DESCRIPTION HYDROXYAMIDE COMPOUNDS HAVING ACTIVITY AS INHIBITORS OF HISTONE DΞACETYLASE (HDA C)

The present invention relates to a compound useful as a 5 medicament, and to a pharmaceutical composition comprising the same. BACKGROUND ART Histone deacetylase (hereinafter also referred as HDAC) is known to play an essential role in the transcriptional machinery for regulating gene expression, induce histone hyperacetylation and 10 to affect the gene expression. Therefore, it is useful as a therapeutic or prophylactic agent for diseases caused by abnormal gene expression such as inflammatory disorders, diabetes, diabetic complications, homozygous thalassemia, fibrosis, cirrhosis, acute promyelocytic leukaemia (APL), organ transplant rejections, 15 autoimmune diseases, protozoal infections, tumors, etc. WO 01/38322 discloses an inhibitor of histone deacetylase represented by the following formula:

Cy-L1-Ar-Y1-C(O)-NH-Z 20 wherein Cy is cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is optionally substituted; L1 is-(CH2)m-W- wherein m is an integer of 0 to 4, and W is selected from the group consisting of -C(O)NH-, -S(O)2NH-, etc.; 25 Ar is optionally substituted arylene, which is optionally fused to an aryl, heteroaryl ring, etc. ; Y1 is a chemical bond or a straight- or branched-chain saturated alkylene, wherein said alkylene is optionally substituted; and Z is selected from the group consisting of anilinyl, pyridyl, 30 thiadiazolyl and -O-M wherein M is H or a pharmaceutically acceptable cation. WO 02/22577 discloses the following hydroxamate compound as a deacetylase inhibitor:

wherein Ri is H, halo or a straight chain Ci-C6 alkyl; R2 is selected from H, Ci-Ci0 alkyl, C4-C9 cycloalkyl, C4-C9 heterocycloalkyl, C4-C9 heterocyclόalkylalkyl, cycloalkylalkyl, aryl, heteroaryl, etc. ; R3 and R4 are the same or different and independently H, Ci-C6 alkyl, acyl or acylamino, or R3 and R4 together with the carbon to which they are bound to represent C=O, C=S, etc., or R2 together with the nitrogen to which it is bound and R3 together with the carbon to which it is bound to form a C4-C9 heterocycloalkyl, a heteroaryl, a polyheteroaryl, a non-aromatic polyheterocycle, or a mixed aryl and non-aryl polyheterocycle ring; R5 is selected from H, Ci-C6 alkyl, etc.; n, ni, n2 and n3 are the same or different and independently selected from 0-6, when ni is 1-6, each carbon atom can be optionally and independently substituted with R3 and/or R4; X and Y are the same or different and independently selected from H, halo, Ci-C4 alkyl, etc.; or a pharmaceutically acceptable salt thereof. SUMMARY OF THE INVENTION The present invention relates to a novel compound useful as a medicament, and to a pharmaceutical composition comprising the same. More particularly, the present invention relates to a compound having a potent inhibitory effect on the activity of histone deacetylase. The inventors of the present invention have also found that histone deacetylase inhibitors, such as a compound of the formula (I) (hereinafter compound (I)), have a potent immunosuppressive effect and potent antitumor effect. Therefore, a histone deacetylase inhibitors such as compound (I) is useful as an active ingredient for an immunosuppressant and an antitumor agent, and useful as an active ingredient for a therapeutic or prophylactic agent for diseases such as inflammatory disorders, diabetes, diabetic complications, homozygous thalassemia, fibrosis, cirrhosis, acute promyelocytic leukaemia (APL), organ transplant rejections, autoimmune diseases, protozoal infections, tumors, etc. Accordingly, one object of the present invention is to provide a compound having biological activities for treating or preventing the diseases as stated above. A further object of the present invention is to provide a pharmaceutical composition containing the compound (I) as an active ingredient. A yet further object of the present invention is to provide use of the histone deacetylase inhibitors, such as compound (I) , for treating and preventing the diseases as stated above. A yet further object of the present invention is to provide a commercial package comprising the pharmaceutical composition containing the compound (I) and a written matter associated therewith, the written matter stating that the pharmaceutical composition may or should be used for treating or preventing the diseases as stated above. Thus, the present invention provides A compound having the following formula (I):

wherein R1 is hydrogen, lower alkyl, lower alkenyl, lower or higher alkynyl, cyclo(lower)alkyl, cyclo(higher)alkyl, cyclo(lower)alkyl(lower)alkyl, cyclo(higher)alkyl(lower)alkyl, cyclo(lower)alkenyl(lower)alkyl, aryl-fused cyclo(lower)alkyl, lower alkoxy, acyl, aryl, ar(lower)alkoxy, ar(lower)alkyl, heteroar(lower)alkyl, amino, heteroaryl, heterocyclyl or heterocyclyl(lower)alkyl, which may be substituted with one or more suitable substituent(s) , R2 is hydrogen or lower alkyl, X is arylene, heteroarylene, cycloalkylene, heterocycloalkylene or aryl-fused cycloalkylene, Y is arylene or heteroarylene, which may be substituted with one or more suitable substituent(s) , Z is lower alkenylene, which may be substituted with lower alkyl or halogen, or a salt thereof.

The above-mentioned compound or a salt thereof can be prepared by the processes as illustrated in the following reaction schemes or by the methods disclosed in the Preparations and Examples. In the above and subsequent descriptions of the present specification, suitable examples and illustration of the various definitions which the present invention intends to include within the scope thereof are explained in detail as follows.

Process A

R3 -X NH HaI- -E

R2 (A-I) (A-2)

(A-3) Process B R1 X N- Reduction R] -X N-

R2 R2 (A-3) (B-I)

Process C

R1—X N- Oxidation R1 X N-

R2 R^ (B-I) (C-I)

Process D

Wittig Reaction R1 X- -N- ►

R2 (C-I) Rx X- -N- -R4

R2 (D-Ia)

Process E

(E-2)

Process F

( E - 2 ) (F-I)

Process G

(F-I) (G-I)

Process H

Hydrolysis RJ -X N- -RA R2 or P Rx X- -N- -COOH (H-I) R2 or P (H-2)

Process I

H2N- -OR2

(1-2) Process J

Hal Y— HaI- -R^

(A-2) (J-D Process K

R1 — X- -NH HaI- -R<

R^ (J-I)

(K-I)

Process L

R5 — Xa-NH HaI- -R4

R' (J-I) (L-I) R5 — Xa-N Y Z R'

R^ (L-2)

Process M

Z R4

(L-2) (M-I) Process N Elimination Reaction of amino protecting group

(N-I)

Process O

R; /

SR8 H— -Xa-N- — Y- -z — — R4 (0- 1 )

R9 or P •o l X N- -R4 (N-I) R9 or P (0-2) wherein R1, R2, X, Y and Z are as defined above, Hal is halogen, E is protected carboxy or protected carboxy(lower)alkyl, F is hydroxy(lower)alkyl, G is formyl or formyl(lower)alkyl, R3 is hydroxy protecting group, R4 is protected carboxy, J is a single bond or lower alkylene, R5 and P is amino protecting group, Xa is divalent saturated 3 to 8-membered heteromonocyclic ring containing one nitrogen atom, Rxa is cyclo(lower)alkyl or lower alkyl substituted with cyclo(lower)alkyl, R6 is cyclo(lower)alkylidene or cyclo(lower)alkylene, and R7 is hydrogen, R8 is forrayl(lower)alkyl, or R7 and R8 are taken together to form oxo, R9 is lower alkyl. In the above-mentioned Processes A, B, C, D, E, F, G, H, I, J, K, L, M, N and O, each of the starting compounds can be prepared, for example, according to the procedures as illustrated in Preparations in the present specification or in a manner similar thereto. The compound (I) of the present invention is obtained from compound [1-2], for example, according to the following processes or methods disclosed in the Examples.

Process 1 Elimination Reaction R1 X N Y Z G N OR3 ►

R2 or P 0 (1-2) H R3 -X N- -N- -OH

R^ O

(D wherein R1, R2, R3, X, Y, P and Z are as defined above.

Process 1 The compound (I) is obtained by subjecting the compound (F- 2) to the elimination reaction of hydroxy protecting group in the presence of an acid. The acid includes such as hydrogen chloride solution (e.g. hydrogen chloride in solvent such as methanol, dioxane, ethyl acetate, diethyl ether, etc.), acetic acid, p-toluenesulfonic acid, boric acid, etc. Optionally,* one or more suitable solvent(s) for the deprotection is(are) used. Such solvent includes such as methanol, ethanol, ethyl acetate, dioxane, diethyl ether, acetic acid, etc. The temperature of the reaction is not critical, and the reaction is usually carried out. from under cooling to heating.

. The compound (I) may be a salt, which is also encompassed in the scope of the present invention. For example, when a basic group such as an amino group is present in a molecule, the salt is exemplified by an acid addition salt (e.g. salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, etc., salt with an organic acid such as methanesulfonic acid, benzenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid (e.g., [(lS,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-l- yl]methanesulfonic acid or an enantiomer thereof, etc.), fumaric acid, maleic acid, mandelic acid, citric acid, salicylic acid, malonic acid, glutaric acid, succinic acid, etc.), etc., and when an acidic group such as carboxyl group is present, the salt is exemplified by a basic salt (e.g. salt with a metal such as lithium, sodium, potassium, calcium, magnesium, aluminium, etc., a salt with amino acid such as lysine, etc.), etc. In addition, solvates (e.g. hydrate, ethanolate, etc.), anhydrous forms and other polymorphic forms or pharmaceutically acceptable salts of the compound (I) are also encompassed in the scope of the present invention. When the compound (I) has stereoisomers based on asymmetric carbon atom(s) or double bond(s), such as an optically active form, a geometric isomer and the like, such isomers and mixtures thereof are also encompassed in the scope of the present invention. In the above and subsequent descriptions of the present specification, suitable examples and illustration of the various definitions which the present invention intends to include within the scope thereof are explained in detail as follows. Each of the terms "halogen", "halo" and "Hal" may include fluorine, chlorine, bromine and iodine. The term "lower" used in the description is intended to mean 1 to 6 carbon atom(s) unless otherwise indicated. The term "higher" used in the description is intended to mean 7 to 11 carbon atom(s) unless otherwise indicated. Suitable "one or more" may include the number of 1 to 6, preferably 1 to 3. Suitable "lower alkyl" and "lower alkyl" moiety may include straight or branched alkyl having 1 to 6 carbon atom(s) such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- butyl, pentyl, tert-pentyl, neopentyl, hexyl, isohexyl, etc. Suitable "lower alkenyl" and "lower alkenyl" moiety may include straight or branched alkenyl having 2 to 6 carbon atom(s) such as vinyl, allyl, isopropenyl, pentenyl, hexenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, etc. Suitable "lower alkynyl" and "lower alkynyl" moiety may include straight or branched alkynyl having 2 to 6 carbon atom(s) such as ethynyl, propargyl, 3-methyl-1-pentynyl, etc. Suitable "higher alkynyl" and "heigher alkynyl" moiety may include straight or branched alkynyl having 7 to 11 carbon atom(s) such as heptynyl, octynyl, etc. Suitable "cyclo(lower)alkyl" and "cyclo(lower)alkyl" moiety may include σycloalkyl having 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. Suitable "cyclo(higher)alkyl" and "cyclo(higher)alkyl" moiety may include cycloalkyl having 7 to 11 carbon atoms such as cycloheptyl, cyclooctyl, adamantyl, etc. Suitable "cyclo(lower)alkenyl" and "cyclo(lower)alkenyl" moiety may include cycloalkenyl having 3 to 6 carbon atoms such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, etc. , Suitable "aryl-fused cyclo(lower)alkyl" and "aryl-fused cyclo(lower)alkyl" moiety may include aryl-fused cycloalkyl having 8 to 12 carbon atoms such as tetrahydronaphthyl, indanyl, benzocyclobutanyl, etc. Suitable "lower alkoxy" and "lower alkoxy" moiety may include straight or branched alkoxy having 1 to 6 carbon atom(s) such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, tert-pentyloxy, neopentyloxy, hexyloxy, isohexyloxy, etc. Suitable "halo(lower)alkyl" may include lower alkyl substituted with 1 to 3 halogen atom(s) such as monochloromethyl, dichloromethyl, trichloromethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monobromomethyl, dibromomethyl, tribromomethyl, monochloroethyl, dichloroethyl, trichloroethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, etc. Suitable "halo(lower)alkoxy" may include lower alkoxy substituted with 1 to 3 halogen atom(s) such as monochloromethoxy, dichloromethoxy, trichloromethoxy,, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monobromomethoxy, dibromomethoxy, tribromomethoxy, monochloroethoxy, dichloroethoxy, trichloroethoxy, monofluoroethoxy, difluoroethoxy, trifluoroethoxy, etc. Suitable "lower alkenylene" may include straight or branched alkenylene having 2 to 6 carbon atom(s) such as vinylene, 1- methylvinylene, 2-methylvinylene, 1-propenylene, 2-propenylene, 2- methyl-1-propenylene, 2-methyl-2-propenylene, 1-butenylene, 2- butenylene, 3-butenylene, 1-pentenylene, 2-pentenylene, 3- pentenylene, 4-pentenylene, 1-hexenylene, 2-hexenylene, 3- hexenylene, 4-hexenylene, 5-hexenylene, etc. Suitable lower alkenylene for Z may be, for example, vinylene, 1-methylvinylene, 2-methylvinylene, etc. Suitable "aryl" or "aryl" moiety described below may include C6-Ci6 aryl such as phenyl, naphthyl, anthryl, pyrenyl, phenanthryl, , azulenyl, etc., and this "aryl" or "aryl" moiety described below may be substituted with one or more substituent(s) selected from the group consisting of lower alkyl, halogen, lower alkoxy, amino, hydroxy, cyano, aryl, aryloxy, acyl, cyclo(lower)alkyl, heteroaryl, halo(lower)alkyl or halo(lower)alkoxy. Suitable "aryloxy" may include C6-C16 aryloxy such as phenoxy, naphthyloxy, anthryloxy, pyrenyloxy, phenanthryloxy, azulenyloxy, etc. Suitable "ar(lower)alkyl" may include phenyl(Ci-C6)alkyl such as benzyl, phenethyl, phenylpropyl, phenylbutyl, phenylhexyl, etc. , naphthyl(Ci-C6)alkyl such as naphthylmethyl, naphthylethyl, naphthylpropyl, naphthylbutyl, naphthylpentyl, naphtylhexyl, etc. Suitable "ar(lower)alkoxy" may include phenyl(Ci-C6)alkoxy such as benzyloxy, phenethyloxy, phenylpropoxy, phenylbutoxy, phenylhexyloxy, etc. , naphthyl(Ci-C6)alkoxy such as naphthylmethoxy, naphthylethoxy, naphthylpropoxy, naphthylbutoxy, naphthylpentyloxy, naphtylhexyloxy, etc. The "acyl" as used herein includes, for example, alkanoyl [e.g., formyl, lower alkyl-carbonyl (e.g., acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, pivaloyl, 2,2- dimethylpropanoyl, hexanoyl and the like), heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, icosanoyl and the like]; alkoxycarbonyl [e.g., lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl and the like) and the like]; lower alkyl-carbonyloxy(lower)alkylcarbonyl (e.g. acetyloxyacetyl, ethylcarbonyloxyacetyl and the like); arylcarbonyl [e.g., C6-I0 arylcarbonyl (e.g., benzoyl, toluoyl, naphthoyl, fluorenylcarbonyl and the like) ] ; arylalkanoyl [e.g., phenyl(lower)alkanoyl (e.g., phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutanoyl, phenylpentanoyl, phenylhexanoyl and the like), naphthyl(lower)alkanoyl (e.g., • naphthylacetyl, naphthylpropanoyl, naphthylbutanoyl and the like) and the like] ; arylalkenoyl [e.g., aryl(C3-C6)alkenoyl (e.g., phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl, phenylhexenoyl and the like) and the like)]; naphthylalkenoyl [e.g., naphthyl(C3-C6)alkenoyl (e.g., naphthylpropenoyl, naphthylbutenoyl, naphthyljmethacryloyl, naphthylpentenoyl, naphthylhexenoyl and the like) and the like]; arylalkoxycarbonyl [e.g., aryl(lower)alkoxycarbonyl such as phenyl(lower)alkoxycarbonyl (e.g., benzyloxycarbonyl and the like), fluorenyl(lower)alkoxycarbonyl (e.g., fluorenylmethyloxycarbonyl and the like) and the like] ; aryloxycarbonyl (e.g. , phenoxycarbonyl, naphthyloxycarbonyl and the like); aryloxyalkanoyl [e.g. , aryloxy(lower)alkanoyl (e.g., phenoxyacetyl, phenoxypropionyl and the like) and the like] ; heterocyclic acyl (e.g., heterocycliccarbonyl and the like); heterocyclicalkanoyl [e.g., heterocyclic(lower)alkanoyl (e.g., heterocyclicacetyl, heterocyclicpropanoyl, heterocyclicbutanoyl, heterocyclicpentanoyl, heterocyclichexanoyl and the like) and the like]; heterocyclicalkenoyl [e.g., heterocyclic(lower)alkenoyl (e.g. , heterocyclicpropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl, heterocyclichexenoyl and the like)]; carbamoyl; alkylcarbamoyl [e.g., lower alkylcarbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl and the like) ] ; alkoxycarbamoyl [e.g., lower alkoxycarbamoyl (e.g., methoxycarbamoyl, ethoxycarbamoyl and the like) ] and the like; arylcarbamoyl [e.g., Cβ-io arylcarbamoyl (e.g., phenylcarbamoyl, naphthylcarbamoyl and the like) and the like]; arylthiocarbamoyl [e.g., C6-io arylthiocarbamoyl (e.g., phenylthiocarbamoyl, naphthylthiocarbamoyl and the like) and the like]; alkylsulfonyl [e.g., lower alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl and the like)]; alkoxysulfonyl [e.g. , lower alkoxysulfonyl (e.g. , methoxysulfonyl, ethoxysulfonyl and the like) ] and the like; arylsulfonyl (e.g., phenylsulfonyl and the like); arylglyoxyloyl [e.g., C6-io arylglyoxyloyl (e.g., phenylglyoxyloyl, naphthylglyoxyloyl and the like) and the like]; heterocyclicglyoxyloyl; and the like. Each of these acyl is optionally substituted by one or more suitable substituent(s) . Suitable "lower alkanoyl" may include formyl and alkanoyl in which the alkyl portion is straight or branched alkyl having 1 to 6 carbon atom(s) such as acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, sec- butylcarbonyl, tert-butylcarbonyl, pentylcarbonyl, tert- pentylcarbonyl, neopentylcarbonyl, hexylcarbonyl, isohexylcarbonyl, etc. Suitable "cyclo(lower)alkylcarbonyl" may include cycloalkylcarbonyl, in which the cycloalkyl portion is cycloalkyl having 3 to 6 carbon atoms, such as cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc. Suitable "lower alkoxycarbonyl" may include alkoxycarbonyl in which the alkyl portion is straight or branched alkyl having 1 to 6 carbon atom(s) such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, tert-pentyloxycarbonyl, neopentyloxycarbonyl, hexyloxycarbonyl, isohexyloxycarbonyl, etc. Suitable "arylcarbonyl" may include arylcarbonyl in which the aryl portion is C6-Ci6 aryl such as phenylcarbonyl (benzoyl) , naphthylcarbonyl, anthrylcarbonyl, pyrenylcarbonyl, phenanthrylcarbonyl, azulenylcarbonyl, etc. Suitable "carbamoyl optionally mono- or di- substituted with lower alkyl(s)" includes carbamoyl; N-(lower)alkylcarbamoyl in which the alkyl portion is alkyl having 1 to 6 carbon atom(s) such as N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N- butylcarbamoyl, N-isobutylcarbamoyl, N-tert-butylcarbamoyl, N- pentylcarbamoyl, N-neopentylcarbamoyl, N-isopentylcarbamoyl, N- hexylcarbamoyl, etc.; N,N-di(lower)alkylcarbamoyl in which the alkyl portions are each alkyl having 1 to 6 carbon atom(s) such as N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N,N-dipropylcarbamoyl, N,N-dibutylcarbamoyl, N,N-diisobutylcarbamoyl, N,N-di-tert- butylcarbamoyl, N,N-dipentylcarbamoyl, N,N-dineopentylcarbamoyl, N,N-diisopentylcarbamoyl, N,N-dihexylcarbamoyl, N-ethyl-N- methylcarbamoyl, N-methyl-N-propylcarbamoyl, N-butyl-N- methylcarbamoyl, N-methyl-N-isobutylcarbamoyl, etc. Each of these carbamoyl is optionally substituted by one or more suitable substituent(s) . Suitable "arylcarbamoyl" may include arylcarbamoyl in which the aryl portion is C6-Ci6 aryl such as phenylcarbamoyl, naphthylcarbamoyl, anthrylcarbamoyl, pyrenylcarbamoyl, phenanthrylcarbamoyl, azulenylcarbamoyl, etc. Suitable "aryl(lower)alkenyl" may include phenyl(C2- C6)alkenyl such as styryl, phenylpropenyl, phenylbutenyl, phenylhexenyl, etc. , naphthyl(C2-C6)alkenyl such as naphthylvinyl, naphthylpropenyl, naphthylbutenyl, naphthylpentenyl, naphtylhexenyl, etc. Suitable "amino" may include unsubstituted amino, and amino mono- or di-substituted with substituent(s) selected from lower alkyl, lower alkanoyl, lower alkylsulfonyl and cycloalkyl such as N-(Ci-C6 alkyl)amino (e.g., N-methylamino, N-ethylamino, N- propylamino, N-(n-butyl)amino, N-isobutylamino, N-(t-butyl)amino, etc.), N-(Ci-C6 alkanoyl)amino (e.g., N-acetylamino, N- ethylcarbonylamino, N-propylcarbonylaminό, N-(n-butylcarbonyl)amino, N-isobutylcarbonylamino, N-(t-butylcarbonyl)amino, etc.), N-(Ci-C6) alkylsulfonylamino(e.g. , N-methanesulfonylamino, N- ethanesulfonylamino, N-buthylsulfonylamino, etc.), N-(C3-C6 cycloalkyl)amino (e.g. , N-cyclopropylamino, N-cyclobutylamino, N- cyclopentylamino, N-cyclohexylamino, etc. ) , N,N-di(Ci-C6 alkyl)amino (e.g., N,N-dimethylamino, N,N-diethylamino, N-ethyl-N- methylamino, etc. ) , etc. Suitable example of "heteroaryl" and "heteroar" moiety may include unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl, IH-I,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g. lH-tetrazolyl, 2H-tetrazolyl, etc.), etc.; unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), for example, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, etc.; unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.), etc.; unsaturated condensed heterocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl, benzoxadiazolyl, etc.; unsaturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolyl, isothiazolyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4- thiadiazolyl, 1,2,5-thiadiazolyl, etc.), dihydrothiazinyl, etc.; unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 or 2 sulfur atom(s), for example, thienyl, dihydrodithiinyl, dihydrodithionyl, etc.; unsaturated condensed heterocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl, benzothiadiazolyl, imidazothiadiazolyl, etc.; unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing an oxygen atom, for example, furyl etc. ; unsaturated condensed heterocyclic group containing an oxygen atom, for example, benzofuranyl or benzotetrahydrofuranyl, etc.; unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing an oxygen atom and 1 or 2 sulfur atom(s), for example, dihydroox'athiinyl, etc.; unsaturated condensed heterocyclic group containing 1 or 2 sulfur atom(s), for example benzothienyl, benzodithiinyl, etc.; unsaturated condensed heterocyclic group containing an oxygen atom and 1 or 2 sulfur atom(s), for example, benzoxathiinyl, etc. Suitable example of "heterocyclyl" or "heterocyclyl" moiety may include saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, azetidinyl, etc.; saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, morpholino, etc.; saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example thiazolidinyl, thiomorpholinyl, thiomorpholino, etc. ; saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 or 2 oxygen atom(s), for example, tetrahydrofuranyl, tetrahydropyranyl, dioxacyclopentanyl, dioxacyclohexanyl, etc.; saturated condensed heterocyclic group containing 1 to 3 nitrogen atom(s), for example, hexahydropyrrolopyrazinyl, etc.; and the like, and this "heterocyclic group" may have one or more suitable substituent(s) selected from the group consisting of halogen, lower alkyl and aryl. The term "arylene" refers to the diradical group derived from aryl (including substituted aryl) as defined above and is exemplified by 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 1,2- naphthylene and the like. The term "heteroarylene" refers to the diradical group derived from heteroaryl (including substituted heteroaryl) as defined above and is exemplified by the groups 2,6-pyridylene, 3,6- pyridazinylene, 2,5-pyrazinylene, 2,5-pyrimidinylene, 1,2- quinolinylene, 1,8-quinolinylene, 1,4-benzofuranylene, 2,5- prudinylene, 2,5-indolenyl, and the like. The term "cycloalkylene" refers to the diradical group derived from cycloalkyl (including substituted cycloalkyl) as defined above and is exemplified by the groups 1,4-cyclohexylene, 1,3-cyclopentylene, 1,3-cyclobutylene, and the like. The term "heterocycloalkylene" refers to the diradical group derived from heterocyclyl (including substituted heterocyclyl) as defined above and is exemplified by the groups piperidine, pyrrolidine, piperidone, pyrrolidone and the like. The term "aryl-fused cycloalkylene" refers to the diradical group derived from aryl-fused cyclo(lower)alkyl (including substituted aryl-fused cyclo(lower)alkyl) as defined above and is exemplified by the groups indanyl, tetrahydronaphthalene and the like. Suitable "suitable substituent" may include lower alkyl, aryl, cyclo(lower)alkyl, cyclo(lower)alkenyl, heterocyclic group, and the like. Suitable "protected carboxy" or "protected carboxy" moiety in the "protected carboxy(lower)alkyl" may be a conventional protecting group such as an esterified carboxy group, or the like, and concrete examples of the ester moiety in said esterified carboxy group may be the ones such as lower alkyl ester [e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester, hexyl ester, 1-cyclopropylethyl ester, etc.] which may have suitable substituent(s), for example, lower alkanoyloxy(lower)alkyl ester [e.g. acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, 1-acetoxyethyl ester, 1-propionyloxyethyl ester, pivaloyloxyethyl ester, 2- propionyloxyethyl ester, hexanoyloxymethyl ester, etc.], lower alkanesulfonyl(lower)alkyl ester [e.g. 2-mesylethyl ester, etc.] or mono(or di or tri)halo(lower)alkyl ester [e.g. 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.]; higher alkyl ester [e.g. heptyl ester, octyl ester, 3,5-dimethyloctyl ester, 3,7-dimethyloctyl ester, nonyl ester, decyl ester, undecyl ester, dodecyl ester, tridecyl ester, tetradecyl ester, pentadecyl ester, hexadecyl ester, heptadecyl ester, octadecyl ester, nonadecyl ester, adamantyl ester, etc.]; lower alkenyl ester [e.g. (C2-Cg)alkenyl ester (e.g. vinyl ester, allyl ester, etc.)]; lower alkynyl ester [e.g. (C2-C6)alkynyl ester (e.g. ethynyl ester, propynyl ester, etc.)]; ar(lower)alkyl ester which may have one or more suitable substituent(s) [e.g. phenyl(lower)alkyl ester which may have 1 to 4 lower alkoxy, halogen, nitro, hydroxy, lower alkyl, phenyl, or halo(lower)alkyl (e.g. benzyl ester, 4-methoxybenzyl ester, 4-chlorobenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-tert-butylbenzyl ester, 4-trifluoromethylbenzyl ester, etc.)]; aryl ester which may have one or more suitable substituent(s) [e.g. phenyl ester which may have 1 to 4 lower alkyl, or halogen (e.g. phenyl ester, 4-chlorophenyl ester, tolyl ester, 4-tert-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc.)]; cycloalkyloxycarbonyloxy(lower)alkyl ester which may have lower alkyl (e.g., cyclopentyloxycarbonyloxymethyl ester, cyclohexyloxycarbonyloxymethyl ester, cycloheptyloxycarbonyloxymethyl ester, 1-methylcyclohexyloxycarbonyloxymethyl ester, 1-(or 2-) [cyclopentyloxycarbonyloxy]ethyl ester, 1-(or 2-) [cyclohexyloxycarbonyloxy]ethyl ester, l-(or 2-)- [cycloheptyloxycarbonyloxy]ethyl ester, etc.), etc.]; (5-(lower)alkyl-2-oxo-l,3-dioxol-4-yl) (lower)alkyl ester [e.g., (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl ester, (5-ethyl-2-oxo-l,3- dioxol-4-yl)methyl ester, (5-propyl~2-oxo-l,3-dioxol-4-yl)methyl ester, l-(or 2-) (5-methyl-2-oxo-l,3-dioxol-4-yl)ethyl ester, l-(or 2-)(5-ethyl-2-oxo-l,3-dioxol-4-yl)ethyl ester, l-(or 2-) (5-propyl- 2-oxo-l,3-dioxol-4-yl)ethyl ester, etc.]; and the like, in which the preferred one may be lower alkyl ester, lower alkanoyloxy(lower)alkyl ester, ar(lower)alkyl ester which may have one or more suitable substituent(s) , cycloalkyloxycarbonyloxy(lower)alkyl ester which may have lower alkyl, higher alkyl ester, and [5-(lower)alkyl-2~oxo-l,3-dioxol-4- yl] (lower)alkyl ester; and the more preferred one may be methyl ester, ethyl ester, isobutyl ester, butyl ester, pentyl ester, hexyl ester, benzyl ester, 4-trifluoromethylbenzyl ester, 4-chlorobenzyl ester, adamantyl ester, (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl ester, (1- cyclohexyloxycarbonyloxy)ethyl ester and pivaloyloxymethyl ester, , and the like, in which the preferred one may be (C^-C^)alkyl ester, and the most preferred one may be ethyl ester. Suitable "amino protecting group" may include a conventional protective group such as ar(lower)alkoxycarbonyl and lower alkoxycarbonyl, in which the preferred one may be PhCnYl(C1-C4 )alkoxycarbonyl and fluorenyl(C1-C4)alkoxycarbonyl and (C1-C4 )alkoxycarbonyl, and the most preferred one may be benzyloxycarbonyl, fluorenylmethoxycarbonyl and tert-butoxycarbonyl. Suitable "hydroxy(lower)alky1" may included hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, and the like. Suitable nformyl(lower)alkyl" may include formylmethyl, formylethyl, formylpropyl, formylisopropyl, formylbutyl, formylpentyl, formylhexyl, and the like. Suitable "hydroxy protecting group" is as follows: lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, etc.), preferably methyl; lower alkoxy(lower)alkyl (e.g. methoxymethyl, etc. ) ; lower alkoxy(lower)alkoxy(lower)alkyl (e.g. 2-methoxyethoxymethyl, etc. ) ; ar(lower)alkyl in which the aryl portion is optionally substituted with one or more suitable substituent(s) (e.g. benzyl (Bn), p- methoxybenzyl, m,p-dimethoxybenzyl, etc.), preferably benzyl; ar(lower)alkoxy(lower)alkyl in which the aryl portion is optionally substituted with one or more suitable substituent(s) (e.g. benzyloxymethyl, p-methoxybenzyloxymethyl, etc.); (lower)alkylthio(lower)alkyl (e.g. methylthiomethyl, ethylthiomethyl, propylthiomethyl, isopropylthiomethyl, butylthiomethyl, isobutylthiomethyl, hexylthiomethyl, etc.), etc., preferably methylthiomethyl; trisubstituted silyl such as tri(lower)alkylsilyl (e.g. trimethylsilyl, triethylsilyl, tributylsilyl, tert- butyldimethylsilyl, tri-tert-butylsilyl, etc.), lower alkyldiarylsilyl (e.g. methyldiphenylsilyl, ethyldiphenylsilyl, propyldiphenylsilyl, tert-butyldiphenylsilyl (TBDPS), etc.), etc., preferably tert-butyldimethylsilyl (TBDMS) and tert- butyldiphenylsilyl; heterocyclic group (e.g. tetrahydropyranyl, etc. ) ; acyl as described below [e.g. aliphatic acyl such as lower alkanoyl (e.g. acetyl, propanoyl, pivaloyl, etc.); aromatic acyl (e.g. benzoyl (Bz), toluoyl, naphthoyl, fluorenylcarbonyl, etc.); lower alkoxy-carbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc. ) , etc. ; ar(lower)alkoxycarbonyl in which the aryl portion is optionally substituted with one or more suitable substituent(s) (e.g. benzyloxycarbonyl, bromobenzyloxycarbonyl, etc.); lower alkylsulfonyl (e.g. methylsulfonyl, ethylsulfonyl, etc.); lower alkoxysulfonyl (e.g. methoxysulfonyl, ethoxysulfonyl, etc. ); ar(lower)alkanoyl (e.g. phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutanoyl, phenylpentanoyl, phenylhexanoyl, naphthylacetyl, naphthylpropanoyl, naphthylbutanoyl, nap'hthylisobutanoyl, naphthylpentanoyl, naphthylhexanoyl, etc. ) ; ar(lower)alkenoyl such as ar(C3-C6)alkenoyl (e.g. phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl, phenylhexenoyl, naphthylpropenoyl, naphthylbutenoyl, naphthylmethacryloyl, naphthylpentenoyl, naphthylhexenoyl, etc. ) , etc. ] ; lower alkenyl (e.g. vinyl, allyl, etc. ); , etc. The preferable hydroxy protecting group for the present invention is, for example, tetrahydropyranyl, trimethylsilyl, t- butyldimethylsilyl, etc. The following abbreviations are also used in the present specification: Boc (t-butyloxycarbonyl); HOBT or HOBt (1- hydroxybenzotriazole) ; WSCD (l-ethyl-3-(3'-dimethylaminbpropyl)- carbodiimide); WSCD'HCl or EDCI (l-^ethyl-S-O'- dimethylaminopropyl)carbodiimide hydrochloride); DMF (N,N- dimethylformamide) ; aq. (aqueous solution); Me (methyl); MeOH (methanol) ; MeCN(acetonitrile) ; Et (ethyl) ; Et3N (triethylamine) ; EtOH (ethanol); IPE (diisopropyl ether); tBu (t-butyl); TsCl (p- toluenesulfonyl chloride); Ac (acetyl); AcOH (acetic acid); AcOEt (ethyl acetate); AcONH4 (ammonium acetate); Ph (phenyl); DIEA (diisopropylethylamine); THP (tetrahydropyranyl); THF (tetrahydrofuran) and TFA or TFAOH (trifluoroacetic acid). Test Method In order to show the usefulness of the, compound (I) of the invention, the pharmacological test result of the representative 62 compound of the present invention is shown in the following.. Test 1; Determination of histone deacetylase inhibitor activity The partial purification of human histone deacetylase', the preparation of [3H] acetyl histones, and the assay for histone deacetylase activity were performed basically according to the method as proposed by Yoshida et al. as follows. Partial purification of human histone deacetylase The human histone deacetylase was partially purified from human T cell leukemia Jurkat cells. Jurkat cells (5 x 108 cells) were suspended in 40 mL of the HDA buffer consisting of 15 iriM potassium phosphate, pH 7.5, 5% glycerol and 0.2 mM EDTA. After homogenization, nuclei were collected by centrifugation (35,000 x g, 10 min) and homogenized in 20 mL of the same buffer supplemented with 1 M (NH4J2SO4. The viscous homogenate was sonicated and clarified by centrifugation (35,000 x g, 10 min), and the deacetylase was precipitated by raising the concentration of (NH4J2SO4 to 3.5 M. The precipitated protein was dissolved in 10 mL of the HDA buffer and dialyzed against 4 liters of the same buffer. The dialyzate was then.loaded onto a DEAE-cellulose (Whatman DE52) column (25 x 85 mm) equilibrated with the same buffer and eluted with 300 mL of a linear gradient (0-0.6 M) of NaCl. A single peak of histone deacetylase activity appeared between 0.3 and 0.4 M NaCl. Preparation of [3H] acetyl histone To obtain [3H] acetyl-labeled histone as the substrate for the histone deacetylase assay, 1 x 108 cells of Jurkat in 20 mL of RPMI-1640 medium (supplemented with 10% FBS, penicillin (50 units/mL) and streptomycin (50 μg/mL)) were incubated with 300 MBq [3H] sodium acetate in the presence of 5 mM sodium butyrate for 30 minutes in 5% CO2-95% air atmosphere at 37°C in a 75 cm2 flask, harvested into a centrifuge tube (50 mL), collected by centrifugation at 1000 rpm for 10 minutes, and washed once with phosphate-buffered saline. The washed cells were suspended in 15 mL of ice-cold lysis buffer (10 mM Tris-HCl, 50 mM sodium bisulfite, 1% Triton X-100, 10 mM MgCl2, 8.6% sucrose, pH 6.5). After Dounce homogenization (30 stroke), the nuclei were collected by centrifugation at 1000 rpm for 10 minutes, washed 3 times with 15 mL of the lysis buffer, and once with 15 itiL of ice-cooled washing buffer (10 mM Tris-HCl, 13 mM EDTA, pH 7.4) successively. The pellet was suspended in 6 πlL of ice-cooled water using a mixer, and 68 μl of H2SO4 was added to the suspension to give a concentration of 0.4 N. After incubation at 4°C for 1 hour, the suspension was centrifuged for 5 minutes at 15, 000 rpm, and the supernatant was taken and mixed with 60 mL of acetone. After overnight incubation at -200C, the coagulated material was collected by microcentrifugation, air-dried, and stored at -8O0C. Assay for histone deacetylase activity For the standard assay, 10 μl of [3H] acetyl-labeled histones were' added to 90 μl of the enzyme fraction, and the mixture was incubated at 25°C for 30 minutes. The reaction was stopped by addition of 10 μl of HCl. The released [3H] acetic acid was extracted with 1 mL of ethyl acetate, and 0.9 mL of the solvent layer was taken into 10 mL of toluene scintillation solution for determination of radioactivity. Test 2; Determination of T-cell growth inhibitor activity The T lymphocyte blastogenesis test was performed in microtiter plates with each well containing 1.5 x 105 splenic cells of Lewis rats in 0.1 mL RPMI-1640 medium supplemented with 10% fetal bovine serum (FBS), 50 mM 2-mercaptoethanol, penicilln (100 units/mL) and streptomycin (100 μg/mL), to which Concanavalin A (1 μg/mL) was added. The cells were incubated at 37°C in a humidified atmosphere of 5% CO2 for 72 hours. After the culture period, suppressive activities of the test compounds in T lymphocyte blastogenesis were quantified by AlamarBlue (trademark) Assay. The test samples were dissolved in DMSO and further diluted with RPMI- 1640 medium and added to the culture. The activities of the test compounds were expressed as IC5O. The results of those tests are shown in the Table 1.

Table 1: HDAC inhibitory activity and T-cell growth inhibitory activity of the compound of the present invention Examples Test 1: Test 2: HDAC T-cell inhibitory growth activity inhibitory IC50 (nM) activity IC50 (nM) Example 3 < 10 < 25 Example 60 < 10 < 25 Example 74 < 10 < 25 Example 76 < 10 < 25 Example 82 < 10 < 25 Example 116 < 10 < 25 Example 119 < 10 < 25 Example 123 < 10 < 25 Example 174 < 10 < 25 Example 189 < 10 < 25

The pharmaceutical composition of the present invention comprising histone deacetylase inhibitor such as the compound (I) is useful as a therapeutic or prophylactic agent for diseases caused by abnormal gene expression, such as inflammatory disorders, diabetes, diabetic complications, homozygous thalassemia, fibrosis, cirrhosis, acute promyelocytic leukaemia (APL), protozoal infection, etc. Furthermore, it is useful as an antitumor agent or immunosuppressant, which prevents an organ transplant rejection and autoimmune diseases as exemplified below: rejection reactions by transplantation of organs or tissues such as the heart, kidney, liver, bone marrow, skin, cornea, lung, pancreas, small intestine, limb, muscle, nerve, intervertebral disc, trachea, myoblast, cartilage, etc. ; graft-versus-host reactions following bone marrow transplantation; autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes, etc. ; and infections caused by pathogenic microorganisms (e.g. Aspergillus fumigatus, Fusarium oxysporum. Trichophyton asteroides, etc.). Furthermore, pharmaceutical preparations of the histone deacetylase inhibitor, such as the compound (I), are useful for the therapy or prophylaxis of the following diseases. Inflammatory or hyperproliferative skin diseases or cutaneous, manifestations of immunologically-mediated diseases (e.g. psoriasis, atopic dermatitis, contact dermatitis, eczematoid dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides, erythema, dermal eosinophilia, lupus erythematosus, acne, alopecia areata, etc.); autoimmune diseases of the eye (e.g. keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, conical keratitis, corneal epithelial dystrophy, keratoleukoma, ocular premphigus, Mooren's ulcer, scleritis. Grave's ophthalmopathy, Vogt-Koyanagi-Harada syndrome, keratoconjunctivitis sicca (dry eye), phlyctenule, iridocyclitis, sarcoidosis, endocrine ophthalmopathy, etc.); reversible obstructive airways diseases [asthma (e.g. bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, etc.), particularly chronic or inveterate asthma (e.g. late asthma, airway hyper-responsiveness, etc.), bronchitis, etc.]; mucosal or vascular inflammations (e.g. gastric ulcer, ischemic or thrombotic vascular injury, ischemic bowel diseases, enteritis, necrotizing enterocolitis, intestinal damages associated with thermal burns, leukotriene B4-mediated diseases, etc.); intestinal inflammations/allergies (e.g. coeliac diseases, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, etc. ) ; food-related allergic diseases with symptomatic manifestation remote from the gastrointestinal tract (e.g. migrain, rhinitis, eczema, etc.); renal diseases (e.g. intestitial. nephritis, Goodpasture's syndrome, hemolytic uremic syndrome, diabetic nephropathy, etc.); nervous diseases (e.g. multiple myositis, Guillain-Barre syndrome, Meniere's disease, multiple neuritis, solitary neuritis, cerebral infarction, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), radiculopathy, etc.); cerebral ischemic diseases (e.g., head injury, hemorrhage in brain (e.g., subarachnoid hemorrhage, intracerebral hemorrhage, etc. ) , cerebral thrombosis, cerebral embolism, cardiac arrest, stroke, transient ischemic attack (TIA) , hypertensive encephalopathy, etc.); endocrine diseases (e.g. hyperthyroidism, Basedow's disease, etc.); hematic diseases (e.g. pure red cell aplasia, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, anerythroplasia, etc.); bone diseases (e.g. osteoporosis, etc.); respiratory diseases (e.g. sarcoidosis, pulmonary fibrosis, idiopathic interstitial pneumonia, etc.); skin diseases (e.g. dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, photosensitivity, cutaneous T-cell lymphoma, etc.); circulatory diseases (e.g. arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, myocardosis, etc.); collagen diseases (e.g. scleroderma, Wegener's granuloma, Sjogren's syndrome, etc. ) ; adiposis; eosinophilic fasciitis; periodontal diseases (e.g. damage to gingiva, periodontium, alveolar bone or substantia ossea dentis, etc. ) ; nephrotic syndrome (e.g. glomerulonephritis, etc.); male pattern alopecia, alopecia senile; muscular dystrophy; pyoderma and Sezary syndrome; chromosome abnormality-associated diseases (e.g. Down's syndrome, etc. ) ; Addison's disease; active oxygen-mediated diseases {e.g. organ injury [e.g. ischemic circulation disorders of organs (e.g. heart, liver, kidney, digestive tract, etc.) associated with preservation, transplantation, ischemic diseases (e.g. thrombosis, cardial infarction, etc. ) , etc. ] ; intestinal diseases (e.g. endotoxin shock, pseudomembranous colitis, drug- or radiation-induced colitis, etc.); renal diseases (e.g. ischemic acute renal insufficiency, chronic renal failure, etc. ) ; pulmonary diseases (e.g. toxicosis caused by pulmonary oxygen or drugs (e.g. paracort, bleomycin, etc.), lung cancer, pulmonary emphysema, etc.); ocular diseases (e.g. cataracta, iron-storage disease (siderosis bulbi) , retinitis, pigmentosa, senile plaques, vitreous scarring, corneal alkali burn, etc. ) ; dermatitis (e.g. erythema multiforme, linear immunoglobulin A bullous dermatitis, cement dermatitis, etc.); and other diseases (e.g. gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by.environmental pollution (e.g. air pollution, etc. ), aging, carcinogen, metastasis of carcinoma, hypobaropathy, etc. )}; diseases caused by histamine release or leukotriene C4 release; restenosis of coronary artery following angioplasty and prevention Of postsurgical adhesions; autoimmune diseases and inflammatory conditions (e.g., primary mucosal edema, autoimmune atrophic gastritis, premature menopause, male sterility, juvenile diabetes mellitus, pemphigus vulgaris, pemphigoid, sympathetic ophthalmitis, lens-induced uveitis, idiopathic leukopenia, active chronic hepatitis, idiopathic, cirrhosis, discoid lupus erythematosus, autoimmune orchitis, arthritis (e.g. arthritis deformans, etc.), polychondritis, etc.); Human Immunodeficiency Virus (HIV) infection, AIDS; allergic conjunctivitis; hypertrophic cicatrix, keloid due to trauma, burn or surgery, etc. Therefore, the pharmaceutical composition of the present invention is useful for the therapy and prophylaxis of liver diseases [e.g. immunogenic diseases (e.g. chronic autoimmune liver diseases such as autoimmune hepatic diseases, primary biliary cirrhosis, sclerosing cholangitis, etc.), partial liver resection, acute liver necrosis (e.g. necrosis caused by toxins, viral hepatitis, shock, anoxia, etc.), hepatitis B, non-A non-B hepatitis, hepatocirrhosis, hepatic failure (e.g. fulminant hepatitis, late- onset hepatitis, "acute-on-chronic" liver failure (acute liver failure on chronic liver diseases, etc.) , etc. ) , etc. ] . The pharmaceutical composition of the present invention can be used in the form of pharmaceutical preparation, for example, in a solid, semisolid or liquid form, which contains the histone deacetylase inhibitor, such as the compound (I), as an active ingredient in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral administrations. The active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, injections, ointments, liniments, eye drops, lotion, gel, cream, and any other form suitable for use. The carriers those can be used for the present invention include water, glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea and other carriers suitable for use in manufacturing preparations in a solid, semisolid, or liquid form. Furthermore, auxiliary, stabilizing, thickening, solubilizing and coloring agents and perfumes may be used. For applying the composition to human, it is preferable to apply it by intravenous, intramuscular, topical or oral administration, or by a vascular stent impregnated with the compound (I) . While the dosage of therapeutically effective amount of the histone deacetylase inhibitor, such as the compound (I), varies from and also depends upon the age and condition of each individual patient to be treated, when an individual patient is to be treated, in the case of intravenous administration, a daily dose of 0.01-10 mg of the histone deacetylase inhibitor, such as the compound (I), per kg weight of human being, in the case of intramuscular administration, a daily dose of 0.1-10 mg of the histone deacetylase inhibitor, such as the compound of the formula (I), per kg weight of human being, and in the case of oral administration, a daily dose of 0.5-50 mg of the histone deacetylase inhibitor, such as the compound (I), per kg weight of human being, is generally given for treatment. During the preparation of the above-mentioned pharmaceutical administration forms, the compound (I) or a salt thereof can also be combined together with other immunosuppressive substances, for example rapamycin, mycophenolic acid, cyclosporin A, tacrolimus or brequinar sodium. Hereinafter the reactions in each Preparations and Examples for preparing the compound (I) of the present invention are explained in more detail. The invention should not be restricted by the following Preparations and Examples in any way.

Preparation 1 A mixture of methyl 6-chloronicotinate (5.Og), l-benzyl-3- aminopyrrolidine (6.16g) and K2CO3 (4.83g) in DMF (20ml) was stirred at 100 °C for 10 hours under atmospheric pressure of nitrogen. The reaction mixture was poured into a mixture of AcOEt and water and the organic layer was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (97:3). The eluted fractions containing the desired product were collected and evaporated in vacuo to give methyl 6-[(l-benzylpyrrolidin-3- yl)amino]nicotinate (4.17g) NMR (DMSO-d6, δ ) : 1.58-1.71 (IH, m) , 2.17-2.34 (IH, m) , 2.37-2.89 (4H, m), 3.51 (2H, s), 3.65 (2H, s), 4.39 (IH, m) , 6.42 (IH, d, J= 8.80Hz), 7.19-7.33 (5H, m) , 7.59 (IH, d, J= 6.78Hz), 7.80 (IH, dd, J= 2.20Hz and 8.80Hz), 8.56 (IH, d, J= 2.20Hz)

The following compounds were obtained according to a similar manner to that of Preparation 1. Preparation 2 Methyl 6-[N-(I-benzylpyrrolidin-3-yl)-N- methylamino]nicotinate NMR (DMSO-de, <5 ) : 173-1.76 ((1H, m) , 2.23-2.44 (2H, m) , 2.48-2.67 (2H, m), 2.81-2.85 (IH, m) , 2.85 (3H, s), 3.53, 3.63 (2H, ABq, J= 13.02Hz), 3.66 (3H, s), 5.34-5.39 (IH, m) , 6.6,6 (IH, d, J= 90.6Hz), 7.20-7.34 (5H, m) , 7.92 (IH, dd, J= 2.06Hz, 9.06Hz), 8.63 (IH, d, J= 2.06Hz)

Preparation 3 Methyl 6-[ [1-(tert-butoxycarbonyl)piperidin-4-yl]- amino]nicotinate NMR (CDCl3, <5): 1.47(9H, s), 1.15-2.08(4H, m) , 2.79-3.02(2H, m) , 3.90(3H, s), 3.96-4.10(2H, m), 4.95(1H, d, J= 7.7 Hz), 6.35(1H, d, J= 8.8 Hz), 7.98(1H, dd, J= 2.0, 8.8 Hz), 8.73(1H, d, J= 2.0 Hz) Mass (APCI): 358 (M+H)+

Preparation 4 Benzyl 6-[1-(tert-butoxycarbonyl)-4-piperidylamino]-5- chloronicotinate NMR (DMSO-de, <5 ) : 1.40(9H, s), 1.48-1.60(2H, m), 1.70-1.90(2H, m) , 2.60-2.90(2H, m) , 3.85-4.01(2H, m) , 4.10-4.40(1H, m) , 5.30(2H, s), 7.05(1H, d, J= 8.2 Hz), 7.30-7.47(5H, m) , 7.97(1H, d, J= 2.0 Hz), 8.6O(1H, d, J=,2.0 Hz) Mass (APCI): 445(M+Na)+

Preparation 5 Methyl 6-[ [l-(tert-butoxycarbonyl)-4-piperidyl](methyl)amino]- nicotinate NMR (DMSO-d6, <5 ) : 1.41(9H, s), 1.50-1.80(4H, m), 2.65-2.85(2H, m), 2.89(3H, s), 3.78(3H, s), 4.05-4.20(2H, m) , 4.60-4.80(1H, m) , 6.72(1H, d, J= 8.8 Hz), 7.94(1H, dd, J= 2.0, 8.8 Hz), 8.64(1H, d, J= 2.0 Hz) Mass (APCI): 372(M+Na)+

Preparation 6 Lithium aluminium hydride (256mg) was added to a solution of methyl 6-[ (l-benzyl-3-pyrrolidinyl)amino]nicotinate (1.4g) in THF (50ml) with stirring at 5-10 °C under atmospheric pressure of nitrogen, and the reaction mixture was stirred at 5-20 °C for 4 hours. The reaction mixture was cooled at 5 °C and water (0.26ml), 15% NaOH solution (0.26ml) and water (0.72ml) was added , the resultant mixture was, stirred at ambient temperature for 20 minutes. The reaction mixture was filtrated and the filtrate was dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (85:15). The eluted fractions containing the desired product were collected and evaporated in vacuo to give {6-[(1-benzyl-3-pyrrolidinyl)amino]-3- pyridyl}methanol (0.96g) ' NMR (DMSO-de, <5 ) : 1.58-1.65 (IH, m) , 2.06-2.52 (3H, m) , 2.59-2.81 (2H, m), 3.42 (2H, s), 4.18-4.37 (IH, m) , 4.26 (2H, d, J= 5.28Hz), 4.87 (IH, t, J= 5.28Hz), 6.43 (IH, d, J= 8.54Hz), 6.53 (IH, d, J= 6.80Hz), 7.18-7.36 (6H, m) , 7.85 (IH, d, J= 2.10Hz)

The following compounds were obtained according to a similar manner to that of Preparation 6.

Preparation 7 {6-[ (l-Benzyl-3-pyrrolidinyl) (methyl)amino]-3-pyridyl}- methanol NMR (DMSO-d6, δ): 1.67-1.73 (IH, m) , 2.07-2.11 (IH, m) , 2.24-2.33 (IH, m),2.43-2.58 (2H, m) , 2.76-2.83 (IH, m) , 2.90 (3H, s), 3.52,3.63 (2H, ABq, J= 13.08Hz), 4.32 (2H, d, J= 4.78Hz), 4.94 (IH, t, J= 4.78Hz), 5.18-5.29 (IH, m) , 6.58 (IH, d, J= 8.74Hz), 7.21- 7.47 (5H, m), 7.44 (IH, dd, J= 2.22Hz, 8.74Hz),7.98 (IH, d, J= 2.22Hz)

Preparation 8 (6-{ [(3R)-1-Benzyl-3-pyrrolidinyl]amino}-3-pyridyl)- methanol NMR (DMSO-d6, <5 ) : 1.59-1.65 (IH, m) , 2.09-2.51 (3H, m) , 2.59-2.63 (IH, m), 2.73-2.81 (IH, m) , 3.53, 3.59 (2H, ABq, J= 12.98Hz), 4.23 (2H, d, J= 5.34Hz), 4.18-4.28 (IH, m) , 4.88 (IH, t, J= 5.34Hz), 6 .44 ( IH, d, J= 8..52Hz ) , 6. 53 ( IH, d, J= 6 .84Hz ) , 7 . 16-7.36 ( 6H, m) , 7 .85 ( IH, d, J= 2. 10Hz )

Preparation 9 (6-{[ (3S)-l-Benzyl-3-pyrrolidinyl]aπιino}-3-pyridyl)- methanol NMR (DMSO-d6, <5): 1.59-1.66 (IH, m) , 2.16-2.55 (3H, m) , 2.56-2.60 (IH, m), 2.63-2.81 (IH, m) , 3.44-3.63 (2H, m) , 4.19-4.35 (3H, m) , 4.89 (IH, brs), 6.44 (IH, d, J= 8.50Hz), 6.54 (IH, d, J= 6.82Hz), 7.18-7.34 (6Hfl m) , 7.87 (IH, d, J= 2.04Hz)

Preparation 10 tert-Butyl 4-{[5-(hydroxymethyl)-2-pyridyl]amirio}-l-piperidine- carboxylate MMR (CDCl3, δ) : 1.20-1.40(2H, m) , 1.47(9H, s), 1.98-2.06(2H, m), 2.84-3.01(2H, m) , 3.76-4.00(1H, m) , 4.00-4.39(2H, m) , 4.4O(1H, d, J= 15.8 Hz), 4.52(2H, s), 6.38(1H, d, J= 8.8 Hz); 7.46(1H, dd, J= 2.0, 8.8 Hz), 8.01(1H, d, J= 2.0 Hz) Mass (APCI): 308(M+H)+

Preparation 11 tert-Butyl 4-{[3-chloro-5-(hydroxymethyl)-2-pyridyl]amino}-l- piperidinecarboxylate Mass (APCI): 343(M+H)+

Preparation 12 tert-Butyl 4-[ [5-(hydroxymethyl)-2-pyridyl] (methyl)amino]-1- piperidinecarboxylate NMR (DMSO-de, δ): 1.41(9H, s), 1.54-1.63(4H, m) , 2.78(3H, s), 2.75-2.99(2H, m) , ^.01-4.20(2H, m) , 4.32(2H, d, J= 5.3 Hz), 4.50- 4.80(IH, m), 4.90-4.96(IH, m) , 6.61(IH, d, J= 8.8 Hz), 7.46(IH, dd, J= 2.0, 8.8 Hz), 8.00(1H, d, J= 2.0 Hz) Mass (APCI): 344(M+Na)+

Preparation 13 A mixture of {6-[(l-benzyl-3-pyrrolidinyl)amino]-3- pyridyl}methanol (0.96g) and MnO2 (2.95Ig) in AcOEt (50ml) was refluxed under stirring for 1.5 hour. After removal of the insoluble material, and the solvent was evaporated in vacuo to give 6-[(l-benzyl-3-pγrrolidinyl)amino.]nicotinaldehyde (0.75g) NMR (DMSO-d6, 6 ) : 1.66-1.72 (IH, m) , 2.06-2.52 (3H, m) , 2.62-2.82 (2H, m), 3.60 (2H, s), 4.39-4.45 (IH, m) , 6.58 (IH, d, J= 8.80Hz), 7.16-7.32 (5H, m) , 7.73 (IH, dd, J= 2.18Hz, 8.80Hz), 7.93 (IH, d, J= 5.52Hz), 8.47 (IH, d, J= 2.18Hz), 9.66 (IH, s)

The following compounds were obtained according to a similar manner to that of Preparation 13.

Preparation 14 6-{[ (3R)-1-Benzyl-3-pyrrolidinyl]amino}nicotinaldehyde NMR (DMSO-d6, <5): 1.66-1.99 (IH, m), 2.23-2.38 (IH, m) , 2.41-2.52 (2H, m), 2.61-2.82 (2H, m), 3.52 (2H, s), 4.39-4.45 (IH, m) , 6.58 (IH, d, J= 8.84Hz), 7.16-7.33 (5H, m) , 7.73 (IH, dd, J= 2.20Hz, 8.84Hz), 7.90 (IH, d, J= 6.64Hz), 8.47 (IH, d, J= 2.20Hz), 9.66 (IH, s) '

Preparation 15 6-{[(3S)-l-Benzyl-3-pyrrolidinyl]amino}nicotinaldehyde NMR (DMSO-d6, <5 ) : 1.66-2.00 (IH, m) , 2.21-2.26 (IH, m), 2.38-2.52 (2H, m), 2.61-2.82 (2H, m) , 3.52 (2H, s), 4.45 (IH, m) , 6.58 (IH, d, J= 8.88Hz), 7.16-7.33 (5H, m) , 7.73 (IH, dd, J= 2.18Hz, 8.88Hz), 7.90 (IH, d, J= 6.72Hz), 8.47 (IH, d, J= 2.18Hz), 9.66 (IH, s)

Preparation 16 6-{[ (3R)-l-Benzyl-3-pyrrolidinyl]amino}-5- chloronicotinaldehyde NMR (DMSO-d6, <5 ) : 1.86-1.96 (IH, m) , 2.00-2.26 (IH, m), 2.43-2.61 (3H, m), 2.61-2.68 (IH, m), 3.60 (2H, s), 4.60-4.67 (IH, m) , 7.19- 7.37 (5H, m), 7.91 (IH, d, J= 1.88Hz), 8.52 (IH, d, J= 1.88Hz), 9.72 (IH, s)

Preparation 17 6-{[(3S)-1-Benzyl-3-pyrrolidinyl]amino}-5- chloronicotinaldehyde NMR (DMSOd6, δ): 1.78-1.99 (IH, m) , 2.18-2.30 (IH, m) , 2.42-2.68 (3H, m), 2.82-2.90 (IH, m) , 3.60 (2H, s), 4.59-4.64 (IH, m) , 7.19- 7.37 (6H, m), 7.91 (IH, d, J= 1.96Hz), 8.52 (IH, d, J= 1.96HZ), 9.72 (IH, s)

Preparation 18 6-[(l-Benzyl-3-pyrrolidinyl) (methyl)amino]- . nicotinaldehyde NMR (DMSO-d6, <5): 1.65-1.78 (IH, m) , 2.20-2.31 (2H, m) , 2.45-2.54 (2H, m), 2.63-2.70 (IH, m) , 2.82-2.89 (IH, m) , 3.07 (3H, s), 3.55,3.64 (2H, ABq, J= 13.04Hz), 5.40-5.42 (IH, m) , 6.76 (IH, d, J= 9.10Hz), 7.23-7.35 )5H, m) , 7.76 (IH, dd, J= 2.24Hz, 9.10Hz), 8.56 (IH, d, J= 2.24Hz), 9.74 (IH, s)

Preparation 19 tert-Butyl 4-[(5-foππyl-2-pyridyl)amino]-1-piperidinecarboxylate NMR (CDCl3, δ) : 1.2-1.47(11H, m), 2.0-2.10(2H, m), 2.88-3.21(2H, m), 3.92-4.23(3H, m) , 5.04(1H, d, J= 15.8 Hz), 6.42(1H, d, J= 8.8 Hz), 7.88(1H, dd, J= 2.0, 8.8 Hz), 8.51(1H, d, J= 2.0 Hz), 9.77(1H, s) Mass (APCI): 328(M+Na)+

Preparation 20 tert-Butyl 4-[ (3-chloro-5-formyl-2-pyridyl)amino]-1- piperidinecarboxylate NMR (DMSO-de, 6): 1.40(9H, s), 1.48-1.60(2H, m) , 1.70-1.90(2H, m) , 2.60-2.90(2H, m) , 3.85-4.01(2H, m) , 4.10-4.40(1H, m) , 7.26(1H, d, J= 8.2 Hz), 7.93(1H, d, J= 2.0 Hz), 8.54(1H, d, J= 2.0 Hz), 9.72(1H, s) Mass (APCI): 362(M+Na)+

Preparation 21 tert-Butyl 4-[ (5-formyl-2-pyridyl) (methyl)amino]-1- piperidinecarboxylate NMR (DMSOd6, δ): 1.42(9H, s), 1.56-1.75(4H, m) , 2.70-2.80(2H, m) , 2.94 ( 3H, S ) , 4.03-4.20 ( 2H, m) , 4.70-4 .90 ( 1H, m) , 6.82 ( 1H, d, J= 8.8 Hz ) , 7.88 ( 1H, dd, J= 2.0 , 8. 8 Hz ) , 8. 59 ( 1H, d, J= 2 .0 Hz ) , 9. 72 ( 1H, s ) Mass (APCI): 342(M+Na)+

Preparation 22 5-Chloro-6-{[(3R)-l-(4-fluorobenzyl)-3-pyrrolidinyl]amino}- nicotinaldehyde Mass (ESI): 334(M+H)+

Preparation 23 5-Chloro-6-{[ (3R)-1-(4-methylbenzyl)-3-pyrrolidinyl]amino}- nicotinaldehyde NMR (DMSO-de, δ): 1.72-1.85(1H, m) , 2.08-2.85(5H, m) , 2.27(3H, s), 3.52(2H, s), 4.51-4.64(1H, m) , 7.10(2H, d, J= 8.8 Hz), 7.19(2H, d, J= 8.8 Hz), 7.28(1H, d, J= 7.0 Hz), 7.91(1H, d, J= 2.0 Hz), 8.52(1H, d, J= 2.0 Hz), 9.72(1H, s) Mass (APCI): 330(M+H)+

Preparation 24 5-Chloro-6-{[(3R)-1-(4-methoxybenzyl)-3- pyrrolidinyl]amino}nicotinaldehyde Mass (ESI): 346(M+H)+

Preparation 25 A solution of diethylphosphonoacetic acid ethyl ester (896mg) in THF (10ml) was added dropwise to a mixture of 60% sodium hydride in oil (170mg) in THF (2OmL) with stirring at 10-20 °C under atmospheric pressure of nitrogen, and the reaction mixture was stirred at ambient temperature for 30 minutes. A solution of 6-[(l-benzyl-3-pyrrolidinyl)amino]nicotinaldehyde (0.75g) in THF (10ml) solution was added the above mixture, and resultant mixture was stirred at ambient temperature for 1.5 hour. The reaction mixture was poured into a mixture of AcOEt-H2O and the organic layer was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (95:5). The eluted fractions containing the desired product were collected and evaporated in vacuo to give ethyl (2E)-3-{6-[(l-benzyl-3-pyrrolidinyl)amino]-3- pyridyl}acrylate (0.83g) . NMR. (DMSO-d6, 6): 1.24 (3H, t, J= 7.06Hz), 1.50-1.73 (IH, m) , 2.36-2.52 (3H, m) , 2.73-2.77 (2H, m) , 3.57 (2H, s), 4.14 (2H,g, J= 7.06Hz), 4.30 (IH, m) , 6.31 (IH, d, J= 15.80Hz), 6.52 (IH, d, J= 8.86Hz), 7.18-7.36 (5H, m), 7.49 (IH, d, J= 15.80Hz), 7.77 (IH, dd, J= 2.10Hz, 8.86Hz), 8.20 (IH, d, J= 2.10Hz)

The following compounds were obtained according to a similar manner to that of Preparation 25.

Preparation 26 Ethyl (2E)-3-{6-[(1-benzyl-3-pyrrolidinyl)(methyl)amino]-3- pyridyl}acrylate NMR (DMSO-d6, 6): 1.24 (3H, t, J= 7.06Hz), 1.56-1.82 (IH, m), 2.27-2.61 (4H, m) , 2.83-2.84 (IH, m) , 3.00 (3H, s), 3.58 and 3.63 (2H, ABq, J= 13.02Hz), 5.25-5.39 (IH, m) , 6.38 (IH, d, J= 15.94Hz), 6.67 (IH, d, J= 9.06Hz), 7.19-7.34 (5H, m) , 7.53 (IH, d, J= 15.94Hz), 7.90 (IH, dd, J= 2.26Hz, 9.06Hz), 8.30 (IH, d, J= 2.26Hz)

Preparation 27 Ethyl (2E)-3-(6-{[(3R)-l-benzyl-3-pyrrolidinyl]amino}-3- pyridyl)acrylate NMR (DMSO-dβ, 6): 125 (3H, t, J= 7.06Hz), 1.56-1.78 (IH, m) , 2.10- 2.20 (IH, m), 2.34-2.52 (2H, m) , 2.52-2.78 (2H, m) , 3.57 (2H, s), 4.15 (2H, q, J= 7.06Hz), 4.36 (IH, m) , 6.41 (IH, d, J= 15.92Hz), 6.52 (IH, d, J= 8.82Hz), 7.18-7.37 (6H, m), 7.50 (IH, d, J= 15.92Hz), 7.78 (IH, dd, J= 2.10Hz, 8.82Hz), 8.20 (IH, d, J= 2.10Hz)

Preparation 28 Ethyl (2E)-3-(6-{[(3S)-l-benzyl-3-pyrrolidinyl]amino}-3- pyridyl)acrylate NMR (DMSO-d6, 6): 1.24 (3H, t, J= 7.06Hz), 1.56-1.73 (IH, m) , 2.21-2.37 (IH, m) , 2.39-2.52 (2H, m) , 2.73-2.78 (2H, m) , 3.57 (2H, s), 4.15 (2H, q, J= 7.06Hz), 4.36 (IH, m) , 6.31 (IH, d, J= 15.90Hz), 6.52 (IH, d, J= 8.86Hz), 7.18-7.36 (5H, m), 7.50 (IH, d, J= 15.90Hz ) , 7. 77 ( IH, dd, J= 2. 14Hz , 8.86Hz ) , 8. 20 ( IH, d, J= 2. 14Hz )

Preparation 29 Ethyl (2E)-3-(6-{[(3R)-l-benzyl-3-pyrrolidinyl]amino}-5-chloro-3- pyridyl)acrylate NMR (DMSOd6, <5 ) : 1.24 (3H, t, J= 7.06Hz), 1.84-1.97 (IH, m) , 2.00-2.30 (IH, m), 2.39-2.53 (2H, m) , 2.62-2.78 (IH, m) , 2.79-2.87 (IH, m), 3.59 (2H, s), 4.16 (2H, q, J= 7.06Hz), 4.49-4.56 (IH, m) , 6.49 (IH, d, J= 15.96Hz), 6.73 (IH, d, J= 6.90Hz), 7.19-7.32 (5H, m), 7.51 (IH, d, J= 15.96Hz), 8.10 (IH, d, J= 1.88Hz), 8.26 (IH, d, J= 1.88Hz)

Preparation 30 Ethyl (2E)-3-(6-{[(3S)-l-benzyl-3-pyrrolidinyl]amino}-5-chloro-3- pyridyl)acrylate / NMR (DMSOd6, <5 ) : 1.24 (3H, t, J= 7.06Hz), 1.84-1.99 (IH, m) , 2.16-2.30 (IH, m), 2.39-2.46 (2H, m) , 2.62-2.66 (IH, m) , 2.79-2.88 (IH, m), 3.58 (2H, s), 4.16 (2H, q, J= 7.06Hz), 4.49-4.56 (IH, m) , 6.49 (IH, D, J= 15.98Hz), 6.72 (IH, d, J= 6.92Hz), 7.18-7.36 (5H, m), 7.51 (IH,. d, J= 15.98Hz), 8.10 (IH, d, J= 1.96Hz), 8.26 (IH, d, J= 1.96Hz)

Preparation 31 tert-Butyl 4-({5-[ (IE)-3-ethoxy-3-oxo-l-propen-l-yl]-2- pyridyl}amino)-1-piperidinecarboxylate NMR (DMSOd6, (5): 1.33(3H, t, J= 7.1 Hz), 1.36-1.42(2H, m) , 1.47(9H, s), 2.00-2.08(2H, m), 2.88-3.02(2H, m) , 3.80-4.00(lH, m) , 4.03-4.20(2H, m) , 4.24(2H, q) , 4.6(1H, m) , 6.22(1H, d, J= 16.0 Hz), 6.38(1H, d, J= 8.7 Hz), 7.57(1H, d, J= 16.0 Hz), 7.61(1H, dd, J= 2.4, 8.7 Hz), 8.19(1H, d, J= 2.4 Hz) Mass (APCI): 398(M+H)+

Preparation 32 tert-Butyl 4-({3-chloro-5-[(lE)-3-ethoxy-3-oxo-l-propen-l-yl]-2- pyridyl}amino)-l-piperidinecarboxylate Mass (ESI): 410(M+H)+ Preparation 33 tert-Butyl 4-[{5-[(IE)-S-ethoxy-S-oxo-l-propen-l-yl]-2-pyridyl}- (methyl)amino]-1-piperidinecarboxylate Mass (ESI): 390(M+H)+

Preparation 34 Ethyl (2E)-3-(5-chloro-6-{[(3R)-1-(4-fluorobenzyl)-3- pyrrolidinyl]amino}-3-pyridyl)aerylate Mass (ESI): 4O4'(M+H)+

Preparation 35 Ethyl (2E)-3-(5-chloro-6-{[(3R)-1-(4-methylbenzyl)-3- pyrrolidinyl]amino}-3-pyridyl)aerylate NMR (DMSO-dβ, δ): 1.24(3H, t, J= 7.4 Hz), 1.7O-1.95(1H, m) , 2.10- 2.29(1H, m), 2.27(3H, s), 2.35-2.84(4H, m) , 3.53(2H, s), 4.15(2H, q, J= 7.4 Hz), 4.44-4.54(1H, m), 6.48(1H, d, J= 16.0 Hz), 6.72(1H, d, J= 7.0 Hz), 7.10(2H, d, J= 8.8 Hz), 7.18(2H, d, J= 8.8 Hz), 7.5O(1H, d, J= 16.0 Hz), 8.1O(1H, άt J= 2.0 Hz), 8.26(1H, d, J= 2.0 Hz) Mass (APCI): 400(M+H)+

Preparation 36 Ethyl (2E)-3-(5-chloro-6-{[(3R)-1-(4-methoxybenzyl)-3- pyrrolidinyl]amino}-3-pyridyl)aerylate NMR (DMSO-dβ, ^): 1.45-1.85(9H, m) , 1.90-2.10(2H, m) , 2.70-2.85(2H, m), 3.44(2H, s), 3.45-3.58(1H, m) , 3.85-4.15(2H, m) , 4.9O(1H, s), 6.32(1H, d, J= 16.0 Hz), 6.51(1H, d, J= 7.0 Hz), 7.10-7.478(5H, m) , 7.84(1H, s), 8.21(1H, s), 11.09(1H, brs)

Preparation 37 A mixture of ethyl (2E)-3-{6-[(l-benzyl-3- pyrrolidinyl)amino]-3-pyridyl}- aerylate (830mg) and IN NaOH solution (4.7ml) in MeOH (20ml) was stirred at 70-751C for 2 hours. The reaction mixture was evaporated in vacuo, and the residue was dissolved with saturated NaCl solution (20ml). The solution was adjusted to pH6.0 with aq. HCl, and the precipitate was collected by filtration to give (2E)- 3-{6-[(1-benzyl-3-pyrrolidinyl)amino]-3-pyridyl}- acrylic acid (700mg) NMR (DMSOd6, 6): 1.92-2.01 (IH, m) , 2.30-2.43 (IH, m) , 2.94-3.52 (4H, m), 4.29 (2H, s), 4.53-4.56 (IH, m) , 6.28 (IH, d, J= 15.82Hz), 6.62 (IH, d, J= 8.78Hz), 7.39-7.64 (6H, m) , 7.75-7.83 (2H, m) , 8.20 (IH, d, J= 2.00Hz), 11.92 (IH, m)

The following compounds were obtained according to a similar manner to that of Preparation 37.

Preparation 38 (2E)-3-{6-[(1-Benzyl-3-pyrrolidinyl)(methyl)amino]-3- pyridyl}acrylic acid NMR (DMSO-de, <5 ) : 2.08-2.16 (IH, m), 2.80-3.60 (5H, m) , 4.23 (2H, brs), 5.54-5.61 (IH, m) , 6.35 (IH. d, J= 15.92Hz), 6.72 (IH, d, J= 9.02Hz), 7.39-7.62 (6H, m) , 7.92 (IH, dd, J= 2.04Hz, 9.06Hz), 8.32 (IH, d, J= 2.04Hz)

Preparation 39 (2E)-3-(6-{[(3R)-l-Benzyl^3-pyrrolidinyl]amino}-3- pyridyl)acrylic acid NMR (DMSOd6, δ): 1.87-1.93 (IH, m) , 2.28-2.38 (IH, m), 2.83-3.37 (4H, m), 4.15 (2H, s), 6.29 (IH, d, J= 15.92Hz), 6.62 (IH, d, J= 8.88Hz), 7.32-7.43 (3H,m), 7.51-7.58 (2H, m) , 7.77-7.81 (2H, m) , 8.20 (IH, d, J= 1.94Hz)

Preparation 40 (2E)-3-(6-{[(3S)-l~Benzyl-3-pyrrolidinyl]amino}-3- pyridyl)acrylic acid NMR (DMSO-d6, δ): 1.98-2.04 (IH, m) , 2.31-2.38 (IH, m) , 2.95-3.56 (4H, m), 4.35 (2H, s), 4.55-4.58 (IH, m), 6.29 (IH, d, J= 15.86Hz), 6.63 (IH, d, J= 8.82Hz), 7.40-7.67 (6H, m) , 8.10 (IH, dd, J= 2.08Hz, 8.82Hz), 7.92 (IH, brs), 8.20 (IH, d, J= 2.08Hz)

Preparation 41 (2E)-3-(6-{[(3R)-l-Benzyl-3-pyrrolidinyl]amino}-5-chloro-3- pyridyl)acrylic acid NMR (DMSO-d6, δ): 1.76-1.99 (IH, m), 2.19-2.24 (IH, m), 2.48-2.77 ( 3H, m) , 2 .91-2. 96 ( IH, m) , 3. 60 ( 2H, s ) , 4 .49-4. 56 ( IH, m) , 6 . 39 ( IH, d, J= 15.88Hz ) , 6. 74 ( IH, d, J= 6 .88Hz ) , 7.21-7.35 ( 5H, m) , 7.45 ( IH, d, J= 15.88Hz ) , 8.07 ( IH, d, J= 1.82Hz ) , 8.24 ( IH, d, J= 1 .82Hz )

Preparation 42 , (2E)-3-(6-{[(3S)-l-Benzyl-3-pyrrolidinyl]amino}-5-chloro-3- pyridyl)acrylic acid NMR (DMSO-d6, <5 ) : 1.89-1.99 (IH, m) , 2.19-2.27 (IH, m) , 2.58-3.07 (4H, m), 3.74 (2H, s), 4.44-4.59 (IH, m) , 6.40 (IH, d, J= 15.96Hz), 6.82 (IH, d, J= 6.88Hz), 7.25-7.40 (5H, m) , 7.46 (IH, d, J= 15.96Hz), 8.08 (IH, d, J= 1.82Hz), 8.24 (IH, d, J= 1.82Hz)

Preparation 43 (2E)-3-(6-{[(3R)-l-(4-Methoxybenzyl)-3-pyrrolidinyl]amino}-3 - pyridyl)acrylic acid NMR (DMSO-de, <5 ) : 1.60-1.95 (IH, m) , 2.10-2.40 (IH, m) , 2.50-4.00 (6H, m), 3.74 (3H, s), 4.30-4.60 (IH, m) , 6.24 (IH, d, J= 6Hz), 6.54 (IH, d, J= 8.8Hz), 6.92 (2H, d, J= 8.5Hz ), 7.30-7.60 (4H, m), 7.78 (IH, dd, J= 2.1Hz, J= 8.8Hz), 8.18 (IH, d, J= 2.1Hz ), 11.80 (IH, br) MASS(API-ES); 354 (M+H)+

Preparation 44 (2E)-3-(6-{[(3R)-l-(4-Fluorobenzyl)-3-pyrrolidinyl]amino}- 3-pyridyl)acrylic acid NMR (DMSO-d6, <5 ) : 1.50-1.80 (IH, m) , 2.05-2.90 (5H, m) , 3.50-3.70 (2H, m), 4.20-4.50 (IH, m), 6.22 (IH, d, J = 16Hz), 6.53 (IH, d, J= 8.8Hz ), 7.05-7.18 (2H, m) , 7.30-7.40 (3H, m) , 7.43 (IH, d, J= 6Hz ), 7.74 (IH, dd, J= 2.1 and 8.8Hz), 8.15 (IH, d, J= 2.1Hz) MASS(API-ES, Nega); 340 (M-H)+

Preparation 45 (2E)-3-(6-{t(3R)-1-(4-Chlorobenzyl)-3-pyrrolidinyl]amino}- 3-pyridyl)acrylic acid NMR (DMSO-de, δ)ι 1.60-1.85 (IH, m) , 2.10-3.00 (5H, m) , 3.10-3.90 (2H, m), 4.25-4.50 (IH, m), 6.23 (IH, d, J= 16Hz ), 6.53 (IH, d, J= 8.8Hz ) , 7.30-7. 55 ( 6H, m) , 7 .75 ( IH, dd, J= 2 . 1Hz , J= 8.8Hz ) , 8 . 17 ( IH, d, J= 2. 1Hz ) MASS (API-ES) ; 358 (M+H) + 360

Preparation 46 (2E)~3-(6-{[ (3R)-1-(4-Methylbenzyl)-3-pyrrolidinyl]amino}-3- pyridyl)acrylic acid NMR (DMSO-d6, δ): 1.60-1.90 (IH, m) , 2.10-3.15 (5H, m) , 2.28 (3H, s), 3.50-3.95 (2H, m) , 4.25-4.50 (IH, m) , 6.24 (IH, d, J= 16Hz ), 6.54 (IH, d, J= 8.8Hz), 7.15 (2H, d, J= 7.8Hz), 7.29 (2H, d, J= 7.8Hz), 7.44 (IH, d, J= 16Hz), 7.48(1H, m) , 7.76 (IH, dd, J= 2.1Hz, J= 8.8Hz), 8.17 (IH, d, J= 2.1Hz) MASS(API-ES); 338 (M+H)+

Preparation 47 (2E)-3-(6-{[(3R)-l-(Cyclopropylmethyl)-3-pyrrolidinyi]- amino}-3-pyridyl)acrylic acid NMR (DMSO-d6, <5): 0.05-0.25 (2H, m) , 0.40-0.60 (2H, m) , 0.80-1.05 (IH, m), 1.60-1.85 (IH, m) , 2.10-3.90 (7H, m), 4.25-4.55 (IH, m) , 6.24 (IH, d, J= 16Hz), 6.55 ( IH, d, J=8.8Hz), 7.44 (IH, d, J= 16Hz ), 7.47 (IH, d, J= 6.1Hz), 7.77 (IH, dd, J= 2.1Hz, J= 8.8Hz), 8.19 (IH, d, J= 2.1Hz) MASS(API-ES); 288 (M+H)+

Preparation 48 (2E)-3-(6-{[(3R)-l-Benzoyl-3-pyrrolidinyl]amino}-5-chloro- 3-pyridyl)acrylic acid NMR (DMSO-d6, 6): 1.90-2.40 (2H, m) , 3.20-4.00 (4H, m) , 4.40-4.80 (IH, m), 6.30-6.50 (IH, m) , 6.95-7.10 (IH, m) , 7.35-7.60 (6H, m) , 8.05-8.15 (IH, m) , 8.20-8.35 (IH, m) , 12.26 (IH, br) MASS(API-ES); 372 (M+H)+ ,374

Preparation 49 (2E)-3-(5-Chloro-6-{[ (3R)-1-(cyclopropylcarbonyl)-3- pyrrolidinyi]amino}-3-pyridyl)acrylic acid NMR (DMSOd6, <5 ) : 0.60-0.80 (4H, m) , 1.60-1.85 (IH, m) , 1.87-2.40 (2H, m), 3.20-4.10 (4H, m), 4.45-4.80 (IH, m) , 6.42 (IH, d, J= 16Hz ) , 6.90-7.05 ( IH, m) , 7. 48 ( IH, d, J= 16Hz ) , 8.07-8 . 14 ( IH, m) , 8.25-8.32 ( IH, m) , 12. 21 ( IH, br) MASS(API-ES, Nega) ; 334 (M-H) -

Preparation 50 (2E)-3-{6-[(l-Benzoyl-4-piperidyl)amino]-3-pyridyl}- acrylic acid NMR (DMSO-dβ, <5 ) : 1.20-1.60(2H, m) , 1.70-2.10(2H, m), 3.00-3.60(3H, m), 4.00-4.20(1H, m) , 4.20-4.60(1H, m) , 6.23(1H, d, J= 16.0 Hz), 6.53(1H, d, J= 8.8 Hz), 7.1O-7.3O(1H, m) , 7.35-7.48(6H, m) , 7.78(1H, dd, J= 2.0, 8.8 Hz), 8.19(1H, d, J= 2.0 Hz) Mass (APCI): 352(M+H)+

Preparation 51 (2E)-3-(6-{[l-(4-Fluorobenzoyl)-4-piperidyl]amino}-3- pyridyl)acrylic acid NMR (DMSO-de, δ ) : 1.30-1.55(2H, m) , 1.85-2.10(2H, m) , 3.00-3.30(2H, m), 3.58(1H, brs), 4.05-4.11(1H, m) , 4.33(1H, brs), 6.22(H, d) , 6.22(1H, d, J= 8.4 Hz), 6.52(1H, d, J= 8.8 Hz), 7.17(1H, brs), 7.26-7.30(2H, m) , 7.42-7.48(3H, m) , 7.77(1H, dd, J= 2.2, 8.8 Hz), 8.19(1H, d, J= 2.2 Hz), 12.06(1H, brs) Mass (APCI): 392(M+Na)+

Preparation 52 (2E)-3-(6-{[l-(4-Methylbenzoγl)-4-piperidyl]amino}-3- pyridyl)acrylic acid NMR (DMSO-dβ, <5): 1.20-1.60(2H, m), 1.80-2.10(2H, m) , 2.34(3H, s), 3.03-4.40(6H, m) , 6.22(1H, d, J= 16.0 Hz), 6.5O(1H, d, J= 8.8 Hz), 7.14(1H, d, J= 7.4 Hz), 7.21-7.31(4H, m) , 7.44(1H, d, J= 16.0 Hz), 7.76(1H, dd, J= 2.0, 8.8 Hz), 8.18(1H, d, J= 2.0 Hz). Mass (APCI): 383(M+Na)+

Preparation 53 (2E)-3-(6-{[l-(4-Methoxybenzoyl)-4-piperidyl]amino}-3- pyridyl)acrylic acid NMR (DMSO-de, <5 ) : 1.31-1.16(2H, m) , 1.80-2.00(2H, m) , 3.00-3.20(2H, m), 3.82(3H, s), 4.00-4.20(2H, m) , 6.24(1H, d, J= 16.0 Hz), 6.55(1H, .

d, J= 8.8 Hz), 6.99(2H, d, J= 8.8 Hz), 7.27(1H, brs), 7.36(2H, d, J= 8.8 Hz), 7.44(1H, d, J= 16.0 Hz), 7.78(1H, dd, J= 2.1, 8.8 Hz), 8.19(1H, d, J= 2.1 Hz), 12.13(1H, brs) Mass (APCI): 404(M+Na)+

Preparation 54 (2E)-3-[6-({l-[4-(lH-Pyrrol-l-yl)benzoyl]-4-piperidyl>- amino)-3-pyridyl]acrylic acid NMR (DMSO-de, <5 ) : 1.35-1.60(2H, m) , 1.85-2.10,(2H, m) , 3.10-3.40(2H, in), 3.50-4.50(3H, m) , 6.28-6.33(3H, m) , 6.54(1H, d, J= 8.8 Hz), 7.23(1H, d, J= 7.4 Hz), 7.42-7.50(6H, m) , 7.66(2H, d, J= 8.6 Hz), 7.77(IH, dd, J= 2.0, 8.8 Hz), 8f.20(IH, d, J= 2.0 Hz), 12.13(IH, brs)

Preparation 55 (2E)-3-{6-[(l~{[(4-Chlorophenyl)amino]carbonyl}-4- piperidyl)amino]-3-pyridyl}acrylic acid NMR (DMSOd6, <5) : 1.29-1.45(2H, m) , 1.80-2.05(2H, m) , 2.85-3.10(2H, m), 3.80-4.20(3H, m) , 6.25(1H, d, J= 16.0 Hz), 6.75(1H, d, J= 8.8 Hz), 7.20-7.60(6H, m) , 7.82(1H, dd, J= 2.0, 8.8 Hz), 8.2Od(IH, d, J= 2.0 Hz), 8.69(1H, s), 12.09(1H, brs). Mass (APCI): 399(M-H)-

Preparation 56 (2E)-3-{6-[(l-{[(4-Methylphenyl)amino]carbonyl}-4- piperidyl)amino]-3-pyridyl}acrylic acid NMR (DMSO-de, <5 ) : 1.23-1.43(2H, m) , 1.89-2.10(2H, m) , 2.22(3H, s), ' 2.84-3.01(2H, m) , 4.02-7.10(3H, m) , 6.23(1H, d, J= 16.0 Hz), 6.52(1H, d, J= 8.8 Hz), 7.02(2H, d, J= 8.8 Hz), 7.18(1H, d, J= 7.0 Hz), 7.34(2H, d, J= 8.8 Hz), 7.45(1H, d, J= 16.0 Hz), 7.76(1H, dd, J= 2.0, 8.8 Hz), 8.2O(1H, d, J= 2.0 Hz), 8.43(1H, s), 12.04(1H, brs) Mass (APCI): 403(M+Na)+

Preparation 57 (2E)-3-{6-[(1-{[(4-Methoxyphenyl)amino]carbonyl}-4- piperidyl)amino]-3-pyridyl}acrylic acid NMR (DMSOd5, δ ) : 1.28-1.43(2H, m) , 1.76-1.94(2H, m) , 2.89-3.01(2H, m) , 3.70(3H, s) , 4.01-4.08(3H, m) , 6.23(1H, d, J= 16.0 Hz) , 6.52(1H, d, J= 8.8 Hz) , 6.81 (2H, d, J= 8.8 Hz) , 7. 18-7.22( 1H, m) , 7.34 ( 2H, d, J= 8.8 Hz ) , 7.45 ( 1H, d, J= 16.0 Hz ) , 7.77 ( 1H, dd, J= 2.0, 8.8 Hz ) , 8.2O( 1H, d, J= 2.0 Hz ) , 8.36 ( 1H, s) , 12.04( lH, brs) Mass (APCI) : 419,(M+Na) +

Preparation 58 (2E)-3-{6-[(1-Benzoyl-4-piperidyl)amino]-5-chloro-3- pyridyl}acrylic acid NMR (DMSOd6, <5 ) : 1.50-2.01(4H, m) , 2.60-3.80(4H, m) , 4.2-4.7(2H, m), 6.38(1H, d, J= 16.0 Hz), 6.70(1H, d, J= 8.0 Hz), 7.35-7.49(6H, m), 8.08(1H, d, J= 2.0 Hz), 8.26(1H, d, J= 2.0 Hz) Mass (APCI): 408(M+Na)+

Preparation 59 (2E)-3-(5-Chloro-6-{[l-(4-chlorobenzoyl)-4-piperidyl]amino}- 3- pyridyl)acrylic acid NMR (DMSO-dβ, δ): 1.50-2.01(4H, m) , 2.60-3.80(4H, m) , 4.2-4.7(2H, m), 6.38(1H, d, J= 16.0 Hz), 6.7O(1H, d, J= 8.0 Hz), 7.35-7.57(5H, m), 8.08(1H, d, J= 2.0 Hz), 8.26(1H, d, J= 2.0 Hz) Mass (APCI): 442(M+Na)+

Preparation 60 (2E)-3-(5-Chloro-6~{[l-(4-phenoxybenzoyl)-4-piperidyl]amino} -3- pyridyl)acrylic acid NMR (DMSO-de, δ): 1.45-1.75(2H, m) , 1.75-2.10(2H, m) , 2.70-4.70(6H, m), 6.37(1H, d, J= 16.0 Hz), 6.61(1H, d, J= 8.0 Hz), 7.07-7.47(9H, m), 7.99(1H, s), 8.19(1H, s) Mass (APCI): 476(M-H)-

Preparation 61 (2E)-3-(5-Chloro-6-{[1-(4-fluorobenzyl)-4-piperidyl]amino}-3 - pyridyl)acrylic acid NMR (DMSOd6, δ): 1.80-2.20(4H, m) , 2.90-3.24(2H, m) , 4.10-4.40(3H, m), 6.38(1H, d, J= 16.0 Hz), 6.98(1H, d, J= 7.8 Hz), 7.26-7.35(2H, m), 7.46(1H, d, J= 16.0 Hz), 7.67-7.73(2H, m) , 8.09(1H, s), 8.23(1H, s ) , 1O .98 ( 1H, brs) , 12 .21 ( 1H, brs)

Preparation 62 A mixture of (2E)-3-{6-[(l-benzyl-3-pyrrolidinyl)amino]-3- pyridyl}acrylic acid (400mg), 0-(tetrahydro-2H-pyran-2- yl)hydroxylamine (159mg), HOBt (175mg) and EDCI (202mg) in DMF (10ml) was stirred at ambient temperature for 15 hours. The reaction mixture was poured into a mixture of AcOEt-H2O and the organic layer was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (9:1). The eluted,fractions containing the desired product were collected and evaporated in vacuo to give (2E)-3-{6-[(l-benzyl-3-pyrrolidinyl)amino]-3- pyridyl}-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (170mg) NMR (DMSO-d6, <5 ) : 1.52-1.68 (7H, m) , 2.09-2.50 (3H, m), 2.61-2.81 (2H, m), 3.34 (2H, s), 3.34-3.57 (2H, m) , 3.92-3.98 (IH, m) , 4.32- 4.33 (IH, m), 4.87 (IH, s), 6.20 (IH, d, J= 15.20Hz), 6.53 (IH, d, J= 8.82Hz), 7.20-7.37 (7H, m) , 7.58 (IH, d, J= 7.90Hz), 8.11 (IH d, J= 1.84Hz), 11.03 (IH. brs)

The following compounds were obtained according to a similar manner to that of Preparation 62.

Preparation 63 (2E)-3-{6-[(l-Benzyl-3-pyrrolidinyl)(methyl)amino]-3- pyridyl}-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide NMR (DMSO-d6, 6): 1.17-1.76 (7H, m), 1.99-2.44 (2H, m), 2.49-3.00 (3H, m), 2.99 (3H, s), 3.49-3.69 (4H, m) , 3.93-4.01 (IH, m) , 4.89 (IH, s), 5.29-5133 (IH, m) , 6.28 (IH, d, J= 15.44Hz), 6.69 (IH, d, J= 9.02Hz), 7.19-7.42 (6H, m) , 7.71 (IH, d, J= 9.02Hz), 8.24 (IH, s), 11.05 (IH, s) '

Preparation 64 (2E)-3-(6-{[(3R)-l-Benzyl-3-pyrrolidinyl]amino}-3-pyridyl)-N - (tetrahydro-2H-pyran-2-yloxy)acrylamide NMR (DMSO-d6, <5 ) : 1.52-1.99 (7H, m) , 2.22-2.50 (3H, m) , 2.62-2.89 (2H, m), 3.57 (2H, s), 3.34-3.57 (2H, m) , 3.98-4.05 (IH, m) , 4.30 ( IH, m) , 8.47 ( IH, brs ) , 6.30 ( IH, d, J= 15.90Hz) , 6.52 ( IH, d, J= 8.80Hz ) , 7.20-7.37 ( 7H, m) , 7.58 ( IH, d, J= 8.80Hz) , 8.11 ( IH, s) , 11.03 ( IH, s)

Preparation 65 (2E)-3-(6-{[ (3S)-l-Benzyl-3~pyrrolidinyl]amino}-3-pyridyl)-N- (tetrahydro-2H-pyran-2-yloxy)acrylamide NMR (DMSO-d6, 6): 1.52-1.99 (7H, m) , 2.22-2.45 (3H, m) , 2.62-2.81 (2H, m), 3.51 (2H, s), 3.34-3.57 (2H, m) , 3.92-4.00 (IH, m) , 4.31 (IH, m), 4.87 (IH, s), 6.20 (IH, d, J= 16.10Hz), 6.52 (IH, d, J= 8.84Hz), 7.20-7.37 (7H, m) , 7.58 (IH, d, J= 7.76Hz), 8.11 (IH, d, J= 1.92Hz), 11.03 (IH, s)

Preparation 66 , (2E)-3-(6-{[(3R)-l-Benzyl-3-pyrrolidinyl]amino}-5-chloro-3- pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide NMR (DMSO-d6, <5): 1.53-2.00 (7H, m) , 2.00-2.30 (IH, m) , 2.30-2.78 (3H, m), 2.82-2.89 (IH, m) , 3.59 (2H, s), 3.36-3.59 (2H, m), 3.96- 4.01 (IH, m), 4.41-4.55 (IH, m) , 4.89 (IH, s), 6.32 (IH, d, J= 15.68Hz), 6.42 (IH, d, J= 6.88Hz), 7.19-7.40 (6H, m) , 7.84 (IH, s), 8.20 (IH, s), 11.08 (IH, brs)

Preparation 67 (2E)-3-(6-{[ (3S)-l-Benzyl-3-pyrrolidinyl]amino}-5-chloro-3- pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide NMR (DMSO-d6, 6): 1.53-2.00 (7H, m) , 2.10-2.32 (IH, m) , 2.39-2.53 (2H, m), 2.63-2.67 (IH, m) , 2.74-2.89 (IH, m) , 3.56 (2H, s), 3.50- 3.59 (2H, m), 3.96-4.05 (IH, m) , 4.48-4.53 (IH, m) , 4.90 (IH, s), 6.33 (IH, d, J= 15.74Hz), 6.94 (IH, d, J= 6.88Hz), 7.19-7.33 (6H, m), 7.85 (IH, s), 7.9,9 (IH, s), 8.20 (IH, s), 11.09 (IH, brs)

Preparation 68 (2E)-3-(6-{[(3R)-1-(4-Methoxybenzyl)-3-pyrrolidinyl]amino}-3 - pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide NMR (DMSO-d6, <5 ) : 1.40-1.80 (7H, m) , 2.05-2.90 (5H, m) , 3.40-3.60 (3H, m), 3.72 (3H, s), 3.80-4.05 (IH, m) , 4.20-4.45 (IH, m) , 4.87 (IH, s), 6.20 (IH, d, J = 16Hz), 6.51 (IH, d, J= 8.8Hz), 6.86 ( 2H, d, J= 8.5Hz ) , 7.21 (2H, d, J= 8.5Hz) , 7.20-7.30 ( IH, m) , 7.33 ( IH, d, J= 16Hz) , 7.58 ( IH, dd, J= 1.9Hz , J= 8.8Hz) , 8 .11 ( IH, d, J= 1.9Hz ) , 11 .03 ( IH, br) MASS(API-ES) ; 453 (M+H) +

Preparation 69 (2E)-3-(6-{[ (3R)-1-(4-Fluorobenzyl)-3-pyrrolidinyl]amino}- 3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide NMR (DMSO-de, δ ) -. 1.45-1.80 (7H, m) , 2.05-3.00 (5H, m) , 3.20-3.65 (3H, m), 3.80-4.05 (IH, m) , 4.20-4.45 (IH, m) , 4.87 (IH, s), 6.20 (IH, d, J= 16Hz), 6.51 (IH, d, J= 8.8Hz), 7.05-7.40 (6H, m) , 7.59 (IH, dd, J= 1.8Hz, J= 8.8Hz), 8.12 (IH, d, J= 1.8Hz), 11.05 (IH, br) MASS(API-ES); 441 (M+H)+

Preparation 70 (2E)-3-(6-{[(3R)-1-(4-Chlorobenzyl)-3-pyrrolidinyl]amino}-3- pyridyl)-N-(tetrahycLro-2H-pyran-2-yloxy)acrylamide NMR (DMSOd6, <5 ) : 1.40-1.80 (7H, m) , 2.05-2.90 (5H, m), 3.40-3.65 (3H, m), 3.80-4.05 (IH, m), 4.20-4.50 (IH, m) , 4.87 (IH, s), 6.20 (IH, d, J= 16Hz), 6.52 (IH, d, J= 8.8Hz), 7.22 (IH, d, J= 6.6Hz), 7.27-7.45 (5H, m) , 7.59 (IH, dd, J= 1.9Hz, J= 8.8Hz), 8.12 (IH, d, J= 1.9Hz), 11.04 (IH, br) MASS(API-ES); 457 (M+H)+ 459

Preparation 71 (2E)~3-(6-{[(3R)-l-.(4-Methylbenzyl)-3-pyrrolidinyl]amino}-3 - pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide NMR (DMSO-d6, 6): 1.40 - 1.80 (7H, m) , 2.05 - 2.85 (5H, m) , 2.27 (3H, s), 3.40 - 3.65( 3H, m) , 3.80 - 4.05 (IH, m) , 4.20 - 4.45 (IH, m), 4.87 (IH, s), 6.20 (IH, d, J = 16Hz), 6.51 (IH, d, J = 8.8Hz ), 7.05 - 7.25 (5H, m) , 7.33 (IH, d, J = 16Hz), 7.58 (IH, dd, J= 1.9 and 8.8Hz), 8.11 (IH, d, J = 1.9Hz), 11.03 (IH, br) MASS(API-ES); 437 (M+H)+

Preparation 72 (2E)-3-(6-{[(3R)-l-(Cyclopropylmethyl)-3-pyrrolidinyl]amino} -3- pyridyl) -N- ( tetrah.ydro-2H-pyran-2-yloxy)acrylamide NMR (DMSO-d6, <5 ) : 0.00 - 0.15 (2H, m) , 0.35 - 0.50 (2H, m) , 0.70 - 0.95 (IH, m), 1.40 - 1.85 (7H, m) , 2.08 - 2.53 (5H, m) , 2.55 - 2.82 (2H, m), 3.40 - 3.60 (IH, m) , 3.80 - 4.10 (IH, m) , 4.20 - 4.50 (IH, m), 4.87 (IH, s), 6.21 (IH, d, J = 16Hz), 6.52 (IH, d, J = 8.8Hz), 7.23 (IH, d, J = 6.8Hz), 7.34 (IH, d, J = 16Hz), 7.59 (IH, dd, J=I.9 and 8.8Hz), 8.14 (IH, d, J = 1.9Hz), 11.04 (IH, br) MASS(API-ES); 387 (M+H) +

Preparation 73 (2E) -3- (6-{ [ (3R) -l-Benzoyl-3-pyrrolidinyl]amino}-5-chloro-3- pyridyl) -N- (tetrahydro-2H-pyran-2-yloxy)acrylamide NMR (DMSO-de, <5 ) : 1.40 - 1.80 (6H, m) , 1.90 - 2.40 (2H, m) , 3.10 - 4.10 (6H, m), 4.40 - 4.85 (IH, m) , 4.89 (IH, s), 6.20 - 6.50 (IH, m), 6.90 - 7.05 (IH, m) , 7.25 - 7.60 (6H, m), 7.80 - 7.95 (IH, m), 8.15 - 8.30 (IH, m), 11.10 (IH, br) MASS(API-ES); 471 (M+H)+ ÷473

Preparation 74 (2E)-3-(5-Chloro-6-{[ (3R)-1-(cyclopropylcarbonyl)-3- pyrrolidinyl]amino}-3-pyridyl)-N-(tetrahydro-2H-pyran-2- yloxy)acrylamide NMR (DMSOd5, δ): 0.60 - 0.80 (4H, m) , 1.40 - 1.85 (7H, m) , 1.90 - 2.40 (2H, m), 3.15 - 4.10 (6H, m) , 4.40 - 4.85 (IH, m) , 4.89 (IH, s), 6.35 (IH, d, J= 16Hz), 6.85 - 7.00 (IH, m) , 7.38 (IH, d, J= 16Hz), 7.88 (IH, s), 8.25 (IH, s), 11.09 (IH, br) MASS(API-ES); 435 (M+H)+ , 437

Preparation 75 (2E)-3-(5-Chloro-6-{[l-(4-phenoxybenzoyl)-4-piperidyl]amino} -3- pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide Mass (APCI): 599(M+Na)+

Preparation 76 (2E)-3-(5-Chloro-6-{[l-(4-chlorobenzyl)-4-piperidyl]amino}-3 - pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide NMR (DMSO-d6, 6); 1.45-1.90(9H, m) , 1.95-2.15(2H, m) , 2.70-2.82(2H, m) , 3.46 ( 2H, s ) , .3.46-3. 55 ( 1H, m) , 3. 85-4. 10 ( 2H, m) , 4.88 ( 1H, s ) , 6.3O ( 1H, d, J= 16.0 Hz ) , 6. 51 ( 1H, d, J= 7.0 Hz ) , 7.29-7 .46 ( 5H, m) , 7.83 ( 1H, s ) , 8.2O ( 1H, s ) , 11.08 ( 1H, brs )

Preparation 77 (2E)-3-(5-Chlorb-6-{[1-(4-fluorobenzyl)-4-piperidyl]amino}-3 r pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide NMR (DMSO-de, <5 ) : 1.50-2.10(10H, m), 2.80-3.60(2H, m) , 3.80- 4.20(2H, m), 4.88(1H, s), 6.32(1H, d, J= 16.0 Hz), 6.8O(1H, brs), 7.10-60(4H, m), 7.36(1H, d, J= 16.0 Hz), 7.86(1H, s), 8.2O(1H, s), 11.09(lH, s),1

Preparation 78 A mixture of methyl 6-chloronicotinate (8.Og), (3R)-(-)-!- benzyl-3-aminopyrrolidine (9.86g), CuO (371mg) and K2CO3 (8.38g) in DMF (60ml) was stirred at 1000C for 10 hours under atmospheric pressure of nitrogen. The reaction mixture was poured into a mixture of AcOEt and water and the organic layer was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was chfomatographed on silicagel eluting with AcOEt-MeOH (97:3). The eluted fractions containing the desired product were collected and evaporated in vacuo to give methyl 6- {[(3R)-l-benzyl-3-pyrrolidinyl]amino}nicotinate (9.9g) . NMR (DMSO-d6, δ): 1.60-1.67 (l.H, m), 2.19-2.36 (IH, m) , 2.38-2.89 (2H, m), 2.62-2.81 (2H, m) , 3.56 (2H, s), 3.58 (3H, s), 4.38 (IH, m), 6.51 (IH, d, J= 8.84Hz), 7.18-7.33 (5H, m) , 7.58 (IH, d, J= 6.78Hz), 8.00 (IH, dd, J= 2.22Hz, 8.84Hz), 8.55 (IH, d, J= 2.22Hz)

The following compounds were obtained according to a similar manner to that of Preparation 78.

Preparation 79 Methyl 6-{[ (3S)-l-benzyl-3-pyrrolidinyl]amino}nicotinate NMR (DMSO-d6, <5 ) : 1.58-1.68 (IH, m) , 2.17-2.24 (IH, m)', 2.37-2.44 (2H, m), 2.62-2.82 (2H, m) , 3.51 (2H, s), 3.76 (3H, s), 4.39 (IH, m), 6.53 (IH, d, J= 8.96Hz), 7.19-7.33 (5H, m) , 7.59 (IH, d, J= 6.80Hz), 7.81 (IH, dd, J= 2.20Hz, 8.96Hz), 8.56 (IH, d, J= 2.20Hz) Preparation 80 A mixture of ethyl 5,6-dichloronicotinate (10.Og) , (3R)-(-)- 1-benzyl-3-aminopyrrolidine (9.6Ig), K2CO3 (8.38g) and CuO (371mg) in DMF (60ml) was stirred at 100 °C for 10 hours under atmospheric pressure of nitrogen. The reaction mixture was poured into a mixture of AcOEt and water and the organic layer was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-n-Hexane (7:3). The eluted fractions containing the desired product were collected and evaporated in vacuo to give ethyl 6- {[ (SRj-l-benzyl-S-pyrrolidinyllaminol-S-chloronicotinate (15.95g) NMR (DMSO-d6, <5): 1.29 (3H, t, J= 7.08Hz), 1.87-2.01 (IH, m) , 2.17-2.21 (IH, m), 2.41-2.53 (2H, m) , 2.67-2.87 (2H, m) ; 3.59 (2H, s), 4.25 (2H, q, J= 7.08Hz), 4.54-4.59 (IH, m) , 7.02 (IH, d, J= 6.98Hz), 7.19-7.33 (5H, m), 7.92 (IH, d, J= 1.96Hz), 8.53 (IH, d, J= 1.96Hz)

The following compounds were obtained according to a similar manner to that of Preparation 80.

Preparation 81 Ethyl (2E)-3-(6-{[(3R)-l-benzyl-3-pyrrolidinyl]amino}-5-chloro-3- pyridyl)aerylate NMR (DMSO-dβ, <5 ) : 1.28 (3H, t, J= 7.08Hz), 1.87-1.96 (IH, m) , 2.00-2.16 (2H, m), 2.40-2.67 (3H, m) , 2.80-2.87 (IH, m) , 3.59 (2H, s), 4.25 (2H, q, J= 7.08Hz), 4.54-4.58 (IH, m) , 7.03 (IH, d, J= 6.9,8Hz), 7.19-7.33 (5H, m) , 7.92 (IH, d, J= 1.96Hz), 8.53 (IH, d, J= 1.96Hz)

Preparation 82 A diisobutylaluminium hydride in toluene solution (15.7ml) was dropwise added to a solution of ethyl 6-{[ (3R)-l-benzyl-3- pyrrolidinyl]amino}-5-chloronicotinate (4.7g) in toluene (50ml) with stirring at -30—500C under atmospheric pressure of nitrogen, and the reaction mixture was stirred at -20—40 °C for 2 hours. A MeOH (5ml) was added to a reaction mixture at -40 °C and saturated sodium potassium tartrate aqueous solution (10ml) and MgSO4 (1Og) and the resultant mixture was stirred at ambient temperature for 20 minutes. The reaction mixture was filtrated and the filtrate was dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on siliσagel eluting with AcOEt-MeOH (9:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to give (6-{[(3R)-l-benzyl-3- pyrrolidinyl]amino}-5-chloro-3-pyridyl)methanol (1.87g) . NMR (DMSO-de, S ) : 1.77-1.99 (IH, m) , 2.16-2,35 (IH, m) , 2.36-2.52 (2H, m), 2.77-2.85 (2H, m), 3.58 (2H, s), 4.32 (2H, s), 4.42-4.49 (IH, m), 5.10 (IH, m), 6.00 (IH, d, J= 6.98Hz), 7.18-7.32 (5H, m) , 7.53 (IH, d, J= 1.90Hz), 7.91 (IH, d, J= 1.90Hz)

The following compounds were obtained according to a similar manner to that of Preparation 82.

Preparation 83 (6-{[ (3S)-l-Benzyl-3-pyrrolidinyl]amino}-5-chloro-3- pyridyl)methanol NMR (DMSO-d6, δ): 1.76-1.99 (IH, m), 2.08-2.33 (IH, m), 2.34-2.52 (2H, m), 2.62-2.76 (IH, m) , 2.80-2.84 (IH, m) , 3.57 (2H, s), 4.32 (2H, d, J= 4.76Hz), 4.41-4.45 (IH, m) , 5.06 (IH, t, J= 4.76Hz), 6.03 (IH, d, J= 6.96Hz), 7.18-7.36 (5H, m) , 7.53 (IH, d, J= 1.94Hz), 7.90 (IH, d, J= 1.94Hz)

Preparation 84 (5-Chloro-6-{[(3R)-I-(4-fluorobenzyl)-3-pyrrolidinyl]amino}- 3- pyridyl)methanol NMR (DMSO-d6, δ): 1.7O-1.89(1H, m) , 2.15-2.29(1H, m) , 2.34-2.86(4H, m), 3.56(2H, s), 4.31(2H, d, J= 5.5 Hz), 4.32-4.48(1H, m) , 5.06(1H, t, J= 5.5 Hz), 6.04(1H, d, J= 7.0 Hz), 7.08-7.34(4H, m) , 7.54(1H, d, J= 2.0 Hz), 7.91(IH, d, J= 2.0 Hz). Mass (APCI): 336(M+H)+

Preparation 85 (5-Chloro-6-{[(3R)-I-(4-methylbenzyl)-3-pyrrolidinyl]amino}- 3- pyridyl)methanol NMR (DMSO-de, δ ) : 1.72-1.85( 1H, m) , 2.08-2.85( 5H, m) , 2.27 ( 3H, s) , 3.52 (2H, s ) , 4.31 (2H, d, J= 5.5 Hz ) , 4.32-4.47 ( 1H, m) , 5.05 ( 1H, t , J= 5.5 Hz ) , 6.02 ( 1H, d, J= 7.0 Hz) , 7.10 ( 2H, d, J= 8.8 Hz) , 7.18( 2H, d, J= 8.8 Hz) , 7.53 ( 1H, d, J= 2.0 Hz) , 7.9O( 1H, d, J= 2.0 Hz) Mass (APCI ) : 332 (M+H)+

Preparation 86 (5-Chloro-6-{[(3R)-l-(4-methoxybenzyl)-3-pyrrolidinyl]amino} -3- pyridyl)methanol Mass (ESI): 348(M+H)+

Preparation 87 A mixture of methyl 6-chloronicotinate (5.14g), l-benzyl-4- aminopiperidine (6.84g) and K2CO3 (5.38g) in DMF (30ml) was stirred at 100 °C for 12 hours under atmospheric pressure of nitrogen. The reaction mixture was poured into a mixture of AcOEt and water and the organic layer was washed with brine and dried over MgSU4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (98:2). The eluted fractions containing the desired product were collected and evaporated in vacuo to give methyl 6-[ (1-benzyl-4- piperidyl)amino]nicotinate (4.77g) NMR (DMSO-de, ^): 1.35-1.52 (2H, m) , 1.84-1.89 (2H, m) , 1.99-2.11 (2H, m), 1.73-2.81 (2H, m) , 3.46 (2H, s), 3.75 (3H, s), 3.75-3.79 (IH, m), 6.48 (IH, d, J= 8.80Hz), 7.19-7.36 (6H, m) , 7.79 (IH, dd, J= 2.28Hz, 8.80Hz), 8.55 (IH, d, J= 2.28Hz)

Preparation 88 Lithium aluminium hydride (304mg) was added to a solution of methyl 6-[ (1-benzyl-4-piperidyl)amino]nicotinate (1.3g) in THF (20ml) with stirring at 5-100C under atmospheric pressure of nitrogen, and the reaction mixture was stirred at 5-20 X^ for 4 hours. The reaction mixture was cooled at 5 "C and water (0.3ml), 15% NaOH solution (0.3ml) and water (0.9ml) was added , the ' resultant mixture was stirred at ambient temperature for 20 minutes. The reaction mixture was filtrated and the filtrate was dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (9:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to give {6-[(l-benzyl-4-piperidyl)amino]-3- pyridyl}methanol (67Omg) NMR (DMSO-d6, δ): 1.32-1.50 (2H, m) , 1.84-1.89 (2H, m) , 2.00-2.10 (2H, m), 2.74-2.80 (2H, m) , 3.46-3.74 (IH, m) , 3.41 (2H, s), 4.22 (2H, d, J= 5.44Hz), 4.87 (IH, t, J= 5.44Hz), 6.28 (IH, d, J= 8..52Hz), 6.42 (IH, d, J= 8.52Hz), 7.19-7.36 (6H, m) , 7.85 (IH, s)

The following compound(s) were obtained according to a similar manner to that of Preparation 88.

Preparation 89 (6-{[1-(4-Chlorobenzoyl)-4-piperidyl]amino}-3-pyridyl)methan ol NMR (DMSO-de, <5 ) : 1.42-1.49 (2H, m), 1.84-1.89 (2H, m), 2.00-2.11 (2H, m), 2.72-2.78 (2H, m) , 3.63-3.73 (IH, m), 4.26 (2H, d, J= 5.26Hz), 4.86 (IH, d, J= 5.26Hz), 6.28 (IH, d, J= 7.60Hz), 6.42 (IH, d, J= 8.50Hz), 7.27-7.40 (5H, m), 7.85 (IH, d, J= 2.08Hz)

Preparation 90 4-{[5-(Hydroxymethyl)-2-pyridyl]amino}-N-phenyl-1- piperidinecarboxamide NMR (DMSO-de, δ ) : 1.36-1.43 (2H, m) , 1.89-1.94 (2H, m) , 2.92-3.03 (2H, m), 3.90-4.08 (3H, m), 4.28 (2H, d, J= 5.52Hz), 4.88 (IH, t, J= 5.52Hz), 6.37 (2H, m) , 6.88-6.96 (IH, m) , 7.18-7.36 (3H, m) , 7.45 (IH, dd, J= 2.02Hz, 8.38Hz), 7.88 (IH, d, J= 2.02Hz), 8.50 (IH, s)

Preparation 91 A mixture of methyl 6-[(1-benzyl-4- piperidyl)amino]nicotinate (4.2g) in MeOH (50ml) was hydrogenated over 10% palladium-carbon (1.5g) under an atmospheric pressure of hydrogen at ambient temperature under stirring for 15 hours. After removal of the catalyst and solvent was evaporated in vacuo and the residue was triturated with AcOEt and IPE. The precipitate was collected by filtration to give methyl 6-(4- piperidylamino)nicotinate (1.77g) . NMR (DMSO-d6, <5 ) : 1.18-1.41 ( 2H, in) , 1.81-1.87 (2H, m) , 2.60-2.64 ( 2H, m) , 2.99-3.14 (2H, m) , 3.46 ( 3H, s) , 3.46-3.76 ( IH, m) , 6.49 ( IH, d, J= 8.84Hz) , 7.28-7.39 ( 2H, m) , 7.78 ( IH, dd, J= 2.26Hz , 8.84Hz) , 8.55 ( IH, d, J= 2.26Hz )

Preparation 92 A mixture of {6-[(l-benzyl-4-piperidyl)amino]-3- pyridyl}methanol (670mg) and MnO2 (2.94g) in AcOEt (30ml) was refluxed under stirring for 2 hours. After removal of the insoluble material, and the solvent was evaporated in vacuo to give 6-[(l-benzyl-4-piperidyl)amino]nicotinaldehyde (560mg) NMR (DMSO-d6, <5): 1.39-1.56 (2H, m) , 1.86-1.91 (2H, m) , 1.99-2.12 (2H, m), 2.76-2.82 (2H, 'm), 3.47 (2H, s), 3.87 (IH, m) , 6.55 (IH, d, J= 8.90Hz), 7.29-7.37 (5H, m) , 7.65-7.74 (2H, m) , 8.47 (IH, d, J= 1.4Hz), 9.65 (IH, s)

The following compounds were obtained according to a similar manner to that of Preparation 92.

Preparation 93 6-{[l-(4-Chlorόbenzoyl)-4-piperidyl]amino}nicotinaldehyde NMR (DMSO-d6, <5 ) : 1.37-1.56 (2H, m) , 1.86-1.91 (2H, m) , 2.02-2.13 (2H, m), 2.74-2.80 (2H, m) , 3.86 (IH, m), 6.51 (IH, d, J= 8.06Hz), 7.30-7.41 (3H, m) , 7.92-7.96 (2H, m) , 8.47 (IH, d, J= 2.06Hz), 9.65 (IH, s)

Preparation 94 4-[ (5-Formyl-2-pyridyl)amino]-N-phenyl-1-piperidinecarboxamide NMR (DMSO-d6, <5): 1.31-1.50 (2H, m) , 1.91-1.99 (2H, m) , 2.94-3.05 (2H, m), 3.98-4.12 (3H, m) , 6.75 (IH,d, J= 8.86Hz), 6.89-6.96 (IH, m), 7.19-7.26 (2H, m) , 7.44-7.49 (2H, m) , 7.73-7.77 (2H, m) , 8.50- 8.54 (2H, m), 9.67 (IH, s)

Preparation 95 A solution of diethylphosphonoacetic acid ethyl ester (850mg) in THF (10ml) was added dropwise to a mixture of 60% sodium hydride in oil (167mg) in THF (15mL) with stirring at 10-20 *C under atmospheric pressure of nitrogen, and the reaction mixture was stirred at ambient temperature for 30 minutes. A solution of to the above mixture and resultant mixture was stirred at ambient temperature for 1.5 hour. The reaction mixture was poured into a mixture of AcOEt-H2O and the organic layer was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was crystallized with IPE and n-hexane to give ethyl (2E)- 3-{6-[ (1-benzyl-4-piperidyl)amino]-3-pyridyl}acrylate (450mg) . NMR (DMSO-de, <5 ) : 1.23 (3H, t, J= 7.06Hz), 1.36--1.53 (2H, m) , 1.84-1.90 (2H, m) ,1.99-2.10 (2H, m) , 2.75-2.81 (2H, m) , 3.46 (2H, s), 3.75-3.79 (IH, m) , 4.15 (2H, q, J= 7.06Hz), 6.30 (IH, d, J= 15.90Hz), 6.49 (IH, d, J= 8.86Hz), 7.11 (IH, d =7.52Hz), 7.19-7.37 (5H, m), 7.49 (IH, d, J= 15.90Hz), 7.76 (IH, dd, J= 2.10Hz, 8.86Hz), 8.20 (IH, d, J= 2.10Hz)

The following compounds were obtained according to a similar manner to that of Preparation 95.

Preparation 96 A solution of diethylphosphonoacetiσ acid ethyl ester (274mg) in THF (10ml) was added dropwise to a mixture of 60% sodium hydride in oil (55mg) in THF (1OmL) with stirring at 10-20 °C under atmospheric pressure of nitrogen, and the reaction mixture was stirred at ambient temperature for 30 minutes. A solution of 6- ' { [l-(4-chlorobenzoyl)-4-piperidyl]amino}nicotinaldehyde (210mg) in THF (10ml) solution was added to the above mixture and resultant mixture was stirred at ambient temperature for 1.5 hour. The reaction mixture was poured into a mixture of AcOEt-H2O and the organic layer was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (95:5). The eluted fractions containing the desired product were collected and evaporated in vacuo to give ethyl (2E)-3-(6-{[l-(4-chlorobenzoyl)-4- piperidyl]amino}-3-pyridyl)acrylate (190mg) NMR (DMSO-de, 8): 1.23 (3H, t, J= 7.06Hz), 1.41-1.51 (2H, m) , 1.84-1.90 (2H, m), 2.01-2.11 (2H, m) , 2.73-2.79 (2H, m) , 3.78 (IH, m), 4.14 (2H, q, J= 7.06Hz), 6.30 (IH, d, J= 15.86Hz), 6.48 (IH, d, J= 8.88Hz ) , 7.11 ( IH, d, J= 7.48Hz ) , 7 .30-7.41 ( 4H, m) , 7.49 ( IH, d, J= 15.86Hz ) , 7. 76 ( IH, dd, J= 2.04Hz , 8. 88Hz ) , 8. 19 ( IH, d, J= 2.04Hz )

The following compounds were obtained according to a similar manner to that of Preparation 96.

Preparation 97 Ethyl (2E)-3-(6-{[l-(anilinocarbonyl)-4-piperidyl]amino}-3- pyridyl)acrylate NMR (DMSO-d6, δ) : 1.23 (3H, t, J= 7.06Hz), 1.35-1.45 (2H, m) , 1.90-1.95 (2H, m), 2.92-3.05 (2H, m) , 3.97-4.20 (4H, m) , 6.32 (IH, d, J= 15.90Hz), 6.51 (IH, d, J= 8.80Hz), 6.88-6.96 (IH, m) , 7.17- 7.26 (2H, m), 7.44-7.55 (3H, m) , 8.23 (IH, d, J= 2.08Hz), 8.53 (IH, s)

Preparation 98 A mixture of ethyl (2E)-3-{6-[(l-benzyl-4-piperidyl)amino]- 3-pyridyl}acrylate(470mg) and IN NaOH solution (2.6ml) in MeOH (15ml) was stirred at 65-70 °C for 2 hours. The reaction mixture was evaporated in vacuo and the residue was dissolved with AcOEt and H2O. The aqueous solution was adjusted to PH6.0 with aq.HCl and evaporated in vacuo. The residue was chromatographed on silicagel eluting with AcOEt-MeOH (85:15). The eluted fractions containing the desired product were collected and evaporated in vacuo to give (2E)-3-{6-[(l-benzyl-4-piperidyl)amino]-3- pyridyl}acrylic acid (430mg). NMR (DMSO-de, <5 ) : 1.91-2.13 (4H, m) , 2.80-3.60 (2H, m) , 3.39-3.49 (2H, m), 3.67 (2H, brs), 4.30-4.50 (IH, m) , 6.27 (IH, d, J= 15.85Hz), 6.70 (IH, m) , 7.39-7.47 (4H, m) , 7.67-7.79 (4H, m) , 8.51 (IH, s)

Preparation 99 A mixture of methyl 6-(4-piperidylamino)nicotinate (1.Og), 4-chlorobenzoic acid (699mg), HOBt (603mg) and EDCI (693mg) in DMF (20ml) was stirred at ambient temperature for 15 hours. The reaction mixture was poured into a mixture of AcOEt-H2O and the organic layer was washed with brine and dried over MgSO4 . The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-n-hexane (7:3). The eluted fractions containing the desired product were collected and evaporated in vacuo to give methyl 6-{[l-(4-chlorobenzoyl)~4- piperidyl]amino}nicotinate (1.2Ig) NMR (DMSO-de, <5 ) : 1.42 (2H, m), 1.92-1.99 (2H, m) , 2.94-3.34 (4H, m), 3.76 (3H, s), 4.09-4.13 (IH, m) , 6.52 (IH, d, J= 8.84Hz), 7.40- 7.54 (5H, m), 7.81 (IH, dd, J= 2.26Hz, 8.84Hz), 8.56 (IH, d, J= 2.26Hz)

Preparation 100 A mixture of (2E)-3-{6-[(l-benzyl-4-piperidyl)amino]-3- pyridyl}acrylic acid(430mg) , 0-(tetrahydro-2H-pyran-2- yl)hydroxylamine (157mg), HOBt (181mg) and EDCI(208mg) in DMF , (20ml) was stirred at ambient temperature for, 15 hours. The reaction mixture was poured into a mixture of AcOEt-H2O and the organic layer was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (9:1-8:2). The eluted fractions containing the desired product were collected and evaporated in vacuo to give (2E)-3-{6-[ (l-benzyl-4- piperidyl)amino]-3-pyridyl}-N-(tetrahydro-2H-pyran-2- yloxy)aerylamide (18Omg) . NMR (DMSO-de, <5 ) : 1.35-1.68 (8H, m), 1.84-1.90 (2H, m), 1.99-2.10 (2H, m), 2.73-2.89 (2H, m) , 3.54 (2H, s), 3.73-3.79 (4H, m) , 3.42- 3.98 (IH, m), 4.87 (IH, s), 6.20 (IH, d, J= 14.96Hz), 6.50 (IH, d, J= 8.82Hz), 7.00 (IH, d, J= 7.54Hz), 7.21-7.37 (6H, m) , 7.58 (IH, d, J= 8.82Hz), 8.12 (IH, s), 11.02 (IH, s)

The following compounds were obtained according to a similar manner to that of Preparation 100.

Preparation 101 4-[(5-{(IE)-3-0x0-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-l-p ropen- 1-yl}-2-pyridyl)amino]-N-phenyl-1vpiperidinecarboxamide NMR (DMSO-de, <5 ) : 1.29-1.68 (8H, m) , 1.90-1.99 (2H, m) , 2.89-3.04 ( 2H, m) , 3.56-3.60 ( IH, m) , 3.95-4.10 ( 4H, m) , 4.88 ( IH, s) , 6.22 ( IH, d, J= 15.18Hz) , 6.52 ( IH, d, J= 8.78Hz) , 6.86-6.96 ( IH, m) , 7.18-7.48 ( 5H, m) , 7.59-8.15 ( IH, m) , 8. 16 ( IH, s) , 8.51 ( IH, s) , 11.03 ( IH, s)

Preparation 102 (2E)-3-(6-{[1-(4-Chlorobenzoyl)-4-piperidyl]amino}-3-pyridyl )-N- (tetrahydro-2H-pyran-2-yloxy)acrylamide NMR (DMSO-de, <5 ) : 1.36-1.83 (1OH, m) , 1.90-2.12 (4H, m) , 2.52-2.73 (2H, m), 3.54 (IH, m) , 3.93 (IH, m), 4.87 (IH, brs), 6.12-6.22 )1H, m), 6.49 (IH, d, J= 8.82Hz), 6.95-7.00 (IH, m) , 7.30-7.41 (4H, m), 7.53-7.62 (IH, m) , 8.12 (IH, s) , 11.00 (IH, s)

Preparation 103 A mixture of methyl 6-(4-piperidylamino)nicotinate (0.73g) and phenyl isocyanate (388mg) in THF (30ml) was stirred at ambient temperature for 12 hours. IPE (30ml) was added to a reaction mixture and the precipitate was collected by filtration to give methyl 6-{[1-(anilinocarbonyl)-4-piperidyl]amino}nicotinate (0.72g) NMR (DMSO-de, <5 ) : 1.27-1.48 (2H, m) , 1.90-1.95 (2H, m) , 2.93-3.04 (2H, m), 3.77 (3H, s), 4.04-4.11 (3H, m) , 6.51 (IH, d, J= 8.88Hz), 6.88-6.96 (2H, m) , 7.12-7.26 (2H; m), 7.40-7.49 (3H, m) , 7.81 (IH, dd, J= 8.88Hz), 8.53 (IH, s), 8.57 (IH, d, J= 2.26Hz)

Preparation 104 A mixture of ethyl (2E)-3-(6-{[l-(4-chlorobenzoyl)-4- piperidyl]amino)-3-pyridyl)aerylate (190mg) and IN NaOH solution (1.0ml) in MeOH (20ml) was stirred at 70-75 °C for 2 hours. The reaction mixture was evaporated in vacuo and the residue was dissolved in a mixture of AcOEt and water. The aqueous solution was adjusted to PH4.5 and extract with AcOEt and THF. The organic layer was washed with brine and dried over MgSO4. The solvent was concentrated in vacuo and the precipitate was collected by filtration to give (2E)-3-(6-{[l-(4-chlorobenzoyl)-4- piperidyl]amino}-3-pyridyl)acrylic acid (85mg) NMR (DMSO-d6, <5 ) : 1.36-2.23 (6H, m) , 2.92-3.03 (2H, m) , 4.17 (IH, m) , 6 .24 ( IH, d, J= 15 .88Hz ) , 6 .54 ( IH, d, J= 7. 94Hz ) , 7.34-7 . 60 ( 4H, m) , 7.76 ( IH, dd, J= 1.82Hz , 7.94Hz ) , 8.18 ( IH, d, J= 1.82Hz) , 12.02 ( IH, m)

The following compounds were obtained according to a similar manner to that of Preparation 104.

Preparation 105 (2E)-3-(6-{[1-(Anilinocarbonyl)-4-piperidyl]amino}-3- pyridyl)acrylic acid NMR (DMSO-de, <5 ) : 1.35-1.45 (2H, m) , 1.91-1.95 (2H, m) , 3.03-3.05 (2H, m), 3.96-4.10 (3H, m) , 6.22 (IH, d, J= 15.92Hz), 6.51 (IH, d, J= 8.80Hz), 6.88-6.96 (IH, m) , 7.13-7.26 (3H, m) , 7.41-7.49 (3H, m) , 7.76 (IH, dd, J= 2.08Hz, 8.80Hz), 8.19 (IH, d, J= 2.08Hz), 8.52 (IH, s), 12.05 (IH, s)

Preparation 106 (2E)-3-(5-Chloro-6-{[l-(4-chlorobenzyl)-4-piperidyl]amino}-3 - pyridyl)acrylic acid NMR (DMSO-d6, S): 1.50-2.20(6H, m) , 2.65-2.85(2H, m) , 3.45(2H, s), 4.88-4.22(1H, m), 6.37(1H, d, J= 16.0 Hz), 6.49(1H, d, J= 8.0 Hz), 7.29-7.52(5H, m) , 8.00(1H, d, J= 2.0 Hz), 8.2O(1H, d, J= 2.0 Hz)

Preparation 107 To a solution of ethyl (2E)-3-(6-{[(3R)-l-benzyl-3- pyrrolidinyl]amino}-3-pyridyl)acrylate (4.74g) and 4- (Dimethylamino)pyridine(41.2mg) in tetrahydrofuran (70ml) was added di-tert-butyldicarbonate (5.89g) at 2θ"C and then stirred at 60°C for 14 hours. The mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (7Og) using a mixed solvent of dichloromethane and methanol(60:1 to 15:1). The fractions containing the objective compound were collected and evaporated under reduced pressure. Ethyl (2E)-3-{6-[[(3R)-l-benzyl-3-pyrrolidinyl](tert- butoxycarbonyl)amino]-3-pyridyl}acrylate (5.49g) was obtained as colorless oil. NMR (DMSO-d6, <5 ) : 1.27 (3H, t, J = 6.8Hz), 1.41 (9H, s), 1.80 - 2'.20 ( 2H, m) , 2.40 - 2 .80 ( 4H, m) , 3.44 , 3. 55 ( 2H, ABq, J = 13Hz ) , 4 .21 ( 2H, q, J = 6.8Hz ) , 4.60 - 4.90 ( IH, m) , 6. 78 ( IH, d, J = 16Hz ) , 7.00 - 7. 30 ( 5H, m) , 7.34 ( IH, d, J = 8. 5Hz ) , 7. 71 ( IH, d, J = 16Hz ) , 8.20 ( IH, dd, J= 2 .4Hz , J= 8. 5Hz ) , 8. 73 ( IH, d, J = 2.4Hz ) , MASS(API-ES) ; 452 (M+H) + .

Preparation 108 To a solution of ethyl (2E)-3-{6-[ [ (3R)-l-benzyl-3- pyrrolidinyl] (tert-butoxycarbonyl) amino]-3-pyridyl}acrylate (5.45g) in toluene (55ml) was added 1-chloroethyl chloroformate (2.59g) at room temperature and stirred at 20°C for 1 hour. 1- Chloroethyl chloroformate (795mg) and N,N-diisopropylethylamine (0.736ml) was added to the mixture, and the solution was stirred at 20°C for 15 minutes. After it was concentrated under reduced pressure, the resulting residue was dissolved in EtOH(70ml). The mixture was stirred at 65°C for 30minutes, and concentrated under reduced pressure. The residue was poured into a mixture of aq NaHCO3 solution (80 ml) and dichloromethane (100 ml). The organic layer was separated and dried over sodium sulfate, and evaporated under reduced pressure to give crude oil. The oil was purified by column chromatography (silica gel 125g, dichloromethane / MeOH (60/1 to 15/1) to give ethyl (2E)-3-(6-{(tert-butoxycarbonyl) [(3R)- 3-pyrrolidinyl]amino}-3-pyridyl)acrylate as oil (2.Og). NMR (DMSO-d6, <5 ) : 1.26 (3H, t, J = 7.1Hz), 1.31 - 1.40 (9H, m), 1.60 - 2.10 (2H, m), 2.30 - 3.20 (4H, m) , 4.20 (2H, q, J = 7.1Hz), 4.50 - 4.80 (IH, m), 6.76 (IH, d, J = 16Hz), 7.36 (IH, d, J = 8.5Hz), 7.68 (IH, d, J = 16Hz), 8.19 (IH, dd, J= 2.4Hz, J= 8.5Hz), 8.72 ( IH, d, J = 2.4Hz ) MASS(API-ES); 362 (M+H)+

Preparation 109 To a mixture of ethyl (2E)-3-(6-{(tert-butoxycarbonyl) [ (3R)- 3-pyrrolidinyl]amino}-3-pyridyl)acrylate (350mg) and 4- methoxybenzaldehyde(145mg) in dichloromethane(5ml) was added sodium triacetoxyborohydride(410mg) at 20°C ,and then it was stirred at the same temperature for 18 hours. The reaction was quenched with saturated aq NaHCO3 solution, and the mixture was extracted with dichloromethane. The organic layer was dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Hg) using a mixed solvent of dichloromethane and MeOH (100:1 to 35:1). The fractions containing the objective compound were collected and evaporated under reduced pressure, ethyl (2E)-3-(6-{(tert-butoxycarbonyl) [ (3R)-l-(4- methoxybenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate (362mg) was obtained as colorless syrup. NMR (DMSO-de, <5 ) : 1.27 (3H, t, J = 7.1Hz), 1.35 (9H, s), 1.80 - 2.20 (2H, m), 2.30 - 2.90 (4H, m) , 3.36, 3.48 (2H, ABq, J = 13Hz), 3.71 (3H, s), 4.21( H, q, J = 7.1Hz), 4.60 - 4.85 (IH, m) , 6.78 (IH, d, J = 16Hz), 6.81 (2H, d, J = 8.6Hz , 7.06 (2H, d, J = 8.6Hz), 7.33 (IH, d, J = 8.4Hz), 7.71(1H, d, J = 16Hz), 8.20 (IH, dd, J= 2.4Hz, J= 8.4Hz), 8.72 (IH, d, J = 2.4Hz) MASS(API-ES); 482 (M+H)+

The following compounds were obtained according to a similar manner to that of Preparation 109.

