Patent Application
20090054464
The present invention relates to a compound useful as a medicament, and to a pharmaceutical composition comprising the same.
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 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, 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
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.;
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, 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
R1 is H, halo or a straight chain C1-C6 alkyl;
R2 is selected from H, C1-C10 alkyl, C4-C9 cycloalkyl, C4-C9 heterocycloalkyl, C4-C9 heterocycloalkylalkyl, cycloalkylalkyl, aryl, heteroaryl, etc.;
R3 and R4 are the same or different and independently H, C1-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, C1-C6 alkyl, etc.;
n, n1, n2 and n3 are the same or different and independently selected from 0-6, when n1 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, C1-C4 alkyl, etc.;
or a pharmaceutically acceptable salt thereof.
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
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.
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,
R1a 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 formyl(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 [I-2], for example, according to the following processes or methods disclosed in the Examples.
wherein R1, R2, R3, X, Y, P and Z are as defined above.
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., [(1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-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 “higher 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 cycloalkyl 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-C16 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(C1-C6)alkyl such as benzyl, phenethyl, phenylpropyl, phenylbutyl, phenylhexyl, etc., naphthyl(C1-C6)alkyl such as naphthylmethyl, naphthylethyl, naphthylpropyl, naphthylbutyl, naphthylpentyl, naphthylhexyl, etc.
Suitable “ar(lower)alkoxy” may include phenyl(C1-C6)alkoxy such as benzyloxy, phenethyloxy, phenylpropoxy, phenylbutoxy, phenylhexyloxy, etc., naphthyl(C1-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., C6-10 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, naphthylmethacryloyl, 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, methoxycarbamoyl and the like)] and the like; arylcarbamoyl [e.g., C6-10 arylcarbamoyl (e.g., phenylcarbamoyl, naphthylcarbamoyl and the like) and the like];
arylthiocarbamoyl [e.g., C6-10 arylthiocarbamoyl (e.g., phenylthiocarbamoyl, naphthylthiocarbarnoyl 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., C6-10 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-C16 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-C16 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—(C1-C6 alkyl)amino (e.g., N-methylamino, N-ethylamino, N-propylamino, N-(n-butyl)amino, N-isobutylamino, N-(t-butyl)amino, etc.), N—(C1-C6 alkanoyl)amino (e.g., N-acetylamino, N-ethylcarbonylamino, N-propylcarbonylamino, N-(n-butylcarbonyl)amino, N-isobutylcarbonylamino, N-(t-butylcarbonyl)amino, etc.), N—(C1-C6) alkylsulfonylamino(e.g., N-methanesulfonylamino, N-methanesulfonylamino, N-buthylsulfonylamino, etc.), N—(C3-C6 cycloalkyl)amino (e.g., N-cyclopropylamino, N-cyclobutylamino, N-cyclopentylamino, N-cyclohexylamino, etc.), N,N-di(C1-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, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g. 1H-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, dihydrodithionyl, 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, dihydrooxathiinyl, 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-C6)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.)];
cycloalkyloxycarbonyl(lower)alkyl ester which may have lower alkyl (e.g., cyclopentyloxycarbonyloxymethyl ester, cyclohexyloxycarbonyloxymethyl ester, cycloheptylcycarbonyloxymethyl ester, 1-methylcyclohexyloxycarbonyloxymethyl ester, 1-(or 2-)[cyclopentyloxycarbonyloxy]ethyl ester, 1-(or 2-)[cyclohexyloxycarbonyloxy]ethyl ester, 1-(or 2-)-[cycloheptyloxycarbonyloxy]ethyl ester, etc.), etc.]; (5-(lower)alkyl-2-oxo-1,3-dioxol-4-yl)(lower)alkyl ester [e.g., (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester, (5-ethyl-2-oxo-1,3-dioxol-4-yl)methyl ester, (5-propyl-2-oxo-1,3-dioxol-4-yl)methyl ester, 1-(or 2-)(5-methyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, 1-(or 2-)(5-ethyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, 1-(or 2-)(5-propyl-2-oxo-1,3-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-1,3-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-1,3-dioxol-4-yl)methyl ester, (1-cyclohexyloxycarbonyloxy)ethyl ester and pivaloyloxymethyl ester, and the like, in which the preferred one may be (C1-C4)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 phenyl(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)alkyl” may included hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, and the like.
Suitable “formyl(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, naphthylisobutanoyl, 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 (1-ethyl-3-(3′-dimethylaminopropyl)-carbodiimide); WSCD.HCl or EDCI (1-ethyl-3-(3′-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).
In order to show the usefulness of the compound (I) of the invention, the pharmacological test result of the representative compound of the present invention is shown in the following.
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.
The human histone deacetylase was partially purified from human T cell leukemia Jurkat cells. Jurkat cells (5×108 cells) were suspended in 40 mL of the HDA buffer consisting of 15 mM potassium phosphate, pH 7.5, 5% glycerol and 0.2 mM EDTA. After homogenization, nuclei were collected by centrifugation (35,000×g, 10 min) and homogenized in 20 mL of the same buffer supplemented with 1 M (NH4)2SO4. The viscous homogenate was sonicated and clarified by centrifugation (35,000×g, 10 min), and the deacetylase was precipitated by raising the concentration of (NH4)2SO4 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 (25×85 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.
To obtain [3H] acetyl-labeled histone as the substrate for the histone deacetylase assay, 1×108 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 mL of ice-cooled washing buffer (10 mM Tris-HCl, 13 mM EDTA, pH 7.4) successively. The pellet was suspended in 6 mL 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 −20° C., the coagulated material was collected by microcentrifugation, air-dried, and stored at −80° C.
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 μmL 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 1.5×105 splenic cells of Lewis rats in 0.1 mL RPMI-1640 medium supplemented with 10% fetal bovine serum (FBS), 50 mM 2-mercaptoethanol, penicillin (100 units/mL) and streptomycin (100 μg/mL), to which Concanavalin A (1 μl/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 IC50.
The results of those tests are shown in the Table 1.
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, etch];
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. migraine, 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, Sjögren'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 multiform, 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.
A mixture of methyl 6-chloronicotinate (5.0 g), 1-benzyl-3-aminopyrrolidine (6.16 g) and K2CO3 (4.83 g) in DMF (20 ml) was stirred at 100 W 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-[(1-benzylpyrrolidin-3-yl)amino]nicotinate (4.17 g)
NMR (DMSO-d6, δ): 1.58-1.71 (1H, m), 2.17-2.34 (1H, m), 2.37-2.89 (4H, m), 3.51 (2H, s), 3.65 (2H, s), 4.39 (1H, m), 6.42 (1H, d, J=8.80 Hz), 7.19-7.33 (5H, m), 7.59 (1H, d, J=6.78 Hz), 7.80 (1H, dd, J=2.20 Hz and 8.80 Hz), 8.56 (1H, d, J=2.20 Hz)
The following compounds were obtained according to a similar manner to that of Preparation 1.
NMR (DMSO-d6, δ): 173-1.76 ((1H, m), 2.23-2.44 (2H, m), 2.48-2.67 (2H, m), 2.81-2.85 (1H, m), 2.85 (3H, s), 3.53, 3.63 (2H, ABq, J=13.02 Hz), 3.66 (3H, s), 5.34-5.39 (1H, m), 6.66 (1H, d, J=90.6 Hz), 7.20-7.34 (5H, m), 7.92 (1H, dd, J=2.06 Hz, 9.06 Hz), 8.63 (1H, d, J=2.06 Hz)
NMR (CDCl3, δ): 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)+
NMR (DMSO-d6, δ): 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), 8.60 (1H, d, J=2.0 Hz)
Mass (APCI): 445(M+Na)+
NMR (DMSO-d6, δ): 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)+
Lithium aluminium hydride (256 mg) was added to absolution of methyl 6-[(1-benzyl-3-pyrrolidinyl)amino]nicotinate (1.4 g) in THF (50 ml) 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 (0.26 ml), 15% NaOH solution (0.26 ml) and water (0.72 ml) 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 (0.96 g)
NMR (DMSO-d6, δ): 1.58-1.65 (1H, m), 2.06-2.52 (3H, m), 2.59-2.81 (2H, m), 3.42 (2H, s), 4.18-4.37 (1H, m), 4.26 (2H, d, J=5.28 Hz), 4.87 (1H, t, J=5.28 Hz), 6.43 (1H, d, J=8.54 Hz), 6.53 (1H, d, J=6.80 Hz), 7.18-7.36 (6H, m), 7.85 (1H, d, J=2.10 Hz)
The following compounds were obtained according to a similar manner to that of Preparation 6.
NMR (DMSO-d6, δ): 1.67-1.73 (1H, m), 2.07-2.11 (1H, m), 2.24-2.33 (1H, m), 2.43-2.58 (2H, m), 2.76-2.83 (1H, m), 2.90 (3H, s), 3.52, 3.63 (2H, ABq, J=13.08 Hz), 4.32 (2H, d, J=4.78 Hz), 4.94 (1H, t, J=4.78 Hz), 5.18-5.29 (1H, m), 6.58 (1H, d, J=8.74 Hz), 7.21-7.47 (5H, m), 7.44 (1H, dd, J=2.22 Hz, 8.74 Hz), 7.98 (1H, d, J=2.22 Hz)
NMR (DMSO-d6, δ): 1.59-1.65 (1H, m), 2.09-2.51 (3H, m), 2.59-2.63 (1H, m), 2.73-2.81 (1H, m), 3.53, 3.59 (2H, ABq, J=12.98 Hz), 4.23 (2H, d, J=5.34 Hz), 4.18-4.28 (1H, m), 4.88 (1H, t, J=5.34 Hz), 6.44 (1H, d, J=8.52 Hz), 6.53 (1H, d, J=6.84 Hz), 7.16-7.36 (6H, m), 7.85 (1H, d, J=2.10 Hz)
NMR (DMSO-d6, δ): 1.59-1.66 (1H, m), 2.16-2.55 (3H, m), 2.56-2.60 (1H, m), 2.63-2.81 (1H, m), 3.44-3.63 (2H, m), 4.19-4.35 (3H, m), 4.89 (1H, brs), 6.44 (1H, d, J=8.50 Hz), 6.54 (1H, d, J=6.82 Hz), 7.18-7.34 (6H, m), 7.87 (1H, d, J=2.04 Hz)
NMR 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), 4.40 (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)+
Mass (APCI): 343(M+H)+
NMR (DMSO-d6, δ): 1.41 (9H, s), 1.54-1.63 (4H, m), 2.78 (3H, s), 2.75-2.99 (2H, m), 4.01-4.20 (2H, m), 4.32 (2H, d, J=5.3 Hz), 4.50-4.80 (1H, m), 4.90-4.96 (1H, m), 6.61 (1H, d, J=8.8 Hz), 7.46 (1H, dd, J=2.0, 8.8 Hz), 8.00 (1H, d, J=2.0 Hz)
Mass (APCI): 344(M+Na)+
A mixture of {6-[(1-benzyl-3-pyrrolidinyl)amino]-3-pyridyl}methanol (0.96 g) and MnO2 (2.951 g) in AcOEt (50 ml) was refluxed under stirring for 1.5 hour. After removal of the insoluble material, and the solvent was evaporated in vacuo to give 6-[(1-benzyl-3-pyrrolidinyl)amino]nicotinaldehyde (0.759)
NMR (DMSO-d6, δ): 1.66-1.72 (1H, m), 2.06-2.52 (3H, m), 2.62-2.82 (2H, m), 3.60 (2H, s), 4.39-4.45 (1H, m), 6.58 (1H, d, J=8.80 Hz), 7.16-7.32 (5H, m), 7.73 (1H, dd, J=2.18 Hz, 8.80 Hz), 7.93 (1H, d, J=5.52 Hz), 8.47 (1H, d, J=2.18 Hz), 9.66 (1H, s)
The following compounds were obtained according to a similar manner to that of Preparation 13.
NMR (DMSO-d6, δ): 1.66-1.99 (1H, m), 2.23-2.38 (1H, m), 2.41-2.52 (2H, m), 2.61-2.82 (2H, m), 3.52 (2H, s), 4.39-4.45 (1H, m), 6.58 (1H, d, J=8.84 Hz), 7.16-7.33 (5H, m), 7.73 (1H, dd, J=2.20 Hz, 8.84 Hz), 7.90 (1H, d, J=6.64 Hz), 8.47 (1H, d, J=2.20 Hz), 9.66 (1H, s)
NMR (DMSO-d6, δ): 1.66-2.00 (1H, m), 2.21-2.26 (1H, m), 2.38-2.52 (2H, m), 2.61-2.82 (2H, m), 3.52 (2H, s), 4.45 (1H, m), 6.58 (1H, d, J=8.88 Hz), 7.16-7.33 (5H, m), 7.73 (1H, dd, J=2.18 Hz, 8.88 Hz), 7.90 (1H, d, J=6.72 Hz), 8.47 (1H, d, J=2.18 Hz), 9.66 (1H, s)
NMR (DMSO-d6, δ): 1.86-1.96 (1H, m), 2.00-2.26 (1H, m), 2.43-2.61 (3H, m), 2.61-2.68 (1H, m), 3.60 (2H, s), 4.60-4.67 (1H, m), 7.19-7.37 (5H, m), 7.91 (1H, d, J=1.88 Hz), 8.52 (1H, d, J=1.88 Hz), 9.72 (1H, s)
NMR (DMSO-d6, δ): 1.78-1.99 (1H, m), 2.18-2.30 (1H, m), 2.42-2.68 (3H, m), 2.82-2.90 (1H, m), 3.60 (2H, s), 4.59-4.64 (1H, m), 7.19-7.37 (6H, m), 7.91 (1H, d, J=1.96 Hz), 8.52 (1H, d, J=1.96 HZ), 9-72 (1H, s)
NMR (DMSO-d6, δ): 1.65-1.78 (1H, m), 2.20-2.31 (2H, m), 2.45-2.54 (2H, m), 2.63-2.70 (1H, m), 2.82-2.89 (1H, m), 3.07 (3H, s), 3.55, 3.64 (2H, ABq, J=13.04 Hz), 5.40-5.42 (1H, m), 6.76 (1H, d, J=9.10 Hz), 7.23-7.35) 5H, m), 7.76 (1H, dd, J=2.24 Hz, 9.10 Hz), 8.56 (1H, d, J=2.24 Hz), 9.74 (1H, s)
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)+
NMR (DMSO-d6, δ): 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)+
NMR (DMSO-d6, 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)+
Mass (ESI): 334(M+H)+
NMR (DMSO-d6, 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)+
Mass (ESI): 346(M+H)+
A solution of diethylphosphonoacetic acid ethyl ester (896 mg) in THF (10 ml) was added dropwise to a mixture of 60% sodium hydride in oil (170 mg) in THF (20 mL) 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-[(1-benzyl-3-pyrrolidinyl)amino]nicotinaldehyde (0.75 g) in THP (10 ml) 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-[(1-benzyl-3-pyrrolidinyl)amino]-3-pyridyl}acrylate (0.83 g).
NMR (DMSO-d6, δ): 1.24 (3H, t, J=7.06 Hz), 1.50-1.73 (1H, m), 2.36-2.52 (3H, m), 2.73-2.77 (2H, m), 3.57 (2H, s), 4.14 (2H, q, J=7.06 Hz), 4.30 (1H, m), 6.31 (1H, d, J=15.80 Hz), 6.52 (1H, d, J=8.86 Hz), 7.18-7.36 (5H, m), 7.49 (1H, d, J=15.80 Hz), 7.77 (1H, dd, J=2.10 Hz, 8.86 Hz), 8.20 (1H, d, J=2.10 Hz)
The following compounds were obtained according to a similar manner to that of Preparation 25.
NMR (DMSO-d6, δ): 1.24 (3H, t, J=7.06 Hz), 1.56-1.82 (1H, m), 2.27-2.61 (4H, m), 2.83-2.84 (1H, m), 3.00 (3H, s), 3.58 and 3.63 (2H, ABq, J=13.02 Hz), 5.25-5.39 (1H, m), 6.38 (1H, d, J=15.94 Hz), 6.67 (1H, d, J=9.06 Hz), 7.19-7.34 (5H, m), 7.53 (1H, d, J=15.94 Hz), 7.90 (1H, dd, J=2.26 Hz, 9.06 Hz), 8.30 (1H, d, J=2.26 Hz)
NMR (DMSO-d6, δ): 125 (3H, t, J=7.06 Hz), 1.56-1.78 (1H, m), 2.10-2.20 (1H, m), 2.34-2.52 (2H, m), 2.52-2.78 (2H, m), 3.57 (2H, s), 4.15 (2H, q, J=7.06 Hz), 4.36 (1H, m), 6.41 (1H, d, J=15.92 Hz), 6.52 (1H, d, J=8.82 Hz), 7.18-7.37 (6H, m), 7.50 (1H, d, J=15.92 Hz), 7.78 (1H, dd, J=2.10 Hz, 8.82 Hz), 8.20 (1H, d, J=2.10 Hz)
NMR (DMSO-d6, δ): 1.24 (3H, t, J=7.06 Hz), 1.56-1.73 (1H, m), 2.21-2.37 (1H, m), 2.39-2.52 (2H, m), 2.73-2.78 (2H, m), 3.57 (2H, s), 4.15 (2H, q, J=7.06 Hz), 4.36 (1H, m), 6.31 (1H, d, J=15.90 Hz), 6.52 (1H, d, J=8.86 Hz), 7.18-7.36 (5H, m), 7.50 (1H, d, J=15.90 Hz), 7.77 (1H, dd, J=2.14 Hz, 8.86 Hz), 8.20 (1H, d, J=2.14 Hz)
NMR (DMSO-d6, δ): 1.24 (3H, t, J=7.06 Hz), 1.84-1.97 (1H, m), 2.00-2.30 (1H, m), 2.39-2.53 (2H, m), 2.62-2.78 (1H, m), 2.79-2.87 (1H, m), 3.59 (2H, s), 4.16 (2H, q, J=7.06 Hz), 4.49-4.56 (1H, m), 6.49 (1H, d, J=15.96 Hz), 6.73 (1H, d, J=6.90 Hz), 7.19-7.32 (5H, m), 7.51 (1H, d, J=15.96 Hz), 8.10 (1H, d, J=1.88 Hz), 8.26 (1H, d, J=1.88 Hz)
NMR (DMSO-d6, δ): 1.24 (3H, t, J=7.06 Hz), 1.84-1.99 (1H, m), 2.16-2.30 (1H, m), 2.39-2.46 (2H, m), 2.62-2.66 (1H, m), 2.79-2.88 (1H, m), 3.58 (2H, s), 4.16 (2H, q, J=7.06 Hz), 4.49-4.56 (1H, m), 6.49 (1H, D, J=15.98 Hz), 6.72 (1H, d, J=6.92 Hz), 7.18-7.36 (5H, m), 7.51 (1H, d, J=15.98 Hz), 8.10 (1H, d, J=1.96 Hz), 8.26 (1H, d, J=1.96 Hz)
NMR (DMSO-d6, δ): 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 (1H, 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)+
Mass (ESI): 410(M+H)+
Mass (ESI): 390(M+H)+
Mass (ESI): 404(M+H)+
NMR (DMSO-d6, δ): 1.24 (3H, t, J=7.4 Hz), 1.70-1.95 (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), 7.50 (1H, d, J=16.0 Hz), 8.10 (1H, d, J=2.0 Hz), 8.26 (1H, d, J=2.0 Hz)
Mass (APCI): 400(M+H)+
NMR (DMSO-d6, δ): 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), 4.90 (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)
A mixture of ethyl (2E)-3-{6-[(1-benzyl-3-pyrrolidinyl)amino]-3-pyridyl}-acrylate (830 mg) and 1N NaOH solution (4.7 ml) in MeOH (20 ml) was stirred at 70-75° C. for 2 hours. The reaction mixture was evaporated in vacuo, and the residue was dissolved with saturated NaCl solution (20 ml). 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 (700 mg)
NMR (DMSO-d6, δ): 1.92-2.01 (1H, m), 2.30-2.43 (1H, m), 2.94-3.52 (4H, m), 4.29 (2H, s), 4.53-4.56 (1H, m), 6.28 (1H, d, J=15.82 Hz), 6.62 (1H, d, J=8.78 Hz), 7.39-7.64 (6H, m), 7.75-7.83 (2H, m), 8.20 (1H, d, J=2.00 Hz), 11.92 (1H, m)
The following compounds were obtained according to a similar manner to that of Preparation 37.
NMR (DMSO-d6, δ): 2.08-2.16 (1H, m), 2.80-3.60 (5H, m), 4.23 (2H, brs), 5.54-5.61 (1H, m), 6.35 (1H, d, J=15.92 Hz), 6.72 (1H, d, J=9.02 Hz), 7.39-7.62 (6H, m), 7.92 (1H, dd, J=2.04 Hz, 9.06 Hz), 8.32 (1H, d, J=2.04 Hz)
NMR (DMSO-d6, δ): 1.87-1.93 (1H, m), 2.28-2.38 (1H, m), 2.83-3.37 (4H, m), 4.15 (2H, s), 0.29 (1H, d, J=15.92 Hz), 6.62 (1H, d, J=8.88 Hz), 7.32-7.43 (3H, m), 7.51-7.58 (2H, m), 7.77-7.81 (2H, m), 8.20 (1H, d, J=1.94 Hz)
NMR (DMSO-d6, δ): 1.98-2.04 (1H, m), 2.31-2.38 (1H, m), 2.95-3.56 (4H, m), 4.35 (2H, s), 4.55-4.58 (1H, m), 6.29 (1H, d, J=15.86 Hz), 6.63 (1H, d, J=8.82 Hz), 7.40-7.67 (6H, m), 8.10 (1H, dd, J=2.08 Hz, 8.82 Hz), 7.92 (1H, brs), 8.20 (1H, d, J=2.08 Hz)
NMR (DMSO-d6, δ): 1.76-1.99 (1H, m), 2.19-2.24 (1H, m), 2.48-2.77 (3H, m), 2.91-2.96 (1H, m), 3.60 (2H, s), 4.49-4.56 (1H, m), 6.39 (1H, d, J=15.88 Hz), 6.74 (1H, d, J=6.88 Hz), 7.21-7.35 (5H, m), 7.45 (1H, d, J=15.88 Hz), 8.07 (1H, d, J=1.82 Hz), 8.24 (1H, d, J=1.82 Hz)
NMR (DMSO-d6, δ): 1.89-1.99 (1H, m), 2.19-2.27 (1H, m), 2.58-3.07 (4H, m), 3.74 (2H, s), 4.44-4.59 (1H, m), 6.40 (1H, d, J=15.96 Hz), 6.82 (1H, d, J=6.88 Hz), 7.25-7.40 (5H, m), 7.46 (1H, d, J=15.96 Hz), 8.08 (1H, d, J=1.82 Hz), 8.24 (1H, d, J=1.82 Hz)
NMR (DMSO-d6, δ): 1.60-1.95 (1H, m), 2.10-2.40 (1H, m), 2.50-4.00 (6H, m), 3.74 (3H, s), 4.30-4.60 (1H, m), 6.24 (1H, d, J=6 Hz), 6.54 (1H, d, J=8.8 Hz), 6.92 (2H, d, J=8.5 Hz), 7.30-7.60 (4H, m), 7.78 (1H, dd, J=2.1 Hz, J=8.8 Hz), 8.18 (1H, d, J=2.1 Hz), 11.80 (1H, br)
MASS(API-ES); 354 (M+H)+
NMR (DMSO-d6, δ): 1.50-1.80 (1H, m), 2.05-2.90 (5H, m), 3.50-3.70 (2H, m), 4.20-4.50 (1H, m), 6.22 (1H, d, J=16 Hz), 6.53 (1H, d, J=8.8 Hz), 7.05-7.18 (2H, m), 7.30-7.40 (3H, m), 7.43 (1H, d, J=6 Hz), 7.74 (1H, dd, J=2.1 and 8.8 Hz), 8.15 (1H, d, J=2.1 Hz)
MASS(API-ES, Nega); 340 (M−H)+
NMR (DMSO-d6, δ): 1.60-1.85 (1H, m), 2.10-3.00 (5H, m), 3.10-3.90 (2H, m), 4.25-4.50 (1H, m), 6.23 (1H, d, J=16 Hz), 6.53 (1H, d, J=8.8 Hz), 7.30-7.55 (6H, m), 7.75 (1H, dd, J=2.1 Hz, J=8.8 Hz), 8.17 (1H, d, J=2.1 Hz)
MASS(API-ES); 358 (M+H)+360
NMR (DMSO-d6, δ): 1.60-1.90 (1H, m), 2.10-3.15 (5H, m), 2.28 (3H, s), 3.50-3.95 (2H, m), 4.25-4.50 (1H, m), 6.24 (1H, d, J=16 Hz), 6.54 (1H, d, J=8.8 Hz), 7.15 (2H, d, J=7.8 Hz), 7.29 (2H, d, J=7.8 Hz), 7.44 (1H, d, J=16 Hz), 7.48 (1H, m), 7.76 (1H, dd, J=2.1 Hz, J=8.8 Hz), 8.17 (1H, d, J=2.1 Hz)
MASS(API-ES); 338 (M+H)+
NMR (DMSO-d6, δ): 0.05-0.25 (2H, m), 0.40-0.60 (2H, m), 0.80-1.05 (1H, m), 1.60-1.85 (1H, m), 2.10-3.90 (7H, m), 4.25-4.55 (1H, m), 6.24 (1H, d, J=16 Hz), 6.55 (1H, d, J=8.8 Hz), 7.44 (1H, d, J=16 Hz), 7.47 (1H, d, J=6.1 Hz), 7.77 (1H, dd, J=2.1 Hz, J=8.8 Hz), 8.19 (1H, d, J=2.1 Hz)
MASS(API-ES); 288 (M+H)+
NMR (DMSO-d6, δ): 1.90-2.40 (2H, m), 3.20-4.00 (4H, m), 4.40-4.80 (1H, m), 6.30-6.50 (1H, m), 6.95-7.10 (1H, m), 7.35-7.60 (6H, m), 8.05-8.15 (1H, m), 8.20-8.35 (1H, m), 12.26 (1H, br)
MASS(API-ES); 372 (M+H)+, 374
NMR (DMSO-d6, δ): 0.60-0.80 (4H, m), 1.60-1.85 (1H, m), 1.87-2.40 (2H, m), 3.20-4.10 (4H, m), 4.45-4.80 (1H, m), 6.42 (1H, d, J=16 Hz), 6.90-7.05 (1H, m), 7.48 (1H, d, J=16 Hz), 8.07-8.14 (1H, m), 8.25-8.32 (1H, m), 12.21 (1H, br)
MASS(API-ES, Nega); 334 (M−H)—
NMR (DMSO-d6, δ): 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), 7.10-7.30 (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)+
NMR (DMSO-d6, 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)+
NMR (DMSO-d6, δ): 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), 6.50 (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)+
NMR (DMSO-d6, δ): 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)+
NMR (DMSO-d6, δ): 1.35-1.60 (2H, m), 1.85-2.10 (2H, m), 3.10-3.40 (2H, m), 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 (1H, dd, a=2.0, 8.8 Hz), 8.20 (1H, d, J=2.0 Hz), 12.13 (1H, brs)
NMR (DMSO-d6, δ): 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), 8.20d(1H, d, J=2.0 Hz), 8.69 (1H, s), 12.09 (1H, brs).
Mass (APCI): 399(M−H)—
NMR (DMSO-d6, δ): 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), 8.20 (1H, d, J=2.0 Hz), 8.43 (1H, s), 12.04 (1H, brs)
Mass (APCI): 403(M+Na)+
NMR (DMSO-d6, 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), 8.20 (1H, d, J=2.0 Hz), 8.36 (1H, s), 12.04 (1H, brs)
Mass (APCI): 419(M+Na)+
NMR (DMSO-d6, 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), 6.70 (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)+
NMR (DMSO-d6, 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), 6.70 (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)+
NMR (DMSO-d6, 5): 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)—
NMR (DMSO-d6, 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), 10.98 (1H, brs), 12.21 (1H, brs)
A mixture of (2E)-3-{6-[(1-benzyl-3-pyrrolidinyl)amino]-3-pyridyl}acrylic acid (400 mg), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (159 mg), HOBt (175 mg) and EDCI (202 mg) in DMF (10 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 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-[(1-benzyl-3-pyrrolidinyl)amino]-3-pyridyl}-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (170 mg)
NMR (DMSO-d6, δ): 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 (1H, m), 4.32-4.33 (1H, m), 4.87 (1H, s), 6.20 (1H, d, J=15.20 Hz), 6.53 (1H, d, J=8.82 Hz), 7.20-7.37 (7H, m), 7.58 (1H, d, J=7.90 Hz), 8.11 (1H d, J=1.84 Hz), 11.03 (1H, brs)
The following compounds were obtained according to a similar manner to that of Preparation 62.
