (1H, 5). ethyl 5-cyano-4-(4-methylphenyl)-2,6-dineopentyl-1 A4-dihydro (8 ° 5,5 g yield 10) is obtained (as a white powder from V, o) pyridine-3 -carboxylate p-tolualdehyde (mmol) 11 g 4 ( dimethyl-3-oxohexanenitrile

Y,0) ethyl 3-amino-5,5-dimethylhex-2-enoate 5 mmol) 11 g; 1 ) (YY mmol) according to the method similar to that of the example 11 g 111-018 )00 08,01 : 1.01 (9H, 5), 1.03 (9H, 5), 1.17 3H, 1 7.2 Hz), 2.06 (1H, 00-400)

J=13.7 Hz), 2.27 (1H, 4,3 = 13.7 Hz), 2.31 (3H, 5), 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, 5), 5.44 (1H, brs), 7.09 (2H, bc J = 8.0 Hz), 7.17 (2H, d, J = 8.0 Hz).

Ca v,Y ) ethyl 5-cyano-4-(4-methylphenyl)-2,6-dineopentylnicotinate yields ( ethyl 5-cyano-4-(4-methylphenyl)-2,6- yield 7%) As a white powder of 10 mM (AY aa 4) dineopentyl-1,4-dihydro pyridine-3-carboxylate (FY according to method similar to example "H-NMR :5(J00) 0.91 (3H, t, J = 7.2 Hz), 1.01 (9H, s), 1.08 (9H, s), 2.40 (3H, s), 2.87 (2H, 5), 3.02 (2H, 5), 3.99 (2H, g, J = 7.2 Hz), 7.20-7.30 (4H, m).ethyl 5-(aminomethyl)-4-(4-methylphenyl)-2,6-dineopentylnicotinate we get ( 0 1 ethyl 5-cyano-4 -(4-methylphenyl)-2,6- as a colorless oil of (0 900 yield aa +1) g; 7.8 mmol) according to analogous method 1 (dineopentylnicotinate 4-1). for the example method

IH.NMR (15J020): 0.89 (3H, t, 127.2 Hz), 0.99 (9H, 5), 1.04 (9H, 5), 1.33 (2H, brs), 2.38 (3H, 5), 2.78 (2H, 5), 2.88 (2H, 5), 3.72 (2H, 5), 3.89 (2H, q, J = 7.2 Hz), Yo 7.12 (2H, d, J = 8.0 Hz), 7.20 (2H, d, J = 8.0 Hz). 4 Example you 3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3-yl] methoxy} propane-1-ol dihydrochloride [5-{[( tert-butoxycarbonyl)amino] hr mixture of 11 sad stirred at **C ** (0 methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl)pyridin-3-yljmethyl methane 1.0 g (Y,+0) 1,3-propanediol c (£0 mmol); 0 41) sulfonate © in oil; 1.1 g; (£4 mMol) (71 mmol sodium hydride) (mL). The reaction mixture is cooled to room temperature (©) tetrahydrofuran (ool se) with a standard Sela to stop the reaction. The mixture of 1 hydrochloric acid is diluted, added, and washed with saturated brine. The organic layer is dried over ethyl acetate and the solvent is evaporated under Residual purified by hydrolyzing magnesium sulfate |0 tert-butyl {[5-[(3-hydroxypropoxy)methyl]- to give silica; -4-(4-methylphenyl)pyridin-3-ylJmethyl} carbamate (yield 47 7) as a white powder. 5), 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, 11-8 Vo

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). 3- {[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) Ali Saad (¥ (AER mg; yield 1©) (Ben «Matta[3-1] propane-1-ol dihydrochloride tert-butyl {[5-[(3-hydroxypropoxy)methyl]-2-isobutyl-6- as a white powder from | 0 mL 0,0749454 cana 1 A) methyl -4-(4-methylphenyl)pyridin-3-yl]methyl} carbamate (FY molecule) according to a method similar to that of Example 111-1111 01/150-405:0.99 (6H, with J = 6.4 Hz ), 1.70-2.3 (2H, m), 2.38 (3H, 5), 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). Ye vie J

Yov carbonyl }oxy)methyl]phthalic acid dihydrochloride dimethyl 4-[({[5- {[(tert-butoxycarbonyl)amino]methy!} -6-isobutyl- you get (\ra A) 2-methyl -4-(4-methylphenyl)pyridin-3-yl]carbonyl } oxy)methyl]phthalate 5-{[(tert-butoxycarbonyl)amino]methyl}-6- Yield 10% (as colorless oil from aa©) AG R mmol A) isobutyl-2-methyl-4-(4-methylphenyl)nicotinic acid mol) lle 7,87 cans E0 ( dimethyl 4-(bromomethyl)phthalate 5 gram) 1174 According to the method similar to that of Example 111-1111 (CDCl;) 8:0.97 (6H, d, J = 6.6 Hz), 1.38 (9H, 5), 2.17-2.26 (1H, m), 2.33 (3H, s) ), 2.54 (3H, 5), 2.78 (2H, d, J = 7.4 Hz), 3.92 (3H, 5), 3.93 (3H, 5), 4.11-4.15 Ve (2H, m), 4.21 (1H, brs ), 4.95 (2H, s), 7.00 (2H, d,J=8.1Hz), 7.09 211.41-9

Hz), 7.16 (1H, d, J = 7.9, 1.7 Hz), 7.47 (1H, d, J = 1.5 Hz), 7.62 (11,4d,J=7.7

Hz). 4-[({[5- {[(tert-butoxycarbonyl)amino }methyl}-6-isobutyl-2-methyl- we get ( Y g 0 ) 4-(4-methylphenyl)pyridin-3- yl]carbonyl} oxy)methyl] phthalic acid 0 dimethyl 4-[({[5-{[(tert-butoxycarbonyl)amino] Yield 94%) as colorless oil of methyl }-6-isobutyl-2 -methyl- 4-(4-methylphenyl)pyridin-3-ylJcarbonyl} oxy)methyl] mmol) according to the method similar to that of 7,77 can 1A) phthalate 1-4. Example “H-NMR (CDCl) ;) 8: 1.00 (6H, d, J = 6.6 Hz), 1.38 (9H, 5), 2.16-2.27 (1H, m), 2.39 Y. (3H, 8), 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), 8.13 (1H, d,J=79

Hz). 4-[( {[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) we get (yvan yield) pyridin-3-yl]carbonyl} oxy)methyl ]phthalic acid dihydrochloride Y° 4-[({[5-{[(tert-butoxycarbonyl)amino]Jmethyl}-6- as a white solid of (% Ag isobutyl-2-methyl-4-(4-methylphenyl) )pyridin-3-ylJcarbonyl} oxy)methyl] phthalic

YoA mmol) according to the method similar to that of Example 870 (oa 0,29) acid . -?) 'H.NMR (DMSO-dg) :0.96 (6H, d, J = 6.6 Hz), 2.17-2.26 (1H, m), 2.33 3H, 5), 2.56 (3H, brs), 2.91 (2H, brs), 3.81 (2H, d, J = 4.9 Hz), 5.05 (2H, 5), 7.13 2H, d, J = 7.9 Hz), 717-721 3H, m), 7.39 (1H, d , J = 1.5 Hz), 7.59 (1H, d, J = 7.9 Hz), 8.32 ° (3H, brs). Example 13? -3-fluorobenzyl 5-{[(tert-butoxycarbonyl)amino]methyl}-6- isobutyl-2-methyl-4-(4-) as a non-oil (VA) methylphenyl)nicotinate 5-1 [(tert-butoxycarbonyl)amino]methyl }-6-isobutyl-2-methyl-4-(4-methyl) color from (4-bromo-3-fluoro) and lle 91,?pa 0 ( phenyD)nicotinic acid mmol) according to the analogous method 11,7 (No 04 mg phenyl)methanol 0-7 9 of the example method Ne

H-NMR (YL02) 8: 0.97 (6H, d, J = 6.8 Hz), 1.39 (9H, 5), 2.16-2.25 (1H, m), 2.36 (3H, s), 2.55 (3H, 5) ), 2.78 (2H, d, T = 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) ). 3-fluoro-4-(methoxycarbonyl)benzyl 5-{ [(tert-butoxycarbonyl) we get ( Y (pa OV ) amino]methyl }-6-isobutyl-2-methyl-4-(4-methylphenyl)nicotinate Ye. (4-methylphenyl)nicotinate .)?-771 milligrams) according to the method similar to that of the example

H-NMR (J00) 8: 0.96 (6H, d, J = 6.6 Hz), 1.38 (9H, 5), 2.15-2.25 (1H, m), 2.33 (3H, s), 2.55 (3H, 5) ), 2.78 (2H, d, J = 7.4 Hz), 3.94 (3H, 5), 4.09-4.15 (2H, m), 4.21 Yo (1H, brs), 4.94 (2H, s), 6.81-6.85 (1H , m), 7.00 (2H, d, J = 8.1 Hz), 7.1 0(2H, d,J = 7.9 Hz), 7.63-7.67 (2H, m).

YY\Y

4e0 we get {[(tert-butoxycarbonyl)amino]methyl } -6-isobutyl-2-methyl- -5[{([-4 EAL) 4-(4-methylphenyl)pyridin-3-yl] carbonyl} oxy)methyl]-2-fluorobenzoic 40 mg; Yield 19% (as colorless oil) of -5,3-fluoro-4-(methoxycarbonyl)benzyl ‎{[(tert-butoxycarbonyl) amino]methyl }-6-isobutyl-2-methyl-4-(4-m ethylphenyl) (0) nicotinate © combined AR + mmol) according to the method similar to that of Example 1-9.” H-NMR (CDCls) 8:0.97 (6H, d, J = 6.6 Hz ), 1.38 (9H, 5), 2.1 6-2.26 (1H, m), 2.33 (3H, 5), 2.56 (3H, 5), 2.81 (2H, d, J = 7.4 Hz), 4.09-4.16 (2H, m), 4.24 (1H, brs), (2H, s), 6.88-6.92 (1H, m), 7.02 (2H, d, J = 7.9 Hz), 7.11 (2H, d,J = 7.9 Hz), 4.96 (2H, m).Ye 7.69-7.73;) you get 4-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) 07( pyridin-3-yl]carbonyl} oxy)methyl]-2-fluorobenzoic acid dihydrochloride mg; yield £Y 8 as a white solid of [4-[({[5-{[(tert-) butoxycarbonyl)amino] methyl }-6-isobutyl-2-methyl-4- (4-methylphenyl)pyridin-3-yl]carbonyl} oxy) 0 ( methyl]-2-fluorobenzoic acid 05 volume 856 ml mol) according to a method similar to that of the example (FY H-NMR (DMSO-dg) 8:0.96 (6H, d, J = 6.8 Hz), 2.12-2.26 (1H, m), 2.30 (3H, s) ), (3H, 5), 2.86 (2H, d, J = 7.0 Hz), 3.79 (2H, d, J = 5.7 Hz), 5.05 (2H, s), 7.05-2.53 (5H, m ), 7.59-7.64 (2H, m), 8.24 (3H, brs). 7.16 0 ex. yiv 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 we get N-[5-(aminomethyl)-6-isobutyl-2- methyl-4-(4-methylphenyl) pyridin-3-yl]-4-0x0-4,5,6,7-tetrahydro-1 -benzofuran-3-carboxamide dihydrochloride 1177 Yo ) mg; yield of 7676% (as white powder of tert-butyl {[5-amino-2-isobutyl-6- methyl-4-(4-methylphenyl)pyridin-3-yljmethyl} carbamate) 7 mg; 0,+ ms

Ye

V+) 4-0x0-4,5,6,7-tetrahydro-1 -benzofuran-3-carbonyl chloride 5 mol)

YY mmol) according to method similar to example method 15 mg; m), 2.11-2.31 (1H, m), 2.31 3H, s), 2.44 2H, t, J = 6.3 Hz), 2.59 (3H, 5), 2.93 (2H, t, J] = 6.3 Hz), 3 .06 (2H, s), 3.85 (2H, 5), 7.24 (4H, 5), 8.35 (1H, s), 8.36 (3H, brs), 11.42 (1H, brs). 8

TIA Example N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3-yl]-2- phenyl-1,3-thiazole-4-carboxamide dihydrochloride

N-[5-(aminomethy!)-6-isobutyl-2-methyl-4-(4-methylphenyl) we get mg } 00) pyridin-3-yl]-2-phenyl-1 ,3- Thiazole-4-carboxamide dihydrochloride | 0 tert-butyl {[5-amino-2-isobutyl-6-methyl-4-(4- as a white powder of (% ov yield mmol) 15 vol 14 7 methylphenyl)pyridin -3-ylJmethyl ( carbamate mM) + VO mg; V1V) 2-phenyl-1,3-thiazole-4-carbonyl = chloride according to a method similar to that of Example 777. z "H-NMR (DMSO-dg) 5: 1.00 (6H, d, J = 6.6 Hz), 2.20-2.29 (1H, m), 2.28 (3H, 5), vo 2.61 (3H, 5), 3.04 (2H, 5), 3.85 (2H, 5), 7.26 (4H, 5), 7.53-7.55 (3H, m), 7.95-7.98 (2H, m), 8.35 (1H, 5), 8.36 (3H, brs), 9.85 (1H, brs).14 Example N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3-yl]pyrazine- 2-carboxamide dihydrochloride Ye

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) we obtain (% + yield aaa 8) (no pyridin-3-yl]pyrazine-2- tert-butyl carboxamide dihydrochloride {[5-amino-2-isobutyl-6-methyl-4-(4-methyl as white powder of mg; +0,0 mmol) V4 Y)phenyl)pyridin-3 -yl]methyl } carbamate (molecule) according to (dle +, VO compound; 0 (No) pyrazine-2-carbonyl chloride 5 Yo

YY The method similar to the example method Dance vu

IH.NMR (DMSO-dg) 8: 1.01 (6H, d, J = 6.6 Hz), 2.18-2.28 (1H, m), 2.27 3H, 5), 2.63 (3H, 5), 3.12 (2H, 5) , 3.85 (2H, 5), 7.21 (2H, d,J=8.1Hz), 7.26 (2H, d,J=8.1

Hz), 8.46 (3H, brs), 8.70 (1H, s), 8.88 (1H, 5), 9.08 (1H, s), 10.48 (1H, brs). vv. Example 4-[({[5-(aminomethyl)-2-methyl-4-( 4-methylphenyl)-6-neopentylpyridin-3-yi] ° acetyl }oxy)methyl]benzoic acid dihydrochloride tert-butyl { [5-(cyano mL) to Y” +) 1 N hydrochloric acid add (1 methyl)-6-methyl-4-(4-methylphenyl)-2-neopentylpyridin-3-ylJmethyl } carbamate hour. Y£ was washed for gids mM) and the mixture was stirred at TV g; 1) the (1:7) toluene—tetrahydrofuran reaction mixture was concentrated with a mixed solvent of 0 aqueous; reduced sodium hydroxide. The remainder is dissolved in water and becomes alkaline by adding solution and concentrated under reduced pressure. ethyl acetate N. The resulting alkali solution is washed with mL) to the remainder and the mixture is vigorously stirred. 0 (mL) and + V water +) tetrahydrofuran added mmol) and stirred VV 0 milliliters A,0) di-tert-butyl dicarbonate added dropwise to 1 hydrochloric acid h. VV is added to the mixture at room temperature for 0. The ethyl acetate substances combine in the reaction mixture to acidify the aqueous layer and the anhydrous mixture is extracted. The extracted magnesium sulfate is evaporated; It was washed with saturated brine and dried over [5-{[(tert-) to give ethyl acetate ~hexane the solvent under reduced pressure and the rest crystallized from butoxycarbonyl)amino]methyl} -2-methyl-4-(4-methylphenyl) -6-neopentylpyridin-3- As a white powder. (AA+ yield can VY) yllacetic acid Y

H-NMR (CDCly)8: 1.09 (9H, 5), 1.39 (9H, 5), 2.43 (3H, 5), 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, 24112, 7.26 (2H, dd, J = 7.5, 29 Hz).] 5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4- cooled with ice a mixture of (Y mmol 1.1 g; ey 0) methylphenyl)-6- neopentylpyridin-3-yl]acetic acid 5 tetrahydrofuran s (mol) lle 0.7 ¢ jllle +,1V) triethylamine gram); 71 g (2,4,6-trichlorobenzoyl chloride mL) and add drip solution of Y +)

iY The resulting mixture was stirred at 0 °C (Y) tetrahydrofuran mmol) in 1" h. The reaction mixture was filtered and the filter was concentrated under pressure VE sad at room temperature 2-0x0-2-phenylethyl 4-mL); add 01 (reduced tetrahydrofuran. The remainder is dissolved in 4-dimethylamino mmol) and 1.4 cpa 0, 1/( (hydroxymethyl)benzoate mmol). The resulting solution was stirred at a temperature of 1.6 cpa (1 V) pyridine © and water. The organic layer, ethyl acetate, was washed a minute. The reaction mixture is divided between the Yo chamber for sodium hydrogen i>1 grams of aqueous citric acid respectively with anhydrous solution. Saturated aqueous magnesium sulfate and saturated brine; And dried at 56 °C, the solvent evaporates under reduced pressure, and the residue is purified by flash chromatography gel 2-0x0-2-phenylethyl 4-])4]5- {[(tert-butoxycarbonyl)amino methyl }-2- to give silica 0 methyl -4-(4-methylphenyl)-6-neopentylpyridin-3-yl]acetyl }oxy)methyl]benzoate as a white powder.

H-NMR (CDCl3)3: 1.02 (9H, 5), 1.37 (9H, 5), 2.39 (3H, 5), 2.49 (3H, s), 2.84 (2H, ), 3.43 (2H, 5), 4.08 (2H, with J = 4.0 Hz), 4.15-4.25 (1H, m), 5.11 (2H, 5), 5.59 (2H, s), 6.94 (2H, d, J = 7.9 Hz), 7.17 (2H , d, J] = 7.9 Ha), 7.31 (2H, d, J = 8.3 Hz), 7.45- Vo 7.55 (2H, m), 7.60-7.70 (1H, m), 7.95-8.00 (2H, m), 8.11 (2H, d, J = 8.3 Hz). 2-0x0-2-phenylethyl 4-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-2- dissolves ( methyl-4-(4-methylphenyl)-6-neopentylpyridin-3- yl] acetyl }oxy)methyl]benzoate mL) and (ethyl acetate mM) in AA (11 g (£Y,) zinc mL) and acetic acid powder (©) are added respectively to the solution Yield is water (¥ milliliters); Ye h. TE stands for milligrams). The resulting mixture was stirred at 5*”C for LY g; the reaction mixture was stirred and the filtrate was concentrated under reduced pressure. The resulting remainder is divided between water and water. The organic layer was washed with saturated brine and dried over anhydrous ethyl acetate. The solvent is evaporated under reduced pressure; The remainder was purified by magnesium sulfate VO by silica gel column chromatography and further recrystallized from ethyl acetate —hexane to give {[(tert-butoxycarbonyl)amino]methy!} -2-methyl-4-(4-methylphenyl) )-6- -5[{([-4 vy (ZEA yield pa 1 ) neopentylpyridin-3-yl]acetyl }oxy)methyl]benzoic acid as white powder.