Preparation 110 Ethyl (2E)-3-(6-{(tert-butoxycarbonyl) [(3R)-1-(4-fluorobenzyl)-3- pyrrolidinyl]amino}-3-pyridyl)aerylate NMR (DMSO-dβ, <5 ) : 1.27 (3H, t, J = 7.1Hz), 1.36 (9H, s), 1.80 - 2.20 (2H, m), 2.25 - 2.90 (4H, m) , 3.42, 3.54 (2H, ABq, J = 13Hz), 4.21(2H, q, J = 7.1Hz), 4.60 - 4.90 (IH, m) , 6.78 (IH, d, J = 16Hz), 7.00 - 7.25 (4H, m) , 7.34 (IH, d, J = 8.4Hz ), 7.71(IH, d, J = 16Hz), 8.20 (IH, dd, J= 2.4Hz, J= 8.4Hz), 8.73 (IH, d, J = 2.4Hz) MASS(API-ES); 470 (M+H)+

Preparation 111 Ethyl (2E)-3-(6-{(tert-butoxycarbonyl) [ (3R)-1-(4-chlorobenzyl)-3- pyrrolidinyl]amino}-3-pyridyl)aerylate NMR (DMSO-de, <5 ) : 1.27 (3H, t, J = 7.1Hz), 1.35 (9H, s), 1.85 - 2.25 (2H, m) , 2.30 - 2.90 (4H, m) , 3.42, 3.55 (2H, ABq, J = 13Hz), 4.22 (2H, q, J = 7.1Hz), 4.60 - 4.90 (IH, m) , 6.78 (IH, d, J = 16Hz), 7.17 (2H, d, J = 8.4Hz), 7.31 (2H, d, J = 8.4Hz), 7.34 (IH, d, J = 8. 5Hz ) , 7. 71 ( 1H, d, J = 16Hz ) , 8. 20 ( IH, dd, J= 2.3 and 8.5Hz ) , 8. 73 ( IH, d, J = 2.3Hz ) MASS(API-ES) ; 486 (M+H) + 488

Preparation 112 Ethyl (2E)-3-(6-{(tert-butoxycarbonyl) [(3R)-1-(4-methylbenzyl)-3- pyrrolidinyl]amino}-3-pyridyl)aerylate NMR (DMSO-d5, δ): 1.27 (3H, t, J = 7.1Hz , 1.35 (9H, s), 1.75 - 2.24 (2H, m), 2.26 (3H, s), 2.30 - 2.85 (4H,, m), 3.38, 3.50 (2H, ABq, J = 13Hz ), 4.21 (2H, q, J = 7.1Hz), 4.60 - 4.85 (IH, m) , 6.77 (IH, d, J = 16Hz), 6.95 - 7.10 (4H, m) , 7.33 (IH, d, J = 8.4Hz), 7.70 (IH, d, J = 16Hz), 8.19 (IH, dd, J= 2.4Hz, J= 8.4Hz), 8.71 (IH, d, J = 2.4Hz) MASS(API-ES); 466 (M+H)+ , . Preparation 113 To an ice-cooled solution of ethyl (2E)-3-(6-{(tert- butoxycarbonyl) [(3R)-1-(4-methoxybenzyl)-3-pyrrolidinyl]amino}-3- pyridyl)acrylate (360mg) in dichloromethane (2ml) was added anisole (1.0ml) and TFA (2.0ml), the mixture was stirred at 20°C for 1 hour. The mixed solution was poured into a mixture of water (20ml) and AcOEt (20 ml). The pH of the aqueous layer was adjusted to ca.9 with NaHC03. The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated under reduced pressure to give ethyl (2E)-3-(6-{[(3R)-l-(4-methoxybenzyl)-3- pyrrolidinyl]amino} -3-pyridyl)acrylate as syrup (295mg) . NMR (DMSO-de, <5 ) : 1.24 (3H, t, J = 7.1Hz), 1.60 - 2.00 (IH, m) , 2.10 - 3.65 (7H, m) , 3.74 (3H, s) , 4.15 (2H, q, J = 7.1Hz), 4.25 - 4.55 (IH, m), 6.35 (IH, d, J = 16Hz), 6.53 (IH, d, J = 8.8Hz), 6.93 (2H, d, J = 8.5Hz), 7.25 - 7.43 (3H, m) , 7.51(1H, d, J = 16Hz), 7.82 (IH, dd, J= 2.0 and 8.8Hz), 8.22 (IH, d, J = 2.0Hz) MASS(API-ES); 382 (M+H)+

The following compounds were obtained according to a similar manner to that of Preparation 113.

Preparation 114 Ethyl (2E)-3-(6-{[(3R)-l-(4-fluorobenzyl)-3-pyrrolidinyl]amino}-3- pyridyl)acrylate NMR (DMSO-d6, <5 ) : 1.23 (3H, t, J = 7.1Hz), 1.50 - 1.80 (IH, m) , 2.10 - 2.90 (5H, m), 3.58 (2H, br) , 4.14 (2H, q, J = 7.1Hz), 4.20 - 4.50 (IH, m), 6.31 (IH, d, J = 16Hz), 6.51 (IH, d, J = 8.8Hz), 7.05 - 7.40 (5H, m), 7.49 (IH, d, J = 16Hz), 7.78 (IH, dd, J= 2.1 and 8.8Hz), 8.20 (IH, d, J = 2.1Hz) MASS(API-ES); 370 (M+H)+

Preparation 115 Ethyl (2E)-3-(6-{[(3R)-1-(4-chlorobenzyl)-3-pyrrolidinyl]amino}-3- pyridyl)acrylate NMR (DMSO-de, <5 ) : 1.23 (3H, t, J = 7.1Hz), 1.50 - 1.85 (IH, m) , 2.10 - 3.00 (5H, m), 3.20 - 3.90 (2H, m) , 4.14 (2H, q, J = 7.1Hz), 4.20 - 4.50 (IH, m) , 6.32 (IH, d, J = 16Hz), 6.51 (IH, d, J = 8.8Hz), 7.30 - 7.45 (5H, m) , 7.49 (IH, d, J = 16Hz), 7.79 (IH, dd, J= 2.1Hz, J= 8.8Hz), 8.20 (IH, d, J = 2.1Hz) MASS(API-ES); 386 (M+H)+ 388

Preparation 116 Ethyl (2E)-3-(6-{[(3R)-1-(4-methylbenzyl)-3-pyrrolidinyl]amino}-3- pyridyl)acrylate NMR (DMSO-de, <5 ) : 1.23 (3H, t, J = 7.1Hz), 1.55 - 1.85 (IH, m) , 2.10 - 3.10 (5H, m), 2.29 (3H, s), 3.20 - 4.00 (2H, m), 4.14 (2H, q, J = 7.1Hz), 4.25 - 4.50 (IH, m), 6.33 (IH, d, J = 16Hz), 6.52 (IH, d, J = 8.8Hz), 7.10 - 7.30 (4H, m) , 7.40 (IH, d, J = 6.5Hz), 7.50 (IH, d, J = 16Hz), 7.80 (IH, dd, J= 2.1 and 8.8Hz), 8.21 (IH, d, J = 2.IHz) MASS(API-ES); 366 (M+H)+

Preparation 117 Ethyl (2E)-3-(6-{[(3R)-l-(cyclopropylmethyl)-3-pyrrolidinyl]amino} - 3-pyridyl)acrylate NMR (DMSO-de, <5 ) : 0.00- - 0.20 (2H, m) , 0.40 - 0.60 (2H, m) , 0.75 - 1.00 (IH, m), 1.24 (3H, t, J = 7.1Hz), 1.55 - 1.80 (IH, m) , 2.10 - 3.60 (7H, m), 4.15 (2H, q, J = 7.1Hz), 4.25 - 4.50 (IH, m) , 6.33 (IH, d, J = 16Hz), 6.53 (IH, d, J = 8.8Hz), 7.39 (IH, d, J = 6.5Hz), 7.51 ( IH, d, J = 16Hz ) , 7.80 ( IH, dd, J= 2.2Hz , J= 8.8Hz ) , 8.23 ( IH, d, J = 2 .2Hz ) MASS(API-ES) ; 316 (M+H) +

Preparation 118 To a solution of ethyl (2E)-3-(6-{(tert- butoxycarbonyl) [(3R)-3-pyrrolidinyl]amino}-3- pyridyl)acrylate (310mg) and cyclopropylmethyl bromide (116mg) in acetonitrile (7ml) was added potassium hydrogencarbonate (85.9mg) and potassium iodide (28.5mg) at 20°C and then the mixture was stirred at 50°C for 3 hours. The mixed solution was poured into a mixture of water (20ml) and AcOEt (20 ml). The pH of the aqueous layer was adjusted to ca.9 with NaHCO3. The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (8g) using a mixed solvent of dichloromethane and MeOH (40:1 to 20:1). The fractions containing the objective compound were collected and evaporated under reduced pressure. Ethyl (2E)- 3-(6-{(tert-butoxycarbonyl) [(3R)-1-(cyclopropylmethyl) -3-pyrrolidinyl]amino}-3-pyridyl)acrylate (170mg) was obtained as colorless syrup. NMR (DMSO-dβ, δ ) : 0.00 - 0.10 (2H, m) , 0.30 - 0.50 (2H, m) , 0.65 - 0.90 (IH, m), 1.27 (3H, t, J = 7.1Hz), 1.39 (9H, s), 1.80 - 3.40 (8H, m), 4.21(2H, q, J = 7.1Hz), 4.60 - 4.90 (IH, m) , 6.76 (IH, d, J = 16Hz), 7.37 ( IH, d, J = 8.5Hz), 7.69 (IH, d, J = 16Hz), 8.20 (IH, dd, J= 2.3 and 8.5Hz), 8.73 (IH, d, J = 2.3Hz) MASS(API-ES); 416 (M+H)+

Preparation 119 To a stirred suspension of ethyl (2E)-3-(6-{(tert- butoxycarbonyl) [ (3R)-1-(4-tert-butylbenzyl)-3-pyrrolidinyl]amino}- 3-pyridyl)acrylate(430mg) in dichloromethane(2mL) was added trifluoroacetic acid(2mL) and the resulting mixture was stirred at ambient temperature for 2 hours. The mixture was concentrated in ' vacuo. The residue was dissolved in ethanol(5mL) and to this solution was added IN sodium hydroxide aqueous solution(5.ImL) and the mixture was stirred at fifty degree for 12 hours. The,mixture was allowed to cool to ambient temperature. To the mixture was added concentrated hydrogen chloride in an ice bath until pH of the mixture became neutral. The mixture was concentrated in vacuo. The mixture was dissolved in DMF(5mL) and to the resulting solution was added O-(tetrahydro-2H-pyran-2-yl)hydroxylamine(129mg) , 1- hydroxybenzotriazole(149mg) and EDCI hydrochloride(2llmg) . After stirring at ambient temperature for 2 hours, the mixture was cooled in an ice bath and to this was added saturated aqueous sodium bicarbonate(5mL) and water(5mL). The precipitate was filtered, washed with water and dried to afford (2E)-3-(6-{[(3R)-l-(4-tert- butylbenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-(tetrahydro- 2H- pyran-2-yloxy)acrylamide(280mg) as a pale tan solid. NMR (DMSO-de, <5 ) : 1.26 (9H, s), 1.42-1.78 (6H, m) , 2.07-2.82 (6H, m), 3.28-3.41 (IH, m) , 3.49 (IH, d, J= 13.9 Hz), 3.55 (IH, d, J= 13.9 Hz), 3.84-4.01 (IH, m) , 4.24-4.39 (IH, m) , 4.85 (IH, brs), 6.20 (IH, br.d, J= 16.5 Hz), 6.50 (IH, d, J= 8.6 Hz), 7.14-7.29 (IH, m), 7.22 (2H, d, J= 8.4 Hz), 7.32 (2H, d, J= 8.4 Hz), 7.57 (IH, br.d, J= 8.6 Hz), 8.09 (IH, brs) MS (ES+) m/z 479.36

Preparation 120 tert-Butyl (5-{(lE)-3-oxo-3-[ (tetrahydro-2H-pyran-2-yloxy)amino]-l- propen-1-yl}-2-pyridyl){(3R)-l-[4-(trifluoromethyl)benzyl]-3 - pyrrolidinyl}carbamate NMR (DMSO-dg, <5 ) : 1.35 (9H, s) , 1.45-1.79 (6H, m) , 1.87-2.23 (2H, m), 2.44-2.67 (3H, m) , 2.72-2.82 (IH, m) , 3.48-3.59 (IH, m) , 3.54 (IH, d, J= 13.6 Hz), 3.65 (IH, d, J= 13.6 Hz), 3.88-4.04 (IH, m) , 4.68-4.83 (IH, m) , 4.92 (IH, brs), 6.60 (IH, d, J= 16.1 Hz), 7.35 (IH, d, J= 8.1 Hz), 7.39 (2H, d, J= 8.4 Hz), 7.55 (IH, d, J= 16.1 Hz), 7.63 (2H, d, J= 8.4 Hz), 8.02 (IH, br.d, J= 8.1 Hz), 8.63 (IH, brs) MS (ES+) m/z 591.28(M+1).

Preparation 121 tert-Butyl (5-{(lE)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1- propen-1-yl}-2-pyridyl){(3R)-1-[4-(trifluoromethoxy)benzyl]- 3- pyrrolidinyl}carbamate NMR (DMSO-de, #): 1.35 (9H, s), 1.46-1.81 (6H, m) , 1.86-2.20 (2H, m), 2.45-2.65 (3H, m) , 2.71-2.81 (IH, m) , 3.43-3.65 (3H, m) , 3.90- 4.06 (IH, m), 4.66-4.84 (IH, m) , 4.92 (IH, brs) , 6.59 (IH, d, J= 15.8 Hz), 7.25 (2H, d, J= 8.8 Hz), 7.29 (2H, d, J= 8.8 Hz), 7.34 (IH, d, J= 8.1 Hz), 7.55 (IH, d, J= 15.8 Hz), 8.02 (IH, brd, J= 8.1 Hz), 8.63 (IH, brs) MS (ES+) m/z 607.29(M+l)

Preparation 122 tert-Butyl [(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl](5-{(IE)-3- oxo-3-[ (tetrahydro-2H-pyran-2-yloxy)amino]-l-propen-l-yl}-2- pyridyl)carbamate NMR (DMSO-d6, <5 ) : 0.59-1.77 (17H, m) , 1.37 (9H, s), 1.85-2.22 (4H, m), 2.23-2.78 (4H, m) , 3.47-3.59 (IH, m) , 3.88-4.04 (IH, m), 4.64- -. 4.84 (IH, m), 4.92 (IH, brs), 6.58 (IH, d, J= 16.5 Hz), 7.35 (IH, d, J= 8.1 Hz), 7.53 (IH, d, J= 16.5 Hz), 8.01 (IH, br.d, J= 8.1 Hz), 8.63 (IH, brs) MS (ES+) m/z 529.44(M+1)

Preparation 123 tert-Butyl [(3R)-1-(1-cyclohexen-l-ylmethyl)-3-pyrrolidinyl] (5- {(IE)-3-OXO-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen- l-yl}- 2-pyridyl)carbamate NMR (DMSO-d6, <5): 1.14-2.20 (16H, m) , 1.36 (9H, s), 2.33-2.50 (3H, m), 2.56-2.73 (2H, m) , 2.78-2.88 (IH, m) ,3.49-3.61 (IH, m) , 3.90- 4.04 (IH, m), 4.64-4.79 (IH, m) , 4.92 (IH, brs), 5.43 (IH, brs), 6.58 (IH, d, J= 16.1 Hz), 7.33 (IH, d, J= 8.4 Hz), 7.53 (IH, d, J= 16.1 Hz), 8.00 (IH, br.d, J= 8.4 Hz), 8.63 (IH, brs) MS (ES+) m/z 527.54(M+1)

Preparation 124 The mixture of l-chloro-3- (triphenylphosphoranylidene)acetone (6.6g) and ethyl glyoxylate (50% in toluene, 4.6g) in dioxane (66mL) was stirred at 801G for 1.5 hour. The solvent was removed by concentration. The residue was purified by column chromatography on silica gel using a mixture of chloroform and hexane (1 : 1 v/v) as an eluent. The eluted fractions containing the desired product were collected and evaporated in vacuo to give ethyl (2E)-5-chloro-4-oxo-2-pentenoate (1.58g). NMR(DMSO-d6, δ): 1.25(3H, t, J= 7.1 Hz), 4.22(2H, q, J= 7.1 Hz), 4.85(2H, s), 6.78(1H, d, J= 16.1 Hz), 7.07(1H, d, J= 16.1 Hz)

Preparation 125 The mixture of ethyl (2E)-5-chloro-4-oxo-2-pentenoate (0.5g) and N-[l-(4-chlorobenzoyl)-3-pyrrolidinyl]thiourea (0.8g) in acetonitrile (1OmL) was stirred at 701C for 3 hours, and the mixture was evaporated in vacuo. To the residue was added a solution of AcOEt and water, and the mixture was adjusted to pH 8 with 20% aqueous potassium carbonate. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel using AcOEt as an eluent. The eluted fractions containing the desired product were collected and evaporated in vacuo to give ethyl (2E)-3-(2-{[l-(4-chlorobenzoyl)-3- pyrrolidinyl]amino}-1,3-thiazol-4-yl)acrylate (1.Og) . NMR (DMSO-de, <5 ): 1.24(3H, t, J= 7.1 Hz), 1.88-2.28(2H, m) , 3.29- 3.72(3H, m), 3.74-3.87(1H, m) , 4.07-4.40(3H, m) , 6.27 and 6.49('total' IH, each d, J= 15.3 Hz), 7.16 and 7.21(total IH, each s), 7.31 and 7.37(total IH, each d, J= 15.3 Hz), 7.44-7.62(4H, m) , 8.07 and 8.11 (total IH, each d, J= 6.0 Hz) (+)ESI-MS:406(M+H)+,428(M+Na)+

The following compounds were obtained according to a similar manner to that of Preparation 125.

Preparation 126 Ethyl (2E)-3-{2-[ (l-benzyl-4-piperidyl)amino]-l,3-thiazol-4- yl}acrylate MMR(DMSO-d6, <5 ) : 1.23(3H, t, J= 7.1 Hz), 1.35-1.58(2H, m) , 1.85- 2.16(4H, m), 2.68-2.83(2H, m), 3.42-3.62(1H, m) , 3.46(2H, s), 4.15(2H, q, J= 7.1 Hz), 6.32(1H, d, J= 15.2 Hz), 7.12(1H, s), 7.20- 7.37(6H, m), 7.76(IH, d, J= 7.1 Hz) (+)ESI-MS:372(M+H)+ Preparation 127 ' The mixture of ethyl (2E)-3-(2-{[l-(4-chlorobenzoyl)-3- pyrrolidinyl]amino}~l,3-thiazol-4-yl)acrylate (0.9g) and IN-NaOH (4.4mL) in MeOH (14inL) was stirred at 50 °C for 3 hours and the mixture was evaporated in vacuo. To the residue was added a solution of AcOEt, THF and water, and the mixture was adjusted to pH 4 with IN-HCl. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated ,in vacuo to give (2E)- 3-(2-{[l-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-l,3-thiazσ l-4- yl)acrylic acid (0.64g). , NMR(DMSO-d6, <5 ) : 1.84-2.32(2total IH, m) , 3.27-3.71(3H, iff), 3.72- 3.88(1H, m), 4.20-4.40(1H, m) , 6.24 and 6.34(total IH, each d, J= 15.3 Hz), 7.11 and 7.16(total IH, each s), 7.25 and 7.31(total IH, each d, J= 15.3 Hz), 7.45-7.62(4H, m) , 8.02-8.15(1H, m) , 12.27(1H, S) (+)ESI-MS:400(M+Na)+

The following compounds were obtained according to a similar manner to that of Preparation 127.

Preparation 128 (2E)-3-{2-[(1-Benzyl-4-piperidyl)amino]-1,3-thiazol-4-yl}acr ylic acid NMR(DMSO-d6, 6): 1.38-1.60(2H, m), 1.87-2.04(2H, m) , 2.04-2.26(2H, m), 2.72-2.87(2H, m) , 3.46-3.63(3H, m) , 6.27(1H, d, J= 15.1 Hz), 7.07(1H, s), 7.20-7.36(6H, m) , 7.77(1H, d, J= 7.2 Hz)

Preparation 129 (2E)-3~(2-{[l-(4-Chlorobenzoyl)-4-piperidyl]amino}-l,3-thiaz ol-4- yl)acrylic acid NMR(DMSO-d6, <5 ) : 1.31-1.56(2H, m) , 1.88-2.13(2H, m) , 3.05-3.29(2H, m), 3.46-3.67(1H, m) , 3.75-3.93(1H, m) , 4.14-4.36(1H, m) , 6.29(1H, d, J= 15.3 Hz), 7.1O(1H, s), 7.27(1H, d, J= 15.3 Hz), 7.42(2H, d, J= 8.5 Hz), 7.52(2H, d, J= 8.5 Hz), 7.84(1H, d, J= 6.9 Hz), 12.26(1H, s) (+)ESI-MS:414(M+Na)+ Preparation 130 EDCI (0.3Og) was added to the solution of (2E)-3-(2-{[l-(4- chlorobenzoyl)-3-pyrrolidinyl]amino}-1,3-thiazol-4-yl)acryli c acid (0.6g), 0-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.22g), and HOBT (0.26g) in DMF (10ml) under ice-cooling and the mixture was stirred at ambient temperature for 20 hours. The reaction mixture was poured into a mixture of AcOEt and water. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo to give (2E)-3-(2-{ [l-(4-chlorobenzoyl)-3- pyrrolidinyl]amino}-1,3-thiazol-4-yl)-N-(tetrahydro-2H-pyran -2- yloxy)aerylamide (0.66g) . NMR(DMSO-d6, δ ) : 1.44-1.75(6H, m) , 1.90-2.29(2H, m) , 3.27-3.68(4H, m), 3.69-4.05(2H, m) , 4.2O-4.38(1H, m) , 4.85-4.94(1H, m) , 6.39 and 6.47(total IH, each d, J= 15.2 Hz), 7.01 and 7.06(total IH, each s), 7.16 and 7.21(total IH, each d, J= 15.2 Hz), 7.46-7.61(4H, m) , 7.99-8.08(1H, m) , 11.18 and 11.24(total IH, each s) (+)ESI-MS:477(M+H)+",499(M+Na)+

The following compounds were obtained according to a similar manner to that of Preparation 130.

Preparation 131 (2E)-3-{2-[(l-Benzyl-4-piperidyl)amino]-l,3-thiazol-4-yl}-N- (tetrahydro-2H-pyran-2-yloxy)acrylamide NMR(DMSO-d6, δ): 1.39-1.76(8H, <m) , 1.85-2.20(4H, m) , 2.68-2.84(2H, m), 3.42-3.64(2H, m) , 3.47(2H, s), 3.86-4.02(1H, m) , 4.85-4.92(1H, m), 6.4O(1H, d, J= 15.1 Hz), 6.96(1H, s), 7.17(1H, d, J= 15.1 Hz), 7.22-7.35(5H, m) , 7.68(1H, d, J= 7.2 Hz), 11.2O(1H, s) (+)ESI-MS:443(M+H)+

Preparation 132 (2E)-3-(2-{[l-(4-Chlorobenzoyl)-4-piperidyl]amino}-l,3-thiaz ol-4- yl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide NMR(DMSO-d5, <5 ) : 1.33-1.76(8H, m) , 1.89-2.11(2H, m) , 3.05-3.26(2H, m), 3.44-3.64(2H, m) , 3.74-4.02(2H, m) , 4.14-4.35(1H, m) , 4.84- 4.92(1H, m), 6.41(1H, d, J= 15.1 Hz), 7.00(1H, s), 7.18(1H, d, J= 15. 1 Hz ) , 7.42 ( 2H, d, J= 8. 5 Hz ) , 7.53 ( 2H, d, J= 8. 5 Hz ) , 7.79 ( 1H, d, J= 7.2 Hz ) , 11.21 ( 1H, s )

Preparation 133 1-Chloroethyl chloroformate (1.88πiL) was added a mixture of ethyl (2E)-3-{2-[(l-benzyl-4-piperidyl)amino]-1,3-thiazol-4- yl}acrylate (2.7g) in dichloromethane (4OmL) at ambient temperature and the mixture was stirred at same temperature for 1.5 hour., The solvent was removed by concentration. To the residue was added an EtOH (42.7mL) and the mixture was stirred at 70 °C for 2 hours. The reaction mixture was added 2N-ethanolic hydrogen chloride (7.3mL) at ambient temperature and the mixture was stirred at same temperature for 20 hours. The isolated precipitate was collected by filtration to give ethyl (2E)-3-[2-(4-piperidylamino)-l,3-thiazol- 4-yl]acrylate dihydrochloride (1.44g). NMR(DMSO-d6, δ): 1.24(3H, t, J= 7.1 Hz), 1.66-1.88(2H, m) , 2.04- 2.21(2H, m), 2.88-3.11(2H, m) , 3.21-3.38(2H, m) , 4.05-4.24(1H, m) , 4.17(2H, q, J= 7.1 Hz), 6.67(1H, d, J= 15.6 Hz), 7.32(1H, s), 7.61(1H, d, J= 15.6 Hz), 9.14(4H, br s) (+)ESI-MS:282(M+H)+

Preparation 134 4-Chlorobenzoyl chloride (0.19mL) was added to a mixture of ethyl (2E)-3-[2-(4-piperidylamino)-l,3-thiazol-4-yl]acrylate dihydrochloride (0.5g) and triethylamine (0.63mL) in DMF (10ml) under ice-cooling arid the mixture was stirred at same temperature for 4.5 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and the mixture was extracted with an AcOEt. The extract layer was washed with water, dried over magnesium sulfate and evaporated in vacuo to give ethyl (2E)-3-(2- { [1-(4-chlorobenzoyl)-4-piperidyl]amino}-1,3-thiazol-4-yl)aer ylate (0.48g). NMR(DMSO-d6, 6): 1.24(3H, t, J= 7.1 Hz), 1.32-1.56(2H, m) , 1.87- 2.13(2H, m), 3.05-3.29(2H, m) , 3.44-3.65(1H, m) , 3.76-3.95(1H, m) , 4.07-4.35(1H, m), 4.15(2H, q, J= 7.1 Hz), 6.34(1H, d, J= 15.2 Hz), 7.16(1H, s), 7.34(1H, d, J= 15.2 Hz), 7.42(2H, d, J= 8:5 Hz), 7.52(2H, d, J= 8.5 Hz), 7.86(IH, d, J= 7.0 Hz) ( + )ESI-MS : 442 (M+Na) +

Preparation 135 To a solution of ethyl (2E)-3-(6-{[(3R)-l-benzyl-3- pyrrolidinyl]amino}-5-chloro -3-pyridyl)acrylate (770mg) in toluene (14ml) was added 1-chloroethyl chloroformate (713mg) at 23°C and stirred at the same temperature for 1 hour. N,N- Diisopropylethylamine (0.348ml) was added to the mixture, and the solution was stirred at 23°C for 15 minutes. After it was concentrated under reduced pressure, the resulting residue was dissolved in EtOH(15ml). The mixture was stirred at 65°C for 30 minutes, and concentrated under reduced pressure. The residue was dissolved into EtOH(15ml), and mixed with 2N-hydrogen chloride in EtOH solution (2ml). The mixture was stirred at 86°C for 5 hours. After it was concentrated under reduced pressure, the resulting residue was triturated with IPE (15ml). Ethyl (2E)-3-{5-chloro-6- [ (3R)-3-pyrrolidinylamino] -3-pyridyl}acrylate dihydrochloride (l.lg) was obtained as brown syrup. NMR (DMSO-d6, δ): 1.29 ( 3H, t, J = 6.9Hz ), 1.90 - 2.35 ( 2H, m) , 3.00 - 4.10 ( 4H, m), 4.17 ( 2H, q, J = 6.9Hz ) , 4.30 - 4.85 ( IH, m), 6.55 ( IH, d, J = 16fHz ), 7.55 ( IH, d, J = 16Hz ), 8.15 - 8.20 ( IH, m), 8.30 - 8.40 ( IH, m) , 9.56 ( 4H, br) MASS(API-ES); 296 (M+H)+ Free ,298

Preparation 136 To an ice-cooled solution of ethyl (2E)-3-{5-chloro-6-[(3R)- 3-pyrrolidinylamino] -3-pyridyl}acrylate dihydrochloride (330mg) and Et3N (0.437ml) in dichloromethane (8ml) was added benzoyl chloride (132mg), the mixture was stirred at 23°C for 1 hour. The mixed solution was poured into a mixture of water (20ml) and DCM (15 ml). The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (12g) using a mixed solvent of dichloromethane and MeOH (100:1 to 40:1). The fractions containing the objective compound were collected and evaporated under reduced pressure, ethyl (2E)-3-(6- { [ (3R)-1-benzoyl-3-pyrrolidinyl]amino}-5-chloro -3-pyridyl)aerylate (245mg) was obtained as colorless syrup. NMR (DMSOd6, δ): 1.18 - 1.32 (3H, m) , 1.90 - 2.40 (2H, m), 3.20 - 4.10 (4H, m), 4.11 - 4.25 (2H, m) , 4.40 - 4.80 (IH, m) , 6.40 - 6.60 (IH, m), 7.00 - 7.15 (IH, m) , 7.35 - 7.65 (6H, m), 8.10 - 8.20 (IH, 5 m), 8.22 - 8.40 (IH, m) MASS(API-ES); 400 (M+H)+

The following compounds were obtained according to a similar manner to that of Preparation 136. 10 Preparation 137 Ethyl (2E)-3-(5-chloro-6-{[(3R)-l-(cyclopropylcarbonyl)-3- pyrrolidinyl]amino}-3-pyridyl)aerylate NMR (DMSOd6, δ): 0.60 - 0.80 (4H, m), 1.24 (3H, t, J= 7.1Hz), ,15 1.60 - 1.85 (IH, m) , 1.87 - 2.40 (2H, m) , 3.20 - 4.10 (4H, m) , 4.16 (2H, q, J= 7.1Hz), 4.40 - 4.80 (IH, m) , 6.52 (IH, d, J= 16Hz), 6.95 - 7.10 (IH, m), 7.53 (IH, d, J= 16Hz), 8.10 - 8.20 (IH, m) , 8.30 - 8.40 (IH, m) MASS(API-ES); 364 (M+H)+ 20 Preparation 138 To a stirred solution of ethyl (2E)-3-(6-{(tert- butoxycarbonyl) [ (3R)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate (330 mg) in dimethylformamide (6 mL) was added potassium carbonate (158 25 mg) and 1,1'-(bromomethylene)dibenzene (225mg), and the mixture was stirred at 60°C for 2 hours. The resulting mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by chromatography (hexane : ethyl 30 acetate = 4 : 1 then chloroform : methanol = 20 : 1) to give ethyl (2E)-3-(6-{(tert-butoxycarbonyl) [(3R)-1-(diphenylmethyl)-3- pyrrolidinyl]amino}-3-pyridyl)aerylate (210 mg) as an oil. NMR (DMSOd6, δ): 1.36 (3H, t, J= 7 Hz), 1.42 (3x3H, s), 2.02-2.30 (2H, m), 2.42-2.61 (2H, m) , 2.64 (IH, dd, J= 9.5, 7 Hz), 2.78 (IH, 35 dd, J= 9.5, 8 Hz), 4.17 (IH, s), 4.29 (2H, q, J= 7 Hz), 4.91 (IH, m), 6.49 (IH, d, J= 16 Hz), 7.08-7.38 (HH, m) , 7.69 (IH, d, J= 16 Hz), 7.83 (IH, dd, J= 8.5, 2 Hz), 8.57 (IH, d, J= 2 Hz) MS (ES+ ) m/z 528.

Preparation 139 To a stirred solution of ethyl (2E)-3-(6-{(tert- butoxycarbonyl) [ (3R)-1-(diphenylmethyl)-3-pyrrolidinyl]amino}-3- pyridyl)aerylate (205 mg) in methanol (5 mL) was added IN-NaOH solution (0.8 mL). The mixture was stirred at ambient temperature for 12 hours. Methanol was evaporated in vacuo and the aqueous layer was washed with diisopropyl ether. The aqueous layer was acidified by hydrochloric acid to pH 4, and the precipitate was collected and washed with water to give (2E)-3-(6-{(tert- butoxycarbonyl) [ (3R)-1-(diphenylmethyl)-3-pyrrolidinyl]amino}-3- pyridyl)acrylic acid (161 mg) as a white powder. NMR (DMSQ-de, <5 ) : 1.34 (3x3H, br-s) ,1.97-2.74 (6H, m),4.17 (IH, br),4.75 (IH, br),6.70 (IH, br-d, J= 16 Hz) ,7.12-7.90 (i2H, m),8.23 (IH, m),8.76 (IH, s) MS (ES+) m/z 500

Preparation 140 To a stirred solution of (2E)-3-(6-{(tert- butoxycarbonyl)[(3R)-1-(diphenylmethyl)-3-pyrrolidinyl]amino }-3- pyridyl)acrylic acid (142 mg) in DMF (3 mL) was added O- (tetrahydro-2H-pyran-2~yl)hydroxylamine (67 mg), HOBT (77 mg) , and EDCI hydrochloride (109 mg) , and the resulting mixture was stirred at ambient temperature for 7 hours. The reaction mixture was diluted with ethyl acetate and washed successively with water; saturated NaHCO3 solution, and brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform : methanol = 5 . 1) to give tert-butyl [(3R)-I-(diphenylmethyl)-3-pyrrolidinyl] (5- {(lE)-3-oxo-3-[ (tetrahydro-2H-pyran-2-yloxy)amino]-l-propen-l-yl}- 2-pyridyl)carbamate (100 mg) as a pale yellow oil. NMR (DMSO-de, <5 ) : 1.34 (3x3H, s), 1.46-1.76 (6H, m) , 1.93-2.21 (2H, m), 2.25-2.64 (4H, m) , 3.54 (IH, m) , 3.97 (IH, m) , 4.17 (IH, s), 4.75 (IH, m), 4.93 (IH, m), 6.64 (IH, d, J= 16 Hz), 7.07-7.43 (HH, m), 7.59 (IH, d, J= 16 Hz), 8.08 (IH, m) , 8.68 (IH, d, J= 1.5 Hz), 11.34 (IH, s) MS (ES+ ) m/z 599 .

Preparation 141 To a mixture of ethyl (2E)-3-(6-{(tert-butoxycarbonyl) [ (3R)- 3-pyrrolidinyl]amino}-3-pyridyl)acrylate dihydrochloride (150 mg), [4-(bromomethyl)phenyl](phenyl)methanone (143 mg) , and THF (3.5 mL) was added Et3N (0.168 mL). After stirring for 2 hours at room temperature, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give ethyl (2E)- 3-{6-[[(3R)-l-(4-benzoylbenzyl)-3-pyrrolidinyl](tert- butoxycarbonyl)amino]-3-pyridyl}acrylate (149 mg) . NMR (CDCl3, 6): 1.35 (3H, t, J = 7 Hz), 1.45 (9Hf s) , 2.03-2.32 (2H, m), 2.61-3.05 (4H, m) , 3.61-3.76 (2H, m) , 4.28 (2H, q, J = 7 Hz), 4.87-5.00 (IH, m) , 6.46 (IH, d, J = 16 Hz), 7.30 (IH, d, J = 8 Hz), 7.37 (2H, d, J = 8 Hz), 7.45-7.51 (2H, m) , 7.56-7.62 (IH, m) , 7.66 (IH, d, J = 16 Hz), 7.74 (2H, d, J = 8 Hz), 7.77-7.83 (3H, m) , 8.54 (IH, d, J = 2 Hz) MS (ES+) m/z 556 (M+l)

Preparation 142 To a mixture of ethyl (2E)-3-(6-{(tert-butoxycarbonyl) [(3R)- 3-pyrrolidinyl]amino}-3-pyridyl)aerylate dihydrochloride (110 mg) , 4-(chloromethyl)-2-phenyl-l,3-thiazole (53.1 mg) , and DMF (2.5 mL) was added K2CO3 (123 mg) . After stirring for 2 hours at 60°C, the reaction mixture was. partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4, filtered, and evaporated in vacuo to give ethyl (2E)-3-[6-( (tert- butoxycarbonyl){(3R)-l-[ (2-phenyl-l,3-thiazol-4-yl)methyl]-3- pyrrolidinyl}amino)-3-pyridyl]acrylate (133 mg) . NMR (DMSO-de, δ) : 1.35 (3H, t, J = 7 Hz), 1.44 (9H, s), 2.01-2.36 (2H, m), 2.70-3.16 (4H, m) , 3.77-3.92 (2H, m) , 4.28 (2H, q, J = 7 Hz), 4.90-5.01 (IH, m) , 6.42 (IH, d, J = 16 Hz), 7.07 (IH, s), 7.31 (IH, d, J = 8 Hz), 7.40-7.45 (3H, m), 7.62 (IH, d, J = 16 Hz), 7.78 (IH, dd, J = 2, 8 Hz), 7.91-7.95 (2H, m) , 8.51 (IH, d, J = 2 Hz) MS (ES+) m/z 535 (M+l) Preparation 143 To a mixture of 2,3-dihydro-l-benzofuran-5-ylmethanol (95.1 mg) , Et3N (0.120 mL), and THF (3 mL) was added methanesulfonyl chloride (0.053 mL) at 4°C. The reaction mixture was stirred for 3 hours, and added ethyl (2E)-3-(6-{(tert-butoxycarbonyl) [(3R)-3- pyrrolidinyl]amino}-3-pyridyl)aerylate dihydrochloride (250 mg) and Et3N (0.281 mL) . After stirring for 2 hours at 60°C, the resulting mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give ethyl (2E)-3-(6-{(tert- butoxycarbonyl) [(3R)-l-(2,3-dihydro-l-benzofuran-5-ylmethyl),-3- pyrrolidinyl]amino}-3-pyridyl)acrylate (134 mg) . NMR (CDCl3, <5 ) : 1.35 (3H, t, J = 7 Hz), 1.44 (9H, s), 1.98-2.27 (2H, m), 2.51-3.00 (4H, m) , 3.16 (2H, t, J = 9 Hz), 3.44-3.57 (2H, m), 4.28 (2H, q, J = 7 Hz), 4.55 (2H, t, J = 9 Hz), 4.83-4.96 (IH, m), 6.46 (IH, d, J = 16 Hz), 6.68 (IH, d, J = 8 Hz), 6.9.5 (IH, d, J = 8 Hz), 7.08 (IH, s), 7.29 (IH, d, J = 8 Hz), 7.66 (IH, d, J = 16 Hz), 7.80 (IH, dd, J = 2, 8 Hz), 8.53 (IH, d, J = 2 Hz) MS (ES+) m/z 494 (M+l)

Preparation 144 To a solution of ethyl (2E)-3-{6-[ [(3R)-I-(4-benzoylbenzyl)- 3-pyrrolidinyl] (tert-butoxycarbonyl)amino]-3-pyridyl}acrylate (111 mg) in dioxane (2 mL) was added IN sodium hydroxide (0.6 mL). After stirring at 601C for 2 hours, the reaction mixture was added H2O(IO mL) and acidified with IN hydrochloric acid (to pH 1). A resulting mixture was extracted with CHCl3, and the organic layer was dried over MgSO4, filtered, and evaporated in vacuo to give (2E)-3-{6-[[(3R)-l-(4-benzoylbenzyl)-3-pyrrolidinyl] (tert- butoxycarbonyl)amino]-3-pyridyl}acrylic acid dihydrochloride (97 mg). NMR (DMSO-d6, (5): 1.46 (9H, s), 2.37-2.77 (2H, m) , 3.51-3.99 (4H, m), 4.38-4.47 (2H, m) , 5.12-5.24 (IH, m), 6.41 (IH, d, J = 16 Hz), 7.30 (IH, d, J = 8 Hz), 7.47-7.65 (4H, m) , 7.78-7.90 (7H, m) , 8.42- 8.49 (IH, m) MS (ES+) m/z 528 (M+l)

The following compounds were obtained according to a similar manner to that of Preparation 144.

Preparation 145 (2E)-3-[6-((tert-Butoxycarbonyl){(3R)-l-[(2-phenyl-l,3-thiaz ol-4- yl)methyl]-3-pyrrolidinyl}amino)-3-pyridyl]acrylic acid dihydrochloride NMR (CDCl3, <5): 1.44 (9H, s), 2.28-2.68 (2H, m) , 3.47-4.00 (4H, m) , 4.51-4.56 (2H, m) , 5.18-5.32 (IH, m) , 6.38 (IH, d, J = 16 Hz), 7.33 (IH, d, J = 8 Hz), 7.42-7.48 (3H, m) , 7.52 (IH, d, J = 16 Hz),, 7.78 (IH, dd, J = 2 and 8 Hz), 7.89-7.96 (3H, m) , 8.42-8.47 (IH, m) MS (ES+) m/z 507 (M+l)

Preparation 146 (2E)-3-(6-{(tert-Butoxycarbonyl) [(3R)-1-(2,3-dihydro-l-benzofuran- 5-ylmethyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylic acid dihydrochloride NMR (DMSO-d6, 6): 1.46 (9H, s), 2.27-2.79 (2H, m) , 3.24 (2H, t, J = 9 Hz), 3.39^3.94 (4H, m) , 4.20-4.26 (2H, m) , 4.60 (2H, t, J = 9 Hz), 5.08-5.21 (IH, m) , 6.40 (IH, d, J = 16 Hz), 6.79 (IH, d, J = 8 Hz), 7.22-7.33 (2H, m), 7.54-7.64 (2H, m), 7.77-7.82 (IH, m), 8.39-8.42 (IH, m) MS (ES+) m/z 466 (M+l)

Preparation 147 (2E)-3-{6-[[(3R)-I-(I-Benzofuran-2-ylmethyl)-3-pyrrolidinyl] (tert- butoxycarbonyl)amino]-3-pyridyl}acrylic acid dihydrochloride NMR (DMSO-dg, <5 ) : 1.41 (9H, s), 2.25-2.71 (2H, m) , 3.44-4.00 (4H, m), 4.50-4.56 (2H, m), 5.16-5.30 (IH, m) , 6.36 (IH, d, J = 16 Hz), 7.16 (IH, s), 7.29-7.40 (3H, m) , 7.47-7.65 (3H, m) , 7.77 (IH, dd, J = 2, 8 Hz), 8.14-8.35 (IH, m) MS (ES+) m/z 464 (M+l)

Preparation 148 (2E)-3-{6-[ [(3R)-1-(1-Benzofuran-5-ylmethyl)-3-pyrrolidinyl] (tert- butoxycarbonyl)amino]-3-pyridyl}acrylic acid dihydrochloride NMR (DMSO-de, S ) : 1.45 (9H, s), 2.33-2.76 (2H, m) , 3.39-3.99, (4H, m), 4.37-4.50 (2H, m) , 5.09-5.23 (IH, mj , 6.39 (IH, d, J = 16 Hz), 6.82 (IH, d, J = 2 Hz), 7.30 (IH, d, J = 8 Hz), 7.50-7.62 (3H, m) , 7.68 (IH, d, J = 2 Hz), 7.78 (IH, dd, J = 2, 8 Hz), 7.95 (IH, s), 8.30-8.44 (IH, m) MS (ES+) m/z 464 (M+l)

Preparation 149 To a mixture of (2E)-3-{6-[[(3R)-l-(4-benzoylbenzyl)-3- pyrrolidinyl] (tert-butoxycarbonyl)amino]-3-pyridyl}acrylic acid dihydrochloride (93 mg) , 0-tetrahydro-2H-pyran-2-ylhydroxylamine (27 mg.), and 1-hydroxybenzotriazole (31 mg) in N,N- dimethyIformamide (1.6 mL) was added 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide (36 mg) at 4°C. The mixture was warmed to ambient temperature and stirred for 8 hours. The reaction mixture was added saturated NaHCO3 (2 mL) and water (8 mL), and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give tert-butyl [(3R)-1-(4-benzoylbenzyl)-3-pyrrolidinyl] (5-{(IE)-3-oxo- 3-[(tetrahydro-2H-pyran-2-yloxy)amino]-l-propen-l-yl}-2- pyridyl)carbamate (35 mg) . NMR (DMSO-dβ, <5): 1.36 (9H, s), 1.49-1.72 (6H, m) , 1.88-2.20 (2H, m), 2.50-2.86 (4H, m), 3.50-3.70 (3H, m) , 3.89-4.02 (IH, m), 4.70- 4.83 (IH, m), 4.90-4.94 (IH, m) , 6.59 (IH, d, J = 16 Hz), 7.33-8.05 (12H, m), 8.62-8.65 (IH, m),. MS (ES+) m/z 627 (M+l).

The following compounds were obtained according to a similar manner to that of Preparation 149.

Preparation 150 tert-Butyl (5-{(lE)-3-oxo-3-[ (tetrahydro-2H-pyran-2-yloxy)amino]-1- propen-l-yl}-2-pyridyl){(3R)-l-[(2-phenyl-l,3-thiazol-4-yl)m ethyl]- 3-pyrrolidinyl}carbamate NMR (DMSO-de, <5 ) : 1.35 (9H, s), 1.49-1.75 (6H, m) , 1.88-2.18 (2H, m) , 2. 52-2. 99 ( 4H, m) , 3. 50-3. 59 ( IH, m) , 3. 65-3. 79 ( 2H, m) , 3.91- 4.03 ( IH, m) , 4. 68-4.81 ( IH, m) , 4.90-4.96 ( IH, m) , 6.56 ( IH, d, J = 16 Hz ) , 7.33-7 .55 ( 6H, m) , 7. 87-8.02 ( 3H, m) , 8.58-8. 62 ( IH, m) . MS (ES+ ) m/z 606 (M+l ) .

Preparation 151 tert-Butyl [ (3R)-l-(2,3-dihydro-l-benzofιαran-5-ylmethyl)-3- pyrrolidinyl] (5-{(IE)-3-oxo-3-[ (tetrahydro-2H-pyran-2-yloxy)amino]- 1-propen-1-yl}-27pyridyl)carbamate NMR (DMSO-d6, <5 ) : 1.35 (9H, s), 1.49-1.75 (6H, m) , 1.93-2.12 (2H, m), 3.11 (2H, t, J = 9 Hz), 3.28-3.58 (7H, m) , 3.92-4.02 (IH, m) , 4.48 (2H, t, J = 9 Hz), 4.67-4.79 (IH, m) , 4.90-4.94 (IH, m) , 6.55- 7.02 (4H, m), 7.32-7.60 (2H, m) , 7.99-8.05 (IH, m), 8.61-8.63 (IH, m) MS (ES+) m/z 565 (M+l)

Preparation 152 tert-Butyl [(3R)-I-(I-benzofuran-2-ylmetbyl)-3-pyrrolidinyl] (5- {(IE)-3-OXO-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen- 1-yl}- 2-pyridyl)carbamate NMR (DMSO-de, <5 ) : 1.34 (9H, s), 1.49-1.76 (6H, m) , 1.87-2.19 (2H, m), 2.52-2.99 (4H, m) , 3.49-3.59 (IH, m) , 3.65-3.78 (2H, m) , 3.90- 4.03 (IH, m), 4.67-4.80 (IH, m) , 4.89-4.96 (IH, m) , 6.56 (IH, d, J = 16 Hz), 6.66 (IH, s), 7.17-7.29 (2H, m) , 7.34 (IH, d, J = 8 Hz), 7.47-7.59 (3H, m) , 7.95-8.01 (IH, m) , 8.55-8.59 (IH, m) MS (ES+) m/z 563 (M+l)

Preparation 153 v tert-Butyl [(3R)-1-(1-benzofuran-5-ylmethyl)-3-pyrrolidinyl] (5- {(lE.)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-l-propen -l-yl}- 2-pyridyl)carbamate NMR (DMSO-de, <5 ) : 1.35 (9H, s), 1.49-1.76 (6H, m) , 1.89-2.19 (2H, m), 2.43-2.81 (4H, m) , 3.41-3.66 (3H, m) , 3.90-4.04 (IH, m) , 4.67- 4.80 (IH, m), 4.91-4.97 (IH, m) , 6.60 (IH, d, J = 16 Hz), 6.88 (IH, d, J = 2 Hz), 7.10 (IH, d, J = 8 Hz), 7.33 (IH, d, J = 8 Hz), 7.42 (IH, s), 7.46 (IH, d, J = 8 Hz), 7.55 (IH, d, J = 16 Hz), 7.95 (IH, d, J = 2 Hz), 8.01 (IH, d, J = 8 Hz), 8.62 (IH, s) MS (ES+ ) m/z 563 (M+l )

Prepaxation 154 To a solution of tert-butyl 4-({5-[ (lE)-3-ethoxy-3-oxo-l- propen-l-yl]-2-pyridyl}amino)-l-piperidinecarboxylate (2.8g) in EtOH (20ml) was added 4N HCl in dioxane (18.6ml), the mixture was stirred at 23°C for 30 minutes. The precipitate was collected, washed with IPE, dried under reduced pressure to give ethyl (2E)-3-[6-(4-piperidylamino)-3-pyridyl]aerylate dihydrochloride. NMR (DMSO-d6, <5 ) : 1.25(3H, t, J= 7.0 Hz), 1.6-2.0(2H, m) , 2.0-2.3- (2H, m), 2.8-3.1(2H, m) , 3.33-3.40(2H, m) , 4.18(2H, q, J= 7.0 Hz), 6.58(1H, d, J= 16.0 Hz), 7.11(1H, d, J= 9.7 Hz), 7.65(1H, d, J= 16.0 Hz), 8.24-8.28(2H, m) , 9.11(2H, brs) Mass (APCI): 276(M+H)+

The following compounds were obtained according to a similar manner to that of Preparation 154.

Preparation 155 Ethyl (2E)-3-[5-chloro-6-(4-piperidylamino)-3-pyridyl]aerylate dihydrochloride NMR (DMSO-d6, δ): 1.24(3H, t, J= 7.4 Hz), 1.8-2.8(4H, m) , 2.8- 3.1(2H, m), 3.2-3.4(2H, m) , 4.16(2H, q, J= 7.4 Hz), 6.44(1H, d, J= 16.0 Hz), 7.53(1H, d, J= 16.0 Hz), 8.17(1H, d, J= 2.0 Hz), 8.3O(1H, d, J= 2.0 Hz) Mass (APCI): 310(M+H)+

Preparation 156 Ethyl (2E)-3-{6-[methyl(4-piperidyl)amino]-3-pyridyl}aerylate dihydrochloride NMR (DMSO-d6, <5 ) : 1.25(3H, t, J= 7.4 Hz), 1.80-1.86(2H, m) , 2.10- 2.26(2H, m), 2.95-3.20(2H, m) , 3.04(3H, s), 3.27-3.39(2H, m) , 4.18(2H, q, J= 7.4 Hz), 4.6O-4.85(1H, m) , 6.64(1H, d, J= 16.0 Hz), 7.27(1H, d, J= 8.0 Hz), 7.67(1H, d, J= 16.0 Hz), 8.31-8.36(2H, m) , 9.10-6.40(2H, m) Mass (APCI): 290(M+H)+ Preparation 157 To an ice-cooled solution of ethyl (2E)-3-[6-(4- piperidylamino)-3-pyridyl]acrylate dihydrochloride (309mg) and Et3N (0.448ml) in DMF (8ml) was added benzoyl chloride (124mg), the mixture was stirred at 23°C for 1 hour. The mixed solution was poured into water (20ml). The precipitate was collected, washed with water, dried under reduced pressure to give ethyl (2E)-3-{6- [ (l-benzoyl-4-piperidyl)amino]-3-pyridyl}acrylate. NMR (DMSO-d6, <5 ) : 1.33(3H, t, J= 7.0 Hz), 1.22-1.46(2H, m) , 2.04- 2.30(2H, m), 3.00-3.30(2H, m) , 3.50-4.20(2H, m) , 4.20(2H, q, J= 7.0 Hz), 4.50-4.80(2H, m) , 6.22(1H, d, J= 15.8 Hz), 6.39(1H, d, J= 8.8 Hz), 7.32-7.46(5H, m) , 7.46-7.63(2H, m) , 8.19(1H, d, J= 2.1 Hz) Mass (APCI): 380(M+H)+

The following compounds were obtained according to a similar manner to that of Preparation 157.

Preparation 158 Ethyl (2E)-3-(6-{[l-(4-fluorobenzoyl)-4-piperidyl]amino}-3- pyridyl)acrylate NMR (DMSO-de, <5 ) : 1.32(3H, t, J= 7.1 Hz), 1.30-1.60(2H, m) , 2.10- 2.30(2H, m), 3.00-3.30(2H, m) , 3.99-4.14(2H, m) , 4.25(2H, q, J= 7.1 Hz), 4.68(1H, d, J= 7.8 Hz), 6.22(1H, d, J= 16.0 Hz), 6.39(1H, d, J= 8.8 Hz), 7.07-7.13(2H, m) , 7.39-7.64(4H, m), 8.19(1H, d, J= 2.2 Hz) Mass (APCI): 398(M+H)+

Preparation 159 Ethyl (2E)-3-(6-{[l-(4-methylbenzoyl)-4-piperidyl]amino}-3- pyridyl)acrylate NMR (DMSO-d6, 6): 1.32(3H, t, J= 7.1 Hz), 1.30-1.60(2H, m) , 2.10- 2.30(2H, m), 2.37(3H, s), 3.00-3.30(2H, m) , 3.99-4.14(2H, m) , 4.25(2H, q, J= 7.1 Hz), 4.68(1H, d, J= 7.8 Hz), 6.21(1H, d, J= 16.0 Hz), 6.38(1H, d, J= 8.8 Hz), 7.18-7.34(4H, m), 8.187.56-7.63(2H, m) , 8.18(1H, d, J= 2.0 Hz) Mass (APCI): 394(M+H)+ Preparation 160 Ethyl (2E)-3-(6-{[l-(4-methoxybenzoyl)-4-piperidyl]amino}-3- pyridyl)acrylate NMR (DMSO-dβ, <5 ) : 1.32(3H, t, J= 7.1 Hz), 1.30-1.60(2H, m) , 2.10- 2.30(2H, m), 3.00-3.30(2H, m) , 3.80(3H, s), 3.99-4.14(2H, m) , 4.25(2H, q, J= 7.1 Hz), 4.68(1H, d, J= 7.8 Hz), 6.21(1H, d, J= 16.0 Hz), 6.28(1H, d, J= 8.8 Hz), 7.92(2H, d, J= 8.8 Hz), 7.39(2H, d, J= 8.8 Hz), 7.53-7.64(2H, m) , 8.18(1H, d, J= 2.0 Hz) Mass (APCI): 410(M+H)+

Preparation 161 Ethyl (2E)-3-{6-[(1-benzoyl-4-piperidyl)amino]-5-chloro-3- pyridyl}acrylate NMR (DMSO-dβ, <5 ) : 1.24(3H, t, J= 7.2 Hz), 1.5-2.1(4H, m), 2.70- 3.25(2H, m), 3.50-3.70(1H, m) , 4.15(2H, q, J= 7.2 Hz), 4.20-4.60(2H, m), 6.48(1H, d, J= 16.0 Hz), 6.74(1H, d, J= 8.0 Hz), 7.3-7.55(6H, m), 8.12(1H, d, J= 2.0 Hz), 8.29(1H, d, J= 2.0 Hz) Mass (APCI): 436(M+Na)+

Preparation 162 Ethyl (2E)-3-(5-chloro-6-{[l-(4-chlόrobenzoyl)-4-piperidyl]amino} - 3-pyridyl)acrylate NMR (DMSO-de, <5 ) : 1.24(3H, t, J= 7.2 Hz), 1.5-2.1(4H, m) , 2.70- 3.25(2H, m) , 3.50-3.70(1H, m) , 4.15(2H, q, J= 7.2 Hz), 4.20-4.60(2H, m), 6.49(1H, d, J= 16.0 Hz), 6.72(1H, d, J= 8.0 Hz), 7.30-7.60(5H, m), 8.12(1H, d, J= 2.0 Hz), 8.29(1H, d, J= 2.0 Hz) Mass (APCI): 470(M+Na)+

Preparation 163 Ethyl (2E)-3-(5-chloro^6-{[l-(3-chlorobenzoyl)-4-piperidyl]amino}- 3-pyridyl)acrylate NMR (DMSO-de, <5 ) : 1.24(3H, t, J= 7.4 Hz), 1.53-1.94(4H, m) , 2.75- 3.30(2H, m), 3.45-3.70(1H, m), 4.60(2H, q, J= 7.4 Hz), 4.20-4.60(2H, m), 6.49(1H, d, J= 16.0 Hz), 6.72(1H, d, J= 7.0 Hz), 7.33-7.56(5H, m), 8.13(1H, d, J= 2.0 Hz), 8.3O(1H, d, J= 2.0 Hz) Preparation 164 Ethyl (2E)-3-(5-chloro-6-{[l-(2-chlorobenzoyl)-4-piperidyl]amino}- 3-pyridyl)aerylate Mass (ESI): 448(M+H)+

Preparation 165 ' Ethyl (2E)-3-{6-[ [l-(4-chlorobenzoyl)-4-piperidyl] (methyl)amino]-3- pyridyl}acrylate NMR (DMSO-d6, 6): 1.24(3H, t, J= 7.4 Hz), 1.,55-1.99(4H, m) , 2.80- 3.87(3H, m), 3.08(3H, s), 4.15(2H, q, J= 7.4 Hz), 4.50-5.00(2H, m) , 6.4O(1H, d, J= 16.0 Hz), 6.73(1H, d, J= 8.8 Hz), 7.45-7.58(4H, m) , 7.93(1H, dd, J= 2.0, 8.8 Hz), 8.34(1H, d, J= 2.0 Hz) Mass (APCI): 428(M+H)+

Preparation 166 To a suspension of (2E)-3-{6-[(l-benzoyl-4-piperidyl)amino]- 3-pyridyl}acrylic acid (170mg) in DMF (3ml) was added 0- (tetrahydro-2H-pyran-2-yl)hydroxylamine (62.3mg), EDCI • HCl (102mg), HOBt (71.9mg), Et3N(0.201ml) , the mixture was stirred at,23°C for 8 hours. The mixed solution was poured into a mixture of water (20ml) and AcOEt(20ml). The organic layer was separated, washed with water twice and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with 8% MeOH in dichloromethane to give (2E)-3-{6-[(l-benzoyl-4-piperidyl)amino]-3-pyridyl}-N- (tetrahydro-2H-pyran-2-yloxy)acrylamide(50mg) . NMR (DMSO-d5, <5 ) : 1.20-1.70(8H, m) , 1.80-2.10(4H, m) , 3.00-3.30(2H, m), 3.40-3.80(2H, m) , 3.80-4.20(2H, m) , 4.20-4.50(1H, m) , 4.87(1H, s), 6.19(1H, d, J= 16.0 Hz), 6.52(1H, d, J= 8.8 Hz), 7.07(1H, d, J= 7.4 Hz), 7.30-7.47(6H, m) , 7.6O(1H, d, J= 8.8 Hz), 8.13(1H, d, J= 2.0 Hz), 11.03(1H, brs). Mass (APCI): 451(M+H)+

The following compounds were obtained according to a similar manner to that of Preparation 166.

Preparation 167 (2E)-3-(6-{[1-(4-Fluorobenzoyl)-4-piperidyl]amino}-3-pyridyl )-N- (tetrahydro-2H-pyraii-2-yloxy)acrylamide NMR (DMSO-d5, δ ) : 1.20-1.80(6H, m) , 1.80-2.10(2H, m) , 3.01-3.25(2H, m), 3.50-3.60(2H, m) , 4.90-4.18(2H, m) , 4.33(1H, brs), 4.87(1H, s), 6.2O(1H, m), 6.52(1H, d, J= 8.8 Hz), 6.96(1H, d, J= 4.0 Hz), 7.26- 7.36(2H, m), 7.44-7.48(2H, m), 7.60(1H, d) , 8.14(1H, s), 11.04(1H, s) Mass (APCI): 491(M+Na)+

Preparation 168 (2E)-3-(6-{[1-(4-Methylbenzoyl)-4-piperidyl]amino}-3-pyridyl )-N- (tetrahydro-2H-pyran-2-yloxy)acrylamide NMR (DMSOd6, <5 ) : 1.24-1.80(6H, m) , 1.80-2.10(2H, m) , 2.33(3H, s), 3.10-3.29(2H, m) , 3.43-3.70(2H, m) , 3.90-4.15(2H, m) , 4.33(1H, brs), 4.87(1H, s), 6.2O(1H, d, J= 15.4 Hz), 6.52(1H, d, J= 8.8 Hz), 7.07(1H, d, J= 7.3 Hz), 7.23-7.29(3H, m) , 7.34(1H, d, J= 15.4 Hz), 7.6O(1H, d, J= 8.8 Hz), 8.14(1H, s) Mass (APCI): 465(M+H)+

Preparation 169 (2E)-3-(6-{[1-(4-Methoxybenzoyl)-4-piperidyl]amino}-3-pyridy l)-N- (tetrahydro-2H-pyran-2-yloxy)acrylamide NMR (DMSOd6, <5): 1.20-1.45(4H, m) , 1.50-1.60(3H, m) , 1.30-1.75(3H, m), 1.80-2.0(2H, m) , 2.90-3.20(2H, m) , 3.5O-3.55(1H, m) , 3.95- 4.20(2H, m), 4.87(1H, s), 6.2O(1H, d, J= 15.4 Hz), 6.53(1H, d, J= 8.8 Hz), 6.98(2H, d, J= 8.8 Hz), 7.07(1H, d, J= 7.4 Hz), 7.33- 7.37(3H, m), 7.6O(1H, d, J= 8.8 Hz), 8.1(1H, s), 11.04(1H, s) Mass (APCI): 503(M+Na)+

Preparation 170 (2E)-3-[6-({1-[4-(lH-Pyrrol-l-yl)benzoyl]-4-piperidyl}amino) -3- pyridyl]-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide NMR (DMSOd6, δ): 1.30-1.80(9H, m) , 1.85-2.10(2H, m) , 3.10-3.20(2H, m), 3.45-3.60(1H, m) , 3.80-4.20(2H, m) , 4.88(1H, s), 6.25-6.35(2H, m), 6.53(1H, d, J= 8.8 Hz), 7.1O(1H, d, J= 7.3 Hz), 7.35(1H, d, J= 16.0 Hz), 7.43-7.84(7H, m) , 8.15(1H, d, J= 2.0 Hz), 11.04(lH, s) Preparation 171 N-(4-Chlorophenyl)-4-[(5-{(IE)-3-OXO-3-[ (tetrahydro-2H-pyran-2- yloxy)amino]-l-propen-l-yl}-2-pyridyl)amino]-l- piperidinecarboxamide NMR (DMSO-de, 6): 1.20-1.80(8H, m) , 1.80-2.10(2H, m) , 2.85-3.13(2H, m), 3.40-3.46(1H, m) , 3.84-4.12(4H, m) , 4.88(1H, s), 6.23(1H, d, J= 16.0 Hz), 6.53(1H, d, J= 8.8 Hz), 7.13-7.70(7H, m) , 8.15(1H, d, J= 2.0 Hz), 8.66(1H, s), 11.04(1H, brs) Mass (APCI): 522(M+Na)+

Preparation 172 N-(4-Methylphenyl)-4-[ (5-{(IE)-3-oxp-3-[ (tetrahydro-2H-pyran-2- yloxy)amino]-l-propen-l-yl}-2-pyridyl)amino]-1- piperidinecarpoxamide NMR (DMSO-de, <5 ) : 1.20-1.45(3H, m) , 1.50-1.60(3H, m) , 1.30-1.75(3H, m), 1.80-2.0(2H, m) , 2.22(3H, s), 2.90-3.20(2H, m) , 3.5O-3.55(1H, m), 3.95-4.07(4H, m) , 4.89(1H, s), 6.2O(1H, d, J= 15.4 Hz), 6.51(1H, d, J= 8.8 Hz), 7.02(2H, d, J= 8.8 Hz), 7.07(1H, d, J= 7.4 Hz), 7.33(2H, d, J= 8.8 Hz), 7.36(1H, d, J= 15.4 Hz), 7.6O(1H, d, J= 8.8 Hz), 8.15(1H, s), 8.42(1H, s), 11.05(1H, s) Mass (APCI): 502(M+Na)+

Preparation 173 N-(4-Methoxyphenyl)-4-[ (5-{(lE)-3-oxo-3-[(tetrahydro-2H-pyran-2- yloxy)amino]-l-propen-l-yl}-2-pyridyl)amino]-l- piperidinecarboxamide NMR (DMSO-d6, <5 ) : 1.20-1.45(3H, m) , 1.50-1.60(3H, m) , 1.30-1.75(3H, m), 1.80-2.0(2H, m) , 2.90-3.20(2H, m) , 3.50-3.55(2H, m) , 3.70(3H, s), 3.95-4.07(4H, m) , 4.87(1H, s), 6.2O(1H, d, J= 15.4 Hz), 6.51(1H, d, J= 8.8 Hz), 6.81(2H, d, J= 8.8 Hz), 7.07(1H, d, J= 7.4 Hz), 7.32-7.37(3H, m) , 7.60(1H, d, J= 8.8 Hz), 8.15(1H, s), 8.37(1H, s), 11.05(1H, s) Mass (APCI): 518(M+Na)+

Preparation 174 (2E)-3-{6-[(l-Benzoyl-4-piperidyl)amino]-5-chloro-3-pyridyl} -N- (tetrahydro-2H-pyran-2-yloxy)acrylamide NMR (DMSO-de, <5 ) : 1.56-2.00(11H, m) , 2.60-3.30(2H, m) , 3.40- 3.70(2H, m), 3.89-4.10(1H, m) , 4.20-4.60(2H, m) , 4.88(1H, s), 6.33(1H, d, J= 15.7 Hz), 6.64(1H, d, J= 8.0 Hz), 7.33-7.48(6H, m) , 7.86(1H, s), 8.21(1H, s), 11.08(1H, s) Mass (APCI): 507(M+Na)+

Preparation 175 (2E) -3-(5-Chloro-6-{ [l-(4-chlorobenzoyl) -4-piperidyl]amino}-3- pyridyl) -N- ( tetrahydro-2H-pyran-2-yloxy)acrylaπιide NMR (DMSOd6, <5 ) : 1.56-2.00(11H, m) , 2.60-3.30(2H, m) , 3.40- 3.70(2H, m), 3.89-4.10(1H, m) , 4.20-4.60(2H, m) , 4.88(1H, s), 6.31(1H, d, J= 15.7 Hz), 6.62(1H, d, J= 8.0 Hz), 7.33-7.55(5H, m) , 7.86(1H, s), 8.21(1H, s), 11.08(1H, s) Mass (APCI): 541(M+Na)+

Preparation 176 To a suspension of ethyl (2E)-3-[6-(4-piperidylamino)-3- pyridyl]acrylate dihydrochloride (500mg) in DMF (5ml) was added 4- (lH-pyrrol-1-yl)benzoic acid(309mg), EDCI • HCl (317mg), HOBt (223mg), Et3N(0.63ml) , the mixture was stirred at 23°C for 8 hours. The mixed solution was poured into a mixture of water (20ml) and AcOEt(2OmI). The organic layer was separated, washed with water twice and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with 5% MeOH in dichloromethane to give ethyl (2E)-3-[6- ({1-[4-(lH-pyrrol-1-yl)benzoyl]-4-piperidyl}amino)-3- pyridyl]acrylate(686mg) . NMR (DMSO-dβ, <5): 1.24(3H, t, J= 7.4 Hz), 1.40-1.55(2H, m) , 1.80- 2.10(2H, m), 3.10-3.30(2H, m) , 3.55-3.80(1H, m) , 4.14(2H, q, J= 7.4 Hz), 4.20-4.40(1H, m), 6.28-6.36(3H, m), 6.52(1H, d, J= 8.8 Hz), 7.2O(1H, d, J= 7.4 Hz), 7.44-7.51(5H, m) , 7.66(2H, d, J= 8.6 Hz), 7.46-7.83(1H, m) , 8.23(1H, d, J= 2.0 Hz) Mass (APCI): 445(M+H)+

The following compounds were obtained according to a similar manner to that of Preparation 176. Preparation 177 Ethyl (2E)-3-(5-chloro-6-{[1-(4-phenoxybenzoyl)-4-piperidyl]amino} - 3-pyridyl)acrylate NMR (DMSO-dβ, <5) : 1.24(3H, t, J= 7.4 Hz), 1.45-3.00(4H, m), 4.15(2H, q, J= 7.4 Hz), 4.25-4.60(2H, m) , 6.49(1H, d, J= 16.0 Hz), 6.75(1H, d, J= 8.4 Hz), 7.01-7.24(5H, m) , 7.39-7.47(4H, m), 7.41(1H, d, J= 16.0 Hz), 7.12(1H, d, J= 2.0 Hz), 8.29(1H, d, J= 2.0 Hz) Mass (APCI): 528(M+Na)+

Preparation 178 To an ice-cooled solution of ethyl (2E)-3-[6-(4- piperidylamino)-3-pyridyl]acrylate dihydrochloride (309mg) and Et3N (0.448ml) in DMF (3ml) was added 1-chloro-4-isocyanatobenzene (136mg), the mixture was stirred at 231C for 1 hour. The mixed solution was poured into water (20ml). The precipitate was collected, washed with hexane and water, dried under reduced pressure to give ethyl (2E)-3-{6-[ (l-{[(4- chlorophenyl)amino]carbonyl}-4-piperidyl)amino]-3-pyridyl}ac rylate (341mg). NMR (DMSOd6, <5 ) : 1.20-1.63(7H, m) , 2.10-2.19(2H, m) , 3.04-3.19(3H, m), 3.94-4.03(3H, m), 4.23(2H, q, J= 7.0 Hz), 4.67(1H, d, J= 7.8 Hz), 6.2O(1H, d, J= 16.0 Hz), 6.36-6.45(2H, m) , 7.21-7.34(5H, m) , 7.53-7.64(2H, m) , 8.2O(1H, d, J= 2.0 Hz) Mass (APCI): 429(M+H)+

The following compounds were obtained according to a similar manner to that of Preparation 178.

Preparation 179 Ethyl (2E)-3-{6-[(l-{[(4-methylphenyl)amino]carbonyl}-4- piperidyl)amino]-3-pyridyl}acrylate NMR (DMSO-d6, <5 ) : 1.32(3H, t, J= 7.1 Hz), 1.40-1.60(2H, m) , 2.10- 2.18(2H, m), 2.29(3H, s), 3.90-4.14(2H, m), 4.25(2H, q, J= 7.1 Hz), 7.42(1H, d, J= 7.8 Hz), 6.22(1H, d, J= 16.0 Hz), 6.36-6.40(2H, m) , 7.08(2H, d, J= 8.8 Hz), 7.22(2H, d, J= 8.8 Hz), 7.54(1H, d, J= 16.0 Hz), 7.62(1H, dd, J= 2.0, 8.8 Hz), 8.19(1H, d, J= 2.0 Hz) Mass (APCI): 431(M+Na)+ Preparation 180 Ethyl (2E)-3-{6~[(l-{[(4-methoxyphenyl)amino]carbonyl}-4- piperidyl)amino]-3-pyridyl}acrylate Mass (APCI): 425(M+H)+

Preparation 181 Ethyl (2E)-3-{5-chloro-6-[(l-{[(4~chlorophenyl)amino.]carbonyl}-4- piperidyl)amino]-3-pyridyl}acrylate NMR (DMSO-de, 6): 1.24(3H, t, J= 7.4 Hz), 1.50-1.67(2H, m) , 1.82- 1.88(2H, m), 2.84-2.96(2H, m) , 4.10-4.26(3H, m) , 4.15(2H, q, J= 7.4 Hz), 6.49(1H, d, J= 16.0 Hz), 6.78(1H, d, J= 8.0 Hz), 7.26(2H, d, J= 8.8 Hz), 7.49(2H, d, J= 8.8 Hz), 7.5O(1H, d, J= 16.0 Hz), 8.12(1H, d, J= 2.0 Hz), 8.3O(1H, d, J= 2.0 Hz), 8.68(1H, s)

Preparation 182 To a solution of ethyl (2E)-3-{5-chloro-6-[ (l-{[(4- chlorophenyl)amino]carbonyl}-4-piperidyl)amino]-3-pyridyl}ae rylate (363mg) in THF (3ml) and MeOH (3ml) was added IN NaOH aq (2.35ml), the mixture was stirred at 80°C for 1 hour. The pH of the mixture was adjusted to ca.4.5 with IN HCl aq. The solution was evaporated under reduced pressure to give crude 3-{5-Chloro-6-[l-(4-chloro- phenylσarbamoyl)-piperidin-4-ylamino]-pyridin-3-yl}-acrylic acid. To a suspension of crude 3-{5-Chloro-6-[l-(4-chloro- phenylcarbamoyl)-piperidin-4-ylamino]-pyridin-3-yl}-acrylic acid (247mg) in DMF (3ml) was added 0-(tetrahydro-2H-pyran-2- yl)hydroxylamine(73.1mg), EDCI (96.9mg), HOBt (84.3mg,), the mixture was stirred at 23°C for 8 hours. The mixed solution was poured into a mixture of water (20ml) and AcOEt(20ml). The organic layer was separated, washed with water twice and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with 5% MeOH in dichloromethane to give 4-[(3-chloro-5-{(lE)-3-oxo-3-[ (tetrahydro- 2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridyl)amino]-N-(4 - chlorophenyl)-1-piperidinecarboxamide(246mg) . NMR (DMSO~d6, <5): 1.45-1.95(1OH, m) , 2.75-3.00(2H, m), 3.45- 3.5O(1H, m), 3.80-4.30(3H, m) , 4.89(1H, s), 6.31(1H, d, J= 16.0 Hz), 6.68(1H, d, J= 8.4 Hz), 7.27(2H, d, J= 8.8 Hz), 7.36(1H, d, J= 16.0 Hz), 7.51(2H, d, J= 8.8 Hz), 7.85(1H, s), 8.22(1H, s), 8.68(1H, s) Mass (APCI): 556(M+Na)+\ .

The following compounds were obtained according to a similar manner to that of Preparation 182.

Preparation 183 (2E)-3-(5-Chloro-6-{[l-(3-chlorobenzoyl)-4-piperidyl]amino}- 3- pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide Mass (ESI): 519(M+H)+

Preparation 184 (2E)-3-(5-Chloro-6-{[l-(2-chlorobenzoyl)-4-piperidyl]amino}- 3- pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide Mass (ESI): 519(M+H)+

Preparation 185 (2E)-3-{6-[(1-Benzyl-4-piperidyl)amino]-5-chloro-3-pyridyl}- N- (tetrahydro-2H-pyran~2-yloxy)acrylamide NMR (DMSO-de, δ ) : 1.4O-2.35(11H, m), 2.80-3.10(2H, m) , 3.40- 3.75(3H, m), 3.82-4.15(2H, m) , 4.88(1H, s), 6.32(1H, d, J= 16.0 Hz), 9.59(1H, m), 7.20-7.40(6H, m), 7.84(1H, s), 8.2O(1H, s), 11.10(IH, s)

Preparation 186 (2E)-3-(5-Chloro-6-{[1-(4-methylbenzyl)-4-piperidyl]amino}-3 - pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide NMR (DMSO-de, 6): 1.45-1.85(9H, m) , 1.90-2.10(2H, m) , 2.28(3H, s), 2.75-2.85(2H, m) , 3.41(2H, s), 3.49-3.55(1H, m) , 3.85-4.10(2H, m) , 4.89(1H, s), 6.31(1H, d, J= 16.0 Hz), 6.5O(1H, d, J= 7.0 Hz), 7.11(2H, d, J= 8.8 Hz), 7.18(2H, d, J= 8.8 Hz), 7.36(1H, d, J= 16.0 Hz), 7.83(1H, s), 8.2O(1H, s), 11.08(1H, brs)

Preparation 187 (2E)-3-(5-Chloro-6-{[1-(4-methoxybenzyl)-4-piperidyl]amino}- 3- pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide NMR (DMSO-de, <5 ) : 1.45-1.9O( 11H, m) , 1.90-2.15( 2H, m) , 2.78- 2.84 (2H, m) , 3.40( 2H, s) , 3.48-3.55 ( 1H, m) , 3.74(3H, s) , 3.80- 4.05 ( 2H, m) , 4.89 ( 1H, s) , 6.3O( 1H, d, J= 16.0 Hz ) , 6.5O ( 1H, d, J= 7.0 Hz) , 6.88( 1H, d, J= 8.8 Hz ) , 7.2O ( 1H, d, J= 8.8 Hz) , 7.35 ( 1H, d, 5 J= 16.0 Hz ) , 7.83( 1H, s) , 8.2O ( 1H, s) , 11.08( 1H, s)

Preparation 188 (2E)-3-{5-Chloro-6-[(l-isobutyl-4-piperidyl)amino]-3-pyridyl }-N- (tetrahydro-2H-pyran-2-yloxy)ac±ylamide 10 NMR (DMSO-de, <5 ) : 0.86(6H, d, J= 6.5 Hz), 1.40-2.10(15H, m) , 2.70- 2.90(2H, m), 3.45-3.70(1H, m), 3.80-4.00(2H, m), 4.88(1H, brs), 6.3O(1H, d, J= 16.0 Hz), 6.5O(1H, d, J= 8.0 Hz), 7.35(1H, d, J= 16.0 Hz), 7.83(1H, s), 8.2O(1H, s), 11.06(1H, brs)

15 Preparation 189 (2E)-3-(5-Chloro-6-{[1-(cyclopropylmethyl)-4-piperidyl]amino }-3- pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide NMR (DMSO-de, <5 ) : 0.05-0.15(2H, m) , 0.42-0.51(2H, m) , 0.75-0.95(1H, m), 1.40-2.30(14H, m) , 2.90-3.15(2H, m) , 3.40-3.60(1H, m) , 3.80- ,20 4.10(2H, m), 4.89(1H, s) , 6.31(1H, d, J= 16.0 Hz), 6.53(1H, d, J= 8.0 Hz), 7.35(1H, d, J= 16.0 Hz), 7.85(1H, s), 8.21(1H, s), 11.07(1H, brs)

Preparation 190 25 (2E)-3-{6-[ [l-(4-Chlorobenzoyl)-4-piperidyl] (methyl)amino]-3- pyridyl}-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide NMR (DMSO-de, d) : 1.40-1.90(11H, m), 2,75-3.30(2H, m), 2.90(3H, s) , 3.45-3.60(2H, m) , 3.85-4.10(1H, m) , 4.45-4.90(3H, m) , 6.27(1H, d, J= 16.0 Hz), 6.74(1H, d-, J= 8.8 Hz), 7.39(1H, d, J= 16.0 Hz), 7.45- 30 7.55(4H, m), 7.74(1H, dd, J= 2.0, 8.8 Hz), 8.27(1H, d, J= 2.0 Hz), 11.08(1H, brs)

Preparation 191 (2E)-3-(5-Chloro-6-{[(3R)-l-(4-fluorobenzyl)-3-pyrrolidinyl] amino}- 35 3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide NMR (DMSO-de, <5 ) : 1.50-19.0(7H, m) , 2.08-2.29(1H, m), 2.37-2.65(2H, m), 2.78-2.87(1H, m) , 3.4O-3.65(1H, m) , 3.57(2H, s), 3.86-4.12(1H, m) , 4.45-4.55 ( 1H, m) , 4.89 ( 1H, s , J=16.0 Hz ) , 6.32( 1H, d, J= 7.0 Hz) , 6.62 ( 1H, d) , 7.09-7. 17 ( 2H, m) , 7.857.30-7.40(3H, m) , 8.2O7.85( 1H, s) , 8.2O( 1H, s) , 11.08( 1H, brs)

Preparation 192 (2E)-3-(5-Chloro-6-{[(3R)-l-(4-methylbenzyl)-3-pyrrolidinyl] amino}- 3-pyridyl)-N-(tetrahydro~2H~pyran-2-yloxy)acrylamide NMR (DMSO-de, <5 ) : 1.45-1.90(7H, m) , 2.10-2.30(1H, m) , 2.27(3H, s), 2.36-2.84(3H, m) , 3.45-3.53(1H, m) , 3.60(2H, s), 3.94-4..05(lH, m) , 4.40-4.60(1H, m) , 4.89(1H, s), 6.32(1H, d, J= 16.0 Hz), 6.6.O(1H, d, J= 7.0 Hz), 7.10(2H, d, J= 8.8 Hz), 7.28(2H, d, J= 8.8 Hz), 7.36(1H, d, J= 16.0 Hz), 7.84(1H, s), 8.2O(1H, s), 11.08(1H, brs) c

Preparation 193 (2E)-3-(5-Chloro-6-{[(3R)-1-(4-methoxybenzyl)-3- pyrrolidinyl]amino}-3-pyridyl)-N-(tetrahydro-2H-pyran-2- yloxy)acrylamide NMR (DMSO-de, <5 ) : 1.76-1.92(7H, m) , 2.12-2.3O(1H, m) , 2.32-2.86(3H, m), 3.40-3.60(1H, m), 3.51(2H, s), 3.72(3H, s), 3.β6-4.05(lH, m) , 4.35-4.60(1H, m), 4.89(1H, s), 6.31(1H, d, J= 16.0 Hz), 6.61(1H, d, J= 7.0 Hz), 6.86(2H, d, J= 8.8 Hz), 7.21(2H, d, J= 8.8 Hz), 7.35(1H, d, J= 16.0 Hz), 7.84(1H, s), 8.19(1H, s), 11.07(1H, brs)

Preparation 194 To a solution of ,ethyl (2E)-3-[6-(4-piperidylamino)-3- pyridyl]acrylate dihydroohloride (309mg) in EtOH (5ml) was added Et3N(0.92ImI), then benzaldehyde(0.117ml) and titanium(IV) isopropoxide (0.463ml), the mixture was stirred at 23°C for 12 hours. To the mixture was added sodium borohydride, the mixture was stirred at 23"C for 24 hours. The reaction mixture was poured into sat.NaHCO3aq. (2OmI)-AcOEt(20ml), the insoluble material was removed by filtration , then the filtrate was extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography eluted with 5% MeOH in dichloromethane to give ethyl (2E)-3-{6-[(l-benzyl-4- piperidyl)amino]-5-chloro-3-pyridyl}acrylate(328mg) . NMR (DMSO-(I6, <5 ) : 1.24 (3H, t , J= 7.4 Hz ) , 1.55-1.68( 4H, in) , 1.95- 2.07 (2H, m) , 2.75-2.87 ( 2H, m) , 3.46 ( 2H, s) , 3.90-4.10( 1H, m) , 4.15(2H, q, J= 7.4 Hz) , 6.47(1H, d, J= 16.0 Hz) , 6.63(1H, d, J= 8.0 Hz) , 7.21-7.37(5H, m) , 7.5O( 1H, d, J= 16.0 Hz) , 8.1O( 1H, d, J= 2.0 Hz ) , 8.27( 1H, d, J= 2.0 Hz) . Mass (APCI ) : 400 (M+H)+

The following compounds were obtained according to a similar manner to that of Preparation 194.

Preparation 195 Ethyl (2E)-3-(5-chloro-6-{[1-(4-chlorobenzyl)-4-piperidyl]amino}-3 - pyridyl)aerylate NMR (DMSO-d6, <5): 1.24(3H, t, J= 7.2 Hz), 1.50-2.10(6H, m) , 2.67- 2.89(2H, m), 3.46(2H, s), 3.89-4.10(1H, m) , 4.15(2H, q, J= 7.2 Hz), 6.47(1H, d, J= 16.0 Hz), 6.63(1H, d, J= 8.0 Hz), 7.30-7.41(4H, m) , 7.5O(1H, d, J= 16.0 Hz), 8.1O(1H, d, J= 2.0 Hz), 8.27(1H, d, J= 2.0 Hz) Mass (APCI): 434(M+H)+

Preparation 196 Ethyl (2E)-3-(5-chloro-6-{[l-(4-fluorobenzyl)-4-piperidyl]amino}-3 - pyridyl)acrylate NMR (DMSO-de, <5 ) : 1.24(3H, t, J= 7.4 Hz), 1.55-1.68(4H, m) , 1.95- 2.07(2H, m), 2.75-2.87(2H, m) , 3.46(2H, s), 3.90-4.10(1H, m) , 4.15(2H, q, J= 7.4 Hz), 6.47(1H, d, J= 16.0 Hz), 6.63(1H, d, J= 8.0 Hz), 7.09-7.38(4H, m), 7.5O(1H, d, J= 16.0 Hz), 8.1O(1H, d, J= 2.0 Hz), 8.27(1H, d, J= 2.0 Hz). Mass (APCI): 418(M+H)+

Preparation 197 tert-Butyl 4-(methylamino)-1-piperidinecarboxylate NMR (DMSO-de, <5 ) : 0.95-1.12(2H, m) , 1.38(9H, s), 1.68-1.76(2H, m) , 2.25(3H, s), 2.30-2.40(1H, m) , 2.65-2.95(2H, m) , 3.32(1H, brs), 3.70-3.85(2H, m) .

Preparation 198 To a solution of ethyl (2E)-3-[5-chloro~6-(4- piperidylaitιino)-3-pyridyl]acrylate dihydrochloride (710mg) in CH2Cl2 (14ml) was added Et3N(0.517ml) , the mixture was stirred at 23°C for 30 minutes. To the mixture was added 4-Methyl-benzaldehyde (0.241ml) and SODIUM triacetoxyborohydride(590mg) , the mixture was stirred at 23°C for 24 hours. The reaction mixture was poured into sat.NaHCO3aq. (20ml)-AcOEt(20ml) . The organic layer was washed with water, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography eluted with 5% MeOH in dichloromethane to give ethyl (2E)-3-(5-chloro-6- {[1-(4-methylbenzyl)-4-piperidyl]amino}-3-pyridyl)acrylate(6 7lmg) . NMR (DMSO-de, <5 ) : 1.24(3H, t, J= 7.4 Hz), 1.50-1.87(4H, m), 1.94- 2.05(2H, m), 2.28(3H, s), 2.77-2.83(2H, m) , 3.41(2H, s), 3.85- 4.07(1H, m), 4.15(2H, q, J= 7.4 Hz), 6.47(1H, d, J= 16.0 Hz), 6.62(1H, d, J= 7.0 Hz), 7.11(2H, d, J= 8.8 Hz), 7.18(2H, d, J= 8.8 Hz), 7.5O(1H, d, J= 16.0 Hz), 8.1O(1H, d, J= 2.0 Hz), 8.27(1H, d, J= 2.0 Hz),

The following compounds were obtained according to a similar manner to that of Preparation 198.

Preparation 199 Ethyl (2E)-3-(5-chloro-6-{[1-(4-methoxybenzyl)-4-piperidyl]amino}- 3-pyridyl)acrylate NMR (DMSO~d6, <5 ) : 1.21(3H, t, J= 7.4 Hz), 1.56-1.89(4H, m) , 1.90- 2.15(2H, m), 2.78-2.84(2H, m), 3.40(2H, s), 3.74(3H, s) , 3.85- 4.1O(1H, m), 4.16(2H, q, J= 7.4 Hz), 6.47(1H, d, J= 16.0 Hz), 6.61(2H, d, J= 8.8 Hz), 7.20(2H, d, J= 8.8 Hz), 7.5O(1H, d, J= 16.0 Hz), 8.09(1H, d, J= 2.0 Hz), 8.27(1H, d, J= 2.0 Hz)

Preparation 200 Ethyl (2E)-3-{5-chloro-6~[(l-isobutyl-4-piperidyl)amino]-3- pyridyl}acrylate Mass (ESI): 366(M+H)+

Preparation 201 Ethyl (2E)-3-(5-chloro-6-{[1-(cyclopropylmethyl)-4- piperidyl]amino}-3-pyridyl)aerylate Mass (ESI): 364(M+H)+

Preparation 202 To a solution of (3R)-(+)-3-(tert- butoxycarbonylamino)pyrrolidine (5.Og) in DME (50ml) was added 4- fuluorobenzylchloride (3.38ml) and N,N- diisopropylethylamine(9.35ml), the mixture was stirred at 701C for 2 hours. The mixed solution was poured into, a mixture of water (300ml) and AcOEt (30 OmI). The organic layer was separated, washed with water twice and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with 5% MeOH in dichloromethane to give [1-(4-fluoro-benzyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (6.8g). To a solution of [1-(4-fluoro-benzyl)-pyrrolidin-3- yl]-carbamic acid tert-butyl ester (6.8g) in MeOH(34ml) was treated with 4N HCl in AcOEt (29ml) and was stirred at 251C for 12 hours. The solvent was removed under reduced pressure. Recrystallization (acetonitrile-MeOH) provided (3R)-l-(4-fluorobenzyl)-3- pyrrolidinamine dihydrόchloride as white solid(3.77g) . NMR (DMSO-d6, <5 ) : 1.96-2.55(2H, m) , 3.10-3.78(4H, m) , 3.8O-4.22(1H, m), 4.47-4.52(2H, m) , 7.26-7.36(2H, m) , 7.61-7.72(2H, m) , 8.60- 8.90(2H, m), 11.50-11.99(1H, m) Mass (APCI): 195(M+H)+

The following compounds were obtained according to a similar manner to that of Preparation 202.

Preparation 203 (3R)-l-(4-Methylbenzyl)-3-pyrrolidinamine dihydrochloride NMR (DMSO-d6, <5 ) : 1.96-2.55(2H, m) , 2.33(3H, s), 3.10-3.78(4H, m), 3.8O-4.22(1H, m) , 4.47-4.52(2H, m) , 7.25(2H, d, J= 8.8 Hz), 7.50(2H, brs), 8.73-8.23(2H, m) , 11.39-11.87(1H, m) . Mass (APCI): 191(M+H)+

Preparation 204 (3R)-1-(4-Methoxybenzyl)-3-pyrrolidinamine dihydrochloride NMR (DMSO-d6, <5 ) : 1.90-2.30(2H, m) , 3.10-3.75( 4H, m) , 3.78(3H, s) , 3.8O-4.15( 1H, m) , 7.37 (2H, brs) , 7.00 ( 2H, d, J= 8.8 Hz) , 7.54 (2H, brs) , 8.67-8.76 ( 2H,- m) Mass (APCI ) : 206 (M+H)+

Preparation 205 To a solution of (3R)-l-(4-fluorobenzyl)-3-pyrrolidinamine dihydrochloride(3i5g) in DMF (35ml) was added 5,6-dichloronicotinic acid ethyl ester (3.38ml) and K2CO3 (6.34g),, the mixture was stirred at 100°C for 4 hours under N2 atmosphere. The mixed solution was poured into a mixture of water (250ml) and AcOEt (250ml). The organic layer was separated, washed with water twice and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with AcOEt:hexane=l:2 to give ethyl 5-chloro-6-{[(3R)-l-(4- fluorobenzyl)-3-pyrrolidinyl]amino}nicotinate (3.75g) . NMR (DMSO-de, <5 ) : 1.28(3H, t, J= 7.4 Hz), 1.73-1.98(1H, m), 2.10- 2.3O(1H, m), 2.40-2.70(3H, m) , 2.82-2.87(1H, m) , 3.57(2H, s), 4.25(2H, q, J= 7.4 Hz), 4.51-4.61(1H, m) , 4.02-7.18(3H, m) , 7.31- 7.38(2H, m), 7.93(1H, d, J= 2.0 Hz), 8.54(1H, d, J= 2.0 Hz) Mass (APCI): 378(M+H)+

The following compounds were obtained according to a similar manner to that of Preparation 205.

Preparation 206 Ethyl 5-chloro-6-{[(3R)-l-(4-methylbenzyl)-3- pyrrolidinyl]amino}nicotinate NMR (DMSO-d6, <5 ) : 1.24(3H, t, J= 7.4 Hz), 1.76-1.95(1H, m) , 2.12- 2.34(1H, m), 2.27(3H, s), 2.45-2.70(3H, m) , 2.71-2.85(1H, m) , 3.54(2H, s), 4.24(2H, q, J= 7.4 Hz), 4.46-4.60(1H, m) , 7.00-7.21(5H, m), 7.93(1H, d, J= 2.0 Hz), 8.53(1H, d, J= 2.0 Hz) Mass (APCI): 374(M+H)+

Preparation 207 Ethyl 5-chloro-6-{[(3R)-l-(4-methoxybenzyl)-3- pyrrolidinyl]amino}nicotinate Mass (ESI ) : 390 (M+H) +

Preparation 208 To a solution of 2-chloro-5-iodopyridine(37.7 g) in DMF (300 mL) was added palladium(II) acetate (1.77g), ,tri-o-tolylphosphine (7.19 g), diisopropylethylamine (82 mL), and ethyl aerylate (17.9 mL), and the mixture was heated at 100°C for 10 hours. Resulting mixture was poured into water and extracted with AcOEt. The organic layer was washed with water and brine and dr.ied over Na2SO4, and the solvent was removed in vacuo. Obtained brown solid was suspended in a mixture of liexane and AcOEt(4:1), and the precipitate was filtered off. The filtrate was concentrated in vacuo, and residual brown oil was purified by silica gel column chromatography eluted with AcOEt and hexane (1:4-1:2). Resulting solid was triturated with IPE to give ethyl (2E)-3-(6-chloro-3- pyridyl)acrylate as pale yellow powder(20.58 g) . NMR (DMSO-de, δ ) : 1.35 (3H, t, J= 7.0 Hz), 4.28 (2H, q, J= 7.0 Hz), 6.49 (IH, d, J= 16.1 Hz), 7.37 (IH, d, J= 8.1 Hz), 7.63 (IH, d, J= 16.1 Hz), 7.80 (IH, dd, J= 8.2,2.6 Hz), 8.52 (IH, d, J= 2.6 Hz) MS (ES+) m/z 212 (M+l)

Preparation 209 To a solution of ethyl (2E)-3-(6-chloro-3- pyridyl)acrylate(14.3 g) in dioxane (140 mL) was added palladium(II) acetate (1.52g) , 2'-(dicyclohexylphosphino)-N,N- dimethyl-2-biphenylamine (3.99 g) , cesium carbonate (30.2 g) , and (3R)-(-)-1-benzyl-3-aminopyrrolidine (13.I g), and the mixture was heated at 95°C for 2.5days. The resulting mixture was poured into sat.NH4Cl aqueous solution and extracted with AcOEt. The organic layer was washed with sat. NH4Cl aq solution, water, and brine, and dried over Na2SO4. The solvent was removed in vacuo and residual brown oil was purified by silica gel column chromatography eluted with AcOEt to give ethyl (2E)-3-(6-{[ (3R)-I-benzyl-3- pyrrolidinyl]amino}-3-pyridyl)acrylate as pale yellow oil(10.7 g) . NMR (DMSO-d6, <5 ) : 1.32 (3H, t, J= 7.0 Hz), 1.70 (IH, m) , 2.39 (2H, m), 2.61 (IH, m), 2.75 (IH, m) , 2.84 (IH, m) , 3.64 (2H, d, J= 2.2 Hz), 4.24 (2H, q, J= 7.0 Hz), 4.35 (IH, m) , 5.09 (IH, d, J= 8.0 Hz), 6.20 ( IH, d, J= 16. 1 Hz) , 6.36 ( IH, d, J= 8.8 Hz ) , 7.27 (2H, m) , 7.32 (3H, m) , 7.56 (IH, d, J= 15.8 Hz) , 7.60 (IH, d, J= 8.8 , 2.2 Hz) , , 8.19 ( IH, d, J= 2.2 Hz ) MS (ES+ ) m/z 352 (M+l)

Preparation 210 To a solution of ethyl (2E)-3-(6-{[(3R)-l-benzyl-3- pyrrolidinyl]amino}-3-pyridyl)acrylate(11 g) in THF (105 irtL) was added di-tert-butyl bicarbonate (13.7 g) and, 4- dimethylaminopyridine (95.6 mg), and the mixture was heated at 60°C for 13 hours. The solvent was removed in vacuo and residual oil was purified by silica gel column chromatography eluted with AcOEt to give ethyl (2E)-3-{6-[ [(3R)-l-benzyl-3-pyrrolidinyl] (tert- butoxycarbonyl)amino]-3-pyridyl}acrylate as pale yellow oil (13.0 g). NMR (DMSO-dβ, 6): 1.35 (3H, t, J= 7.0 Hz), 1.44 (9H, s), 2.08 (IH, m), 2.23 (IH, m) , 2.57-2.73 (3H, m) , 2.93 (IH, t, J= 8.8 Hz), 3.53 (IH, d, J= 12.6 Hz), 3.63 (IH, d, J= 12.8 Hz), 4.29 (2H, q, J= 7.0 Hz), 4.91 (IH, m), 6.46 (IH, d, J= 16.1 Hz), 7.20-7.27 (5H, m) , 7.29 (IH, d, J= 8.8 Hz), 7.66 (IH, d, J= 16.1 Hz), 7.80 (IH, dd, J= 8.4,2.2 Hz), 8.53 (IH, d, J= 2.2 Hz) MS (ES+) m/z 452 (M+l)

' Preparation 211 To a solution of ethyl (2E)-3-{6-[ [(3R)-l-benzyl-3- pyrrolidinyl] (tert-butoxycarbonyl)amino]-3-pyridyl}acrylate as pale yellow oil (16.6 g) in toluene (80 mL) was added diisopropylethylamine(2.17 mL) and 1-chloroethyl chloridecarbonate (5.76 mL) at 5X^. The mixture was warmed to ambient temperature and stirred for 1 hour, and diluted with IPE (150 mL) . The precipitate was removed by filtration and the solvent was removed in vacuo. Residual colorless oil was purified by silica gel column chromatography eluted with AcOEt and hexane (1:2-1:1). Obtained oil was dissolved in EtOH (70 mL) and heated at 70°C for 1 hour. The solvent was removed in vacuo to give ethyl (2E)-3-(6-{(tert- butoxycarbonyl) [ (3R)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate dihydrochloride (8.9 g) as pale yellow oil. NMR (DMSO-d6, <5): 1.27 (3H, t, J= 7.0 Hz), 1.42 (9H, s), 1.98 (IH, m), 2.23 (IH, m) , 3.15 (IH, m) , 3.34 (3H, br) , 4.21 (2H, q, J= 7.0 Hz), 4.96 (IH, m), 6.78 (IH, d, J= 16.1 Hz), 7.45 (IH, d, J= 8.4 Hz), 7.70 (IH, d, J= 16.1 Hz), 8.25 (IH, dd, J= 8.6,2.2 Hz), 8.75 (IH, d, J= 2.2 Hz), MS (ES+) m/z 362 (M+l)

Preparation 212 To a solution of ethyl (2E)-3-(6-{(tert- butoxycarbonyl) [ (3R)-3-pyrrolidinyl]amino}-3-pyridyl)aerylate dihydrochloride (3.0 g) in 1,2-dichloroethane (30 mL) was added diisopropylethylamine (2.41 mL) and 3-fluorobenzaldehyde (857 mg), and the mixture was stirred at room temperature for 5 minutes. To the mixture was added sodium triacetoxyborohydride (3.1 g) and stirred for 3 hours, and resulting mixture was poured into sat NH4Cl aq solution, and extracted with AcOEt. The organic layer was washed with sat NH4Cl aq solution, water, and brine, and dried over Na2SO4. The solvent was removed in vacuo and the residual oil was purified by silica gel column chromatography eluted with AcOEt and hexane (1:1) to give ethyl (2E)-3-(6-{(tert-butoxycarbonyl) [(3R)-I- (2-fluorobenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate (2.40 g) as colorless oil. NMR (DMSO-de, <5 ) : 1.35 (3H, t, J= 7.0 Hz), 1.44 (9H, s), 2.09 (IH, m), 2.24 (IH, m) , 2.64 (2H, t, J= 7.4 Hz), 2.74 (IH, dd, J= 9.2,7.0 Hz), 2.89 (IH, t, J= 8.1 Hz), 3.51 (IH, d, J= 13.3 Hz), 3.62 (IH, d, J= 13.3 Hz), 4.28 (2H, q, J= 7.0 Hz), 4.91 (IH, m) , 6.47 (IH, d, J= 16.1 Hz), 6.91 (2H, m) , 6.99 (IH, d, J= 8.0 Hz), 7.21 (IH, m) , 7.28 (IH, d, J= 8.4 Hz), 7.66 (IH, d, J= 16.1 Hz), 7.81 (IH, dd, J= 8.4,2.6 Hz), 8.54 (IH, d, J= 2.2 Hz) MS (ES+) m/z 470 (M+l)

The following compounds were obtained according to a similar manner to that of Preparation 212.

Preparation 213 Ethyl (2E)-3-(6-{(tert-butoxycarbonyl) [(3R)-1-(4-tert-butylbenzyl)- 3-pyrrolidinyl]amino}-3-pyridyl)acrylate NMR (DMSO-d6, <5 ) : 1.31 (9H, s), 1.36 (3H, t, J= 7.0 Hz), 1.44 (9H, s),1.97-2.32 (2H, m) ,2.53-2.77 (3H, m) ,2.89-3.01 (IH, m),, 3.54 (IH, d, J= 12.1 Hz), 3.60 (IH, d, J= 12.1 Hz), 4.83-4.98 (IH, m) , 6.47 (IH, d, J= 16.1 Hz), 7.16 (2H, d, J= 8.1 Hz), 7.23-7.34 (IH, in), 5 7.30 (2H, d, J= 8.1 Hz), 7.67 (IH, d, J= 16.1 Hz), 7.81 (IH, dd, J= 8.4, 2.6 Hz), 8.54 (IH, d, J= 2.6 Hz) MS (ES+) m/z 508.36

Preparation 214 10 Ethyl (2E)-3-[6-((tert-butoxycarbonyl){(3R)-l-[4- (trifluoromethyl)benzyl]-3-pyrrolidinyl}amino)-3-pyridyl]acr ylate NMR (DMSO-de, <5 ) : 1.35 (3H, t, J= 7.0 Hz), 1.44 (9H, s), 1.97-2.14 (IH, m), 2.16-2.31 (IH, m), 2.56-2.79 (3H, m), 2.88-2.97 (IH, m) , 3.59 (IH, d, J= 13.2 Hz), 3.67 (IH, d, J= 13.2 Hz), 4.29 (}2H, q, J= 15 7.0 Hz), 4.83-4.99 (IH, m) , 6.47 (IH, d, J= 16.1 Hz), 7.29 (IH, d, J= 8.4 Hz), 7.35 (2H, d, J= 8.1 Hz), 7.53 (2H, d, J= 8.1 Hz), 7.66 (IH, d, J= 16.1 Hz), 7.80 (IH, dd, J= 8.4, 2.6 Hz), 8.53 (IH, d, J= 2.6 Hz) MS (ES+) m/z 520.32(M+l) 20 Preparation 215 Ethyl (2E)-3-[6-((tert-butoxycarbonyl){(3R)-l-[4- (trifluoromethoxy)benzyl]-3-pyrrolidinyl}amino)-3-pyridyl]ae rylate NMR (DMSO-de, <5 ) : 1.35 (3H, t, J= 7.3 Hz), 1.43 (9H, s), 1.97-2.32 25 (2H, m), 2.53-2.77 (3H, m) , 2.87-2.98 (IH, m) , 3.54 (IH, d, J= 13.2 Hz), 3.62 (IH, d, J= 13.2 Hz), 4.29 (2H, q, J= 7.3 Hz), 4.83-4.97 (IH, m), 6.47 (IH, d, J= 16.1 Hz), 7.12 (2H, d, J= 8.1 Hz), 7.25 (2H, d, J= 8.1 Hz), 7.29 (IH, d, J= 8.4 Hz), 7.66 (IH, d, J= 16.1 Hz), 7.80 (IH, dd, J= 8.4, 2.6 Hz), 8.53 (IH, d, J= 2.6 Hz) 30 MS (ES+) m/z 536.24(M+1)

Preparation 216 Ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(cyclohexylmethyl)-3 - pyrrolidinyl]amino}-3-pyridyl)aerylate •35 NMR (CDCl3, δ): 0.69-0.95 (2H, m),' 1.02-1.48 (3H, m), 1.35 (3H, t, J= 7.0 Hz), 1.45 (9H, s), 1.52-1.80 (6H, m) , 1.92-2.34 (4H, m) , 2.41-2.74 (3H, m) , 2.80-3.02 (IH, m) , 4.29 (2H, q, J= 7.0 Hz), 4.82-4.98 ( IH, m) , 6.46 ( IH, d, J= 16.1 Hz) , 7.31 ( IH, d, J= 8.4 Hz) , 7.66 (IH, d, J= 16.1 Hz ) , 7.81 ( IH, dd, J= 8.4, 2.6 Hz) , 8.86 ( IH, d, J= 2.6 Hz) MS (ES+) m/z 458.37 (M+1)

Preparation 217 Ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-l-(l-cyclohexen-l- ylmethyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate NMR (DMSO-de, <5 ) : 1.35 (3H, q, J= 7.0 Hz), 1.45 (9H, s), 1.48-1.73 (4H, m), 1.83-2.09 (5H, m) , 2.14-2.32 (IH, m), 2.45-2.67 (3H, m) , 2.77-2.99 (3H, m), 4.28 (2H, q, J= 7.0 Hz), 4.80-4.95 (IH, m) , 5.52 (IH, brs), 6.46 (IH, d, J= 16.1 Hz), 7.31 (IH, d, J= 8.4 Hz), 7.66 (IH, d, J= 16.1 Hz), 7.81 (IH, dd, J= 8.4, 2.6 Hz), 8.56 (IH, d, J= 2.6 Hz) MS (ES+) m/z 456.54(M+l)

Preparation 218 Ethyl (2E)-3-{6^[[(3R)-l-(l-benzof\iran-2-ylmethyl)-3- pyrrolidinyl] (tert-butoxycarbonyl)amino]-3-pyridyl}aσrylate NMR (CDCl3, <5 ) : 1.35 (3H, t, J = 7 Hz), 1.43 (9H, s), 2.01-2.35 (2H, m), 2.70-3.23 (4H, m) , 3.76-3.90 (2H, m) , 4.28 (2H, q, J = 7 Hz), 4.90-5.02 (IH, m) , 6.42 (IH, d, J = 16 Hz), 6.57 (IH, s), 7.17-7.27 (2H, m) , 7.29 (IH, d, J = 8 Hz), 7.42-7.54 (2H, m), 7.61 (IH, d, J = 16 Hz), 7.76 (IH, dd, J = 2, 8 Hz), 8.45 (IH, d, J = 2 Hz) MS (ES+) m/z 492 (M+l)

Preparation 219 Ethyl (2E)-3-{6-[[(3R)-l-(l-benzofuran-5-ylmethyl)-3- pyrrolidinyl] (tert-butoxycarbonyl)amino]-3-pyridyl}acrylate NMR (CDCl3, <5): 1.35 (3H, t, J = 7 Hz), 1.43 (9H, s), 2.06-2.42 (2H, m), 2.79-3.27 (4H, m) , 3.80-3.96 (2H, m) , 4.29 (2H, q, J = 7 Hz), 4.91-5.04 (IH, m) , 6.45 (IH, d, J = 16 Hz), 6.73-6.75 (IH, m) , 7.28 (2H, d, J = 8 Hz), 7.44 (IH, d, J = 8 Hz), 7.57-7.67 (3H, m) , 7.78 (IH, dd, J = 2, 8 Hz), 8.49 (IH, d, J = 2. Hz) MS (ES+) m/z 492 (M+l) Preparation 220 Ethyl (2E)-3-(6-{(tert-butoxycarbonyl) [(3R)-1-(3-methoxybenzyl)-3- pyrrolidinyl]amino}-3-pyridyl)aerylate NMR (CDCl3, <5): 1.35 (3H, t, J= 7.0 Hz), 1.44 (9H, s), 2.07 (IH, m), 2.24 (IH, m) , 2.58-2.76 (3H, m) , 2.94 (IH, m) , 3.53 (IH, d, J= 12.8 Hz), 3.61 (IH, d, J= 12.8 Hz), 4.29 (2H, q, J= 7.0 Hz), 4.91 (IH, m), 6.47 (IH, d, J= 16.1 Hz), 6.76-6.83 (3H, m) , 7.19 (IH, t, J= 8.1 Hz), 7.29 (IH, d, J= 8.4 Hz), 7.66 (IH, d, J= 16.1 Hz), 7.80 (IH, dd, J= 8.4,2.6 Hz), 8.54 (IH, d, J= 2.2 Hz) MS (ES+) m/z 482 (M+l)

Preparation 221 Ethyl (2E)-3-(6-{(tert-butoxycarbonyl) [(3R)-1-(3-phenylpropyl)-3- pyrrolidinyl]amino}-3-pyridyl)aerylate NMR (CDCl3, δ): 1.35 (3H, t, J= 7.0 Hz), 1.45 (9H, s), 1.78 (2H, m), 2.01 (IH, m), 2.19 (IH, m) , 2.36-2.77 (7H, m) , 3.02 (IH, t, J= 8.4 Hz), 4.28 (2H, q, J= 7.0 Hz), 4.89 (IH, m) , 6.44 (IH, d, J= 16.1 Hz), 7.14-7.19 (3H, m), 7.23-7.28 (2H, m), 7.31 (IH, d, J= 8.4 Hz), 7.65 (IH, d, J= 16.1 Hz), 7.80 (IH, dd, J= 8.4,2.6 Hz), 8.54 (IH, d, J= 2.6 Hz) MS (ES+) m/z 480 (M+l)

Preparation 222 Ethyl (2E)-3-[6-((tert-butoxycarbonyl){(3R)-1-[4- (dimethylamino)benzyl]-3-pyrrolidinyl}amino)-3-pyridyl]aeryl ate NMR (CDCl3, <5): 1.36 (3H, t, J= 7.1 Hz), 1.45 (9H, s), 2.19 (IH, br), 2.46 (IH, br) , 2.96 (6H, s), 3.14 (2H, br) , 3.42 (IH, br) , 3.92 (IH, br), 4.29 (2H, q, J= 7.1 Hz), 5.04 (IH, br) , 6.45 (IH, d, J= 16.1 Hz), 6.69 (2H, d, J= 8.8 Hz), 7.29 (3H, m) , 7.63 (IH, d, J= 16.1 Hz), 7.79 (IH, dd, J= 8.4,2.5 Hz), 8.46 (IH, br) MS (ES+) m/z 495 (M+l)

Preparation 223 Ethyl (2E)-3-(6-{(tert-butoxycarbonyl) [(3R)-1-(2-methoxybenzyl)-3- pyrrolidinyl]amino}-3-pyridyl)aerylate NMR (CDCl3, <5): 1.35 (3H, t, J= 7.0 Hz), 1.44 (9H, s), 2.20 (IH, m), 2.52 (IH, m) , 3.29 (3H, m) , 3.60 (IH, m) , 3.86 (3H, s), 4.18 ( 2H, br) , 4.28 ( 2H, q, J= 7.0 Hz) , 5.10 ( IH, m) , 6.44 ( IH, d, J= 16.1 Hz ) , 6.91 ( IH, d, J= 7.4 Hz) , 6.98 ( IH, dd, J= 7.5 , 1.1 Hz) , 7.32 ( IH, d, J= 84 Hz) , 7.35 ( IH, td, J= 7.8 , 1.8 Hz) , 7.50 ( IH, dd, J= 7.7 , 1.1 Hz ) , 7.63 ( IH, d, J= 16.1 Hz) , 7.79 ( IH, dd, J= 8.4 , 2.2 Hz) , 8.44 ( IH, d, J= 2.2 Hz ) MS (ES+) m/z 482 (M+l)

Preparation 224 Ethyl (2E)-3-(6-{(tert-butoxycarbonyl) [(3R)-l-(2-fluorobenzyl)-3- pyrrolidinyl]amino}-3-pyridyl)aerylate NMR (CDCl3, <5): 1.35 (3H, t, J= 7.0 Hz), 1.44 (9H, s), 2.H (IH, br), 2.33 (IH, br) , 2.89 (3H, br) , 3.13 (IH, br) , 3.82 (IH, br) , 4.29 (2H, q, J= 7.0 Hz), 4.97 (IH, br) , 6.45 (IH, d, J= 16.1 Hz), 7.02 (IH, t, J= 8.0 Hz), 7.11 (IH, t, J= 7.3 Hz), 7.25 (IH, br) , 7.31 (IH, d, J= 8.8 Hz), 7.40 (IH, br) , 7.65 (IH, d, J= 16.1 Hz), 7.79 (IH, dd, J= 8.4,2.6 Hz), 8.49 (IH, d) MS (ES+) m/z 470 (M+l)

Preparation 225 Ethyl (2E)-3-(6-{(tert-butoxycarbonyl) [(3R)-1-(2-quinolinylmethyl)- 3-pyrrolidinyl]amino}-3-pyridyl)acrylate NMR (DMSO-de, <5 ) : 1.36 (3H, t, J= 7.0 Hz), 1.45 (9H, s), 2.20 (IH, m), 2.43 (IH, m) , 3.17 (3H, br) , 3.44 (IH, br) , 4.29 (2+2H, q, J= 7.0 Hz), 5.09 (IH, m), 6.45 (IH, d, J= 16.1 Hz), 7.32 (IH, d, J= 8.4 Hz), 7.55 (IH, tm, J=7.0 Hz), 7.63 (IH, d, J= 16.1 Hz), 7.70 (IH, dd, J= 7.0,1.5 Hz), 7.73 (IH, dd, J= 7.0,1.7 Hz), 7.79 (IH, dd, J= 8.8,2.2 Hz), 7.82 (IH, d, J= 8.4 Hz), 7.06 (IH, d, J= 8.4 Hz), 7.26 (IH, d, J= 8.4 Hz), 8.50 (IH, d, J= 2.2 Hz) MS (ES+) m/z 503 (M+l) ' Preparation 226 Ethyl (2E)-3-(6-{(tert-butoxycarbonyl) [(3R)-1-(3- isoquinolinylmethyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylat e NMR (CDCl3, S): 1.37 (3H, t, J= 7.0 Hz), 1.45 (9H, s), 2.12 (IH, m), 2.25 (IH, m) , 2.72 (2H, m) , 2.81 (IH, m) , 2.89 (IH, m) , 3.72 (IH, m), 3.75 (IH, d, J= 12.8 Hz), 3.84 (IH, d, J= 12.8 Hz), 4.30 (2H, q, J= 7.0 Hz), 4.93 (IH, m) , 6.46 (IH, d, J= 16.1 Hz), 7.28 (IH, d, J= 8.0 Hz), 7.54 (IH, m) , 7.65 (IH, d, J= 16.1 Hz), 7.70 (IH, m), 7.79 (2H, m) , 8.00 (IH, br) , 8.10 (IH, d, J= 8.4 Hz), 8.51 (IH, d, J= 2.2 Hz), 8.83 (IH, d, J= 2.2 Hz) MS (ES+) m/z 503 (M+l) ■•' Preparation 227 Ethyl (2E)-3-[6-( (tert-butoxycarbonyl){(3R)-1-[ (5-methyl-2- thienyl)methyl]-3-pyrrolidinyl}amino)-3-pyridyl]aerylate NMR (CDCl3, <5): 1.35 (3H, t, J= 7.0 Hz), 1.45 (9H, s), 2.06 (IH, br), 2.22 (IH, br), 2.44 (3H, s), 2.64 (IH, br), 2.74 (2H, br) , 3.01 (IH, br), 3.72 (2H, br) , 4.27 (2H, q, J= 7.0 Hz), 4.91 (IH, m) 6.46 (IH, d, J= 16.1 Hz), 6.54 (IH, br) , 6.64 (IH, br) , 7.31 (IH, d, J= 8.4 Hz), 7.66 (IH, d, J= 16.1 Hz), 7.81 (IH, dd, J= 8.4,2.6 Hz), 8.54 (IH, d, J= 2.2 Hz) MS (ES+) m/z 472 (M+l)

Preparation 228 Ethyl (2E)-3-[6-((tert-butoxycarbonyl){(3R)-1-[(5-methyl-2- furyl)methyl]-3-pyrrolidinyl}amino)-3-pyridyl]aerylate NMR (CDCl3, δ): 1.36 (3H, t, J= 7.0 Hz), 1.46 (9H, s), 2.14 (IH, m), 2.29 (3H, s). 2.39 (IH, m) , 3.10 (3H, br) , 3.42 (IH, br) , 3.89 (2H, br), 4.29 (2H, q, J= 7.0 Hz), 5.03 (IH, m) , 5.95 (IH, br) , 6.28 (IH, br), 6.46 (IH, d, J= 16.1 Hz), 7.33 (IH, d, J= 8.4 Hz), 7.65 (IH, d, J= 16.1 Hz), 7.81 (IH, dd, J= 8.4,2.2 Hz), 8.50 (IH, d) MS (ES+) m/z 456 (M+l)

Preparation 229 Ethyl (2E)-3-{6-[(tert-butoxycarbonyl)((3R)-l-{(2E)-3-[4- (dimethylamino)phenyl]-2-propen-l-yl}-3-pyrrolidinyl)amino]- 3- pyridyl}acrylate NMR (CDCl3, δ): 1.35 (3H, t, J= 7.0 Hz), 1.47 (9H, s), 2.33 (2H, br), 2.61 (2H, br) , 2.99 (6H, s), 3.45 (2H, br) , 3.82 (2H, br) , 4.28 (2H, q, J= 7.0 Hz), 5.12 (IH, m) , 6.19 (IH, dt, J= 15.4,7.0 Hz), 6.44 (IH, d, J= 16.1 Hz), 6.63 (IH, d, J= 15.4 Hz), 6.66 (2H, d, J= 9.2 Hz), 7.31 (2H, d, J= 8.8 Hz), 7.31 (IH, d, J= 8.8 Hz), 7.63 (IH, d, J= 16.1 Hz), 7.80 (IH, dd, J= 8.4,2.6 Hz), 8.47 (IH, br) MS (ES+ ) m/z 521 (M+l )

Preparation 230 Ethyl (2E)-3-(6-{(tert-butoxycarbonyl) [(3R)-1-(2,2-dimethylpropyl)- 3-pyrrolidinyl]amino}-3-pyridyl)acrylate NMR (CDCl3, δ): 0.81 (9H, s), 1.35 (3H, t, J= 7.0 Hz), 1.44 (9H, s), 2.01 (IH, m), 2.17 (2H, br.), 2.66 (2H, br.), 2.88 (2H, br. ) , 4.28 (2H, q, J= 7.0 Hz), 4.86 (IH, br.), 6.46 (IH, d, J= 16.1 Hz), 7.31 (IH, d, J= 8.4 Hz), 7.66 (IH, d, J= 16.1 Hz), 7.81 (IH, dd, J= 8.1,2.2 Hz), 8.56 (IH, d, J= 2.2 Hz) MS (ES+) m/z 432 (M+l)

Preparation 231 To a solution of ethyl (2E)-3-(6-{(tert- butoxycarbonyl) [(3R)-1-(2-fluorobenzyl)-3-pyrrolidinyl]amino}-3- pyridyl)acrylate (2.40 g) in MeOH (10 mL) and dioxane (10 mL) was added IN NaOH aq solution (10.2 mL), and the mixture was stirred for 3 hours at ambient temperature. The pH value of the mixture was adjusted to 7 with IN HCl, and the solvent was removed in vacuo. Obtained solid was suspended in toluene and the residual water was geotropically removed to give (2E)-3-(6-{(tert- butoxycarbonyl) [(3R)-1-(3-fluorobenzyl)-3-pyrrolidinyl]amino}-3- pyridyl)acrylic acid and the crude product was used in next reaction without further purification. NMR (DMSO-de, <5 ): 1.36 (9H, s), 1.99 (IH, m), 2.12 (IH, m), 2.62 (IH, dd, J= 8.9,7.0 Hz), 2.74 (IH, t, J= 8.2 Hz), 3.46 (IH, d, J= 13.6 Hz), 3.58 (IH, d, J= 13.6 Hz), 4.76 (IH, m) , 6.66 (IH, d, J= 16.1 Hz), 6.95 (IH, m) , 7.03 (IH, m) , 7.29 (IH, m) , 7.32 (IH, m) , 7.33 (IH, d, J= 8.4 Hz), 7.62 (IH, d, J= 16.1 Hz), 8.16 (IH, dd, J= 8.4,2.6 Hz), 8.69 (IH, d, J= 2.2 Hz) MS (ES+) m/z 442 (M+l)

The following compounds were obtained according to a similar manner to that of Preparation 231.

Preparation 232 (2E)-3-(6-{(tert-Butoxycarbonyl) [(3R)-1-(3-methoxybenzyl)-3- pyrrolidinyl]amino}-3-pyridyl)acrylic acid NMR (DMSO-d6, <5 ) : 1.36 (9H, s), 1.96 (IH, m) , 2.12 (IH, m) , 2.62 (IH, m), 2.77 (IH, m) , 3.45 (IH, d, J= 17.5 Hz), 3.53 (IH, d, J= 17.5 Hz), 3.71 (3H, s), 4.75 (IH, m) , 6.66 (IH, d, J= 16.1 Hz), 6.76 (3H, m), 7.16 (IH, t, J= 8.1 Hz), 7.33 (IH, d, J= 8.4 Hz), 7.63 (IH, d, J= 15.8 Hz), 8.16 (IH, dd, J= 8.4,2.2 Hz), 8.69 (IH, d, J= 2.2 Hz) MS (ES+) m/z 454 (M+l)

Preparation 233 (2E)-3-(6-{(tert-Butoxycarbonyl) [(3R)-1-(3-phenylpropyl)-3- pyrrolidinyl]amino}-3-pyridyl)acrylic acid NMR (DMSO-d6, <5 ) : 1.37 (9H, s), 1.62 (2H, m), 1.93 (IH, m) , 2.06 (IH, m), 2.27 (IH, m) , 2.29 (2H, m) , 2.55 (IH, m) , 2.79 (2H, m) , 4.73 (IH, m), 6.61 (IH, d, J= 16.1 Hz), 7.15 (3H, m) , 7.24 (2H, m), 7.32 (IH, d, J= 8.4 Hz), 7.52 (IH, d, J= 16.1 Hz), 8.12 (IH, d, J= 8.4,2.2 Hz), 8.66 (IH, d, J= 2.2 Hz) MS (ES+) m/z 452 (M+l)

Preparation 234 (2E)-3-[6-((tert-Butoxycarbonyl){(3R)-l-[4-(dimethylamino)be nzyl]- 3-pyrrolidinyl}amino)-3-pyridyl]acrylic acid NMR (DMSO-de, <5 ) : 1.37 (9H, s), 2.03 (IH, m) , 2.24 (IH, m) , 2.89 (6H, s), 4.00 (2H, br) , 4.90 (IH, m) , 6.66 (IH, d, J= 16.1 Hz), 6.69 (2H, d, J= 8.4 Hz), 7.25 (2H, d, J= 8.4 Hz), 7.38 (IH, d, J= 8.1 Hz), 7.63 (IH, d, J= 16.1 Hz), 8.19 (IH, dd, J= 8.1,2.2 Hz), 8.66 (IH, d, J= 2.2 Hz) MS (ES+) m/z 467 (M+l)

Preparation 235 (2E)-3-(6-{(tert-Butoxycarbonyl) [ (3R)-1-(2-methoxybenzyl)-3- pyrrolidinyl]amino}-3-pyridyl)acrylic acid NMR (DMSO-dβ, <5 ) : 1.34 (9H, s), 1.93 (IH, m) , 2.09 (IH, m) , 2.61 (IH, m), 2.72 (IH, m) , 3.43 (IH, d, J= 14.3 Hz), 3.52 (IH, d, J= 14.3 Hz), 3.72 (3H, s), 4.69 (IH, m) , 6.48 (IH, d, J= 16.1 Hz), 6.82 (IH, t, J= 8.1 Hz), 6.91 (IH, d, J= 8.1 Hz), 7.01 (IH, d, J= 8.1 Hz) , 7.09 (IH, d, J= 16.1 Hz) , 7.19 (2H, m) , 7.93 ( IH, dd, J= 8.4 , 2.2 Hz) , 8.49 ( IH, d, J= 2.2 Hz) MS (ES+) m/z 454 (M+l)

Preparation 236 (2E)-3-(6-{(tert-Butoxycarbonyl) [ (3R)-1-(2-fluorobenzyl)-3- pyrrolidinyl]amino}-3-pyridy1)acrylic acid NMR (DMSOd6, <5): 1.35 (9H, s), 1.96 (IH, br), 2.10 (IH, br) , 2.61 (IH, br), 2.81 (IH, br), 3.46 (IH, m) , 3.58,(IH, m), 4.73 (IH, br), 6.66 (IH, d, J= 16.1 Hz), 7.13 (2H, m), 7.25 (2H, m) , 7.33 (IH, d, J= 8.4 Hz), 7.62 (IH, d, J= 16.1 Hz), 8.15 (IH, dd, J= 8.4,2.2 Hz), 8.67 (IH, d, J= 2.2 Hz) MS (ES+) m/z 442 (M+l)

Preparation 237 (2E)-3-(6-{(tert-Butoxycarbonyl)[(3R)-1-(2-quinolinylmethyl) -3- pyrrolidinyl]amino}-3-pyridyl)acrylic acid NMR (DMSO-dg, 6): 1.40 (9H, s), 2.09 (IH, m), 2.35 (IH, m) , 3.16 (2H, br), 4.50 (2H, br) , 5.04 (IH, br),6 .67 (IH, d, J= 16.1 Hz), 7.44 (IH, d, J= 8.4 Hz), 7.64 (IH, d, J= 16.1 Hz), 7.64 (2H, m) , 7.79 (IH, t, J= 7.7 Hz), 8.00 (3H, m) , 8.21 (IH, dd, J= 8.4,2.2 Hz), 8.43 (IH, d, J= 8.1 Hz), 8.71 (IH, s) MS (ES+) m/z 475 (M+l)

Preparation 238 (2E)-3-(6-{(tert-Butoxycarbonyl) [(3R)-1-(3-isoquinolinylmethyl)-3- pyrrolidinyl]amino}-3-pyridyl)acrylic acid NMR (DMSO-d6, <5 ) : 1.35 (9H, s), 2.00 (IH, m), 2.14 (IH, m) , 2.58 (2H, m), 2.67 (IH, m) , 2.84 (IH, m) , 3.68 (IH, d, J= 13.9 Hz), 3.78 (IH, d, J= 13.9 Hz), 4.77 (IH, m) , 6.65 (IH, d, J= 16.1 Hz), 7.33 (IH, d, J= 8.4 Hz), 7.58 (IH, t, J= 7.7 Hz), 7.61 (IH, d, J= 16.1 Hz), 7.72 (IH, t, J= 8.1 Hz), 7.93 (IH, d, J= 8.4 Hz), 7.99 (IH, d, J= 8.4 Hz), 8.10 (IH, s), 8.15 (IH, dd, J= 8.4,2.2 Hz), 8.66 (IH, d, J= 2.2 Hz), 8.74 (IH, d, J= 2.2 Hz) MS (ES+) m/z 475 (M+l)

Preparation 239 (2E)-3-[6-((tert-Butoxycarbonyl){(3R)-1-[(5-methyl-2- thienyl)methyl]-3-pyrrolidinyl}amino)-3-pyridyl]acrylic acid NMR (DMSO-d6, <5): 1.36 (9H, s), 1.94. (IH, m) , 2.08 (IH, m) , 2.37 (3H, s), 2.58 (IH, m), 2.82 (IH, m), 3.57 (IH, d, J= 13.5 Hz), 3.65 (IH, d, J= 13.5 Hz)," 4.72 (IH, m) , 6.58 (IH, m) , 6.65 (IH, d, J= 2.9 Hz), 6.66 (IH, d, J= 16.1 Hz), 7.32 (IH, d, J= 8.4 Hz), 7.61 (IH, d, J= 16.1 Hz), 8.15 (IH, d, J= 8.4,2.2 Hz), 8.68 (IH, d, J= 2.2 Hz) MS (ES+) m/z 444 (M+l)

Preparation 240 (2E)-3-[6-((tert-Butoxycarbonyl){(3R)-I-[ (5-methyl-2-furyl)methyl]- 3-pyrrolidinyl}amino)-3-pyridyl]acrylic acid NMR (DMSO-d6, δ): 1.37 (9H, s), 1.97 (4H, m) , 2.15 (4H, m) , 2.23 (3H, s), 2.90 (2H, br) , 3.85 (2H, br) , 4.82 (IH, m) , 6.04 (IH, br) , 6.28 (IH, br), 6.67 (IH, d, J= 16.1 Hz),7 .37 (IH, d, J= 8.4 Hz), 7.62 (IH, d, J= 16.1 Hz), 8.18 (IH, dd, J= 8.4,2.2 Hz) , 8.67 (IH, d, J= 2.2 Hz), MS (ES+) m/z 428 (M+l)

Preparation 241 (2E)-3-{6-[(tert-Butoxycarbonyl) ((3R)-l-{(2E)-3-[4- (dimethylamino)phenyl]-2-propen-l-yl}-3-pyrrolidinyl)amino]- 3- pyridyl}acrylic acid NMR (DMSO^d6, <5 ) : 1.40 (9H, s), 2.07 (IH, m) , 2.28 (IH, m) , 2.92 (6H, s), 3.17 (2H, d), 3.81 (2H, br) , 5.00 (IH, br), 6.04 (IH, m) , 6.65 (IH, d, J= 16.1 Hz), 6.69 (IH, d, J= 8.1 Hz), 6.69 (2H, d, J= 8.1 Hz), 7.30 (2H, d, J= 8.1 Hz), 7.43 (IH, d, J= 8.4 Hz), 7.61 (IH, d, J= 16.1 Hz), 8.20 (IH, br.d, J= 8.4 Hz),8.68 (IH, br) MS (ES+) m/z 493 (M+l)

Preparation 242 (2E)-3-(6-{(tert-Butoxycarbonyl) [ (3R)-1-(2,2-diinethylpropyl)-3- pyrrolidinyl]amino}-3-pyridyl)acrylic acid NMR (DMSO-de, <5 ) : 0.75 (9H, s), 1.37 (9H, s), 1.94 (IH, m) , 2.05 (IH, m), 2.07 (IH, d, J= 13.1 Hz), 2.15 (IH, d, J= 13.1 Hz), 2.58 (2H, m), 2.77 (2H, m) , 4.73 (IH, m) , 6.64 (IH, d, J= 16.1 Hz), 7.33 ( IH, d, J= 8.4 Hz ) , 7.60 ( IH, d, J= 16 . 1 Hz ) , 8. 15 ( IH, dd, J= 8.4.2.2 Hz ) , 8. 70 ( IH, d, J= 2 .2 Hz ) MS (ES+ ) m/z 404 (M+l )

Prepaxation 243 To a solution of (2E)-3-(6-{(tert-butoxycarbonyl) [(3R)-l-(3- fluorobenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylic acid (2.25 g, crude) in DMF (23 mL) was added was added 0-(tetrahydro-2H-pyran-2- yl)hydroxylamine (776mg), HOBt (1.03 g), and EDCI (1.19 g) and the resulting mixture was stirred at ambient temperature for 3 hours. The reaction mixture was diluted with water and extracted with AcOEt. The organic phase was washed with sat NH4Cl aq solution, sat NaHCO3 aq solution, and brine, and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography eluted with AcOEt to give tert-butyl [(3R)-I- (3-fluorobenzyl)-3-pyrrolidinyl] (5-{(IE)-3-oxo-3-[(tetrahydro-2H- pyran-2-yloxy)amino]-l-propen-l-yl}-2-pyridyl)carbamate (2.51 mg) as pale yellow form. NMR (CDCl3, δ): 1.44 (9H, s), 1.63 (3H, br) , 1.87 (3H, br) , 2.08 (IH, m), 2.23 (IH, m), 2.63 (2H, t, J= 7.3 Hz), 2.73 (IH, dd, J= 9.2.7.3 Hz), 2.88 (IH, t, J= 8.0 Hz), 3.51 (IH, d, J= 13.2 Hz), 3.62 (IH, d, J= 13.2 Hz), 3.67 (IH, m) , 3.99 (IH, m) , 4.90 (IH, m) , 5.05 (IH, br), 6.41 (IH, br) , 6.91 (2H, m) , 6.98 (IH, m) , 7.21 (IH, m), 7.27 (IH, m) , 7.70 (IH, d, J= 16.1 Hz), 7.78 (IH, dd, J= 8.8,2.2 Hz), 8.56 (IH, d, J= 2.2 Hz) MS (ES+) m/z 541 (M+l)

The following compounds were obtained according to a similar manner to that of Preparation 243.