NMR (DMSO-d6, δ): 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 (1H, m), 4.89 (1H, s), 5.29-5.33 (1H, m), 6.28 (1H, d, J=15.44 Hz), 6.69 (1H, d, J=9.02 Hz), 7.19-7.42 (6H, m), 7.71 (1H, d, J=9.02 Hz), 8.24 (1H, s), 11.05 (1H, s)
NMR (DMSO-d6, δ): 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 (1H, m), 4.30 (1H, m), 8.47 (1H, brs), 6.30 (1H, d, J=15.90 Hz), 6.52 (1H, d, J=8.80 Hz), 7.20-7.37 (7H, m), 7.58 (1H, d, J=8.80 Hz), 8.11 (11, s), 11.03 (1H, s)
NMR (DMSO-d6, δ): 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 (1H, m), 4.31 (1H, m), 4.87 (1H, s), 6.20 (1H, d, J=16.10 Hz), 6.52 (1H, d, J=8.84 Hz), 7.20-7.37 (7H, m), 7.58 (1H, d, J=7.76 Hz), 8.11 (1H, d, J=1.92 Hz), 11.03 (1H, s)
NMR (DMSO-d6, δ): 1.53-2.00 (7H, m), 2.00-2.30 (1H, m), 2.30-2.78 (3H, m), 2.82-2.89 (1H, m), 3.59 (2H, s), 3.36-3.59 (2H, m), 3.96-4.01 (1H, m), 4.41-4.55 (1H, m), 4.89 (1H, s), 6.32 (1H, d, J=15.68 Hz), 6.42 (1H, d, J=6.88 Hz), 7.19-7.40 (6H, m), 7.84 (1H, s), 8.20 (1H, s), 11.08 (1H, brs)
NMR (DMSO-d6, δ): 1.53-2.00 (7H, m), 2.10-2.32 (1H, m), 2.39-2.53 (2H, m), 2.63-2.67 (1H, m), 2.74-2.89 (1H, m), 3.56 (2H, s), 3.50-3.59 (2H, m), 3.96-4.05 (1H, m), 4.48-4.53 (1H, m), 4.90 (1H, s), 6.33 (1H, d, J=15.74 Hz), 6.94 (1H, d, J=6.88 Hz), 7.19-7.33 (6H, m), 7.85 (1H, s), 7.99 (1H, s), 8.20 (1H, s), 11.09 (1H, brs)
NMR (DMSO-d6, δ): 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 (1H, m), 4.20-4.45 (1H, m), 4.87 (1H, s), 6.20 (1H, d, J=16 Hz), 6.51 (1H, d, J=8.8 Hz), 6.86 (2H, d, J=8.5 Hz), 7.21 (2H, d, J=8.5 Hz), 7.20-7.30 (1H, m), 7.33 (1H, d, J=16 Hz), 7.58 (1H, dd, J=1.9 Hz, J=8.8 Hz), 8.11 (1H, d, J=1.9 Hz), 11.03 (1H, br)
MASS(API-ES); 453 (M+H)+
NMR (DMSO-d6, δ): 1.45-1.80 (7H, m), 2.05-3.00 (5H, m), 3.20-3.65 (3H, m), 3.80-4.05 (1H, m), 4.20-4.45 (1H, m), 4.87 (1H, s), 6.20 (1H, d, J=16 Hz), 6.51 (1H, d, J=8.8 Hz), 7.05-7.40 (6H, m), 7.59 (1H, dd, J=1.8 Hz, J=8.8 Hz), 8.12 (1H, d, J=1.8 Hz), 11.05 (1H, br)
MASS(API-ES); 441 (M+H)+
NMR (DMSO-d6, δ): 1.40-1.80 (7H, m), 2.05-2.90 (5H, m), 3.40-3.65 (3H, m), 3.80-4.05 (1H, m), 4.20-4.50 (1H, m), 4.87 (1H, s), 6.20 (1H, d, J=16 Hz), 6.52 (1H, d, J=8.8 Hz), 7.22 (1H, d, J=6.6 Hz), 7.27-7.45 (5H, m), 7.59 (1H, dd, J=1.9 Hz, J=8.8 Hz), 8.12 (1H, d, J=1.9 Hz), 11.04 (1H, br)
MASS(API-ES); 457 (M+H)+459
NMR (DMSO-d6, δ): 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 (1H, m), 4.20-4.45 (1H, m), 4.87 (1H, s), 6.20 (1H, d, J=16 Hz), 6.51 (1H, d, J=8.8 Hz), 7.05-7.25 (5H, m), 7.33 (1H, d, J=16 Hz), 7.58 (1H, dd, J=1.9 and 8.8 Hz), 8.11 (1H, d, J=1.9 Hz), 11.03 (1H, br)
MASS(API-ES); 437 (M+H)+
NMR (DMSO-d6, δ): 0.00-0.15 (2H, m), 0.35-0.50 (2H, m), 0.70-0.95 (1H, m), 1.40-1.85 (7H, m), 2.08-2.53 (5H, m), 2.55-2.82 (2H, m), 3.40-3.60 (1H, m), 3.80-4.10 (1H, m), 4.20-4.50 (1H, m), 4.87 (1H, s), 6.21 (1H, d, J=16 Hz), 6.52 (1H, d, J=8.8 Hz), 7.23 (1H, d, J=6.8 Hz), 7.34 (1H, d, J=16 Hz), 7.59 (1H, dd, J=1.9 and 8.8 Hz), 8.14 (1H, d, J=1.9 Hz), 11.04 (1H, br)
MASS(API-ES); 387 (M+H)+
NMR (DMSO-d6, δ): 1.40-1.80 (6H, m), 1.90-2.40 (2H, m), 3.10-4.10 (6H, m), 4.40-4.85 (1H, m), 4.89 (1H, s), 6.20-6.50 (1H, m), 6.90-7.05 (1H, m), 7.25-7.60 (6H, m), 7.80-7.95 (1H, m), 8.15-8.30 (1H, m), 11.10 (1H, br)
MASS(API-ES); 471 (M+H)+, 473
NMR (DMSO-d6, 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 (1H, m), 4.89 (1H, s), 6.35 (1H, d, J=16 Hz), 6.85-7.00 (1H, m), 7.38 (1H, d, J=16 Hz), 7.88 (1H, s), 8.25 (1H, s), 11.09 (1H, br)
MASS(API-ES); 435 (M+H)+, 437
Mass (APCI): 599(M+Na)+
NMR (DMSO-d6, δ): 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), 6.30 (1H, d, J=16.0 Hz), 6.51 (1H, d, J=7.0 Hz), 7.29-7.46 (5H, m), 7.83 (1H, s), 8.20 (1H, s), 11.08 (1H, brs)
NMR (DMSO-d6, δ): 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), 6.80 (1H, brs), 7.10-60(4H, m), 7.36 (1H, d, J=16.0 Hz), 7.86 (1H, s), 8.20 (1H, s), 11.09 (1H, s),
A mixture of methyl 6-chloronicotinate (8.0 g), (3R)-(−)-1-benzyl-3-aminopyrrolidine (9.86 g), CuO (371 mg) and K2CO3 (8.38 g) in DMF (60 ml) 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-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}nicotinate (9.9 g).
NMR (DMSO-d6, δ): 1.60-1.67 (1.H, m), 2.19-2.36 (1H, m), 2.38-2.89 (2H, m), 2.62-2.81 (2H, m), 3.56 (2H, s), 3.58 (3H, s), 4.38 (1H, m), 6.51 (1H, d, J=8.84 Hz), 7.18-7.33 (5H, m), 7.58 (1H, d, J=6.78 Hz), 8.00 (1H, dd, J=2.22 Hz, 8.84 Hz), 8.55 (1H, d, J=2.22 Hz)
The following compounds were obtained according to a similar manner to that of Preparation 78.
NMR (DMSO-d6, δ): 1.58-1.68 (1H, m), 2.17-2.24 (1H, m), 2.37-2.44 (2H, m), 2.62-2.82 (2H, m), 3.51 (2H, s), 3.76 (3H, s), 4.39 (1H, m), 6.53 (1H, d, J=8.96 Hz), 7.19-7.33 (5H, m), 7.59 (1H, d, J=6.80 Hz), 7.81 (1H, dd, J=2.20 Hz, 8.96 Hz), 8.56 (1H, d, J=2.20 Hz)
A mixture of ethyl 5,6-dichloronicotinate (10.0 g), (3R)-(−)-1-benzyl-3-aminopyrrolidine (9.61 g), K2CO3 (8.38 g) and CuO (371 mg) in DMF (60 ml) 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-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-chloronicotinate (15.95 g)
NMR (DMSO-d6, δ): 1.29 (3H, t, J=7.08 Hz), 1.87-2.01 (1H, m), 2.17-2.21 (1H, m), 2.41-2.53 (2H, m), 2.67-2.87 (2H, m), 3.59 (2H, s), 4.25 (2H, q, J=7.08 Hz), 4.54-4.59 (1H, m), 7.02 (1H, d, J=6.98 Hz), 7.19-7.33 (5H, m), 7.92 (1H, d, J=1.96 Hz), 8.53 (1H, d, J=1.96 Hz)
The following compounds were obtained according to a similar manner to that of Preparation 80.
NMR (DMSO-d6, δ): 1.28 (3H, t, J=7.08 Hz), 1.87-1.96 (1H, m), 2.00-2.16 (2H, m), 2.40-2.67 (3H, m), 2.80-2.87 (1H, m), 3.59 (2H, s), 4.25 (2H, q, J=7.08 Hz), 4.54-4.58 (1H, m), 7.03 (1H, d, J=6.98 Hz), 7.19-7.33 (5H, m), 7.92 (1H, d, J=1.96 Hz), 8.53 (1H, d, J=1.96 Hz)
A diisobutylaluminum hydride in toluene solution (15.7 ml) was dropwise added to a solution of ethyl 6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-chloronicotinate (4.7 g) in toluene (50 ml) with stirring at −30˜−50° C. under atmospheric pressure of nitrogen, and the reaction mixture was stirred at −20˜−40° C. for 2 hours. A MeOH (5 ml) was added to a reaction mixture at −40° C. and saturated sodium potassium tartrate aqueous solution (10 ml) and MgSO4 (10 g) 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 silicagel eluting with AcOEt-MeOH (9:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to give (6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-chloro-3-pyridyl)methanol (1.87 g).
NMR (DMSO-d6, δ): 1.77-1.99 (1H, m), 2.16-2.35 (1H, 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 (1H, m), 5.10 (1H, m), 6.00 (1H, d, J=6.98 Hz), 7.18-7.32 (5H, m), 7.53 (1H, d, J=1.90 Hz), 7.91 (1H, d, J=1.90 Hz)
The following compounds were obtained according to a similar manner to that of Preparation 82.
NMR (DMSO-d6, δ): 1.76-1.99 (1H, m), 2.08-2.33 (1H, m), 2.34-2.52 (2H, m), 2.62-2.76 (1H, m), 2.80-2.84 (1H, m), 3.57 (2H, s), 4.32 (2H, d, J=4.76 Hz), 4.41-4.45 (1H, m), 5.06 (1H, t, J=4.76 Hz), 6.03 (1H, d, J=6.96 Hz), 7.18-7.36 (5H, m), 7.53 (1H, d, J=1.94 Hz), 7.90 (1H, d, J=1.94 Hz)
NMR (DMSO-d6, δ): 1.70-1.89 (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 (1H, d, J=2.0 Hz).
Mass (APCI): 336(M+H)+
NMR (DMSO-d6, 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), 7.90 (1H, d, J=2.0 Hz)
Mass (APCI): 332(M+H)+
Mass (ESI): 348(M+H)+
A mixture of methyl 6-chloronicotinate (5.14 g), 1-benzyl-4-aminopiperidine (6.84 g) and K2CO3 (5.38 g) in DMF (30 ml) 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 MgSO4. 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 (4.77 g)
NMR (DMSO-d6, δ): 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 (1H, m), 6.48 (1H, d, J=8.80 Hz), 7.19-7.36 (6H, m), 7.79 (1H, dd, J=2.28 Hz, 8.80 Hz), 8.55 (1H, d, J=2.28 Hz)
Lithium aluminium hydride (304 mg) was added to a solution of methyl 6-[(1-benzyl-4-piperidyl)amino]nicotinate (1.3 g) in THF (20 ml) 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 (0.3 ml), 15% NaOH solution (0.3 ml) and water (0.9 ml) 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-[(1-benzyl-4-piperidyl)amino]-3-pyridyl}methanol (670 mg)
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 (1H, m), 3.41 (2H, s), 4.22 (2H, d, J=5.44 Hz), 4.87 (1H, t, J=5.44 Hz), 6.28 (1H, d, J=8.52 Hz), 6.42 (1H, d, J=8.52 Hz), 7.19-7.36 (6H, m), 7.85 (1H, s)
The following compound(s) were obtained according to a similar manner to that of Preparation 88.
NMR (DMSO-d6, δ): 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 (1H, m), 4.26 (2H, d, J=5.26 Hz), 4.86 (1H, d, J=5.26 Hz), 6.28 (1H, d, J=7.60 Hz), 6.42 (1H, d, J=8.50 Hz), 7.27-7.40 (5H, m), 7.85 (1H, d, J=2.08 Hz)
NMR (DMSO-d6, 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=5.52 Hz), 4.88 (1H, t, J=5.52 Hz), 6.37 (2H, m), 6.88-6.96 (1H, m), 7.18-7.36 (3H, m), 7.45 (1H, dd, J=2.02 Hz, 8.38 Hz), 7.88 (1H, d, J=2.02 Hz), 8.50 (1H, s)
A mixture of methyl 6-[(1-benzyl-4-piperidyl)amino]nicotinate (4.2 g) in MeOH (50 ml) was hydrogenated over 10% palladium-carbon (1.5 g) 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 (1.77 g).
NMR (DMSO-d6, δ): 1.18-1.41 (2H, m), 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 (1H, m), 6.49 (1H, d, J=8.84 Hz), 7.28-7.39 (2H, m), 7.78 (1H, dd, J=2.26 Hz, 8.84 Hz), 8.55 (1H, d, J=2.26 Hz)
A mixture of {6-[(1-benzyl-4-piperidyl)amino]-3-pyridyl}methanol (670 mg) and MnO2 (2.94 g) in AcOEt (30 ml) was refluxed under stirring for 2 hours. After removal of the insoluble material, and the solvent was evaporated in vacuo to give 6-[(1-benzyl-4-piperidyl)amino]nicotinaldehyde (560 mg)
NMR (DMSO-d6, δ): 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 (1H, m), 6.55 (1H, d, J=8.90 Hz), 7.29-7.37 (5H, m), 7.65-7.74 (2H, m), 8.47 (1H, d, J=1.4 Hz), 9.65 (1H, s)
The following compounds were obtained according to a similar manner to that of Preparation 92.
NMR (DMSO-d6, δ): 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 (1H, m), 6.51 (1H, d, J=8.06 Hz), 7.30-7.41 (3H, m), 7.92-7.96 (2H, m), 8.47 (1H, d, J=2.06 Hz), 9.65 (1H, s)
NMR (DMSO-d6, δ): 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 (1H, d, J=8.86 Hz), 6.89-6.96 (1H, 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 (1H, s)
A solution of diethylphosphonoacetic acid ethyl ester (850 mg) in THF (10 ml) was added dropwise to a mixture of 60% sodium hydride in oil (167 mg) in THF (15 mL) 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 (450 mg). NMR (DMSO-d6, δ): 1.23 (3H, t, J=7.06 Hz), 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 (1H, m), 4.15 (2H, q, J=7.06 Hz), 6.30 (1H, d, J=15.90 Hz), 6.49 (1H, d, J=8.86 Hz), 7.11 (1H, d=7.52 Hz), 7.19-7.37 (5H, m), 7.49 (1H, d, J=15.90 Hz), 7.76 (1H, dd, J=2.10 Hz, 8.86 Hz), 8.20 (1H, d, J=2.10 Hz)
The following compounds were obtained according to a similar manner to that of Preparation 95.
A solution of diethylphosphonoacetic acid ethyl ester (274 mg) in THF (10 ml) was added dropwise to a mixture of 60% sodium hydride in oil (55 mg) in THF (10 mL) 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-{[1-(4-chlorobenzoyl)-4-piperidyl]amino}nicotinaldehyde (210 mg) in THF (10 ml) 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-{[1-(4-chlorobenzoyl)-4-piperidyl]amino}-3-pyridyl)acrylate (190 mg)
NMR (DMSO-d6, δ): 1.23 (3H, t, J=7.06 Hz), 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 (1H, m), 4.14 (2H, q, J=7.06 Hz), 6.30 (1H, d, J=15.86 Hz), 6.48 (1H, d, J=8.88 Hz), 7.11 (1H, d, J=7.48 Hz), 7.30-7.41 (4H, m), 7.49 (1H, d, J=15.86 Hz), 7.76 (1H, dd, J=2.04 Hz, 8.88 Hz), 8.19 (1H, d, J=2.04 Hz)
The following compounds were obtained according to a similar manner to that of Preparation 96.
NMR (DMSO-d6, δ): 1.23 (3H, t, J=7.06 Hz), 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 (1H, d, J=15.90 Hz), 6.51 (1H, d, J=8.80 Hz), 6.88-6.96 (1H, m), 7.17-7.26 (2H, m), 7.44-7.55 (3H, m), 8.23 (1H, d, J=2.08 Hz), 8.53 (1H, s)
A mixture of ethyl (2E)-3-{6-[(1-benzyl-4-piperidyl)amino]-3-pyridyl}acrylate (470 mg) and 1N NaOH solution (2.6 ml) in MeOH (15 ml) 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-[(1-benzyl-4-piperidyl)amino]-3-pyridyl}acrylic acid (430 mg).
NMR (DMSO-d6, δ): 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 (1H, m), 6.27 (1H, d, J=15.85 Hz), 6.70 (1H, m), 7.39-7.47 (4H, m), 7.67-7.79 (4H, m), 8.51 (1H, s)
A mixture of methyl 6-(4-piperidylamino)nicotinate (1.0 g), 4-chlorobenzoic acid (699 mg), HOBt (603 mg) and EDCI (693 mg) in DMF (20 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 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-{[1-(4-chlorobenzoyl)-4-piperidyl]amino}nicotinate (1.21 g)
NMR (DMSO-d6, δ): 1.42 (2H, m), 1.92-1.99 (2H, m), 2.94-3.34 (4H, m), 3.76 (3H, s), 4.09-4.13 (1H, m), 6.52 (1H, d, J=8.84 Hz), 7.40-7.54 (5H, m), 7.81 (1H, dd, J=2.26 Hz, 8.84 Hz), 8.56 (1H, d, J=2.26 Hz)
A mixture of (2E)-3-{6-[(1-benzyl-4-piperidyl)amino]-3-pyridyl}acrylic acid (430 mg), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (157 mg), HOBt (181 mg) and EDCI (208 mg) in DMF (20 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 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-[(1-benzyl-4-piperidyl)amino]-3-pyridyl}-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (180 mg).
NMR (DMSO-d6, δ): 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 (1H, m), 4.87 (1H, s), 6.20 (1H, d, J=14.96 Hz), 6.50 (1H, d, J=8.82 Hz), 7.00 (1H, d, J=7.54 Hz), 7.21-7.37 (6H, m), 7.58 (1H, d, J=8.82 Hz), 8.12 (1H, s), 11.02 (1H, s)
The following compounds were obtained according to a similar manner to that of Preparation 100.
NMR (DMSO-d6, δ): 1.29-1.68 (8H, m), 1.90-1.99 (2H, m), 2.89-3.04 (2H, m), 3.56-3.60 (1H, m), 3.95-4.10 (4H, m), 4.88 (1H, s), 6.22 (1H, d, J=15.18 Hz), 6.52 (1H, d, J=8.78 Hz), 6.86-6.96 (1H, m), 7.18-7.48 (5H, m), 7.59-8.15 (1H, m), 8.16 (1H, s), 8.51 (1H, s), 11.03 (1H, s)
NMR (DMSO-d6, δ): 1.36-1.83 (10H, m), 1.90-2.12 (4H, m), 2.52-2.73 (2H, m), 3.54 (1H, m), 3.93 (1H, m), 4.87 (1H, brs), 6.12-6.22) 1H, m), 6.49 (1H, d, J=8.82 Hz), 6.95-7.00 (1H, m), 7.30-7.41 (4H, m), 7.53-7.62 (1H, m), 8.12 (1H, s), 11.00 (1H, s)
A mixture of methyl 6-(4-piperidylamino)nicotinate (0.73 g) and phenyl isocyanate (388 mg) in THF (30 ml) was stirred at ambient temperature for 12 hours. IPE (30 ml) was added to a reaction mixture and the precipitate was collected by filtration to give methyl 6-{[1-(anilinocarbonyl)-4-piperidyl]amino}nicotinate (0.72 g)
NMR (DMSO-d6, δ): 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 (1H, d, J=8.88 Hz), 6.88-6.96 (2H, m), 7.12-7.26 (2H, m), 7.40-7.49 (3H, m), 7.81 (1H, dd, J=8.88 Hz), 8.53 (1H, s), 8.57 (1H, d, J=2.26 Hz)
A mixture of ethyl (2E)-3-(6-{[1-(4-chlorobenzoyl)-4-piperidyl]amino}-3-pyridyl)acrylate (190 mg) and 1N NaOH solution (1.0 ml) in MeOH (20 ml) 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-{[1-(4-chlorobenzoyl)-4-piperidyl]amino}-3-pyridyl)acrylic acid (85 mg)
NMR (DMSO-d6, δ): 1.36-2.23 (6H, m), 2.92-3.03 (2H, m), 4.17 (1H, m), 6.24 (1H, d, J=15.88 Hz), 6.54 (1H, d, J=7.94 Hz), 7.34-7.60 (4H, m), 7.76 (1H, dd, J=1.82 Hz, 7.94 Hz), 8.18 (1H, d, J=1.82 Hz), 12.02 (1H, m)
The following compounds were obtained according to a similar manner to that of Preparation 104.
NMR (DMSO-d6, δ): 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 (1H, d, J=15.92 Hz), 6.51 (1H, d, J=8.80 Hz), 6.88-6.96 (1H, m), 7.13-7.26 (3H, m), 7.41-7.49 (3H, m), 7.76 (1H, dd, J=2.08 Hz, 8.80 Hz), 8.19 (1H, d, J=2.08 Hz), 8.52 (1H, s), 12.05 (1H, s)
NMR (DMSO-d6, δ): 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), 8.20 (1H, d, J=2.0 Hz)
To a solution of ethyl (2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-3-pyridyl)acrylate (4.74 g) and 4-(Dimethylamino)pyridine(41.2 mg) in tetrahydrofuran (70 ml) was added di-tert-butyldicarbonate (5.89 g) at 20° 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 (70 g) 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)-1-benzyl-3-pyrrolidinyl](tert-butoxycarbonyl)amino]-3-pyridyl}acrylate (5.49 g) was obtained as colorless oil.
NMR (DMSO-d6, δ): 1.27 (3H, t, J=6.8 Hz), 1.41 (9H, s), 1.80-2.20 (2H, m), 2.40-2.80 (4H, m), 3.44, 3.55 (2H, ABq, J=13 Hz), 4.21 (2H, q, J=6.8 Hz), 4.60-4.90 (1H, m), 6.78 (1H, d, J=16 Hz), 7.00-7.30 (5H, m), 7.34 (1H, d, J=8.5 Hz), 7.71 (1H, d, J=16 Hz), 8.20 (1H, dd, J=2.4 Hz, J=8.5 Hz), 8.73 (1H, d, J=2.4 Hz),
MASS(API-ES); 452 (M+H)+.
To a solution of ethyl (2E)-3-{6-[[(3R)-1-benzyl-3-pyrrolidinyl](tert-butoxycarbonyl)amino]-3-pyridyl}acrylate (5.45 g) in toluene (55 ml) was added 1-chloroethyl chloroformate (2.59 g) at room temperature and stirred at 20° C. for 1 hour. 1-Chloroethyl chloroformate (795 mg) and N,N-diisopropylethylamine (0.736 ml) 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 (70 ml). The mixture was stirred at 65° C. for 30 minutes, 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 125 g, dichloromethane/MeOH (60/1 to 15/1) to give ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate as oil (2.0 g).
NMR (DMSO-d6, δ): 1.26 (3H, t, J=7.1 Hz), 1.31-1.40 (9H, m), 1.60-2.10 (2H, m), 2.30-3.20 (4H, m), 4.20 (2H, q, J=7.1 Hz), 4.50-4.80 (1H, m), 6.76 (1H, d, J=16 Hz), 7.36 (1H, d, J=8.5 Hz), 7.68 (1H, d, J=16 Hz), 8.19 (1H, dd, J=2.4 Hz, J=8.5 Hz), 8.72 (1H, d, J=2.4 Hz
MASS(API-ES); 362 (M+H)+
To a mixture of ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate (350 mg) and 4-methoxybenzaldehyde (145 mg) in dichloromethane (5 ml) was added sodium triacetoxyborohydride (410 mg) 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 (11 g) 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)-1-(4-methoxybenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate (362 mg) was obtained as colorless syrup.
NMR (DMSO-d6, δ): 1.27 (3H, t, J=7.1 Hz), 1.35 (9H, s), 1.80-2.20 (2H, m), 2.30-2.90 (4H, m), 3.36, 3.48 (2H, ABq, J=13 Hz), 3.71 (3H, s), 4.21 (H, q, J=7.1 Hz), 4.60-4.85 (1H, m), 6.78 (1H, d, J=16 Hz), 6.81 (2H, d, J=8.6 Hz, 7.06 (2H, d, J=8.6 Hz), 7.33 (1H, d, J=8.4 Hz), 7.71 (1H, d, J=16 Hz), 8.20 (1H, dd, J=2.4 Hz, J=8.4 Hz), 8.72 (1H, d, J=2.4 Hz)
MASS(API-ES); 482 (M+H)+
The following compounds were obtained according to a similar manner to that of Preparation 109.
NMR (DMSO-d6, δ): 1.27 (3H, t, J=7.1 Hz), 1.36 (9H, s), 1.80-2.20 (2H, m), 2.25-2.90 (4H, m), 3.42, 3.54 (2H, ABq, J=13 Hz), 4.21 (2H, q, J=7.1 Hz), 4.60-4.90 (1H, m), 6.78 (1H, d, J=16 Hz), 7.00-7.25 (4H, m), 7.34 (1H, d, J=8.4 Hz), 7.71 (1H, d, J=16 Hz), 8.20 (1H, dd, J=2.4 Hz, J=8.4 Hz), 8.73 (1H, d, J=2.4 Hz)
MASS(API-ES); 470 (M+H)+
NMR (DMSO-d6, δ): 1.27 (3H, t, J=7.1 Hz), 1.35 (9H, s), 1.85-2.25 (2H, m), 2.30-2.90 (4H, m), 3.42, 3.55 (2H, ABq, J=13 Hz), 4.22 (2H, q, J=7.1 Hz), 4.60-4.90 (1H, m), 6.78 (1H, d, J=16 Hz), 7.17 (2H, d, J=8.4 Hz), 7.31 (2H, d, J=8.4 Hz), 7.34 (1H, d, J=8.5 Hz), 7.71 (1H, d, J=16 Hz), 8.20 (1H, dd, J=2.3 and 8.5 Hz), 8.73 (1H, d, J=2.3 Hz)
MASS(API-ES); 486 (M+H)+488
NMR (DMSO-d6, δ): 1.27 (3H, t, J=7.1 Hz, 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=13 Hz), 4.21 (2H, q, J=7.1 Hz), 4.60-4.85 (1H, m), 6.77 (1H, d, J=16 Hz), 6.95-7.10 (4H, m), 7.33 (1H, d, J=8.4 Hz), 7.70 (1H, d, J=16 Hz), 8.19 (1H, dd, J=2.4 Hz, J=8.4 Hz), 8.71 (1H, d, J=2.4 Hz)
MASS(API-ES); 466 (M+H)+
To an ice-cooled solution of ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(4-methoxybenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate (360 mg) in dichloromethane (2 ml) was added anisole (11.0 ml) and TFA (2.0 ml), the mixture was stirred at 20° C. for 1 hour. The mixed solution was poured into a mixture of water (20 ml) 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 to give ethyl (2E)-3-(6-{[(3R)-1-(4-methoxybenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate as syrup (295 mg).
NMR (DMSO-d6, δ): 1.24 (3H, t, J=7.1 Hz), 1.60-2.00 (1H, m), 2.10-3.65 (7H, m), 3.74 (3H, s), 4.15 (2H, q, J=7.1 Hz), 4.25-4.55 (1H, m), 6.35 (1H, d, J=16 Hz), 6.53 (1H, d, J=8.8 Hz), 6.93 (2H, d, J=8.5 Hz), 7.25-7.43 (3H, m), 7.51 (1H, d, J=16 Hz), 7.82 (1H, dd, J=2.0 and 8.8 Hz), 8.22 (1H, d, J=2.0 Hz)
MASS(API-ES); 382 (M+H)+
The following compounds were obtained according to a similar manner to that of Preparation 113.