H-NMR (CDCl3)8: 1.02 (9H, s), 1.36 (9H, 5), 2.38 (3H, s), 2.47 (3H, 5), 2.88 (2H, s), 3.43 (2H, 5), 4.10 2H, d, J = 5.1 Hz), 4.1 5-4.25 (1H, m), 5.11 (2H, 5), 6.94 (2H, 0.1-7.7 12( 1 7 )211, d, J = 7.7 Hz), 7.30 (2H, d, J = 8.1 Hz), 7 (2H, 01-1°

Hz). 4-[( {[5-(aminomethyl)-2-methyl-4-(4-methylphenyl)-6-neopentyl ¢ g yield 0, VY ) pyridin-3-ylJacetyl} oxy)methyl] benzoic acid dihydrochloride 4-[({[5-{[(tert-butoxycarbonyl)amino] ‎;.4)) as a pale yellow powder of methyl}-2-methyl-4-(4-methylphenyl)-6-neopentylpyridin -3-ylJacetyl }oxy)methyl] Ve mmol) according to the method similar to that of 1.44 pa +,Y) benzoic acid Example 7 ?-?). 111-1111 (DMSO-d)3: 1.01 (9H, brs), 2.37 (3H, 5), 2.73 (3H, brs), 3.00-3.30 (2H, m), 3.57 (2H, brs), 3.82 (2H, brs), 5.11 (2H, ), 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). Vo "1 example 2-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3-yl] carbonyl }oxy)methyl]furan-3- carboxylic acid dihydrochloride [3-(methoxycarbonyl)-2-furyl methyl 5-{[(tert-butoxycarbonyl) 1 mg YY. ) aminojmethyl} _6-isobutyl-2-methyl-4-(4-methylphenyl) )nicotinate AK 5-{[(tert-butoxycarbonyl) amino]methyl}-6- as colorless oil from (% 419 mmol yield 0.77 can;© ), isobutyl-2-methyl -4-(4-methylphenyl)nicotinic acid mmol 0.77 mg; 1 ( methyl 2-(bromomethyl)furan-3-carboxylate 5 grams): (1-4 grams) according to To the method similar to that of Example 117-111 (CDCl) 6: 0.96 (6H, d, J = 6.8 Hz), 1.38 (911 5), 2.1 5-2.26 (1H, m), 2.37 Ye (3H, s), 2.55 (3H, 5), 2.77 (2H, d, } = 7.4 Hz), 3.82 (3H, s), 4.09-4.13 (2H, m), 4.19

r (1H, brs), 5.27 (2H, 5), 6.68 (111 0.19 Hz), 7.00 (2H, d, J = 8.1 Hz), 7.11 (2H, d,J=79Hz), 7.31 (1H,d,J=1.9 Hz). -(4-methylphenyl)pyridin-3-ylJcarbonyl} oxy)methyl]furan-3-carboxylic acid (cae©) yield of 19%) as a colorless oil of [5-(methoxycarbonyl)-2-furyljmethyl]3 {[(tert-butoxycarbonyl) amino]methyl }-6-isobutyl-2-methyl-4- (4-methylphenyl) aaa 0 ( nicotinate 949 mmol) according to the method similar to that of Example 1-9 ( (6H, d, J = 6.6 Hz), 1.38 (9H, 5), 2.13-2.22 (1H, m), 2.37 8:0.96 (J020) trs (3H, s), 2.55 (3H, 5), 2.80 (2H, d, ] = 7.4 Hz), 4.09-4.16 (2H, m), 4.23 (1H, brs), Ve (2H, s), 6.72 (1H, d, J = 1.9 Hz), 7.02 (2H, 0.1 = 79 Hz), 7.13 2H,d, J = 7.4 5.27 Hz), 7.34 (1H, d, J = 1.9 Hz). ¥ (we get {[5-(aminomethyl) -6-isobutyl-2-methyl-4-(4-methylphenyl) ([-2,1 ) pyridin-3-yljcarbonyl} oxy)methyl]furan-3-carboxylic acid dihydrochloride VO total yield 781 As a pale yellow solid of 2-[({[5-{[(tert-butoxycarbonyl) amino]methyl} _6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-Yi ) yl]carbonyl }oxy)methyl]furan-3-carboxylic acid mg 9/81 mmol) according to the method similar to that of Example 3-7). H-NMR )01150-05:0.96 (6H, d, J = 6.6 Hz), 2.16-2.25 (1H, m), 2.35 (3H, s), (3H, brs), 2.90 (2H, brs), 3.80 (2H, d, J = 5.1 Hz), 5.26 (2H, 5), 6.71 (1H, d, I= T 2.53 Hz), 7.12 2H, d, J = 7.9 Hz), 7.19 ( 2H, d, J = 7.9 Hz), 7.72 (1H, 0.12 1.9 Hz), 1.9 (3H, brs). 8.32 Example IVY 4-[({[5-(aminomethyl)-6) -isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3-vl] carbonyl }oxy)methyl]-3-nitrobenzoic acid dihydrochloride Yo 1) we get 4-(methoxycarbonyl)-2 -nitrobenzyl 5- {[(tert-butoxycarbonyl)amino] ‎a 51 ) methyl} -6-isobutyl-2-methyl-4-(4-methylphenyl)nicotinate yield 777)

m as a colorless oil of 5-{[(tert-butoxycarbonyl)amino] methyl }-6-isobutyl-2-methyl- 4-(4-methylphenyD)nicotinic anid ) 1.41 g; 4.17 mmol) 5 -4 methyl AY A (hydroxymethyl)-3-nitrobenzoate mg; £17 mmol) according to a method similar to that of Example 497 (VY 'H-NMR (CDCl) 68:0.98 (6H, d, J = 6.6 Hz), 1.39 (9H, 5), 2.1 8-2.28 (1H, m), 2.34 ° (3H, 5), 2.57 (3H, 5), 2.79 (2H, d, } = 7.4 Hz), 3 99 (3H, s), 4.10-4.17 (2H, m ), 4.23 (3H, m), 7.13 (2H, d, J = 7.9 Hz), 8.08 (1H, dd, J = 7.03-7.09 rz (1H, brs), 5.41 (2H, Hz) ), 8.68 (1H, d, J = 1.5 Hz). Yeo ) 4-(4-methylphenyl)pyridin-3-yl]carbonyl }oxy)methyl]-3-nitrobenzoic acid cana yield 797) as a colorless oil of 4-(methoxycarbonyl)-2-nitrobenzyl 5 -{[(tert- butoxycarbonyl)amino Jmethyl}-6-i sobutyl-2-methyl -4-(4-methylphenyl)nicotinate 1948 cpa 0 TY) milligram) according to the method similar to that of the example J = 6.6 Hz.) , s), 2.83 (2H, 4, J = 6.8 Hz), 4.10-4.18 (2H, m), 4.26 (1H, brs), 5.42 (2H, s), 'eo (5H, m), 8.12 -8.16 (1H, m), 8.73 (1H, s).7.02-7.20 aa 0 on {[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) ( [-4 Y¢ v)pyridin-3-yl]carbonyl }oxy)methyl]-3-nitrobenzoic acid dihydrochloride mg; AT yield %( as a white solid of (tert-butoxycarbonyl)amino] [{-5[{([-4 methyl}-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin) -3-yljcarbonyl} oxy) Ye. H-NMR (DMSO0-d)5:0.97 (6H, d, J = 6.8 Hz), 2.16-2.25 (1H, m), 2.29 (3H, s), (3H, brs), 2.94-3.00 (2H, m), 3.81 (2H, d.

J = 5.5 Hz), 5.42 (2H, s), 7.17 (4H, 2.60 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, Yo d, J = 1.7 Hz). Example FY methyl 3-{[5-(aminomethyl )-2-methyl-4-(4-methylphenyl ) -6-neopentylpyridin-3- ylmethoxy}-1-methyl-1 H-pyrazole-4-carboxylate dihydrochloride ethyl 3-{[5-{[(tert-butoxycarbonyl)amino]methyl} -2-methyl-4-(4) - We obtain () methylphenyl)-6-neopentylpyridin-3 -ylJmethoxy}-1-methyl-1H-pyrazole-4- tert-butyl {[5-(hydroxy) as colorless oil from 0 AY yield cea , 4 ) carboxylate © methyl)-6-methyl-4-(4-methylphenyl)-6-neopentylpyridin-3 -ylJmethyl} carbamate ethyl 3-hydroxy-1-methyl-1H-pyrazole-4-5 g; 0.09 mmol) (5 mmol) according to the method similar to that of 5.17 mg; AT ¥) carboxylate. ( 1-18 Jad "H-NMR (CDCl) 6:1.03 (9H, s), 1.26-1.28 (3H, m), 1.37 (9H, s), 2.36 (3H, 5), 2.66 01 (3H, s) ), 2.86 (2H, 5), 3.68 (3H, 5), 4.13 (1H, brs), 423 (2H, q,J = 7.1 Hz), 4.90 (2H, s), 7.11 (2H, d,J = 8.3 Hz), 7.16 (2H, d, J = 1 Hz), 7.62 (1H, s).3-{[5-{[(tert-butoxycarbonyl)amino]methyl} -2-methyl-4-(4- methyl (Y phenyl)-6-neopentylpyridin-3 -ylmethoxy}-1-methyl-1 H-pyrazole-4-carboxylic acid ethyl 3-{[5-{[(tert-butoxycarbonyl)) yield £29 (as colorless oil of aa Y,YY) 0 amino]methyl} - 2-methyl-4-(4-methylphenyl)-6-neopentylpyridin-3 -yllmethoxy}-1- .4; mmol) according to aa 4 ) methyl-1H-pyrazole-4-carboxylate .( 1-4 Similar to example method 'H-NMR (J00) 8:1.04 (9H, s), 1.37 (9H, 5), 2.35 (3H, 5), 2.66 (3H, s), 2.88 (2H, s), 3.70 (3H, 5), 4.09-4.18 (2H, m), 4.24 (1H, brs), 4.95 (2H, s), 7.08 CH, 3 5 Years

Hz), 7.18 (2H, d, J = 7.7 Hz), 7.68 (1H, s). methyl 3-{[5- {[(tert-butoxycarbonyl)amino]methyl} -2-methyl-4-(4- we get ( methylphenyl)-6-neopentylpyridin-3 -yl]methoxy}-1-methyl -1H-pyrazole-4- 3-{[5-{[(tert-butoxy) yield (£9) as colorless oil from cane EA ) carboxylate carbonyl)amino]methyl} -2-methyl-4-(4- methyl phenyl)-6-neopentylpyridin-3- 8 mM +, 40 (aa 51 ) ylmethoxy}-1-methyl-1H-pyrazole-4-carboxylic acid . (¥- veo mole) according to the method similar to that of the example

YY

IH-NMR (CDCl) 8: 1.03 (9H, 5), 1.37 (9H, 5), 2.36 (3H, 5), 2.66 (3H, 5), 2.86 (2H, s), 3.68 (3H , 5), 3.76 (3H, 5), 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,] = 8.1 Hz), 7.62 (1H, s). ;) you get methyl 3-{[5-(aminomethyl)-2-methyl-4-(4-methylphenyl)-6- neopentylpyridin-3-yljmethoxy}-1 -methyl-1H-pyrazole-4-carboxylate ~~ © VE 4) dihydrochloride collected (ZV) as a white solid of -5[{-3 methyl { [(tert-butoxycarbonyl)amino] methyl }-2-methyl -4-(4-methylphenyl)-6-neopentyl ‎AVY aaa 0 ) pyridin-3-yljmethoxy}-1 -methyl-1H-pyrazole-4-carboxylate mmol) according to a method similar to that of the example? (Y- . 'H-NMR )01/50-1(5:1.05 (9H, s), 2.38 (3H, 3), 2.91 (3H, brs), 3.28 (2H, brs), 3.65 00 (3H, s), 3.66 (3H, 5), 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). neopentylpyridin-3 -yl] ‎methoxy}-1-methyl-1 H-pyrazole-4-carboxylic acid dihydrochloride Vo we get {[5-(aminomethyl)-2-methyl-4-(4-methylphenyl)- 6-neopentyl -3 pyridin-3-yljmethoxy}-1 -methyl-1H-pyrazole-4-carboxylic acid dihydrochloride ( 0 ?V1 yield % ) as a white solid 3-{[5- {[(tert-butoxycarbonyl) ~(—e ‎amino Jmethyl} -2-methyl-4-(4-methylphenyl)-6-neopentylpyridin-3 -ylJmethoxy}-1-mM) according to 1,956 C 1 ( methyl-1H-pyrazole-4-carboxylic acid 000 . (YY) to the method similar to the example method 'H-NMR 5:1.04,01/80-0) (9H, s), 2.38 (3H , 5), 2.87 (3H, brs), 3.23 (2H, brs), 3.64 (3H, s), 3.89 (2H, brs), 4.86 (2H, 5), 7.27 (2H, d,J=79Hz), 7.33(2H,d,J=7.9

Hz), 8.00 (1H, s), 8.26 (3H, brs). Ty Jo. ve 3-{[5-(aminomethyl)-2-methyl-4-( 4-methylphenyl)-6-neopentylpyridin-3-yl] methoxy}-1-methyl-1 H-pyrazole-4-carboxamide dihydrochloride

Juans mole ( 1 on tert-butyl {[5-({[4-(aminocarbonyl)-1-methyl-1 H-pyrazol-3-yljoxy} methyl)-6-methyl-4-(4) -methylphenyl)-2-neopentylpyridin-3 -ylJmethyl } carbamate cana 0 ) yield YA ( as colorless oil of {[(tert-butoxycarbonyl)amino] -5[{-3 methyl} -2 -methyl-4-(4-methylphenyl)-6-neopentylpyridin-3 -ylJmethoxy}-1-methyl- 0 ( 1H-pyrazole-4-carboxylic acid ~~ © » VY col. To the method similar to the example method (V7 “H-NMR (CDCls) 6: 1.04 (9H, s), 1.37 (9H, 5), 2.37 (3H, 5), 2.64 (3H, 5), 2.87 (2H , (3H, 5), 4.11-4.16 (2H, m), 4.97 (2H, 5), 5.24 (1H, brs), 6.43 (1H, brs), 7.01 3.69 (5), (2H, d , J = 7.7 Hz), 7.20 (2H, d, J = 8.3 Hz), 7.69 (1H, s). -methylphenyl)-6-neopentyl -3 pyridin-3-ylJmethoxy}-1-methyl-1H-pyrazole-4-carboxamide dihydrochloride aaa Ve 1,1(% yield TY) as a white solid of tert-butyl {[5-({[4-(amino carbonyl)-1-methyl-1H-pyrazol-3-ylJoxy} methyl)-6-methyl-4-(4-methylphenyl)-2- Yo ) neopentylpyridin-3-ylJmethyl} carbamate mg; Yeo millimolecules —(Ve according to the method similar to that of Example 7-7). H-NMR (DMSO-d)5: 1.04 (9H, 5), 2.38 (3H, 5), 2.91 (3H, brs), 3.25 (2H, brs), 3.63 (3H, s), 3.88 (2H, brs), 4.92 (2H, 5), 6.35 (1H, brs), 7.09 (1H, brs), 7.27 (2H, d,J= Hz), 7.34 (2H, d, J = 7.5 Hz ), 7.91 (1H, s), 8.29 (3H, brs). 7.0 Ex. 6" £2-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) pyridin-3 -vl] Ye carbonyl } oxy)methyl]phenyl acetic acid dihydrochloride 1 ( you get 2-(2-ethoxy-2-oxoethyl)benzyl 5-{ [(tert-butoxycarbonyl)amino ] 0 ) methyl }-6-isobutyl-2-methyl-4-(4-methylphenyl)nicotinate mg; Yield 71% (as a colorless oil of 5-{[(tert-butoxycarbonyl)amino] methyl}-6-isobutyl-2-methyl- 1 ) 4-(4-methylphenyl)nicotinic acid ~~ Y° g 0.1 mmol) and -2] ethyl 04 ( (bromomethyl)phenyl]acetate i.e. 7.47 mmol) according to a method similar to that of Example 1649-1.

IH.NMR (CDCl3)8: 0.96 (6H, d, J = 6.8 Hz), 1.20 (3H,t,J = 7.2 Hz), 1.38 (94, 5), 2.15-2.26 (1H, m), 2.35 3H , 5), 2.51 3H, 5), 2.77 (2H, d, J = 7.4 Hz), 3.51 (2H, 3), 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-) we get ( ° °

Teo ) 4-(4-methylphenyl)pyridin-3-yl]carbonyl } oxy)methyl phenyl} acetic acid 2-(2-ethoxy-2-oxoethyl)benzyl 5-{[(tert-) as a colorless oil of ( AY mg;yield of butoxycarbonyl)amino]methyl}-6-i sobutyl-2 -methyl-4-(4-methylphenyl)nicotinate .) 10-4 to the method similar to the example method (ala milligrams) L ,Y) q mg; 3H, 5), 2.49 (3H, 5), 2.76 (2H, d, 1 = 7.2 Hz), 3.53 (2H, 5), 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). 2-6 {[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) we get (58 mg; 58 ) pyridin-3-yl]carbonyl} oxy)methyl} phenyl}acetic acid dihydrochloride 0 {2-[({[5-{[(tert-butoxycarbonyl)amino] yield 777) as a white solid from 1026031 -6-180111-2 -methyl-4-(4-methylphenyl) )pyridin-3-yl] carbonyl }oxy)methyl] milligram) according to the similar method 1,774 pe Y\ +) phenyl}acetic acid . -?) 1 for example method 111-111 (DMSO0-dg)8:0.96 (6H, d, J = 6.6 Hz), 2.1 6-2.28 (1H, m), 2.36 (3H, s), AR 2.88 (2H, brs), 3.47 (2H, s), 3.81 (2H, d, J - 5.1 Hz), 4.99 (2H, 5), 6.98 (1H, d,J= 7.5 Hz), 7.13-7.32 (7H , m), 8.27 (3H, brs).