Preparation 244 tert-Butyl [(3R)-1-(3-methoxybenzyl)-3-pyrrolidinyl] (5-{(IE)-3-oxo- 3-[ (tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2- pyridyl)carbamate NMR (CDCl3, δ ) : 1.44 (9H, s), 1.64 (3H, br), 1.87 (3H, br) , 2.08 (IH, m), 2.25 (IH, m) , 2.70 (3H, br) , 2.97 (IH, br) , 3.63 (2H, m) , 3.70 (IH, m), 3.98 (IH, m) , 4.91 (IH, m) , 5.03 (IH, br) , 6.40 (IH, br) , 6.78 ( IH, br. d, J= 8.4 Hz ) , 6 .83 ( 2H, br. d, J= 7.0 Hz ) , 7 . 19 ( IH, t , J= 7.7 Hz ) , 7 .28 ( IH, d, J= 7 .7 Hz ) , 7 . 69 ( IH. d, J= 16. 1 Hz ) , 7 .77 ( IH, dd, J= 8.4 and 2. 2 Hz ) , 8 .55 ( IH, d, J= 2.0 Hz ) MS (ES+) m/z 553 (M+l)

Preparation 245 tert-Butyl (5-{(IE)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-l- propen-1-yl}-2-pyridyl) [ (3R)-1-(3-phenylpropyl)-3- pyrrolidinyl]carbamate NMR (CDCl3, <5): 1.45 (9H, s), 1.63 (3H, br) , 1.82 (2H, br) , 1.86 (3H, br), 2.03 (IH, br) , 2.23 (IH, br) , 2.51 (2H, br) , 2.60 (IH, m) , 2.73 (2H, br), 3.05 (IH, br) , 3.69 (IH, m) , 3.97 (IH, m) , 4.91 (IH, m), 5.02 (IH, br), 6.31 (IH, br) , 7.17 (3H, m) , 7.27 (2H, m) , 7.29 (IH, d, J= 8.4 Hz), 7.68 (IH, d, J= 16.1 Hz), 7.77 (IH, dd, J= 8.4 and 2.2 Hz), 8.55 (IH, br) MS (ES+) m/z 551 (M+l)

Preparation 246 tert-Butyl {(3R)-l-[4-(dimethylamino)benzyl]-3-pyrrolidinyl}(5- {(lE)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-l-propen- l-yl}- 2-pyridyl)carbamate NMR (CDCl3, <5): 1.44 (9H, s), 1.63 (3H, br) , 1.87 (3H, br) , 2.08 (IH, br), 2.28 (IH, br) , 2.78 (3H, br) , 2.93 (3H, s), 3.07 (IH, br) , 3.63 (2H, br), 3.68 (IH, m) , 3.99 (IH, m), 4.94 (IH, br), 5.04 (IH, br), 6.44 (IH, br) , 6.67 (IH, d, J= 8.1 Hz), 7.16 (2H, br.d, J= 7.0 Hz), 7.28 (IH, d, J= 8.4 Hz), 7.68 (IH, d, J= 16.1 Hz), 7.75 (IH, d, J= 8.4 Hz), 8.52 (IH, s) MS (ES+) m/z 566 (M+l)

Preparation 247 tert-Butyl [ (3R)-l-(2-methoxybenzyl)-3-pyrrolidinyl] (5-{(lE)-3-oxo- 3-[ (tetrahydro-2H-pyran-2-yloxy)amino]-l-propen-l-yl}-2- pyridyl)carbamate NMR (CDCl3, (5): 1.44 (9H, s), 1.63 (3H, br) , 1.86 (3H, br) , 2.05 (IH, br), 2.26 (IH, br) , 2.68 (IH, br) , 2.77 (2H, br), 3.03 (IH, br), 3.68 (2H, br) , 3.80 (2H, s), 3.97 (IH, m) , 4.92 (IH, m) , 5.03 (IH, br), 6.43 (IH, br) , 6.84 (IH, d, J= 8.1 Hz),_ 6.88 (IH, t, J= 7.4 Hz ) , 7 .22 ( 2H, m) , 7.29 ( IH, d, J= 8.8 Hz ) , 7.69 ( IH, d, J= 16. 1 Hz ) , 7. 75 ( IH, d, J= 8. 1 Hz ) , 8. 53 ( IH, s ) MS (ES+ ) m/z 553 (M+l )

Preparation 248 tert-Butyl [ (3R)-l-(2-fluorobenzyl)-3-pyrrolidinyl] (5-{(lE)-3-oxo- 3-[(tetrahydro-2H-pyran-2-yloxy)amino]-l-propen-l-yl}-2- pyridyl)carbamate NMR (CDCl3, δ): 1.43 (9H, s), 1.63 (3H, br) ,, 1.86 (3H, br) , 2.05 (IH, m), 2.23 (IH, m) , 2.72 (3H, m) , 2.99 (IH, m) , 3.64 (IH, d, J= 12.8 Hz), 3.69 (IH, d, J= 12.8 Hz), 3.71 (IH, m), 4.91 (IH, m) , 5.04 (IH, s), 6.43 (IH, br) , 7.00 (IH, t, J= 8.4 Hz), 7.07 (IH, d, J= 7.7 Hz), 7.24 (2H, m) , 7.28 (IH, d, J= 8.4 Hz), 7.68 (IH, d, J= 16.1 Hz), 7.75 (IH, dd, J= 8.4,2.2 Hz), 8.52 (IH, d, J= 2.2 Hz) MS (ES+) m/z 541 (M+l)

Preparation 249 tert-Butyl (5-{(IE)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1- propen-l-yl}-2-pyridyl) [ (3R)-1-(2-quinolinylmethyl)-3- pyrrolidinyl]carbamate ' " NMR (CDCl3, δ): 1.45 (9H, s), 1.63 (3H, br) , 1.87 (3H, br) , 2.12 (IH, br), 2.29 (IH, br) , 2.74 (IH, br) , 2.80 (IH, br) , 3.04 (IH, br),3.68 (IH, m) , 3.94 (2H, d) , 3.98 (IH, m) , 4.96 (IH, br) , 5.03 (IH, br), 6.36 (IH, br) , 7.29 (IH, d, J= 8.4 Hz), 7.46 (IH, m) , 7.53 (IH, d, J= 8.1 Hz), 7.69. (2H, m) , 7.78 (2H, m) , 8.07 (2H, m),8.55 (IH, br) MS (ES+) m/z 574 (M+l)

Preparation 250 tert-Butyl [ (3R)-1-(3-isoquinolinylmethyl)-3-pyrrolidinyl] (5-{(IE)- 3-OXO-3-[ (tetrahydro-2H-pyran-2-yloxy)amino]-l-propen-l-yl}-2- pyridyl)carbamate NMR (CDCl3, δ): 1.43 (9H, s)., 1.64 (3H, br) , 1.86 (3H, br) , 2.09 (IH, m), 2.25 (IH, m) , 2.70 (2H, m) , 2.82 (IH, m) , 2.94 (IH, m) , 3.67 (IH, m), 3.73 (IH, d, J= 13.6 Hz), 3.82 (IH, d, J= 13.6 Hz), 3.99 (IH, m), 4.92 (IH, m) , 5.05 (IH, br) , 6.48 (IH, br) , 7.25 (IH, d, J= 7.5 Hz), 7.54 (lH, t, J= 7.5 Hz), 7.69 (2H, m) , 7.76 (2H, m) , 8.00 ( IH, br) , 8. 10 ( IH, d, J= 8.8 Hz ) , 8. 51 ( IH, br) , 8.80 ( IH, dd, J= 1.8 Hz) MS (ES+) m/z 574 (M+l)

5 Preparation 251 tert-Butyl {(3R)-1-[(5-methyl-2-thienyl)methyl]-3-pyrrolidinyl}(5- {(IE)-3-OXO-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen- l-yl}- 2-pyridyl)carbamate NMR (CDCl3, δ): 1.44 (9H, s), 1.64 (3H, br) , 1.87 (3H, br) , 2.05 10 (IH, m), 2.22 (IH, m) , 2.64 (IH, m) , 2.74 (2H, m) , 3.01 (IH, t), 3.66 (IH, m), 3.69 (IH, d, J= 13.6 Hz), 3.75 (IH, d, J= 13.2 Hz), 3.98 (IH, m), 4.90 (IH, m) , 5.03 (IH, br) , 6.43 (IH, br) , 6.54 (IH, d, J= 2.9 Hz), 6.64 (IH, d, J= 3.3 Hz), 7.30 (IH, d, J= 8.4 Hz), 7.69 (IH, d, J= 16.1 Hz), 7.77 (IH, d, J= 8.4,2.6 Hz) ,8.55 (IH, br) , 15 MS (ES+) m/z 543 (M+l)

Preparation 252 tert-Butyl {(3R)-1-[(5-methyl-2-furyl)methyl]-3-pyrrolidinyl}(5- {(lE)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-l-propen- l-yl}- 20 2-pyridyl)carbamate NMR (CDCl3, 6): 1.45 (9H, s) , 1.63 (3H, br) , 1.86 (3H, br) , 2.03 (IH, m), 2.22 (IH, m), 2.26 (3H, s), 2.59 (IH, q, J= 8.4 Hz), 2.69 (IH, t, J= 8.6 Hz), 2.82 (IH, m) , 3.11 (IH, t, J= 8.4 Hz), 3.55 (IH, d, J= 13.9 Hz), 3.62 (IH, d, J= 13.6 Hz), 3.66 (IH, m) , 3.98 (IH, 25 m), 4.92 (IH, m) , 5.03 (IH, br), 5.86 (IH, dd, J= 2.9,1.0 Hz), 6.03 (IH, d, J= 2.9 Hz), 6.40 (IH, br) , 7.30 (IH, d, J= 8.4 Hz), 7.68 (IH, d, J= 15.4 Hz), 7.76 (IH, dd, J= 8.4 and 2.2 Hz), 8.53 (IH, d, J= 2.2 Hz) MS (ES+) m/z 527 (M+l) 30 Preparation 253 tert-Butyl ((3R)-l-{(2E)-3-[4-(dimethylamino)phenyl]-2-propen-1- yl}-3-pyrrolidinyl) (5-{(IE)-3-oxo-3-[ (tetrahydro-2H-pyran-2- yloxy)amino]-l-propen-l-yl}-2-pyridyl)carbamate ,35 NMR (CDCl3, <5 ) : 1.45 (9H, s), 1.62 (3H, br) , 1.85 (3H, br) , 2.05 (IH, br), 2.26 (IH, br), 2.69 (IH, br), 2.86 (2H, br), 3.18 (IH, br), 3.28 (2H, br) , 3.66 (IH, m), 3.98 (IH, m), 4.93 (IH, m), 5.02 (IH, br), 6.06 (IH, dt, J= 15.8 and 6.6 Hz), 6.43 (IH, d, J= 15.4 Hz), 6.54 (IH, br), 6.67 (2H, d, J= 8.8 Hz), 7.25 (2H, d, J= 8.1 Hz), 7.29 (IH, d, J= 8.4 Hz), 7.67 (IH, d, J= 16.1 Hz), 7.76 (IH, d, J= 8.4 Hz), 8.53 (IH, s) MS (ES+) m/z 592 (M+l)

Preparation 254 tert-Butyl [(3R)-1-(2,2-dimethylpropyl)-3-pyrrolidinyl] (5-{(IE)-3- oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-l-propen-l-yl}-2- pyridyl)carbamate NMR (CDCl3, 6): 0.81 (9H, s) , 1.44 (9H, s), 1.62 (3H, br) , 1.86 (3H, br), 2.01 (IH, m) , 2.17 (3H, m) , 2.67 (2H, m) , 2.88 (2H, m) , 3.67 (IH, m), 3.97 (IH, m), 4.86 (IH, m), 5.03 (IH, br) , 6.41 (IH, br), 7.30 (IH, d, J= 8.4 Hz), 7.71 (IH, br.d, J= 15.8 Hz), 7.78 (IH, d, J= 8.1 Hz), 8.58 (IH, s), MS (ES+) m/z 503 (M+l)

Preparation 255 To a solution of ethyl (2E)-3-(4-bromophenyl)acrylate(300 mg) in toluene (3 mL) was added palladium(II) acetate (26.4 mg) , (R)-(+)-2,2I-bis(diphenylphosphino)-l,l'-binaphthyl (110 mg) , cesium carbonate (583 mg) , and (3R)-l-(4~chlorobenzoyl)-3- pyrrolidinamine (291 mg) . The mixture was heated at 90°C for 2 days. The resulting mixture was poured into sat.NH4Cl aq solution and extracted with AcOEt. The organic layer was washed with sat. NH4Cl aq solution, water, and brine, and dried over Na2SO4. The solvent was removed in vacuo and residual brown oil was purified by preparative thin layer chromatography (chloroform : methanol = 95 : 5) to give ethyl (2E)~3-(4-{[ (3R)-l-(4-chlorobenzoyl)-3- pyrrolidinyl]amino}phenyl)aerylate (297 mg) as pale yellow form. NMR (CDCl3, 6): 1.33 (3H, t, J= 7.1 Hz), 2.00 (IH, m) , 2.23 (0.5H, m), 2.36 (0.5H, m) , 3.35 (0.5H, m) , 3.60 (1.5H, m) , 3.81 (IH, m) , 4.03 (IH, m), 4.10 (IH, m) , 4.24 (2H, q, J= 7.1 Hz), 6.22 (0.5H, d, J= 15.8 Hz), 6.24 (0.5H, d, J= 15.8 Hz), 6.51 (IH, d, J= 8.4 Hz), 6.62 (IH, d, J= 8.1 Hz), 7.33-7.62 (7H, m) MS (ES+) m/z 399 (M+l) Preparation 256 To a solution of ethyl (2E)-3-(4-{ [ (3R)-l-(4-chlorobenzoyl)- 3-pyrrolidinyl]amino}phenyl)acrylate (297 mg) in dioxane (3 mL) was added IN NaOH aq solution (2.23 mL) , and the mixture was heated at 70°C for 18 hours. Resulting mixture was diluted with water and washed with ether. The pH value of aqueous phase was adjusted to 5, and the precipitate was collected by filtration and dried in vacuo to give (2E)-3-(4-{[(3R)-I-(4-chlorobenzoyl)-3- pyrrolidinyl]amino}phenyl)acrylic acid (103 mg) as pale yellow powder. NMR (DMSO-d6, <5 ) : 1.88 (IH, m) , 2.19 (IH, m) , 3.25 (IH, m) , 3.43 (IH, m), 3.59 (IH, m) , 3.79 (IH, m) , 4.07 (IH, m) , 6.14 (0.5H, d, J= 16.1 Hz), 6.18 (0.5H, d, J= 16.1 Hz), 6.57 (IH, d, J= 8.8 Hz), 6.64 (IH, d, J= 8.8 Hz), 7.36-7.47 (2H, m) , 7.5O1(IH, s), 7.53 (2H, d, J= 8.1 Hz), 7.57 (2H, d, J= 8.1 Hz), 7.93 (IH, d, J= 8.4 Hz) MS (ES+) m/z 371 (M+l)

Preparation 257 To a solution of (2E)-3-(4-{[ (3R)-I-(4-chlorobenzoyl)-3- pyrrolidinyl]amino}phenyl)acrylic acid (103 mg) in DMF (2 mL) was added O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (35.8 mg), HOBt (48.8 mg) , and EDCI (56.1 mg) and the resulting mixture was stirred at ambient temperature for 3 hours. The reaction mixture was diluted with water and extracted with AcOEt. The organic phase was washed with sat NH4Cl aq solution, sat NaHCO3 aq solution, and brine, and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by preparative thin layer chromatography (chloroform : methanol = 10 : 1) to give (2E)-3-(4-{[ (3R)-I-(4-chlorobenzoyl)-3- pyrrolidinyl]amino}phenyl)-N-(tetrahydro-2H-pyran-2- yloxy)acrylamide (76 mg) as pale yellow form. NMR (DMSO-de, <5 ) : 1.54 (3H, br) , 1.68 (3H, br), 1.89 (IH, br) , 2.19 (IH, br), 3.24 (IH, br) , 3.53 (3H, br) , 3.79 (IH, m) , 3.95 (IH, br), 4.07 (IH, br) , 4.87 (IH, br) , 6.17 (IH, br) , 6.44 (0.5H, d, J= 16.1 Hz), 6.46 (0.5H, d, J= 16.1 Hz), 6.57 (IH, d, J= 8.8 Hz), 6.65 (IH, d, J= 8.4 Hz), 7.26-7.37 (3H, m) , 7.47-7.58 (4H, m) MS (ES+) m/z 470 (M+l) Preparation 258 To a solution of ethyl (2E)-3-(6-chloro-3- pyridyl)aerylate(3.5 g) in dioxane (70 mL) was added palladium(II) acetate (371 mg) and 2'-(dicyclohexylphosphino)-N,N-dimethyl-2- biphenylamine (110 mg) and cesium carbonate (583 mg) , and (3R)-I- (4-chlorobenzoyl)-3-pyrrolidinamine (4.09 g) . The mixture was heated at 90°C for 3 hours. The resulting mixture was diluted with AcOEt, and the precipitate was removed by filtration. The filtrate was concentrated and residual brown oil was purified by purified by silica gel column chromatography eluted with AcOEt and hexane (l:4)-AcOEt to give ethyl (2E)-3-(6.-{[(3R)-l-(4-chlorobenzoyl)-3- pyrrolidinyl]amino}-3-pyridyl)acrylate (2.16 g) as dark yellow form. NMR (CDCl3, δ): 1.33 (3H, t, J= 7.0 Hz), 2.01 (IH, m) , 2.35 (IH, m), 3.37 (0.5H, dd, J= 11.0,5.5 Hz), 3.60 (1.5H, m) , 3.78 (0.5H, m), 3.88 (IH, m), 4.04 (0.5H, m) , 4.25 (2H, q, J= 7.0 Hz), 4.53 (IH, m) , 4.77 (0.5H, d, J= 6.9 Hz), 4.89 (0.5H, d, J= 6.6 Hz), 6.22 (0.5H, d, J= 16.1 Hz), 6.26 (0.5H, d, J= 16.1 Hz), 6.38 (0.5H, d, J= 8.4 Hz), 6.46 (0.5H, d, J= 8.8 Hz), 7.38 (2H, m) , 7.48 (2H, m) , 7.62 (2H, m) , 8.16 (0.5H, s), 8.23 (0.5H, s) MS (ES+) m/z 400 (M+l)

The following compounds were obtained according to a similar manner to that of Preparation 258.

Preparation 259 Ethyl (2E)-3-(6-{[(3S)-l-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-3 - pyridyl)acrylate NMR (CDCl3, <5): 1.33 (3H, t, J= 7.0 Hz), 2.01 (IH, m) , 2.35 (IH, m), 3.37 (0.5H, dd, J= 11.0,5.5 Hz), 3.60 (1.5H, m) , 3.78 (0.5H, m) , 3.88 (IH, m), 4.04 (0.5H, m) , 4.25 (2H, q, J= 7.0 Hz), 4.53 (IH, m) , 4.77 (0.5H, d, J= 6.9 Hz), 4.89 (0.5H, d, J= 6.6 Hz), 6.22 (0.5H, d, J= 16.1 Hz), 6.26 (0.5H, d, J= 16.1 Hz), 6.38 (0.5H, d, J= 8.4 Hz), 6.46 (0.5H, d, J= 8.8 Hz), 7.38 (2H, m) , 7.48 (2H, m) , 7.62 (2H, m) , 8.16 (0.5H, s), 8.23 (0.5H, s) MS (ES+) m/z 400 (M+l) Preparation 260 To a solution of ethyl (2E)-3-(6-{[(3R)-I-(4-chlorobenzoyl)- 3-pyrrolidinyl]amino}-3-pyridyl)acrylate (2.16 g) in MeOH (30 mL) and dioxane (30 mL) was added IN NaOH aq solution (27.1 mL). The mixture was heated at 70°C for 1.5 hour and diluted with water (12OmL) and washed with ether. The pH value of aqueous phase was adjusted to 5.5, and the precipitate was collected by filtration and dried in vacuo to give (2E)-3-(6-{[ (3R)-I-(4-chlorobenzoyl)-3- pyrrolidinyl]amino}-3-pyridyl)acrylic acid (1.58 g) as pale yellow powder. NMR (DMSO-d6, δ ) : 1.93 (IH, m) , 2.20 (IH, m) , 3.25-3.72 (4H, m) , 3.80 (IH, m), 4.37 (0.5H, m) , 4.50 (0.5H, m) , 6.24 (0.5H, d, J= 16.1 Hz), 6.27 (0.5H, d, J= 15.8 Hz), 6.52 (0.5H, d, J= 8.9 Hz), 6.57 (0.5H, d, J= 9.1 Hz), 7.39-7.60 (5H, m) , 7.77 (0.5H, dd, J= 9.1,2.2 Hz), 7.82 (0.5H, dd, J= 9.1,2.2 Hz), 8.15 (0.5H, d, J= 2.2 Hz), 8.25 (0.5H, d, J= 1.8 Hz) MS (ES+) m/z 372 (M+l)

The following compounds were obtained according to a similar manner to that of Preparation 260.

Preparation 261 (2E)-3-(6-{[(3S)-1-(4-Chlorobenzoyl)-3-pyrrolidinyl]amino}-3 - pyridyl)acrylic acid NMR (DMSO-de, <5 ) : 1-93 (IH, m) , 2.20 (IH, m) , 3.25-3.72 (4H, m) , 3.80 (IH, m), 4.37 (0.5H, m) , 4.50 (0.5H, m) , 6.24 (0.5H, d, J= 16.1 Hz), 6.27 (0.5H, d, J= 15.8 Hz), 6.52 (0.5H, d, J= 8.9 Hz), 6.57 (0.5H, d, J= 9.1 Hz), 7.39-7.60 (5H, m) , 7.77 (0.5H, dd, J= 9.1,2.2 Hz), 7.82 (0.5H, dd, J= 9.1,2.2 Hz), 8.15 (0.5H, d, J= 2.2 Hz), 8.25 (0.5H, d, J= 1.8 Hz) MS (ES+) m/z 372 (M+l)

Preparation 262 To a solution of (2E)-3-(6-{ [(3R)-I-(4-chlorobenzoyl)-3- pyrrolidinyl]amino}-3-pyridyl)acrylic acid (1.58 g) in DMF (16 mL) was added O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (546 mg) , HOBt (744 mg) , and EDCI * HCl (1.06 mg) and the resulting mixture was stirred at ambient temperature for 4 hours. The reaction mixture was diluted with water and extracted with AcOEt. The organic phase was washed with sat NH4Cl aq solution and sat NaHCO3 aq solution, and brine, and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography eluted with chloroform : methanol = 97.5 : 2.5 to give. (2E)-3-(6- {[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-3-pyridyl)- N- (tetrahydro-2H-pyran-2-yloxy)acrylamide (1.89 g) as colorless oil. NMR (DMSO-de, <5 ) : 1.53 (brH, ), 1.69 (brH, ),1 .92 (πtH, ), 2.19 (mH, ), 3.23-3.70 (mH, ), 3.80 (mH, ), 3.95 (mH, ), 4.36 (mH, ), 4.49 (mH, ), 4.87 (brH, ), 6.22 (dH, 16.1), 6.25 (dH, 16.1), 6.52 (dH, 8.8), 6.56 (dH, 9.1), 7.36 (mH, ), 7.47-7.66 (mH, ), 8.11 (SH, ), 8.20 CsH, ) MS (ES+) m/z 471 (M+l)

The following compounds were obtained according to a similar manner to that of Preparation 262.

Preparation 263 (2E)-3-(6-{[(3S)-l-(4-Chlorobenzoyl)-3-pyrrolidinyl]amino}-3 - pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide NMR (DMSO-de, ^): 1.53 (3H, br) , 1.69 (3H, br) , 1.92 (IH, m) , 2.19 (IH, m), 3.23-3.70 (4H, m) , 3.80 (IH, m) , 3.95 (IH, m) , 4.36 (0.5H, m),4.49 (0.5H, m),4.87 (IH, br),6.22 (0.5H, d, J= 16.1 Hz), 6.25 (0.5H, d, J= 16.1 Hz), 6.52 (0.5H, d, J= 8.8 Hz), 6.56 (0.5H, d, J= 9.1 Hz), 7.36 (2H, m) , 7.47-7.66 (4H, m) , 8.11 (IH, s), 8.20 (IH, s) MS (ES+) m/z 471 (M+l)

Preparation 264 To a solution of ethyl (2E)-3-(4-bromophenyl)acrylate (1.0 g) in dioxane (70 mL) was added palladium(II) acetate (88 mg) , 2'- (dicyclohexylphosphino)-N,N-dimethyl-2-biphenylamine (231 mg) , cesium carbonate (1.79 g) , and (3R)-l-benzyl-3-pyrrolidinamine (760 mg) . The mixture was heated at 90°C for 24 hours. The resulting mixture was poured into sat NH4C1 aq solution and extracted with AcOEt. The organic layer was washed with sat. NH4Cl aq solution, water, and brine, and dried over Na2SO4. The solvent was removed in vacuo and residual brown oil was purified by silica gel column chromatography eluted with chloroform : methanol = 9 : 1 to give ethyl (2E)-3-(4-{[(3R)-l-benzyl-3- pyrrolidinyl]amino}phenyl)acrylate (1.017 g) as pale yellow oil. NMR (CDCl3, δ): 1.32 (3H^ t, J= 7.0 Hz), 2.33 (IH, m), 2.44 (IH, m), 2.56 (IH, m) , 2.78 (2H, m) , 3.63 (2H, s), 4.03 (IH, m) , 4.23 (2H, q, J= 7.0 Hz), 4.26 (IH, m) , 6.20 (IH, d, J= 15.8 Hz), 6.52 (2H, d, J= 8.8 Hz), 7.32 (7H, m) , 7.58 (IH, d, J= 15.8 Hz) MS (ES+) m/z 351 (M+l)

Preparation 265 To a solution of ethyl (2E)-3-(4-{[ (3R)-l-benzyl-3- pyrrolidinyl]amino}phenyl)aerylate (1.017 g) in MeOH (3 mL) and dioxane (3 mL) was added IN NaOH aq solution (5.8 mL), and the mixture was stirred at ambient temperature for 2 hours. To the mixture was added IN NaOH aq solution (5.8 mL) and heated at 50°C for 2 hours. The pH value of the mixture was adjusted to 7 with IN HCl, and the solvent was removed in vacuo. Obtained solid was suspended in toluene arid the residual water was geotropically removed to give (2E)-3-(4-{[(3R)-l-benzyl-3- pyrrolidinyl]amino}phenyl).acrylic acid and the crude product was used in next reaction without further purification. NMR (DMSO-d6, <5 ) : 1.65 (IH, br) , 2.26 (IH, br) , 2.74 (IH, br) , 2.89 (IH, br), 3.43 (IH, br) , 3.69 (IH, br) , 3.97 (IH, br) , 4.10 (0.5H, br), 4.37 (0.5H, br) , 6.14 (IH, d, J= 15.8 Hz), 6.46 (IH, d, J= 5.9 Hz), 6.55 (2H, d, J= 8.4 Hz), 7.28 (IH, br), 7.37 (4H, m) , 7.42 (IH, d, J= 15.8 Hz), 7.04 (IH, m) MS (ES+) m/z 323 (M+l)

Preparation 266 To a solution of (2E)-3-(4-{[(3R)-l-benzyl-3- pyrrolidinyl]amino}phenyl)acrylic acid (936 mg, crude) in DMF (10 mL) was added was added 0-(tetrahydro-2H-pyran-2-yl)hydroxylamine (442 mg), HOBt (588 mg) , and EDCI (676 mg) and the resulting mixture was stirred at ambient temperature for 3 hours. The reaction mixture was diluted with water and extracted with AcOEt. The organic phase was washed with sat NH4Cl aq solution, sat NaHCO3 aq solution, and brine, and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by preparative thin layer chromatography (chloroform : methanol = 10 : 1) to give (2E)- 3-(4-{[(3R)-l-benzyl-3-pyrrolidinyl]amino}phenyl)-N-(tetrahy dro-2H- pyran-2-yloxy)acrylamide (945 mg) as pale yellow form. NMR (CDCl3, <5): 1.63 (3H, br), 1.85 (3H, br), 2.33 (IH, m) , 2.45 (IH, m), 2.59 (IH, dd, J= 9.9,3.3 Hz), 2.80 (IH, m) , 3.64 (2H, s), 2.64 (IH, m), 4.00 (IH, m) , 4.00 (IH, m),4 .29 (IH, d, J= 7.7 Hz), 4.99 (IH, s), 6.26 (IH, br) , 6.51 (IH, d, J= 8.4 Hz), 7.27 (IH, m),7.32 (6H, m),7.62 (IH, d, J= 15.8 Hz), MS (ES+) m/z 422 (M+l)

Preparation 267 To a solution of 3-methyl-2-pyridinamine (10 g) in a mixed solution of AcOH (60 mL), water (12 mL), and sulfuric acid ( 4.2 mL) was added periodic acid dihydrate (4.22 g) and iodine (9.39 g) , and the mixture was heated at 80°C for 2 hours. The reaction mixture was poured into 5% Na2S2O3 aq solution and extracted with ether. The organic layer was washed with IN NaOH aq solution and brine, and dried over Na2SO4. The solvent was removed in vacuo and obtained residual solid was recrystallized with EtOH to give 5- iodo-3-methyl-2-pyridinamine (9.00 g) as pale yellow powder. NMR (CDCl3, 6): 2.09 (3H, s), 4.95 (2H, br) , 7.54 (IH, m) , 8.03 (IH, m)

Preparation 268 To a suspension of 5-iodo-3-methyl-2-pyridinamine(7.0 g) in 47% hydrobromic acid was successively added bromine (2.31 mL) and aq solution of NaNO2 (5.16 g) , the temperature being kept below 0°C during addition. The reaction mixture was stirred for 1 hour at 5°C and warmed to ambient temperature. The reaction was continued for 4 hours at ambient temperature and the mixture was diluted with NaOH(18g in water 150 mL) and extracted with AcOEt. The organic phase was washed with 5% Na2S2O3 aq solution, water, and brine, and dried over Na2SO4. The solvent was removed in vacuo, and the residue was purified by silica gel column chromatography eluted with chloroform to give 2-bromo-5-iodo-3-methylpyridine(2.95 g) as pale yellow powder. NMR (CDCl3, δ): 2.36 (3H, s), 7.83 (IH, s); 8.41 (IH, s),

Preparation 269 To a solution of 2-bromo-5-iodo-3-methylpyridine (1.5 g) in DMF (15 mli) was added palladium(II) acetate (56.5 mg) and tri-o- tolylphosphine (230 mg) and diisopropylethylamine (3.5 mL), and ethyl aerylate (1.09 mL). The mixture was heated at 90*0 for lhour. Resulting mixture was poured into water and extracted with AcOEt. The organic layer was washed with water and brine, and dried over Na2SO4, and the solvent was removed in vacuo. Residual brown oil was purified by silica gel column chromatography eluted with AcOEt and hexane (1:4-1:2) to give ethyl (2E)-3-(6-bromo-5-methyl-3- pyridyl)aerylate (1.00 g) as pale yellow powder. NMR (CDCl3, δ): 1.35 (3H, t, J= 7.0 Hz), 2.43 (3H, s), 4.29 (2H, q, J= 7.0 Hz), 6.50 (IH, d, J= 16.1 Hz), 7.60 (IH, d, J= 16.1 Hz), 7.66 (IH, m), 8.33 (IH, m) MS (ES+) m/z 270 (M+l)

Preparation 270 To a solution of ethyl (2E)-3-(6-bromo-5-methyl-3- pyridyl)acrylate (500 mg) in dioxane (5 mL) was added palladium(II) acetate (41.6 mg) and 2'-(dicyclohexylphosphino)-N,N-dimethyl-2- biphenylamine (109 mg) and cesium carbonate (843 mg) , and (3R)-(-)- l-benzyl-3-aminopyrrolidine (359 mg). The mixture was heated at lOO'C for 18 hours. The resulting mixture was poured into sat.NH4Cl aqueous solution and extracted with AcOEt. The organic layer was washed with sat. NH4Cl aq solution, water, and brine, and dried over Na2SO4. The solvent was removed in vacuo and residual brown oil was purified by preparative thin layer chromatography (chloroform : methanol = 90 : 10) to give ethyl (2E)-3-(6-{[ (3R)-I- benzyl-3-pyrrolidinyl]amino}-5-methyl-3-pyridyl)acrylate (366 mg) as pale yellow oil. NMR (CDCl3, δ ) : 1.32 (3H, t, J= 7.0 Hz),1.72 (IH, m),2.10 (3H, s),2.38 (2H, m),2.72 (2H, m),2.95 (IH, m),6.67 (2H, s),4.24 (2H, q, J= 7.0 Hz),4.72 (IH, m),4.89 (IH, m),6.20 (IH, d, J= 16.1 Hz),7.33 ( 5H, m) , 7.42 ( IH, s ) , 7 . 56 ( IH, d, J= 16. 1 Hz ) , 8.09 ( IH, s ) MS (ES+) m/z 366 (M+l )

Preparation 271 To a solution of ethyl (2E)-3-(6-{[ (3R)-l-benzyl-3- . pyrrolidinyl]ainino}-5-methyl-3~pyridyl)acrylate (366 mg) in MeOH (2 mli) and dioxane (2 iriL) was added IN NaOH aq solution (2.0 mL), and the mixture was stirred at ambient temperature for 3 hours. The pH value of the mixture was adjusted to 7 with IN HCl, and the solvent was removed in vacuo. Obtained solid was suspended in toluene and the residual water was geotropically removed to give (2E)-3-(6-{[(3R)-l-benzyl-3-pyrrolidinyl]amino}-5-methyl-3- pyridyl)acrylic acid and the crude product was used in next reaction without further purification. NMR (DMSO-ds, <5 ) : 1.92 (IH, br) , 2.11 (3H, s), 2.26 (IH, br) , 2.60-2.89 (2H, br) , 2.97-3.23 (2H, br) , 3.85 (2H, br) , 4.59 (IH, br), 6.25 (IH, d, J= 16.1 Hz), 7.34 (5H, m) , 7.43 (IH, d, J= 16.1 Hz), 7.67 (IH, s), 8.08 (IH, s) MS (ES+) m/z 338 (M+l)

Preparation 272 To a solution of (2E)-3-(6-{ [(3R)-l-benzyl-3- pyrrolidinyl]amino}-5-methyl-3-pyridyl)acrylic acid (338 mg, crude) in DMF (4 mL) was added 0-(tetrahydro-2H-pyran-2-yl)hydroxylamine (153 mg), HOBt (203 mg), and EDCI (233 mg) and the resulting mixture was stirred at ambient temperature for 3 hours. The reaction mixture was diluted with water and extracted with AcOEt. The organic phase was washed with sat NH4Cl aq solution, sat NaHCO3 aq solution, and brine, and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by preparative thin layer chromatography (chloroform : methanol = 90 : 10) to give (2E)-3-(6-{[(3R)-l-benκyl-3-pyrrolidinyl]amino}-5-methyl-3- pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (306 mg) as pale yellow form. NMR (CDCl3, <5 ) : 1.67 (3H, br) , 1.85 (3H, br), 2.10 (3H, s), 2.39 (2H, m), 2.72 (2H, m) , 2.95 (IH, m) , 3.65 (IH, m) , 3.67 (2H, s), 4.72 (IH, m), 4.87 (IH, m) , 5.00 (IH, br) , 6.25 (IH, br) , 7.33 (5H, m) , 7.38 ( IH, s ) , 7.61 ( IH, d, J= 16 . 1 Hz) , 8. 11 ( IH, s ) MS (ES+ ) m/z 437 (M+l )

The following compound was obtained in a similar manner to that of Preparation 274.

Preparation 273 tert-Butyl (3R)-3-({5-[ (lE)-3-ethoxy-3-oxo-l-propen-l-yl]-2- pyrazinyl}amino)-1-piperidinecarboxylate IH-NMR (300 MHz, CDC13)<5l.33 (3H, t, J=7 Hz),1.43 (9H, s),1.59- 1.81 (3H, m),1.87-2.03 (IH, m),3.30-3.47 (3H, m),3.71 (IH, d, J=IO Hz),3.96 (IH, br peak),4.25 (2H, q, J=7 Hz),4.96 (IH, br peak),6.70 (IH, d, J=15 Hz),7.57 (IH, d, J=15 Hz),7.91 (IH, d, J=2 Hz),8.07 (IH, d, J=2 Hz) , MS (ES+) m/z 377

Preparation 274 Ethyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate(4.70g) and (3R)-I- (cyclohexylmethyl)-3-piperidinainine(4.77g) were combined in 1,4- dioxane(80mL) at ambient temperature. To this solution were added palladium(II) acetate(248mg) and 2-dicyclohexylphosphino-2'-(N,N- dimethylamino)biphenyl(652mg) at the same temperature and the mixture was stirred for 5 minutes. To the resulting mixture was added cesium carbonate(10.Ig) and the mixture was heated at 951C for twenty-four hours. The reaction mixture was allowed to cool to ambient temperature and the insoluble solid was filtered off. The filtrate was concentrated in vacuo and the residue was extracted with chloroform(30OmL) . The chloroform phase was washed with saturated sodium bicarbonate(10OmL) and brine(10OmL). The aqueous layer was reextracted with chloroform(10OmL) . The organic phase were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by a flash column chromatography eluting with a gradient solvent system from EtOAc-Hexane(l:l v/v) to EtOAc to afford ethyl (2E)-3-(5-{[(3R)-l-(cyclohexylmethyl)-3- piperidinyl]amino}-2-pyrazinyl)acrylate(4.80g) as a yellow amorphous solid. 1H-NMR (300 MHz, CDCl3) 5 0.78-0.96 (mH, 2),1.08-1.29 (3H, m),1.33 (3H, t, J=7.3 Hz),1.41-1.85 (1OH, m) ,2.04-2.19 (3H, m),2.35-2.46 (IH, m),2.51-2.69 (2H, m),4.04-4.15 (IH, m),4.25 (2H, q, J=7.3 Hz),5.63 (IH, br.s),6.67 (IH, d, J=15.4 Hz),7.58 (IH, d, J=15.4 Hz),7.89 (IH, d, J=I.1 Hz),8.05 (IH, d, J=I.1 Hz) MS (ES+) m/z 373(M+l)

Preparation 275 To a solution of ethyl (2E)-3-{5-[ (3R)-3-piperidinyland.no]-2- pyrazinyl}aerylate dihydrochloride (300 mg) in 1,2-dichloroethane (5 mL) were added diisopropylethylamine (222 mg) and cyclohexanone (93 mg) , and the mixture was stirred at ambient temperature for 5 min. To the mixture was added sodium triacetoxybrohydryde (364 mg) and stirred for 4 hrs, and resulting mixture was poured into saturated sodium bicarbonate solution, and extracted with chloroform. The organic layer was washed with water, and brine, and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by preparative thin layer chromatography (chloroform-MeOH=10-l) to give ethyl (2E)-3-(5-{[(3R)-l-cyclohexyl- 3-piperidinyl]amino}-2-pyrazinyl)aerylate (235 mg) as an amorphous powder. 1H-NMR (300 MHz, CDCl3) <5 0.96-1.36 (9H, m),1.49-1.88 (8H, m),2.24- 2.38 (IH, m),2.38-2.51 (IH, m),2.57-2.75 (3H, m),4.06 (IH, br peak),4.25 (2H, q, J=7 Hz),5.69 (IH, br peak),6.66 (IH, d, J=15 Hz),7.56 (IH, d, J=15 Hz),7.90 (IH, d, J=2 Hz),8.05 (IH, d, J=2 Hz) MS (ES+) m/z 359

The following compounds were obtained in a similar manner to that of Preparation 275.

Preparation 276 tert-Butyl [(3R)-1-(cyclohexylmethyl)-3-piperidinyl]carbamate 1H-NMR (300 MHz, CDCl3) δ 0.73-0.92 (2H, m),1.08-1.31 (3H, m),1.35- 1.82 (1OH, m),1.45 (9H, s),1.98-2.51 (6H, m),3.65-3.80 (IH, m),4.91-5.11 (IH, m) MS (ES+ ) m/z 297 (M+l )

Preparation 277 Ethyl (2E)-3-(5-{[(3R)-l~(4-methylbenzyl)-3-piperidinyl]amino}-2- pyrazinyl)aerylate 1H-NMR (300 MHz, CDCl3)S 1.32 (3H, t, J=7 Hz),1.50-1.84 (4H, m), 2.10-2.30 (IH, m),2.34 (3H, s),2.40-2.74 (3H, m),3.44 (IH, d, J=12 Hz),3.53 (IH, d, J=12 Hz),4.10 (IH, br peak),4.25 (2H, q, J=7 Hz),5.57 (IH, br peak),6.67 (IH, d, J=15 Hz),7.14 (2H, d, J=8 Hz),7.20 (2H, d, J=8 Hz),7.56 (IH, d, J=15 Hz),7÷89 (IH, d, J=2 Hz),8.04 (IH, d, J=2 Hz) MS (ES+) m/z 381

Preparation 278 Ethyl (2E)-3-(5-{[ (3R)-l-(4-chlorobenzyl)-3-piperidinyl]amino}-2- pyrazinyl)aerylate 1H-NMR (300 MHz , CDCl3) S 1 .32- (3H, t , J=7 Hz ) , 1 , 40-1 .85 ( 4H, m) , 2 . 15-2. 32 ( IH, m) , 2.45-2.65 ( 3H, m) , 3.44 ( IH, d, J=12 Hz ) , 3.51 ( IH, d, J=12 Hz),4.10 (IH, br peak),4.25 (2H, q, J=7 Hz),5.45 (IH, br peak)„6.65 (IH, d, J=15 Hz),7.16-7.32 (4H, m),7.56 (IH, d, J=15 Hz),7.89 (IH, s),8.04 (IH, s) MS (ES+) m/z 401

Preparation 279 Ethyl (2E)-3-(5-{[(3R)-l-cyclopentyl-3-piperidinyl]amino}-2- pyrazinyl)aerylate 1H-NMR (300 MHz, CDCl3)S 1.21-1.93 (14H, m),2.20-2.39 (IH, m),2.47- 2.76 (4H, m),4.09 (IH, br peak),4.25 (2H, q, J=7 Hz),5.58 (IH, br peak),6.68 (IH, d, J=15 Hz),7.58 (IH, d, J=15 Hz),7.93 (IH, s),8.06 (IH, s) MS (ES+) m/z 345

Preparation 280 Ethyl (2E)-3-(5-{[(3R)-l-(cyclopentylmethyl)-3-piperidinyl]amino}- 2-pyrazinyl)acrylate 1H-NMR (300 MHz, CDCl3) 6 1.11-1.29 (2H, m),1.22 (3H, t/ J=7 Hz), 1.45-1.65 (6H, m) ,1.65-1.85 (4H, m) ,1.97-2.30 (4H, m),2.36-2.50 (IH, m),2.58-2.77 (2H, m),4.10 (IH, br peak),4.25 (2H, q, J=7 Hz),5.66 (IH, br peak),6.66 (IH, d, J=15 Hz),7.58 (IH, d, J=15 Hz),7.90 (IH, s),8.05 (IH, s) MS (ES+) m/z 359

Preparation 281 To a solution of mixture of ethyl (2E)-3-(5-{[(3R)-l-cyclohexyl-3- piperidinyl]amino}-2-pyrazinyl)acrylate (227 mg) in EtOH (2 mL) was added IN sodium hydroxide solution (1.3 mL) at ambient temperature and the mixture was allowed to stand for 18 hrs. The reaction mixture was adjusted to pH 6.0 with lmol/L hydrochloric acid and evaporated iri vacuo. The residue was dissolved in a mixture of chloroform and MeOH (5-1) and the precipitate was filtered off. The filtrate was concentrated in vacuo to give (2E)- 3-(5-{[(3R)-l-cyclohexyl-3-piperidinyl]amino}-2-pyrazinyl)ac rylic acid (209 mg) as a solid. 1H-NMR (300 MHz, DMSO-d6) 6 0.96-1.49 (6H, m) ,1.49-1.64 (2H, m) , 1.64-2.00 (6H, m),2.50-3.60 (5H, m),4.04 (IH, br peak),6.46 (IH, d, J=15 Hz),7.49 (IH, d, J=15 Hz),7.48 (IH, br peak),8.01 (IH, s),8.21 (IH, s)

The following compounds were obtained in a similar manner to that of Preparation 281.

Preparation 282 (2E)-3-(5-{[(3R)-l-Benzyl-3-piperidinyl]amino}-2-pyrazinyl)a crylic acid 1H-NMR OOO MHz, DMSO-d5) δ 1.15-1.45 (IH, m),1.45-2.20 (3H, m) , 2.55-3.07 (2H, m),3.40-3.50 (2H, m),4.25-4.42 (3H, m),6.46 (IH, d, J=15 Hz),7.16-7.54 (6H, m),8.00 (IH, s),8.16 (IH, s) MS (ES+) m/z 339

Preparation 283 (2E)-3-(5-{[(3R)-l-( Cyclohexylmethyl ) - 3 -pyrrolidinyl ] amino } - 2 - pyrazinyl) acrylic acid 1H-NMR (300 MHz, DMSO-d6) δ 0.74-0.94 (2H, m) ,1.04-1.30 (3H, m),1.41 (IH, m), 1.52-1.82 (6H, m), 2.11-2.31 (3H, m) ,2.34-2.47 (2H, m),2.52- 2.80 (2H, m),4.30 (IH, m),6.45 (IH, d, J=15.5 Hz), 7.47 (IH, d, J=15.5 Hz), 7.85 (IH, d, J=6.6 Hz), 8.00 (IH, s),8.19 (IH, s) MS (ES+) m/z 331

Preparation 284 (2E)-3-(5-{[(3R)-l-(4-Methylbenzyl)-3-piperidinyl]amino}-2- pyrazinyl) acrylic acid 1H-NMR (300 MHz, DMSOd6) <5 1.30-1.54 (IH, m) , 1.69-2.15 (3H, m),2.33 (3H, s), 2.44-3.05 (2H, m), 3.21-3.56 (2H, m), 4.20-4.40 (3H, m),6.50 (IH, d, J=15 Hz), 7.28 (2H, d, J=8 Hz), 7.44 (2H, d, J=8 Hz), 7.51 (IH, d, J=15 Hz), 7.86 (IH, d, J=8 Hz), 8.01 (IH, s),8.21 (IH, s) MS (ES+) m/z 353

Preparation 285 (2E)-3-(5-{[(3R)-l-(4-Chlorobenzyl)-3-piperidinyl]amino}-2- pyrazinyl) acrylic acid 1H-NMR (300 MHz, DMSO-de) δ 1.35-1.65 (IH, m) , 1.65-2.14 (3H, m) , 2.56-2.75 (IH, m), 2.75-2.95 (IH, m), 3.25-3.59 (2H, m) , 4.16-4.49 (3H, m),6.50 (IH, d, J=15 Hz) ,7.45-7.70 (5H, m),7.85 (IH, d, J=8 Hz), 8.01 (IH, s), 8.22 (IH, s) MS (ES+) m/z 373

Preparation 286 A mixture of (2E)-3-(5-{[(3R)-l-cyclohexyl-3-piperidinyl]amino}-2- pyrazinyl)acrylic acid (209 mg), 0-(tetrahydro-2H-pyran-2ryl)- hydroxylamine (89 mg) , HOBt (111 mg) and EDCI (158 mg) in DMF (4.5 mL) was stirred at 0 °C for 1 hr and the mixture was stirred at ambient temperature for 18 hrs. The reaction mixture was evaporated in vacuo and the residue was partitioned between saturated sodium bicarbonate solution and EtOAc. The organic layer was separated, washed water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform-MeOH =95-5) to give (2E)-3-(5-{[(3R)-I- cyclohexyl-3-piperidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2 H- pyran-2-yloxy)acrylamide (198 mg) as an amorphous powder. 1H-NMR (300 MHz, CDCl3) δ 0.91-1.35 (6H, m),1.35-1.95 (13H, m),2.20- 2.38 (IH, m),2.38-2.53 (IH, m) ,2.53-2.74 (3H, m) ,3.59-3.70 (IH, m),3.90-4.02 (IH, m) ,4.02-4.14 (IH, m),5.01 (IH, br s),5.60-5.75 (IH, m),6.65 (IH, br peak),7.63 (IH, d, J=15 Hz),7.88 (IH, s),8.04 (IH, s),8.31 (IH, br peak) . MS (ES+) m/z 430

The following compounds were obtained in a similar manner to that of Preparation 286.

Preparation 287 (2E)-3-(5-{[(3R)-l-Benzyl-3-piperidinyl]amino}-2-pyrazinyl)- N- (tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (300 MHz, CDCl3)O 1.35-1.96 (9H, m),2.14-2.35 (IH, m),2.40- 2.70 (3H, m),3.49 (IH, d, J=13 Hz),3.55 (IH, d, J=13 Hz) ,3.60-3.78 (IH, m),3.86-4.03 (IH, m),4.03-4.15 (IH, m) ,4.94-5.05 (IH, m),5.45- 5.60 (IH, m),6.65 (IH, br peak) ,7.15-7.35 (5H, m),7.62 (IH, d, J=15 Hz),7.86 (IH, s),8.01 (IH, s),8.19-8.35 (IH, m)

Preparation 288 (2E)-3-(5-{[(3R)-1-(4-Methylbenzyl)-3-piperidinyl]amino}-2- pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (300 MHz, CDCl3)O 1.45-1.96 (9H, m),2.11-2.29 (IH, m),2.34 (3H, s),2.43-2.72 (3H, m),3.43 (IH, d, J=12 Hz),3.52 (IH, d, J=12 Hz),3.59-3.71 (IH, m),3.90-4.04 (IH, m),4.04 (IH, br peak),5.01 (IH, br s),5.58 (IH, br peak),6.66 (IH, br peak),7.14 (2H, d, J=8 Hz),7.19 (2H, d, J=8 Hz),7.61 (IH, d, J=15 Hz),7.87 (IH, s),8.00 (IH, s),8.35 (IH, br peak) MS (ES+) m/z 452

Preparation 289 (2E)-3-(5-{[(3R)-l-(4-Chlorobenzyl)-3-piperidinyl]amino}-2- pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (300 MHz, CDCl3) <5 1.56-1.95 (9H, m),2.15-2.33 (IH, in),2.43- 2.66 (3H, m),3.44 (IH, d, J=12 Hz),3.50 (IH, d, J=12 Hz) ,3.59-3.71 (IH, m),3.86-4.04 (IH, m),4.10 (IH, br peak),5.00 (IH, br s),5.48 (IH, br peak),6.70 (IH, br peak) ,7.19-7.35 (4H, m),7.53 (IH, d, J=15 Hz),7.86 (IH, s),8.01 (IH, s),8.35 (IH, br peak) MS (ES+) m/z 472

Preparation 290 ' (2E)-3-(5-{[(3R)-l-(Cyclohexy-ϋmethyl)-3-pyrrolidinyl]amino }-2- pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (300 MHz, DMSO-de) <5 0.73-0.93 (2H, m),1.06-1.28 (3H, m) , 1.30-1.83 (13H, m),2.10-2.30 (3H, m) ,2.31-2.44 (2H, m),2.61 (IH, m),2.72 (IH, m),3.52 (IH, m),3.95 (IH, m),4.29 (IH, m),4.89 (IH, m),6.60 (IH, d, J=15.2 Hz),7.38 (IH, d, J=15.2 Hz),7.73 (IH, d, J=6.6 Hz),7.98 (IH, s),8.11 (IH, s),11.18 (IH, s) MS (ES+) m/z 430

Preparation 291 To a mixture of tert-butyl (3R)-3-pyrrolidinylcarbamate(4.0g) and l-(chloromethyl)-4-methylbenzene(3.17g) in DMF(40mL) was added N- ethyl-N-isopropyl-2-propanamine(5.55g) at ambient temperature and the resulting mixture was heated at 70 °C for four hours. The mixture was allowed to cool to ambient temperature and extracted with ethyl acetate(10OmL) . The, organic phase was washed with water(5OmL) and brine(5OmL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by a flash chromatography etluting with gradient solvent system (ethyl acetate-hexane from 1:4 v/v to 1:1 v/v) to give tert- butyl [(3R)-1-(4-methylbenzyl)-3-pyrrolidinyl]carbamate(4.69g) as a pale yellow syrup. 1H-NMR (300 MHz , CDCl3) <5 1.43 (9H, s) , 1.49-1.64 ( IH, m) , 2.12-2.37 (2H, m) , 2.34 (3H, s) , 2.43-2.64 (2H, m) , 2.68-2.84 (IH, m) , 3.55 (2H, s) , 4.07-4.23 (IH, m) , 4.76-4.92 (IH, m) , 7.12 (2H, d, J=8.1 Hz) , 7.19 ( 2H, d, J=8.1 Hz ) MS (ES+ ) m/z 291 (M+l )

The following compounds were obtained in a similar manner to that of Preparation 291.

Preparation 292 tert-Butyl [(3R)-1-(cyclohexyHinethyl)-3-pyrrolidinyl]carbamate 1H-NMR (300 MHz, CDCl3)S 0.75-0.95 (2H, m),1.06-1.31 (3H, m),1.44 (3x3H, s),1.50-1.83 (7H, m),2.11-2.30 (4H, m),2.39-2.58 (2H, m),2.73 (IH, m),4.13 (IH, m),4.,82 (IH, m) MS (ES+) m/z 283

Preparation 293 To a stirred solution of tert-butyl [(3R)-l-(4-methylbenzyl)-3- pyrrolidinyl]carbamate(4.6g) in ethyl acetate(1OmL) was added 4N hydrogen chloride in ethyl acetate(6OmL) at ambient temperature and the resulting mixture was stirred at the same temperature for three hours. The mixture was concentrated in vacuo and the residual syrup was dissolved in chloroform(10OmL) . To this solution was added saturated sodium bicarbonate(5OmL) and the resulting biphasic mixture was vigorously stirred at ambient temperature for half an hour. The organic layer was separated and the aqueous layer was reextracted with chloroform(5OmL) two times. The combined organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo to afford (3R)-l-(4-methylbenzyl)-3-pyrrolidinamine(2.1g) as a pale brown viscous oil, which was used in the next step without further purification. 1H-NMR (300 MHz, CDCl3)S 1.43-1.57 (IH, m),1.81 (2H, br.s),2.12- 2.37 (IH, m),2.28-2.37 (IH, m),2.34 (3H, S-) ,2.43-2.55 (IH, m),2.67- 2.79 (2H, m),3.46-3.55 (IH, m),3.56 (IH, d, J=12.8 Hz),3.62 (IH, d, J=12.8 Hz),7.12 (2H, d, J=7.7 Hz),7.22 (2H, d, J=7.7 Hz) MS (ES+) m/z 191(M+l)

The following compound was obtained in a similar manner to that of Preparation 293.

Preparation 294 (3R)-1-(Cyclohexylmethyl)-3-pyrrolidinamine dihydrochloride 1H-NMR (300 MHz, DMSOd6) <5 0.83-1.03 (2H, m) ,1.04-1.34 (3H, m) , 1.52-1.77 (4H, m) ,1.77-1.97 (2H, m),2.12 (IH, m),2.39 (IH, m),2.95- 3.26 (3H, m),3.28-4.09 (4H, m),8.65 (2H, br) MS (ES+) m/z 183

Preparation 295 To a solution of ethyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate (300 mg) and potassium carbonate (4.94 mg) in DMF (15 mL) was added (3R)-l-benzyl-3-piperidinamine dihydrochloride (668 mg) under nitrogen at ambient, temperature and the mixture was stirred at 85 °C for 18 hrs. The reaction mixture was evaporated in vacuo and the residue was partitioned between water and ethyl acetate. The organic layer was washed with water and brine,dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform-MeOH=97-3) to give ethyl (2E)-3-(5-{[(3R)-l-benzyl-3-piperidinyl]amino}-2- pyrazinyl)aerylate (125 mg) as an oil. 1H-NMR (300 MHz, CDCl3) δ 1.32 (3H, t, J=7.1 Hz),1.47-1.83 (3H, m), 2.16-2.33 (IH, m),2.42-2.73 (3H, m),3.49 (IH, d, J=13.0 Hz),3.56 (IH, d, J=13.0 Hz),4.06-4.17 (IH, m),4.25 (2H, q, J=7.1 Hz),5.55 (IH, br peak),6.67 (IH, d, J=15.5 Hz) ,7.23-7.38 (5H, m),7.57 (IH, d, J=15.5 Hz),7.89 (IH, d, J=I.3 Hz),8.04 (IH, d, J=I.3 Hz) MS (ES+) m/z 367

The following compound was obtained in a similar manner to that of Preparation 295.

Preparation 296 Ethyl (2E)-3-(5-{[(3R)-l-(cyclohexylmethyl)-3-pyrrolidinyl]amino}- 2-pyrazinyl)acrylate 1H-NMR (300 MHz, CDCl3)S 0.80-0.98 (2H, m),1.08-1.31 (3H, m),1.33 (3H, t, J=7 Hz),1.44 (IH, m),1.57-1.85 (6H, m) ,2.18-2.42 (4H, m),2.54-2.69 (2H, m),2.88 (IH, m),4.25 (2H, q, J=7 Hz),4.43 (IH, m),5.23 (IH, d, J=8 Hz),6.68 (IH, d, J=15.5 Hz),7.57 (IH, d, J=15.5 Hz),7.89 (IH, s),8.06 (IH, s) MS (ES+) m/z 359

Preparation 297 • To a solution of tert-butyl (3R)-3-({5-[(lE)-3-ethoxy-3-oxo-l- propen-l-yl]-2-pyrazinyl}amino)-l-piperidinecarboxylate (6.26 g-) in a mixture of 1, 4-dioxane (25 mL) and MeOH (5 mL) was added 4N hydrogen chloride solution in ethyl acetate (30 mL) in water bath. The mixture was stirred at same temperature for 3 hrs. After evaporation of solvent, the residue was triturated with isopropylether to give ethyl (2E)-3-{5-[(3R)-3-piperidinylamino]-2- pyrazinyl}acrylate dihydrochloride (5.8 g) as an amorphous powder. 1H-NMR (300 MHz, DMSO-O6) <5 1.25 (3H, t, J=7 Hz) ,1.46-1.65 (IH, m), 1.65-1.85 (IH, m),1.85-2.06 (3H, m) ,2.66-3.00 (2H, m),3.05-3.25 (IH, m),3.25-3.41 (IH, m),4.18 (2H, q, J=7 Hz),6.54 (IH, d, J=15 Hz),7.57 (IH, d, J=15 Hz) ,7.95-8.19 (2H, m),8.28 (IH, s),9.14 (2H, br peak) MS (ES+) m/z 277

The following compound was obtained in a similar manner to that of Preparation 297.

Preparation 298 (3R)-1-(Cyclohexylmethyl)-3-piperidinamine 1H-NMR (300 MHz, CDCl3) d 0.75-0.92 (2H, m),1.02-1.31 (4H, m),1.31- 1.61 (4H, m),1.60-1.87 (8H, m),1.92-2.07 (IH, m),2.08 (2H, d, J=7.2 Hz),2.46-2.58 (IH, m),2.62-2.73 (IH, m),2.80-2.92 (IH, m) MS (ES+) m/z 197(M+l)

Preparation 299 To a solution of (5-chloro-2-pyrazinyl)methanol (11.0 g) in dioxane (110 mL) was added manganese(IV) oxide (26.5 g) and (carbethoxymethylene)triphenylphosphorane (29.2 g) . After stirring for 2 hours at room temperature, a resulting precipitate was filtered and the filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica gel to give ethyl (2E)- 3-(5-chloro-2-pyrazinyl)acrylate (11.0 g) . 1H-NMR (300 MHz, CDCl3) δ 1.35 (3H, t, J = 7 Hz), 4.30 (2H, q, J = 7 Hz), 7.01 (IH, d, J = 15 Hz), 7.66 (IH, d, J = 15 Hz), 8.43 (IH, s), 8.60 (IH, s)

Preparation 300 To a solution of ethyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate (1.50 g) in DMF (21 mL) was added (3R)-l-benzyl-3-pyrrolidinamine (2.24 g) arid Et3N (3.44 mL) . After stirring for 3 hours at 100°C , the reaction mixture was partitioned between' ethyl acetate and H2O. The organic layer was washed with brine, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give ethyl (2E)-3-(5-{[(3R)-I- benzyl-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate (1.15 g) . 1H-NMR (300 MHz, CDCl3) . <5 1.32 (3H, t, J = 7 Hz), 1.65-1.76 (IH, m) , 2.32-2.43 (2H, m) , 2.66-2.70 (2H, m) , 2.87-2.95 (IH, m) , 3.62-3.66 (2H, m), 4.25 (2H, q, J = 7 Hz), 4.40-4.52 (IH, m) , 5.21 (IH, d, J = 8 Hz), 6.67 (IH, d, J = 15 Hz), 7.24-7.35 (5H, m) , 7.57 (IH, d, J = 15 Hz), 7.87 (IH, s), 8.05 (IH, s) MS (ES+) m/z 353 (M+l)

Preparation 301 To a solution of ethyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate (1.78 g) and (3R)-l-(4-chlorobenzyl)-3-pyrrolidinamine (2.65 g) in DMF (25 mL) was added K2CO3 (5.79 g) . After stirring for 3 hours at 100"C, the reaction .mixture was partitioned between ethyl acetate and H2O. The organic layer was washed with H2O, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give ethyl (2E)-3-(5-{[(3R)- 1-(4-chlorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylat e (1.58 g). 1H-NMR (300 MHz, CDCl3) <5 1.32 (3H, t, J = 7 Hz), 1.66-1.74 (IH, m) , 2.31-2.43 (2H, m) , 2.62-2.71 (2H, m), 2.85-2.92 (IH, m) , 3.59-3.62 (2H, m), 4.25 (2H, q, J = 7 Hz), 4.41-4.52 (IH, m) , 5.19 (IH, d, J = 8 Hz), 6.68 (IH, d, J = 15 Hz), 7.23-7.32 (4H, m) , 7.57 (IH, d, J = 15 Hz), 7.88 (IH, s), 8.05 (IH, s) MS (ES+) m/z 387 (M+l)

The following compound was obtained in a similar manner to that of Preparation 301.

Preparation 302 Ethyl (2E)-3-(5-{[ (3R)-l-(4-methylbenzyl)-3-pyrrolidinyl]amino}-2- pyrazinyl)acrylate 1H-NMR (300 MHz , CDCl3) δ 1.32 (3H, t , J = 7 Hz) , 1.67-1.73 ( IH, m) , 2.32-2.42 (2H, m) , 2.34 ( 3H, s) , 2.66-2.69 ( 2H, m) , 2.88-2.95 ( IH, m) , 3.60-3.63 ( 2H, m) , 4.25 ( 2H, q, J = 7 Hz) , 4.41-4.51 ( IH, m) , 5.24-5.31 ( IH, m) , 6.67 ( IH, d, J = 15 Hz ) , 7.13 ( 2H, d, J = 8 Hz ) , 7.21 (2H, d, J = 8 Hz ) , 7.57 ( IH, d, J = 15 Hz ) , 7.87 ( IH, s) , 8.05 ( IH, s) MS (ES+) m/z 367 (M+l )

Preparation 303 1) To a solution of ethyl (2E)-3-(5-{ [ (3R)-l-(4-chlorobenzyl)-3- pyrrolidinyl]amino}-2-pyrazinyl)acryiate (1.57 g) in dioxane (20 mL) was added IN sodium hydroxide (12.2 mL) . After stirring at 60°C for 2 hours, the reaction mixture was added H2O(100 mL) and acidified with IN hydrochloric acid (to pH 4) . A resulting mixture was evaporated in vacuo . 2) To a mixture of above product, 0-tetrahydro-2H-pyran-2- ylhydroxylamine (713 mg), and 1-hydroxybenzotriazole (823 mg) in N,N-dimethylformamide (20 mL) was added l-(3-dimethylaminopropyl)- 3-ethylcarbodiimide (945 mg) at 4 °C . The mixture was warmed to ambient temperature and stirred for 8 hours. The reaction mixture was added saturated NaHCO3 (20 mL) and water (80 mL), and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give (2E)-3-(5-{[(3R)-l-(4- chlorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahyd ro-2H- pyran-2-yloxy)acrylamide (1.44 g) . 1H-NMR (300 MHz, DMSOd6) δ 1.47-1.74 (7H, m) , 2.16-2.30 (IH, m) , 2.37-2.45 (2H, m) , 2.61-2.80 (2H, m) , 3.48-3.60 (3H, m) , 3.89-4.00 (IH, m), 4.25-4.35 (IH, m) , 4.89 (IH, brs), 6.59 (IH, d, J = 15 Hz), 7.32-7.42 (5H, m) , 7.77 (IH, d, J = 6 Hz), 7.97 (IH, s), 8.09 (IH, s), 11.2 (IH, brs) MS (ES+) m/z 458 (M+l)

The following compounds were obtained in a similar manner to that of Preparation 303.

Preparation 304 (2E)-3-(5-{[(3R)-l-Cyclopentyl-3-piperidinyl]amino}-2-pyrazi nyl)-N- (tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (300 MHz, CDCl3) <5 1.20-1.96 (2OH, m),2.20-2.37 (IH, m),2.47- 2.80 (4H, m),3.59-3.71 (IH, m),3.88-4.02 (IH, m) ,4.02-4.15 (IH, m),5.02 (IH, br s),5.56 (IH, br peak),6.68 (IH, br peak),7.63 (IH, d, J=15 Hz),7.90 (IH, s),8.02 (IH, s),8.30 (IH, br peak) MS (ES+) m/z 416

Preparation 305 (2E)-3-(5-{[(3R)-l-(Cyclopentylmethyl)-3-piperidinyl]amino}- 2- pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (300 MHz, CDCl3)S 1.11-1.30 (2H, m),1.45-1.98 (16H, m),1.96- 2.29 (4H, m),2.35-2.51 (IH, m),2.56-2.76 (2H, m) ,3.59-3.70 (IH, m),3.90-4.03 (IH, m),4.10 (IH, br peak),5.01 (IH, br s),5.65 (IH, br peak),6.67 (IH, br peak),7.62 (IH, d, J=15 Hz),7.87 (IH, s),8.03 (IH, s),8.34 (IH, br peak) MS (ES+) m/z 430

Preparation 306 (2E)-3-(5-{[(3R)-l-Benzyl-3-pyrrolidinyl]amino}-2-pyrazinyl) -N- (tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (300 MHz, DMSO-Cl6) 6 1.47-1.74 (7H, m) , 2.16-2.30 (IH, m) , 2.36-2.46 (2H, m) , 2.60-2.80 (2H, m) ; 3.47-3.60 (3H, m), 3.88-4.00 (IH, m), 4.25-4.35 (IH, m) , 4.89 (IH, brs), 6.59 (IH, d, J = 15 Hz), 7.21-7.34 (5H, m) , 7.37 (IH, d, J = 15 Hz), 7.77 (IH,. d, J = 6 Hz), 7.97 (IH, s), 8.09 (IH, s), 11.2 (IH, brs) MS (ES+) m/z 424 (M+l)

Preparation 307 (2E)-3-(5-{[(3R)-l-(4-Methylbenzyl)-3-pyrrolidinyl]amino}-2- pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (300 MHz, DMSO-de) 8 1.47-1.74 (7H, m) , 2.15-2.30 (IH, m) , 2.27 (3H, s), 2.34-2.45 (2H, m) , 2.60-2.77 (2H, m) , ,3.47-3.57 (3H, m), 3.89-4.01 (IH, m) , 4.24-4.36 (IH, m) , 4.89 (IH, brs), 6.59 (IH, d, J = 15 Hz), 7.11 (2H, d, J = 8 Hz), 7.19 (2H, d, J = 8 Hz), 7.37 (IH, d, J = 15 Hz), 7.76 (IH, d, J = 6 Hz), 7.97 (IH, s), 8.09 (IH, s), 11.2 (IH, brs) MS (ES+) m/z 438 (M+l)

The following compound was obtained in similar manners to those of Preparations 281 and 286.

Preparation 308 (2E)-3-(5-{[(3R)-1-(Cyclohexylmethyl)-3-piperidinyl]amino}-2 - pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (300 MHz, DMSO-de) δ 0.70-0.91 (2H, m),1.02-1.32 (3H, m) , 1.36-2.00 (16H, m) ,2.02-2.11 (2H, m),2.44-2.55 (2H, m),2.56-2.67 (IH, m),2.75-2.86 (IH, m) ,3.46-3.58 (IH, m),3.82-4.03 (2H, m),4.89 (IH, br.s),6.59 (IH, d, J=15.4 Hz),7.38 (IH, d, J=15.4 Hz),7.43 (IH, br.s),7.97 (IH, s),8.11 (IH, s) MS (ES+) m/z 444(M+l)

Preparation 309 To a solution of 5,6-dichloronicotinic acid (7.0 g, 35 mmol) in DMF were added iodoethane (6.0 g, 38.5 mmol) and K2CO3 (5.8 g, 42 mmol) at ambient temperature and the mixture was stirred at 45 °C for 5 hrs. To the reaction mixture were added (3R)-l-benzyl-3- piperidinamine dihydrochloride (10.1 g, 38.5 mmol) and K2CO3 (16.9 g, 122 mmol) and the reaction mixture was stirred at 90 "C for.18 hrs. The reaction mixture was evaporated in vacuo and the residue was partitioned between water and EtOAc. The organic layer was separated, washed water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (EtOAc-hexane/l-4~l-3) to give ethyl 6- {[(3R)-l-benzyl-3-piperidinyl]amino>-5-chloronicotinate (6.75 g, 52%) as a powder. 1H-NMR (300 MHz, CDCl3) <5l.36 (3H, t, J=7.1 Hz) ,1.51-1.69 (2H, m),1.69-1.88 (2H, m),2.18-2.33 (IH, m),2.41-2.54 (IH, m),2.54-2.67 (IH, m),2.67-2.79 (IH, m),3.45 (IH, d, J=13 Hz),3.61 (IH, d, J=13 Hz),4.32 (2H, q, J=7.1 Hz),6.24 (IH, br peak) ,7.21-7.41 (5H, m),8.00 (IH, d, J=2 Hz),8.65 (IH, d, J=2 Hz); MS (ES+) m/z 374.

Preparation 310 A mixture of ethyl (2E)-3-(5-bromo-2-pyridinyl)acrylate (480mg), (3R)-l-benzyl-3-pyrrolidinamine (363mg), cesium carbonate (855mg, 1.4eq. ) , CyDMABP (2-Dicyclohexylphosphino-2'-(N,N- dimethylaminojbiphenyl, 63mg, 0.15eq.), and palladium acetate (250mg, 0.6eq.) in dioxane (25ml) was stirred at 100 °C for 2 days. Water and ethyl acetate was added and aqueous layer was separated. Aqueous layer was extracted with ethyl acetate (twice). Combined organic layer was washed with water and brine, dried over MgSO4, filtered and evaporated. The residue was column chromatographed on silica gel to give 37mg (6%) of ethyl (2E)-3-(5-{[(3R)-l-benzyl-3-pyrrolidinyl]amino}-2- pyridinyl)acrylate as an oil. MASS (ESI+): m/z = 352.3 (M+l). 1HNMR ( 400MHz, CDCl3): δ 1.31 (3H, t, J=7.1Hz), 1.68-1.78 (IH, m) , 2.31-2.95 (5H, m) , 3.69 (2H, s), 4.01-4.09 (IH, m) , 4.24 (2H, q, J=7.1Hz), 4.44-4.51 (IH, m) , 6.62 (IH, d, J=15.5Hz), 6.79 (IH, dd, J=8.5 and 2.9Hz ) , 7.23-7.36 ( 6H, m) , 7 .18 ( IH, d, J=8.4Hz ) , 7 .24 ( IH, d, J=8.5Hz ) , 7.32-7.40 ( 5H, m) , 7 . 60 ( IH, d, J=15. 5Hz ) , 8.01 ( IH, d, J=2.9Hz ) .

Preparation 311 To a solution of ethyl (2E)-3-(6-{(tert-butoxycarbonyl) [(3R)-3- pyrrolidinyl]amino}-3-pyridinyl)aerylate dihydrochloride (220 mg, 0.51 mmol) in 1,2-dichloroethane (4 iriL) were added diisopropylethylamine (131 mg, 1.01 mmol) and cyclopentanecarboxaldehyde (52 mg, 0.53 mmol), and the mixture was stirred at ambient temperature for 5 min. To the mixture was added sodium triacetoxyborohydride (215 mg, 1.01 mmol) and stirred for 2 hrs, and resulting mixture was poured into saturated sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was washed with water, and brine, and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by preparative thin layer chromatography (chloroform- MeOH=IO-I) to give ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-I- (cyclopentylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)aeryla te (225 mg, 100%) as an amorphous powder. 1H-NMR (300 MHz, CDCl3) (51.00-1.21 (2H, m),1.36 (3H, t, J=7.5 Hz),1.46 (9H, s),1.48-1.80 (8H, m),1.80-2.10 (2H, m),2.10-2.44 (2H, m),2.44-2.80 (2H, m) ,2.90-3.06 (IH, m),4.29 (2H, q, J=7.5 Hz),4.80- 4.96 (IH, m),6.46 (IH, d, J=15 Hz),7.32 (IH, d, J=8 Hz),7.66 (IH, d, J=15 Hz),7.80 (IH, dd, J=8,2 Hz),8.55 (IH, d, J=2 Hz); MS (ES+) m/z 444.

The following compounds were obtained in a similar manner to that of Preparation 311. Preparation 312 ethyl 6-{[(3R)-1-benzyl-3-piperidinyl]amino}nicotinate 1H-NMR (300 MHz, CDC13)<5l.36 (3H, t, J=7.1 Hz) ,1.46-1.84 (5H, m),2.20-2.40 (IH, m),2.40-2.67 (2H, m),3.45-3.58 (2H, m),3.97 (IH, br peak),4.32 (2H, q, J=7.1 Hz),5.54 (IH, br peak),6.33 (IH, d, J=8.7 Hz),7.23-7.40 (5H, m),7.96 (IH, dd, J=8.8, 2.2 Hz),8.73 (IH, d, J=2. 2 Hz ) ; MS (ES+ ) m/z 340 .

Preparation 313 ethyl 6-{[(3R)-l-(cyclohexylmethyl)-3-piperidinyl]amino}nicotinate 1H-NMR (300 MHz, CDC13) <50.77-0.97 (2H, m),1.05-1.30 (3H, m),1.36 (3H, t, J=7.1 Hz),1.40-1.86 (1OH, m),1.97-2.25 (3H, m),2.37-2.64 (3H, m),3.84-4.08 (IH, m),4.30 (2H, q, J=7.1 Hz),5.59 (IH, br peak),6.35 (IH, d, J=8.4 Hz),7.97 (IH, dd, J=8.6, 2.0 Hz),8.74 (IH, d, J=2.0 Hz).

Preparation 314 ethyl (2E)-3-(6-{[(3R)-l-(4-chlorobenzyl)-3-piperidinyl]amino}-3- pyridinyl)aerylate 1H-NMR (300 MHz, CDC13)<5l.33 (3H, t, J=7.1 Hz) ,1.46-1.84 (3H, m),2.18-2.36 (IH, m) ,2.36-2.66 (3H, m),3.43 (IH, d, J=13.5 Hz),3.50 (IH, d, J=13.5 Hz),3.88-4.04 (IH, m),4.24 (2H, q, J=7.1 Hz),5.21- 5.41 (IH, m),6.20 (IH, d, J=15.9 Hz),6.38 (IH, d, J=8.8 Hz),7.18- 7.38 (4H, m),7.56 (IH, d, J=16.1 Hz),7.60 (IH, dd, J=9.4, 2.3 Hz),8.18 (IH, d, J=2.3 Hz); MS (ES+) m/z.400.

Preparation 315 ethyl (2E)-3-(6-{[ (3R)-1-cyclopentyl-3-piperidinyl]amino}- 3-pyridinyl)aerylate 1H-NMR (300 MHz, CDC13) δ1.16-1.90 (15H, m),2.20-2.77 (5H, m),3.92 (IH, br peak),4.24 (2H, q, J=7.1 Hz),5.40 (IH, br peak),6.20 (IH, d, J=15.9 Hz),6.40 (IH, d, J=8.8 Hz),7.56 (IH, d, J=15.9 Hz),7.61 (IH, dd, J=8.7, 2.3 Hz),8.18 (IH, d, J=2.1 Hz); MS (ES+) m/z 344.

Preparation 316 ethyl (2Z)-3-(6-{[ (3R)-l-cyclohexyl-3-pyrrolidinyl]amino>- 3-pyridinyl)-2-fluoroacrylate 1H-NMR (300 MHz, CDCl3) δ1.06-1.33 (6H, m),1.38 (3H, t, J=7.1 Hz),1.44-1.84 (3H, m),1.84-2.00 (2H, m),2.00-2.15 (IH, m),2.25-2.56 (2H, m),2.68-2.89 (2H, m) ,2.89-3.05 (IH, m) ,4.23-4.45 (3H, m),5.24 (IH, br peak),6.40 (IH, d, J=8.8 Hz),6.81 (IH, d, J=36.3 Hz),7.82 (IH, dd, J=8.8, 1.9 Hz),8.24 (IH, s); MS (ES+) m/z 362.

Preparation 317 ethyl (2E)-3-{6-[ [(3R)-I-(1-adamantylmethyl) -3-pyrrolidinyl] (tert-butoxycarbonyl)amino]-3-pyridinyl}acrylate 1H-NMR (300 MHz, CDCl3)Sl.35 (3H, t, J=7.1 Hz),1.44 (9H, s),1.50- 2.30 (2OH, m),2.65-3.20 (IH, m),4.29 (2H, q, J=7.2 Hz),6.46 (IH, d, J=16.1 Hz),8.31 (IH, d, J=8.2 Hz),7.66 (IH, d, J=16.5 Hz),7.81 (IH, dd, J=8.3, 2.7 Hz),8.56 (IH, d, J=2.7 Hz); MS (ES+) m/z 510.

Preparation 318 ethyl (2E)-3-(6-{[(3R)-1-(4-methylbenzyl) -3-piperidinyl]amino}-3-pyridinyl)aerylate 1H-NMR (300 MHz, CDCl3)Sl.32 (3H, t, J=7.1 Hz),1.47-1.84 (4H, m),2.18-2.37 (4H, m),2.40-2.70 (3H, m),3.44 (IH, d, J=13.1 Hz),3.50 (IH, d, J=13.1 Hz),3.95 (IH, br peak),4.24 (2H, q, J=7.1 Hz),5.40 (IH, br peak),6.20 (IH, d, J=15.9 Hz),6.38 (IH, d, J=8.8 Hz),7.12 (2H, d, J=7.9 Hz),7.20 (2H, d, J=7.9 Hz),7.55 (IH, d, J=15.5 Hz),7.60 (IH, dd, J=8.8, 2.2 Hz),8.17 (IH, d, J=2.1 Hz).

Preparation 319 ethyl (2Z)-2-fluoro-3-(6-{[ (3R)-l-(4-methylbenzyl) -3-pyrrolidinyl]amino}-3-pyridinyl)acrylate 1H-NMR (300 MHz, CDCl3) <5l.37 (3H, t, J=7.1 Hz) ,1.59-1.78 (IH, m),2.26-2.47 (5H, m),2.60 (IH, dd, J=9.6, 3.2 Hz),2.74 (IH, dd, J=9.7, 6.4 Hz),2.78-2.90 (IH, m),3.56 (IH, d, J=12.8 Hz),3.64 (IH, d, J=12.8 Hz),4.25-4.41 (3H, m),5.12 (IH, br d, J=7.8 Hz),6.38 (IH, d, J=8.9 Hz),6.79 (IH, d, J=36.2 Hz),7.12 (2H, d, J=7.9 Hz),7.21 (2H, d, J=7.9 Hz),7.81 (IH, dd, J=8.9, 2.2 Hz),8.23 (IH, d, J=I.8 Hz); MS (ES+) m/z 384. Preparation 320 ethyl (2Z)-3-(6-{[(3R)-l-(4-chlorobenzyl)-3-pyrrolidinyl]amino}-3- pyridinyl)-2-fluoroacrylate 1H-NMR (300 MHz, CDCl3)Sl.37 (3H, t, J=7.1 Hz) ,1.56-1.78 (IH, m),2.28-2.46 (2H, mj,2.60 (IH, dd, J=9.7, 3.2 Hz),2.73 (IH, dd, 3=9.1. 6.3 Hz),2.77-2.88 (IH, m),3.56 (IH, d, J=13.6 Hz),3.61 (IH, d, J=13.6 Hz),4.26-4.42 (3H, m) ,5.08 (IH, br d, 3=1.9 Hz),6.38 (IH, d, J=8.8 Hz),6.80 (IH, d, J=36.2 Hz),7.25 (2H, d, J=8.7 Hz),7.30 (2H, d, J=8.7 Hz),7.82 (IH, dd, J=8.9, 2.2 Hz),8.24 (IH, d, J=2.0 Hz).

Preparation 321 ethyl (2E)-3-(5-{[ (3R)-I-(3-chlorobenzyl)-3-piperidinyl]amino}-2- pyrazinyl)acrylate 1H-NMR (300 MHz, CDCl3)Sl.32 (3H, 't, J=7.1 Hz),1.5-1.85 (4H, m),2.20-2.35 (IH, m) ,2.49-2.71 (3H, m),3.46 (IH, d, J=13.5 Hz),3.53 (IH, d, J=13.5 Hz),4.12 (IH, br peak),4.25 (2H, q, J=7.1 Hz),5.50 (IH, br peak),6.67 (IH, d, J=15.5 Hz) ,7.15-7.40 (4H, m),7.58 (IH, d, J=15.5 Hz),7.91 (IH, s),8.05 (IH, s); MS (ES+) m/z 401.

Preparation 322 ethyl (2E)-3-(5-{[(3R)-I-(2-chlorobenzyl)-3-piperidinyl]amino}-2- pyrazinyl)acrylate 1H-NMR (300 MHz, CDC13)<5l.32 (3H, t, J=7.1 Hz) ,1.48-1.88 (4H, m),2.20-2.36 (IH, m),2.54-2.80 (3H, m),3.56 (IH, d, J=13.6 Hz),3.64 (IH, d, J=13.6 Hz),4.14 (IH, br peak),4.25 (2H, q, J=7.1 Hz),5.72 (IH, br peak),6.66 (IH, d, J=15.5 Hz) ,7.16-7.25 (2H, m),7.34-7.42 (2H, m),7.56 (IH, d, J=15.5 Hz),7.89 (IH, s),8.03 (IH, s); MS (ES+) m/z 401.

Preparation 323 ethyl (2E)-3-(5-{[(3R)-l-(4-fluorobenzyl)-3-piperidinyl]amino}-2- pyrazinyl)acrylate 1H-NMR (300 MHz, CDC13)<5l.32 (3H, t, J=7.1 Hz) , 1.50-1.82 (4H, m), 2.18-2.31 (IH, m) ,2.44-2.66 (3H, m),3.45 (IH, d, J=13.2 Hz), 3.51 (IH, d, J=13.1 Hz), 4.10 (IH, br peak), 4.25 (2H, q, J=7.1 Hz), 5.46 (IH, br peak), 6.67 (IH, d, J=15.6 Hz), 7.01 (2H, t, J=8.7 Hz), 7.21- 7.33 (2H, m),7.56 (IH, d, J=15.6 Hz), 7.90 (IH, s),8.03 (IH, s); MS (ES+) m/z 385.

Preparation 324 . ' ethyl (2E)-3-(5-{[(3R)-l-(2-thienylmethyl)-3-piperidinyl]amino}-2- pyrazinyl)acrylate 1H-NMR (300 MHz, CDCl3) 51.33 (3H, t, J=7.1 Hz) ,1.50-1.69 (2H, m),1.69-1.89 (2H, m),2.24-2.37 (IH, m),2.43-2.55 (IH, m) ,2.60-2.84 (2H, m),3.70 (IH, d, J=13.9 Hz),3.80 (IH, d, J=13.9 Hz) ;4.14 (IH, br peak),4.25 (2H, q, J=7.1 Hz),5.64 (IH, br peak),6.68 (IH, d, J=15.5 Hz),6.88-6.93 (IH, m) ,6.93-6.99 (IH, m),7.20-7.30 (IH, m),7.58 (IH, d, J=15.5 Hz) ,7.92 (IH, s),8.05 (IH, s); MS (ES+) m/z 373.

Preparation 325 ethyl (2E)-3-(5-{[(3R)-l-(3-thienylmethyl)-3-piperidinyl]amino}-2- pyrazinyl)acrylate 1H-NMR (300 MHz, CDCl3)Sl.32 (3H, t, J=7.1 Hz) ,1.40-1.82 (4H, m),2.17-2.32 (IH, m),2.43-2.72 (3H, m),3.51 (IH, d, J=13.4 Hz),3.60 ■ (IH, d, J=13.4 Hz),4.10 (IH, brpeak),4.25 (2H, q, J=7.1 Hz),5.52 (IH, br peak),6.67 (IH, d, J=15.5 Hz),7.06 (IH, d, J=4.9 Hz),7.10 (IH, d, J=2.3 Hz),7.29 (IH, dd, J=7.7, 3.0 Hz),7.56 (IH, d, J=15.6 Hz),7.9 (IH, s),8.05 (IH, s); MS (ES+) m/z 373.

Preparation 326 ethyl (2E)-3-(5-{[(3R)-l-(2-pyridinylmethyl)-3-piperidinyl]amino}- 2-pyrazinyl)acrylate 1H-NMR (300 MHz, CDCl3)Sl.32 (3H, t, J=7.1 Hz) ,1.53-1.91 (4H, m),2.26-2.45 (IH, m),2.50-2.75 (3H, m),3.63 (IH, d, J=13.8 Hz),3.71 (IH, d, J=13.8 Hz) ,4.05-4.18 (IH, m),4.25 (2H, q, J=7.1 Hz),5.68 ( IH, br peak) , 6.65 ( IH, d, J=15.5 Hz) , 7.19 ( IH, dd, J=7.5 , 5.5 Hz) , 7.38 ( IH, d, J=7.7 Hz ) , 7.56 ( IH, d, J=15.5 Hz) , 7.66 ( IH, t , J=7.5 Hz) , 7.91 ( IH, s) , 8.01 ( IH, s) , 8 .55 ( IH, d, J=4.4 Hz) ; MS (ES+) m/z 368.

Preparation 327 ethyl (2E)-3-(5-{[(3R)-l-(3-pyridinylmethyl)-3-piperidinyl]amino}- 2-pyrazinyl)acrylate 1H-NMR (300 MHz, CDCl3)Ol.32 (3H, t, J=7.1 Hz) ,1.50-1.84 (4H, m),2.20-2.35 (IH, m) ,2.45-2.68 (3H, m),3.50 (IH, d, J=14.7 Hz),3.66 (IH, d, J=14.7 Hz),4.14 (IH, br peak),4.25 (2H, q, J=7.1 Hz),5.45 (IH, br peak),6.66 (IH, d, J=15.5 Hz) ,7.23-7.32 (IH, m),7.56 (IH, d, J=15.5 Hz),7.66 (IH, d, J=7.8 Hz),7.90 (IH, s),8.04 (IH, s),8.51 (IH, d, J=4.7 Hz),8.54 (IH, s); MS (ES+) m/z 368.

Preparation 328 ethyl (2E)-3-(5-{[(3R)-I-(cycloheptylmethyl)-3-piperidinyl]amino}- 2-pyrazinyl)aerylate 1H-NMR (300 MHz, CDCl3) <51.04-1.23 (2H, m),1.23-1.84 (18H, m),2.01- 2.19 (3H, m),2.33-2.48 (IH, m),2.48-2.70 (2H, m),4.10 (IH, br peak),4.25 (2H, q, J=7.0 Hz),5.64 (IH, br peak),6.66 (IH, d, J=15.8 Hz),7.57 (IH, d, J=15.4 Hz),7.89 (IH, d, J=I.1 Hz),8.05 (IH, d, J=I.5 Hz); MS (ES+) m/z 387.

Preparation 329 ethyl (2E)-3-(5-{[(3R)-1-(2-phenylethyl)-3-piperidinyl]amino}-2- pyrazinyl)aerylate 1H-NMR (300 MHz, CDCl3)Sl.32 (3H, t, J=7.1 Hz) ,1.50-1.85 (4H, m),2.20-2.35 (IH, m),2.46-2.86 (7H, m),4.11 (IH, br peak),4.25 (2H, q, J=7.1 Hz),5.46 (IH, br peak),6.67 (IH, d, , J=15.5 Hz) ,7.16-7.37 (5H, m),7.56 (IH, d, J=15.5 Hz),7.77 (IH, s),8.04 (IH, s); MS (ES+) m/z 381. Preparation 330 ethyl (2E)-3-(5-{[(3R)-I-cycloheptyl-3-piperidinyl]amino} -2-pyrazinyl)aerylate 1H-NMR (300 MHz, CDCl3) 61.22-1.90 (19H, m),2.35-2.72 (5H, m),4.06 (IH, br peak),4.25 (2H, q, J=7.1 Hz),5.68 (IH, br d, J=7.0 Hz),6.66 (IH, d, J=15.5 Hz),7.58 (IH, d, J=15.5 Hz),7.91 (IH, s),8.05 (IH, S); MS (ES+) m/z 373.

Preparation 331 ethyl (2E)-3-(5-{[ (3R)-1-(4-pyridinylmethyl)-3-piperidinyl]amino}- 2-pyrazinyl)aerylate 1H-NMR (300 MHz, CDCl3)Ol.33 (3H, t, J=7.1 Hz) ,1.50-1.86 (4H, m),2.24-2.36 (IH, m),2.44-2.71 (3H, m),3.48 (IH, d, J=14.8 Hz),3.55 (IH, d, J=14.8 Hz),4.06-4.20 (IH, m),4.25 (2H, q, J=7.1 Hz),5.42 (IH, br peak),6.68 (IH, d, J=15.5 Hz) ,7.21-7.29 (2H, m),7.57 (IH, d, J=15.5 Hz),7.92 (IH, s),8.05 (IH, s),8.55 (2H, d, J=5.8 Hz); MS (ES+) m/z 368. < .

Preparation 332 ethyl (2E)-3-(6-{[(3R)-I-cyclohexyl-3-piperidinyl]amino} -3-pyridinyl)aerylate 1H-NMR (300 MHz, CDCl3) <50.96-1.36 (1OH, m),1.46-1.86 (7H, m),2.20- 2.40 (IH, m),2.40-2.65 (3H, m),4.74 (IH, br d, J=Il Hz) ,3.81-3.98 (IH, m),4.24 (2H, q, J=7.1 Hz) ,5.36-5.55 (IH, m),6.20 (IH, d, J=15.9 Hz),6.40 (IH, d, J=8.8 Hz),7.57 (IH, d, J=15.8 Hz),7.60 (IH, dd, J=8.7, 2.3 Hz),8.18 (IH, d, J=2.2 Hz); MS (ES+) m/z 358.

Preparation 333 ethyl (2E)-3-(6-{(tert-butoxycarbonyl) [ (3R)-I-(cycloheptylmethyl)- 3-pyrrolidinyl]amino}-3-pyridinyl)acrylate 1H-NMR (300 MHz, CDCl3) 60.98-1.15 (2H, m),1.21-1.91 (24H, m),1.93- 2.30 (4H, m),2.50-2.76 (2H, m),2.91 (IH, br peak),4.28 (2H, q, J=7.2 Hz),4.90 (IH, br peak),6.46 (IH, d, J=16 Hz),7.31 (IH, d, J=8 Hz ) , 7 .65 ( IH, d, J=16 Hz ) , 7.80 ( IH, dd, J=8 , 2 Hz ) , 8.55 ( IH, d, J=2 Hz) ; MS (ES+ ) m/z 472 .

Preparation 334 ethyl (2E)-3-(5-{[(3R)-l-(2,3-dihydro-lH-inden-2-yl) -3-piperidinyl]amino}-2-pyrazinyl)aerylate 1H-NMR (300 MHz, CDCl3) δ1.19-1.38 (4H, m) ,1.57-1.86 (3H, m),2.28- 2.43 (IH, m),2.55-2.80 (3H, m),2.80-2.98 <2H, m) ,2.98-3.16 (2H, m),3.16-3.35 (IH, m),4.14 (IH, br peak),4.26 (2H, q, J=7.3 Hz),5.57 (IH, br peak),6.68 (IH, d, J=15.8 Hz),7.10-7.22 (4H, m),7.59 (IH, d, J=15.8 Hz),7.93 (IH, s),8.06 (IH, s); MS (ES+) m/z 392.

Preparation 335 A mixture of ethyl (2E)-3-(2-chloro-5-pyrimidinyl)acrylate (200 mg), (3R)-l-benzyl-3-pyrrolidinamine (0.244 mL), and N,N- dimethylformamide (5 mL) was stirred for 3 hours at 60°C. The reaction mixture was partitioned between ethyl acetate and H2O. The organic layer was washed with saturated NaHCO3 and brine, dried over MgSO4, filtered, and evaporated in vacuo to give ethyl (2E)-3- (2-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-pyrimidinyl)aeryl ate (330 mg) . IH-NMR (300 MHz, CDCl3) <5l.33 (3H, t, J = 7 Hz), 1.64-1.78 (IH, m) , 2.30-2.43 (2H, m), 2.61-2.75 (2H, m) , 2.82-2.92 (IH, m) , 3.59-3.70 (2H, m), 4.25 (2H, q, J = 7 Hz), 4.50-4.62 (IH, m) , 5.74 (IH, d, J = 8 Hz), 6.28 (IH, d, J = 16 Hz), 7.22-7.34 (5H, m) , 7.47 (IH, d, J = 16 Hz), 8.43 (2H, s). MS (ES+) m/z 353 (M+l) .

Preparation 336 To a solution of ethyl (2E)-3-(6-{(tert-butoxycarbonyl) [ (3R)-1- (cyclopentylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)aeryla te (225 mg, 0.51 mmol) in EtOH (2.5 mL) was added IN sodium hydroxide solution (1.0 mL) at ambient temperature and the mixture was allowed to stand for 18 hrs. The reaction mixture was adjusted to PH 5.0 with lmol/L hydrochloric acid and evaporated in vacuo to give (2E)-3-(6-{(tert-butoxycarbonyl) [ (3R)-1-(cyclopentylmethyl)-3- pyrrolidinyl]amino}-3-pyridinyl)acrylic acid. A mixture of (2E)-3-(6-{(tert-butoxycarbonyl) [ (3R)-I- (cyclopentylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acryli c acid, 0-(tetrahydro-2H-pyran-2-yl)hydroxylamine (77 mg, 0.66 mmol), HOBt (89 mg, 0.66 mmol) and EDCI (126 mg, 0.66 mmol) in DMF (4.5 inL) was stirred at 0 °C for 1 hr and the mixture was stirred at ambient temperature for 18 hrs. The reaction mixture was evaporated in vacuo and the residue was partitioned between saturated sodium bicarbonate solution and EtOAc. The organic layer was separated, washed water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform-MeOH=10-l) to give tert-butyl [ (3R)-I-(cyclopentylmethyl)-3-pyrrolidinyl] (5-{(lE)~3-oxo-3- [ (tetrahydro-2H-pyran-2-yloxy)amino]-l-propen-l-yl}-2- pyridinyl)carbamate (181 mg, 69%) as an amorphous powder. 1H-NMR (300 MHz, CDCl3) <51.05-1.21 (2H, m),1.46 (9H, s),1.46-2.10 (16H, m),2.10-2.48 (2H, m),2.48-2.85 (2H, m),2.90-3.09 (IH, m),3.60-3.76 (IH, m),3.90-4.05 (IH, m),4.80-4.96 (IH, m),4.96-5.11 (IH, m),6.41 (IH, br peak),7.30 (IH, d, J=8 Hz),7.69 (IH, d, J=15 Hz),7.78 (IH, d, J=8 Hz),8.56 (IH, s) .

The following compounds were obtained in a similar manner to that of Preparation 336. Preparation 337 (2E)-3-(6-{[(3R)-l-(cyclohexylmethyl)-3-pyrrolidinyl]amino}- 3- pyridinyl)-2-methyl-N-(tetrahydro-2H-pyran-2-yloxy)acrylamid e 1H-NMR (300 MHz, CDCl3) 60.80-0.97 (2H, m),1.11-1.34 (4H, m),1.34- 1.53 (IH, m),1.53-1.97 (1OH, m),2.11 (3H, d, J=I.3 Hz) ,2.19-2.41 (4H, m),2.56 (IH, dd, J=9.4, 3.2 Hz),2.69 (IH, dd, J=9.6, 6.3 Hz),2.77-2.86 (IH, m),3.62-3.73 (IH, m) ,3.95-4.07 (IH, m),4.23-4.37 (IH, m),4.99-5.08 (2H, m),6.38 (IH, d, J=8.7 Hz),7.11 (IH, s),7.47 (IH, dd, J=8.9, 2.4 Hz),8.14 (IH, d, J=2.3 Hz),8.58 (IH, br peak); MS (ES+ ) m/z 443 .

Preparation 338 (2E)-3-(6-{[ (3R)-l-benzyl-3-piperidinyl]amino}-3-pyridinyl)-N- (tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (300 MHz, CDCl3) δ1.30-1.71 (8H, m),1.75-1.91 (2H, m),2.15- 2.65 (3H, m),3.40-3.55 (2H, m) ,3.55-3.72 (IH, m) ,3.85-4.05 (2H, m),4.90-5.10 (2H, m),6.36 (IH, d, J=8 Hz),6.64 (IH, br peak),7.19- 7.40 (5H, m),7.53-7.68 (2H, m),8.20 (IH, d, J=2 Hz); MS (ES+) m/z 437.

Preparation 339 (2E)-3-(6-{[(3R)-1-(4-chlorobenzyl)-3-piperidinyl]amino}-3- pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (300 MHz, CDCl3) <51.46-1.95 (1OH, m),2.19-2.36 (IH, m),2.36- 2.66 (3H, m),3.43 (IH, d, J=13.5 Hz),3.50 (IH, d, J=13.5 Hz),3.56- 3.70 (IH, m),3.85-4.01 (2H, m),5.00 (IH, br s),5.32 (IH, br peak),6.24 (IH, br peak),6.36 (IH, d, J=8.8 Hz) ,7.20-8.34 (4H, m),7.57 (IH, d, J=9.3 Hz),7.63 (IH, d, J=15.9 Hz),8.21 (IH, s),8.26 (IH, br peak); MS (ES+) m/z 471.

Preparation 340 (2E)-3-(6-{[ (3R)-l-cyclόpentyl-3-piperidinyl]amino}-3-pyridinyl)-N- (tetrahydro-2H-pyrah-2-yloxy)acrylamide 1H-NMR (300 MHz, CDCl3) <51.00-1.97 (18H, m),2.23-2.84 (5H, m),3.56- 3.80 (IH, m),3.80-4.07 (2H, m),5.00 (IH, br s),5.88 (IH, br peak),6.27 (IH, br peak),6.41 (IH, d, J=8.8 Hz) ,7.50-7.72 (2H, m),8.14-8.42 (2H, m)'; MS (ES+) m/z 415.

Preparation 341 (2Z)-3-(6-{[ (3R)-l-(4-chlorobenzyl)-3-pyrrolidinyl]amino}-3- pyridinyl)-2-fluoro-N-(tetrahydro-2H-pyran-2-yloxy)acrylamid e 1H-NMR (300 MHz, CDCl3) δ1.50-1.77 (6H, m),1.77-1.98 (3H, m),2.26- 2.46 (2H, m),2.60 (IH, dd, J=9.6, 3.0 Hz),2.74 (IH, dd, J=9.6, 6.3 Hz),2.80-2.90 (IH, m),3.60 (2H, s),3.61-3.75 (IH, m),3.91-4.07 (IH, m),4.35 (IH, br peak) ,4.96-5.13 (2H, m),6.36 (IH, d, J=8.8 Hz),6.82 (IH, d, J=40.4 Hz),7.14-7.34 (4H, m),7.72 (IH, dd, J=8.8, 2.1 Hz),8.25 (IH, d, J=I.8 Hz),8.93 (IH, br peak) .

Preparation 342 (2E)-3-(5-{[(3R)-1-(2-pyrimidinyl)-3-piperidinyl]amino}-2- pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (300 MHz, CDCl3) <51.50-1.75 (2H, m) ,1.75-1.95 (6H, m),1.95- 2.11 (IH, m),3.58-3.83 (4H, m) ,3.83-4.13 (4H, m) ,4.13-4.25 (IH, m),5.00 (IH, br s),5.12 (IH, br d, J=7.3 Hz),6.51 (IH, t, J=4.7 Hz),6.70 (IH, br peak),7.65 (IH, d, J=15.2 Hz),7.90 (IH, s),8.05 (IH, s),8.30 (2H, d, J=4.7 Hz),8.35 (IH, br peak); MS (ES+) m/z 426.

Preparation 343 (2E)-3-(5-{[(3R)-1-(4-fluorobenzyl)-3-piperidinyl]amino}-2- pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (300 MHz, CDCl3) <51.50-1.96 (9H, m) ,2.12-2.34 (IH, m),2.44- 2.70 (3H, m),3.45 (IH, d, J=13.3 Hz),3.51 (IH, d, J=13.3 Hz),3.90- 4.04 (IH, m),4.04-4.16 (IH, m),5.00 (IH, br s),5.4β (IH, br peak),6.68 (IH, br peak),7.03 (2H, t, J=8.6 Hz) ,7.22-7.35 (2H, m),7.64 (IH, d, J=15.2 Hz),7.88 (IH, s),8.04 (IH, s),8.32 (IH, br peak); MS (ES+) m/z 456.

Preparation 344 (2E)-3-(5-{[(3R)-l-(2-pyridinylmethyl)-3-piperidinyl]amino}- 2- pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylainide 1H-NMR (300 MHz, CDCl3) δ1.54-1.96 (1OH, m),2.29-2.49 (IH, m),2.54- 2.78 (3H, m),3.60-3.76 (3H, m),3.90-4.03 (IH, m),4.06-4.19 (IH, m),5.01 (IH, br s),5.72 (IH, br peak),7.68 (IH, br peak),7.19 (IH, dd, J=7.0, 4.9 Hz),7.38 (IH, d, J=7.7 Hz) ,7.56-7.73 (2H, m),7.90 (IH, s),8.00 (IH, s),8.36 (IH, br peak),8.56 (IH, d, J=4.7 Hz); MS (ES+) m/z 439. Preparation 345 (2E)-3-(5-{[(3R)-l-(3-pyridinylmethyl)-3-piperidinyl]amino}- 2- pyrazinyl)-N-Ctetrahydro-2H-pyran-2-yloxy)acrylamide '5 1H-NMR (300 MHz, CDCl3) δ1.50-1.96 (1OH, m) ,2.20-2.40 (IH, m),2.40- 2.70 (3H, m),3.55 (2H, s),3.60-3.73 (IH, m) ,3.90-4.05 (IH, m),4.05- 4.20 (IH, m),5.02 (IH, br s),5.36-5.51 (IH, m),6.68 (IH, br peak),7.23-7.36 (IH, m) ,7.58-7.74 (2H, m),7.90 (IH, s),8.04 (IH, s),8.39 (IH, br peak),8.50-8.63 (2H, m) ; 0 MS (ES+) m/z 439.

Preparation 346 (2E)-3-(5-{ [ ('3R)-1-(2-phenylethyl)-3-pyrrolidinyl]amino}-2- pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 5 1H-NMR (300 MHz, CDCl3) δ1.50-1.98 (8H, m),2.30-2.48 (2H, m),2.61- 2.88 (6H, m),2.96-3.11 (IH, m) ,3.57-3.72 (IH, m),3.90-4.04 (IH, m),4.41-4.55 (IH, m),5.01 (IH, br s),5.30 (IH, d, J=7.7 Hz),6.70 (IH, br peak),7.15-7.35 (5H, m),7.64 (IH, d, J=15.0 Hz),7.85 (IH, s),8.05 (IH, s); 0 MS (ES+) m/z 438.

Preparation 347 (2E)-3-(5-{[(3R)-l-(cycloheptylmethyl)-3-piperidinyl]amino}- 2- pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 5 1H-NMR (300 MHz, CDCl3) <51.04-1.23 (2H, m) ,1.30-1.96 (2OH, m),1.96- 2.20 (3H, m),2.33-2.48 (IH, m),2.48-2.69 (2H, m),3.58-3.72 (IH, m),3.89-4.03 (IH, m),4.03-4.15 (IH, m),5.01 (IH, br s),5.61 (IH, br peak),6.71 (IH, br peak),7.64 (IH, d, J=15 Hz),7.86 (IH, s),8.03 (IH, s),8.28 (IH, br peak); 0 MS (ES+) m/z 458.

Preparation 348 (2E)-3-(5-{ [ (3R)-1-(2-phenylethyl)-3~piperidinyl]amino}-2- pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 5 1H-NMR (300 MHz, CDCl3) <51.35-1.96 (1OH, m),2.17-2.35 (IH, m),2.43- . 2.88 ( 7H, m) , 3.60-3.72 ( IH, m) , 3.90-4.04 ( IH, m) , 4.11 ( IH, br peak) , 5.01 ( IH, br s) , 5.38-5.55 ( IH, m) , 6.70 ( IH, br peak) , 7. 15- 7.38 ( 5H, m) , 7.51 ( IH, d, J=15 Hz ) , 7.75 ( IH, s) , 8.01 ( IH, s ) , 8.34 ( IH, br peak) ; MS (ES+) m/z 452.

Preparation 349 (2E)-3-(5-{[(3R)-l-cycloheptyl-3-piperidinyl]amino}-2-pyrazi nyl)-N- (tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (300 MHz, CDCl3) 61.30-1.96 (21H, m),2.35-2.46 (IH, m),2.46- 2.70 (4H, m),3.59-3.70 (IH, m) ,3.86-4.01 (IH, m),4.05 (IH, br peak),5.02 (IH, br s),5.61-5.74 (IH, m),6.65 (IH, br peak),7.63 (IH, d, J=15 Hz),7.88 (IH, s),8.02 (IH, s),8.34 (IH, br peak) ; MS (ES+) m/z 444.

Preparation 350 tert-butyl [(3R)-l-(l-adamantylmethyl)-3-pyrrolidinyl](5-{(lE)-3- oxo-3-[ (tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2- pyridinyl)carbamate 1H-NMR (300 MHz, CDCl3) δ1.18-2.40 (36H, m),2.64 (IH, br peak),2.87 (IH, br peak),3.63-3.76 (IH, m) ,3.91-4.10 (IH, m),4.86 (IH, br peak),4.95-5.10 (IH, m),6.41 (IH, br peak),7.30 (IH, d, J=9 Hz),7.59-7.90 (2H, m),8.59 (IH, s); MS (ES+) m/z 581.

Preparation 351 (2Z)-3-(6-{[ (3R)-l-cyclohexyl-S-pyrrolidinyllaπάnol-S-pyridinyl)-2- fluoro-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (300 MHz, CDCl3) <51.08-1.35 (6H, m) ,1.45-1.99 (1OH, m),1.99- 2.12 (IH, m),2.25-2.41 (IH, m) ,2.41-2.54 (IH, m),2.71 (IH, dd, J=9.3, 2.5 Hz),2.82 (IH, dd, J=9.8, 6.7 Hz) ,2.89-3.01 (IH, m),3.61- 3.75 (IH, m),3.94-4.06 (IH, m),4.27-4.43 (IH, m),4.99-5.06 (IH, m),5.06-5.21 (IH, m),6.37 (IH, d, J=8.8 Hz),6.82 (IH, d, J=40.4 Hz),7.72 (IH, dd, J=8.8, 2.1 Hz),8.26 (IH, s); MS (ES+) m/z 433. Preparation 352 (2E)-3-(6-{[(3R)-l-(4-methylbenzyl)-3-piperidinyl]amino}-3- pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (300 MHz, CDCl3) <51.40-1.95 (1OH, m) ,2.10-2.35 (4H, m),2.35- 2.66 (3H, m),3.43 (IH, d, J=12.9 Hz),3.50 (IH, d, J=12.9 Hz),3.60- 3.71 (IH, m),3.86-4.03 (2H, m),4.99 (IH, br peak),5.40 (IH, br peak),6.25 (IH, br peak),6.36 (IH, d, J=8.7 Hz),7.13 (IH, d, J=7.9 Hz),7.20 (IH, d, J=7.9 Hz),7.52-7.69 (2H, m) ,8.14-8.35 (2H, m); MS (ES+) m/z 451. '

Preparation 353 (2E)-N-(tetrahydro-2H-pyran-2-yloxy)-3-(5-{[(3R)-1-(2- thienylmethyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylamide 1H-NMR (300 MHz, CDCl3) <51.50-1.96 (9H, m),2.21-2.39 (IH, m),2.39- 2.55 (IH, m),2.55-2.85 (2ft,, m),3.59-3.70 (IH, m),3.70 (IH, d, J=13.9 Hz),3.80 (IH, d, J=13.9 Hz) ,3.90-4.04 (IH, m),4.06-4.20 (IH, m),5.00 (IH, br s),5.64 (IH, br peak),6.68 (IH, br peak) ,6.85-6.91 (IH, m),6.95 (IH, dd, J=4.8, 3.5 Hz) ,7.21-7.30 (IH, m),7.63 (IH, d, J=15.1 Hz),7.90 (IH, s),8.02 (IH, s),8.34 (IH, br peak); MS (ES+) m/z 444.

Preparation 354 (2E)-3-(5-{[ (3R)-1-(4-fluorobenzyl)-3-pyrrolidinyl]amino}-2- pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (300 MHz, CDCl3) δ1.50-1.78 (4H, m) ,1.78-1.95 (3H, m),2.28- 2.48 (2H, m),2.60-2.72 (2H, m),2.82-2.95 (IH, m),3.60 (2H, s),3.61- 3.71 (IH, m),3.90-4.04 (IH, m),4.46 (IH, br peak),5.01 (IH, br s),5.21 (IH, d, J=7 Hz),6.67 (IH, br peak),7.00 (IH, dd, J=8.7, 8.7 Hz),7.27 (IH, dd, J=8;4, 5.6 Hz),7.61 (IH, d, J=15.1 Hz),7.85 (IH, s),8.03 (IH, s),8.34 (IH, br peak); MS (ES+) m/z 442. ,

Preparation 355 (2E)-3-(6-{t(3R)-1-cyclohexyl-3-piperidinyl]amino}-3-pyridin yl)-N- (tetrahydro-2H-pγran-2-yloxy)acrylamide 1H-NMR (300 MHz, CDCl3) δ0.96-1.35 (7H, in) ,1.35-1.95 (13H, m),2.20- 2.40 (IH, m),2.40-2.67 (3H, m) ,2.67-2.83 (IH, m) ,3.60-3.72 (IH, m),3.80-4.06 (2H, m),4.99 (IH, br s),5.30-5.51 (IH, m),6.26 (IH, br peak),6.39 (IH, d, J=8.7 Hz),7.57 (IH, d, J=8.2 Hz),7.62 (IH, d, J=15.0 Hz),8.13-8.35 (IH, m); MS -(ES+) m/z 429.

Preparation 356 tert-butyl [(3R)-1-(cycloheptylmethyl)-3-pyrrolidinyl](5-{(IE)-3- oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-l-propen-l-yl}-2- pyridinyl)carbamate 1H-NMR (300 MHz, CDCl3) 00.95-1.18 (2H, m),1.18-1.93 (28H, m),1.93- 2.09 (IH, m),2.09-2.38 (2H, m) ,2.38-2.75 (2H, m),2.75-2.95 (IH, m),3.61-3.75 (IH, in) ,3.89-4.06 (IH, m) ,4.82-4.96 (IH, m) ,4.96-5.09 (IH, m),6.20-6.50 (IH, m),7.29 (IH, d, J=8.4 Hz),7.70 (IH, d, J=16.5 Hz),7.78 (IH, dd, J=8.3, 2.6 Hz),8.57 (IH, s); MS (ES+) m/z 543.

Preparation 357 (2E)-3-(5-{[(3R)-l-(4-pyridinylmethyl)-3-piperidinyl]amino}- 2- , pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (300 MHz, CDCl3) <51.45-1.97 (1OH, m) ,2.20-2.36 (IH, m),2.44- 2.71 (3H, m),3.52 (2H, s),3.60-3.71 (IH, m),3.88-4.04 (IH, m),4.15 (IH, br peak),5.02 (IH, br s),5.43 (IH, br peak),6.65 (IH, br peak),7.20-7.31 (2H, m),7.63 (IH, d, J=15.0 Hz),7.90 (IH, s),8.03 (IH, s),8.39 (IH, br peak),8.56 (2H, d, J=5.8 Hz); MS (ES+) m/z 439.

Preparation 358 (2E)-N-(tetrahydro-2H-pyran-2-yloxy)-3-(5-{[(3R)-1-(3- thienylmethyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylamide ,1H-NMR (300 MHz, CDC13) <51.48-1.95 (1OH, m),2.18-2.34 (IH, m),2.45- 2.74 (3H, m),3.51 (IH, d, J=13.5 Hz),3.59 (IH, d, J=13.5 Hz),3.61- 3.71 (IH, m),3.90-4.05 (IH, m) ,4.05-4.15 (IH, m),5.01 (IH, br s),5.53 (IH, br peak),6.66 (IH, br peak),7.05 (IH, d, J=5.0 Hz),7.10 (IH, d, J=2.3 Hz) ,7.23-7.32 (IH, m),7.62 (IH, d, J=15.0 Hz),7.88 (IH, s),8.02 (IH, s),8.31 (IH, br peak); MS (ES+) m/z 444.

Preparation 359 (2E)-3-(5-{[(3R)-l-(2,3-dihydro-lH-inden-2-yl)-3- piperidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2- yloxy)acrylamide 1H-NMR (300 MHz, CDCl3) <51.50-1.96 (1OH, m) ,2.25-2.45 (IH, m),2.54- 2.80 (3H, m),2.80-2.98 (2H, m),2.98-3.15 (2H, m) ,3.20-3.35 (IH, m),3.59-3.71 (IH, m),3.90-4.04 (IH, m) ,4.09-4.20 (IH, m),5.02 (IH, br s),5.59 (IH, br peak),6.68 (IH, br peak) ,7.10-7.30 (5H, m),7.65 (IH, d, J=15.4 Hz),7.91 (IH, s),8.05 (IH, s),8.34 (IH, br peak); MS (ES+) m/z 464.

Preparation 360 (2Z)-2-fluoro-3-(6-{[(3R)-l-(4-methylbenzyl)-3-pyrrolidinyl] amino}- 3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (300 MHz, CDCl3) <51.52-1.98 (9H, m),2.25-2.49 (5H, m),2.60 (IH, dd, J=9.7, 3.1 Hz),2.75 (IH, dd, J=9.7, 6.4 Hz) ,2.78-2.90 (IH, m),3.57 (IH, d, J=12.9 Hz),3.64 (IH, d, J=12.9 Hz) ,3.64-3.74 (IH, m),3.93-4.08 (IH, m),4.26-4.42 (IH, m),5.00-5.07 (IH, m),5.11 (IH, d, J=7.7 Hz),6.35 (IH, d, J=8.8 Hz),6.82 (IH, d, J=40.5 Hz),7.13 (2H, d, J=7.9 Hz),7.21 (2H, d, J=7.9 Hz),7.71 (IH, dd, J=8.8, 2.2 Hz),8.25 (IH, d, J=I.9 Hz); MS (ES+) m/z 455, 909.

, Preparation 361 To a suspension of lithium aluminum hydride (70 mg, 1.8 mmol) in tetrahydrofuran (2 mL) was added a solution of ethyl 6-{[(3R)-I- benzyl-3-piperidinyl]amino}nicotinate (250 mg, 0.74 mmol) in tetrahydrofuran (5 mL) dropwise at 0 1C under nitrogen and the mixture was stirred at same temperature for 3 hrs. To the reaction mixture was added methanol and water dropwise at 0 °C and the mixture was stirred for Ih. The precipitate was removed by vacuum filtration .and the filtrate was evaporated in vacuo. The residue was partitioned between water and ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated in vacuo to give (6-{[ (3R)-l-benzyl-3- piperidinyl]amino}-3-pyridinyl)methanol (219 mg, 100%) as an oil. MS (ES+) m/z 298.

The following compound was obtained in a similar manner to that of Preparation 361. Preparation 362 (6-{[(3S)-l-(cyclohexylmethyl)-3-piperidinyl]amino}-3- pyridinyl)methanol 1H-NMR (300 MHz, CDCl3) d 0.75-0.95 (2H, m), 1.06-1.31 (3H, m),1.38- 1.85 (1OH, m), 2.00-2.14 (2H, m), 2.14-2.30 (IH, m), 2.30-2.59 (3H, m),3.80-3.93 (IH, m),4.52 (2H, s),5.11 (IH, br peak), 6.40 (IH, d, J=8.6 Hz), 7.46 (IH, dd, J=8.5, 2.3 Hz), 8.04 (IH, d, J=2.3 Hz).

Preparation 363 To a solution of 6-{[(3R)-l-benzyl-3- piperidinyl]amino}nicotinaldehyde (110 mg, 0.37 mmol) in tetrahydrofuran (4 mL) was added (carbethoxymethylene)triphenylphosphorane (260 mg, 0.75 mmol) and the mixture was stirred at ambient temperature for 18 hrs. The reaction mixture was evaporated in vacuo and the residue was partitioned between water and EtOAc. The organic layer was separated, washed water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform-MeOH=15-l) to give ethyl (2E)-3-(6-{[(3R)-I-benzyl-3-piperidinyl]amino}-3-pyridinyl)a crylate (77 mg, 57%) as an oil. 1H-NMR (300 MHz, CDCl3) <51.19-1.40 (3H, m), 1.49-1.82 (4H, m),2.19- 2.36 (IH, m), 2.36-2.68 (3H, m), 3.40-3.59 (2H, m), 4.06-4.40 (3H, m),5.40 (IH, br peak), 6.19 (IH, d, J=15.8 Hz), 6.38 (IH, d, J=8.1 Hz), 7.19-7.40 (5H, m) , 7.40-7.75 (2H, m),8.16 (IH, s); MS (ES+) m/z 366. The following compounds were obtained in a similar manner to that of Preparation 363. Preparation 364 ethyl (2E)-3-(6-{[(3R)-l-(cyclohexylmethyl)-3-pyrrolidinyl]amino}- 3-pyridinyl)-2-methylacrylate 1H-NMR (300 MHz, CDCl3) 60.80-0.97 (2H, m),1.11-1.28 (4H, .m) ,1.34 (3H, t, J=7.1 Hz),-1.37-1.52 (IH, m) ,1.60-1.85 (5H, m),2.13 (3H, d, J=I.4 Hz),2.19-2.41 (4H, m),2.57 (IH, dd, J=IO,3 Hz),2.69 (IH, dd, J=IO,6 Hz),2.81 (IH, dt, J=8,4 Hz) ,4.20-4.38 (3H, m),5.04 (IH, d, J=7.7 Hz),6.39 (IH, d, J=8.7 Hz),7.53 (IH, s),7.56 (IH, dd, J=8.7, 2.3 Hz),8.21 (IH, d, J=2.3 Hz); . MS (ES+) m/z 372.

Preparation 365 ethyl (2E)-3-(6-{[(3S)-l-(cyclohexylmethyl)-3-piperidinyl]amino}-3 - pyridinyl)aerylate 1H^NMR (300 MHz, , CDCl3) <50.78-0.96 (2H, m), 1.06-1.40 (5H, m),1.40- 1.84 (HH, m), 2.00-2.25 (3H, m), 2.38-2.64 (3H, m),3.96 (IH, br peak), 4.25 (2H, q, J=7.1 Hz), 5.49 (IH, br peak), 6.21 (IH, d, J=15.9 Hz), 6.39 (IH, d, J=8.8 Hz), 7.57 (IH, d, J=15.9 Hz), 7.61 (IH, dd, J=8.7, 2.4 Hz), 8.19 (IH, d, J=2.2 Hz).

Preparation 366 To a solution of tert-butyl (3R)-3-({3-chloro-5-[ (lZ)-3-ethoxy-2- fluoro-3-oxo-l-propen-l-yl]-2-pyridinyl}amino)-1- piperidinecarboxylate (3.3g) in EtOH (19.3ml) was added solution of 4N HCl in dioxane(19.3ml) at ambient temperature and the mixture was stirred at same temperature for 1.5 hr. Diisopropylether was added to the mixture and precipitate was collected by filtration to give ethyl (2Z)-3-{5-chloro-6-[ (3R)-3-piperidinylamino]~3- pyridinyl}-2-fluoroacrylate dihydrochloride (2.98g) . 1H-NMRtDMSO-d6): S 1.29(3H, t, J=7.2 Hz), 1.61-1.97(4H, m) , 2.70- 2.81(1H, m), 2.88-2.99(1H, m) , 3.13-3.22(1H, m) , 3.23-3.31(1H, m) , 4.28(2H, q, J=7.2 Hz), 4.42-4.51(1H, m) , 7.03(1H, d, J=37.6 Hz), 7.96 ( 1H, d, J=I . 9 Hz ) , 8. 37 ( 1H, d, J=I .9 Hz ) , ( + )ESI-MS : 328 (M+H) + .

The following compounds were obtained in a similar manner to that of Preparation 366. Preparation 367 ethyl (2E)-3-{6-[(3R)-3-piperidinylamino] -3-pyridinyl}acrylate dihydrochloride 1H-NMR (300 MHz, DMSO-d6) δ1.25 (3H, t, J=7.1 Hz) ,1.54-1.68 (IH, m),1.68-1.86 (IH, m) ,1.86-2.11 (2H, m),2.84-3.02 (2H, m),3.10-3.23 (IH, m),3.23-3.44 (IH, m),4.10-4.30 (3H, m),6.55 (IH, d, J=16.0 Hz),7.00 (IH, d, J=8.9 Hz),7.63 (IH, d, j=16.1. Hz),8.21 (IH, d, J=8.9 Hz),8.31 (IH, d, J=I.7 Hz) ,8.80-9.15 (2H, m),9.26-9.43 (IH, m) .

Preparation 368 ethyl (2Z)-2-fluoro-3-{6-[(3R)-3-pyrrolidinylamino] -3-pyridinyl}acrylate dihydrochloride 1H-NMR (300 MHz, DMSO-d6) 61.29 (3H, t, J=7.1 Hz) ,1.93-2.09 (IH, m),2.20-2.40 (IH, m),3.12-3.60 (4H, m),4.28 (2H, q, J=7.1 Hz),4.60 (IH, br peak),6.99 (IH, d, J=9.2 Hz),7.10 (IH, d, J=37.3 Hz),8.05 (IH, d, J=9.2 Hz),8.34 (IH, s),9.10 (IH, br peak),9.45 (2H, br peak) ; MS (ES+) m/z 280.

Preparation 369 ethyl (2Z)-2-fluoro-3-{6-[ (3R)-3-piperidinylamino] -3-pyridinyl}acrylate dihydrochloride 1H-NMR(DMSO-d6): δ 1.30(3H, t, J=7.0 Hz), 1.59-1.69(1H, m) , 1.74- 1.84(1H, m), 1.89-1.99(1H, m) , 2.00-2.08(1H, m) , 2.89-3.04(2H, m) , 3.11-3.2O(1H, m), 3.34-3.44(1H, m) , 4.24-4.36(3H, m) , 7.16(1H, d, J=36.8 Hz), 7.18(1H, d, J=9.2 Hz), 8.14(1H, d, J=9.2 Hz), 8.34(IH, s), 9.13-9.73(3H, m) , (+JESI-MS:294(M+H)+. Preparation 370 To a solution of ethyl 6-{[(3R)-I-benzyl-3-piperidinyl]amino}-5- chloronicotinate (6.75 g, 18.1 mmol) in ethanol (200 iriL) were added ammonium formate (6.83 g, 108 mmol) and 10% Pd/C (20%w/w, 1.2 g) at ambient temperature and the mixture was heated to reflux with stirring for 8 hrs. After cooling, the catalyst in the reaction mixture was removed by filtration. The solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (NH, CHCl3 OnIy-CHCl3:MeOH/50:1-25:1) to give ethyl 6-[(3R)-3- piperidinylamino]nicotinate (4.5 g, 100%) as an oil. 1H-NMR (300 MHz, CDCl3)Sl.36 (3H, t, J=7.1 Hz),1.40-1.67 (3H, m),1.67-1.83 (IH, m),1.83-1.99 (IH, m),2.65 (IH, dd, J=Il.6, 7.0 Hz),2.70-2.81 (IH, m),2.81-2.93 (IH, m),3.16 (IH, dd, J=Il.4, 3.3 Hz),3.77-3.92 (IH, m),4.33 (2H, q, J=7.1 Hz),5.29 (IH, br d, J=7.1 Hz),6.37 (IH, d, J=8.9 Hz),7.97 (IH, dd, J=8.8, 2.3 Hz),8.74 (IH, d, J=2.3 Hz); MS (ES+) m/z 250.

The following compound was obtained in a similar manner to that of Preparation 370. Preparation 371 ethyl 6-{[(3S)-l-(cyclohexylmethyl)-3-piperidinyl]amino}nicotinate 1H-NMR (300 MHz, CDCl3) 60.77-0.97 (2H, m),1.05-1.30 (3H, m),1.36 (3H, t, J=7.1 Hz),1.40-1.86 (1OH, m),1.97-2.25 (3H, m),2.37-2.64 (3H, m),3.84-4.08 (IH, m),4.30 (2H, q, J=7.1 Hz),5.59 (IH, br peak),6.35 (IH, d, J=8.4 Hz),7.97 (IH, dd, J=8.6, 2.0 Hz),8.74 (IH, d, J=2.0 Hz).

Preparation 372 1) To a mixture of tert-butyl (3R)-3-pyrrolidinylcarbamate (1.00 g), 2,3-dimethylbenzaldehyde (720 mg) , N,N-diisopropylethylamine (1.87 mli), and ethanol (10 itiL) was added sodium triacetoxyborohydride (2.28 g) . After stirring for 3 hours at room temperature, the reaction mixture . was partitioned between ethyl acetate and saturated NH4Cl. The organic layer was washed with H2O, dried over MgSO4, filtered, and evaporated in vacuo. 2) To a mixture of above product and ethyl acetate (10 mL) was added 4N hydrogen chloride in ethyl acetate (8.40 mL) at 4 0C. After stirring at room temperature for 5 hours, the reaction mixture was neutrized with saturated NaHCO3. The resulting mixture was evaporated in vacuo. The residue was added chloroform, dried over Na2SO4, filtered, and evaporated in vacuo to give (3R)-l-(2,3- dimethylbenzyl)-3-pyrrolidinamine (193 mg) . 1H-NMR (300 MHz, CDCl3) δl.41-1.53 (IH, m) , 2.12-2.46 (3H, m) , 2.27 (3H, s), 2.29 (3H, s), 2.64-2.77 (2H, m) , 3.42-3.51 (IH, m) , 3.58 (2H, s), 7.00-7.14 (3H, m) , MS (ES+) m/z 205 (M+l) .

Preparation 373 To a suspension of sodium hydride (60%, 208 mg, 5.2 mmol) in tetrahydrofuran (2 mL) was added a solution of ethyl (diethoxyphosphoryl)(fϊuoro)acetate (1.26 g, 5.2 mmol) in tetrahydrofuran (5 mL) dropwise at 0 °C and the mixture was stirred at same temperature for 1 hr. To the mixture was added a solution of 6-{[(3R)-l-(cyclohexylmethyl)-3- pyrrolidinyl]amino}nicotinaldehyde (1.0 g, 3.5 mmol) in tetrahydrofuran (10 mL) dropwise at 0 °C and the mixture was stirred at same temperature for 4 hrs. The reaction mixture was evaporated in vacuo and the residue was partitioned between water and EtOAc. The organic layer was separated, washed water and brine, dried over magnesium sulfate, and evaporated in vacuo to a mixture of ethyl (2Z)-3-(6-{[(3R)-l-(cyclohexylmethyl)-3- pyrrolidinyl]amino}-3-pyridinyl)-2-fluoroacrylate and ethyl (2E)-3- (6-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-3-pyrid inyl)- 2-fluoroacrylate (1:1) as an oil. 1H-NMR (300 MHz, CDCl3) <50.80-1.00 (2H, m) ,1.10-1.51 (9H, m),1.51- 1.85 (4H, m),2.15-2.40 (4H, m),2.51-2.61 (IH, m),2.61-2.72 (IH, m),2.72-2.86 (IH, m),4.20-4.40 (3H, m),5.11 (IH, br d, J=8.4 Hz),6.39 (IH, d, J=8.8 Hz),6.80 (IH, d, J=36.3 Hz),8.03 (IH, dd, J=9.2, 2.6 Hz),8.25 (IH, d, J=2.6 Hz). Preparation 374 To a solution of ethyl 6-[(3R)-3-piperidinylamino]nicotinate (3.9 g, 15.6 mmol) in ethanol (40 mL) was added di-tert-butyl dicarbonate (3.76 g, 17.2 mmol) at ambient temperature and the mixture was stirred at same temperature for 18 hrs. The reaction mixture was evaporated in vacuo and the residue was partitioned between water and EtOAc. The organic layer was separated, washed water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane:EtOAc/l:l) to give ethyl 6-{[(3R)-l-(tert-butoxycarbonyl)-3- piperidinyl]amino}nicotinate (5.4 g, 99%) as an oil. 1H-NMR (300 MHz, CDCl3) <5l.37 (3H, t, J=7.1 Hz),1.44 (9H, s),1.51- 1.82 (2H, m),1.90-2.06 (IH, m),3.09-3.36 (2H, m),3.48-3.60 (IH, m),3.70-3.91 (2H, m),4.33 (2H, q, J=7.1 Hz) ,4.39-5.03 (IH, m),6.40 (IH, d, J=8.8 Hz),8.01 (IH, dd, J=8.7, 2.3 Hz),8.75 (IH, d, J=2.2 Hz); MS (ES+) m/z 350.

Preparation 375 To a solution of ethyl (2E)-3-{6-[(3R)-3-piperidinylamino]-3- pyridinyl}acrylate dihydrochloride (300 mg, 0.86 mmol) in DMF (4 mL) were added triethylamine (349 mg, 3.45 mmol) and 4- chlorobenzoyl chloride (181 mg, 1.03 mmol) at 0 X^ under nitrogen and the mixture was stirred at same temperature for 1 hr and at ambient temperature for 2hrs. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (hexane-EtOAc=l-l) to give ethyl (2E)-3-(6- {[(3R)-1-(4-chlorobenzoyl)-3-piperidinyl]amino}-3- pyridinyl)aerylate (270 mg, 76%) as an amorphous powder. 1H-NMR (300 MHz, DMSO-d6) <51.24 (3H, t, J=7.1 Hz) ,1.41-1.76 (2H, m),1.76-2.07 (2H, m) ,2.78-3.49 (3H, m) ,3.49-4.46 (4H, m),6.33 (IH, d, J=15.9 Hz),6.44-6.60 (IH, m),7.08-7.28 (IH, m) ,7:28-7.59 (5H, m) , 7 . 70-7.87 ( IH, m) , 8 .00-8. 32 ( IH, m) ; MS (ES+ ) m/z 414 .

Preparation 376 The mixture of ethyl (2E)-5-chloro-4-oxo-2-pentenoate (0.8 g) and 1-[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]thiourea (1.09 g) in CH3CN (16 mli) was stirred at 70 °C for 2 hrs. To the reaction mixture was added an AcOEt (32mL) and isolated precipitate was collected by filtration to give ethyl (2E)-3-(2-{[(3R)-I- (cyclohexylmethyl)-3-pyrrolidinyl]amino}thiazol-4-yl)acrylat e hydrochloride (1.10 g) . ^-NMRCDMSO-dδ): <5 0.80-1.36(6H, m) , 1.24(3H, t, J=7.1 Hz), 1.52- 2.56(8H, m), 2.92-4.06(5H, m) , 4.16(2H, q, J=7.1 Hz), 4.31-4.61(1H, m), 6.38 and 6.40(total IH, each d, J=each 15.3 Hz), 7.24(1H, s), 7.36(1H, d, J=15.3 Hz), 8.26-8.45(1H, m) , 1O.51(1H, s) (+JESI-MS:364(M+H)+.

Preparation 377 A mixture of 5-bromo-2-pyrazinecarboxylic acid (650mg) in thionyl chloride (2.35ml) was stirred under reflux condition. After 3 hrs, the reaction mixture was evaporated. To this residue in tetrahydrofuran (10ml) was added sodium borohydride (465mg) under ice cooling. The mixture was quenched with water and extracted with ethyl acetate (three times). The combined organic layer was washed with water, dried over Na2SO4, filtered and evaporated to give 230mg (39%) of (5-bromo-2- pyridinyl)methanol as an oil. MASS (ESI+,): 210.1, 211.0 (M+Na) . 1H-NMR ( 400MHz, CDCI3) : O 4.73 (2H, s), 7.20 (IH, d, J=8.2Hz), 7.82 (IH, dd, J=8.2 and 1.8Hz), 8.63 (IH, d, J=I.8Hz).

Preparation 378 A mixture of (5-bromo-2-pyridinyl)methanol (200mg), ethyl (triphenylphosphoranylidene)acetate (408mg) and manganese oxide (370mg) in dioxane (5ml) was stirred at 60 °C for 5 hrs. After cooling, the reaction mixture was filtered. Filtrate was evaporated. The residue was column chromatographed on silica gel to give 150mg (55%) of ethyl (2E)-3-(5-bromo-2-pyridinyl)acrylate as a solid. MASS (ESI+): m/z = 258.1(M+1), 259.0 (M+2). 1HNMR ( 400MHz, CDCl3): δ 1.34 (3H, t, J=7.1Hz), 4.28 (2H, q, J=7.1Hz), 6.91 (IH, d, J=15.5Hz), 7.31 (IH, d, J=8.3Hz), 7.62 (IH, d, J=15.5Hz), 7.84 (IH, dd, J=8.3 and 2.2Hz), 8.69 (IH, d, J=2.2Hz).