NMR (DMSO-d6, δ): 1.23 (3H, t, J=7.1 Hz), 1.50-1.80 (1H, m), 2.10-2.90 (5H, m), 3.58 (2H, br), 4.14 (2H, q, J=7.1 Hz), 4.20-4.50 (1H, m), 6.31 (1H, d, J=16 Hz), 6.51 (1H, d, J=8.8 Hz), 7.05-7.40 (5H, m), 7.49 (1H, d, J=16 Hz), 7.78 (1H, dd, J=2.1 and 8.8 Hz), 8.20 (1H, d, J=2.1 Hz)
MASS(API-ES); 370 (M+H)+
NMR (DMSO-d6, δ): 1.23 (3H, t, J=7.1 Hz), 1.50-1.85 (1H, m), 2.10-3.00 (5H, m), 3.20-3.90 (2H, m), 4.14 (2H, q, J=7.1 Hz), 4.20-4.50 (1H, m), 6.32 (1H, d, J=16 Hz), 6.51 (1H, d, J=8.8 Hz), 7.30-7.45 (5H, m), 7.49 (1H, d, J=16 Hz), 7.79 (1H, dd, J=2.1 Hz, J=8.8 Hz), 8.20 (1H, d, J=2.1 Hz)
MASS(API-ES); 386 (M+H)+388
NMR (DMSO-d6, δ): 1.23 (3H, t, J=7.1 Hz), 1.55-1.85 (1H, m), 2.10-3.10 (5H, m), 2.29 (3H, s), 3.20-4.00 (2H, m), 4.14 (2H, q, J=7.1 Hz), 4.25-4.50 (1H, m), 6.33 (1H, d, J=16 Hz), 6.52 (1H, d, J=8.8 Hz), 7.10-7.30 (4H, m), 7.40 (1H, d, J=6.5 Hz), 7.50 (1H, d, J=16 Hz), 7.80 (1H, dd, J=2.1 and 8.8 Hz), 8.21 (1H, d, J=2.1 Hz)
MASS(API-ES); 366 (M+H)+
NMR (DMSO-d6, δ): 0.00-0.20 (2H, m), 0.40-0.60 (2H, m), 0.75-1.00 (1H, m), 1.24 (3H, t, J=7.1 Hz), 1.55-1.80 (1H, m), 2.10-3.60 (7H, m), 4.15 (2H, g, J=7.1 Hz), 4.25-4.50 (1H, m), 6.33 (1H, d, J=16 Hz), 6.53 (1H, d, J=8.8 Hz), 7.39 (1H, d, J=6.5 Hz), 7.51 (1H, d, J=16 Hz), 7.80 (1H, dd, J=2.2 Hz, J=8.8 Hz), 8.23 (1H, d, J=2.2 Hz)
MASS(API-ES); 316 (M+H)+
To a solution of ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate (310 mg) and cyclopropylmethyl bromide (116 mg) in acetonitrile (7 ml) was added potassium hydrogencarbonate (85.9 mg) and potassium iodide (28.5 mg) 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 (20 ml) 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 (8 g) 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 (170 mg) was obtained as colorless syrup.
NMR (DMSO-d6, δ): 0.00-0.10 (2H, m), 0.30-0.50 (2H, m), 0.65-0.90 (1H, m), 1.27 (3H, t, J=7.1 Hz), 1.39 (9H, s), 1.80-3.40 (8H, m), 4.21 (2H, q, J=7.1 Hz), 4.60-4.90 (1H, m), 6.76 (1H, d, J=16 Hz), 7.37 (1H, d, J=8.5 Hz), 7.69 (1H, d, J=16 Hz), 8.20 (1H, dd, J=2.3 and 8.5 Hz), 8.73 (1H, d, J=2.3 Hz)
MASS(API-ES); 416 (M+H)+
To a stirred suspension of ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(4-tert-butylbenzyl)-3-pyrrolidinyl]amino)}-3-pyridyl)acrylate (430 mg) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL) and the resulting mixture was stirred at ambient temperature for 2 hours. The mixture was concentrated in vacuo. The residue was dissolved in ethanol (5 mL) and to this solution was added 1N sodium hydroxide aqueous solution (5.1 mL) 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(5 mL) and to the resulting solution was added 0-(tetrahydro-2H-pyran-2-yl)-hydroxylamine 129 mg), 1-hydroxybenzotriazole (149 mg) and EDCI hydrochloride (211 mg). 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 (5 mL) and water (5 mL). The precipitate was filtered, washed with water and dried to afford (2E)-3-(6-{[(3R)-1-(4-tert-butylbenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (280 mg) as a pale tan solid.
NMR (DMSO-d6, δ): 1.26 (9H, s), 1.42-1.78 (6H, m), 2.07-2.82 (6H, m), 3.28-3.41 (1H, m), 3.49 (1H, d, J=13.9. Hz), 3.55 (1H, d, J=13.9 Hz), 3.84-4.01 (1H, m), 4.24-4.39 (1H, m), 4.85 (1H, brs), 6.20 (1H, br.d, J=16.5 Hz), 6.50 (1H, d, J=8.6 Hz), 7.14-7.29 (1H, m), 7.22 (2H, d, J=8.4 Hz), 7.32 (2H, d, J=8.4 Hz), 7.57 (1H, br.d, J=8.6 Hz), 8.09 (1H, brs)
NMR (DMSO-d6, δ): 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 (1H, m), 3.48-3.59 (1H, m), 3.54 (1H, d, J=13.6 Hz), 3.65 (1H, d, J=13.6 Hz), 3.88-4.04 (1H, m), 4.68-4.83 (1H, m), 4.92 (1H, brs), 6.60 (1H, d, J=16.1 Hz), 7.35 (1H, d, J=8.1 Hz), 7.39 (2H, d, J=8.4 Hz), 7.55 (1H, d, J=16.1 Hz), 7.63 (2H, d, J=8.4 Hz), 8.02 (1H, br.d, J=8.1 Hz), 8.63 (1H, brs)
MS (ES+) m/z 591.28(M+1).
NMR (DMSO-d6, δ): 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 (1H, m), 3.43-3.65 (3H, m); 3.90-4.06 (1H, m), 4.66-4.84 (1H, m), 4.92 (1H, brs), 6.59 (1H, d, J=15.8 Hz), 7.25 (2H, d, J=8.8 Hz), 7.29 (2H, d, J=8.8 Hz), 7.34 (1H, d, J=8.1 Hz), 7.55 (1H, d, J=15.8 Hz), 8.02 (1H, brd, J=8.1 Hz), 8.63 (1H, brs)
MS (ES+) m/z 607.29 (M+1)
NMR (DMSO-d6, δ): 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 (1H, m), 3.88-4.04 (1H, m), 4.64-4.84 (1H, m), 4.92 (1H, brs), 6.58 (1H, d, J=16.5 Hz), 7.35 (1H, d, J=8.1 Hz), 7.53 (1H, d, J=16.5 Hz), 8.01 (1H, br.d, J=8.1 Hz), 8.63 (1H, brs)
MS (ES+) m/z 529.44(M+1)
NMR (DMSO-d6, δ): 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 (1H, m), 3.49-3.61 (1H, m), 3.90-4.04 (1H, m), 4.64-4.79 (1H, m), 4.92 (1H, brs), 5.43 (1H, brs), 6.58 (1H, d, J=16.1 Hz), 7.33 (1H, d, J=8.4 Hz), 7.53 (1H, d, J=16.1 Hz), 8.00 (1H, br.d, J=8.4 Hz), 8.63 (1H, brs)
MS (ES+) m/z 527.54(M+1)
The mixture of 1-chloro-3-(triphenylphosphoranylidene)acetone (6.6 g) and ethyl glyoxylate (50% in toluene, 4.6 g) in dioxane (66 mL) was stirred at 80° C. 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 (1.58 g).
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)
The mixture of ethyl (2E)-5-chloro-4-oxo-2-pentenoate (0.5 g) and N-[1-(4-chlorobenzoyl)-3-pyrrolidinyl]thiourea (0.8 g) in acetonitrile (10 mL) was stirred at 70° C. 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-{[1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-1,3-thiazol-4-yl)acrylate (1.0 g).
NMR (DMSO-d6, δ): 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 1H, each d, J=15.3 Hz), 7.16 and 7.21(total 1H, each s), 7.31 and 7.37(total 1H, each d, J=15.3 Hz), 7.44-7.62 (4H, m), 8.07 and 8.11 (total 1H, 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.
NMR (DMSO-d6, δ): 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 (1H, d, J=7.1 Hz)
(+)ESI-MS:372(M+H)+
The mixture of ethyl (2E)-3-(2-{[1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-1,3-thiazol-4-yl)acrylate (0.9 g) and 1N-NaOH (4.4 mL) in MeOH (14 mL) 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 1N-HCl. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo to give (2E)-3-(2-{[1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-1,3-thiazol-4-yl)acrylic acid (0.64 g).
NMR (DMSO-d6, δ): 1.84-2.32 (2 total 1H, m), 3.27-3.71 (3H, m), 3.72-3.88 (1H, m), 4.20-4.40 (1H, m), 6.24 and 6.34(total 1H, each d, J=15.3 Hz), 7.11 and 7.16(total 1H, each s), 7.25 and 7.31(total 1H, 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.
NMR (DMSO-d6, δ): 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)
NMR (DMSO-d6, δ): 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), 7.10 (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)+
EDCI (0.30 g) was added to the solution of (2E)-3-(2-{[1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-1,3-thiazol-4-yl)acrylic acid (0.6 g), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.22 g), and HOBT (0.26 g) in DMF (10 ml) 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-{[1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-1,3-thiazol-4-yl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (0.66 g).
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), 4.20-4.38 (1H, m), 4.85-4.94 (1H, m), 6.39 and 6.47(total 1H, each d, J=15.2 Hz), 7.01 and 7.06(total 1H, each s), 7.16 and 7.21(total 1H, each d, J=15.2 Hz), 7.46-7.61 (4H, m), 7.99-8.08 (1H, m), 11.18 and 11.24(total 1H, 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.
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), 6.40 (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), 11.20 (1H, s)
(+)ESI-MS:443(M+H)+
NMR (DMSO-d6, δ): 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)
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)+
NMR (DMSO-d6, δ): 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 (1H, d, J=7.0 Hz)
(+)ESI-MS:442(M+Na)+
To a solution of ethyl (2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-chloro-3-pyridyl)acrylate (770 mg) in toluene (14 ml) was added 1-chloroethyl chloroformate (713 mg) at 23c and stirred at the same temperature for 1 hour. N,N-Diisopropylethylamine (0.348 ml) 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(15 ml). The mixture was stirred at 65c for 30 minutes, and concentrated under reduced pressure. The residue was dissolved into EtOH(15 ml), and mixed with 2N-hydrogen chloride in EtOH solution (2 ml). The mixture was stirred at 86° C. for 5 hours. After it was concentrated under reduced pressure, the resulting residue was triturated with IPE (15 ml). Ethyl (2E)-3-{5-chloro-6-[(3R)-3-pyrrolidinylamino]-3-pyridyl}acrylate dihydrochloride (1.1 g) was obtained as brown syrup.
NMR (DMSO-d6, δ): 1.29 (3H, t, J=6.9 Hz), 1.90-2.35 (2H, m), 3.00-4.10 (4H, m), 4.17 (2H, q, J=6.9 Hz), 4.30-4.85 (1H, m), 6.55 (1H, d, J=16 Hz), 7.55 (1H, d, J=16 Hz), 8.15-8.20 (1H, m), 8.30-8.40 (1H, m), 9.56 (4H, br)
MASS(API-ES); 296 (M+H)+Free, 298
To an ice-cooled solution of ethyl (2E)-3-{5-chloro-6-[(3R)-3-pyrrolidinylamino]-3-pyridyl}acrylate dihydrochloride (330 mg) and Et3N (0.437 ml) in dichloromethane (8 ml) was added benzoyl chloride (132 mg), the mixture was stirred at 23° C. for 1 hour. The mixed solution was poured into a mixture of water (20 ml) 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 (12 g) 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)acrylate (245 mg) was obtained as colorless syrup.
NMR (DMSO-d6, 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 (1H, m), 6.40-6.60 (1H, m), 7.00-7.15 (1H, m), 7.35-7.65 (6H, m), 8.10-8.20 (1H, m), 8.22-8.40 (1H, m)
MASS(API-ES); 400 (M+H)+
The following compounds were obtained according to a similar manner to that of Preparation 136.
NMR (DMSO-d6, δ): 0.60-0.80 (4H, m), 1.24 (3H, t, J=7.1 Hz), 1.60-1.85 (1H, m), 1.87-2.40 (2H, m), 3.20-4.10 (4H, m), 4.16 (2H, g, J=7.1 Hz), 4.40-4.80 (1H, m), 6.52 (1H, d, J=16 Hz), 6.95-7.10 (1H, m), 7.53 (1H, d, J=16 Hz), 8.10-8.20 (1H, m), 8.30-8.40 (1H, m)
MASS(API-ES); 364 (M+H)+
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 mg) and 1,1′-(bromomethylene)dibenzene (225 mg), 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 acetate=4:1 then chloroform:methanol 20:1) to give ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(diphenylmethyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate (210 mg) as an oil.
NMR (DMSO-d6, δ): 1.36 (3H, t, J=7 Hz), 1.42 (3×3H, s), 2.02-2.30 (2H, m), 2.42-2.61 (2H, m), 2.64 (1H, dd, J=9.5, 7 Hz), 2.78 (1H, dd, J=9.5, 8 Hz), 4.17 (1H, s), 4.29 (2H, q, J=7 Hz), 4.91 (1H, m), 6.49 (1H, d, J=16 Hz), 7.08-7.38 (11H, m), 7.69 (1H, d, J=16 Hz), 7.83 (1H, dd, J=8.5, 2 Hz), 8.57 (1H, d, J=2 Hz)
MS (ES+) m/z 528.
To a stirred solution of ethyl (2E)-3-(6-{(tert-butoxycarbonyl) [(3R)-1-(diphenylmethyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate (205 mg) in methanol (5 mL) was added 1N-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 (DMSO-d6, δ): 1.34 (3×3H, br-s), 1.97-2.74 (6H, m), 4.17 (1H, br), 4.75 (1H, br), 6.70 (1H, br-d, J=16 Hz), 7.12-7.90 (12H, m), 8.23 (1H, m), 8.76 (1H, s)
MS (ES+) m/z 500
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)-1-(diphenylmethyl)-3-pyrrolidinyl](5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridyl)carbamate (100 mg) as a pale yellow oil.
NMR (DMSO-d6, δ): 1.34 (3×3H, s), 1.46-1.76 (6H, m), 1.93-2.21 (2H, m), 2.25-2.64 (4H, m), 3.54 (1H, m), 3.97 (1H, m), 4.17 (1H, s), 4.75 (1H, m), 4.93 (1H, m), 6.64 (1H, d, J=16 Hz), 7.07-7.43 (11H, m), 7.59 (1H, d, J=16 Hz), 8.08 (1H, m), 8.68 (1H, d, J=1.5 Hz), 11.34 (1H, s)
MS (ES+) m/z 599.
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)-1-(4-benzoylbenzyl)-3-pyrrolidinyl](tert-butoxycarbonyl)amino]-3-pyridyl}acrylate (149 mg).
NMR (CDCl3, δ): 1.35 (3H, t, J=7 Hz), 1.45 (9H, 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 (1H, m), 6.46 (1H, d, J=16 Hz), 7.30 (1H, d, J=8 Hz), 7.37 (2H, d, J=8 Hz), 7.45-7.51 (2H, m), 7.56-7.62 (1H, m), 7.66 (1H, d, J=16 Hz), 7.74 (2H, d, J=8 Hz), 7.77-7.83 (3H, m), 8.54 (1H, d, J=2 Hz)
MS (ES+) m/z 556 (M+1)
To a mixture of ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate dihydrochloride (110 mg), 4-(chloromethyl)-2-phenyl-1,3-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)-1-[(2-phenyl-1,3-thiazol-4-yl)methyl]-3-pyrrolidinyl}amino)-3-pyridyl]acrylate (133 mg).
NMR (DMSO-d6, 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 (1H, m), 6.42 (1H, d, J=16 Hz), 7.07 (1H, s), 7.31 (1H, d, J=8 Hz), 7.40-7.45 (3H, m), 7.62 (1H, d, J=16 Hz), 7.78 (1H, dd, J=2, 8 Hz), 7.91-7.95 (2H, m), 8.51 (1H, d, J=2 Hz)
MS (ES+) m/z 535 (M+1)
To a mixture of 2,3-dihydro-1-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)acrylate dihydrochloride (250 mg) and Et3N (0.281 mL). After stirring for 2 hours at 60w, 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)-1-(2,3-dihydro-1-benzofuran-5-ylmethyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate (134 mg).
NMR (CDCl3, δ): 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 (1H, m), 6.46 (1H, d, J=16 Hz), 6.68 (1H, d, J=8 Hz), 6.95 (1H, d, J=8 Hz), 7.08 (1H, s), 7.29 (1H, d, J=8 Hz), 7.66 (1H, d, J=16 Hz), 7.80 (1H, dd, J=2, 8 Hz), 8.53 (1H, d, J=2 Hz)
MS (ES+) m/z 494 (M+1)
To a solution of ethyl (2E)-3-{6-[[(3R)-1-(4-benzoylbenzyl)-3-pyrrolidinyl](tert-butoxycarbonyl)amino]-3-pyridyl}acrylate (111 mg) in dioxane (2 mL) was added 1N sodium hydroxide (0.6 mL). After stirring at 60° C. for 2 hours, the reaction mixture was added H2O(10 mL) and acidified with 1N 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)-1-(4-benzoylbenzyl)-3-pyrrolidinyl](tert-butoxycarbonyl)amino]-3-pyridyl}acrylic acid dihydrochloride (97 mg).
NMR (DMSO-d6, δ): 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 (1H, m), 6.41 (1H, d, J=16 Hz), 7.30 (1H, d, J=8 Hz), 7.47-7.65 (4H, m), 7.78-7.90 (7H, m), 8.42-8.49 (1H, m)
MS (ES+) m/z 528 (M+1)
The following compounds were obtained according to a similar manner to that of Preparation 144.
NMR (CDCl3, δ): 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 (1H, m), 6.38 (1H, d, J=16 Hz), 7.33 (1H, d, J=8 Hz), 7.42-7.48 (3H, m), 7.52 (1H, d, J=16 Hz), 7.78 (1H, dd, J=2 and 8 Hz), 7.89-7.96 (3H, m), 8.42-8.47 (1H, m)
MS (ES+) m/z 507 (M+1)
NMR (DMSO-d6, δ): 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 (1H, m), 6.40 (1H, d, J=16 Hz), 6.79 (1H, d, J=8 Hz), 7.22-7.33 (2H, m), 7.54-7.64 (2H, m), 7.77-7.82 (1H, m), 8.39-8.42 (1H, m)
MS (ES+), m/z 466 (M+1)
NMR (DMSO-d6, 8): 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 (1H, m), 6.36 (1H, d, J=16 Hz), 7.16 (1H, s), 7.29-7.40 (3H, m), 7.47-7.65 (3H, m), 7.77 (1H, dd, J=2, 8 Hz), 8.14-8.35 (1H, m)
MS (ES+) m/z 464 (M+1),
NMR (DMSO-d6, δ): 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 (1H, m), 6.39 (1H, d, J=16 Hz), 6.82 (1H, d, J=2 Hz), 7.30 (1H, d, J=8 Hz), 7.50-7.62 (3H, m), 7.68 (1H, d, J=2 Hz), 7.78 (1H, dd, J=2, 8 Hz), 7.95 (1H, s), 8.30-8.44 (1H, m)
MS (ES+) m/z 464 (M+1)
To a mixture of (2E)-3-{6-[[(3R)-1-(4-benzoylbenzyl)-3-pyrrolidinyl](tert-butoxycarbonyl)amino]-3-pyridyl}acrylic acid dihydrochloride (93 mg), O-tetrahydro-2H-pyran-2-ylhydroxylamine (27 mg.), and 1-hydroxybenzotriazole (31 mg) in N,N-dimethyl for aide (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-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridyl)carbamate (35 mg)
NMR (DMSO-d6, δ): 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 (1H, m), 4.70-4.83 (1H, m), 4.90-4.94 (1H, m), 6.59 (1H, d, J=16 Hz), 7.33-8.05 (12H, m), 8.62-8.65 (1H, m).
MS (ES+) m/z 627 (M+1).
The following compounds were obtained according to a similar manner to that of Preparation 149.
NMR (DMSO-d6, δ): 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 (1H, m), 3.65-3.79 (2H, m), 3.91-4.03 (1H, m), 4.68-4.81 (1H, m), 4.90-4.96 (1H, m), 6.56 (1H, d, J=16 Hz), 7.33-7.55 (6H, m), 7.87-8.02 (3H, m), 8.58-8.62 (1H, m).
MS (ES+) m/z 606 (M+1).
NMR (DMSO-d6, δ): 1.35 (9H, s), 1.49-1.75 (6H, m), 1.93-2.1.2 (2H, m), 3.11 (2H, t, J=9 Hz), 3.28-3.58 (7H, m), 3.92-4.02 (1H, m), 4.48 (2H, t, J=9 Hz), 4.67-4.79 (1H, m), 4.90-4.94 (1H, m), 6.55-7.02 (4H, m), 7.32-7.60 (2H, m), 7.99-8.05 (1H, m), 8.61-8.63 (1H, m)
MS (ES+) m/z 565 (M+1)
NMR (DMSO-d6, δ): 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 (1H, m), 3.65-3.78 (2H, m), 3.90-4.03 (1H, m), 4.67-4.80 (1H, m), 4.89-4.96 (1H, m), 6.56 (1H, d, J=16 Hz), 6.66 (1H, s), 7.17-7.29 (2H, m), 7.34 (1H, d, J=8 Hz), 7.47-7.59 (3H, m), 7.95-8.01 (1H, m), 8.55-8.59 (1H, m)
MS (ES+) m/z 563 (M+1)
NMR (DMSO-d6, δ): 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 (1H, m), 4.67-4.80 (1H, m), 4.91-4.97 (1H, m), 6.60 (1H, d, J=16 Hz), 6.88 (1H, d, J=2 Hz), 7.10 (1H, d, J=8 Hz), 7.33 (1H, d, J=8 Hz), 7.42 (1H, s), 7.46 (1H, d, J=8 Hz), 7.55 (1H, d, J=16 Hz), 7.95 (1H, d, J=2 Hz), 8.01 (1H, d, J=8 Hz), 8.62 (1H, s)
MS (ES+) m/z 563 (M+1)
To a solution of tert-butyl 4-({5-[(1E)-3-ethoxy-3-oxo-1-propen-1-yl]-2-pyridyl}amino)-1-piperidinecarboxylate (2.8 g) in EtOH (20 ml) was added 4N HCl in dioxane (18.6 ml), 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]acrylate dihydrochloride.
NMR (DMSO-d6, δ): 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.
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), 8.30 (1H, d, J=2.0 Hz)
Mass (APCI): 310(M+H)+
NMR (DMSO-d6, δ): 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), 4.60-4.85 (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)+
To an ice-cooled solution of ethyl (2E)-3-[6-(4-piperidylamino)-3-pyridyl]acrylate dihydrochloride (309 mg) and Et3N (0.448 ml) in DMF (8 ml) was added benzoyl chloride (124 mg), the mixture was stirred at 23r for 1 hour. The mixed solution was poured into water (20 ml). The precipitate was collected, washed with water, dried under reduced pressure to give ethyl (2E)-3-{6-[(1-benzoyl-4-piperidyl)amino]-3-pyridyl}acrylate.
NMR (DMSO-d6, δ): 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.
NMR (DMSO-d6, 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)+
NMR (DMSO-d6, δ): 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), 8.18-7.56-7.63 (2H, m), 8.18 (1H, d, J=2.0 Hz)
Mass (APCI): 394(M+H)+
NMR (DMSO-d6, δ): 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)+
NMR (DMSO-d6, δ): 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)+
NMR (DMSO-d6, δ): 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)+
NMR (DMSO-d6, δ): 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), 8.30 (1H, d, J=2.0 Hz)
Mass (ESI): 448(M+H)+
NMR (DMSO-d6, δ): 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), 6.40 (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)+
To a suspension of (2E)-3-{6-[(1-benzoyl-4-piperidyl)amino]-3-pyridyl}acrylic acid (170 mg) in DMF (3 ml) was added O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (62.3 mg), EDCI HCl (102 mg), HOBt (71.9 mg), Et3N(0.201 ml), the mixture was stirred at 23° C. for 8 hours. The mixed solution was poured into a mixture of water (20 ml) and AcOEt (20 ml). 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-[(1-benzoyl-4-piperidyl)amino]-3-pyridyl}-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (50 mg).
NMR (DMSO-d6, δ): 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), 7.60 (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.
NMR (DMSO-d6, 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), 6.20 (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)+
NMR (DMSO-d6, δ): 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), 6.20 (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), 7.60 (1H, d, J=8.8 Hz), 8.14 (1H, s)
Mass (APCI): 465(M+H)+
NMR (DMSO-d6, δ): 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), 3.50-3.55 (1H, m), 3.95-4.20 (2H, m), 4.87 (1H, s), 6.20 (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), 7.60 (1H, d, J=8.8 Hz), 8.1 (1H, s), 11.04 (1H, s)
Mass (APCI): 503(M+Na)+
NMR (DMSO-d6, 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), 7.10 (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 (1H, s)
NMR (DMSO-d6, δ): 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)+
NMR (DMSO-d6, δ): 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), 3.50-3.55 (1H, m), 3.95-4.07 (4H, m), 4.89 (1H, s), 6.20 (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), 7.60 (1H, d, J=8.8 Hz), 8.15 (1H, s), 8.42 (1H, s), 11.05 (1H, s)
Mass (APCI): 502(M+Na)+
NMR (DMSO-d6, δ): 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), 6.20 (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)+
NMR (DMSO-d6, δ): 1.56-2.00 (11H, m), 2.60-3.30 (2H, m), 3.40-3.70 (211, 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)+
NMR (DMSO-d6, δ): 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)+
To a suspension of ethyl (2E)-3-[6-(4-piperidylamino)-3-pyridyl]acrylate dihydrochloride (500 mg) in DMF (5 ml) was added 4-(1H-pyrrol-1-yl)benzoic acid (309 mg), EDCI HCl (317 mg), HOBt (223 mg), Et3N(0.63 ml), the mixture was stirred at 23° C. for 8 hours. The mixed solution was poured into a mixture of water (20 ml) and AcOEt (20 ml). 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-(1H-pyrrol-1-yl)benzoyl]-4-piperidyl}amino)-3-pyridyl]acrylate (686 mg).
NMR (DMSO-d6, δ): 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), 7.20 (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.
NMR (DMSO-d6, δ): 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)+
To an ice-cooled solution of ethyl (2E)-3-[6-(4-piperidylamino)-3-pyridyl]acrylate dihydrochloride (309 mg) and Et3N (0.448 ml) In DMF (3 ml) was added 1-chloro-4-isocyanatobenzene (136 mg), the mixture was stirred at 23° C. for 1 hour. The mixed solution was poured into water (20 ml). The precipitate was collected, washed with hexane and water, dried under reduced pressure to give ethyl (2E)-3-{6-[(1-{[(4-chlorophenyl)amino]carbonyl}-4-piperidyl)amino]-3-pyridyl}acrylate (341 mg).
NMR (DMSO-d6, δ): 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), 6.20 (1H, d, J=16.0 Hz), 6.36-6.45 (2H, m), 7.21-7.34 (5H, m), 7.53-7.64 (2H, m), 8.20 (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.
NMR (DMSO-d6, δ): 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)+
Mass (APCI): 425(M+H)+
NMR (DMSO-d6, δ): 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), 7.50 (1H, d, J=16.0 Hz), 8.12 (1H, d, J=2.0 Hz), 8.30 (1H, d, J=2.0 Hz), 8.68 (1H, s)
To a solution of ethyl (2E)-3-{5-chloro-6-[(1-{[(4-chlorophenyl)amino]carbonyl}-4-piperidyl) amino]-3-pyridyl}acrylate (363 mg) in THF (3 ml) and MeOH (3 ml) was added 1N NaOH aq (2.35 ml), the mixture was stirred at 80° C. for 1 hour. The pH of the mixture was adjusted to ca.4.5 with 1N HCl aq. The solution was evaporated under reduced pressure to give crude 3-{5-Chloro-6-[1-(4-chloro-phenylcarbamoyl)-piperidin-4-ylamino]-pyridin-3-yl}-acrylic acid. To a suspension of crude 3-{5-Chloro-6-[1-(4-chloro-phenylcarbamoyl)-piperidin-4-ylamino]-pyridin-3-yl}-acrylic acid (247 mg) in DMF (3 ml) was added O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (73.1 mg), EDCI (96.9 mg), HOBt (84.3 mg,), the mixture was stirred at 23° C. for 8 hours. The mixed solution was poured into a mixture of water (20 ml) and AcOEt (20 ml). 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-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridyl)amino]-N-(4-chlorophenyl)-1-piperidinecarboxamide (246 mg).
NMR (DMSO-d6, δ): 1.45-1.95 (10H, m), 2.75-3.00 (2H, m), 3.45-3.50 (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.