IVY Example 2-(2-amino-2-oxoethyl)benzyl 5-( aminomethyl)-6-isobutyl-2-methyl-4-(4- methylphenyl)nicotinate dihydrochloride Yo 2-(2-amino-2- oxoethyl)benzyl 5-{ [(tert-butoxycarbonyl)amino] we get () (% AY aggregate; yield YY ¥) methyl} -6-isobutyl-2-methyl-4-(4-methylphenyl)nicotinate

YY\V

It is a colorless oil of {[(tert-butoxycarbonyl)amino]methyl} -6-isobutyl-2- -5[{([-2{ methyl-4-(4-methylphenyl)pyridin-3 -yl] carbonyl }oxy)methyl]phenyl} acetic acid 0 v4) g; 1.195 mmol) according to the method similar to that of Example ?-1). H-NMR (CDCl3)8:0.96 (6H, d, J = 6.6 Hz), 1.38 (9H, 5), 2.1 3-2.26 (1H, m), 2.35 (3H, 5), 2.50 (3H, 5), 2.76 (2H, d, J = 7.4 Hz), 3.47 (2H, 5), 4.06-4.13 (2H, m), 4.24 © (1H, brs), 5.01 (2H, 5), 6.99 (2H, d, J = 8.1 Hz), 7.06-7. 10 (3H, m), 7.19-7.35 (3H, m). - 4-(4-methylphenyl)nicotinate dihydrochloride ) 4 mg; Yield of TA (as a 0 white solid) of 2-(2-amino-2-oxoethyl)benzyl 5- {[(tert-butoxycarbonyl)amino] ¥YY) methyl} -6-isobutyl- 2-methyl-4-(4-methylphenyl)nicotinate mg; 59/7 mmol) according to the method similar to that of the example (FY H-NMR (DMSO0-dg)8:0.96 (6H, d, J = 6.6 Hz), 2.14-2.25 (1H, m), 2.36 3H, s), (3H, s), 2.93 (2H, brs), 3.32 (2H, 5), 3.82 (2H, d, 7 = 5.1 Hz), 5.08 (2H, 5), 6.94 2.55 (2H, d, J = 7.4 Hz), 7.14-7.30 (7H, m), 7.51 (1H, brs), 8.35 (3H, brs). Ne Joe 8 no" methyl 3-{[5-(aminomethyl )-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3- yl]methoxy}thiophene-2-carboxylate dihydrochloride (I get methyl 3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2- methyl-4-(4-methylphenyl)pyridin-3-yljmethoxy} thiophene-2-carboxylate XY. (£7 cane TA yield %) as colorless oil of tert-butyl {[5-(hydroxymethyl)-2-isobutyl-6- methyl-4-( 4-methylphenyl)pyridin-3-ylJmethyl } carbamate ) , + V,Y body (0 mmol) 0.01 (methyl 3-hydroxythiophene-2-carboxylate s 0.9 mmol) According to the method similar to the example method (VY E H-NMR (CDCl) 8:0.98 (6H, d, J = 6.8 Hz), 1.39 (9H, 5), 2.18-2.27 (1H, m), 2.38 Yo (3H, 5), 2.72 (3H, 5), 2.77 (2H, d, J = 7.4 Hz), 3.80 3H, s), 4.06-4.11 (2H, m), 4.20 YyYw

TVA

(1H, brs), 4.79 (2H, 5), 6.50 (1H, d, J = 5.5 Hz), 7.06 (2H, d, J = 8.1 Hz), 7.18 (2H, d,J=179Hz), 7.29 ( 1H, d, J = 5.5 Hz). 3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-on-Ja a5 (¥ 7 ) methylphenyl)pyridin-3-ylJmethoxy)thiophene-2-carboxylate dihydrochloride methyl 3-{ [5-{[(tert-) as a white solid of ( LAE mg « yield © butoxycarbonyl)amino]methyl }-6-isobutyl-2 -methyl-4-(4-methylphenyl)pyridin-3- aggregate; Hz), 2.15-2.28 (1H, m), 2.37 (3H, s), 2.88 (3H, 5), 3.11 (2H, brs), 3.71 (3H, 5), 3.82 (2H, 5), 4.87 (2H , s), 6.86 (1H, d, J = 01 5.7 Hz), 7.21-7.34 (4H, m), 7.77 (1H, d, J = 5.5 Hz), 8.36 (3H, brs). 4-{[5-(aminomethyl)-6-isobutyl-2 -methyl-4-(4-methylphenyl)pyridin-3- ylimethoxy}-2-methyl-1.3 -thiazole-5-carboxylate dihydrochloride ethyl 4-{[5] - {[(tert-butoxycarbonyl)amino]jmethyl} -6-isobutyl-2- you get ( 1 Vo methyl-4-(4-methylphenyl)pyridin-3-ylJmethoxy} -2-methyl-1,3 - thiazole-5- tert-butyl {[5-volume yield 797 (as colorless oil of 0) carboxylate (hydroxymethyl)-2-isobutyl-6-methyl -4-(4-methylphenyl)pyridin-3- ethyl 4- hydroxy-2-5 mmol) 0,17 pa 1 ) yllmethyl } carbamate mmol) according to 0,17 pa 71) methyl-1,3-thiazole-5-carboxylate 0 . ( 1-716 method similar to example method 111-1114 (CDCl;) 6:0.98 (6H, d, ] = 6.6 Hz), 1.28 (3H, t, J = 7.2 Hz), 1.39 (OH, 5), 2.17-2.26 (1H, m), 2.37 (3H, 5), 2.53 (3H, 5), 2.77 (2H, d, J = 7.2 Hz), 4.08 (2H, d,J =4.5 Hz), 4.25 (2H , q, ] = 7.0 Hz), 5.13 (2H, 5), 7.09 (2H, d, J = 8.1 Hz), 7.16 (2H, d,J=7.9 Hz).Yo 4-{[5-{ [(tert-butoxycarbonyl)amino methyl} -6-isobutyl-2-methyl-4- we get ( Y (4-methylphenyl)pyridin-3-yljmethoxy}-2-methyl-1,3 -thiazole-5- carboxylic acid

YY\Y

for pa Vo. ) oS yield (% AY colorless aged ethyl 4-{[5-{ [(tert- butoxycarbonyl)amino]methyl}-6-isobutyl-2 -methyl-4-(4-methylphenyl)pyridin -3- 0 ) yl]methoxy}-2-methyl-1,3-thiazole-5-carboxylate mg 0.1 mmol) according to the method similar to that of (1-49 Jha). Hz), 1.38 (9H, 5), 2.18-2.30 (1 H, m), 2.38 ° 6.6 = 1b 'H-NMR (CDCl;) 8:1.01 (6H, (3H, s), 2.57 (3H, 5), 2.81 (3H, brs), 2.95 (2H, d, J = 7.0 Hz), 4.09-4.15 (2H, m), (1H, brs), 5.22 (2H, 5), 7.05 (2H, d, J] = 7.9 Hz), 7.22 (2H, d,J=7.9 Hz).4.31 Juans (v over methyl 4-{[5-{[(tert-butoxycarbonyl)amino]methyl }-6-isobutyl-2- methyl-4-(4-methylphenyl)pyridin-3 -ylJmethoxy}-2-methyl-1,3-thiazole-5-£Y +)carboxylate 0 mg;yield (AVY as a pale yellow solid of A-{[5-{[(tert- butoxycarbonyl)amino]methyl}-6-isobutyl-2 -methyl-4-(4-methylphenyl)pyridin-3- 0 ( yl}methoxy }-2-methyl-1,3-thiazole-5-carboxylic acid mg; AAT mmol) according to a method similar to that of the example (vv co . “H- NMR (CDCl3) 8: 0.98 (6H, d, J = 6.6 Hz), 1.39 (9H, 5), 2.15-2.27 (1H, m), 2.37 (3H, s), 2.54 (3H, 5), 2.68 (3H, 5), 2.77 (2H, d, J = 7.4 Hz), 3.79 (3H, s), 4.08 2H, d, 0 J=4.9 Hz, 4.21 (1H, brs), 5.14 (2H , 5), 7.09 (2H, d, J = 8.1 Hz), 6 (2H, d,J = Hz). -isobutyl-2-methyl-4-(4- methylphenyl) pyridin-3-yl}methoxy}-2-methyl-1,3 -thiazole-5-carboxylate YET) dihydrochloride Y-coupler yield ( AC as a pale yellow solid of -4 methyl {[(tert-butoxycarbonyl)amino methyl } -6-isobutyl-2-methyl-4-(4- -5[{ 0 ) methylphenyl)pyridin- 3-yljmethoxy}-2-methyl-1 ,3-thiazole-5-carboxylate total 1,799 mmol) according to a method similar to that of the example (YY 'H-NMR (DMS0-dg)8 :0.99 (6H, d, J = 6.6 Hz), 2.13-2.28 (1H, m), 2.38 (3H, s), (3H, s), 2.93 (3H, brs), 3.13 (2H, brs) , 3.70 3H, s), 3.80 (2H, brs), 5.17 (2H, s), Y° 2.55 (2H, m), 7.31 (2H, d, J = 7.4 Hz), 8.38 (3H, brs) 7.20-7.26 TA Joe YYvwy

PMM 4- {[5-(aminomethyl )-6-isobutyl-2-methyl-4-(4-methylphenyl )pyridin-3-yl] methoxy}-2-methyl-1,3-thiazole-5-carboxylic acid dihydrochloride 4- {[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-a3 (methylphenyl)pyridin-3-yljmethoxy} -2-methyl-1,3-thiazole-5-carboxylic) acid 4-{[5-{[(tert-mg yield 779) as a white solid of 105( dihydrochloride © butoxycarbonyl)amino]methyl }-6-isobutyl-2 -methyl-4-(4-methylphenyl)pyridin -3- mM a YY +) yl}methoxy}-2-methyl-1 ,3-thiazole-5-carboxylic acid gram molecule) according to the method similar to that of Example 7-?). H-NMR )0180-15: 0.99 (6H, d, J = 6.6 Hz), 2.15-2.28 (1H, m), 2.38 (3H, s), 2.53 (3H, 5), 2.90 (3H, brs) , 3.10 (2H, brs), 3.75-3.85 (2H, m), 5.11 (2H, s), 7.25 Ve (2H, d, J = 6.4 Hz), 7.32 (2H, 4,1 = 7.7 Hz), 8.15 -8.42 (3H, m).

TA) Example 3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenylpyridin-3-yl] methoxy}-1-(carboxymethyl)-1 H-pyrazole-4 -carboxylic acid dihydrochloride ethyl 1-acetyl-3-{[5- {[(tert-butoxycarbonyl)amino methyl} -6- on a plate) 105 isobutyl-2-methyl-4-(4-methylphenyl)pyridin -3-ylJmethoxy}-1H-pyrazole-4- tert-butyl {[5-] as a white solid of (AVY c-yield V,)Y) carboxylate (hydroxymethyl)-2-isobutyl-6-methyl- 4- (4-methylphenyl) pyridin-3- ethyl 1-acetyl-4-hydroxy- 5 mmol) 7.01 g; 1 ( yllmethyl } carbamate mmol) according to method 5, 10 (Not 9 mg; 1H-pyrazole-4-carboxylate 0 .) 1.31 161 2 Hz), 1.39 (9H, s), 2.14-2.27 (1H, m), 2.36 (3H, s), 2.51 (3H, 5), 2.67 (3H, 5), 2.78 (2H, d, J =17.4 Hz), 4.09 (2H, d, J = 5.1 Hz), 4.20 (1H, brs), 4.28 (2H, q, J = 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).Yo ethyl 1-acetyl-3-{[5- {[(tert-butoxycarbonyl)amino methyl }-6- ?) to a solution of isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3 -ylmethoxy}-1H-pyrazole-4-

0AM AT carboxylate (total 0.49 milligrams) in tetrahydrofuran (01 milliliters)-methanol (© milliliters) saturated Sle sodium hydrogen carbonate (01 milliliters) is added and the mixture is stirred at room temperature for Ye min. The reaction mixture with cethylacetate was diluted with saturated brine and dried over anhydrous magnesium sulfate. © The solvent was evaporated under reduced pressure and the resulting residue was purified by silica gel column chromatography ethyl 3-{[5- {[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2- YaA) methyl- 4-(4-methylphenyl)pyridin-3-yljmethoxy}-1 H-pyrazole-4-carboxylate cane yield 789) as a colorless oil. NMR (CDCly) 8:0.91 (3H, d, J = 6.6 Hz), 0.97 (3H, d, ] = 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), 01 (2H, m), 4.08-4.35 (5H, m), 4.87 (1H, brs), 6.91-7.01 (2H, m), 7.07-7.15 3.87 -4.04 (2H, m), 7.84 (1H, s).¥) to a solution of ethyl 3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2- methyl-4-(4-methylphenyl)pyridin-3-yljmethoxy}-1 H-pyrazole-4-carboxylate 10 ( 4 g; 0.17 mmol) in Y +) N,N- dimethylformamide (male) add sodium hydride (+ 7%) in oil; A mg 44,? mmol) and the mixture was stirred at room temperature for 0 4383 days A) tert-butyl bromoacetate (lie 7.54 mmol) was added to the reaction mixture and the mixture was stirred under heating at 0°C for 0 min . The reaction mixture was diluted with cethylacetate, washed with saturated yo-saline solution, and dried on anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by silica gel column chromatography to give ethyl 3-{[5-{[(tert- butoxycarbonyl)amino]methyl}-6-isobutyl-2 -methyl-4-(4) -methylphenyl)pyridin-3- ylJmethoxy}-1-(2-tert-butoxy-2-oxoethyl)-1 H-pyrazole-4-carboxylate ) .47 mg; Yield 777) as a colorless oil. 'H-NMR (CDCls) 8:0.98 (6H, d, J = 6.6 Hz), 1.28 (3H, t, J = 7.1 Hz), 1.39 (OH, s), Yo (9H, 5), 2.14-2.25 (1H, m), 2.36 (3H, 8), 2.66 (3H, 5), 2.76 (2H, d, J = 7.4 Hz), 1.44 YY/Y

Yve 4.08 (2H, d, ] = 4.9 Hz), 4.17-4.27 (3H, m), 4.52 (2H, 5), 4.91 (2H, s), 7.09 (2H, d, J =8.1 Hz), 7.16 2H , d, I = 8.1 Hz), 7.73 (1H, s). ethyl 3-{[5-{[(tert-butoxycarbonyl)amino]methyl} -6- to a mixed solution of ( ¢ isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3 -ylJmethoxy}-1 -(2-tert-butoxy-2- mmol) in 0.44 cana 47+)oxoethyl)-1H-pyrazole-4-carboxylate © sodium sodium 01 (methanol ml)- is added. ©) tetrahydrofuran condensation of steam for an hour (sale) in milliliters) and the mixture is heated with (01 N) 1 water 56 +,© hydrochloric acid one. The reaction mixture is cooled to room temperature, acidified mm, and the extracted substance is washed With a standard cethyl acetate brine, the mixture was extracted with the solvent under reduced pressure to give anhydrous Ady. magnesium sulfate was saturated and dried over 0 3-{[5-¢ [(tert-butoxycarbonyl)amino]methyl} -6-isobutyl-2-methyl-4-(4- methylphenyl)pyridin-3-yljmethoxy}-1 ~(carboxymethyl)-1H-pyrazole-4-carboxylic 3-{[5-(aminomethyl)-6-isobutyl- 2- mg; yield 19% (as oil. we get AYA) acid methyl-4-(4-methylphenyl)pyridin-3 -ylJmethoxy}-1-(carboxymethyl)-1 H-pyrazole- yield 709) as solid In white color (cana ©A,Y) 4-crboxylic acid dihydrochloride 0 mmol) according to the similar method VAY aaa 0117 (from the oil produced by the method of Example 7-?).

H-NMR 01180-05: 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, 4, J = 7.9 Hz), 8.04 (1H, and 8.27 (3H, brs). AR

YAY Example methyl 3- {[5-(aminomethyl)-6-isobutyl-2 -methyl-4-(4-methylphenyDpyridin-3-y1] methoxy}-1-(2-methoxy-2-oxoethyl)- 1 H-pyrazole-4-carboxylate dihydrochloride methyl 3-{[5-{[(tert-butoxy carbonyl)amino]methyl}-6-isobutyl-2- we get ( 1 methyl-4-(4-methylphenyl) pyridin-3 -ylJmethoxy}-1-(2-methoxy-2-oxoethyl)-1H- Yo mg; 177 mmol) as colorless oil of 0 ) pyrazole-4-carboxylate 3-{[5-{[ (tert-butoxy carbonyl)amino]methyl }-6-isobutyl-2-methyl-4-(4-

A methylphenyl)pyridin-3-yl]methoxy}-1 -(carboxymethyl)-1H-pyrazole-4-carboxylic

JL to the method similar to that of lb mg mM (AV ) acid (¥-Y.o 'H-NMR (CDCl;) 8:0.98 (6H, d, J = 6.6 Hz), 1.39 (9H, 3 ), 2.15-2.25 (1H, m), 2.36 (3H, s), 2.66 (3H, 5), 2.76 (2H, d, J = 7.2 Hz), 3.76 (3H, s), 3.77 3H, 5), 4.08 2H, d, °

J = 4.7 Hz), 4.22 (1H, brs), 4.65 (2H, 5), 4.91 (2H, 5), 7.08 (2H, d,J=8.1Hz), 7.16 (2H, d,J = 7.9 Hz) , 7.74 (1H, s). methyl 3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-?)methylphenyl)pyridin-3-yljmethoxy}-1 -(2-methoxy-2-oxoethyl) -1H-pyrazole-4- from Lard mg; Yield 67% (as solid color 04, A) carboxylate dihydrochloride 01 methyl 3-{[5-{ [(tert-butoxycarbonyl)amino methyl} -6-isobutyl-2-methyl-4-(4- methylphenyl)pyridin -3-ylJmethoxy}-1 -(2-methoxy-2-oxoethyl)-1H-pyrazole-4- mmol) according to the method similar to that of the 1,176 mg;4 A,Y) carboxylate example 7-?). 3H, brs), 2.94 (2H, brs), 3.67 (3H, 5), 3.68 (3H, 3), 4.86 (2H, s), 4.91 (2H, 5), 7.23 (2H, d, J = 8.1 Hz ), 7.29 (2H, d, J = 8.1 Hz), 8.09-8.19 (4H, m).