Preparation 379 To a solution of ethyl 5,6-dichloronicotinate (10.Og) and N,N- diisopropylethylamine (17.4mL) in 1,3-dimethyl-2-imidazolidinone (100 mL) was added tert-butyl (3R)-3-amino-l-piperidinecarboxylate (10.9) at ambient temperature and the mixture was stirred at 100 0C for 9 hr. The reaction mixture was poured into a mixture of AcOEt and water. The separated organic layer was added ice-water and the mixture was adjusted to pH 3.5 with IN-HCl. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo to give ethyl 6-{[(3R)-I-(tert-butoxycarbonyl)- 3-piperidinyl]amino}-5-chloronicotinate (16.74g) . ^-NMRfDMSO-dδ): 6 1.26-1.51(1OH, m) , 1.30(3H, t, J=7.1 Hz), 1.60- 1.71(2H, m), 1.83-1.95(1H, m) , 2.78-3.25(2H, m) , 3.56-4.12(3H, m) , 4.27(2H, q, J=7.1 Hz), 6.82(1H, s), 7.96(1H, d, J=I.9 Hz), 8.56(1H, d, J=I.9 Hz), (+)ESI-MS:384(M+H)+,406(M+Na)+.

Preparation 380 0.94 M solution of diisobutylaluminium hydride in hexane (139ml) was added to dropwise a solution of ethyl 6-{[(3R)-I-(tert- butoxycarbonyl)-3-piperidinyl]amino}-5-chloronicotinate (16.7g) in THF (250ml) with stirred at -5 to 0 °C under atmospheric pressure of nitrogen, and the reaction mixture was stirred at 0 0C for 1.5 hr. To the reaction mixture was added MeOH (26.4ml) was stirred at 0 to 10 for 20 minutes. The potassium sodium tartarate tetrahydrate (36.8g) was added to a above solution and the resultant mixture was stirred at ambient temperature for 3 hours. The reaction mixture was filtrated and the filtrate was evaporated in vacuo. The residue was chromatographed on silicagel eluting with solution of CHCl3 and AcOEt (3:2). The eluted fractions containing the desired product were collected and evaporated in vacuo to give tert-butyl tert-butyl (3R)-3-{[3-chloro-5-(hydroxymethyl)-2- pyridinyl]amino}-1-piperidinecarboxylate(10.29g) . (+)ESI-MS:342(M+H)+,364(M+Na)+ <5 1.24-1.48(10H, m) , 1.59-1.71(2H, m) , 1.82- 1.92(1H, m), 2.75-3.14(2H, m) , 3.53-3.96(3H, m) , 4.33(2H, d, J=5.6 Hz), 5.08(1H, t, J=5.6 Hz), 5.82(1H, s), 7.56(1H, d, J=2.0 Hz), 7.93(1H, d, J=2.0 Hz).

The following compound was obtained in a similar manner to that of Preparation 380. Preparation 381 tert-butyl (3R)-3-{ [5-(hydroxymethyl)-2-pyridinyl]amino}-1- piperidinecarboxylate 1H-NMR ( 300 MHz , CDCl3) <5 l .44 ( 9H, S ) , 1.50-1.66 ( 3H, m) , 1.66-1.81 ( IH, m) , 1.89-2.07 ( IH, m) , 2.90-3.30 ( 2H, m) , 3.52-3.66 ( IH, m) , 3.66- 3.78 ( IH, m) , 3.78-4.03 ( IH, m) , 4.44-4.61 (3H, m) , 6.44 ( IH, d, J=9.1 Hz ) , 7.49 ( IH, dd, J=8.5 , 2.4 Hz ) , 8.06 ( IH, d, J=2.1 Hz ) ; MS (ES+) m/z 308.

Preparation 382 A mixture of tert-butyl (3R)-3-{[3~chloro~5-(hydroxymethyl)-2- pyridinyl]amino}-1-piperidinecarboxylate (10.Og) and MnO2 (25.4g) in CHCl3 (200ml) was stirred at 60 0C for 3.5 hours. After removal of the insoluble material, and the solvent was evaporated in vacuo to give tert-butyl (3R)-3-[(3- chloro-5-formyl-2-pyridinyl)amino]-l-piperidinecarboxylate (9.08g) . 1H-NMRtDMSO-d6): δ 1.24-1.52(1OH, m) , 1.63-1.81(2H, m) , 1.85- 1.95(1H, m), 2.79-3.21(2H, m), 3.59-4.00(2H, m) , 4.04-4.16(1H, m), 7 .08 ( 1H, s ) , 7.96 ( 1H, d, J=I .9 Hz ) , 8.56 ( 1H, d, J=I . 9 Hz ) , 9. 76 ( 1H, s ) , ( + JESI-MS : 340 (M+H) + .

The following compounds were obtained in a similar manner to that of Preparation 382. Preparation 383 6-{[(3R)-1-benzyl-3-piperidinyl]amino}nicotinaldehyde 1H-NMR (300 MHz, CDCl3) <51.44-2.38 (5H, m),2.38-2.71 (3H, m),3.41- 3.60 (2H, m),4.00-4.40 (IH, m),6.41 (IH, d, J=8.8 Hz) ,7.13-7.41 (5H, m),7.86 (IH, d, J=8.8 Hz),8.46 (IH, s),9.74 (IH, s); MS (ES+) m/z 296.

Preparation 384 6-{[(3R)-l-(cyclohexylmethyl)-3-piperidinyl]amino}nicotinald ehyde 1H-NMR (300 MHz, CDCl3) <5θ.76-0.95 (2H, m) ,1.06-1.331 (3H, m),1.39- 1.85 (1OH, m),2.00-2.20 (3H, m),2.31-2.49 (IH, m),2.49-2.70 (2H, m),3.92-4.20 (IH, m),5.88 (IH, br peak),6.42 (IH, d, J=8.8 Hz) ,7.88 (IH, dd, J=8.5, 1.7 Hz),8.50 (IH, d, J=2.2 Hz),9.75 (IH, s); MS (ES+) m/z 302.

Preparation 385 6-{[(3S)-l-(cyclohexylmethyl)-3-piperidinyl]amino}nicotinald ehyde 1H-NMR (300 MHz, CDCl3)S0.77-0.97 (2H, m) ,1.07-1.32 (3H, m),1.40- 1.84 (1OH, m),2.00-2.23 (3H, m),2.34-2.68 (3H, m),4.02 (IH, br peak),5.87 (IH, br peak),6.42 (IH, d, J=8.8 Hz),7.87 (IH, d, J=8.8 Hz),8.49 (IH, d, J=I.9 Hz),9.75 (IH, s); MS (ES+) m/z 302.

Preparation 386 The mixture of ethyl (diethoxyphosphoryl)(fluoro)acetate (2.5ImL), MgBr2 (2.73g), Et3N (1.89mL) in THF (45mL) was stirred at 3-5 0C for lhr and to the mixture was dropwise added a solution of tert-butyl (3R)-3-[ (3-chloro-5-formyl-2-pyridinyl)amino]-1- piperidinecarboxylate (3.Og) in THF (2ImL) at 3-5 0C. The reaction mixture was stirred at same temperature for 2.5hrs. The reaction mixture was poured into a mixture of AcOEt and ice-water and the mixture was adjusted to pH 3.5 with IN-HCl. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel using a mixture of AcOEt and hexane (1 : 2 v/v) as an eluant. The eluted fractions containing the desired product were collected and evaporated in vacuo to give tert-butyl (3R)-3-({3-chloro-5-[(lZ)-3-ethoxy-2-fluoro-3-oxo-l- propen-1-yl]-2-pyridinyl}amino)-1-piperidinecarboxylate (3.38g) . 1H-NMR(DMSO-d6): δ 1.25-1.48(1OH, m) , 1.29(3H, t, 3=1.1 Hz), 1.64- 1.75(2H, m), 1.84-1.93(1H, m) , 2.77-3.20(2H, m) , 3.57-4.07(3H, m) , 4.27(2H, q, J=7.1 Hz), 6.60(1H, s), 7.01(1H, d, J=37.5 Hz), 7,94(1H, d, J=I.8 Hz), 8.36(1H, d, J=I.8 Hz), (+)ESI-MS:428(M+H)+.

The following compounds were obtained in a similar manner to that of Preparation 386. Preparation 387 (3R)-3-({5-[(IZ)-3-ethoxy-2-fluoro-3-oxo-l-propen-l-yl]-2- pyridinyl}amino)-1-pyrrolidinecarboxylate 1H-NMR (300 MHz, CDCl3)Sl.38 (3H, t, J=7.1 Hz),1.47 (9H, s),1.93 (IH, br peak),2.16-2.33 (IH, m) ,3.15-3.39 (IH, m),3.39-3.59 (2H, m),3.74 (IH, dd, J=Il.3, 6.0 Hz),4.35 (2H, q, J=7.1 Hz),4.43 (IH, br peak),7.77-4.90 (IH, m),6.43 (IH, d, J=8.8 Hz),6.80 (IH, d, J=36.1 Hz),7.83 (IH, dd, J=8.8, 2.1 Hz),8.26 (IH, s); MS (ES+) m/z 380.

Preparation 388 tert-butyl (3R)-3-({5-[(lZ)-3-ethoxy-2-fluoro-3-oxo-l-propen-l-yl]- 2-pyridinyl}amino)-1-piperidinecarboxylate (+JESI-MS:394(M+H)+

Preparation 389 To a solution of ethyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate (416 mg) in DMF (10 mL) was added (SRj-l-cyclohexyl-S-pyrrolidinamine dihydrochloride (849 mg) and K2CO3 (1.35 g) • After stirring for 2 hours at 1200C, the reaction mixture was partitioned between ethyl acetate and H2O. The organic layer was washed with H2O, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give ethyl (2E)-3-(5- {[(3R)-l-cyclohexyl-3-pyrrolidinyl]amino}-2-pyrazinyl)acryla te (318 mg). 1H-NMR (300 MHz, CDCl3) 01.11-1.34 (6H, m) , 1.32 (3H, t, J = 7 Hz), 1.57-2.09 (6H, m) , 2.30-2.44 (2H, m) , 2.67-2.74 (IH, m) , 2.78-2.84 (IH, m), 2.98-3.06 (IH, m) , 4.25 (2H, q, J = 7 Hz), 4.39-4.50 (IH, m), 5.32 (IH, d, J = 8 Hz), 6.68 (IH, d, J = 16 Hz), 7.57 (IH, d, J = 16 Hz), 7.88 (IH, d, J = 1 Hz), 8.06 (IH, d, J = 1 Hz). MS (ES+) m/z 345 (M+l).

Preparation 390 The mixture of ethyl (2E)-3-(5-{[ (3R)-l-(3-chlorobenzyl)-3- piperidinyl]amino}-2-pyrazinyl)acrylate (235 mg, 0.59 mmol) and IN- NaOH (1.2 mL) in EtOH (2 mL) was stirred at ambient temperature for 1 hr and the mixture was allowed to stand for 18 hrs. The reaction mixture was adjusted to PH 5.0 with lmol/L hydrochloric acid and evaporated in vacuo to give (2E)-3-(5-{[(3R)-l-(3-chlorobenzyl)-3- piperidinyl]amino}-2-pyrazinyl)acrylic acid (218 mg, 100%). 1H-NMR (300 MHz, DMSO-d6) <51.21-1.40 (IH, m),1.40-1.60 (IH, m),1.60-1.77 (IH, m) ,1.77-1.90 (IH, m),1.90-2.15 (2H, m),2.53-2.90 (2H, m),3.35-3.60 (2H, m),3.90-4.03 (IH, m),6.45 (IH, d, J=15.5 Hz),7.24-7.40 (4H, m),7.46 (IH, d, J=7.9 Hz),7.98 (IH, s),8.10 (IH, S); MS (ES+) m/z 373, 375.

The following compounds were obtained in a similar manner to that of Preparation 390. Preparation 391 (2E)-3-(6-{[(3R)-l-(cyclohexylmethyl)-3-piperidinyl]amino}-3 - pyridinyl)acrylic acid 1H-NMR (300 MHz, DMSO-d6) δ0.74-1.01 (2H, m) ,1.01-1.34 (3H, m),1.34-2.10 (1OH, m) ,2.59-3.65 (6H, m) ,4.04-4.45 (IH, m),6.26 (IH, d, J=16.9 Hz),6.55 (IH, d, J=8.7 Hz),7.28 (IH, br peak),7.47 (IH, d, J=15.8 Hz),7.81 (IH, d, J=8.1 Hz),8.21 (IH, s); MS (ES+) m/z 344.

Preparation 392 (2E)-3-(6-{[(3S)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-3 - pyridinyl)acrylic acid 1H-NMR (300 MHz, DMSO-d6) δ0.78-1.05 (2H, m) ,1.05-1.34 (3H, m),1.34-2.11 (1OH, m) ,2.53-3.66 (6H, m) ,3.94-4.41 (IH, m),6.28 (IH, d, J=16.1 Hz),6.55 (IH, d, J=8.8 Hz),7.31 (IH, br peak),7.48 (IH, d, J=15.4 Hz),7.83 (IH, d, J=9.5 Hz),8.24 (IH, s),9.25 (IH, ,br peak).

Preparation 393 (2Z)-3-(6-{(tert-butoxycarbonyl) [(3R)-I-(cyclohexylmethyl)-3- pyrrolidinyl]amino}-3-pyridinyl)-2-fluoroacrylic acid 1H-NMR (300 MHz, DMSO-d6) δ0.81-1.03 (2H, m),1.03-1.31 (3H, m),1.39 (9H, s),1.53-1.82 (6H, m) ,1.90-2.08 (IH, m),2.19-2.40 (IH, m),2.79- 3.00 (2H, m),3.00-3.81 (4H, m),5.10 (IH, br peak),6.87 (IH, d, J=34.1 Hz),7.41 (IH, d, J=8.4 Hz),8.09 (IH, dd, J=8.1, 1.8 Hz),8.15 (IH, s).

Preparation 394 (2E)-3-(6-{[(3R)-1-(cyclohexylcarbonyl)-3-piperidinyl]amino} -3- pyridinyl)acrylic acid 1H-NMR (300 MHz, DMSO-d6) δ0.83-2.04 (13H, m),2.22-2.64 (2H, m),2.94-3.20 (2H, m) ,3.51-4.41 (3H, m),6.24 (IH, d, J=15.9 Hz),6.45-6.64 (IH, m),7.03-7.28 (IH, m),7.41-7.54 (IH, m),7.74-7.85 (IH, m),8.20 (IH, br sJ.¬ MS (ES+) m/z 358,.

Preparation 395 (2E)-3-(5-{[(3R)-1-(2-chlorobenzyl)-3-piperidinyl]amino}-2- pyrazinyl)acrylic acid , 1H-NMR ( 300 MHz , DMSO-dβ) δ 1.24-1.41 ( IH, m) , 1.45-1.65 ( IH, m) , 1.65-1.80 ( IH, m) , 1.80-1.95 ( IH, m) , 1.95-2.25 ( 2H, m) , 2.56-2.76 ( IH, m) , 2.83-2.98 ( IH, m) , 3.59 (2H, s ) , 3.90-4.05 ( IH, m) , 6.45 ( IH, d, J=15.5 Hz ) , 7.22-7.45 ( 3H, m) , 7.50-7.60 ( IH, m) , 8.00 ( IH, s) , 8.11 ( IH, s) ; MS (ES+) m/z 373 , 375.

Preparation 396 , (2E)-3-(6-{[(3R)-1-(4-chlorobenzoyl)-3-piperidinyl]amino}-3- pyridinyl)acrylic acid 1H-NMR (300 MHz, DMSO-d6) 61.43-2.09 (2H, m) ,2.65-3.21 (IH, m),3.54-3.95 (2H, m) ,4.03-4.20 (IH, m) ,4.39-4.44 (2H, m),6.24 (IH, d, J=15.9 Hz),6.45-6.60 (IH, m) ,7.07-7.21 (IH, m),7.29-7.60 (5H, m),7.67-7.84 (IH, m),7.94-8.27 (IH, m); MS (ES+) m/z 386.

Preparation 397 A mixture of (2E)-3-(5-{[ (3R)-l-(3-chlorobenzyl)-3- piperidinyl]amino}-2-pyrazinyl)acrylic acid (218 mg, 0.59 mmol), O- (tetrahydro-2H-pyran-2-yl)hydroxylamine (82 mg, 0.70 mmol), HOBt (103 mg, 0.76 mmol) and EDCI (146 mg, 0.76 mmol) in DMF (6 mL) was stirred at 0 °C. for 1 hr and the mixture was stirred at ambient temperature for 18 hrs. The reaction mixture was evaporated in vacuo and the residue was partitioned between saturated sodium bicarbonate solution and EtOAc. The organic layer was separated, washed water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform-MeOH =95-5) to give (2E)-3-(5-{[(3R)-I- (3-chlorobenzyl)-3-piperidinyl]amino}-2-pyrazinyl)-N-(tetrah ydro- 2H-pyran-2-yloxy)acrylamide (251 mg, 91%) as an amorphous powder. 1H-NMR (300 MHz, CDCl3) δ1.50-1.99 (1OH, m),2.19-2.36 (IH, m),2.44- 2.70 (3H, m),3.45 (IH, d, J=13.4 Hz),3.53 (IH, d, J=13.4 Hz),3.58- 3.74 (IH, m),3.90-4.04 (IH, m),4.04-4.20 (IH, m),5.01 (IH, br s),5.49 (IH, br peak),6.70 (IH, br peak) ,7.15-7.36 (4H, m),7.64 (IH, d, J=15.2 Hz),7.90 (IH, s),8.03 (IH, s),8.36 (IH, br peak) ; MS (ES+ ) m/z 472.

The following compounds were obtained in a similar manner to that of Preparation 397. Preparation 398 (2E)-3-(6-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-3 - pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (300 MHz, CDCl3) <5θ.76-0.96 (3H, m),1.08-1.32 (3H, m),1.39- 1.94 (15H, m),1.98-2.25 (3H, m),2.35-2.61 (3H, m),3.59-3.62 (IH, m),3.86-4.03 (2H, m),5.00 (IH, br s),5.46 (IH, br peak),6.25 (IH, br peak),6.37 (IH, d, J=8.7 Hz) ,7.53-7.70 (2H, m),8.22 (IH, d, J=2.0 Hz),8.25 (IH, br peak); MS (ES+) m/z 443.

Preparation 399 (2E)-3-(6-{[(3S)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-3 - pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (300 MHz, CDCl3) 60.76-0.96 (3H, m),1.08-1.32 (3H, m),1.39- 1.94 (15H, m),1.98-2.25 (3H, m),2.35-2.61 (3H, m),3.59-3.62 (IH, m),3.86-4.03 (2H, m),5.00 (IH, br s),5.46 (IH, br peak),6.25 (IH, br peak),6.37 (IH, d, J=8.7 Hz) ,7.53-7.70 (2H, m),8.22 (IH, d, J=2.0 Hz),8.25 (IH, br peak); MS (ES+) m/z 443.

Preparation 400 tert-butyl [ (3R)-l-(cyclohexylmethyl)-3-pyrrolidinyl] (5-{(lZ)-2- fluoro-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen -l-yl}- 2-pyridinyl)carbamate 1H-NMR (300 MHz, CDCl3) 60.66-0.93 (2H, m) ,1.04-1.46 (18H, m),1.48- 2.06 (8H, m),2.06-2.29 (3H, m),2.36-2.71 (3H, m),2.81-2.96 (IH, m),3.60-3.75 (IH, m),3.93-4.06 (IH, m),4.78-4.95 (IH, m),5.06 (IH, s),6.96 (IH, d, J=39.2 Hz),7.31 (IH, d, J=8.5 Hz),7.92 (IH, dd, J=8.4, 2.3 Hz),8.61 (IH, d, J=2.2 HzJ.¬ MS (ES+) m/z 547. Preparation 401 (2E)-3-(5-{[(3R)-1-(2-chlorobenzyl)-3-piperidinyl]amino}-2- pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (300 MHz, CDCl3) <51.48-1.95 (1OH, m) ,2.20-2.35 (IH, m),2.54- 2.80 (3H, m),3.50-3.72 (3H, m) ,3.89-4.04 (IH, m) ,4.06-4.20 (IH, m),5.00 (IH, br s),5.71 (IH, br peak),6.66 (IH, br peak) ,7.16-7.28 (2H, m),7.30-7.43 (2H, m),7.62 (IH, d, J=15.1 Hz),7.86 (IH, s),8.00 (IH, s),8.35 (IH, br peak); MS (ES+) m/z 472.

Preparation 402 (2E)-3-(6-{[(3R)-l-(cyclohexylcarbonyl)-3-piperidinyl]amino} -3- pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (300 MHz, DMSO-d6) δ0.93-1.97 (18H, m),1.97-2.15 (IH, m),2.32-2.59 (IH, m),2.98-3.42 (2H, m),3.53-3.81 (2H, m),3.81-4.28 (4H, m),4.50-4.95 (IH, m),5.00 (IH, br s),6.10-6.76 (2H, m),7.54- 7.75 (2H, m),8.10-8.40 (2H, m) ; MS (ES+) m/z 457.

Preparation 403 (2E)-3-(6-{[(3R)-l-(4-chlorobenzoyl)-3-piperidinyl]amino}-3- pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (300 MHz, CDCl3) <51.35-1.96 (8H, m),1.96-2.17 (IH, m),3.08- 3.71 (4H, m),3.71-4.06 (4H, m),4.04-4.75 (IH, m),5.00 (IH, br s),6.10-6.63 (2H, m),7.14-7.46 (4H, m),7.46-7.70 (2H, m),7.94-8.43 (2H, m); MS (ES+) m/z 485.

Preparation 404 To a solution of ethyl (2E)-3-{5-[ (3R)-3-piperidinylamino]-2- pyrazinyl}acrylate dihydrochloride (300 mg, 0.86 mmol) in DMF (6 mL) were added diiopropylethylamine (366 mg, 2.84 mmol) and 6- chloropyrimidine (128 mg, 1.11 mmol) at ambient temperature and the mixture was stirred at ambient temperature for 18 hrs. The reaction mixture was evaporated in vacuo and the residue was partitioned between water and EtOAc. The organic layer was separated, washed water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform-MeOH=95-5/hexane-EtOAc=l/4) to give ethyl (2E)-3-(5- {[(3R)-1-(2-pyrimidinyl)-3-piperidinyl]amino}-2-pyrazinyl)ae rylate (141 mg, 46%) as an amorphous powder. 1H-NMR (300 MHz, CDCl3) <5l.33 (3H, t, J=7.1 Hz) ,1.61-1.75 (IH, m),1.75-1.91 (2H, m),1.96-2.12 (IH, m),3.66-3.84 (2H, m) ,3.84-3.98 (IH, m),4.00-4.14 (IH, m),4.20 (IH, dd, J=13.6, 3.2 Hz),4.25 (2H, q, J=7.1 Hz),5.13 (IH, br d, J=7.4 Hz),6.52 (IH, t, J=4.7 Hz),6.69 (IH, d, J=15.6 Hz),7.58 (IH, d, J=15.6 Hz),7.94 (IH, s),8.09 (IH, s),8.32 (2H, d, J=4.7 Hz); MS (ES+) m/z 355.

Preparation 405 The mixture of ethyl (2Z)-3-(5-chloro-6-{[ (3R)-I- (cyclohexylmethyl)-3-piperidinyl]amino}-3-pyridinyl)-2- fluoroacrylate (0.73g) and IN-NaOH (3.44mL) in MeOH (2OmL) was stirred at 60 0C for 3. hr. To the reaction mixture was added IN- NaCl 3.44mL and the mixture was evaporated in vacuo to give (2Z)-3- (5-chloro-6-{[(3R)-l-(cyclohexylmethyl)-3-piperidinyl]amino} -3- pyridinyl)-2-fluoroacrylic acid (0.68g). 1H-NMRtDMSO-d6): <5 0.83-0.96(2H, m) , 1.08-1.28(3H, m), 1.56- 1.86(1OH, m), 2.42-2.75(4H, m) , 2.75-3.10(2H, m) , 4.33-4.45(1H, m) , 6.73(1H, s), 7.77(1H, d, J=37.5 Hz), 7.88(1H, d, J=I.7 Hz), 8.26(1H, d, J=I.7 Hz), (-)ESI-MS:394(M-H)-.

The following compounds were obtained in a similar manner to that of Preparation 405. Preparation 406 (2E)-3-(2-{[(3R)-l-(cyclohexylmethyl)-3-pyrrolidinyl]amino}- 1,3- thiazol-4-yl)acrylic acid (-)ESI-MS:334(M-H)-. Preparation 407 (2Z)-3-(6-{[(3R)-l -benzyl- 3 -piperidinyl ] amino } - 5 -chloro- 3 - pyridinyl)-2-fluoroacrylic acid (- JESI-MS: 388 (M-H)-.

Preparation 408 (2Z)-3-(5-chloro-6-{ [ (3R)- l-cyclopentyl-3- piperidinyl] amino} -3- pyridinyl)- 2-fluoroacrylic acid (-)ESI-MS: 366 (M-H)-. ' , Preparation 409 (2Z)-3-(5-chloro-6-{[(3R)-l-cyclohexyl-3-piperidinyl]amino}- 3- pyridinyl) -2-fluoroacrylic acid ^-NMRfDMSO-dδ): δ 1.00-1.15(1H, m) , 1.16-1.31(2H, m) , 1.31-1.45(2H, m), 1.50-2.07(9H, m) , 2.66-3.29(5H, m) , 4.4O-4.56(1H, m), 6.54- 6.73(1H, m), 6.66(1H, d, J=37.6 Hz), 7.86(1H, d, J=I.7 Hz), 8.22(1H, d, J=I.7 Hz), (-)ESI-MS: 380 (M-H)-.

Preparation 410 (2Z)-3-(6-{[(3R)-l-benzyl-3-piperidinyl]aπiino}-3-pyridinyl )-2- fluoroacrylic acid 1H-NMR(DMSO-d6): <5 1.29-1.43(1H, m) , 1.64-1.93(3H, m) , 2.25-2.54(2H, m), 2.85-2.98(1H, m), 3.07-3.18(1H, m) , 3.91(2H, s), 4.12-4.24(1H, m), 6.58(1H, d, J=8.9 Hz), 6.78(1H, d, J=38.1 Hz), 7.21-7.41(4H, m) , 7.44-7.52(2H, m) , 7.71(1H, dd, J=2.2Hz,8.9 Hz), 8.2O(1H, d, J=2.2 Hz), (-)ESI-MS:354(M-H)-.

Preparation 411 (2Z)-3-(6-{[(3R)-l-(cyclohexylmethyl)-3-piperidinyl]amino}-3 - pyridinyl)-2-fluoroacrylic acid (-)ESI-MS:360(M-H)-.

Preparation 412 (2Z)-3-(6-{[(3R)-l-cyclohexyl-3-piperidinyl]amino}-3-pyridin yl)-2- fluoroacrylic acid (-)ESI-MS:346(M-H)-.

Preparation 413 (2Z)-3-(6-{[(3R)-l-cyclopentyl-3-piperidinyl]amino}-3-pyridi nyl)-2- fluoroacrylic acid (-)ESI-MS:332(M-H)-.

Preparation 414 EDCI (0.32g) was added to the solution of (2Z)-3-(5-chloro-6- {[ (3R)r1-(cyclohexylmethyl)-3-piperidinyl]amino}-3-pyridinyl)- 2- fluoroacrylic acid (0.68g) , O-(tetrahydro-2H-pyran-2- yl)hydroxylamine (0.24g), and HOBT (0.28g) in DMF (13.6ml) and the mixture was stirred at ambient temperature for 20 hr. The reaction mixture was poured into a mixture of AcOEt and aq NaHCO3. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallization with solution of iPE and hexane to give (2Z)-3-(5-chloro-6-{ [(3R)- 1-(cyclohexylmethyl)-3-piperidinyl]amino}-3-pyridinyl)-2-flu oro-N- (tetrahydro-2H-pyran-2-yloxy)acrylamide (0.57g) . 1H-NMRfDMSO-d6): δ 0.77-0.92(2H, m) , 1.06-1.27(3H, m) , 1.40- 1.81(16H, m), 2.08(2H, d, J=7.1 Hz), 2.16-2.44(3H, m), 2.48-2.61(1H, m), 3.47-3.56(1H, m) , 4.01-4.11(1H, m) , 4.12-4.22(1H, m) , 4.97(1H, s), 6.43(1H, d, J=8.2 Hz), 6.79(1H, d, J=39.7 Hz), 7.87(1H, s, J=I.8 Hz), 8.29(1H, d, J=I.8 Hz), 11.76(1H, s), (+JESI-MS:495(M+H)+.

The following compounds were obtained in a similar manner to that of Preparation 414. Preparation 415 (2Z)-3-(6-{[(3R)-l-benzyl-3-piperidinyl]amino}-5-chloro-3- pyridinyl)-2-fluoro-N-(tetrahydro-2H-pyran-2-yloxy)acrylamid e 1H-NMR(DMSO-d6):d 1.45-1.76(1OH, m) , 2.12-2.28(2H, m) , 2.44-2.55(IH, m), 2.62-2.73(lH, m) , 3.42-3.58(3H, m) , 4.01-4.U(IH, m) , 4.14- 4.25 ( 1H, m) , 4.97 ( 1H, s ) , 6.47( 1H, d, J=8.2 Hz ) , 6.77 ( 1H, d, J=39.8 Hz) , 7.21-7.27 ( 1H, m) , 7.29-7.34( 4H, m) , 7.86 ( 1H, d, J=I .9 Hz ) , 8.27 ( 1H, d, J=I .9 Hz ) , 11.76 ( 1H, s ) , ( + JESI-MS: 489 (M+H) + .

Preparation 416 (2E)-3-(2-{[ (3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-l,3- thiazol-4-yl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMRfDMSO-d6): δ 0.74-0.91(2H, m) , 1.07-1.27(3H, m) , 1.32- 1.83(13H, m), 2.11-2.79(7H, m) , 3.48-3.56(1H, m) , 3.88-3.98(1H, m) , 4.1O-4.21(1H, m), 4.89(1H, s), 6.44(1H, d, J=15.2 Hz), 6.97(1H, s), 7.17(1H, d, J=15.2 Hz), 7.86(1H, d, J=6.6 Hz), 11.19(1H, s), (+)ESI-MS:435(M+H)+.

Preparation 417 (2Z)-3-(5-chloro-6-{[(3R)-l-cyclopentyl-3-piperidinyl]amino} -3- pyridinyl)-2-fluoro-N-(tetrahydro-2H-pyran-2-yloxy)acrylamid e (+)ESI-MS:467(M+H)+.

Preparation 418 (2Z)-3-(5-chloro-6-{[(3R)-l-cyclohexyl-3-piperidinyl]amino}- 3- pyridinyl)-2-fluoro-N-(tetrahydro-2H-pyran-2-yloxy)acrylamid e 1H-NMRtDMSO-d6): δ 0.98-1.10(1H, m) , 1.11-1.29(4H, m) , 1.39- 1.78(15H, m), 2.24-2.34(1H, m) , 2.36-2.46(2H, m) , 2.49-2.60(1H, m) , 2.68-2.76(1H, m) , 3.47-3.55(1H, m) , 4.00-4.18(2H, m) , 4.97(1H, s), 6.43(1H, d, J=8.2 Hz), 6.78(1H, d, J=39.7 Hz), 7.87(1H, d, J=I.9 Hz), 8.29(1H, d, J=I.9 Hz), 11.76(1H, s), (+)ESI-MS:481(M+H)+.

Preparation 419 (2Z)-3-(6-{[(3R)-l-benzyl-3-piperidinyl]amino}-3-pyridinyl)- 2- fluoro-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR(DMSO-d6): <5 1.17-1.3O(1H, m) , 1.44-1.75(8H, m) , 1.77-2.04(3H, m), 2.57-2.67(1H, m) , 2.82-2.92(1H, m) , 3.43-3.54(3H, m) , 3.90- 4.12(2H, m), 4.96(1H, s), 6.52(1H, d, J=8.8 Hz), 6.69(lH, d, J=40.4 Hz), 6.95(1H, d, J=8.0 Hz), 7.2O-7.27(1H, m) , 7.28-7.34(4H, m) , 7.65 and 7.67(total IH, each d, J=each 2.2 Hz), 8.19(1H, d, J=2.2 Hz), 11.66(1H, s), (+JESI-MS:455(M+H)+.

Preparation 420 (2Z)-3-(6-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-3 - pyridinyl)-2-fluoro-N-(tetrahydro-2H-pyran-2-yloxy)acrylamid e 1H-NMR(DMSO-d6): δ 0.73-0.88(2H, m) , 1.05-1.29(4H, m) , 1.37- 1.94(17H, m), 2.05(2H, d, J=7.2 Hz), 2.57-2.67(1H, m) , 2.79-2.88(1H, m), 3.47-3.54(1H, m) , 3.93(1H, s), 4.02-4.11(1H, m) , 4.96(1H, s), 6.53(1H, d, J=8.9 Hz), 6.7O(1H, d, J=38.9 Hz), 6.89(1H, d, J=7.8 Hz), 6.67(1H, dd, J=2.2Hz, 8.9 Hz), 8.21(1H, d, J=2.2 Hz), 11.66(1H, s), (+JESI-MS:461(M+H)+.

Preparation 421 (2Z)-3-(6-{[ (3R)-l-cyclohexyl-3-piperidinyl]amino}-3-pyridinyl)-2- fluoro-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR(DMSO-d6): δ 0.96-1.29(6H, m) , 1.39-1.85(14H, m) , 2.01- 2.11(1H, m), 2.16-2.32(2H, m) , 2.61-2.71(1H, m) , 2.86-2.96(1H, m), 3.47-3.55(1H, m) , 3.87(1H, s), 4.02-4.11(1H, m) , 4.96(1H, s), 6.53(1H, d, J=8.9 Hz), 6.7O(1H, d, J=40.0 Hz), 6.9O(1H, d, J=7.8 Hz), 7.67(1H, dd, J=2.2Hz, 8.9 Hz), 8.21(1H, d, J=2.2 Hz), 11.66(1H, s), (+)ESI-MS:447(M+H)+.

Preparation 422 (2Z)-3-(6-{[(3R)-1-cyclopentyl-3-piperidinyl]amino}-3-pyridi nyl)-2- fluoro-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR(DMSO-d6): δ 1.14-2.06(19H, m) , 2.44-2.56(2H, m) , 2.64- 2.75(1H, m), 2.88-2.98(1H, m) , 3.46-3.54(1H, m) , 3.84-3.97(1H, m) , 4.00-4.11(1H, m), 4.94-4.98(1H, m) , 6.54(1H, d, J=9.0 Hz), 6.7O(1H, d, J=40.0 Hz), 6.94(IH, d, J=7.9 Hz), 7.67(IH, dd, J=2.2Hz, 9.0 Hz), 8.21(1H, d, J=2.2 Hz), 11.66(1H, s), ( + )ESI-MS : 433 (M+H) + .

Preparation 423 A mixture of ethyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate (300 mg, 1.41 mmol) , (3R)-l-(4-fluorobenzyl)-3-pyrrolidinamine dihydrochloride (565 mg, 2.11 mmol) and triethylamine (928 mg, 9.17 mmol) was stirred at 100 °C for 6 hrs. The reaction mixture was evaporated in vacuo and the residue was partitioned between water and EtOAc. The organic layer was separated, washed water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (35% EtOAc/hexane~50% EtOAc/hexane) to give ethyl (2E)-3-(5-{[(3R)-l-(4- fluorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)aerylate (245 mg, 47%) as an oil. 1H-NMR (300 MHz, CDCl3)Sl.32 (3H, t, J=7.1 Hz) ,1.65-1.80 (IH, m),2.30-2.46 (2H, m),2.60-2.73 (2H, m),2.82-2.95 (IH, m),3.60 (2H, s),4.25 (2H, q, J=7.1 Hz),4.46 (IH, br peak),5.20 (IH, d, J=7.7 Hz),6.68 (IH, d, J=15.5 Hz),7.01 (IH, dd, J=8.6, 8.6 Hz),7.28 (IH, dd, J=8.4, 5.6 Hz),7.56 (IH, d, J=15.5 Hz),7.88 (IH, s),8.05 (IH, s); MS (ES+) m/z 371.

The following compound was obtained in a similar manner to that of Preparation 423. Preparation 424 ethyl (2E)-3-(5-{[(3R)-l-(2-phenylethyl)-3-pyrrolidinyl]amino}-2- pyrazinyl)acrylate 1H-NMR (300 MHz, CDCl3)S1.33 (3H, t, J=7.1 Hz) ,1.56-1.79 (IH, m),2.30-2.47 (2H, m),2.61-2.87 (6H, m),2.96-3.09 (IH, m),4.26 (2H, q, J=7.1 Hz),4.41-4.55 (IH, m),5.25 (IH, d, J=7.8 Hz),6.68 (IH, d, J=15.5 Hz),7.16-7.35 (5H, m),7.58 (IH, d, J=15.5 Hz),7.87 (IH, s),8.06 (IH, s); MS (ES+) m/z 367.

Preparation 425 To a mixture of 2-chloro-5-iodopyrimidine (7.62 g) , palladium(II) acetate (356 mg) , tri(o-tolyl)phosphine (965 mg) , and DMF (32 itiL) was added ethyl acrylate (17.2 mL) and N,N-diisopropylethylamine (13.8 mL) . After stirring for 3 hours at 1000C, the reaction mixture was partitioned between ethyl acetate and H2O. The organic layer was dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give ethyl (2E)-3-(2-chloro-5-pyrimidinyl)acrylate (2.32 g) . 1H-NMR (300 MHz, CDCl3) <5l.35 (3H, t, J = 7 Hz), 4.30 (2H, q, J = 7 Hz), 6.58 (IH, d, J = 16 Hz), 7.58 (IH, d, J = 16 Hz), 8.76 (2H, s).

Preparation 426 Sodium triacetoxyborohydride (0.56g) was added a mixture of ethyl (2Z)-3-{5-chloro-6~[ (3R)-3-piperidinylamino]-3-pyridinyl}-2- fluoroacrylate dihydrochloride (0.7g), Et3N (0.49mL) and cyclohexanecarboxaldehyde (0.23mL) in CH2Cl2 ,(14mL) and the mixture was stirred at ambient temperature for 20hr. The reaction mixture was poured into a mixture of CHCl3 and aq NaHCO3. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo to give ethyl (2Z)-3-(5-chloro-6-{[(3R)-I- (cyclohexylinethy1)-3-piperidinyl]amino}-3-pyridinyl)-2- fluoroacrylate (0.74g). 1H-NMR(DMSO-d6): δ 0.77-0.89(2H, m) , 1.09-1.24(3H, m) , 1.29(3H, t, J=7.1 Hz), 1.41-1.54(2H, m) , 1.55-1.79(8H, m) , 2.08(2H, d, J=7.1 Hz), 2.20-2.40(3H, m) , 2.9O-2.59(1H, m) , 4.14-4.22(1H, m) , 4.27(2H, q, J=7.1 Hz), 6.51(1H, d, J=8.2 Hz), 6.99(1H, d, J=37.6 Hz), 7.92(1H, d, J=I.9 Hz), 8.34(1H, d, J=I.9 Hz), (+)ESI-MS:424(M+H)+.

The following compounds were obtained in a similar manner to that of Preparation 426. Preparation 427 ethyl (2Z)-3-(6-{[(3R)-l-benzyl-3-piperidinyl]atnino}-5-chloro-3- pyridinyl)-2-fluoroacrylate 1H-NMR(DMSO-d6): <5 1.29(3H, t, J=7.1 Hz), 1.46-1.73(4H, m) , 2.15- 2.27(2H, m), 2.46-2.55(1H, m) , 2.62-2.73 (IH , m) , 3.43-3.58(2H, m), 4.15-4.3O(1H, m), 4.27(2H, q, J=7.1 Hz), 6.57(1H, d, 3=8.2 Hz), 6.98(1H, d, J=37.5 Hz), 7.2O-7.27(1H, m) , 7.29-7.34(4H, m) , 7.91(1H, d, J=I.9 Hz),, 8.32 (IH, d, J=I.9 Hz), (+)ESI-MS:418(M+H)+.

Preparation 428 ethyl (2Z)-3-(5-chloro-6-{[(3R)-l-cyclopentyl-3-piperidinyl]amino} - 3-pyridinyl)-2-fluoroacrylate 6 1.25-1.37(2H, m) , 1.29(3H, t, J=7.1 Hz), 1.41- 1.80(1OH, m), 2.13-2.25(2H, m) , 2.49-2.62(2H, m) , 2.72-2.80(1H, m) , 4.12-4.21(1H, m), 4.27(2H, q, J=7.1 Hz), 6.55(1H, d, J=8.2 Hz), 6.99(1H, d, J=37.6 Hz), 7.91(1H, d, J=I.9 Hz), 8.34(1H, d, J=I.9 Hz), (+)ESI-MS:396(M+H)+.

Preparation 429 ethyl (2Z)-3-(5-chloro-6-{[(3R)-l-cyclohexyl-3-piperidinyl]amino}- 3-pyridinyl)-2-fluoroacrylate 1H-NMR(DMSO-d6): δ 0.98-1.10(1H, m) , 1.00-1.26(4H, m) , 1.29(3H, t, J=7.1 Hz), 1.4O-1.51(1H, m) , 1.51-1.79(8H, m) , 2.24-2.33(1H, m) , 2.35-2.46(2H, m) , 2.49-2.59(1H, m) , 2.68-2.75(1H, m) , 4.09-4.19(1H, m), 4.27(2H, q, J=7.1 Hz), 6.52(1H, d, J=8.1 Hz), 6.99(1H, d, J=37.6 Hz), 7.91(1H, d, J=I.9 Hz), 8.33(1H, d, J=I.9 Hz), (+)ESI-MS:410(M+H)+.

Preparation 430 ethyl (2Z)-3-(6-{[ (3R)-l-cyclopentyl-3-piperidinyl]amino}-3- pyridinyl)-2-fluoroacrylate 1H-NMR(DMSO-d6): 6 1.18-1.40(3H, m) , 1.28(3H, t, J=7.1 Hz), 1.40- 1.94(1OH, m), 1.94-2.O5(1H, m) , 2.45-2.56(1H, m) , 2.64-2.75(1H, m) , 2.87-2.99(1H, m) , 3.87-3.99(1H, m) , 4.26(2H, q, J=7.1 Hz), 6.56(1H, d, J=8.9 Hz), 6.91(1H, d, J=38.2 Hz), 7.06(1H, d, J=8.0 Hz), 7.73(1H, dd, J=2.0Hz,8.9 Hz), 8.27(1H, d, J=2.0 Hz), (+JESI-MS:362(M+H)+. Preparation 431 ethyl (2Z)-3-(6-{[ (3R)-l-cyclohexyl-3-piperidinyl]amino}-3- pyridinyl)-2-fluoroacrylate 1H-NMR(DMSO-d6): 6 0.98-1.33(5H, m) , 1.28(3H, t, J=7.1 Hz), 1.39- 1.84(9H, m), 2.03-2.11(1H, m) , 2.17-2.30(2H, m) , 2.62-2.69(1H, m) , 2.87-2.93(1H, m), 3.89(1H, s), 4.26(2H, q, J=7.1 Hz), 6.55(1H, d, J=9.0 Hz), 6.?1(1H, d, J=38.2 Hz), 7.01(1H, d, J=7.8 Hz), 7.72(1H, dd, J=2.3Hz, 9.0 Hz), 8.26(1H, d, J=2.3 Hz), (+)ESI-MS:376(M+H)+.

Preparation 432 ethyl (2Z)-3-(6-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-3 - pyridinyl)-2-fluoroacrylate 1H-NMR(DMSO-d6): 6 0.74-0,87(2H, m) , 1.08-1.31(4H, m) , 1.28(3H, t, J=7.0 Hz), 1.37-1.94(11H, m) , 2.03-2.07(2H, m) , 2.57-2.65(lH, m) , 2.79-2.86(1H, m) , 3.89-3.99(1H, m) , 4.26(2H, q, J=7.0 Hz), 6.54(1H, d, J=8.9 Hz), 6.91(1H, d, J=38.2 Hz), 7.02(1H, d, J=7.8 Hz), 7.73(1H, dd, J=2.3Hz, 8.9 Hz), 8.26(1H, d, J=2.3 Hz), (+JESI-MS:390(M+H)+.

Preparation 433 ethyl (2Z)-3-(6-{[(3R)-l-benzyl-3-piperidinyl]amino}-3-pyridinyl)- 2-fluoroacrylate 1H-NMR(DMSO-d6): δ 1.21-1.31(1H, m) , 1.28(3H, t, ,J=7.1 Hz),. 1.47- 1.56(1H, m), 1.64-1.72(1H, m) , 1.80-1.94(2H, m) , 1.94-2.O3(1H, m) , 2.57-2.66(1H, m) , 2.83-2.90(1H, m) , 3.48(2H, dd, J=13.4Hz, 17.6 Hz), 3.93-4.05(1H, m) , 4.25(2H, q, J=7.1 Hz), 6.54(1H, d, J=8.9 Hz), 6.91(1H, d, J=38.2 Hz), 7.08(1H, d, J=8.0 Hz), 7.2O-7.27(1H, m) , 7.28-7.34(4H, m) , 7.72(1H, dd, J=2.2Hz,8.9 Hz), 8.25(1H, d, J=2.2 Hz), (+)ESI-MS:384(M+H)+.

Preparation 434 A mixture of cyclohexanecarboxylic acid (133 mg, 1.03 mmol), ethyl (2E)-3-{6-[(3R)-3-piperidinylamino]-3-pyridinyl}acrylate dihydrochloride (300 mg, 0.86 mmol) , HOBt (163 mg, 1.21 mmol) and EDCI (174 mg, 1.12 iriinol) in DMF (6 mL) was stirred at 0 0C for 1 hr and the mixture was stirred at ambient temperature for 18 hrs. The reaction mixture was evaporated in vacuo and the residue was partitioned between saturated sodium bicarbonate solution and EtOAc. The organic layer was separated, washed water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (hexane-EtOAc=l- 1) to give ethyl (2E)-3-(6-{[(SRj-l-fcyclohexylcarbonylJ-S- piperidinyl]amino}-3-pyridinyl)aerylate (313 mg, 94%) as an amorphous powder. 1H-NMR (300 MHz, CDCl3) <50.95-2.14 (17H, m),2.34-2.61 (IH, m),3.05- 3.43 (2H, m),3.43-4.31 (4H, m),4.56-4.94 (IH, m) ,6.16-6.29 (IH, m),6.36-6.54 (IH, m),7.51-7.66 (2H, m),8.15-8.25 (IH, m); MS (ES+) m/z 386.

Preparation 435 . To a solution of ethyl .(2E)-3-(5-{[(3R)-I-benzyl-3- pyrrolidinyl]amino}-2-pyridinyl)aerylate (360mg) in methanol (10ml) was added INNaOH (5ml) at room temperature and stirred for 2 hrs. After then, the reaction mixture was neutralized with IN HCl (5ml). The mixture was evaporated under reduced pressure and co- evaporated with toluene (twice). To the residue in DMF(IOmI) was added 0-(tetrahydro-2H-pyran-2- yl)hydroxylamine (180mg), HOBt (138mg) and WSCD (318mg) and the mixture was stirred overnight. After 12 hours, water was added and extracted with ethyl acetate (Three times) . Combined organic layer was washed with water, dried over Na2SO4, filtered and evaporated. The reside was column chromatographed on silica gel ( CHC13 : MeOH) to give crude product. Crude product was purified by HPLC (Yamazene packed column, 26mm x 100mm) to give 190mg (44%) of (2E)-3-(5-{[(3R)-I-benzyl-3- pyrrolidinyl]amino}-2-pyridinyl)-N-(tetrahydro-2H-pyran-2- yloxy)acrylamide as an oil. MASS (ESI+): m/z = 423.3(M+1). 5 1HNMR ( 400MHz, CDCl3): δ 1.50-2.20 (7H, m) , 2.30-3.00 (5H, m) , 3.69 (2H, s), 3.90-4.10 (2H, m) , 4.48 (IH, br.s), 5.01 (IH, br.s), 6.77 (IH, dd, J=8.4 and 2.8Hz), 7.18 (IH, d, J=8.4Hz), 7.25-7.40 (6H, m), 7.61 (IH, d, J=15.2Hz), 7.98 (IH, s).

0 Preparation 436 A mixture of ethyl (2Z)-3-(6-{[ (3R)-l-(cyclohexylmethyl)-3- pyrrolidinyl]amino}-3-pyridinyl)-2-fluoroacrylate and ethyl (2E)-3- (6-{[(3R)-l-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-3-pyrid inyl)- 2-fluoroacrylate (1:1, 1.15g), di-tert-butyl dicarbonate (1.34g, 5 6.1 mmol) and 4-d-unethylaminopyridine (11 mg) in tetrahydrofuran (20 mli) was stirred at 60 °C for 48 hrs. The reaction mixture was evaporated in vacuo and the residue was partitioned between water and EtOAc. The organic layer was separated, washed water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue 0 was purified by silica gel column chromatography (CHCl3/methanol=95/5) and preparative thin layer chromatography (CHCl3/methanol=15/l) to give ethyl (2Z)-3-(6-{(tert- butoxycarbonyl) [(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-3- pyridinyl)-2-fluoroacrylate (575 mg) as an oil. 5 1H-NMR (300 MHz, CDCl3) <50.70-0.90 (2H, m) ,1.04-1.30 (3H, m),1.30- 1.49 (12H, m),1.49-1.78 (7H, m),1.89-2.10 (IH, m),2.10-2.30 (3H, m),2.40-2.74 (3H, m) ,2.84-2.99 (IH, m),4.36 (2H, g, J=7.1 Hz),4.89 (IH, br peak),6.90 (IH, d, J=35.0 Hz),7.32 (IH, d, J=9.0 Hz),8.0 (IH, d, J=9.0 Hz),8.60 (IH, d, J=2.2 Hz); 0 MS (ES+) m/z 476.

Preparation 437 / Ethyl (2E)-3-(5-chloro-2-Pyrazinyl)acrylate (250 mg, 1.18 mmol) and (5R)-5-amino-l-(benzyloxy)-2-piperidinone (388 mg, 1.86 mmol) were 5 combined in l,4-dioxane(4 mL) at ambient temperature. To this solution were added palladium(II) acetate(18 mg, 0.8 iπmol) and 2- dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (46 mg, O.lmmol) at the same temperature and the mixture was stirred for 5 minutes. To the resulting mixture was added cesium carbonate(536 mg, 1.86 mmol) and the mixture was heated at 95 0C for 24 hrs. The reaction mixture was evaporated in vacuo and the residue was partitioned between water and EtOAc. The organic layer was separated, washed water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (CHCl3/methanol=95/l) to give ethyl (2E)-3- (5-{[(3R)-I-(benzyloxy)-6-oxo-3-piperidinyl]amino}-2- pyrazinyl)aerylate (202 mg, 43%) as an amorphous solid. n 1H-NMR (300 MHz, CDCl3) δ1.54-1.75 (3H, m),1.75-1.94 (3H, m),1.94- 2.07 (2H, m),2.50-2.60 (2H, m),3.20 (IH, dd, J=Il.7', 5.1 Hz),3.61- 3.79 (2H, m),3.90-4.05 (IH, m),4.23-4.36 (IH, m),4.61 (IH, br d, J=6.6 Hz),4.98 (IH, d, J=Il.0 Hz),5.03 (IH, br peak),5.08 (IH, d, J=Il.0 Hz),6.70 (IH, br peak) ,7.31-7.41 (3H, m) ,7.41-7.50 (2H, m),7.64 (IH, d, J=15.8 Hz),7.80 (IH, s),8.00 (IH, s),8.36 (IH, br peak) ; MS (ES+) m/z 468, 935.

Preparation 438 To a solution of tert-butyl (3R)-3-{[5-(hydroxymethyl)-2- pyridinyl]amino}-1-piperidinecarboxylate (3.65 g, 11.9 mmol) in dioxane (50 mL) was added manganese(IV) oxide (7.7 g, 89 mmol) and (carbethoxymethylene)triphenylphosphorane (6.2 g, 17.8 mmol). After stirring for 18 hrs at 60 0C , a resulting precipitate was filtered and the filtrate was evaporated in vacuo and the residue was partitioned between water and EtOAc. The organic layer was separated, washed water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (CHCl3/methanol=95/5)to give tert-butyl (3R)- 3-({5-[(IE)-3-ethoxy-3-oxo-l-propen-l-yl]-2-pyridinyl}amino) -1- piperidinecarboxylate (3.99 g, 89%). 1H-NMR (300 MHz, CDCl3)Sl.33 (3H, t, J=7.1 Hz),1.43 (9H, s),1.50- 1.82 (2H, m) , 1.90-2.06 (IH, m) , 3.09-3.36 (2H, m) ,3.48-3.62 (IH, m) , 3.71-3.90 ( 2H, m) , 4.25 ( 2H, g, J=7.1 Hz) , 4. 76-4.90 (IH, m) , 6.23 ( IH, d, J=15.9 Hz) , 6.43 ( IH, d, J=8.8 Hz ) , 7.58 ( IH, d, J=16.0 Hz ) , 7.64 ( IH, dd, J=8.8 , 2.3 Hz) , 8.21 ( IH, d, J=2.2 Hz) ; MS (ES+) m/z 376.

Preparation 439 To a solution of ethyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate (500 mg) in DMF (5 mL) was added (3R).-l-(4-chlorobenzoyl)-3- pyrrolidinamine (951 mg) and Et3N (1.15 mL) . After stirring for 3 hours at 120 0C, the reaction mixture was partitioned between ethyl acetate and H2O. The organic layer was washed with H2O, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give ethyl (2E)- 3-(5-{[(3R)-l-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-2- pyrazinyl)aerylate (601 mg) . 1H-NMR (300 MHz, DMSO-d6) δ1.21-1.28 (3H, m) , 1.84-2.29 (2H, m) , 3.25-3.85 (4H, m) , 4.10-4.21 (2H, m) , 4.33-4.53 (IH, m) , 6.47-6.58 (IH, m), 7.46-7.61 (6H, m), 7.96-8.31 (3H, m) . MS (ES+) m/z 401 (M+l) .

The following compounds were obtained in a similar manner to that of Preparation 439. Preparation 440 ethyl (2E)-3-(5-{[(3R)-l-(2,3-dimethylbenzyl)-3- pyrrolidinyl]amino}-2-pyrazinyl)aerylate 1H-NMR (300 MHz, CDCl3) <5l.32 (3H, t, J = 7 Hz), 1.58-1.75 (IH, m) , 2.28 (3H, s), 2.30 (3H, s), 2.33-2.43 (2H, m) , 2.62-2.73 (2H, m) , 2.86-2.94 (IH, m) , 3.58-3.68 (2H, m) , 4.25 (2H, q, J = 7 Hz), 4.39- 4.50 (IH, m), 5.20 (IH, d, J = 7 Hz), 6.67 (IH, d, J = 16 Hz), 7.01-7.12 (3H, m), 7.57 (IH, d, J = 16 Hz), 7.87 (IH, d, J = I Hz), 8.05 (IH, d, J = 1 Hz). MS (ES+) m/z 381 (M+l).

Preparation 441 ethyl (2E)-3-(5-{[ (3R)-1-(2-chlorobenzyl)-3-pyrrolidinyl]amino}-2- pyrazinyl)aerylate 1H-NMR (300 MHz, CDCl3) <5l.32 (3H, t, J = 7 Hz), 1.67-1.76 (IH, m) , 2.33-2.51 (2H, m) , 2.69-2.82 (2H, m) , 2.63-3.01 (IH, m) , 3.78 (2H, s), 4.25 (2H, q, J = 7 Hz), 4.42-4.53 (IH, m) , 5.25 (IH, d, J = 8 Hz), 6.68 (IH, d, J = 16 Hz), 7.16-7.28 (2H, m) , 7.34-7.45 (2H, m) , 7.57 (IH, d, J = 16 Hz), 7.88 (IH, d, J = 1 Hz), 8.05 (IH, d, J = 1 Hz). MS (ES+) m/z 385 (M-I).

Preparation 442 ethyl (2E)-3-(6-{(tert-butoxycarbonyl) [(3R)-1-(2-ethylbutyl)-3- pyrrolidinyl]amino}-3-pyridinyl)acrylate 1H-NMR (300 MHz, CDCl3) <5θ.8O (6H, t, J = 7 Hz), 1.16-1.66 (5H, m) , 1.35 (3H, t, J = 7 Hz), 1.44 (9H, s), 1.94-2.09 (IH, m) , 2.14-2.28 (3H, mh 2.50-2.70 (3H, m) , 2.80-2.89 (IH, m) , 4.28 (2H,, q, J = 7 Hz), 4.83-4.94 (IH, m) , 6.46 (IH, d, J = 16 Hz), 7.26-7.34 (IH, m) , 7.66 (IH, d, J = 16 Hz), 7.81 (IH, dd, J = 2, 8 Hz), 8.56 (IH, d, J = 2 Hz) . MS (ES+) m/z 446 (M+l).

Preparation 443 ethyl (2E)-3-(6-{(tert-butoxycarbonyl) [ (3R)-l-isobutyl-3- pyrrolidinyl]amino}-3-pyridinyl)acrylate 1H-NMR (300 MHz, CDCl3) <5θ.84 (6H, d, J = 7 Hz), 1.35 (3H, t, J = 7 Hz), 1.45 (9H, s), 1.58-1.72 (IH, m) , 1.94-2.06 (IH, m) , 2.10-2.27 (3H, m), 2.47-2.68 (3H, m) , 2.86-2.94 (IH, m) , 4.28 (2H, q, J = 7 Hz), 4.86-4.94 (IH, m) , 6.46 (IH, d, J = 16 Hz), 7.32 (IH, d, J = 8 Hz), 7.66 (IH, d, J = 16 Hz), 7.81 (IH, dd, J = 2, 8 Hz), 8.55 (IH, d, J = 2 Hz). MS (ES+) m/z 418 (M+l).

Preparation 444 ethyl (2E)-3-(5~{[(3R)~l-benzyl-3-pyrrolidinyl]amino}-6-methyl-2- pyrazinyl)acrylate 1H-NMR (300 MHz, CDCl3) <5l.32 (3H, t, J = 7 Hz), 1.60-1.77 (IH, m) , 2.22-2.97 (8H, m) , 3.64-3.67 (2H, m) , 4.24 (2H, q, J = 7 Hz), 4.56- 4.66 (IH, m), 5.00-5.06 (IH, m) , 6.71 (IH, d, J = 16 Hz), 7.25-7.35 (5H, m), 7.56 (IH, d, J = 16 Hz), 7.95 (IH, s) . MS (ES+) m/z 367 (M+l) .

Preparation 445 ethyl (2E)-3-(5-{ [ (3R)-1-(3-chlorobenzyl)-3-pyrrolidinyl]amino}-2- pyrazinyl)acrylate 1H-NMR (300 MHz, CDCl3) <5l.32 (3H, t, J = 7 Hz), 1.64-1.77 (IH, m) , 2.32-2.47 (2H, m) , 2.63-2.75 (2H, m) , 2.85-2.93 (IH, m) , 3.61 (2H, s), 4.25 (2H, q, J = 7 Hz), 4.43-4.52 (IH, m) , 5.20 (IH, d, J = 8 Hz), 6.68 (IH, d, J = 16 Hz), 7.18-7.28 (3H, m) , 7.33 (IH, s), 7.57 (IH, d, J = 16 Hz), 7.89 (IH, d, J = 1 Hz), 8.05 (IH, d, J = 1 Hz). MS (ES+) m/z 387 (M+l). c Preparation 446 1) To a solution of ethyl (2E)-3-(5-{ [ (3R)-l-(4-chlorobenzoyl)-3- pyrrolidinyl]amino}-2-pyrazinyl)acrylate (591 mg) in dioxane (15 mli) was added IN sodium hydroxide (4.40 mL). After stirring at 60 °C for 2 hours, the reaction mixture was added H2O(15 mL) and neutrized with IN hydrochloric acid (to pH 7) . A resulting mixture was evaporated in vacuo. 2) To a mixture of above product, 0-tetrahydro-2H-pyran-2- ylhydroxylamine (259 mg) , and 1-hydroxybenzotriazole (299 mg) in N,N-dimethylformamide (7.4 mL) was added 1-(3-dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride (424 mg) . The mixture was stirred for 6 hours at room temperature. The reaction mixture was added saturated NaHCO3 (8 mL) and water (30 mL), and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give (2E)-3-(5-{[(3R)-l-(4- chlorobenzoyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahy dro-2H- pyran-2-yloxy)acrylamide 1H-NMR (300 MHz, DMSO-d6) δl.48-1.74 (6H, m) , 1.82-2.31 (2H, m) , 3.25-4.02 ( 6H, m) , 4.31-4.50 ( IH, m) , 4. 90 ( IH, brs ) , 6 . 57-6 . 69 ( IH, m) , 7.33-8. 19 ( 7H, m) , 11.2 ( IH, brs ) . MS (ES+ ) m/z 472 (M+l ) .

The following compounds were obtained in a similar manner to that of Preparation 446. Preparation 447 (2E)-3-(5-{ [ (3R)-1-(2,3-d±tnethylbenzyl)-3-pyrrolidinyl]amino}-2- pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (300 MHz, DMSO-d6) (5l.46-l.74 (7H, m) , 2.11-2.28 (IH, m) , 2.22 (3H, s), 2.23 (3H, s), 2.34-2.53 (2H, m) , 2.59-2.83 (2H, m) , 3.30-3.60 (3H, m) , 3.90-4.01 (IH, m) , 4.23-4.35 (IH, m) , 4.89 (IH, brs), 6.59 (IH, d, J = 16 Hz), 6.97-7.11 (3H, m) , 7.37 (IH, d, J = 16 Hz), 7.75 (IH, d, J = 6 Hz), 7.97 (IH, s), 8.09 (IH, s) . MS (ES+) m/z 452 (M+l).

Preparation 448 (2E)-3-(5-{[ (3R)-1-(2-chlorobenzyl)-3-pyrrolidinyl]amino}-2- pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (300 MHz, DMSO-d6) δ1.47-1.74 (7H, m) , 2.18-2.31 (IH, m) , 2.44-2.56 (2H, m) , 2.69-2.89 (2H, m) , 3.48-3.57 (IH, m) , 3.65-3.77 (2H, m), 3.90-4.01 (IH, m) , 4.27-4.39 (IH, m) , 4.89 (IH, brs), 6.60 (IH, d, J = 16 Hz), 7.24-7.54 (5H, m) , 7.80 (IH, d, J = 6 Hz), 7.98 (IH, s), 8.10 (IH, s), 11.2 (IH, brs). MS (ES+) m/z 458 (M+l).

Preparation 449 (2E)-3-(5-{[ (3R)-1-(3-chlorobenzyl)-3-pyrrolidinyl]amino}-2- pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (300 MHz, DMSO-d6) δ1.46-1.74 (7H, m) , 2.17-2.30 (IH, m) , 2.38-2.48 (2H, m) , 2.63-2.81 (2H, m) , 3.48-3.57 (IH, m) , 3.60 (2H, s), 3.89-4.01 (IH, m), 4.25-4.37 (IH, m) , 4.89 (IH, brs), 6.60 (IH, d, J = 16 Hz), 7.26-7.42 (5H, m) , 7.79 (IH, d, J = 6 Hz), 7.98 (IH, s), 8.10 (IH, s), 11.2 (IH, brs). MS (ES+) m/z 458 (M+l). Preparation 450 To a mixture of tert-butyl (3R)-3-pyrrolidinylcarbamate (450mg) and 3-methoxybenzaldehyde (352uL) in CH2CI2 (4.5mL) was added sodium triacetoxyborohydride (922mg), which was stirred at room temperature for 2 hours. To the resultant was added sat. NaHCO3 aq. , which was stirred for 20 min. The mixture was extracted with CH2Cl2. The organic phase was washed with brine and dried over Na2Sθ4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give tert-butyl [(3R)-I-(3- methoxybenzyl)-3-pyrrolidinyl]carbamate (744mg) as a off-white solid. 1H NMR (200 Mz, CDCl3) d 1.43 (9H, s), 1.49-1.72 (IH, m) , 2.16-2.46 (2H, m), 2.58-2.72 (2H, m) , 2.80-2.98 (IH, m), 3.63 (2H, br. s), 3.82 (3H, s), 4.08-4.31 (IH, br) , 4.90-5.14 (IH, br) , 6.76-6.95 (3H, m), 7.24 (IH, t, J = 8.1 Hz); MS (ES+) m/z 307 (M+l).

The following compound was obtained in a similar manner to that of Preparation 450. Preparation 451 tert-butyl [(3R)-l-(3-cyanobenzyl)-3-pyrrolidinyl]carbamate 1H NMR (CDCl3, 200MHz) d 1.44 (9H, s), 1.50-1.82 (IH, m) , 2.12-2.42 (2H, m), 2.48-2.72 (2H, m) , 2.72-2.89 (IH, m) , 3.63 (2H, s), 4.08- 4.31 (IH, br), 4.70-4.99 (IH, br) , 7.36-7.68 (4H, m) ; MS (ES+) 302 (M+l).

Preparation 452 To a solution of tert-butyl [(3R)-l-(3-methoxybenzyl)-3- pyrrolidinyl]carbamate (739mg) in ethyl acetate (3.7mL) was added 4N HCl-ethyl acetate (6.OmL), which was stirred at room temperature for 1.5 hours. The mixture was concentrated to give (3R)-I-(3- methoxybenzyl)-3-pyrrolidinamine dihydrochloride (702 mg) as a off- white amorphous. 1H NMR (DMSO-d6, 200 MHz) δ 1.90-2.42 (2H, m) , 3.06-4.16 (5H, m) , 3. 79 ( 3H, s ) , 4.34-4. 58 ( 2H, br) , 6 .95-7 .42 ( 4H, m) , 8. 47-8. 58 ( 2H, br) ; MS (ES+ ) m/z 207 (M+l ) .

The following compounds were obtained in a similar manner to that of Preparation 452. Preparation 453 3-{[(3R)-3-amino-l-pyrrolidinyl]methyl}benzonitrile dihydrochloride 1H NMR(DMSO-d6, 200MHz) <5 1.89-2.34 (2H, m) , 3.05-4.22 (5H, m) , 4.41-4.71 (2H, m) , 7.69 (IH, t, J = 7.8 Hz), 7.89-8.23 (3H, m) , 8.25-8.82 (2H, m); MS (ES+) m/z 202 (M+l).'

Preparation 454 N-(3-{[(3R)-3-amino-1-pyrrolidinyl]methyl}phenyl)acetamide dihydrochloride 1H NMR (DMSO-d6, 200MHz) δ 2.06 (3H, s), 1.91-2.35 (2H, m) , 3.03- 4.19 (5H, m), 4.42 (2H, m) , 7.23-7.46 (2H, m) , 7.49-7.65 (2H, m) , 7.82 (IH, s), 8.39-8.85 (3H, m) , 10.21 (IH, s), 11.10-11.67 (IH, m); MS (ES+) m/z 234 (M+l).

Preparation 455 '(3R)-l-[3-(dimethylamino)benzyl]-3-pyrrolidinamine trihydrochloride 1H NMR (DMSO-d6, 200MHz) 6 1.94-2.41 (2H, m) , 3.03 (6H, s), 3.03- 4.18 (5H, m), 4.31-4.63 (2H, m) , 7.02-7.74 (4H, m) , 8.51-9.05 (3H, m), 11.29-12.15 (IH, m) ; MS (ES+) m/z 220 (M+l).

Preparation 456 N-(3-{[(3R)-3-amino-l-pyrrolidinyl]methyl}phenyl)methanesulf onamide dihydrochloride 1H NMR (DMSO-d6, 200 MHz) δ 1.95-2.37 (2H, m) , 3.10 (3H, s), 3.11- 4.17 (5H, m), 4.32-4.58 (2H, br) , £.93-7.51 (4H, m, J = q Hz), 8.34-8.94 (3H, m) , 10.00 (IH, s), 11.16-11.98 (IH, m) ; MS (ES+) m/z 270 (M+l). Preparation 457 To a mixture of ethyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate (278mg) in l,3-dimethyl-2-±midazolidinone (2.78mL) was added (3R)-I-(3- methoxybenzyl)-3-pyrrolidinamine dihydrochloride (547.5mg) and K2CO3 (l.Oδg), which was stirred at 106 °C for 3 hours. To the resultant was added H2O, which was extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give ethyl (2E)-3-(5-{[(3R)- l-(3-methoxybenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acryla te (367.5 mg) as a brown solid. 1H ISIMR(CDCI3, 200MHZ) <5l.32 (3H, t, J = 7.1 Hz), 1.62-1.86 (IH, m), 2.28-2.50 (2H, m) , 2.72 (2H, d, J = 4.6 Hz), 2.89-3.04 (IH, m) , 3.66 (2H, s), 3.81 (3H, s), 4.25 (2H, q, J = 7.1 Hz), 4.39-4.58 (IH, m), 5.29-5.44 (IH, m) , 6.68 (IH, d, J = 15.5 Hz), 6.74-6.96 (3H, m), 7.25 (IH, t, J = 7.9 Hz), 7.57 (IH, d, J = 15.5 Hz), 7.89 (IH, d, J = 1.2 Hz), 8.22 (IH, d, J = 1.2 Hz); MS (ES+) m/z 383 (M+l).

The following compounds were obtained in a similar manner to that of Preparation 457. Preparation 458 ethyl (2E)-3-(5-{[ (3R)-1-(3-cyanobenzyl)-3-pyrrolidinyl]amino}-2- pyrazinyl)aerylate 1H NMR <5- (DMSO-d6, 400 MHz) d 1.24 (3H, t, J = 7.0 Hz), 1.62-1.72 (IH, m), 2.18-2.30 (IH, m) , 2.39-2.48 (2H, m) , 2.64-2.73 (IH, m) , 2.75-2.83 (IH, m) , 3.66 (2H, s), 4.17 (2H, q, J = 7.12 Hz), 4.34 (IH, br), 6.50 (IH, d, J = 15.6 Hz), 7.50-7.58 (2H, m) , 7.65-7.79 (3H, m), 7.92-7.79 (IH, m) , 8.00 (IH, s), 8.21 (IH, s); MS (ES+) m/z 378 (M+l).

Preparation 459 ethyl (2E)-3-[5-({(3R)-1-[3-(acetylamino)benzyl]-3- pyrrolidinyl}amino)-2-pyrazinyl]acrylate 1H NMR (DMSO-d6, 400MHz) δ 1.24 (3H, t, J = 7.2 Hz), ϊ.60-1.71 (IH, m), 2.02 (3H, s), 2.16-2.29 (IH, m) , 2.31-2.53 (2H, m) , 2.59-2.68 (IH, m), 2.75-2.83 (IH, m) , 3.54 (2H, s), 4.16 (2H, q, J = 7.1 Hz), 4.26-4.37 (IH, m) , 6.49 (IH, d, J = 15.5 Hz), 6.97 (IH, d, J = 7.5 Hz), 7.21 (IH, t, J = 7.8 Hz), 7.45 (IH, d, J = 8.2 Hz), 7.49-7.57 5 (2H, m), 7.92 (IH, d, J = 6.6 Hz), 7.99 (IH, s), 8.20 (IH, s) , 9.89 (IH, s); MS (ES+) m/z 410 (M+l).

Preparation 460 10. ethyl (2E)-3-[5-({(3R)-l-[3-(dimethylamino)benzyl]-3- pyrrolidinyl}amino)-2-pyrazinyl]acrylate 1H NMR (DMSO-d6, 400MHz) δ 1.24 (3H, t, J = 7.2 Hz), 1.60-1.71 (IH, m), 2.17-2.28 (IH, m) , 2.38-2.57 (2H, m) , 2.63-2.78 (2H, m) , 2.86 (6H, s), 3.49 (IH, d, J = 12.9 Hz), 3.54 (IH, d, J = 12.9 Hz), 4.16 15 (2H, q, J = 7.12 Hz), 4.26-4.39 (IH, m) , 6.49 (IH, d, J = 15.6 Hz), 6.56-6.68 (3H, m) , 7.10 (IH, t, J = 7.8 Hz), 7.52 (IH, d, J = 15.6 Hz), 7.90-7.97 (IH, m) , 7.99 (IH, d, J = 1.0 Hz), 8.20 (IH, d, J = 1.1 Hz); MS (ES+) m/z 396 (M+l). 20 Preparation 461 ethyl (2E)-3-(5-{[(3R)-l-{3-[(methylsulfonyl)amino]benzyl}-3- pyrrolidinyl]amino}-2-pyrazinyl)acrylate 1H NMR (DMSO~d6, 400MHz) δ 1.24 (3H, t, J = 7.0 Hz), 1.59-1.72 (IH, 25 m), 2.16-2.29 (IH, m) , 2.37-2.53 (2H, m) , 2.61-2.70 (IH, m) , 2.74- 2.82 (IH, m), 2.94 (3H, s), 3.50-3.61 (2H, m) , 4.16 (2H, q, J = 7.1 Hz), 4.25-4.37 (IH, m) , 6.49 (IH, d, J = 15.4 Hz), 7.00-7.11 (2H, m), 7.16 (IH, s), 7.26 (IH, t, J = 7.7 Hz), 7.53 (IH, d, J = 15.6 Hz), 7.93 (IH, d, J = 6.5 Hz), 7.99 (IH, d, J = 1.0 Hz), 8.20 (IH, 30 d, J = 1.1 Hz), 9.20-9.70 (IH, br) ; MS (ES+) 446 (M+l).

Preparation 462 To a solution of ethyl (2E)-3-(5-{[ (3R)-l-(3~methoxybenzyl)^3- 5 pyrrolidinyl]amino}-2-pyrazinyl)acrylate (362mg) in methanol (2.9mL) was added IN NaOH aq. (947uL), which was stirred at 55 °C for 45 minutes. The reaction mixture was added IN HCl aq. (947uL), and evaporated in vacuo to give (2E)-3-(5-{[ (3R)-I-(3- methoxybenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylic acid, which was used in the next step without further purification.

The following compounds were obtained in a similar manner to that of Preparation 462. Preparation 463 (2E)-3-(5-{[(3R)-l-(3-cyanobenzyl)-3-pyrrolidinyl]amino}-2- pyrazinyl)acrylic acid

Preparation 464 (2E)-3-[5-({(3R)-1-[3-(acetylamino)benzyl]-3-pyrrolidinyl}am ino)-2- pyrazinyl]acrylic acid

Preparation 465 (2E)-3-[5-({(3R)-l-[3-(dimethylamino)benzyl]-3-pyrrolidinyl} amino)- 2-pyrazinyl]acrylic acid

Preparation 466 (2E)-3-(5-{[(3R)-l-{3-[(methylsulfonyl)amino]benzyl}-3- pyrrolidinyl]amino}-2-pyrazinyl)acrylic acid

Preparation 467 (2E)-3-(5-{[(3R)-1-(2-hydroxybenzyl)-3-pyrrolidinyl]amino}-2 - pyrazinyl)acrylic acid

Preparation 468 (2E)-3-(5-{[ (3R)-1-(2-methoxybenzyl)-3-pyrrolidinyl]amino}-2- pyrazinyl)acrylic acid

Preparation 469 (2E)-3-(5-{[(3R)-1-(3-hydrpxybenzyl)-3-pyrrolidinyl]amino}-2 - pyrazinyl)acrylic acid Preparation 470 (2E)-3-(5-{[(3R)-1-(3-isopropoxybenzyl)-3-pyrrolidinyl]amino }-2- pyrazinyl)acrylic acid

Preparation 471 To a mixture of (2E)-3-(5-{[ (3R)-l-(3-methoxybenzyl)-3- pyrrolidinyl]amino}-2-pyrazinyl)acrylic acid (crude of reaction), 0-(tetrahydro-2H-pyran-2-yl)hydroxylamine (166.4 mg), and 1- hydroxybenzotriazole (191.9mg) in DMF (3.4mL) was added N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide (25IuL), which was stirred at room temperature for 16.5 hours. To the resultant was added sat. NaHCO3 aq. The mixture was extracted with CH2Cl2. The organic phase was washed with brine, dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give (2E)-3-(5-{[(3R)-1-(3- methoxybenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahy dro-2H- pyran-2-yloxy)acrylamide (312mg) as a yellow amorphous. 1H NMR (200MHz, DMSO-d.6) <51.42-1.83 (7H, m), 2.12-2.34 (IH, m) , 2.37-2.57 (2H, m), 2.58-2.88 (2H, m), 3.44-3.63 (3H, m) , 3.73 (3H, s), 3.84-4.08 (IH, m) , 4.12-4.42 (IH, m) , 4.89 (IH, br) , 6.59 (IH, , d, J = 15.0 Hz), 6.73-6.96 (3H, m) , 7.22 (IH, t, J = 7.9 Hz), 7.37 (IH, d, J = 15.3 Hz), 7.77 (IH, d, J = 6.8 Hz), 7.97 (IH, s), 8.09 (IH, s), 11.17. (IH, br); MS (ES+) m/z 454 (M+l))

The following compounds were obtained in a similar manner to that of Preparation 471. Preparation 472 (2E)-3-(5-{[(3R)-1-(3-cyanobenzyl)-3-pyrrolidinyl]amino}-2- pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H NMR (DMSO-d6, 400MHz) δ 1.45-1.60. (3H, m) , 1.60-1.80 (4H, m) , 2.17-2.30 (IH, m), 2.39-2.48 (2H, m), 2.64-2.73 (IH, m) , 2.74-2.83 (IH, m), 3.46-3.57 (IH, m) , 3.66 (2H, s), 3.89-4.01 (IH, br) , 4.23- 4.39 (IH, br), 4.90 (sH, s), 6.69 (IH, d, J = 15.1 Hz), 7.38 (IH, d, J = 15.4 Hz), 7.54 (IH, t, J = 7.7 Hz), 7.68 (IH, d, J = 7.8 Hz), 7.73 (IH, d, J = 7.7 Hz), 7.74-7.83 (2H, m) , 7.98 (IH, s), 8.10 (IH, S), 11.18 (IH, S); MS (ES+) m/z 449 (M+l).

Preparation 473 (2E) -3- [5- ( { (3R) -1- [3- ( acetylamino ) benzyl ] -3-pyrrolidinyl}amino) -2- pyrazinyl] -N- (tetrahydro-2H-pyran-2-yloxy)acrylamide 1H NMR (DMSO-d6, 400MHz) <5 1.45-1.77 (7H, m) , 1.02 (3H, s), 2.16- 2.29 (IH, m), 2.33-2.40 (IH, m) , 2.41-2.53 (IH, m) , 2.58-2.69 (IH, m), 2.75-2.84 (IH, m) , 3.47-3.60 (3H, m) , 3.88-4.02 (IH, m) , 4.21- 4.38 (IH, m), 4.89 (IH, s), 6.60 (IH, d, J = 15.1 Hz), 6.97 (IH, d, J = 7.6 Hz), 7.21 (IH, t, J = 7.8 Hz), 7.37 (IH, d, J = 15.2 Hz), 7.45 (IH, d, J = 8.1 Hz), 7.54 (IH, s), 7.77 (IH, d, J = 6.3 Hz), 7.96 (IH, s), 8.09 (IH, s), 9.90 (IH, s), 11.18 (IH, s); MS (ES+) m/z 481 (M+l).

Preparation 474 (2E) -3- (5-{ [ (3R) -l-{3- [ (methylsulf onyl) amino] benzyl} -3- pyrrolidinyl]amino}-2-pyrazinyl) -N- ( tetrahydro-2H-pyran-2- yloxyjacrylamide 1H NMR (DMSO-d6, 400MHz) δ 1.44-1.78 (7H, m) , 2.15-2.28 (IH, m) , 2.31-2.57 (2H, m) , 2.61-2.71 (IH, m) , 2.73-2.83 (IH, m) , 2.94 (3H, s), 3.48-3.61 (3H, m) , 3.88-4.00 (IH, m), 4.24-4.36 (IH, m) , 4.89 (IH, s), 6.59 (IH, d, J = 15.2 Hz), 7.01-7.11 (2H, m) , 7.16 (IH, s), 7.26 (IH, t, J = 7.8 Hz), 7.37 (IH, d, J = 15.2 Hz), 7.77 (IH, d, J = 6.3 Hz), 7.97 (IH, s), 8.09 (IH, s), 9.55-9.85 (IH, br), 11.07- 11.29 (IH, br); MS (ES+) m/z 517 (M+l).

Preparation 475 (2E)-3-[5-({(3R)-1-[3-(dimethylamino)benzyl]-3-pyrrolidinyl} amino)- 2-pyrazinyl]-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H NMR (DMSO-d6, 400MHz) δ 1.42-1.77 (7H, m) , 2.13-2.28 (IH, m) , 2.34-2.57 (2H, m) , .2.62-2.78 (2H, m), 2.86 (6H, s), 3.43-3.58 (3H, m), 3.89-4.01 (IH, m) , 4.24-4.34 (IH, m) , 4.89 (IH, s), 6.54-6.67 (4H, m), 7.10 (IH, t, J. = 8.0 Hz), 7.36 (IH, d, J = 15.2 Hz), 7.77 ( IH, d, J = 6 . 5 Hz ) , 7 . 97 ( IH, s ) , 8 . 09 ( IH, s ) , 11 . 18 ( IH , s ) ; MS (ES+ ) m/z 467 (M+l ) .

Preparation 476 (2E)-3-(5-{[(3R)-l-(2-methoxybenzyl)-3-pyrrolidinyl]amino}-2 - pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H NMR (DMSO-d6, 400 MHz) 6 1.44-1.77 (7H, m) , 2.13-2.28 (IH, m) , 2.40-2.55 (2H, m), 2.65-2.74 (IH, m), 2.74-2.81 (IH, m) , 3.48-3.65 (3H, m), 3.77 (3H, s), 3.89-4.00 (IH, m) , ,4.25-4.36 (IH, m) , 4.89 (IH, s), 6.59 (IH, d, J = 15.1 Hz), 6.91 (IH, t, J = 7.5 Hz), 6.96 (IH, d, J = 8.2 Hz), 7.24 (IH, t, J = 7.3 Hz), 7.31 (IH, d, J = 7.4 Hz), 7.37 (IH, d, J = 15.4 Hz), 7.77 (IH, d, J = 6.3 Hz), 7.97 (IH, s), 8.09 (IH, s), 11.17 (IH, s); MS (ES+) m/z 454 (M+l).

Preparation 477 (2E)-3-(5-{[(3R)-1-(3-hydroxybenzyl)-3-pyrrolidinyl]amino}-2 - pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H NMR (DMSO-d6, 400 MHz) δ 1.41-1.79 (7H, m) , 2.15-2.29 (IH, m) , 2.33-2.48 (2H, m), 2.59-2.69 (IH, m) , 2.73-2.81 (IH, m) , 3.40-3.56 (3H, m), 3.87-4.00 (IH, m) , 4.24-4.35 (IH, m) , 4.83-4.93 (IH, m) , 6.54-6.66 (2H, m) , 6.66-6.77 (2H, m) , 7.08 (IH, t, J = 8.1 Hz), 7.37 (IH, d, J = 15.2 Hz), 7.76 (IH, d, J = 6.4 Hz), 7.97 (IH, s), 8.09 (IH, s), 9.29 (IH, s), 11.17 (IH, br) ; MS (ES+) m/z, 440 (M+l).

Preparation 478 (2E)-3-(5-{[ (3R)-I-(3-isopropoxybenzyl)-3-pyrrolidinyl]amino}-2- pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H NMR (DMSO-d6, 400 MHz) δ 1.20-1.27 (6H, m) , 1.47-1.76 (7H, m) , 2.14-2.28 (IH, m) , 2.37-2.47 (2H, m) , 2.63-2.77 (2H, m) , 3.47-3.61 (3H, m), 3.89-4.00 (IH, m) , 4.25-4.35 (IH, m), 4.56 (IH, septet, J = 6.0 Hz), 4.89 (IH, S), 6.59 (IH, d, J = 15.2 Hz), 6.77 (IH, d, J = 7.8 Hz), 6.82-6.87 (2H, m) , 7.19 (IH, t, J = 8.0 Hz), 7.37 (IH, d, J = 15.2 Hz), 7.77 (IH, d, J = 6.2 Hz), 7.97 (IH, s), 8.09 (IH, s), 11. 17 ( IH, s ) ; MS (ES+ ) m/z 482 .

Preparation 479 (2E)-3~(5-{[(3R)-l-(2-hydroxybenzyl)-3-pyrrolidinyl]amino}-2 - pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide. 1H NMR (DMSO-d6, 400 MHz) δ 1.44-1.79 (7H, m) , 2.19-2.35 (IH, m) , 2.44-2.56 (2H, m), 2.71-2.86 (2H, m), 3.12-3.60 (3H, m), 3.87-4.01 (IH, m), 4.27-4.39 (IH, m) , 4.82-4.92 (IH, m) , 6.62 (IH, d, J = 15.2 Hz), 6.69-6.80 (3H, m) , 7.00-7.14 (2H, m) , 7.38 (IH, d, J = 15.3 Hz), 7.77-7.87 (IH, m) , 7.98 (IH, s), 8.10 (IH, s), 11.17 (IH, br); MS (ES+) m/z 440 (M+l) .

Preparation 480 To a mixture of tert-butyl (3R)-3-pyrrolidinylcarbamate (450mg), 1- (chloromethyl)-3-nitrobenzene (435mg) in DMF (4.5mL) was added N,N- diisopropylamine (463uL), which was stirred at 75 0C for 4 hours. To the resultant was added H2O. The mixture was extracted with ethyl acetate. The organic phase was washed brine, dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give tert-butyl [(3R)-I- (3-nitrobenzyl)-3-pyrrolidinyl]carbamate (, 757mg) as a orange oil. 1H NMR (200 MHz, CDCl3)Sl.44 (9H, s), 1.50-1.77 (IH, m), 2.17-2.96 (5H, m), 3.60-3.80 (2H, m) , 4.19 (IH, br) , 4.84 (IH, br) , 7.49 (IH, t, J = 7.9 Hz), 7.68 (IH, d, J = 7.4 Hz), 7.99-8.24 (2H, m) ; MS (ES+) 322 (M+l).

Preparation 481 tert-butyl [(3R)-l-(3-aminobenzyl)-3-pyrrolidinyl]carbamate To a solution of tert-butyl [(3R)-l-(3-nitrobenzyl)-3- pyrrolidinyl]carbamate (750 mg) in ethanol (5.6 mL) and H2O (1.9 mL) was added NH4CI (62.4 mg) and Fe (391 mg) , which was stirred under reflux for 1 hour. The resultant was filtered and evaporated in vacuo. The residue was washed water and brine. The organic layer was dried over Na2SO4, filtered, and evaporated in vacuo to give tert- butyl [ ( 3R) -l- ( 3-aminobenzyl) -3-pyrrolidinyl] carbamate ( 645mg) as a brown oil . 1H NMR(CDCl3 , 200MHz ) 6 1.43 ( 9H, s ) , 1.48-1. 71 ( IH, m) , 2.12-2.43 ( 2H, m) , 2.44-3.00 ( 3H, m) , 3. 51 ( 2H, s ) , 3. 65 ( 2H, br) , 4. 17 ( IH, br) , 4. 88 ( IH, br) , 6. 53-6. 73 ( 3H, m) , 7.09 (IH, t , J = 7 . 9 Hz ) ; API-ES(posi) 292 (M+l ) .

Preparation 482 To a solution of tert-butyl [(3R)-l-(3-aminobenzyl)-3- pyrrolidinyl]carbamate (640 mg) in CH2Cl2 (6.4 mL) was added 35% HCHO aq. (1.42 mL) and sodium triacetoxyborohydride (1.4 g), which was stirred at room temp temperature at 24 hours. To the resultant was added sat. NaHCO3 aq. , which was stirred for 20 min. The mixture was extracted with ethyl acetate. The organic phase was washed by brine, dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give tert-butyl {(3R)-l-[3-(dimethylamino)benzyl]-3- pyrrolidinyl}carbamate (365 mg) as a white solid. 1H NMR(CDCI3^OOMHZ) 6 1.43 (9H, s), 1.50-1.76 (IH, m), 2.12-2.44 (2H, m), 2.47-2.70 (2H, m) , 2.72-2.93 (IH, m) , 2.95 (6H, s), 3.57 (2H, s), 4.17 (IH, br), 4.90 (IH, br) , 6.58-6.74 (3H, m) , 7.18 (IH, t, J = 7.7 Hz); MS (ES+) m/z 320 (M+l).

Preparation 483 To a solution of tert-butyl [(3R)-l-(3-aminobenzyl)-3- pyrrolidinyl]carbamate (681 mg) in CH2C12 (6.8 mL) was added pyridine (284 uL), acetic anhydride (265 uL), and N,N- dimethylaminopyridine (14 mg) , which was stirred at room temperature for 1.5 hours. To the resultant was added H2O. The mixture was extracted with CH2Cl2. The organic phase was washed by brine, dried over Na2SO4, filtered, and evaporated in vacuo to give tert-butyl {(3R)-l-[3-(acetylamino)benzyl]-3-pyrrolidinyl}carbamate (944 mg) as a off-white amorphous. 1H NMR(CDCl3, 200MHz) <5 1.42 (9H, s), 1.71-2.00 (IH, m) , 2.18 (3H, s ) , 36-2 .47 ( IH, m) , 2 .58-2. 75 ( IH, m) , 2.78-3.07 ( 2H, m) , 3.07- 3.36 ( IH, m) , 3.86 ( 2H, s) , 4.34 ( IH, br) , 5.06 ( IH, br) , 7.10 ( IH, d, J = 7 .5 Hz ) , 7.30 ( IH, t , J = 7. 6 Hz ) , 7.56-7.69 ( 2H, m) , 7 .81 ( IH, br) ; MS (ES+ ) m/z 334 (M+l ) .

Preparation 484 To tert-butyl [(3R)-1-(3-fluorobenzyl)-3-pyrrolidinyl]carbamate (3.Og) was added 4NHC1/Dioxane (38ml) at room temperature. The mixture was stirred for.2 hrs at the same temperature. Evaporated and decantated with diisopropyl ether (three times) . Evaporated to give 2.85g of (3R)-I-(3-fluorobenzyl)-3- pyrrolidinamine dihydrochloride as an amorphous. MASS (ESI+): m/z = 195.2 (M+l). 1HNMR ( 400MHz, CDCl3): δ 2.00-2.42 (2H, m), 3.00-4.20 (6H, m), 4.40-4.64 (2H, br.s), 7.20-7.40 (IH, m) , 7.40-7.70 (3H, m) , 8.67 and 8.84 (3H, br.s).

Preparation 485 To a solution of tert-butyl [(3R)-l-(3-aminobenzyl)-3- pyrrolidinyl]carbamate (659 mg) in CH2CI2 (6.6 mL) was added pyridine (274uL) and methanesulfonyl chloride (193uL), which was stirred at room temperature for 20 hours. To the resultant was added H2O. The mixture was extracted with 1-butanol. The organic phase was washed brine, dried Na2SO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give tert-butyl [(3R)-l-{3-[(methylsulfonyl)amino]benzyl}-3- pyrrolidinyl]carbamate (845 mg) as pale yellow amorphous. 1H NMR (CDC13. 200MHz) <5 1.43 (9H, s), 1.44-1.78 (IH, m) , 2.16- 2.46 (2H, m), 2.50-2.76 (2H, m) , 2.78-2.95 (IH, m), 3.02 (3H, s), 3.62 (2H, s), 4.20 (IH, br) , 4.93 (IH, br) , 7.08-7.36 (4H, m) ; MS(ES+) m/z 370.3 (M+l).

Preparation 486 To a mixture of tert-butyl (3R)-3-pyrrolidinylcarbamate (2.Og) and 2-fluorobenzaldehyde (1.4g) was added NaBH(OAc)3 2.73g ( 1.2eq) under ice-cooling. After 30min, the mixture was allowed to warm to room temperature and stirred for 8 hrs. Dichloromethane and water was added. Separated organic layer. Extracted with dichloromethane. sat. aq. NaHCO3 was added to combined organic layer. Separated organic layer. Dried with Na2SCi. Evaporated to give 3.21g of tert-butyl [ (3R)-l-(2-fluorobenzyl)-3- pyrrolidinyl]carbamate. MASS (ESI+): m/z = 295.3 (M+l). 1HNMR ( 400MHz, CDCl3): δ 1.43 (9H, s), 1.5 - 1.7 (IH, m) , 2.2 - 2.9 (5H, m), 3.67 (2H, s), 4.17 (IH, br.s), 4.87 (IH, br.s), 7.00 - 7.05 (IH, m), 7.08 - 7.12 (IH, m), 7.21 - 7.24 (IH, m) , 7.33 - 7.37 (IH, m).

Preparation 487 To tert-butyl [(3R)-I-(2-fluorobenzyl)-3-pyrrolidinyl]carbamate (3.Og) was added 4NHC1/Dioxane (38ml) at room temperature. The mixture was stirred for 2 hrs at the same temperature. Evaporated and decantated with diisopropyl ether (three times) . Evaporated to give 3.74g of (3R)-l-(2-fluorobenzyl)-3- pyrrolidinamine dihydrochloride. MASS (ESI+): m/z = 195.2 (M+l). 1HNMR ( 400MHz, CDCl3): O 2.0 - 2.6 (2H, m) , 3.18 - 4.15 (4H, m) , 3.57 (s» 2H), 4.52 (2H, br.s), 7.29 - 7.36 (2H, m) , 7.50 - 7.56 (IH, m), 7.70 - 7.80 (IH, m) , 8.63 and 8.76 (3H, br.s).

Preparation 488 A mixture of (3R)-I-(3-fluorobenzyl)-3-pyrrolidinamine dihydrochloride (1.Og) , methyl (2E)-3-(5-chloro-2- pyrazinyl)aerylate (1.74g) and Na2CO3 (4.18g) was stirred under heating condition (oil bath temperature: 206°C). After 8 hours, the reaction mixture was added to ice water and extracted with CHCl3. Aqueous layer was extracted with CHCl3 (twice) . Combined organic layer was washed with water (three times) , dried over MgSO4, filtered and evaporated. Residue was column chromatographed on silica gel (Hex:EtOAc to CHC13:MeOH=8:l) to give 1.68g ( 94%) of methyl (2E)-3-(5-{[ (3R)-1- (3-fluorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)aerylate as an oil. MASS (ESI+): m/z = 357.2 (M+l). 1HNMR ( 400MHz, CDCl3): <5 1.70-1.80 (IH, m) , 2.35-2.50 (2H, m) , 2.65-2.75 (2H, m) , 2.79 (3H, s), 2.90-3.00 (IH, m) , 3.65 (2H, s), 4.50 (IH, br.s), 5.45 (IH, d, J= 6.6Hz), 6.68 (IH, d, J=15.6Hz), 6.95-7.35 (4H, m) , 7.58 (IH, d, J= 15.6Hz), 7.90 (IH, d, J=I.28Hz), 8.03 (IH, d, J=I.28Hz).

Preparation 489 To a solution of methyl (2E)-3-(5-{[(3R)-l-(3-fluorobenzyl)-3- pyrrolidinyl]amino}-2-pyrazinyl)acrylate (1.98g) in methanol (42ml) was added INNaOH (21ml) at room temperature. After stirring for 2 hrs, IN HCl (21ml) was added. The mixture was evaporated under reduced pressure. To a residue was added DMF(40ml), 0-(tetrahydro- 2H-pyran-2-yl)hydrόxylamine (815mg), HOBt (940mg) and WSCD (1.25g) at room temperature. After stirring for 12 hrs, water was added, the mixture was extracted with CHCl3 (3 times), and organic layer was washed with water (twice) , dried over Na2SO4, filtered and evaporated. The residue was column chromatographed on silica gel ( Hex : EtOAc to CHCl3 : MeOH) to give crude product. The crude product was purified with HPLC (Yamazene packed column 26x 100mm) to give 730mg (30%) of (2E)-3-(5-{[(3R)-l-(3- fluorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahyd ro-2H- pyran-2-yloxy)acrylamide as an oil. MASS (ESI+): m/z = 442.3 (M+l). MASS (ESI-): m/z = 440.4 (M+l). 1HNMR ( 400MHz, CDCl3): δ 1.51-2.03 (7H, m) , 2.33-2.46 (2H, m) , 2.71 (2H, d, J=4.8Hz), 2.90-2.97 (IH, m) , 3.65 (2H, s), 3.96 (IH, t, J= 9.8Hz ) , 4.44-4.53 ( IH, m) , 5.01 ( IH, br. s . ) , 5.38 ( IH, d, J=8.0Hz ) , 6.96 ( IH, dt , J= 2.5 and 8.4Hz) , 7.04-7.12 ( 2H, m) , 7.27 ( IH, s) , 7.25-7.31 ( IH, m) , 7.61 ( IH, d, J=15.1Hz) , 7.87 ( IH, s) , 8.02 ( IH, s) .

Preparation 490 A mixture of (3R)-l-(2-fluorobenzyl)-3-pyrrolidinamine dihydrochloride (1.Og), methyl (2E)-3-(5-chloro-2- pyrazinyl)acrylate (1.74g) and Na2CO3 (4.18g) was stirred under heating condition (oil bath temperature: 206 °C). After 8 hours, the reaction mixture was added to ice water and extracted with CHCl3. Aqueous layer was extracted with CHCl3 (twice). Combined organic layer was washed with water (three times) , dried over MgSO4, filtered and evaporated. Residue was column chromatographed on silica gel (Hex:EtOAc to CHC13:MeOH=8:l) to give 1.22g ( 68%) of methyl (2E)-3-(5-{[(3R)-I- (2-fluorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate as an oil. MASS (ESI+): m/z = 357.2 (M+l). v 1HNMR ( 400MHz, CDCl3): 6 1.61-1.84 (IH, m) , 2.25-3.00 (m, 5H), 3.79 (2H, s), 4.45-4.53 (IH, m) , 5.45 (IH, d, J=6.6Hz), 6.68 (IH, d, J=15.6Hz), 7.00-7.45 (4H, m) , 7.27 (2H, s), 7.57 (IH, d, J= 15.6Hz), 7.88 (IH, d, J=I.28Hz), 8.03 (IH, d, J=I.28Hz).

Preparation 491 To a solution of methyl (2E)-3-(5-{[(3R)-l-(2-fluorobenzyl)-3- pyrrolidinyl]amino}-2-pyrazinyl)acrylate (1.2Og) in methanol (34ml) was added INNaOH (16.9ml) at room temperature and stirred for 2 hrs. After then, the reaction mixture was neutralized with IN HCl (16.9ml). The mixture was evaporated under reduced pressure and co- evaporated with toluene (twice). To the residue in DMF(30ml) was added O-(tetrahydro-2H-pyran-2- yl)hydroxylamine (513mg), HOBt (591mg) and WSCD (784mg) and the mixture was stirred overnight. After 12 hours, water was added and extracted with CHC13 (Three times) . Combined organic layer was washed with water, dried over Na2SO4, filtered and evaporated. The reside was column chromatographed on silica gel ( Hex : EtOAc to CHCl3 : MeOH) to give crude (2E)-3-(5-{[ (3R)-I-(2-fluorobenzyl)- 3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2- yloxy)acrylamide. - Crude product was purified with HPLC (Yamazene packed column, 26mm x 100mm) to give 540mg (36%) of (2E)-3-(5-{[ (3R)-l-(2- fluorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahyd ro-2H- pyran-2-yloxy)acrylamide as an oil. MASS (ESI+): m/z = 442.3 (M+l). 1HNMR ( 400MHz): δ 1.56-2.13 (7H, m) , 2.26-2.53 (2H, m) , 2.63-3.06 (3H, m), 3.57-3.83 (3H, m), 3.97 (IH, m) , 4.49 (IH, m) , 5.01 (IH, br.s), 5.46 (IH, m) , 7.05 (IH, ddd, J= 1.0, 8.2 and 9.8Hz), 7.12 (IH, dt, J=I.2 and 7.5Hz), 7.22-7.30 (IH, m) , 7.26 (2H, s), 7.38 (IH, dt, J=I.6 and 7.5Hz), 7.61 (IH, d, J=14.1Hz), 7.85 (IH, s), 8.02 (IH, s).

Preparation 492 To a suspension of methyl (2E)-3-{5-[(3R)-3-pyrrolidinylamino]-2- pyrazinyl}aerylate dihydrochloride (260 mg) in CH2Cl2 (2.6 mL) was added N,N-diisopropylethylamine (282 uL), 2-methoxybenzaldehyde (121.2 mg) , and sodium triacetoxyborohydride (343 mg) , which was stirred at room temperature for 1 hour. To the resultant was added sat. NaHCO3 aq., which was stirred for 20 min. The mixture was extracted with CH2Cl2. The organic phase was washed with brine and dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give methyl (2E)-3-(5-{[(3R)-1-(2-methoxybenzyl)-3-pyrrolidinyl]amino}-2 - pyrazinyl)aerylate ( 193 mg) as a yellow amorphous. 1H NMR (DMSO-d6, 400 MHz) δ 1.59-1.70 (IH, m) , 2.16-2.28 (IH, m) , 2.40-2.53 (2H, m) , 2.65-2.74 (IH, m) , 2.74-2.81 (IH, m) , 3.53-3.64 (2H, m), 3.69 (3H, s), 3.77 (3H, s), 4.26-4.38 (IH, m) , 6.51 (IH, d, J = 15.4 Hz), 6.91 (IH, t, J = 7.4 Hz), 6.96 (IH, d, J = 8.2 Hz), 7.22 (IH, t, J = 8.2 Hz), 7.31 (IH, d, J = 7.2 Hz), 7.55 (IH, d, J = 15.6 Hz), 7.95 (IH, d, J = 6.6 Hz), 8.00 (IH, s), 8.21 (IH, s); MS (ES+) m/z 369 (M+l).

The following compounds were obtained in a similar manner to that of Preparation 492. Preparation 493 methyl (2E)-3-(5-{ [(3R)-l-(3-hydroxybenzyl)-3-pyrrolidinyl]amino}- 2-pyrazinyl)aerylate 1H NMR (DMSO-d6, ,400 MHz) (5 1.60-1.71 (IH, m) , 2.16-2.28 (IH, m) , 2.32-2.47 (2H, m) , 2.59-2.69 (IH, m) , 2.73-2.81 (IH, m) , 3.49 (2H, s), 3.69 (3H, s), 4.25-4.37 (IH, m) , 6.51 (IH, d, J = 15.4 Hz), 6.62 (IH, d, J = 7.0 Hz), 6.67-6.79 (2H, m) , 7.08 (IH, t, J = 8.0 Hz), 7.55 (IH, d, J = 15.4 Hz), 7.94 (IH, d, J = 6.5 Hz), 8.00 (IH, S), 8.20 (IH, s), 9.28 (IH, s); MS (ES+) m/z 355 (M+l).

Preparation 494 methyl (2E)-3-(5-{[ (3R)-l-(3-isopropoxybenzyl)-3- pyrrolidinyl]amino}-2-pyrazinyl)acrylate 1H NMR (DMSO-d6, 400 MHz) δ 1.18-1.31 (6H, m) , 1.61-1.73 (IH, m) , 2.16-2.29 (IH, m) , 2.37-2.47 (2H, m) , 2.61-2.79 (2H, m) , 3.52 (IH, d, J = 13.1 Hz), 3.57 (IH, d, J = 13.2 Hz), 3.69 (3H, s), 4.23-4.38 (IH, m), 4.56 (IH, septet, J = 6.0 Hz), 6.51 (IH, d, J = 15.5 Hz), 6.77 (IH, dd, J = 2.0, 8.0 Hz), 6.80-6.90 (2H, m) , 7.19 (IH, t, J = 8.0 Hz), 7.55 (IH, d, J = 15.5 Hz), 7.94 (IH, d, J = 6.7 Hz), 8.00 (IH, d, J = 2.4 Hz), ,8.20 (IH, s); MS (ES+) m/z 397 (M+l).

Preparation 495 methyl (2E)-3-(5-{[(3R)-l-(2-hydroxybenzyl)-3-pyrrolidinyl]amino}- 2-pyrazinyl)acrylate 1H NMR (DMSO-d6, 400 MHz) δ 1.66-1.79 (IH, m) , 2.19-2.35 (IH, m) , 2.43-2.58 ( 2H, m) , 2.72-2.88 (2H, m) , 3.70 (3H, s ) , 3.71 ( 2H, s) , 4.27-4.42 ( IH, m) , 6.52 ( IH, d, J = 15.5 Hz ) , 6.67-6.79 ( 2H, m) , 7.02-7. 15 ( 2H, m) , 7.56 ( IH, d, J = 15.5 Hz ) , 7.95-8.04 (2H, m) , 8.21 ( IH, d, J = 1. 1 Hz ) ; MS (ES+) m/z 355 (M+l ) .

Preparation 496 To a solution of methyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate (680 mg) in DMI (1.4 mL) was added tert-butyl (3R)-3-amino-l- pyrrolidinecarboxylate (957 mg) and K2CO3 (1.42 g) , which was stirred at 120 °C for 2 hours. The reaction mixture was filtered and evaporated in vacuo. To the residue was added H2O, which was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2Sθ4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give tert-butyl (3R)-3-({5-[(lE)-3-methoxy-3-oxo-l-propen-l-yl]-2- pyrazinyl}amino)-l-pyrrolidinecarboxylate (834mg) as a off-white powder. 1H NMR (400 MHz, CDCl3) <5 1.47 (9H, s), 1.88-2.03 (IH, br), 2.20- 2.33 (IH, m), 3.19-3.40 (IH, m) , 3.41-3.58 (2H, m) , 3.69-3.77 (IH, m), 3.80 (3H, s), 4.51 (IH, br) , 5.08 (IH, br) , 6.72 (IH, d, J = 15.5 Hz), 7.60 (IH, d, J = 15.6 Hz), 7.95 (IH, d, J = 1.3 Hz), 8.08 (IH, s); MS (ES+) m/z 371 (M+23).

Preparation 497 To a solution of tert-butyl (3R)-3-({5-[(lE)-3-methoxy-3-oxo-l- propen-l-yl]-2-pyrazinyl}amino)-l-pyrrolidinecarboxylate (830 mg) in dioxane (8.3 mL) was added 4N HCl/diόxane (6.0 mL), which was stirred at room temperature for 1 hour. To the reaction mixture was added diisopropylether, and the precipitate was filtered to give methyl (2E)-3-{5-[(3R)-3-pyrrolidinylamino]-2-pyrazinyl}acrylate dihydrochloride (742 mg) as a yellow powder. 1H NMR (DMSO-d6, 400MHz) δ 1.92-2.02 (IH, m) , 2.16-2.28 (IH, m) , 3.05-3.15 (IH, m) , 3.21-3.49 (3H, m) , 3.71 (3H, s), 4.43-4.52 (IH, br) , 6 .57 ( IH, d, J = 15. 7 Hz ) , 7.60 ( IH, d, J = 15. 6 Hz ) , 8.07 ( IH, d, J = 1. 1 Hz ) , 8.23-8.39 ( 2H, m) , 9 .43 ( 2H, br) ; MS (ES+ ) m/z 249 (M+l ) .

Preparation 498 To a solution of ethyl (2E)-3-(6-{ [ (3R)-l-phenyl-3- pyrrolidinyl]amino}-3-pyridinyl)acrylate (47 mg) in dioxane (1.4 mL) was added IN sodium hydroxide (0.42 mL). After stirring at 6O0C for 2 hours, the reaction mixture was added H2O(7 mL) and acidified with IN hydrochloric acid (to pH 4). A resulting precipitate was collected by filtration, and washed with water to give (2E)-3-(6-{[(3R)-I-phenyl-3-pyrrolidinyl]amino}-3- pyridinyl)acrylic acid hydrochloride (39 mg) . 1H-NMR (300 MHz, DMSO-d6) δ1.93-2.05 (IH, m) , 2.23-2.36 (IH, m) , 3.09-3.64 (4H, m) , 4.54-4.62 (IH, m) , 6.25 (IH, d, J = 16 Hz), 6.51-6.63 (4H, m) , 7.12-7.21 (2H, m) , 7.44-7.51 (2H, m) , 7.79 (IH', d, J = 9 Hz), 8.24 (IH, brs), 12.1 (IH, brs). MS (ES+) m/z 310 (M+l).

Preparation 499 To a solution of ethyl (2E)-3-(6-{(tert-butoxycarbonyl) [(3R)-I-(4- nitrophenyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate (297 mg) in ethanol (3 mL) was added tin(II) chloride (583 mg) , and the mixture was heated at reflux for 6 hours. After cooling, the reaction mixture was basified with 2N sodium hydroxide and extracted with ethyl acetate. The organic layer was dried over Na2SC^, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give ethyl (2E)-3-(6-{[ (SRJ-l-^- aminophenylJ-S-pyrrolidinyllamino^S-pyridinylJacrylate (186 mg) . 1H-NMR (300 MHz, CDCl3) <5l.33 (3H, t, J = 7 Hz), 1.97-2.08 (IH, m) , 2.32-2.45 (IH, m) , 3.19-3.61 (4H, m), 4.25 (2H, q, J = 7 Hz)., 4.53- 4.64 (IH, m), 4.96-5.00 (IH, m) , 6.23 (IH, d, J = 16 Hz), 6.41 (IH, d, J = 9 Hz), 6.49 (2H, d, J = 9 Hz), 6.68 (2H, d, J = 9 Hz), 7.58 (IH, d, J = 16 Hz), 7.63 (IH, dd, 3 = 2, 9 Hz), 8.22 (IH, d, J = 2 Hz), MS (ES+ ) m/z 353 (M+l ) .

Preparation 500 To a mixture of ethyl (2E)-3-(6-{[ (3R)-l-(4-aminophenyl)-3- pyrrolidinyl]amino}-3-pyridinyl)acrylate (178 mg) and 50% phosphinic acid (5 mL) was added sodium nitrite (62.7 mg) in H2O at 40C. The reaction mixture was stirred for 2 hours at 4°C. The resulting mixture was neutrized with saturated NaHCO3 and extracted with chloroform. The organic layer was dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give ethyl (2E)-3-(6-{[(3R)-I- phenyl-3-pyrrolidinyl]amino}-3-pyridinyl)aerylate (49.0 mg) . 1H-NMR (300 MHz, CDCl3) <5l.33 (3H, t, J = 7 Hz), 2.01-2.13 (IH, m) , 2.34-2.47 (IH, m) , 3.25-3.74 (4H, m) , 4.25 (2H, q, J = 7 Hz), 4.57- 4.67 (IH, m), 4.91-4.97 (IH, m) , 6.24 (IH, d, J = 16 Hz), 6.42 (IH, d, J = 9 Hz), 6.59 (2H, d, J = 9 Hz), 6.69-6.76 (IH, m) , 7.22-7.30 (2H, m), 7.58 (IH, d, J = 16 Hz), 7.63 (IH, dd, J = 2, 9 Hz), 8.23 (IH, d, J = 2 Hz). MS (ES+) m/z 338 (M+l).

Preparation 501 To a solution of ethyl (2E)-3-(6-{(tert-butoxycarbonyl) [(3R)-3- pyrrolidinyl]amino}-3-pyridinyl)acrylate dihydrochloride (268 mg) in DMF (3 mL) was added 1-fluoro-4-nitrobenzene (91.4 mg) and N,N- diisopropylethylamine (0.376 mL) . After stirring for 3 hours at 120°C, the reaction mixture was partitioned between ethyl acetate and H2O. The organic layer was washed with H2O and brine, dried over MgSO4, filtered, and evaporated in vacuo to give ethyl (2E)-3- (6-{(tert-butoxycarbonyl) [(3R)-1-(4-nitrophenyl)-3- pyrrolidinyl]amino}-3-pyridinyl)acrylate (299 mg) . 1H-NMR (300 MHz, CDCl3) <5l.34 (3H, t, J = 7 Hz), 1.45 (9H, s), 2.27-2.48 (2H, m) , 3.33-3.52 (2H, m) , 3.67-3.82 (2H, m) , 4.28 (2H, q, J = 7 Hz), 5.06-5.18 (IH, m) , 6.44 (2H, d, J = 9 Hz), 6.45 (IH, d, J = 16 Hz), 7.32 (IH, d, J = 8 Hz), 7.63 (IH, d, J = 16 Hz), 7.83 (IH, dd, J = 2, 8 Hz), 8.11 (2H, d, J = 9 Hz), 8.50 (IH, d, J = 2 Hz) , MS (ES+ ) m/z 483 (M+l ) .

Preparation 502 1) To a mixture of ό-chloro-S-pyridazinecarbaldehyde (500 mg) and THF (10 πiL) was added (carbethoxymethylene)triphenylphosphorane (1.35 g) . The reaction mixture was stirred for 2 hours at room temperature, and evaporated in vacuo. 2) To a mixture of above product and DMF (11 mL) was added (3R)-I- (cyclohexylmethyl)-3-pyrrolidinamine dihydrochloride (1.34 g) and K2CO3 (2.42 g). After stirring for 5 hours at 120°C, the reaction mixture was partitioned between ethyl acetate and H2O. The organic layer was washed with H2O, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give ethyl (2E)-3-(6-{[(3R)-I- (cyclohexylmethyl)-3-pyrrolidinyl]amino}-3-pyridazinyl)acryl ate (499 mg). 1H-NMR (300 MHz, CDCl3) δ 0.81-0.96 (2H, m), 1.22-1.28 (4H, m), 1.34 (3H, t, J = 7 Hz), 1.37-1.49 (IH, m) , 1.62-1.83 (5H, m) , 2.19- 2.45 (4H, m), 2.59-2.72 (2H, m), 2.82-2.93 (IH, m) , 4.27 (2H, q, J = 7 Hz), 4.46-4.59 (IH, m) , 5.29-5.35 (IH, m) , 6.61 (IH, d, J = 16 Hz), 6.62 (IH, d, J = 9 Hz), 7.37 (IH, d, J = 9 Hz), 7.79 (IH, d, J = 16 Hz). MS (ES+) m/z 359 (M+l).

Preparation 503 To a mixture of ethyl (2E)-3-(6-{(tert-butoxycarbonyl) [(3R)-3- pyrrolidinyl]amino}-3-pyridinyl)acrylate dihydrochloride (250 mg) , 4-(chloromethyl)-l,2-dimethylbenzene (89.0 mg) , and DMF (5.8 mL) was added K2CO3 (278 mg). After stirring for 2 hours at room temperature, the reaction mixture was partitioned between ethyl acetate and H2O. The organic layer was washed with brine, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give ethyl (2E)- 3-(6-{(tert-butoxycarbonyl)[(3R)-l-(3,4-dimethylbenzyl)-3- pyrrolidinyl]amino}-3-pyridinyl)acrylate (263 mg) . 1H-NMR (300 MHz, CDCl3) <5l.35 (3H, t, J = 7 Hz), 1.44 (9H, s), 1.98-2.27 (8H, m) , 2.53-3.00 (4H, m) , 3.46-3.60 (2H, m) , 4.28 (2H, q, J = 7 Hz), 4.84-4.96 (IH, m) , 6.46 (IH, d, J = 16 Hz), 6.93-7.06 (3H, m), 7.25-7.31 (IH, m) , 7.66 (IH, d, J = 16 Hz), 7.75-7.82 (IH, m), 8.53 (JLH, d, J = 2 Hz). MS (ES+) m/z 480 (M+l).

Preparation 504 To a solution of (2E)-3-(6-{[(3R)-l-phenyl-3-pyrrolidinyl]amino}-3- pyridinyl)acrylic acid hydrochloride (37 mg) , O-tetrahydro-2H- pyran-2-ylhydroxylamine (19 mg) , and 1-hydroxybenzotriazole (22 mg) in N,N-dimethγlformamide (1 mL) was added l-(3- dimethylaminopropyl)-3-ethylcarbodiimide (25 mg) at 4°C. The mixture was warmed to ambient temperature and stirred for 8 hours. The reaction mixture was added saturated NaHCO3 (1 mL) and water (4 mL) . A resulting precipitate was collected by filtration, and washed with water to give (2E)-3-(6-{[(3R)-l-phenyl-3- pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2- yloxy)acrylamide (43 mg) . 1H-NMR (300 MHz, DMSO-d6) 61.48-1.74 (6H, m) , 1.92-2.04 (IH, m), 2.23-2.36 (IH, m) , 3.09-3.64(5H, m) , 3.89-4.00 (IH, m) , 4.52-4.63 (IH, m), 4.88 (IH, brs), 6.23 (IH, d, J = 16 Hz), 6.51-6.62 (4H, m) , 7.12-7.19 (2H, m), 7.32-7.41 (2H, m) , 7.59-7.66 (IH, m) , 8.2O(1H, brs), 11.1 (IH, brs). MS (ES+) m/z 409 (M+l).

Preparation 505 i) A mixture of 5-chloro-6-methyl-2-pyrazinecarboxylic acid (3.83 g) and thionyl chloride (8.09 mL) was stirred for 3 hours at reflux. After cooling, the reaction mixture was evaporated in vacuo, ii) To a suspension of sodium borohydride (2.52 g) in H2O (110 mL) was added above product in dioxane (10 mL) at 100C. After stirring for 1 hours at 1O0C, the reaction mixture was extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, and evaporated in vacuo to give (5-chloro-6-methyl-2-pyrazinyl)methanol (2.36 g). 1H-NMR (300 MHz, CDC13) (52.67 (3H, s), 2.86-2.95 (IH, m) , 4.79 (2H, d, J = 3 Hz), 8.25 (IH, s). MS (ES+) m/z 159 (M+l). -

Preparation 506 1) To a mixture of (5-chloro-6-methyl-2-pyrazinyl)methanol (2.35 g) , ethyl acetate (50 mL), and dioxane (25 mL) was added manganese(IV) oxide (12.9 g) . After stirring for 2 hours at reflux, a resulting precipitate was filtered and the filtrate was evaporated in vacuo. 2) To a mixture of above product and THF (50 mL) was added (carbethoxymethylene)triphenylphosphorane (6.19 g) . The reaction mixture was stirred for 6 hours at room temperature, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give ethyl (2E)-3-(5-chloro-6- methyl-2-pyrazinyl)aerylate (863 mg) . 1H-NMR (300 MHz, CDC13) <5l.35 (3H, t, J = 7 Hz), 2.68 (3H, s), 4.29 (2H, q, J = 7 Hz), 7.01 (IH, d, J = 16 Hz), 7.63 (IH, d, J = 16 Hz), 8.26 (IH, s). MS (ES+) m/z 227 (M+l).

Preparation 507 1) To a mixture of 6-chloroτ3-pyridazinecarbaldehyde (300 mg) and THF (6 mL) was added (carbethoxymethylene)triphenylphosphorane (805 mg) . The reaction mixture was stirred for 2 hours at room temperature, and evaporated in vacuo. 2) To a mixture of above product and DMF (10 mL) was added (3R)-I- benzyl-3-pyrrolidinamine (556 mg) and Et3N (0.880 mL) . After stirring for 5 hours at 1000C, the reaction mixture was partitioned between ethyl acetate and H2O. The organic layer was washed with brine, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give ethyl (2E)-3-(6-{[(3R)-l-benzyl-3-pyrrolidinyl]amino}- 3-pyridazinyl)acrylate (237 mg) . 1H-NMR (300 MHz, CDCl3) <5l.33 (3H, t, J = 7 Hz), 1.60-1.79 (IH, m) , 2.25-2.94 (5H, m) , 3.63-3.66 (2H, m) , 4.27 (2H, q, J = 7 Hz), 4.48- 4.6O (1H, m), 5.17-5.23 (IH, m) , 6.59 (IH, d, J = 9 Hz), 6.61 (IH, d, J = 16 Hz), 7.25-7.38 (6H, m) , 7.78 (IH, d, J = 16 Hz). MS (ES+) m/z 353 (M+l).

Preparation 508 To a mixture of ethyl (2E)-3-(6-{(tert-butoxycarbonyl) [(3R)-3- pyrrolidinyl]amino}-3-pyridinyl)aerylate dihydrochloride (500 mg) , (2-bromoethoxy)benzene (347 mg), and DMF (5 mL) was added Na2CO3 (488 mg) . After stirring for 3 hours at 100°C, the reaction mixture was partitioned between ethyl acetate and H2O. The organic layer was washed with H2O, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give ethyl (2E)-3-(6-{(tert- butoxycarbonyl) [ (3R)-1-(2-phenoxyethyl)-3-pyrrolidinyl]amino}-3- pyridinyl)acrylate (516 mg) . 1H-NMR (300 MHz, CDCl3) <5l.35 (3H, t, J = 7 Hz), 1.46 (9H, s), 1.98-2.10 (IH, m), 2.16-2.30 (IH, m) , 2.63-2.73 (IH, m) , 2.78-2.98 (4H, m), 3.08-3.16 (IH, m) , 4.00-4.16 (2H, m) , 4.28 (2H, q, J = 7 Hz), 4.87-4.98 (IH, m) , 6.44 (IH, d, J = 16 Hz), 6.86-6.97 (3H, m) , 7.24-7.34 (3H, m) , 7.63 (IH, d, J = 16 Hz), 7.78 (IH, dd, J = 2, 8 Hz), 8.51 (IH, d, J = 2 Hz). MS (ES+) m/z 482 (M+l).

The following compound was obtained in a similar manner to that of Preparation 508. Preparation 509 ethyl (2E)-3-(6-{(tert-butoxycarbonyl) [(3R)-l-butyl-3- pyrrolidinyl]amino}-3-pyridinyl)acrylate 1H-NMR (300 MHz, CDC13) <5θ.93 (3H, t, J = 7 Hz), 1.23-1.51 (2H, m) , 1.35 (3H, t, J = 7 Hz), 1.46 (9H, s), 1.57-1.71 (2H, m) , 2.08-2.20 (IH, m), 2.33-2.48 (IH, m) , 2.60-3.50 (6H, m) , 4.28 (2H, q, J = 7 Hz), 4.95-5.08 (IH, m) , 6.47 (IH, d, J = 16 Hz), 7.33 (IH, d, J = 8 Hz), 7.65 (IH, d, J = 16 Hz), 7.81 (IH, dd, J = 2, 8 Hz), 8.57 (IH, brs ) . MS (ES+ ) m/z 418 (M+l ) .

Preparation 510 1) To a solution of ethyl (2E)-3-(6-{(tert-butoxycarbonyl) [ (3R)-I- isobutyl-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate (464 mg) in dioxane (11 iriL) was added IN sodium hydroxide (3.30 mL). After stirring at 600C for 2 hours, the reaction mixture was added H2O(55 mL) and acidified with IN hydrochloric acid (to pH 4). A resulting mixture was evaporated in vacuo . 2) To a mixture of above product, 0-tetrahydro-2H-pyran-2- ylhydroxylamine (195 mg) , and 1-hydroxybenzotriazole (225 mg) in N,N-dimethylformamide (6 mL) was added l-(3-dimethylaminopropyl)-3- ethylcarbodiimide (259 mg) at 4°C. The mixture was warmed to ambient temperature and stirred for 8 hours. The reaction mixture was added saturated NaHCO3 (6 mL) and water (24 mL), and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give (2E)-3-(5-{(tert- butoxycarbonyl){(3R)^l-isobutyl-3-pyrrolidinyl}amino}-2-pyri dinyl)- N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (300 MHz, DMSO-d6) δθ.71-0.79 (6H, m) , 1.36 (9H, s), 1.48- 1.76 (7H, m), 1.86-2.14 (4H, m) , 2.35-2.59 (3H, m) , 2.69-2.76 (IH, m), 3.49-3.58 (IH, m) , 3.90-4.03 (IH, m) , 4.67-4.78 (IH, m) , 4.92 (IH, brs), 6.58 (IH, d, J = 16 Hz), 7.34 (IH, d, J = 8 Hz), 7.52 (IH, d, J = 16 Hz), 8.00 (IH, d, J = 8 Hz), 8.62 (IH, brs), 11.3 (IH, brs). MS (ES+) m/z 489 (M+l).

The following compounds were obtained in a similar manner to that of Preparation 510. Preparation 511 (2E)-3-(5-{[(3R)-I-cyclohexyl-3-pyrrolidinyl]amino}-2-pyrazi nyl)-N- (tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (300 MHz, DMSO-d6) 61.08-1.29 (6H, m) , 1.47-2.25 (13H, m) , 2.39-2.53 (2H, m) , 2.68-2.84 (2H, m) , 3.49-3.57 (IH, m) , 3.90-4.01 (IH, m), 4.22-4.33 (IH, m) , 4.89 (IH, brs), 6.60 (IH, d, J = 16 Hz), 7.38 (IH, d, J = 16 Hz), 7.71-7.76 (IH, m) , 7.97 (IH, brs), 8.11 (IH, brs), 11.2 (IH, brs). MS (ES+) m/z 416 (M+l) .

Preparation 512 (2E)-3-(2-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-pyrimidiny l)-N- (tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (300 MHz, DMSO-d6) <51.47-1.79 (7H, m) , 2.08-2.21 (IH, m) , 2.30-2.37 (IH, m) , 2.44-2.63 (2H, m) , 2.78-2.84 (IH, m) , 3.47-3.61 (3H, m), 3.88-3.99 (IH, m) , 4.27-4.37 (IH, m) , 4.88 (IH, brs), 6.34 (IH, d, J = 16 Hz), 7.20-7.34 (5H, m) , 7.74-7.82 (IH, m) , 8.51 (2H, s), 11.1 (IH, brs). MS (ES+) m/z 424 (M+l).

Preparation 513 (2E)-3-(6-{[ (3R)-l-benzyl-3-pyrrolidinyl]amino}-3-pyridazinyl)-N- (tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (300 MHz, CDCl3) 61.52-1.96 (7H, m) , 2.34-2.52 (2H, m) , 2.62-2.93 (3H, m) , 3.58-3.68 (3H, m) , 3.95-4.07 (IH, m) , 4.34-4.50 (IH, m), 4.97-5.03 (IH, m) , 6.60 (IH, d, J = 9 Hz), 7.23-7.35 (7H, m), 7.67 (IH, d, J = 16 Hz). MS (ES+) m/z 424 (M+l).

Preparation 514 (2E)-3-(5-{[(3R)-l-benzyl-3-pyrrolidinyl]amino}-6-methyl-2- pyrazinyl) -N- (tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (300 MHz, DMSO-d6) δ -1.48-1.71 (6H, m) , 1.79-1.92 (IH, m) , 2.06-2.68 (7H, m) , 2.81-2.93 (IH, m) , 3.48-3.63 (3H, m) , 3.88-3.99 (IH, m), 4.36-4.48 (IH, m) , 4.90 (IH, brs), 6.63 (IH, d, J = 16 Hz), 6.81 (IH, d, J = 7 Hz), 7.20-7.39 (6H, m) , 8.00(1H, s), 11.2 (IH, brs) . MS (ES+) m/z 438 (M+l). Preparation 515 (2E)-3-(6-{[(3R)-l-(cyclohexylmethyl)-3-pyrrolidinyl]amino}- 3- pyridazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (300 MHz, DMSO-d6) 60.76-0.92 (2H, m) , 1.08-1.27 (4H, m) , 1.32-1.81 (12H, m) , 2.15-2.29 (3H, m) , 2.34-2.45 (2H, m) , 2.56-2.66 (IH, m), 2.73-2.81 (IH, m) , 3.49-3.58 (IH, m) , 3.91-4.03 (IH, m) , 4.35-4.48 (IH, m) , 4.92 (IH, brs), 6.62 (IH, d, J = 16 Hz), 6.83 (IH, d, J = 9 Hz), 7.33-7.55 (3H, m) , 11.3 (IH, brs). MS (ES+) m/z 430 (M+l).

Preparation 516 To a solution of ethyl (2E)-3-(6-{(tert-butoxycarbonyl) [ (3R)-1- butyl-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate (308 mg) in dioxane (7.4 mL) was added IN sodium hydroxide (2.21 mL) . After stirring at 60°C for 2 hours, the reaction mixture was added H2O(37 mL) and acidified with IN hydrochloric acid (to pH 1). A resulting mixture was extracted with CHCl3, and the organic layer was dried over MgSO4, filtered, and evaporated in vacuo to give (2E)-3-(6- {(tert-butoxycarbonyl) [ (3R)-l-butyl-3-pyrrolidinyl]amino}-3- pyridinyl)acrylic acid dihydrochloride (214 mg). 1H-NMR (300 MHz, DMSO-d6) δθ.88 (3H, t, J = 7 Hz), 1.23-1.37 (2H, m), 1.40 (9H, s), 1.52-1.65 (2H, m) , 1.91-3.85 (9H, m) , 6.65 (IH, d, J = 16 Hz), 7.42 (IH, d, J = 8 Hz), 7.62 (IH, d, J = 16 Hz), 8.20 (IH, dd, 3 = 2, 8 Hz), 8.70 (IH, d, J = 2 Hz). MS (ES+) m/z 390 (M+l).

The following compounds were obtained in a similar manner to that of Preparation 516. Preparation 517 (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-l-(3,4-dimethylbenzyl) -3- pyrrolidinyl]amino}-3-pyridinyl)acrylic acid dihydrochloride 1H-NMR (300 MHz, CDCl3) <5l.45 (9H, s), 2.23-2.89 (8H, m) , 3.37-4.46 (6H, m), 5.10-5.24 (IH, m) , 6.39 (IH, dd, J = 2, 16 Hz), 7.16-7.40 (4H, m), 7.55 (IH, dd, J = 2, 16 Hz), 7.78 (IH, dd, J = 2, 8 Hz), 8.35-8.43 (IH, m) . MS (ES+ ) m/z 452 (M+l ) ' .

Preparation 518 (2E)-3-(6-{(tert-butoxycarbonyl) [(3R)-1-(2-ethylbutyl)-3- pyrrolidinyl]amino}-3-pyridinyl)acrylic acid dihydrochloride 1H-NMR (300 MHz, DMSO-d6) δθ.80-0.92 (6H, m), 1.15-5.22 (14H, m) , 1.42 (9H, s), 6.68 (IH, d, J = 16 Hz), 7.42-7.51 (IH, m) , 7.61-7.70 (IH, m), 8.20-8.28 (IH, m) , 8.67-8.75 (IH, m) . MS (ES+) m/z 418 (M+l).

Preparation 519 (2E)-3-(6-{(tert-butoxycarbonyl) [(3R)-1-(2-phenoxyethyl)-3- pyrrolidinyl]amino}-3-pyridinyl)acrylic acid dihydrochloride 1H-NMR (300 MHz, DMSO-d6) <5l.40 (9H, s), 1.87-5.20 (HH, m) , 6.63 (IH, d, J = 16 Hz), 6.94-7.02 (3H, m) , 7.28-7.35 (2H, m) , 7.40-7.48 (IH, m), 7.60 (IH, d, J = 16 Hz), 8.20 (IH, dd, J = 2, 8 Hz), 8.67 (IH, d, J = 2 Hz). MS (ES+) m/z 454 (M+l).

Preparation 520 To a mixture of (2E)-3-(6-{(tert-butoxycarbonyl) [(3R)-I-(2- ethylbutyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylic acid dihydrochloride (303 mg) , 0-tetrahydro-2H-pyran-2-ylhydroxylamine (109 mg.), and 1-hydroxybenzotriazole (125 mg) in N,N- dimethylformamide (3.1 mL) was added l-(3-dimethylaminopropyl)-3- ethylcarbodiimide (144 mg) at 4°C. The mixture was warmed to ambient temperature and stirred for 8 hours. The reaction mixture was added saturated NaHCO3 (3 mL) and water (12 mL), and extracted with ethyl acetate. The organic layer was washed with H2O and brine, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give (2E)-3-(5-{(tert-butoxycarbonyl){(3R)-1-(2-ethylbutyl)-3- pyrrolidinyl}amino}-2-pyridinyl)-N-(tetrahydro-2H-pyran-2- yloxy)acrylamide (135 mg) . 1H-NMR (300 MHz, DMSO-d6) <5θ.74 (6H, t, J = 7 Hz), 1.09-1.25 (5H, m), 1.36 (9H, s), 1.49-1.75 (6H, m) , 1.88-2.19 (4H, m) , 2.36-2.71 (4H, m), 3.49-3.58 (IH, m) , 3.90-4.02 (IH, m) , 4.67-4.78 (IH, m) , 4.92 (IH, brs), 6.58 (IH, d, J = 16 Hz), 7.33 (IH, d, J = 8 Hz), 7.53 (IH, d, J = 16 Hz), 8.00 (IH, d, J = 8 Hz), 8.63 (IH, brs). MS (ES+) m/z 517 (M+l).

The following compounds were obtained in a similar manner to that of Preparation 520. Preparation 521 (2E)-3-(5-{(tert-butoxycarbonyl){(3R)-1-(3,4-dimethylbenzyl) -3- pyrrolidinyl}amino}-2-pyridinyl)-N-(tetrahydro-2H-pyran-2- yloxy)acrylamide 1H-NMR (300 MHz, DMSO-d6) <5l.35 (9H, s), 1.50-1.77 (6H, m) , 1.88- 2.23 (8H, m), 2.42-3.59 (7H, m) , 3.91-4.03 (IH, m) , 4.68-4.77 (IH, m), 4.91-4.95 (IH, m) , 6.59 (IH, d, J = 16 Hz), 6.85 (IH, d, J = 8 Hz), 6.93 (IH, s), 7.00 (IH, d, J = 8 Hz), 7.33 (IH, d, J = 8 Hz), 7.54 (IH, d, J = 16 Hz), 7.97-8.03 (IH, m) , 8.61 (IH, brs), 11.3 (IH, brs). MS (ES+) m/z 551 (M+l).

Preparation 522 (2E)-3-(5-{(tert-butoxycarbonyl){(3R)-1-butyl-3- pyrrolidinyl}amino}-2-pyridinyl)-N-(tetrahydro-2H-pyran-2- yloxy)acrylamide 1H-NMR (300 MHz, CDCl3) <5θ.91 (3H, t, J = 7 Hz), 1.23-3.45 (12H, m) , 1.46 (9H, s), 3.64-3.72 (IH, m) , 3.93-4.04 (IH, m) , 4.89-5.06 (2H, m), 6.30-7.34 (2H, m), 7.68 (IH, d, J = 16 Hz), 7.78 (IH, dd, J = 2, 8 Hz), 8.56 (IH, brs). MS (ES+) m/z 489 (M+l).