Mass (ESI): 519(M+H)+
Mass (ESI): 519(M+H)+
NMR (DMSO-d6, δ): 1.40-2.35 (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), 8.20 (1H, s), 11.10 (1H, s)
NMR (DMSO-d6, δ): 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), 6.50 (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), 8.20 (1H, s), 11.08 (1H, brs)
NMR (DMSO-d6, δ): 1.45-1.90 (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), 6.30 (1H, d, J=16.0 Hz), 6.50 (1H, d, J=7.0 Hz), 6.88 (1H, d, J=8.8 Hz), 7.20 (1H, d, J=8.8 Hz), 7.35 (1H, d, J=16.0 Hz), 7.83 (1H, s), 8.20 (1H, s), 11.08 (1H, s)
NMR (DMSO-d6, δ): 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), 6.30 (1H, d, J=16.0 Hz), 6.50 (1H, d, J=8.0 Hz), 7.35 (1H, d, J=16.0 Hz), 7.83 (1H, s), 8.20 (1H, s), 11.06 (1H, brs)
NMR (DMSO-d6, δ): 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), 3.80-4.10 (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)
NMR (DMSO-d6, δ): 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), 7.45-7.55 (4H, m), 7.14 (1H, dd, J=2.0, 8.8 Hz), 8.27 (1H, d, J=2.0 Hz), 11.08 (1H, brs)
NMR (DMSO-d6, δ): 1.50-19.0(7H, m), 2.08-2.29 (1H, m), 2.37-2.65 (2H, m), 2.78-2.87 (1H, m), 3.40-3.65 (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), 7.85-7.30-7.40 (3H, m), 8.20-7.85(1H, s), 8.20 (1H, s), 11.08 (1H, brs)
NMR (DMSO-d6, δ): 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 (1H, m), 4.40-4.60 (1H, m), 4.89 (1H, s), 6.32 (1H, d, J=16.0 Hz), 6.60 (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), 8.20 (1H, s), 11.08 (1H, brs)
NMR (DMSO-d6, δ): 1.76-1.92 (7H, m), 2.12-2.30 (1H, m), 2.32-2.86 (3H, m), 3.40-3.60 (1H, m), 3.51 (2H, s), 3.72 (3H, s), 3.86-4.05 (1H, 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)
To a solution of ethyl (2E)-3-[6-(4-piperidylamino)-3-pyridyl]acrylate dihydrochloride (309 mg) in EtOH (5 ml) was added Et3N(0.921 ml), then benzaldehyde (0.117 ml) and titanium(IV) isopropoxide (0.463 ml), 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. (20 ml)-AcOEt (20 ml), 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-[(1-benzyl-4-piperidyl)amino]-5-chloro-3-pyridyl}acrylate (328 mg).
NMR (DMSO-d6, δ): 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), 7.21-7.37 (5H, m), 7.50 (1H, d, J=16.0 Hz), 8.10 (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.
NMR (DMSO-d6, δ): 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), 7.50 (1H, d, J=16.0 Hz), 8.10 (1H, d, J=2.0 Hz), 8.27 (1H, d, J=2.0 Hz)
Mass (APCI): 434(M+H)+
NMR (DMSO-d6, δ): 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), 7.50 (1H, d, J=16.0 Hz), 8.10 (1H, d, J=2.0 Hz), 8.27 (1H, d, J=2.0 Hz).
Mass (APCI): 418(M+H)+
tert-Butyl 4-(methylamino)-1-piperidinecarboxylate
NMR (DMSO-d6, δ): 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).
To a solution of ethyl (2E)-3-[5-chloro-6-(4-piperidylamino)-3-pyridyl]acrylate dihydrochloride (710 mg) in CH2Cl2 (14 ml) was added Et3N(0.517 ml), the mixture was stirred at 23° C. for 30 minutes. To the mixture was added 4-Methyl-benzaldehyde (0.241 ml) and SODIUM triacetoxyborohydride (590 mg), the mixture was stirred at 23° C. for 24 hours. The reaction mixture was poured into sat.NaHCO3ag. (20 ml)-AcOEt (20 ml). 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 (671 mg).
NMR (DMSO-d6, δ): 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), 7.50 (1H, d, J=16.0 Hz), 8.10 (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.
NMR (DMSO-d6, δ): 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), 3.85-4.10 (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), 7.50 (1H, d, J=16.0 Hz), 8.09 (1H, d, J=2.0 Hz), 8.27 (1H, d, J=2.0 Hz)
Mass (ESI): 366(M+H)+
Mass (ESI): 364(M+H)+
To a solution of (3R)-(+)-3-(tert-butoxycarbonylamino)pyrrolidine (5.0 g) in DMF (50 ml) was added 4-fluorobenzoylchloride (3.38 ml) and N,N-diisopropylethylamine (9.35 ml), the mixture was stirred at 70° C. for 2 hours. The mixed solution was poured into a mixture of water (300 ml) and AcOEt (30 0 ml). 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 (6.8 g). To a solution of [1-(4-fluoro-benzyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (6.8 g) in MeOH(34 ml) was treated with 4N HCl in AcOEt (29 ml) and was stirred at 25c for 12 hours. The solvent was removed under reduced pressure. Recrystallization (acetonitrile-MeOH) provided (3R)-1-(4-fluorobenzyl)-3-pyrrolidinamine dihydrochloride as white solid (3.77 g).
NMR (DMSO-d6, δ): 1.96-2.55 (2H, m), 3.10-3.78 (4H, m), 3.80-4.22 (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.
NMR (DMSO-d6, δ): 1.96-2.55 (2H, m), 2.33 (3H, s), 3.10-3.78 (4H, m), 3.80-4.22 (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)+
NMR (DMSO-d6, δ): 1.90-2.30 (2H, m), 3.10-3.75 (4H, m), 3.78 (3H, s), 3.80-4.15 (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)+
To a solution of (3R)-1-(4-fluorobenzyl)-3-pyrrolidinamine dihydrochloride(3-59) in DMF (35 ml) was added 5,6-dichloronicotinic acid ethyl ester (3.38 ml) and K2CO3 (6.34 g), the mixture was stirred at 100° C. for 4 hours under N2 atmosphere. The mixed solution was poured into a mixture of water (250 ml) and AcOEt (250 ml). 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=1:2 to give ethyl 5-chloro-6-{[(3R)-1-(4-fluorobenzyl)-3-pyrrolidinyl]amino}nicotinate (3.75 g).
NMR (DMSO-d6, δ): 1.28(3H, t, J=7.4 Hz), 1.73-1.98 (1H, m), 2.10-2.30 (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.
NMR (DMSO-d6, δ): 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)+
Mass (ESI): 390(M+H)+
To a solution of 2-chloro-5-iodopyridine(37.7 g) in DMF (300 mL) was added palladium(II) acetate (1.77 g), tri-o-tolylphosphine (7.19 g), diisopropylethylamine (82 mL), and ethyl acrylate (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 dried over Na2SO4, and the solvent was removed in vacuo. Obtained brown solid was suspended in a mixture of hexane 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-d6, δ): 1.35 (3H, t, J=7.0 Hz), 4.28 (2H, q, J=7.0 Hz), 6.49 (1H, d, J=16.1 Hz), 7.37 (1H, d, J=8.1 Hz), 7.63 (1H, d, j=16.1 Hz), 7.80 (1H, dd, J=8.2, 2.6 Hz), 8.52 (1H, d, J=2.6 Hz)
MS (ES+) m/z 212-(M+1)
To a solution of ethyl (2E)-3-(6-chloro-3-pyridyl)acrylate (14.3 g) in dioxane (140 mL) was added palladium(II) acetate (1.52 g), 2′-(dicyclohexylphosphino)-N,N-di-methyl-2-diphenylamine (3.99 g), cesium carbonate (30.2 g), and (3R)-(−)-1-benzyl-3-aminopyrrolidine (13.1 g), and the mixture was heated at 95° C. for 2.5 days. 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)-1-benzyl-3-pyrrolidinyl]amino}-3-pyridyl)acrylate as pale yellow oil (10.7 g).
NMR (DMSO-d6, δ): 1.32 (3H, t, J=7.0 Hz), 1.70 (1H, m), 2.39 (2H, m), 2.61 (1H, m), 2.75 (1H, m), 2.84 (1H, m), 3.64 (2H, d, J=2.2 Hz), 4.24 (2H, q, J=7.0 Hz), 4.35 (1H, m), 5.09 (1H, d, J=8.0 Hz), 6.20 (1H, d, J=16.1 Hz), 6.36 (1H, d, J=8.8 Hz), 7.27 (2H, m), 7.32 (3H, m), 7.56 (1H, d, J=15.8 Hz), 7.60 (1H, d, J=8.8, 2.2 Hz), 8.19 (1H, d, J=2.2 Hz)
MS (ES+) m/z 352 (M+1)
To a solution of ethyl (2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]-amino}-3-pyridyl)acrylate(11 g) in THF (105 mL) 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)-1-benzyl-3, pyrrolidinyl](tert-butoxycarbonyl)amino]-3-pyridyl)acrylate as pale yellow oil (13.0 g).
NMR (DMSO-d6, δ): 1.35 (3H, t, J=7.0 Hz), 1.44 (9H, s), 2.08 (1H, m), 2.23 (1H, m), 2.57-2.73 (3H, m), 2.93 (1H, t, J=8.8 Hz), 3.53 (1H, d, J=12.6 Hz), 3.63 (1H, d, J=12.8 Hz), 4.29 (2H, q, J=7.0 Hz), 4.91 (1H, m), 6.46 (1H, d, J=16.1 Hz), 7.20-7.27 (5H, m), 7.29 (1H, d, J=8.8 Hz), 7.66 (1H, d, J=16.1 Hz), 7.80 (1H, dd, J=8.4, 2.2 Hz), 8.53 (1H, d, J=2.2 Hz)
MS (ES+) m/z 452 (M+1)
To a solution of ethyl (2E)-3-{6-[[(3R)-1-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 5° C. 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, δ): 1.27 (3H, t, J=7.0 Hz), 1.42 (9H, s), 1.98 (1H, m), 2.23 (1H, m), 3.15 (1H, m), 3.34 (3H, br), 4.21 (2H, q, J=7.0 Hz), 4.96 (1H, m), 6-78 (1H, d, J=16.1 Hz), 7.45 (1H, d, J=8.4 Hz), 7.70 (1H, d, J=16.1 Hz), 8.25 (1H, dd, J=8.6, 2.2 Hz), 8.75 (1H, d, J=2.2 Hz),
MS (ES+) m/z 362 (M+1)
To a solution of ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate 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)-1-(2-fluorobenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate (2.40 g) as colorless oil.
NMR (DMSO-d6, δ): 1.35 (3H, t, J=7.0 Hz), 1.44 (9H, s), 2.09 (1H, m), 2.24 (1H, m), 2.64 (2H, t, J=7.4 Hz), 2.74 (1H, dd, J=9.2, 7.0 Hz), 2.89 (1H, t, J=8.1 Hz), 3.51 (1H, d, J=13.3 Hz), 3.62 (1H, d, J=13.3 Hz), 4.28 (2H, q, J=7.0 Hz), 4.91 (1H, m), 6.47 (1H, d, J=16.1 Hz), 6.91 (2H, m), 6.99 (1H, d, J=8.0 Hz), 7.21 (1H, m), 7.28 (1H, d, J=8.4 Hz), 7.66 (1H, d, J=16.1 Hz), 7.81 (1H, dd, J=8.4, 2.6 Hz), 8.54 (1H, d, J=2.2 Hz)
MS (ES+) m/z 470 (M+1)
The following compounds were obtained according to a similar manner to that of Preparation 212.
NMR (DMSO-d6, δ): 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 (1H, m), 3.54 (1H, d, J=12.1 Hz), 3.60 (1H, d, J=12.1 Hz), 4.83-4.98 (1H, m), 6.47 (1H, d, J=16.1 Hz), 7.16 (2H, d, J=8.1 Hz), 7.23-7.34 (1H, m), 7.30 (2H, d, J=8.1 Hz), 7.67 (1H, d, J=16.1 Hz), 7.81 (1H, dd, J=8.4, 2.6 Hz), 8.54 (1H, d, J=2.6 Hz)
MS (ES+) m/z 508.36
NMR (DMSO-d6, δ): 1.35 (3H, t, J=7.0 Hz), 1.44 (9H, s), 1.97-2.14 (1H, m), 2.16-2.31 (1H, m), 2.56-2.79 (3H, m), 2.88-2.97 (1H, m), 3.59 (1H, d, J=13.2 Hz), 3.67 (1H, d, J=13.2 Hz), 4.29 (2H, q, J=7.0 Hz), 4.83-4.99 (1H, m), 6.47 (1H, d, J=16.1 Hz), 7.29 (1H, d, J=8.4 Hz), 7.35 (2H, d, J=8.1 Hz), 7.53 (2H, d, J=8.1 Hz), 7.66 (1H, d, J=16.1 Hz), 7.80 (1H, dd, J=8.4, 2.6 Hz), 8.53 (1H, d, J=2.6 Hz)
MS (ES+) m/z 520.32(M+1)
NMR (DMSO-d6, δ): 1.35 (3H, t, J=7.3 Hz), 1.43 (9H, s), 1.97-2.32 (2H, m), 2.53-2.77 (3H, m), 2.87-2.98 (1H, m), 3.54 (1H, d, J=13.2 Hz), 3.62 (1H, d, 3J=13.2 Hz), 4.29 (2H, q, J=7.3 Hz), 4.83-4.97 (1H, m), 6.47 (1H, d, J=16.1 Hz), 7.12 (2H, d, J=8.1 Hz), 7.25 (2H, d, J=8.1 Hz), 7.29 (1H, d, J=8.4 Hz), 7.66 (1H, d, J=16.1 Hz), 7.80 (1H, dd, J=8.4, 2.6 Hz), 8.53 (1H, d, J=2.6 Hz)
MS (ES+) m/z 536.24(M+1)
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 (1H, m), 4.29 (2H, q, J=7.0 Hz), 4.82-4.98 (1H, m), 6.46 (1H, d, J=16.1 Hz), 7.31 (1H, d, J=8.4 Hz), 7.66 (1H, d, J=16.1 Hz), 7.81 (1H, dd, J=8.4, 2.6 Hz), 8.86 (1H, d, J=2.6 Hz)
MS (ES+) m/z 458.37(M+1)
NMR (DMSO-d6, δ): 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 (1H, 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 (1H, m), 5.52 (1H, brs), 6.46 (1H, d, J=−16.1 Hz), 7.31 (1H, d, J=8.4 Hz), 7.66 (1H, d, J=16.1 Hz), 7.81 (1H, dd, J=8.4, 2.6 Hz), 8.56 (1H, d, J=2.6 Hz)
MS (ES+) m/z 456.54(M+1)
NMR (CDCl3, δ): 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 (1H, m), 6.42 (1H, d, J=16 Hz), 6.57 (1H, s), 7.17-7.27 (2H; m), 7.29 (1H, d, J=8 Hz), 7.42-7.54 (2H, m), 7.61 (1H, d, J=16 Hz), 7.76 (1H, dd, J=2, 8 Hz), 8.45 (1H, d, J=2
MS (ES+) m/z 492 (M+1)
NMR (CDCl3, δ): 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 (1H, m), 6.45 (1H, d, J=16 Hz), 6.73-6.75 (1H, m), 7.28 (2H, d, J=8 Hz), 7.44 (1H, d, J=8 Hz), 7.57-7.67 (3H, m), 7.78 (1H, dd, J=2, 8 Hz), 8.49 (1H, d, J=2 Hz)
MS (ES+) m/z 492 (M+1)
NMR (CDCl3, a): 1.35 (3H, t, J=7.0 Hz), 1.44 (9H, s), 2.07 (1H, m), 2.24 (1H, m), 2.58-2.76 (3H, m), 2.94 (1H, m), 3.53 (1H, d, J=12.8 Hz), 3.61 (1H, d, J=12.8 Hz), 4.29 (2H, q, J=7.0 Hz), 4.91 (1H, m), 6.47 (1H, d, J=16.1 Hz), 6.76-6.83 (3H, m), 7.19 (1H, t, J=8.1 Hz), 7.29 (1H, d, J=8.4 Hz), 7.66 (1H, d, J=16.1 Hz), 7.80 (1H, dd, J=8.4, 2.6 Hz), 8.54 (1H, d, J=2.2 Hz)
MS (ES+) m/z 482 (M+1)
NMR (CDCl3, δ): 1.35 (3H, t, J=7.0 Hz), 1.45 (9H, s), 1.78 (2H, m), 2.01 (1H, m), 2.19 (1H, m), 2.36-2.77 (7H, m), 3.02 (1H, t, J=8.4 Hz), 4.28 (2H, q, J=7.0 Hz), 4.89 (1H, m), 6.44 (1H, d, J=16.1 Hz), 7.14-7.19 (3H, m), 7.23-7.28 (2H, m), 7.31 (1H, d, J=8.4 Hz), 7.65 (1H, d, J=16.1 Hz), 7.80 (1H, dd, J=8.4, 2.6 Hz), 8.54 (1H, d, J=2.6 Hz)
MS (ES+) m/z 480 (M+1)
NMR (CDCl3, δ): 1.36 (3H, t, J=7.1 Hz), 1.45 (9H, s), 2.19 (1H, br), 2.46 (1H, br), 2.96 (6H, s), 3.14 (2H, br), 3.42 (1H, br), 3.92 (1H, br), 4.29 (2H, q, J=7.1 Hz), 5.04 (1H, br), 6.45 (1H, d, J=16.1 Hz), 6.69 (2H, d, J=8.8 Hz), 7.29 (3H, m), 7.63 (1H, d, J=16.1 Hz), 7.79 (1H, dd, J=8.4, 2.5 Hz), 8.46 (1H, br)
MS (ES+) m/z 495 (M+1)
NMR (CDCl3, δ): 1.35 (3H, t, J=7.0 Hz), 1.44 (9H, s), 2.20 (1H, m), 2.52 (1H, m), 3.29 (3H, m), 3.60 (1H, m), 3.86 (3H, s), 4.18 (2H, br), 4.28 (2H, q, J=7.0 Hz), 5.10 (1H, m), 6.44 (1H, d, J=16.1 Hz, 6.91 (1H, d, J=7.4 Hz), 6.98 (1H, dd, J=7.5, 1.1 Hz), 7.32 (1H, d, J=84 Hz), 7.35 (1H, td, J=7.8, 1.8 Hz), 7.50 (1H, dd, J=7.7, 1.1 Hz), 7.63 (1H, d, J=16.1 Hz), 7.79 (1H, dd, J=8.4, 2.2 Hz), 8.44 (1H, d, J=2.2 Hz)
MS (ES+) m/z 482 (M+1)
NMR (CDCl3, δ): 1.35 (3H, t, J=7.0 Hz), 1.44 (9H, s), 2.11 (1H, br), 2.33 (1H, br), 2.89 (3H, br), 3.13 (1H, br), 3.82 (1H, br), 4.29 (2H, q, J=7.0 Hz), 4.97 (1H, br), 6.45 (1H, d, J=16.1 Hz), 7.02 (1H, t, J=8.0 Hz), 7.11 (1H, t, J=7.3 Hz), 7.25 (1H, br), 7.31 (1H, d, J=8.8 Hz), 7.40 (1H, br), 7.65 (1H, d, J=16.1 Hz), 7.79 (1H, dd, J=8.4, 2.6 Hz), 8.49 (1H, d)
MS (ES+) m/z 470 (M+1)
NMR (DMSO-d6, δ): 1.36 (3H, t, J=7.0 Hz), 1.45 (9H, s), 2.20 (1H, m), 2.43 (1H, m), 3.17 (3H, br), 3.44 (1H, br), 4.29 (2+2H, q, J=7.0 Hz), 5.09 (1H, m), 6.45 (1H, d, J=16.1 Hz), 7.32 (1H, d, J=8.4 Hz), 7.55 (1H, tm, J=7.0 Hz), 7.63 (1H, d, J=16.1 Hz), 7.70 (1H, dd, J=7.0, 1.5 Hz), 7.73 (1H, dd, J=7.0, 1.7 Hz), 7.79 (1H, dd, J=8.8, 2.2 Hz), 7.82 (1H, d, J=8.4 Hz), 7.06 (1H, d, J=8.4 Hz), 7.26 (1H, d, J=8.4 Hz), 8.50 (1H, d, J=2.2 Hz)
MS (ES+) m/z 503 (M+1)
NMR (CDCl3, δ): 1.37 (3H, t, J=7.0 Hz), 1.45 (9H, s), 2.12 (1H, m), 2.25 (1H, m), 2.72 (2H, m), 2.81 (1H, m), 2.89 (1H, m), 3.72 (1H, m), 3.75 (1H, d, J=12.8 Hz), 3.84 (1H, d, J=12.8 Hz), 4.30 (2H, q, J=7.0 Hz), 4.93 (1H, m), 6.46 (1H, d, J=16.1 Hz), 7.28 (1H, d, J=8.0 Hz), 7.54 (1H, m), 7.65 (1H, d, J=16.1 Hz), 7.70 (1H, m), 7.79 (2H, m), 8.00 (1H, br), 8.10 (1H, d, J=8.4 Hz), 8.51 (1H, d, J=2.2 Hz), 8.83 (1H, d, J=2.2 Hz)
MS (ES+) m/z 503 (M+1)
NMR (CDCl3, δ): 1.35 (3H, t, J=7.0 Hz), 1.45 (9H, s), 2.06 (1H, br), 2.22 (1H, br), 2.44 (3H, s), 2.64 (1H, br), 2.74 (2H, br), 3.01 (1H, br), 3.72 (2H, br), 4.27 (2H, q, J=7.0 Hz), 4.91 (1H, m) 6.46 (1H, d, J=16.1 Hz), 6.54 (1H, br), 6.64 (1H, br), 7.31 (1H, d, J=8.4 Hz), 7.66 (1H, d, J=16.1 Hz), 7.81 (1H, dd, J=8.4, 2.6 Hz), 8.54 (1H, d, J=2.2 Hz)
MS (ES+) m/z 472 (M+1)
NMR (CDCl3, δ): 1.36 (3H, t, J=7.0 Hz), 1.46 (9H, s), 2.14 (1H, m), 2.29 (3H, s), 2.39 (1H, m), 3.10 (3H, br), 3.42 (1H, br), 3.89 (2H, br), 4.29 (2H, q, J=7.0 Hz), 5.03 (1H, m), 5.95 (1H, br), 6.28 (1H, br), 6.46 (1H, d, J=16.1 Hz), 7.33 (1H, d, J=8.4 Hz), 7.65 (1H, d, J=16.1 Hz), 7.81 (1H, dd, J=8.4, 2.2 Hz), 8.50 (1H, d)
MS (ES+) m/z 456 (M+1)
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 (1H, m), 6.19 (1H, dt, J=15.4, 7.0 Hz), 6.44 (1H, d, J=16.1 Hz), 6.63 (1H, d, J=15.4 Hz), 6.66 (2H, d, J=9.2 Hz), 7.31 (2H, d, J=8.8 Hz), 7.31 (1H, d, J=8.8 Hz), 7.63 (1H, d, J=16.1 Hz), 7.80 (1H, dd, J=8.4, 2.6 Hz), 8.47 (1H, br)
MS (ES+) m/z 521 (M+1)
NMR (CDCl3, δ): 0.81 (9H, s), 1.35 (3H, t, J=7.0 Hz), 1.44 (9H, s), 2.01 (1H, m), 2.17 (2H, br.), 2.66 (2H, br.), 2.88 (2H, br.), 4.28 (2H, q, J=7.0 Hz), 4.86 (1H, br.), 6.46 (1H, d, J=16.1 Hz), 7.31 (1H, d, J=8.4 Hz), 7.66 (1H, d, J=16.1 Hz), 7.81 (1H, dd, J=8.1, 2.2 Hz), 8.56 (1H, d, J=2.2 Hz)
MS (ES+) m/z 432 (M+1)
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 1N 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 1N 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-d6, δ): 1.36 (9H, s), 1.99 (1H, m), 2.12 (1H, m), 2.62 (1H, dd, J=8.9, 7.0 Hz), 2.74 (1H, t, J=8.2 Hz), 3.46 (1H, d, J=13.6 Hz), 3.58 (1H, d, J=13.6 Hz), 4.76 (1H, m), 6.66 (1H, d, J=16.1 Hz), 6.95 (1H, m), 7.03 (1H, m), 7.29 (1H, m), 7.32 (1H, m), 7.33 (1H, d, J=8.4 Hz), 7.62 (1H, d, J=16.1 Hz), 8.16 (1H, dd, J=8.4, 2.6 Hz), 8.69 (1H, d, J=2.2 Hz)
MS (ES+) m/z 442 (M+1)
The following compounds were obtained according to a similar manner to that of Preparation 231.
NMR (DMSO-d6, δ): 1.36 (9H, s), 1.96 (1H, m), 2.12 (1H, m), 2.62 (1H, m), 2.77 (1H, m), 3.45 (1H, d, J=17.5 Hz), 3.53 (1H, d, J=17.5 Hz), 3.71 (3H, s), 4.75 (1H, m), 6.66 (1H, d, J=16.1 Hz), 6.76 (3H, m), 7.16 (1H, t, J=8.1 Hz), 7.33 (1H, d, J=8.4 Hz), 7.63 (1H, d, J=15.8 Hz), 8.16 (1H, dd, J=8.4, 2.2 Hz), 8.69 (1H, d, J=2.2 Hz)
MS (ES+) m/z 454 (M+1)
NMR (DMSO-d6, δ): 1.37 (9H, s), 1.62 (2H, m), 1.93 (1H, m), 2.06 (1H, m), 2.27 (1H, m), 2.29 (2H, m), 2.55 (1H, m), 2.79 (2H, m), 4.73 (1H, m), 6.61 (1H, d, J=16.1 Hz), 7.15 (3H, m), 7.24 (2H, m), 7.32 (1H, d, J=8.4 Hz), 7.52 (1H, d, J=16.1 Hz), 8.12 (1H, d, J=8.4, 2.2 Hz), 8.66 (1H, d, J=2.2 Hz)
MS (ES+) m/z 452 (M+1)
NMR (DMSO-d6, δ): 1.37 (9H, s), 2.03 (1H, m), 2.24 (1H, m), 2.89 (6H, s), 4.00 (2H, br), 4.90 (1H, m), 6.66 (1H, d, J=16.1 Hz), 6.69 (2H, d, J=8.4 Hz), 7.25 (2H, d, J=8.4 Hz), 7.38 (1H, d, J=8.1 Hz), 7.63 (1H, d, J=16.1 Hz), 8.19 (1H, dd, J=8.1, 2.2 Hz), 8.66 (1H, d, J=2.2 Hz)
MS (ES+) m/z 467 (M+1)
(2E)-3-(6-{(tert-Butoxycarbonyl)[(3R)-1-(2-methoxybenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylic acid
NMR (DMSO-d6, δ): 1.34 (9H, s), 1.93 (1H, m), 2.09 (1H, m), 2.61 (1H, m), 2.72 (1H, m), 3.43 (1H, d, J=14.3 Hz), 3.52 (1H, d, J=14.3 Hz), 3.72 (3H, s), 4.69 (1H, m), 6.48 (1H, d, J=16.1 Hz), 6.82 (1H, t, J=8.1 Hz), 6.91 (1H, d, J=8.1 Hz), 7.01 (1H, d, J=8.1 Hz), 7.09 (1H, d, J=16.1 Hz), 7.19 (2H, m), 7.93 (1H, dd, J=8.4, 2.2 Hz), 8.49 (1H, d, J=2.2 Hz)
MS (ES+) m/z 454 (M+1)
NMR (DMSO-d6, δ): 1.35 (9H, s), 1.96 (1H, br), 2.10 (1H, br), 2.61 (1H, br), 2.81 (1H, br), 3.46 (1H, m), 3.58 (1H, m), 4.73 (1H, br), 6.66 (1H, d, J=16.1 Hz), 7.13 (2H, m), 7.25 (2H, m), 7.33 (1H, d, J=8.4 Hz), 7.62 (1H, d, J=16.1 Hz), 8.15 (1H, dd, J=8.4, 2.2 Hz), 8.67 (1H, d, J=2.2 Hz)
MS (ES+) m/z 442 (M+1)
NMR (DMSO-d6, δ): 1.40 (9H, s), 2.09 (1H, m), 2.35 (1H, m), 3.16 (2H, br), 4.50 (2H, br), 5.04 (1H, br), 6.67 (1H, d, J=16.1 Hz), 7.44 (1H, d, J=8.4 Hz), 7.64 (1H, d, J=16.1 Hz), 7.64 (2H, m), 7.79 (1H, t, J=7.7 Hz), 8.00 (3H, m), 8.21 (1H, dd, J=8.4, 2.2 Hz), 8.43 (1H, d, J=8.1 Hz), 8.71 (1H, s)
MS (ES+) m/z 475 (M+1)
NMR (DMSO-d6, δ): 1.35 (9H, s), 2.00 (1H, m), 2.14 (1H, m), 2.58 (2H, m), 2.67 (1H, m), 2.84 (1H, m), 3.68 (1H, d, J=13.9 Hz), 3.78 (1H, d, J=13.9 Hz), 4.77 (1H, m), 6.65 (1H, d, J=16.1 Hz), 7.33 (1H, d, J=8.4 Hz), 7.58 (1H, t, J=7.7 Hz), 7.61 (1H, d, J=16.1 Hz), 7.72 (1H, t, J=8.1 Hz), 7.93 (1H, d, J=8.4 Hz), 7.99 (1H, d, J=8.4 Hz), 8.10 (1H, s), 8.15 (1H, dd, J=8.4, 2.2 Hz), 8.66 (1H, d, J=2.2 Hz), 8.74 (1H, d, J=2.2 Hz)
MS (ES+) m/z 475 (M+1)
NMR (DMSO-d6, δ): 1.36 (9H, s), 1.94 (1H, m), 2.08 (1H, m), 2.37 (3H, s), 2.58 (1H, m), 2.82 (1H, m), 3.57 (1H, d, J=13.5 Hz), 3.65 (1H, d, J=13.5 Hz), 4.72 (1H, m), 6.58 (1H, m), 6.65 (1H, d, J=2.9 Hz), 6.66 (1H, d, J=16.1 Hz), 7.32 (1H, d, J=8.4 Hz), 7.61 (1H, d, J=16.1 Hz), 8.15 (1H, d, J=8.4, 2.2 Hz), 8.68 (1H, d, J=2.2 Hz)
MS (ES+) m/z 444 (M+1)
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 (1H, m), 6.04 (1H, br), 6.28 (1H, br), 6.67 (1H, d, J=16.1 Hz), 7.37 (1H, d, j=8.4 Hz), 7.62 (1H, d, J=16.1 Hz), 8.18 (1H, dd, J=8.4, 2.2 Hz), 8.67 (1H, d, J=2.2 Hz),
MS (ES+) m/z 428 (M+1)
NMR (DMSO-d6, δ): 1.40 (9H, s), 2.07 (1H, m), 2.28 (1H, m), 2.92 (6H, s), 3.17 (2H, d), 3.81 (2H, br), 5.00 (1H, br), 6.04 (1H, m), 6.65 (1H, d, J=16.1 Hz), 6.69 (1B, d, J=8.1 Hz), 6.69 (2H, d, J=8.1 Hz), 7.30 (2H, d, J=8.1 Hz), 7.43 (1H, d, J=8.4 Hz), 7.61 (1H, d, J=16.1 Hz), 8.20 (1H, br.d, J=8.4 Hz), 8.68 (1H, br)
MS (ES+) m/z 493 (M+1)
NMR (DMSO-d6, δ): 0.75 (9H, s), 1.37 (9H, s), 1.94 (1H, m), 2.05 (1H, m), 2.07 (1H, d, J=13.1 Hz), 2.15 (1H, d, J=13.1 Hz), 2.58 (2H, m), 2.77 (2H, m), 4.73 (1H, m), 6.64 (1H, d, J=16.1 Hz), 7.33 (1H, d, J=8.4 Hz), 7.60 (1H, d, J=16.1 Hz), 8.15 (1H, dd, J=8.4, 2.2 Hz), 8.70 (1H, d, J=2.2 Hz)
MS (ES+) m/z 404 (M+1)
To a solution of (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(3-fluorobenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylic acid (2.25 g, crude) in DMF (23 mL) was added was added O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (776 mg), 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)-1-(3-fluorobenzyl)-3-pyrrolidinyl](5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-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 (1H, m), 2.23 (1H, m), 2.63 (2H, t, J=7.3 Hz), 2.73 (1H, dd, J=9.2, 7.3 Hz), 2.88 (1H, t, J=8.0 Hz), 3.51 (1H, d, J=13.2 Hz), 3.62 (1H, d, J=13.2 Hz), 3.67 (1H, m), 3.99 (1H, m), 4.90 (1H, m), 5.05 (1H, br), 6.41 (1H, br), 6.91 (2H, m), 6.98 (1H, m), 7.21 (1H, m), 7.27 (1H, m), 7.70 (1H, d, J=16.1 Hz), 7.78 (1H, dd, J=8.8, 2.2 Hz), 8.56 (1H, d, J=2.2 Hz)
MS (ES+) m/z 541 (M+1)
The following compounds were obtained according to a similar manner to that of Preparation 243.