TAY Joe [3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3-yl] methoxy} -4-(methoxycarbonyl)-1H-pyrazol-1-yl [acetic acid dihydrochloride] Ye. methyl 3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2- to a solution of 1) methyl-4-(4-methylphenyl)pyridin-3 -ylJmethoxy}-1 (2-methoxy-2-oxoethyl)-1H- tertrahydrofurane mM) in +, VVO pa 1 ) pyrazole-4-carboxylate mL) and the mixture was stirred at V) 1N anhydrous sodium hydroxide A standard solution of 1.8 hydrochloric acid is added min. The reaction mixture was acidified with Ve at room temperature for © and extracted with p60:57186681. The extract was washed with saturated brine and dried over 3-{[5-{[(tert-) anhydrous. The solvent was evaporated under reduced pressure to give magnesium sulfate.

a [butoxycarbonyl)amino]methyl } -6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3- 0 ) ylmethoxy}-4-(methoxycarbonyl)-1 H-pyrazole-1-yl] acetic acid mg; Yield 4 (as colorless oil. (1H, m), 2.43 2.21-2.34 , 1.38 (CDCl;) 8:1.03 (6H, d, J = 6.6 Hz), 111-777 (3H, 5), 3.02-3.26 (5H, m), 3.76 (3H, 5), 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). (Y we get [3-{[5-(aminomethyl)-6) -isobutyl-2-methyl-4-(4-methylphenyl) pyridin-3-yljmethoxy} -4-(methoxycaronyl)-1 H-pyrazole-1-ylJacetic acid dihydrochloride (4 mg; yield of 44) as A white solid of [3-{[5-{[(tert- butoxycarbonyl)amino methyl }-6-isobutyl-2 -methyl-4-(4-methylphenyl)pyridin-3- 0 SAVY aaa 0 ) ylJmethoxy}-4-(methoxycarbonyl)-1H-pyrazole-1 -yljacetic acid mmol) according to the method similar to that of the example ?-?). H-NMR )01/80-105:0.99 (6H, d, J = 6.6 Hz), 2.14-2.28 (1H, m), 2.38 (3H, S), (3H, brs), 3.07 ( 2H, brs), 3.68 (3H, 5), 3.75-3.85 (2H, m), 4.78 (2H, s), 4.90 2.85 (2H, 5), 7.25 (2H, d, J = 7.9 Hz), 7.31 (2H, d, J = 7.9 Hz), 8.12 (1H, 5), 8.31 (3H, Vo brs).

TAL Example methyl 3- {[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3 -yl] methoxy} -1-(2-amino-2-oxoethyl) )-1H-pyrazole-4-carboxylate dihydrochloride methyl ~~ 1-(2-amino-2-oxoethyl)-3-{[S-{[(tert-on da a3()Y OY butoxycarbonyl)amino]methyl }-6-isobutyl-2 -methyl-4-(4-methylphenyl)pyridin-3- 30S solid (LV yield complex ) 0+) yl]methoxy}-1H-pyrazole-4-carboxylate [3 -{[5-{[(tert-butoxy carbonyl) amino] methyl} -6-isobutyl-2-methyli-4-(4-white from methylphenyl)pyridin-3-yljmethoxy}-4-(methoxycarbonyl)- 1 H-pyrazole-1-yl] acetic mg 189 mmol) according to the method similar to that of the article acid Ye. ( 0-?

YYvWy

YYA

'H-NMR (CDCl;) 8: 0.99 (6H, d, J = 6.6 Hz), 1.39 (9H, 5), 2.18-2.29 (1H, m), 2.36 (3H, s), 2.68 (3H, 5) ), 2.77 (2H, d, J = 7.4 Hz), 3.78 3H, 5), 4.08 (2H, d, J = 5.1 Hz), 4.22 (1H, brs), 4.54 (2H, s), 4.94 (2H, 5), 7.09 2H, d, J = 8.1 Hz), 7.1 6 (2H, d,J = 7.9 Hz), 7.74 (1H, s). methyl 3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4- ali da a3 (Y 0 methylphenyl)pyridin-3-ylJmethoxy}-1 -(2-amino-2- oxoethyl)-1H-pyrazole-4- from ard as a color solid (£9A mg yield V€)) carboxylate dihydrochloride methyl 1-(2-amino-2-oxoethyl)-3-{[5- { [(tert-butoxycarbonyl)amino methyl} -6- isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3 -yljmethoxy}-1H-pyrazole-4- milligram) according to the method similar to that of +, TOR comprising 0 ) carboxylate 0 Example 7-?). 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, 3), 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). -[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyri din-3-yl] terephthalamide dihydrochloride tert-butyl {[5-{[4-(aminocarbonyl)benzoyl]amino} -2-isobutyl-6- We get (1 ( AA yield) cane YE A) methyl-4-(4-methylphenyl) pyridin-3-yl]methyl} carbamate | 0 4-({[5-{[(tert-butoxycarbonyl)amino]methyl }-6-isobutyl-2- as a white powder of 0 mg 0 ) methyl-4-(4-methylphenyl)pyridin-3- yl]Jamino} carbonyl)benzoic acid (VY mM) according to a method similar to that of the example 4 "H-NMR (CDCl;) 8:0.99 (6H, d, J = 6.6 Hz), 1.38 (9H, 5 ), 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), Ye 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).

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin- ng yield 799) as a white powder (cane YY) 3-y1] terephthalamide dihydrochloride tert- butyl {[5-{[4-(aminocarbonyl)benzoylJamino} -2-isobutyl-6-methyl-4-(4-mM) 1.497 mg TE A)methylphenyl)pyridin- 3-yljmethyl} carbamate (FY) according to the method similar to that of the example ©

H-NMR (DMSO-dg) 5: 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, 5), 7.51 (1H, brs), 7.68 (2H, b J = 8.1 Hz), 7.89 (2H, d, J = 8.1 Hz), 8.09 (1H, brs), 8.37 (3H, brs), 10.16 (1H, brs).

TAY Joe ethyl 1-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3- Ve yl]amino} carbonyl)piperidine-4-carboxylate dihydrochloride ethyl 1-( {[5-{[(tert-butoxycarbonyl)amino]methyl} -6-isobutyl-2- we get (I methyl-4-(4-methylphenyl)pyridin-3-ylJamino } carbonyl)piperidine-4-carboxylate 5-{[(tert-butoxycarbonyl)aminojmethyl} -6-isobutyl-2-methyl-4-(4- as oil of ethyl isonipecotate s mmol) 1 mg; EV ) methylphenylnicotinic acid 0 (Ve mg; ¥ mmol) according to the method similar to that of Example YN E (.07Y): (M+1) EIMS ethyl 1-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-) 4- On Joa a3 (¥ methylphenyl)pyridin-3-yl]amino } carbonyl)pp eridine-4-carboxylate (1 mg yield 14) (as a white powder from oil produced in 77 4 (0 dihydrochloride) 7-7 The aforementioned according to the method similar to the example method

JH-NMR )01150-15:0.98 (6H, d, J = 6.3 Hz), 1.20 3H, t, ] = 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). Yo

TAY is an example

alum ethyl 2-[({[5-(aminomethyl)-6-isobutyl-2 -methyl-4-(4-methylphenyl)pyridin-3- yl]amino } carbonyl)amino]-1,3 —oxazole-4 -carboxylate dihydrochloride \ (you get ethyl 2-[({[5-{[(tert-butoxycarbonyl)amino methyl} -6-isobutyl-2- methyl-4-(4-methylphenyl)pyridin-3- yl]amino }carbonyl)amino]-1,3-oxazole-4-© carboxylate as oil from 5-{[(tert-butoxycarbonyl)amino] methyl} -6-isobutyl-2- methyl-4 -(4-methylphenyl)nicotinic acid ) 7 mg; 1 mmol) and 17 ethyl (2-amino-1,3-oxazole-4-carboxylate mg; ? mmol) according to a method similar to that of Example (V0 EIMS (1 +1l0: L071 7" № ( ethyl 2-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4- methylphenyl)pyridin-3-ylJamino ) carbonyl) amino]-1,3-oxazole-4-carboxylate cane (YY£) dihydrochloride (yield 744) as a white powder from the oil produced in (1) above according to a method similar to that of Example 2-7). 'H-NMR )01180-105:0.99 (6H, d, J = 6.6 Hz), 1.29 311,641 2 Hz), 2.13-2.26 (1H, m), 2.29 (3H, s), 2.63 3H, 5 ), 3.06 (2H, brs), 3.82 (2H, s), 4.27 (2H,q,1=7.2 Vo Hz), 7.15-7.29 (4H, m), 8.44 (3H, brs), 8.45 (1H , 5), 9.32 (1H, brs), 11.14 (1H, brs). Example TAA ethyl 2-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4- methylphenyl)pyridin-3- yllamino } carbonyl)amino]-1 J3-thiazole-4-carboxylate dihydrochloride 00 01) we get ethyl 2-[({[5- {[(tert-butoxycarbonyl) amino]methyl} -6-isobutyl-2- methyl-4-(4-methylphenyl)pyridin-3-yljJamino }carbonyl)amino]-1,3-thiazole-4- carboxylate as 5- {[(tert-butoxycarbonyl)amino]methyl} -6-isobutyl-2-methyl- ENN ( 4-(4-methylphenyl)nicotinic acid mg; 1 mmol) 4 ethyl 2-amino- YEE ) 1,3-thiazole-4-carboxylate mg; 1 milligram) according to the Yo method similar to that of Example 56 9- A) EIMS (01+1: has

YAN ethyl 2-] {[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4- methylphenyl)pyridin-3-yl}amino} carbonyl)aminol-1,3-thiazole -4-carboxylate )1 mg; Yield (70) as a white powder from the oil produced in (YAY) dihydrochloride mentioned above according to the method similar to that of Example 7-?).

H-NMR (DMSO-d¢)3: 1.00 (6H, d, J = 6.6 Hz), 1.27 (3H, 1 7.2 Hz), 2.11-2.30 ° (1H, m), 2.35 (3H, s), 2.62 (3H, 5), 3.06 (2H, brs), 3.81 (2H, s), 424 (2H, q,J=7.2

Hz), 7.21 (2H, d,J = 7.8 Hz), 7.30 (2H, d, J = 7.8 Hz), 7.91 (1 H, s), 8.42 (3H, s), 8.76 (1H, brs), 11.21 (1H, brs).

TAS example N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3-vi}-4- Ve phenylpiperidine-1-carboxamide dihydrochloride tert-butyl [( 2-isobutyl-6-methyl-4-(4-methylphenyl)-5- {[(4- te nh_sul) ( 1 as oil of phenylpiperidin-1 -yl)carbonyl]amino ( pyridin-3-yl)methyl ]carbamate 5-{[(tert-butoxycarbonyl)amino Jmethyl} -6-isobutyl-2-methyl-4-(4- 4-phenylpiperidine s mmol) 1 mg; 1 Y) methylphenyl)nicotinic acid (0-8).

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin- (Y )744 yield aaa 0 ) 3-yl]-4-phenylpiperidine-1 -carboxamide dihydrochloride mentioned above according to the similar method (1) as a white powder from the oil produced in 0 of the example method 7-?).

JH-NMR 01150-15: 0.99 (6H, d, J = 6.6 Hz), 1.54-1.58 (2H, m), 2.14-2.26 (1H, m), 2.26 (3H, 5), 2.50 (3H, s) , 2.58-2.75 (SH, 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). 90 Je.ve methyl 1-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3- yl]amino } carbonyl)pyrrolidine-2-carboxylate dihydrochloride

YAY methyl 1-({[5- {[(tert-butoxycarbonyl)amino]methyl} -6-isobutyl-2- 1 methyl-4-(4-methylphenyl)pyridin-3-yl] amino } carbonyl )pyrrolidin-2-carboxylate 5- {[(tert-butoxycarbonyl)amino]methyl} -6-isobutyl-2-methyl-4-(4- chyme from

DL-proline methyl mmol) is 1 mg; ? YAT) ester © 6 .6Y4 :(M+1) 5 methyl 1-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4- on Jaa (¥ methylphenyl) pyridin -3-yl]amino} carbonyl)pyrrolidin-2-carboxylate)1 (yield 798) as a white powder from oil produced in cane €++) dihydrochloride 0 according to a method similar to that of Example 7-?). Said 'H-NMR 01450-05:0.98 (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=7.8Hz), 732(2H,d,J = 7.8 Hz), 7.93 (1H, brs), 8.39 (3H, brs). For example, ethyl 1-({[5-(aminomethyl)-6 -isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3- yllamino } carbonyl)piperidine-3-carboxylate dihydrochloride ethyl 1- (([5-{[(tert-butoxycarbonyl)amino]methyl} -6-isobutyl-2- we get () methyl-4-(4-methylphenyl)pyridin-3-yl}amino }carbonyl)pyridine- 3-carboxylate 00 5-{[(tert-butoxycarbonyl)amino]methyl } -6-isobutyl-2-methyl-4-(4- of SS ethyl 3-piperidin mmol) and 1 mg; ‎ £17 ( methylphenyl) nicotinic acid mmol) according to the method similar to that of the example ¥ cane 70 €) carboxylate (Y-40) ((M+1) EIMS Ye ethyl 1 _({[5-( aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) we get (Y stereosome 1 ) pyridin-3-yl]amino [ carbonyl)piperidin-3-carboxylate dihydrochloride

YY\V

YAY

The aforementioned according to method 1 (yield 744) as a white powder from the oil produced in (FY) similar to the example method

H-NMR )01180-15: 0.98 (6H, d, J = 6.6 Hz), 1.19 (3H, t, ] = 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, 5), 3.03 (2H, s), 3.66-3.72 (1H, m), 3.82 (2H, brs), 4.05 2H, Glo 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). rav J 2-[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3-yl]tetrahydroimidazo[1,5-a]pyridine-1.3(2H,5H)-dione tert-butyl dihydrochloride {[5-(1,3-dioxohexahydroimidazo[1,5-a]pyridin-2(3H)-yl)- we get 1 0 5- as oil from 2-isobutyl-6- methyl-4-(4-methylphenyl)pyridin-3-yl methyl} carbamate {[(tert-butoxycarbonyl)amino methyl} -6-isobutyl-2-methyl-4-(4-methylphenyl) ethyl 2-piperidin carboxylate s ‏ millimole) 1 pao £1 ) nicotinic acid (Ye grouped? millimole) according to the method similar to that of the example vit) oof :(M+1) EIMS 0 2-[5-(aminomethyl)-6- isobutyl-2-methyl-4-(4-methylphenyl)pyridin-on Jans ?) YAY ) 3-yl]tetrahydroimidazo[1,5 -aJpyridine-1,3(2H,5H)-dione dihydrochloride aforementioned according to 1) as a white powder from the oil produced in (FOV mg yield) method similar to that of Example 7-?). J = 6.6 Hz), 1.20-1.35 (1H, m), 1.36-1.50 (1H, Ye 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).

Fay Example 2-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl )pyridin-3-y1]-10,10a- Yo dihydroimidazo[1,5-blisoquinoline-1.3 (2H.5H)-dione dihydrochloride

YAEL tert-butyl {[5-(1,3-dioxo-1,5,1 0,10a-tetrahydroimidazol[1,5-on-Jaa (0 blisoquinolin-2(3H)-y1)-2-isobutyl- 6 -methyl-4-(4-methylphenyl)pyridin-3- 5- {[(tert-butoxycarbonyl)amino]methyl}-6-kz of yllmethyl} carbamate mM 1 mg; ) isobutyl-2-methyl-4-(4-methylphenyl)nicotinic acid mg; ? m (0 ) ethyl 1 2.3 4-tetrahydroisoquinoline-3-carboxylate 5 g) 8

Co .)1-46 mol) according to the method similar to the example method T: (M+1) EIMS 2-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) ) pyridin- (Y 3-y1]-10,10a-dihydroimidazo[1,5-b] isoquinoline-1,3(2H,5H)-dione dihydrochloride mentioned above 1) is obtained as a white powder from Oil produced in (ATA TIA yield aggregate) 0 (TY according to method similar to example method “H-NMR) 01450-05:0.99 (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, 1 7.1 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). vo

Taf Example methyl 2-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3- yllamino } carbonylbenzoate dihydrochloride methyl 2-({[5-(aminomethyl) )-6-isobutyl-2-methyl-4-(4- we get mg YY. ) methylphenyl) pyridin-3-yl]Jamino} carbonyl) benzoate dihydrochloride | 0 tert-butyl [{5-amino-2-isobutyl-6-methyl-4-(4-) yield 89% (as white powder, mmol) 15 cana 7 (methylphenyl) pyridin-3-yljmethyl } carbamate mmol) according to 175 mg; 1 lb 4) methyl 2-(chlorocarbonyl)benzoate and YY method similar to the example method "H-NMR (DMSO-d) 6:1.00 ( 6H, d, J = 6.6 Hz), 2.18-2.27 (1H, m), 2.40 (3H, s), Ye 2.66 (3H, s), 2.95 (2H, brs), 3.77 (3H, 5), 3.79 ( 2H, brs), 6.58 (1H, d, J=7.5 Hz),

m (2H, d, J =7.8 Hz), 7.34 (2H, d, 1 = 7.8 Hz), 7.49 (1H, t,J = 7.5 Hz), 7.53 (1H, 7.23 t,J=7.5Hz ), 7.70 (1H,d, J = 5 Hz), 8.25 (3H, brs), 10.03 (1H, brs). Example yao 2-({[5-(aminomethyl)-6-i sobutyl- 2-methyl-4-(4-methylphenyl )pyridin-3-yl] ‎amino } carbonyl)benzoic acid dihydrochloride 8 )( we get {[(tert-butoxycarbonyl)amino methyl} _6-isobutyl-2-methyl -4- -5[{(-2 VE 7/( (4-methylphenyl)pyridin-3-yl]Jamino }carbonyl)benzoic acid mg; yield aA %) as a white powder of -} methyl 2-({[5- {[(tert-butoxycarbonyl)amino]methyl 6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3 -yl]amino } carbonyl)benzoate lle 1. 18 cpa 0 ( 0 mol) according to the method similar to that of the example (VT '.NMR (CDCl;) 8:0.92 (6H, d, J = 6.6 Hz), 1.38 (9H, 5), -2.04 2.18 (1H, m), 1 (3H, 5), 2.55 (3H, 5), 2.82 (2H, brs), 4.09 (3H, brs), 6.17 (1H, brs), 6.91 (1H, brs) , (2H, brs), 7.25-7.27 (3H, m), 7.37 (1H, brs), 7.88 (1H, brs). 7.09 Ja a3 (¥ on 2-({[5-( aminomethyl)-6-isobutyl-2-methyl-4-(4- YY +) methylphenyl)pyridin-3 -ylJamino } carbonyl) benzoic acid dihydrochloride 0 mg; Yield of £9 (as a white powder of 2-({[5-{[(tert butoxycarbonyl)amino]methyl ( -6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3- denatured) 1.497 cana YE Y) yljamino}carbonyl)benzoic mmol) according to the method similar to that of the example (YY (6H, d, J = 6.6 Hz), 2.18-2.26 (1H, m), 2.43 (3H, s), Y. 5:1.00 (J01/150-0 111-1111 (3H, s), 3.05 (2H, brs), 3.86 (2H, brs), 6.38 (1H, d, J = 6.9 Hz), 7.25 (2H, d,J= 2.74 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), 8.1 (1H, d, ] = 6.9 Hz), 8.35 (3H, brs), 10.02 (1H, brs). 7.76

Yat JA 2-[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3-yl]-1H- Yo isoindole-1,3(2H)-dione dihydrochloride

YAR tert-butyl {[5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-isobutyl-6- yields (1) 794 cama YY ) methyl-4-(4-methylphenyl)pyridin-3-yl methyl } carbamate 2-({[5-{[(tert-butoxycarbonyl)amino]methyl } -6-isobutyl-2- as a white powder of mg ‎ Yo ) methyl-4-(4-methylphenyl)pyridin-3-yl)amino} carbonyl)benzoic acid (VF mmol) according to the method similar to that of Example 48 0 "H-NMR (J02) 8 : 1.03 (6H, d, J = 6.6 Hz), 1.39 (9H, 5), 2.02 (3H, 5), 2.21 -2.31 (1H, m), 2.40 (3H, 5), 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). 49 mg yield 1 9 3-yl]-1H-isoindole-1,3(2H)-dione dihydrochloride tert-butyl {[5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2) -y1)-2- as a white powder of mgm; 771 isobutyl-6-methyl-4-(4-methylphenyl)pyridin-3-ylJmethyl } carbamate (FY mmol) according to a method similar to that of the example 5 "H-NMR (DMSO-de) 5: 1.01 (6H, d, J = 6.3 Hz), 2.19 (3H, 5), 2.19-2.32 (1H, m), Vo 2.35 (3H, s), 2.83 ( 2H, d, J = 6.3 Hz), 3.69 (2H, brs), 7.05 2H, 012 7.8 Hz), 7.1 3 (2H, d, J = 7.8 Hz), 7.85 (4H, brs), 8.03 (3H, brs ).