Preparation 523 (2E)-3-(5-{(tert-butoxycarbonyl){(3R)-1-(2-phenoxyethyl)-3- pyrrolidinyl}amino}-2-pyridinyl)-N-(tetrahydror2H-pyran-2- yloxy)acrylamide 1H-NMR (300 MHz, CDCl3) <5l.45 (9H, s), 1.54-1.90 (6H, m) , 1.98-2.10 ( IH, m) , 2. 16-2. 31 ( IH, ra) , 2.65-2 .98 ( 5H, m) , 3.07-3. 19 ( IH, m) , 3.63-3. 74 ( IH, m) , 3. 93-4.07 ( 3H, m) , 4 .86-5.07 ( 2H, m) , 6.86-6 . 98 ( 3H, m) , 7.24-7. 34 ( 4H, m) , 7.62-7.79 ( 2H, m) , 8. 53 ( IH, brs ) . MS (ES+ ) m/z 553 (M+l ) .

The following compound was obtained in a similar manner to that of Preparation 309. Preparation 524 ethyl 5-chloro-6-{[ (3S)-1-(σyclohexylmethyl)-3- piperidinyl]amino}nicotinate 1H-NMR (300 MHz, CDCl3) δ0.79-0.98 (2H, m),1.07-1.31 (4H, m),1.36 (3H, t, J=7.1 Hz),1.40-1.88 (9H, m),2.01-2.24 (3H, m),2.30-2.43 (IH, m),2.58-2.76 (2H, m),4.24-4.39 (3H, m),6.37 (IH, br peak),8.00 (IH, d, J=2.0 Hz),8.66 (IH, d, J=2.0 Hz); MS (ES+) m/z 380.

The following compound was obtained in a similar manner to that of Preparation 3. Preparation 525 ethyl (2E)-3-[5-chloro-6-(cyclopentylamino)-3-pyridinyl]acrylate 1H-NMR (DMSO-d6):<5 1.25 (3H, t J=7.08Hz), 1.51-1.71 (6H, m) , 1.92- 1.99 (2H, m),4.16 (2H, q J=7.08Hz), 4.32-4.43 (IH, m) , 6.47 (IH, d J=15.84Hz), 6.65 (IH, d J=7.24Hz), 7.51 (IH, d J=15.84Hz), 8.08 (IH, d J=I.96Hz), 8.28 (IH, d J=I.96Hz).

The following compound was obtained in a similar manner to that of Preparation 426. Preparation 526 ethyl (2E)-3-{6-[(tert-butoxycarbonyl){(3R)-I-[(2,6,6-trimethyl-l- cyclohexen-1-yl)methyl]-3-pyrrolidinyl}amino]-3-pyridinyl}ac rylate 1H-NMR (300 MHz, CDCl3) <50.91-1.02 (6H, m),1.35 (3H, t, J=7.3 Hz),1.44 (9H, s),1.50-1.72 (13H, m),1.85-2.01 (3H, m) ,2.07-2.33 (IH, m),2.44-2.59 (2H, m),2.61-2.74 (IH, m) ,2.76-2.89 (IH, m),2.96-3.10 (2H, m),4.28 (2H, q, J=7.3 Hz) ,4.76-4.91 (IH, m),6.46 (IH, d, J=16.1 Hz),7.28 (IH, d, J=8.8 Hz),7.66 (IH, d, J=16.1 Hz),7.80 (IH, dd, J=8.8, 2.6 Hz), 8.56 (IH, d, J=2.6 Hz); MS (ES+) m/z 498 (M+l).

The following compounds were obtained in a similar manner to that of Preparation 405,Preparation 414. Preparation 527 tert-butyl (5-{(IE)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1- propen-l-yl}-2-pyridinyl){(3R)-I-[(2,6,6-trimethyl-l-cyclohe xen-1- yl)methyl]-3-pyrrolidinyl}carbamate 1H-NMR (300 MHz, DMSO-d6) <5θ.9O (3H, s),0.92 (3H, s),1.21-2.20 (7H, m),1.36 (9H, s),2.35-2.78 (4H, m),2.95 (2H, br.s) ,3.48-3.61 (IH, m),3.89-4.04 (IH, m) ,4.62-4.80 (IH, m),4.92 (IH, br.s),6.58 (IH, d, J=16.5 Hz),7.33 (IH, d, J=8.4 Hz),7.53 (IH, d, J=16.5 Hz),7.99 (IH, br.d, J=8.4 Hz),8.62 (IH, br.s); MS (ES+) m/z 569(M+1).

Preparation 528 (2E)-3-(5-{[(3R)-1-(phenylacetyl)-3-piperidinyl]amino}-2- pyrazinyl)-N-(tet'rahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (300 MHz, DMSO-d6) 61.21-2.01 (1OH, m),2.66-2.78 (0.6H, m),3.01-4.03 (8H, m),4.24-4.34 (0.4H, m),4.90 (IH, br.s) ,6.56-6.69 (IH, m),7.11-7.68 (6H, m),8.13 (0.4H, s),8.18 (0.6H, s).

The following compound was obtained in a similar manner to that of Preparation 439. Preparation 529 ethyl (2E)-3-(5-{[(3R)-l-(3-methylbenzyl)-3-pyrrolidinyl]amino}-2- pyrazinyl)aerylate 1H-NMR (300 MHz, CDCl3)S 1.32 (3H, t, J=7.0 Hz) , 1.63-1.77 (IH, m), 2.31-2.46 (2H, m),2.35 (3H, s), 2.62-2.75 (2H, m), 2.85-2.95 (IH, m),3.60 (2H, br.s), 4.25 (2H, q, J=7.0 Hz) ,4.39-4.54 (IH, m),5.23 (IH, br.d, J=8.1 Hz), 6.67 (IH, d, J=15.8 Hz) ,7.04-7.15 (3H, m), 7.18-7.25 (IH, m),7.57 (IH, d, J=15.8 Hz), 7.87 (IH, br.s), 8.05 (IH, br.s); MS (ES+) m/z 367(M+1). The following compound was obtained in a similar manner to that of Preparation 405,Preparation 414. Preparation 530 (2E)-3-(5-{[(3R)-1-(3-methylbenzyl)-3-pyrrolidinyl]amino}-2- pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylaiτιide 1H-NMR (300 MHz, DMSO-d6) δ1.44-1.77 (7H, m),2.14-2.33 (IH, m),2.28 (3H, s),2.34-2.50 (2H, m) ,2.58-2.70 (IH, m),2.71-2.80 (IH, m),3.47- 3.57 (IH, m),3.54 (2H, s),3.87-4.03 (IH, m) ,4.23-4.37 (IH, m),4.89 (IH, br.s),6.59 (IH, d, J=15.0 Hz) ,7.01-7.14 (3H, m) ,7.15-7.23 (IH, m),7.37 (IH, d, J=15.0 Hz),7.77 (IH, br.d),7.97 (IH, br.s),8.09 (IH, br.s); MS (ES+) m/z 438(M+l).

The following compound was obtained in a similar manner to that of Preparation 506. Preparation 531 ethyl (2E)-3-(5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3- piperidinyl]amino}-3-pyridinyl)aerylate 1H-NMR (300 MHz, CDCl3) 60.79-0.99 (2H, m),1.09-1.39 (4H, m),1.33 (3H, t, J=7.0 Hz),1.39-1.90 (9H, m),2.03-2.20 (3H, m),2.32-2.43 (IH, m),2.55-2.76 (2H, m),4.22-4.33 (IH, m),4.24 (2H, q, J=7.0 Hz),6.19 (IH, d, J=15.8 Hz),7.53 (IH, d, J=15.8 Hz),7.66 (IH, d, J=I.8 Hz),8.10 (IH, d, J=I.8 Hz); MS (ES+) m/z 406(M+l).

The following compound was obtained in a similar manner to that of Preparation 426. Preparation 532 ethyl (2E)-3-(6-{(tert-butoxycarbonyl) [ (3R)-1-(3,3,5,5- tetramethylcyclohexyl)-3-pyrrolidinyl]amino}-3-pyridinyl)aer ylate 1H-NMR (300 MHz, CDCl3)<5θ.9O (6H, br.s),1.01 (6H, br.s),1.36 (3H, t, J=7.0 Hz),1.47 (9H, s),1.57-1.75 (6H, m),1.90-2.26 (2H, m),2.32- 2.97 (4H, m),3.17-3.30 (IH, m),4.29 (2H, q, J=7.0 Hz) ,4.77-4.94 (IH, m),6.47 (IH, d, J=16.1 Hz),7.32 (IH, d, J=8.4 Hz),7.67 (IH, d, J=16.1 Hz),7.82 (IH, dd, J=8.4, 2.6 Hz),8.56 (IH, d, J=2.6 Hz); MS (ES+) m/z 550(M+l). The following compound was obtained in a similar manner to that of Preparation 405,Preparation 414. Preparation 533 tert-butyl (5-{(lE)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-l- propen-l-yl}-2-pyridinyl) [ (3R)-I-(3,3,5,5-tetramethylcyclohexyl)-3- pyrrolidinyl]carbamate 1H-NMR (300 MHz, DMSO-d6) <5θ.86 (6H, s),0.95 (6H, s),1.12-1.77 (12H, m),1.37 (9H, s),1.78-2.08 (2H, m) ,2.23-2.54 (2H, m),2.54-2.77 (2H, m),2.88-3.01 (IH, m),3.49-3.60 (IH, m),3.87-4.06 (IH, m),4.57-4.72 (IH, m),4.89-4.96 (IH, m),6.58 (IH, d, J=15.8 Hz),7.34 (IH, d, J=8.4 Hz),7.52 (IH, d, J=15.8 Hz) ,7.97-8.05 (IH, m),8.60-8.66 (IH, m) .

The following compounds were obtained in a similar manner to that of Preparation 426. Preparation 534 ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-l-(2,2,6,6-tetramethyl - 4-piperidinyl)-3-pyrrolidinyl]amino}-3-pyridinyl)aerylate 1H-NMR (300 MHz, CDCl3) δ0.74-0.90 (2H, m),0.98 (6H, s),1.08 (6H, s),1.27 (3H, t, J=7.3 Hz),1.37 (9H, s),1.54-1.68 (4H, m) ,1.78-1.93 (IH, m),1.93-2.09 (IH, m),2.34-2.69 (4H, m) ,2.87-2.98 (IH, m),4.21 (2H, q, J=7.3 Hz),4.58-4.73 (IH, m),6.76 (IH, d, J=16.1 Hz),7.35 (IH, d, J=8.8 Hz),7.69 (IH, d, J=16.1 Hz),8.19 (IH, dd, J=8.8, 2.6 Hz),8.73 (IH, d, J=2.6 Hz); MS (ES+) m/z 501(M+l).

Preparation 535 ethyl (2E)-3-(6-{(tert-butoxycarbonyl) [(3R)-1-(tetrahydro-2H-pyran- 4-yl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate 1H-NMR (300 MHz, CDCl3) <5l.35 (3H, t, J=7.3 Hz) ,1.40-1.59 (2H, m),1.46 (9H, s),1.72-1.82 (2H, m),1.96-2.09 (IH, m) ,2.11-2.35 (2H, m),2.50-2.63 (IH, m),2.69 (IH, t, J=8.4 Hz) ,2.76-2.88 (IH, m),3.15 (IH, t, J=8.4 Hz),3.32-3.44 (2H, m),3.90-4.00 (2H, m),4.28 (2H, q, J=7.3 Hz),4.81-4.97 (IH, m),6.46 (IH, d, J=16.1 Hz),7.32 (IH, d, J=8.4 Hz) , 7.66 ( IH, d, 3=16.1 Hz) , 7.81 ( IH, dd, J=8.4 , 2.6 Hz) , 8.54 ( IH, d, J=2.6 Hz ) ; MS (ES+) m/z 446 (M+l) .

The following compound was obtained in a similar manner to that of Example 129. Preparation 536 (3R)-1-(cyclohexylmethyl)-3-piperidinamine dihydrochloride 1H-NMR (300 MHz, DMSO-d6) δ0.83-2.13 (15H, m),2.69-3.95 (7H, m),8.42-8.66 (2H, m) .

The following compound was obtained in a similar manner to that of Preparation 405,Preparation 414. Preparation 537 (2E)-3-(5-chloro-6-{[(3R)-I-(cyclohexylmethyl)-3- piperidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2- yloxy)acrylamide 1H-NMR (300 MHz, DMSO-d6) <5θ.72-0.94 (2H, m),1.01-1.31 (4H, m),1.37-1.82 (15H, m),2.03-2.61 (6H, m),3.46-3.59 (IH, m),4.11-4.25 (IH, m),4.89 (IH, br.s) ,6.26-6.46 (2H, m),7.36 (IH, d, J=15.8 Hz),7.87 (IH, br.s),8.18-8.26 (IH, m) ; MS (ES+) m/z 477(M+1).

Preparation 538 ' A mixture of tert-butyl (3R)-3-({3-chloro-5-[(lE)-3-ethoxy-3-oxo- 1-propen-l-yl]-2-pyridinyl}amino)-1-pyrrolidinecarboxylate (0.98g) and 4N hydrogen chloride in dioxane solution (5ml) in EtOH (10ml) was stirred at ambient temperature for 4 hours. The reaction mixture was evaporated in vacuo and the residue was triturated with hexane was collected by filtration to give ethyl (2E)-3-{5-chloro- 6-[(3R)-3-pyrrolidinylamino]-3-pyridinyl}aerylate dihydrochloride (0.9g).ethyl (2E)-3-{5-chloro-6-[ (3R)-3-pyrrolidinylamino]-3- pyridinyl}aerylate dihydrochloride 1H-NMR (DMSO-d6):<5 1.25 (3H, t J=7.08Hz), 1.99-2.12 (2H, m), 3.19- 3.45 (3H, m), 3.56-3.65 (IH, m) , 4.16 (2H, q J=7.08Hz), 4.52-4.57 (IH, m), 6.52 (IH, d J=15.94Hz), 6.95 (IH, d J=6.52Hz), 7.53 (IH, d J=15. 94Hz ) , 8 .13 ( IH, d J=I .90Hz ) , 8.31 ( IH, d J=I .90Hz ) .

The following compound was obtained in a similar manner to that of Preparation 538. Preparation 539 ethyl (2E)-3-{6-[(3R)-3-pyrrolidinylamino]-3-pyridinyl}acrylate dihydrochloride 1H-NMR (DMSO-d6):<5 1.25 (3H, t J=7.06Hz), 2.04-2.05 (IH, m) , 2.29- 2.34 (IH, m), 3.24-3.29 (2H, m), 3.40-3.43 (IH, m) , 3.45-3.52 (IH, m), 4.18 (2H, q J=7.06Hz), 4.66 (IH, br.s), 6.59 (IH, d J=16.00Hz), 7.11 (IH, d J=9.12Hz), 7.65 (IH, d J=16.00Hz), 8.27-8.32 (2H, m), 9.56 (IH, br.s), 9.69 (IH, br,s).

Preparation 540 A solution of benzyl 4-methyl-2-(methylthio)-5- pyrimidinecarboxylate (6.Og) and 1-benzyl-3-aminopyrrolidine (5.78g) in dioxane (10ml) was stirred at 130°C for 15 hours under atmospheric pressure of nitrogen. The reaction mixture was poured into a mixture of AcOJSt and H2O and the organic layer was washed with brine and dried over MgSO4 . The solvent was evaporated in vacuo and the residue was chromatographed on allunima eluting with AcOEt-n-hexane (6:4). The eluted fractions containing the desired product were collected and evaporated in vacuo to give benzyl 2- [ (1-benzyl-3-pyrrolidinyl)amino]-4-methyl-5-pyrimidinecarboxy late (3.06g). 1H-NMR (DMSO-d6):<5 1.71-1.81 (IH, m) , 2.09-2.17 (IH, m) , 2.47 (3H, s), 2.35-2.60 (3H, m) , 2.79-2.81 (IH, m) , 3.56 (2H, s), 4.39 (IH, m), 5.27 (2H, s), 7.22-7.47 (1OH, m) , 8.11-8.16 (IH, m) , 8.70 & 8.75 (total IH, each s).

Preparation 541 A solution of benzyl 4-methyl-2-(methylsulfinyl)~5- pyrimidinecarboxylate (3.27g) , 1-benzyl-3-aminopyrrolidine (2.98g) and N,N-diisopropylethylamine (1.75g) in dioxane (15ml) was stirred at 130°C for 11 hours under atmospheric pressure of nitrogen. The reaction mixture was poured into a mixture of AcOEt and H2O and the organic layer was washed with brine and dried over MgSU4 . The solvent was evaporated in vacuo and the residue was chromatographed on allumina eluting with AcOEt-n-hexane (5:5). The eluted fractions containing the desired product were collected and evaporated in vacuo to give benzyl 2-[(l-benzyl-3- pyrrolidinyl)amino]-4-methyl-5-pyrimidinecarboxylate (3.9g) . 1H-NMR (DMS0-d6):δ 1.71-1.81 (IH, m) , 2.09-2.17 (IH, m) , 2.47 (3H, s), 2.35-2.60 (3H, m) , 2.79-2.81 (IH, m) , 3.56 (2H, s), 4.39 (IH, m), 5.27 (2H, s), 7.22-7.47 (1OH, m) , 8.11-8.16 (IH, m) , 8.70 & 8.75 (total IH, each s).

The following compounds were obtained in a similar manner to that of Preparation 541. Preparation 542 benzyl 2-[ (l-benzyl-4-piperidinyl)amino]-4-methyl-5- pyrimidinecarboxylate 1H-NMR (DMSO-d6):<5 1.45-1.62 (2H, m) , 1.78-1.83 (2H, m) , 1.94-2.06 (2H, s), 2.52 (3H, s), 2.76-2.82 (2H, m), 3.36 (2H, s)m 3.78-3.81 (IH, m), 5.27 (2H, s), 7.23-7.44 (1OH, m) , 7.91-8.00 (IH, m) , 8.68 & 8.77 (total IH, each s).

Preparation 543 benzyl 4-methyl-2-{[(3R)-l-(4-methylbenzyl)-3-pyrrolidinyl]amino}- 5-pyrimidinecarboxylate 1H-NMR (DMSO-d6):<5 1.73-1.76 (IH, m) , 2.13-2.60 (4H m), 2.27 (3H, s), 2.45 (3H, s), 2.74-2.89 (IH, m) , 3.51 (2H, s), 4.37 (IH, m) , 5.26 (2H, s), 7.08-7.20 (5H, m) , 7.30-7.48 (4H, m) , 8.10-8.15 (IH, m), 8.69 & 8.75 (total IH, each s) .

Preparation 544 benzyl 2-{ [(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-4- methyl-5-pyrimidinecarboxylate 1H-NMR (DMSO-d6):<5 0.77-0.86 (2H, m) , 1.12-1.32 (5H, m) , 1.61-1.76 (5H, m), 2.00-2.56 (6H, m) , 2.43 (3H, s), 2.74-2.78 (IH, m) , 4.37- 4.51 ( IH, m) , 5.27 ( 2H, s ) , 7. 22-7. 70 ( 5H, m) , 8 . 65-8 .69 ( IH, m) , 8 .69 & 8. 77 ( total IH, each s ) .

Preparation 545 A solution of benzyl 4τmethyl-2-(methylthio)-5- pyriinidinecarboxylate (3.6g) and m-chloroperbenzoic acid (P=75%) (2.72g) in AcOEt (30ml) was stirred at ambient temperature for 2 hours. The reaction mixture was poured into a mixture of AcOEt and H2O and the organic layer was washed with saturated NaHCO3 solution, brine and dried over MgSO4 . The solvent was evaporated in vacuo to give benzyl 4-methyl-2-(methylsulfinyl)-5- pyrimidinecarboxylate (3.2g) 1H-NMR (DMSO-d6):<5 2.81 (3H, s), 2.90 (3H, s), 5.42 (2H, s) 7.23- 7.55 (5H, m), 9.27 (IH, s).

Preparation 546 A mixture of {2-[(l-benzyl-3-pyrrolidinyl)amino]-4-methyl-5- pyrimidinyl}methanol (1.75g) and MnO2 (5.Ig) in AcOEt (30ml) was refluxed under stirring for 1.5 hours. After removal of the insoluble material, and the solvent was evaporated in vacuo to give 2-[(1-benzyl-3-pyrrolidinyl)amino]-4-methyl-5- pyrimidinecarbaldehyde (1.58g) . 1H-NMR (DMSO-d6):<5 1.72-1.78 (IH, m) , 2.15-2.19 (IH, m) , 2.36-2.61 (3H, m),2.48 (3H, s), 2.80-2.88 (IH, m) , 3.35 (2H, s), 4.39-4.47 (IH, m), 7.18-7.32 (5H, m) , 8.34-8.43 (IH, m), 8.58 & 8.62 (total IH, each s), 9.81 & 9.84 (total IH, each s).

The following compounds were obtained in a similar manner to that of Preparation 546. Preparation 547 2-[(l-benzyl-4-piperidinyl)amino]-4-methyl-5-pyrimidinecarba ldehyde 1H-NMR (DMSO-d6):<5 1.44-1.63 (2H, m) , 1.78-1.84 (2H, m) , 1.96-2.07 (2H, m), 2.49 (3H, s), 2.77-2.83 (2H, m) , 3.45 (2H, s), 3.81-3.87 (IH, m), 7.19-7.37 (5H, m) , 8.14-8.26 (IH, m) , 8.18 & 8.26 (total IH, each s), 9.81 & 9.84 (total IH, each s) . Preparation 548 4-methyl-2-{[(3R)~l-(4-methylbenzyl)-3-pyrrolidinyl]amino}-5 - pyrimidinecarbaldehyde 1H-NMR (DMSO-d6):<5 1.74-1.77 (IH, m) , 2.14-2.60 (4H, m) , 2.27 (3H, s), 2.46 (3H, s), 2.77-2.86 (IH, m), 3.52 (2H, s), 4.41-4.48 (IH, m), 7.10 (2H, d J=8.02Hz), 7.19 (2H, d J=8.02Hz), 8.32-8.42 (IH, m) , 8.58 & 8.61 (total IH, each s), 9.81 & 8.93 (total IH, each s).

Preparation 549 2-{[(3R)-l-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-4-methyl -5- pyrimidinecarbaldehyde 1H-NMR (DMSO-d6):<5 0.78-0.84 (2H, m) , 1.13-1.73 (1OH, m) , 2.00- 2.57 (6H, m), 2.47 (3H, s), 2.79-2.82 (IH, m) , 4.41-4.51 (IH, m) , 8.28-8.34 (IH, m) , 8.64 & 8.73 (total IH, each s)» 9.86 & 9.90 (total IH, each s).

Preparation 550 A solution of diethylphosphonoacetcacid ethyl ester (1.79g) in THF (5ml) was added dropwise to a mixture of 60% sodium hydride in oil (341mg) in THF (6OmL) with stirring at 10-20 °C under atmospheric pressure of nitrogen, and the reaction mixture was stirred at ambient temperature for 30 minutes. A solution of 2- [(1-benzyl-3-pyrrolidinyl)amino]-4-methyl-5-pyrimidinecarbal dehyde (1.58g) in THF (10ml) solution was added the above mixture and resultant mixture was stirred at ambient temperature for 1.5 hours. The reaction mixture was poured into a mixture of AcOEt-H2O and the organic layer was washed with brine and dried over MgSO4 . The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (9:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to give ethyl (2E)-3-{2-[(l-benzyl-3-pyrrolidinyl)amino]-4- methyl-5-pyrimidinyl}acrylate (1.7g) . 1H-NMR (DMSO-d6):<5 1.24 (3H, t J=7.06Hz), 1.63-1.82 (IH, m) , 2.04- 2.30 (IH, m), 2.34 (3H, s), 2.38-2.57 (3H, m) , 2.79-2.84 (IH, m) , 3 . 56 ( 2H, s ) , 4 . 18 ( 2H, q J=7.06Hz ) , 4.35 ( IH, m) , 6.40 ( IH, d J=15 .94Hz ) , 7.18-7. 32 ( 5H, m) , 7.63 ( IH, d J=15.94Hz ) , 7. 78-7.80 ( IH, m) , 8. 63 ( IH, s ) .

The following compounds were obtained in a similar manner to that of Preparation 550. Preparation 551 ethyl (2E)-3-{2-[(l-benzyl-4-piperidinyl)amino]-4-methyl-5- pyrimidinyl}acrylate 1H-NMR (DMSO-d6):<5 1.24 (3H,t J=7.06Hz), 1.47-1.54 (2H, m) , 1.78- 1.83 (2H, m), 1.95-2.06 (2H, m) , 2.37 (3H, s), 2.76-2.82 (2H, m) , 3.45 (2H, s), 3.80 (IH, m) , 4.18 (2H, q J=7.06Hz), 6.39 (IH, d J=15.94Hz), 7.19-7.36 (6H, m) , 7.63 (IH, d J=15.94Hz), 8.64 (IH, s).

Preparation 552 ethyl (2E)-3-(4-methyl-2-{[(3R)-l-(4-methylbenzyl)-3- pyrrolidinyl]amino}-5-pyrimidinyl)aerylate 1H-NMR (DMSO~d6):<5 1.24 (3H, t J=7.06Hz), 1.67-1.80 (IH, m) , 2.02- 2.49 (2H, m), 2.27 (3H, s), 2.45 (3H, s), 2.49-2.55 (2H, m) , 2.77- 2.81 (IH, m), 3.51 (2H, s),4.17 (2H, q J=7.06Hz), 4.35 (IH, m), 6.39 (IH, d J=15.96Hz), 7.10 (2H, d J=8.02Hz), 7.18 (2H, d J=8.02Hz), 7.63 (IH, d J=15.96Hz), 7.76-7.79 (IH, m) , 8.63 (IH, s).

Preparation 553 ethyl (2E)-3-(2-{[(3R)-l-(cyclohexylmethyl)-3-pyrrolidinyl]amino}- 4-methyl-5-pyrimidinyl)acrylate ' 1H-NMR (DMSO-d6):<5 0.77-0.83 (2H, m) , 1.25 (3H, t J=7.08Hz), 1.15- 1.17 (4H, m), 1.23-1.26 (IH, m) , 1.63-1.74 (6H, m) , 2.15-2.19 (3H, m), 2.37 (3H, s), 2.19-2.52 (2H, m) , 2.76-2.78 (IH, m) , 4.17 (2H, q J=7.08Hz), 4.33-4.34 (IH, m) , 6.40 (IH, d J=15.96Hz), 7.63 (IH, d J=15.96Hz), 7.74 (IH, m) , 8.65 (IH, s).

Preparation 554 ' Lithium aluminium hydride (646mg) was portionwise added to a solution of benzyl 2-[(1-benzyl-3-pyrrolidinyl)amino]-4-methyl-5- pyrimidinecarboxylate (4.56g) in THF (60ml) with stirring at 5- 15 °C under atmospheric pressure of nitrogen, and the reaction mixture was stirred at 5-20 0C for 2 hours. The reaction mixture was cooled at 5 0C and H2O (0.7ml), 15% NaOH solution (0.7ml) and H2O (2.1ml) was added and the resultant mixture was. stirred at ambient temperature for 30 minutes. The reaction mixture was filtrated and the filtrate was dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (9:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to give {2-[ (l-benzyl-3-pyrrolidinyl)amino]-4-methyl-5-pyrimidinyl}metha nol (l.ig). 1H-NMR (DMSO-d6):<5 1.69-1.72 (IH, m) , 2.12-2.36 (2H, m) , 2.29 (3H, s), 2.47-2.59 (2H, m) , 2.79-2.87 (IH, m) , 3.52 (IH, d J=13.02Hz), 3.59 (IH, d J=13.02Hz), 4.29-4.32 (3H, m) , 4.90 (IH, br.s), 7.07 (IH, d J=6.94Hz), 7.12-7.32 (5H, m) , 8.04 (IH, s) .

The following compounds were obtained in a similar manner to that of Preparation 554. Preparation 555 {2-[ (l-benzyl-4-piperidinyl)amino]~4-methyl-5-pyrimidinyl}methan ol 1H-NMR (DMSO~d6):<5 1.37-1.56 (2H, m) , 1.77-1.82 (2H, m) , 1.96-2.06 (2H, m), 2.27 (3H, s), 2.74-2.80 (2H, m) , 3.44 (2H, s), 3.66-3.71 (IH, m), 4.30 (2H, d J=5.16Hz), 4.85 (IH, t J=5.16Hz), 6.85 (IH, d J=7.96Hz), 7.19-7.36 (5H, m) -. 8.02 (IH, s).

Preparation 556 (4-methyl-2-{[ (3R)-1-(4-methylbenzyl)-3-pyrrolidinyl]amino}-5- pyrimidinyl)methanol 1H-NMR (DMSO-d6):<5 1.68-1.70 (IH, m) , 1.91-2.33 (2H, m) , 2.27 (3H, s), 2.45 (3H, s), 2.45-2.58 (2H, m) , 2.76-2.84 (IH, m) , 3.47 (IH, d J=12.90Hz), 3.55 (IH, d J=12.90Hz), 4.31 (2H, s), 3.98-7.04 (IH, m) , 7.02-7.20 (6H, m) , 8.02 (IH, s). Preparation 557 (2-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-4-methy l-5~ pyrimidinyl)methanol 1H-NMR (DMSO-d6):<5 0.78-0.89 (2H, m) , 1.13-1.62 (5H, m) , 1.69-1.99 (5H, m), 2.28 (3H, s), 2.00-2.28 (4H, m) , 2.42-2.52 (2H, m) , 2.73- 2.81 (IH, m), 4.41-4.49 (IH, m) , 4.49 (2H, s), 5.27 (IH, m) , 6.91 (IH, d J=6.98Hz), 8.03 (IH, s).

Preparation 558 A solution of ethyl (2E)-3-{2-[(l-benzyl-3-pyrrolidinyl)amino]-4- methyl-5-pyrimidinyl}acrylate (750mg) and IN NaOH solution (4.1ml) in MeOH (10ml) and THF (10ml) was stirred at 80-85 °C for 2 hours. The reaction mixture was evaporated in vacuo and the residue was dissolved in a mixture was AcOEt and H2O. The aqueous solution was adjusted to PH 5.4 with 5% HCl solution and resultant solution was evaporated in vacuo and the residue was dissolved in a MeOH and THF. The solvent was evaporated in vacuo and dried to give (2E)-3-{2- [ (l-benzyl-3-pyrrolidinyl)amino]-4-methyl-5-pyrimidinyl}acryl ic acid (693mg). 1H-NMR (DMSO-d6):<5 1.72-1.84 (IH, m), 2.13-2.30 (IH, m) , 2.34 (3H, s), 2.34-2.87 (4H, m) , 3.57 (2H, s), 4.27-4.33 (IH, m) , 6.29 (IH, d J=15.?0Hz), 7.11-7.32 (6H, m) , 7.41-7.62 (2H, m) , 8.47 (IH, s).

The following compounds were obtained in a similar manner to that of Preparation 558. Preparation 559 (2E)-3-{2-[(l-benzyl-4-piperidinyl)amino]-4-methyl-5- pyrimidinyl}acrylic acid 1H-NMR (DMSO-d6):<5 1.74-2.09 (4H, m) , 2.38 (3H, s), 2.69 (2H, m) , 3.04-3.09 (2H, m) , 3.95-4.11 (3H, m) , 6.34 (IH, d J=15.96Hz), 7.38- 7.54 (5H, m), 7.58 (IH, d J=15.96Hz), 7.72 (IH, d J=7.20Hz), 8.61 (IH, s).

Preparation 560 (2E)-3-(4-methyl-2-{[(3R)-1-(4-methylbenzyl)-3-pyrrolidinyl] amirio}- 5-pyr±midinyl)acrylic acid 1H-NMR (DMSO-d6):<5 1.73-1.82 (IH, m) , 2.00-2.33 (2H, m) , 2.27 (3H, s), 2.45 (3H, s), 2.45-2.68 (2H, m) , 2.77-2.85 (IH, m) , 3.51-3.52 (2H, m), 4.31-4.34 (IH, m) , 6.26 (IH, d J=15.68Hz), 7.08-7.36 (5H, m), 7.47 (IH, d J=6.90Hz), 8.45 (IH, s).

Preparation 561 (2E)-3-(2-{[(3R)-l-(cyclohexylmethyl)-3-pyrrolidinyl]amino}- 4- methyl-5-pyrimidinyl)acrylic acid 1H-NMR (DMSO-d6):<5 0.78-0.9,0 (2H, m) , 1.13-1.63 (5H, m) , 1.50-1.84 (6H, m), 2.00-2.53 (5H, m) , 2.35 (3H, s), 2.75-2.80 (IH, m) , 4.20 (IH, m), 6.29 (IH, d J=15.86Hz), 7.32 (IH, d J=15.86Hz), 7.42-7.49 (IH, m), 8.49 (IH, s).

Preparation 562 A mixture of A mixture of (2E)-3-{2-[ (l-benzyl-3- pyrrolidinyl)amino]-4-methyl-5-pyrimidinyl}acrylic acid (693mg) , O- (tetrahydro-2H-pyran-2-yl)hydroxylamine (264mg), HOBt (290mg) and EDCI (334mg) in DMF (20ml) was stirred at ambient temperature for 15 hours. The reaction mixture was poured into a mixture of AcOEt-H2O and the organic layer was washed with brine and dried over MgSU4 . The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (9:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to give (2E)-3-{2-[(l-benzyl-3- pyrrolidinyl)amino]-4-methyl-5-pyrimidinyl}-N-(tetrahydro-2H -pyran- 2-yloxy)acrylamide (20Omg) . 1H-NMR (DMSO-d6):<5 1.59-1.74 (7H, m) , 1.99-2.59 (4H, m) , 2.37 (3H, s), 2.79-2.87 (IH, m) , 3.56 (2H, s), 3.98-4.05 (IH, m) , 4.34 (IH, m), 4.89 (IH, s), 6.26 (IH, d J=15.98Hz), 7.18-7.36 (5H, m) , 7.46 (IH, d J=15.98Hz), 7.64-7.69 (IH, m) , 8.42 (IH, s), 11.13 (IH, s).

The following compounds were obtained in a similar manner to that of Preparation 562. Preparation 563 (2E)-3-{2-[(l-benzyl-4-piperidinyl)amino]-4-methyl-5-pyrimid inyl}- N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (DMSO-d6):<5 1.42-1.83 (1OH, m) , 1.95-2.12 (2H, m) , 2.36 (3H, s), 2.73-2.82 (2H, m) , 3.33 (2H, s), 3.27-3.45 (IH, m) , 3.78-3.80 (IH, m), 3.95 (IH, m) , 4.88 (IH, s), 6.25 (IH, d J=15.50Hz), 7.23- 7.72 (6H, m), 7.46 (IH, d J=15.50Hz), 8.42 (IH, s), 11.13 (IH, s).

Preparation 564 (2E)-3-(4-methyl-2-{[(3R)-l-(4-methylbenzyl)-3-pyrrolidinyl] amino}- 5-pyrimidinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (DMSO-d6):<5 1.65-1.99 (7H, m) , 2.09-2.36 (4H, m) , 2.27 (3H, S), 2.45 (3H, s), 2.76-2.84 (IH, m) , 3.51-3.55 (3H, m) , 3.98-7.02 (IH, m), 7.32 (IH, m) , 4.88 (IH, s), 6.26 (IH, d J=15.62Hz), 7.10 (2H, d J=8.04Hz), 7.18 (2H, d J=8.04Hz), 7.46 (IH, d 7.63 (IH, d J=6.52Hz), 8.41 (IH, s), 11.12 (IH, s).

Preparation 565 (2E)-3-(2-{[(3R)-l-(cyclohexylmethyl)-3-pyrrolidinyl]amino}- 4- methyl-5-pyrimidinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylam ide 1H-NMR (DMSO-d6):<5 0.79-0.84 (2H, m) , 1.06-1.77 (15H, m) , 2.09- 2.52 (7H, m), 2.35 (3H, s), 3.54-3.56 (IH, m) , 3.93-3.99 (IH, m) , 4.32 (IH, m), 4.89 (IH, s), 6.27 (IH, d J=15.52Hz), 7.48 (IH, d J=15.52Hz), 7.59 (IH, d J=6.72Hz), 8.43 (IH, s), 11.13 (IH, br.s).

Preparation 566 A mixture of ethyl 5,6-dichloronicotinate (5.Og), tert-butyl (3R)-3-amino-l-pyrrolidinecarboxylate (5.08g) and K2CO3 (4.7Ig) in DMF (40ml) was stirred at 100 0C for 12 hours under atmospheric pressure of nitrogen. The reaction mixture was poured into a mixture of AcOEt and H2O and the organic layer was washed with brine and dried over MgSO4 . The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with n- Hexane- AcOEt (9:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to give ethyl 6- {[ (3R)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]amino}-5- chloronicotinate (6.6g) . 1H-NMR (DMSO-d6):<5 1.26 (3H, t J=7.06Hz), 1.40 (9H, s), 1.96-2.13 (2H, m), 3.18-3.45 (3H, m) , 3.58-3.66 (IH, m) , 4.27 (2H, q J=7.06Hz), 4.58-4.62 (IH, m),7.24 (IH, d J=6.64Hz), 7.95 (IH, d J=I.96Hz), 8.57 (IH, d J=I.96Hz).

The following compounds were obtained in a similar manner to that of Preparation 566. Preparation 567 ethyl 6-[ (4-1ert-butylcyclohexyl)amino]-5-chloronicotinate 1H-NMR (DMSO~d6):<5 0.85(9H, s), 0.94-2.05(9H, m) , 1.29(3H, t, J=7.0 Hz), 3.85-4.05 and 4.16-4.33(total IH,, each m), 1.18-4.33(2H, m), 6.03 and 6.83(total I H, each d, J=6.4 Hz), 7.90 and 7.97(total IH, each d, J=2.0 Hz), 8.53 and 8.57(total IH, each d, J=2.0 Hz).

Preparation 568 ethyl 5-chloro-6-(cyclopentylamino)nicotinate 1H-NMR (DMSO-d6):<5 1.26 (3H, t J=7.06Hz), 1.56-1.73 (6H, m) , 1.93- 2.00 (2H, m),4.26 (2H, q J=7.06Hz), 4.37-4.48 (IH, m) , 6.93 (IH, d J=7.34Hz), 7.91 (IH, d J=I.98Hz), 8.54 (IH, d J=I.98Hz).

Preparation 569 methyl 6-{ [ (3R)-1-(tert-butoxycarbonyl)-3- pyrrolidinyl]amino}nicotinate 1H-NMR (DMSO-d6):<5 1.40 (9H, s), 1.80-1.89 (IH, m) , 2.10-2.16 (IH, m), 3.11-3.16 (IH, m) , 3.32-3.38 (2H, m) , 3.42-3.56 (IH, m) , 3.77 (3H, s), 4.43 (IH, m), 6.54 (IH, d J=8.86Hz), 7.65 (IH, d J=6.34Hz), 7.83 (IH, dd J=2.24Hz, 8.86Hz), 8.59 (IH, d J=2.24Hz).

Preparation 570 A solution of diisobutylaluminium hydride in hexane solution (0.93M) (138ml) was added to dropwise a solution of ethyl 6- {[(3R)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]amino}-5- chloronicotinate (15.9g) in THF (200ml) with stirring at 0-15 0C under atmospheric pressure of nitrogen, and the reaction mixture was stirred at 5-20 0C for 4 hours. The reaction mixture was cooled at 5 °C and MeOH (10ml) was added and the reaction mixture was stirred at ambient temperature for 20 minutes. The potassium sodium tatarate tetrahydrate (36.4g) was added to a above solution and the resultant mixture was stirred at ambient temperature for 2 hours. The reaction mixture was filtrated and the filtrate was dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-n-hexane (9:1). The eluted fractions containing the desired product were collected and evaporated iri vacuo to give tert-butyl (3R)-3-{[3-chloro-5- (hydroxymethyl)-2-pyridinyl]amino}-1-pyrrolidinecarboxylate( 5.85g). 1H-NMR (DMSO-d6):<5 1.39 (9H, s), 1.90-2.14 (2H, m), 3.11-3.46 (3H, m), 3.56-3.65 (IH, m), 4.35 (2H, d J=5.56Hz), 4.38-4.48 (IH, m), 5.09 (IH, t J=5.56Hz), 6,38 (IH, d J=6.20Hz), 7.56 (IH, d J=I.90Hz), 7.95 (IH, d J=I.90Hz).

Preparation 571 A mixture of tert-butyl (3R)-3-{[3-chloro-5-(hydroxymethyl)-2- pyridinyl]amino}-1-pyrrolidinecarboxylate(0.95g) and MnO2 (3.02g) in AcOEt (30ml) was refluxed under stirring for 1.5 hours. After removal of the insoluble material, and the solvent was evaporated in vacuo to give tert-butyl (3R)-3-[(3~chloro-5-formyl-2- pyridinyl)amino]-1-pyrrolidinecarboxylate (0•95g) . 1H-NMR (DMSO-d6):<5 1.40 (9H, s), 1.99-2.15 (2H, m) , 3.20-3,46 (3H, m), 3.56-3.67 (IH, m) , 4.64-4.72 (IH, m) , 7.49 (IH, d J=6.70Hz), 7.95 (IH, d J=I.90Hz), 8.57 (IH, d J=I.90Hz), 9.76 (IH, s) .

The following compounds were obtained in a similar manner to that of Preparation 571. Preparation 572 5-chloro-6-(cyclopentylamino)nicotinaldehyde 1H-NMR (DMSO~d6):<5 1.53-1.73 (6H, m) , 1.80-1.97 (2H, m), 4.40-4.57 (IH, m), 7.24 (IH, d J=7.32Hz), 7.90 (IH, d J=I.88Hz), 8.53 (IH, d J=I.88Hz), 9.72 (IH, s). Preparation 573 6-[(4-tert-butylcyclohexyl)amino]-5-chloronicotinaldehyde 1H-NMR (DMSO-d6):<5 0.98 (9H, s), 0.98-1.65 (6H, m) , 1.61-1.93 (3H, m), 4.39-4.10 & 4.29-4.30 (total IH, m) , 6.25 & 7.14 (total IH,each d J=6.40Hz),7.89 & 7.96 (total IH, each d J=I.82Hz), 8.52 & 8.57 (total IH, each d J=I.82Hz) ,9.71 & 9.75 (total IH, each s).

Preparation 574 tert-butyl (3R)-3-[ (5-formyl-2-pyridinyl)amino]-1- pyrrolidinecarboxylate 1H-NMR (DMSO-d6):<5 1.40 (9H, s), 1.82-1.88 (IH, m) , 2.12-2.14 (IH, m), 3.13-3.18 (IH, m) , 3.33-3.44 (2H, m) , 3.56-3.63 (IH, m) , 4.48 (IH, m), 6;61 (IH, d J=8.78Hz), 7.56 (IH, dd J=2.18Hz, 8.78Hz), 8.53 (IH, d J=2.18Hz), 9.70 (IH, s).

Preparation 575 A solution of diethylphosphonoacetcacid ethyl ester (980mg) in THF (5ml)was added dropwise to a mixture of 60% sodium hydride in oil (187mg) in THF (3OmL) with stirring at 10-20 °C under atmospheric pressure of nitrogen, and the reaction mixture was stirred at ambient temperature for 30 minutes. A solution of tert-butyl (3R)-3-[ (3-chloro-5-formyl-2-pyridinyl)amino]-l- pyrrolidinecarboxylate (0.95g) in THF (10ml) solution was added the above mixture and resultant mixture was stirred at ambient temperature for 1.5 hours. The reaction mixture was poured into a mixture of AcOEt-H2O and the organic layer was washed with brine and dried over MgSO4 . The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-n- hexane (6:4). The eluted fractions containing the desired product were collected and evaporated in vacuo to give tert-butyl (3R)-3- ({3-chloro-5~[(lE)-3-ethoxy-3-oxo-l-propen-l-yl]-2- pyridinyl}amino)-1-pyrrolidinecarboxylate (0.98g) 1H-NMR (DMSO-d6):<5 1.25 (3H, t J=7.10Hz), 1.40 (9H, s), 1.90-2.12 (2H, m), 3.19-3.45 (3H, m), 3.56-3.65 (IH, m) , 4.16 (2H, q J=7. 10Hz ) , 4. 57-4.60 ( IH, m) , 6 . 52 ( IH, d J=15.96Hz ) , 6.96 ( IH, d J=6. 50Hz ) , 7. 53 ( IH, d J=15. 96Hz ) , 8. 13 ( IH, d J=I .82Hz ) , 8.31 ( IH, d J=I .82Hz ) .

The following compounds were obtained in a similar manner to that of Preparation 575. Preparation 576 ethyl (2E)-3~{6-[(4-tert-butylcyclohexyl)amino]-5-chloro-3- pyridinyl}acrylate 1H-NMR (DMSO-d6):<5 0.97 (9H, s), 1.01-2.00 (9H, m),1.24 (3H, t J=7.06Hz), 3.96-4.02 (IH, m) , 4.16 (2H, q J=7.06Hz), 5.78 & 6.53 (total IH, each d J=6.58Hz), 6.46 & 6.50 (total IH, each d J=15.98Hz), 7.50 & 7.52 (total IH, each d J=15.98Hz), 8.08 & 8.14 (total IH, each d J=I.94Hz), 8.25 & 8.30 (total IH, each d J=I.94Hz), APCI-MS (m/z):395( M+H)+.

Preparation 577 tert-butyl (3R)-3-({5-[(lE)-3-ethoxy-3-oxo-l-propen-l-yϊ]-2- pyridinyl}amino)-1-pyrrolidinecarboxylate 1H-NMR (DMSO-d6):<5 1.24 (3H, t J=7.06Hz), 1.40 (9H, s), 1.80-1.86 (IH, m), 2.10-2.13 (IH, m) , 3.05-3.16 (IH, m) , 3.31-3.40 (2H, m) , 3.53-3.58 (IH, m) , 4.13 (2H, q, J=7.06Hz), 4.39 (IH, m) , 6.35 (IH, d J=15.86Hz), 6.55 (IH, d J=8.84Hz), 7.46 (IH, d J=6.78Hz), 7.52 (IH, d J=15.86Hz), 7.83 (IH, dd J=2.02Hz, 8.84Hz), 8.25 (IH, d J=2.02Hz).

Preparation 578 Lithium aluminium hydride (1.02g) was added to a solution of methyl 6-{[ (3R)-l-(tert-butoxycarbonyl)-3- pyrrolidinyl]amino}nicotinate (5.76g), in THF (80ml) with stirring at 5-15 0C under atmospheric pressure of nitrogen, and the reaction mixture was stirred at 5-20 °C for 3 hours. The reaction mixture was cooled at 5 °C and H2O (ImI), 15% NaOH solution (ImI) and H2O (3ml) was added and the resultant mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was filtrated and the filtrate was dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (9:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to give tert-butyl (3R)-3-{[5-(hydroxymethyl)-2- pyridinyl]amino}-1-pyrrolidinecarboxylate (1.82g) . 1H-NMR (DMSO-d6):<5 1.39 (9H, s), 1.76-1.99 (IH, m) , 2.07-2.12 (IH, m), 3.06-3.13 (IH, m) , 3.29-3.41 (2H, m) , 3.42-3.57 (IH, m) , 4.29 (2H, d J=5.52Hz), 4.28-4.38 (IH, m) , 4.91 (IH, t J=5.52Hz), 6.47 (IH, d J=8.50Hz), 6.66 (IH, d J=5.80Hz) ,7.35 (IH, dd J=2.02Hz, 8.50Hz), 7.90 (IH, d J=2.02Hz).

The following compounds were obtained in a similar manner to that of Preparation 578. Preparation 579 [5-chloro-6-(cyclopentylamino)-3-pyridinyl]methanol 1H-NMR (DMSO-d6):<5 1.44-1.68 (6H, m) , 1.87-1.99 (2H, m) , 4.20-4.37 (IH, m), 4.32 (2H, d J=5.72Hz), 5.04 (IH, t J=5.72Hz), 5.90 (IH, d J=7.12Hz), 7.51 (IH, d J=I.94Hz), 7.92 (IH, d J=I.94Hz).

Preparation 580 {6-[ (4-tert-butylcyclohexyl)amino]-5-chloro-3-pyridinyl}methanol 1H-NMR (DMSO-d6):<5 0.97 (9H, s), 0.97-1.56 (6H, m) , 1.73-1.99 (3H, m), 3.78-3.82 (IH, m) , 4.16-4.35 (2H, m) , 5.01-5.10 (IH, m) , 5.27 & 5.74 (total IH, each d J=5.88Hz), 7.50 & 7.56 (total IH, each d J=I.92Hz), 7.89 & 7.94 (total IH, each d J=I.92Hz).

Preparation 581 A solution of ethyl (2E)-3-{5-chloro-6-[ (3R)-3-pyrrolidinylamino]- 3-pyridinyl}acrylate dihydrochloride (2.Og) in H2O (10ml) was adjusted to pH 8.5 With 20% K2CO3 solution and extracted with CHCl3. The extract was dried over MgSO4, the solvent was evaporated in vacuo to give ethyl (2E)-3-{5-chloro-6-[ (3R)-3-pyrrolidinylamino]- 3-pyridinyl}acrylate (1.47g). 1H-NMR (DMSO-d6):<5 1.25 (3H, t J=7.08Hz), 1.99-2.09 (2H, m) , 2.64- 2.75 (2H, m), 2.87-3.01 (2H, m) , 4.16 (2H, q J=7.08Hz), 4.44-4.47 (IH, m), 6.49 (IH, d J=15.94Hz), 6.72 (IH, d J=7.14Hz), 7.52 (IH, d J=15.94Hz), 8.09 (IH, d J=I.96Hz), 8.28 (IH, d J=I.96Hz).

Preparation 582 A mixture of tert-butyl (3R)-3-({5r-[(lE)-3-ethoxy-3-oxo-l- propen-1-yl]~2-pyridinyl}amino)-1-pyrrolidinecarboxylate (600mg) and IN NaOH solution (3.3ml) in MeOH (10ml)and THF (10ml) was stirred at 70-75 °C for 2 hours. The reaction mixture was evaporated in vacuo and the residue was dissolved in a mixture of AcOEt and H2O. The aqueous solution was adjusted to PH4.5 and extracted with AcOEt and THF. The osrganic layer was washed with brine and dried over MgSO4 . The solvent was concentrated in vacuo and the precipitate was collected by filtration to give (2E)-3-(6-{[(3R)-I-(jtert- butoxycarbonyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylic acid (0.45g). 1H-NMR (DMSO-d6):<5 1.41 (9H, s), 1.84-1.87 (IH, m) , 2.11-2.14 (IH, m), 3.10-3.19 (IH, m) , 3.34-3.42 (2H, m) , 3.55-3.58 (IH, m) , 4.36- 4.42 (IH, m), 6.29 (IH, d J=15.88Hz), 6.62 (IH, d J=8.76Hz), 7.48 (IH, d J=15.88Hz), 7.64 (IH, m) , 7.85 (IH, dd J=2.16Hz, 8.76Hz), 8.23 (IH, d J=2.16Hz), 11.14 (IH, s).

Preparation 583 A mixture of (2E)-3-(6-{[(3R)-l^tert-butoxycarbonylJ-S- pyrrolidinyllaminol-S-pyridinylJacrylic acid (450mg), 0- (tetrahydro-2H-pyran-2-yl)hydroxylamine (174mg), HOBt (191mg) and EDCI(220mg) in DMF (20ml) was stirred at ambient temperature for 15 hours. The reaction mixture was poured into a mixture of AcOEt-H2O and the organic layer was washed with brine and dried over MgSO4 . The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (95:5). The eluted fractions containing the desired product were collected and evaporated in vacuo to give tert-butyl (3R)-3-[(5-{(lE)-3-oxo-3- [(tetrahydro-2H-pyran-2-yloxy)amino]-l-propen-l-yl}-2- pyridinyl ) amino ] - 1 -pyrrolidinecarboxylate ( 450mg ) . 1H-NMR (DMSO-d6): <5 1.39 (9H, s), 1.69-2.00 (7H, m) , 2.00-2.12 (IH, m), 3.09-3.15 (IH, m) , 3.34-3.43 (3H, m) , 3.50-3.55 (2H, m) , 3.93- 3.95 (IH, m), 4.37 (IH, m) , 4.88 (IH, s), 6.24 (IH, d J=15.74Hz), 6.55 (IH, d J=8.76Hz), 7.30 (IH, d J=8.12Hz), 7.37 (IH, d J=15.74Hz), 7.63 (IH, d J=8.76Hz), 8.17 (IH, s), 11.06 (IH, s) .

Preparation 584 A solution of ethyl (2E)-3-(5-chloro-6-{[(3R)-I- (cyclohexylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylat e (330mg) and IN NaOH solution (1.5ml) in MeOH (30ml) was stirred at 80-85 °C for 2 hours. The reaction mixture was evaporated in vacuo and the residue was dissolved in a mixture was AcOEt and H2O. The aquous solution was adjusted to PH 5.4 with 5% HCl solution and resultant solution was evaporated in vacuo and the residue was dissolved in a MeOH and THF. The solvent was evaporated in vacuo and dried to give (2E)-3-(5-chloro-6-{[(3R)-I-(cyclohexylmethyl)-3- pyrrolidinyl]amino},-3-pyridinyl)acrylic acid (306mg). 1H-NMR (DMSO-d6):<5 0.80-0.91 (2H, m), 1.14-1.62 (4H, m) , 1.71-1.84 (7H, m), 2.13-2.62 (4H, m), 2.73-2.81 (IH, m) , 4.39-4.45 (IH, m) , 6.36 (IH, d J=15.88Hz),6.45 (IH, d J=7.08Hz), 7.26 (IH, d J=15.88Hz), 7.94 (IH, d J=I.76Hz), 8.17 (IH, d J=I.76Hz).

The following compounds were obtained in a similar manner to that of Preparation 584. Preparation 585 (2E)-3-(5-chloro-6-{[(3R)-1-(cyclobutylmethyl)-3- pyrrolidinyl]amino}-3-pyridinyl)acrylic acid 1H-NMR (DMSO-d6):<5 1.62-1.81 (9H, m) , 2.30-2.52 (5H, m) , 2.75-2.79 (IH, m), 4.38-4.45 (IH, m) , 6.29 (IH, d J=15.84Hz), 6.30 (IH, d J=7.20Hz), 7.07 (IH, d J=15.84Hz), 7.84 (IH, d J=I.84Hz), 8.10 (IH, d J=I.84Hz).

Preparation 586 (2E)-3-(5-chloro-6-{[ (3R)-1-(3-methyl-2-buten-l-yl)-3- pyrrolidinyl]amino}-3-pyridinyl)acrylic acid 1H-NMR (DMSO-d6):<5 1.61 (3H, s), 1.68 (3H, s), 1.68-1.79 (IH, m) , 2.00-2.30 (IH, m), 2.42-2.82 (4H, m) , 3.00 (2H, m) , 4.44-4.49 (IH, m), 5.20-5.27 (IH, m) , 6.37 (IH, d J=15.88Hz), 6.50 (IH, d J=6.98Hz), 7.27 (IH, d J=15.68Hz), 7.96 (IH, d J=I.86Hz), 8.18 (IH, d J=I.86Hz).

Preparation 587 (2E)-3-(5-chloro-6-{[(3R)-l-(2-pyridinylmethyl)-3- pyrrolidinyl]amino}-3-pyridinyl)acrylic acid 1H-NMR (DMSO-d6):<5 1.80-1.87 (IH, m) , 2.18-2.47 (IH, m) , 2.47-2.57 (2H, m), 2.66-2.73 (IH, m) , 2.85-2.90 (IH, m) , 3.72 (2H, s), 4.48- 4.51 (IH, m), 6.34 (IH, d J=15.90Hz), 6.46 (IH, d J=6.94Hz), 7.13- 7.28 (2H, m), 7.42-7.46 (IH, m) , 7.72-7.76 (IH, m) , 7.88 (IH, d J=I.80Hz), 8.12 (IH, d J=I.80Hz), 8.47-8.50 (IH, m) .

Preparation 588 (2E)-3-(5-chloro-6-{[(3R)-1-(cyclopropylmethyl)-3- pyrrolidinyl]amino}-3-pyridinyl)acrylic acid 1H-NMR (DMSO-d6):<5 0.08-0.13 (2H, m) , 0.40-0.49 (2H, m) , 0.78-0.95 (IH, m), 1.70-1.90 (IH, m) , 2.08-2.25 (IH, m) , 2.31 (2H, d J=6.60Hz), 2.50-2.60 (2H, m) , 2.73-2.90 (2H, m) , 4.49-4.56 (IH, m) , 6.38 (IH, d J=15.90Hz), 6.56 (IH, d J=7.06Hz), 7.26 (IH, d J=15.90Hz), 7.94 (IH, d J=I.84Hz), 8.18 (IH, d J=I.84Hz).

Preparation 589 (2E)-3-(5-chloro-6-{[(3R)-1-(cyclopentylmethyl)-3- pyrrolidinyl]amino}-3-pyridinyl)acrylic acid 1H-NMR (DMSO-d6):<5 1.16-1.22 (2H, m) , 1.45-2.30 (14H, m) , 2.52- 2.67 (IH, m), 2.79-2.84 (IH, m) , 4.44-4.51 (IH, m) , 6.39 (IH, d J=15.86Hz), 6.55 (IH, d J=7.08Hz), 7.34 (IH, d J=15.86Hz), 7.99 (IH, d J=I.82Hz), 8.20 (IH, d J=I.82Hz).

Preparation 590 A solution of ethyl (2E)-3-{5-chloro-6-[.(3R)-3-pyrrolidinylamino]- 3-pyridinyl}acrylate dihydrochloride (1.Og), bromomethylcyclobutane (456mg) and N,N-diisopropylethylamine (1.26g) in DMF (30ml) was stirred at 80-85°C for 12 hours under atmospheric pressure of nitrogen. The reaction mixture was poured into a mixture of AcOEt and H2O and the organic layer was washed with brine and dried over MgSO4 . The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (95:5). The eluted fractions containing the desired product were collected and evaporated in vacuo to give ethyl (2E)-3-(5-chloro-6-{[ (3R)-I- (cyclobutylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)aerylat e (356mg). 1H-NMR (DMSO-d6):<5 1.24 (3H, t J=7.08Hz), 1.70-2.09 (9H, m) , 2.46- 2.52 (6H, m), 2.73-2.77 (IH, m), 4.16 (2H, q J=7.08Hz), 4.43-4.50 (IH, m), 6.49 (IH, d J=15.96Hz), 6.67 (IH, d J=7.00Hz), 7.52 (IH, d J=15.96Hz), 8.10 (IH, d J=I.92Hz), 8.28 (IH, d J=I.92Hz).

The following compound was obtained in a similar manner to that of Preparation 590. Preparation 591 ethyl (2E)-3-(5-chloro-6-{[(3R)-l-(3-methyl-2-buten-l-yl)-3- pyrrolidinyl]amino}-3-pyridinyl)aerylate 1H-NMR (DMSO-d6):<5 1.24 (3H, t J=7.08Hz), 1.61 (3H, s), 1.68 (3H, s), 1.78-1.81 (IH, m), 2.14-2.19 (IH, m) , 2.43-2.52 (2H, m) , 2.60- 2.89 (2H, m), 3.02 (2H, d J=6.76Hz), 3.39 (IH, m), 4.16 (2H, q J=7.08Hz), 4.44-4.51 (IH, m) , 5.20-5.26 (IH, m) , 6.49 (IH, d J=15.94Hz), 6.69 (IH, d J=6.94Hz), 7.52 (IH, d J=15.94Hz), 8.10 (IH, > d J=I.94Hz), 8.28 (IH, d J=I.94Hz).

Preparation 592 A mixture of ethyl (2E)-3-{5-chloro-6-[ (3R)-3-pyrrolidinylamino]- 3-pyridinyl}acrylate (0.73g), m-tolualdehyde (356mg) and sodium triacetoxyborohydride (1.57g) in CH2Cl2 (30ml) was stirred at 25- 30 °C for 15 hours. The 10% K2CO3 solution (20ml) was added to a reaction mixture and resultant mixture was stirred at ambient temperature for 30 minutes and extracted with CH2Cl2 and washed with brine and dried over MgSO4 . The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (97:3). The eluted fractions containing the desired product were collected and evaporated in vacuo to give ethyl (2E)- 3-(5-chloro-6-{[(3R)-l-(3-methylbenzyl)-3-pyrrolidinyl]amino }-3- pyridinyl)acrylate (820mg). 1H-NMR (DMSO-d6):<5 1.24 (3H, t J=7.06Hz), 1.86-1.99 (IH, m) , 2.16- 2.40 (IH, m), 2.40 (3H, s), 2.42-2.53 (2H, m), 2.62-2.66 (IH, m) , 2.77-2.85 (IH, m) , 3.54 (2H, s), 4.16 (2H, q J=7.06Hz), 4.45-4.53 (IH, m), 6.49 (IH, d J=15.96Hz), 6.72 (IH, d J=6.92Hz), 7.02- 7.24 )4H, m), 7.51 (IH, d J=15.96Hz), 8.10 (IH, d J=I.90Hz) ,8.20 (IH, d J=I.90Hz).

The following compounds were obtained in a similar manner to that of Preparation 592. Preparation 593 ethyl (2E)-3-(5-chloro-6-{[(3R)-l-(cyclohexylmethyl)-3- pyrrolidinyl]amino}-3-pyridinyl)acrylate 1H-NMR (DMSO-d6):<5 0.80-0.92 (2H, m) , 1.12-1.34 (4H, m) , 1.24 (3H, t J=7.08Hz), 1.63-1.78 (5H, m) , 2.18-2.22 (2H, m) , 2.37-2.52 (3H, m), 2.76-2.80 (IH, m) , 3.16-3.22 (2H, m) , 4.16 (2H, q J=7.08Hz), 4.48-4.51 (IH, m) , 6.49 (IH, d J=15.96Hz), 6.95 (IH, d J=7.02Hz), 7.52 (IH, d J=15.96Hz), 8.10 (IH, d J=I.90Hz), 8.28 (IH, d J=I.90Hz).

Preparation 594 ethyl (2E)-3-(5-chloro-6-{[ (3R)-1-(3-fluorobenzyl)-3- pyrrolidinyl]amino}-3-pyridinyl)acrylate 1H-NMR (DMSO~d6):<5 1.25 (3H, t J=7.08Hz), 1.85-1.92 (IH, m) , 2.18- 2.22 (IH, m), 2.42-2.49 (2H, m) , 2.61-2.68 (IH, m) , 2.80-2.89 (IH, m), 3.62 (2H, s), 4.16 (2H, q J=7.08Hz), 5.31-5.36 (IH, m) , 6.49 (IH, d J=15.92Hz), 6.74 (IH, d J=6.92Hz), 7.01-7.17 (3H, m) , 7.30- 7.41 (IH, m), 7.52 (IH, d J=15.92Hz), 8.10 (IH, d J=I.84Hz), 8.27 (IH, d J=I.84Hz). Preparation 595 ethyl (2E)-3-(5-chloro~6-{[ (3R)-1-(2-pyridinylmethyl)-3- pyrrolidinyl]amino}-3-pyridinyl)acrylate 1H-NMR (DMSO-d6):<5 1.24 (3H, t J=7.06Hz), 1.84-1.91 (IH, m) , 2.10- 2.23 (IH, m), 2.49-2.58 (2H, m) , 2.70-2.74 (IH, m) , 2.86-2.95 (IH, m), 3.73 (2H, s), 4.16 (2H, q J=7.06Hz), 4.52-4.59 (IH, m) , 6.49 (IH, d J=15.90Hz), 6.75 (IH, d J=6.92Hz), 7.22-7.28 (IH, m) , 7.42- 7.48 (IH, m), 7.52 (IH, d J=15.90Hz), 7.72-7.76 (IH, m),8.10 (IH, d J=I.92Hz), 8.27 (IH, d J=I.92Hz), 8.47-8.50 (IH, m) .

Preparation 596 ethyl (2E)-3-(5-chloro-6-{[ (3R)-1-(cyclopropylmethyl)-3- pyrrolidinyl]amino}-3-pyridinyl)acrylate 1H-NMR (DMSO-d6):<5 0.34-0.11 (2H, m) , 0.39-0.48 (2H, m) , 0.70-0.92 (IH, m), 1.24 (3H, t J=7.06Hz), 1.70-1.90 (IH, m) , 2.05-2.26 (IH, m), 2.26 (2H, d J=6.64Hz), 2.46-2.67 (2H, m) , 2.67-2.71 (IH, m) , 2.80-2.88 (IH, m), 4.16 (IH, d J=7.06Hz), 6.49 (IH, d J=15.90Hz), 6.70 (IH, d J=6.98Hz), 7.52 (IH, d J=15.90Hz), 8.10 (IH, d J=I.90Hz), 8.28 (IH, d J=I.90Hz).

Preparation 597 ethyl (2E)-3-(5-chloro-6-{[ (3R)-1-(cyclopentylmethyl)-3- pyrrolidinyl]amino}-3-pyridinyl)acrylate 1H-NMR (DMSO-d6):<? 1.06-1.28 (2H, m) , 1.24 (3H, t J=7.06Hz), 1.47-2.50 (14H, m) , 2.55-2.69 (IH, m) , 2.70-2.82 (IH, m) , 4.16 (2H, q J=7.06Hz), 6.49 (IH, d J=15.92Hz), 6.66 (IH, d J=7.02Hz), 7.52 (IH, d J=15.92Hz), 8.10 (IH, d J=I.92Hz), 8.28 (IH, d J=I.92Hz).

Preparation 598 A solution of ethyl (2E)-3-(5-chloro-6-{[(3R)-I-(3-methylbenzyl)- 3-pyrrolidinyl]amino}-3-pyridinyl)acrylate (820mg) and IN NaOH solution (4.1ml) in MeOH (20ml) was stirred at 80-85 °C for 2 hours. The reaction mixture was evaporated in vacuo and the residue was dissolved in a mixture of AcOEt and brine. The aquous solution was adjusted to PH 5.4 with 5% HCl solution and extracted with THF and AcOEt. The solvent was evaporated in vacuo and The precipitate was washed with n-hexane to give (2E)-3-(5-chloro-6~{[ (3R)-I-(3- methylbenzyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylic acid (410mg). 1H-NMR (DMSO-d6):<5 1.76-1.90 (IH, m) , 2.17-2.29 (IH, m) , 2.49 (3H, s), 2.49-2.61 (2H, m) , 2.74-2.77 (IH, m), 2.87-2.95 (IH, m) , 3.60 (2H, s), 4.46-4.58 (IH, m) , 6.39 (IH, d J=15.92Hz), 6.75 (IH, d J=6.88Hz), 7.05-7.25 (4H, m) , 7.45 (IH, d J=15.92Hz), 8.07 (IH, d J=I.82Hz), 8.24 (IH, d J=I.82Hz).

The following compounds were obtained in a similar manner to that of Preparation 598. Preparation 599 (2E)-3-[5-chloro-6-(cyclopentylamino)-3-pyridinyl]acrylic acid 1H-NMR (DMSO-d6):<5 1.54-1.71 (6H, m) , 1.90-2.00 (2H, m) , 4.32-4.46 v (IH, m),6.38 (IH, d J=15.84Hz), 6.60 (IH, d J=7.26Hz), 7.47 (IH, d J=15.84Hz), 8.04 (IH, d J=I.96Hz), 8.25 (IH, d J=I.96Hz).

Preparation 600 (2E)-3-{6-[(4-tert-butylcyclohexyl)amino]-5-chloro-3- pyridinyl}acrylic acid 1H-NMR (DMSO-d6):<5 0.97 (9H1, s), 1.02-1.99 (9H, m) , 3.85-3.98 & 4.20 (total IH, each m) , 5.78 & 6.50 (total IH, each d J=6.58Hz), 6.36 & 6.58 (total IH, each d J=15.96Hz), 7.45 & 7.47 (total IH, each d J=15.96Hz), 8.03 & 8.11 (total IH, each d J=I.90Hz), 8.23 & 8.28 (total IH, each d J=Ii90Hz).

Preparation 601 (2E)-3-(5-chloro-6-{[(3R)-l-(3-flu9robenzyl)-3-pyrrolidinyl] amino}- 3-pyridinyl)acrylic acid 1H-NMR (DMSO-d6):<5 1.76-1.93 (IH, m) , 2.19-2.26 (IH, m) , 2.50-2.63 (2H, m), 2.77-2.80 (IH, m) , 2.91-2.99 (IH, m) , 3.73 (2H, s), 4.53- 4.61 (IH, m), 6.41 (IH, d J=15.94Hz), 6.78 (IH, d J=6.90Hz) ,6.88- 7.22 (3H, m) , 7.33-7.40 (IH, m) , 7.47 (IH, d J=15.94Hz), 8.07 (IH, d J=I . 84Hz ) , 8 . 25 ( IH, d J=I .84Hz ) .

Preparation 602 (2E)-3-(5-chloro-6-{[(3R)-1-(cyclohexylcarbonyl)-3- pyrrolidinyl]amino}-3-pyridinyl)acrylic acid 1H-NMR (DMSO-d6): <5 1.14-1.36 (6H, m) , 1.66-1.69 (4H, m) , 1.91-2.18 (3H, m), 3.27-3.71 (4H, m) , 4.52-4.72 (IH, m) , 6.42 (IH, d J=15.90Hz), 6.87-6.98 (IH, m) , 7.48 (IH, d J=15.90Hz), 8.10 (IH, d J=I.92Hz), 8.28 (IH, d J=I.92Hz), 12.21 (IH, br.s).

Preparation 603 (2E)-3-[5-chloro-6-({(3R)-1-[(4-methylphenyl)sulfonyl]-3- pyrrolidinyl}amino)-3-pyridinyl]acrylic acid 1H-NMR (DMSO-d6):<5 1.90-2.06 (2H, m) , 2.39 (3H, s), 3.09-3.52 (4H, m), 4.28-4.37 (IH, m) , 6.42 (IH, d J=15.90Hz), 6.61 (IH, d J=5.92Hz), 7.36 (2H, d J=8.14Hz), 7.47 (IH, d J=15.90Hz), 7.64 (2H, d J=8.14Hz), 8.06 (IH, d J=I.90Hz), 8.24 (IH, d J=I.90Hz), 12.23 (IH, br.s). -

Preparation 604 (2E)-3-[6-({(3R)-l-[(4-methylphenyl)sulfonyl]-3- pyrrolidinyl}amino)-3-pyridinyl]acrylic acid 1H-NMR (DMSO-d6):<5 1.72-1.74 (IH, m) , 1.91-2.02 (IH, m) , 2.39 (3H, s), 3.03-3.10 (IH, m), 3.19-3.45 (3H, m) , 4.18-4.26 (IH, m) , 6.26 (IH, d J=15.82Hz), 6.41 (IH, d J=8.82Hz), 7.28 (IH, m) , 7.38 (2H, d J=8.06Hz), 7.46 (IH, d J=15.82Hz), 7.65 (2H, d J=8.06Hz), 7.78 (IH, dd J=2.04Hz, 8.82Hz), 8.18 (IH, d J=2.04Hz).

Preparation 605 (2E)-3-(6-{[(3R)-l-(l-piperidinylcarbonyl)-3-pyrrolidinyl]am ino}-3- pyridinyl)acrylic acid 1H-NMR (DMSO-d6):<5 1.36-1.49 (6H, m) , 1.71-1.91 (IH, m) , 1.99-2.13 (IH, m), 3.12-3.17 (4H, m) , 3.34-3.47 (3H, m) , 3.57-3.66 (IH, m) , 4.30-4.36 (IH, m) , 6.25 (IH, d J=15.92Hz), 6.55 (IH, d J=8.86Hz), 7.38 (IH, d J=6.16Hz), 7.46 (IH, d J=15.92Hz), 7.79 (IH, dd J=2. 08Hz , 8.86Hz ) , 8.21 ( IH, d J=2 .08Hz ) , 12 .06 ( IH, s ) .

Preparation 606 (2E)-3-(5-chloro-6-{[ (3R)-1-(1-piperidinylcarbonyl)-3- pyrrolidinyl]amino}-3-pyridinyl)acrylic acid 1H-NMR (DMSO-d6):<5 1.76 (6H, br.s), 1.91-2.12 (2H, m) , 3.12 (4H, br.s), 3.25-3.43 (3H, m) , 3.53-3.62 (IH, m) , 4.46-4.56 (IH, m) , 6.41 (IH, d J=15.98Hz), 6.69 (IH, d J=6.40Hz), 7.47 (IH, d J=15.98Hz), 8.09 (IH, d J=I.84Hz), 8.28 (IH, d J=I.84Hz) .

Preparation 607 (2E)-3-(5-chloro-6-{[ (3R)-1-(cyclopentylcarbonyl)-3- pyrrolidinyl]amino}-3-pyridinyl)acrylic acid 1H-NMR (DMSO-d6):<5 1.49-1.77 (8H, m) , 1.90-2.30 (2H, m) , 2.70-2.86 (IH, m), 3.28-3.67 (3H, m) , 3.68-3.84 (IH, m) , 4.49-4.68 (IH, m) , 6.42 (IH, d J=15.96Hz), 6.87-6.98 (IH, m) , 7.48 (IH, d J=15.96Hz), 8.10 (IH, d J=I.76Hz), 8.29 (IH, d J=I.78Hz), 12.15 (IH, br.s).

Preparation 608 (2E)-3-(5-chloro-6-{[ (3R)-1-(cyclobutylcarbonyl)-3- pyrrolidinyl]amino}-3-pyridinyl)acrylic acid 1H-NMR (DMSO-d6):<5 1.72-2.18 (9H, m) , 3.21-3.71 (4H, m) , 4.48-4.64 (IH, m), 6.41 (IH, d J=15.94Hz), 6.85-6.97 (IH, m) , 7.44 (IH, d J=15.94Hz), 8.11 (IH, s), 8.29 (IH, s), 12.21 (IH, br.s).

Preparation 609 (2E)-3-(5-chloro~6-{[(3R)-l-(4-chlorobenzoyl)-3- pyrrolidinyl]amino}-3-pyridinyl)acrylic acid IH-NMR (DMSO-d6):<5 2.12-2.18 (2H, m) , 3.38-3.66 (4H, m) , 4.54- 4.69 (IH, m),6.36-6.47 (IH, m) , 6.88-7.07 (IH, m) , 7.40-7.59 (5H, m), 8.09 & 8.12 (total IH, each s), 8.22-- & 8.31 (total IH, each s).

Preparation 610 (2E)-3-(5-chloro-6-{[(3R)-l-(2-pyrimidinyl)-3-pyrrolidinyl]a mino}- 3 -pyridinyl) acrylic acid 1H-NMR (DMSO-d6):<5 2.06-2.31 (2H, m) , 3.55-3.70 (3H, m) , 3.84- 3.93 (IH, m), 4.67-4.77 (IH, m) , 6.42 (IH, d J=15.90Hz), 6.49-6.59 (IH, m), 7.00 (IH, d J=6.42Hz), 7.49 (IH, d J=15.90Hz), 8.10 (IH, d J=I.90Hz), 8.31-8.46 (3H, m) , 12.17 (IH, br,s).

Preparation 611 (2E)-3-(5-chloro-6-{[(3R)-l-(4-fluorobenzoyl)-3- pyrrolidinyl]amino}-3-pyridinyl)acrylic acid 1H-NMR (DMSO-d6):<5 2.09-2.21 (2H, m) , 3.34-3.76 (4H, m) , 4.54- 4.68 (IH, m), 6.39 & 6.43 (total IH, each d J=15.96Hz), 6.98 & 7.04 (total IH, each d J=6.32Hz), 7.21 (2H, m) , 7.44 & 7.49 (total IH, each d J=15.96Hz), 7.56-7.65 (2H, m) , 8.08 & 8.11 (total IH, each s), 8.22 & 8.31 (total IH, each s), 12.26 (IH, br.s).

Preparation 612 (2E)-3-(5-chloro-6-{[(3R)-l-(3-methylbenzoyl)-3- pyrrolidinyl]amino}-3-pyridinyl)acrylic acid 1H-NMR (DMSO~d6):<5 2.09-2.21 (2H, m) , 2.32 & 2.35 (total IH, each s), 3.36-3.74 (4H, m) , 4.52-4.69 (IH, m) , 6.39 & 6.43 (total IH, each d J=15.92Hz), 6.97 & 7.03 (total IH, each d J=6.52Hz), 7.29- 7.36 (4H, m), 7.43 & 7.49 (total IH, d each d J=15.92Hz), 8.08 & 8.12 (total IH, each d J=I.40Hz), 8.23 & 8.31 (total IH, each d J=I.40Hz), 12.20 (IH, br.s).

Preparation 613 (2E)-3-(5-chloro-6-{[(3R)-l-(3-chlorobenzoyl)-3- pyrrolidinyl]amino}-3-pyridinyl)acrylic acid 1H-NMR (DMSO-d6):<5 2.09-2.19 (2H, m) , 3.35-3.73 (4H, m) , 4.55- 4.70 (IH, m), 6.40 & 6.43 (total IH, each d J=15.96Hz), 6.93 & 7.00 (total IH, each d J=6.26Hz), 7.36-7.57 (5H, m) , 8.08 & 8.12 (total IH, each d J=I.70Hz), 8.23 & 8.31 (total IH, each d J=I.70Hz), 12.19 (IH, br.s).

Preparation 614 (2E)-3-(5-chloro-6-{[(3R)-l-(2-chlorobenzoyl)-3- pyrrolidinyl]amino}-3-pyridinyl)acrylic acid 1H-NMR (DMSO-d6):<5 2.07-2.18 (2H, m) , 3.09-3.56 (3H, m) , 3.83- 3.86 (IH, m), 4.57-4.67 (IH, m) , 6.40 & 6.43 (total IH, each d J=15.96Hz), 6.93 & 7.00 (total IH, each d J=6.40Hz), 7.36-7.57 (5H, m), 8.08 & 8.11 (total IH, each d J=I.86Hz), 8.22 & 8.31 (total IH, each d J=I.86Hz), 12.19 (IH, br.s).

Preparation 615 A mixture of A mixture of (2E)-3-(5-chloro-6-{[(3R)-I-(3- methylbenzyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylic acid (410mg), 0-(tetrahydro-2H-pyran-2-yl)hydroxylamine (142mg), HOBt (156mg) and EDCI (180mg) in DMF (15ml) was stirred at ambient temperature for 15 hours. The reaction mixture was poured into a mixture of AcOEt-H2O and the organic layer was washed with brine and dried over MgSO4 . The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (9:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to give (2E)-3-(5-chloro-6- {[(3R)-1-(3-methylbenzyl)-3-pyrrolidinyl]amino}-3-pyridinyl) -N- (tetrahydro-2H-pyran-2-yloxy)acrylamide (400mg). 1H-NMR (DMSO-d6):<5 1.23-1.84 (7H, m) , 2.09-2.29 (IH, m) , 2.29 (3H, s), 2.37-2.53 (2H, m) , 2.63-2.65 (IH, m) , 2.74-2.89 (IH, m) , 3.55 (2H, s), 3.30-3.57 (2H, m),3.94-4.01 (IH, m) , 4.44-4.55 (IH, m) , 4.89 (IH, s), 6.32 (IH, d J=15.64Hz), 6.61 (IH, d J=6.88Hz), 7.02- 7.23 (4H, m), 7.36 (IH, d J=15.64Hz), 7.84 (IH, s), 7.20 (IH, s), 11.07 (IH, S).

The following compounds were obtained in a similar manner to that of Preparation 615. Preparation 616 (2E)-3-[5-chloro-6-(cyclopentylamino)-3-pyridinyl]-N-(tetrah ydro- 2H-pyran-2-yloxy)acrylamide 1H-NMR (DMSO-d6):<5 1.53-1.84 (12H, m) , 1.89-1.99 (2H, m) , 3.49- 3.55 (IH, m)-, 3.93-4.05 (IH, m) , 4.30-4.41 (IH, m) , 4.89 (IH, s), 6.31 ( IH, d J=15. 76Hz ) , 6. 54 ( IH, d J=7. 26Hz ) , 7.36 ( IH, d J=15.76Hz ) , 7 .82 ( IH, s ) , 8.21 ( IH, s ) , 11.07 ( IH, s ) .

Preparation 617 (2E)-3-{6-[(4-tert-butylcyclohexyl)amino]-5-chloro-3-pyridin yl}-N- (tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (DMSO-d6):<5 0.85 (9H, s), 1.00-2.00 (15H, m) , 3.49-3.55 (IH, m), 3.86-4.20 (2H, m) , 4.89 (IH, s), 5.70 & 6.43 (total IH, each d J=6.58Hz), 6.34-6.41 (IH, m) , 7.32-7.40 (IH, m) , 7.82 & 7.87 (total IH, each s), 8.19 & 8.23 (total IH, each s), 11.07 (IH, s).

Preparation 618 A mixture of (2E)-3-(5-chloro-6-{[(3R)-l-tcyclohexylmethylJ-S- pyrrolidinyllamino^S-pyridinylJacryiic acid (306mg), O- (tetrahydro-2H-pyran-2-yl)hydroxylainine (108mg) HOBt (119mg) and EDCI (137mg) in DMF (15ml) was stirred at ambient temperature for 15 hours. The reaction mixture was poured into a mixture of AcOEt- H2O and the organic layer was washed with brine and dried over MgSO4 . The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (9:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to give (2E)-3-(5-chloro-6-{[ (3R)-I- (cyclohexylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N- (tetrahydro-2H-pyran-2-yloxy)acrylamide (lOOmg). 1H-NMR (DMSO-d6):<5 0.64-0.92 (2H, m) , 1.02-1.23 (4H, m) , 1.23-1.91 (12H, m), 2.09-3.06 (7H, m) , 3.49-3.55 (IH, m) , 3.95-4.02 (IH, m) , 4.48-4.56 (IH, m) , 4.89 (IH, s), 6.32 (IH, d J=15.76Hz), 6.59 (IH, d J=5.04Hz), 7.36 (IH, d J=15.76Hz), 7.85 (IH, s), 8.21 (IH, s), 11.08 (IH, s).

The following compounds were obtained in a similar manner to that of Preparation 618. Preparation 619 (2E)-3-(5-chloro-6-{[(3R)-l-(cyclobutylmethyl)~3- pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2- yloxy) acrylamide 1H-NMR (DMSO-d6):<5 1.53-2.09 (15H, m) , 2.39-2.52 (6H, m) , 2.78- 2.79 (1H, m), 3.36-3.55 (3H, m) , 3.93-3.49 (IH, m) , 4.39-4.46 (IH, m), 4.89 (IH, s), 6.32 (IH, d J=15.80Hzj, 6.58 (IH, d J=7.00Hz), 7.36 (IH, d J=15.80Hz),, 7.84 (IH, d J=I.60Hz), 8.21 (IH, d J=I.60Hz), 11.07 (IH, br.s).

Preparation 620 (2E)-3-(5-chloro-6-{[(3R)-1-(3-methyl-2-buten-l-yl)-3- pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2- yloxy)acrylamide 1H-NMR (DMSO-d6):<5 1.14-1.91 (7H, m) , 1.63 (3H, s), 1.69 (3H, s), 2.09-2.16 (IH, m), 2.49-2.57 (2H, m) , 2.73-2.92 (2H, m) , 2.92-3.10 (2H, m), 3.49-3.51 (IH, m) , 3.95 (IH, m) , 4.48-4.52 (IH, m) , 4.89 (IH, s), 5.24-5.27 (IH, m), 6.33 (IH, d J=15.74Hz), 6.65 (IH, d J=6.90Hz), 7.36 (IH, d J=15.74Hz), 7.86 (IH, s), 8.21 (IH, s), 11.08 (IH, s).

The following compounds were obtained in a similar manner to that of Preparation 615. Preparation 621 i (2E)-3-(5-chloro-6-{[(3R)-1-(3-fluorobenzyl)-3-pyrrolidinyl] amino}- 3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (DMSO-d6):<5 1.22-2.00 (7H, m) , 2.18-2.20 (IH, m) , 2.41-2.52 (2H, m), 2.61-2.68 (IH, m) , 2.81-2.90 (IH, m) , 3.50-3.55 (2H, m), 3.55 (2H, m), 3.94-4.05 (IH, m) , 4.47-4.57 (IH, m) , 4.90 (IH, s), 6.33 (IH, d J=15.66Hz), 6.65 (IH, d J=6.88Hz), 7.01-7.18 (3H, m) , 7.30-7.41 (2H, m) , 7.85 (IH, s), 8.20 (IH, s), 10.96 (IH, s).

Preparation 622 (2E)-3-[5-chloro-6-({(3R)-1-[ (4-methylphenyl)sulfonyl]-3- pyrrolidinyl}amino)-3-pyridinyl]-N-(tetrahydro-2H-pyran-2- yloxy)acrylamide 1H-NMR (DMSO-d6):<5 1.53-1.69 (6H, m) , 1.95-2.05 (2H, m) , 2.39 (3H, s), 3.11-3.28 (3H, m) , 3.34-3.55 (2H, m) , 3.96-3.98 (iH, m) , 4.30- 4.33 ( IH, m) , 4.89 ( IH, s) , 6.35 ( IH, d J=15.92Hz ) , 6. 56 ( IH, d J=5.78Hz) , 7.36 ( 2H, d J=8.14Hz ) , 7.48 ( IH d J=15.92Hz) , 7.64 ( 2H, d J=8.14Hz ) , 7.84 ( IH, s) , 8.20 ( IH, s) , 11.10 ( IH, br. s) .

Preparation 623 (2E)-3-(5-chloro-6-{[(3R)-1-(cyclohexylcarbonyl)-3- pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2- yloxy)acrylamide 1H-NMR (DMSO-d6): δ 1.14-1.29 (6H, m) , 1.53-1.69 (1OH, m) , 1.96-2.14 (3H, m), 3.23-3.96 (6H, m) , 4.51-4.68 (IH, m) , 4.89 (IH, s), 6.35 (IH, d J=15.90Hz), 6.84-6.92 (IH, m) , 7.38 (IH, d J=15.90Hz), 7.88 (IH, s), 8.25 (IH, s), 11.10 (IH, s).

Preparation 624 (2E)-3-[6-({(3R)-l-[(4-methylphenyl)sulfonyl]-3- pyrrolidinyl}amino)-3-pyridinyl]-N-(tetrahydro-2H-pyran-2- yloxy)acrylamide 1H-NMR (DMSO-d6):<5 1.52-1.77 (7H, m) , 1.99-2.02 (IH, m) , 2.39 (3H, s), 3.02-3.09 (IH, m) , 3.20-3.55 (4H, m) , 3.98-4.01 (IH, m) , 4.20- 4.23 (IH, m), 4.88 (IH, s), 6.24 (IH, d J=15.48Hz), 6.40 (IH, d J=8.76Hz), 7.13 (IH, d J=5.74Hz), 7.36 (IH, d J=15.48Hz), 7.38 (2H, d J=8.18Hz), 7.61 (IH, d J=8.76Hz), 7.65 (2H, d J=8.18Hz), 8.18 (IH, s), 11.07 (IH, s).

Preparation 625 (2E)-3-(6-{[(3R)-I-(I-piperidinylcarbonyl)-3-pyrrolidinyl]am ino}-3- pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (DMSO-d6):<5 1.23-1.84 (13H, m) , 2.07-2.09 (IH, m) , 3.11 (4H, m), 3.35-3.66 (4H, m) , 3.93-3.95 (IH, m) , 4.30-4.35 (IH, m), 4.88 " (IH, s), 6.24 (IH, d J=15.44Hz), 6.55 (IH, d J=8.80Hz), 7.28 (IH, d J=6.24Hz), 7.37 (IH, d J=15.44Hz), 7.63 (IH, d J=8.80Hz), 8.17 (IH, s), 11.06 (IH, s).

Preparation 626 (2E)~3-(5-chloro-6-{[(3R)-l-(l-piperidinylcarbonyl)-3- pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2- yloxy)acrylamide 1H-NMR (DMSO-d6):<5 1.14-1.70 (12H, m) , 1.85-2.12 (2H, m) , 3.08 (4H, br.s), 3.25-3.62 (4H, m) , 3.98-4.01 (IH, m) , 4.44-4.48 (IH, m) , 4.90 (IH, s), 6.35 (IH, d J=15.78Hz), 6.81 (IH, d J=6.58Hz), 7.38 (IH, d J=15.78Hz), 7.96 (IH, s), 8.24 (IH, s), 11.08 (IH, br.s).

Preparation 627 (2E)-3-(5-chloro-6-{[ (3R)-1-(cyclopentylcarbonyl)-3- pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2- yloxy)acrylamide 1H-NMR (DMSO-d6):<5 1.53-1.69 (14H, m) , 1.99-2.12 (2H, m) , 2.73- 2.89 (IH, m), 3.28-4.00 (6H, m) , 4.51-4.70 (IH, m) , 4.89 (IH, s), 6.35 (IH, d J=15.84Hz), 6.85-6.92 (IH, m) , 7.38 (IH, d J=15.84Hz), 7.88 (IH, s), 8.25 (IH, s), 11.09 (IH, br.s).

Preparation 628 (2E)-3-(5-chloro-6-{[(3R)-l-(c3yclobutylcarbonyl)-3- pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2- yloxy)acrylamide 1H-NMR (DMSO-d6):<5 1.53-2.18 (15H, m) , 3.25-3.71 (4H, m) , 3.93- 3.95 (IH, m), 4.50-4.60 (IH, m) , 4.89 (IH, s), 6.35 (IH, d J=15.98Hz), 6.84-6.91 (IH, m) , 7.38 (IH, d J=15.98Hz), 7.95 (IH, s), 8.24 (IH, s), 11.08 (IH, br.s).

The following compounds were obtained in a similar manner to that of Preparation 618. Preparation 629 (2E)-3-(5-chloro-6-{[(3R)-l-(2-pyridinylmethyl)-3- pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2- yloxy)acrylamide 1H-NMR (DMSO-d6):<5 1.53-1.99 (8H, m) , 2.00-2.18 (IH, m) , 2.47-2.58 (2H, m), 2.69-2.73 (IH, m) , 2.86-2.94 (IH, m) , 3.34 (2H, s), 3.49- 3.50 (IH, m), 3.98-4.05 (IH, m) , 4.50-4.56 (IH, m) , 4.89 (IH, s), 6.36 (IH, d J=15.90Hz), 6.96 (IH, d J=6.90Hz), 7.22-7.28 (IH, m) , 7 . 41-7 . 45 ( IH, m) , 7 . 72-7 . 85 ( 2H , m) , 7 . 96 ( IH, s ) , 8 . 26 ( IH, s ) , 8.46-8.50 ( IH, m) , 11.07 ( IH, br. s ) .

The following compound was obtained in a similar manner to that of Preparation 615. Preparation 630 (2E)-3-(5-chloro-6-{[(3R)-l-(4-chlorobenzoyl)-3- pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2- yloxy)aerylamide IH-NMR (DMSO-d6):<5 1.69-1.74 (6H, m) , 1.99-2.21 (2H, m) , 3.34- 3.91 (5H, m), 4.54-4.72 (2H, m) , 4.89 (IH, s), 6.28-6.36 (IH, m) , 6.91-6.97 (IH, m) , 7.31-7.60 (5H, m) , 7.86-7.96 (IH, m) , 8.11-8.27 (IH, m), 11.09 (IH, s) .

The following compounds were obtained in a similar manner to that of Preparation 618. Preparation 631 (2E)-3-(5-chloro-6-{[(3R)-1-(cyclopropylmethyl)-3- pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2- yloxy)aerylamide 1H-NMR (DMSO-d6):<5 0.04-0.11 (2H, m) , 0.39-0.48 (2H, m) , 0.70-0.90 (IH, m), 1.53-1.90 (7H, m) , 2.09-2.24 (IH, m) , 2.26 (2H, d J=6.62Hz), 2.46-2.52 (2H, m) , 2.68-2.71 (IH, m) , 2.80-2.88 (IH, m) , 3.34-3.49 (IH, m), 3.93-3.96 (IH, m) , 4.47-4.58 (IH, m) , 4.89 (IH, s), 6.33 (IH, d J=15.78Hz), 6.59 (IH, d J=6.98Hz), 7.37 (IH, d J=15.78Hz), 7.85 (IH, s), 8.22 (IH, s), 11.07 (IH, br.s).

Preparation 632 (2E)-3-(5-chloro-6-{[(3R)-1-(cyclopentylmethyl)-3- pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2- yloxy)acrylamide 1H-NMR (DMSO-d6):<5 1.16-1.21 (2H, m) , 1.49-2.52 (2OH, m) , 2.52- 2.69 (IH, m), 2.70-2.90 (IH, m) , 3.49-3.55 (IH, m) , 3.94-3.99 (IH, m), 4.41-4.47 (IH, m) , 4.89 (IH, s), 6.34 (IH, d J=15.78Hz), 6.55 (IH, d J=7.04Hz), 7.33 (IH, d J=15.78Hz), 7.85 (IH, s), 8.21 (IH, s ) , 11.07 ( IH, br. s ) .

The following compounds were obtained in a similar manner to that of. Preparation 615. Preparation 633 (2E)-3-(5-chloro-6-{[(3R)-1-(2-pyrimidinyl)-3-pyrrolidinyl]a mino}- 3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (DMSO-d6):<5 1.54 (3H, br.s), 1.69 (IH, br.s), 1.74-2.09 (IH, m), 2.15-2.17 (IH, m) , 3.35-3.55 (3H, m), 3.67-3.69 (IH, m), 3.86-3.96 (2H, m) , 4.66-4.71 (IH, m) , 4.89 (IH, s), 6.35 (IH, d J=15.78Hz), 6.58-6.60 (IH, m) , 6.95 (IH, d J=6.40Hz), 7.88 (IH, s), 8.27 (IH, s), 8.32-8.33 (2H, m) , 11.11 (IH, s) .

Preparation 634 (2E)-3-(5-chloro-6-{[ (3R)-1-(4-fluorobenzoyl)-3- pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2- yloxy)acrylamide 1H-NMR (DMSO-d6):<5 1.53 (3H, s), 1.69 (3H, s), 2.09-2.15 (2H, m) , 3.35-3.59 (4H, m) , 3.59-3.95 (2H, m) , 4.53-4.68 (IH, m) , 4.90 (IH, s), 6.30-6.34 (IH, m) , 6.93 & 6.99 (total IH, each d J=6.06Hz), 7.27-7.41 (3H, m) , 7.58-7.64 ' (2H, m) , 7.86 & 7.89 (total IH, each s), 8.18 & 8.27 (total IH, each s), 11.10 (IH, s).

Preparation 635 (2E)-3-(5-chloro-6-{[(3R)-l-(3-methylbenzoyl)-3- pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2- yloxy)acrylamide 1H-NMR (DMSO-d6):<5 1.53 (3H, s), 1.69 (3H, s), 1.99-2.11 (2H, m) , 2.32 & 2.35 (total 3H, each s), 3.30-3.55 (4H, m) , 3.71-4.02 (2H, m), 4.52-4.54 (IH, m) , 4.89 (IH, s), 6.30-6.37 (IH, m) , 6.91 & 6.98 (total IH, each d J=6.12Hz), 7.24-7.47 (5H, m) , 7.85 & 7.89 (total IH, each s), 8.17 & 8.27 (total IH, each s), 11.10 (IH, s) .

Preparation 636 (2E)-3-(5-chloro-6-{[(3R)-l-(3-chlorobenzoyl)-3- pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2- yloxy)acrylamide 1H-NMR (DMSO-d6):<5 1.53 (3H, s), 1.69 (3H, s), 1.99-2.22 (2H, m) , 3.35-3.58 (4H, m) , 3.72-4.04 (2H, m) , 4.55-4.68 (IH, m) , 4.89 (IH, s), 6.30-6.34 (IH, m) , 6.93 & 7.02 (total IH, each d J=6.10Hz), 7.33-7.58 (5H, m) , 7.85 & 7.89 (total IH, each s), 8.19 & 8.27 (total IH, each s), 11.10 (IH, s).

Preparation 637 (2E)-3-(5-chloro-6-{[(3R)-l-(2-chlorobenzoyl)-3- pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2- yloxy)acrylamide 1H-NMR (DMSO-d6):<5 1.53 (3H, s), 1.69 (3H, s), 2.09-2.17 (2H, m) , 3.16-3.55 (4H, m) , 3.87-4.04 (2H, m) , 4.58-4.66 (IH, m) , 4.90 (IH, s), 6.34 (IH, m), 6.87-6.94 (IH, m) , 7.37-7.53 (5H, m) , 7.86 & 7.90 (total IH, each s), 8.17 & 8.27 (total IH, each s), 11.11 (IH, s).

Preparation 638 A solution of ethyl (2E)-3-{5-chloro-6-[ (3R)-3-pyrrolidinylamino]- 3-pyridinyl}acrylate dihydrochloride (560mg), p-toluenesulfonyl chloride (318mg) and Et3N (0.7ml) in DMF (15ml) was stirred at ambient temperature for 10 hours. The reaction mixture was poured into a mixture of AcOEt and H2O and the organic layer was washed with brine and dried over MgSO4 . The solvent was evaporated in vacuo and the residue was crystallized from AcOEt-n-hexane to give ethyl (2E)-3-[5-chloro-6-({(3R)-1-[ (4-methylphenyl)sulfonyl]-3- pyrrolidinyl}amino)-3-pyridinyl]aerylate (49Omg) . 1H-NMR (DMSO-d6):<5 1.25 (3H, t J=7.12Hz), 1.98-2.05 (2H, m) , 2.38 (3H, s), 3.14-3.17 (IH, m), 3.23-3.34 (2H, m) , 3.45-3.49 (IH, m) , 4.16 (2H, q J=7.12Hz), 4.32-4.33 (IH, m) , 6.53 (IH, d J=15.96Hz), 6.65 (IH, d J=5.92Hz), 7.36 (2H, d J=8.12Hz), 7.54 (IH, d J=15.96Hz), 7.62 (2H, d J=8.12Hz), 8.11 (IH, d J=I.96Hz), 8.27 (IH, d J=I.96Hz).

The following compound was obtained in a similar manner to that of Preparation 638. Preparation 639 ethyl (2E)-3-[6-({(3R)-1-[(4-methylphenyl)sulfonyl]-3- pyrrolidinyl}amino)-3-pyridinyl]acrylate 1H-NMR (DMSO-d6):<5 1.24 (3H, t =7.06Hz), 1.68-1.82 (IH, m) , 1.92- 2.22 (IH, m),2.39 (3H, s), 3.04-3.11 (IH, m) , 3.21-3.45 (3H, m) , 4.18 (2H, q J=7.06Hz), 6.34 (IH, d J=15.90Hz), 6.39 (IH, d J=8.76Hz), 7.23 (IH, d J=5.86Hz), 7.38 (2H, d J=8.08Hz), 7.52 (IH, d J=15.90Hz), 7.65 (2H, d J=8.08Hz), 7.79 (IH, dd J=2.08Hz, 8.78Hz), 8.21 (IH, d J=2.08Hz).

Preparation 640 A solution of ethyl (2E)-3-{5-chloro-6-[(3R)-3-pyrrolidinylamino]- 3-pyridinyl}acrylate dihydrochloride (610mg), C3yclohexanecarbonyl chloride (267mg) and Et3N (0.76ml) in DMF (15ml) was stirred at ambient temperature for 8 hours. The reaction mixture was poured into a mixture of AcOEt and H2O and the organic layer was washed with brine and dried over MgSO4 . The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (95:5). The eluted fractions containing the desired product were collected and evaporated in vacuo to give ethyl (2E)- 3-(5-chloro-6-{[(3R)-l-(cyclohexylcarbonyl)-3-pyrrolidinyl]a mino}- 3-pyridinyl)acrylate (630mg). 1H-NMR (DMS0-d6):δ 1.21-1.31 (6H, m) , 1.25 (3H, t J=7.08Hz), 1.63- 1.69 (5H, m), 1.93-2.10 (2H, m) , 3.28-3.84 (4H, m) , 4.15 (2H, q J=7.08Hz), 4.67-4.68 (IH, m) , 6.52 (IH, d J=15.98Hz), 6.95-7.19 (IH, m), 7.53 (IH, d J=15.98Hz), 8.14 (IH, d J=I.86Hz), 8.32 (IH, d J=I.86Hz).

The following compounds were obtained in a similar manner to that of Preparation 640. Preparation 641 ethyl (2E)-3-(6-{[(3R)-I-(I-piperidinylcarbonyl)-3- pyrrolidinyl]amino}-3-pyridinyl)acrylate 1H-NMR (DMSO-d6):<5 1.24 (3H, t J=7.06Hz), 1.49 (6H, br.s), 1.70- 1.89 (IH, m), 2.00-2.16 (IH, m) , 3.15 (4H, br,s), 3.15-3.46 (3H, m) , 3.58-3.66 (IH, m) , 4.18 (2H, q J=7.06Hz), 4.34-4.40 (IH, m) , 6.34 (IH, d J=15.82Hz), 6.55 (IH, d J=8.84Hz), 7.39 (IH, d J=6.28Hz), 7.52 (IH, d J=15.82Hz), 7.81 (IH, dd J=2.14Hz, 8.84Hz), 8.24 (IH, d J=2.14Hz).

Preparation 642 ethyl (2E)-3-(5-chloro-6-{[(3R)-l-(l-piperidinylcarbonyl)-3- pyrrolidinyl]amino}-3-pyridinyl)aerylate 1H-NMR (DMSO-d6):<5 1.24 (3H, t J=7.08Hz), 1.49 (6H, br.s), 1.90- 2.12 (2H, m), 3.12 (4H, br.s), 3.25-3.43 (3H, m) , 3.53-3.62 (IH, m) , 4.16 (2H, q J=7.08Hz), 4.46-4.56 (IH, m) , 6.51 (IH, d J=15.90Hz), 6.91 (IH, d J=6.62Hz), 7.53 (IH, d J=15.90Hz), 8.13 (IH, d J=I.90Hz), 8.31 (IH, d J=I.90Hz).

Preparation 643 ethyl (2E)-3-(5-chloro-6-{[(3R)-l-(cyclobutylcarbonyl)-3- pyrrolidinyl]amino}-3-pyridinyl)acrylate 1H-NMR (DMSO-d6):<5 1.25 (3H, t J=7.06Hz), 1.97-2.18 (9H, m) , 3.21- 3.60 (3H, m), 3.60-3.72 (IH, m) , 4.16 (2H, q J=7.06Hz), 4.52-4.62 (IH, m), 6.52 (IH, d J=15.86Hz), 6.89-7.01 (IH, m) , 7.53 (IH, d J=15.86Hz), 8.13 (IH, s), 8.32(1H, s) .

Preparation 644 ethyl (2E)-3-(5-chloro-6-{[(3R)-l-(cyclopentylcarbonyl)-3- pyrrolidinyl]amino}-3-pyridinyl)acrylate 1H-NMR (DMSO-d6):<5 1.25 (3H, t J=7.06Hz), 1.49-1.77 (8H, m) , 1.90- 2.20 (2H, m), 2.70-2.86 (IH, m) , 3.30-3.51 (3H, m) , 3.98-4.02 (IH, m), 4.16 (2H, q J=7.06Hz), 4.53-4.69 (IH, m) , 6.52 (IH,d J=15.96Hz), 6.94-7.02 (IH, m), 7.54 (IH, d J=15.96Hz), 8.13-8.15 (IH, m) , 8.31- 8.33 (IH, m).

Preparation 645 A solution of ethyl (2E)-3-{5~chloro-6-[ (3R)-3- pyrrolidinylamino]-3-pyridinyl}acrylate dihydrochloride (500mg), 4- chlorobenzoyl chloride (249mg) and Et3N (0.624ml) in DMF (20ml) was stirred at ambient temperature for 10 hours. The reaction mixture was poured into a mixture of AcOEt and H2O and the organic layer was washed with brine and dried over MgSU4 . The solvent was evaporated in vacuo and the residue was washed with IPE and n- hexane to give ethyl (2E)-3-(5-chloro-6-{[(3R)-l-(4-chlorobenzoyl)- 3-pyrrolidinyl]amino}-3-pyridinyl)aerylate (570mg). 1H-NMR (DMSO-d6):<5 1.20-1.28 (3H, m) , 2.11-2.18 (2H, m) , 3.34- 3.63 (4H, m), 4.10^4.18 (2H, m) , 4.43-4.71 {1H, m) , 6.46-6.57 (IH, m), 7.00-7.07 (IH, m) , 7.46-7.60 (5H, m) , 8.11-8.18 (IH, m) , 8.25 & 8.34 (total IH, each s).

The following compounds were obtained in a similar manner to that of Preparation 645. Preparation 646 ethyl (2E)-3-(5-chloro-6-{[(3R)-l-(4-fluorobenzoyl)-3- pyrrolidinyl]amino}-3-pyridinyl)acrylate 1H-NMR (DMSO-d6): O 1.24 (3H, t J=7.08Hz), 2.00-2.16 (2H, m) , 3.35- 3.78 (4H, m), 4.15 (2H, q J=7.08Hz), 4.56-4.70 (IH, m) , 6.50 & 6.54 (total IH, each d J=15.88Hz), 7.03 & 7.04 (total IH, each d J=6.32Hz), 7.23-7.28 (2H, m) , 7.48-7.63 (3H, m) , 8.12 & 8.16 (total IH, each d J=I.72Hz), 8.26 & 8.34 (total IH, each d J=I.72Hz).

Preparation 647 . ethyl (2E)~3-(5-chloro-6-{[(3R)-1-(3-methylbenzoyl)-3- pyrrolidinyl]amino}-3-pyridinyl)aerylate 1H-NMR (DMSO-d6):<5 1.24 (3H, t J=7.08Hz), 2.03-2.14 (2H, m) , 2.31 & 2.35 (total 3H, each s), 3.43-3.73 (4H, m) , 4.15 (2H, q J=7.08Hz), 4.53-4.70 (IH, m) , 6.50 & 6.54 (total IH, each d J=15.86Hz), 7.01 & 7.08 (total IH, each d J=6.56Hz), 7.24-7.33 (4H, m) , 7.49 & 7.54 (total IH, each d J=15.86Hz), 8.12 & 8.16 (total IH, each d J=I.76Hz), 8.25 & 8.34 (total IH, each d J=I.76Hz).

Preparation 648 ethyl (2E)-3-(5-chloro-6-{[(3R)-l-(3-chlorobenzoyl)-3- pyrrolidinyl]amino}-3-pyridinyl)acrylate 1H-NMR (DMSO-d6):<5 1.24 (3H, t J=7.06Hz), 1.99-2.30 (2H, m), 3.34- 3.58 (3H, m), 3.58-3.74 (IH, m) , 4.15 (2H, q J=7.06Hz), 4.56-4.70 (IH, m), 6.50 & 6.53 (total IH, each d J=15.92Hz), 7.03 & 7.04 (total IH, each d J=6.32Hz), 7.47-7.58 (5H, m) , 8.12 & 8.16 (total IH, each d J=I.92Hz), 8.26 & 8.34 (total IH, each d J=I.92Hz-).

Preparation 649 ethyl (2E)-3-(5-chloro-6-{[(3R)-l-(2-chlorobenzoyl)-3- pyrrolidinyl]amino}-3-pyridinyl)acrylate 1H-NMR (DMSO-d6):<5 1.24 (3H, t J=7.06Hz), 2.09-2.17 (2H, m) , 3.13- 3.43 (2H, m), 3.40-3.55 (IH, m) , 3.70-3.76 (IH, m) , 4.15 (2H, q J=7.06Hz), 4.56-4.70 (IH, m) , 6.50 & 6.54 (total IH, each d J=16.00Hz), 6.97 & 6.99 (total IH, each d J=6.52Hz), 7.38-7.52 (5H, m), 8.12 & 8.16 (total IH, each d J=2.00Hz), 8.25 & 8.34 (total IH, each d J=2.00Hz) .

Preparation 650 A solution of ethyl (2E)-3-{5-chloro-6-[(3R)-3- pyrrolidinylamino]-3-pyridinyl}acrylate dihydrochloride (700mg), 2- chloropyrimidine (283mg) and N,N-diisopropylethylamine (1.09ml) in DMF (20ml) was stirred at 80-85°C for 12 hours under atmospheric pressure of nitrogen. The reaction mixture was poured into a mixture of AcOEt and H2O and the organic layer was washed with brine and dried over MgSO4 . The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt. The eluted fractions containing the desired product were collected and evaporated in vacuo to give ethyl (2E)-3-(5-chloro-6-{[(3R)-l- (2-pyrimidinyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate (56Omg) . 1H-NMR (DMSO-d6):<5 1.25 (3H, t J=7.12Hz), 2.16-2.27 (2H, m) , 3.35- 3.56 (2H, m), 3.67-3.70 (IH, m) , 3.84-3.93 (IH, m) , 4.17 (2H, q J=7.12Hz), 4.65-4.71 (IH, m) , 6.52 (IH, d J=16.12Hz), 6.60 (IH, d J=4.48Hz), 7.04 (IH, d J=6.42Hz), 7.54 (IH, d J=16.14Hz), 8.32-8.35 (3H, m). Preparation 651 To a mixture of ethyl (diethoxyphosphoryl) (fluoro)acetate (2.08g) and magnesium bromide (1.9g) in THF (20ml) was added dropwise to a Et3N (1.32ml) with stirring at 0-15 0C under atmospheric pressure of nitrogen, and the reaction mixture was stirred at same condition for an hour. A solution of tert-butyl (3R)-3-[(3-chloro- 5-formyl-2-pyridinyl)amino]-1-pyrrolidinecarboxylate (2.Og) in THF (10ml) solution was added the above mixture and resultant mixture was stirred at 0-15 0C for 4 hours. The reaction mixture was poured into a mixture of AcOEt-H2O and the organic layer was washed with brine and dried over MgSO4 . The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-n-hexane (3:7). The eluted fractions containing the desired product were collected and evaporated in vacuo to give tert-butyl (3R)-3-({3-chloro-5-[ (lZ)-3-ethoxy-2- fluoro-3-oxo-l-propen-l-yl]-2-pyridinyl}amino)-1- pyrrolidinecarboxylate (2.34g) 1H-NMR (CDCl3) :δ 1.37 (3H, t J=7.08Hz), 1.40 (9H, s), 1.96 (IH, m) , 2.24-2.33 (IH, m) , 3.21-3.35 (IH, m) , 3.48-3.55 (2H, m) , 3.76-3.81 (IH, m), 4.34 (2H, q J=7.08Hz), 4.66-4.67 (IH, m), 5.30-5.32 (IH, m), 6.78 (IH, d J=35.36Hz), 7.90 (IH, d J=I.64Hz), 8.15 (IH, d J=I.64Hz).

Preparation 652 A mixture of tert-butyl (3R)-3-({3-chloro-5-[ (lZ)-3-ethoxy-2- fluoro-3-oxo-l-propen-l-yl]-2-pyridinyl}amino)-1- pyrrolidinecarboxylate (2.34g) and 4N hydrogen chloride in dioxane solution (11ml) in EtOH (10ml) was stirred at ambient temperature for 4 hours. IPE (100ml) was added to a reaction mixture and the precipitate was collected by filtration to give ethyl (2Z)-3-{5- chloro-6-[ (3R)-3-pyrrolidinylamino]-3-pyridinyl}-2-fluoroacrylate dihydrochloride (1.95g) . 1H-NMR (DMSO-d6):<5 1.29 (3H, t J=7.10Hz), 2.03-2.04 (IH, m) , 2.22- 2.26 (IH, m), 3.19-3.25 (2H, m) , 3.35-3.57 (2H, m) , 4.28 (2H, g J=7.10Hz), 4.73-4.86 (IH, m),7.03 (IH, d J=37.48Hz), 7.97 (IH, d J=I . 82Hz ) , 8. 38 ( IH, d J=I .82Hz ) , 9 .65 ( 2H, br. s ) .

Preparation 653 A mixture of ethyl (2Z)-3-{5-chloro-6-[(3R)-3-pyrrolidinylamino]- 3-pyridinyl}-2-fluoroacrylate dihydrochloride (720mg), cyclopentanone (188mg) , sodium triacetoxyborohydride (l.lδg) and Et3N (0.52ml) in CHCl3 (20ml) was stirred at 25-30 0C for 15 hours. The 10% K2CO3 solution (20ml) was added to a reaction mixture and stirred at ambient temperature for 30 minutes and extracted with CH2Cl2 and washed with brine and dried over MgSO4 . The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with CHCl3-MeOH (96:4). The eluted fractions containing the desired product were collected and evaporated in vacuo to give ethyl (2Z)-3-(5-chloro-6-{[ (3R)-l-cyclopentyl-3- pyrrolidinyl]amino}-3-pyridinyl)-2-fluoroacrylate (7lOmg) . 1H-NMR (CDCl3) :6 1.37 (3H, t J=7.16Hz), 1.53-1.57 (3H, m) , 1.71- 1.74 (5H, m), 2.39-2.42 (3H, m) , 2.73-2.81 (2H, m) , 2.95 (IH, m) , 4.33 (2H, q J=7.16Hz), 4.64-4.68 (IH, m) , 5.61-5.63 (IH, m) , 6.76 (IH, d J=35.52Hz), 7.87 (IH, d J=I.84Hz), 8.15 (IH, d J=I.84Hz).

The following compounds were obtained in a similar manner to that of Preparation 653. Preparation 654 ethyl (2Z)-3-(5-chloro-6-{[ (3R)-l-cyclohexyl-3-pyrrolidinyl]amino}- 3-pyridinyl)-2-fluoroacrylate 1H-NMR (CDCl3) :δ 1.21-1.28 (4H, m) , 1.37 (3H, t J=7.16Hz), 1.73- 1.77 (4H, m), 1.93 (2H, m) , 2.17 (IH, m) , 2.42-2.45 (2H, m) , 2.78- 2.85 (2H, m), 3.00 (IH, m) , 4.33 (2H, q J=7.16Hz), 4.62-4.66 (IH, m), 5.61-5.63 (IH, m) , '6.76 (IH, d J=35.52Hz), 7.87 (IH, d J=I.84Hz), 8.15 (IH, d J=I.84Hz).

Preparation 655 ethyl (2Z)-3-(5-chloro-6-{[ (3R)-1-(cyclohexylmethyl)-3- pyrrolidinyl]amino}-3-pyridinyl)-2-fluoroacrylate 1H-NMR (CDCl3): 6 0.88-0.91 (2H, m) , 1.19-1.21 (3H, m) , 1.37 (3H, t J=7.16Hz), 1.40-1.60 (IH, m) , 1.68-1.73 (6H, m) , 2.27-2.34 (4H, m), 2.65-2.66 (2H, m) , 2.89 (IH, m) , 4.33 (2H, q J=7.16Hz), 4.62- 4.67 (IH, m), 5.63-5.65 (IH, m) , 6.77 (IH, d J=35.52Hz), 7.87 (IH, d J=I.76Hz), 8.17 (IH, d J=I.76Hz).

Preparation 656 A mixture of ethyl (2Z)-3-(5-chloro-6-{[ (3R)-l-cyclopentyl-3- pyrrolidinyl]amino}-3-pyridinyl)-2-fluoroacrylate (710mg) and IN NaOH solution (3.8ml) in MeOH (20ml) was stirred at 75-80 0C for 2 hours. To the reaction mixture was added IN HCl solution (3.8ml) and the resultant solution was evaporated in vacuo and the residue was dissolved in a mixture of MeOH and toluene and evaporated in vacuo and the residue was driedto give (2Z)-3-(5-chloro-6-{[ (3R)-I- cyclopentyl-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoroacryl ic acid (658mg). 1H-NMR (DMSO-d6):<5 1.75-2.12 (9H, m) , 2.35-2.52 (2H, m) , 2.99-3.81 (4H, m), 4.78-4.91 (IH, m) , 6.67 (IH, d J=37.52Hz), 7.09 (IH, d J=7.34Hz), 7.86 (IH, d J=I.64Hz), 8.24 (IH, d J=I.64Hz).

The following compounds were obtained in a similar manner to that of Preparation 656. Preparation 657 (2Z)-3-(5-chloro-6-{[(3R)-l-cyclohexyl-3-pyrrolidinyl]amino} -3- pyridinyl)-2-fluoroacrylic acid 1H-NMR (DMSO-d6):<5 1.06-1.62 (7H, m) , 1.76-1.81 (2H, m) , 1.97-2.06 (2H, m) , 2.30-2.50 (2H, m) , 3.04-3.52 (4H, m) , 4.77-4.80 (IH, m) , 6.66 (IH, d J=37.56Hz), 7.09 (IH, d J=7.33Hz), 7.86 (IH, d J=I.28Hz), 8.23 (IH, d J=I.28Hz).

Preparation 658 (2Z)-3-(5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3- pyrrolidinyl]amino}-3-pyridinyl)-2-fluoroacrylic acid 1H-NMR (DMSO-d6):<5 0.89-1.26 (6H, m) , 1.64-2.06 (7H, m) , 2.30-2.44 (2H, m), 2.84-2.88 (2H, m) , 3.17-3.20 (IH, m) , 3.40 (IH, m) , 4.76- 4.79 (IH, m), 6.69 (IH, d J=37.54Hz), 7.06 (IH, d J=7.21Hz), 7.87 (IH, d J=I.68Hz), 8.24 (IH, d J=I.68Hz).

Preparation 659 . (2Z)-3-(6-{[(3R)-l-benzyl-3-pyrrolidinyl]amino}-5-chloro-3- pyridinyl)-2-fluorόacrylic acid 1H-NMR (DMSO-d6):<5 1.99-2.11 (IH, m) , 2,30-2.41 (IH, mj , 3.11-3.52 (4H, m), 4.30 (2H, s), 4.71-4.81 (IH, m) , 6.82 (IH, d J=37.42Hz), 7.11-7.29 (3H, m) , 7.40-7.47 (2H, m) , 7.60-7.62 (IH, m) , 7.90 (IH, s), 8.28 (IH, s). J

Preparation 660 (2Z)-3-(6-{[(3R)-l-benzyl-3-pyrrolidinyl]amino}-3-pyridinyl) -2- fluoroacrylic acid 1H-MMR (DMSO-d6):<5 1.83-1.89 (IH, m) , 2.26-2.36 (IH, m) , 2.75- 3.28 (4H, m), 3.96-4.09 (2H, m) , 4.46-4.49 (IH, m) , 6.57 (IH, d J=8.88Hz), 6.75 (IH, d J=37.98Hz), 7.14-7.51 (6H, m) , 7.74 (IH, dd J=I.92Hz, 8.88Hz), 8.23 (IH, d J=I.92Hz).

Preparation 661 A mixture of (2Z)-3-(5-chloro-6-{[(3R)-l-cyclopentyl-3- pyrrolidiηyl]amino}-3-pyridinyl)-2-fluoroacrylic acid (658mg), 0,- (tetrahydro-2H-pyran-2-yl)hydroxylamine (229mg) , HOBt (264mg) and EDCI(303mg) in DMF (15ml) was stirred at ambient temperature for 15 hours. The reaction mixture was poured into a mixture of AcOEt-H2O and the organic layer was washed with brine and dried over MgSO4 . The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (95:5). The eluted fractions containing the desired product were collected and evaporated in vacuo to give . (2Z)-3-(5-chloro-6-{ [(3R)-I- cyclopentyl-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoro-N- (tetrahydro-2H-pyran-2-yloxy)acrylamide (62Omg) . 1H-NMR (DMSO-d6):<5 1.37-1.72 (12H, m) , 2.09-2.20 (IH, m) , 2.73 (IH, m), 2.89 (IH, m) , 3.36 (6H, m) , 3.50-3.52 (IH, m), 4.05-4.07 (IH, m), 4.48-4.50 (IH, m), 4.97 (IH, s), 6.66 (IH,. d J=7.00Hz), 7.85 (IH, d J=I.88Hz), 8.28-8.32 (IH, m) . The following compounds were obtained in a similar manner to that of Preparation 661. Preparation 662 (2Z)-3-(5-chloro-6-{[(3R)-l-cyclohexyl-3-pyrrolidinyl]aminp} -3- pyridinyl)-2-fluoro-N-(tetrahydro-2H-pyran-2-yloxy)acrylamid e 1H-NMR (DMSO-d6):<5 1.09-1.23 (4H, m) , 1.54-1.84 (9H, m) , 2.09-2.13 (2H, m), 2.50-2.52 (2H, m) , 2.74-2.75 (IH, m) , 2.88-2.92 (IH, m), 3.36 (4H, m), 3.36 (4H, m) , 3.50-3.53 (IH, m), 4.03-4.08 (IH, m) , 4.46-4.50 (IH, m) , 4.97 (IH, s), 6.50 (IH, d J=6.96Hz), 6.78 (IH, d J=39.72Hz), 7.85 (IH, d J=I.88Hz), 8.29-8.32 (IH, m).

Preparation 663 (2Z)-3-(5-chloro-6-{[ (3R)-1-(cyclohexylmethyl)-3- pyrrolidinyl]amino}-3-pyridinyl)-2-fluoro-N-(tetrahydro-2H-p yran-2- yloxy)acrylamide 1H-NMR (DMSO-d6):<5 0.81-0.84 (2H, m) , 1.15-1.17 (3H, m) , 1.53-1.57 (IH, m), 1.63-1.84 (14H-, m) , 2.17-2.23 (3H, m) , 2.41-2.43 (2H, m) , 2.51-2.52 (2H, m) , 2.74-2.78 (IH, m), 3.50-3.53 (IH, m) , 4.07-4.08 (IH, m), 4.49-4.51 (IH, m) , 4.98 (IH, s), 6.62 (IH, d J=7.04Hz), 6.79 (IH, d J=69.72Hz), 7.85 (IH, d J=I.88Hz), 8.29 (IH, d J=I.88Hz).

Preparation 664 (2Z)-3-(6-{[(3R)-l-benzyl-3-pyrrolidinyl]amino}-5-chloro-3- pyridinyl)-2-fluoro-N-(tetrahydro-2H-pyran-2-yloxy)acrylamid e 1H-NMR (DMSO-d6):<? 1.54 (3H, m) , 1.70 (3H, s), 1.81-1.84 (IH, m), 2.10-2.22 (IH, m), 2.37-2.40 (2H, m) , 2.64-2.65 (IH, m) , 2.81-2.85 (IH, m), 3.50-3.52 (IH, m) , 3.59 (2H, s), 4.02-4.07 (IH, m) , 4.49- 4.52 (IH, m), 4.98 (IH, s), 6.68 (IH, d J=6.96Hz), 6.78 (IH, d J=39.68Hz), 7.21-7.26 (IH, m) , 7.28-7.34 (IH, m) , 7.85 (IH, d J=I.88Hz), 8.31 (IH, d J=I.88Hz).

Preparation 665 (2Z)-3-(6-{[(3R)-l-benzyl-3-pyrrolidinyl]amino}-3-pyridinyl) -2- f luoro-N- ,( tetrahydro- 2H-pyran- 2 -yloxy ) acrylamide 1H-NMR (DMSO-d6):<5 1.63 (3H, s), 1.64-1.69 (4H, m) , 2.20 (IH, m) , 2.35-2.45 (2H, m) , 2.63-2.64 (IH, m) , 2.75-2.79 (IH, m) , 3.49-3.51 (IH, m), 3.57 (2H, d J=4.76Hz), 4.03-4.06 (IH, m) , 4.32 (IH, m) , 4.96 (IH, s), 6.53 (IH, d J=8.90Hz), 6.69 (IH, d J=40.40Hz), 7.21- 7.26 (2H, m), 7.28-7.33 (4H, m) , 7.67 (IH, dd J=2.20Hz, 8.90Hz), 8.19 (IH, d J=2.20Hz), 11.66 (IH, s) .

Preparation 666 To a mixture of ethyl (diethoxyphosphoryl)(fluoro)acetate (1.46g) and magnesium bromide (1.33g) in THF (20ml) was added dropwise to a EtβN (0.92ml) with stirring at 0-15 0C under atmospheric pressure of nitrogen, and the reaction mixture was stirred at same condition for an hour. A solution of 6-{[(3R)-l-benzyl-3- pyrrolidinyl]amino}-5-chloronicotinaldehyde (1.36g) in THF (10ml) solution was added the above mixture and resultant mixture was stirred at 0-15 0C for 4 hours. The reaction mixture was poured into a mixture of AcOEt-H2O and the organic layer was washed with brine and dried over MgSθ4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-n- hexane (3:7). The eluted fractions containing the desired product were collected and evaporated in vacuo to give ethyl (2Z)-3-(6- {t(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-chloro-3-pyridinyl)- 2- fluoroacrylate (1.42g). 1H-NMR (CDCl3) :δ 1.36 (3H, t J=7.16Hz), 1.33-1.39 (IH, m), 1.68- 1.73 (IH, m), 2.38-2.40 (IH, m) , 2.66-2.67 (IH, m) , 1.73-2.74 (IH, m), 2.89 (IH, m) , 3.65 (2H, s), 4.33 (2H, q J=7.16Hz), 5.69 (IH, d J=7.70Hz), 6.75 (IH, d J=35.52Hz), 7.23-7.34 (5H, m) , 7.86 (IH, d J=I.84Hz), 8.15 (IH, d J=I.84Hz).

The following compound was obtained in a similar manner to that of Preparation 666. Preparation 667 ethyl (2Z)-3-(6-{[(3R)-l-benzyl-3-pyrrolidinyl]amino}-3-pyridinyl) - 2-fluoroacrylate 1H-NMR (CDCl3) : <5 1.36 ( 3H, t J=7.14Hz ) , 1.71-1.72 ( IH, m) , 2.33- 2.45 (2H, m) , 2.57-2.88 ( 3H, m) , 3.64 (2H, s) , 4.29 ( 2H, q J=7. 14Hz) , 5.19 ( IH, d J=7.84Hz) , 6.37 ( IH, d J=8.80Hz) , 6.79 ( IH, d J=36.28Hz ) , 7.2-7.33 (5H, m) , 7.81 ( IH, dd J=2.10Hz , 8.80Hz ) , 8.22 ( IH, d J=2. 10Hz) .

Preparation 668 To a stirred suspension of ethyl (2E)-3-{5-[(3R)-3- piperidinylamino]-2-pyrazinyl}acrylate dihydrochloride (300mg) in dichloromethane (6πiL) was added N,N-diisopropylethylamine (348mg) and phenylacetyl chloride (139mg) in dichloromethane (ImL) in an ice bath and the resulting mixture was stirred at the same temperature for three hours. The mixture was extracted with chloroform and washed with saturated sodium bicarbonate and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate to afford ethyl (2E)-3- (5-{[(3R)-l-(phenylacetyl)-3-piperidinyl]amino}-2- pyrazinyl)aerylate (225mg) as a pale brown viscous oil. 1H-NMR (300 MHz, CDCl3) <5l.33 (3H, t, J=7.3 Hz) ,1.35-1.50 (IH, m),1.57-2.03 (3H, m),3.19-3.57 (2H, m),3.67-4.07 (4H, m),4.26 (2H, q, J=7.3 Hz),4.65 (0.6H, br.d, J=7.0 Hz),4.98 (0.4H, br.d, J=6.2 Hz),6.69 (0.4H, d, J=15.4 Hz),6.71 (0.6H, d, J=15.4 Hz) ,7.19-7.41 (5H, m),7.57 (0.4H, d, J=15.4 Hz),7.58 (0.6H, d, J=15.4 Hz),7.67 (0.6H, br.s),7.87 (0.4H, br.s) ,8.03-8.06 (IH, m) ; MS (ES+) m/z 395.

Preparation 669 A mixture of 5,6-dichloronicotinic acid(356mg), iodoethane(318mg) and potassium carbonate(308mg) in N,N-dimethylformamide(3mL) was heated at eighty degree for fourteen hours. The mixture was allowed to cool to ambient temperature and to this was added (3R)-I- (cyclohexylmethyl)-3-piperidinamine dihydrochloride(549mg) and potassium carbonate(898mg) and heated at eighty degree for thirtyeight hours. The mixture was allowed to cool to ambient temperature and was added water. The mixture was extracted with ethyl acetate(10OmL) and aqueous phase was separated. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was filtered and evaporated in vacuo to give an amorphous solid. The crude solid was purified by a flash chromatography eluting with 3% methanol-chloroform(v/v) to give ethyl 5-chloro-6-{[(3R)-l-(cyclohexylmethyl)-3- piperidinyl]amino}nicotinate(154mg) as a pale yellow, amorphous solid. 1H-NMR (300 MHz, CDCl3) 60.79-0.98 (2H, m),1.12-1.32 (4H, m),1.37 (3H, t, J=7.3 Hz),1.43-1.88 (9H, m) ,,2.03-2.21 (3H, m),2.33-2.43 (IH, m),2.59-2.75 (2H, m),4.33 (2H, q, J=7.3 Hz) ,4.36-4.48 (IH, m),6.36 (IH, br.s),8.00 (IH, d, J=I.8 Hz),8.66 (IH, d, J=I.8 Hz).

Preparation 670 To a stirred solution of ethyl 5-chloro-6-{[(3R)-I- (cyclohexylmethyl)-3-piperidinyl]amino}nicotinate (321mg) in tetrahydrofuran (6mL) was added lithium aluminurrihydride (80.2mg) portionwise in an ice bath and the resulting suspension was stirred at the same temperature for three hours. To this was added saturated aqueous potassium sodium (+)-tartrate tetrahydrate solution portionwise at the same temperature and the mixture was stirred at ambient temperature for one hour. The mixture was extracted with ethyl acetate and the aqueous phase was removed. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethylacetate-hexane l:l(v/v) to afford (5-chloro-6-{[(3R)-I-(cyclohexylmethyl)-3- piperidinyl]amino}-3-pyridinyl)methanol (210mg) as a colorless oil. 1H-NMR (300 MHz, CDCl3) <50.77-0.98 (2H, m),1.08-1.34 (4H, m),1.39- 1.89 (9H, m),2.03-2.21 (3H, m),2.34-2.48 (IH, m) ,2.52-2.71 (2H, m),4.17-4.29 (IH, m),4.52 (2H, s),5.87 (IH, br.s),7.51 (IH, d, J=2.2 Hz),7.96 (IH, d, J=2.2 Hz); MS (ES+) m/z 338(M+1).

Preparation 671 To a stirred solution of ethyl (2E)-3-(6-{(tert- butoxycarbonyl)[(3R)-l-(2,2,6,6-tetramethyl-4-piperidinyl)-3 - pyrrolidinyl]amino}-3-pyridinyl)ac-τylate (265mg, 0.529πnnol) in methanol (5mL) was added hydroxylamine hydrochloride (184mg, 2.65mmol) at ambient temperature. To this mixture was added IN potassium methoxide in methanol (5.29mL, 5.29mmol) dropwise in an ice bath and the resulting mixture was stirred at ambient temperature for three hours. To the mixture was added IN hydrogen chloride to neutralize the solution. The solvent was removed in vacuo and the residue was desalted using ion-exchange resin. The crude product was purified by preparative high-pressure liquid chromatography to afford tert-butyl {5-[(lE)-3-(hydroxyamino)-3- oxo-1-propen-l-yl]-2-pyridinyl}[(3R)-I-(2,2,6,6-tetramethyl- 4- piperidinyl)-3-pyrrolidinyl]carbamate (103mg) as a colorless wax. 1H-NMR (300 MHz, DMSO-d6) δ0.74-0.90 (2H, m),0.99 (6H, s),1.09 (6H, s),1.36 (9H, s),1.54-1.69 (2H, m) ,1.74-2.11 (2H, m),2.34-2.53 (2H, m),2.53-2.67 (2H, m),2.87-2.98 (IH, m),4.57-4.72 (IH, m),6.54 (IH, d, J=16.1 Hz),7.32 (IH, d, J=8.4 Hz),7.48 (IH, d, J=16.1 Hz),7.99 (IH, dd, J=8.4, 2.2 Hz),8.60 (IH, d, J=2.2 Hz); MS (ES+) m/z 488(M+1).

The following compound was obtained in a similar manner to that of Preparation 671. Preparation 672 tert-butyl {5-[(1E)-3-(hydroxyamino)-3-oxo-l-propen-l-yl]-2- pyridinyl}[(3R)-l-(tetrahydro-2H-pyran-4-yl)-3- pyrrolidinyl]carbamate 1H-NMR (300 MHz, DMSO-d6) 61.13-1.36 (2H, m),1.37 (9H, s),1.60-1.74 (2H, m),1.80-2.21 (3H, m),2.35-2.67 (3H, m),2.86-2.97 (IH, m),3.19- 3.33 (2H, m),3.70-3.83 (2H, m) ,4.61-4.78 (IH, m),6.54 (IH, d, J=15.8 Hz),7.34 (IH, d, J=8.4 Hz),7.49 (IH, d, J=15.8 Hz),7.99 (IH, br.d, J=8.8 Hz),8.61 (IH, br.s); MS (ES+) m/z 433(M+1).

The following compound was obtained in a similar manner to that of Preparation 871.. Preparation 673 ethyl 6-[(2-benzylphenyl)amino]-5-chloronicotinate 1H-NMR (300 MHz, CDCl3)Sl.37 (3H, t, J=7 Hz),4.03 (2H, s),4.34 (2H, q,, J=7 Hz),6.93 (IH, s),7.14-7.38 (8H, m),7.88 (IH, d, J=8 Hz),8.08 (IH, d, J=2 Hz),8.69 (IH, d, J=2 Hz); MS (ES+) m/z 367.