NMR (CDCl3, δ): 1.44 (9H, s), 1.64 (3H, br), 1.87 (3H, br), 2.08 (1H, m), 2.25 (1H, m), 2.70 (3H, br), 2.97 (1H, br), 3.63 (2H, m), 3.70 (1H, m), 3.98 (1H, m), 4.91 (1H, m), 5.03 (1H, br), 6.40 (1H, br), 6.78 (1H, br.d, J=8.4 Hz), 6.83 (2H, br.d, J=7.0 Hz), 7.19 (1H, t, J=7.7 Hz), 7.28 (1H, d, J=7.7 Hz), 7.69 (1H, d, J=16.1 Hz), 7.77 (1H, dd, J=8.4 and 2.2 Hz), 8.55 (1H, d, J=2.0 Hz)
MS (ES+) m/z 553 (M+1)
NMR (CDCl3, δ): 1.45 (9H, s), 1.63 (3H, br), 1.82 (2H, br), 1.86 (3H, br), 2.03 (1H, br), 2.23 (1H, br), 2.51 (2H, br), 2.60 (1H, m), 2.73 (2H, br), 3.05 (1H, br), 3.69 (1H, m), 3.97 (1H, m), 4.91 (1H, m), 5.02 (1H, br), 6.31 (1H, br), 7.17 (3H, m), 7.27 (2H, m), 7.29 (1H, d, J=8.4 Hz), 7.68 (1H, d, J=16.1 Hz), 7.77 (1H, dd, J=8.4 and 2.2 Hz), 8.55 (1H, br)
MS (ES+) m/z 551 (M+1)
NMR (CDCl3, δ): 1.44 (9H, s), 1.63 (3H, br), 1.87 (3H, br), 2.08 (1H, br), 2.28 (1H, br), 2.78 (3H, br), 2.93 (3H, s), 3.07 (1H, br), 3.63 (2H, br), 3.68 (1H, m), 3.99 (1H, m), 4.94 (1H, br), 5.04 (1H, br), 6.44 (1H, br), 6.67 (1H, d, J=8.1 Hz), 7.16 (2H, br.d, J=7.0 Hz), 7.28 (1H, d, J=8.4 Hz), 7.68 (1H, d, J=16.1 Hz), 7.75 (1H, d, J=8.4 Hz), 8.52 (1H, s)
MS (ES+) m/z 566 (M+1)
NMR (CDCl3, δ): 1.44 (9H, s), 1.63 (3H, br), 1.86 (3H, br), 2.05 (1H, br), 2.26 (1H, br), 2.68 (1H, br), 2.77 (2H, br), 3.03 (1H, br), 3.68 (2H, br), 3.80 (2H, s), 3.97 (1H, m), 4.92 (1H, m), 5.03 (1H, br), 6.43 (1H, br), 6.84 (1H, d, J=8.1 Hz), 6.88 (1H, t, J=7.4 Hz), 7.22 (2H, m), 7.29 (1H, d, J=8.8 Hz), 7.69 (1H, d, J=16.1 Hz), 7.75 (1H, d, J=8.1 Hz), 8.53 (1H, s)
MS (ES+) m/z 553 (M+1)
NMR (CDCl3, δ): 1.43 (9H, s), 1.63 (3H, br), 1.86 (3H, br), 2.05 (1H, m), 2.23 (1H, m), 2.72 (3H, m), 2.99 (1H, m), 3.64 (1H, d, J=12.8 Hz), 3.69 (1H, d, J=12.8 Hz), 3.71 (1H, m), 4.91 (1H, m), 5.04 (1H, s), 6.43 (1H, br), 7.00 (1H, t, J=8.4 Hz), 7.07 (1H, d, J=7.7 Hz), 7.24 (2H, m), 7.28 (1H, d, J=8.4 Hz), 7.68 (1H, d, J=16.1 Hz), 7.75 (1H, dd, J=8.4, 2.2 Hz), 8.52 (1H, d, J=2.2 Hz)
MS (ES+) m/z 541 (M+1)
NMR (CDCl3, δ): 1.45 (9H, s), 1.63 (3H, br), 1.87 (3H, br), 2.12 (1H, br), 2.29 (1H, br), 2.74 (1H, br), 2.80 (1H, br), 3.04 (1H, br), 3.68 (1H, m), 3.94 (2H, d), 3.98 (1H, m), 4.96 (1H, br), 5.03 (1H, br), 6.36 (1H, br), 7.29 (1H, d, J=8.4 Hz), 7.46 (1H, m), 7.53 (1H, d, J=8.1 Hz), 7.69 (2H, m), 7.78 (2H, m), 8.07 (2H, m), 8.55 (1H, br)
MS (ES+) m/z 574 (M+1)
NMR (CDCl3, δ): 1.43 (9H, s), 1.64 (3H, br), 1.86 (3H, br), 2.09 (1H, m), 2.25 (1H, m), 2.70 (2H, m), 2.82 (1H, m), 2.94 (1H, m), 3.67 (1H, m), 3.73 (1H, d, J=13.6 Hz), 3.82 (1H, d, J=13.6 Hz), 3.99 (1H, m), 4.92 (1H, m), 5.05 (1H, br), 6.48 (1H, br), 7.25 (1H, d, J=7.5 Hz), 7.54 (1H, t, J=7.5 Hz), 7.69 (2H, m), 7.76 (2H, m), 8.00 (1H, br), 8.10 (1H, d, J=8.8 Hz), 8.51 (1H, br), 8.80 (1H, dd, J=1.8 Hz)
MS (ES+) m/z 574 (M+1)
NMR (CDCl3, δ): 1.44 (9H, s), 1.64 (3H, br), 1.87 (3H, br), 2.05 (1H, m), 2.22 (1H, m), 2.64 (1H, m), 2.74 (2H, m), 3.01 (1H, t), 3.66 (1H, m), 3.69 (1H, d, J=13.6 Hz), 3.75 (1H, d, J=13.2 Hz), 3.98 (1H, m), 4.90 (1H, m), 5.03 (1H, br), 6.43 (1H, br), 6.54 (1H, d, J=2.9 Hz), 6.64 (1H, d, J=3.3 Hz), 7.30 (1H, d, J=8.4 Hz), 7.69 (1H, d, J=16.1 Hz), 7.77 (1H, d, J=8.4, 2.6 Hz), 8.55 (1H, br),
MS (ES+) m/z 543 (M+1)
NMR (CDCl3, δ): 1.45 (9H, s), 1.63 (3H, br), 1.86 (3H, br), 2.03 (1H, m), 2.22 (1H, m), 2.26 (3H, s), 2.59 (1H, q, J=8.4 Hz), 2.69 (1H, t, J=8.6 Hz), 2.82 (1H, m), 3.11 (1H, t, J=8.4 Hz), 3.55 (1H, d, J=13.9 Hz), 3.62 (1H, d, J=13.6 Hz), 3.66 (1H, m), 3.98 (1H, m), 4.92 (1H, m), 5.03 (1H, br), 5.86 (1H, dd, J=2.9, 1.0 Hz), 6.03 (1H, d, J=2.9 Hz), 6.40 (1H, br), 7.30 (1H, d, J=8.4 Hz), 7.68 (1H, d, J=15.4 Hz), 7.76 (1H, dd, J=8.4 and 2.2 Hz), 8.53 (1H, d, J=2.2 Hz)
MS (ES+) m/z 527 (M+1)
NMR (CDCl3, δ): 1.45 (9H, s), 1.62 (3H, br), 1.85 (3H, br), 2.05 (1H, br), 2.26 (1H, br), 2.69 (1H, br), 2.86 (2H, br), 3.18 (1H, br), 3.28 (2H, br), 3.66 (1H, m), 3.98 (1H, m), 4.93 (1H, m), 5.02 (1H, br), 6.06 (1H, dt, J=15.8 and 6.6 Hz), 6.43 (1H, d, J=15.4 Hz), 6.54 (1H, br), 6.67 (2H, d, J=8.8 Hz), 7.25 (2H, d, J=8.1 Hz), 7.29 (1H, d, J=8.4 Hz), 7.67 (1H, d, J=16.1 Hz), 7.76 (1H, d, J=8.4 Hz), 8.53 (1H, s)
MS (ES+) m/z 592 (M+1) preparation 254
NMR (CDCl3, δ): 0.81 (9H, s), 1.44 (9H, s), 1.62 (3H, br), 1.86 (3H, br), 2.01 (1H, m), 2.17 (3H, m), 2.67 (2H, m), 2.88 (2H, m), 3.67 (1H, m), 3.97 (1H, m), 4.86 (1H, m), 5.03 (1H, br), 6.41 (1H, br), 7.30 (1H, d, J=8.4 Hz), 7.71 (1H, br.d, J=15.8 Hz), 7.78 (1H, d, J=8.1 Hz), 8.58 (1H, s),
MS (ES+) m/z 503 (M+1)
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)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (110 mg), cesium carbonate (583 mg), and (3R)-1-(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 ag 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)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}phenyl)acrylate (297 mg) as pale yellow form.
NMR (CDCl3, δ): 1.33 (3H, t, J=7.1 Hz), 2.00 (1H, m), 2.23 (0.5H, m), 2.36 (0.5H, m), 3.35 (0.5H, m), 3.60 (1.5H, m), 3.81 (1H, m), 4.03 (1H, m), 4.10 (1H, 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 (1H, d, J=8.4 Hz), 6.62 (1H, d, J=8.1 Hz), 7.33-7.62 (7H, m)
MS (ES+) m/z 399 (M+1)
To a solution of ethyl (2E)-3-(4-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}phenyl)acrylate (297 mg) in dioxane (3 mL) was added 1N 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)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}phenyl)acrylic acid (103 mg) as pale yellow powder.
NMR (DMSO-d6, δ): 1.88 (1H, m), 2.19 (1H, m), 3.25 (1H, m), 3.43 (1H, m), 3.59 (1H, m), 3.79 (1H, m), 4.07 (1H, m), 6.14 (0.5H, d, J=16.1 Hz), 6.18 (0.5H, d, J=16.1 Hz), 6.57 (1H, d, J=8.8 Hz), 6.64 (1H, d, J=8.8 Hz), 7.36-7.47 (2H, m), 7.50 (1H, s), 7.53 (2H, d, J=8.1 Hz), 7.57 (2H, d, J=8.1 Hz), 7.93 (1H, d, J=8.4 Hz)
MS (ES+) m/z 371 (M+1)
To a solution of (2E)-3-(4-{[(3R)-1-(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)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}phenyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (76 mg) as pale yellow form.
NMR (DMSO-d6, δ): 1.54 (3H, br), 1.68 (3H, br), 1.89 (1H, br), 2.19 (1H, br), 3.24 (1H, br), 3.53 (3H, br), 3.79 (1H, m), 3.95 (1H, br), 4.07 (1H, br), 4.87 (1H, br), 6.17 (1H, br), 6.44 (0.5H, d, J=16.1 Hz), 6.46 (0.5H, d, J=16.1 Hz), 6.57 (1H, d, J=−8.8 Hz), 6.65 (1H, d, J=8.4 Hz), 7.26-7.37 (3H, m), 7.47-7.58 (4H, m)
MS (ES+) m/z 470 (M+1)
To a solution of ethyl (2E)-3-(6-chloro-3-pyridyl)acrylate (3.5 g) in dioxene (70 mL) was added palladium(II) acetate (371 mg) and 2′-(dicyclohexylphosphino)-N,N-dimethyl-2-diphenylamine (110 mg) and cesium carbonate (583 mg), and (3R)-1-(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 (1:4)—AcOEt to give ethyl (2E)-3-(6-{[(3R)-1-(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 (1H, m), 2.35 (1H, m), 3.37 (0.5H, dd, J=11.0, 5.5 Hz), 3.60 (1.5H, m), 3.78 (0.5H, m), 3.88 (1H, m), 4.04 (0.5H, m), 4.25 (2H, q, J=7.0 Hz), 4.53 (1H, 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+1)
The following compounds were obtained according to a similar manner to that of Preparation 258.
NMR (CDCl3, δ): 1.33 (3H, t, J=7.0 Hz), 2.01 (1H, m), 2.35 (1H, m), 3.37 (0.5H, dd, J=11.0, 5.5 Hz), 3.60 (1.5H, m), 3.78 (0.5H, m), 3.88 (1H, m), 4.04 (0.5H, m), 4.25 (2H, q, J=7.0 Hz), 4.53 (1H, 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+1)
To a solution of ethyl (2E)-3-(6-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate (2.16 g) in MeOH (30 mL) and dioxane (30 mL) was added 1N NaOH aq solution (27.1 mL). The mixture was heated at 70° C. for 1.5 hour and diluted with water (120 mL) 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)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylic acid (1.58 g) as pale yellow powder.
NMR (DMSO-d6, δ): 1.93 (1H, m), 2.20 (1H, m), 3.25-3.72 (4H, m), 3.80 (1H, 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+1)
The following compounds were obtained according to a similar manner to that of Preparation 260.
NMR (DMSO-d6, δ): 1.93 (1H, m), 2.20 (1H, m), 3.25-3.72 (4H, m), 3.80 (1H, 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+1)
To a solution of (2E)-3-(6-{[(3R)-1-(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-d6, δ): 1.53 (brH,), 1.69 (brH,), 1.92 (mH,), 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 (sH,)
MS (ES+) m/z 471 (M+1)
The following compounds were obtained according to a similar manner to that of Preparation 262.
NMR (DMSO-d6, δ): 1.53 (3H, br), 1.69 (3H, br), 1.92 (1H, m), 2.19 (1H, m), 3.23-3.70 (4H, m), 3.80 (1H, m), 3.95 (1H, m), 4.36 (0.5H, m), 4.49 (0.5H, m), 4.87 (1H, 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 (1H, s), 8.20 (1H, s)
MS (ES+) m/z 471 (M+1)
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-diphenylamine (231 mg), cesium carbonate (1.79 g), and (3R)-1-benzyl-3-pyrrolidinamine (760 mg). The mixture was heated at 90° C. for 24 hours. 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 silica gel column chromatography eluted with chloroform:methanol=9:1 to give ethyl (2E)-3-(4-{[(3R)-1-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 (1H, m), 2.44 (1H, m), 2.56 (1H, m), 2.78 (2H, m), 3.63 (2H, s), 4.03 (1H, m), 4.23 (2H, q, J=7.0 Hz), 4.26 (1H, m), 6.20 (1H, d, J=15.8 Hz), 6.52 (2H, d, J=8.8 Hz), 7.32 (7H, m), 7.58 (1H, d, J=15.8 Hz)
MS (ES+) m/z 351 (M+1)
To a solution of ethyl (2E)-3-(4-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}phenyl)acrylate (1.017 g) in MeOH (3 mL) and dioxane (3 mL) was added 1N NaOH aq solution (5.8 mL), and the mixture was stirred at ambient temperature for 2 hours. To the mixture was added 1N 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 1N 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-(4-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}phenyl)acrylic acid and the crude product was used in next reaction without further purification.
NMR (DMSO-d6, δ): 1.65 (1H, br), 2.26 (1H, br), 2.74 (1H, br), 2.89 (1H, br), 3.43 (1H, br), 3.69 (1H, br), 3.97 (1H, br), 4.10 (0.5H, br), 4.37 (0.5H, br), 6.14 (1H, d, J=15.8 Hz), 6.46 (1H, d, J=5.9 Hz), 6.55 (2H, d, J=8.4 Hz), 7.28 (1H, br), 7.37 (4H, m), 7.42 (1H, d, J=15.8 Hz), 7.04 (1H, m)
MS (ES+) m/z 323 (M+1)
To a solution of (2E)-3-(4-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}phenyl)acrylic acid (936 mg, crude) in DMF (10 mL) was added was added O-(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 at 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)-1-benzyl-3-pyrrolidinyl]amino}phenyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (945 mg) as pale yellow form.
NMR (CDCl3, δ): 1.63 (3H, br), 1.85 (3H, br), 2.33 (1H, m), 2.45 (1H, m), 2.59 (1H, dd, J=9.9, 3.3 Hz), 2.80 (1H, m), 3.64 (2H, s), 2.64 (1H, m), 4.00 (1H, m), 4.00 (1H, m), 4.29 (1H, d, J=7.7 Hz), 4.99 (1H, s), 6.26 (1H, br), 6.51 (1H, d, J=8.4 Hz), 7.27 (1H, m), 7.32 (6H, m), 7.62 (1H, d, J=15.8 Hz),
MS (ES+) m/z 422 (M+1)
To a solution of 3-methyl-2-pyridineamine (10 g) in a mixed solution of AcOH (60 mL), water (12 mL), and sulfuric acid (4.2 mL) was added periodic acid dehydrate (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 1N 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, δ): 2.09 (3H, s), 4.95 (2H, br), 7.54 (1H, m), 8.03 (1H, m)
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(18 g 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 (1H, s), 8.41 (1H, s),
To a solution of 2-bromo-5-iodo-3-methylpyridine (1.5 g) in DMF (15 mL) was added palladium(II) acetate (56.5 mg) and tri-o-tolylphosphine (230 mg) and diisopropylethylamine (3.5 mL), and ethyl acrylate (1.09 mL). The mixture was heated at 90° C. for 1 hour. 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)acrylate (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 (1H, d, J=16.1 Hz), 7.60 (1H, d, J=16.1 Hz), 7.66 (1H, m), 8.33 (1H, m)
MS (ES+) m/z 270 (M+1)
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-diphenylamine (109 mg) and cesium carbonate (843 mg), and (3R)-(−)-1-benzyl-3-aminopyrrolidine (359 mg). The mixture was heated at 100° 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)-1-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 (1H, m), 2.10 (3H, s), 2.38 (2H, m), 2.72 (2H, m), 2.95 (1H, m), 6.67 (2H, s), 4.24 (2H, q, J=7.0 Hz), 4.72 (1H, m), 4.89 (1H, m), 6.20 (1H, d, J=16.1 Hz), 7.33 (5H, m), 7.42 (1H, s), 7.56 (1H, d, J=16.1 Hz), 8.09 (1H, s)
MS (ES+) m/z 366 (M+1)
To a solution of ethyl (2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-methyl-3-pyridyl)acrylate (366 mg) in MeOH (2 mL) and dioxane (2 mL) was added 1N 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 1N 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)-1-benzyl-3-pyrrolidinyl]amino}-5-methyl-3-pyridyl)acrylic acid and the crude product was used in next reaction without further purification.
NMR (DMSO-d6, δ): 1.92 (1H, br), 2.11 (3H, s), 2.26 (1H, br), 2.60-2.89 (2H, br), 2.97-3.23 (2H, br), 3.85 (2H, br), 4.59 (1H, br), 6.25 (1H, d, J=16.1 Hz), 7.34 (5H, m), 7.43 (1H, d, J=16.1 Hz), 7.67 (1H, s), 8.08 (1H, s)
MS (ES+) m/z 338 (M+1)
To a solution of (2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-methyl-3-pyridyl)acrylic acid (338 mg, crude) in DMF (4 mL) was added O-(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)-1-benzyl-3-pyrrolidinyl]amino}-5-methyl-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (306 mg) as pale yellow form.
NMR (CDCl3, δ): 1.67 (3H, br), 1.85 (3H, br), 2.10 (3H, s), 2.39 (2H, m), 2.72 (2H, m), 2.95 (1H, m), 3.65 (1H, m), 3.67 (2H, s), 4.72 (1H, m), 4.87 (1H, m), 5.00 (1H, br), 6.25 (1H, br), 7.33 (5H, m), 7.38 (1H, s), 7.61 (1H, d, J=16.1 Hz), 8.11 (1H, s)
MS (ES+) m/z 437 (M+1)
The following compound was obtained in a similar manner to that of Preparation 274.
1H-NMR (300 MHz, CDCl3) δ1.33 (3H, t, J=7 Hz), 1.43 (9H, s), 1.59-1.81 (3H, m), 1.87-2.03 (1H, m), 3.30-3.47 (3H, m), 3.71 (1H, d, J=10 Hz), 3.96 (1H, br peak), 4.25 (2H, q, J=7 Hz), 4.96 (1H, br peak), 6.70 (1H, d, J=15 Hz), 7.57 (1H, d, J=15 Hz), 7.91 (1H, d, J=2 Hz), 8.07 (1H, d, J=2 Hz)
MS (ES+) m/z 377
1H-NMR (300 MHz, CDCl3) δ 0.78-0.96 (mH, 2), 1.08-1.29 (3H, m), 1.33 (3H, t, J=7.3 Hz), 1.41-1.85 (10H, m), 2.04-2.19 (3H, m), 2.35-2.46 (1H, m), 2.51-2.69 (2H, m), 4.04-4.15 (1H, m), 4.25 (2H, q, J=7.3 Hz), 5.63 (1H, br.s), 6.67 (1H, d, J=15.4 Hz), 7.58 (1H, d, J=15.4 Hz), 7.89 (1H, d, J=1.1 Hz), 8.05 (1H, d, J=1.1 Hz)
MS (ES+) m/z 373(M+1)
To a solution of ethyl (2E)-3-{5-[(3R)-3-piperidinylamino]-2-pyrazinyl}acrylate 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-10-1) to give ethyl (2E)-3-(5-{[(3R)-1-cyclohexyl-3-piperidinyl]amino}-2-pyrazinyl)acrylate (235 mg) as an amorphous powder.
1H-NMR (300 MHz, CDCl3) δ 0.96-1.36 (9H, m), 1.49-1.88 (8H, m), 2.24-2.38 (1H, m), 2.38-2.51 (1H, m), 2.57-2.75 (3H, m), 4.06 (1H, br peak), 4.25 (2H, q, J=7 Hz), 5.69 (1H, br peak), 6.66 (1H, d, J=15 Hz), 7.56 (1H, d, J=15 Hz), 7.90 (1H, d, J=2 Hz), 8.05 (1H, d, J=2 Hz)
MS (ES+) m/z 359
The following compounds were obtained in a similar manner to that of Preparation 275.
1H-NMR (300 MHz, CDCl3) δ 0.73-0.92 (2H, m), 1.08-1.31 (3H, m), 1.35-1.82 (10H, m), 1.45 (9H, s), 1.98-2.51 (6H, m), 3.65-3.80 (1H, m), 4.91-5.11 (1H, m)
MS (ES+) m/z 297(M+1)
1H-NMR (300 MHz, CDCl3) δ 1.32 (3H, t, J=7 Hz), 1.50-1.84 (4H, m), 2.10-2.30 (1H, m), 2.34 (3H, s), 2.40-2.74 (3H, m), 3.44 (1H, d, J=12 Hz), 3.53 (1H, d, J=12 Hz), 4.10 (1H, br peak), 4.25 (2H, q, J=7 Hz), 5.57 (1H, br peak), 6.67 (1H, d, J=15 Hz), 7.14 (2H, d, J=8 Hz), 7.20 (2H, d, J=8 Hz), 7.56 (1H, d, J=15 Hz), 7.89 (1H, d, J=2 Hz), 8.04 (1H, d, J=2 Hz)
MS (ES+) m/z 381
1H-NMR (300 MHz, CDCl3) δ 1.32 (3H, t, J=7 Hz), 1.40-1.85 (4H, m), 2.15-2.32 (1H, m), 2.45-2.65 (3H, m), 3.44 (1H, d, J=12 Hz), 3.51 (1H, d, J=12 Hz), 4.10 (1H, br peak), 4.25 (2H, q, J=7 Hz), 5.45 (1H, br peak), 6.65 (1H, d, J=15 Hz), 7.16-7.32 (4H, m), 7.56 (1H, d, J=15 Hz), 7.89 (1H, s), 8.04 (1H, s)
MS (ES+) m/z 401
1H-NMR (300 MHz, CDCl3) δ 1.21-1.93 (14H, m), 2.20-2.39 (1H, m), 2.47-2.76 (4H, m), 4.09 (1H, br peak), 4.25 (2H, q, J=7 Hz), 5.58 (1H, br peak), 6.68 (1H, d, J=15 Hz), 7.58 (1H, d, J=15 Hz), 7.93 (1H, s), 8.06 (1H, s)
MS (ES+) m/z 345
1H-NMR (300 MHz, CDCl3) δ1.11-1.29 (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 (1H, m), 2.58-2.77 (2H, m), 4.10 (1H, br peak), 4.25 (2H, q, J=7 Hz), 5.66 (1H, br peak), 6.66 (1H, d, J=15 Hz), 7.58 (1H, d, J=15 Hz), 7.90 (1H, s), 8.05 (1H, s)
MS (ES+) m/z 359
To a solution of mixture of ethyl (2E)-3-(5-{[(3R)-1-cyclohexyl-3-piperidinyl]amino}-2-pyrazinyl)acrylate (227 mg) in EtOH (2 mL) was added 1N 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 1 mol/L hydrochloric acid and evaporated in 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)-1-cyclohexyl-3-piperidinyl]amino}-2-pyrazinyl)acrylic acid (209 mg) as a solid.
1H-NMR (300 MHz, DMSO-d6) δ 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 (1H, br peak), 6.46 (1H, d, J=15 Hz), 7.49 (1H, d, J=15 Hz), 7.48 (1H, br peak), 8.01 (1H, s), 8.21 (1H, s)
The following compounds were obtained in a similar manner to that of Preparation 281.