Fav Example methyl 3-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3- yl]amino } carbonyl)oxy]benzoate dihydrochloride Ye methyl 3 -[({[5- {[(tert-butoxycarbonyl)amino]methyl } -6-isobutyl-2- we get ( \ as oil from methyl-4-(4-methylphenyl)pyridin-3-yl] amino } carbonyl)oxylbenzoate 5-{[(tert-butoxycarbonyl)amino methyl } -6-isobutyl-2-methyl-4-(4- methyl 3-hydroxy mM) r 1 mg; £1 ) methylphenyl)nicotinic acid mg; ? millimol) according to the method similar to that of the analogue (4) benzoate Y° (10-8 EIMS) (M+1).

YY\W

YAY methyl 3-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-) we get (¥ 1 ) (methylphenyl) pyridin-3-ylJamino }carbonyl)oxy]benzoate dihydrochloride tis aforementioned 1) yield 777) as a white powder from oil produced in pe (FY method similar to example method “H-NMR 05:0.98, 0150-1) (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, 5), 3.89 (3H, 8), 7.26 (2H , d,J = 8.1 Hz), 7.36 (1H, s), 7.39 (2H, d,] = 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).

FAA example methyl 4-[({[5-(aminomethyl )-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3- Ve yllamino }carbonyl)oxy]benzoate dihydrochloride methyl 4-[ (([5-{[(tert-butoxycarbonyl)amino methyl} -6-isobutyl-2- we get ( \ as oil from methyl-4-(4-methylphenyl)pyridin-3-ylJamino } carbonyl)oxylbenzoate 5-4 [(tert-butoxycarbonyl)amino]methyl} -6-isobutyl-2-methyl-4-(4-methylphenyl)

Y+ £) methyl 4-hydroxybenzoate s (mmol) 1 mg; £3 ( nicotinic acid 05 ). 1-8 mg? mmol) according to the method similar to that of the example EIMS: (M+1) 01Y.

Methyl 4-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4- ?) we get

VAY ) methylphenyl)pyridin-3-yl]amino} carbonyl)oxy]benzoate dihydrochloride aforementioned according to 1 (vol. yield 774) as a white powder from the oil produced in the 0-1 method similar to that of the example. 'H-NMR )01/50-005:0.98 (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, 5), 3.85 (3H, 5), 7.00 (2H, d,J=8.7Hz), 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). Yo vad Example YY\Y

YAA methyl 5-(aminomethyl)-6-isobutyl-2 -methyl-4-(4-methylphenyl)pyridin-3- yljcarbamate dihydrochloride methyl 5-{[(tert-butoxycarbonyl)amino]methyl} -6-isobutyl-2- You obtain -(4-methylphenyl)nicotinic 2 mole) lle mg; ? -2-methyi-4-(4- on Ja ad (Y (7 Av yield poe 0 ) methylphenyl)pyridin-3-yl] carbamate dihydrochloride 0 aforementioned according to similar method 1) as a colored powder White from the resulting oil in (Y = for the example method

H-NMR (DMS0-d)5: 0.98 (6H, d, 1 = 6.6 Hz), 2.11-2.18 (1H, m), 2.39 (3H, s), 2.63 (3H, 5), 3.11 (2H, 5) ), 3.48 (3H, 5), 3.82 (2H, 5), 7.18 (2H, d, J = 7.8 Hz), 7.33 (2H, d, J = 7.8 Hz), 8.44 (3H, brs), 9.03 (1H , brs). Yo 500 eg ethyl {3-[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3-yl]- 2,4-dioxoimidazolidin-1-yl acetate dihydrochloride diethyl 2 ,2'-[({[5-{[(tert-butoxycarbonyl)amino methyl} -6-isobutyl-) we get ( 1 crystals 2-methyl-4-(4-methylphenyl)pyridin-3-ylJamino }carbonyl)imino}diacetate ~~ 0 5-{[(tert-butoxycarbonyl)aminoJmethyl}-6- of (% £Y mg; yield 0 ) white mmol 1 mg; £1Y) isobutyl-2-methyl-4-(4-methylphenyl)nicotinic acid mg; ¥ milligram) according to 00 (diethyl 2,2"-iminodiacetate 3 gram) 1-95. Similar method to example method

H-NMR (CDCl3)5:0.96 (6H, d, J = 6.6 Hz), 1.24 (6H, t,] = 6.9 Hz), 1.3 8 (9H, s), Yo 2.09-2.24 (1H, m), 2.40 (3H, s), 2.49 (3H, 5), 2.75 (2H, d, J = 6.9 Hz), 3.87 (4H, s),

Yyw

4.12 (4H, gq, 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). ethyl {3-[5-(aminomethyl-6-isobutyl-2-methyl-4-(4-on-Joa (Y methylphenyl)pyridin-3-yl]-2,4-dioxoimidazolidin-1-yl} acetate dihydrochloride diethyl 2,2'-[({[5-{[(tert-) as a white powder of (% AA mg « yield ) ° butoxycarbonyl)amino methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl)pyridin-3- mmol) according to 1.47 vol 0) yl]Jamino}carbonyl)imino]diacetate in a manner similar to that of Example 7-?). DMSO-d)3:0.99 (6H, d, J = 6.6 Hz), 1.19 (6H, 1 2 Hz), 2.22-2.35 (1H, m), 2.35 (3H, 5), 2.50 (3H, 5), 2.86 (2H, d, J = 7.2 Hz), 3.74-3.80 (3H, m), 01 4.02-4.17 (5H, m), 7.04-7.11 (2H, m), 7.21-7.27 (2H, m), 8.25 (3H, brs).£0) Ex. ethyl 6-({[5-(aminomethyl )-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl] amino } carbonyl) pyridine-2-carboxylate dihydrochloride ethyl 6-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4- Nah__pray Vo methylphenyl)pyridin-3-yl]Jamino } carbonyl)pyridine- 2-carboxylate dihydrochloride tert-butyl {[5-amino-2-isobutyl-6-] as a white powder of (AA volume YY yield) mg 0,+7 mL) methyl-4-(4-methylphenyl )pyridin-3-yljmethyl} carbamate +, VO (aaa) £4) ethyl 6-(chlorocarbonyl)piperidin-2-carboxylate rm) ru mmol) according to the method similar to that of Example 0

H-NMR (DMSO-de) 8: 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, 0.1 = 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). 67 Example Yo 6-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3- yl]amino } carbonyl)pyridine-2-carboxylic acid dihydrochloride va. 6-({[5- {[(tert-butoxycarbonyl)amino)methyl} -6-isobutyl-2-methyl-4- we get )1

YE) (4-methylphenyl)pyridin-3-ylJamino} carbonyl)pyridine-2-carboxylic acid ethyl 6-({[5-{[(tert-) as a white powder of (%aA solid; yield of butoxycarbonyl) amino]methyl} -6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3- mmol) + EA aaa 0 ( yllamino }carbonyl)pyridine-2-carboxylate © .) 10-7 According to the method similar to the example method "H-NMR (CDCl3) 8: 0.98 (6H, d, J = 6.6 Hz), 1.38 (9H, (2 14-2.26 (1H, m), 2.28 (3H, 5) , 2.52 (3H, 5), 2.84 (2H, brs), 4.15 (2H, 5), 4.42 (1H, brs), 7.01 (2H, 0,1 8

Hz), 7.10 (2H, d, J = 7.8 Hz), 7.99 (1H, brs), 8.21-8.31 (2H, m), 9.36 (1H, brs). 6-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4- on a ad (xy 0 methylphenyl)pyridin-3-ylJamino} carbonyl)pyridine-2-carboxylic acid 6- (([5-{[(tert- ligand; yield 7494) as a white powder of YY) ( dihydrochloride butoxycarbonyl)amino]methyl}-6-isobutyl-2 -methyl-4-(4-methylphenyl)pyridin-3 - milligram)‎ EV aaa VE Y) yl]amino } carbonyl)pyridine-2-carboxylic acid . )- according to the method similar to that of the example? , 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).oY Example N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3 -yljpyridine- p 2,6-dicarboxamide dihydrochloride tert-butyl {[ 5-({[6-(aminocarbonyl) pyridin-2-yl]carbonyl } amino)-2- we get ( \ mg YY ) isobutyl-6-methyl-4-(4-methylphenyl)pyridin-3-yljmethyl} carbamate 6-({[5-{[(tert-butoxycarbonyl)amino]methyl}- yield 4¢ (as white powder of 6 -isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl]Jamino 'carbonyl)pyridin-2- ¥° mmol) according to similar method LEAN (mg A ) carboxylic acid (VF of the example method va "H-NMR (CDCls) 8: 1.00 (6H, with J = 6.6 Hz), 1.39 (9H, 5), 2.18-2.29 (1H, m), 2.35 ( 3H, s), 2.57 (3H, 5), 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). 5

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin- (¥ mg; yield 7494) is obtained as powder Yo ( 3-yllpyridine-2,6- dicarboxamide dihydrochloride tert-butyl {[5-({ [6-aminocarbonyl)pyridin-2-yljcarbonyl }amino)-2- in white from; 771 mg ) isobutyl-6-methyl-4-(4-methylphenyl)pyridin -3-ylJmethyl ( carbamate (PY mM) according to a method similar to that of the example 1.40 00 "H-NMR (DMSO-dg) 8:1.00 (6H, d, J = 6.3 Hz), 2.12-2.28 (1H, m), 2.25 (3H, 5), 2.63 (3H, 5), 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, 5), 8.08-8.20 (3H, m), 8.43 (3H, brs), 8.80 (1H, s), 10.77 (1H, brs). af dh. 10

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3-yl]-1-benzyl- 4-methoxy-1H-pyrazole-3-carboxamide dihydrochloride

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-Also a aS methylphenyl)pyridin-3-yl]-1-benzyl-4-methoxy-1 H-pyrazole-3 -carboxamide tert-butyl )]5- as a white powder from (LAY yield cane YY.) dihydrochloride 00 amino-2-isobutyl-6-methyl-4-(4-methylphenyl)pyridin-3-yljmethyl } carbamate -benzyl-4-methoxy-1H-pyrazole-3- mg; 0,* mmol) and 7 mmol) according to analogous method 1.75 mg; YAA) carbonylchloride

IVY for example method 'H-NMR (DMSO-dg) 6:0.98 (6H, d, J = 6.6 Hz), 2.18-2.26 (1H, m), 2.35 (3H, 5), Yo 2.51 (3H, s) ), 2.91 (2H, brs), 3.67 (3H, s), 3.81 (2H, brs), 5.15 (2H, 8), 7.1 6-7.39 (9H, m), 8.11 (1H, s), 8.21 (3H , brs).

YYvw vay £0 Example N-[5-(aminomethy!)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3 -yl1-1.5- dimethyl-1H-pyrazole-3-carboxamide dihydrochloride

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl]-1,5-dimethyl-1H-pyrazole-3-carboxamide ~~ © tert-butyl )]5- as a white powder of (£4Y yield cane YY) dihydrochloride amino-2-isobutyl-6-methyl-4-(4-methylphenyl)pyridin-3-yljmethyl ( carbamate 1, 5-dimethyl-1H-pyrazole-3-carbonylchloride (mg 0,+ mmol) 7 )

YY mg; mmol) according to the method similar to that of Example 11 A) “H-NMR (DMSO-dg) 8:0.99 (6H, d, J = 6.6 Hz), 2.18-2.25 (1H, m), 2.32 (3H , s), Ye 2.33 (3H, 5), 2.53 (2H, brs), 3.73 (3H, 5), 3.82 (2H, brs), 6.38 (1H, 5), 7.20 (2H, d, ] = 7.8 Hz ), 7.24 (2H, d, J = 7.8 Hz), 8.31 (3H, s), 9.58 (1H, brs).£0 Joe [5-(aminomethyl)-2-methyl-4-(4-methylphenyl)- 6-neopentylpyridin-3-yl]acetic acid dihydrochloride 0 [5-(aminomethyl)-2-methyl-4-(4-methylphenyl)-6-neopentylpyridin- (yield 744) as a white powder of cpa + ,07) 3-ylJacetic acid dihydrochloride [5-{[(tert-butoxycarbonyl)amino]methyl} -2-methyl-4-(4-methylphenyl)-6- mmol) according to VEY C1 ¥) neopentylpyridin-3-yljacetic acid .(*-Y Method similar to example method Ye.” H-NMR (DMSO0-d¢)8: 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).

EY (5-methyl-2-0x0-1.3-dioxol-4-yl)methyl [5-(aminomethyl)-2-methyl-4-(4- Yo methylphenyl)-6-neopentylpyridin-3-yllacetate dihydrochloride just yay (5-methyl-2-oxo0-1,3-dioxol-4-ylymethyl ~~ [5- {[(tert- on Joma (0 butoxycarbonyl)amino]methyl} -2-methyl- 4-(4-methylphenyl)-6-neopentylpyridin-3 - [5-{[(tert-) as a white powder of (IVA max yield 0,0 91( yllacetate butoxycarbonyl) amino]methyl }-2-methyl -4-(4-methylphenyl)-6-neopentylpyridin- mmol) according to the similar method 0.47 c 1 ¥) 3-ylJacetic acid ©

IVT for example method

H-NMR (CDCl3)8: 1.02 (9H, s), 1.37 (9H, 5), 2.14 (3H, 5), 2.40 (3H, s), 2.48 (3H, 5), 2.83 (2H, 5), 3.39 (2H, 5), 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). (5-methyl-2-oxo-1 .3-dioxol-4-yl)methyl[5-(aminomethyl)-2-methyl- ?) we get 0 g 0 Ao ) 4-(4-methylphenyl )-6-neopentylpyridin-3-yl]acetate dihydrochloride (5-methyl-2-0x0-1,3-dioxol-4- yield £99) as a pale yellow powder of [5-yl]methyl[(tert) -butoxy carbonyl)amino]methyl}-2-methyl-4-(4-methylphenyl)- mmol) according to 1,17c 0 4) 6-neopentylpyridin-3-yl]acetate similar method For example method 7-?). , 3.52 (2H, brs), 3.73 (2H, brs), 4.92 (2H, 5), 7.1 0 (2H, d, J = 7.5 Hz), 7.31 (2H, d, J = 7.5 Hz), 8.15 (3H , brs).54 ex. methyl 5-(aminomethyl)-6-isobutyl-2-( methoxymethyl)-4-(4-methylphenyl) Xe. nicotinate (g; 56 mmol)); 0A 0) methyl 4-methoxyacetate A mixture of () « lille Y,Y) acetic acid (mmol), 001 gm, (V 0,2) ammonium acetate is heated by steam using a GAS trap (mL) with reconstitution 0 (5 mmol toluene) 0 Wash with Gi al hr. The reaction mixture is cooled to 0 °C for Dean-stark*? anhydrous. The solvent was evaporated under pressure (magnesium sulfate saturated brine) and dried to (g). We get (©,A) pla as a product methyl 3-amino-4-mehoxybut-2-enoate reduced to give vat methyl 5-cyano-6-isobutyl-2-(methoxymethyl)-4-(4-methylphenyl)- 1 4 on a yield of 100 (as a pale yellow powder of aa ,/a A) dihydropyridin-3-carboxylate purity 789.5 40 mL can 0,Y) 5-methyl-3-oxohexanenitrile « (aa ©,A) Crude product mM) according to the method Er pa,A) p-tolualdehyde 5 mol) (Y=) similar to the example method © 'H-NMR (CDCl3) 8: 0.97 (6H, dd, J = 1 2.8 Hz), 1.80-2.00 (1H, m), 2.20-2.40 (2H, m), 2.31 (3H, 5), 3.48 (3H, f) (3.57 ( 3H, 5), 4.56 (1H, 5), 4.64 (1H, d, J = 16.4

Hz), 4.73 (1H, d, J = 16.4 Hz), 7.05-7. 15 (SH, m). methyl 5-cyano-6-isobutyl-2-(methoxymethyl)-4-(4-a hae a3 (Y methyl 5-yield 44#) (as white powder of can V,0) methylphenyl)nicotinate 01 cyano -6-isobutyl-2-(methoxymethyl)-4-(4-methylphenyl)- 1,4-dihydropyridin-3- mmol) according to the method similar to that of the example YY g; V,V) carboxylate. -?) YY 'H.NMR (CDCl3)8: 1.00 (6H, d, J = 6.6 Hz), 2.20-2.35 (1H, m), 2.41 3H, 5), 2.97 (2H, d, J] = 7.2 Hz), 3.37 (3H, 5), 3.59 (3H, s), 4.71 (2H, 5), 7.15-7.35 (4H, m). \o methyl 5-(aminomethyl)-6-isobutyl-2-(methoxymethyl)-4-(4-) (¥ methyl g; yields ??%) are obtained as a pale yellow oil of VN ) methyiphenyl)nicotinate 7, not g; ( 5-cyano-6-isobutyl-2-(methoxy methyl)-4-(4-methylphenyl) nicotinate .(1-4 mmol) according to the method similar to that of the example