Preparation 674 To a mixture of ethyl 5~chloro-6-(2,3-dihydro-lH-inden-2- ylamino)nicotinate (395 mg) and ammonium formate (472 mg) in ethanol (10 mL) was added 10% palladium on carbon (40 mg) , and the mixture was stirred at 100 0C for 10 hours. The catalyst in the reaction mixture was removed by filtration. The solvent was evaporated in vacuo. The residual solid was collected with hexane and ethyl acetate (2/1 v/v) to give ethyl 6-(2,3-dihydro-lH-inden- 2-ylamino)nicotinate (104 mg) . The mother liquid was concentrated in vacuo, and the residue was purified by preparative thin layer column chromatography (hexane / ethyl acetate = 2 / 1) to give ethyl 6-(2,3-dihydro-lH-inden-2-ylamino)nicotinate(209 mg) as a pale yellow solid. 1H-NMR (300 MHz, DMSO-d6) <51.28 (3H, t, J=7 Hz),2.84 (2H, dd, J=16, 6 Hz),3.29 (2H, dd, J=16, 7 Hz),4.24 (2H, q, J=7 Hz),4.67 (IH, m),6.52 (IH, d, J=9 Hz),7.11-7.19 (2H, m),7.20-7.29 (2H, m),7.72 (IH, d, J=6.5 Hz),7.81 (IH, dd, 3=9, 2.5 Hz),8.60 (IH, d, J=2.5 Hz); MS (ES+) m/z 283.

Preparation 675 tert-Butyl [(IR)-1-{[(cyclohexylmethyl)amino]carbonyl}-3- (methylthio)propyl]carbamate (5.12 g) was dissolved in methyl iodide (23 mL) and stirred at room temperature for 18 hours. The excess methyl iodide was evaporated in vacuo. The residue was dissolved in tetrahydrofuran (50 mL), added lithium bis(trimethylsilyl)amide 1.0M solution in hexane (16.3 mL) at 00C, and then allowed to warm to room temperature and stirred for 5 hours. The resulting mixture was poured into aqueous ammonium chloride and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4, concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = from 80 / 20 (v/v) to 60 / 40 (v/v) ) to give tert- butyl [ (3R)-1-(cyclohexylmethyl)-2-oxo-3-pyrrolidinyl]carbamate (2.0 g) as a pale yellow solid. 1H-NMR (300 MHz, CDCl3) <50.86-1.04 (2H, m) ,1.10-1.29 (3H, m),1.45 (3x3H, s),1.51-1.91 (7H, m),2.65 (IH, m),3.03-3.41 (4H, m),4.17 (IH, m),5.14 (IH, m); MS (ES+) m/z 297.

Preparation 676 ethyl (2E)-3-(5-{[ (3R)-l-benzyl-3-pyrrolidinyl]amino}-2- pyrazinyl)aerylate To an ice-cooled solution of ethyl (2E)-3-(5-{[ (3R)-l-benzyl-3- pyrrolidinyl] (tert-butoxycarbonyl)amino}-2-pyrazinyl)aeryIa1te (4.63g) in dichlόromethane (7.8ml) were added anisole (4.7ml) and trifluoroacetic acid (15.6ml), the mixture was stirred at 25°C for 3.5 hours. The mixed solution was poured into a mixture of water and AcOEt. The pH of the aqueous layer was adjusted to ca.8 with NaHCO3. The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated under reduced pressure to give crude powder. The resulting residue was purified by column chromatography on silica gel (5Og) using a mixed solvent of CH2Cl2 and MeOH(100:1 to 20:1). The fractions containing the objective compound . were collected and evaporated under reduced pressure. Title compound (3.05g, 85%) was obtained as slightly yellowish powder. MASS(API-ES); 353 (M+H) , 1H-NMR ( 200MHz), (DMSO-d6, <5 ) : 1.24 ( 3H, t, J = 7.1Hz ), 1.50 - 1.80 ( IH, m), 2.10 - 2.35 ( IH, m), 2.36 - 2.55 ( 2H, m) , 2.60 - 2.85 ( 2H, m), 3.50 - 3.66 ( 2H, m) , 4.16 ( 2H, q, J = 7.1Hz ) , 4.25 - 4.45 ( IH, m) , 6.49 ( IH, d; J = 15Hz ), 7.15 - 7.40 ( 5H, m), 7.53 ( IH, d, J = 15Hz ), 7.93 ( IH, d, J = 6.6Hz ), 8.00 ( IH, s ), 8.20 ( IH, s).

The following compound was obtained in a similar manner to that of Preparation 676. Preparation 677 ethyl 3-(5-{[(3R)-l-benzyl-3-pyrrolidinyl]amino}-2-pγrazinyl)-2- fluoroacrylate(E,Z-Mixture) MASS(API-ES); 371 (M+H)+, 1H-NMR ( 200MHz), (CDCl3, <5 ) : 1.20 - 1.50 ( 3H, m) , 1.60 - 1.90 ( IH, m), 2.25 - 2.50 ( 2H, m) , 2.60 - 2.80 ( 2H, m) , 2.85 - 3.03 ( IH, m), 3.67 ( 2H, s) , 4.33 ( 2H, q, J = 7.2Hz), 4.37 - 4.65 ( IH, m), 5.24 ( 0.5H, d, J = 7.6Hz ), 5.37 ( 0.5H, d, J = 7.6Hz ), 6.78 ( 0.5H, d, J = 22Hz ), 6.98 ( 0.5H, d, J = 37Hz ), 7.20 - 7.40 ( 5H, m), 7.83 ( 0.5H, d, J = 1.1Hz ) , 7.89 ( 0.5H, d, J = 1.1Hz ), 8.47 ( 0.5H, d, J = 1.1Hz ), 8.56 ( 0.5H, d, J = 1.IHz ) .

Preparation 678 To a mixture of ethyl (2E)-3-(6-{(tert-butoxycarbonyl) [ (3R)-3- pyrrolidinyl]amino}-3-pyridinyl)aerylate dihydrochloride (256 mg) and cyclohexanone (64 mg) in 1,2-dichloroethane (5 mL) was added sodium triacetoxyborohydride (253 mg) and N,N-diisopropylethylamine (0.21 mL), and the mixture was stirred at room temperature for 2 hours. To the resultant was added saturated aqueous ammonium chloride and ethyl acetate, and the mixture was stirred for 20 min. The organic phase was separated, washed with brine and dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform / methanol = 95 / 5 v/v) to give ethyl (2E)-3-(6-{(tert-butoxycarbonyl) [(3R)- l-cyclohexyl-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate (338 mg) as a pale yellow foam. 1H-NMR (300 MHz, CDCl3) δ1.18-1.38 (4H, m),1.35 (3H, t, J=7 Hz),1.46 (9H, s),1.58-1.86 (5H, m),2.06-2.35 (3H, m),2.68 (IH, m),2.95 (IH, m),3.41 (IH, m),3.65 (IH, m),3.96 (IH, m),4.28 (2H, q, J=7 Hz),5.09 (IH, m),6.46 (IH, d, J=16 Hz),7.30 (IH, d, 3=9 Hz),7.64 (IH, d, J=16 Hz),7.81 (IH, d, J=9 Hz),8.48 (IH, s); MS (ES+) m/z 444.

The following compounds were obtained in a similar manner to that of Preparation 678. Preparation 679 ethyl (2E)-3-(6-{(tert-butoxycarbonyl) [(3R)-l-cycloheptyl-3- pyrrolidinyl]amino}-3-pyridinyl)acrylate 1H-MMR (300 MHz, CDCl3) δ1.21-1.72 (HH, m),1.35 (3H, t, J=7 Hz),1.45 (9H, s),1.73-1.88 (2H, m),1.99 (IH, m),2.18 (IH, m),2.35 (IH, m),2.60 (IH, m),2.75 (IH, m),3.10 (IH, m),4.28 (2H, q, J=7 Hz),4.86 (IH, m),6.46 (IH, d, J=16 Hz),7.31 (IH, d, J=8.5 Hz),7.65 (IH, d, J=16 Hz),7.81 (IH, d, J=8.5, 2.5 Hz),8.54 (IH, d, J=2.5 Hz); MS (ES+) m/z 458.

Preparation 680 ethyl (2E)-3-(6-{(tert-butoxycarbonyl) [(3R)-1-cyclopentyl-3- pyrrolidinyl]amino}-3-pyridinyl)acrylate 1H-NMR (300 MHz, CDCl3) <51.20-1.86 (8H, m),1.35 (3H, t, J=7 Hz),1.46 (9H, s),2.01 (IH, m),2.21 (IH, m) ,2.42-2.57 (2H, m),2.63 (IH, m),2.83 (IH, m),3.14 (IH, m),4.28 (2H, q, J=7 Hz),4.90 (IH, m),6.46 (IH, d, J=16 Hz),7.32 (IH, d, J=8.5 Hz),7.65 (IH, d, J=16 Hz),7.81 (IH, dd, J=8.5, 2 Hz),8.54 (IH, d, 3=2 Hz); MS (ES+) m/z 430.

Preparation 681 0.94 M solution of diisobutylaluminium hydride in hexane (2.73ml) was added dropwise to a solution of ethyl 6-{[(3R)-l-benzyl-3- pyrrolidinyl]amino}-5-fluoronicotinate (294mg) in THF (10ml) with stirred below 5 °C under atmospheric pressure of nitrogen, and the reaction mixture was stirred at the same temperature for 1.5 hrs. To the reaction mixture was added saturated aqueous ammonium chloride (0.727ml) below 5 0C, then the mixture was stirred at 25 °C for 30 minutes. Na2SO4(2.87g) was added to the solution, and the mixture was stirred at 25 0C for 15 minutes. The reaction mixture was filtrated, the filtrate was evaporated in vacuo. Toluene(15ml) was added to the residue , and the mixture was evaporated in vacuo. The resulting residue and activated MnO2 (744mg) in ethyl acetate (20ml) were stirred at 750C for 1 hour. After removal of the insoluble material by filtration, the filtrate was evaporated in vacuo to give 6-{[(3R)-l-benzyl-3-pyrrolidinyl]amino}-5- fluoronicotinaldehyde(250mg, 98%) as syrup. The compound was used in the next step reaction without purification.

Preparation 682 To an ice-cooled solution of ethyl (2E)-3-(6-{(tert- butoxycarbonyl) [ (3R)-1-(cyclohexylcarbonyl)-3-pyrrolidinyl]amino}- 3-pyridinyl)acrylate (355mg) in dichloromethane (2ml) was added anisole (1.0ml) and trifluoroacetic acid (2.0ml), the mixture was stirred at 25°C for 1 hour. The mixed solution was poured into a mixture of water and AcOEt. The pH of the aqueous layer was adjusted to ca.9 with NaHCO3. The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated under reduced pressure to give syrup. The residue was dissolved in a mixed solvent of tetrahydrofuran(6ml) and methanol(2.5ml) , and lmol/L-NaOH (1.5 mL) was added to the solution at 25°C. The mixture was stirred at 50°C for 1.5 hours. The reaction mixture was evaporated in vacuo , the resulting residue was poured into a mixture of water and AcOEt. The pH of the aqueous layer was adjusted to ca.5 with lmol/L hydrochloric acid. The organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure to give (2E)- 3-(6-{[(3R)-l-(cyclohexylcarbonyl)-3-pyrrolidinyl]amino}-3- . pyridinyl)acrylic acid (250 mg, 97%) as powder. MASS(API-ES); 344 (M+H)+ Free 1H-NMR ( 200MHz), (DMSO-d6, δ): 1.05 - 1.77 ( 1OH, m) , 1.78 - 2.47 ( 3H, m), 3.10 - 3.90 ( 4H, m) , 4.24 - 4.57 ( IH, m) , 6.25 ( IH, d, J = 16Hz ), 6.54 ( IH, dd, J = 2.2Hz, J = 8.8Hz ), 7.30 - 7.45 ( IH, m), 7.46 ( IH, d, J = 16Hz ), 7.79 ( IH, d, J = 8.8Hz ), 8.22 ( IH, d, J = 2.2Hz ).

Preparation 683 To a stirred solution of 6-(2,3~dihydro-lH-inden~2- ylamino)nicotinaldehyde (160 mg) and malonic acid (84 mg) in pyridine ( 6 mL) was added piperidine (0.01 mL), and the mixture was stirred at 100°C for 2 hours. The solvent was evaporated in vacuo and the resulting powder was collected by filtration to give (2E)-3-[6-(2,3-dihydro-IH-inden-2-ylamino)-3-pyridinyl]acryl ic acid (190 mg) as a pale yellow powder. ' 1H-NMR (300 MHz, DMSO-d6) (52.83, (2H, dd, J=16, 6 Hz),3.29 (2H, dd, J=16, 7 Hz),4.64 (IH, m),6.24 (IH, d, J=16 Hz),6.52 (IH, d, 3=9 Hz),7.10-7.29 (4H, m),7.4-7.52 (2H, m),7.77 (IH, dd, J=9, 2.2 Hz),8.23 (IH, d, J=2.2 Hz),12.06 (IH, br) ; MS (ES+) m/z 281.

The following compounds were obtained in a similar manner to that of Preparation 683. Preparation 684 (2E)-3-(6-{{ (IR,2R)-2-(benzyloxy)cyclopentyl]amino}-5-chloro-3- pyridinyl)acrylic acid 1H-NMR (300 MHz, CDCl3)S1.50 (IH, m),1.68-2.06 (4H, m),2.33 (IH, m),3.87 (IH, m),4.49 (IH, m),4.67 (2H, s),5.21 (IH, d, J=7 Hz),6.23 (IH, d, J=16 Hz),7.23-7.38 (5H, m),7.65 (IH, d, J=16 Hz),7.68 (IH, d, J=I.8 Hz),8.18 (IH, d, J=I.8 Hz); MS (ES+) m/z 373.

Preparation 685 (2E)-3-(5-chloro-6-{[(IS,2R)-2-phenylcyclopropyl]amino}-3- pyridinyl)acrylic acid 1H-NMR (300 MHz, .CDCl3) <51.26 (IH, m) ,1.40 (IH, m),2.14 (IH, ddd, J=9, 6, 3 Hz),3.09 (IH, m),5.65 (IH, d, J=3 Hz),6.25 (IH, d, J=15.7 Hz),7.17-7.36 ' (5H, m),7.64 (IH, d, J=15.7 Hz),7.70 (IH, d, J=2 Hz),8.24 (IH, d, J=2 Hz); MS (ES+) m/z 315.

Preparation 686' (2E)-3-{6-[ (2-benzylphenyl)amino]-5-chloro-3-pyridinyl}acrylic acid xH-NMR (300 MHz, DMSO-d6) <53.92 (2H, s),6.44 (IH, br),7.07-7.30 (8H, m),7.39 (IH, br),7.45 (IH, d, J=8 Hz) ,8.08-8.25 (3H, m); MS (ES+) m/z 365.

Preparation 687 (2E)-3-[5-chloro-6-({2-[ (cyclohexylcarbonyl)amino]phenyl}amino)-3- pyridinyl]acrylic acid 1H-NMR (300 MHz, DMSO-d6) 61.10-1.86 (1OH, m),2.41 (IH, m),6.49 (IH, d, J=16 Hz),7.11-7.30 (3H, m),7.48 (IH, d, J=16 Hz),7.77 (IH, d, J=7.5 Hz),8.24 (IH, d, J=I Hz),8.26 (IH, d, J=I Hz),8.36 (IH, s),9.93 (IH, s),12.28 (IH, br-s); MS (ES+) m/z 400.

Preparation 688 (2E)-3-[5-chloro-6-({3-[(cyclohexylcarbonyl)amino]phenyl}ami no)-3- pyridinyl]acrylic acid 1H-NMR (300 MHz, DMSO-d6) δ1.13-1.48 (5H, m),1.58-1.84 (5H, m),2.33 (IH, m),6.51 (IH, d, J=16 Hz) ,7.16-7.34 (3H, m),7.52 (IH, d, J=16 Hz),7.95 (IH, s),8.25 (IH, d, J=2 Hz),8.33 (IH, d, J=2 Hz),8.70 (IH, s),9.80 (IH, s); MS (ES+) m/z 400.

Preparation 689 A mixture of ethyl (2E)-3-{5-chloro-6-[(3R)-3-pyrrolidinylamino]- 3-pyridinyl}acrylate dihydrochloride (2.Og), trans-4-{[(tert- butoxycarbonyl)amino]methyl}cyclohexanecarboxylate (1.68g), HOBt (880mg) and WSCD (1.26g) in dichloromethane (40ml) and Et3N (1.51ml) (2.0eq) was stirred at room temperature for 8 hours. After then, water was added and the reaction mixture was extracted with dichloromethane (twice) . Combined organic layer was washed with water(twice) and brine, dried over MgSO4, filtered and evaporated. Residue was column chromatographed on silica gel to give 2.85g (98%) of ethyl (2E)-3-[6-({(3R)-1-[(trans-4-{[ (tert- butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-3- pyrrolidinyl}amino)-5-chloro-3-pyridinyl]aerylate. MASS (ESI+): m/z = 557.2 (M+Na) . 1HNMR ( 400MHz, CDCl3): δ 0.8 - 2.4 ( 12H, m) , 1.43 and 1.44 ( 9H, s), 1.33 ( 3H, t, J = 7.1Hz ), 2.8 - 4 ( 6H, m) , 4.24 ( IH, t, J = 7.1Hz ), 4.25 ( IH, t, J = 7.1Hz ), 4.53 - 4.8 ( 2H, m) , 5.26 ( IH, dd, J = 6.4 ,20Hz), 6.25 ( IH, dd, J = 6.6 ,16Hz), 7.54 ( IH, dd, J = 4.6 ,16Hz), 7.69 ( IH, dd, J = 2 ,7.9Hz), 8.15 ( IH, dd, J = 2 ,7.6Hz). Preparation 690 4NHC1/Dioxane (14ml ) was added to ethyl (2E)-3-[6-({(3R)-l- [ (trans-4-{[ (tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]- 3-pyrrolidinyl}amino)-5-chloro-3-pyridinyl]acrylate (3.Og) under ice cooling. After 2 hours, IPE was added to this reaction mixture. The mixture was decantated and dioxane and IPE was separated. Residue was evaporated under reduced pressure to give 2.8Og (98%) of ethyl (2E)-3-{6-[( (3R)-l-{[trans-4- (aminomethyl)cyclohexyl]carbonyl}-3-pyrrolidinyl)amino]-5-ch loro-3- pyridinyl}aerylate dihydrochloride as an amorphous. MASS (ESI+): m/z = 435.2 (M+l). 1HNMR ( 400MHz, CDCl3): <5 0.90 - 2.80 ( 12H, m) , 1.24 ( 3H, t, J = 7.1Hz ), 2.94 - 3.88 ( 6H, m) , 4.16 ( 2H, q, J = 7.1Hz ), 4.54 and 4.68 ( IH, br.s), 6.53 ( IH, dd, J = 3.2,,15.9Hz), 7.54 ( IH, dd, J = 2.6 ,15.9Hz), 7.9 - 8.02 ( 2H, m) , 8.17 ( IH, dd, J = 1.9 ,5.8Hz), 8.33 ( IH, dd, J = 1.9 ,4.8Hz).

Preparation 691 A mixture of ethyl (2E)-3-{6-[ ((3R)-l-{[trans-4- (aminomethyl)cyclohexyl]carbonyl}-3-pyrrolidinyl)amino]-5-ch loro-3- pyridinyl}aerylate dihydrochloride (1.Og) , Formaldehyde (1.0ml) , NaBH(OAc)3 (1.25g) and triethylamine (2.0eq. 398mg, 0.55ml) in dichloromethane (20ml) was stirred at room temperature for 8 hours. After then, water was added and the reaction mixture was extracted with dichloromethane (twice) . Combined organic layer was washed with sat. sodium bicarbonate and water, and dried over MgSO4, filtered and evaporated. Residue was column chromatographed on silica gel to give 660mg (72%) of ethyl (2E)-3-(5-chloro-6-{[(3R)-l-({trans-4- [ (dimethylamino)methyl]cyclohexyl}carbonyl)-3-pyrrolidinyl]am ino}- 3-pyridinyl)aerylate. MASS (ESI+): m/z = 463.3 (M+l). 1HNMR ( 400MHz): δ 0.80 - 2.45 ( 14H, m) , 1.33 ( 3H, t, J = 7.2Hz ), 1.33 ( 3H, t, J = 7.1Hz ), 2.23 and 2.24 ( 6H, s), 3.36 - 4.01 ( 4H, m), 4.25 ( IH, q, J = 7.2Hz ), 4.26 ( IH, q, J = 7.1Hz ), 4.6 - 4.75 ( IH, m), 5.26 ( IH, dd, J = 6.5 ,21.2Hz), 6.25 ( IH, dd, J = 6 ,15.9Hz), 7.54 ( IH, dd, J = 4 ,15.9Hz), 7.69 ( IH, dd, J = 2 ,7.7Hz), 8.15 ( IH, dd, J = 2 ,6.3Hz).

Preparation 692 A mixture of I (610mg) and INNaOH (5ml) in THF (20ml) and MeOH (20ml) was stirred at 60°C for 3 hrs. IN HCl (5ml) was added. The mixture was evaporated under reduced pressure. Toluene was added and evaporated again to give 600mg (quant.) of (2E)-3-(5-chloro-6-{[(3R)-l-({trans-4- [ (dimethylamino)methyl]cyclohexyl}carbonyl)-3-pyrrolidinyl]am ino}- 3-pyridinyl)acrylic acid. This product was used for next transformation. MASS (ESI-): m/z = 433.3 (M-I).

Preparation 693 A mixture of (2E)-3-(5-chloro-6-{[(3R)-l-({trans-4- [ (dimethylamino)methyl]cyclohexyl}carbonyl)-3-pyrrolidinyl]am ino}- 3-pyridinyl)acrylic acid (600mg) , 0-(tetrahydro-2H-pyran-2- yl)hydroxylamine (194mg), HOBt (242mg) and WSCD (321mg) in DMF (40ml) was stirred at room temperature for 8 hours. After then, water was added and the reaction mixture was extracted with dichloromethane (twice). Combined organic layer was washed with water(twice) and brine, dried over MgSO4, filtered and evaporated. Residue was column chromatographed on silica gel to give 530mg (72%) of (2E)-3-(5-chloro-6-{[(3R)-l-({trans-4- [ (dimethylamino)methyl]cyclohexyl}carbonyl)-3-pyrrolidinyl]am ino}- 3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide. " MASS (ESI+): m/z = 534.2 (M+l). 1HNMR ( 400MHz, CDCl3): O 0.82 - 2.44 ( 2OH, m) , 2.23 and 2.24 (6H, s), 3.32 - 4.05 ( 6H, m) , 4.60 - 4.75 ( IH, m) , 5.01 ( IH, br.s), 5.23 ( IH, dd, J = 6.5 ,20.6Hz), 7.56 ( IH, d, J = 5.2Hz ), 7.6 ( IH, d, J = 5.2Hz ), 7.66 ( IH, d, J = 8.8Hz ), 8.16 ( H, d, J = 8.8Hz ) .

Preparation 694 A diisobutylaluminium hydride in toluene solution (4.6 mL) was dropwise added to a solution of ethyl ethyl 5-chloro-6-{[ (IS,2R)-2- phenylcyclopropyl]amino}nicotinate (488 mg) in tetrahydrofuran (15 mL) with stirring at 0 °C under atmospheric pressure of nitrogen, and the reaction mixture was stirred at 0 0C for 1 hour. A methanol (1 mL) was added to a reaction mixture at 0 0C and allowed to warm to room temperature. Tetrahydrofuran (20 mL) and saturated sodium potassium tartarate aqueous solution (5 mL) was added and the resultant mixture was stirred at ambient temperature for 1 hour. The reaction mixture was filtrated and the filtrate was dried over MgSO4. The solvent was evaporated in vacuo and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2:1 v/v) to give (5-chloro-6-{[(lS,2R)-2-phenylcyclopropyl]amino}-3- pyridinyl)methanol (398 mg) . 1H-NMR (300 MHz, CDCl3)Sl.24 (IH, m),1.37 (IH, m),1.62 (IH, t, J=5 Hz),2.10 (IH, m),3.03 (IH, m),4.56 (IH, d, J=5 Hz),5.37 (IH, s),7.16-7.34 (6H, m),7.54 (IH, d, J=2 Hz),8.07 (IH, d, J=2 Hz); MS (ES+) m/z 275.

The following compounds were obtained in a similar manner to that of Preparation 694. Preparation 695 N-(2-{[3-chloro-5-(hydroxymethyl)-2- pyridinyl]amino}phenyl)cyclohexanecarboxamide 1H-NMR (300 MHz, CDCl3) δ1.18-1.38 (3H, m),1.42-1.59 (2H, m),1.68 (IH, m),1.74-1.97 (4H, m),2.28 (IH, m),3.68 (IH, t, J=5.5 Hz),4.54 (2H, d, J=5.5 Hz),7.13 (IH, ddd, 3=1.1, 1.1, 1.5 Hz),7.21 (IH, ddd, 3=1.1, 1.1, 1.5 Hz),7.44 (IH, dd, 3=1.1, 1.5 Hz),7.48 (IH, s),7.65- 7.72 (2H, m),7.99 (IH, d, J=I.8 Hz),8.37 (IH, s); MS (ES+) m/z 360. Preparation 696 {6-[ (2-benzylphenyl)amino]-5-chloro-3-pyridinyl}methanol 1H-NMR (300 MHz, CDCl3)Sl.60 (IH, t, J=5.5 Hz),4.03 (2H, s),4.56 (2H, d, J=5.5 Hz),6.65 (IH, s),7.08-7.36 (8H, m),7.59 (IH, d, J=2 Hz),7.92 (IH, d, J=8 Hz),8.02 (IH, d, 3=2 Hz); MS (ES+) m/z 325.

Preparation 697 A mixture of ethyl (2E)-3-{5-chloro-6-[ (3R)-3-pyrrolidinylamino]- 3-pyridinyl}acrylate dihydrochloride (600mg), cyclohexylacetic acid (255mg), HOBt (264mg) and WSCD (379mg) in dichlroromethane (20ml) was stirred at room temperature for 8 hours. After then, water was added and the reaction mixture was extracted with dichloromethane (twice) . Combined organic layer was washed with water(twice) and brine, dried over MgSO4, filtered and evaporated. Residue was column chromatographed on silica gel to give 630mg (92%) of ethyl (2E)-3-(5-chloro-6-{[ (3R)-l-tcyclohexylacetylJ-S- pyrrolidinyl]amino}-3-pyridinyl)aerylate. MASS (ESI+): m/z = 442.3 (M+Na) . 1HNMR ( 400MHz, CDCl3): δ 0.85 - 1.38 ( 3H, m) , 1.33 ( 3H, t, J = 7.1Hz ), 1.6 - 2.4 ( 12H, m) , 3.35 - 3.95 ( 4H, m) , 4.25 ( IH, q, J = 7.1Hz ), 4.26 ( IH, q, J = 7.1Hz ), 4.61 - 4.75 ( IH, m) , 5.26 ( IH, dd, J = 6.4 ,15.5Hz),, 6.25 ( IH, dd, J = 5.2 ,16Hz), 7.54 ( IH, dd, J = 3.3 ,15.9Hz), 7.69 ( IH, dd, J = 2.1 ,6.4Hz), 8.15 ( IH, dd, J = 2 ,4.7Hz).

Preparation 698 A mixture of ethyl (2E)-3-(5-chloro-6-{[(3R)-I- (cyclohexylacetyl)-3-pyrrolidinyl]amino}-3-pyridinyl)aerylat e (600mg) and IN NaOH (6ml) in THF (20ml) and MeOH (20ml) was stirred at 5Ot: for 2 hrs. IN HCl (6ml) was added. Evaporated under reduced pressure. Added toluene and evaporated to give 550mg of crude (2E)-3-(5- chloro-6-{[(3R)-l-(cyclohexylacetyl)-3-pyrrolidinyl]amino}-3 - pyridinyl)acrylic acid. This product was used for next transformation. MASS (ESI-): m/z = 390.2 (M-I).

Preparation 699 ethyl 6-{[ (3R)-l-benzyl-3-pyrrolidinyl]amino}-5-fluoronicotinate To a solution of ethyl 6-{[ (3R)-1-benzyl-3-pyrrolidinyl]amino}-2- chloro-5-fluoronicotinate (500mg) in ethanol (20 inL) were added ammonium formate (584mg) and 10% Pd/C (300mg) at 25°C and the mixture was heated to reflux with stirring for lhour. After cooling, the catalyst in the reaction mixture was removed by filtration. The filtrate was evaporated in vacuo. To the residue were added CH2Cl2(30ml), ethanol (7mL), and benzaldehyde(140mg) at 25°C. After stirring for 5minutes, sodium triacetoxyborohydride(280mg) was added to the mixture. The reaction mixture was stirred at 25°C for 3hours, and then poured into a mixture of CH2Cl2 and aqueous NaHCO3. The organic layer was separated, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Hg) using a mixed solvent of dichloromethane and MeOH (100:1 to 40:1). The fractions containing the objective compound were collected and evaporated under reduced pressure. Title compound (302mg, 66%) was obtained as colorless syrup. MASS(API-ES); 344 (M+H)+ 1H-NMR ( 200MHz), (DMSO-d6, <5 ) : 1.28 ( 3H, t, J = 7.1Hz ), 1.70 - 1.95 ( IH, m), 2.05 - 2.30 ( IH, m) , 2.35 - 2.70 ( 3H, m) , 2.80 - 2.90 ( IH, m), 3.58 ( 2H, s), 4.24 ( 2H, q, J = 7.1Hz ) , 4.40 - 4.60 ( IH, m), 7.15 - 7.35 ( 5H, m), 7.54 ( IH, d, J = 6.3Hz ), 7.64 ( IH, dd, J = 1.9Hz, J = 12Hz ), 8.41 ( IH, d, J = 1.9Hz-).

Preparation 700 A mixture of m-phenylenediamine (2.00 g) , cyclohexanecarboxylic acid (2.37 g), HOBt (2.75 g) and EDCI (3.9 g) in DMF (20 mL) was stirred at ambient temperature for 2 hours . The reaction mixture was diluted with water and the resulting solid was collected by- filtration. The solid was purified by silica gel column chromatography (hexane / ethyl acetate = 4 / 1 to 1 / 2 v/v) to give N-(3-aminophenyl)cyclohexanecarboxamide (2.2 g) as a white powder. 1H-NMR (300 MHz, CDCl3) δ1.20-1.39 (3H, m),1.44-1.62 (2H, m),1.70 (IH, m),1.77-2.00 (4H, m),2.20 (IH, m),3.68 (2H, s),6.42 (IH, dd, J=8, 2 Hz),6.64 (IH, dd, J=8, 2 Hz),7.06 (IH, dd, J=8, 8 Hz),7.07 (IH, br),7.23 (IH, s); MS (ES+) m/z 219.

The following compound was. obtained in a similar manner to that of Preparation 700. Preparation 701 N-(2-aminophenyl)cyclohexanecarboxamide 1H-NMR (300 MHz, CDCl3) δ1.20-2.06 (1OH, m),2.31 (IH, m),3.83 (2H, br-s),6.74-6.86 (2H, m),7.05 (IH, m),7.10-7.23 (2H, m) ; MS (ES+) m/z 219.

Preparation 702 ethyl (2E)-3-(5-{[(3R)-l-benzyl-3-pyrrolidinyl](tert- butoxycarbonyl)amino}-2-pyrazinyl)acrylate 0.94 M solution. of diisobutylaluminium hydride in hexane (4.82ml) was added dropwise to a solution of methyl 5-{[(3R)-l-benzyl-3- pyrrolidinyl] (tert-butoxycarbonyl)amino}-2-pyrazinecarboxylate (l.Olg)in THF (20ml) with stirred below -60 0C under atmospheric pressure of nitrogen, and the reaction mixture was stirred at -55 to -50 °C for 1 hr. To the reaction mixture was added saturated aqueous ammonium chloride (1.28ml) at the same temperature, then the mixture was stirred at 25 0C for 40 minutes. THF(14ml) and MgSO4(4.36G) were added to the solution, and the mixture was stirred at 25 °C for 15 minutes. The reaction mixture was filtered, and then to the filtrate was added ETHYL (triphenylphosphoranylidene)acetate (1.07g), and the mixture was stirred at 25 0C for 16hr. The reaction mixture was poured into a mixture of AcOEt and 5% aqueous NaCl. The separated organic layer was washed with brine, dried over sodium sulfate and evaporated in vacuo. The resulting residue was purified by column chromatography on silica gel (5Ig) using a mixed solvent of hexane and ethyl acetate(7:2 to 2:1). The fractions containing the objective compound were collected and evaporated under reduced pressure. Title compound (584mg, 53%) was obtained as slightly yellowish oil. MASS(API-ES); 453 (M+H)+ 1H-NMR ( 200MHz), (DMSO-d6, 6): 1.21 - 1.42 ( 13H, m) , 1.88 - 2.30 ( 2H, m), 2.35 - 2.77 ( 3H, m), 3.42, 3.51.( 2H, ABq, J = 13Hz ), 4.24 ( 2H, q, J = 7.1Hz ), 4.66 - 4.88 ( IH, m), 6.94 ( IH, d, J = 16Hz ), 7.03 - 7.33 ( 5H, m) , 7.76 ( IH, d, J = 16Hz ), 8.67 ( IH, d, J = 1.0Hz ), 8.80 ( IH, d, J = 1.0Hz ).

Preparation 703 Palladium(II) acetate (75 mg) and 2,2'-bis(diphenylphosphino)- 1,1'-binaphthalene (313 mg) in dioxane (5 mL) was stirred at ambient temperature for 15 minutes. To this suspension was added 2,6-dichloropyrazine (1.00 g), (3R)-(-)-l-benzyl-3-aminopyrrolidine (1.42 g) , and cesium carbonate(3.28 g), and the mixture was heated at 8OC for 8 hours. The resulting mixture was allowed to cool to ambient temperature, poured into water, and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform / methanol = 96 / 4 v/v) to give N-[(3R)-l-benzyl-3-pyrrolidinyl]-6-chloro-2- pyrazinamine (1.00 g) as a yellow solid. 1H-NMR (300 MHz, CDCl3)S1.67 (IH, m),2.30-2.44 (2H, m),2.64 (IH, dd, J=IO, 4 Hz),2.68 (IH, dd, J=IO, 5.5 Hz),2.89 (IH, m),3.62 (IH, d, J=13 Hz),3.66 (IH, d, J=13 Hz),4.38 (IH, m),5.09 (IH, d, J=8 Hz),7.22-7.38 (5H, m),7.71 (IH, s),7.77 (IH, s); MS (ES+) m/z 289.

The following compounds were obtained in a similar manner to that of Preparation 703. Preparation 704 ethyl (2E)-3-(5-{[2-(l-piperidinyl)phenyl]amino}-2- pyrazinyl)acrylate 1H-NMR (300 MHz, CDCl3)Sl.34 (3H, t, J=7 Hz),1.63 (2H, m) ,1.69-1.80 (4H, m),2.79-2.88 (4H, m),4.27 (2H, q, J=7 Hz),6.78 (IH, d, J=15.5 Hz),7.04 (IH, ddd, J=7.5, 7.5, 1.5 Hz) ,7.11-7.20 (2H, m),7.63 (IH, d, J=15.5 Hz),8.19-8.24 (3H, m),8.28 (IH, dd, J=7.5, 1.5 Hz); MS (ES+) m/z 353.

Preparation 705 ethyl (2E)-3-[4-({2- [ (cyclohexylcarbonyl)amino]phenyl}amino)phenyl]acrylate 1H-NMR (300 MHz, CDCl3) 01.18-1.38 (5H, m),1.33 (3H, t, J=7 Hz),1.42 (IH, m),1.65 (IH, m) ,1.72-1.91 (4H, m),2.20 (IH, m),4.24 (2H, q, J=7 Hz),6.08 (IH, s),6.27 (IH, d, J=15.7 Hz),6.75 (2H, d, J=8.5 Hz),7.12-7.22 (2H, m),7.31 (IH, m),7.38 (2H, d, J=8.5 Hz),7.53 (IH, s),7.61 (IH, d, J=15.7 Hz),7.82 (IH, m); MS (ES+) m/z 393.

Preparation 706 ethyl 3-(5-{[ (3R)-1-benzyl-3-pyrrolidinyl] (tert- butoxycarbonyl)amino}-2-pyrazinyl)-2-fluoroacrylate(E,Z-Mixt ure) 0.94 M solution of diisobutylaluminium hydride in hexane (5.79ml) was added dropwise to a solution of methyl 5-{[ (3R)-l-benzyl-3- pyrrolidinyl] (tert-butoxycarbonyl)amino}-2-pyrazinecarboxylate (l.lδg) in THF (25ml) with stirred below -60 °C under atmospheric pressure of nitrogen, and the reaction mixture was stirred at -55 to -50 °C for 1 hr. To the reaction mixture was added saturated aqueous ammonium chloride (1.54ml) at the same temperature, then the mixture was stirred at 25 0C for 40 minutes. THF(15ml), MgSO4(7G) and Na2SO4(15g)were added to the solution, and the mixture was stirred at 25 0C for 15 minutes. The reaction mixture was filtered, the filtrate was Filtrate(A). On the other hand, to an ice-cooled solution of ethyl (diethoxyphosphoryl)(fluoro)acetate (970mg) in THF(2ImI) was added MgBr2(885mg) , and triethylamine(0.614ml) , then the mixture was stirred at 50 °C for 2hours. The reaction mixture was poured into a mixture of AcOEt and 5% aqueous NaCl. The separated organic layer was washed with brine, dried over sodium sulfate and evaporated in vacuo. The resulting residue was purified by column chromatography on silica gel (2Og) using a mixed solvent of hexane and ethyl ' acetate(2:l to 1:1). The fractions containing the objective compound were collected and evaporated under reduced pressure. Title compound (674mg, 50%) was obtained as oil. MASS(API-ES); 471 (M+H)+

Preparation 707 A mixture of N-[ (3R)-l-benzyl-3-pyrrolidinyl]-6-chloro-2- pyrazinamine (980 mg) , di-tert-butyl dicarbonate (1.48 g) and 4- dimethylaminopyridine (83 mg) in acetonitrile(20 mL) was stirred at 100 °C for 3 days. The reaction mixture was poured into brine and extracted with ethyl acetate. The organic phase was washed with aqueous ammonium chloride, aqueous sodium hydrogen carbonate, and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane / ethyl acetate=75 / 25) to give tert-butyl [(3R)-l-benzyl-3- pyrrolidinyl] (6-chloro-2-pyrazinyl)carbamate (925 mg) as a pale yellow oil. 1H-NMR ( 300 MHz , CDCl3) δ 1.44 ( 9H, s ) , 1.90-2. 11 ( 2H, m) , 2. 26 ( IH, m) , 2 .58-2. 78 ( 3H, m) , 2.88 ( IH, m) , 3.53 ( IH, d, J=13 Hz ) , 3.62 ( IH, d, J=13 Hz ) , 4.92 ( IH, m) , 7. 17-7.36 ( 5H, m) , 8. 35 ( IH, s ) , 8. 51 ( IH, s ) ; MS (ES+ ) m/z 389.

The following compound was obtained in a similar manner to that of Preparation 336. ! Preparation 708 tert-butyl [ (3R)-l-cyclopentyl-3-pyrrolidinyl] (5-{(IE)-3-oxo-3- [ (tetrahydro-2H-pyran-2-yloxy)amino]-l-propen-l-yl}-2- pyridinyl)carbamate 1H-NMR (300 MHz, DMSO-d6) <51.20-1.78 (14H, m),1.38 (9H, s),1.82- 2.15 (2H, m),2.20-2.53 (4H, m),3.54 (IH, m),3.96 (IH, m),4.72 (IH, m),4.92 (IH, m),6.58 (IH, d, J=16 Hz),7.36 (IH, d, J=7 Hz),7.53 (IH, d, J=16 Hz),8.01 (IH, dd, J=7, 2 Hz),8.63 (IH, d, J=2 Hz),11.32 (IH, br-s ) ; MS (ES+) m/z 501.

Preparation 709 To a stirred solution of l-(bromomethyl)-2-nitrobenzene (2.10 g) in DMF (20 mL) was added pyrrolidine (0.95 mL) and N,N- diisopropylethylamine (2.54 mL), and the mixture was stirred at 60°C for 24 hours. The resulting mixture was poured into ethyl acetate and brine. The organic phase was separated and washed with brine, dried over sodium sulfate. The solvent was evaporated in vacuo and the residue was purified by silica gel column chromatography to give l-(2-nitrobenzyl)pyrrolidine (1.92 g) as a pale yellow oil. 1H-NMR (300 MHz, CDC13) <51.71-1.83 (4H, m),2.46-2.57 (4H, m),3.93 (2H, s),7.37 (IH, ddd, J=8, 7.5, 1.5 Hz),7.55 (IH, ddd, J=8, 7.5, 1.5 Hz),7.69 (IH, br-d, J=8 Hz),7.85 (IH, dd, J=8, 1.5 Hz); MS (ES- ) m/z 205.

Preparation 710 A mixture of (2E)-3-(5-chloro-6-{[ (3R)-I-(cyclohexylacetyl)-3- pyrrolidinyl]amino}-3-pyridinyl)acrylic acid (550mg) , O- (tetrahydro-2H-pyran-2-yl)hydroxylamine (198mg), HOBt (247mg) and WSCD (218mg) in DMF (40ml) was stirred at room temperature for 8 hours. After then, water was added and the reaction mixture was extracted with dichloromethane (twice) . Combined organic layer was washed with water(twice) and brine, dried over MgSO4, filtered and evaporated. Residue was column chromatographed on silica gel to give 680mg (99%) of (2E)-3-(5-chloro-6-{[(3R)-l-(cyclohexylacetyl)-3- pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2- yloxy)acrylamide. MASS (ESI+): m/z = 513.3 (M+Na) . 1HNMR ( 400MHz, CDCl3): δ 0.85 - 1.35 ( 5H, m) , 1.55 - 2.41 ( 15H, m), 3.35 - 4.05 ( 6H, m) , 4.60 - 4.73 (IH, m) , 4.99 ( IH, br.s ), 5.19 - 5.28 ( IH, m ), 4.61 - 4.75 ( IH, m) , 7.56 - 7.70 ( 2H, m) , 8 .02 ( IH, s ) , 8. 16 ( IH, s ) , 8.48 - 8.52 ( IH, m) .

Preparation 711 ethyl (2E)-3-(6-{[(3R)-l-benzyl-3-pyrrolidinyl]amino}-5-fluoro-3- pyridinyl)aerylate To an ice-cooled suspension of sodium hydride(38.5mg) in THF(IOmI) was added ethyl (diethoxyphosphoryl)acetate (206mg), and the mixture was stirred at 24 0C for 40 minutes. To the mixture was added 6-{[ (3R)-1-benzyl-3-pyrrolidinyl]amino}-5- fluoronicotinaldehyde(250mg) at 24 0C, the reaction mixture was stirred at same temperature for 30 minutes. The reaction mixture was poured into a mixture of AcOEt and 5% aqueous NaCl. The separated organic layer was washed with brine, dried over sodium sulfate and evaporated in vacuo. The resulting residue was purified by column chromatography on silica gel (8.2g) using a mixed solvent of CH2Cl2 and MeOH(100:1 to 35:1). The fractions containing the objective compound were collected and evaporated under reduced "pressure. Title compound (lllmg, 36%) was obtained as oil. MASS(API-ES); 370 (M+H)+ 1H-NMR ( 200MHz), (DMSO-d6, δ ) : 1.23 ( 3H, t, J = 7.0Hz ), 1.45 - 2.70 ( 5H, m), 2.80 - 2.90 ( IH, m) , 3.57 ( 2H, s), 4.15 ( 2H, q, J = 7.0Hz ), 4.35 - 4.60 ( IH, m), 6.41 ( IH, d, J = 16Hz ), 7.15 - 7.40 ( 6H, m), 7.53 ( IH, d, J = 16Hz ), 7.84 ( IH, dd, J = 1.1Hz, J=13Hz), 8.08 ( IH, d, J = 1.1Hz ).

Preparation 712 ethyl (2E)-3-(5-{[(3R)-l-benzyl-3-pyrrolidinyl](tert- butoxycarbonyl)amino}-2-pyrazinyl)acrylate 0.94 M solution of diisobutylaluminium hydride in hexane (38.3ml) was added dropwise to a solution of methyl 5-{[ (3R)-l-benzyl~3- pyrrolidinyl] (tert-butoxycarbonyl)amino}-2-pyrazinecarboxylate (8.42g) in THF (170ml) with stirred below -60 0C under atmospheric pressure of nitrogen, and the reaction mixture was stirred at -55 to -50 °C for 1 hr. To the reaction mixture -was added saturated aqueous ammonium chloride (10.2ml) at the same temperature, then the mixture was stirred at 25 0C for 40 minutes. THF(60ml) and MgSO4(34.IG) were added to the solution, and the mixture was stirred at 25 °C for 15 minutes. The reaction mixture was filtrated, the filtrate was Filtrate(A) . On the other hand, to an ice-cooled suspension of sodium hydride(938mg) in THF(9OmI) was added ethyl (diethoxyphosphoryl)acetate (5.26g), and the mixture was stirred at 250C for lhr. To the mixture was added Filtrate (A) at 25 0C, the reaction mixture was stirred at same temperature for 30minutes. The reaction mixture was poured into a mixture of AcOEt and 5% aqueous NaCl. The separated organic layer was washed with brine, dried over sodium sulfate and evaporated in vacuo. The resulting residue was purified by column chromatography on silica gel (116g) using a mixed solvent of hexane and ethyl acetate(5:l to 1:1). The fractions containing the objective compound were collected and evaporated under reduced pressure. Title compound (6.74g, 73%) was obtained as slightly yellowish oil. MASS(API-ES); 453 (M+H)+, 1H-NMR ( 200MHz), (DMSO-d6, <5 ) : 1.24 - 1.45 ( 13H, m) , 1.90 - 2.30 ( 2H, m), 2.35 - 2.80 ( 3H, m), 3.42, 3.51 ( 2H, ABq, J = 13Hz ), 4.24 ( 2H, q, J = 7.1Hz ), 4.65 - 4.90 ( IH, m) , 6.94 ( IH, d, J = 16Hz ), 7.00 - 7.30 ( 5H, m), 7.76 ( IH, d, J = 16Hz ), 8.67 ( IH, d, J = 1.0Hz ), 8.80 ( IH, d, J = 1.0Hz- ).

Preparation 713 ethyl 6-{[ (3R)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]amino}-5- fluoronicotinate To a solution of ethyl 6-{[(3R)-I-benzyl-3-pyrrolidinyl]amino}-2- chloro-5-fluoronicotinate (1.43g) in ethanol (30 mL) were added ammonium formate (1.67g) and 10% Pd/C (600mg) at 25°C and the mixture was heated to reflux with stirring for 30minutes. After cooling, the catalyst in the reaction mixture was removed by filtration. The filtrate was evaporated in vacuo. To the residue were added CH2Cl2(15ml) , ethanol (3mL), di~tert~butyl dicarbonate(830mg) , and N,N-diisopropylethylamine(0.66ml) at 25°C. After stirring for 5minutes, sodium triacetoxyborohydride(280mg) was added to the mixture. The reaction mixture was stirred at 25°C for 2hours, and then evaporated under reduced pressure. The residue was poured into a mixture of ethyl acetate, THF and water. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (34g) using a mixed solvent of hexane and ethyl acetate (4:1 to 3:1). The fractions containing the objective compound were collected and evaporated under reduced pressure. Title compound (1.088g, 81%) was obtained as colorless syrup. MASS(API-ES); 354 (M+H)+, 1H-NMR ( 200MHz), (DMSO-d6, <5) : 1.29 ( 3H, t, J = 7.1Hz ), 1.39 ( 9H, s), 1.80 - 2.30 ( 2H, m), 3.10 - 3.70 ( 4H, m) , 4.26 ( 2H, q, J = 7.1Hz ), 4.45 - 4.65 ( IH, m) , 7.67 ( IH, d, J = 6.8Hz ), 7.69 ( IH, dd, J = 1.7Hz, J = 12Hz ), 8.46 ( IH, d, J = 1.7Hz ) .

Preparation 714 tert-butyl (3R)-3-({5-[(lE)-3-ethoxy-3-oxo-l-propen-l-yl]-3-fluoro- 2-pyridiny1}amino)-1-pyrrolidinecarboxylate Tert-butyl (3R)-3-{[3-fluoro-5-(hydroxymethyl)-2-pyridinyl]amino}- l-pyrrolidinecarboxylate(990mg) and activated MnO2 (2.76g) in ethyl acetate (20ml) were stirred at 75 °C for 1 hour. After removal of the insoluble material by filtration, the filtrate was evaporated in vacuo to give syrup (A) . On the other hand, to an ice-cooled suspension of sodium hydride(159mg) in THF(2OmI) was added ethyl (diethoxyphosphoryl)acetate (855mg), and the mixture was stirred at 24 0C for 60minutes. To the mixture was added syrup (A) at 24 °C, the reaction mixture was stirred at same temperature for 30minutes. The reaction mixture was poured into a mixture of AcOEt and 5% aqueous NaCl. The separated organic layer was washed with brine, dried over sodium sulfate and evaporated in vacuo. The resulting residue was purified by column chromatography on silica gel (19g) using a mixed solvent of hexane and ethyl acetate(5:l to 3:2). The fractions containing the objective compound were collected and evaporated under reduced pressure. Title compound (1.09g, 90%) was obtained as colorless oil. MASS(API-ES); 380 (M+H)+, 1H-NMR ( 200MHz), (DMSO-d6, δ ) : 1.24 ( 3H, t, J = 7.1Hz ), 1.39 ( 9H, s), 1.80 - 2.30 ( 2H, m) , 3.10 - 3.70 ( 4H, m) , 4.16 ( 2H, q, J = 7.1Hz ), 4.35 - 4.65 ( IH, m), 6.46 ( IH, d, J = 16Hz ), 7.42 ( IH, d, J = 5.9Hz ), 7.56 ( IH, dd, J = 1.8Hz, J = 16Hz ), 7.89 ( IH, dd, J = 1.5Hz, J = 13Hz ), 8.14 ( IH, d, J = 1.5Hz ).

Preparation 715 To a stirred solution of tert-butyl [(3R)-l-benzyl-3- pyrrolidinyl] (6-chloro-2-pyrazinyl)carbamate (910 mg) in DMF (15 mli) was added ethyl aerylate (1.27 mL), paliadium(II) acetate (26 mg) , tris(2-methylphenyl)phosphine (107 mg) , and N,N- diisopropylethylamine (1.22 mL). The mixture was stirred in the sealed tube at 150°C for 3 days. The resulting mixture was allowed to cool to ambient temperature, poured into water, and extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SC>4, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of chloroform and methanol (96:4 v/v) to give ethyl (2E)-3-(6-{[(3R)- 1-benzyl-3-pyrrolidinyl] (tert-butoxycarbonyl)amino}-2- pyrazinyl)aerylate (755 mg) as a pale yellow foam. 1H-NMR (300 MHz, CDCl3) <5l.36 (3H, t, J=7 Hz),1.45 (9H, s),2.12 (IH, m),2.27 (IH, m) ,2.58-2.70 (2H, m),2.77 (IH, dd, J=9, 7 Hz),2.94 (IH, dd, J=9, 8 Hz),3.54 (IH, d, J=13 Hz),3.63 (IH, d, J=13 Hz),4.30 (2H, q, J=7 Hz),4.95 (IH, m),6.96 (IH, d, J=15.5 Hz) ,7.04-7.49 (5H, m),7.64 (IH, d, J=15.5 Hz),8.38 (IH, s),8.54 (IH, s); MS (ES+) m/z 453.

Preparation 716 A mixture of (2R)-2-[(tert-butoxycarbonyl)amino]-4- (methylthio)butanoic acid(4.57 g), cyclohexanemethylamine (2.28 g), HOBt (2.72 g) , and EDCI (3.87 g) in DMF (50 mL) was stirred at ambient temperature for 15 hours. The reaction mixture was poured into a mixture of AcOEt-H2O and the organic layer was washed with aqueous ammonium chloride, aqueous sodium hydrogen carbonate, and brine and dried over MgSO4 . The solvent was evaporated in vacuo and the residue was crystallized from ethyl acetate and hexane to give tert-butyl [(IR)-1-{[(cyclohexylmethyl)amino]carbonyl}-3- (methylthio)propyl]carbamate (5.65 g) . 1H-NMR (300 MHz, CDCl3) <50.84-1.00 (2H, m),1.08-1.32 (3H, m),1.45 (3x3H, s),1.45 (IH, m),1.60-1.77 (5H, m),1.92 (IH, m),2.09 (IH, m),2.11 (3H, s),2.45-2.65 (2H, m) ,3.02-3.18. (2H, m),4.21 (IH, m),5.14 (IH, m),6.22 (IH, br-t, J=6 Hz); MS (ES+) m/z 345.

Preparation 717 1) A solution of methyl 5-chloro-2-pyrazinecarboxylate (1Og) in THF (100ml) was cooled under -5°C by NaCl-ice bath. To this solution was added dropwise DIBAL (60ml) for 15min under -8-0°C. After stirring for 30min under 0 °C , the reaction mixture was quenched with EtOH (17ml). 2) To a solution of ethyl (diethoxyphosphoryl)acetate (14.2g) in THF (100ml) was added portionwise NaH under ice-cooling. The reaction mixture was allowed stirred at 30°C for lhr. To a solution of 1) was added dropwise 2) under 0°C. After stirring for lhr, the reaction mixture was added to water and EtOAc, adjusted pH at 3.0. Aqueous layer was separated and extracted twice with EtOAc, washed with water, dried over MgSO4, filtered and evaporated. The residue was column chromatographed on silica gel(Yamazen HPLC). Desired Fraction was evaporated and hexane was added. . Crystal was filtered and dried to give 3.15g of ethyl (2E)-3- (5-chloro-2-pyrazinyl)acrylate. Combined unpure fractions was chromatographed to give additional 1.6g of ethyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate. 1HNMR ( 400MHz, CDCl3): 6 1.35 (3H, t, J=7.1Hz), 4.30 (2H, q, J=7 . 1Hz ) , 7.00 ( IH, d, J=15. 7Hz ) , 7.66 ( IH, d, J=15.7Hz ) , 8.43 ( IH, d, J=I .3Hz ) , 8.60 ( IH, d, J=I .3Hz ) .

Preparation 718 To an ice-cooled solution of tert-butyl (3R)-3-({5-[(lE)-3-ethoxy- 3-oxo-1-propen-1-yl]-3-fluoro-2-pyridinyl}amino)-1- pyrrolidinecarboxylate (11.6g) in EtOH (70ml) was added solution of 4N HCl in dioxane(76.4ml) . The mixture was stirred at 24°C for 3.5 hr, and evaporated under reduced pressure. The residue was poured into a mixture of water and CH2Cl2. The pH of the aqueous layer was adjusted to ca.9 with NaHCO3. The organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure to give ethyl (2E)-3-{5-fluoro-6-[ (3R)-3-pyrrolidinylamino]-3- pyridinyl}acrylate(7.Ig, 83%) as colorless powder. MASS(API-ES); 280 (M+H)+, 1H-NMR ( 200MHz), (DMSO-d6, <5 ) : 1.23 ( 3H, t, J = 7.1Hz ), 1.50 - 2.20 ( 2H, m), 2.60 - 3.03 ( 4H, m) , 3.18 ( IH, br) , 4.16 ( 2H, q, J = 7.1Hz ), 4.30 - 4.50 ( IH, m), 6.42 ( IH, d, J = 16Hz ), 7.19 ( IH, d, J = 6.4Hz ), .7.55 ( IH, dd, J = 2.0Hz, J = 16Hz )„ 7.84 ( IH, dd, J = 1.8Hz, J = 13Hz ), 8.11 ( IH, d, J = 1.8Hz ) .

Preparation 719 ethyl (2E)-3-[5-fluoro-6-({(3R)-l-[2-(lH-pyrazol-l-yl)ethyl]-3- pyrrolidinyl}amino)-3-pyridinyl]aσrylate To a mixed solution of l-(2,2-dimethoxyethyl)-lH-pyrazole (705mg) in dioxane ( 3mL) and water( 3ml) were added 4N-HC1 in 1,4-dioxane solution (3.01ml) at 25°C and the mixture was heated at 600C with stirring for 40minutes. After cooling, to the reaction mixture was added ethyl acetate, THF, and water. The pH of the aqueous layer was adjusted to ca.3 with NaHCO3. The organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure. To the resulting residue were added CH2Cl2(6ml), ethyl (2E)-3-{5-fluoro-6- [(3R)-3-pyrrolidinylamino]-3-pyridinyl}acrylate (420mg) at 250C. After stirring for 5minutes, sodium triacetoxyborohydride(637mg) was added to the mixture. The reaction mixture was stirred at 25°C for 5hours, and then poured into a mixture of CH2CI2 and aqueous NaHCO3. The organic layer was separated, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel using a mixed solvent of dichloromethane and MeOH (60:1 to 20:1). The fractions containing the objective compound were collected and evaporated under reduced pressure. Title compound (165mg, 29%) was obtained as colorless oil. MASS(API-ES); 374 (M+H)+ 1H-NMR ( 200MHz), (DMSO-d6, <5 ) : 1.23 ( 3H, t, J = 7.0Hz ), 1.67 - 1.92 ( IH, m), 2.00 - 2.25 ( IH, m) , 2.40 - 2.95 ( 6H, m) , 3.95 - 4.28 ( 4H, m), 4.34 - 4.58 ( IH, m) , 6.20 ( IH, t, J = 2.0Hz ), 6.43 ( IH, d, J = 16Hz ), 7.23 ( IH, d, J = 6.4Hz ), 7.40 ( IH, d, J = 2.0Hz ), 7.55 ( IH, dd, J = 1.8Hz, J = 16Hz ), 7.74 ( IH, d, J = 2.0Hz ), 7.85 ( IH, dd, J = 1.6Hz, J = 13Hz ), 8.10 ( IH, d, J » 1.6Hz ).

The following compound was obtained in a similar manner to that of Preparation 336. Preparation 720 N-{2-[(4-{(IE)-3-OXO-3-[(tetrahydro-2H-pyran-2-yloxy)amino]- l- propen-1-yl}phenyl)amino]phenyllcyclohexanecarboxamide 1H-NMR (300 MHz, DMSO-d6) <51.08-1.42 (5H, m),1.46-1.78 (HH, m),2.33 (IH, m),3.52 (IH, m),3.95 (IH, m),4.88 (IH, m),6.26 (IH, d, J=16 Hz),6.80 (2H, d, J=8.5 Hz),7.02-7.19 (2H, m),7.28 (IH, dd, J=7.5, 1 Hz),7.33-7.44 (3H, m),7.59 (IH, dd, J=7.5, 1 Hz),7.71 (IH, s),9.23 (IH, s),11.07 (IH, s); MS (ES-) m/z 462.

The following compound was obtained in a similar manner to that of Preparation 382. Preparation 721 6-[(2-benzylphenyl)amino]-5-chloronicotinaldehyde 1H-NMR (300 MHz, CDCl3) (54.04 (2H, s),7.09 (IH, is) ,7.12-7.41 (8H, m),7.85 (IH, d, J=8 Hz),7.99 (IH, d, J=2 Hz),8.45 (IH, d, J=2 Hz),9.80 (IH, s); MS (ES+) m/z 323. The following compound was obtained in a similar manner to that of Preparation 379. Preparation 722 ethyl 6-{[ (3R)-l-benzyl-3-pyrrolidinyl]amino}-2~chloro-5- 5 fluoronicotinate MASS(API-ES); 378 (M+H)+, 1H-NMR ( 200MHz), (DMSO-d6, <5 ) : 1.28 ( 3H, t, J = 7.1Hz ), 1.70 - 1.95 ( IH, m), 2.05 - 2.30 ( IH, m) , 2.35 - 2.75 ( 3H, m) , 2.80 - 2.90 ( IH, m), 3.50 - 3.70 ( 2H, m) , 4.23 ( 2H, q, J = 7.1Hz ), 10 4.30 - 4.55 ( IH, m) , 7.15 - 7.40 ( 5H, m) , 7.77 ( IH, d, J = HHz ), 7.89 ( IH, d, J = 6.4Hz ).

The following compound was obtained in a similar manner to that of Preparation 336. 15 Preparation 723 tert-butyl (5-{(IE)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1- propen-l-yl}-2-pyrimidinyl) [ (3R)-l-(2-phenylethyl)-3- pyrrolidinyl]carbamate 1H-NMR (300 MHz, CDCl3). <51.47 (3x3H, s),1.56-1.95 (6H, m) ,2.06-2.32 20 (2H, m),2.56-2.84 (7H, m),3.08 (IH, dd, J=8, 8 -Hz),3.68 (IH, m),3.97 (IH, m) ,4.92-5.10 (2H, m),6.46 (IH, br) ,7.13-7.33 (5H, m),7.63 (IH, d, J=15.5 Hz),8.78 (2xlH, s); MS (ES+) m/z 538.

The following compounds were obtained in a similar manner to that 25 of Preparation 414. Preparation 724 (2E)-3-(5-{[2-(l-piperidinyl)phenyl]amino}-2-pyrazinyl)-N- (tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (300 MHz, DMSO-d6) δ1.42-1.76 (12H, m),2.71-2.83 (4H, 30 m),3.52 (IH, m),3.96 (IH, m),4.91 (IH, m),6.74 (IH, d, J=15.5 Hz),7.03-7.10 (2H, m),7.14 (IH, m),7.48 (IH, d, J=15.5 Hz),7.92 (IH, dd, J=6, 3.5 Hz),8.27 (IH, s),8.32 (IH, s),8.78 (IH, s),11.26 (IH, s); MS (ES+) m/z 424.

35. The following compound was obtained in a similar manner to that of Preparation 375. Preparation 725 ethyl (2E)-3-(6-{[ (3R)-1-(cyclohexylcarbonyl)-3- pyrrolidinyl]amino>-5-fluoro-3-pyridinyl)acrylate MASS(API-ES); 390 (M+H)+ 1H-NMR ( 200MHz), (DMSO-d6, <5 ) : 1.05 - 1.79 ( 1OH, m) , 1.24 ( 3H, t, J = 7.1Hz ), 1.80 - 2.55 ( 3H, m), 3.15 - 3.90 ( 4H, m), 4.16 ( 2H, q, J = 7.1Hz ), 4.35 - 4.75 ( IH, m) , 6.46 ( IH, d, J = 16Hz ), 7.38 - 7.50 ( IH, m) , 7.56 ( IH, d, J = 16Hz ), 7.90 ( IH, d, J = 13Hz ), 8.15 ( IH, s ).

The following compound was obtained in a similar manner to that of Preparation 450. Preparation 726 tert-butyl [(3R)-l-(2,3-dihydro-lH-inden-2-yl)-3- pyrrolidinyl]carbamate 1H-NMR (300 MHz, CDCl3) (51.46 (9H, s),1.63 (IH, m), 2.20-2.47 (2H, m), 2.56-2.76 (2H, m), 2.79-2.96 (3H, m) ,2.97-3.11 (3H, m),4.20 (IH, m),4.86 (IH, m), 7.10-7.22 (4H, m) ; MS (ES+) m/z 303.

The following compound was obtained in a similar manner to that of Preparation 452. Preparation 727 (3R)-l-(2,3-dihydro-lH-inden-2-yl)-3-pyrrolidinamine dihydrochloride 1H-NMR (300 MHz, DMSO-d6) δ2.00-2.40 (IH, m) ,3.05-4.32 (HH, m),7.17-7.30 (4H, m),8.59 (2H, br) ; MS (ES+) m/z 203.

The following compound was obtained in a similar manner to that of Preparation 439. Preparation 728 ethyl (2E)-3-(5-{[(3R)-l-(2,3-dihydro-lH-inden-2-yl)-3- pyrrolidinyl ] amino } - 2 -pyrazinyl ) acrylate 1H-NMR (300 MHz, CDCl3)Sl.33 (3H, t, J=7 Hz), 1.75 (IH, m), 2.35-2.50 (2H, m),2.75 (IH, dd, J=IO, 6 Hz), 2.79 (IH, dd, J=IO, 3 Hz), 2.83- 3.19 (6H, m), 4.25 (2H, q, J=7 Hz), 4.51 (IH, m),5.25 (IH, d, J=8 Hz), 6.69 (IH, d, J=15.5 Hz) ,7.10-7.23 (4H, m),7.58 (IH, d, J=15.5 Hz), 7.90 (IH, d, J=I Hz), 8.07 (IH, d, J=I Hz); MS (ES+) m/z 379.

The following compound was obtained in a similar manner to that of Preparation 397. Preparation 729 (2E)-3-(6-{[(3R)-l-( cyclohexylcarbonyl ) - 3 -pyrrolidinyl ] amino } - 5 - f luoro-3-pyridinyl) -N- ( tetrahydro-2H-pyran-2-yloxy)acrylamide MASS(API-ES); 461 (M+H)+, 1H-NMR ( 200MHz), (DMSO-d6, δ): 1.05 - 1.80 ( 16H, m) , 1.82 - 2.55 ( 3H, m), 3.15 - 4.10 ( 6H, m) , 4.35 - 4.70 ( IH, m) , 4.89 ( IH, s), 6.29 ( IH, d, J = 16Hz ), 7.25 - 7.38 ( IH, m) , 7.41 ( IH, d, J = 16Hz ), 7.62 ( IH, d, J = 12Hz ), 8.09 ( IH, s ).

The following compound was obtained in a similar manner to that of Preparation 311. Preparation 730 ethyl (2E)-3-(6-{[(3R)-1-(2,6-difluorobenzyl)-3- pyrrolidinyl]amino}-5-fluoro-3-pyridinyl)acrylate MASS(API-ES); 406 (M+H)+, 1H-NMR ( 200MHz), (DMSO-d6. <5 ) : 1.24 ( 3H, t, J = 7.1Hz ), 1.65 - 1.90 ( IH, m), 2.00 - 2.30 ( IH, m), 2.35 - 2.73 ( 3H, m) , 2.80 - 2.95 ( IH, m), 3.69 ( 2H, s), 4.15 ( 2H, q, J = 7.1Hz ), 4.30 - 4.55 ( IH, m), 6.42 ( IH, d, J = 16Hz ), 7.00 - 7.20 ( 2H, m) , 7.25 - 7.50 ( 2H, m) , 7.53 ( IH, dd, J = 1.9Hz ,J = 16Hz ), 7.84 ( IH, dd, J = 1.7Hz, J=13Hz), 8.09 ( IH, d, J = 1.7Hz ).

The following compound was obtained in a similar manner to that of Preparation 414. Preparation 731 (2E)-3-(5-{[(3R)-l-(2,3-dihydro-lH-inden-2-yl)-3- pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahγdro-2H-pyran-2- yloxy)acrylamide 1H-NMR (300 MHz, CDCl3) 61.52-1.94 (7H, m),2.36-2.50 (2H, m),2.74 ( IH, dd, J=IO , 6 Hz) , 2.78-3.17 ( 7H, m) , 3.65 ( IH, m) , 3.96 ( IH, m) , 4.51 ( IH, m) ,, 5.02 ( IH, m) , 5.33 ( IH, d, J=7 Hz) , 6.70 ( IH, br) , 7.12-7.22 (4H, m) , 7.63 ( IH, d, J=15.5 Hz) , 7.88 ( IH, s) , 8.05 ( IH, s ) ; MS (ES+) m/z 450.

The following compound was obtained in a similar manner to that of Preparation 405. Preparation 732 (2E)-3-(5-{[(3R)-l-(2,3-dihydro-lH-inden-2-yl)-3- pyrrolidinyl]amino}-2-pyrazinyl)acrylic acid 1H-NMR (300 MHz, DMSO-d6) <51.68 (IH, m),2.25 (IH, m),2.44-2.56 (IH, m),2.71-2.90 (4H, m) ,2.94-3.60 (4H, m),4.35 (IH, m),6.46 (IH, d, J=15.3 Hz),7.07-7.22 (4H, m),7.48 (IH, d, J=15.3 Hz),7.92 (IH, d, J=6.5 Hz),8.00 (IH, d, J=I Hz),8.20 (IH, d, J=I Hz); MS (ES+) m/z 351.

The following compound was obtained in a similar manner to that of Preparation 414. Preparation 733 tert-butyl [(3R)-l-cyclohexyl-3-pyrrolidinyl] (5-{(lE)-3-oxo-3- [ (tetrahydro-2H-pyran-2-yloxy)amino]-l-propen-l-yl}-2- pyridinyl)carbamate 1H-NMR (300 MHz, DMSO-d6) δ1.00-2.15 (18H, m),2.30-3.20 (5H, m),3.54 (IH, m),3.96 (IH, m),4.72 (IH, m),4.92 (IH, m),6.59 (IH, d, J=16 Hz),7.36 (IH, d, J=8 Hz),7.53 (IH, d, J=16 Hz),8.01 (IH, d, J=8 Hz),8.63 (IH, s),11.31 (IH, br-s); MS (ES+) m/z 515.

The following compound was obtained in a similar manner to that of Preparation 397. Preparation 734 (2E)-3-(6-{[(3R)-1-(2,6-difluorobenzyl)-3-pyrrolidinyl]amino }-5- fluoro-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamid e MASS(API-ES); 477 (M+H)+, 1H-NMR ( 200MHz), (DMSO-d6, <5 ) : 1.40 - 1.90 ( 7H, m) , 2.00 - 2.28 ( IH, m), 2.30 - 2.75 ( 3H, m) , 2.80 - 3.00 ( IH, m) , 3.40 - 3.60 ( IH, m) , 3.69 ( 2H, s ) , 3.80 - 4.05 ( IH, m) , 4.25 - 4.60 ( IH, m) , 4.88 ( IH, s) , 6.25 ( IH, d, J = 15Hz ) , 7.00 - 7.25 ( 3H, m) , 7.30 - 7.75 ( 3H, m) , 8.03 ( IH, S ) .

The following compounds were obtained in a similar manner to that of Preparation 336. Preparation 735 (2E)-3-(6-{[(3R)-l-benzyl-3-pyrrolidinyl]amino}-5-fluord-3- pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide MASS(API-ES); 441 (M+H)+, 1H-NMR ( 200MHz), (DMSO-d6, <5 ) : 1.40 - 1.95 ( 7H, m) , 2.05 - 2.30 ( IH, m), 2.32 - 2.70 ( 3H, m) , 2.80 - 2.90 ( IH, m), 3.40 - 3.65 ( 3H, m), 3.80 - 4.10 ( IH, m), 4.30 - 4.60 ( IH, m), 4.88 ( IH, s), 6.25 ( IH, d, J = 15Hz ), 7.15 ( IH, d, J = 6.5Hz ), 7.18 - 7.45 ( 6H, m), 7.56 ( IH, d, J = 12Hz ) , 8.02 ( IH, s ) .

Preparation 736 tert-butyl [ (3R) -l- (csyclohexylmethyl) ^3-pyrrolidinyl] ( 5-{ ( lE) -3- oxo-3- [ (tetrahydro-2H-pyran-2-yloxy)amino] -l-propen-l-yl}-2- pyrimidinyl)carbamate 1H-NMR (300 MHz, DMSO-d6) (50.54-0.72 (2H, m),1.00-1.78 (15H, m),1.33 (3x3H, s),1.94-2.14 (4H, m),2.25 (IH, m),2.37-2.58 (2H, m),2.68 (IH, m),3.54 (IH, m),3.96 (IH, m),4.76 (IH, m),4.93 (IH, m),6.70 (IH, d, J=16 Hz),7.51 (IH, d, J=16 Hz),9.01 (2xlH, s),11.41 (IH, s); MS (ES+) m/z 530.

The following compound was obtained in a similar manner to that of Preparation 810. Preparation 737 ethyl (2E)-3-(6-{[l-(4-fluorobenzyl)-4-piperidinyl]amino}-3- pyridinyl)acrylate 1H NMR (DMSO-d6, δ) :1.23 (3H, t, J = 7.4 Hz), 1.26-1.50 (2H, m) , 1.85-1.90 (2H, m), 1.99-2.11 (2H, m) , 2.74-2.80 (2H, m) , 3.45 (2H, s), 3.77-3.90 (IH, m), 4.14 (2H, q, J = 7.4 Hz), 6.29 (IH, d, J = 15.9 Hz), 6.48 (IH, d, J = 7.8 Hz), 7.09-7.18 (3H, m) , 7.30-7.37 ( 2H, m) , 7.48 ( IH, d, J = 15.9 Hz) , 7.76 ( IH, dd, J = 1.9 , 8.0 Hz ) , 8.20 ( IH, d, J = 1.9 Hz ) , Mass (ESI ) : 384 (M+H) + . '

The following compound was obtained in a similar manner to that of Preparation 198. Preparation 738 ethyl (2E)-3-(6-{[l-(cyclohexylmethyl)-4-piperidinyl]amino}-3- pyridinyl)acrylate 1H NMR (DMSO-d6, <5 ) :0.79-0.91 (2H, m) , 1:02-2.15 (17H, m) , 1.23 (3H, t, J = 7.4 Hz), 2.80 (2H, brs), 3.65-3.85 (IH, m) , 4.14 (2H, q, J = 7.4 Hz), 6.30 (IH, d, J = 15.9 Hz), 6.49 (IH, d, J = 8.8 Hz), 7.12 (IH, d, J = 7.2 Hz), 7.49 (IH, d, J = 15.9 Hz), 7.76 (IH, dd, J = 2.2, 8.8 Hz), 8.20 (IH, d, J = 2/2 Hz), Mass (ESI) : 372(M+H)+.

The following compounds were obtained in a similar manner to that of Preparation 862. Preparation 739 (2E)-3-(6-{[l-(4-fluorobenzyl)-4-piperidinyl]amino}-3- pyridinyl)acrylic acid Mass (ESI) : 356(M+H)+.

Preparation 740 (2E)-3-(6-{[l-(cyclohexylmethyl)-4-piperidinyl]amino}-3- pyridinyl)acrylic acid Mass (ESI) : 344(M+H)+.

The following compounds were obtained in a similar manner to that of Preparation 62. Preparation 741 (2E)-3-(6-{[1-(4-fluorobenzyl)-4-piperidinyl]amino}-3-pyridi nyl)-N- (tetrahydro-2H-pyran-2-yloxy)acrylamide MASS(API-ES); 455 (M+H)+. Preparation 742 (2E)-3-(6-{[l-(cyclohexylmethyl)-4-piperidinyl]amino}-3-pyri dinyl)- N-(tetrahydro-2H-pyran-2-yloxy)acrylamide MASS(API-ES); 443 (M+H)+.

The following compound was obtained in a similar manner to that pf Preparation 375. Preparation 743 ethyl (2E)-3-(6-{(tert-butoxycarbonyl) [(3R)-1-(cyclohexylcarbonyl)- 3-pyrrolidinyl]amino}-3-pyridinyl)aerylate MASS(API-ES); 472 (M+H)+ Free 1H-NMR ( 200MHz), (DMSO-d6, <5 ) : 1.10 - 1.80 ( 22H, m) , 1.85 - 2.40 ( 3H, m), 3.00 - 3.90 ( 4H, m) , 4.21 ( 2H, q, J = 7.1Hz ), 4.61 - 4.97 ( IH, m) , 6.78 ( IH, d, J = 16Hz ), 7.38 ( IH, dd, J = 3.4Hz, J = 8.6Hz ), 7.69 ( IH, d, J = 16Hz ), 8.22 ( IH, d, J = 8.6Hz ), 8.73 ( IH, d, J = 3.4Hz ).

The following compound was obtained in a similar manner to that of Preparation 397. i Preparation 744 (2E)-3-(6-{[(3R)-1-(cyclohexylcarbonyl)-3-pyrrolidinyl]amino }-3- pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide MASS(API-ES); 443 (M+H)+ Free 1H-NMR ( 200MHz), (DMSO-d6, <5 ) : 1.03 - 2.57 ( 19H, m) , 3.10 - 4.08 ( 6H, m), 4.20 - 4.60 ( IH, m), 4.88 ( IH, s), 6.23 ( IH, d, J = 15Hz ), 6.55 ( IH, dd, J = 3.2Hz, J = 8.8Hz ), 7.28 ( IH, d, J = 6.7Hz), 7.37 ( IH, d, J = 15Hz ), 7.63 ( IH, d, J = 8.8Hz ), 8.18 ( IH, s ).

The following compounds were obtained in a similar manner to that of Preparation 871. Preparation 745 ethyl 6-{[ (IR,2R)-2-(benzyloxy)cyclopentyl]amino}-5- chloronicotinate 1H-NMR (300 MHz, CDCl3) <5l.37 (3H, t, J=7 Hz),1.51 (IH, m),1.67-2.03 ( 4H, m) , 2.33 ( IH, m) , 3.87 ( IH, m) , 4.34 (2H, q, J= 7 Hz ) , 4.52' ( IH, m) , 4.67 ( IH, d, J=12.7 Hz ) , 4.69 ( IH, d, J=12.7 Hz) , 5.27 ( IH, d, J=7 Hz) , 7.22-7.38 (5H, m) , 8.01 ( IH, d, J=2.2 Hz ) , 8.71 ( IH, d, J=2.2 Hz ) ; MS (ES+) m/z 375.

The following compound was obtained in a similar manner to that of Preparation 361. Preparation 746 [6-(2,3-dihydro-lH-inden-2-ylamino)-3-pyridinyl]methanol 1H-NMR (300 MHz, CDCl3) 02.88 (2H, dd, J=16, 4.5 Hz),3.39 (2H, dd, J=16, 7 Hz),4.54 (2H, s),4.60 (IH, m),4.82 (IH, br-d, J=6 Hz),6.43 (IH, d, J=9 Hz),7.14-7.30 (4H, m),7.49 (IH, dd, J=8.5, 2.5 Hz),8.06 (IH, d, J=2.5 Hz); MS (ES+) m/z 241.

The following compound was obtained in a similar manner to that of Preparation 382. Preparation 747 6-(2,3-dihydro-lH-inden-2-ylamino)nicotinaldehyde 1H-NMR (300 MHz, CDCl3) (52.93 (2H, dd, J=16, 4.5 Hz),3.43 (2H, dd, J=16, 7 Hz),4.75 (IH, br),5.42 (IH, br),6.45 (IH, d, J=8.8 Hz),7.16-7.30 (4H, m),7.90 (IH, dd, J=8.8, 2.2 Hz),8.52 (IH, d, J=2.2 Hz),9.78 (IH, s); MS (ES+) m/z 239.

The following compound was obtained in a similar manner to that of Preparation 414. Preparation 748 (2E)-3-[6-(2,3-dihydro-lH-inden-2-ylamino)-3-pyridinyl]-N- (tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (300 MHz, DMSO-d6) δ1.45-1.78 (6H, m),2.83 (2H, dd, J=16, 5.5 Hz),3.29 (IH, dd, J=16, 7 Hz),3.53 (IH, m),3.95 (IH, m),4.64 (IH, m),4.88 (IH, m),6.22 (IH, br-d, J=16 Hz),6.54 (IH, d, J=8.5 Hz),7.11-7.28 (4H, m) ,7.31-7.45 (2H, m),7.61 (IH, br-d, J=8.5 Hz),8.19 (IH, s),11.16 (IH, br) ; MS (ES+) m/z 380.

The following compound was obtained in a similar manner to that of Preparation 405. Preparation 749 (2E)-3-{4-[(6-methyl-2-pyridinyl)amino]phenyl}acrylic acid 1H-NMR (300 MHz, DMSO-d6) δ2.40 (3H, s),6.33 (IH, d, J=16 Hz),6.67 (IH, d, J=7.5 Hz),6.69 (IH, d, J=7.5 Hz),7.49 (IH, dd, J=7.5, 7.5 Hz),7.51 (IH, d, J=16 Hz),7.57 (2H, d, J=8.5 Hz),7.77 (2H, d, J=8.5 Hz),9.29 (IH, s),12.13 (IH, br); MS (ES+) m/z 255.

The following compound was obtained in a similar manner to that of Preparation 414. Preparation 750 (2E)-3-{4-[ (6-methyl-2-pyridinyl)amino]phenyl}-N-(tetrahydro-2H- pyran-2-yloxy)acrylamide 1H-NMR (300 MHz, DMSO-τd6) δ1.46-1.76 (6H, m),2.39 (3H, s),3.53 (IH, m),3.96 (IH, m),4.90 (IH, m),6.33 (IH, br-d, J=16 Hz),6.66 (IH, d, J=7 Hz),6.68 (IH, d, J=7 Hz) ,7.37-7.54 (4H, m),7.77 (2xlH, d, J=8.5 Hz),9.25 (IH, s),11.12 (IH, s); MS (ES+) m/z 354.

The following compound was obtained in a similar manner to that of Preparation 361. Preparation 751 (6-{[(IR,2R)-2-(benzyloxy)cyclopentyl]amino}-5-chloro-3- pyridinyl)methanol 1H-NMR (300 MHz, CDCl3)Sl.49 (IH, m) ,1.68-2.02 (4H, m),2.31 (IH, m),3.87 (IH, m),4.44 (IH, m),4.54 (2H, s),4.66 (IH, d, J=12 Hz),4.69 (IH, d, J=12 Hz),4.89 (IH, d, J=7.5 Hz) ,7.23-7.42 (4H, m),7.51 (IH, d, J=2 Hz),8.02 (IH, d, 3=2 Hz); MS (ES+) m/z 333.

The following compound was obtained in a similar manner to that of Preparation 382. Preparation 752 6-{[(lR,2R)-2-(benzyloxy)cyclopentyl]amino}-5-chloronicotina ldehyde 1H-NMR (300 MHz, CDCl3)Sl.53 (IH, m) ,1.68-2.06. (4H, m),2.34 (IH, m),3.89 (IH, m),4.56 (IH, m),4.67 (2H, s),5.50 (IH, d, J=7 Hz),7.22-7.38 (5H, m),7.93 (IH, d, 3=2 Hz),8.47 (IH, d, 3=2 Hz ) , 9 .78 ( IH, s ) ; MS (ES+ ) m/z 331 .

The following compound was obtained in a similar manner to that of Preparation 414. Preparation 753 (2E)-3-(6-{[(lR,2R)-2-(benzyloxy)cyclopentyl]amino}-5-chloro -3- pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (300 MHz, DMSO-d6) δ1.45-1.78 (1OH, m),1.87-2.12 (2H, m),3.53 (IH, m),3.90-4.02 (2H, m),4.45 (IH, m),4.54 (2H, s),4.89 (IH, m),6.33 (IH, br-d, J=16 Hz),6.74 (IH, d, J=7.7 Hz) ,7.22-7.37 (5H, m),7.37 (IH, d, J=16 Hz),7.84 (IH, s),8.24 (IH, s),11.08 (IH, s); MS (ES+) m/z 472.

The following compound was obtained in a similar manner to that of Preparation 336. Preparation 754 tert-butyl [ (3R)-l-cycloheptyl-3-pyrrolidinyl] (5-{(lE)-3-oxo-3- [ (tetrahydro-2H-pyran-2-yloxy)amino]-l-propen-l-yl}-2- pyridinyl)carbamate 1H-NMR (300 MHz, DMSO-d6) (5l.13-l.78 (2OH, m),1.89 (IH, m),2.03 (IH, m),2.25 (IH, m),2.62 (IH, m),2.81 (IH, m),3.54 (IH, m),3.95 (IH, m),4.68 (IH, m),4.92 (IH, m),6.58 (IH, d, J=15 Hz),7.34 (IH, d, J=8 Hz),7.52 (IH, d, J=15 Hz),8.00 (IH, d, J=8, 2 Hz),8.62 (IH, d, J=2 Hz),11.32 (IH, br-s); MS (ES+) m/z 529.

The following compound was obtained in a similar manner to that of Preparation 486. Preparation 755 tert-butyl [(3R)-1-(3-fluorobenzyl)-3-pyrrolidinyl]carbamate 1HNMR ( 400MHz, CDCl3): δ 1.44 (9H, s), 1.54-1.66 (IH, m) , 2.20-2.35 (2H, m), 2.51-2.64 (2H, m) , 2.74-2.84 (IH, m) , 3.56, 3.61 (2H, q, Jab=13.2Hz), 4.18 (IH, br.s), 4.92 (IH, br.s), 7.11 (IH, dt, J=2.7, 8.3Hz), 7.02-7.09 (2H, m) , 7.23-7.29 (IH, m) , MASS (ESI): m/z = 295.3 (M+l). The following compound was obtained in a similar manner to that of Preparation 871. Preparation 756 ethyl 5-chloro-6-{[ (IS,2R)-2-phenylcyclopropyl]amino}nicotinate 1H-NMR (300 MHz, CDCl3) <5l.26 (IH, m),1.37 (3H, t, J=7 Hz),1.39 (IH, m),2.13 (IH, m),3.10 (IH, m),4.34 (2H, q, J=7 Hz),5.70 (IH, br),7.17-7.35 (5H, m),8.04 (IH, d, J=2 Hz),8.77 (IH, d, J=2 Hz); MS (ES+) m/z 317.

The following compound was obtained in a similar manner to that of Preparation 382. Preparation 757 5-chloro-6-{[(lS,2R)-2-phenylcyclopropyl]amino}nicotinaldehy de 1H-NMR (300 MHz, CDCl3)(H.29 (IH, m),1.44 (IH, m),2.17 (IH, ddd, J=9, 6, 3 Hz),3.15 (IH, m),5.91 (IH, br-s) ,7.19-7.36 (5H, m),7.96 (IH, d, J=I.8 Hz),8.53 (IH, d, J=I.8 Hz),9.81 (IH, s); MS (ES+) m/z 273.

The following compound was obtained in a similar manner to that of Preparation 414. Preparation 758 (2E)-3-(5-chloro-6-{[(lS,2R)-2-phenylcyclopropyl]amino}-3- pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (300 MHz, DMSO-d6) δ1.24 (IH, m),1.42 (IH, m),1.46-1.77 (6H, m),2.06 (IH, m),3.03 (IH, m),3.52 (IH, m),3.95 (IH, m),4.88 (IH, m),6.33 (IH, d, J=16 Hz) ,7.13-7.22 (3H, m),7.24-7.32 (3H, m),7.36 (IH, d, J=16 Hz),7.85 (IH, br-s),8.22 (IH, br-s),11.09 (IH, br-s); MS (ES+) m/z 414.

The following compound was obtained in a similar manner to that of Preparation 871. Preparation 759 ethyl 5-chloro-6-({3- [ (cyσlohexylcarbonyl)amino]phenyl}amino)nicotinate 1H-NMR (300 MHz, CDC13) δ1.20-1.42 (3H, m),1.39 (3H, t, J=7 Hz ) , 1.48-1.64 ( 2H, m) , 1.72 ( IH, m) , 1.80-1.90 (2H, m) , 1.92-2.02 (2H, m) , 2.24 ( IH, m) , 4.36 ( 2H, q, J=7 Hz ) , 7.15-7.36 ( 4H, m) , 7.46 ( IH, m) , 8.09 ( IH, s) , 8.16 ( IH, d, J=2 Hz ) , 8.79 ( IH, d, J=2 Hz) ; MS (ES+) m/z 402.

The following compound was obtained in a similar manner to that of Preparation 414. . Preparation 760 (2E)-3-{6-[(2-benzylphenyl)amino]-5-chloro-3-pyridinyl}-N- (tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (300 MHz, DMSO-d6) <51.46-1.78 (6H. m),3.53 (IH, m),3.92 (2H, s),3.95 (IH, m),4.89 (IH, m),6.36 (IH, d, J=16 Hz) ,7.07-7.30 (8H, m),7.37 (IH, d, J=16 Hz),7.44 (IH, d, J=8 Hz),7.95 (IH, s),8.13 (IH, s),8.23 (IH, s),11.13 (IH, s); MS (ES+) m/z 464.

The following compound was obtained in a similar manner to that of Preparation 361. Preparation 761 N-(3-{[3-chloro-5-(hydroxymethyl)-2- pyridinyl]amino}phenyl)cyclohexanecarboxamide 1H-NMR (300 MHz, CDCl3) δ1.20-1.40 (3H, m),1.45-1.75 (3H, m),1.76- 2.01 (4H, m),2.22 (IH, m),4.59 (2H, s),7.03 (IH, s),7.13 (IH, d, J=8 Hz),7.22-7.32 (2H, m),7.39 (IH, d, J=8 Hz),7.65 (IH, d, J=2 Hz),8.04 (IH, s),8.09 (IH, d, J=2 Hz); MS (ES+) m/z 360.

The following compound was obtained in a similar manner to that of Preparation 414. Preparation 762 N~{2-[(3-chloro-5-{(lE)-3-oxo-3-[(tetrahydro-2H-pyran-2- yloxy)amino]-l-propen-l-yl}-2- pyridinyl)amino]phenyl}cyclohexanecarboxamide 1H-NMR (300 MHz, DMSO-d6) δ1.12-1.34 (3H, m),1.36-1.86 (13H, m),2.41 (IH, m),3.53 (IH, m),3.96 (IH, m),4.89 (IH, m),6.40 (IH, d, J=16 Hz),7.14 (IH, dd, J=7.5, 7.5 Hz) ,7.21-7.29 (2H, m),7.40 (IH, d, J=16 Hz),7.78 (IH, d, J=7.5 Hz),8.02 (IH, s),8.22 (IH, s),8.32 (IH, s ) , 9 .92 ( IH, s ) , 11. 16 ( IH, s ) ; MS (ES+) m/z 499. f The following compound was obtained in a similar manner to that of Preparation 871. Preparation 763 ethyl 5-chloro-6-({2- [ (cyclohexylcarbonyl)amino]phenyl}amino)nicotinate 1H-NMR (300 MHz, CDCl3) δ1.20-1.40 (3H, m),1.37 (3H, t, J=7 Hz),1.43-1.59 (2H, in),1.69 (IH, m),1.75-1.99 (4H, m),2.27 (IH, m),4.35 (2H, q, J=7 Hz),7.19 (IH, ddd, 3=1.1. 1.1., 1.5 Hz),7.24- 7.37 (2H, m),7.58 (IH, s),7.70 (IH, dd, J=7.7, 1.5 Hz),7.95 (IH, s),8.15 (IH, d, J=I.7 Hz),8.67 (IH, d, J=I.7 Hz); MS (ES+) m/z 402.

The following compounds were obtained in a similar manner to that of Preparation 382. Preparation 764 N-{2-[(3-chloro-5-formyl-2- pyridinyl)amino]phenyl}cyclohexanecarboxamide 1H-NMR (300 MHz, CDCl3) <51.18-1.38 (3H, m) ,1.42-1.64 (2H, m),1.70 (IH, m),1.76-1.88 (2H, m),1.90-2.00 (2H, m),2.30 (IH, m),7.17-7.36 (5H, m),7.50 (IH, s),7.77 (IH, d, J=7.5 Hz),8.05 (IH, d, J=I.5 Hz),8.34 (IH, s),8.44 (IH, d, J=I.5 Hz),9.81 (IH, s); MS (ES+) m/z 358.

Preparation 765 N-{3-[(3-chloro-5-formyl-2- pyridinyl)amino]phenyl}cyclohexanecarboxamide 1H-NMR (300 MHz, CDCl3) δ1.22-1.41 (3H, m),1.48-1.64 (2H, m),1.72 (IH, m),1.79-1.91 (2H, m),1.92-2.02 (2H, m),2.25 (IH, m),7.17 (IH, d, J=8 Hz),7.23 (IH, s),7.33 (IH, dd, J=8, 8 Hz) ,7.44-7.54 (2H, m),8.07 (IH, d, J=2 Hz),8.14 (IH, s),8.56 (IH, d, J=2 Hz),9.85 (IH, s); MS (ES+) m/z 358.

The following compound was obtained in a similar manner to that of Preparation 414. Preparation 766 N-{3-[(3-chloro-5-{(lE)-3-oxo-3-[(tetrahydro-2H-pyran-2- yloxy)amino]-l-propen-l-yl}-2- pyridinyl)amino]phenyl}cyclohexanecarboxamide 1H-NMR (300 MHz, DMSO-d6) δ1.13-1.85 (16H, m),2.33 (IH, m),3.53 (IH, m),3.96 (IH, m),4.90 (IH, m),6.43 (IH, d, J=16 Hz) ,7.16-7.34 (4H, m),7.43 (IH, d, J=16 Hz),7.95 (IH, s),8.03 (IH, s),8.29 (IH, s),8.66 (IH, s),9.79 (IH, s),11.19 (IH, s); MS (ES+) m/z 499.

The following compound was obtained in a similar manner to that of Preparation 405. Preparation 767 (2E)-3-(5-{[2-(l-piperidinyl)phenyl]amino}-2-pyrazinyl)acryl ic acid 1H-NMR (300 MHz, DMSO-d6) <5l.5O (2H, m),1.56-1.68 (4H, m),2.76-2.88 (4H, m),6.58 (IH, d, J=15.5 Hz) ,7.04-7.14 (2H, m),7.17 (IH, m),7.56 (IH, d, J=15.5 Hz),7.90 (IH, m),8.33-8.38 (2H, m),8.92 (IH, br-s); MS (ES+) m/z 325.

The following compound was obtained in a similar manner to that of Preparation 366. Preparation 768 ethyl (2E)-3-{5-fluoro-6-[(3R)-3-pyrrolidinylamino]-3- pyridinyl}acrylate dihydrochloride MASS(API-ES); 280 (M+H)+ Free 1H-NMR ( 200MHz), (DMSO-d6, <5 ) : 1.24 ( 3H, t, J = 7.1Hz ), 1.90 - 2.35 ( 2H, m), 3.05 - 3.60 ( 4H, m) , 4.17 ( 2H, q, J = 7.1Hz ), 4.55 - 4.75 ( IH, m), 6.50 ( IH, d, J = 16Hz ), 7.58 ( IH, dd, J = 1.8Hz, J = 16Hz), 7.65 ( IH, br) , 7.97 ( IH, dd, J = 1.6Hz, J = 13Hz ), 8.17 ( IH, d, J = 1.6Hz ), 9.47 ( 2H, br).

The following compound was obtained in a similar manner to that of Preparation 452. Preparation 769 (3R)-1-(2-quinolinylmethyl)-3-pyrrolidinamine trihydrochloride 1H-NMR (300 MHz, DMSO-d.6) δ2.21 (IH, m),2.44 (IH, m),3.55 (IH, m),3.66 (IH, m) ,3.76-3.94 (2H, m),4.04 (IH, m),4.91 (2H, s),7.69 (IH, m),7.73 (IH, d, J=8.5 Hz),7.86 (IH, ddd, J=7, 7, 1.5 Hz),8.03- 8.13 (2H, m),8.52 (IH, d, J=8.5 Hz),8.77 (2H, br-s); MS (ES+) m/z 228.

The following compound was obtained in a similar manner to that of Preparation 439. Preparation 770 ethyl (2E)-3-(5-{[ (3R)-l-^-quinoliny.ljnethylJ-S- pyrrolidinyl]amino}-2-pyrazinyl)acrylate 1H-NMR (300 MHz, CDCl3)Sl.32 (3H, t, J=7 Hz),1.76 (IH, m),2.42 (IH, m),2.54 (IH, m),2.75-2.88 (2H, m),3.03 (IH, m),3.98 (IH, d, J=13.5 Hz),4.02 (IH, d, J=13.5 Hz),4.25 (2H, q, J=7 Hz),4.51 (IH, m),5.39 (IH, d, J=8 Hz),6.68 (IH, d, J=15.5 Hz) ,7.49-7.62 (3H, m),7.71 (IH, ddd, J=7, 7, 1.5 Hz),7.81 (IH, dd, J=8, 1.5 Hz),7.89 (IH, d, J=I Hz),8.04 (IH, d, J=I Hz),8.08 (IH, d, J=8 Hz),8.15 (IH, d, J=8 Hz); MS (ES+) m/z 404.

The following compound was obtained in a similar manner to that of Preparation 390. Preparation 771 (2E)-3-(5-fluoro-6-{[(3R)-1-(2-phenylethyl)-3-pyrrolidinyl]a mino}- 3-pyridinyl)acrylic acid MASS(API-ES); 356 (M+H)+ .

The following compound was obtained in a similar manner to that of Preparation 452. Preparation 772 (3R)-l-(2-methylbenzyl)-3-pyrrolidinamine dihydrochloride 1H-NMR (300 MHz, DMSO-d6) <52.00-2.65 (2H, m),2.46 (3H, s),3.16-4.16 (5H, m),4.37-4.62 (2H, m),7.22-7.38 (3H, m),7.60 (IH, m),8.44-8.75 (2H, m); MS (ES+) m/z 191.

The following compounds were obtained in a similar manner to that of Preparation 450. Preparation 773 tert-butyl [ (3R)-1-(2-phenylethyl)-3-pyrrolidinyl]carbamate 1H-NMR (300 MHz, CDCl3) δl.44 (9H, s),2.25 (IH, m),2.51 (IH, m),2.77 (IH, m),3.02 (IH, m) ,3.14-3.40 (4H, m),3.64 (IH, m),3.90 (IH, m),4.63 (IH, m),6.45 (IH, d, J=8.5 Hz) ,7.20-7.38 (5H, m); MS (ES+) m/z 291.

The following compound was obtained in a similar manner to that of Preparation 439. Preparation 774 ethyl (2E)-3-(5-{[(3R)-l-(2-methylbenzyl)-3-pyrrolidinyl]amino}-2- pyrazinyl)acrylate 1H-NMR (300 MHz, CDCl3)Sl.32 (3H, t, J=7 Hz),1.69 (IH, m) ,2.29-2.45 (2H, m),2.38 (3H, s),2.66 (IH, dd, J=IO, 3 Hz),2.70 (IH, dd, J=IO, 6 Hz),2.91 (IH, m),3.62 (2H, s),4.25 (2H, q, J=7 Hz),4.45 (IH, m),5.19 (IH, d, J=8 Hz),6.68 (IH, d, J=15.5 Hz) ,7.11-7.20 (3H, m),7.26 (IH, m),7.56 (IH, d, J=15.5 Hz),7.87 (IH, d, J=I Hz),8.05 (IH, d, J=I Hz); MS (ES+) m/z 367.

The following compound was obtained in a similar manner to that of Preparation 397. Preparation 775 , , (2E)-3-(5-fluoro-6-{[ (3R)-1-(2-phenylethyl)-3-pyrrolidinyl]amino}- 3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide MASS(API-ES); 455 (M+H)+. 1H-NMR ( 200MHz), (DMSO-d6, <5 ) : 1.40 - 1.95 ( 7H, m) , 2.00 - 2.30 ( IH, m), 2.45 - 2.80 ( 7H, m), 2.85 - 3.00 ( IH, m) , 3.40 - 3.65 ( IH, m), 3.80 - 4.10 ( IH, m) , 4.35 - 4.60 ( IH, m) , 4.89 ( IH, s), 6.27 ( IH, d, J = 16Hz ), 7.05 - 7.35 ( 6H, m), 7.39 ( IH, d, J = 16Hz ), 7.58 ( IH, d, J = 12Hz ), 8.05 ( IH, s ) .

The following compound was obtained in a similar manner to that of Preparation 439. Preparation 776 ethyl (2E)-3-(2-{[(3R)-l-(cyclohexylmethyl)-3-pyrrolidinyl]amino}- 5-pyrimidinyl)acrylate 1H-NMR (300 MHz, CDCl3) δ0.78-0.96 (2H, m),1.10-1.29 (4H, m),1.33 (3H, t, J=7 Hz),1.43 (IH, m),1.58-1.84 (5H, m) ,2.18-2.38 (4H, m),2.61 (2H, d, J=5 Hz),2.83 (IH, m),4.25 (2H, q, J=7 Hz),4.53 (IH, m),5.75 (IH, d, J=8 Hz),6.30 (IH, d, J=16 Hz),7.48 (IH, d, J=16 Hz),8.44 (2xlH, s); MS (ES+) m/z 359.

The following compound was obtained in a similar manner to that of Preparation 480. Preparation 777 tert-butyl [(3R)-I-(I-phenylethyl)-3-pyrrolidinyl]carbamate 1H-MMR (300 MHz, CDCl3) 01.35 (1.5H, d, J=6.6 Hz),1.37 (1.5H, d, J=6.6 Hz),1.42 (4.5H, s),1.44 (4.5H, s) ,1.47-1.68 (IH, m) ,2.10-2.36 (2.5H, m),2.49-2.68 (2H, m),2.88 (0.5H, m),3.19 (IH, q, J=6.6 Hz),4.12 (IH, m),4.82 (IH, m),7.19-7.36 (5H, m); MS (ES+) m/z 291.

The following compound was obtained in a similar manner to that of Preparation 336. Preparation 778 (2E)-3-(5-{[(3R)-1-(1-phenylethyl)-3-pyrrolidinyl]amino}-2- pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (300 MHz, DMSO-d6) δ1.29 (1.5H, d, J=6.5 Hz),1.30 (1.5H, d, J=6.5 Hz),1.46-1.76 (7H, m),2.11-2.34 (2H, m),2.37-2.56 (IH, m),2.65-2.83 (2H, m),3.20-3.42 (IH, m),3.52 (IH, m),3.95 (IH, m),4.27 (IH, m),4.89 (2H, m),6.60 (IH, d, J=15 Hz) ,7.19-7.37 (5H, m),7.36 (IH, d, J=15 Hz),7.73 (0.5H, d, J=6 Hz),7.76 (0.5H, d, J=6 Hz),7.97 (IH, s),8.08 (0.5H, s),8.09 (0.5H, s),11.18 (IH, br-s); MS (ES+) m/z 438. l

The following compounds were obtained in a similar manner to that of Preparation 452. Preparation 779 (3R)-I-(I-phenylethyl)-3-pyrrolidinamine 1H-NMR (300 MHz, CDCl3)Sl.37 (1.5H, d, J=6.6 Hz),1.38 (1.5H, d, J=6.6 Hz ) , 1.39-1.70 ( 3H, m) , 2.08-2.23 ( 1.5H, m) , 2.32 ( IH, m) , 2.54 ( IH, dd, J=7 , 7 Hz) , 2.62 (0.5H, dd, J=9.5 , 6. 5 Hz) , 2.67-2.82 ( IH, m) , 3.20 ( IH, q, J=6.6 Hz) , 3.46 ( IH, m) , 7.18-7.36 ( 5H, m) ; MS (ES+) m/z 191.

Preparation 780 (3R)-1-(2-phenylethyl)-3-pyrrolidinamine 1H-NMR (300 MHz, CDCl3) δ1.42-1.66 (3H, m),2.21 (IH, dddd, J=13, 8.5, 8.5, 5.5 Hz),2.37 (IH, dd, J=9.5, 4.5 Hz),2.53 (IH, ddd, J=8.5, 8.5, 6.5 Hz),2.60-2.86 (4H, m),3.53 (IH, m) ,7.15-7.33 (5H, m) ; MS (ES+) m/z 191.

Preparation 781 (3R)-1-(2,3-dihydro-lH-inden-2-yl)-3-pyrrolidinamine 1H-NMR (300 MHz, CDCl3)Sl.35 (2H, br),1.52 (IH, m),2.24 (IH, dddd, J=13, 8.5, 8.5, 5 Hz),2.36 (IH, dd, J=9.5, 5 Hz),2.59 (IH, ddd, J=8.5, 8.5, 6 Hz),2.77 (IH, ddd, J=8.5, 8.5,, 6 Hz) ,2.82-2.97 (3H, m),2.98-3.14 (3H, m),3.57 (IH, m),7.08-7.22 (4H, m) ; MS (ES+) m/z 203.

The following compound was obtained in a similar manner to that of Preparation 405. Preparation 782 (2E)-3-(6-{(tert-butoxycarbonyl) [(3R)-l-cyclohexyl-3- pyrrolidinyl]amino}-3-pyridinyl)acrylic acid 1H-NMR (300 MHz, DMSO-d6) δ1.00-2.38 (12H, m),1.39 (3H, s),1.42 (6H, s),3.00-4.00 (5H, m),4.97. (IH, m),6.68 (0.7H, d, J=16 Hz),6.70 (0.3H, d, J=16 Hz),7.43 (IH, d, J=8.5 Hz),7.63 (0.7H, d, J=16 Hz),7.64 (0.3H, d, J=16 Hz),8.23 (IH, m),8.73 (IH, m),11.48 (IH, br); MS (ES+) m/z 416.

The following compound was obtained in a similar manner to that of Preparation 452. Preparation 783 (3R)-3-amino-l-(cyclohexylmethyl)-2-pyrrolidinone 1H-NMR (300 MHz, CDCl3) <50.86-1.06 (2H, m),1.10-1.30 (3H, m),1.52- 1.80 (9H, m),2.42 (IH, m),3.08 (IH, dd, J=14, 7 Hz),3.15 (IH, dd, J=14, 7 Hz),3.23-3.35 (2H, m),3.53 (IH, dd, J=IO, 8.5 Hz); MS (ES+) m/z 197.

The following compound was obtained in a similar manner to that of Preparation 414. Preparation 784 (2E)-3-(5-{[(3R)-l-(cyclohexyljnethyl)-3-pyrrolidinyl]amino} -2- pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (300 MHz, DMSO-d6) <5θ.73-0.93 (2H, m),1.06-1.28 (3H, m),1.30-1.83 (13H, m),2.10-2.30 (3H, m),2.31-2.44 (2H, m),2.61 (IH, m),2.72 (IH, m),3.52 (IH, m),3.95 (IH, m),4.29 (IH, m),4.89 (IH, m),6.60 (IH, d, J=15.2 Hz),7.38 (IH, d, J=15.2 Hz),7.73 (IH, d, J=6.6 Hz),7.98 (IH, s),8.11 (IH, s),11.18 (IH, s); MS (ES+) m/z 430.

The following compound was obtained in a similar manner to that of Preparation 480. Preparation 785 tert-butyl [ (3R)-1-(2-methylbenzyl)-3-pyrrolidinyl]carbamate 1H-NMR (300 MHz, CDCl3)Sl.43 (9H, s),1.67 (IH, m),2.16-2.33 (2H, m),2.52 (IH, m),2.59 (IH, dd, J=9.5, 6 Hz),2.79 (IH, m),3.56 (2H, s),4.16 (IH, m),4.80 (IH, m) ,7.10-7.20 (3H, m),7.25 (IH, m); MS (ES+) m/z 291.

The following compound was obtained in a similar manner to that of Preparation 336. Preparation 786 (2E)-3-(5-{[(3R)-1-(cyclohexylmethyl)-2-oxo-3-pyrrolidinyl]a mino}- 2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (300 MHz, DMSO-d6) δθ.80-0.96 (2H, m),1.10-1.30 (3H, m),1.45-1.76 (12H, m),1.84 (IH, m),2.44 (IH, m),2.97-3.12 (2H, m),3.27-3.39 (2H, m),3.52 (IH, m),3.95 (IH, m),4.64 (IH, m),4.90 (IH, m),6.64 (IH, d, J=15.5 Hz),7.41 (IH, d, J=15.5 Hz),7.88 (IH, d, J=7.5 Hz),8.06 (IH, s),8.10 (IH, s),11.21 (IH, s); MS (ES+) m/z 444. The following compound was obtained in a similar manner to that of Preparation 390. Preparation 787 (2E)-3-(6-{[(3R)-l-(cyclohexylcarbonyl)-3-pyrrolidinyl]amino }-5- fluoro-3-pyridinyl)acrylic acid MASS(API-ES); 362 (M+H)+. 1H-NMR ( 200MHz), (DMSO-d6, <5 ) : 1.05 - 1.79 ( 1OH, m) , 1.80 - 2.55 ( 3H, m), 3.15 - 3.90 ( 4H, m) , 4.40 - 4.70 ( IH, m) , 6.36 ( IH, d, J = 16Hz ), 7.35 - 7.45 ( IH, m) , 7.51 ( IH, d, J = 16Hz ), 7.86 ( IH, dd, J = 1.8Hz, J = 12Hz ), 8.12 ( IH, d, J = 1.8Hz ).

The following compound was obtained in a similar manner to that of Preparation 336. Preparation 788 (2E)-3-(5-{[ (3R)-1-(2-quinolinylmethyl)-3-pyrrolidinyl]amino}-2- pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (300 MHz, DMSO-d6) 61.46-1.77 (7H, m),2.26 (IH, m),2.46-2.60 (2H, m),2.77 (IH, m),2.89 (IH, dd, J=9.5, 7 Hz),3.52 (IH, m),3.90 (2H, s),3.95 (IH, m),4.35 (IH, m),4.89 (IH, m),6.59 (IH, d, J=15 Hz),7.37 (IH, d, J=15 Hz),7.57 (IH, m),7.65 (IH, d, J=8.5 Hz),7.73 (IH, m),7.81 (IH, d, J=7 Hz) ,7.93-8.02 (3H, m),8.09 (IH, s),8.33 (IH, d, J=8.5 Hz),11.18 (IH, s); MS (ES+) m/z 475.

The following compound was obtained in a similar manner to that of Preparation 859. Preparation 789 ethyl (2E)-3-(2-{(tert-butoxycarbonyl) [(3R)-1-(2-phenylethyl)-3- pyrrolidinyl]amino}-5-pyrimidinyl)acrylate 1H-NMR (300 MHz, CDCIa)Sl.35 (3H, t, J=7 Hz),1.47 (3x3H, s),2.07- 2.33 (2H, m),2.56-2.83 (7H, m),3.08 (IH, dd, J=8, 8 Hz),4.29 (2H, q, J=7 Hz),5.00 (IH, m),6.54 (IH, d, J=16 Hz) ,7.14-7.33 (5H, m),7.59 (IH, d, J=16 Hz),8.79 (2xlH, s); MS (ES+) m/z 467.

The following compound was obtained in a similar manner to that of Preparation 436. Preparation 790 methyl 5-[ [(3R)-1-benzyl-3-pyrrolidinyl] (tert- butoxycarbonyl)amino]-2-pyrazinecarboxylate MASS(API-ES); 413 (M+H)+ 1H-NMR ( 200MHz), (DMSO-d6, <5 ) : 1.39 ( 1OH, s), 1.95 - 2.30 ( 2H, m), 2.40 - 2.85 ( 3H, m), 3.45, 3.53 ( 2H, ABq, J = 13Hz ), 3.93 ( 3H, s), 4.70 - 4.95 ( IH, m) , 7.05 - 7.30 ( 5H, m) , 8.79 ( IH, d, J = 1.3Hz ), 9.00 ( IH, d, J = 1.3Hz ).

The following compound was obtained in a similar manner to that of Preparation 379. Preparation 791 methyl 5-{[(3R)-I-benzyl-3-pyrrolidinyl]amino}-2- pyrazinecarboxylate MASS(API-ES); 313 (M+H)+ 1H^NMR ( 200MHz), (DMSO-d6, <5 ) : 1.55 - 1.80 ( IH, m) , 2.10 - 2.55 ( 3H,ι m), 2.60 - 2.85. ( 2H, m) , 3.59 ( 2H, s), 3.78 ( 3H, s), 4.25 - 4.45 ( IH, m) , 7.20 - 7.35 ( 5H, m), 7.96 ( IH, d, J = 1.0Hz ) , 8. 16 ( IH, d, J = 6.7Hz ) , 8. 56 ( IH, d, J = 1.0Hz ) .

The following compound was obtained in a similar manner to that of Preparation 439. Preparation 792 ethyl (2E)-3-(5-{[(3R)-l-(cyclohexylmethyl)-2-oxo-3- pyrrolidinyl]amino}-2-pyrazinyl)acrylate 1H-NMR (300 MHz, CDCl3) δ0.88-1.06 (2H, m),1.12-1.36 (3H, m),1.33 (3H, t, J=7 Hz),1.54-1.80 (5H, m),1.87 (IH, m),2.85 (IH, m),3.16 (IH, dd, J=14, 7 Hz),3.22 (IH, dd, J=14, 7 Hz) ,3.30-3.50 (2H, m),4.25 (2H, q, J=7 Hz),4.47 (IH, m),5.75 (IH, d, J=4 Hz),6.72 (IH, d, J=15.5 Hz),7.57 (IH, d, J=15.5 Hz) ,8.01 (IH, d, J=I Hz),8.05 (IH, d, J=I Hz); MS (ES+) m/z 373.

The following compound was obtained in a similar manner to that of Preparation 480. Preparation 793 tert-butyl [ (3R)-1-(2-quinolinylmethyl)-3-pyrrolidinyl]carbamate 1H-NMR (300 MHz, CDCl3)<5l.44 (9H, s),1.64 (IH, m),2.29 (IH, m) ,2.48 (IH, m),2.62 (IH, m),2.78 (IH, dd, J=9.5, 6.5 Hz),2.89 (IH, m),3.95 (2H, s),4.21 (IH, m),4.96 (IH, br-d, J=8 Hz),7.52 (IH, m),7.56 (IH, d, J=8.5 Hz),7.70 (IH, m),7.81 (IH, dd, J=8, 1.5 Hz),8.08 (IH, d, J=8 Hz),8.13 (IH, d, J=8.5 Hz); MS (ES+) m/z 328.

i The following compound was obtained in a similar manner to that of Preparation 336. t Preparation 794 (2E)-3-(5-{[(3R)-l-(2-methylbenzyl)-3-pyrrolidinyl]amino}-2- pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (300 MHz, DMSO-d6) δ1.42-1.78 (7H, m),2.24 (IH, m),2.32 (3H, s),2.36-2.53 (2H, m),2.66 (IH, m),2.79 (IH, m),3.52 (IH, m),3.55 (2H, s),3.95 (IH, m),4.30 (IH, m),4.89 (IH, m),6.60 (IH, d, J=15 Hz),7.09-7.18 (3H, m),7.26 (IH, m),7.37 (IH, d, J=15 Hz),7.76 (IH, d, J=6.5 Hz),7.97 (IH, s),8.09 (IH, s),11.18 (IH, s); MS (ES+) m/z 438.

The following compound was obtained in a similar manner to that of Preparation 450. Preparation 795 tert-butyl [ (3R)-I-(4-ethoxybenzyl)-3-pyrrolidinyl]carbamate 1H-NMR (300 MHz, CDCl3) <5l.41 (3H, t, 3=7 Hz),1.43 (3x3H, s),1.61 (IH, m),2.16-2.39 (2H, m),2.48-2.67 (2H, m),2.81 (IH, m),3.56 (2H, s),4.02 (2H, q, J=7 Hz),4.18 (IH, m),4.96 (IH, m),6.84 (2xlH, d, J=8.5 Hz),7.21 (2xlH, d, J=8.5 Hz); MS (ES+) m/z 321.

The following compound was obtained in a similar manner to that of Preparation 452. Preparation 796 (3R)-1-(4-ethoxybenzyl)-3-pyrrolidinamine 1H-NMR (300 MHz, CDCl3)(Jl.41 (3H, t, J=7 Hz) ,1.44-1.58 (3H, m),2.19 (IH, dddd, J=13, 8.5, 8, 6 Hz),2.27 (IH, dd, 3=9, 4.5 Hz),2.46 (IH, ddd, J=8.5, 8.5, 6 Hz),2.68 (IH, ddd, J=8.5, 8.5, 6 Hz),2.71 (IH, dd, 3=9, 5.5 Hz),3.49 (IH, m),3.51 (IH, d, J=12.5 Hz),3.56 (IH, d, J=12.5 Hz),4.02 (2H, q, J=7 Hz),6.84 (2xlH, d, J=8.7 Hz),7.21 (2xlH, d, J=8.7 Hz); MS (ES+) m/z 221.

The following compound was obtained in a similar manner to that of Preparation 439. Preparation 797 ethyl (2E)-3-(5-{[(3R)-I-(4-ethoxybenzyl)-3-pyrrolidinyl]amino}-2- pyrazinyl)aerylate 1H-NMR (300 MHz, CDCl3)Sl.32 (3H, t, 3=7 Hz),1.41 (3H, t, 3=7 Hz),1.68 (IH, m),2.28-2.44 (2H, m),2.60-2.70 (2H, m),2.88 (IH, m),3.55 (IH, d, J=13 Hz),3.59 (IH, d, J=13 Hz),4.02 (2H, q, 3=7 Hz),4.25 (2H, q, 3=7 Hz),4.45 (IH, m),5.24 (IH, d, J=7.5 Hz),6.68 (IH, d, J=15.5 Hz),6.85 (2xlH, d, J=8.5 Hz),7.21 (2xlH, d, J=8.5 Hz),7.56 (IH, d, J=15.5 Hz),7.86 (IH, d, J=I Hz),8.04 (IH, d, J=I Hz); MS (ES+) m/z 397.

The following compound was obtained in a similar manner to that of Preparation 336. Preparation 798 (2E)-3-(5-{[ (3R)-1-(4-ethoxybenzyl)-3-pyrrolidinyl]amino}-2- pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (300 MHz, DMSO-d6) 01.31 (3H, t, J=7 Hz) ,1.44-1.76 (7H, m),2.21 (IH, m),2.31-2.45 (2H, m),2.63 (IH, m),2.73 (IH, dd, J=9.5, 7 Hz),3.33 (IH, m),3.50 (2H, s),3.53 (IH, m),3.96 (IH, m),3.98 (2H, q, J=7 Hz),4.29 (IH, m),4.89 (IH, m),6.60 (IH, d, J=16 Hz),6.85 (2xlH, d, J=8.5 Hz),7.19 (2xlH, d, J=8.5 Hz),7.37 (IH, d, J=15.5 Hz),7.76 (IH, d, J=6.5 Hz),7.96 (IH, s),8.09 (IH, s),11.09 (IH, s); MS (ES+) m/z 468.

The following compound was obtained in a similar manner to that of Preparation 380. Preparation 799 tert-butyl (3R)-3-{[3-fluoro-5-(hydroxymethyl)-2-pyridinyl]amino}- 1-pyrrolidinecarboxylate MASS(API-ES); 312 (M+H)+ 1H-NMR ( 200MHz), (DMSO-d6, <5 ) : 1.30 - 1.50 ( 9H, m) , 1.65 - 2.25 ( 2H, m), 3.05 - 3.70 ( 4H, m) , 4.34 ( 2H, d, J = 5.6Hz ), 4.30 - 4.50 ( IH, m), 5.07 ( IH, t, J = 5.6Hz ), 6.68 ( IH, d, J = 6.1Hz ), 7.30 ( IH, dd, J = 1.7Hz, J = 12Hz ), 7.79 ( IH, d, J = 1.7Hz ).

The following compound was obtained in a similar manner to that of Preparation 405. Preparation 800 (2E)-3-{6-[ [(3R)-l-benzyl-3-pyrrolidinyl] (tert- butoxycarbony1)amino]-2-pyrazinyl}acrylic acid 1H-NMR (300 MHz, CDCl3) δ1.48 (9H, s),2.38-2.57 (2H, m),3.22-3.47 (3H, m),3.97 (IH, m),4.10 (IH, d, J=12.5 Hz),4.42 (IH, d, J=12.5 Hz),5.20 (IH, m),7.26 (IH, d, J=15.5 Hz) ,7.36-7.45 (3H, m),7.49 (IH, d, J=15.5 Hz),7.49-7.58 (2H, m),8.28 (IH, s),8.60 (IH, s); MS (ES+) m/z 425.

The following compound was obtained in a similar manner to that of Preparation 414. Preparation 801 tert-butyl [ (3R)-l-benzyl-3-pyrrolidinyl](6-{(IE)-3-oxo-3- [ (tetrahydro-2H-pyran-2-yloxy)amino]-l-propen-l-yl}-2- pyrazinyl)carbamate 1H-NMR (300 MHz, DMSO-d6) 61.35 (9H, s) ,1.44-1.76 (6H, m),1.92-2.44 (3H, m),2.62-2.75 (2H, m),3.15-3.59 (4H, m),3.96 (IH, m),4.78 (IH, m),4.95 (IH, m),6.97 (IH, d, J=15.5 Hz),7.04 (2xlH, d, J=7 Hz),7.14-7.28 (3H, m),7.61 (IH, d, J=15.5 Hz),8.58 (IH, s),8.71 (IH, s),11.51 (IH, br-s); MS (ES+) m/z 524.

The following compound was obtained in a similar manner to that of Preparation 439. Preparation 802 ' ethyl (2E)-3-(2-{[(3R)-1-(2-phenylethyl)-3-pyrrolidinyl]amino}-5- pyrimidinyl)aerylate 1H-NMR (300 MHz, CDCl3)Sl.33 (3H, t, J=7 Hz),1.72 (IH, m) ,2.30-2.48 (2H, m),2.64-2.86 (6H, m),2.95 (IH, m),4.25 (2H, q, J=7 Hz),4.56 (IH, m),5.73 (IH, d, J=7 Hz),6.30 (IH,1 d, J=16 Hz) ,7.14-7.34 (5H, m),7.49 (IH, d, J=16 Hz),8.45 (2xlH, s); MS (ES+) m/z 367.

The following compounds were obtained in a similar manner to that of Preparation 336. Preparation 803 (2Z)-3-(5-{[(3R)-l-benzyl-3-pyrrolidinyl]amino}-2-pyrazinyl) -2- fluoro-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide MASS(API-ES); 442 (M+H)+, 1H-NMR ( 200MHz), (CDCl3, δ): 1.50 - 2.00 ( 7H, m) , 2.30 - 2.60 ( 2H, m), 2.70 - 3.10 ( 3H, m) , 3.30 - 3.70 ( IH, m) , 3.72 ( 2H, s), 3.95 - 4.20 ( IH, m) , 4.40 - 4.60 ( IH, m) , 5.00 - 5.10 ( IH, m), 6.89 ( IH, d, J = 39Hz ), 7.20 - 7.45 ( 5H, m), 7.89 ( IH, d, J = 1.3Hz ), 8.35 ( IH, d, J = 1.3Hz ). (2E)~3-(5-{[(3R)-l-benzyl-3-pyrrolidinyl]amino}~2-pyrazinyl) -2- fluoro-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide MASS(API-ES); 442 (M+H)+, 1H-NMR ( 200MHz), (CDCl3, <5 ) : 1.50 - 2.00 ( 7H, m) , 2.10 - 2.55 ( 2H, m), 2.65 - 2.85 ( 2H, m) , 2.90 - 3.10 ( IH, m), 3.60 - 3.80 ( IH, m), 3.71 ( 2H, s), 3.95 - 4.15 ( IH, m) , 4.40 - 4.60 ( IH, m), 5.07 ( IH, s), 5.69 ( IH, d, J = 7.7Hz ), 6.60 ( IH, d, J = 25Hz ), 7.20 - 7.43 ( 5H, m) , 7.77 ( IH, d, J = 1.0Hz j, 8.04 ( IH, d, J = 1.0Hz ).

The following compound was obtained in a similar manner to that of Preparation 311. Preparation 804 ethyl (2E)-3-(5-fluoro-6-{[(3R)-l-(2-phenylethyl)-3- pyrrolidinyl]amino}-3-pyridinyl)acrylate MASS(API-ES); 384 (M+H)+, 1H-NMR ( 400MHz), (DMSO-d6, <5 ) : 1.23 ( 3H, t, J = 7.0Hz ), 1.70 - 1.90 ( IH, m), 2.00 - 2.25 ( IH, m), 2.30 - 2.83 ( 7H, m), 2.85 - 2.95 ( IH, m), 4.16 ( 2H, q, J = 7.0Hz ), 4.35 - 4.55 ( IH, m) , 6.43 ( IH, d, J = 16Hz ), 7.00 - 7.30 ( 6H, m) , 7.55 ( IH, dd, J = 2.0Hz ,J = 16Hz ), 7.85 ( IH, dd, J = 1.8Hz, J=13Hz), 8.11 ( IH, d, J = 1.8Hz ). ,

The following compound was obtained in a similar manner to that of Preparation 390. Preparation 805 (2E)-3-[5-fluoro-6-({(3R)-l-[2-(lH-pyrazol-l-yl)ethyl]-3- pyrrolidinyl}amino)-3-pyridinyl]acrylic acid MASS(API-ES); 346 (M+H)+.

The following compound was obtained in a similar manner to that of Preparation 397. Preparation 806 (2E)-3-[5-fluoro-6-({(3R)-l-[2-(lH-pyrazol-l-yl)ethyl]-3- pyrrolidinyl}amino)-3-pyridinyl]-N-(tetrahydro-2H-pyran-2- yloxy)acrylamide MASS(API-ES); 445 (M+H)+, 1H-NMR ( 200MHz), (DMSO-d6, 6): 1.40 - 1.88 ( 7H, m) , 2.00 - 2.25 ( IH, m), 2.38 - 2.95 ( 6H, m) , 3.43 - 3.62 ( IH, m) , 3.83 - 4.05 ( IH, m), 4.20 ( 2H, t, J = 6.6Hz ), 4.32 - 4.55 ( IH, m), 4.88 ( IH, s), 6.20 ( IH, t, J = 1.7Hz ), 6.26 ( IH, d, J = 16Hz ), 7.10 ( IH, d, J = 6.2Hz ), 7.39 ( IH, d, J = 16Hz ), 7.40 ( IH, d, J = 1.7Hz ), 7.57 ( IH, d, J = 12Hz ), 7.74 ( IH, d, J = 1.7Hz ) , 8.04 ( IH, s).

Preparation 807 To a stirred solution of 5-bromo-2-chloropyrimidine (500 mg) in DMF (5 mL) was added ethyl acrylate (1.41 mL), palladium(II) acetate (29 mg) , tris(2-methylphenyl)phosphine (118 mg) , and N,N- diisopropylethylamine (1.35C mL) . The mixture was stirred at 100°C for 4 hours. The resulting mixture was allowed to cool to ambient temperature, poured into brine, and extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (90:10 v/v) to give ethyl (2E)-3-(2-chloro-5- pyrijnidinyl)aerylate (494 mg) as a yellow powder. 1H-NMR (300 MHz, CDCl3)Sl.35 (3H, t, J=7 Hz),4.30 (2H, q, J=7 Hz),6.59 (IH, d, J=16 Hz),7.58 (IH, d, J=16 Hz),8.76 (2xlH, s); MS () m/z not detected.

The following compound was obtained in a similar manner to that of Preparation 439. Preparation 808 ethyl (2E)-3-(5-{[(3R)-1-(1-phenylethyl)-3-pyrrolidinyl]amino}-2- pyrazinyl)aerylate . 1H-NMR (300 MHz, CDCl3)Sl.32 (1.5H, t, J=7 Hz),1.33 (1.5H, t, J=7 Hz),1.39 (1.5H, d, J=6.6 Hz),1.41 (1.5H, d, J=6.6 Hz) ,1.56-1.80 (IH, m),2.26-2.40 (2H, m),2.46 (0.5H, dd, J=IO, 3 Hz) ,'2.56-2.72 (1.5H, m),2.79 (0.5H, dd, J=IO, 3 Hz),3.04 (IH, m),3.26 (IH, q, J=6.6 Hz),4.24 (IH, q, J=7 Hz),4.25 (IH, q, J=7 Hz),4.42 (IH, m),5.18 (0.5H, d, J=7.5 Hz),5.25 (0.5H, d, J=7.5 Hz),6.67 (0.5H, d, J=15.5 Hz),6.69 (0.5H, d, J=15.5 Hz) ,7.20-7.37 (5H, m),7.55 (0.5H, d, J=15.5 Hz),7.57 (0.5H, d, J=15.5 Hz),7.86 (0.5H, d, J=I Hz),7.90 (0.5H, d, J=I Hz),8.03 (0.5H, d, J=I Hz),8.06 (0.5H, d, J=I Hz); MS (ES+) m/z 367. . The following compound was obtained in a similar manner to that of Preparation 390. Preparation 809 (2E)-3-(6-{[ (3R)-1-(2,6-difluorobenzyl)-3-pyrrolidinyl]amino}-5- fluoro-3-pyridinyl)acrylic acid MASS(API-ES); 378 (M+H)+, 1H-NMR ( 200MHz), (DMSO-d6, <5 ) : 1.60 - 2.25 ( 2H, m) , 2.30 - 2.70 ( 3H, m), 2.80 - 3.00 ( IH, m), 3.69 ( 2H, s), 4.30 - 4.55 ( IH, m), 6.31 ( IH, d, J = 16Hz ), 7.00 - 7.44 ( 4H, m) , 7.45 ( IH, d, J = 16Hz ), 7.80 ( IH, d, J=13Hz), 8.05 ( IH, S ) . The following compound was obtained in a similar manner to that of Preparation 198. Preparation.810 ethyl (2E)-3~(5-chloro-6-{[l-(2-pyridinylmethyl)-4- piperidinyl]amino}-3-pyridinyl)acrylate 1H NMR (DMSO-d6, <5 ) :1.24(3H, t, 3=7.1 Hz), 1.55-1.89(4H, m) , 2.05-2.17(2H, m) , 2.81-2.87(2H, m) , 3.59(2H, s), 3.90-4.10(1H, m) , 4.16(2H, q, J=7.1 Hz), 6.47(1H, d, J=15.9 Hz), 6.65(1H, d, J=8.0 Hz), 7.23-7.29(1H, m) , 7.43(1H, d, J=7.8 Hz), 7.5O(1H, d, J=16.0 Hz), 7.73-7.81(lH, m) , 8.1O(1H, d, J=I.9 Hz), 8.27(1H, d, J=I.9 Hz), 8.49(1H, d, J=4.1 Hz)', Mass (APCI) : 401(M+H)+.

The following compound was obtained in a similar manner to that of Preparation 850. Preparation 811 ethyl (2E)-3-(5-chloro-6-{[l-(4-pyridinylmethyl)-4- piperidinyl]amino}-3-pyridinyl)acrylate 1H NMR (DMSO-d6, δ ) :1.24(3H, t, J=7.1 Hz), 1.60-1.84(4H, m) , 2.03-2.13(2H, m) , 2.78-2.83(2H, m) , 3.51(2H, s), 3.91-4.1O(1H, m) , 4.16(2H, q, J=7.1 Hz), 6.47(1H, d, J=15.9 Hz), 6.64(1H, d, J=7.9 Hz), 7.32(2H, d, J=5.8 Hz), 7.5O(1H, d, J=15.9 Hz), 8.1O(1H, d, J=I.9 Hz), 8.27(1H, d, J=I.9 Hz), 7.51(1H, d, J=5.8 Hz), Mass (APCI) : 401(M+H)+.

The following compounds were obtained in a similar manner to that of Preparation 62. Preparation 812 (2E)-3-(5-chloro-6-{[l-(2-pyridinylmethyl)-4-piperidinyl]ami no}-3- pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H NMR (DMSO-d6, 6) :1.50-1.84(1OH, m) , 2.08-2.18(2H, m) , 2.81- 2.87(2H, m), 8.49-8.54(1H, m) , 8.60(2H, s), 3.93-4.08(2H, m) , 4.88(1H, brs), 6.3O(1H, d, J=15.9 Hz), 6.53(1H, d, J=7.9 Hz), 7.23- 7.29(1H, m), 7.38(1H, d, J=15.9 Hz), 7.43(1H, d, J=7÷9 Hz), 7.23- 7 .84 ( 2H, m) , 8.2O ( 1H, s ) , 8 .49 ( 1H, d, J=4.2 Hz ) , 11 .07 ( 1H, brs ) . Mass (APCI ) : 472 (M+H) + .

Preparation 813 (2E)-3-(5-chloro-6-{[l-(2-chlorobenzyl)-4-piperidinyl]amino} -3- pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H NMR (DMSO-d6, <5 ) :1.45-1.90(1OH, m) , 2.10-2.20(2H, m) , 2.82- 2.89(2H, m), 3.49-3.60(1H, m) , 3.57(2H, s), 3.80-4.10(2H, m) , 4.89(1H, brs), 6.3O(1H, d, J=15.9 Hz), 6.53(1H, d, J=7.9 Hz), 7.27- 7.50(5H, m), 7.84(1H, s), 8.21(1H, s), 11.07(1H, brs). Mass (APCI) : 505(M+H)+.

The following compound was obtained in a similar manner to that of Preparation 366. Preparation 814 ethyl (2E)-3-{4-[(3R)-3-pyrrolidinylamino]phenyl}aerylate hydrochloride 1H-NMR (300 MHz, DMSO-d6) 61.24 (3H, t, J=7 Hz),1.89 (IH, m),2.21 (IH, m),3.04 (IH, m),3.16-3.50 (4H, m),4.14 (2H, q, J=7 Hz),6.30 (IH, d, J=16 Hz),6.62 (2H, d, J=8.5 Hz),7.49 (2H, d, J=8.5 Hz),7.50 (IH, d, J=8.5 Hz),9.20-9.38 (2H, br) .

The following compound was obtained in a similar manner to that of Preparation 678. , Preparation 815 ethyl (2E)-3-(4-{[(3R)-1-(cyclohexylmethyl)-3- pyrrolidinyl]amino}phenyl)acrylate 1H-NMR (300 MHz, CDCl3) δ0.80-0.97 (2H, m),1.10-1.31 (3H, m),1.32 (3H, t, J=7 Hz),1.44 (IH, m),1.58-1.84 (4H, m),2.18-2.42 (4H, m),2.56 (IH, dd, J=9.5, 3 Hz),2.68 (IH, dd, J=9.5, 6.5 Hz),2.78 (IH, m),4.01 (IH, m),4.24 (2H, q, J=7 Hz),4.30 (IH, m),6.21 (IH, d, J=15.8 Hz),6.56 (2xlH, d, J=8.5 Hz),7.36 (2H, d, J=8.5 Hz),7.59 (IH, d, J=15.8 Hz); MS (ES+) m/z 357.