1H-NMR (300 MHz, DMSO-d6) δ 1.15-1.45 (1H, 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 (1H, d, J=15 Hz), 7.16-7.54 (6H, m), 8.00 (1H, s), 8.16 (1H, s)
MS (ES+) m/z 339
1H-NMR (300 MHz, DMSO-d6) δ 0.74-0.94 (2H, m), 1.04-1.30 (3H, m), 1.41 (1H, 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 (1H, m), 6.45 (1H, d, J=15.5 Hz), 7.47 (1H, d, J=15.5 Hz), 7.85 (1H, d, J=6.6 Hz), 8.00 (1H, s), 8.19 (1H, s)
MS (ES+) ma/z 331
1H-NMR (300 MHz, DMSO-d6) δ 1.30-1.54 (1H, 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 (1H, d, J=15 Hz), 7.28 (2H, d, J=8 Hz), 7.44 (2H, d, J=8 Hz), 7.51 (1H, d, J=15 Hz), 7.86 (1H, d, J=8 Hz), 8.01 (1H, s), 8.21 (1H, s)
MS (ES+) m/z 353
1H-NMR (300 MHz, DMSO-d6) δ 1.35-1.65 (1H, m), 1.65-2.14 (3H, m), 2.56-2.75 (1H, m), 2.75-2.95 (1H, m), 3.25-3.59 (2H, m), 4.16-4.49 (3H, m), 6.50 (1H, d, J=15 Hz), 7.45-7.70 (5H, m), 7.85 (1H, d, J=8 Hz), 8.01 (1H, s), 8.22 (1H, s)
MS (ES+) m/z 373
A mixture of (2E)-3-(5-{[(3R)-1-cyclohexyl-3-piperidinyl]amino}-2-pyrazinyl)acrylic acid (209 mg), 0-(tetrahydro-2H-pyran-2-yl)-mL) 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)-1-cyclohexyl-3-piperidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-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 (1H, m), 2.38-2.53 (1H, m), 2.53-2.74 (3H, m), 3.59-3.70 (1H, m), 3.90-4.02 (1H, m), 4.02-4.14 (1H, m), 5.01 (1H, br s), 5.60-5.75 (1H, m), 6.65 (1H, br peak), 7.63 (1H, d, J=15 Hz), 7.88 (1H, s), 8.04 (1H, s), 8.31 (1H, br peak)
MS (ES+) m/z 430
The following compounds were obtained in a similar manner to that of Preparation 286.
1H-NMR (300 MHz, CDCl3) δ 1.35-1.96 (9H, m), 2.14-2.35 (1H, m), 2.40-2.70 (3H, m), 3.49 (1H, d, J=13 Hz), 3.55 (1H, d, J=13 Hz), 3.60-3.78 (1H, m), 3.86-4.03 (1H, m), 4.03-4.15 (1H, m), 4.94-5.05 (1H, m), 5.45-5.60 (1H, m), 6.65 (1H, br peak), 7.15-7.35 (5H, m), 7.62 (1H, d, J=15 Hz), 7.86 (1H, s), 8.01 (1H, s), 8.19-8.35 (1H, m)
1H-NMR (300 MHz, CDCl3) δ 1.45-1.96 (9H, m), 2.11-2.29 (1H, m), 2.34 (3H, s), 2.43-2.72 (3H, m), 3.43 (1H, d, J=12 Hz), 3.52 (1H, d, J=12 Hz), 3.59-3.71 (1H, m), 3.90-4.04 (1H, m), 4.04 (1H, br peak), 5.01 (1H, br s), 5.58 (1H, br peak), 6.66 (1H, br peak), 7.14 (2H, d, J=8 Hz), 7.19 (2H, d, J=8 Hz), 7.61 (1H, d, J=15 Hz) 7.87 (1H, s), 8.00 (1H, s), 8.35 (1H, br peak)
MS (ES+) m/z 452
1H-NMR (300 MHz, CDCl3) δ 1.56-1.95 (9H, m), 2.15-2.33 (1H, m), 2.43-2.66 (3H, m), 3.44 (1H, d, J=12 Hz), 3.50 (1H, d, J=12 Hz), 3.59-3.71 (1H, m), 3.86-4.04 (1H, m), 4.10 (1H, br peak), 5.00 (1H, br s), 5.48 (1H, br peak), 6.70 (1H, br peak), 7.19-7.35 (4H, m), 7.53 (1H, d, J=15 Hz), 7.86 (1H, s), 8.01 (1H, s), 8.35 (1H, br peak)
MS (ES+) m/z 472
1H-NMR (300, MHz, DMSO-d6) δ 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 (1H, m), 2.72 (1H, m), 3.52 (1H, m), 3.95 (1H, m), 4.29 (1H, m), 4.89 (1H, m), 6.60 (1H, d, J=15.2 Hz), 7.38 (1H, d, J=15.2 Hz), 7.73 (1H, d, J=6.6 Hz), 7.98 (1H, s), 8.11 (1H, s), 11.18 (1H, s)
MS (ES+) m/z 430
To a mixture of tert-butyl (3R)-3-pyrrolidinylcarbamate (4.0 g) and 1-(chloromethyl)-4-methylbenzene (3.17 g) in DMF(40 mL) was added N-ethyl-N-isopropyl-2-propanamine (5.55 g) 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 (100 mL). The organic phase was washed with water (50 mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by a flash chromatography eluting 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 (4.69 g) as a pale yellow syrup.
1H-NMR (300 MHz, CDCl3) δ 1.43 (9H, s), 1.49-1.64 (1H, m), 2.12-2.37 (2H, m), 2-34 (3H, s), 2.43-2.64 (2H, m), 2.68-2.84 (1H, m), 3.55 (2H, s), 4.07-4.23 (1H, m), 4.76-4.92 (1H, m), 7.12 (2H, d, J=8.1 Hz), 7.19 (2H, d, J=8.1 Hz)
MS (ES+) m/z 291(M+1)
The following compounds were obtained in a similar manner to that of Preparation 291.
1H-NMR (300 MHz, CDCl3) δ 0.75-0.95 (2H, m), 1.06-1.31 (3H, m), 1.44 (3×3H, s), 1.50-1.83 (7H, m), 2.11-2.30 (4H, m), 2.39-2.58 (2H, m), 2.73 (1H, m), 4.13 (1H, m), 4.82 (1H, m)
MS (ES+) m/z 283
To a stirred solution of tert-butyl [(3R)-1-(4-methylbenzyl)-3-pyrrolidinyl]carbamate (4.6 g) in ethyl acetate (10 mL) was added 4N hydrogen chloride in ethyl acetate (60 mL) 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 (100 mL). To this solution was added saturated sodium bicarbonate (50 mL) 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 (50 mL) two times. The combined organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo to afford (3R)-1-(4-methylbenzyl)-3-pyrrolidinamine (2.1 g) as a pale brown viscous oil, which was used in the next step without further purification.
1H-NMR (300 MHz, CDCl3) δ 1.43-1.57 (1H, m), 1.81 (2H, br.s), 2.12-2.37 (1H, m), 2.28-2.37 (1H, m), 2.34 (3H, s), 2.43-2.55 (1H, m), 2.67-2.79 (2H, m), 3.46-3.55 (1H, m), 3.56 (1H, d, J=12.8 Hz), 3.62 (1H, 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+1)
The following compound was obtained in a similar manner to that of Preparation 293.
1H-NMR (300 MHz, DMSO-d6) δ 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 (1H, m), 2.39 (1H, m), 2.95-3.26 (3H, m), 3.28-4.09 (4H, m), 8.65 (2H, br)
MS (ES+) m/z 183
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)-1-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)-1-benzyl-3-piperidinyl]amino}2-pyrazinyl)acrylate (125 mg) as an oil.
1H-NMR (300 MHz, CDCl3) δ1.32 (3H, t, J=7.1 Hz), 1.47-1.83 (3H, m), 2.16-2.33 (1H, m), 2.42-2.73 (3H, m), 3.49 (1H, d, J=13.0 Hz), 3.56 (1H, d, J=13.0 Hz), 4.06-4.17 (1H, m), 4.25 (2H, q, J=7.1 Hz), 5.55 (1H, br peak), 6.67 (1H, d, J=15.5 Hz), 7.23-7.38 (5H, m), 7.57 (1H, d, J=15.5 Hz), 7.89 (1H, d, J=1.3 Hz), 8.04 (1H, d, J=1.3 Hz)
MS (ES+) m/z 367
The following compound was obtained in a similar manner to that of Preparation 295.
1H-NMR (300 MHz, CDCl3) δ 0.80-0.98 (2H, m), 1.08-1.31 (3H, m), 1.33 (3H, t, J=7 Hz), 1.44 (1H, m), 1.57-1.85 (6H, m), 2.18-2.42 (4H, m), 2.54-2.69 (2H, m), 2.88 (1H, m), 4.25 (2H, q, J=7 Hz), 4.43 (1H, m), 5.23 (1H, d, J=8 Hz), 6.68 (1H, d, J=15.5 Hz), 7.57 (1H, d, J=15.5 Hz), 7.89 (1H, s), 8.06 (1H, s)
MS (ES+) m/z 359
To a solution of tert-butyl (3R)-3-({5-[(1E)-3-ethoxy-3-oxo-1-propen-1-yl]-2-pyrazinyl}amino)-1-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-d6) δ 1.25 (3H, t, J=7 Hz), 1.46-1.65 (1H, m), 1.65-1.85 (1H, m), 1.85-2.06 (3H, m), 2.66-3.00 (2H, m), 3.05-3.25 (1H, m), 3.25-3.41 (1H, m), 4.18 (2H, q, J=7 Hz), 6.54 (1H, d, J=15 Hz), 7.57 (1H, d, J=15 Hz), 7.95-8.19 (2H, m), 8.28 (1H, 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.
30 1H-NMR (300 MHz, CDCl3)(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 (1H, m), 2.08 (2H, d, J=7.2 Hz), 2.46-2.58 (1H, m), 2.62-2.73 (1H, m), 2.80-2.92 (1H, m)
MS (ES+) m/z 197(M+1)
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, g, J=7 Hz), 7.01 (1H, d, J=15 Hz), 7.66 (1H, d, J=15 Hz), 8.43 (1H, s), 8.60 (1H, s)
To a solution of ethyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate (1.50 g) in DMF (21 mL) was added (3R)-1-benzyl-3-pyrrolidinamine (2.24 g) and 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)-1-benzyl-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate (1.15 g)
1H-NMR (300 MHz, CDCl3) δ 1.32 (3H, t, J=7 Hz), 1.65-1.76 (1H, m), 2.32-2.43 (2H, m), 2.66-2.70 (2H, m), 2.87-2.95 (1H, m), 3.62-3.66 (2H, m), 4.25 (2H, q, J=7 Hz), 4.40-4.52 (1H, m), 5.21 (1H, d, J=8 Hz), 6.67 (1H, d, J=15 Hz), 7.24-7.35 (5H, m), 7.57 (1H, d, J=15 Hz), 7.87 (1H, s), 8.05 (1H, s)
MS (ES+) m/z 353 (M+1)
To a solution of ethyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate (1.78 g) and (3R)-1-(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)acrylate (1.58 g).
1H-NMR (300 MHz, CDCl3) δ 1.32 (3H, t, J=7 Hz), 1.66-1.74 (1H, m), 2.31-2.43 (2H, m), 2.62-2.71 (2H, m), 2.85-2.92 (1H, m), 3.59-3.62 (2H, m), 4.25 (2H, q, J=7 Hz), 4.41-4.52 (1H, m), 5.19 (1H, d, J=8 Hz), 6.68 (1H, d, J=15 Hz), 7.23-7.32 (4H, m), 7.57 (1H, d, 3=15 Hz), 7.88 (1H, s), 8.05 (1H, s)
MS (ES+) m/z 387 (M+1)
The following compound was obtained in a similar manner to that of Preparation 301.
1H-NMR (300 MHz, CDCl3) δ 1.32 (3H, t, J=7 Hz), 1.67-1.73 (1H, m), 2.32-2.42 (2H, m), 2.34 (3H, s), 2.66-2.69 (2H, m), 2.88-2.95 (1H, m), 3.60-3.63 (2H, m), 4.25 (2H, q, J=7 Hz), 4.41-4.51 (1H, m), 5.24-5.31 (1H, m), 6.67 (1H, d, J=15 Hz), 7.13 (2H, d, J=8 Hz), 7.21 (2H, d, J=8 Hz), 7.57 (1H, d, J=15 Hz), 7.87 (1H, s), 8.05 (1H, s)
MS (ES+) m/z 367 (M+1)
1) To a solution of ethyl (2E)-3-(5-{[(3R)-1-(4-chlorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate (1.57 g) in dioxane (20 mL) was added 1N sodium hydroxide (12.2 mL). After stirring at 60° C. for 2 hours, the reaction mixture was added H2O (100 mL) and acidified with 1N hydrochloric acid (to pH 4). A resulting mixture was evaporated in vacuo
2) To a mixture of above product, O-tetrahydro-2H-pyran-2-ylhydroxylamine (713 mg), and 1-hydroxybenzotriazole (823 mg) in N,N-dimethylformamide (20 mL) was added 1-(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)-1-(4 chlorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (1.44 g).
1H-NMR (300 MHz, DMSO-d6) δ 1.47-1.74 (7H, m), 2.16-2.30 (1H, m), 2.37-2.45 (2H, m), 2.61-2.80 (2H, m), 3.48-3.60 (3H, m), 3.89-4.00 (1H, m), 4.25-4.35 (1H, m), 4.89 (1H, brs), 6.59 (1H, d, J=15 Hz), 7.32-7.42 (5H, m), 7.77 (1H, d, J=6 Hz), 7.97 (1H, s), 8.09 (1H, s), 11.2 (1H, brs)
MS (ES+) m/z 458 (M+1)
The following compounds were obtained in a similar manner to that of Preparation 303.
1H-NMR (300 MHz, CDCl3) δ 1.20-1.96 (20H, m), 2.20-2.37 (1H, m), 2.47-2.80 (4H, m), 3.59-3.71 (1H, m), 3.88-4.02 (1H, m), 4.02-4.15 (1H, m), 5.02 (1H, br s), 5.56 (1H, br peak), 6.68 (1H, br peak), 7.63 (1H, d, J=15 Hz), 7.90 (1H, s), 8.02 (1H, s), 8.30 (1H, br peak)
MS (ES+) m/z 416
1H-NMR (300 MHz, CDCl3) δ 1.11-1.30 (2H, m), 1.45-1.98 (16H, m), 1.96-2.29 (4H, m), 2.35-2.51 (1H, m), 2.56-2.76 (2H, m), 3.59-3.70 (1H, m), 3.90-4.03 (1H, m), 4.10 (1H, br peak), 5.01 (1H, br s), 5.65 (1H, br peak), 6.67 (1H, br peak), 7.62 (1H, d, J=15 Hz), 7.87 (1H, s), 8.03 (1H, s), 8.34 (1H, br peak)
MS (ES+) m/z 430
1H-NMR (300 MHz, DMSO-d6) δ 1.47-1.74 (7H, m), 2.16-2.30 (1H, m), 2.36-2.46 (2H, m), 2.60-2.80 (2H, m), 3.47-3.60 (3H, m), 3.88-4.00 (1H, m), 4.25-4.35 (1H, m), 4.89 (1H, brs), 6.59 (1H, d, J=15 Hz), 7.21-7.34 (5H, m), 7.37 (1H, d, J=15 Hz), 7.77 (1H, d, J=6 Hz), 7.97 (1H, s), 8.09 (1H, s), 11.2 (1H, brs)
MS (ES+) m/z 424 (M+1)
1H-NMR (300 MHz, DMSO-d6) δ 1.47-1.74 (7H, m), 2.15-2.30 (1H, 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 (1H, m), 4.24-4.36 (1H, m), 4.89 (1H, brs), 6.59 (1H, d, J=15 Hz), 7.11 (2H, d, J=8 Hz), 7.19 (2H, d, J=8 Hz), 7.37 (1H, d, J=15 Hz), 7.76 (1H, d, J=6 Hz), 7.97 (1H, s), 8.09 (1H, s), 11.2 (1H, brs)
MS (ES+) m/z 438 (M+1)
The following compound was obtained in similar manners to those of Preparations 281 and 286.
1H-NMR (300 MHz, DMSO-d6) 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 (1H, m), 2.75-2.86 (1H, m), 3.46-3.58 (1H, m), 3.82-4.03 (2H, m), 4.89 (1H, br.s), 6.59 (1H, d, J=15.4 Hz), 7.38 (1H, d, J=15.4 Hz), 7.43 (1H, br.s), 7.97 (1H, s), 8.11 (1H, s)
MS (ES+) m/z 444(M+1)
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 S hrs. To the reaction mixture were added (3R)-1-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/1-4˜1-3) to give ethyl 6-{[(3R)-1-benzyl-3-piperidinyl]amino}-5-chloronicotinate (6.75 g, 52%) as a powder.
1H-7NMR (300 MHz, CDCl3)(1.36 (3H, t, J=7.1 Hz), 1.51-1.69 (2H, m), 1.69-1.88 (2H, m), 2.18-2.33 (1H, m), 2.41-2.54 (1H, m), 2.54-2.67 (1H, m), 2.67-2.79 (1H, m), 3.45 (1H, d, J=13 Hz), 3.61 (1H, d, J=13 Hz), 4.32 (2H, q, J=7.1 Hz), 6.24 (1H, br peak), 7.21-7.41 (5H, m), 8.00 (1H, d, J=2 Hz), 8.65 (1H, d, J=2 Hz);
MS (ES+) m/z 374.
A mixture of ethyl (2E)-3-(5-bromo-2-pyridinyl)acrylate (480 mg), (3R)-1-benzyl-3-pyrrolidinamine (363 mg), cesium carbonate (855 mg, 1.4 eq.), CyDMABP (2-Dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl, 63 mg, 0.15 eq.), and palladium acetate (250 mg, 0.6 eq.) in dioxane (25 ml) 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 37 mg (6%) of ethyl (2E)-3-(5-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-2-pyridinyl)acrylate as an oil.
MASS (ESI+): m/z=352.3 (M+1).
1HNMR (400 MHz, CDCl3): δ 1.31 (3H, t, J=7.1 Hz), 1.68-1.78 (1H, m), 2.31-2.95 (5H, m), 3.69 (2H, s), 4.01-4.09 (1H, m), 4.24 (2H, q, J=7.1 Hz), 4.44-4.51 (1H, m), 6.62 (1H, d, J=15.5 Hz), 6.79 (1H, dd, J=8.5 and 2.9 Hz), 7.23-7.36 (6H, m), 7.18 (1H, d, J=8.4 Hz), 7.24 (1H, d, J=8.5 Hz), 7.32-7.40 (5H, m), 7.60 (1H, d, J=15.5 Hz), 8.01 (1H, d, J=2.9 Hz).
To a solution of ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate dihydrochloride (220 mg, 0.51 mmol) in 1,2-dichloroethane (4 mL) 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=10-1) to give ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(cyclopentylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate (225 mg, 100%) as an amorphous powder.
1H-NMR (300 MHz, CDCl3) δ1.00-1.21 (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 (1H, m), 4.29 (2H, q, J=7.5 Hz), 4.80-4.96 (1H, m), 6.46 (1H, d, J=15 Hz), 7.32 (1H, d, J=8 Hz), 7.66 (1H, d, J=15 Hz), 7.80 (1H, dd, J=8.2 Hz), 8.55 (1H, d, J=2 Hz);
MS (ES+) m/z 444.
The following compounds were obtained in a similar manner to that of Preparation 311.
1H-NMR (300 MHz, CDCl3) δ1.36 (3H, t, J=7.1 Hz), 1.46-1.84 (5H, m), 2.20-2.40 (1H, m), 2.40-2.67 (2H, m), 3.45-3.58 (2H, m), 3.97 (1H, br peak), 4.32 (2H, q, J=7.1 Hz), 5.54 (1H, br peak), 6.33 (1H, d, J=8.7 Hz), 7.23-7.40 (5H, m), 7.96 (1H, dd, J=8.8, 2.2 Hz), 8.73 (1H, d, J=2.2 Hz);
MS (ES+) m/z 340.
1H-NMR (300 MHz, CDCl3) δ1.33 (3H, t, J=7.1 Hz), 1.46-1.84 (3H, m), 2.18-2.36 (1H, m), 2.36-2.66 (3H, m), 3.43 (1H, d, J=13.5 Hz), 3.50 (1H, d, J=13.5 Hz), 3.88-4.04 (1H, m), 4.24 (2H, q, J=7.1 Hz), 5.21-5.41 (1H, m), 6.20 (1H, d, J=15.9 Hz), 6.38 (1H, d, J=8.8 Hz), 7.18-7.38 (4H, m), 7.56 (1H, d, J=16.1 Hz), 7.60 (1H, dd, J=9.4, 2.3 Hz), 8.18 (1H, d, J=2.3 Hz); MS (ES+) m/z 400.
1H-NMR (300 MHz, CDCl3) δ1.16-1.90 (15H, m), 2.20-2.77 (5H, m), 3.92 (1H, br peak), 4.24 (2H, q, J=7.1 Hz), 5.40 (1H, br peak), 6.20 (1H, d, J=15.9 Hz), 6.40 (1H, d, J=8.8 Hz), 7.56 (1H, d, J=15.9 Hz), 7.61 (1H, dd, J=8.7, 2.3 Hz), 8.18 (1H, d, J=2.1 Hz);
MS (ES+) m/z 344.
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 (1H, m), 2.25-2.56 (2H, m), 2.68-2.89 (2H, m), 2.89-3.05 (1H, m), 4.23-4.45 (3H, m), 5.24 (1H, br peak), 6.40 (1H, d, J=8.8 Hz), 6.81 (1H, d, J=36.3 Hz), 7.82 (1H, dd, J=8.8, 1.9 Hz), 8.24 (1H, s);
MS (ES+) m/z 362.
1H-NMR (300 MHz, CDCl3) δ 1.35 (3H, t, J=7.1 Hz), 1.44 (9H, s), 1.50-2.30 (20H, m), 2.65-3.20 (1H, m), 4.29 (2H, q, J=7.2 Hz), 6.46 (1H, d, J=16.1 Hz), 8.31 (1H, d, J=8.2 Hz), 7.66 (1H, d, J=16.5 Hz), 7.81 (1H, dd, J=8.3, 2.7 Hz), 8.56 (1H, d, J=2.7 Hz);
MS (ES+) m/z 510.
1H-NMR (300 MHz, CDCl3)(1.32 (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 (1H, d, J=13.1 Hz), 3.50 (1H, d, J=13.1 Hz), 3.95 (1H, br peak), 4.24 (2H, q, J=7.1 Hz), 5.40 (1H, br peak), 6.20 (1H, d, J=15.9 Hz), 6.38 (1H, d, J=8.8 Hz), 7.12 (2H, d, J=7.9 Hz), 7.20 (2H, d, J=7.9 Hz), 7.55 (1H, d, J=15.5 Hz), 7.60 (1H, dd, J=8.8, 2.2 Hz), 8.17 (1H, d, J=2.1 Hz).
1H-NMR (300 MHz, CDCl3) δ 1.37 (3H, t, J=7.1 Hz), 1.59-1.78 (1H, m), 2.26-2.47 (5H, m), 2.60 (1H, dd, J=9.6, 3.2 Hz), 2.74 (1H, dd, J=9.7, 6.4 Hz), 2.78-2.90 (1H, m), 3.56 (1H, d, J=12.8 Hz), 3.64 (1H, d, J=12.8 Hz), 4.25-4.41 (3H, m), 5.12 (1H, br d, J=7.8 Hz), 6.38 (1H, d, J=8.9 Hz), 6.79 (1H, d, J=36.2 Hz), 7.12 (2H, d, J=7.9 Hz), 7.21 (2H, d, J=7.9 Hz), 7.81 (1H, dd, J=8.9, 2.2 Hz), 8.23 (1H, d, J=1.8 Hz);
MS (ES+) m/z 384.
1H-NMR (300 MHz, CDCl3) δ1.37 (3H, t, J=7.1 Hz), 1.56-1.78 (1H, m), 2.28-2.46 (2H, m), 2.60 (1H, dd, J=9.7, 3.2 Hz), 2.73 (1H, dd, J=9.7, 6.3 Hz), 2.77-2.88 (1H, m), 3.56 (1H, d, J=13.6 Hz), 3.61 (1H, d, J=13.6 Hz), 4.26-4.42 (3H, m), 5.08 (1H, br d, J=7.9 Hz), 6.38 (1H, d, J=8.8 Hz), 6.80 (1H, d, J=36.2 Hz), 7.25 (2H, d, J=8.7 Hz), 7.30 (2H, d, J=8.7 Hz), 7.82 (1H, dd, J=8.9, 2.2 Hz), 8.24 (1H, d, J=2.0 Hz).
1H-NMR (300 MHz, CDCl3) δ 1.32 (3H, t, J=7.1 Hz), 1.5-1.85 (4H, m), 2.20-2.35 (1H, m), 2.49-2.71 (3H, m), 3.46 (1H, d, J=13.5 Hz), 3.53 (1H, d, J=13.5 Hz), 4.12 (1H, br peak), 4.25 (2H, q, J=7.1 Hz), 5.50 (1H, br peak), 6.67 (1H, d, J=15.5 Hz), 7.15-7.40 (4H, m), 7.58 (1H, d, J=15.5 Hz), 7.91 (1H, s), 8.05 (1H, s);
MS (ES+) m/z 401.
1H-NMR (300 MHz, CDCl3) δ1.32 (3H, t, J=7.1 Hz), 1.48-1.88 (4H, m), 2.20-2.36 (1H, m), 2.54-2.80 (3H, m), 3.56 (1H, d, J=13.6 Hz), 3.64 (1H, d, J=13.6 Hz), 4.14 (1H, br peak), 4.25 (2H, q, J=7.1 Hz), 5.72 (1H, br peak), 6.66 (1H, d, J=15.5 Hz), 7.16-7.25 (2H, m), 7.34-7.42 (2H, m), 7.56 (1H, d, J=15.5 Hz), 7.89 (1H, s), 8.03 (1H, s);
MS (ES+) m/z 401.
1H-NMR (300 MHz, CDCl3) δ 1.32 (3H, t, J=7.1 Hz), 1.50-1.82 (4H, m), 2.18-2.31 (1H, m), 2.44-2.66 (3H, m), 3.45 (1H, d, J=13.2 Hz), 3.51 (1H, d, J=13.1 Hz), 4.10 (1H, br peak), 4.25 (2H, q, J=7.1 Hz), 5.46 (1H, br peak), 6.67 (1H, d, J=15.6 Hz), 7.01 (2H, t, J=8.7 Hz), 7.21-7.33 (2H, m), 7.56 (1H, d, J=15.6 Hz), 7.90 (1H, s), 8.03 (1H, s);
MS (ES+) m/z 385.
1H-NMR (300 MHz, CDCl3) δ1.33 (3H, t, J=7.1 Hz), 1.50-1.69 (2H, m), 1.69-1.89 (2H, m), 2.24-2.37 (1H, m), 2.43-2.55 (1H, m), 2.60-2.84 (2H, m), 3.70 (1H, d, J=13.9 Hz), 3.80 (1H, d, J=13.9 Hz), 4.14 (1H, br peak), 4.25 (2H, q, J=7.1 Hz), 5.64 (1H, br peak), 6.68 (1H, d, J=15.5 Hz), 6.88-6.93 (1H, m), 6.93-6.99 (1H, m), 7.20-7.30 (1H, m), 7.58 (1H, d, J=15.5 Hz), 7.92 (1H, s), 8.05 (1H, s);
MS (ES+) m/z 373.
1H-NMR (300 MHz, CDCl3) δ1.32 (3H, t, J=7.1 Hz), 1.40-1.82 (4H, m), 2.17-20.32 (1H, m), 2.43-2.72 (3H, m), 3.51 (1H, d, J=13.4 Hz), 3.60 (1H, d, J=13.4 Hz), 4.10 (1H, brpeak), 4.25 (2H, q, J=7.1 Hz), 5.52 (1H, br peak), 6.67 (1H, d, J=15.5 Hz), 7.06 (1H, d, J=4.9 Hz), 7.10 (1H, d, J=2.3 Hz), 7.29 (1H, dd, J=7.7, 3.0 Hz), 7.56 (1H, d, J=15.6 Hz), 7.9 (1H, s), 8.05 (1H, s);
MS (ES+) m/z 373.
1H-NMR (300 MHz, CDCl3) δ1.32 (3H, t, J=7.1 Hz), 1.53-1.91 (4H, m), 2.26-2.45 (1H, m), 2.50-2.75 (3H, m), 3.63 (1H, d, J=13.8 Hz), 3.71 (1H, d, J=13.8 Hz), 4.05-4.18 (1H, m), 4.25 (2H, q, J=7.1 Hz), 5.68 (1H, br peak), 6.65 (1H, d, J=15.5 Hz), 7.19 (1H, dd, J=7.5, 5.5 Hz), 7.38 (1H, d, J=7.7 Hz), 7.56 (1H, d, J=15.5 Hz), 7.66 (1H, t, J=7.5 Hz), 7.91 (1H, s), 8.01 (1H, s), 8.55 (1H, d, J=4.4 Hz);
MS (ES+) m/z 368.