H-NMR (CDCl): 0.97 (6H, d, J = 6.8 Hz), 1.22 (2H, brs), 2.15-2.30 (1H, m), 2.39 ¥ (3H, 5), 2.82 (2H, d, J = 7.4 Hz), 3.36 (3H, 5), 3.49 (3H, 5), 3.67 (2H, 5), 4.65 (2H, 5), 7.11 (2H, d, J = 8.1 Hz), 7.21 (2H, d , J = 8.1 Hz). {6-methyl-4-(4-methylphenyl)-2-neopentyl-5-[( pyridin-2-ylthio)methyl]pyridin-3- yl}methylamine trihydrochloride Yo tert-butyl ( {6-methyl-4-( 4-methylphenyl)-2-neopentyl-5-[ (pyridin-2-) we get ( 1 as a powder of (AYA mg yield £41) 1 thio)methyl]pyridin-3-yl}methyl)carbamate

Yao [5-{[(tert-butoxycarbonyl)amino]methyl} -2-methyl-4-(4-methylphenyl)-6-mM) 1,1 cana 00 ) neopentylpyridin-3-yljmethyl methansulfonate mM mol) according to analogous method 0.7 mg; 8) 2-mercaptopyridine 5 (VT for example method)

H-NMR (CDCl3) 8: 1.02 (9H, ,L 1.37 (9H, 5), 2.35 (3H, 5), 2.62 3H, 5), 2.83 2H, ° s), 4.08 (2H, d, J =4.9 Hz), 4.14 (2H, 5), 4.19 (1H, 5), 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). {6-methyl-4-(4-methylphenyl)-2-neopentyl-5-[(pyridin-2- on Jaa (¥)787 mg; yield VV)ylthio)methyl]pyridin-3-yl} methylamine trihydrochloride tert-butyl ( {6-methyl-4-(4-methylphenyl)-2-neopentyl-5-[ (pyridin-2-yl as powder of 0 mmol) 1.795 mg; 001( thio)methyl]pyridin-3-yl}methyl)carbamate (TY according to method similar to example 111-11 (DMSO-dg) 5:1.03 (9H, :(, 2.36 (3H, 5), 2.90) (3H, 5), 3.28 (2H, s), 3.83 (2H, ,l J=4.7 Hz), 4.19 (2H, 5), 7.11-7.16 (1H, m), 7.23-7.33 (SH, m ), 7.62-7.67 (1H, m), 8.31 (3H, brs), 8.33-8.34 (1H, m).Vo 501 Example {6-methyl-4-(4-methylphenyl)-2-neopentyl- 5-[(1H-1 .2,4-triazol-3-ylthio)methyl]pyridin-3-yl} methylamine dihydrochloride tert-butyl ) {6-methyl-4-(4-methylpheny1)-2-neopentyl-5 -[(4H-1 2.4) we get )1 (#1 mg; yield £00 ) triazole-3-ylthio)methyl]pyridin-3-yl}methyl) carbamate AK [5-{[(tert- butoxycarbonyl)amino]methyl } -2-methyl-4-(4- as a derivative of

LY (00 mg) methylphenyl)-6-neopentylpyridin-3-ylJmethyl methansulfonate (mmol) 017 mg; VT) 3-mercapto-1,2,4-triazole s (mmol) z (VF according to method similar to example method) 'H-NMR (CDCl) 8: 1.01 (9H, s), 1.37 (9H, 5), 2.37 (3H, 5), 2.64 GH, 5), 2.83 (2H , Yo s), 4.08 (2H, d, J=4.9 Hz), 4.12 (2H, 5), 4.22 (1H, 5), 7.04 (2H, d, J=7.7 Hz), 7.20 (2H, d, J = 7.7 Hz), 8.02 (1H, 5).

van (6-methyl-4-(4-methylphenyl)-2-neopentyl-5-[(1H-1,2,4-triazole-3-) we obtain (V (Fhe yield cama 0 ) ylthio) methyl]pyridin-3-yl} methylamine dihydrochloride tert-butyl( {6-methyl-4-(4-methylphenyl)-2-neopentyl-5-[(4H-1 24) as a powder from a volume of 407,. mL Yer) triazole-3-ylthio)methyl]pyridin-3-yl}methyl)carbamate (FoF molecular) according to a method similar to that of Example 0 "H-NMR (YH-01150) 6:1.02 (9H, s), 2.39 (3H, 5), 2.86 (3H, s), 3.21 (2H, 5), 3.81 (2H, , for J=4.1 Hz), 4.08 (2H, 5), 7.24 (2H, d , J=8.0 Hz), 7.35 (2H, m, J=8.0 Hz), 8.23 (3H, brs), 8.45 (1H, 5).511 Examples [5-[(1H-imidazol-2-ylthio) )methyl] -6-methyl-4-(4-methylphenyl)-2- ye neopentylpyridin-3-yljmethylamine trihydrochloride tert-butyl {[5-[(1H-imidazol-2-ylthio)methyl]-6-methyl-4 -(4- We obtain () (Ye yield of cane TV Y) methylphenyl)-2-neopentylpyridin-3-ylJmethyl} carbamate [5-{[(tert-butoxycarbonyl)amino]methyl } -2-methyl- 4-(4- MSN Gsm oS 1 mg; On ) methylphenyl)-6-neopentylpyridin-3-yl methyl methansulfonate 05 mmol) according to 011 mg; 0 ) 2- mercaptoimidazole 5 mol

YY The method similar to the example method

IH.NMR (CDCl) 8: 1.01 (OH, 5), 1.37 (9H, 5), 2.41 (3H, 5), 2.55 (3H, 5), 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). Ye. [5-[(1 H-imidazole-2-ylthio)methyl]-6-methyl-4-(4-methylphenyl)-2- yields Y (AVA) ame 0 ( neopentylpyridin-3-ylJmethylamine tert-butyl trihydrochloride {[5-[(1H-imidazol-2-ylthio)methyl]-6-methyl-4-(4- as aged powder : 0.464 mg Yoo ) methylphenyl)-2-neopentylpyridin-3 -yl]methyl } carbamate (Gramic PY) according to a method similar to that of the example esa 0

Yay' H-NMR (DMSO-de) 8: 1.01 (9H, 5), 2.40 (3H, 5), 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, 1-7.9 Hz), 7.70 (2H, s), 8.26 (3H, brs).

DY Example {6-methyl-4-(4-methylphenyl)-2-neopentyl-5-[( pyrimidin-2-ylthio)methyl]pyridin- ~~ © 2-711 methylamine trihydrochloride tert-butyl ( {6 -methyl-4-(4-methylphenyl)-2-neopentyl-5-[ (pyrimidin- ( 1 mg; YAS powder yield ) 2-ylthio)methyl]pyridin-3-yl}methyl) carbamate [5-{[(tert-butoxycarbonyl)amino]methyl} -2-methyl-4-(4-methylphenyl)-6-mM)1 c) neopentylpyridin-3-ylJmethyl ~methansulfonate Yo (mmol) according to similar method 111 mg; VY Y) 2-mercaptopyrimidin s (VY for example method)

H-NMR (CDCl3) 8: 1.02 (9H, s), 1.37 (9H, 5), 2.35 (3H, (, 2.65 (3H, s), 2.83 (2H, 5), 4.08 (2H, d, 14.9 Hz) ), 4.14 (2H, s), 4.19 (1H, brs), 6.92 (1H, ba J=4.9 Hz), 7.06 (2H, d, J=7.8 Hz), 7.18 (2H, d, 17.8 Hz) , 8.43 (2H, d, J=4.9 Hz). mg;yield of 00 ( ylthio)methyl]pyridin-3-yl} methylamine trihydrochloride tert-butyl ( {6-methyl-4-(4-methylphenyl)-2-neopentyl-5-[(pyrimidin-2-) as powder from mMol +, YAO mg 0 ( ylthio)methyl]pyridin-3-ylmethyl)carbamate (FY in grams) according to the method similar to that of Example 0

H-NMR (DMSO-dg) 5: 1.02 (9H, 5), 2.35 (3H, 5), 2.85 (3H, 8), 3.17 (2H, brs), 3.80 (2H, s), 4.18 (2H, 5) ), 7.21-7.13 (5H, m), 8.22 (3H, brs), 8.57 (2H, d, J=4.9 Hz).

DY Example [5-{[(5-methoxy-1H-benzimidazol-2-yl)thio Jmethyl}-6-methyl-4-(4-methylphenyl)- 2-neopentylpyridin-3-yl]methylamine trihydrochloride Yo tert-butyl {[5-{[(5-methoxy-1H-benzimidazole-2-yl)thio]methyl}-6- ( 1 mg; OF ) methyl-4-(4-methylphenyl) -2-neopentylpyridin-3-yl]methyl } carbamate

Yaa Yield 97 (as a powder of {[(tert-butoxycarbonyl)amino]methyl} -2-methyl-4-(4- -5[ 06 nitrate 100] methylphenyl)-6-neopentylpyridin- 3-yl (1 mmol) and V4 A) 5-methoxy-2-benzimidazolethiol (0.1 mmol) (1-77 mg) according to the method similar to that of the example

IH.NMR (CDCl3) 5:1.02 (9H, s), 1.37 (OH, 5), 2.33 (3H, 5), 2.64 (3H, :(, 2.83 2H, ~~ ° 5), 3.82 3H, 5) , 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). [5- {[(5-methoxy-1H-benzimidazol-2-yl)thio]Jmethyl} -6-methyl-4-(4- ?) we get mg; 54 ) methylphenyl)-2-neopentylpyridin -3-yljmethylamine trihydrochloride tert-butyl {[5-{[(5-methoxy-1H-benzimidazole-2-) as a powder of (791) yielding 0 yl)thio]methyl} -6-methyl-4-(4 (-methylphenyl)-2-neopentyl pyridin-3-mM) according to the method 1.775 cana 0 ( yllmethyl } carbamate similar to the example method (FY "H-NMR (DMSO-dg) 5:1.02 (9H) , 5), 2.30 (3H, 5), 2.83 (3H, 5), 3.12 (2H, brs), 3.77 (2H, s), 3.81 (3H, 5), 4.37 (2H, 5), 6.94-7.02 ( 2H, m), 7.20-7.27 (4H, m), 7.46 (1H, Vo d, J=8.9 Hz), 8.23 (3H, brs).516 Example methyl 3-{[5-(aminomethyl)- 2-methyl-4-(4-methylphenyl)-6-neopentylpyridin-3- ylmethoxy}-1H-pyrazole-5-carboxylate dihydrochloride methyl 3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-2 -methyl-4-(4- we get ( \ Ye

Aes ) methylphenyl)-6-neopentylpyridin-3-yljmethoxy}-1 H-pyrazole-5-carboxylate [5- {[(tert-butoxycarbonyl)amino]methyl}-2-methyl- mg; Yield of 57% (as a powder of 3gm) 4-(4-methylphenyl)-6-neopentylpyridin-3-yljmethylmethanesulfonate £Y1) methyl 3-hydroxy-1H-pyrazole-5-carboxylate 5 mmol) 1 Y = mg; ? millimol) according to a method similar to that of Example YO

YY\VW

H-NMR (CDCl;) 8:1.02 (9H, s), 1.37 (9H, 5), 2.36 (3H, 5), 2.62 (3H, 5), 2.86 (2H, s), 3.89 ( 3H, s), 4.13 (2H, d, J=4.5 Hz), 4.20 (1H, brs), 4.84 (2H, 5), 6.13 (1H, 5), 7.04 (2H, d, J=7.8 Hz), 7.16 (2H, d, J=7.8 Hz), 9.89 (1H, brs). methyl 3-4]5- {[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4- we get (¥ methylphenyl)-6-neopentylpyridin-3-yljmethoxy} -1H-pyrazole- 5-carboxylate ~~ © methyl 3-{[5-(aminomethyl)- as powder from 0 Vo dal) cane VEY ) dihydrochloride 2-methyl-4-(4-methylphenyl)-6-neopentylpyridin-3 -yljmethoxy}- 1H-pyrazole-5- total 77/7 mmol) according to the method similar to that of 0) carboxylate. example? -?) “H-NMR (DMSO-de) 5:1.03 (9H, 5), 2.37 (3H, 5), 2.84 (3H, s), 3.23 (2H, brs), 3.81 01 (3H, 5) , 3.87 (2H, brs), 4.83 (2H, 5), 6.17 (1H, 5), 7.25 (2H, d, J=7.9 Hz), 7.33 (1H, d, 1=7.9 Hz), 8.29 (3H, brs).$e Example 3-{[5-(aminomethyl)-2-methyl-4-( 4-methylphenyl)-6-neopentylpyridin-3-y1] methoxy} -1H-pyrazole-5-carboxylic acid dihydrochloride Ve 3-{[5- {[(tert-butoxycarbonyl)amino]methyl} -2-methyl-4-(4- we get ( 1 methylphenyl)-6-neopentylpyridin-3-yi] methoxy} -1H -pyrazole-5-carboxylic acid methyl 3-{[5-{[(tert-) as a white solid of (AY mg; yield AN ) butoxycarbonyl)amino]methyl}-2 _methyl-4-(4- methylphenyl)-6-neopentylpyridin-3 - mM) according to YT Cm. V,11) yljmethoxy}-1 H-pyrazole-5-carboxylate 0 (1-49) to the method similar to that of the example

H-NMR (DMSO-de) 8: 1.00 (9H, s), 1.34 (9H, 5), 2.32 (3H, s), 2.53 (3H, 5), 2.69 (2H, s), 3.87 (2H, d , J=3.2 Hz), 4.73 (2H, 5), 6.06 (1H, s), 6.83 (1H, t, J=4.1 Hz), 7.13-7.21 (4H, m), 12.91 (1H, s). 3- {[5-(aminomethyl)-2-methyl-4-(4-methylpheny1)-6- on Jaa (Y ve neopentylpyridin-3-yljmethoxy} -1H-pyrazole-5-carboxylic acid dihydrochloride 3-{ [5-{[(tert-) as a white powder of (lao na mg; yield)

$a ‎butoxycarbonyl)amino]methyl} -2-methyl-4-(4-methylphenyl)-6-neopentylpyridin-3 - cana Yoo)yl]methoxy}-1H-pyrazole-5-carboxylic acid 7475 mmol) according to the method similar to that of Example 3-7). (DMSO-dg) 6: 1.03 (9H, 5), 2.37 3H, 5), 2.51 (3H, s), 2.78 (2H, 5), 3.85 7-1111 (2H, s), 4.80 (2H , s), 6.09 (1H, s), 7.23 (2H, 4.3-7.9 7.32 (2H, d, J=7.9 Hz), © (3H, brs). 8.16 Ex 53 4-(methoxycarbonylbenzyl 5- ( aminomethyl)-2-methyl-4-(4-methylphenyl)-6- neopentylnicotinate dihydrochloride )1 00 we get 4-(methoxycarbonyl)benzyl 5-{[(tert-butoxycarbonyl)amino] V, 15 ) methyl} -2-methyl-4-(4-methylphenyl)-6-neopentylnicotinate (Ve) yield particle %) as a white solid of {[(tert-butoxycarbonyl)amino]methyl }-2- methyl- -5 VY, A) 4-(4-methylphenyl)-6-neopentylnicotinic acid g YAY mM) according to a method similar to the example NAAR H-NMR (CDCl) 8:1.01 method (9H, 5), 1.36 (9H, 5), 2.35 (3H, 3), 2.53 (3H, s), 2.87 (2H, Vo s), 3.93 (3H, 5), 4.17 (2H, 5) , 4.98 (2H, 5), 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, 1-2 Hz). %( Ye as a white powder of 4-(methoxycarbonyl)benzyl 5- {[(tert-butoxycarbonyl) Yoo ) amino]methyl} -2-methyl-4-(4-methylphenyl)-6-neopentylnicotinate mgm YEA mmol) according to the method similar to that of the example (YY H-NMR (DMSO-dg) 5:1.00 (9H, 5), 2.33 (3H, 5), 2.51 3H, s), 2.90 ( 2H, s), 3.83 (2H, 5), 3.86 (3H, 5), 5.07 (2H, 5), 7.12-7.21 (6H, m), 7.87 (2H, d, J=8.3 Hz), 8.13 (3H, brs). Yo is an example of DY

A 61 4-[({[5-(aminomethyl)-2-methyl-4-(4-methylphenyl )-6-neopentylpyridin-3-yl] carbonyl }oxy)methyl]benzoic acid dihydrochloride )( we get on 4-[({[5-{[(tert-butoxycarbonyl)amino]methyl} -2-methyl-4-(4-YMA) methylphenyl)-6-neopentylpyridin-3-yl]carbonyl } oxy) methyl]benzoic acid © g; Yield of (ZA as a white solid of 4-(methoxycarbonyl)benzyl 5-{[(tert- butoxycarbonyl)amino]methyl} -2-methyl-4-(4-methylphenyl)-6-neopentylnicotinate can ) 7.46 mmol) according to the method similar to that of Example 1-4 ( “H-NMR (CDCl) 8: 1.01 (9H, s), 1.37 (9H, 5), 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). -yl]carbonyl joxy)methyl]benzoic acid dihydrochloride mg yield of AL! as a white powder of (tert-butoxycarbonyl)amino]methyl}-2- [{-5[{([-4 methyl-4] -(4-methylphenyl)-6-neopentylpyridin-3-yi] carbonyl }oxy)methylJbenzoic 001( acid combined FOV + mMg) according to the method similar to that of the example (¥-Y 0 : H-NMR (DMSO-de) 6: 1.00 (9H, 5), 2.34 (3H, 5), 2.51 (3H, 5), 2.90 (2H, 5), 3.84 (2H, d, 125.7 Hz) , 5.06 (2H, s), 7.10-7.18 (6H, m), 7.85 (2H, d, J=8.3 Hz), 8.11 (3H, brs).