The following compound was obtained in a similar manner to that of Preparation 434. Preparation 816 ethyl (2E)-3-(4-{[ (3R)-1-(cyclohexylcarbonyl)-3- pyrrolidinyl]amino}phenyl)acrylate 1H-NMR (300 MHz, CDCl3) 61.10-2.12 (HH, m),1.33 (3H, t, J=7 Hz),2.18-2.42 (2H, m),3.42 (IH, m) ,3.55-3.70 (2H, m),3.84 (IH, m),4.06 (IH, m),4.18 (IH, m),4.24 (IH, q, J=7 Hz),4.25 (IH, q, J=7 Hz),6.23 (0.5H, d, J=15.8 Hz),6.24 (0.5H, d, J=15.5 Hz),6.58 (IH, d, J=7.7 Hz),6.59 (IH, d, J=7.7 Hz),7.38 (IH, d, J=7.7 Hz),7.40 (IH, d, J=7.7 Hz),7.59 (0.5H, d, J=15.8 Hz),7.60 (0.5H, d, J=15.8 Hz); MS (ES+) m/z 371.

The following compound was obtained in a similar manner to that of Preparation 198. Preparation 817 ethyl (2E)-3-(5-chloro-6-{[1-(cyclohexylmethyl)-4- piperidinyl]amino}-3-pyridinyl)acrylate 1H NMR (DMSO-d6, 6) :0.78-0.90 (2H, m) , 1.14-1.36 (3H, m) , 1.23 (3H, t, J = 7.4 Hz), 1.41-2.08 (13H, m) , 2.77-2.83 (2H, m) , 3.92- 4.01 (IH, m), 4.15 (2H, q, J = 7.4 Hz), 6.48 (IH, d, J = 15.9 Hz), 6.59 (IH, d, J = 7.8 Hz), 7.50 (IH, d, J = 15.9 Hz), 8.09 (IH, d, J = 1.9 Hz), 8.27 (IH, d, J = 1.9 Hz), Mass (ESI) : 406(M+H)+.

The following compound was obtained in a similar manner to that of Preparation 405. Preparation 818 (2E)-3-(4-{[(3R)-1-(cyclohexylcarbonyl)-3- pyrrolidinyl]amino}phenyl)acrylic acid 1H-NMR (300 MHz, CDCl3) 61.16-2.43 (13H, m),3.36-3.70 (3H, m),3.83 (IH, m),4.04-4.24 (IH, m),6.24 (0.5H, d, J=15.8 Hz),6.26 (0.5H, d, J=15.8 Hz),6.59 (IH, d, J=8 Hz),6.61 (IH, d, J=8 Hz),7.40 (IH, d, J=8 Hz),7.43 (IH, d, J=8 Hz),7.68 (0.5H, d, J=15.8 Hz),7.69 (0.5H, d, J=15.8 Hz); MS (ES+) m/z 343. The following compound was obtained in a similar manner to that of Preparation 414. Preparation 819

(2E)-3-(4-{[(3R)-l-(cyclohexylcarbonyl)-3- pyrrolidinyl]amino}phenyl)-N-(tetrahydro-2H-pyran-2- yloxy)acrylamide 1H-NMR (300 MHz, DMSO-d6) δ1.06-2.44 (19H, m),3.17-3.66 (4H, m),3.78-4.13 (3H, m),4.87 (IH, m) ,6.19 (IH, br),6.40 (IH, m),6.61 (IH, d, J=8.5 Hz),6.64 (IH, d, J=8.5 Hz) ,7.28-7.41 (3H, m),10.99 (IH, s); MS () m/z not detected.

The following compounds were obtained in a similar manner to that of Preparation 62. ' Preparation 820 (2E)-3-(5-chloro-6-{[1-(3-fluorobenzyl)-4-piperidinyl]amino} -3- pyridinyl)-N-(tetrahydro-2H-pyrari-2-yloxy)acrylamide 1H NMR (DMSO-d6) : <5 1.50-1.90 (HH, m) , 2.05-2.11 (2H, m) , 2.73- 2.78 (2H, m), 3.49 (2H, s), 3.95-4.05 (2H, m) , 4.89 (lΗ; S), 6.30 (IH, d, J = 15.9 Hz), 6.52 (IH, d, J = 7.8 Hz), 7.02-7.16 (3H, m) , 7.32-7.42 (2H, m), 7.84 (IH, s), 8.20 (IH, s), 11.07 (IH, brs). Mass (ESI) : 489(M+H)+.

Preparation 821 (2E)-3-(5-chloro-6-{[l-(3-methyl-2-buten-l-yl)-4- piperidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2- yloxy)acrylamide 1H NMR (DMSO-d6) : δ 1.53-1.85 (18H, m) , 1.93-2.20 (2H, m) , 2.87- 3.07 (4H, m), 3.49-.355 (IH, m) , 3.80-4.10 (2H, m) , 4.87 (IH, s), 5.17-5.24 (IH, m) , 6.31 (IH, d, J = 15.9 Hz), 6.55 (IH, d, J = 7.8 Hz), 7.35 (IH, d, J = 15.9 Hz), 7.84 (IH, s), 8.20 (IH, s), 11.08 (IH, brs). Mass (ESI) : 449(M+H)+.

Preparation 822 (2E)-3-(5-chloro-6-{[l-(cyclohexylmethyl)-4-piperidinyl]amin o}-3- pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H NMR. (DMSO-d6, <5 ) :0.78-0.90 (2H, m) , 1.14-1.30 (3H, m) , 1.46- 2.08 (2OH, m), 2.78-2.83 (2H, m) , 3.49-3.55 (IH, m) , 3.80-4.0.5 (2H, m), 4.88 (IH, s), 6.30 (IH, d, J = 15.9 Hz), 6.49 (IH, d, J = 7.8 Hz), 7.35 (IH, d, J = 15.9 Hz), 7.83 (IH, s), 8.20 (IH, sj, 11.07 (IH, brs). Mass (ESI) : 477(M+H)+.

The following compound was obtained in a similar manner to that of Preparation 370. Preparation 823 ethyl 6-[ (4-methylphenyl)amino]nicotinate ., 1H-NMR (300 MHz, CDCl3)Sl.38 (3H, t, J=7 Hz),2.36 (3H, s),4.35 (2H, q, J=7 Hz),6.75 (IH, d, J=9 Hz),6.89 (IH, br-s) ,7.15-7.26 (4H, m),8.03 (IH, dd, J=9, 2.5 Hz),8.82 (IH, d, J=2.5 Hz); MS (ES+) m/z 257.

The following compound was obtained in a similar manner to that of Preparation 361. Preparation 824 {6-[(4-methylphenyl)amino]-3-pyridinyl}methanol 1H-NMR (300 MHz, CDCl3) 02.33 (3H, s),4.58 (2H, s),6.54 (IH, br- s),6.82 (IH, d, J=8.5 Hz) ,7.11-7.22 (4H, m),7.52 (IH, dd, J=8.5, 2.5 Hz),8.14 (IH, d, J=2.5 Hz); MS (ES+) m/z 215.

The following compound was obtained in a similar manner to that of Preparation 382. I Preparation 825 6-[(4-methylphenyl)amino]nicotinaldehyde 1H-NMR (300 MHz, CDCl3) «52.37 (3H, s),6.79 (IH, d, J=8.5 Hz),7.15 (IH, br-s),7.18-7.30 (4H, m),7.94 (IH, dd, J=8.5, 2 Hz),8.60 (IH, d, J=2 Hz),9.83 (IH, s); MS (ES+) m/z 213.

The following compound was obtained in a similar manner to that of Preparation 683. Preparation 826 (2E)-3-{6~[ (4-methylphenyl)amino]-3-pyridinyl}acrylic acid 1H-NMR (300 MHz, DMSO-d6) 62.25 (3H, s),6.35 (IH, d, J=16 Hz),6.81 (IH, d, J=8.5 Hz),7.10 (2xlH, d, J=8.5 Hz),7.51 (IH, d, J=16 Hz),7.58 (2H, d, J=8.5 Hz),7.93 (IH, dd, J=8;5, 2 Hz),8.35 (IH, d, J=2 Hz),9.33 (IH, s); MS (ES+) m/z 255.

The following compound was obtained in a similar manner to that of Preparation 414. Preparation 827 (2E)-3-{6-[ (4-methylphenyl)amino]-3-pyridinyl}-N-(tetrahydro-2H- pyran-2-yloxy)acrylamide 1H-NMR (300 MHz, DMSO-d6) <51.45-1.78 (6H, m),2.25 (3H, s),3.53 (IH, m),3.96 (IH, m),4.89 (IH, m),6.32 (IH, d, J=16 Hz),6.83 (IH, d, J=8.8 Hz),7.10 (2H, d, J=8.5 Hz),7.42 (IH, d, J=16 Hz),7.57 (2H, d, J=8.5 Hz),7.76 (IH, br-d, J=8.8 Hz),8.30 (IH, d, J=I.5 Hz),9.29 (IH, s),11.13 (IH, br-s); MS (ES+) m/z 354.

The following compound was obtained in a similar manner to that of Preparation 674. Preparation 828 ethyl 6-[(2-ethoxyphenyl)amino]nicotinate 1H-NMR (300 MHz, CDCl3) 6l.39 (3H, t, J=7 Hz),1.46 (3H, t, J=7 Hz),4.12 (2H, q, J=7 Hz),4.36 (2H, q, J=7 Hz),6.84 (IH, d, J=8.8 Hz),6.89-7.06 (3H, m),7.28 (IH, s),8.03 (IH, dd, J=7.5, 2 Hz),8.07 (IH, dd, J=8.8, 2.2 Hz),8.89 (IH, d, J=2.2 Hz); MS (ES+) m/z 287.

The following compound was obtained in a similar manner to that of Preparation 361. Preparation 829 {6-[ (2-ethoxyphenyl)amino]-3-pyridinyl}methanol 1H-NMR (300 MHz, CDCl3)Gl.45 (3H, t, J=7 Hz),1.71 (IH, br),4.11 (2H, q, J=7 Hz),4.60 (2H, s),6.86-6.99 (4H, m),7.05 (IH, s),7.56 (IH, dd, J=8.5, 2.5 Hz),7.97 (IH, m),8.20 (IH, d, J=2.5 Hz); MS (ES+) m/z 245.

The following compound was obtained in a similar manner to that of Preparation 414. Preparation 830 (2E)-3-{6~[(2-ethόxyphenyl)amino]-3-pyridinyl}-N-(tetrahydr o-2H- pyran-2-yloxy)acrylamide 1H-NMR (300 MHz, DMSO-d6) δ1.35 (3H, t, 3=1 Hz) ,1.46-1.78 (6H, m),3.53 (IH, m),3.96 (IH, m),4.10 (2H, q, 3=1 Hz),4.89 (IH, m),6.33 (IH, d, J=16 Hz),6.87-7.07 (4H, m),7.42 (IH, d, J=16 Hz),7.77 (IH, m),8.08 (IH, dd, J=8, 1 Hz),8.29 (IH, d, J=2 Hz),8.37 (IH, s),11.13 (IH, s); MS (ES+) m/z 384.

The following compound was obtained in a similar manner to that of Preparation 382. Preparation 831 6-[(2-ethoxyphenyl)amino]nicotinaldehyde 1H-NMR (300 MHz, CDCl3)(Sl.46 (3H, t, J=7 Hz),4.13 (2H, q, 3=1 Hz),6.88 (IH, d, J=8.8 Hz),6.91-7.11 (3H, m),7.43 (IH, s),7.97 (IH, dd, J=8.8, 2.2 Hz),8.09 (IH, dd, 3=1.1, 1.8 Hz),8.66 (IH, d, J=2.2 Hz),9.86 (IH, s); MS (ES+) m/z 243.

The following compound was obtained in a similar manner to that of Preparation 683. Preparation 832 (2E)-3-{6-[(2-ethoxyphenyl)amino]-3-pyridinyl}acrylic acid 1H-NMR (300 MHz, DMSO-d6) <51.35 (3H, t, 3=1 Hz),4.10 (2H, q, 3=1 Hz),6.37 (IH, d, J=16 Hz) ,6.86-7.07 (4H, m),7.50 (IH, d, J=16 Hz),7.93 (IH, dd, J=8.8, 2.2 Hz),8.09 (IH, dd, J=8, 1.4 Hz),8.33 (IH, d, J=2.2 Hz),8.42 (IH, s); MS (ES+) m/z 285.

The following compound was obtained in a similar manner to that of Preparation 405. Preparation 833 (2E)-3-(4-{[(3R)-l-(cyclohexylmethyl)-3- pyrrolidinyl]amino}phenyl)acrylic acid 1H-NMR (300 MHz, DMSO-d6) <5θ.82-1.03 (2H, m) ,1.04-1.32 (3H, m),1.54- 2.02 (7H, m),2.24-2.46 (IH, m) ,2.83-3.45 (5H, m) ,3.56-4.34 (2H, m),6.21 (IH, d, J=16 Hz),6.61 (2H, d, J=8.5 Hz),6.69 (IH, m),7.46 (2H, d, J=8.5 Hz),7.46 (IH, d, J=16 Hz),10.29 (IH, br),12.00 (IH, s); MS (ES+) m/z 329.

The following compound was obtained in a similar manner to that of Preparation 363. Preparation 834 ethyl (2E)-3-(6-{[ (3R)-l-(cyclohexylmethyl)-3-piperidinyl]amino}-3- pyridinyl)acrylate 1H-NMR (300 MHz, CDCl3) <5θ.78-0.96 (2H, m),1.06-1.40 (5H, m),1.40- 1.84 (HH, m),2.00-2.25 (3H, m),2.38-2.64 (3H, m),3.96 (IH, br peak),4.25 (2H, q, J=7.1 Hz),5.49 (IH, br peak),6.21 (IH, d, J=15.9 Hz),6.39 (IH, d, J-8.8 Hz),7.57 (IH, d, J=15.9 Hz),7.61 (IH, dd, J=8.7, 2.4 Hz),8.19 (IH, d, J=2.2 Hz).

The following compound was obtained in a similar manner to that of Preparation 414. . Preparation 835 (2E)-3~(4-{[(3R)-l-(cyclohexylmethyl)-3-pyrrolidinyl]amino}p henyl)- N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (300 MHz, DMSO-d6) <50.74-0.91 (2H, m),1.04-1.30 (3H, m),1.40 (IH, m),1.46-1.81 (12H, m),2.11-2.29 (3H, m),2.33 (IH, dd, 3=9, 4.5 Hz),2.42 (IH, m),2.56 (IH, m),2.75 (IH, dd, 3=9, 7 Hz),3.53 (IH, m),3.82-4.01 (2H, m),4.87 (IH, m),6.16 (IH, br-d, J=16 Hz),6.29 (IH, d, ,J=6.5 Hz),6.56 (2H, d, J=8.8 Hz) ,7.26-7.38 (3H, m),10.97 (IH, s); MS (ES+) m/z 428.

The following compound was obtained in a similar manner to that of Preparation 361. Preparation 836 [5-chloro-6-(2,3-dihydro-lH-inden-l-ylamino)-3-pyridinyl]met hanol 1H-NMR (300 MHz, CDCl3)Sl.62 (IH, t, J=4. Hz),1.88 (IH, m),2.72 (IH, m), 2.84-3.10 (2H, m),4.57 (2H, d, J=4 Hz), 5.25 (IH, br-d, J=8 Hz), 5.70 (IH, ddd, J=8, 7.5, 7.5 Hz) ,7.17-7.37 (4H, m),7.57 (IH, d, J=2 Hz), 8.05 (IH, d, J=2 Hz); MS (ES+) m/z 275.

The following compound was obtained in a similar manner to that of Preparation 382. Preparation 837 5-chloro-6- ( 2 , 3-dihydro-lH-inden-l-ylamino)nicotinaldehyde 1H-NMR (300 MHz, CDCl3) <5l.94 (IH, m) , 2.74 ' (IH, m), 2.85-3.13 (2H, m), 5.76-5.92 (2H, m), 7.18-7.38 (4H, m),7.98 (IH, d, J=2 Hz), 8.51 (IH, d, J=2 Hz), 9.80 (IH, s); MS (ES+) m/z 273.

The following compound was obtained in a similar manner to that of Preparation 683. Preparation 838 ( 2E) -3- [5-chloro-6- ( 2 , 3-dihydro-lH-inden-l-ylamino) -3- pyridinyl] acrylic acid ' 1H-NMR (300 MHz, CDCl3) Sl.92 (IH, m),2.74 (IH, m), 2.86-3.12 (2H, m),5.58 (IH, d, J=8 Hz), 5.76 (IH, ddd, J=8, 7.5, 7.5 Hz).,6.26 (IH, d, J=15.7 Hz), 7.19-7.40 (4H, m),7.66 (IH, d, J=15.7 Hz), 7.73 (IH, d, J=I.8 Hz), 8.22 (IH, d, J=I.8 Hz); MS (ES+) m/z 315.

The following compound was obtained in a similar manner to that of Preparation 414. Preparation 839 (2E)-3-[5-chloro-6-(2,3-dihydro-lH-inden-l-ylamino)-3-pyridi nyl]- N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H-NMR (300 MHz, DMSO-d6) 61.44-1.76 (IH, m),2.08 (IH, m) ,2.76-3.15 (3H, m),3.53 (IH, m),3.95 (IH, m),4.90 (IH, m),5.78 (IH, ddd, J=8, 7.5, 7.5 Hz),6.35 (IH, d, J=16 Hz),7.06 (IH, d, J=8.5 Hz) ,7.13-7.32 (5H, m),7.40 (IH, d, J=16 Hz),7.90 (IH, s),8.26 (IH, s),ll.ll (IH, br-s); MS (ES+) m/z 414.

The following compound was obtained in a similar manner to that of Preparation 390. Preparation 840 (2E)~3-(4-{[(3R)-l-benzyl-3-pyrrolidinyl]amino}-3- fluorophenyl)acrylic acid MASS(API-ES); 341 (M+H)+. 1H-NMR ( 200MHz), (DMSO-d6, δ): 1.55 - 1.86 ( IH, m) , 2.07 - 2.73 ( 4H, m),' 2.77 - 2.93 ( IH, m) , 3.57, 3.64 ( 2H, ABq, J = 13Hz ), 3.90 - 4.10 ( IH, m), 5.99 ( IH, d, J = 5.2Hz ), 6.26 ( IH, d, J = 16Hz ), 6.67 ( IH, t, J = 8.8Hz ), 7.10 - 7.37 ( 7H, m) , 7.43 ( IH, d, J = 16Hz ) .

The following compound was obtained in a similar manner to that of Preparation 397. Preparation 841 (2E)-3-(4-{[(3R)-l-benzyl-3-pyrrolidinyl]amino}-3-fluorophen yl)-N- (tetrahydro-2H-pyran-2-yloxy)acrylamide MASS(API-ES); 440 (M+H)+, 1H-NMR ( 200MHz), (DMSO-d6, δ ) : 1.39 - 1.89 ( 7H, m) , 2.07 - 2.33 ( IH, m), 2.36 - 2.70 ( 3H, m), 2.75 - 2.93 ( IH, m), 3.44 - 3.70 ( 3H, m), 3.83 - 4.12 ( 2H, m), 4.88 ( IH, s ), 5.90 ( IH, d, J = 5.3Hz ), 6.23 ( IH, d, J = 16Hz ), 6.69 ( IH, t, J = 8.9Hz ), 7.11 - 7.44 ( 8H, m) .

The following compound was obtained in a similar manner to that of Preparation 198. Preparation 842 ethyl (2E)-3-(5-chloro-6-{[l-(3-fluorobenzyl)-4-piperidinyl]amino& gt;- 3-pyridinyl)aerylate 1H NMR (DMSO-d6, δ) :1.23(3H, t, J=7.1 Hz), 1.58-1.83(4H, m) , 2.00-2.11(2H, m), 2.78-2.84(2H, m) , 3.50(2H, s), 3.96-4.05(1H, m) , 4.15(2H, q, J=7.1 Hz), 6.47(1H, d, J=15.9 Hz), 6.63(1H, d, J=8.0 Hz), 7.02-7.16(3H, m) , 7.32-7.42(1H, m) , 7.5O(1H, d, J=15.9 Hz), 8.1O(1H, d, J=I.9 Hz), 8.27(IH, d, J=I.9 Hz), Mass (APCI) : 418(M+H)+.

The following compounds were obtained in a similar manner to that of Preparation 62. ' Preparation 843 (2E)-3-(5-chloro-6-{[l-(3-chlorobenzyl)-4-piperidinyl]amino} -3- pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H NMR (DMSO-d6, <5 ) :1.45-1.90(1OH, m) , 1.99-2.11(2H, m) , 2.78- 2.83(2H, m), 3.40-3.60(1H, m) , 3.55(2H, s), 3.90-4.10(2H, m) , 4.89(1H, brs), 6.3O(1H, d, J=15.9 Hz), 6.52(1H, d, J=7.9 Hz), 7.25- 7.41(5H, m), 7.84(1H, s), 8.2O(1H, s), 11.07(1H, brs). Mass (APCI) : 505(M+H)+.

Preparation 844 (2E)-3-(5-chloro-6-{[l-(2-fluorobenzyl)-4-piperidinyl]amino} -3- pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H NMR (DMSO-d6, δ) :1.53-1.69(8H, m) , 1.79-1.81(2H, m) , 2.05- 2.12(2H, m), 2.81-2.83(2H, m) , 3.50-3.60(1H, m) , 3.52(2H, s), 3.92- 3.98(2H, m), 4.88(1H, s), 6.3O(1H, d, J=15.7 Hz), 6.53(1H, d, J=7.9 Hz), 7.14-7.20(2H, m) , 7.31-7.43(3H, m) , 7.83(1H, s), 8.17(1H, s), 11.07(1H, s). Mass (APCI) : 489(M+H)+.

The following compound was obtained in a similar manner to that of Preparation 198. Preparation 845 ethyl (2E)-3-(5-chloro-6-{[l-(3-methyl-2-buten-l-yl)-4- piperidinyl]amino}-3-pyridinyl)acrylate 1H NMR (DMSO-d6, 6) :1.25 (3H, t, J = 7.4 Hz), 1.61-1.81 (4H, m) , 1.61 (3H, s), 1.70 (3H, s), 1.91-2.01 (2H, m) , 2.81-2.89 (4H, m) , 3.87-4.02 (IH, m) , 4.16 (2H, q, J = 7.4 Hz), 5.15-5.22 (IH, m) , 6.47 (IH, d, J = 15.9 Hz), 6.62 (IH, d, J = 7.9 Hz), 7.50 (IH, d, J = 15.9 Hz), 8.10 (IH, d, J = 1.9 Hz), 8.27 (IH, d, J = 1.9 Hz), Mass (ESI) : 378(M+H)+.

The following compound was obtained in a similar manner to that of Preparation 414. Preparation 846 (2E)-3-(5-chloro-6-{[2-(1-pyrrolidinylmethyl)phenyl]amino}-3 - pyridinyl)-N-(tetraliydro-2H-pyraii-2-yloxy)acrylamide 1H-NMR (300 MHz, CDCl3) <51.50-1.95 (1OH, m) ,2.50-2.62 (4H, m),3.67 (IH, m),3.71 (2H, s),3.97 (IH, m),5.00 (IH, m),6.30. (IH, br),6.97 (IH, ddd, J=7.5, 7.5, 1 Hz),1,15 (IH, dd, J=7.5, 1 Hz),7.31 (IH, dd, J=7.5, 7.5 Hz),7.64 (IH, d, J=15.5 Hz),7.74 (IH, d, J=2 Hz),8.24 (IH, d, J=2 Hz),8.34 (IH, d, J=7.5 Hz),8.36 (IH, br),10.95 (IH, s); MS ( ) m/z not detected.

The following compound was obtained in a similar manner to that of Preparation 62. Preparation 847 (2E)-3-(5-chloro-6-{[1-(3-pyridinylmethyl)-4-piperidinyl]ami no}-3- pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H NMR (DMSO-d6, δ) :1.53-1.84(1OH, m) , 1.99-2.11(2H, m), 2.78- 2.84(2H, m), 3.45-3.55(1H, m) , 3.50(2H, s), 3.85-4.10(2H, m) , 4.88(1H, brs), 6.3O(1H, d, J=15.9 Hz), 6.52(1H, d, J=7.9 Hz), 7.32- 7.39(2H, m), 7.68-7.72(lH, m) , 7.84(1H, s), 8.2O(1H, s), 8.45- 8.50(2H, m), 11.07(1H, brs), Mass (APCI) : 472(M+H)+.

The following compound was obtained in a similar manner to that of Preparation 198. Preparation 848 ethyl (2E)-3-(5-chloro-6-{[l-(2-fluorobenzyl)-4-piperidinyl]amino} - 3-pyridinyl)aerylate 1H NMR (DMSO-d6, δ) :1.24(3H, t, J=7.1 Hz), 1.61-1.78(4H, m) , 2.03-2.13(2H, m) , 2.80-2.86(2H, m) , 3.53(2H, s), 3.93-4.05(1H, m) , 4.15(2H, q, J=7.1 Hz), 6.47(1H, d, J=15.9 Hz), 6.62(1H, d, J=8.0 Hz), 7.15-7.44(4H, m) , 7.5O(1H, d, J=15.9 Hz), 8.09(1H, d, J=I.9 Hz), 8.27(1H, d, J=I.9 Hz), Mass (APCI) : 418(M+H)+.

The following compound was obtained in a similar manner to that of Preparation 62. Preparation 849 (2E)-3-(5-chloro-6-{[1-(4-pyridinylmethyl)-4-piperidinyl]ami no}-3- pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide 1H NMR (DMSO-d6, δ) :1.53-1.85(1OH, m) , 2.03-2.14(2H, m) , 2.77-, 2.83(2H, m), 3.5O-3.54(1H, m) , 3.51(2H, s), 3.90-4.10(2H, m) , 4.88(1H, brs), 6.31(1H, d, J=15.3 Hz), 6.53(1H, d, J=7.9 Hz), 7.31(2H, d, J=5.9 Hz), 7.35(1H, d, J=15.9 Hz), 7.84(1H, s), 8.2O(1H, s), 8.51(2H, d, J=5.9 Hz), 11.07(1H, brs). Mass (APCI) : 472(M+H)+.

The following compound was obtained in a similar manner to that of Preparation 198. Preparation 850 ethyl (2E)-3-(5-chloro-6-{[l-(3-pyridinylmethyl)-4- piperidinyl]amino}-3-pyridinyl)aerylate 1H NMR (DMSO-d6, <5 ) :1.24(3H, t, J=7.1 Hz), 1.55-1.83(4H, m) , 2.01-2.11(2H, m), 2.77-2.84(2H, m) , 3.50(2H, s), 3.90-4.05(1H, m) , 4.16(2H, q, J=7.1 Hz), 6.47(1H, d, J=15.9 Hz), 6.63(1H, d, J=7.9 Hz), 7.33-7.39(1H, m) , 7.5O(1H, d, J=15.9 Hz), 7.68-7.73(1H, m),8.09(lH, d, J=I.9 Hz), 8.27(1H, d, J=I.9 Hz), 8.45-8.50(2H, m), Mass (APCI) : 401(M+H)+.

The following compound was obtained in a similar manner to that of Preparation 683. Preparation 851 (2E)-3-(5-chloro-6-{[2-(1-pyrrolidinylmethyl)phenyl]amino}-3 - pyridinyl)acrylic acid 1H-NMR (300 MHz, DMSO-d6) δ1.72-1.86 (4H, m),2.44-2.58 (4H, m),3.73 (2H, s),6.52 (IH, d, J=16 Hz),6.98 (IH,' dd, J=7.5, 7.5 Hz),7.23 (IH," d, J=7.5 Hz),7.29 (IH, dd, J=7.5, 7.5 Hz),7.52 (IH, d, J=7.5 Hz),8.28 (IH, d, J=2 Hz),8.33 (IH, d, J=7.5 Hz),8.39 (IH, d, J=2 Hz),10.97 (IH, s); MS (ES+) m/z 358.

The following compound was obtained in a similar manner to that of Preparation 361. Preparation 852 (5-chloro-6-{[2-(l-pyrrolidinylmethyl)phenyl]amino}-3- pyridinyl)methanol 1H-NMR (300 MHz, CDCl3) <51.77-1.88 (4H, m),2.50-2.60 (4H, m),3.70 (2H, s),4.59 (2H, s),6.92 (IH, ddd, J=7.5, 7.5, 1.5 Hz),7.14 (IH, dd, J=7.5, 1.5 Hz),7.30 (IH, m),7.64 (IH, d, J=2 Hz),8.07 (IH, d, J=2 Hz),8.32 (IH, d, J=7.5 Hz),10.56 (IH, s); MS (ES+) m/z 318.

The following compound was obtained in a similar manner to that of Preparation 382. Preparation 853 5-chloro-6-{[2-(1-pyrrolidinylmethyl)phenyl]amino}nicotinald ehyde 1H-NMR (300 MHz, CDCl3) δ1.76-1.91 (4H, m),2.49-2.62 (4H, m),3.74 (2H, s),7.04 (IH, ddd, J=7.5, 7.5, 1.5 Hz),7.18 (IH, d, J=7.5 Hz),7.35 (IH, ddd, J=7.5, 7.5, 1.5 Hz),8.03 (IH, d, J=2 Hz),8.38 (IH, d, J=7.5 Hz),8.52 (IH, d, J=2 Hz),9.82 (IH, s),11.39 (IH, br- s); MS (ES+) m/z 316.

The following compound was obtained in a similar manner to that of Preparation 714. Preparation 854 ethyl (2E)~3-(4-{[(3R)-l-benzyl-3-pyrrolidinyl]amino}-3- fluorophenyl)aerylate MASS(API-ES); 369 (M+H)+ 1H-NMR ( 200MHz), (DMSO-d6, <5 ) : 1.23 ( 3H, t, J = 7.1Hz ), 1.63 - 1.87 ( IH, m), 2.08 - 2.33 ( IH, m) , 2.37 - 2.70 ( 3H, m) , 2.75 - 2.90 ( IH, m), 3.55, 3.62 ( 2H, ABq, J = 13Hz ), 3.88 - 4.11 ( IH, m), 4.15 ( 2H, q, J = 7.1Hz ), 6.02 ( IH, d, J = 5.1Hz ), 6.34 ( IH, d, J = 16Hz ), 6.67 ( IH, t, J = 8.8Hz ), 7.16 - 7.37 ( 6H, m), 7.41 - 7.59 ( 2H, m).

The following compound was obtained in a similar manner to that of Preparation 380. Preparation 855 (4-{[(3R)-l-benzyl-3-pyrrolidinyl]amino}-3-fluorophenyl)meth anol MASS(API-ES); 301 (M+H)+, 1H-NMR ( 200MHz), (DMSO-d6, <5 ) : 1.52 - 1.86 ( IH, m) , 2.05 - 2.31 ( IH, m), 2.32 - 2.69 ( 3H, m) , 2.71 - 2.88 ( IH, m) , 3.46 - 3.68 ( 2H, m), 3.81 - 4.05 ( IH, m) , 4.32 ( 2H, d, J = 5.6Hz ), 4.98 ( IH, t, J = 5.6Hz ), 5.15 ( IH, d, J = 5.7Hz ), 6.62 ( IH, t, J = 8.7Hz ), 6.84 - 7.00 ( 2H, m), 7.15 - 7.40 ( 5H, m) .

The following compounds were obtained in a similar manner to that of Preparation 379. Preparation 856 methyl 4-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-3-fluorobenzoate MASS(API-ES); 329 (M+H)+ , 1H-NMR ( 200MHz), (DMSO-d6, <5 ) : 1.64 - 1.94 ( IH, m) , 2.06 - 2.35 ( IH, m), 2.38 - 2.95 ( 4H, m), 3.55, 3.63 ( 2H, ABq, J = 13Hz ), 3.76 ( 3H, s ), 3.92 - 4.14 ( IH, m) , 6.30 ( IH, d, J = 6.8Hz ), 6.74 ( IH, t, J = 8.7Hz ), 7.16 - 7.38 ( 5H, m) , 7.49 ( IH, dd, J = 1.9Hz, J = 13Hz ), 7.60 ( IH, dd, J = 1.9Hz, J = 8.7Hz1 ).

The following compounds were obtained in a similar manner to that of Preparation 703. Preparation 857 tert-butyl (3R)-3-({4-[ (lE)-3-ethoxy-3-oxo-l-propen-l- yl]phenyl}amino)-1-pyrrolidinecarboxylate 1H-NMR (300 MHz, CDCl3)Sl.33 (3H, t, J=7 Hz),1.47 (9H, s),1.92 (IH, m),2.20 (IH, m),3.26 (IH, m),3.38-3.56 (2H, m),3.71 (IH, m),4.00- 4.12 (2H, m),4.24 (2H, q, J=7 Hz),6.23 (IH, d, J=16 Hz),6.57 (2H, d, J=8.5 Hz),7.38 (2H, d, J=8.5 Hz),7.60 (IH, d, J=16 Hz).

Preparation 858 ethyl (2E) -3-{4- [ (6-methyl-2-pyridinyl)amino]phenyl}acrylate 1H-NMR (300 MHz, CDCl3)Sl.34 (3H, t, J=7 Hz), 2.47 (3H, s),4.26 (2H, q, J=7 Hz), 6.34 (IH, d, J=15.7 Hz), 6.64 (IH, s),6.68 (IH, d, J=7.5 Hz), 6.76 (IH, d, J=7.5 Hz), 7.37 (2H, d, J=9 Hz), 7.45 (IH, dd, J=7.5, 7.5 Hz), 7.48 (2H, d, J=9 Hz), 7.64 (IH, d, J=15.7 Hz); MS (ES+) m/z 283. Preparation 859 To a stirred solution of ethyl (2E)-3-(2-{[(3R)-I- (cyclohexylmethyl)-3-pyrrolidinyl]amino}-5-pyrimidinyl)acryl ate (384 mg) in acetonitrile (5 inL) was added di-tert-butyl dicarbonate (468 mg) and 4-dimethylaminopyridine (26 mg) , and the mixture was stirred at 80°C for 18 hours. Additional di-tert-butyl dicarbonate (1.0 g) and 4-dimethylaminopyridine (50 mg) was added and the mixture was stirred at 8OC , for 24 hours. The solvent was evaporated in vacuo and the residue was purified by silica gel column chromatography (chloroform / methanol = 90 / 10 v/v) to give ethyl (2E)-3-(2-{(tert-butoxycarbonyl) [(3R)-1-(cyclohexylmethyl)-3- pyrrolidinyl]amino}-5-pyrimidinyl)acrylate (330 mg) as a tan solid. 1H-NMR OOO MHz, CDCl3) <5θ.66-0.86 (2H, m),1.04-1.72 (9H, m),1.35 (3x3H, t, J=7 Hz),1.46 (9H, s),2.06-2.30 (4H, m),2:54 (2H, t, J=7 Hz),2.70 (IH, dd, 3=9, 7 Hz),2.84 (IH, dd, J=9, 8 Hz),4.29 (2H, q, J=7 Hz),4.96 (IH, m),6.54 (IH, d, J=16 Hz),7,.59 (IH, d, J=16 Hz),8.80 (2xlH, s); MS (ES+) m/z 459.

Preparation 860 To a solution of ethyl (2E)-3-[5-chloro-6-(4-piperidinylamino)-3- pyridinyl]acrylate dihydrochloride(500mg) in DMF (5ml) was added l-chloro-3-(chloromethyl)benzene (0.173ml) and N,N- diisopropylethylamine (0.91ml), the mixture was stirred at 70°C for 7 hour. The mixed solution was poured into a mixture of water (30ml) and AcOEt (30ml). The organic layer was separated, washed with water twice and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with 5% MeOH in dichloromethane to give ethyl (2E)-3-(5-chloro-6-{[l-(3-chlorobenzyl)-4- piperidinyl]amino}-3-pyridinyl)acrylate (261mg, 46%). 1H NMR (DMSO-d6, δ) :1.23(3H, t, J=7.1 Hz), 1.62-1.83(2H, m) , 1.99-2.11(2H, m), 2.78-2.83(2H, m) , 3.48(2H, s), 3.90-4.10(1H, m) , 4.15(2H, q, J=7.1 Hz), 6.47(1H, d, J=15.9 Hz), 6.62(1H, d, J=7.9 Hz), 7.25-7.40(4H, m) , 7.5O(1H, d, J=15.9 Hz), 8.09(ΪH, d, J=I.9 Hz), 8.27(1H, d, J=I.9 Hz). Mass (APCI) : 434(M+H) + .

The following compound was obtained in a similar manner to that of Preparation 860. Preparation 861 , ethyl (2E)-3-(5-chloro-6-{[1-(2-chlorobenzyl)-4-piperidinyl]amino} - 3-pyridinyl)aerylate 1H NMR (DMSO-d6, <5 ) :1.24(3H, t, J=7.1 Hz), 1.59-1.84(4H, m) , 2.09-2.20(2H, m) , 2.52-2.88(2H, m) , 3.56(2H, s), 3.9O-4.15(1H, m) , 4.15(2H, q, J=7.1 Hz), 6.47(1H, d, J=15.9 Hz), 6.65(1H, d, J=7.9 Hz), 7.24-7.55(4H, m) , 7.5O(1H, d, J=15.9 Hz), 8.1O(1H, d, J=I.9 Hz), 8.28(1H, d, J=I.9 Hz). Mass (APCI) : 434(M+H) + . . Preparation 862 To a solution of ethyl (2E)-3-(5-chloro-6-{[l-(4-pyridinylmethyl)- 4-piperidinyl]amino}-3-pyridinyl)acrylate (308mg) in THF (3ml) and MeOH (3ml) was added IN NaOHaq (2.3ml), the mixture was stirred at 80°C for 1 hour. The pH of the mixture was adjusted to ca.4.5 with IN HClaq. The solution was evaporated under reduced pressure to give crude (2E)-3-(5-chloro-6-{[l-(4-pyridinylmethyl)-4- piperidinyl]amino}-3-pyridinyl)acrylic acid (469mg, 164%) 1H NMR (DMSO-d6, δ ) :1.59-1.87(4H, m) , 2.03-2.14(2H, m) , 2.77- 2.83(2H, m) , 3.51(2H, s), 3.94-4.03(1H, m) , 6.38(1H, d, J=15.7 Hz), 6.48(1H, d, J=7.9 Hz), 7.31(1H, d, J=15.7 Hz), 7.32(2H, d, J=5.9 Hz), 7.98(1H, d, J=2.0 Hz), 8.19(1H, d, J=2.0 Hz), 8.51(2H, d, J=5.9 Hz), Mass (APCI) : 373(M+H)+.

The following compounds were obtained in a similar manner to that of Preparation 862. Preparation 863 (2E)-3-(5-chloro-6-{[1-(2-pyridinylmethyl)-4-piperidinyl]ami no}-3- pyridinyl)acrylic acid 1H NMR (DMSO-d6, δ) : 1.58-1.85(4H, m) , 2.07-2.18(2H, m) , 2.81- 2.86(2H, m), 3.59(2H, s), 3.87-4.02(1H, m) , 6.34(1H, d, J=15.7 Hz), 6.39(1H, d, J=7.3 Hz), 7.21(1H, d, J=15.7 Hz), 7.23-7.29(1H, m) , 7.43(1H, d, J=7.8 Hz), 7.73-7.82(1H, m) , 7.92(1H, d, J=2.0 Hz), 8.15(1H, d, J=2.0 Hz), 8.48-8.50(1H, m) , Mass (APCI) : 373(M+H) + .

Preparation 864 (2E)-3-(5-chloro-6-{[l-(2-fluorobenzyl)-4-piperidinyl]amino} -3- pyridinyl)acrylic acid 1H NMR (DMSO-d6, δ) :1.80-2.10 (4H, m) , 2.60-3.20 (4H, m) , 3.16 (2H, s), 6.40 (IH, d, J = 15.9 Hz), 6.79 (IH, brs), 7.23-7.71 (5H, m), 8.07 (IH, d, J = 1.9 Hz), 8.25 (IH, d, J = 1.9 Hz), Mass (ESI) : 390(M+H)+.

Preparation 865 (2E)-3-(5-chloro-6-{[l-(3-pyridinylmethyl)-4-piperidinyl]ami no}-3- pyridinyl)acrylic acid 1H NMR (DMSO-d6, <5 ) .:1.55-1.86(4H, m) , 2.01-2.11(2H, m) , 2.78- 2.83(2H, m), 3.50(2H, s), 3.88-4.02(1H, m) , 6.38(1H, d, J=15.7 Hz), 8.44(IH, d, J=7.9 Hz), 7.28(IH, d, J=15.7 Hz), 7.35-7.39(IH, m) , 7.69-7.73(1H, m) , 7.95(1H, d, J=2.0 Hz), 8.18(1H, d, J=2.0 Hz), 8.45-8.50(2H, m) , Mass (APCI) : 373(M+H)+.

Preparation 866 (2E)-3-(5-chloro-6-{[l-(3-chlorobenzyl)-4-piperidinyl]amino} -3- pyridinyl)acrylic acid 1H NMR (DMSO-d6, <5 ) :1.57-1.89(4H, m) , 2.01-2.11(2H, m) , 2.78- 2.83(2H, m), 3.48(2H, s), 3.85-4.10(1H, m) , 6.37(1H, d, J=15.9 Hz), 6.51(1H, d, J=7.9 Hz), 7.11-7.40(5H, m) , 8.21(1H, d, J=I.9 Hz), 8.62(1H, d, J=I.9 Hz), . Mass (APCI) : 406(M+H)+.

Preparation 867 (2E)-3-(5-chloro-6-{[l-(3-fluorobenzyl)-4-piperidinyl]aπάn o}-3- pyridinyl)acrylic acid 1H NMR (DMSO-d6, δ) .1.23-1.43 (2H, m) , 1.64-1.67 (2H, m) , 1.95- 2.06 (2H, m), 2.73-2.79 (2H, m) , 3.16 (2H, s), 3.65-3.75 (IH, m) , 5.58 (IH, d, J = 15.9 Hz), 6.85 (IH, d, J = 15.9 Hz), 7.01-7.17 (4H, m), 7.30-7.41 (IH, m) , 7.44 (IH, d, J = 1.9 Hz), Mass (ESI) : 390(M+H)+.

Preparation 868 (2E)-3-(5-chloro-6-{[l-(cyclohexylmethyl)-4-piperidinyl]amin o}-3- pyridinyl)acrylic acid Mass (APCI) : 378(M+H)+. .

Preparation 869 (2E)-3~(5-chloro-6-{[l-(3-methyl-2-buten-l-yl)-4- piperidinyl]amino}-3-pyridinyl)acrylic acid 1H NMR (DMSO-d6, δ) :1.56-1.90 (2H, m) , 1.62 (3H, s), 1.70 (3H, s), 1.96-2.06 (2H, m) , 2.83-2.93 (4H, m) , 3.87-4.02 (IH, m) , 5.16-5.23 (IH, m), 6.37 (IH, d, J = 15.9 Hz), 6.55 (IH, d, J = 7.9 Hz), 7.40 (IH, d, J = 15.9 Hz), 8.03 (IH, d, J = 1.9 Hz), 8.22 (IH, d, J = 1.9 Hz), Mass (ESI) : 350(M+H)+.

Preparation 870 (2E)-3-(5-chloro-6-{[l-(2-chlorobenzyl)-4-piperidinyl]amino} -3- pyridinyl)acrylic acid 1H NMR (DMSO-d6, δ) :1.59-1.91(4H, m) , 2.10-2.20(2H, m) , 2.82- 2.88(2H, m), 3.57(2H, s), 3.97-4.06(lH, m) , 6.38(1H, d, J=15.9 Hz), 6.56(1H, d, J=7.9 Hz), 7.26-7.52(5H, m) , 8.03(1H, d, J=I.9 Hz), 8.23(1H, d, J=I.9 Hz), Mass (APCI) : 406(M+H)+.

Preparation 871 Palladium(II) acetate (25 mg) and 2,2'-bis(diphenylphosphino)- 1,1'-binaphthalene (106 mg) in dioxane (10 mL) was stirred at ambient temperature for 15 minutes. To this suspension was added ethyl 5,6-dichloronicotinate (500 mg) , 2-aminoindane (363 mg) , and cesium carbonate(1.1 g), and the mixture was heated at 1001C for 8 hours. The resulting mixture was allowed to cool to ambient temperature, poured into water, and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 10 / 1 v/v) to give ethyl 5-chloro-6-(2,3-dihydro-lH-inden-2- ylamino)nicotinate (420 mg) as a pale tan solid. 1H-NMR (300 MHz, CDCl3)Sl.37 (3H, t, J=7 Hz),2.86 (2H, dd, J=16, 5 Hz),3.43 (2H, dd, J=16, 7 Hz),4.27 (2H, q, J=7 Hz),4.99 (IH, m),5.59 (IH, br-d, J=3 Hz) ,7.17-7.25 (4H, m),8.02 (IH, d, J=2 Hz),8.73 (IH, d, 3=2 Hz); MS (ES+) m/z 317.

The following compounds were obtained in a similar manner to that of Preparation 871. Preparation 872 ethyl 5-chloro-6-[ (4-methylphenyl)amino]nicotinate 1H-NMR (300 MHz, CDCl3)Sl.38 (3H, t, J=7 Hz),2.35 (3H, s),4.35 (2H, q, J=7 Hz),7.19 (2H, d, J=8.5 Hz),7.20 (IH, s),7.50 (2H, d, J=8.5 Hz),8.14 (IH, d, J=2 Hz),8.75 (IH, d, J=2 Hz); MS (ES+) m/z 291.

Preparation 873 ethyl 5-chloro-6-[(2-ethoxyphenyl)amino]nicotinate 1H-NMR (300 MHz, CDCl3) Sl.39 (3H, t, J=7 Hz),1.51 (3H, t, J=7 Hz),4.16 (2H, q, J=7 Hz),4.36 (2H, q, J=7 Hz),6.92 (IH, m),6.98-7.05 (2H, m),8.15 (IH, d, J=2 Hz),8.27 (IH, br-s),8.66 (IH, m),8.82 (IH, d, J=2 Hz); MS (ES+) m/z 321.

Preparation 874 ethyl 5-chloro-6-(2,3-dihydro-lH-inden-l-ylamino)nicotinate 1H-NMR (300 MHz, CDCl3) Sl.38 (3H, t, J=7 Hz), 1.92 (IH, m),2.74 (IH, m), 2.87-3.12 (2H, m),4.35 (2H, q, J=7 Hz), 5.63 (IH, br-d, J=8 Hz), 5.80 (IH, ddd, J=8, 7.5, 7.5 Hz) ,7.19-7.36 (4H, m),8.06 (IH, d, J=2 Hz ) , 8. 75 ( IH, d, J=2 Hz ) ; MS (ES+ ) m/z 317.

Preparation 875 ethyl 5-chloro-6-{[2-(l-pyrrolidinylmethyl)phenyl]amino}nicotinate 1H-NMR (300 MHz, CDCl3)Sl.39 (3H, t, J=7 Hz) ,1.78-1.88 (4H, m),2.51-2.62 (4H, m),3.72 (2H, s),4.36 (2H, q, 3=1 Hz),6.99 (IH, ddd, J=7.5, 7.5, 1.5 Hz),7.16 (IH, dd, J=7.5, 1.5 Hz),7.32 (IH, ddd, J=7.5, 7.5, 1.5 Hz),8.12 (IH,. d, J=2 Hz),8.36 (IH, dd, J=7.5, 1.5 Hz),8.76 (IH, d, J=2 Hz),11.07 (IH, s); MS (ES+) m/z 360.

Preparation 876 A mixture of ethyl l-(2-nitrobenzyl)pyrrolidine (1.90 g) and 10% palladium on carbon (200 mg) in methanol (40 mL) was hydrogenated at ambient temperature. After completion of the reaction, the catalyst in the reactioni mixture was removed by filtration. The solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform / methanol=20 /1 v/v) to give [2-(l-pyrrolidinylmethyl)phenyl]amine (1.65 g) as a pale yellow solid. 1H-NMR (300 MHz, CDCl3) δ1.72-1.87 (4H, m) ,2.46-2.62 (4H, m),3.65 (2H, s),6.61-6.72 (2H, m),7.01 (IH, br-d, J=8 Hz),7.09 (IH, br-dd, J=8, 8 Hz); MS (ES+) m/z 177.

Preparation 877 To a solution of 5,6-dichloronicotinic acid (7.0 g, 35 mmol) in DMF were added iodoethane (6.0 g, 38.5 mmol) and K2CO3 (5.8 g, 42 mmol) at ambient temperature and the mixture was stirred at 45 °C for 5 hrs. To the reaction mixture were added (3R)-l-benzyl-3- piperidinamine dihydrochloride (10.1 g, 38.5 mmol) and K2CO3 (16.9 g, 122.mmol) and the reaction mixture was stirred at 90 °C for 18 hrs. The reaction mixture was evaporated in vacuo and the residue was partitioned between water and EtOAc. The organic layer was separated, washed water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (EtOAc-hexane/l-4~l-3) to give ethyl 6- {[ (SRj-l-benzyl-S-piperidinyllaminol-S-chloronicotinate (6.75 g, 52%) as a powder. 1H-NMR (300 MHz, CDCl3) <5l.36 (3H, t, J=7.1 Hz) ,1.51-1.69 (2H, m),1.69-1.88 (2H, m) ,2.18-2.33 (IH, m) ,2.41-2.54 (IH, m) ,2.54-2.67 (IH, m),2.67-2.79 (IH, m),3.45 (IH, d, J=13 Hz),3.61 (IH, d, J=13 Hz),4.32 (2H, q, J=7.1 Hz),6.24 (IH, br peak) ,7.21-7.41 (5H, m),8.00 (IH, d, J=2 Hz),8.65 (IH, d, J=2 Hz); MS (ES+) m/z 374.

Example 1 A solution of 10% HCl-MeOH solution (0.75ml) was added to a mixture of (2E)-3-{6-[(l-benzyl-3-pyrrolidinyl)amino]-3-pyridyl}-N- (tetrahydro-2H-pyran-2-yloxy)acrylamide (170mg) in MeOH 3ml) and stirred at 15-25°C for 2 hours. The reaction mixture was evaporated in vacuo and the residue was triturated with small amount MeOH and acetone and the precipitate was collected by filtration to give (2E)-3-{6-[(l-benzyl-3-pyrrolidinyl)amino]-3-pyridyl}-N- hydroxyacrylamide dihydrochloride (107mg) NMR (DMSO-dβ, <5): 2.04-2.40 (2H, m) , 3.18-3.83 (4H, m) , 4.43-4.58 (2H, m), 4.80 (IH, m) , 6.42 (IH, d, J= 15.80Hz), 7.04 (IH, d, J= 9.20Hz), 7.25 (IH, d, J= 9.20H), 7.40-7.46 (4H, m) , 7.65-7.70 (2H, m), 8.01-8.10 (IH, m) , 8.18 (IH, s), 11043-11.78 (IH m)

The following compounds were obtained according to a similar manner to that of Example 1.

Example 2 (2E)-3-{6-[(l-Benzyl-3-pyrrolidinyl)(methyl)amino]-3-pyridyl }-N- hydroxyacrylamide dihydrochloride NMR (DMSO-de, <5 ) : 2.09-2.40 (2H. m) , 3.10 (3H, s), 3.10-3.28 (2H, m), 3.46-3.63 (2H, m) , 4.41-4.49 (2H, m) , 5.24-5.51 (IH, m) , 6.38- 6.50 (IH, m), 7.03-7.19 (IH, m) , 7.38-7.47 (4H, m), 7.64-7.69 (2H, m), 7.98-8.07 (IH, m) , 8.26 (IH,s)

Example 3 (2E)-3-(6-{[(3R)-l-Benzyl-3-pyrrolidinyl]amino}-3-pyridyl)-N - hydroxyacrylainide dihydrochloride NMR (DMSO-de, δ): 1.99-2.50 (2H, m) , 3.25-3.83 (4H, m), 4.43, 4.55 (2H, ABq, J= 5.38Hz), 4.77 (IH, m) , 6.36-6.45 (IH, m) , 6.99 (0.5H, d, J= 9.00Hz), 7.19 (0.5H d, J= 9.00Hz), 7.74-7.46 (4H, m) , 7.63- 7.66 (2H, m), 7.98-8.06 (IH, m) , 8.18 (IH, s)

Example 4 (2E)-3-(6-{[(3S)-l-Benzyl-3-pyrrolidinyl]ami.no}-3-pyridyl)- N- hydroxyacrylamide dihydrochloride NMR (DMSO-de, <5 ) : 2.06-2.62 (2H, m) , 3.26-3.83 (4H, m) , 4.44, 4.56 (2H, ABq, J= 5.48Hz), 4.79 (IH, m) , 6.42 (IH, d, J= 15.72Hz), 7.02 (0.5H, d, J= 9.16Hz), 7.22 (0.5H, d, J= 9.16Hz), 7.40-7.46 (4H, m) , 7.64-7.70 (2H, 'm), 8.00-8.08 (IH, m),8.18 (IH, s)

Example 5 (2E)-3-(6-{[(3R)-l-Benzyl-3-pyrrolidinyl]amino}-5-chloro-3- pyridyl)-N-hydroxyacrylamide dihydrochloride NMR (DMSO-d6, d): 1.91-2.16 (IH, m) , 2.30-2.40 (IH, m) , 3.08-3.68 (4H, m), 4.41 (2H, d, J= 5.56Hz), 4.70-4.89 (IH, m) , 6.38 (IH, d, J= 15.82Hz), 7.34 (IH, d, J= 15.82Hz), 7.30-7.46 (3H, m) , 7.62-7.66 (2H, m), 7.91 (IH, s), 8.21 (IH, s)

Example 6 (2E)-3-(6-{[ (3S)-l-Benzyl-3-pyrrolidinyl]amino}-5-chloro-3- pyridyl)-N-hydroxyacrylamide dihydrochloride NMR (DMSO-d6, δ)z 1.95-2.16 (2H, m) , 3.06-3.70 (4H, m) , 4.41 (2H, d, J= 5.50Hz), 4.70-4.89 (IH, m) , 6.39 (IH, d, J= 15.82Hz), 7.35 (IH, d, J= 15.82Hz), 7.39-7.51 (4H, m) , 7.62-7.66 (2H, m) , 7.91 (IH, s), 8.21 (IH, s)

Example 7 (2E)-N-Hydroxy-3-(6-{t (3R)-1-(4-methoxybenzyl)-3- pyrrolidinyl]amino}-3-pyridyl)acrylamide dihydrochloride NMR (DMSO-de, <5 ) : 1.95 - 2.80 (2H, m) , 3.10 - 3.90 (4H, m) , 3.77 (3H, s), 4.30 - 4.49 (2H, m) , 4.50 - 4.90 (IH, m) , 6.40 (IH, dd, J= 3.0Hz, J= 16Hz), 6.90 - 7.21 (3H, m) , 7.35 - 7.62 (3H, m) , 7.95 - 8.08 ( IH, m) , 8. 18 ( IH, s ) , 8.70 - 10.40 ( IH, m) , 11 . 10 - 11 .60 ( IH, m) MASS(API-ES); 369 (M+H)+ Free

Example 8 (2E)-3-(6-{[ (3R)-1-(4-Fluorobenzyl)-3-pyrrolidinyl]amino}-3- pyridyl)-N-hydroxyacrylamide dihydrochloride NMR (DMSOd6, <5): 1.95 - 2.90 (2H, m), 3.10 - 3.90 (4H, m) , 4.40 - 4.90 (3H, m), 6.40 (IH, dd, J= 2.5Hz, J= 16Hzj, 6.90 - 7.35 (3H, m), 7.42 (IH, dd, J= 2.5Hz, J= 16Hz), 7.60 - 7.80 (2H, m) , 7.90 - 8.10 (IH, m), 8.18 (IH, s), 8.70 - 10.40 (IH, m) , 11.30 - 11.80 (IH,

MASS(API-ES); 357 (M+H)+ Free

Example 9 (2E)-3-(6-{[(3R)-l-(4-Chlorobenzyl)~3-pyrrolidinyl]amino}-3- pyridyl)-N-hydroxyacrylamide dihydrochloride NMR (DMSO-d6, <5 ) : 1.90 - 2.80 (2H, m) , 3.10 - 3.90 (4H, m) , 4.35 - 4.85 (3H, m), 6.40 (IH, dd, J= 2.0Hz, J= 16Hz), 6.95 - 7.25 (IH, m), 7.44 (IH, dd, J= 2.0Hz, J= 16Hz), 7.48 - 7.60 (2H, m) , 7.64 - 7.80 (2H, m), 7.95 - 8.10 (IH, m) , 8.18 (IH, s), 8.80 - 10.40 (IH, m), 11.40 - 11.80 (IH, m) MASS(API-ES); 373 (M+H)+ ,375 (M+H+2)+ Free

Example 10 (2E)-N-Hydroxy-3-(6-{[ (3R)-1-(4-methylbenzyl)-3- pyrrolidinyl]amino}-3-pyridyl)acrylamide dihydrochloride MASS(API-ES); 353 (M+H)+ Free NMR (DMSO-de, 6 ) : 1.95 - 2.75 (2H, m) , 2.32 (3H, s), 3.10 - 3.90 (4H, m), 4.25 - 4.90 (3H, m) , 6.40 (IH, dd, J= 2.8Hz, J= 16Hz), 6.95 - 7.30 (3H, m) , 7.43 (IH, dd, J= 2.5Hz, J= 16Hz), 7.47 - 7.60 (2H, m), 7.95 - 8.10 (IH, m), 8.18 (IH, s), 8.80 - 10.30 (IH, m), 11.20 - 11.70 (IH, m)

Example 11 (2E)-3-(6-{[(3R)-l-(Cyclopropylmethyl)-3-pyrrolidinyl]amino} -3- pyridyl)-N-hydroxyacrylamide dihydrochloride NMR (DMSO-d6, δ ) : 0.30 - 0.70 ( 4H, m) , 1.00 - 1.30 ( IH, m), 1.95 - 2.80 ( 2H, m) , 3.00 - 4.10 ( 6H, m) , 4.55 - 4.90 ( IH, m) , 6.44 (IH, d, J= 16Hz), 7.05 - 7.30 ( IH, m) , 7.45 (IH, d, J= 16Hz), 8.07 (IH, d, J= 9.3Hz), 8.20 ( IH,, s), 9.20 - 10.60 ( IH, m), 11.00 - 11.40 ( IH, m) MASS(API-ES); 303 (M+H)+ Free

Example 12 (2E)-3-(6-{[(3R)-l-Benzoyl-3-pyrrolidinyl]amino}-5-chloro-3- pyridyl)-N-hydroxyacrylamide hydrochloride NMR (DMSO-d6, <5 ) : 1.90 - 2.40 (2H, m) , 3.20 - 4.00 (4H, m) , 4.40 - 4.80 (IH, m), 6.25 - 6.42 (IH, m) , 7.04 (IH, br) , 7.25 - 7.60 (6H, m), 7.85 - 8.00 (IH, m), 8.10 - 8.30 (IH, m) MASS(API-ES); 387 (M+H)+ Free ,389

Example 13 (2E)-3-(5-Chloro-6-{[(3R)-1-(cyclopropylcarbonyl)-3- pyrrolidinyl]amino}-3-pyridyl)-N-hydroxyacrylamide hydrochloride NMR (DMSO-de, <5 ) : 0.60 - 0.80 (4H, m), 1.60 - 1.85 (IH, m), 1.90 - 2.40 (2H, m), 3.20 - 4.10 (4H, m) , 4.45 - 5.00 (IH, m) , 6.35 (IH, d, J= 16Hz), 7.01 (IH, br), 7.35 (IH, d, J= 16Hz), 7.91 (IH, s), 8.23 (IH, s) MASS(API-ES); 351 (M+H)+ Free

Example 14 (2E)-3-{6-[(1-Benzoyl-4-piperidyl)amino]-3-pyridyl}-N- hydroxyacrylamide hydrochloride NMR (DMSO-d6, δ ) : 1.30-1.60(2H, m) , 1.85-2.10(2H, m) , 2.90-4.50(5H, m), 6.4O(1H, d, J= 16.0 Hz), 7.13(1H, d, J= 9.0 Hz), 7.38-7.49(6H, m), 7.05(1H, d, J= 9.0 Hz), 8.16(1H, s), 9.26(1H, brs)

Example 15 (2E)-3-(6-{[1-(4-Fluorobenzoyl)-4-piperidyl]amino}-3-pyridyl )'-N- hydroxyacrylamide hydrochloride NMR (DMSOd6, δ ) : 1.45-1.60(2H, m) , 1.95-2.10(2H, m) , 3.00-4.60(5H, m), 6.39(1H, d, J= 16.0 Hz), 7.13(1H, d, J= 8.9 Hz), 7.25-7.53(5H, m), 8.06(1H, d, J= 8.9 Hz), 8.17(1H, s) Mass (ESI ) : 385 (M+H) +

Example 16 (2E)-N-Hydroxy-3-(6-{[l-(4-methylbenzoyl)-4-piperidyl]amino} -3- pyridyl)acrylamide hydrochloride NMR (DMSOd6, 6): 1.40-1.60(2H, m) , 1.85-2.10(2H, m) , 2.34(3H, s), 3.00-4.50(5H, m), 6.39(1H, d, J= 16.0 Hz), 7.1O(1H, d, J= 8.9 Hz), 7.25(1H, d, J= 8.8 Hz), 7.31(1H, d, J= ,8.8 Hz), 7.44(1H, d, J= 16.0 Hz), 8.05(1H, d, J= 8.9 Hz), 8.16(1H, s) Mass (ESI): 381(M+H)+

Example 17 (2E)-N-Hydroxy-3-(6-{[1-(4-methoxybenzoyl)-4-piperidyl]aminq }-3- pyridyl)acrylamide hydrochloride NMR (DMSO-d6, <5 ) : 1.30-1.60(2H, m) , 1.95-2.10(2H, m) , 3.15-3.80(4H, m), 3.79(3H, s), 3.90-4.15(2H, m) , 6.38(1H, d, J= 16.0 Hz), 6.99(2H, d, J= 8.8 Hz), 7.1O(1H, d, J= 8.9 Hz), 7.38(2H, d, J= 8.8 Hz), 7.44(1H, d, J= 16.0 Hz), 8.04(1H, d, J= 8.9 Hz), 8.17(1H, s) Mass (ESI): 397(M+H)+

Example 18 (2E)-N-Hydroxy-3-[6-({1-[4-(lH-pyrrol-1-yl)benzoyl]-4- piperidyl}amino)-3-pyridyl]acrylamide hydrochloride NMR (DMSOd6, δ): 1.35-1.60(2H, m) , 1.85-2.15(2H, m) , 3.00-4.50(5H, m), 6.28-6.30(2H, m) , 6.4O(1H, d, J= 16.0 Hz), 7.15(1H, d, J= 9.5 Hz), 7.42-7.53(5H, m) , 7.67(2H, d, J= 8.6 Hz), 8.07(1H, d, J= 9.5 Hz), 8.17(1H, s), 9.3O(1H, brs) Mass (ESI): 432(M+H)+

Example 19 N-(4-Chlorophenyl)-4-({5-[(IE)-3-(hydroxyamino)-3-oxo-l-prop en-l- yl]-2-pyridyl}amino)-1-piperidinecarboxamide hydrochloride NMR (DMSO-d6, <5 ) : 1.40-1.45(2H, m), 1.90-2.10(2H, m) , 2.94-3.01(2H, m), 3.99(1H, brs), 4.10-4.15(2H, m) , 6.37-6.40(1H, m) , 7.00-7.14(1H, m), 7.27(2H, d, J= 8.8 Hz), 7.43-7.53(3H, m), 8.03(1H, m) , 8.18(1H, s), 8.76(1H, s), 1O.81(1H, brs) Mass (ESI): 416(M+H)+ Example 20 4-({5-[(IE)-3-(Hydroxyamino)-3-oxo-l-propen-l-yl]-2-pyridyl} amino)- N-(4-methylphenyl)-1-piperidinecarboxamide hydrochloride NMR (DMSO-dβ, <5 ) : 1.30-1.60(2H, m) , 1.90-2.05(2H, m), 2.23(3H, s), 2.85-3.10(2H, m) , 4.00-4.25(3H, m) , 6.4O(1H, d, J= 15.4 Hz), 7.04(2H, d, J= 8.8 Hz), 7.11(1H, brs), 7.34(2H, d, J= 8.8 Hz), 7.45(1H, d, J= 15.4 Hz), 8.04(1H, d, J= 9.6 Hz), 8.17(1H, s), 8.51(IH, s) Mass (ESI): 396(M+H)+

Example 21 4-({5-[(IE)-3-(Hydroxyamino)-3-oxo-l-propen-l-yl]-2-pyridyl} amino)- N-(4-methoxyphenyl)-1-piperidinecarboxamide hydrochloride NMR (DMSO-de, <5 ) : 1.30-1.60(2H, m) , 1.90-2.05(2H, m) , 2.85-3.10(2H, m), 3.70(3H, s), 4.00-4.25(3H, m) , 6.41(1H, d, J= 15.4 Hz), 6.82(2H, d, J= 8.8 Hz), 7.15(1H, d, J= 9.4 Hz), 7.34(2H, d, J= 8.8 Hz), 7.46(1H, d, J= 15.4 Hz), 8.06(1H, d, J= 9.4 Hz), 8.17(1H, s), 8.46(1H, s) Mass (ESI): 412(M+H)+ ,

Example_22 (2E)-3-{6-[(l-Benzoyl-4-piperidyl)amino]-5-chloro-3-pyridyl} -N- hydroxyacrylamide hydrochloride NMR (DMSO-d6, <5 ) : 1.50-2.10(6H, m) , 2.80-3.00(2H, m) , 6.33(1H, d, J= 16.0 Hz), 7.25-7.60(6H, m) , 7.92(1H, s), 8.2O(1H, s)

Example 23 (2E)-3-(5-Chloro-6-{[l-(4-chlorobenzoyl)-4-piperidyl]amino}- 3- pyridyl)-N-hydroxyacrylamide hydrochloride NMR (DMSO-dg, (5): 1.50-2.10(6H, m) , 2.80-3.10(2H, m) , 6.31(1H, d, J= 16.0 Hz), 6.77(1H, brs), 7.34(1H, d, J= 16.0 Hz), 7.42(2H, d, J= 8.8 Hz), 7.54(2H, d, J= 8.8 Hz), 7.91(1H, s), 8.19(1H, s)

Example 24 (2E)-3-(5-Chloro-6-{[l-(3-chlorobenzoyl)-4-piperidyl]ariιin o}-3- pyridyl)-N-hydroxyacrylamide hydrochloride IH NMR (DMSO-d6, <5 ) : 1.45-2.10(4H, m) , 2.70-3.30(2H, m) , 3.40- 3.7O(1H, m), 6.35(1H, d, J= iβ.O Hz), 6.89(1H, brs), 7.31-7.57(5H, m), 7.95(1H, s), 8.2O(1H, s)

Example 25 (2E)-3-(5-Chloro-6-{[l-(2-chlorobenzoyl)-4-piperidyl]amino}- 3- pyridyl)-N-hydroxyacirylainide hydrochloride NMR (DMSO-d6, <5 ): 1.45-2.05(4H, m), 2.80-3.40(3H, m)> 4.10-4.30(1H/ brs), 4.30-4.70(1H, m) , 6.35(1H, d, J= 16.0 Hz), 6.80-7.20(1H, m) , 7.31-7.57(5H, m) , 7.96(1H, s), 8.19(1H, s)

Example 26 (2E)-3-(5-Chloro-6-{[l-(4-phenoxybenzoyl)-4-piperidyl]amino} -3- pyridyl)-N-hydroxyacrylamide hydrochloride NMR (DMSO-dβ, <5 ) : 1.45-2.05(4H, m) , 2.70-3.30(2H, m) , 3.50-3.90(1H, m), 4.20-4.70(2H,, m), 6.36(1H, άt) J= 16.0 Hz), 7.01-7.48(11H, m) , 7.97(1H, s), 8.2O(1H, s) Mass (ESI): 493(M+H)+

Example 27 4-({3-Chloro-5-[ (lE)-3-(hydroxyamino)-3-oxo-l-propen-l-yl]-2- pyridyl}amino)-N-(4-chlorophenyl)-1-piperidinecarboxamide hydrochloride NMR (DMSO-de, <5 ) : 1.45-1.75(2H, m) , 1.75-1.95(2H, m) , 2.83-2.98(2H, m), 4.12-4.40(3H, m) , 6.36(1H, d, J= 15.8 Hz), 7.06(1H, brs), 7.28(2H, d, J= 8.8 Hz), 7.36(1H, d, J= 15.8 Hz), 7.53(2H, d, J= 8.8 Hz), 7.58(1H, s), 8.21(1H, s), 8.76(1H, s) Mass (ESII): 450(M+H)+

Example 28 (2E)-3-(5-Chloro-6-{[l-(4-chlorobenzyl)-4-piperidyl]amino}-3 - pyridyl)-N-hydroxyacrylamide dihydrochloride NMR (DMSO-d6, δ): 1.95-2.20(4H, m) , 2.95-3.45(4H, m) , 4.27(2H, m), 6.33(1H, brs), 7.03(1H, d, J= 16.0 Hz), 7.34(1H, d, J= 16.0 Hz), 7.54(1H, d, J= 8.8 Hz), 7.71(1H, d, J= 8.8 Hz), 7.9O(1H, s), 8.18(1H, s), 11.04(lH, brs) Mass (APCI): 406(M+H)+ Example 29 A solution of 10% HCl-MeOH solution (0.5ml) was added to a mixture of (2E)-3-{6-[(l-benzyl-4-piperidyl)amino]-3~pyridyl}~N- (tetrahydro-2H-pyran-2-yloxy)acrylamide (180mg) in MeOH (5ml) and stirred at 15-25 °C for 2 hours. The reaction mixture was evaporated in vacuo and the residue was triturated with small amount MeOH and acetone and the precipitate was collected by filtration to give (2E)-3-{6-[(l-benzyl-4-piperidyl)amino]-3- pyridyl}-N-hydroxyacrylamide dihydrochloride (120mg) IH-NMR(DMSO-d6): δ 1.90-2.30 (4H, m), 2.85-3.45 (4H, m), 4.32 (2H, s), 6.38 and 6.46 ( IH, s), 7.08 ( IH, d, J = 18.8Hz ), 7.47 ( 5H, s), 7.58 - 7.72 ( 2H, m) , 8.04 ( IH, d, J = 18.8Hz ), 8.13 ( IH, s), 9.33 ( IH, br.s), 11.2 ( 2H, br.s).

The following compounds were obtained according to a similar manner to that of Example 29.

Example 30 4-({5-[(lE)-3-(Hydroxyamino)-3-oxo-l-propen-l-yl]-2-pyridyl} amino)- N-phenyl-1-piperidinecarboxamide hydrochloride NMR (DMSO-d6, <5 ) : 1.39-1.55 (2H, m) , 1.96-2.02 (2H, m) , 2.93-3.05 (2H, m), 4.19-4.29 (3H, m) , 6.43 (IH, d, J= 15.82Hz), 6.89-6.97 (IH, m), 7.15-7.27 (3H, m) , 7.42-7.50 (3H, m) , 8.08 (IH, d, J= 9.56Hz), 8.28 (IH, S), 8.63 (IH, s), 9.40 (IH, m)

Example 31 (2E)-3-(6-{[l-(4-Chlorobenzoyl)-4-piperidyl]amino}-3-pyridyl )-N- hydroxyacrylamide hydrochloride NMR (DMSO-d6, δ): 1.91-2.18 (6H, m) , 2.95-3.01 (2H, m) , 4.33-4.35 (IH, m), 6.41 (IH, d, J= 15.86Hz), 7.08 (IH, d, J= 9.38Hz), 7.44 (IH, d, J= 15.86Hz), 7.54 (2H, d, J= 8.42Hz), 7.71 (2H, d, J= 8.42Hz), 8.03-8.14 (2H, m), 11.37 (IH, m)

Example 32 (2E)-3-(6-{[(3R)-l-Benzyl-3-pyrrolidinyl]amino}-3-pyridyl)- N-hydroxyacrylamide dihydrochloride (860mg) was dissolved into water (40ml), and the solution was adjusted to ca. pH4.0 by addition of a few drops of aq NaHCO3 solution. The aqueous solution was chromatographed with HP-20(100ml) , washing with water and eluting with 75% aqueous MeOH. The elute was concentrated to ca. 10ml in vacuo, and the resulting precipitate was collected by filtration. (2E)-3-(6-{[(3R)-l-benzyl-3-pyrrolidinyl]amino}-3- pyridyl)-N-hydroxyacrylamide (240mg) was obtained as colorless powder. NMR (DMSO-dβ, δ ) : 1.50 - 1.80 (IH, m) , 2.10 - 2.90 (5H, m) , 3.45 - 3.70 (2H, m), 4.20 - 4.45 (IH, m), 6.16 (IH, d, J = 16Hz), 6.51 (IH, d, J = 8.8Hz), 7.10 - 7.40 (7H, m) , 7.57 (IH, dd, J= 1.5Hz, J= 8.8Hz), 8.10 (IH, d, J = 1.5Hz), 8.91 ( IH, br) , 10.57 (IH, br) MASS(API-ES); 339 (M+H)+

Example 33 To a suspension of (2E)-3-(6-{[ (3R)-l-(4-tert-butylbenzyl)- 3-pyrrolidinyl]amino}-3-pyridyl)-N-(tetrahydro-2H-pyran-2- yloxy)acrylamide(270mg) was suspended in methanol(ImL) and to this suspension was added hydrogen chloride in methanol solution(10%, 3mL) . The mixture was stirred at ambient temperature for 15 minutes and concentrated in vacuo. The residual solid was triturated with acetonitrile to give (2E)-3-(6-{[(3R)-l-(4-tert~butylbenzyl)-3- pyrrolidinyl]amino}-3-pyridyl)-N-hydroxyacrylamide dihydrochloride(228mg) as a pale tan solid. NMR (DMSO-d6, δ ) : 1.29 (9H, s),1.96-2.67 (2H, m),3.12-4.02 (2H, m),4.34-4.54 (4H, m),4.54-4.84 (IH, m),6.33-6.45 (IH, m),6.90-7.21 (IH, m),7.36-7.51 (3H, m) ,7.54-7.63 (2H, m),7.89-8.09 (IH, m),8.18 (IH, s) MS (ES+) m/z 395.32(free, M+l)

Example 34 10% Metallic hydrogen chloride (1.4mL) was added to the solution of (2E)-3-(2-{[l-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}~ 1,3-thiazol-4-yl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (0.6g) in MeOH (12ml) and the mixture was stirred at ambient temperature for 3.5 hours. To the reaction mixture was added ethyl ether and isolated precipitate was collected by filtration to give (2E)-3-(2- {[1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-1,3-thiazol-4-yl )-N- hydroxyacrylamide hydrochloride (0.42g) NMR(DMSO-d6, <5 ) : 1.89-2.33(2H, m) , 3.31-3.71(3H, m) , 3.72-3.87(1H, m), 4.30-4.49(IH, m), 4.63 and 4.50(total IH, each d, J= 15.3 Hz), 7.06 and 7.11(total IH, each s), 7.18 and 7.22(total IH, each d, J= 15.3 Hz), 7.45-7.66(4H, m) , 8.91(1H, br s) (+)ESI-MS:393(M+H)+

. The following compounds were obtained according to a similar manner to that of Example 34.

Example 35 (2E)-3-{2-[(l-Benzyl-4-piperidyl)amino]-l,3-thiazol-4-yl}-N- hydroxyacrylamide dihydrochloride lH-NMR(DMSO-d6): 6 1.30-1.84 (4H, m), 2.89-3.46 (4H, m), 3.82-4.15 (IH, m), 4.30 (2H, s), 6.52 (IH, d, J=15.4Hz), 7.09 (IH, s), 7.21 (IH, d, J=15.4Hz), 7.39-7.51 (3H, mj , 7.59-7.72 (2H, m), ,8.99 (IH, br.s), 11.21 (IH, s), (+)ESI-MS: 359 (M+l).

Example 36 (2E)-3-(2-{[l-(4-Chlorobenzoyl)-4-piperidyl]amino}-l,3-thiaz ol-4- yl)-N-hydroxyacrylamide hydrochloride NMR(DMSO-d6, <5): 1.37-1.66(2H, m), 1.87-2.15(2H, m) , 3.04-3.30(2H, m), 3.48-3.75(lH, m) , 3.93-4.14(1H, m) , 4.17-4.43(1H, m) , 6.51(1H, d, J= 15.5 Hz), 7.13(1H, s), 7.23(1H, d, J= 15.5 Hz), 7.43(2H, d, J= 8.5 Hz), 7.53(2H, d, J= 8.5 Hz), 9.16(1H, br s) (+JESI-MS:407(M+H)+

Example 37 To a stirred solution of tert-butyl [(3R)-I- (diphenylmethyl)-3-pyrrolidinyl](5-{(IE)-3-oxo-3-[(tetrahydr o-2H- pyran-2-yloxy)amino]-l-propen-l-yl}-2-pyridyl)carbamate (94 mg) in methanol (2 mL) was added hydrogen chloride methanol reagent 10 (0.5 mL, Tokyo Kasei) , and the mixture was stirred at ambient temperature for 30 minutes. The solvent was evaporated to dryness and the residue was dissolved in the mixture of dioxane (3ml) and methanol (ImI). To this solution was added 4N-hydrogen chloride in dioxane (3ml) and the mixture was stirred at ambient temperature for 3 hours. The solvent was evaporated to dryness and the residue was triturated with acetonitrile to give (2E)-3-(6-{[(3R)-I- (diphenylmethyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N- hydroxyacrylamide dihydrochloride (63 mg) as a pale yellow powder. NMR (CDCl3, <5): 1.36 (3H, t, J= 7 Hz), 1.42 (3x3H, s), 2.02-2.30 (2H, m), 2.42-2.61 (2H, m) , 2.64 (IH, dd, J= 9.5, 7 Hz), 2.78 (IH, dd, J= 9.5, 8 Hz), 4.17 (IH, s), 4.29 (2H, q, J= 7 Hz), 4.91 (IH, m), 6.49 (IH, d, J= 16 Hz), 7.08-7.38 (HH, m), 7.69 (IH, d, J= 16 Hz), 7.83 (IH, dd, J= 8.5, 2 Hz), 8.57 (IH, d, J= 2 Hz) MS (ES+) m/z 528.

Example 38 To a solution of (2E)-3-{6-[(l-benzyl-4-piperidyl)amino]-5- chloro-3-pyridyl}-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide( 168mg) in EtOH(2ml) was treated with 10% HCl in MeOH (1.76ml) and was stirred at 250C for 1 hour. The precipitate was collected, washed with EtOH, dried under reduced pressure to give (2E)-3-{6-[(l- benzyl-4-piperidyl)amino]-5-chloro-3-pyridyl}-N-hydroxyacryl amide dihydrochloride(137mg) . NMR (DMSO-d6, <5 ) : 1.90-2.30(4H, m) , 2.90-3.45(4H, m) , 4.05-4.30(1H, m), 4.25-4.28(2H, m) , 6.37(1H, d, J= 16.0 Hz), 6.86(1H, brs), 7.16(1H, d, J= 16.0 Hz), 7.44-7.69(5H, m) , 8.04(1H, s), 8.19(1H, s) Mass (ESI): 387(M+H)+

The following compounds were obtained according to a similar manner to that of Example 38.

Example 39 (2E)-3-(5-Chloro-6-{[l~(4-fluorobenzyl)-4-piperidyl]amino}-3 - pyridyl)-N-hydroxyacrylamide dihydrochloride NMR (DMSO-d6, <5): 1.90-2.30(4H, m) , 2.90-3.45(4H, m) ,' 4.05-4.30(1H, m), 4.25-4.28(2H, m) , 6.37(1H, d, J= 16.0 Hz), 6.86(1H, brs), 7.26- 7.45(3H, m), 7.71-7.78(2H, m), 7.95(1H, s), 8.19(1H, s) Mass (ESI): 405(M+H)+

Example 40 5 (2E)-3-{6-[[l-(4-Chlorobenzoyl)-4-piperidyl](methyl)ainino]- 3- pyridyl}-N-hydrόxyacrylamide hydrochloride NMR (DMSO-d6, <5 ) : 1.50-2.00(4H, m) , 2.80-3.30(2H, m) , 3.07(3H, s), 4.50-4.80(1H, brs), 6.46(1H, d, J= 16.0 Hz), 7.25-7.60(6H, m) , 8.09(1H, d, J= 8.8 Hz), 8.23(1H, s). 10 Mass (ESI): 415(M+H)+

Example 41 ' To a solution of (2E)-3-(5-ch!oro-6~{[lτ(4-methylbenzyl)-4- piperidyl]amino}-3-pγridyl)-N-(tetrahydro-2H-pyran-2- 15 yloxy)acrylamide (470mg) in EtOH(2ml) was treated with 2N HCl in EtOH (2.42ml) and was stirred at 251C for 1 hour. The precipitate was collected, .washed with EtOH, dried under reduced pressure to give (2E)-3-(5-chloro-6-{ [1-(4-methylbenzyl)-4-piperidyl]amino}-3- pyridyl)-N-hydroxyacrylamide dihydrochloride(308mg) . 20 NMR (DMSO-d6, <5 ) : 1.90-2.20(4H, m) , 2.34(3H, s), 2.90-2.45(4H, m), 4.1O-4.25(1H, m), 4.20-4.23(2H, m) , 6.39(1H, d, J= 16.0 Hz), 7.26(1H, d, J= 8.8 Hz), 7.35(1H, d, J= 16.0 Hz), 7.54(1H, d, J= 8.8 Hz), 7.95(1H, s), 8.18(1H, s), 11.08(1H, brs) Mass (ESI): 403(M+H)+ 25 > The following compounds were obtained according to a similar manner to that of Example 41.

Example 42 30 (2E)-3-(5-Chloro-6-{[l-(4-methoxybenzyl)-4-piperidyl]amino}- 3- pyridyl)-N-hydroxyaσrylamide dihydrochloride NMR (DMSO-d6, <5 ) : 1.90-2.20(4H, m) , 2.90-2.45(4H, m) , 3.79(3H, s), 4.1O-4.25(1H, m), 4.20-4.23(2H, m) , 6.38(1H, d, J= 16.0 Hz), 7.00(1H, d, J= 8.8 Hz), 7.35(1H, d, J= 16.0 Hz), 7.58(1H, d, J= 8.8 35. Hz), 7.94(1H, s), 8.18(1H, s), 1O.98(1H, brs) Mass (ESI): 417(M+H)+ Example 43 (2E)-3-{5-Chloro-6-[(l-isobutyl-4-piperidyl)amino]-3-pyridyl }-N- hydroxyacrylamide dihydrochloride NMR (DMSO-de, δ): 1.00(6H, d, J= 6.5 Hz), 2.0-2.30(5H, m) , 2.80- 3.17(4H, m), 3.20-3.30(IH, m) , 3.40-3.60(IH, m) , 4.10-4.30(1H, m) , 6.4O(1H, d, J= 16.0 Hz), 7.35(1H, d, J= 16.0 Hz), 7.95(1H, s), 8.2O(1H, s), 1O.26(1H, brs) Mass (ESI): 353(M+H)+

Example 44 (2E)-3-(5-Chloro-6-{[1-(cyclopropylmethyl)-4-piperidyl]amino }-3- pyridyl)-N-hydroxyacrylamide dihydrochloride NMR (DMSO-de, <5 ) : 0.36-0.42(2H, m) , 0.59-0.68(2H, m) , 1.05-1.30(1H, - m), 1.90-2.25(4H, m) , 2.80-3.20(4H, m) , 3.40-3.70(2H, m), 4.10- 4.4O(1H, m), 6.41(1H, d, J= 16.0 Hz), 7.36(1H, d, J= 16.0 Hz), 7.98(1H, s), 8.2O(1H, s), 1O.86(1H, brs) Mass (ESI): 351(M+H)+

Example 45 (2E)-3-(5-Chloro-6-{[(3R)-1-(4-fluorobenzyl)-3-pyrrolidinyl] amino}- 3-pyridyl)-N-hydroxyacrylamide dihydrochloride NMR (DMSO-de, <5 ) : 1.95-2.16(2H, m) , 3.06-3.70(4H, m), 4.42(2H, d, J= 5.5 Hz), 4.60-5.00(1H, m), 6.4O(1H, d, J= 16.0 Hz), 7.25-7.39(4H, m), 7.68-7.76(2H, m), 7.92(1H, s), 8.21(1H, s)

Example 46 (2E)-3-(5-Chloro-6-{[(3R)-1-(4-methylbenzyl)-3-pyrrolidinyl] amino}- 3-pyridyl)-N-hydroxyacrylamide dihydrochloride NMR (DMSO-d6l, <5 ) : 2.03-2.30(2H, m) , 3.10-3.66(4H, m) , 4.35(2H, d, J= 5.5 Hz), 4.65-5.00(1H, m) , 6.39(1H, d, J= 16.0 Hz), 7.25(2H, d, J= 8.8 Hz), 7.34(1H, d, J= 16.0 Hz), 7.51(1H, d, J= 8.8 Hz), 7.91(1H, s), 8.2O(1H, s)

Example 47 (2E)-3-(5-Chloro-6-{[(3R)-l-(4-methoxybenzyl)-3- pyrrolidinyl]amino}-3-pyridyl)-N-hydroxyacrylamide dihydrochloride NMR (DMSO-d6, <5 ) : 1.95-2.30(2H, m) , 3.07-3.70(4H, m) , 3.48(3H, s), 4 .33 ( 2H, d, J= 5 .5 Hz ) , 4 . 60-5.00 ( 1H, m) , 6 .4O ( 1H, d, J= 16.0 Hz ) , 6 .99 (2H, d, J= 8 .8 Hz ) , 7 . 15-7 . 4O ( 1H, m) , 7 .34 ( 1H, d, J= 16.0 Hz ) , 7.53-7.89 ( 2H, m) , 7.92( 1H, s) , 8.21( 1H, s)

Example 48 To [ (3R)-1-(3-methoxybenzyl)-3-pyrrolidinyl] (5-{(IE)-3-oxo- 3-[(tetrahydro-2H-pyran-2-yloxy)amino]-l-propen-l-yl}~2- pyridyl)carbamate (275 mg) was added 4N HCl in dioxane (1.4 mL) and stirred for 15 minutes at ambient temperature. To the reaction mixture was added MeOH (5 mL) and stirred for 15 minutes. The solvent was removed in vacuo and the residue was suspended in 4N HCl in dioxane (1.24 mL) and stirred for 0.5 hour. To the reaction mixture was added CH3CN and the solvent was removed in vacuo. Obtained colorless solid was triturated with CH3CN to give (2E)-N- hydroxy-3-(6-{[(3R)-1-(3-methoxybenzyl)-3-pyrrolidinyl]amino }-3- pyridyl)acrylamide dihydrochloride (211 mg) as colorless powder. NMR (DMSO-d6, <5 ) : 2.13 (IH, br) , 2.34 (0.5H, br) , 2.59 (0.5H, br),3.22-3.83 (4H, br) , 3.79 (3H, s), 4.41 (IH, m) , 4.51 (IH, d) , 4.61 (0.5H, br), 4.75 (0.5H, br), 6.39 (0.5H, d, J= 16.1 Hz), 6.40 (0.5H, d, J= 16.1 Hz), 6.99 (1.5H, m) , 7.19 (1.5H, m) , 7.33 (2H, m) , 7.43 (0.5H, d, J= 16.1 Hz), 7.44 (0.5H, d, J= 16.1 Hz), 8.01 (IH, m), 8.18 (IH, s) MS (ES+) m/z 369 (M+l),

The following compounds were obtained according to a similar manner to that of Example 48.

Example 49 (2E)-N-Hydroxy-3-[6-({(3R)-1-[(2-phenyl-l,3-thiazol-4-yl)met hyl]-3- pyrrolidinyl}amino)-3-pyridy1]acrylamide dihydrochloride NMR (DMSO-d6, <5 ) : 1,97-2.62 (2H, m) , 3.30-4.10 (5H, m)', 4.55-4.73 (2H, m), 6.35 (IH, d, J = 16 Hz), 6.88-7.01 (IH, m) , 7.41 (IH, d, J = 16 Hz), 7.48-7.57 (3H, m) , 7.89-8.03 (4H, m) , 8.16-8.23 (IH, m) MS (ES+) m/z 422 (M+l) , Example 50 (2E)-3-(6-{[(3R)-l-(4-Benzoylbenzyl)-3-pyrrolidinyl]amino}-3 - pyridyl)-N-hydroxyacrylamide dihydrochloride NMR (DMSO-de, <5 ) : 2.02-4.73 (9H, m) , 6.32 (IH, d, J = 16 Hz), 7.40 (IH, d, J = 16 Hz), 7.55-7.82 (HH, m) , 8.18-8.21 (IH, m) MS (ES+) m/z 443 (M+l) .

Example 51 (2E)-3-(6-{[(3R)-l-(2,3-Dihydro-l-benzofuran-5-ylmethyl)-3- pyrrolidinyl]amino}-3-pyridyl)-N-hydroxyacrylamide dihydrochloride NMR (DMSO-de, <5 ) : 1.95-2.41 (2H, m) , 3.19..(2H, t, J = 9 Hz), 3.24- 4.69 (7H, m), 4.56 (2H, t, J = 9 Hz), 6.29-6.39 (IH, m) , 6.79-7.09 (2H, m), 7.29-7.50 (3H, m) , 7.87-7.99 (IH, m) , 8.17-8.21 (IH, s) MS (ES+) m/z 381 (M+l)

> Example 52 (2E)-3-(6-{[ (3R)-1-(l-Benzofuran-2-ylmethyl)-3-pyrrolidinyl]amino}- 3-pyridyl)-N-hydroxyacrylamide NMR (DMSO-de, δ): 1.61-4.44 (9H, m) , 6.17 (IH, d, J = 16 Hz), 6.52 (IH, d, J = 8 Hz), 7.19-7.36 (4H, m), 7.52-7.64 (3H, m) , 8.10-8.15 (IH, m) MS (ES+) m/z 379 (M+l)

Example 53 (2E)-3-(6-{[(3R)-I-(I-Benzofuran-5-ylmethyl)-3-pyrrolidinyl] amino}- 3-pyridyl)-N-hydroxyacrylamide NMR (DMSO-d6, <5 ) : 1.72-4.53 (9H, m) , 6.20 (IH, d, J = 16 Hz), 6.54 (IH, d, J = 8 Hz), 6.95-8.16 (8H, m) MS (ES+) m/z 379 (M+l)

Example 54 (2E)-N-Hydroxy-3-(6-{[(3R)-1-(3-phenylpropyl)-3- pyrrolidinyl]amino}-3-pyridyl)acrylamide dihydrochloride NMR (DMSOd6, <5 ) : 2.00 (2H, m) , 2.06 (IH, br) , 2.30 (0.5H, br) , 2.54 (0.5H, br), 2.66 (2H, t, J= 8.0 Hz), 3.12-4.01 (6H, br) , 4.58 (IH, br), 4.69 (IH, br) , 6.38 (IH, d, J= 16.1 Hz), 6.96 (0.5H, d, J= 8.0 Hz), 7.04 (0.5H, d, J= 9.2 Hz), 7.23 (3H, m), 7.31 (2H, m), 7.43 (IH, d, J= 16.1 Hz), 7.99 (IH, m),8.21 (IH, s) MS (ES+) m/z 367 (M+l) Example 55 (2E)-3-[6-({(3R)-1-[4-(Dimethylamino)benzyl]-3-pyrrolidinyl} amino)- 3-pyridyl]-N-hydroxyacrylamide trihydrochloride NMR (DMSO-de, <5 ) : 2.12 (IH, br) , 2.37 (IH, br) , 2.96 (6H, s), 3.18-4.00 (4H, br), 4.30 (IH, br) , 4.40 (IH, d, J= 5.5 Hz), 4.58 (0.5H, br), 4.72 (0.5H, br) , 6.39 (0.5H, d, J= 16.1 Hz), 6.40 (0.5H, d, J= 16.1 Hz), 6.92 (2H, br), 7.01 (0.5H, d, J= 8.1 Hz), 7.15 (0.5H, d, J= 8.1 Hz), 7.43 (IH, m) , 7.48 (2H, m) , 8.03 (IH, m) , 8.20 (IH, s) MS (ES+) m/z 382 (M+l)

Example 56 (2E)-N-Hydroxy-3-(6-{[(3R)-l-(2-methoxybenzyl)-3- pyrrolidinyl]amino}-3-pyridyl)acrylamide dihydrochloride NMR (DMSO-de, <5 ) : 2.11 (IH, br) , 2.39 (IH, br) , 3.11-3.71 (4H, br) , 3.82 (1.5H, s), 3.87 (1.5H, s), 4.39 (IH, br) , 4.45 (IH, br), 4.59 (0.5H, br), 4.71 (0.5H, br) , 6.36 (IH, d, J= 16.1 Hz), 6.93 (IH, m) , 7.02 (IH, m), 7.12 (IH, dd, J= 8.4,4.5 Hz), 7.43 (2H, m) , 7.57 (IH, m), 7.96 (IH, m) , 8.18 (IH, s) MS (ES+) m/z 369 (M+l)

Example 57 To a solution of tert-butyl [(3R)-l-(3-fluorobenzyl)-3- pyrrolidinyl] (5-{(lE)-3-oxo-3-[ (tetrahydro-2H-pyran-2-yloxy)amino]- 1-propen-l-yl}-2-pyridyl)carbamate (2.51 g) in MeOH (37 mL) was added hydrogen chloride methanol reagent 10 (9.28 mL, Tokyo Kasei), and the mixture was stirred at ambient temperature for 1 hour. The solvent was removed in vacuo and the residue was dissolved in dioxane(12 mL). To the reaction mixture was added 4N HCl in dioxane and stirred for 1 hour at ambient temperature. To the reaction mixture was added CH3CN and the solvent was removed in vacuo. Obtained colorless solid was triturated with CH3CN to give (2E)-3- (6-{[(3R)-1-(3-fluorobenzyl)-3-pyrrolidinyl]amino}-3-pyridyl )-N- hydroxyacrylamide dihydrochloride (1.87 g) as colorless powder. NMR (CDCl3, (5): 2.08 (IH, m), 2.34 (IH, m) , 3.23-3.81 (4H, m) , 4.45 (IH, m), 4.54 (IH, d, J= 5.5 Hz), 4.58 (0.5H, br) , 4.69 (0.5H, br) , 6.35 ( 0. 5H, d, J= 16 . 1 Hz ) , 3.36 ( 0. 5H, d, J= 16 . 1 Hz ) , 6.90 ( 0. 5H, br) , 7 .03 ( 0.5H, br) , 7. 30 ( IH, m) , 7 .41 ( IH, m) , 7 .48-7.60 ( 3H, m) , 7.95 ( IH, m) , 8. 18 ( IH, s ) , MS (ES+ ) m/z 357 (M+l )

The following compounds were obtained according to a similar manner to that of Example 57.

Example 58 (2E)-N-Hydroxy-3-[6-({(3R)-1-[4-(trifluoromethyl)benzyl]-3- pyrrolidinyl}amino)-3-pyridy1]acrylamide dihydrochloride NMR (DMSO-d6, <5 ) : 1.98-2.76 (2H, m) , 3.17-4.25 (4H, m) , 4.50-4.79 (3H, m), 6.29-6.45 (IH, m), 6.87-7.18 (IH, m), 7.36-7.48 (IH, m) , 7.81-8.08 (5H, m) , 8.19 (IH, brs) MS (ES+) m/z 407.33(free, M+l)

Example 59 (2E)-N-Hydroxy-3-[6-({(3R)-l-[4-(trifluoromethoxy)benzyl]-3- pyrrolidinyl}amino)-3-pyridyl]acrylamide dihydrochloride NMR (DMSO-dβ, 6): 1.92-2.80 (2H, m) , 3.14-4.23 (4H, m) , 4.43-4.78 (3H, m), 6.30-6.46 (IH, m) , 6.86-7.16 (IH, m) , 7.37-7.53 (3H, m) , 7.76-7.86 (2H, m), 7.88-8.08 (IH, m) , 8.19 (IH, s) MS (ES+) m/z 423.25(free, M+l)

Example 60 (2E)-3-(6-{[(3R)-l-(Cyclohexylmethyl)-3-pyrrolidinyl]amino}- 3- pyridyl)-N-hydroxyacrylamide dihydrochloride NMR (DMSO-de, δ): 0.77-1.34 (5H, m), 1.52-1.91 (6H, m), 1.97-2.62 (4H, m), 3.00-4.09 (4H, m) , 4.51-4.76 (IH, m) , 6.36 (IH, d, J= 15.8 Hz), 6.88-7.10 (IH, m), 7.43 (IH, d, J= 15.8 Hz), 7.91-8.01 (IH, m), 8.20 (IH, s) MS (ES+) m/z 345.41(free, M+l)

Example 61 (2E)-3-(6-{[(3R)-1-(1-Cyσlohexen-l-ylmethyl)-3-pyrrolidinyl ]amino}- 3-pyridyl)-N-hydroxyacrylamide dihydrochloride NMR (DMSO-d6, δ): 1.45-1.66 (4H, m) , 1.90-2.20 (5H, m) , 2.30-2.63 (IH, m), 2.99-3.90 (6H, m) , 4.52-4.81 (IH, m) , 5.94-6.04 (IH, m) , 6.38 (IH, d, J= 15.8 Hz), 6.93-7.17 (IH, m) , 7.43 (IH, d, J= 15.8 Hz), 7.91-8.09 (IH, m) , 8.21 (IH, brs) MS (ES+) m/z 343.50(free, M+l)

Example 62 (2E)-3-(6-{[ (3R)-1-(2-Fluorobenzyl)-3-pyrrolidinyl]amino}-3- pyridyl)-N~hydroxyacrylamide dihydrochloride NMR (DMSO-dβ, <5): 2.12 (IH, br) , 2.37 (IH, br) , 2.60 (IH, br) , 3.25 (IH, br), 3.45 (IH, br), 3.66 (IH, br) , 3.91 (IH, br) , 4.50 (IH, br), 4.56 (IH, d, J= 5.1 Hz), 4.59 (0.5H, br) , 4.70 (0.5H, br) , 6.35 (IH, d, J= 16.1 Hz), 6.91 (0.5H, br), 6.98 (0.5H, br), 7.30 (IH, d, J= 7.3 Hz), 7.35 (IH, d, J= 9.1 Hz), 7.41 (IH, d, J= 16.1 Hz), 7.52 (IH, m), 7.78 (IH, m) , 7.94 (IH, m),8.19 (IH, s) MS (ES+) m/z 357 (M+l)

Example 63 (2E)-N-Hydroxy-3-(6-{[(3R)-1-(2-quinolinylmethyl)ι-3- t pyrrolidinyl]amino}-3-pyridyl)acrylamide trihydrochloride NMR (DMSO-de, <5 ) : 2.21 (IH, br) , 2.51 (IH, br) , 3.61 (2H, br) , 3.76 (IH, br), 3.95 (IH, br), 4.72 (IH, br), 4.93 (2H, s), 6.38 (IH, d, J= 15.8 Hz), 7.08 (IH, d, J= 9.5 Hz), 7.43 (IH, d, J= 15.8 Hz), 7.69 (IH, m), 7.71 (IH, d, J= 8.4 Hz), 7.84 (IH, m) , 8.04 (2H, m) , 8.20 (IH, s), 8.50 (IH, d, J= 8.1 Hz) MS (ES+) m/z 390 (M+l)

Example 64 (2E)-N-Hydroxy-3-(6-{[(3R)-l-(3-quinolinylmethyl)-3- pyrrolidinyl]amino}-3-pyridyl)acrylamide trihydrochloride NMR (DMSO-d6, <5 ) : 2.10 (IH, br) , 2.63 (IH, br) , 3.35 (IH, br) , , 3.49 (IH, br), 3.69 (IH, br) , 3.90 (IH, br) , 4.58 (IH, br) , 4.72 (IH, br), 4.80 (IH, br) , 6.35 (IH, d, J= 16.1 Hz), 6.91 (0.5H, br) , 7.03 (0.5H, br), 7.41 (IH, d, J= 16.1 Hz), 7.76 (IH, t, J= 7.7 Hz), 7.93 (2H, m), 8.08 (IH, d, J= 7.7 Hz), 8.14 (IH, d, J= 8.1 Hz), 8.19 (IH, s), 8.79 (IH, d, J= 6.6 Hz), 9.23 (IH, d, J= 8.1 Hz) MS (ES+) m/z 390 (M+l) Example 65 (2E)-N-Hydroxy-3-[6-({(3R)-1-[(5-methyl-2-thienyl)methyl]-3- pyrrolidinyl}amino)-3-pyridyl]acrylamide dihydrochloride NMR (DMSO-d6, <5): 2.07 (IH, br) , 2.31 (IH, br) , 2.45 (3H, s), 3.23 (IH, br), 3.37 (IH, br) , 3.52 (IH, br) , 3.81 (IH, br) , 4.56 (IH, d, J= 4.4 Hz), 4.57 (0.5H, br) , 4.64 (IH, d, J= 5.1 Hz), 4.67 (0.5H, br), 6.35 (IH, d, J= 16.1 Hz), 6.80 (IH, br) , 6.90 (0.5H, br) , 6.98 (0.5H, br), 7.19 (IH, m) , 7.42 (IH, d, J= 16.1 Hz), 7.93 (IH, m) , 8.19 (IH, s) , MS (ES+) m/z 359 (M+l)

I Example 66 (2E)-N-Hydroxy-3-[6-({(3R)-1-[(5-methyl-2-furyl)methyl]-3- pyrrolidinyl}amino)-3-pyridyl]acrylamide dihydrochloride NMR (DMSO-d6, <5 ) : 2.09 (2H, br.), 2.26 (1.5H, s), 2.29 (1.5H, s), 3.26 (IH, brl), 3.53 (2H, br.), 3.86 (IH, br.), 4.44 (IH, s), 4.53 (IH, s), 4.64 (IH, br.d), 6.15 (IH, m) , 6.39 (IH, d, J= 15.8 Hz), 6.60 (IH, s), 7.04 (IH, m) , 7.43 (IH, d, J= 15.4 Hz), 8.00 (IH, br.), 8.20 (IH, s) MS (ES+) m/z 343 (M+l)

Example 67 (2E)-3-{6-[((3R)-l-{(2E)-3-[4-(D±methylamino)phenyl]-2-prop en-l- yl}-3-pyrrolidinyl)amino]-3-pyridyl}-N-hydroxyacrylamide trihydrochloride NMR (DMSOd6, <5 ) : 2.23 (2H, br.), 3.00 (6H, s), 3.07 (IH, br.), 3.43 (2H, br.), 3.71 (IH, br. ), 3.97 (IH, br.), 4.07 (IH, br.), 4.65 (0.5H, br.), 4.77 (0.5H, br. ) , 6.27 (IH, br. ) , 6.42 (IH, d, J= 15.8 Hz), 6.80 (IH, d, J= 15.4 Hz), 7.09 (2H, br.), 7.22 (IH, d, J= 8.4 Hz), 7.44 (3H, m) , 8.07 (IH, m) , 8.19 (IH, s) MS (ES+) m/z 408 (M+l)

Example 68 (2E)-3-(6-{[ (3R)-1-(2,2-Dimethylpropyl)-3-pyrrolidinyl]amino}-3- pyridyl)-N-hydroxyacrylamide dihydrochloride NMR (DMSOd6, <5 ) : 1.06 (4.5H, s), 1.07 (4.5H, s), 2.08 (IH, m) , 2.45 (IH, m), 3.16 (IH, m) , 3.25 (IH, m) , 3.39-3.92 (4H, br) , 4.12 (IH, m), 4.59 (0.5H, br) , 4.71 (0.5H, br) , 6.35 (IH, d, J= 16.1 Hz), 6.94 (IH, br.d), 7.42 (IH, d, J= 16.1 Hz), 7.94 (IH, br.d), 8.21 (IH, br) MS (ES+) m/z 319 (M+l)

Example 69 To a solution of >(2E)-3-(4-{[(3R)-l-(4-chlorobenzoyl)-3- pyrrolidinyl]amino}phenyl)-N-(tetrahydro-2H-pyran-2- yloxyjacrylamide (76 mg) in MeOH (1.3 mL) was added hydrogen chloride methanol reagent 10 (0.32 mL, Tokyo Kasei) , and the mixture was stirred at ambient temperature for 1 hour. To the reaction mixture was added CH3CN and the solvent was removed in vacuo. Obtained colorless solid was triturated with CH3CN to give (2E)-3~(4-{[(3R)-l-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}ph enyl)- N-hydroxyacrylamide hydrochloride (64.1 mg) as colorless powder. NMR (DMSO-de, <5 ) : 1.89 (IH, m) , 2.18 (IH, m) , 3.24 (0.5H, m) , 3.45 (0.5H, m), 3.59 (IH, m) , 3.67 (IH, m) , 3.78 (IH, m) , 4.03 (0.5H, m) , 4.12 (0.5H, m), 6.15 (0.5H, d, J= 15.8 Hz), 6.20 (0.5H, d, J= 15.8 Hz), 6.59 (IH, d, J= 8.4 Hz), 6.70 (IH, d, J= 8.8 Hz), 7.26-7.36 (3H, m), 7.47-7.59 (5H, m)

Example 70 To a solution of (2E)-3-(6-{[(3R)-I-(4-chlorobenzoyl)-3- pyrrolidinyl]amino}-3-pyridyl)-N-(tetrahydro-2H-pyran-2- yloxy)acrylamide (1.89 g) in MeOH (32 mL) was added hydrogen chloride methanol reagent 10 (8.0 mL, Tokyo Kasei), and the mixture was stirred at ambient temperature for 0.5 hour. The reaction mixture was diluted with AcOEt and the precipitate was collected with filtration to give (2E)-3-(6-{[(3R)-l-(4-chlorobenzoyl)-3- pyrrolidinyl]amino}-3-pyridyl)-N-hydroxyacrylamide hydrochloride (1.18 g) as colorless powder. NMR (DMSO-d6, δ): 2.02 (IH, br) , 2.25 (IH, br) , 3.34-3.64 (4H, br) , 3.85 (IH, m), 4.40 (0.5H, br), 4.50 (0.5H, br), 6.35 (0.5H, d, J= 16.1 Hz), 6.37 (0.5H, d, J= 16.1 Hz), 6.98 (0.5H, m) , 7.06 (0.5H, m), 7.38-7.60 '(5H, m) , 8.01 (IH, m), 8.14 (0.5H, s), 8.23 (0.5H, s) MS (ES+) m/z 387 (M+l) The following compounds were obtained according to a similar manner to that of Example 70.

Example 71 (2E)-3-(6-{[ (3S)-1-(4-Chlorobenzoyl)-3-pyrrolidinyl]amino}-3- pyridyl)-N-hydroxyacrylamide hydrochloride NMR (DMSO-dβ, <5 ) : 2.02 (IH, br) , 2.25 (IH, br) , 3.34-3.64 (4H, br) , 3.85 (IH, m), 4.40 (0.5H, br), 4.50 (0.5H, br), 6.35 (0.5H, d, J= 16.1 Hz), 6.37 (0.5H, d, J= 16.1 Hz), 6.98 (0.5H, m) , 7.06 (0.5H, m), 7.38-7.60 (5H, m) , 8.01 (IH, m) , 8.14 (0.5H, s), 8.23 (0.5H, s) MS (ES+) m/z 387 (M+l)

Example 72 To a solution of (2E)-3-(4-{[ (3R)-l-benzyl-3- pyrrolidinyl]amino}phenyl)-N-(tetrahydro-2H-pyran-2- yloxy)acrylamide (500 mg) in MeOH (5 mL) was added hydrogen chloride methanol reagent 10 (2.38 mL, Tokyo Kasei) , and the mixture was stirred at ambient temperature for 1 hour. To the reaction mixture was added CH3CN and the solvent was removed in vacuo. Obtained colorless solid was triturated with CH3CN to give (2E)-3-(4-{[(3R)-l-benzyl-3-pyrrolidinyl]amino}phenyl)-N- hydroxyacrylamide hydrochloride (257.4 mg) as colorless powder. NMR (DMSO-de, δ): 1.94 (IH, m), 2.01 (0.5H, m) , 2.29 (0.5H, m) , 3.00 (0.5H, m), 3.19 (1.5H, m) , 3.29-3.53 (2.5H, m) , 3.73 (0.5H, m) , 4.18 (0.5H, m), 4.31 (0.5H, m) , 4.40 (IH, d, J= 5.9 Hz), 4.44 (IH, d, J= 5.9 Hz), 6.20 (IH, d, J= 16.1 Hz), 6.61 (IH, d, J= 8.8 Hz), 6.63 (IH, d, J= 8.8 Hz), 7.33 (2H, m), 7.44 (3H, m),7.64 (2H, m) MS (ES+) m/z 338 (M+l)

Example 73 To a solution of (2E)-3-(6-{[(3R)-I-benzyl-3- pyrrolidinyl]amino}-5-methyl-3-pyridyl)-N-(tetrahydro-2H-pyr an-2- yloxy)acrylamide (306 mg) in MeOH (5.6 mL) was added hydrogen chloride methanol reagent 10 (1.4 mL, Tokyo Kasei), and the mixture was stirred at ambient temperature for 2 hours. To the reaction mixture was added Men and the solvent was removed in vacuo. Obtained colorless solid was triturated with Men to give (2E)-3-(6- {[(3R)-l-benzyl-3-pyrrolidinyl]ainino}-5-methyl-3-pyridyl)-N - hydroxyacrylamide dihydrochloride (202.1 mg) as colorless powder. NMR (DMSO-d6, <5 ) : 2.16 (IH, m) , 2.28 (3H, s), 2.65 (IH, m) , 3.22 (IH, m), 3.48 (2H, m) , 3.58 (IH, m), 4.44 (IH, d, J= 5.8 Hz), 4.49 (IH, d, J= 5.8 Hz), 4.98 (IH, br) , 6.39 (IH, d, J= 16.1 Hz), 7.41 (IH, d, J= 16.1 HK), 7.45 (3H, m) , 7.63 (2H, m), 7.88 (IH, be), 8.09 (IH, s) MS (ES+) m/z 353 (M+l)

Example 74 To a solution of (2E)-3-(5-{[(3R)-l-(4-chlorobenzyl)-3- pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2- yloxy)acrylamide (1.43 g) in methanol (16 mL) was added hydrogen chloride in methanol (6.24 mL). After stirring at room temperature for 1 hour, the reaction mixture was evaporated in vacuo and triturated with ethyl acetate to give (2E)-3-(5-{[(3R)-l-(4- chlorobenzyl)-3-pyrrolidinyl]amino}-2-pyraziny1)-N- hydroxyacrylamide dihydrochloride (1.40 g). 1H-NMR (300 MHz, DMSO-dδ) d 1.93-2.38 (2H, m), 3.00-3.79 (4H, m), 4.37-4.63 (3H, m) , 6.63 (IH, d, J = 15 Hz), 7.39 (IH, d, J = 15 Hz), 7.52 (2H, d, J = 8 Hz), 7.67 (2H, d, J = 8 Hz), 8.00-8.16 (2H, m) MS (ES+) m/z 374 (M+l)

The following compounds were obtained in a similar manner to that of Example 74.

Example 75 (2E)-3-(5-{[(3R)-1-(Cyclohexylmethyl)-3-piperidinyl]amino}-2 - pyrazinyl)-N-hydroxyacrylamide dihydrochloride 1H-NMR (300 MHz, DMSO-d6) δ 0.81-1.03 (2H, m),1.04-1.35 (3H, m), 1.35-2.20 (1OH, m),2.56-2.76 (IH, m),2.76-3.13 (3H, m),3.16-3.65 (2H, m),4.03-4.75 (IH, m),6.63 (IH, d, J=15.0 Hz),7.40 (IH, d, J=15.0 Hz),7.76-7.89 (0.6H, m),8.03 (IH, s),8.05-8.35 (0.4H, m),8.15 (IH, s),9.80-10.02 (IH, br.s) MS (ES+) m/z 360(M+l, free) Example 76 (2E)-3-(5-{[(3R)-l-Benzyl-3-piperidinyl]amino}-2-pyrazinyl)- N- hydroxyacrylamide dihydrochloride 1H-NMR (300 MHz, OMSO-U6) 6 1.31-1.53 (IH, m) ,1.74-2.16 (3H, m) , 2.56-2.78 (IH, m) ,2.78-3.05 (IH, m) ,3.23-3.40 (IH, m) ,3.40-3.54 (IH, m),4.20-4.45 (3H, m),6.61 (IH, d, J=15 Hz),7.36 (IH, d, J=15 Hz),7.42-7.54 (3H, m) ,7.54-7.70 (2H, m) ,7.70-7.94 (IH, m),8.00 (IH, s),8.10 (IH, s) MS (ES+) m/z 354

Example 77 (2E)-3-(5-{[(3R)-l-Cyclohexyl-3-piperidinyl]amino}-2-pyrazin yl)-N- hydroxyacrylamide dihydrochloride 1H-NMR (300 MHz, CD3ODJd 1.10-1.30 (IH, m),1.30-1.77 (6H, m),1.85- 2.06 (3H, m),2.06-2.30 (3H, m),2.85 (IH, t, J=Il Hz) ,2.99-3.15 (IH, m),3.15-3.33 (2H, m),3.45-3.58 (IH, m),3.67-3.86 (IH, m),4.28-4.44 (IH, m),6.76 (IH, d, J=15 Hz),7.53 (IH, d, J=15 Hz) ,8.11-8.24 (2H, m) MS (ES+) m/z 346

Example 78 (2E)-N-Hydroxy-3-(5-{[(3R)-l-(4-methylbenzyl)-3-piperidinyl] amino}- 2-pyraziny1)acrylamide dihydrochloride 1H-NMR (300 MHz, DMSO-O6) δ 1.30-1.52 (IH, m),1.70-2.15 (4H, m),2.33 (3H, s),2.54-2.71 (IH, m),2.71-2.99 (IH, m),3.21-3.36 (IH, m),3.36- 3.50 (IH, m),4.23-4.44 (2H, m),6.61 (IH, d, J=15 Hz),7.10 (IH, s),7.25 (2H, d, J=8 Hz),7.30 (IH, s),7-36 (IH, d, J=15 Hz),7.41- 7.55 (3H, m),7.80 (IH, br peak) ,7.93-8.06 (IH, m),8.10 (IH, s) MS (ES+) m/z 368

Example 79 (2E)-3-(5-{[(3R)-l-(4-Chlorobenzyl)-3-piperidinyl]amino}-2- pyrazinyl)-N-hydroxyacrylamide dihydrochloride 1H-NMR (300 MHz, DMSO-d6) δ 1.34-1.56 (IH, m),1.70-2.11 (4H, m) , 2.56-2.75 (IH, m) ,2.75-2.93 (IH, m),3.20-3.38 (IH, m),3.38-3.55 (IH, m) , 4.22-4.45 ( 2H, m) , 6.62 ( IH, d, J=15 Hz) , 7.40 ( IH, d, J=15 Hz) , 7.49-7.58 ( 2H, m) , 7.58-7.70 ( 2H, m) , 7.70-7.82 ( IH, m) , 7.95-8.06 ( IH, m) , 8.11 ( IH, s) MS (ES+) m/z 388

Example 80 (2E)-3-(5-{[(3R)-l-Cyclopentyl-3-piperidinyl]amino}-2-pyrazi nyl)-N- hydroxyacrylamide dihydrochloride 1H-MMR (300 MHz, DMSO-d6) <5 1.39-1.52 (3H, m) ,1.52-2.04 (9H, m) , 2.56-2.78 (IH, m),2.78-3.10 (IH, m) ,3.20-4.50 (4H, m),6.63 (IH, d, J=15 Hz),7.13 (IH, s),7.30 (IH, s),7.39 (IH, d, J=15 Hz),7.47 (IH, s),7.85 (IH, br peak) ,7.98-8.10 (IH, m) ,8.10-8.21 (IH, m) MS (ES+) m/z 332

Example 81 (2E)-3-(5-{[(3R)-l-(Cyclopentylmethyl)-3-piperidinyl]amino}- 2- pyrazinyl)-N-hydroxyacrylamide dihydrochloride 1H-NMR (300 MHz, DMSO-d6) <5 1.16-1.35 (2H, m),1.35-1.69 (4H, m) , 1.69-2.07 (5H, m),2.18-2.36 (IH, m) ,2.56-2.75 (IH, m),2.75-2.96 (IH, m),2.96-3.19 (2H, m) ,3.19-4.20 (3H, m),4.20-4.42 (IH, m),6.63 (IH, d, J=15 Hz),7.11 (IH, s),7.28 (IH, s),7.40 (IH, d, J=15 Hz),7.45 (IH, s),7.76-7.91 (IH, m),8.01-8.11 (IH, m),8.15 (IH, s) MS (ES+) m/z 346

Example 82 (2E)-3-(5-{[(3R)-l-Benzyl-3-pyrrolidinyl]amino}-2-pyrazinyl) -N- hydroxyacrylamide dihydrochloride 1H-NMR (300 MHz, DMSO-de) δ 1.95-2.36 (2H, m) , 2.99-3.78 (4H, m) , 4.33-4.62 (3H, m) , 6.62 (IH, dd, J = 2, 15 Hz), 7.38 (IH, d, J = 15 Hz), 7.43-7.47 (3H, m), 7.59-7.65 (2H, m) , 8.00-8.15 (2H, m) MS (ES+) m/z 340 (M+l)

Example 83 " (2E)-N-Hydroxy-3-(5-{[ (3R)-1-(4-methylbenzyl)-3- pyrrolidinyl]amino}-2-pyrazinyl)acrylamide dihydrochloride 1H-NIy[R ( 300 MHz , DMSO-d6) δ 1.95-2.38 ( 2H, m) , 2.32 ( 3H, s) , 2.98- 3.78 ( 4H, m) , 4.31-4.61 ( 3H, m) , 6.63 ( IH, dd, J = 2 , 15 Hz ) , 7.22- 7.28 (2H, m) , 7.39 ( IH, d, J = 15 Hz) , 7.46-7.52 (2H, m) , 8.00-8.15 ( 2H, m) MS (ES+) m/z 354 (M+l )

Example 84 (2E)-3-(5-{[(3R)-l-(Cyclohexylmethyl)-3-pyrrolidinyl]amino}- 2- pyrazinyl)-N-hydroxyacrylamide dihydrochloride 1H-NMR (300 MHz, DMSO-d6) <5 0.85-1.03 (2H, m) ,1.04-1.32 (3H, m) , 1.54-1.77 (4H, m) ,1.78-1.90 (2H, m),2.04 (IH, m),2.33 (IH, m),2.92- 3.85, (6H, m),4.55 (IH, m),6.63 (IH, d, J=15.3 Hz),7.40 (IH, d, J=15.3 Hz),8.05 (IH, d, J=8.4 Hz) ,8.11-8.32 (3H, m),10.44 (IH, br- s) MS (ES+) m/z 346,

Example 85 To a stirred solution of (2E)-3-(5-{[ (3R)-l-benzyl-3- pyrrolidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamide (300mg) in 95% ethanol (3mL) was added 4-methylbenzenesulfonic acid hydrate(168mg) at ambient temperature. After stirring at the same temperature for one hour, additional 95% ethanol(1.5mL) was added to the mixture. The precipitate was collected after two hours to afford (2E)-3-(5- { [ (3R)-l-benzyl-3-pyrrolidinyl]amino}-2-pyrazinyl)-N- hydroxyacrylamide 4-methylbenzenesulfonate (253mg) as a pale brown solid. 1H-NMR (300 MHz, CD3OD)S 2.07-2.26 (IH, m),2.36 (3H, s),2.43-2.65 (IH, m),3.24-3.49 (2H, m),3.54-3.82 (2H, m),4.38 (IH, d, J=12.8 Hz),4.46 (IH, d, J=12.8 Hz) ,4.51-4.65 (IH, m),6.68 (IH, d, J=15.4 Hz),7.22 (2H, d, J=8.1 Hz) ,7.41-7.57 (6H, m),7.70 (2H, d, J=8.1 Hz),7.98 (IH, s),8.05 (IH, s)

Example 86 To a solution of (2E)-3-(5-{[(3R)-I-benzyl-3-pyrrolidinyl]amino}-2- pyrazinyl)-N-hydroxyacrylamide dihydrochloride (1.00 g) in water (10 mL) was added saturated NaHCO3 at 4°C (to pH 7-8). The mixture was extracted with CHCl3 three times. The conbined organic layer was dried over Na2SO4, filtered, and evaporated in vacuo to give (2E)-3-(5-{[(3R)-l-benzyl-3-pyrrolidinyl]amino}-2-pyrazinyl) -N- hydroxyacrylamide (796 mg). 1H-NMR (300 MHz, DMSO-d6) δ 1.58-1.72 (IH, m), 2.16-2.29 (IH, m) , 2.36-2.48 (2H, m) , 2.61-2.80 (2H, m) , 3.58 (2H, s), 4.24-4.36 (IH, m), 6.56 (IH, d, J = 15 Hz), 7.20-7.38 (6H, m) , 7.73 (IH, d, J = 7 Hz), 7.97 (IH, s), 8.07 (IH, s), 8.97 (IH, brs), 10.70 (IH, brs) MS (ES+) m/z 340 (M+l)

The following compound was obtained in similar manners to those of Examples 74 and 86.

Example 87 (2E)-N-Hydroxy-3-(5-{[(3R)-l-(4-methylbenzyl)-3-pyrrolidinyl ]- amino}-2-pyrazinyl)acrylamide 1H-NMRJSOO MHz, DMSO-dβ) 6 1.55-1.72 (IH, m),2.12-2.29 (IH, m),2.27 (3H, s),2.32-2.49 (2H, m),2.57-2.78 (2H, m),3.51 (IH, d, J=13.2 Hz),3.55 (IH, d, J=13.2 Hz) ,4.21-4.36 (IH, m),6.56 (IH, d, J=15.0 Hz),7.11 (2H, d, J=8.1 Hz),7.19 (2H, d, J=8.1 Hz),7.33 (IH, d, J=15.0 Hz),7.71 (IH, d, J=6.2 Hz) ,7.96 (IH, s),8.06 (IH, s)

Example 88 To a solution of (2E)-3-(5-{[(3R)-l-(2,3-dimethylbenzyl)-3- pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2- yloxy)acrylamide (46 mg) in ethanol (1 mL) was added 2N hydrogen chloride in ethanol (0.26 mL). After stirring at room temperature for 2 hours, the reaction mixture was evaporated in vacuo and triturated with ethyl acetate to give (2E)-3-(5-{[(3R)-l-(2,3- dimethylbenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N- hydroxyacrylamide dihydrochloride (31 mg). 1H-NMR (300 MHz, DMSO-d6) δ1.94-2.39 (8H, m) , 3.04-4.69 (7H, m) , 6.63 (IH, dd, J = 2, 16 Hz), 7.12-7.27 (2H, m) , 7.36-7.46 (2H, m) , 8.01-8.24 (2H, m) . MS (ES+) m/z 368 (M+l ) .

Example 89 To a mixture of (2E)-3-(5-{[(3R)-l-(4-chlorobenzoyl)-3- pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2- yloxy)acrylamide (288 mg) and ethanol (2.9 mL) was added 2N hydrogen chloride in ethanol (1.53 mL). After stirring at room temperature for 2 hours, resulting precipitate was collected by filtration, and washed with ethanol to give (2E)-3-(5-{[(3R)-l-(4- chlorobenzoyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N- hydroxyacrylamide hydrochloride (138 mg) . 1H-NMR (300 MHz, DMSO-d6) δ1.86-2.29 (2H, m) , 3.26-3.84 (4H, m) , 4.32-4.51 (IH, m) , 6.56-6.66 (IH, m) , 7.31-7.61 (5H, m) , 7.98-8.17 (2H, m). MS (ES+) m/z 388 (M+l).

The following compounds were obtained in a similar manner to that of Example 89. Example 90 (2E)-3-(5-{[(3R)-1-(2-chlorobenzyl)-3-pyrrolidinyl]amino}-2- pyrazinyl)-N-hydroxyacrylamide dihydrochloride 1H-NMR (300 MHz, DMSO-d6) δl.94-2.45 (2H, m) , 3.10-4.66 (7H, m) , 6.63 (IH, d, J = 16 Hz), 7.40 (IH, d, J = 16 Hz), 7.45-7.63 (3H, m) , 7.85-8.18 (4H, m) , 11.1 (IH, brs) . MS (ES+) m/z 374 (M+l).

Example 91 (2E)-3-(5-{[ (3R)-l-(3-chlorobenzyl)-3-pyrrolidinyl]amino}-2- pyrazinyl)-N-hydroxyacrylamide dihydrochloride 1H-NMR (300 MHz, DMSO-d6) δ1.94-2.36 (2H, m) , 3.01-3.80 (4H, m) , 4.39-4.62 (3H, m) , 6.63 (IH, d, J = 16 Hz), 7.39 (IH, d, J = 16 Hz), 7.44-7.63 (3H, m) , 7.77 (IH, s), 8.00-8.29 (3H, m) , 11.4 (IH, brs). MS (ES+) m/z 374 (M+l).

Example 92 To a solution of tert-butyl [(3R)-l-(cyclopentylmethyl)-3- pyrrolidinyl] (5-{(IE)-3-oxo-3-[ (tetrahydro-2H-pyran-2~yloxy)amino]- l-propen-l-yl}-2-pyridinyl)carbamate (179 mg, 0.35mmol) in MeOH (1 mL) was added hydrogen chloride methanol reagent 10 (3 mL, Tokyo Kasei) , and the mixture was stirred at ambient temperature for 1 hr. The solvent was removed in vacuo and the residue was dissolved in dioxane(l mL) . To the reaction mixture was added 4N HCl in dioxane (4 mL) and stirred for lhr at ambient temperature. To the reaction mixture was added MeCN and the solvent was removed in vacuo. Obtained colorless solid was triturated with MeCN to give (2E)-3- (6-{[(3R)-l-(cyclopentylmethyl)-3-pyrrolidinyl]amino}-3-pyri dinyl)- N-hydroxyacrylamide dihydrochloride (115 mg, 85%) as colorless powder. 1H-NMR (300 MHz, DMSO-d6) δ1.16-1.40 (2H, m),1.40-1.72 (4H, m),1.72-1.93 (2H, m),1.93-2.53 (3H, m),3.07-3.36 (3H, m),3.36-4.09 (3H, m),4.52-4.75 (IH, m),6.36 (IH, d, J=15.7 Hz) ,6.88-7.08 (IH, m),7.43 (IH, d, J=15.8 Hz) ,7.91-8.01 (IH, m),8.12 (IH, s); .

The following compounds were obtained in a similar manner to that of Example 92. Example 93 (2E)-3-(6-{[(3R)-l-(cycloheptylmethyl)-3-pyrrolidinyl]amino} -3- pyridinyl)-N-hydroxyacrylamide dihydrochloride 1H-NMR (300 MHz, DMSO~d6) 61.15-1.34 (2H, m),1.34-1.71 (7H, m),1.71-1.99 (3H, m) ,1.99-2.19 (IH, m),2.25-2.65 (IH, m),3.02-3.24 (3H, m),3.24-3.92 (3H, m),3.92-4.11 (IH, m),4.53-7.76 (IH, m),6.36 (IH, d, J=15.8 Hz),6.87-7.06 (IH, m),7.43 (IH, d, J=15.8 Hz),7.92- 8.03 (IH, m),8.20 (IH, s),10.27 (IH, br peak); MS (ES+) m/z 359.

Example 94 (2Z)-3-(6-{[ (3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-3~ pyridinyl)-2-fluorp-N-hydroxyacrylamide dihydrochloride 1H-NMR (300 MHz, DMSO-d6) δ0.85-1.06 (2H, m),1.06-1.35 (3H, m),1.54-1.78 (4H, m),1.78-1.95 (2H, m),1.95-2.18 (IH, m),2.25-2.65 (IH, m),2.97-4.09 (6H, m),4.52-4.76 (IH, m) ,6.73-7.00 (2H, m),7.08 ( IH, s ) , 7.25 ( IH, s ) , 7 .42 ( IH, s ) , 7. 95 ( IH, d, J=8. 6 Hz ) , 8 .25 ( IH, S ) ; MS (ES+) m/z 363. ,J

Example 95 (2E)-3-(6-{[(3R)-l-(l-adamantylmethyl)-3-pyrrolidinyl]amino} -3- pyridinyl)-N-hydroxyacrylamide dihydrochloride 1H-NMR (300 MHz, DMSO-d6) <51.55-1.75 (16H, m) ,1.90-2.03 (3H, m),2.03-2.16 (IH, m),2.95-4.20 (3H, m) ,4.53-4.80 (IH, m),6.38 (IH, d, J=15.4 Hz),6.89-7.12 (IH, m),7.44 (IH, d, J=15.4 Hz),8.00 (IH, d, J=9.5 Hz),8.21 (IH, s).

Example 96 To the solution of (2E)-3-(5-{[ (3R)-l-(2-phenylethyl)-3- piperidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2- yloxy)acrylamide (3.2 g, 7.1 mmol) in EtOH (16 ml) was added 2M ethanlic hydrogen chloride (17.5 mL) and the mixture was stirred at ambient temperature for 3 hrs. To the reaction mixture was added IPE and isolated precipitate was collected by filtration to give (2E)-N-hydroxy-3-(5-{[ (3R)-l-(2-phenylethyl)-3-piperidinyl]amino}- 2rpyrazinyl)acrylamide dihydrochloride (2.3g, 74%) as an amorphous powder. 1H-NMR (300 MHz, DMSO-d6) δ1.40-1.61 (IH, m),1.74-2.21 (3H, m),2.60-2.80 (IH, m) ,2.80-3.01 (IH, m),3.01-3.14 (2H, m),3.21-3.38 (2H, m),3.38-3.75 (2H, m),4.23-4.42 (IH, m),6.64 (IH, d, J=15.2 Hz),7.20-7.48 (6H, m),7.84 (IH, br peak) ,8.00-8.12 (IH, m),8.12- 8.26 (IH, m); MS (ES+) m/z 368.

The following compounds were obtained in a similar manner, to that of Example 96. Example 97 (2E)-3-(6-{[(3R)-l-benzyl-3-piperidinyl]amino}-3-pyridinyl)- N- hydroxyacrylamide dihydrochloride 1H-NMR (300 MHz, DMSO-d6) δ1.30-1.66 (IH, m),1.66-2.17 (3H, m),2.60-4.00 (4H, m),4.16-4.60 (3H, m),6.21-6.44 (IH, m),6.55-7.10 (2H, m),7.32-7.67 (6H, m),7.79-8.01 (IH, m),8.11-8.38 (IH, m); MS (ES+) m/z 353.

Example 98 (2E)-3-(6-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}- 3- pyridinyl)-N-hydroxy-2-methylacrylamide dihydrochloride 1H-NMR (300 MHz, DMSO-d6) 50.80-1.04 (2H, m),1.04-1.32 (4H, m),1.53-1.75 (5H, m) ,1.75-1.90 (2H, m),1.90-2.20 (4H, m) ,2.20-2.65 (IH, m),3.00-3.20 (3H, m) ,3.94-4.10 (IH, m),4.51-4.73 (IH, m),6.87- 7.04 (2H, m),7.85 (IH, d, J=9.0 Hz),8.03 (IH, s); MS (ES+) m/z 359.

Example 99 (2E)-3-(6-{[(3S)~l-(cyclohexylmethyl)-3-piperidinyl]amino}-3 - pyridinyl)-N-hydroxyacrylamide dihydrochloride 1H-NMR (300 MHz, DMSO-d6) <5θ.86-l.O5 (2H, m),1.05-1.35 (3H, m),1.35-2.15 (1OH, m),2.65-3.10 (3H, m),3.20-4.00 (3H, m),4.30-4.62 (IH, m),6.37 (IH, d, J=16.1 Hz) ,6.90-7.11 (IH, m),7.35-7.51 (IH, m),7.90-8.10 (IH, m),8.15-8.30 (IH, m); .

Example 100 (2E)-3-(6-{[(3R)-l-cyclohexyl-3-piperidinyl]amino}-3-pyridin yl)-N- hydroxyacrylamide dihydrochloride , 1H-NMR (300 MHz, DMSO-d6) 61.00-1.69 (8H, m),1.75-2.15 (7H, m),2.58-3.90 (4H, m) ,4.25-4.55 (IH, m),6.26-6.41 (IH, m) ,6.80-7.05 (IH, m),7.35-7.50 (IH, m),7.85-8.06 (IH, m),8.21 (IH, s); MS (ES+) m/z 345.

Example 101 (2E)-3-(6-{[(3R)-1-(4-chlorobenzyl)-3-piperidinyl]amino}-3- pyridinyl)-N-hydroxyacrylamide dihydrochloride 1H-NMR (300 MHz, DMSO-d6) δ1.31-1.66 (IH, m),1.73~2.19 (3H, m),2.64-3.09 (2H, m),3.09-4.00 (2H, m),4.20-4.65 (3H, m),6.35 (IH, d, J=15.7 Hz),6.85-7.10 (IH, m),7.41 (IH, d, J=16.0 Hz),7.55 (2H, d, J=8.2 Hz),7.65 (2H, d, J=7.8 Hz) ,7.89-8.11 (IH, m),8.19 (IH, s); MS (ES+) m/z 387. Example 102 . . (2E)-3-(6-{[(3R)-l-cyclopentyl-3-piperidinyl]amino}-3-pyridi nyl)-N- hydroxyacrylamide dihydrochloride 1H-NMR (300 MHz, DMSO-d6) 61.41-1.64 (3H, m) ,1.64-2.18 (1OH, m),2.72-4.00 (4H, m) ,4.21-4.60, (IH, m) ,6.30-6.44 (IH, m) ,6.94-7.11 (IH, m),7.36-7.50 (IH, m) ,7.94-8.08 (IH, m),8.15-8.25 (IH, m) ; MS (ES+) m/z 331. ,

Example 103 (2E)-N-hydroxy-3-(6-{[(3R)-l-(4-methylbenzyl)-3-piperidinyl] amino}- 3-pyridinyl)acrylamide dihydrochloride IH-NMR (300 MHz, DMSO-d6) 61.31-1.65 (IH, m),1.74-2.16 (4H, m),2.33 (3H, s),2.65-4.20 (3H, m),4.20-4.70 (3H, m),6.40 (IH, d, J=15.9 Hz),6.91-7.16 (IH, m),7.27 (2H, d, J=7.7 Hz) ,7.35-7.59 (3H, m),7.95-8.12 (IH, m),8.20 (IH, br s) .