1H-NMR (300 MHz, CDCl3) δ1.32 (3H, t, J=7.1 Hz), 1.50-1.84 (4H, m), 2.20-2.35 (1H, m), 2.45-2.68 (3H, m), 3.50 (1H, d, J=14.7 Hz), 3.66 (1H, d, J=14.7 Hz), 4.14 (1H, br peak), 4.25 (2H, q, J=7.1 Hz), 5.45 (1H, br peak), 6.66 (1H, d, J=15.5 Hz), 7.23-7.32 (1H, m), 7.56 (1H, d, J=15.5 Hz), 7.66 (1H, d, J=7.8 Hz), 7.90 (1H, s), 8.04 (1H, s), 8.51 (1H, d, J=4.7 Hz), 8.54 (1H, s);
MS (ES+) m/z 368.
1H-NMR (300 MHz, CDCl3) δ1.04-1.23 (2H, m), 1.23-1.84 (18H, m), 2.01-2.19 (3H, m), 2.33-2.48 (1H, m), 2.48-2.70 (2H, m), 4.10 (1H, br peak), 4.25 (2H, q, J=7.0 Hz), 5.64 (1H, br peak), 6.66 (1H, d, J=15.8 Hz), 7.57 (1H, d, J=15.4 Hz), 7.89 (1H, d, J=1.1 Hz), 8.05 (1H, d, J=1.5 Hz);
MS (ES+) m/z 387.
1H-NMR (300 MHz, CDCl3) δ1.32 (3H, t, J=7.1 Hz), 1.50-1.85 (4H, m), 2.20-2.35 (1H, m), 2.46-2.86 (7H, m), 4.11 (1H, br peak), 4.25 (2H, q, J=7.1 Hz), 5.46 (1H, br peak), 6.67 (1H, d, J=15.5 Hz), 7.16-7.37 (5H, m), 7.56 (1H, d, J=15.5 Hz), 7.77 (1H, s), 8.04 (1H, s);
MS (ES+) m/z 381.
1H-NMR (300 MHz, CDCl3) δ1.22-1.90 (19H, m), 2.35-2.72 (5H, m), 4.06 (1H, br peak), 4.25 (2H, q, J=7.1 Hz), 5.68 (1H, br d, J=7.0 Hz), 6.66 (1H, d, J=15.5 Hz), 7.58 (1H, d, J=15.5 Hz), 7.91 (1H, s), 8.05 (1H, MS (ES+) m/z 373.
1H-NMR (300 MHz, CDCl3) δ1.33 (3H, t, J=7.1 Hz), 1.50-1.86 (4H, m), 2.24-2.36 (1H, m), 2.44-2.71 (3H, m), 3.48 (1H, d, J=14.8 Hz), 3.55 (1H, d, J=14.8 Hz), 4.06-4.20 (1H, m), 4.25 (2H, q, J=7.1 Hz), 5.42 (1H, br peak), 6.68 (1H, d, J=15.5 Hz), 7.21-7.29 (2H, m), 7.57 (1H, d, J=15.5 Hz), 7.92 (1H, s), 8.05 (1H, s), 8.55 (2H, d, J=5.8 Hz);
MS (ES+) m/z 368.
1H-NMR (300 MHz, CDCl3) δ0.96-1.36 (10H, m), 1.46-1.86 (7H, m), 2.20-2.40 (1H, m), 2.40-2.65 (3H, m), 4.74 (1H, br d, J=11 Hz), 3.81-3.98 (1H, m), 4.24 (2H, q, J=7.1 Hz), 5.36-5.55 (1H, m), 6.20 (1H, d, J=15.9 Hz), 6.40 (1H, d, J=8.8 Hz), 7.57 (1H, d, J=15.8 Hz), 7.60 (1H, dd, J=8.7, 2.3 Hz), 8.18 (1H, d, J=2.2 Hz);
MS (ES+) m/z 358.
1H-NMR (300 MHz, CDCl3) δ 0.98-1.15 (2H, m), 1.21-1.91 (24H, m), 1.93-2.30 (4H, m), 2.50-2.76 (2H, m), 2.91 (1H, br peak), 4.28 (2H, q, J=7.2 Hz), 4.90 (1H, br peak), 6.46 (1H, d, J=16 Hz), 7.31 (1H, d, J=8 Hz), 7.65 (1H, d, J=16 Hz), 7.80 (1H, dd, J=8.2 Hz), 8.55 (1H, d, J=2 Hz);
MS (ES+) m/z 472.
1H-NMR (300 MHz, CDCl3) δ 1.19-1.38 (4H, m), 1.57-1.86 (3H, m), 2.28-2.43 (1H, m), 2.55-2.80 (3H, m), 2.80-2.98 (2H, m), 2.98-3.16 (2H, m), 3.16-3.35 (1H, m), 4.14 (1H, br peak), 4.26 (2H, q, J=7.3 Hz), 5.57 (1H, br peak), 6.68 (1H, d, J=15.8 Hz), 7.10-7.22 (4H, m), 7.59 (1H, d,
MS (ES+) m/z 392.
A mixture of ethyl (2E)-3-(2-chloro-5-pyrimidinyl)acrylate (200 mg), (3R)-1-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)acrylate (330 mg).
1H-NMR (300 MHz, CDCl3) δ1.33 (3H, t, J=7 Hz), 1.64-1.78 (1H, m), 2.30-2.43 (2H, m), 2.61-2.75 (2H, m), 2.82-2.92 (1H, m), 3.59-3.70 (2H, m), 4.25 (2H, q, J=7 Hz), 4.50-4.62 (1H, m), 5.74 (1H, d, J=8 Hz), 6.28 (1H, d, J=16 Hz), 7.22-7.34 (5H, m), 7.47 (1H, d, J=16 Hz), 8.43 (2H, s).
MS (ES+) m/z 353 (M+1).
To a solution of ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(cyclopentylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate (225 mg, 0.51 mmol) in EtOH (2.5 mL) was added 1N 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 1 mol/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)-1-(cyclopentylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylic acid, O-(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 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 preparative thin layer chromatography (chloroform-MeOH=10-1) to give tert-butyl [(3R)-1-(cyclopentylmethyl)-3-pyrrolidinyl](5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridinyl)carbamate (181 mg, 69%) as an amorphous powder.
1H-NMR (300 MHz, CDCl3) δ1.05-1.21 (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 (1H, m), 3.60-3.76 (1H, m), 3.90-4.05 (1H, m), 4.80-4.96 (1H, m), 4.96-5.11 (1H, m), 6.41 (1H, br peak), 7.30 (1H, d, J=8 Hz), 7.69 (1H, d, J=15 Hz), 7.78 (1H, d, J=8 Hz), 8.56 (1H, s).
The following compounds were obtained in a similar manner to that of Preparation 336.
1-NMR (300 MHz, CDCl2) δ0.80-0.97 (2H, m), 1.11-1.34 (4H, m), 1.34-1.53 (1H, m), 1.53-1.97 (10H, m), 2.11 (3H, d, J=1.3 Hz), 2.19-2.41 (4H, m), 2.56 (1H, dd, J=9.4, 3.2 Hz), 2.69 (1H, dd, J=9.6, 6.3 Hz), 2.77-2.86 (1H, m), 3.62-3.73 (1H, m), 3.95-4.07 (1H, m), 4.23-4.37 (1H, m), 4.99-5.08 (2H, m), 6.38 (1H, d, J=8.7 Hz), 7.11 (1H, s), 7.47 (1H, dd, J=8.9, 2.4 Hz), 8.14 (1H, d, J=2.3 Hz), 8.58 (1H, br peak);
MS (ES+) m/z 443.
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 (1H, m), 3.85-4.05 (2H, m), 4.90-5.10 (2H, m), 6.36 (1H, d, J=8 Hz), 6.64 (1H, br peak), 7.19-7.40 (5H, m), 7.53-7.68 (2H, m), 8.20 (1H, d, J=2 Hz);
MS (ES+) m/z 437.
1H-NMR (300 MHz, CDCl3) δ1.46-1.95 (10H, m), 2.19-2.36 (1H, m), 2.36-2.66 (3H, m), 3.43 (1H, d, J=13.5 Hz), 3.50 (1H, d, J=13.5 Hz), 3.56-3.70 (1H, m), 3.85-4.01 (2H, m), 5.00 (1H, br s), 5.32 (1H, br peak), 6.24 (1H, br peak), 6.36 (1H, d, J=8.8 Hz), 7.20-8.34 (4H, m), 7.57 (1H, d, J=9.3 Hz), 7.63 (1H, d, J=15.9 Hz), 8.21 (1H, s), 8.26 (1H, br peak);
MS (ES+) m/z 471.
1H-NMR (300 MHz, CDCl3) δ1.00-1.97 (18H, m), 2.23-2.84 (5H, m), 3.56-3.80 (1H, m), 3.80-4.07 (2H, m), 5.00 (1H, br s), 5.88 (1H, br peak), 6.27 (1H, br peak), 6.41 (1H, d, J=8.8 Hz), 7.50-7.72 (2H, m), 8.14-8.42 (2H, m); MS (ES+) m/z 415.
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 (1H, dd, J=9.6, 3.0 Hz), 2.74 (1H, dd, J=9.6, 6.3 Hz), 2.80-2.90 (1H, m), 3.60 (2H, s), 3.61-3.75 (1H, m), 3.91-4.07 (1H, m), 4.35 (1H, br peak), 4.96-5.13 (2H, m), 6.36 (1H, d, J=8.8 Hz), 6.82 (1H, d, J=40.4 Hz), 7.14-7.34 (4H, m), 7.72 (1H, dd, J=8.8, 2.1 Hz), 8.25 (1H, d, J=1.8 Hz), 8.93 (1H, br peak).
1H-NMR (300 MHz, CDCl3) δ1.50-1.75 (2H, m), 1.75-1.95 (6H, m), 1.95-2.11 (1H, m), 3.58-3.83 (4H, m), 3.83-4.13 (4H, m), 4.13-4.25 (1H, m), 5.00 (1H, br s), 5.12 (1H, br d, J=7.3 Hz), 6.51 (1H, t, J=4.7 Hz), 6.70 (1H, br peak), 7.65 (1H, d, J=15.2 Hz), 7.90 (1H, s), 8.05 (1H, s), 8.30 (2H, d, J=4.7 Hz), 8.35 (1H, br peak);
MS (ES+) m/z 426.
1H-NMR (300 MHz, CDCl3) δ1.50-1.96 (9H, m), 2.12-2.34 (1H, m), 2.44-2.70 (3H, m), 3.45 (1H, d, J=13.3 Hz), 3.51 (1H, d, J=13.3 Hz), 3.90-4.04 (1H, m), 4.04-4.16 (1H, m), 5.00 (1H, br s), 5.48 (1H, br peak), 6.68 (1H, br peak), 7.03 (2H, t, J=8.6 Hz), 7.22-7.35 (2H, m), 7.64 (1H, d, J=15.2 Hz), 7.88 (1H, s), 8.04 (1H, s), 8.32 (1H, br peak);
MS (ES+) m/z 456.
1H-NMR (300 MHz, CDCl3) δ 51.54-1.96 (10H, m), 2.29-2.49 (1H, m), 2.54-2.78 (3H, m), 3.60-3.76 (3H, m), 3.90-4.03 (1H, m), 4.06-4.19 (1H, m), 5.01 (1H, br s), 5.72 (1H, br peak), 7.68 (1H, br peak), 7.19 (1H, dd, J=7.0, 4.9 Hz), 7.38 (1H, d, J=7.7 Hz), 7.56-7.73 (2H, m), 7.90 (1H, s), 8.00 (1H, s), 8.36 (1H, br peak), 8.56 (1H, d, J=4.7 Hz);
MS (ES+) m/z 439.
1H-NMR (300 MHz, CDCl3) δ1.50-1.96 (10H, m), 2.20-2.40 (1H, m), 2.40-2.70 (3H, m), 3.55 (2H, s), 3.60-3.73 (1H, m), 3.90-4.05 (1H, m), 4.05-4.20 (1H, m), 5.02 (1H, br s), 5.36-5.51 (1H, m), 6.68 (1H, br peak), 7.23-7.36 (1H, m), 7.58-7.74 (2H, m), 7.90 (1H, s), 8.04 (1H, s), 8.39 (1H, br peak), 8.50-8.63 (2H, m);
MS (ES+) m/z 439.
1H-NMR (300 MHz, CDCl3) δ1.50-1.98 (8H, m), 2.30-2.48 (2H, m), 2.61-m), 4.41-4.55 (1H, m), 5.01 (1H, br s), 5.30 (1H, d, J=7.7 Hz), 6.70 (1H, br peak), 7.15-7.35 (5H, m), 7.64 (1H, d, J=15.0 Hz), 7.85 (1H, s), 8.05 (1H, s);
MS (ES+) m/z 438.
1H-NMR (300 MHz, CDCl3) δ1.04-1.23 (2H, m), 1.30-1.96 (20H, m), 1.96-2.20 (3H, m), 2.33-2.48 (1H, m), 2.48-2.69 (2H, m), 3.58-3.72 (1H, m), 3.89-4.03 (1H, m), 4.03-4.15 (1H, m), 5.01 (1H, br s), 5.61 (1H, br peak), 6.71 (1H, br peak), 7.64 (1H, d, J=15 Hz), 7.86 (1H, s), 8.03 (1H, s), 8.28 (1H, br peak);
MS (ES+) m/z 458.
1H-NMR (300 MHz, CDCl3) δ1.35-1.96 (16H, m), 2.17-2.35 (1H, m), 2.43-2.88 (7H, m), 3.60-3.72 (1H, m), 3.90-4.04 (1H, m), 4.11 (1H, br peak), 5.01 (1H, br s), 5.38-5.55 (1H, m), 6.70 (1H, br peak), 7.15-7.38 (5H, m), 7.51 (1H, d, J=15 Hz), 7.75 (1H, s), 8.01 (1H, s), 8.34 (1H, br peak);
MS (ES+) m/z 452.
1H-NMR (300 MHz, CDCl3) δ1.30-1.96 (21H, m), 2.35-2.46 (1H, m), 2.46-2.70 (4H, m), 3.59-3.70 (1H, m), 3.86-4.01 (1H, m), 4.05 (1H, br peak), 5.02 (1H, br s), 5.61-5.74 (1H, m), 6.65 (1H, br peak), 7.63 (1H, d, J=15 Hz), 7.88 (1H, s), 8.02 (1H, s), 8.34 (1H, br peak);
MS (ES+) m/z 444.
1H-NMR (300 MHz, CDCl3) δ1.18-2.40 (36H, m), 2.64 (1H, br peak), 2.87 (1H, br peak), 3.63-3.76 (1H, m), 3.91-4.10 (1H, m), 4.86 (1H, br peak), 4.95-5.10 (1H, m), 6.41 (1H, br peak), 7.30 (1H, d, J=9 Hz), 7.59-70.90 (2H, m), 8.59 (1H, s);
MS (ES+) m/z 581.
1H-NMR (300 MHz, CDCl3) δ1.08-1.35 (6H, m), 1.45-1.99 (10H, m), 1.99-2.12 (1H, m), 2.25-2.41 (1H, m), 2.41-2.54 (1H, m), 2.71 (1H, dd, J=9.3, 2.5 Hz), 2.82 (1H, dd, J=9.8, 6.7 Hz), 2.89-3.01 (1H, m), 3.61-3.75 (1H, m), 3.94-4.06 (1H, m), 4.27-4.43 (1H, m), 4.99-5.06 (1H, m), 5.06-5.21 (1H, m), 6.37 (1H, d, J=8.8 Hz), 6.82 (1H, d, J=40.4 Hz), 7.72 (1H, dd, J=8.8, 2.1 Hz), 8.26 (1H, s);
MS (ES+) m/z 433.
1H-NMR (300 MHz, CDCl3) δ1.40-1.95 (11H, m), 2.10-2.35 (4H, m), 2.35-2.66 (3H, m), 3.43 (1H, d, J=12.9 Hz), 3.50 (1H, d, J=12.9 Hz), 3.60-3.71 (1H, m), 3.86-4.03 (2H, m), 4.99 (1H, br peak), 5.40 (1H, br peak), 6.25 (1H, br peak), 6.36 (1H, d, J=8.7 Hz), 7.13 (1H, d, J=7.9 Hz), 7.20 (1H, d, J=7.9 Hz), 7.52-7.69 (2H, m), 8.14-8.35 (2H, m);
MS (ES+) m/z 451.
1H-NMR (300 MHz, CDCl3) δ 1.50-1.96 (9H, m), 2.21-2.39 (1H, m), 2.39-2.55 (1H, m), 2.55-2.85 (2H, m), 3.59-3.70 (1H, m), 3.70 (1H, d, J=13.9 Hz), 3.80 (1H, d, J=13.9 Hz), 3.90-4.04 (1H, m), 4.06-4.20 (1H, m), 5.00 (1H, br s), 5.64 (1H, br peak), 6.68 (1H, br peak), 6.85-6.91 (1H, m), 6.95 (1H, dd, J=4.8, 3.5 Hz), 7.21-7.30 (1H, m), 7.63 (1H, d, J=15.1 Hz), 7.90 (1H, s), 8.02 (1H, s), 8.34 (1H, br peak);
MS (ES+) m/z 444.
1H-NMR (300 MHz, CDCl3) δ 1.50-1.78 (4H, m), 1.78-1.95 (3H, m), 2.28-2.48 (2H, m), 2.60-2.72 (2H, m), 2.82-2.95 (1H, m), 3.60 (2H, s), 3.61-3.71 (1H, m), 3.90-4.04 (1H, m), 4.46 (1H, br peak), 5.01 (1H, br s), 5.21 (1H, d, J=7 Hz), 6.67 (1H, br peak), 7.00 (1H, dd, J=8.7, 8.7 Hz), 7.27 (1H, dd, J=8.4, 5.6 Hz), 7.61 (1H, d, J=15.1 Hz), 7.85 (1H, s), 8.03 (1H, s), 8.34 (1H, br peak);
MS (ES+) m/z 442.
1H-NMR (300 MHz, CDCl3) δ0.96-1.35 (7H, m), 1.35-1.95 (13H, m), 2.20-2.40 (1H, m), 2.40-2.67 (3H, m), 2.67-2.83 (1H, m), 3.60-3.72 (1H, m), 3.80-4.06 (2H, m), 4.99 (1H, br s), 5.30-5.51 (1H, m), 6.26 (1H, br peak), 6.39 (1H, d, J=8.7 Hz), 7.57 (1H, d, J=8.2 Hz), 7.62 (1H, d, J=15.0 Hz), 8.13-8.35 (1H, m);
MS (ES+) m/z 429.
1H-NMR (300 MHz, CDCl3) δ0.95-1.18 (2H, m), 1.18-1.93 (28H, m), 1.93-2.09 (1H, m), 2.09-2.38 (2H, m), 2.38-2.75 (2H, m), 2.75-2.95 (1H, m), 3.61-3.75 (1H, m), 3.89-4.06 (1H, m), 4.82-4.96 (1H, m), 4.96-5.09 (1H, m), 6.20-6.50 (1H, m), 7.29 (1H, d, J=8.4 Hz), 7.70 (1H, d, J=16.5 Hz), 7.78 (1H, dd, J=8.3, 2.6 Hz), 8.57 (1H, s);
MS (ES+) m/z 543.
1H-NMR (300 MHz, CDCl3) δ1.45-1.97 (10H, m), 2.20-2.36 (1H, m), 2.44-2.71 (3H, m), 3.52 (2H, s), 3.60-3.71 (1H, m), 3.88-4.04 (1H, m), 4.15 (1H, br peak), 5.02 (1H, br s), 5.43 (1H, br peak), 6.65 (1H, br peak), 7.20-7.31 (2H, m), 7.63 (1H, d, J=15.0 Hz), 7.90 (1H, s), 8.03 (1H, s), 8.39 (1H, br peak), 8.56 (2H, d, J=5.8 Hz);
MS (ES+) m/z 439.
1H-NMR (300 MHz, CDCl3) δ1.48-1.95 (10H, m), 2.18-2.34 (1H, m), 2.45-2.74 (3H, m), 3.51 (1H, d, J=13.5 Hz), 3.59 (1H, d, J=13.5 Hz), 3.61-3.71 (1H, m), 3.90-4.05 (1H, m), 4.05-4.15 (1H, m), 5.01 (1H, br s), 5.53 (1H, br peak), 6.66 (1H, br peak), 7.05 (1H, d, J=5.0 Hz), 7.10 (1H, d, J=2.3 Hz), 7.23-7.32 (1H, m), 7.62 (1H, d, J=15.0 Hz), 7.88 (1H, s), 8.02 (1H, s), 8.31 (1H, br peak);
MS (ES+) m/z 444.
1H-NMR (300 MHz, CDCl3) δ1.50-1.96 (10H, m), 2.25-2.45 (1H, m), 2.54-2.80 (3H, m), 2.80-2.98 (2H, m), 2.98-3.15 (2H, m), 3.20-3.35 (1H, m), 3.59-3.71 (1H, m), 3.90-4.04 (1H, m), 4.09-4.20 (1H, m), 5.02 (1H, br s), 5.59 (1H, br peak), 6.68 (1H, br peak), 7.10-7.30 (5H, m), 7.65 (1H, d, J=15.4 Hz), 7.91 (1H, s), 8.05 (1H, s), 8.34 (1H, br peak);
MS (ES+) m/z 464.
1H-NMR (300 MHz, CDCl3) δ1.52-1.98 (9H, m), 2.25-2.49 (5H, m), 2.60 (1H, dd, J=9.7, 3.1 Hz), 2.75 (1H, dd, J=9.7, 6.4 Hz), 2.78-2.90 (1H, m), 3.57 (1H, d, J=12.9 Hz), 3.64 (1H, d, J=12.9 Hz), 3.64-3.74 (1H, m), 3.93-4.08 (1H, m), 4.26-4.42 (1H, m), 5.00-5.07 (1H, m), 5.11 (1H, d, J=7.7 Hz), 6.35 (1H, d, J=8.8 Hz), 6.82 (1H, d, J=40.5 Hz), 7.13 (2H, d, J=7.9 Hz), 7.21 (2H, d, J=7.9 Hz), 7.71 (1H, dd, J=8.8, 2.2 Hz), 8.25 (1H, d, J=1.9 Hz); MS (ES+) m/z 455, 909.
To a suspension of lithium aluminum hydride (70 mg, 1.8 mmol) in tetrahydrofuran (2 mL) was added a solution of ethyl 6-{[(3R)-1-benzyl-3-piperidinyl]amino}nicotinate (250 mg, 0.74 mmol) in tetrahydrofuran (5 mL) dropwise at 0° C. 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 1 h. 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)-1-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
25. Preparation 361.
1H-NMR (300 MHz, CDCl3) δ0.75-0.95 (2H, m), 1.06-1.31 (3H, m), 1.38-1.85 (10H, m), 2.00-2.14 (2H, m), 2.14-2.30 (1H, m), 2.30-2.59 (3H, m), 3.80-3.93 (1H, m), 4.52 (2H, s), 5.11 (1H, br peak), 6.40 (1H, d, J=8.6 Hz), 7.46 (1H, dd, J=8.5, 2.3 Hz), 8.04 (1H, d, J=2.3 Hz).
To a solution of 6-{[(3R)-1-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=15-1) to give ethyl (2E)-3-(6-{[(3R)-1-benzyl-3-piperidinyl]amino}-3-pyridinyl)acrylate (77 mg, 57%) as an oil.
1H-NMR (300 MHz, CDCl3) δ1.19-1.40 (3H, m), 1.49-1.82 (4H, m), 2.19-2.36 (1H, m), 2.36-2.68 (3H, m), 3.40-3.59 (2H, m), 4.06-4.40 (3H, m), 5.40 (1H, br peak), 6.19 (1H, d, J=15.8 Hz), 6.38 (1H, d, J=8.1 Hz), 7.19-7.40 (5H, m), 7.40-7.75 (2H, m), 8.16 (1H, s);
MS (ES+) m/z 366.
The following compounds were obtained in a similar manner to that of Preparation 363.
1H-NMR (300 MHz, CDCl3) δ 0.80-0.97 (2H, m), 1.11-1.28 (4H, m), 1.34 (3H, t, J=7.1 Hz), 1.37-1.52 (1H, m), 1.60-1.85 (5H, m), 2.13 (3H, d, J=1.4 Hz), 2.19-2.41 (4H, m), 2.57 (1H, dd, J=10.3 Hz), 2.69 (1H, dd, J=10.6 Hz), 2.81 (1H, dt, J=8.4 Hz), 4.20-4.38 (3H, m), 5.04 (1H, d, J=7.7 Hz), 6.39 (1H, d, J=8.7 Hz), 7.53 (1H, s), 7.56 (1H, dd, J=8.7, 2.3 Hz), 8.21 (1H, d, J=2.3 Hz);
MS (ES+) m/z 372.
1H-NMR (300 MHz, CDCl3) δ0.78-0.96 (2H, m), 1.06-1.40 (5H, m), 1.40-1.84 (11H, m), 2.00-2.25 (3H, m), 2.38-2.64 (3H, m), 3.96 (1H, br peak), 4.25 (2H, q, J=7.1 Hz), 5.49 (1H, br peak), 6.21 (1H, d, J=15.9 Hz), 6.39 (1H, d, J=8.8 Hz), 7.57 (1H, d, J=15.9 Hz), 7.61 (1H, dd, J=8.7, 2.4 Hz), 8.19 (1H, d, J=—2.2 Hz).
To a solution of tert-butyl (3R)-3-({3-chloro-5-[(1Z)-3-ethoxy-2-fluoro-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)-1-piperidinecarboxylate (3.3 g) in EtOH (19.3 ml) was added solution of 4N HCl in dioxane (19.3 ml) 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 (2.98 g).
1H-NMR (DMSO-d6): δ 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=1.9 Hz), 8.37 (1H, d, J=1.9 Hz),
(+)ESI-MS:328(M+H)+.
The following compounds were obtained in a similar manner to that of Preparation 366.
1H-NMR (300 MHz, DMSO-d6) δ1.25 (3H, t, J=7.1 Hz), 1.54-1.68 (1H, m), 1.68-1.86 (1H, m), 1.86-2.11 (2H, m), 2.84-3.02 (2H, m), 3.10-3.23 (1H, m), 3.23-3.44 (1H, m), 4.10-4.30 (3H, m), 6.55 (1H, d, J=16.0 Hz), 7.00 (1H, d, J=8.9 Hz), 7.63 (1H, d, J=16.1 Hz), 8.21 (1H, d, J=8.9 Hz), 8.31 (1H, d, J=1.7 Hz), 8.80-9.15 (2H, m), 9.26-9.43 (1H, m).
1H-NMR (300 MHz, DMSO-d6) δ 1.29 (3H, t, J=7.1 Hz), 1.93-2.09 (1H, m), 2.20-2.40 (1H, m), 3.12-3.60 (4H, m), 4.28 (2H, q, J=7.1 Hz), 4.60 (1H, br peak), 6-99 (1H, d, J=9.2 Hz), 7-10 (1H, d, J=37.3 Hz), 8.05 (1H, d, J=9.2 Hz), 8.34 (1H, s), 9.10 (1H, br peak), 9.45 (2H, br peak);
MS (ES+) m/z 280.
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), 3.11-3.20 (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 (1H, s), 9.13-9.73 (3H, m),
(+)ESI-MS:294(M+H)+.
To a solution of ethyl 6-{[(3R)-1-benzyl-3-piperidinyl]amino}-5-chloronicotinate (6.75 g, 18.1 mmol) in ethanol (200 mL) 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 only —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) δ1.36 (3H, t, J=7.1 Hz), 1.40-1.67 (3H, m), 1.67-1.83 (1H, m), 1.83-1.99 (1H, m), 2.65 (1H, dd, J=11.6, 7.0 Hz), 2.70-2.81 (1H, m), 2.81-2.93 (1H, m), 3.16 (1H, dd, J=11.4, 3.3 Hz), 3.77-3.92 (1H, m), 4.33 (2H, q, J=7.1 Hz), 5.29 (1H, br d, J=7.1 Hz), 6.37 (1H, d, J=8.9 Hz), 7.97 (1H, dd, J=8.8, 2.3 Hz), 8.74 (1H, d, J=2.3 Hz);
MS (ES+) m/z 250.
The following compound was obtained in a similar manner to that of Preparation 370.
1H-NMR (300 MHz, CDCl3) δ0.77-0.97 (2H, m), 1.05-1.30 (3H, m), 1.36 (3H, t, J=7.1 Hz), 1.40-1.86 (10H, m), 1.97-2.25 (3H, m), 2.37-2.64 (3H, m), 3.84-4.08 (1H, m), 4.30 (2H, q, J=7.1 Hz), 5.59 (1H, br peak), 6.35 (1H, d, J=8.4 Hz), 7.97 (1H, dd, J=8.6, 2.0 Hz), 8.74 (1H, d, J=2.0 Hz).
1) To a mixture of tert-butyl (3R)-3-pyrrolidinylcarbamate (1.00 g), 2,3-dimethylbenzaldehyde (720 mg), N,N-diisopropylethylamine (1.87 mL), and ethanol (10 mL) 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° C., After stirring at room temperature for 5 hours, the reaction mixture was neutralized 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)-1-(2,3-dimethylbenzyl)-3-pyrrolidinamine (193 mg).