DA Example 4-(trifluoromethyl)benzyl [5-(aminomethyl)-6-isobutyl-2-methyl-4-(4- Ye methylphenyl)pyridin-3-yl] dihydrochloride 4-(trifluoromethyl)benzyl acetate [5 - {[(tert-butoxycarbonyl)amino]methyl}- we get 1 mg yield VO) 6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl}acetate [5- { [(tert-butoxycarbonyl)amino methyl } -6-isobutyl- as a white powder from (% Ae mmol 707 cana 0 ) 2-methyl-4-(4-methylphenyl)pyridin-3-yljacetic acid 5 mMol 1.00 aaa YOu) 1 -(bromomethyl)-4-(trifluoromethyl)benzene 5 gram) according to the method similar to that of Example 1118(

EY

'H-NMR (CDCl) 6: 0.97 (6H, d, J = 6.8 Hz), 1.37 (9H, 5), 2.11-2.29 (1H, m), 2.37 (3H, s), 2.48 (3H, 5) , 2.75 (2H, d, J = 6.6 Hz), 3.42 (2H, 5), 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, } = 7.7 Hz), 7.33 (2H, d, T= 8.1 Hz), 7.60 (2H, d, J = 8.1 Hz). 4-(trifluoromethyl)benzyl [5-(aminomethyl)-6-isobutyl-2-methyl-4- (Y 2 ( 1? mg; AY yield) (4-methylphenyl)pyridin-3-yl) ]acetate dihydrochloride 4-(trifluoromethyl)benzyl [5-{[(tert-butoxycarbonyl)amino] as a white powder of mg YY. ) methyl} -6-isobutyl-2-methyl-4-(4-methylphenyl (pyridin-3-yljacetate mM) according to the method similar to that of Example 7-?). , 2.09-2.25 (1H, m), 2.36 (3H, 5), Ye 2.77 (3H, 5), 3.12 (2H, s), 3.77 2H, d, J = 5.1 Hz), 5.14 (2H, s), 7.09 (2H, d, J = 1

Hz), 7.24 (2H, d, J = 8.1Hz), 7.47 (2H, d, J = 8.1 Hz), 7.76 (2H, d, J = 8.1 Hz), 8.35 (3H, brs). £13 Joe 4-fluorobenzyl [5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3- Vo yl] dihydrochloride 4-fluorobenzyl acetate [5-{[(tert-butoxycarbonyl) amino]methyl}-6-isobutyl- ( ) as powder (LAT yield cana YYO) 2-methyl-4-(4-methylphenyl)pyridin-3-yl]acetate [S-{[( tert-butoxycarbonyl)amino}methyl} -6-isobutyl-2-methyl-4-(4- white in the amount of 1.07 mmol) and 0-1 ( methylphenyl)pyridin-3-yl]acetic acid 00 mmol) according to 0.15 aaa 5 A) (bromomethyl)-4-fluorobenzene (V1 18) method similar to example method 'H-NMR (CDCl) 6:0.96 (6H, d, J = 6.6 Hz) ), 4.02 (2H, d, ] = 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, Yo 1-7.9 Hz), 7.15-7.25 (2H, m).

YY\v

$7 4-fluorobenzyl [5-(aminomethyl)-6-isobutyl-2-methyl-4-(4- (¥ (% AY yield aaa YY ) methylphenyl)pyridin-3-yl]acetate dihydrochloride 4 -fluorobenzyl [5-{[(tert-butoxycarbonyl)amino]methyl}-6- as a white powder of 6,011 mL volume Yeo) isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl ]acetate (PY mole) according to the method similar to that of the example © “H-NMR (DMS0-d¢)5:0.98 (6H, d, J = 6.6 Hz), 2.12-2.26 (1H, m) , 2.38 (3H, s), 2.84 (3H, 5), 3.26 (2H, d, J = 6.8 Hz), 3.79 (2H, d, J = 4.5Hz), 5.03 2H, s), 7.12 (2H, d , J = 7.9 Hz), 7.17-7.39 (6H, m), 8.57 (3H, brs).??1 Example {[2-isobutyl-6-methyl-4-(4-methylphenyl)-5- ( 2-0x0-2-pyrrolidin-1-ylethyl)pyridin- Ve 3-yllmethyl }amine dihydrochloride tert-butyl {[2-isobutyl-6-methyl-4-(4-methylphenyl)-5-(2-ox0- 2- We obtain () (1 mg yield 0 ) pyrrolidin-1 -ylethyl)pyridin-3-yl]methyl} carbamate [5- {[(tert-butoxycarbonyl)amino methyl} -6-isobutyl-2 - as a white powder of 0 mmol VY mg 0 methyl-4-(4-methylphenyl)pyridin-3-yl]acetic acid 05 mmol) according to like method 7.11 mg; 5 ( pyrrolidine s) (YY for example method "H-NMR (CDCl) 8:0.97 (6H, d, J = 6.6 Hz), 1.37 (9H, 1 2-2.25 (1H, m) , 2.39 (3H, 5), 2.55 (3H, 5), 2.74 (2H, d, J = 7.4 Hz), 2.86-2.97 (4H, m), 3.28 (2H, 5), 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), Y. 7.21 2H, d, J = 7.9 Hz). {[2-isobutyl-6-methyl-4-(4-methylphenyl)-5-(2-ox0-2-pyrrolidin-1-) we get (¥ (1 mg; yield of 84) ylethyl)pyridin- 3-yljmethyl jamine dihydrochloride tert-butyl {[2-isobutyl-6-methyl-4-(4-methylphenyl)-5-(2- as a white powder of 0.01 mg 0) oxo- 2-pyrrolidin-1-ylethyl)pyridin-3-yl]methyl} carbamate 8 (FY mol) according to the method similar to that of the example at

H-NMR (DMSO0-d¢) 5: 0.99 (6H, d, J = 6.6 Hz), 2.11-2.26 (1H, m), 2.40 (3H, 5), 2.80 (3H, 5), 2.88 (2H, t, J = 6.1 Hz), 3.12-3.29 (4H, m), 3.42 (2H, 5), 3.81 (2H, 31 7.17 (2H, d, J = 7.9 Hz), 7.38 (2H, d, J = 7.9) Hz), 8.43 (3H, brs).571 Example ethyl 1-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3-yl] ° acetyl} piperidine-4-carboxylate dihydrochloride ethyl 1-{[5-{[(tert-butoxycarbonyl)amino]methyl} -6-isobutyl-2- you get 100) methyl-4-(4-methylphenyl) pyridin-3-yl]acetyl} piperidine-4-carboxylate [5- {[(tert-butoxycarbonyl)amino]methyl }-6- as a white powder of 0 50 yield VAY mg 0 ) isobutyl- 2-methyl-4-(4-methylphenyl)pyridin-3-ylJacetic acid 0 mM ¥,0Y mg 00Y) ethyl piperidine-4-carboxylate 5 mmol)

NARA RRS Gram) according to the method similar to that of "H-NMR (CDCl) 8: 0.97 (6H, d, J = 6.6 Hz), 1.27 (3H, t, J = 7.2 Hz), 1.37 (9H, 5) , 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, 5), 2.49 (3H, 5), 2.74 (2H, d, J = 7.2 Hz), 2.81-3.01 Vo (3H, m), 3.30 (2H, s), 3.49-3.60 (1H, m) , 4.15 (2H, gq, J = 7.2 Hz), 4.20 (1H, brs), 6.98 (2H, d, J = 8.1 Hz), 7.21 (2H, d, J = 8.1 Hz).ethyl 1-{[5] -(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) we get (¥ mg; yield AY ) pyridin-3-yl]acetyl } piperidine-4-carboxylate dihydrochloride ethyl 1- {[5-{[(tert-butoxycarbonyl)amino Jmethyl}-6-m) as a white powder of 00 isobutyl-2_methyl-4-(4-methylphenyl)pyridin-3 -yl]acetyl } piperidine-4- carboxylate (PY aggregated; 20754 mmol) according to method similar to that of Example EIMS (1+1) (011)

AVY Example 1-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl] Yo acetyl} piperidine-4-carboxylic acid dihydrochloride

1-{[5-{[(tert-butoxycarbonyl)amino]methyl} -6-isobutyl-2-methyl-4- we get (1v yield 750) (4-methylphenyl)pyridin-3-yl ]acetyl } piperidine-4-carboxylic acid ethyl 1-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6- as a white powder of (% AY isobutyl-2-methyl-4-(4-) methylphenyl)pyridin-3-yl] acetyl } piperidine-4-carboxylate (14 mg; 0.517 mmol) according to a method similar to that of Example (YA) 0 "H-NMR (CDCl) 8:1.01 (6H, - 1O 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, 5), 2.77-3.00 (2H, m), 3.06 (2H, d, J = 6.0 Hz), 3.42 (2H, 5), 3.53 (1H, d, J = 12.8 Hz), 4.10 2H, with 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).Ve 1-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) ?) We get the yield of cana YY ) pyridin-3-yl]acetyl}piperidine-4-carboxylic acid dihydrochloride 1-{[5- {[(tert-butoxycarbonyl)amino methyl }-6- as a white powder From 0 You isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yljacetyl} piperidine-4-carboxylic milligram) according to the method similar to that of the weight 1,474 mg 0 ) acid Ye . ( p. YA: (M+1) EIMS 677 Jha

N-2-adamantyl-2-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl]acetamide dihydrochloride Ye. tert-butyl {[5-[2-(2-adamantylamino)-2-oxoethyl]-2-isobutyl-6- on Jaa (VY mg; yield 04) methyl-4-(4-methylphenyl)pyridin -3-ylJmethyl} carbamate [5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2- as a white powder of no mg 0 ) methyl-4-(4-methylphenyl) pyridin-3-yl]acetic acid milligrams) according to the method 7,11 pas YA) 2-adamantanamine 5 grams) Yo

VF similar to the example method

H-NMR (CDCl;) 8: 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, 5), 2.57 (3H, s), 2.77 (2H, d, ] = 7.4 Hz), 3.30 (2H, 5), 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=79Hz), 7.22 (2H, d, J = 7.9 Hz).

N-2-adamantyl-2-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-) = © 0 001 mg; Yield of 8,1 ) methylphenyl)pyridin-3-yl]acetamide dihydrochloride tert-butyl {[5-[2-(2-adamantylamino)-2-oxoethyl]-2- as a white powder from (pon § A) isobutyl-6-methyl-4-(4-methylphenyl)pyridin-3-ylJmethyl ( carbamate (FY mM) according to method similar to example +o AOY "H-NMR 01480-205:0.98 (6H, d , 1 = 6.4 Hz), 1.47 (2H, 4,1 12.1 Hz), 1.63-1.94 00 (12H, m), 2.08-2.26 (1H, m), 2.40 (3H, 5), 2.80 (3H, 5) , 3.22 (2H, d, J = 5.84 Hz), 3.44 (2H, 5), 3.81 (2H, 5), 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).1Ye Joe 2-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyri din-3 -yl]-N-(2- 'Yo thienylmethylacetamide dihydrochloride [5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-butase1|mm) 0.117 mg; cana 1 ( diethyl cyanophosphonate mL) and add 0) 0 h. Pour 11 under refrigeration with ice. The resulting reaction mixture was stirred at room temperature for a period. The substance, ethyl acetate, washed the reaction mixture in a saturated brine; The mixture was extracted with saturated magnesium and dried on Ale sodium hydrogen carbonate extracted with anhydrous. The solvent was evaporated under reduced pressure and the remainder purified by chromatography. tert-butyl sulfate [(2-isobutyl-6-methyl-4-(4-methylphenyl)-5-{2-) columnar silica gel to give YO mg £4 3 0x0-2-[(2-thienylmethyl)amino]ethyl} pyridin-3-yl)methyljcarbamate As a white powder. (1A) High yield

1 uF” H-NMR (CDCls) 8:0.96 (6H, d, J = 6.6 Hz), 1.38 (9H, 5), 2.11-2.27 (1H, m), 2.37 (3H, 5), 2.56 (3H, 5), 2.76 (2H, d, ] = 7.2 Hz), 3.30 (2H, 5), 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). aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin- ? ( we get 0 TVA al mg 0 ) 3-y1]-N-(2-thienylmethyl)acetamide dihydrochloride tert- butyl [(2-isobutyl-6-methyl-4-(4-methylphenyl)-5-{2- as a white powder of mg £ A+) 0x0-2-[(2-thienylmethyl)amino]ethyl} pyridin-3-yl)methyljcarbamate (FY mM) according to method similar to example +8 "H-NMR (DMS0-d¢)3:0.97 (6H, d, J = 6.6 Hz), 2.12-2.33 (1H, m), 2.37 (3H, s), Ve 2.47 3H, 5), 2.59 (2H, s), 3.28 (2H, 5), 3.76 (2H, 5), 4.37 (2H, d, ] = 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). ive example 2-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyDpyridin-3-y1]-N- Yo (pyridin-3-ylmethyl)acetamide trihydrochloride tert-butyl [ (2-isobutyl-6-methyl-4-(4-methylphenyl)-5-{2-0x0-2-) we get ( 1 mg yield 7 14( [(pyridin-3-ylmethyl)amino]ethyl }pyridin-3-yl)methyl]carbamate [5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl- as a white powder of 0 le mM 0111 vol 0+ +) 2 -methyl-4-(4-methylphenyl)pyridin-3-ylJacetic acid Ye mmol) according to 11 mg; V YY) 3-(aminomethyl)pyridine 5 gram) 1-47. 4 Method similar to example method 11-1111 (CDCl) 6: 0.97 (6H, d, J = 6.6 Hz), 1.37 (9H, 5), 2.14-2.29 (1H, m), 2.38 (3H, s), 2.55 3H, 5), 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, 5), 6.88 (2H, d, J = 7.9 Hz), 7.15 (2H, d, J = Yo 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).

M (Y) we get 2-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin- aaa 0 ) 3-yl]-N-(pyridin-3 -ylmethyl)acetamide trihydrochloride yield of AA % (as a white powder of tert-butyl [(2-isobutyl-6-methyl-4-(4-methylphenyl)-5-{2-0)ox0-2) -[(pyridin-3-ylmethyl)amino}ethyl } pyridin-3-yl)methyljcarbamate compound VE 0 + mMg) according to the method similar to that of Example 32-7). H-NMR )01/50-05:0.98 (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, 5), 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 ).

V1 as 0 methyl 4-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3- yl]acetyl}amino)thiophene-3-carboxylate dihydrochloride [5] - {[(tert-butoxycarbonyl)amino]methyl} -6-isobutyl-2-methyl-4-(4- la — ( 1 methyl «(<> 0.11 mM 0 ( methylphenyl)pyridin -3-yljacetic acid

O-(7-5 mmol) 117 mg; 4 ) 4-aminothiophene-3-carboxylate 1 0 (naftate azabenzotriazol-1-y1)-1,1,3,3-tetramethyluromium hexafluorophosphate milliliter) and the mixture was stirred 01 (N,N-dimethylformamide mmol) at 75 p.a.h. The reaction mixture was poured into saturated saline solution; YE at room temperature for sodium hydrogen, the extract was washed with ethyl acetate, and the mixture extracted with anhydrous. The solvent was evaporated under pressure, saturated magnesium sulfate and dried over te carbonate 0 methyl 4-({[5-] to give silica 22a with the remainder by column chromatography reduced Sy {[(tert-butoxycarbonyl)amino]methyl} - 6-isobutyl-2-methyl-4-(4-methylphenyl) (% TVA aly mg; EE ) pyridin-3-yl]acetyl} amino)thiophene-3-carboxylate as white powder. 'H-NMR' (CDCl) 8: 0.98 (6H, d, J = 6.4 Hz), 1.40 (9H, 5), 2.24-2.33 (1H, m), 2.35 Yo (3H, s), 2.53 3H, 5), 2.77 (2H , d, J = 7.2 Hz), 3.52 (2H, 5), 3.79 (3H, 5), 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). methyl 4-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-) (¥ methylpheny!)pyridin-3-yl]acetyl }amino)thiophene-3-carboxylate dihydrochloride methyl 4-({[5-{[(tert-mg; yield £710) (as white powder of 111 ) © butoxycarbonyl)aminoJmethyl} -6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin- 3- mmol) according to 1.47 mg;17 ( yl]acetyl}amino)thiophene-3-carboxylate to the method similar to that of Example 7-?). H-NMR (DMSO-d¢)8:0.98 (6H, d, J = 6.6 Hz), 2.11-2.27 (1H, m), 2.35 (3H, s), (3H, s), 2.80 (2H, s), 3.14 (2H, s), 3.76-3.86 (SH, m), 7.17 (2H, d, J=7.9 Hz), Ve 2.48 (2H, d, J = 7.9 Hz), 7.80 (1H, d, J = 3.2 Hz), 8.26-8.45 (3H brs), 9.69 ( 1H). 7.32

YY Example 4-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3-yljacetyl} amino)thiophene-3-carboxylic acid dihydrochloride 4-({ [5- {[(tert-butoxycarbonyl)amino]methyl } -6-isobutyl-2-methyl-4- (1 VO) mg; 1 AY) (4-methylphenyl)pyridin-3-yl] acetyl} amino)thiophene-3-carboxylic acid methyl 4-({[5-{[(tert-butoxycarbonyl)amino] as a white powder of 0 TV yield of methyl} -6-isobutyl-2-methyl-4 -(4-methylphenyl)pyridin-3-yl]Jacetyl } amino) coagulant; 0890+ milligrams) according to method 0 (thiophene-3-carboxylate 1-4). Similar to example method 0 111-111 (CDCls) 8:0.98 (6H, d, J = 6.6 Hz), 1.40 ( 9H, 5), 2.11-2.24 (1H, m), 2.36 (3H, s), 2.52 (3H, 5), 2.78 (2H, 8), 3.49 (2H, 5), 4.03 (2H, 5), 4.20 (1H, brs), 6.98- 7.25 (4H, m), 7.85-8.05 (2H, m). 4-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) we get (¥ mg; 0 Y) pyridin-3-ylJacetyl} amino)thiophene-3 -carboxylic acid dihydrochloride 5 4-({[5-{[(tert-butoxycarbonyl)amino]methyl}- yield 774) as a white powder of 6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin- 3-yl]acetyl } amino )thiophene-3-

0 mmol) according to the method analogous to the 1.474 aaa 10) carboxylic acid of Method Example 7-?).” H-NMR (DMSO0-d¢)8:0.99 (6H, d, J = 6.6 Hz ), 2.11-2.27 (1H, m), 2.35 (3H, 31 2.50 (3H, 5), 2.79 (2H, 5), 3.14 (2H, 5), 3.81 (2H, 5), 7.17 (2H, d, J = 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).