Example 104 (2Z)-2-fluoro-N-hydroxy-3-(6-{[(3R)-l-(4-methylbenzyl)-3- pyrrolidinyl]amino}-3-pyridinyl)aerylamide dihydrochloride IH-NMR (300 MHz, DMSO-d6.) <51.90-2.20 (2H, m),2.20-2.40 (4H, m),2.40-3.86 (3H, m),4.24-4.76 (3H, m),6.70-7.10 (2H, m),7.20-7.30 (2H, m),7.45-7.55 (2H, m) ,7.91-8.06 (IH, m),8.24 (IH, s); MS (ES+) m/z 371.

Example 105 (2Z)-3-(6-{[(3R)-l-(4-chlorobenzyl)-3-pyrrolidinyl]amino}-3- pyridinyl)-2-fluoro-N-hydroxyacrylamide dihydrochloride 1H-NMR (300 MHz, DMSO-d6) δ1.93-2.21 (2H, m),2.21-4.00 (4H, m),4.34-4.80 (3H, m),6.70-7.15 (2H, m),7.53 (2H, d, J=8.2 Hz),7.62- 7.75 (2H, m),8.00 (IH, t, J=9.9 Hz),8.22 (IH, s); MS (ES+) m/z 391.

Example 106 (2E)-3-(6-{[(3R)-l-(cyclohexylcarbonyl)-3-piperidinyl]amino} -3- pyridinyl)-N-hydroxyacrylamide hydrochloride 1H-NMR (300 MHz, DMSO-d6) 60.96-1.94 (12H, m),1.94-2.14 (IH, m),2.38-2.67 (IH, m),2.94-4.15 (6H, m),6.39 (IH, d, J=16.0 Hz),6.95-7.20 (IH, m),7.45 (IH, d, J=16.3 Hz) ,7.92-8.14 (IH, m),8.20 (IH, br s); MS (ES+) m/z 373.

Example 107 (2E)-3-(6-{[ (3R)~l-(4-chlorobenzoyl)-3-piperidinyl]amino}-3- pyridinyl)-N-hydroxyacrylamide hydrochloride 1H-NMR (300 MHz, DMSO-d6) δ1.37-2.14 (5H, m),3.04-4.20 (4H, m),6.41 (IH, d, J=15.9 Hz),6.95-7.95 (7H, m),7.95-8.38 (IH, m) ; MS (ES+) m/z 401.

Example 108 (2Ej-3-(6-{[ (3R)-I-(cyclohexylmethyl)-3-piperidinyl]amino}-3- pyridinyl)-N-hydroxyacrylamide dihydrochloride 1H-NMR (300 MHz, DMSO-d6) 60.85-1.07 (2H, m) ,1.07-1.36 (3H, m),1.36-2.15 (1OH, m),2.65-3.10 (3H, m) ,3.20-4.10 (3H, m),4.30-4.65 (IH, m),6.39 (IH, d, J=16.1 Hz) ,6.94-7.12 (IH, m),7.34-7.51 (IH, m),7.91-8.09 (IH, m),8.15-8.30 (IH, m) .

Example 109 (2E)-3-(5-{[(3R)-1-(3-chlorobenzyl)-3-piperidinyl]amino}-2- pyrazinyl)-N-hydroxyacrylamide dihydrochloride IH-NMR (300 MHz, DMSO-d6) δ1.34-1.54 (IH, m),1.74-2.15 (4H, m),2.59-3.23 (2H, m),3.23-3.58 (2H, m),4.21-4.46 (2H, m),6.61 (IH, d, J=15.2 Hz),7.38 (IH, d, J=15.2 Hz) ,7.45-7.65 (3H, m),7.70-7.84 (2H, m),7.96-8.06 (IH, m),8.06-8.16 (IH, m); MS (ES+) m/z 388.

Example 110 (2E)-3-(5-{[(3R)-l-(4-fluorobenzyl)~3~piperidinyl]amino}-2- pyrazinyl)-N-hydroxyacrylamide dihydrochloride 1H-NMR (300 MHz, DMSO-d6) (51.30-1.54 (IH, m),1.70-2.15 (4H, m) , 2 . 55-2. 75 ( IH, m) , 2 .75-2 .94 ( IH, m) , 3.22-3.36 ( IH, m) , 3.36-3. 53 (IH, m),4.17-4.45 (2H, m),6.62 (IH, d, J=15.2 HK) ,7.25-7.45 (3H, m),7.65-7.85 (3H, m) ,7.96-8.19 (2H, m) ; MS (ES+) m/z 372.

Example 111 (2E)-N-hydroxy-3-(5-{[ (3R)-1-(2-thienylmethyl)-3- piperidinyl]amino}-2-pyrazinyl)acrylamide dihydrochloride 1H-NMR (300 MHz, DMSO-d6) <51.31-1.60 (IH, m),1.72-2.19 (4H, m),2.56-3.25 (2H, m),3.25-3.58 (2H, m),4.18-4.40 (IH, m),4.52-4.65 (2H, m),6.62 (IH, d, J=15.2 Hz) ,7.09-7.19 (IH, m),7.34-7.46 (2H, m),7.65-7.88 (2H, m),7.96-8.20 (2H, m); MS (ES+) m/z 360.

Example 112 (2E)-N-hydroxy-3-(5-{[(3R)-l-(2-pyridinylmethyl)-3- piperidinyl]amino}-2-pyrazinyl)acrylamide trihydrochloride 1H-NMR (300 MHz, DMSO-d6) <51.40-1.65 (IH, m),1.80-2.05 (3H, m),2.86-3.03 (IH,' m),3,03-3.20 (IH, m),3.28-3.45 (IH, m),3.45-3.57 (IH, m),4.25-4.38 (IH, m),4.51 (2H, s),6.61 (IH, d, J=15.3 Hz),7.40 (IH, d, J=15.2 Hz),7.50 (IH, dd, J=7.0, 5.4 Hz),7.66 (IH, d,, J=7.7 Hz),7.85 (IH, br peak) ,7.90-7.98 (IH, m),8.02 (IH, s),8.10 (IH, s),8.65 (IH, d, J=4.6 Hz); MS (ES+) m/z 355.

Example 113 (2E)-N-hydroxy-3-(5-{[(3R)-l-(4-pyridinylmethyl)-3- piperidinyl]amino}-2-pyrazinyl)acrylamide trihydrochloride 1H-NMR (300 MHz, DMSO-d6) δ1.34-1.59 (IH, m) ,1.74-2.19 (3H, m),2.61-2.84 (IH, m),2.84-3.01 (IH, m) ,3.25-3.46 (IH, m),3.46-3.60 (IH, m),4.30-4.50 (IH, m),4.50-4.70 (2H, m),6.62 (IH, d, J=15.3 Hz),7.39 (IH, d, J=15.2 Hz),7.30 (IH, br peak),8.01 (IH, s),8.07- 8.22 (3H, m),8.94 (2H, d, J=5.9 Hz); MS (ES+) m/z 355. Example 114 (2E)-N-hydroxy-3-(5-{[(3R)-l-(3-pyridinylmethyl)-3- piperidiny1]amino}-2-pyrazinyl)acrylamide trihydrochloride 1H-NMR (300 MHz, DMSO-d6) 61.35-2.15 (4H, m),2.56-3.80 (4H, m),4.45-4.70 (3H, m),6.61 (IH, d, J=15.2 Hz),7.39 (IH, d, J=15.2 Hz),7.80 (IH, br peak) ,7.90-7.98 (IH, m),8.01 (IH, s),8.13 (IH, s),8.55-8.72 (IH, m),8.90 (IH, d, J=5.0 Hz),9.02-9.12 (IH, m),11.59 (IH, br peak); MS (ES+) m/z 355.

Example 115 (2E)-N-hydroxy-3-(5-{[(3R)-1-(3-thienylmethyl)-3- piperidinyl]amino}-2-pyrazinyl)acrylamide dihydrochloride 1H-NMR (300 MHz, DMSO-d6) δ1.31-1.54 (IH, m),1.70-2.15 (3H, m),2.54-3.21 (2H, m),3.21-3.55 (2H, m),4.20-4.43 (3H, m),6.61 (IH, d, J=15.5 Hz),7.30-7.45 (2H, m),7.59-7.70 (IH, m),7.70-85 (2H, m),7.96-8.08 (IH, m),8.08-8.17 (IH, m); MS (ES+) m/z 360.

Example 116 (2E)-3-(5-{[(3R)-l-(4-fluorobenzyl)-3-pyrrolidinyl]amino}-2- pyrazinyl)-N-hydroxyacrylamide dihydrochloride 1H-NMR (300 MHz, DMSO-d6) <51.87-2.16 (IH, m),2.16-2.60 (IH, m),2.96-3.11 (IH, m),3.11-4.10 (3H, m),4.32-4.51 (2H, m),4.57 (IH, br peak),6.63 (IH, d, J=15.2 Hz),7.22 (2H, t-like, J=8.8 Hz),7.39 (IH, d, J=15.2 Hz),7.67 (2H, t-like, J=6.7 Hz),7.90-8.16 (2H, m),8.21 (IH, br peak); MS (ES+) m/z 358.

Example 117 (2E)-3-(5-{[(3R)-l-(cycloheptylmethyl)-3-piperidinyl]amino}- 2- pyrazinyl)-N-hydroxyacrylamide dihydrochloride 1H-NMR (300 MHz, DMSO-d6) 61.11-1.31 (2H, m),1.31-1.69 (8H, m),1.69-1.84 (2H, m) ,1.84-2.06 (3H, m),2.56-2.78 (IH, m) ,2.78-3.09 (3H, m),3.09-4.00 (4H, m),4.30 (IH, br peak),6.62 (IH, d, J=15.4 Hz),7.40 (IH, d, J=15.4 Hz) ,7.73-7.85 (IH, m),7.98-8.10 (IH, m) , 8. 15 ( IH, s) , 9.52 ( IH, br peak) ; MS (ES+ ) m/z 374.

Example 118 (2E)-3-(5-{[(3R)-l-cycloheptyl-3-piperidinyl]amino}-2-pyrazi nyl)-N- hydroxyacrylamide dihydrochloride 1H-NMR (300 MHz, DMSO-d6) δ1.30-2.25 (16H, m) ,2.57-3.50 (5H, m),4.24-4.40 (IH, m),6.64 (IH, d, J=15.2 Hz),7.40 (IH, d, J=15.2 Hz),7.75 (IH, br peak),7.98-8.10 (IH, m),8.10-8.17 (IH, m) ; MS (ES+) m/z 360.

Example 119 . (2E)-N-hydroxy-3-(5-{[(3R)-1-(2-phenylethyl)-3-pyrrolidinyl] amino}- 2-pyrazinyl)acrylamide dihydrochloride 1H-NMR (300 MHz, DMSO-d6) δ1.94-2.16 (IH, m),2.16-2.70 (IH, m),2.96-3.14 (2H, m),3.14-4.10 (6H, m),4.41-4.61 (IH, m),6.64 (IH, d, J=15.2 Hz),7.23-7.50 (5H, m),8.05 (IH, s),8.11-8.24 (IH, m) ; MS (ES+) m/z 354.

Example 120 (2E)-N-hydroxy-3-(5-{[(3R)-l-(2-pyrimidinyl)-3-piperidinyl]a mino}- 2-pyrazinyl)acrylamide dihydrochloride 1H-NMR (300 MHz, DMSO-d6) δ1.45-1.72 (2H, m),1.76-1.94 (IH, m) ,1.94-2.10 (IH, m),3.20-3.44 (2H, m),3.88-4.04 (IH, m) ,4.15-4.26 (IH, m),4.42 (IH, dd, J=12.6, 3.4 Hz),6.60 (IH, d, J=15.3 Hz),6.68 (IH, t, J=4.8 Hz),7.38 (IH, d, J=15.2 Hz),7.80 (IH, br peak),8.04 (IH, s),8.13 (IH, s),8.40 (IH, d, J=4.8 Hz); • MS (ES+) m/z 342.

Example 121 (2E)-3-(5-{[(3R)-l-(2,3-dihydro-lH-inden-2-yl)-3- piperidinyl]amino}-2Tpyrazinyl)-N-hydroxyacrylamide dihydrochloride 1H-NMR (300 MHz, DMSO-d6) δ1.44-1.64 (IH, m),1.76-2.20 (3H, m),2.68-3.17 (2H, m),3.17-3.41 (4H, m),3.41-3.54 (IH, m),3.54-3.65 (IH, m),4.05-4.24 (IH, m),4.24-4.41 (IH, m),6.58-6.69 (IH, m),7.14- 7.31 ( 4H, m) , 7.40 ( IH, d, J=15. 4 Hz ) , 7 .99-8. 11 ( IH, m) , 8. 18 ( IH, s ) ; MS (ES+) m/z 380.

Example 122 (2Z)-3-(6-{[ (3R)-l-cyclohexyl-3-pyrrolidinyl]amino}-3-pyridinyl)-2- fluoro-N-hydroxyacrylamide dihydrochloride 1H-NMR (300 MHz, DMSO-d6) <51.01-1.35 (3H, m) ,1.35-1.54 (2H, m),1.54-1.69 (IH, m) ,1.72-1.89 (2H, m) ,1.94-2.36 (4H, m) ,3.02-4.10 (5H, m),4.50-4.70 (IH, m),6.75-7.07 (2H, m) ,7.94-8.08 (IH, m),8.26 (IH, s); MS (ES+) m/z 349.

Example 123 To a solution of (2E)-3-(5-{[(3R)-l-cyclohexyl-3- pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2- yloxy)acrylamide (274 mg) in methanol (6.6 mL) was added hydrogen chloride in methanol (0.659 mL) . After stirring at room temperature for 1 hour; the reaction mixture was evaporated in vacuo and triturated with ethyl acetate to give (2E)-3-(5-{[(3R)-I- cyclohexyl-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-hydroxyacryl amide dihydrochloride (252 mg). 1H-NMR (300 MHz, DMSO-d6) δ1.01-4.59 (18H, m) , 6.63 (IH, d, J = 16 Hz), 7.40 (IH, d, J = 16 Hz), 8.01-8.19 (2H, m) . MS (ES+) m/z 332 (M+l) .

The following compounds were obtained in a similar manner to that of Example 123. Example 124 (2E)-3-(2-{[ (3R)-l-benzyl-3-pyrrolidinyl]amino}-5-pyrimidinyl)-N- hydroxyacrylamide dihydrochloride 1H-NMR (300 MHz, DMSO-d6) δl.93-4.67 (9H, m) , 6.37 (IH, d, J = 16 Hz), 7.32 (IH, d, J = 16 Hz), 7.41-7.65 (5H, m) , 8.56 (2H, s) . MS (ElS+) m/z 340 (M+l).

Example 125 (2E)-3-(5-{[(3R)-l-benzyl-3-pyrrolidinyl]amino}-6-methyl-2- pyrazinyl)-N-hydroxyacrylamide dihydrochloride 1H-NMR (300 MHz, DMSO-d6) 52.01-4.83 (12H, m) , 6.64 (IH, d, J = 16 Hz), 7.18-7.27 (IH, m) , 7.37 (IH, d, J = 16 Hz), 7.42-7.51 (3H, m) , 7.59-7.68 (2H, m) , 8.03. (IH,' s) . MS (ES+) m/z 354 (M+l).

Example 126 (2E)-3-(6-{[(3R)-l-benzyl-3-pyrrolidinyl]amino}-3-pyridaziny l)-N- hydroxyaerylamide dihydrochloride 1H-NMR OOO MHz, DMSO-d6) 52.02-4.76 (9H, m) , 6.74-6.83 (IH, m) , 7.28-7.69 (7H, m) , 7.84-7.97 (IH, m) , 10.2 (IH, brs), 11.4 (IH, brs) . MS (ES+) m/z 340 (M+l).

Example 127 (2E)-N-hydroxy-3-(6-{[(3R)-l-phenyl-3-pyrrolidinyl]amino}-3- pyridinyl)acrylamide dihydrochloride 1H-NMR (300 MHz, DMSO-d6) (52.04-2.16 (IH, m) , 2.33-2.46 (IH, m) , 3.29-4.65(5H, m) , 6.42 (IH, d, J = 16 Hz), 6.56-6.68 (3H, m) , 7.12- 7.24 (3H, m), 7.49 (IH,.d, J = 16 Hz), 8.06-8.13 (IH, m) , 8.23 (IH, brs) . MS (ES+) m/z 323 (M-I).

Example 128 (2E)-3-(6-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}- 3- pyridazinyl)-N-hydroxyacrylamide dihydrochloride 1H-NMR (300 MHz, DMSO-d6) 00.88-1.02 , (2H, m) , 1.09-4.79 (18H, m) , 6.76-6.85 (IH, m) , 7.35-7.56 (2H, m) , 7.89-7.98 (IH, m) , 10.6 (IH, brs) . MS (ES+) m/z 346 (M+l).

Example 129 2M ethanolic hydrogen chloride (2.0 mL) was added to the solution of (2Z)-3-(5-chloro-6-{[(3R)-I-(cyclohexylmethyl)-3- piperidinyl]amino}-3-pyridinyl)-2-fluoro-N-(tetrahydro-2H-py ran-2- yloxy)acrylamide (0.5 g) in EtOH (5 ml) and the mixture was stirred at ambient temperature for 3 hrs. To the reaction mixture was added AcOEt and isolated precipitate was collected by filtration to give (2Z)-3-(5-chloro-6-{[(3R)-l-(cyclohexylmethyl)-3- piperidinyl]amino}-3-pyridinyl)-2-fluoro-N-hydroxyacrylamide dihydrochloride (0.28g) , (+)ESI-MS:411(M+H)+.

The following compounds were obtained in a similar manner to that of Example 129. Example 130 " (2E)-3-(2-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}- l,3- thiazol-4-yl)-N-hydroxyacrylamide dihydrochloride 1H-NMR(DMSO-d6): <5 0.81-1.40(6H, m) , 1.49-2.62(8H, m) , 2.97-4.09(5H, m), 4.37-4.66(1H, m) , 6.49-6.50(total IH, each d, J=each 15.2 Hz), 7.09(1H, s), 7.2O(1H, d, J=15.2 Hz), (+)ESI-MS:351(M+H)+.

Example 131 (2Z)-3-(6-{ [(3R)-l-benzyl-3-piperidinyl]amino}-5-chloro-3- pyridinyl)-2-fluoro-N-hydroxyacrylamide dihydrochloride 1H-NMR(DMSO-d6): 6 1.48-2.09(4H, m) , 2.66-3.42(4H, m) , 4.31-4.47(2H, m), 4.62 and 4.75(total IH, each s), 6.78 and 6.81(total IH, each d, J=each 39.8 Hz), 6.94(1H, d, J=6.3 Hz), 7.43-7.50(3H, m) , 7.62- 7.74(2H, m), 7.88 and 7.90(total IH, each d, J=each 1.9 Hz), 8.26 and 8.28(total IH, each d, J=each 1.9 Hz), 11.34 and 11.66(total IH, each s) , (+)ESI-MS:405(M+H)+.

Example 132 (2Z)-3-(5-chloro-6-{[ (3R)-l-cyclopentyl-3-piperidinyl]amino}-3- pyridinyl)-2-fluoro-N-hydroxyacrylamide dihydrochloride (+)ESI-MS:383(M+H)+. Example 133 (2Z)-3-(5-chloro-6-{[(3R)-l-cyclohexyl-3-piperidinyl]amino}- 3- pyridinyl)-2-fluoro-N-hydroxyacrylamide dihydrochloride (+JESI-MS:397(M+H)+.

Example 134 (2Z)-3-(6~{[(3R)-l-benzyl-3-piperidinyl]amino}-3-pyridinyl)- 2- fluoro-N-hydroxyacrylamide dihydrochloride (+)ESI-MS:371(M+H)+.

Example 135 (2Z)-3-(6-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-3 - pyridinyl)-2-fluoro-N-hydroxyacrylamide dihydrochloride 1H-NMR(DMSO-d6): <5 0.89-1.02(2H, m) , 1.06-1.30(3H, m) , 1.44- 2.16(1OH, m), 2.75-3.67(6H, m), 4.41 and 4.67(total IH, each s), 6.87 and 6.89(total IH, each d, J=each 39.2 Hz), 7.04-7.14(1H, m) , 8.01τ8.11(lH, m), 8.2O-8.29(1H, m) , (+)ESI-MS:377(M+H)+.

Example 136 (2Z)-3-(6-{[(3R)-I-cyclopentyl-3-piperidinyl]amino}-3-pyridi nyl)-2- fluoro-N-hydroxyacrylamide dihydrochloride 1H-NMR(DMSO-d6): 6 1.45-2.15(12H, m) , 2.79-3.09(2H, m) , 3.34- 3.66(3H, m), 4.31 and 4.67(total IH, each s), 6.88 and 6.89(total IH, each d, J=each 39.1 Hz), 7.07-7.15(1H, m) , 8.04-8.13(1H, m) , 8.20-8.30(1H, m), (+)ESI-MS:349(M+H)+.

Example 137 (2Z)-3-(6-{[(3R)-l-cyclohexyl-3-piperidinyl]amino}-3-pyridin yl)-2- fluoro-N-hydroxyacrylamide dihydrochloride 1H-NMR(DMSO-d6): δ 1.02-1.66(7H, m) , 1.74-2.26(7H, m) , 2.82-3.59(5H, m), 4.41 and 4.69(total IH, each s), 6.89 and 6.90(total IH, each d, J=each 39.0 Hz), 7.09-7.18(1H, m) , 8.05-8.14(1H, m) , 8.21 and 8.27(total IH, each s) ( + )ESI-MS : 363 (M+H) + .

Example 138 A mixture of (2E)-3-(5-{[(3R)-l-benzyl-3-pyrrolidinyl]amino}-2- pyridinyl)-N-(tetraLh.ydro-2H-pyran-2-yloxy)acrylamide (185mg) and 2NHCl/EtOH (9ml, 20eq. ) was stirred at room temperature for 3 hours. After then, IPE (50ml) was added and stirred. Precipitate was filtered, washed with IPE, and dried to give 486mg (95%) of (2E)- 3-(5-{[ (3R)-1-benzyl-3-pyrrolidinyl]amino}-2-pyridinyl)-N- hydroxyacrylamide dihydrochloride as a powder. MASS (ESI+): m/z = 339.13 (M+l). 1HNMR ( 400MHz, DMSO-d6): <5 1.90-2.10 (2H, m) , 2.25-2.60 (2H, m) , 3.10-3.40 (2H, m), 4.31 (IH, br.s), 4.42 (2H, d, J=6.0Hz), 6.74 (IH, d, J=13.9Hz), 7.44 (5H, s), 7.64 (2H, m) , , 7.80 (IH, m) , 8.07 (d, 13.9Hz).

Example 139 To a solution of (2E)-3-(5-{[(3R)-l-(3-methoxybenzyl)-3- pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2- yloxy)acrylamide (240mg) in ethanol (3.6mL) was added 2N HCl-EtOH (1.ImL) , which was stirred at room temperature for 1 hour. To the resultant was added ethyl acetate (9.6mL) , which was stirred for 1 hour. The precipitate was filtered to give (2E)-N-hydroxy-3-(5- {[(3R)-1-(3-methoxybenzyl)-3-pyrrolidinyl]amino}-2- pyrazinyl)acrylamide dihydrochloride ( 223mg) as a yellow powder. 1H NMR (400 MHz, DMSO-d6) δ1.94-2.58 (2H, m) , 2.96-5.02 (1OH, m) , 6.63 (IH, dd, J = 2.6, 15.2 Hz), 6.99 (IH, d, J = 8.2 Hz), 7.15 (IH, d, J = 6.4 Hz), 7.26-7.45 (3H, m) , 8.00-8.34 (3H, m) , 11.32 (IH, br); MS (ES+) m/z 370 (M+l).

The following compounds were obtained in a similar manner to that of Example 139. Example 140 (2E)-3-(5-{[(3R)-l-(3-cyanobenzyl)-3-pyrrolidinyl]amino}-2- pyrazinyl)-N-hydroxyacrylainide dihydrochloride 1H NMR (DMSO-d6, 400MHz) δ 1.19-2.40 (2H, m) , 3.01-3.82 (4H, m) , 3.95-5.05 (3H, m) , 6.29 (IH, dd, J = 2.5, 15.3 Hz), 7.39 (IH, d, J = 15.3 Hz), 7.67 (IH, dt, J = 1.8, 7.8 Hz), 7.93 (J.H, d, J = 7.9 Hz), 7.96-8.11 (3H, m) , 8.11-8.38 (2H, m) , 11.45-11.64 (IH, m); MS (ES+) 365 (M+l).

Example 141 (2E)-3-[5-({(3R)-1-[3-(acetylamino)benzyl]-3-pyrrolidinyl}am ino)-2- pyrazinyl]-N-hydroxyacrylamide dihydrochloride 1H NMR (DMSO-d6, 400MHz) δ 1.92-2.39 (5H, m) , 2.97-3.79 (4H, m), 3.81-4.68 (3H, m) , 6.63 (IH, dd, J = 2.9, 15.4 Hz), 7.23-7.45 (3H, m), 7.53 (IH, d, J = 7.3 Hz), 7.85 (IH, d, J = 9.0 Hz), 7.97-8.33 (3H, m), 10.18 (IH, s), 11.04 (IH, br); MS (ES+) m/z 397 (M+l).

Example 142 (2E)-3-[5-({(3R)-l-[3-(dimethylamino)benzyl]-3-pyrrolidinyl} amino)- 2-pyrazinyl]-N-hydroxyacrylamide trihydrochloride 1H NMR (DMSO-d6, 400 MHz) 6 1.92-2.84 (2H, m), 2.88-4.80 (13H, m) , 6.65 (IH, d, J = 15.3 Hz), 6.83-7.55 (5H, m) , 7.94-8.36 (3H, m) , 11.32 (IH, brJ.¬ MS (ES+) m/z 383 (M+l).

Example 143 (2E)rN-hydroxy-3-(5-{[(3R)-l-{3-[(methylsulfonyl)amino]benzy l}-3- pyrrolidinyl]amino}-2-pyrazinyl)acrylamide dihydrochloride 1H NMR (DMSO-d6, 400 MHz) δ 1.90-2.59 (2H, m) , 3.08 (3H, s), 3.15- 4.81 (7H, m), 6.63 (IH, dd, J = 2.8, 15.2 Hz), 7.21 (IH, dd; J = 2.0, 7.2 Hz), 7.32-7.47 (4H, m) , 7.98-8.41 (3H, m) , 9.98 (IH, s), 11.30 (IH, br); MS (ES+) m/z 433 (M+l).

Example 144 (2E)-N-hydroxy-3-(5-{[ (3R)-1-(2-methoxybenzyl)-3- pyrrolidinyl]amino}-2-pyrazinyl)acrylamide dihydrochloride 1H NMR (DMSO-d6, 400 MHz) δ 1.94-2.43 (2H, m) , 2.93-5.02 (1OH, m) , 6.60 (IH, dd, J = 3.3, 15.3 Hz), 6.96-7.07 (IH, m) , 7.11 (IH, t, J = 9.0 Hz), 7.33-7.49 (2H, m) , 7.50-7.61 (IH, m) , 7.99-8.37 (3H, m) , 10.72 (IH, br); MS (ES+) m/z 369 (M+l).

Example 145 (2E)-N-hydroxy-3-(5-{[ (3R)-1-(2-hydroxybenzyl)-3- pyrrolidinyl]amino}-2-pyrazinyl)acrylamide dihydrochloride 1H NMR (DMSO-d6, 400 MHz) 6 1.92-2.59 (2H, m), 3.01-4.73 (7H, m) , 6.63 (IH, d, J = 15.3 Hz), 6.81-6.93 (IH,' m) , 6.78 (IH, t, J = 8.2 Hz), 7.26 (IH, t, J = 7.5 Hz), 7.39 (IH, d, J = 15.3 Hz), 7.42-7.51 (IH, m), 8.00-8.30 (2H, m) , 10.22-10.69 (2'H, m); MS (ES+) m/z 356 (M+l).

Example 146 (2E)-N-hydroxy-3-(5-{[(3R)-1-(3-hydroxybenzyl)-3- pyrrolidinyl]amino}-2-pyrazinyl)acrylamide dihydrochloride 1H NMR (DMSO-d6, 400 MHz) 6 1.93-2.40 (2H, m) , 2.99-3.80 (4H, m) , 4.17-5.38 (3H, m), 6.63 (IH, dd, J = 2.4, 15.2 Hz), 6.84 (IH, d, J = 7.9 Hz), 6.93-7.08 -(2H1 m) , 7.22 (IH, dt, J = 2.1, 7.8 Hz), 7.38 (IH, d, J = 15.3 Hz), 7.98-8.45 (3H, m) , 11.16 (IH, br) , MS (ES+) m/z 356 (M+l).

Example 147 (2E)-N-hydroxy-3-(5-{[ (3R)-l-(3-isopropoxybenzyl)-3- pyrrolidinyl]amino}-2-pyrazinyl)acrylamide dihydrochloride 1H NMR (DMSO-d6, 400 MHz) δ 1.23-1.32 (6H, m) , 1.94-2.56 (2H, m) , 2.95-3.29 (4H, m) , 3.86-4.84 (4H, m) , 6.63 (IH, dd, J = 2.9, 15.3 Hz), 6.95 (IH, dd, J = 2.1, 8.1 Hz), 7.11 (IH, d, J = 7.0 Hz), 7.21-7.49 (3H, m), 7.98-8.45 (3H, m) , 11.35 (IH, br) ; MS (ES+) m/z 398 (M+l).

Example 148 A mixture of (2E)-3-(5-{[(3R)-l-(2-fluorobenzyl)-3- pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2- yloxy)acrylamide (600mg) and 2N HCl/Ethanol (13.6ml, 20eq) was stirred at room temperature for 2 hours. After then, ethyl acetate (10ml) and IPE (50ml) was added and stirred. Precipitate was filtered, washed with IPE, and dried under reduced pressure to give 486mg (83%) of (2E)-3-(5-{[(3R)-l-(2-fluorobenzyl)-3- pyrrolidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamide dihydrochloride as a powder. MASS (ESI+): m/z = 358.3(M+1). 1HNMR ( 400MHz, DMSOdβ, ): <5 1.96-2.37 (2H, m) , 3.05-3.85 (4H, m) , 4.47 ( IH, d, J=5.5Hz), 4.51 (IH, d, J=5.5Hz), 4.59 (m, IH), 6.63 (IH, dd, J=2.6Hz and 15.1Hz), 7.28-7.39 (2H, m) , 7.39 (IH, d, J=15.1Hz), 7.49-7.56 (IH, m) , 7.72-7.79 (IH, m) 8.02 (IH, d, J=8.3Hz), 8.14 (IH, s), 11.12 (IH, br.s.).

Example 149 A mixture of (2E)-3-(5-{[(3R)-l-(3-fluorobenzyl)-3- pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2- yloxy)acrylamide (700mg) and 2N HCl/Ethanol (16.4ml) was stirred for 2 hrs. EtOAc(IOmI) and IPE (50ml) was added and and stirred. After 1 hr, precipitate was filtered and dried to give 565mg of (2E)-3-(5- {[ (3R)-l-(3-fluorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N - hydroxyacrylamide dihydrochloride as a powder. MASS (ESI+): m/z = 358.3 (M+l). 1HMMR ( 400MHz, CDCl3): δ 1.96-2.56 (2H, m) , 3.03-3.80 (4H, m) , 4.43 ( IH, d, J=5.7Hz), 4.49 (IH, d, J=5.7Hz), 4.60 (m, IH), 6.63 (IH, dd, J=2.2Hz and 15.3Hz), 7.25-7.32 (IH, m) , 7.39 (IH, d, J=15.3Hz), 7.46-7.54 (2H, m) , 7.59 (IH, d, J=IO.OHz), 8.03, 8.10 (IH, s), 8.14 (IH, s), 11.48-11.73 (IH, m) .

Example 150 i) To a solution of tert-butyl [(3R)-l-(2-ethylbutyl)-3- pyrrolidinyl] (5-{(lE)-3-oxo-3-[ (tetrahydro-2H-pyran-2-yloxy)amino]- l-propen-l-yl}-2-pyridinyl)carbamate (128 mg) in methanol (2.5 mL) was added hydrogen chloride in methanol (0.248 mL). After stirring at room temperature for 1 hour, the reaction mixture was evaporated in vacuo. ii) To a mixture of above product and dioxane (2.5 mL) was added 4N hydrogen chloride in dioxane (1.02 mL). After stirring at room temperature for 2 hours, the reaction mixture was evaporated in vacuo and triturated with ethyl acetate to give (2E)-3-(6-{[(3R)-I- (2-ethylbutyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N- hydroxyacrylamide dihydrochloride (92.0 mg) . 1H-NMR (300 MHz, DMSO-d6) <5θ.85 (6H, t, J = 7 Hz), 1.28-1.52 (4H, m), 1.58-1.72 (IH, m) , 2.02-2.15 (IH, m) , 2.32-2.67 (2H, m) , 3.06- 4.78 (6H, m), 6.37 (IH, d, J = 16 Hz), 6.91-7.08 (IH, m) , 7.43 (IH, d, J = 16 Hz), 7.94-8.02 (IH, m) , 8.21 (IH, brs) , 10.4 (IH, brs). MS (ES+) m/z 333 (M+l) .

The following compounds were obtained in a similar manner to that of Example 150. Example 151 (2E)-3-(6-{[(3R)-1-(3,4-dimethylbenzyl)-3-pyrrolidinyl]amino }-3- pyridinyl)-N-hydroxyacrylamide 1H7NMR (300 MHz, DMSO-d6) δ1.87-4.62 (15H, m) , 6.23 (IH, d, J = 16 Hz), 6.57 (IH, d, J = 8 Hz), 7.15-7.69 (5H, m) , 8.15 (IH, brs), 8.93 (IH, brs), 10.7 (IH, brs), 11.0 (IH, brs). MS (ES+) m/z 367 (M+l).

Example 152 (2E)-N-hydroxy-3-(6-{[(3R)-1-(2-phenoxyethyl)-3- pyrrolidinyl]amino}-3-pyridinyl)acrylamide dihydrochloride 1H-NMR (300 MHz, DMSO-d6) δ2.01-4.75 (HH, m) , 6.33-6.42 (IH, m) , 6.96-7.07 (4H, m), 7.29-7.47 (3H, m), 7.92-8.01 (IH, m), 8.21 (IH, brs) . MS (ES+) m/z 369 (M+l).

Example 153 (2E)-3-(6-{[(3R)-l-butyl-3-pyrrolidinyl]amino}-3-pyridinyl)- N- hydroxyacrylamide dihydrochloride 1H-NMR (300 MHz, DMSO-d6) 00.91 (3H, t, J = 7 Hz), 1.26-1.40 (2H, m), 1.57-1.71 (2H, m), 1.95-4.73 (9H, m) , 6.37 (IH, d, J = 16 Hz), 6.90-7.07 (IH, m), 7.43 (IH, d, J = 16 Hz), 7.93-8.02 (IH, m), 8.21 (IH, brs). MS (ES+) m/z 305 (M+l).

Example 154 (2E)-N-hydroxy-3-(6-{[ (3R)-l-isobutyl-3-pyrrolidinyl]amino}-3- pyridinyl)acrylamide dihydrochloride 1H-NMR (300 MHz, DMSO-d6) <5l.00 (6H, d, J = 7 Hz), 1.95-2.15 (2H, m), 2.31-2.60 (2H, m) , 3.02-4.76 (6H, m) , 6.37 (IH, d, J = 16 Hz), 6.90-7.08 (IH, m), 7.43 (IH, d, J = 16 Hz), 7.93-8.02 (IH, m), 8.21 (IH, brs), 10.4 (IH, brs). MS (ES+) m/z 305 (M+l).

Example 155 To a solution of ethyl (2E)-3-(5-{ [ (3R)-I-(benzyloxy)-6-oxo-3- piperidinyl]amino}-2-pyrazinyl)aerylate (200 mg, 0.50 mmol) in methanol (5 mL) was added hydroxylamine hydrochloride (175 mg, 2.52 mmol) at ambient temperature under nitrogen. After cooling, IM sodium methanolate in methanol (5 mL) was added dropwise to the mixture over Ih, the reaction mixture was stirred at 0 O for 2hrs and at ambient temperature for 4hrs. The reaction mixture was adjusted to PH 6.0 with lmol/L hydrochloric acid and evaporated in vacuo. The residue was dissolved in ethanol and the precipitate was removed by filtration. The solvent was evaporated in vacuo. The residue was purified by preparative HPLC (CH3CN, 20%NH4HCO3/30%~90%, gradient) to give (2E)-3-(5-{[(3R)-I-(benzyloxy)-6-oxo-3- piperidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamide (15 mg, 8%) as a powder. 1H-NMR (300 MHz, CD3OD.) δ1.78-1.98 (IH, m),1.98-2.15 (IH, m),2.44- 2.74 (2H, m),-3.40 (IH, dd, J=Il.4, 5.9 Hz),3.76 (IH, dd, J=Il.4, 4.0 Hz),4.31 (IH, br peak),4.93 (2H, s),6.66 (IH, d, J=15.4 Hz),7.20-7.33 (3H, m),7.33-7.43 (2H, m),7.48 (IH, d, J=15.4 Hz ) , 7.94 ( IH, S ) , 8. 03 ( IH, s ) ; MS (ES+ ) m/z 384.

The following compounds were obtained in a similar manner to that of Example 129. Example 156 (2E)-N-hydroxy-3-(5-{[(3R)-l-(phenylacetyl)-3-piperidinyl]am ino}-2- pyrazinyl)acrylamide hydrochloride 1H-NMR (300 MHz, CD3OD) <51.19-2.21 (4H, m),3.12-3.49 (2H, m),3.70- 4.01 (4H, m),4.24-4.35 (IH, m),6.76-6.90 (IH, m),7.09-7.41 (5H, m),7.48-7.58 (IH, m),8.01 (0.6H, br.s),8.06 (0.4H, br.s),8.18 (0.4H, br.s),8.45 (0.6H, br.s).

Example 157 (2E)-N-hydroxy-3-(5-{[(3R)-1-(3-methylbenzyl)-3- pyrrolidinyl]amino}-2-pyrazinyl)acrylamide dihydrochloride 1H-NMR (300 MHz, DMSO-d6) <51.90-2.15 (IH, m),2.31 (1.5H, s),2.33 (1.5H, s),2.98-3.80 (5H, m),4.30-4.66 (3H, m),6.58-6.68 (IH, m),7.21-7.46 (5H, m),8.00-8.35 (3H, m) ; MS (ES+) m/z 354(M+l, free) .

Example 158 (2E)-N-hydroxy-3-(6-{[(3R)-1-(2,2,6,6-tetramethyl-4-piperidi nyl)-3- pyrrolidinyl]amino}-3-pyridinyl)acrylamide trihydrochloride 1H-NMR (300 MHz, DMSO-d6) δ1.43 (3H, s),1.49 (9H, s),1.78-2.32 (6H, m),3.04-4.85 (6H, m),6.32-6.46 (IH, m),6.86-7.27 (IH, m),7.39-7.52 (IH, m),7.91-8.12 (IH, m) ,8.14-8.35 (2H, m),9.51-9.78 (IH, m) ; MS (ES+) m/z 388(M+1, free).

Example 159 (2E)-N-hydroxy-3-(6-{[(3R)-I-(tetrahydro-2H-pyran-4-yl)-3- pyrrolidinyl]amino}-3-pyridinyl)acrylamide dihydrochloride 1H-NMR (300 MHz, DMSO-d6) <51.61-1.86 (2H, m),1.87-2.41 (8H, m),3.06-4.21 (5H, m),4.49-4.73 (IH, m),6.36 (IH, d, J=16.1 Hz),6.84-7.09 (IH, m),7.43 (IH, d, J=16.1 Hz) ,7.89-8.05 (IH, m) , 8.21 ( IH, S ) ; MS (ES+ ) m/z 333 (M+1 , free) .

Example 160 (2E)-3-(5-chloro-6-{[(3R)-1-(cyclohexy-ϋmethyl)-3- piperidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamide dihydrochloride 1H-NMR (300 MHz, DMSO-d6) 60.84-1.05 (2H, m),1.07-1.34 (4H, m),1.52-2.05 (9H, m),2.67-3.10 (4H, m),3.40-3.58 (2H, m),6.35 (IH, d, J=15.8 Hz),6.87 (IH, br.d, J=6.6 Hz),7.36 (IH, d, J=15.8 Hz),7.90 (IH, br.s),8.22 (IH, br.s); MS (ES+) m/z 393(free, M+l).

Example 161 A solution of 2N HCl-EtOH solution (1.2ml) was added to a mixture of (2E)-3-{2-[(l-benzyl-3-pyrrolidinyl)amino]-4-methyl-5- pyrimidinyl}-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (200mg) in EtOH (5ml) and stirred at 20-25 0C for 2 hours. IPE (30ml) was added to a reaction mixture and the resultant mixture was stirred at ambient temperature for 20 minutes. The precipitate was collected by filtration to give (2E)-3-{2-[(l-benzyl-3- pyrrolidinyl)amino]-4-methyl-5-pyrimidinyl}-N-hydroxyacrylam ide dihydrochloride (90mg). 1H-NMR (DMSO-d6):<5 1.70-20.7 (IH, m) , 2.10-2.42 (IH, m), 2.42 (3H, s), 3.10-3.77 (4H, m) , 4.42 (2H, s), 4.57-4.70 (IH, m) , 6.34 (IH,d J=15.80Hz), 7.39-7.46 (4H, m) , 7.62-7.65 (2H, m) , 8.49 (IH, s), 11.40-11.58 (IH, m) .

The following compounds were obtained in a similar manner to that of Example 161. Example 162 (2E)-3-{2-[(l-benzyl-4-piperidinyl)amino]-4-methyl-5-pyrimid inyl}- N-hydroxyacrylamide dihydrochloride 1H-NMR (DMSO-d6):<5 1.86-2.13 (4H, m) , 2.46 (3H, s), 2.78-3.49 (4H, m), 4.03 (IH, m), 4.29 (2H, d J=4.42Hz), 6.37 (IH, d J=15.82Hz), 7.41 (IH, d J=15.82Hz), 7.44-7.47 (3H, m) , 7.65-7.68 (2H, m) , 8.15- 8.25 ( IH, m) , 8.50 & 8.53 (total IH, each s) .

Example 163 (2E)-N-hydroxy-3-(4-methyl-2-{[(3R)-l-(4-methylbenzyl)-3- pyrrolidinyl]amino}-5-pyrimidinyl)acrylamide dihydrochloride 1H-NMR (DMSO-d6):<5 1.80-2.46 (2H, m) , 2.32 (3H, s), 2.49 (3H, s), 3.04-3.74 (4H, m) , 4.35 (2H, s), 4.55-4.68 (IH, m) , 6.33 (IH, d J=15.78Hz), 7.25 (2H d J=7.12Hz), 7.39-7.62 (3H, m) , 8.48 (IH, s).

Example 164 (2E)-3-(2-{[(3R)-l-(cyclohexylmethyl)-3-pyrrolidinyl]amino}- 4- methyl-5-pyrimidinyl)-N-hydroxyacrylamide dihydrochloride 1H-NMR (DMSO-d6):<5 0.90-1.26 (6H, m) , 1.65-2.09 (6H, m), 2.10-2.30 (IH, m), 2.43 (3H, s), 2.98-3.88 (5H, m) , 3.88-3.91 (IH, m) , 4.59- 4.70 (IH, m), 6.34 (IH, d J=15.78Hz), 7.43 (IH, d J=15.78Hz), 8.01- 8.10 (IH, m), 8.49 (IH, s), 10.54-10.64 (IH, m) .

Example 165 A solution of tert-butyl (3R)-3-[ (5-{(lE)-3-oxo-3-[ (tetrahydro-2H- pyran-2-yloxy)amino]-l-propen-l-yl}-2-pyridinyl)amino]-1- pyrrolidinecarboxylate (450mg) and pyridinium p-toluenesulfonate (261mg) in EtOH (10ml) was stirred at 55-60 °C for 9 hours. The reaction mixture was evaporated in vacuo and the residue was dissolved in . a mixture of AcOEt and H2O and adjusted to was adjusted to PHlO with aq.K2CO3 solution. The aqueous solution was adjusted to PH6.5 with aq.HCl solution and extracted with AcOEt. The extract was washed with brine and dried over MgSθ4. The solvent was evaporated in vacuo and the residue was washed with IPE to give tert-butyl (3R)-3-({5-[(IE)-3-(hydroxyamino)-3-oxo-l-propen-l-yl]- 2-pyridinyl}amino)-l-pyrrolidinecarboxylate (118mg). 1H-NMR (DMSO-d6): <5 1.39 (9H, s), 1.69-1.84 (IH, m) , 1.99-2.12 (IH, m), 3.09-3.14 (IH, m) , 3.34-3.43 (2H, m) , 3.52-3.66 (IH, m) , 4.01- 4.05 (IH, m), 6.19 (IH, d J=15.88Hz), 6.50 (IH, d J=8.38Hz), 7.26 (IH, d J=6.62Hz), 7.34 (IH, d J=15.88Hz), 7.61 (IH, d J=8.38Hz), 8.16 (IH, s), 8.91 (IH, s), 10.59 (IH, s). Example 166 A solution of 2N HCl-EtOH solution (2.3ml) was added to a mixture of (2E)-3-(5-chloro-6-{[(3R)-l~(3-methylbenzyl)-3- pyrrolidinyl]ainino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2- yloxy)acrylamide (440mg) in EtOH (5ml) and stirred at 20-25 0C for 2 hours. IPE (20ml) was added to a reaction mixture and the resultant mixture was stirred at ambient temperature for 20 minutes. The precipitate was collected by filtration to give (2E)-3-(5-chloro-6- {[ (3R)-1-(3-methylbenzyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N - hydroxyacrylamide dihydrochlόride (375mg). 1H-NMR (DMSO-d6):<5 1.92-2.25 (2H, m) , 2.32 (3H, s) , 307-3.67 (4H, m), 4.35 (2H, d J=5.30Hz), 4.71 & 4.90 (total IH, each br,s), 6.39 (IH, d J=15.80Hz), 7.22-7.45 (5H, m) , 7.83 (IH, s), 8.21 (IH, s) .

The following compounds were obtained in a similar manner to that of Example 166. ' , Example 167 (2E)-3-(5-chloro-6-{[(3R)-1-(cyclobutylmethyl)-3- pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamide dihydrochloride 1H-NMR (DMSO-d6):<5 1.78-2.09 (8H, m) , 2.73 (IH, m) , 304-3.80 (6H, m), 4.46-4.52 (IH, m), 6.29 (IH, d J=15.60Hz), 7.16-7.20 (IH, m), 7.24 (IH, d J=15.60Hz), 7.91 (IH, s), 8.23 (IH, s) .

Example 168 (2E)-3-[5-chloro-6-(cyclopentylamino)-3-pyridinyl]-N- hydroxyacrylamide hydrochloride 1H-NMR (DMSO-d6):<5 1.37-1.73 (6H, m) , 1.92-2.09 (2H, m) , 4.33-4.39 (IH, m),6.40 (IH, d J=15.80Hz), 7.37 (IH, d J=15.80Hz), 8.03 (IH, s), 8.19 (IH, s).

Example 169 (2E)-3-{6-[ (4-tert-butylcyclohexyl)amino]-5-chloro-3-pyridinyl}-N- hydroxyacrylamide hydrochloride 1H-NMR (DMS0Td6):<5 0.97 (9H, s), 0.97-1.45 (6H, m) , 1.45-1.96 (3H, m), 3.84-3.89 & 4.21 (total IH, each m) , 6.36 & 6.37 (total IH, each d J=15.66Hz), 7.36 (IH, d J=15.66Hz), 7.96 & 8.02 (total IH, each s), 8.17 & 8.21 (total IH,each s).

Example 170 (2E)-3-(5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3- pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamide dihydrochloride 1H-NMR (DMSO-d6):<5 0.91-1.27 (6H, m) , 1.65-1.89 (5H, m) , 2.09-2.10 (IH, m), 2.98-3.91 (6H, m) , 4.79-4.91 (IH,- m), 6.37 (IH, d J=15.78Hz), 7.35 (IH, d J=15.78Hz), 7.91 (IH, s), 8.22 (IH, s), 10.64 (1H°, br.s).

Example 171 (2E)-3-(5-chloro-6-{[(3R)-l-(3-methyl-2-buten-l-yl)-3- pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamide dihydrochloride 1H-NMR (DMSO-d6):<5 1.71 (3H, s), 1.77 (3H, s), 1.81-2.14 (2H, m), 3.02-3.66 (4H, m) , 3.75-3.81 (2H, m) , 4.68 (IH, m), 5.30-5.34 (IH, m), 6.36 (IH, d J=15.68Hz), 7.05-7.15 (IH, m) , 7.35 (IH, d J=15.68Hz), 7.91 (IH, s), 8.24 (IH, s).

Example 172 (2E)-3-(5-chloro-6-{[(3R)-1-(3-fluorobenzyl)-3-pyrrolidinyl] amino>- 3-pyridinyl)-N-hydroxyacrylamide dihydrochloride 1H-NMR (DMSO-d6):<5 1.71-2.52 (2H, m) , 3.06-4.71 (4H, m) , 4.44 (2H, d J=5.58Hz), 4.70-4.89 (IH, m) , 6.37 (IH, d J=15.80Hz), 7.23-7.90 (5H, m), 7.94 (IH, d J=I.88Hz), 8.21 (IH, d J=I.88Hz).

Example 173 (2E)~3-[5-chloro~6-({(3R)-l-[(4-methylphenyl)sulfonyl]-3- pyrrolidinyl}amino)-3-pyridinyl]-N-hydroxyacrylamide hydrochloride 1H-NMR (DMSO-d6):<5 1.95-2.09 (2H, m) , 2.39 (3H, s), 3.11-3.45 (3H, m) , 3.44-3 . 53 ( IH, m) , 4 .30-4.36 ( IH, m) , 6 .35 ( IH, d J=15. 76Hz ) , 7 .34 ( IH, d J=15 .76Hz ) , 7. 37 ( 2H, d J=8 . 16Hz ) , 7 .64 ( 2H, d J=8. 16Hz ) , 7.86 ( IH, d J=I .36Hz) , 8. 18 ( IH, d J=I .36Hz) .

Example 174 (2E)-3-(5-chloro-6-{[(3R)-1-(cyclohexylcarbonyl)-3- pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamide hydrochloride 1H-NMR (DMSO-d6):<5 1.24-1.33 (6H, m) , 1.66-2.52 (5H, m) , 3.26-3.88 (4H, m), 4.51-4.67 (IH, m), 6.38 (IH, d J=15.68Hz), 7.36 (IH, d J=15.68Hz), 7.94 (IH, s), 8.23 (IH, s).

Example 175 (2E)-N-hydroxy-3-[6-({(3R)-1-[(4-methylphenyl)sulfonyl]-3- pyrrolidinyl}amino)-3-pyridinyl]acrylamide hydrochloride 1H-NMR (DMSO-d6): <5 1.85-1.91 (IH, m) , 2.07-2.14 (IH, m) , 2.38 (3H, s), 3.12-3.49 (4H, m) , 4.33 (IH, br.s), 6.41 (IH, d J=15.82Hz), 6.92 (IH, d J=9.18Hz), 7.38 (2H,d J=8.24Hz), 7.44 (IH, d J=15.82Hz), 7.67 (2H, d J=8.24Hz), 8.02 (IH, d J=9.18Hz), 8.15 (IH, s) , 9.10 (IH, m).

Example 176 (2E)-N-hydroxy-3-(6-([(3R)-I-(I-piperidinylcarbonyl)-3- pyrrolidinyl]amino}-3-pyridinyl)acrylamide hydrochloride 1H-NMR (DMSO-d6):<5 1.50 (6H, br.s), 1.89-1.92 (IH, m) , 2.18-2.22 (IH, m), 3.14 (4H, br.s), 3.14-3.54 (3H, m) , 3.64-3.73 (IH, m) , 4.76 (IH, br.s), 6.44 (IH, d J=15.84Hz), 7.20 (IH, d J=9.36Hz), 7.46 (IH, d J=15.84Hz), 8.09 (IH, d J=9.36Hz), 8.18 (IH, s), 9.61 (IH, m).

Example 177 (2E)-3-(5-chloro-6-{[ (3R)-1-(1-piperidinylcarbonyl)-3- pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamide hydrochloride 1H-NMR (DMSO-d6):<5 1.78 (6H, br.s), 1.82-2.10 (2H, m) , 3.12 (4H, br.s), 3.30-3.43 (3H, m) , 3.54-3.63 (IH, m) , 4.47-4.54 (IH, m) , 6.36 (IH, d J=15.76Hz), 7.35 (IH, d J=15.76Hz), 7.93 (IH, s), 8.21 ( IH, S) .

Example 178 (2E)-3-(5-chloro-6-{[(3R)-1-(cyclopentylcarbonyl)-3- pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamide hydrochloride 1H-NMR (DMSO-d6):<5 1.51-1.76 (8H, m) , 1.90-2.30 (2H, m) , 2.70-2.88 (IH, m), 3.28-3.68 (3H, m) , 3.88-3.90 (IH, m) , 4.50-4.69 (IH, m) , 6.36 (IH, d J=15.78Hz), 7.35 (IH, d J=15.78Hz), 7.92 (IH, s), 8.23 (IH,s).

Example 179 (2E)-3-(5-chloro-6-{[(3R)-l-(cyclobutylcarbonyl)-3- pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamide hydrochloride 1H-NMR (DMSO-d6):<5 1.76-2.18 (9H, m) , 3.26-3.68 (4H, m) , 4.49-4.65 (IH, m), 6.35 (IH, d J=15.78Hz), 7.35 (IH, d J=15.78Hz), 7.90 (IH, s), 8.22 (IH, s).

Example 180 (2E)-3-(5-chloro-6-{[ (3R)-1-(2-pyridinylmethyl)-3- pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamide trihydrochloride 1H-NMR (DMSO-d6):<5 1.92-2.17 (IH, m) , 2.18-2.35 (IH, m), 3.39-3.77 (4H, m), 4.66 (2H, s), 4.83 (IH, m) , 6.41 (IH, d J=15.78Hz), 7.54- 7.60 (IH, m), 7.77-7.81 ()1H, m) , 7.92-7.09 (2H, m) , 8.23 (IH, s), 8.70-8.73 (IH, m) .

Example 181 (2E)-3-(5-chloro-6~{[(3R)-l-(4-chlorobenzoyl)-3- pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamide hydrochloride 1H-NMR (DMSO-d6):<5 1.97-2.22 (2H, m) , 3.39-3.85 (4H, m) , 4.52-4.66 (IH, m), 6.28-6.40 (IH, m) , 7.29-7.39 (IH, m) , 7.40-7.69 (5H, m) , 7.88-7.96 (IH, m) , 8.16-8.25 (IH, m) .

Example 182 (2E)-3-(5-chloro-6-{[(3R)-1-(cyclopropylmethyl)-3- pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamide dihy&rochloride 1H-NMR (DMSO~d6):<5 0.04-0.45 (2H, m) , 0.56-0.65 (2H, m) , 1.02- 1.16 (IH, m), 2.08-2.13 (IH, m) , 2.49-2.56 (IH, m) , 2.02-3.93 (6H, m)\ 4.51-4.88 (IH, m) , 6.39 (IH, d J=15.78Hz), 7.35 (IH, d J=15.78Hz), 7.91 (IH, s), 8.24 (IH, s), 11.12 (IH, br.s).

Example 183 (2E)-3-(5-chloro-6-{[(3R)-l-(cyclopentylmethyl)-3- pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamide dihydrochloride 1H-NMR (DMSO-d6):<5 1.65-1.89 (5H, m), 2.06-2.13 (IH, m) , 2.20-2.40 (IH, m), 2.98-3.92 (6H, m) , 4.75-4.90 (IH, m) , 6.37 (IH, d J=15.78Hz), 7.35 (IH, d J=15.78Hz), 7.91 (IH, s), 8.22 (IH, s).

Example 184 (2E)-3-(5-chloro-6-{[(3R)-l-(2-pyrimidinyl)-3-pyrrolidinyl]a mino}- 3-pyridinyl)-N-hydroxyacrylamide dihydrochloride 1H-NMR (DMSO-d6):<5 2.18-2.39 (2H, m) , 3.66-3.84 (3H, m) , 3.95-4.04 (IH, m), 4.76-4.79 (IH, m) , 6.39 (IH, d J=15.76Hz), 6.92-6.98 (IH, m), 7.36 (IH, d J=15.76Hz), 7.92 (IH, s), 8.26 (IH, s), 8.60-8.63 (2H, m) .

Example 185 (2E)-3-(5-chloro-6-{[(3R)-l-(4-fluorobenzoyl)-3- pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamide hydrochloride 1H-NMR (DMSO-d6):<5 2.09-2.22 (2H, m) , 3.39-3.84 (4H, m) , 4.55.-4.67 (IH, m), 6.31 & 6.35 (total IH, each d J=15.68Hz), 7.00 (IH, m) , 7.21-7.40 (3H, m), 7.56-7.63 (2H, m), 7.87 & 7.91 (total IH, each s), 8.16 & 8.24 (total IH, each s) .

Example 186 (2E)-3-(5-chloro-6-{[(3R)-l-(3-methylbenzoyl)-3- pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamide hydrochloride 1H-NMR (DMSO-d6):<5 2.09-2.32 (2H, m) , 2.32 & 2.35 (total 3H, each s ) , 3.40-3.75 ( 4H, m) , 4 .53-4. 66 ( IH, m) , 6.32 & 6.35 ( total IH, each d J=15 .76Hz ) , 6 .98 ( IH, m) , 7.29-7. 73 ( 5H, m) , 7.88 & 7 .92 (total IH, each s) , 8.15 & 8.24 (total IH, each s) .

Example 187 ( 2E) -3- ( 5-chloro-6-{ [ ( 3R) -l- ( 3-chlorobenzoyl) -3- pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamide hydrochloride 1H-NMR (DMSO-d6):<5 2.03-2.23 (2H, m) , 3.43-3.76 (4H, m), 4.53-4.67, (IH, m), 6.33 & 6.36 (total IH, each d J=15.74Hz), 7.05 (IH, m) , 7.27 & 7.36 (total IH, each d J=15.74Hz), 7.45-7.58 (4H, m) , 7.89 & 7.92 (total IH, each s), 8.16 & 8.25(total IH, each s).

Example 188 (2E)-3-(5-chloro-6-{[(3R)-l-(2-chlorobenzoyl)-3- pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamide hydrochloride 1H-NMR (DMSO-d6):<5 2.08-2.21 (2H, m) , 3.15-3.22 (2H, m). 3.27-3.87 (2H, m), 4.55-4.65 (IH, m) , 6.33 &' 6.37 (total IH, each d J=15.86Hz), 6.93 (IH, m) , 7.27-7.55 (5H, m) , 7.88 & 7.93 (total IH, each s), 8.15 & 8.25 (total IH, each s).

Example 189 To a stirred solution of tert-butyl (5-{(lE)-3-oxo-3-[(tetrahydro- 2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridinyl){(3R)-l-[ (2,6,6- trimethyl-1-cyclohexen-l-yl)methyl]-3-pyrrolidinyl}carbamate (80mg) in methanol (ImL) was added 4N hydrogen chloride in methanol (3mL) at ambient temperature and the mixture was stirred at the same temperature for fifteen minutes. The mixture was concentrated in vacuo and the mixture was dissolved in dioxane (ImL). To this solution was added 4N hydrogen chloride in dioxane (3mL) and the mixture was stirred at ambient temperature for two hours. The reaction mixture was concentrated in vacuo and the resulting solid was triturated with acetonitrile to give (2E)-N-hydroxy-3-[6- ({(3R)-1-[ (2,6,6-trimethyl-l-cyclohexen-l-yl)methyl]-3- pyrrolidinyl}amino)-3-pyridinyl]acrylamide dihydroσhloride (4Omg) as a pale tan amorphous solid. 1H-NMR (300 MHz, DMSO-d6) δ1.10 (3H, s),l.ll (3H, S),1.35-1.49 (3H, m),1.52-1.66 (3H, m) ,1.73-1.86 (3H, m),1.97-2.13 (2H, m) ,3.09-4.22 (6H, m),4.57-4.86 (IH, m),6.39 (IH, d, J=16.1 Hz) ,6.92-7.23 (IH, m),7.39-7.54 (IH, m),7.96-8.15 (IH, m) ,8.16-8.27 (IH, m); MS (ES+) m/z 385(free, M+l).

The following compound was obtained in a similar manner to that of Example 189. Example 190 (2E)-N-hydroxy-3-(6-{[(3R)-l-(3,3,5,5-tetramethylcyclόhexyl )-3- pyrrolidinyl]amino}-3-pyridinyl)acrylamide dihydrochloride 1H-NMR (300 MHz, DMSO-d6) δ0.93 (3H, s),0.95 (3H, s),0.97-1.12 (2H, m),1.01 (6H, s),1.20-1.36 (4H, m),1.73-1.92 (2H, m),1.95-2.16 (2H, m),2.18-2.36 (IH, m),2.46-3.62 (2H, m),4.50-4.74 (IH, m),6.37 (IH, d, J=15.4 Hz),6.88-7.15 (IH, m),7.44 (IH, d, J=15.4 Hz) ,7.92-8.06 (IH, m),8.19-8.26 (IH, m) ; MS (ES+) m/z 387(M+l,free) .

Example 191 A solution of 2N HCl-EtOH solution (3.4ml) was added to a mixture of (2Z)-3-(5-chloro-6-{[(3R)-l-cyclopentyl-3- pyrrolidinyl]amino}-3-pyridinyl)-2-fluoro-N-(tetrahydro-2H-p yran-2- yloxy)acrylamide (620mg) in EtOH (5ml) and stirred at 20-25 0C for 2 hours. IPE (20ml) was added to a reaction mixture and the resultant mixture was stirred at ambient temperature for 20 minutes. The precipitate was collected by filtration to give (2Z)-3-(5- chloro-6-{[(3R)-1-cyclopentyl-3-pyrrolidinyl]anu.no}-3-pyrid inyl)-2- fluoro-N-hydroxyacrylamide dihydrochloride (500mg). 1H-NMR (DMSO-d6):<5 1.52-1.55 (2H, m) , 1.75-1.76 (4H, m), 1.97-2.09 (3H, m), 3.04-3.12 (IH, m) ,'3.20-3.81 (4H, m) , 4.73 & 4.89 (total lH,_each m), 6.79 (IH, dd J=3.08Hz, 39.72Hz), 7.27 (IH, m) , 7.90 (IH, d J=I.80Hz), 8.30-8.32 (IH, m) , 11.52 (IH, m) .

The following compounds were obtained in a similar manner to that of Example 191. Example 192 (2Z)-3-(5-chloro-6-{[(3R)-l-cyclohexyl-3-pyrrolidinyl]amino} -3- pyridinyl)-2-fluoro-N-hydroxyacrylamide dihydrochloride 1H-NMR (DMSO-d6):<5 1.04-1.25 (3H, m) , 1.45-1.48 (2H, m) , 1.58-1.62 (IH, m), 1.78-1.80 (2H, m) , 2.04-2.10 (3H, m) , 2.20-2.51 (IH, m) , 3.10-3.15 (2H, m) , 3.26-3.46 (2H, m) , 3.64 & 3.78 (total IH, each m), 4.74 & 4.86 (total IH, each m) , 6.79 (IH, dd J=2.48Hz, 39.72Hz), 7.20-7.30 (IH, m), 7.90 (IH, d J=I.56Hz), 8.30-8.32 (IH, m) , 11.29-11.36 (IH, m) .

Example 193 (2Z)-3-(5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3- pyrrolidinyl]amino}-3-pyridinyl)-2-fluoro-N-hydroxyacrylamid e dihydrochloride 1H-NMR (DMSO-d6):<5 0.93-0.96 (2H, m), 1.03-1.25 (3H, m), 1.60-1.73 (4H, m), 1.86-1.91 (2H, m) , 2.05-2.10 (IH, m) , 2.30-2.50 (IH, m), 2.99-3.11 (3H, m) , 3.20-3.42 (IH, m) , 3.52-3.60 (IH, m) , 3.75 & 3.90-3.92 (total IH, each m) , 4.77 & 4.91 (total IH, each m) , 6.79 (IH, dd J=I.80Hz, 39.74Hz), 7.21 & 7.41 (total IH, each m) , 7.90 (IH, d J=I.88Hz), 8.30-8.32 (IH, m) , 10.71-10.72 (IH, m) .

Example 194 (2Z)-3-(6-{[(3R)-l-benzyl-3-pyrrolidinyl]amino}-5-chloro-3- pyridinyl)-2-fluoro-N-hydroxyacrylamide dihydrochloride 1H-NMR (DMSO-d6):<5 2.05-2.07 (IH, m), 2.30-2.37 & 2.48-2.54 (total IH, each m) , 3.13-3.18 (IH, m) , 3.32-3.68 (3H, m) , 4.40 (2H, d J=5.64Hz), 4.71 & 4.90 (total IH, each m), 6.78 (IH, dd J=3.20Hz, 39.70Hz), 7.27 (IH, m) , 7.44-7.48 (3H, m) , 7.63-7.66 (2H, m) , 7.89- 7.91 (IH, m), 8.29 (IH, m) , 11.56-11.57 (IH, m) .

Example 195 (2Z)-3-(6-{[(3R)-l-benzyl-3-pyrrolidinyl]amino}-3-pyridinyl) -2- fluoro-N-hydroxyacrylamide dihydrochloride 1H-NMR (DMSO-d6):<5 2.09-2.19 (IH, m) , 2.32 & 2.62 (total IH, each m), 3.24-3.47 (2H, m) , 3.57-3.82 (2H, m) , 4.44 & 4.55 (total 2H, each d J=5.68Hz), 4.64 & 4.80 (total IH, each m) , 6.88 (IH, dd J=5. 12Hz , 39 .08Hz ) , 7.00 & 7.20 (total IH, each d J=9 .24Hz ) , 7. 44- 7 .47 ( 3H, m) , 7 .65-7.70 ( 2H, m) , 8.03-8.09 ( IH, m) , 8.22 ( IH, s ) , 11. 52 & 11.65 ( total IH, each br, s ) .

Example 196 A mixture of (2E)-3-(5-chloro-6-{[(3R)-I-({trans-4- [ (dimethylamino)methyl]cyclohexyl}carbony1)-3-pyrrolidinyl]am ino}- 3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (530mg) and 2N HCl/Ethanol (5ml) was stirred for 3 hrs. EtOAc(IOmI) and IPE (50ml) was added and and stirred. After 1 hour, precipitate was filtered and dried to give 462mg (89%) of (2E)-3-(5-chloro-6- {[(3R)-1-({trans-4-[ (dimethylamino)methyl]cyclohexyl}carbonyl)-3- pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamide dihydrochloride. MASS (ESI+): m/z = 450.9 (M+l). 1HNMR (400MHz, DMSO-d6): 6 0.90 - 2.80 ( 14H, m) , 2.51 ( 6H, b.s), 3.2 - 3.8 ( 4H, m), 4.52 and 4.66 ( IH, br.s), 6.35 ( IH, dd, J = 4.9 ,15.8Hz), 6.84 - 6.98 ( IH, m) , 7.34 ( IH, d, J = 15.8Hz ), 7.89 ( IH, dd, J = 1.8 ,4.4Hz), 8.23 ( IH, dd, J = 1.8 ,4.4Hz).

Example 197 A mixture of (2E)-3-(5-chloro-6-{[(3R)-l-(cyclohexylacetyl)-3- pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2- yloxy)acrylamide (680mg) and 2N HCl/Ethanol (13.8ml) was stirred for 2 hrs. EtOAc(IOmI) and IPE (50ml) was added and and stirred. After 1 hr, precipitate was filtered and dried to give 387mg (63%) of (2E)-3-(5-chloro-6-{[(3R)-1-(cyclohexylacetyl)-3- pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamide hydrochloride. MASS (ESI+): m/z = 408.1 (M+l). 1HNMR (400MHz, CDCl3): d 0.82 - 2.27 (15H, m) , 3.20 - 3.80 (4H, m) , 4.51 (IH, m), 4.61 (IH, m) , 6.34 (IH, d, J=15.8Hz), 7.34 (IH, d, J=15.8Hz), 7.90 (IH, s), 8.23 (IH, s) .

Example 198 (2E)-3-(5-fluoro-6-{[(3R)-l-(2-octyn-l-yl)-3-pyrrolidinyl]am ino}-3- pyridinyl)-N-hydroxyacrylamide bis(4-methylbenzenesulfonate) (salt) To a solution of (2E)-3-(5-fluoro-6-{[(3R)-l-(2-octyn-l-yl)-3- pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2- yloxy)acrylamide(155mg) in methanol (3.5ml) was added 4- methylbenzenesulfonic acid hydrate (122mg) at 25°C and then stirred at the same temperature for 1 hour. The mixture was concentrated under reduced pressure. The resulting residue was triturated with a mixed solvent of ethyl acetate, diisopropyl ether and methanol. Title compound (178mg, 73%) was obtained as colorless powder. MASS(API-ES); 375 (M+H)+ Free 1H-NMR ( 200MHz), (DMSO-d6, <5 ) : 0.84 ( 3H, t, J = 6.8Hz ), 1.20 - 1.50 ( 6H, m), 2.00 - 2.60 ( 4H, m) , 2.29 ( 6H, s), 3.00 - 4.05 ( 4H, m), 4.10 - 4.20 ( 2H, m) , 4.63 ( IH, br), 6.32 ( IH, d, J = 16Hz ), 7.12 ( 4H, d, J = 7.9Hz ), 7.39 ( IH, d, J = 16Hz ), 7.49 ( 4H, d, J = 7.9Hz ), 7.70 ( IH, d, J = 13Hz ), 8.08 ( IH, s), 10.30 ( IH, br).

The following compound was obtained in a similar manner to that of Example 198. Example 199 (2E)-3-(5-fluoro-6-{[(3R)-l-(3-phenyl-2-propyn-l-yl)-3- pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamide bis(4- methylbenzenesulfonate) (salt) MASS(API-ES); 381 (M+H)+ Free, 1H-NMR ( 200MHz), (DMSO-d6, <5 ) : 2.00 - 2.65 ( 2H, m) , 2.29 ( 6H, s), 3.10 - 4.20 ( 4H, m), 4.48 ( 2H, br), 4.69 ( IH, br), 6.32 ( IH, d, J = 16Hz ), 7.12 ( 4H, d, J = 7.8Hz ), 7.30 - 7.55 ( HH, m), 7.60 - 7.80 ( IH, m), 8.09 ( IH, s), 10.51 ( IH, br) .

The following compounds were obtained in a similar manner to that of Example 41. Example 200 (2E)-3-(6-{[(3R)-l-acetyl-3-piperidinyl]amino}-5-chloro-3- pyridinyl)-N-hydroxyacrylamide hydrochloride MASS (ESI ) ; 339 (M+H) + .

Example 201 (2E)-N-hydroxy-3-(5-{[(3R)-I-(I-phenylethyl)-3-pyrrolidinyl] amino}- 2-pyrazinyl)acrylamide dihydrochloride 1H-NMR (300 MHz, DMSO-d6) δ1.63 (1.5H, d, ,J=6 Hz),1.65 (1.5H, d, 3=6 Hz),1.84-2.14 (IH, m),2.30-2.53 (IH, m),2.70-4.00 (4H, m),4.32- 4.68 (2H, m),6.61 (0.5H, d, J=15 Hz),6.65 (0.5H, d, J=15 Hz),7.31- 7.53 (4H, m),7.61-7.73 (2H, m),7.95-8.25 (3H, m) ,11.63 (IH, br) ; MS (ES+) m/z .354. ,

Example 202 (2E)-N-hydroxy-3-(5-{[2-(1-piperidinyl)phenyl]amino}-2- pyrazinyl)acrylamide dihydrochloride 1H-NMR (300 MHz, DMSO-d6) 61.59 (2H, m),1.76-1.91 (4H, m),3.16-3.30 (4H, m),6.74 (IH, d, J=15.5 Hz) ,7.21-7.38 (2H, m),7.46 (IH, d, J=15.5 Hz),7.54 (IH, m),7.85 (IH, dd, J=7.5, 1.5 Hz),8.26 (IH, S),8.39 (IH, S); MS (ES+) m/z 340.

The following compound(s) was(were) obtained in a similar manner to that of Example 92. Example 203 (2E)-3-(2-{[(3R)-l-(cyclohexylmethyl)-3-pyrrolidinyl]amino}- 5- pyrimidinyl)-N-hydroxyacrylamide dihydrochloride 1H-NMR (300 MHz, DMSO-d6) δ0.85-1.32 (5H, m) ,1.54-1.90 (6H, m),2.05 (IH, m),2.22-2.54 (IH, m),2.93-3.30 (3H, m),3.34-4.72 (7H, m),6.40 (IH, d, J=16 Hz),7.32 (IH, d, J=16 Hz),8.06 (IH, m),8.59 (2xlH, s),10.41 (IH, m); MS (ES+) m/z 346.

The following compound was obtained in a similar manner to that of Example 89. Example 204 (2E)-3-(6-{[(3R)-l-benzyl-3-pyrrolidinyl]amino}-5-fluoro-3- pyridinyl)-N-hydroxyacrylamide dihydrochloride MASS(API-ES); 357 (M+H)+ Free 1H-NMR ( 200MHz), (DMSO-d6, <5 ) : 1.90 - 2.60 ( 2H, m) , 2.95 - 3.85 ( 4H, m), 4.35 - 4.50 ( 2H, m) , 4.55 - 4.75 ( IH, m) , 4.77 (2H, br), 6.31 ( IH, d, J = 16Hz ), 7.30 - 7.80 ( 8H, m), 8.06 ( IH, s), 11.31 (IH, br).

The following compounds were obtained in a similar manner to that of Example 89. Example 205 (2E)-3-(6-{[ (3R)-1-(2,2-difluoro-2-phenylethyl)-3- pyrrolidinyl]amino}-5-fluoro-3-pyridinyl)-N-hydroxyacrylamid e dihydrochloride MASS(API-ES); 407 (M+H)+ Free 1H-NMR ( 200MHz), (DMSO-d6, <5 ) : 1.95 - 2.60 ( 2H, m) , 3.15 - 4.20 ( 4H, m), 4.31 ( 2H, t, J = 16Hz ), 4.50 - 4.85 ( IH, m) , 6.33 ( IH, d, J = 16Hz ), 7.39 ( IH, d, J = 16Hz ), 7.50 - 7.80 ( 7H, m), 8.08 ( IH, s), 11.28( IH, br) .

Example 206 (2E)-3-(6-{[(3R)-l-(cyclohexylcarbonyl)-3-pyrrolidinyl]amino }-3- pyridinyl)-N-hydroxyacrylamide hydrochloride MASS(API-ES); 359 (M+H)+ Free, 1H-NMR ( 200MHz), (DMSO-d6, 6 ) : 1.10 - 1.40 ( 5H, m) , 1.55 - 1.80 ( 5H, m), 1.85 - 2.55 ( 3H, m), 3.25 - 3.95 ( 4H, m), 4.30 - 4.60 ( IH, m), 6.40 ( IH, d, J = 16Hz ), 7.10 ( IH, d, J = 9.2Hz ), 7.45 ( IH, d, J = 16Hz ), 8.04 ( IH, d, J = 9.2Hz ), 8.20 ( IH, s), 9.30 (IH, br), 10.90 (IH, br) .

The following compound was obtained in a similar manner to that of Example 41. Example 207 (2E)-3-(6-{[l-(cyclohexylmethyl)-4-piperidinyl]amino}-3-pyri dinyl)- N-hydroxyacrylamide dihydrochloride 1H-NMR (200 MHz, DMSO-d6): <5 1.85-1.40 (6H, m) , 1.55-2.40 (12H, m) , 2.75-3.15 (4H, m) , 3.20-4.30 (6H, m) , 6.43 (IH, d, J = 15.8 Hz), 7.14 (IH, d, J = 9.3 Hz), 7.43 (IH, d, J = 15.8 Hz), 8.03-8.18 (2H, m) , 10 . 28 ( IH, brs ) , 10 . 29 ( IH, brs ) .

The following compound was obtained in a similar manner to that of Example 89. Example 208 (2E)-3-(6-{[(3R)-l-benzoyl-3-pyrrolidinyl]amino}-3-pyridinyl )-N- hydroxyacrylamide hydrochloride MASS(API-ES); 353 (M+H)+ Free 1H-NMR ( 200MHz), (DMSO-d6, <5 ) : 1.80 - 2.40 ( 2H, m) , 3.30 - 3.95 ( 4H, m), 4.40 - 4.70 ( IH, m), 6.40 ( 0.5H, d, J = 16Hz ), 6.44 ( 0.5H, d, J = 16Hz ), 7.12 ( 0.5H, d, J = 9.2Hz ), 7.23 ( 0.5H, d, J = 9.2Hz ), 7.30 - 7.70 ( 6H, m) , 8.00 - 8.40 ( 2H, m) , 9.48 (0.5H, br), 9.71 (0.5H, br) , 10.90 (IH, br) .

The following compound was obtained in a similar manner to that of Example 41. Example 209 (2E)-3-(6-{[1-(4-fluorobenzyl)-4-piperidinyl]amino>-3-pyr idinyl)-N- hydroxyacrylamide dihydrochloride 1H NMR (DMSO-d6, <5 ) :1.72 (3H, s), 1.78 (3H, s), 2.90-3.30 (2H, m) , 3.30-3.50 (2H, m) , 3.55-3.80 (2H, m) , 4.10-4.40 (IH, m) , 5.37-5.44 (IH, m), 6.39 (IH, d, J = 15.9 Hz), 7.35 (IH, d, J = 15.9 Hz), 7.94 (IH, s), 8.19 (IH, s). Mass (APCI) : 371(M+H)+.

The following compound was obtained in a similar manner to that of Example 129. Example 210 (2E)-3-[6-(2,3-dihydro-IH-inden-2-ylamino)-3-pyridinyl]-N- hydroxyacrylamide hydrochloride 1H-NMR (300 MHz, DMSO-d6) δ2.95 (2H, dd, J=16.5, 5 Hz),3.40 (2H, dd, J=16.5, 7 Hz),4.64 (IH, m),6.40 (IH, d, J=15.8 Hz),7.05 (IH, d, J=IO Hz),7.16-7.24 (2H, m),7.25-7.33 (2H, m),7.46 (IH, d, J=15.8 Hz),8.04 (IH, d, J=IO Hz),8.20 (IH, s),9.38 (IH, br),10.82 (IH, br); MS (ES+) m/z 296. The following compounds were obtained in a similar manner to that of Example 41. Example 211 (2E)-3-(5-chloro-6-{[(3R)-l-cyclobutyl-3-pyrrolidinyl]amino} -3- pyridinyl)-N-hydroxyacrylamide dihydrochloride 1H-NMR (200 MHz, DMSO-d6) 6 α.90-1.90 (2H, m) , 2.00-2.40 (5H, m) , 2.90-3.90 (5H, m) , 4.69-4.86 (IH, m) , 6.40 (IH, d, J = 15.8 Hz), 7.22 (IH, brs), 7.50 (IH, d, J = 15.8 Hz), 7.92 (IH, s), 8.23 (IH, s), 11.86 (IH, brs), MASS(ESI); 337 (M+H)+.

Example 212 (2E)-3-(5-chloro-6-{[(3R)-1-cyclopentyl-3-pyrrolidinyl]amino }-3- pyridinyl)-N-hydroxyacrylamide dihydrochloride 1H-NMR (200 MHz, DMSO-d6) <5 : 1.40-1.60 (2H, m), 1.61-1.90 (4H, m) , 1.91-2.20 (4H, m), 3.06-3.82 (4H, m) , 4.73-4.88 (IH, m) , 6.37 (IH, d, J = 15.8 Hz), 7.18 (IH, brs), 7.35 (IH, d, J = 15.8 Hz), 7.91 (IH, s), 8.23 (IH, s), .141.39 (IH, brs), MASS(ESI); 351 (M+H)+.

The following compound was obtained in a similar manner to that of Example 129. Example 213 (2E)-N-hydroxy-3-{4-[(6-methyl-2-pyridinyl)amino]phenyl}aery lamide hydrochloride 1H-NMR ( 300 MHz , DMSO-d6 ) 62.50 (3H, s) , 6.43 ( IH, d, J=16 Hz ) , 6.88 ' ( IH, d, J=7.5 Hz ) , 7.01 ( IH, d, J=7.5 Hz) , 7.45 ( IH, d, J=16 Hz ) , 7.53 ( 2H, d, J=8.5 Hz ) , 7.59 ( 2H, d, J=8.5 Hz) , 7.83 ( IH, dd, J=7.5 , 7.5 Hz) , 10.12 (IH, br) ; MS (ES+) m/z 270.

The following compound was obtained in a similar manner to that of Example 41. Example 214 (2E)~3-{5-chloro-6-[(l~methyl-4-piperidinyl)amino]-3-pyridin yl}-N- hydroxyacrylamide dihydrochloride 1H-NMR (200 MHz, DMSO-d6) <5 : 2.06 (4H, m), 2.71 (3H, d, J = 4.6 Hz), 3.04-3.49 (4H, m) ; 4.09-4.40 (IH, m) , 6.40 (IH, d, J = 15.8 Hz), 7.35 (IH, d, J = 15.8 Hz), 7.95 (IH, s), 8.20 (IH, s), 10.88 (IH, brs), MASS(ESI); 311 (M+H)+.

The following compound was obtained in a similar manner to that of Example 129. Example 215 (2E)-3-(6-{[(lR,2R)-2-(benzyloxy)cyclopentyl]amino}-5-chlbro -3- pyridinyl)-N-hydroxyacrylamide hydrochloride 1H-NMR (300 MHz, DMSO-d6) δ1.48-1.78 (4H, m),1.82-2.13 (2H, m);4.00 (IH, m),4.30-4.60 (IH, m),4.54 (2H, s),6.32 (IH, d, J=16 Hz),6.86 (IH, br),7.20-7.38 (6H, m),7.88 (IH, s),8.21 (IH, s); MS (ES+) m/z 388.

The following compound was obtained in a similar manner to that of Example 92. Example 216 (2E)-3-(6-{[(3R)-I-cycloheptyl-3-pyrrolidinyl]amino}-3-pyrid inyl)- N-hydroxyacrylamide dihydrochloride 1H-NMR (300 MHz, DMSO-d6) δ1.34-1.82 (1OH, m),1.94-2.16 (3H, m),2.30 (IH, m),3.08-4.20 (5H, m),4.57 (IH, m),4.66 (IH, m),6.38 (IH, d, J=15.5 Hz),7.00 (IH, m),7.44 (IH, d, J=15.5 Hz),7.98 (IH, m),8.21 (IH, s),10.26 (IH, br-s),ll.ll (IH, br); MS (ES+) m/z 345.

The following compounds were obtained in a similar manner to that of Example 41. Example 217 (2E)-3-(5-chloro-6-{[ (3R)-l-cyclohexyl-3-piperidinyl]amino}-3- pyridinyl)-N-hydroxyacrylamide dihydrochloride 1H-NMR (200 MHz, DMSO-d6) <5 : 1.09-1.62 (7H, m) , 1.78-2.07 (7H, m) , 2.84-3.46 (5H, m) , 6.38 (IH, d, J = 15.8 Hz), 6.77 (IH, d, J = 7.6 Hz), 7.34 (IH, d, J = 15.8 Hz), 7.90 (IH, s), 8.23 (IH, s), 10.44 (IH, brs). MASS(ESI); 379 (M+H)+.

Example 218 (2E)-3-(5-chloro-6-{[(3R)-l-cyclopentyl-3-piperidinyl]amino} -3- pyridinyl)-N-hydroxyacrylamide dihydrochloride 1H-NMR (200 MHz, DMSO-dβ) <5 : 1.56-1.99 (14H, m), 2.79-2.96 (IH, m) , 3.32-3.54 (3H, m) , 6.38 (IH, d, J = 15.8 Hz), 6.84 (IH, d, J = 7.6 Hz), 7.34 (IH, d, J = 15.8 Hz), 7.90 (IH, s), 8.22 (IH, s), 10.71 (IH, brs), MΛSS(ESI); 365 (M+H)+.

The following compound was obtained in a similar manner to that of Example 89. Example 219 (2E)-3-(5-{[(3R)-l-benzyl-3-pyrrolidinyl]amino}-2-pyrazinyl) -2- fluoro-N-hydroxyacrylamide dihydrochloride MASS(API-ES); 358 (M+H)+ Free 1H-NMR ( 200MHz), (DMSO-d6, <5 ) : 1.90. - 2.60 ( 2H, m) , 2.95 - 3.85 ( 4H, m), 4.35 - 4.70 ( 3H, m) , 5.70 (2H, br) , 6.69 ( IH, d, J = 25Hz ), 7.40 - 7.50 ( 3H, m), 7.60 - 7.70 ( 2H, m) , 7.99 ( 0.5H, d, J = 1. 1Hz ) , 8.06 ( 0.5H, d, J = 1.1Hz ) , 8.33 ( IH, s ) , 11.43 ( IH, br) ;

The following compounds were obtained in a similar manner to that of Example 129. Example 220 (2E)-3-(5-{[1-(cyclohexylmethyl)-2-oxo-3-pyrrolidinyl]amino} -2- pyrazinyl)-N-hydroxyacrylamide hydrochloride 1H-NMR (300 MHz, DMSO-d6) 60.78-0.97 (2H, m),1.07-1.28 (3H, m),1.51-1.74 (6H, m),1.85 (IH, m),2.44 (IH, m),2.96-3.12 (2H, m),3.25-3.40 (2H, m),4.63 (IH, t, J=9 Hz),6.61 (IH, d, J=15.5 Hz),7.37 (IH, d, J=15.5 Hz),7.90 (IH, br),8.07 (IH, s),8.08 (IH, s); MS (ES+) m/z 360. Example 221 N-[2-({3~chloro-5-[(lE)-3-(hydroxyaπιino)-3-oxo-l-propen-l -yl]-2- pyridinyl}amino)phenyl]cyclohexanecarboxamlde hydrochloride 1H-NMR (300 MHz, DMSO-d6) 61.13-1.54 (5H, m),1.64 (IH, m) ,1.69-1.86 (4H, m),2.42 (IH, m),6.37 (IH, d, J=16 Hz),7.14 (IH, ddd,. J=7.5, 7.5, 1.5 Hz),7.21-7.30 (2H, m),7.36 (IH, d, J=16 Hz),7.78 (IH, d, J=7.5 Hz),8.02 (IH, d, J=I Hz),8.20 (IH, d, J=I Hz),8.32 (IH, s),9.95 (IH, s); MS (ES+) m/z 415.

Example 222 N-[2-({4-[(IE)-3-(hydroxyamino)-3-oxo-l-propen-i- yl]phenyl}amino)phenyl]cyclohexanecarboxamide hydrochloride 1H-NMR (300 MHz, DMSO-d6) δ1.07-1.43 (5H, m),1.55-1.78 (5H, m),2.34 (IH, m),6.23 (IH, d, J=16 Hz),6.81 (2H, d, J=8 Hz),7.05 (IH, dd, J=7.5, 7.5 Hz),7.12 (IH, dd, J=7.5, 7.5 Hz),7.28 (IH, d, J=7.5 Hz),7.34 (IH, d, J=16 Hz),7.37 (2H, d, J=8 Hz),7.59 (IH, d, J=7.5 Hz),7.72 (IH, br),9.25 (IH, s),10.60 (IH, br); MS (ES+) m/z 380.

Example 223 t N-[3-({3-chloro-5-[(lE)-3-(hydroxyamino)-3-oxo-l-propen-l-yl ]-2- pyridinyl}amino)phenyl]cyclohexanecarboxamide hydrochloride 1H-NMR (300 MHz, DMSO-d6) δ1.12-1.49 (5H, m) ,1.59-1.84 (5H, m),2.34 (IH, m),6.40 (IH, d, J=16 Hz) ,7.16-7.34 (3H, m),7.39 (IH, d, J=16 Hz),7.95 (IH, s),8.03 (IH, s),8.27 (IH, s),8.65 (IH, s),9.81 (IH, s); MS (ES+) m/z 415.

The following compound was obtained in a similar manner to that of Example 89. Example 224 cyclopentyl (3R)-3-({3-chloro-5-[ (lE)-3-(hydroxyamino)-3-oxo-l- propen-1-yl]-2-pyridinyl}amino)-1-pyrrolidinecarboxylate 1H-NMR (200 MHz, DMSO-d6) δ : 1.40-1.90 (8H, m) , 1.90-2.25 (4H, m) , 3.24-3.54 (3H, m) , 3.57-3.66 (IH, m) , 4.54 (IH, m) , 4.99 (IH, brs), 6.23 (IH, d, J = 15.8 Hz), 6.91 (IH, brs), 7.34 (IH, d, J = 15.8 Hz), 7.89 (IH, s), 8.22 (IH, s), MASS(ESI ) ; 395 (M+H) + .

The following compound was obtained in a similar manner to that of Example 41. Example 225 (2E)-3-(6-{[(3R)-l-benzyl-3-piperidinyl]amino}-5-chloro-3- pyridinyl)-N-hydroxyacrylamide dihydrochloride 1H-NMR (200 MHz, DMSO-d6) <5 : 1.52-2.00 (4H, m) , 2.73-2.92 (2H, m) , 2.24-3.59 (2H, m) , 4.34 (2H, d, J = 3.8 Hz), 4.58 (IH, brs), 6.37 (IH, d, J = 15.8 Hz), 6.86 (IH, brs), 7.34 (IH, d, J = 15.8 Hz), 7.45-7.48 (3H, m) , 7.61-7.72 (2H, m) , 7.88 (IH, s), 8.18 (IH, s), 11.15-11.52 (IH, brs), MASS(ESI); 387 (M+H)+.

The following compound was obtained in a similar manner to that of Example 89. Example 226 (2E)-3-(6-{[(3R)-l-(cyclohexylmethyl)-3-pyrrolidinyl]amino}- 5- fluoro-3-pyridinyl)-N-hydroxyacrylamide dihydrochloride MASS(API-ES); 363 (M+H)+ Free 1H-NMR ( 200MHz), (DMSO-d6, δ): 0.80 - 1.40 ( 5H, m) , 1.55 - 1.90 ( 6H, m), l.,95 - 2.60 ( 2H, m) , 2.90 - 4.10 ( 6H, m) , 4.55 - 4.80 ( IH, m), 4.82 (2H, br) , 6.33 ( IH, d, J = 16Hz ), 7.39 ( IH, d, J = 16Hz ), 7.60 (IH, br), 7.69 ( IH, d, J = 12Hz ), 8.07 ( IH, s), 10.53 (IH, br) .

The following compounds were obtained in a similar manner to that of Example 41. Example 227 (2E)-3-(5-chloro-6-{[(3R)-l-(cyclopropylmethyl)-3- piperidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamide dihydrochloride 1H-NMR (200 MHz, DMSO-d6) <5 : 1.58-1.77 (7H, m) , 1.98-2.13 (2H, m) , 3.24-3.66 (4H, m) , 4.54 (IH, m) , 4.97 (IH, m) , 6.34 (IH, d, J = 15.8 Hz), 6.92 (IH, brs), 7.34 (IH, d, J = 15.8 Hz), 7.89 (IH, s), 8.23 (IH, s), MASS(ESI ) ; 351 (M+H) + .

Example 228 (2E)-3-(5-chloro-6-{[(3R)-l-(cyclohexylcarbonyl)-3- piperidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamide hydrochloride 1H-NMR (200 MHz, DMSO-d6) 5:1.02-1.91 (14H, m) , 2.62-3.07 (3H, m) , 3.80-4.25 (3H, m) , 6.38 (IH, d, J = 15.8 Hz), 6.69 (IH, brs), 7.36 (IH, d, J = 15.8 Hz), 7.93 (IH, s), 8.19 (IH, s), MASS(ESI); 407 (M+H)+.

The following compound was obtained in a similar manner to that of Example 89. Example 229 (2E)-3-(6-{[(3R)-l-(cyclohexylcarbonyl)-3-pyrrolidinyl]amino }-5- fluoro-3-pyridinyl)-N-hydroxyacrylamide hydrochloride MASS(API-ES); 377 (M+H)+ Free, 1H-NMR ( 200MHz), (DMSO-d6, 6): 1.10 - 1.45 ( 5H, m), 1.55 - 1.80 ( 5H, m), 1.90 - 2.60 ( 2H, m) , 3.20 - 3.90 ( 4H, m) , 4.40 - 4.70 ( IH, m), 5.40 (IH, br) , 6.33 ( IH, d, J = 16Hz ), 7.40 ( IH, d, J = 16Hz ), 7.75 ( IH, d, J = 13Hz ), 7.80 (IH, br), 8.08 ( IH, S).

The following compound was obtained in a similar manner to that of Example 92. Example 230 (2E)-3-(6-{[(3R)-I-cyclopentyl-3-pyrrolidinyl]amino}-3-pyrid inyl)- N-hydroxyacrylamide dihydrochloride 1H-NMR (300 MHz, DMSO-d6) <51.43-1.62 (2H, m),1.64-1.84 (4H, m),1.90-2.16 (3H, m),2.29 (IH, m),3.10-4.05 (5H, m),4.58 (IH, m),4.70 (IH, m),6.38 (IH, d, J=16 Hz),7.02 (IH, m),7.44 (IH, d, " J=16 Hz),8.00 (IH, m),8.21 (IH, s),10.26 (IH, s) ,11.16-11.44 (IH, br); MS (ES+) m/z 317.

The following compound was obtained in a similar manner to that of Example 129. Example 231 ( 2E) -N-hydroxy-3- (5-{ [ (3R) -1- (2-methylbenzyl) -3- pyrrolidinyl ] amino } - 2 -pyrazinyl ) acrylamide dihydrochloride 1H-NMR (300 MHz, CD3OD) <52.10-2.32 (IH, m), 2.40-2.75 (IH, m),2.47 (1.7H, s),2.49 (1.3H, s), 3.23-3.45 (IH, m), 3.48-3.72 (2H, m),3.84 (0.6H, m),4.00 (0.4H, m), 4.48-4.74 (3H, m),6.73 (IH, d, J=15.5 Hz), 6.74 (IH, d, J=15.5 Hz) ,7.26-7.42 (3H, m), 7.44-7.58 (2H, m), 8.05-8.18 (3H, m) ; MS (ES+) m/z 354.

The following compounds were obtained in a similar manner to that of Example 89. Example 232 (2E) -3- (4-{ [ (3R) -l-benzyl-3-pyrrolidinyl]amino}-3-fluorophenyl) -N- hydroxyacrylamide dihydrochloride MASS(API-ES); 356 (M+H)+ Free 1H-NMR ( 200MHz), (DMSO-d6, <5 ) : 1.90 - 2.70 ( 2H, m) , 3.00 - 3.90 ( 4H, m), 4.00 - 4.50 ( 3H, m), 6.26 ( IH, d, J = 16Hz ), 6.60 - 6.90 ( IH, m), 7.20 - 7.39 ( 3H, m) , 7.40 - 7.50 ( 3H, m) , 7.58 - 7.70 ( 2H, m), 11.10 - 11.50 ( IH, m) .

Example 233 (2E)-3-(6-{[(3R)-l-(2,6-difluorobenzyl)-3-pyrrolidinyl]amino }-5- f luoro - 3 -pyridinyl ) -N-hydroxyacrylamide dihydrochloride MASS(API-ES); 393 (M+H)+ Free, 1H-NMR ( 200MHz), (DMSO-d6, <5 ) : 1.95 - 2.70 ( 2H, m) , 3.10 - 4.00 ( 4H, m), 4.40 - 4.90 ( 3H, m), 6.31 ( IH, d, J = 16Hz ), 7.20 - 7.80 ( 6H, m), 8.07 ( IH, s), 11.22 (IH, br) .

Example 234 (2E)-3-(5-fluoro-6-{[(3R)-l-(l,3-thiazol-2-ylmethyl)-3- pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamide dihydrochloride MASS(API-ES); 364 (M+H)+ Free, 1H-NMR ( 200MHz), (DMSO-d6, <5 ) : 2.00 - 2.60 ( 2H, m) , 3.10 - 4.00 ( 4H, m), 4.55 - 5.00 ( 3H, m) , 6.34 ( IH, d, J = 16Hz ), 7.38 ( IH, d, J = 16Hz ), 7.56 (IH, br) , 7.69 ( IH, d, J = 13Hz ), 7.90 - 8.00 ( 2H, m), 8.07 ( IH, s), 11.58 (IH, br) .

Example 235 (2E)-3-(5-fluoro-6-{[ (3R)-1-(2-phenylethyl)-3-pyrrolidinyl]amino}- 3-pyridinyl)-N-hydroxyacrylamide dihydrochloride MASS(API-ES); 371 (M+H)+ Free, 1H-NMR ( 200MHz), (DMSO-d6, <5 ) : 1.95 - 2.60 ( 2H, m), 3.00 - 4.40 ( 8H, m), 4.50 - 4.90 ( IH, m) , 6.32 ( IH, d, J = 16Hz ), 7.20 - 7.50 ( 6H, m), 7.52 ( IH, br) , 7.69 ( IH, d, J = 12Hz ), 8.06 ( 0.5H, s), 8.09 ( 0.5H, s), 11.00 - 11.30 ( IH, m) .

Example 236 (2E)-3-(5-fluoro-6-{[ (3R)-l-(l-piperidinylacetyl)-3- pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamide dihydrochloride MASS(API-ES); 392 (M+H)+ Free, 1H-NMR ( 200MHz), (DMSO-d6, 6): 1.20 - 1.90 ( 6H, m) , 1.95 - 2.55 ( 2H, m), 2.85 - 3.10 ( 2H, m) , 3.30 - 4.35 ( 8H, m), 4.40 - 4.75 ( IH, m), 6.35 ( IH, d, J = 16Hz ), 7.39 ( IH, d, J = 16Hz ), 7.58 ( IH, br), 7.69 ( IH, d, J = 13Hz ), 8.08 ( IH, s), 9.65 ( IH, br).

Example 237 (2E)-3-[6-({(3R)-1-[(3-chloro-4-pyridinyl)methyl]-3- pyrrolidinyl}amino)-5-fluoro-3-pyridinyl]-N-hydroxyacrylamid e trihydrochloride MASS(API-ES); 392 (M+H)+ Free, 1H-NMR. ( 200MHz), (DMSO-d6, <5 ) : 2.00 - 2.70 ( 2H, m), 3.10 - 4.05 ( 4H, m), 4.60 - 5.00 ( 3H, m) , 6.35 ( IH, d, J = 16Hz ), 7.38 ( IH, d, J = 16Hz ), 7.72 ( IH, d, J = 12Hz ), 7.75 (IH, br) , 8.00 - 8.10 ( 2H, m), 8.66 ( IH, d, J = 5.0Hz ), 8.79 ( IH, s), 11.80 - 12.10 ( IH, m) .

The following compound was obtained in a similar manner to that of Example 129. Example 238 (2E)-N-hydroxy-3-(5-{[ (3R)-1-(2-quinolinylmethyl)-3- pyrrolidinyl]amino}-2-pyrazinyl)acrylamide trihydrochloride 1H-NMR (300 MHz, DMSO-d6) δ2.12 (IH, m),2.44 (IH, m),3.35-4.00 (4H, m),4.59 (IH, m),4.87 (2H, s),6.64 (IH, d, J=15 Hz),7.38 (IH, d, J=15 Hz),7.65-7.76 (2H, m),7.84 (IH, ddd, J=7, 7, 1.5 Hz) ,8.02-8.38 (6H, m),8.50 (IH, d, J=8.5 Hz),11.16 (IH, br-s); MS (ES+) m/z 391.

The following compound was obtained in a similar manner to that of Example 92. Example 239 (2E)-3-(6-{[ (3R)-l-cyclohexyl-3-pyrrolidinyl]amino}-3-pyridinyl)-N- hydroxyacrylamide dihydrochloride 1H-NMR (300 MHz, DMSO-d6) δ1.02-1.52 (6H, m),1.60 (IH, m),1.73-1.86 (2H, m),1.94-2.14 (2H, m),2.27 (IH, m),3.04-4.05 (5H, m),4.58 (IH, m),6.34 (IH, d, J=16 Hz),6.90 (IH, m),7.42 (IH, d, J=16 Hz),8.21 (IH, s); MS (ES+) m/z 331.

The following compound was obtained in a similar manner to that of Example 89. Example 240 (2E)-3-(6-{[(3R)-l-(l,3-benzothiazol-2-ylmethyl)-3- pyrrolidinyl]amino}-5-fluoro-3-pyridinyl)-N-hydroxyacrylamid e dihydrochloride MASS(API-ES); 414 (M+H)+ Free, 1H-NMR ( 400MHz), (DMSO-d6, <5 ) : 2.00 - 2.65 ( 2H, m) , 3.20 - 4.10 ( 4H, m), 4.60 - 5.10 ( 3H, m) , 6.32 ( IH, d, J = 16Hz ), 7.38 ( IH, d, J = 16Hz ), 7.50 - 7.75 ( 4H, m), 8.00 - 8.30 ( 3H, m) , 11.50 - 11.90 ( IH, m) .

The following compounds were obtained in a similar manner to that of Example 41. Example 241 (2E)-3-(6-{[(3R)-l-(2-chlorobenzyl)-3-piperidinyl]amino}-3- pyridinyl)-N-hydroxyacrylamide dihydrochloride 1H-NMR (400 MHz, DMSO-d6) <5 : 1.52 (IH, brs), 1.93-2.06 (3H, m) , 2.92-3.55 (4H, m) , 4.34 (IH, brs), 4.50 (2H, s), 6.39 (IH, d, J = 15.8 Hz), 7.04 (IH, brs), 7.39-7.52 (3H, m) , 7.57-7.60 (IH, m) , 7.97-8.02 (2H, m), 8.19 (IH, brs), 10.95 (IH, brs), MASS(ESI); 387 (M+H)+.

Example 242 (2E)-3-(6-{[ (3R)-1-(3-chlorobenzyl)-3-piperidinyi]amino}-3- pyridinyl)-N-hydroxyacrylamide dihydrochloride 1H-NMR (400 MHz, DMSO-d6) <5 : 1.46 (IH, brs), 1.81-2.08 (3H, m) , 2.89-3.52 (4H, m) , 4.34 (IH, brs), 4.39-4.42 (IH, m) , 6.42 (IH, d, J = 15.8 Hz), 7.08-7.10 (IH, m), 7.42 (IH, d, J = 15.8 Hz), 7.47- 7.55 (3H, m), 7.62 (IH, d, J = 6.8 Hz), 7.79 (IH, s), 8.06 (IH, brs), 8.20 (IH, s), 11.08-11.22 (IH, m) , MASS(ESI); 387 (M+H)+.

Example 243 (2E)-3-(6-{[(3R)-l-acetyl-3-piperidinyl]amino}-5-fluoro-3- pyridinyl)-N-hydroxyacrylamide hydrochloride MASS(ESI); 323 (M+H)+.

The following compounds were obtained in a similar manner to that of Example 129. Example 244 (2E)-3-(5-{[(3R)-l-(2,3-dihydro-lH-inden-2-yl)-3- pyrrolidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamide dihydrochloride 1H-NMR (300 MHz, DMSO-d6) δ2.00-2.40 (2H, m),3.04-4.27 (9H, m),4.52 (0.5H, m),4.60 (0.5H, m),6.64 (IH, d, J=15 Hz) ,7.18-7.32 (5H, m),7.40 (IH, d, J=15 Hz),8.04 (0.5H, s),8.06 (0.5H, s),8.17 (IH, s),11.63 (IH, br); MS (ES+) m/z 366.

Example 245 (2E)-3-{6-[ (2-benzylphenyl)amino]-5-chloro-3-pyridinyl}-N- hydroxyacrylamide hydrochloride 1H-NMR (300 MHz, DMSO-d6) 53.93 (2H, s),6.35 (IH, d, J=16 Hz),7.07- 7.32 (9H, m),7.33 (IH, d, J=16 Hz),7.45 (IH, d, J=8 Hz),7.98 (IH, d, J=I.5 Hz),8.09 (IH, d, J=I.5 Hz),8.31 (IH, s); MS (ES+) m/z 380.

Example 246 (2E)-3-(5-{[ (3R)-1-(4-ethoxybenzyl)-3-pyrrolidinyl]amino}-2- pyrazinyl)-N-hydroxyacrylamide dihydrochloride 1H-NMR (300 MHz, DMSO-d6) <51.32 (3H, t, J=7 Hz),2.00 (IH, m),2.21- 2.53 (IH, m),2.96-3.80 (4H, m),4.03 (2H, q, J=7 Hz),4.33 (2H, m),4.44 (0.5H, m),4.55 (0.5H, m),6.62 (0.5H, d, J=15.5 Hz),6.63 (0.5H, d, J=15.5 Hz),6.97 (IH, d, J=9 Hz),6.98 (IH, d, J=9 Hz),7.38 (IH, d, J=15.5 Hz),7.49 (IH, d, J=9 Hz),7.50 (IH, d, J=9 Hz),7.98 (0.5H, br),8.02 (0.5H, s),8.04 (0.5H, s),8.14 (IH, s),8.16 (0.5H, br),10.87 (IH, br) ; MS (ES+) m/z 384.

The following compounds were obtained in a similar manner to that of Example 92. Example 247 (2E)-3-(6-{[(3R)~l-benzyl-3-pyrrolidinyl]amino}-2-pyrazinyl) -N- hydroxyacrylamide dihydrochloride 1H-NMR (300 MHz, DMSO-d6) δ1.92-2.17 (IH, m),2.24-2.58 (IH, m),3.05 (0.5H, m),3.15-3.42 (2H, m),3.51 (0.5H, m),3.63 (0.5H, m),3.95 (0.5H, m),4.33-4.62 (3H, m),7.01 (0.5H, d, J=15.5 Hz),7.05 (0.5H, d, J=15.5 Hz),7.33 (IH, d, J=15.5 Hz) ,7.40-7.52 (3H, m),7.60-7.71 (2H, m),7.75 (0.5H, m),7.92 (IH, s),7.95 (0.5H, s),7.96 (0.5H, m),7.99 (0.5H, s),11.18 (0.5H, br),11.31 (0.5H, br) ; MS (ES+) m/z 340.

Example 248 (2E)-N-hydroxy-3-(2-{[ (3R)-1-(2-phenylethyl)-3-pyrrolidinyl]amino}- 5-pyrimidinyl)acrylamide dihydrochloride 1H-NMR (300 MHz, DMSO-d6) <51.95-2.16 (IH, m),2.19-2.54 (IH, m),2.96-4.00 (8H, m),4.58 (IH, m),6.40 (IH, d, J=16 Hz) ,7.23-7.42 (7H, m),7.99 (0.5H, br),8.13 (0.5H, br),8.58 (IH, s),8.59 (IH, s),10.89 (0.5H, br),ll.ll (0.5H, br) ; MS (ES+) m/z 354! The following compounds were obtained in a similar manner to that of Example 89. Example 249 (2Z)-3-(5-{[(3R)-l-benzyl-3-pyrrolidinyl]amino}-2-pyrazinyl) -2- fluoro-N-hydroxyacrylamide dihydrochloride MASS(API-ES); 358 (M+H)+ Free, 1H-NMR ( 200MHz), (DMSO-d6, <5 ) : 1.90 - 2.60 ( 2H, m) , 2.95 - 3.90 ( 4H, m), 4.35 - 4.70 ( 3H, m) , 6.21 (2H, br) , 6.70 ( IH, d, J = 39Hz ), 7.40 - 7.50 ( 3H, m), 7.60 - 7.70 ( 2H, m) , 8.04 ( 0.5H, d, J = 1.1Hz ), 8.10 ( 0.5H, d, J = 1.1Hz ), 8.32 ( IH, s), 11.46 , (IH, br).

Example 250 (2E)-3-(6-{[(3R)-l-(2,2-difluoroethyl)~3-pyrrolidinyl]amino} -5- fluoro-3-pyridinyl)-N-hydroxyacrylamide dihydrochloride MASS(API-ES); 331 (M+H)+ Free, 1H-NMR ( 200MHz), (DMSO-d6, <5 ) : 2.00 - 2.60 ( 2H, m) , 3.05 - 4.10 ( 4H, m), 3.87 ( 2H, dt, J = 3.8Hz , J = 13Hz ), 4.50 - 4.90 ( IH, m), 6.33 ( IH, d, J = 16Hz ), 6.57 ( IH, tt, J = 3.8Hz , J = 54Hz ), 7.39 ( IH, d, J = 16Hz ), 7.60 ( IH, br) , 7.69 ( IH, d, J = 13Hz ), 8.08 ( IH, S).

Example 251 (2E)-3-[5-fluoro-6-({(3R)-l-[2-(lH-pyrazol-l-yl)ethyl]-3- pyrrolidinyl}amino)-3-pyridinyl]-N-hydroxyacrylamide dihydrochloride MASS(API-ES); 361 (M+H)+ Free, 1H-NMR ( 200MHz), (DMSO-d6, <5 ) : 1.90 - 2.60 ( 2H, m) , 2.85 - 3.90 ( 6H, m), 4.60 ( 2H, t, J = 6.4Hz ), 4.65 ( IH, br), 6.25 - 6.40 ( 2H, m), 7.38 ( IH, d, J = 16Hz ), 7.54 ( IH, d, J = 1.6Hz ) , 7.69 ( IH, d, J = 13Hz ), 7.85 ( IH, d, J = 2.2Hz ) , 8.06 ( IH, s), 11.20 - 11.60 ( IH, m) .

The following compound was obtained in a similar manner to that of Example 129. Example 252 (2E)-3-(5-chloro-6-{[(1IS,2R)-2-phenylcyclopropyl]amino}-3- pyridinyl)-N-hydroxyacrylamide hydrochloride 1H-NMR (300 MHz, DMSO-d6) <5l.26 (IH, m),1.41 (IH, m),2.12 (IH, m),3.02 (IH, m),6.34 (IH, d, J=16 Hz) ,7.13-7.22 (3H, m),7.24-7.38 (3H, m),7.51 (IH, br),7.92 (IH, s),8.21 (IH, s); MS (ES-) m/z 328.

The following compound was obtained in a similar manner to that of Example 41. Example 253 (2E)-3-(5-chloro-6-{[ (3R)-l-cyclohexyl-3-pyrrolidinyl]amino}-3- pyridinyl)-N-hydroxyacrylamide dihydrochloride 1H-NMR (200 MHz, DMSO-d6) δ : 1.05-1.70 (6H, m), 1.77-1.82 (2H, m), 2.05-2.09 (3H, m) , 3.00-3.78 (5H, m) , 4.72-4.86 (IH, m) , 5.75 (IH, d, J = 15.8 Hz), 7.20 (IH, brs), 7.35 (IH, d, J = 15.8 Hz), 7.91 (IH, s), 8.22 (IH, s), 11.32 (IH, brs).

The following compound.was obtained in a similar manner to that of Example 89. Example 254 tert-butyl (3R)-3-({3-chloro-5-[(lE)-3-(hydroxyamino)-3-oxo-l- propen-1-yl]-2-pyridinyl}amino)-1-pyrrolidinecarboxylate 1H-NMR (200 MHz, DMSO~d6) δ: 1.39 (9H, s), 1.91-2.12 (2H, m) , 3.15-3.65 (4H, m), 4.53 (IH, brs), 6.33 (IH, d, J = 15.8 Hz), 6.85 (IH, brs), 7.34 (IH, d, J = 15.8 Hz), 7.88 (IH, s), 8.22 (IH, s) . MASS(ESI); 383 (M+H)+.

The following compounds were obtained in a similar manner to that of Example 41. Example 255 (2E)-3-(5-chloro-6-{[l-(3-fluorobenzyl)-4-piperidinyl]amino} -3- pyridinyl)-N-hydroxyacrylamide dihydrochloride 1H NMR (DMSO-d6, <5 ) :2.00-2.20 (4H, m) , 3.00-3.46 (4H, m) , 4.10- 4.20 (IH, m), 4.30-4.46 (2H, m), 6.39 (IH, d, J = 15.9 Hz), 7.26- 7.58 (4H, m), 7.66 (IH, d, J = 8.3 Hz), 7.95 (IH, s), 8.18-8.22 (IH, m). Mass (APCI) : 405(M+H)+.

Example 256 (2E)-3-(5-chloro-6-{[1-(2-pyridinylmethyl)-4-piperidinyl]ami no}-3- pyridinyl)-N-hydroxyacrylamide trihydrochloride 1H NMR (DMSO-d6, 6) :2.05-2.10(4H, m) , 3.17-3.25(2H, m) , 3.41- 4.78(2H, m), 4.15-4.25(1H, m) , 4.51(2H, s), 6.37(1H, d, J=15.8 Hz) ; 7.04(1H, brs), 7.34(1H, d, J=15.8 Hz), 7.56-7.59(1H, m) , 7.83(1H, d, J=7.8 Hz), 7.93(1H, s), 8.02-8.06(1H, d) , 8.19(1H, s), 8.73(1H, d, J=4.9 Hz), 1O.97(1H, brs). Mass (APCI) : 388(M+H)+.

Example 257 (2E)-3-(5-chloro-6-{[1-(3-pyridinyLmethyl)-4-piperidinyl]ami no}-3- pyridinyl)-N-hydroxyacrylamide trihydrochloride 1H NMR (DMSO-d6, <5) :2.00-2.30(4H, m) , 3.05-3.45(2H, m), 3.45-3.50(2H, m), 4.15-4.35(1H, m), 4.57(2H, brs), 6.39(1H, d, J=15.9 Hz), 7.23(1H, brs), 7.34(1H, d, J=15.9 Hz), 7.94(1H, s), 8.09-8.16(1H, m), 8.18(1H, s), 8.89(1H, d, J=7.9 Hz), 9.00(1H, d, J=5.4 Hz), 9.24(1H, s), 11.8O(1H, brs). Mass (ESI) : 388(M+H)+. ,

Example 258 (2E)-3-(5-chloro-6-{[1-(4-pyridinylmethyl)-4-piperidinyl]ami no}-3- pyridinyl)-N-hydroxyacrylamide trihydrochloride 1H NMR (DMSO-d6, 6) :2.00-2.30(4H, m) , 3.10-3.60(4H, m) , 4.10- 4.3O(1H, m), 4.62(2H, brs), 6.37(1H, d, J=15.9 Hz), 7.17(1H, brs), 7.34(1H, d, J=15.9 Hz), 7.92(1H, s), 8.18(1H, s), 8.42(2H, m) , 9.04(2H, d, J=5.8 Hz), 12.06(1H, brs). Mass (ESI) : 388(M+H)+.

Example 259 (2E)-3-(5-chloro-6-{[l-(3-chlorobenzyl)-4-piperidinyl]amino} -3- pyridinyl)-N-hydroxyacrylamide dihydrochloride 1H NMR (DMSO-d6, <5 ) :2.00-2.25(4H, m) , 2.90-3.20(2H, m) , 3.20- 3.40(2H, m), 4.10-4.30(1H, m) , 4.29-4.44(2H, m) , 6.38(1H, d, J=15.9 Hz), 7.35(1H, d, J=15.9 Hz), 7.49-7.67(3H, m) , 7.84(1H, s), 8.04(1H, s), 8.19(1H, s), 11.3O(1H, brs). Mass (ESI) : 421(M+H)+.

Example 260 (2E)-3-(5-chloro-6-{[1-(2-chlorobenzyl)-4-piperidinyl]amino} -3- pyridinyl)-N-hydroxyacrylamide dihydrochloride 1H NMR (DMSO-d6, 6) :2.00-2.25(4H, m) , 3.10-3.50(4H, m) , 4.10- 4.3O(1H, m), 4.42-4.56(2H, m), 6.38(1H, d, J=15.9 Hz), 7.35(1H, d, J=15.9 Hz), 7.46-7.62(3H, m) , 7.93(1H, s), 8.04-8.09(1H, m) , 8.19(1H, s), 11.2O(1H, brs), Mass (ESI) : 421(M+H)+.

Example 261 (2E)-3-(5-chloro-6-{[1-(cyclohexylmethyl)-4-piperidinyl]amin o}-3- pyridinyl)-N-hydroxyacrylamide dihydrochloride 1H NMR (DMSO-d6, δ) :0.94-1.29 (7H, m) , 1.65-1.92 (5H, m) , 1.99- 2.17 (3H, m), 2.86-3.04 (3H, m) , 3.10-3.54 (3H, m) , 4.19-4.31 (IH, m), 6.40 (IH, d, J = 15.9 Hz), 7.35 (IH, d, J = 15.9 Hz), 8.20 (IH, s), 8.30 (IH, s), 10.30 (IH, brs). Mass (APCI) : 393(M+H)+.

Example 262 (2E)-3-(5-chloro-6-{[l-(2-fluorobenzyl)-4-piperidinyl]amino} -3- pyridinyl)-N-hydroxyacrylamide dihydrochloride 1H NMR (DMSO-d6, 6) :2.05-2.20(4H, m) , 3.08-3.18(2H, m) , 3.41- 3.44(2H, m), 4.15-4.2O(1H, m) , 4.32-4.46(2H, in), 6.38(1H, d, J=15.9 Hz), 7.30~7.37(3H, m) , 7.52-7.56(1H, m) , 7.86-7.89(1H, m) , 7.93(1H, s), 8.19(1H, s), 11.22(1H, brs). Mass (APCI) : 405(M+H)+.

Example 263 (2E)-3-(5-chloro-6-{[l-(3-methyl-2-buten-l-yl)-4- piperidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamide dihydrochloride 1H NMR (DMSO-d6, <5 ) :1.72 (3H, s), 1.78 (3H, s), 2.90-3.30 (2H, m) , 3.30-3.50 (2H, m) , 3.55-3.80 (2H, m) , 4.10-4.40 (IH, m) , 5.37-5.44 (IH, m), 6.39 (IH, d, J = 15.9 Hz), 7.35 (IH, d, J = 15.9 Hz), 7.94 (IH, s), 8.19 (IH, s). Mass (APCI) : 365(M+H)+.

The following compounds were obtained in a similar manner to that of Example 129. Example 264 (2E)-3-(4-{[(3R)-1-(cyclohexylcarbonyl)-3- pyrrolidinyl]amino}phenyl)-N-hydroxyacrylamide 1H-NMR (300 MHz, DMSO-d6) 61.10-1.40 (5H, m) ,1.54-1.95 (6H, m),2.02- 2.45 (2H, m),3.25-4.15 (5H, m),6.15 (IH, br-d, J=16 Hz),6.34 (IH, m),6.56-6.70 (2H, m),7.26-7.40 (3H, m),8.86 (IH, s),10.53 (IH, s); MS (ES+) m/z 358.

Example 265 (2E)-N-hydroxy-3-{6-[ (4-methylphenyl)amino]-3-pyridinyl}acrylamide hydrochloride 1H-NMR (300 MHz, DMSO-d6) 62.31 (3H, s),6.38 (IH, d, J=16 Hz),7.06 (IH, d, J=9 Hz),7.22 (2H, d, J=8 Hz) ,7.38-7.50 (3H, m),8.00 (IH, br-d, J=8 Hz),8.23 (IH, d, J=I.5 Hz),10.27 (IH, br-s); MS (ES+) m/z 270.

Example 266 (2E)-3-{6-[(2-ethoxyphenyl)amino]-3-pyridinyl}-N-hydroxyacry lamide hydrochloride 1H-NMR (300 MHz, DMSO-d6) <5l.21 (3H, t, J=7 Hz), 4.10 (2H, q, J=7 Hz), 6.44 (IH, d, J=15.8 Hz), 7.03 (IH, dd, J=7.5, 7.5 Hz), 7.17 (IH, d, J=8 Hz), 7.21 (IH, d, J=9.5 Hz), 7.30 (IH, dd, J=7.5, 7.5 Hz), 7.46 (IH, d, J=15.8 Hz), 7.53 (IH, br-d, J=7.5 Hz), 8.13 (IH, br-d, J=9.5 Hz), 8.21 (IH, d, J=I.5 Hz), 10.38 (IH, br),10.82 (IH, br) ; MS (ES+) m/z 300. Example 267 (2E)-3-[5-chloro-6-(2,3-dihydro-lH-inden-l~ylamino)-3-pyridi nyl]-N- hydroxyacrylamide hydrochloride 1H-NMR (300 MHz, DMSO-d6) 52.09 (IH, m),2.77-3.06 (3H, m),5.78 (IH, m),6.35 (IH, d, J=16 Hz) ,7.12-7.32 (5H, m),7.37 (IH, d, J=16 Hz),7.94 (IH, s),8.24 (IH, s); MS (ES+) m/z 330.

The following compound was obtained in a similar manner to that of Example 96. Example 268 (2E)-3-(5~{[(3R)-l-(2-chlorobenzyl)-3-piperidinyl]amino}-2- pyrazinyl)-N-hydroxyacrylamide dihydrochloride 1H-NMR (300 MHz, DMSO-d6) 61.39-1.49 (IH, m),1.70-2.06 (3H, m),2.70-2.94 (IH, m),2.94-3.21 (IH, m) ,3.30-3.61 (2H, m),4.21-4.41 (IH, m),4.41-4.56 (2H, m),6.62 (IH, d, J=15.2 Hz),7.37 (IH, d, J=15.2 Hz),7.44-7.55 (2H, m),7.55-7.65 (IH, m),7.72-7.87 (IH, m),7.87-7.99 (IH, m),7.99-8.06 (IH, m),8.11 (IH, s); MS (ES+) m/z 388.

The following compound was obtained in a similar manner to that of Example 129. Example 269 (2E)-3-(4-{[(3R)-l-(cyclohexylmethyl)-3-pyrrolidinyl]amino}p henyl)- N-hydroxyacrylamide hydrochloride 1H-NMR (300 MHz, DMSO-d6) δ0.84-1.03 (2H, m),1.08-1.32 (3H, m),1.54-1.76 (4H, m),1.79-2.02 (3H, m),2.22-2.50 (IH, m),2.82-3.14 (3H, m),3.40 (IH, m),3.60 (IH, m),3.87-4.40 (2H, m),6.20 (IH, d, J=16 Hz),6.62 (2H, d, J=8 Hz) ,7.26-7.42 (3H, m),10.46 (IH, S); MS (ES+) m/z 344.

The following compounds were obtained in a similar manner to that of Example 41. Example 270 (2E)-3-(6-{[(3R)-l-benzyl-3-piperidinyl]amino}~5-fluoro-3- pyridinyl)-N-hydroxyacrylamide dihydrochloride 1H-NMR (200 MHz, DMSO-d6) δ: 1.30-1.60 (IH, m) , 1.70-1.98 (3H, m) , 2.60-2.90 (2H, m) , 3.25-3.50 (3H, m) , 4.35 (2H, m) , 6.34 (IH, d, J = 16.1 Hz), 7.37 (IH, d, J = 16.1 Hz), 7.41-7.47 (4H, m) , 7.61-7.75 5 (3H, m), 8.03 (IH, s), 11.20 (IH, brs), MASS(ESI); 371 (M+H)+.

Example 271 (2E)-3-(6-{[ (3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-5- 10 fluoro-3-pyridinyl)-N-hydroxyacrylamide dihydrochloride 1H-NMR (200 MHz, DMSO-d6) <5 : 0.92-1.27 (5H, m) , 1.52-2.02 (1OH, m) , 2.73-3.00 (3H, m) , 3.20-3.57 (2H, m) , 4.55-4.60 (2H, m) , 6.34 (IH, d, J = 16.1 Hz), 7.34-7.43 (2H, m), 7.64-7.76 (IH, m) , 8.67 (IH, s), 10.11 (IH, brs), 15 MASS(ESI); 377 (M+H)+.

Example 272 (2E)-3-(2-{[ (3R)-l-benzyl-3-piperidinyl]amino}-5-pyrimidinyl)-N- hydroxyacrylamide dihydrochloride 20 1H-NMR (200 MHz, DMSO-d6) <5 : 1.35-1.60 (IH, m) , 1.70-2.00 (4H, m), 2.61-3.10 (2H, m), 3.20-3.67 (2H, m) , 4.34 (2H, m) , 6.39 (IH, d, J = 16.0 Hz), 7.20 (IH, d, J = 16.0 Hz), 7.44-7.47 (3H, m) , 7.59-7.64 (2H, m), 8.15 (IH, d, J = 8.0 Hz), 8.55 (2H, s), 11.07 (IH, brs), MASS(ESI); 354 (M+H)+. 25 Example 273 (2E)-3-(2-{[(3R)-l-(cyclohexylmethyl)-3-piperidinyl]amino}-5 - pyrimidinyl)-N-hydroxyacrylamide dihydrochloride . 1H-NMR (200 MHz, DMSO-d6) 6: 0.92-1.28 (5H, m) , 1.64-2.10 (1OH, m) , ,30 2.70-3.16 (3H, m) , 3.32-3.57 (2H, m) , 4.44 (2H, brs), 6.47 (IH, d, J = 16.0 Hz), 7.33 (IH, d, J = 16.0 Hz), 8.03 (IH, brs), 8.62 (2H, s), 10.40 (IH, brs), MASS(ESI); 360 (M+H)+.

35 The following compound was obtained in a similar manner to that of Example 129. Example 274 (2E)-3-(5-σhloro-6-{[2-(1-pyrrolidinylmethyl)phenyl]amino}- 3- pyridinyl)-N-hydroxyacrylamide dihydrochloride 1H-NMR (300 MHz, DMSO-d6) δ1.76-2.00 (4H, m),2.96-3.13 (2H, m),3.27-3.42 (2H, m),4.23 (2H, br-s),6.38 (IH, d, J=16 Hz),7.30- 7.52 (4H, m),7.78 (IH, d, J=7.5 Hz),8.02 (IH, s),8.10 (IH, s),8.81 (IH, s),10.96 (IH, br-s); MS (ES+) m/z 373.

Example 275 IN-NaOH (4.7mL) was added to the solution of (2E)-N-hydroxy-3-(5- {[ (3R)-1-(2-phenylethyl)-3-pyrrolidinyl]amino}-2- pyrazinyl)acrylamide dihydrochloride (1.Og) in water (2OmL) under ice-cooling and the mixture was stirred at 5-10 deg for 5 hr. The isolated precipitate was collected by filtration to give (2E)-N- hydroxy-3-(5-{[(3R)-l-(2-phenylethyl)-3-pyrrolidinyl]amino}- 2- pyrazinyl)acrylamide (0.7Ig). lH-NMR(CD3OD):d 1.77-1.89(1H, m) , 2.33-2.46(1H, m) , 2.71-2.91(6H, m), 2.94-3.04(1H, m) , 3.1O-3.17(1H, m) , 4.43-4.52(1H, m) , 6.64(1H, d, J=15.3 Hz), 7.16-7.32(5H, m) , 7.45(1H, d, J=15.3 Hz), 7.95(1H, s), 8.01(1H, s)

The following compounds can be obtained in a similar manner to that of Example 275. • ' . Example 276 (2E)-3-(6-{[ (3R)-l-benzyl-3-pyrrolidinyl]amino}-3-pyridinyl)-N- hydroxyacrylamide

Example 277 (2E)-3-(6-{[(3R)-I-(I-benzofuran-2-ylmethyl)-3-pyrrolidinyl] amino}- 3-pyridinyl)-N-hydroxyacrylamide

Example 278 (2E)-3-(6-{[(3R)-I-(l-benzofuran-5-ylmethyl)-3-pyrrolidinyl] amino}- 3-pyridinyl)-N-hydroxyacrylamide

Example 279 ( 2E) -3- ( 6-{ [ ( 3R) -1- ( 3 , 4-dijnethylbenzyl) -3-pyrrolidinyl] amino}-3- pyridinyl ) -N-hydroxyacrylamide

Example 280 ( 2E ) - 3 - ( 6 - { [ ( 3R ) - 1 - ( 2 , 3 - di-methylbenzyl ) - 3 -pyrrolidinyl ] amino } - 3 - pyridinyl) -N-hydroxyacrylamide

Example 281 (2E)-3-(4-{[(3R)-1-(cyclohexylcarbonyl)-3- pyrrolidinyl]amino}phenyl)-N-hydroxyacrylamide

Example 282 (2E)-3-(6-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-3 - pyridinyl)-N-hydroxyacrylamide

Example 283 tert-butyl (3R)-3-({3-chloro-5-[ (lE)-3-(hydroxyamino)-3-oxo-l- propen-1-yl]-2-pyridinyl}amino)-1-pyrrolidinecarboxylate

Example 284 (2E)-3-(5-{[(3R)-l-benzyl-3-pyrrolidinyl]amino}-2-pyrazinyl) -N- hydroxyacrylamide

Example 285 cyclopentyl (3R)-3-({3-chloro-5-[ (IE)-3-(hydroxyamino)-3-oxo-l- propen-1-yl]-2-pyridinyl}amino)-1-pyrrolidinecarboxylate

Example 286 (2E)-N-hydroxy-3-(5-{[(3R)-1-(4-methylbenzyl)-3- pyrrolidinyl]amino}-2-pyrazinyl)acrylamide

Example 287 ( 2E) -3- ( 5-{ [ ( 3R) -1- ( 4-chlorobenzyl) -3-pyrrolidinyl]amino}-2- pyrazinyl) -N-hydroxyacrylamide

Example 288 (2E)-3-(5-{[(3R)-l-(2-chlorobenzyl)-3-pyrrolidinyl]amino}-2- pyrazinyl)-N-hydroxyacrylamide

Example 289 (2E)-3-(5-{[(3R)-1-(3-chlorobenzyl)-3-pyrrolidinyl]amino}-2- pyrazinyl)-N-hydroxyacrylamide

Example 290 A solution of acetic acid (3.2μL) in acetonitrile (29.2μL) was added to the mixture of (2E)-N-hydroxy-3-(5-{[ (3R)-l-(2- phenylethyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylamide (20mg) in THF (O.lmL) and acetonitrile (O.lmL) and the mixture was stirred at ambient temperature for 5 minutes. To the mixture was added AcOEt (1.5mL) and isolated precipitate was collected by filtration to give (2E)-N-hydroxy-3-(5-{[(3R)-l-(2-phenylethyl)-3- pyrrolidinyl]amino}-2-pyrazinyl)aerylamide acetate (18mg). lH-NMR(DMSO-d6):d 1.59-1.70(1H, m), 1.91(3H, s), 2.15-2.27(1H, m) , 2.43-2.53(2H, m) , 2.60-2.66(2H, m) , 2.70-2.77(3H, m) , 2.79-2.85(1H, m), 4.26-4.36(1H, m) , 6.58(1H, d, J=15.2 Hz), 7.15-7.31(5H, m) , 7.37(1H, d, J=15.2 Hz), 7.73(1H, d, J=6.6 Hz), 7.98(1H, s), 8.1O(1H, s), 1O.71(1H, br-s)

The following compounds can be obtained in a similar manner to that of Example 290.

Example 291 (2E)-3-(6-{[(3R)-l-benzyl-3-pyrrolidinyl]amino}-3-pyridinyl) -N- hydroxyacrylamide acetate

Example 292 (2E)-3-(6-{[(3R)-I-(I-benzofuran-2-ylmethyl)-3-pyrrolidinyl] amino}- 3-pyridinyl)-N-hydroxyacrylamide acetate

Example 293 (2E)-3-(6-{[(3R)-1-(l-benzofuran-5-ylmethyl)-3-pyrrolidinyl] amino}- 3-pyridinyl)-N-hydroxyacrylamide acetate

Example 294 (2E)-3-(6-{[(3R)-1-(3,4-dimethylbenzyl)-3-pyrrolidinyl]amino }-3- pyridinyl)-N-hydroxyacrylamide acetate .

Example 295 (2E)-3^(6-{[ (3R)-1-(2,3-dimethylbenzyl)-3-pyrrolidinyl]amino}-3- pyridinyl)-N-hydroxyacrylamide acetate

Example 296 (2E)-3-(4-{[(3R)-1-(cyclohexylcarbonyl)-3- pyrrolidinyl]amino}phenyl)-N-hydroxyacrylamide acetate

Example 297 (2E)-3-(6-{[ (3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-3- pyridinyl)-N-hydroxyacrylamide acetate

Example 298 tert-butyl (3R)-3-({3-chloro-5-[ (lE)-3-(hydroxyamino)-3-oxo-l- propen-l-yl]-2-pyridinyl}amino)-l-pyrrolidinecarboxylate acetate

Example 299 (2E)-3-(5-{[(3R)-l-benzyl-3-pyrrolidinyl]amino}-2-pyrazinyl) -N- hydroxyacrylamide acetate

Example 300 cyclopentyl (3R)-3-({3-chloro-5-[ (IE)-3-(hydroxyamino)-3-oxo-l- propen-1-yl]-2-pyridinyl}amino)-1-pyrrolidinecarboxylate acetate

Example 301 (2E)-N-hydroxy-3-(5-{[ (3R)-1-(4-methylbenzyl)-3- pyrrolidinyl]amino}-2-pyrazinyl)acrylamide acetate

Example 302 (2E)-3-(5-{[(3R)-1-(4-chlorobenzyl)-3-pyrrolidinyl]amino}-2- pyrazinyl)-N-hydroxyacrylamide acetate

Example 303 (2E)-3-(5~{[(3R)-1-(2-chlorobenzyl)-3-pyrrolidinyl]amino}-2- pyrazinyl)-N-hydroxyacrylamide acetate

Example 304 (2E)-3-(5-{[(3R)-1-(3-chlorobenzyl)-3-pyrrolidinyl]amino}-2- pyrazinyl)-N-hydroxyacrylamide acetate