YA Example methyl 4-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3- yllacetyl }amino)benzoate dihydrochloride methyl 4-({[5- {[(tert-butoxycarbonyl )amino]methyl } -6-isobutyl-2- we get ( 1 Ve mg; yield of 7 ) methyl-4-(4-methylphenyl)pyridin-3-yl]acetyl } amino )benzoate [5-{[(tert-butoxycarbonyl)amino methyl} -6-isobutyl- as a white powder of (£1 mol 117 mg; 0+ +) 2-methyl-4-(4) -methylphenyl)pyridin-3-yl]acetic acid mM) according to 011c 1 (VY) methyl 4-aminobenzoate 5 gram) AV-EYT Method similar to Example 1 "H-NMR" (J001) 8:0.98 (6H, d, J = 6.6 Hz), 1.38 (9H, 5), 2.15-2.28 (1H, m), 2.63 (3H, s), 2.77 (2H, d, J = 7.4 Hz), 3.47 (2H, 5), 3.89 (3H, 5), 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). methyl 4-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-?) = 0 mg; 017( methylphenyl)pyridin-3-ylJacetyl }amino)benzoate dihydrochloride methyl 4-({[5-{[(tert-butoxycarbonyl)amino] Yield 997%) (as white powder of methyl }-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl [Jacetyl } amino) mM) according to the method similar to that of 1,775 101) benzoate (YY) example © "H-NMR)01/50-415:0.99 (6H, d, J = 6.6 Hz), 2.10-2.30 (1H, m), 2.36 (3H, s), 2.49 (3H, s), 2.71 (2H, 5), 3.01 (2H, 5), 3.77 (2H, 5), 3.82 ( 3H, 5), 7.17 2H, d, J =

YYZ

1 8.1 Hz), 7.32 (2H, d, 1 8.1 Hz), 7.62 (2H, d, J = 8.9 Hz), 7.90 (2H, d, J = 8.9 Hz), 8.15 (3H, brs). 574 Example 4-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3-yl]acetyl } amino)benzoic acid dihydrochloride ° 4-({[ 5- {[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4- you get (1 (7 001 yield aaa YVO) (4-methylphenyl)pyridin-3-yljacetyl } amino)benzoic acid methyl 4-({[5-{[(tert-butoxycarbonyl)amino]}methyl}-6- as a white powder from

Ya. ) isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl]acetyl} amino)benzoate.) (J020) 6:0.99 (6H, d, J = 6.2 Hz), 1.37 (9H, 5), 2.12-2.27 (1H, m), 2.35 (3H, s), 2.87 3H, 5), 3.19 (2H , s), 3.87 (2H, 5), 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, ] = 8.5 Hz), 8.68 (2H, d, J = 8.5 Hz).4-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl) ?) we get 0 ( AY mg; yield of YYO ( pyridin-3-yl]acetyl}amino)benzoic acid dihydrochloride 4-({[5-{[(tert-butoxycarbonyl)amino methyl} -6-isobutyl-2- as a white powder of mg YY) methyl-4-(4-methylphenyl)pyridin-3-yl]acetyl }amino)benzoic acid (P= mmol) according to the method Similar to example method +690 "H-NMR 5:1.00(and 01180-0) ‎ (6H, d, J = 6.6 Hz), 2.12-2.28 (1H, m), 2.37 (3H, 5), Y. 2.50 (3H, s), 2.80 (2H, 5), 3.15 (2H, 5), 3.82 (2H, 5), 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).

EY, eg ethyl 2-[({[5-(aminomethyl)-6-isobutyl-2-methyi-4-(4-methylphenyl)pyri din-3- yl]acetyl }amino)methyl]-1, 3-thiazole-4-carboxylate dihydrochloride : Yo ethyl 2-({[(benzyloxy)carbonyljamino}methyl)-1 ,3-thiazole-4-carboxylate dissolved ( 1 1/10 hydrogen bromide acetic acid mmol) in a solution of 01.4 ma 8 )

milliliters); The solution was stirred at room temperature for two hours. A saturated aqueous precipitate (©) is collected. The resulting solution, sodium hydrogen carbonate, is concentrated by filtration and dissolved in ad. The undissolvable substance is separated by filtration. ethyl acetate at reduced pressure; The remainder is dissolved in Caan ethyl 2-(aminomethyl)-1,3- for dissolution and the leachate is concentrated under reduced pressure to give ethyl 2-[({[5- on Jani as oil.) 7400 mg. VAY productivity ) thiazole-4-carboxylate © {[(tert-butoxycarbonyl)amino]methyl}- 6-isobutyl-2-methyl-4-(4-methylphenyl) mg; Yield of 4 ) pyridin-3-yl]acetyl } amino)methyl]-1 ,3-thiazole-4-carboxylate [5- {[(tert-butoxycarbonyl) s mg) V4 ¥) as a white powder in oil ‎ ARE amino]methyl} -6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl]acetic acid —e Ye mmol) according to the method similar to that of the example 0.017 mg 4 (0.1) "H-NMR (CDCl3) 8:0.97 (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, 5), 2.75 (2H, d, J = 7.2 Hz), 3.34 (2H, 5), 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).Yo ethyl 2-[( {[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl) we get ( pyridin-3-yl]acetyl }amino)methyl]- 1,3 -thiazole-4-carboxylate dihydrochloride ethyl 2-[({[5-{[(tert-) as a white powder of (TAY mg; yield VYA) butoxycarbonyl)aminolmethyl}-6-isobutyl-2- methyl-4-(4-methylphenyl) pyridin-3- mM YA compound VV A) yl]acetyl} amino)methyl]-1,3-thiazole-4-carboxylate 0 (TY) according to Method similar to example H-NMR (5:0.98,01/50-0) (6H, d, J = 6.4 Hz), 1.31 (3H, t, J = 7.2 Hz), 2.10-2.23 (1H, m ), 2.38 (3H, 5), 2.49 3H, 5), 2.77 (2H, 5), 3.14 (2H, 5), 3.41 (2H, 5), 3.80 (2H, s), 4.31 (2H, q, J = 7.2 Hz), 4.51 (2H, d, J = 5.8 Hz), 7.17 (2H, d, I = 8.1 Hz), 7.32 (2H, d, J = 8.1 Hz), 8.36 (3H, brs), 8.91 ( 1H, s). A 571 is an example

0 2-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-( 4-methylphenyl)pyridin-3-yl]acetyl} amino)methyl]-1,3-thiazole-4-carboxylic acid dihydrochloride 2-[({[5-{[(tert-butoxycarbonyl)amino]methyl} -6-isobutyl-2-methyl- 4-(4-methylphenyl)pyridin-3-yl]acetyl } amino)methyl]-1,3 -thiazole-4-carboxylic ethyl 2-[({[5-{[(tert-mg; yield 1++) as white powder of £7A)acid © butoxycarbonyl) amino methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl)pyridin-3- mmol 0.077 ax £74) yljacetyl}amino)methyl]-1 ,3-thiazole-4-carboxylate (1-9 grams) according to the method similar to the example method

H-NMR (J0) &: 0.93 (6H, d, J = 6.6 Hz), 1.34 (9H, ,(? 2.09-2.26 (1H, m), 2.34 (3H, 5), 2.40 (2H) , 5), 2.48 (3H, 5), 3.24 (2H, s), 3.80 (2H, 5), 4.20 (1H, brs), 4.48 Ve (2H, d, J = 5.8 Hz), 7.09 (2H, d , J = 7.0 Hz), 7.19 (2H, d, ] = 7.0 Hz), 8.39 (1H, 5).2-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4) - on Joa a (Y methylphenyl)pyridin-3-yl]acetyl }amino)methyl-1,3-thiazole-4-carboxylic acid 2{({[5-{[(tert)-yield (£9) As a white powder of come YO) dihydrochloride butoxycarbonyl)amino]methyl }-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3- Yo mm +, £40 ana TV. ) yl]acetyl }amino)methyl}-1,3-thiazole-4-carboxylic acid gram molecule) according to the method similar to that of Example 7-?). J = 6.6 Hz), 2.12-2.28 (1H, m), 2.37 (3H, s), 2.50 (3H, s), 2.80 (2H, 5), 3.15 (2H, 5), 3.82 (2H, 5), 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). 0 0 7+7 Example methyl 1-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3- yl]acetyl }prolinate dihydrochloride methyl 1-{[ 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-) 1 (AVY mg; yield £07) methyl-4-(4-methylphenyl)pyridin-3-yl ]acetyl]prolinate Yo [5-{[(tert-butoxycarbonyl)amino]}methyl } -6-isobutyl-2- as a white powder of mM YAY cana 0 ) methyl-4-(4-methylphenyl) pyridin-3-yl]acetic acid only

£y¢ 1 4 4 ( methyl proline monohydrochloride combined 0.117 mmol) 1- 477 to the method similar to the example Wh' H-NMR (CDCl;) 6:0.98 (6H) method , 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, 5), -3.15 3.26 (2H, m), 3.48 (2H, s), 3.71 (3H, $), 4.11-4.21 (3H, m), 4.31-4.55 (2H, m), 7.02-7.15 (2H, m), -7.28 7.41 (2H, m).° methyl 1-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-on-Jaa (¥ mg; yield YVV,0) methylphenyl)pyridin -3-yljacetyl}prolinate dihydrochloride methyl 1-{[5-{[(tert-butoxycarbonyl)amino]methyl}- as a white powder of ( 1 mg; £07 ) 6-isobutyl-2-methyl-4 -(4-methylphenyl)pyridin-3-yl]acetyl } prolinate

AY-Y millimol) according to the method similar to that of the example 1.8480000

H-NMR (DMSO-dg)6: 0.97 (6H, d, J = 6.4 Hz), 1.76-1.91 (3H, m), 2.04-2.24 (2H, m), 2.40 (3H, 5), 2.65 (3H , 5), 2.96 (2H, 5), 3.17 (2H, 1, J = 6.7 Hz), 3.42 (2H, 5), 3.61 3H, 5), 3.77 (2H, 5), 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, 5).

YY as 10

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-y1}-3-(5-0xo-4,5-dihydro-1,2.4-oxadiazol- 3-yl)benzamide dihydrochloride tert-butyl {[5-amino-2-isobutyl-6-methyl-4-(4-methylphenyl) to a solution of mM)in 1 mg; VAY) pyridin -3-yl]methyl ( carbamate mM 1,0 cana VE 6) 3-cyanobenzoyl chloride (lll©) tetrahydrofurane ~~ ¥: mmol added). The mixture was stirred 1 µl 0 ( triethylamine µm) saturated aqueous (0 mL) into sodium hydrogen carbonate hr. YA solution was added for 170 h. The organic layer was washed with acetate-brine reaction mixture and the reaction was extracted with anhydrous. The solvent is evaporated under reduced pressure and saturated magnesium sulfate is purified and dried to give oil. to a solution of oil silica obtained by gel column chromatography GU YO mg; ¥ 097 mL ( hydroxylamine hydrochloride mL) add 0) ethanol yielding in mg; ; mmol) and stir the mixture; 701 (sodium carbonate 5 mol)

11 mL) to the reaction mixture and extracted (10 hours). Distilled water 11 Baal was added at 80 °C 1 to 00 Ha. The organic layer was washed with saturated brine and dried over acetate in an anhydrous mixture. The solvent was evaporated under Reduced pressure to give oil to magnesium sulfate solution

N,N'-carbonyldiimidazole (ml) ¥) tetrahydrofurane is added from the resulting oil for two hours. add Ate mg; 7 mmol) and the mixture was stirred at 0 saturated aqueous (YYE) (0 mL) into the reaction mixture and the mixture was extracted with sodium carbonate magnesium solution The organic layer was washed with saturated brine and dried over ethyl acetate The solvent was evaporated under Reduced pressure and the resulting residue is purified by analysis. WY sulfate ethyl to give oil. to a solution of the resulting oil in a silica gel column chromatography

Y); NH hydrogen chloride ethyl acetate solution (olla Y) acetate 0 ml) is added and the mixture is stirred at room temperature for ? hours. The solvent evaporates under pressure

N-[5-(aminomethyl)-6-isobutyl-2- to give a reduced hexane and the resulting residue crystallizes from methyl-4-(4-methylphenyl)pyridine-3-yl]-3-(5-0x0-4 ,5-dihydro-1,2,4-oxadiazole-3- As a white powder. (XY) mg; yield )) 0)yl)benzamide di hydrochloride "H-NMR (DOSO-dg)8:0.99 (6H, d, J = 6.6 Hz), 2.21-2.29 (1H, m), 2.29 (3H, 5), Vo 2.50 (3H, s), 2.96 (2H, s), 3.82 (2H, 5), 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). 47, pp. 1253-1258, 1998))

A NN-4 fF solution using a 97-well flat bottom plate at (14 μl) containing the test compound was added to a mixture of water (1) dimethylformamide (01 μM) 1 Tris-hydrochloride (1 μl) ); stabilizer pH YO 001 (1 mM aqueous Gly-Pro-p-NA and solution (V,0 pH) of rodent blood Yo) plasma μl) To prepare a mixed solution. come

SD in a conventional way and added to the mixed solution mentioned above and the enzyme Jeli starts at 0 “”C. The absorbance is measured after 0 hours and 1 hour using an accurate plate reader at a wavelength of 405 nm and the increment is estimated as 010. At the same time; the increment is estimated (AODc) in the absorbance of the reaction mixture without the test compound; the increase (AODb) in the absorbance of the © reaction mixture without the test compound and enzyme Inhibition 7 of dipeptidyl enzyme activity IV 2000886 is calculated from the following formula: {1-[ (AODs-AODb)/(AODc-AODb)]} x 100 The activity of the dipeptidyl peptidase TV inhibitor test compound group is expressed in ICs (nM) and shown in Table #.As shown above, the The compound of the present invention has superior inhibitory activity for dipeptidyl peptidase IV and is useful as an agent for the prevention or treatment of diabetes mellitus etc. Jha Experimental Y Determination of the inhibitory activity of dipeptidyl peptidase IV in plasma of a rodent vo with the same The method is as in the experimental example 11. The activity of the inhibition test compound is determined for Ldipeptidyl peptidase TV. The results are shown in Table 1. Table + Z

as mentioned above; The compound of the present invention has superior inhibitory activity for “dipeptidyl peptidase IV.” Therefore; It is useful as an agent for the prevention or treatment of diabetes & formulation example 1 (production of capsules) 1) Compound Example Yo 1 mg ¥ (cellulose powder 0 mg?) lactose mg 1 magnesium stearate (¢ mg total 0 mg °mix 1); (VY and ;) and they are packaged in gelatin capsules Example formulation ¥ (production of tablets) 1) Compound Example Ye 1 g?) 0 lactose g?) Corn starch 0 g?) bf carboxymethylcellulose calcium 1 g magnesium stearate (© g total 0001 tablet 05 g mixed with water for the total amounts of (Yo) and); and 10 g of m); Vacuum dried and granulated. The granules are mixed with VE g of 4 (and 1 g of 0) and the mixture is compressed with a tablet making machine, thus yielding 1,000 tablets containing Vo mg of example compound 1 per tablet. 01 Industrial Application

The compound of the present invention does not exhibit superior peptidase inhibitory activity and is advantageous as an agent for the prevention or treatment of diabetes mellitus etc. This application is based on Patent Applications Nos. 10A/Hai.Rd.3 and ;..L14 Filed in Japan' whose contents are incorporated herein by reference.

Claims (1)

Protection_elements 1-1 compound represented by the formula: ylam 4 rR’ Y VF where: ¢ RY and 82 are the same or different and each is a substituted hydrocarbon group | optionally © or an optionally substituted hydroxy group; rR? 1 is an optionally substituted aromatic group; l 3 is the ¢ amino group | of alkylene 4c sans is L A 9© is a hydrocarbon bond or group of a divalent chain ¢ (divalent) and 1" is (1) 11 acyl group with the formula: co-co-co-SO2R5 globular - -CO -NR5aR6a 038586 17 or -CS-NR5aR6a [where 85 and 86 are symmetrics or 1" different and each is a hydrogen atom optionally substituted hydrocarbon group 0 or heterocyclic group optionally substituted V0; 18258 and 8268 are the same or different and each may form a chydrogen atom 1 optionally substituted hydrocarbon group or an optionally substituted 1" heterocyclic group or may form 1658 R6ay heterocycle 1A containing an optionally substituted nitrogen together with the adjacent nitrogen atom]; (Y) 0 hydroxy group substituted; 0 (©) optionally substituted thiol group or 71 ( ; ) optionally substituted amino group; YY provided that: YY when X is a cethoxycarbonyl group then Q is a hydrocarbon group Y¢ divalent chain 1 of it. salt or Yo salt, where 8 and 82 are the same or different. 10 of the protective compound ?-compound 1 optionally substituted. hydrocarbon and each of them is a group 0 adhi Jay acyl group Cua) >?-compound 0000000 of claim 1 . carboxyl group Y where 8 and 82 are same or different 0 of claim compound ;-compound 1 to ¥ Selected substituents 1 optionally substituted by Crp alkyl of which form JS y group and Cp alkoxy-carbonyl group “Ci cycloalkyl group of 1 flexible alkoxy ¢ Cons aryl of the protector (¢ where 13 is the compound #-1 Aad «Cre alkyl group to ? Selected substituents from group 1 optionally substituted by .halogen and atom halogen to ? 1 atoms Optionally by 1 bond © is the Cua 0 bond of the protectant compound 1 carboxyl is the X group Cua 0 is the Cua 0 of the protectant compound 7-compound 1 of claim 1; which is: γ AY 5-(aminomethyl)-2-methyl-4-(4-methylphenyl)-6-neopentylnicotinic acid; 7 5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)nicotinic acid; ¥ methyl 3- {[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3- ¢ ylmethoxy}-1-methyl-1H-pyrazole-4-carboxylate; © { [2-isobutyl-6-methyl-4-(4-methylphenyl)-5-(2-morpholin-4-yl-2-oxoethyl)pyridin-1 : 3-yllmethyl}amine; 1 methyl 3-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3- 4 yljacetyl}amino)benzoate; ~~ * N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)pyridin-3-yl]isoxazole- Ve 4-carboxamide, 1 thereof. VY 14- A pharmaceutical agent comprising a compound of protectant 1 or its Y1 salt. -01-1 Pharmaceutical agent of Clause 4 that is Agent Y for the prevention or treatment of diabetes o(diabetes) Diabetic complications 1 Impaired glucose tolerance 11-1 peptidase inhibitor comprising a compound of protectant 1 or a salt thereof. inhibitor land 11 -1 claimant NY where peptidase is .dipeptidyl dipeptidase-IV Y (VF) Use of a compound of protectant 1 or its salt to produce an agent for the prevention of or Y for the treatment of recurrence disease (0:80616) “diabetic complications” Complications 7 ¢ Impaired glucose tolerance or obesity. : .peptidase to produce a salt or salt 1 inhibitor Using a compound of protection element -1401 -1#1 The method of producing a compound represented by the formula: Jah including CH;-NH, i.e. rR? (l-a) Y Cas ¥;1 and 0 are as specified in the claim RR? WR sala ° an alkylene bond or group t; and Xa 1 - 8085 ¢-SO2RS ¢-CO-ORS “-CORS” with the formula: 1(1) acyl group and 86 symmetrics or RS [where -CS-NR5aR6a or -CO-NR5aR6a 038586 A Two different hydrogen atom hydrocarbon groups, each with an optionally substituted heterocyclic group 9 or a heterocyclic hydrocarbon group 0 1 optionally substituted; 858 and 68 are the same or different and each may be a chydrogen atom 1" optionally substituted hydrocarbon group or an optionally substituted 0" heterocyclic group or R6as RSa may form a heterocycle 04 contain nitrogen optionally substituted together with the adjacent nitrogen atom]; (1) 0 hydroxy group substituted; (©1) 0 optionally substituted thiol group or VY (;) optionally substituted amino group; YA 1 or a salt thereof Which includes the subjugation of a compound represented by the formula: Yalam > , Xa LL La-CN RS 0 Ys (reduction reaction) for a 43a salt reduction reaction, where each symbol is as specified above; or YY salt