1H-NMR (300 MHz, CDCl3) δ1.41-1.53 (1H, 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 (1H, m), 3.58 (2H, s), 7.00-7.14 (3H, m),
MS (ES+) m/z 205 (M+1).
To a suspension of sodium hydride (60%, 208 mg, 5.2 mmol) in tetrahydrofuran (2 mL) was added a solution of ethyl (dimethoxyphosphoryl)(fluoro)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)-1-(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)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoroacrylate and ethyl (2E)-3-(6-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoroacrylate (1:1) as an oil.
1H-NMR (300 MHz, CDCl3) δ0.80-1.00 (2H, m), 1.10-1.51 (9H, m), 1.51-1.85 (4H, m), 2.15-2.40 (4H, m), 2.51-2.61 (1H, m), 2.61-2.72 (1H, m), 2.72-2.86 (1H, m), 4.20-4.40 (3H, m), 5.11 (1H, br d, J=8.4 Hz), 6.39 (1H, d, J=8.8 Hz), 6.80 (1H, d, J=36.3 Hz), 8.03 (1H, dd, J=9.2, 2.6 Hz), 8.25 (1H, d, J=2.6 Hz).
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/1:1) to give ethyl 6-{[(3R)-1-(tert-butoxycarbonyl)-3-piperidinyl]amino}nicotinate (5.4 g, 99%) as an oil.
1H-NMR (300 MHz, CDCl3) δ 1.37 (3H, t, J=7.1 Hz), 1.44 (9H, s), 1.51-1.82 (2H, m), 1.90-2.06 (1H, m), 3.09-3.36 (2H, m), 3.48-3.60 (1H, m), 3.70-3.91 (2H, m), 4.33 (2H, q, J=7.1 Hz), 4.39-5.03 (1H, m), 6.40 (1H, d, J=8.8 Hz), 8.01 (1H, dd, J=8.7, 2.3 Hz), 8.75 (1H, d, J=2.2 Hz);
MS (ES+) m/z 350.
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° C. under nitrogen and the mixture was stirred at same temperature for 1 hr and at ambient temperature for 2 hrs. 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=1-1) to give ethyl (2E)-3-(6-{[(3R)-1-(4-chlorobenzoyl)-3-piperidinyl]amino}-3-pyridinyl)acrylate (270 mg, 76%) as an amorphous powder.
1H-NMR (300 MHz, DMSO-d6) δ 1.24 (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 (1H, d, J=15.9 Hz), 6.44-6.60 (1H, m), 7.08-7.28 (1H, m), 7.28-7.59 (5H, m), 7.70-7.87 (1H, m), 8.00-8.32 (1H, m);
MS (ES+) m/z 414.
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 mL) was stirred at 70° C. for 2 hrs. To the reaction mixture was added an AcOEt (32 mL) and isolated precipitate was collected by filtration to give ethyl (2E)-3-(2-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}thiazol-4-yl)acrylate hydrochloride (1.10 g).
1H-NMR(DMSO-d6): δ 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 1H, 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), 10.51 (1H, s)
(+)ESI-MS:364(M+H)+.
A mixture of 5-bromo-2-pyrazinecarboxylic acid (650 mg) in thionyl chloride (2.35 ml) was stirred under reflux condition. After 3 hrs, the reaction mixture was evaporated.
To this residue in tetrahydrofuran (10 ml) was added sodium borohydride (465 mg) 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 230 mg (39%) of (5-bromo-2-pyridinyl)methanol as an oil.
MASS (ESI+,): 210.1, 211.0 (M+Na).
1H-NMR (400 MHz, CDCl3): δ 4.73 (2H, s), 7.20 (1H, d, J=8.2 Hz), 7.82 (1H, dd, J=8.2 and 1.8 Hz), 8.63 (1H, d, J=1.8 Hz).
A mixture of (5-bromo-2-pyridinyl)methanol (200 mg), ethyl (triphenylphosphoranylidene)acetate (408 mg) and manganese oxide (370 mg) in dioxane (5 ml) 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 150 mg (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 (400 MHz, CDCl3): δ 1.34 (3H, t, J=7.1 Hz), 4.28 (2H, q, J=7.1 Hz), 6.91 (1H, d, J=15.5 Hz), 7.31 (1H, d, J=8.3 Hz), 7.62 (1H, d, J=15.5 Hz), 7.84 (1H, dd, J=8.3 and 2.2 Hz), 8.69 (1H, d, J=2-2 Hz).
To a solution of ethyl 5,6-dichloronicotinate (10.0 g) and N,N-diisopropylethylamine (17.4 mL) in 1,3-dimethyl-2-imidazolidinone (100 mL) was added tert-butyl (3R)-3-amino-1-piperidinecarboxylate (10.9) at ambient temperature and the mixture was stirred at 100° C. 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 1N-NCl. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo to give ethyl 6-{[(3R)-1-(tert-butoxycarbonyl)-3-piperidinyl]amino}-5-chloronicotinate (16.74 g).
1H-NMR (DMSO-d6): δ 1.26-1.51 (10H, 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=1.9 Hz), 8.56 (1H, d, J=1.9 Hz),
(+)ESI-MS:384(M+H)+, 406(M+Na)+.
0.94 M solution of diisobutylaluminum hydride in hexane (139 ml) was added to dropwise a solution of ethyl 6-{[(3R)-1-(tert-butoxycarbonyl)-3-piperidinyl]amino}-5-chloronicotinate (16.7 g) in THF (250 ml) with stirred at −5 to 0° C. under atmospheric pressure of nitrogen, and the reaction mixture was stirred at 0° C. for 1.5 hr. To the reaction mixture was added MeOH (26.4 ml) was stirred at 0 to 10 for 20 minutes. The potassium sodium tartarate tetrahydrate (36.8 g) 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 (10.29 g).
(+)ESI-MS:342(M+H)+, 364(M+Na)+
1H-NMR (DMSO-d6): δ 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.
1H-NMR (300 MHz, CDCl3) δ1.44 (9H, s), 1.50-1.66 (3H, m), 1.66-1.81 (1H, m), 1.89-2.07 (1H, m), 2.90-3.30 (2H, m), 3.52-3.66 (1H, m), 3.66-3.78 (1H, m), 3.78-4.03 (1H, m), 4.44-4.61 (3H, m), 6.44 (1H, d, J=9.1 Hz), 7.49 (1H, dd, J=8.5, 2.4 Hz), 8.06 (1H, d, J=2.1 Hz);
MS (ES+) m/z 308.
A mixture of tert-butyl (3R)-3-{[3-chloro-5-(hydroxymethyl)-2-pyridinyl]amino}-1-piperidinecarboxylate
(10.0 g) and MnO2 (25.4 g) in CHCl3 (200 ml) was stirred at 60° C. 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]-1-piperidinecarboxylate (9.08 g).
1H-NMR(DMSO-d6): δ 1.24-1.52 (10H, 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=1.9 Hz), 8.56 (1H, d, J=1.9 Hz), 9.76 (1H,
(+)ESI-MS:340(M+H)+.
The following compounds were obtained in a similar manner to that of Preparation 382.
1H-NMR (300 MHz, CDCl3) δ1.44-2.38 (5H, m), 2.38-2.71 (3H, m), 3.41-3.60 (2H, m), 4.00-4.40 (1H, m), 6.41 (1H, d, J=8.8 Hz), 7.13-7.41 (5H, m), 7.86 (1H, d, J=8.8 Hz), 8.46 (1H, s), 9.74 (1H, s);
MS (ES+) m/z 296.
1H-NMR (300 MHz, CDCl3)(0.76-0.95 (2H, m), 1.06-1.331 (3H, m), 1.39-1.85 (10H, m), 2.00-2.20 (3H, m), 2.31-2.49 (1H, m), 2.49-2.70 (2H, m), 3.92-4.20 (1H, m), 5.88 (1H, br peak), 6.42 (1H, d, J=8.8 Hz), 7.88 (1H, dd, J=8.5, 1.7 Hz), 8.50 (1H, d, J=2.2 Hz), 9.75 (1H, s);
MS (ES+) m/z 302.
1H-NMR (300 MHz, CDCl3) δ0.77-0.97 (2H, m), 1.07-1.32 (3H, m), 1.40-1.84 (10H, m), 2.00-2.23 (3H, m), 2.34-2.68 (3H, m), 4.02 (1H, br peak), 5.87 (1H, br peak), 6.42 (1H, d, J=8.8 Hz), 7.87 (1H, d, J=8.8 Hz), 8.49 (1H, d, J=1.9 Hz), 9.75 (1H, s);
MS (ES+) m/z 302.
The mixture of ethyl (dimethoxyphosphoryl)(fluoro)acetate (2.51 mL), MgBr2 (2.73 g), Et3N (1.89 mL) in THF (45 mL) was stirred at 3-5° C. for 1 hr and to the mixture was dropwise added a solution of tert-butyl (3R)-3-[(3-chloro-5-formyl-2-pyridinyl)amino]-1-piperidinecarboxylate (3.0 g) in THF (21 mL) at 3-5° C. The reaction mixture was stirred at same temperature for 2.5 hrs. The reaction mixture was poured into a mixture of AcOEt and ice-water and the mixture was adjusted to pH 3.5 with 1N-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-[(1Z)-3-ethoxy-2-fluoro-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)-1-piperidinecarboxylate (3.38 g).
1H-NMR (DMSO-d6): δ 1.25-1.48 (10H, m), 1.29(3H, t, J=7.1 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=1.8 Hz), 8.36 (1H, d, J=1.8 Hz),
(+)ESI-MS:428(M+H)+.
The following compounds were obtained in a similar manner to that of Preparation 386.
1H-NMR (300 MHz, CDCl3) δ 1.38 (3H, t, J=7.1 Hz), 1.47 (9H, s), 1.93 (1H, br peak), 2.16-2.33 (1H, m), 3.15-3.39 (1H, m), 3.39-3.59 (2H, m), 3.74 (1H, dd, J=11.3, 6.0 Hz), 4.35 (2H, q, J=7.1 Hz), 4.43 (1H, br peak), 7.77-4.90 (1H, m), 6.43 (1H, d, J=8.8 Hz), 6.80 (1H, d, J=36.1 Hz), 7.83 (1H, dd, J=8.8, 2.1 Hz), 8.26 (1H, s);
MS (ES+) m/z 380.
(+)ESI-MS:394(M+H)+
To a solution of ethyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate (416 mg) in DMF (10 mL) was added (3R)-1-cyclohexyl-3-pyrrolidinamine dihydrochloride (849 mg) and K2CO3 (1.35 g). After stirring for 2 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-(5-{[(3R)-1-cyclohexyl-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate (318 mg). 1H-NMR (300 MHz, CDCl3) δ 1.11-1.34 (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 (1H, m), 2.78-2.84 (1H, m), 2.98-3.06 (1H, m), 4.25 (2H, q, J=7 Hz), 4.39-4.50 (1H, m), 5.32 (1H, d, J=8 Hz), 6.68 (1H, d, J=16 Hz), 7.57 (1H, d, J=16 Hz), 7.88 (1H, d, J=1 Hz), 8.06 (1H, d, J=1 Hz).
MS (ES+) m/z 345 (M+1).
The mixture of ethyl (2E)-3-(5-{[(3R)-1-(3-chlorobenzyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylate (235 mg, 0.59 mmol) and 1N-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 1 mol/L hydrochloric acid and evaporated in vacuo to give (2E)-3-(5-{[(3R)-1-(3-chlorobenzyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylic acid (218 mg, 100%).
1H-NMR (300. MHz, DMSO-d6) δ1.21-1.40 (1H, m), 1.40-1.60 (1H, m), 1.60-1.77 (1H, m), 1.77-1.90 (1H, m), 1.90-2.15 (2H, m), 2.53-2.90 (2H, m), 3.35-3.60 (2H, m), 3.90-4.03 (1H, m), 6.45 (1H, d, J=15.5 Hz), 7.24-7.40 (4H, m), 7.46 (1H, d, J=7.9 Hz), 7.98 (1H, s), 8.10 (1H, s);
MS (ES+) m/z 373, 375.
The following compounds were obtained in a similar manner to that of Preparation 390.
1H-NMR (300 MHz, DMSO-d6) δ0.74-1.01 (2H, m), 1.01-1.34 (3H, m), 1.34-2.10 (10H, m), 2.59-3.65 (6H, m), 4.04-4.45 (1H, m), 6.26 (1H, d, J=16.9 Hz), 6.55 (1H, d, J=8.7 Hz), 7.28 (1H, br peak), 7.47 (1H, d, J=15.8 Hz), 7.81 (1H, d, J=8.1 Hz), 8.21 (1H, s);
MS (ES+) m/z 344.
1H-NMR (300 MHz, DMSO-d6) δ 0.78-1.05 (2H, m), 1.05-1.34 (3H, m), 1.34-2.11 (10H, m), 2.53-3.66 (6H, m), 3.94-4.41 (1H, m), 6.28 (1H, d, J=16.1 Hz), 6.55 (1H, d, J=8.8 Hz), 7.31 (1H, br peak), 7.48 (1H, d, J=15.4 Hz), 7.83 (1H, d, J=9.5 Hz), 8.24 (1H, s), 9.25 (1H, br peak).
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 (1H, m), 2.19-2.40 (1H, m), 2.79-3.00 (2H, m), 3.00-3.81 (4H, m), 5.10 (1H, br peak), 6.87 (1H, d, J=34.1 Hz), 7.41 (1H, d, J=8.4 Hz), 8.09 (1H, dd, J=8.1, 1.8 Hz), 8.15 (1H, s).
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 (1H, d, J=15.9 Hz), 6.45-6.64 (1H, m), 7.03-7.28 (1H, m), 7.41-7.54 (1H, m), 7.74-7.85 (1H, m), 8.20 (1H, br s);
MS (ES+) m/z 358.
1H-NMR (300 MHz, DMSO-d6) δ1.24-1.41 (1H, m), 1.45-1.65 (1H, m), 1.65-1.80 (1H, m), 1.80-1.95 (1H, m), 1.95-2.25 (2H, m), 2.56-2.76 (1H, m), 2.83-2.98 (1H, m), 3.59 (2H, s), 3.90-4.05 (1H, m), 6.45 (1H, d, J=15.5 Hz), 7.22-7.45 (3H, m), 7.50-7.60 (1H, m), 8.00 (1H, s), 8.11 (1H, s);
MS (ES+) m/z 373, 375.
1H-NMR (300 MHz, DMSO-d6) δ1.43-2.09 (2H, m), 2.65-3.21 (1H, m), 3.54-3.95 (2H, m), 4.03-4.20 (1H, m), 4.39-4.44 (2H, m), 6.24 (1H, d, J=15.9 Hz), 6.45-6.60 (1H, m), 7.07-7.21 (1H, m), 7.29-7.60 (5H, m), 7.67-7.84 (1H, m), 7.94-8.27 (1H, m);
MS (ES+) m/z 386.
A mixture of (2E)-3-(5-{[(3R)-1-(3-chlorobenzyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylic acid (2178 mg, 0.59 mmol), 0-(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)-1-(3-chlorobenzyl)-3-piperidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (251 mg, 91%) as an amorphous powder.
1H-NMR (300 MHz, CDCl3)(1.50-1.99 (10H, m), 2.19-2.36 (1H, m), 2.44-2.70 (3H, m), 3.45 (1H, d, J=13.4 Hz), 3.53 (1H, d, J=13.4 Hz), 3.58-3.74 (1H, m), 3.90-4.04 (1H, m), 4.04-4.20 (1H, m), 5.01 (1H, br s), 5.49 (1H, br peak), 6.70 (1H, br peak), 7.15-7.36 (4H, m), 7.64 (1H, d, J=15.2 Hz), 7.90 (1H, s), 8.03 (1H, s), 8.36 (1H, br peak);
MS (ES+) m/z 472.
The following compounds were obtained in a similar manner to that of Preparation 397.
1H-NMR (300 MHz, CDCl3) δ0.76-0.96 (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 (1H, m), 3.86-4.03 (2H, m), 5.00 (1H, br s), 5.46 (1H, br peak), 6.25 (1H, br peak), 6.37 (1H, d, J=8.7 Hz), 7.53-7.70 (2H, m), 8.22 (1H, d, J=2.0 Hz), 8.25 (1H, br peak);
MS (ES+) m/z 443.
1H-NMR (300 MHz, CDCl3) δ0.76-0.96 (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 (1H, m), 3.86-4.03 (2H, m), 5.00 (1H, br s), 5.46 (1H, br peak), 6.25 (1H, br peak), 6.37 (1H, d, J=8.7 Hz), 7.53-7.70 (2H, m), 8.22 (1H, d, J=2.0 Hz), 8.25 (1H, br peak);
MS (ES+) m/z 443.
1H-NMR (300 MHz, CDCl3) δ0.66-0.93 (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 (1H, m), 3.60-3.75 (1H, m), 3.93-4.06 (1H, m), 4.78-4.95 (1H, m), 5.06 (1H, s), 6.96 (1H, d, J=39.2 Hz), 7.31 (1H, d, J=8.5 Hz), 7.92 (1H, dd, J=8.4, 2.3 Hz), 8.61 (1H, d, J=2.2 Hz);
MS (ES+) m/z 547.
1H-NMR (300 MHz, CDCl3) δ 1.48-1.95 (10H, m), 2.20-2.35 (1H, m), 2.54-2.80 (3H, m), 3.50-3.72 (3H, m), 3.89-4.04 (1H, m), 4.06-4.20 (1H, m), 5.00 (1H, br s), 5.71 (1H, br peak), 6.66 (1H, br peak), 7.16-7.28 (2H, m), 7.30-7.43 (2H, m), 7.62 (1H, d, J=15.1 Hz), 7.86 (1H, s), 8.00 (1H, s), 8.35 (1H, br peak);
MS (ES+) m/z 472.
1H-NMR (300 MHz, DMSO-d6) δ0.93-1.97 (18H, m), 1.97-2.15 (1H, m), 2.32-2.59 (1H, m), 2.98-3.42 (2H, m), 3.53-3.81 (2H, m), 3.81-4.28 (4H, m), 4.50-4.95 (1H, m), 5.00 (1H, 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.
1H-NMR (300 MHz, CDCl3) δ1.35-1.96 (8H, m), 1.96-2.17 (1H, m), 3.08-3.71 (4H, m), 3.71-4.06 (4H, m), 4.04-4.75 (1H, m), 5.00 (1H, 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.
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 diisopropylethylamine (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=¼) to give ethyl (2E)-3-(5-{[(3R)-1-(2-pyrimidinyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylate (141 mg, 46%) as an amorphous powder.
1H-NMR (300 MHz, CDCl3) δ1.33 (3H, t, J=7.1 Hz), 1.61-1.75 (1H, m), 1.75-1.91 (2H, m), 1.96-2.12 (1H, m), 3.66-3.84 (2H, m), 3.84-3.98 (1H, m), 4.00-4.14 (1H, m), 4.20 (1H, dd, J=13.6, 3.2 Hz), 4.25 (2H, q, J=7.1 Hz), 5.13 (1H, br d, J=7.4 Hz), 6.52 (1H, t, J=4.7 Hz), 6.69 (1H, d, J=15.6 Hz), 7.58 (1H, d, J=15.6 Hz), 7.94 (1H, s), 8.09 (1H, s), 8.32 (2H, d, J=4.7 Hz);
MS (ES+) m/z 355.
The mixture of ethyl (2Z)-3-(5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-3-pyridinyl)-2-fluoroacrylate (0.73 g) and 1N-NaOH (3.44 mL) in MeOH (20 mL) was stirred at 60° C. for 3 hr. To the reaction mixture was added 1N-NaCl 3.44 mL and the mixture was evaporated in vacuo to give (2Z)-3-(5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-3-pyridinyl)-2-fluoroacrylic acid (0.68 g).
1H-NMR (DMSO-d6): δ 0.83-0.96 (2H, m), 1.08-1.28 (3H, m), 1.56-1.86 (10H, 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=1.7 Hz), 8.26 (1H, d, J=1.7 Hz),
(−)ESI-MS:394(M−H)-.
The following compounds were obtained in a similar manner to that of Preparation 405.
(−)ESI-MS:334(M−H)-.
(−)ESI-MS:388(M−H)-.
(−)ESI-MS:366(M−H)-.
1H-NMR (DMSO-d6): 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), 4.40-4.56 (1H, m), 6.54-6.73 (1H, m), 6.66 (1H, d, J=37.6 Hz), 7.86 (1H, d, J=1.7 Hz), 8.22 (1H, d, J=1.7 Hz),
(−)ESI-MS:380(M−H)-.
1H-NMR(DMSO-d6): δ 1.29-1.42 (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=2.2 Hz, 8.9 Hz), 8.20 (1H, d, J=2.2 Hz),
(−)ESI-MS:354(M−H)-.
(−)ESI-MS:360(M−H)-.
(−)ESI-MS:346(M−H)—.
(−)ESI-MS:332(M−H)-.
EDCI (0.32 g) was added to the solution of (2Z)-3-(5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-3-pyridinyl)-2-fluoroacrylic acid (0.68 g), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.24 g), and HOBT (0.28 g) in DMF (13.6 ml) 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-fluoro-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (0.57 g).
1H-NMR (DMSO-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=1:8 Hz), 8.29 (1H, d, J=1.8 Hz), 11.76 (1H, s),
(+)ESI-MS:495(M+H)+.
The following compounds were obtained in a similar manner to that of Preparation 414.
1H-NMR (DMSO-d6): δ 1.45-1.76 (10H, m), 2.12-2.28 (2H, m), 2.44-2.55 (1H, m), 2.62-2.73 (1H, m), 3.42-3.58 (3H, m), 4.01-4.11 (1H, 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=1.9 Hz), 8.27 (1H, d, J=1.9 Hz), 11.76 (1H, s),
(+)ESI-MS:489(M+H)+.
1H-NMR (DMSO-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), 4.10-4.21 (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)+.
(+)ESI-MS:467(M+H)+.
1H-NMR(DMSO-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=1.9 Hz), 8.29 (1H, d, J=1.9 Hz), 11.76 (1H, s),
(+)ESI-MS:481(M+H)+.
1H-NMR (DMSO-d6): δ 1.17-1.30 (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 (1H, d, J=40.4 Hz), 6.95 (1H, d, J=8.0 Hz), 7.20-7.27 (1H, m), 7.28-7.34 (4H, m), 7.65 and 7.67(total 1H, each d, J=each 2.2 Hz), 8.19 (1H, d, J=2.2 Hz), 11.66 (1H, s),
(+)ESI-MS:455(M+H)+.
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), 6.70 (1H, d, J=38.9 Hz), 6.89 (1H, d, J=7.8 Hz), 6.67 (1H, dd, J=2.2 Hz, 8.9 Hz), 8.21 (1H, d, J=2.2 Hz), 11.66 (1H, s),
(+)ESI-MS:461(M+H)+.
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), 6.70 (1H, d, J=40.0 Hz), 6.90 (1H, d, J=7.8 Hz), 7.67 (1H, dd, J=2.2 Hz, 8.9 Hz), 8.21 (1H, d, J=2.2 Hz), 11.66 (1H,
(+)ESI-MS:447(M+H)+.
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), 6.70 (1H, d, J=40.0 Hz), 6.94 (1H, d, J=7.9 Hz), 7.67 (1H, dd, J=2.2 Hz, 9.0 Hz), 8.21 (1H, d, J=2.2 Hz), 11.66 (1H, s),
(+)ESI-MS:433(M+H)+.
A mixture of ethyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate (300 mg, 1.41 mmol), (3R)-1-(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)-1-(4-fluorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate (245 mg, 47%) as an oil.
1H-NMR (300 MHz, CDCl3) δ1.32 (3H, t, J=7.1 Hz), 1.65-1.80 (1H, m), 2.30-2.46 (2H, m), 2.60-2.73 (2H, m), 2.82-2.95 (1H, m), 3.60 (2H, s), 4.25 (2H, q, J=7.1 Hz), 4.46 (1H, br peak), 5.20 (1H, d, J=7.7 Hz), 6.68 (1H, d, J=15.5 Hz), 7.01 (1H, dd, J=8.6, 8.6 Hz), 7.28 (1H, dd, J=8.4, 5.6 Hz), 7.56 (1H, d, J=15.5 Hz), 7.88 (1H, s), 8.05 (1H, s);
MS (ES+) m/z 371.
The following compound was obtained in a similar manner to that of Preparation 423.
1H-NMR (300 MHz, CDCl3) δ1.33 (3H, t, J=7.1 Hz), 1.56-1.79 (1H, m), 2.30-2.47 (2H, m), 2.61-2.87 (6H, m), 2.96-3.09 (1H, m), 4.26 (2H, q, J=7.1 Hz), 4.41-4.55 (1H, m), 5.25 (1H, d, J=7.8 Hz), 6.68 (1H, d, J=15.5 Hz), 7.16-7.35 (5H, m), 7.58 (1H, d, J=15.5 Hz), 7.87 (1H, s), 8.06 (1H, s);
MS (ES+) m/z 367.
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 mL) was added ethyl acrylate (17.2 mL) and N,N-diisopropylethylamine (13.8 mL). After stirring for 3 hours at 100° C., 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) δ1.35 (3H, t, J=7 Hz), 4.30 (2H, q, J=7 Hz), 6.58 (1H, d, J=16 Hz), 7.58 (1H, d, J=16 Hz), 8.76 (2H, s).
Sodium triacetoxyborohydride (0.56 g) was added a mixture of ethyl (2Z)-3-{5-chloro-6-[(3R)-3-piperidinylamino]-3-pyridinyl}-2-fluoroacrylate dihydrochloride (0.7 g), Et3N (0.49 mL) and cyclohexanecarboxaldehyde (0.23 mL) in CH2Cl2 (14 mL) and the mixture was stirred at ambient temperature for 20 hr. 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)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-3-pyridinyl)-2-fluoroacrylate (0.74 g).
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), 2.90-2.59 (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=1.9 Hz), 8.34 (1H, d, J=1.9 Hz),
(+)ESI-MS:424(M+H)+.
The following compounds were obtained in a similar manner to that of Preparation 426.
1H-NMR (DMSO-d6): δ 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 (1H, m), 3.43-3.58 (2H, m), 4.15-4.30 (1H, m), 4.27 (2H, q, J=7.1 Hz), 6.57 (1H, d, J=8.2 Hz), 6.98 (1H, d, J=37.5 Hz), 7.20-7.27 (1H, m), 7.29-7.34 (4H, m), 7.91 (1H, d, J=1.9 Hz), 8.32 (1H, d, J=1.9 Hz),
(+)ESI-MS:418(M+H)+.
1H-NMR(DMSO-d6): δ 1.25-1.37 (2H, m), 1.29 (3H, t, J=7.1 Hz), 1.41-1.80 (10H, 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=1.9 Hz), 8.34 (1H, d, J=1.9 Hz),
(+)ESI-MS:396(M+H)+.
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), 1.40-1.51 (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=1.9 Hz), 8.33 (1H, d, J=1.9 Hz),
(+)ESI-MS:410(M+H)+.
1H-NMR (DMSO-d6): δ 1.18-1.40 (3H, m), 1.28 (3H, t, J=7.1 Hz), 1.40-1.94 (10H, m), 1.94-2.05 (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=2.0 Hz, 8.9 Hz), 8.27 (1H, d, J=2.0 Hz),
(+)ESI-MS:362(M+H)+.
1H-NMR (DMSO-d6): δ 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), 6.91 (1H, d, J=38.2 Hz), 7.01 (1H, d, J=7.8 Hz), 7.72 (1H, dd, J=2.3 Hz, 9.0 Hz), 8.26 (1H, d, J=2.3 Hz),
(+)ESI-MS:376(M+H)+.
1H-NMR (DMSO-d6): δ 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 (1H, 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=2.3 Hz, 8.9 Hz), 8.26 (1H, d, J=2.3 Hz),
(+)ESI-MS:390(M+H)+.
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), 1.94-2.03 (1H, m), 2.57-2.66 (1H, m), 2.83-2.90 (1H, m), 3.48 (2H, dd, J=13.4 Hz, 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), 7.20-7.27 (1H, m), 7.28-7.34 (4H, m), 7.72 (1H, dd, J=2.2 Hz, 8.9 Hz), 8.25 (1H, d, J=2.2 Hz),
(+)ESI-MS:384(M+H)+.
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 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 preparative thin layer chromatography (hexane-EtOAc=1-1) to give ethyl (2E)-3-(6-{[(3R)-1-(cyclohexylcarbonyl)-3-piperidinyl]amino}-3-pyridinyl)acrylate (313 mg, 94%) as an amorphous powder.
1H-NMR (300 MHz, CDCl3) δ0.95-2.14 (17H, m), 2.34-2.61 (1H, m), 3.05-3.43 (2H, m), 3.43-4.31 (4H, m), 4.56-4.94 (1H, m), 6.16-6.29 (1H, m), 6.36-6.54 (1H, m), 7.51-7.66 (2H, m), 8.15-8.25 (1H, m);
MS (ES+) m/z 386.
To a solution of ethyl (2E)-3-(5-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-2-pyridinyl)acrylate (360 mg) in methanol (10 ml) was added 1NNaOH (5 ml) at room temperature and stirred for 2 hrs. After then, the reaction mixture was neutralized with 1N HCl (5 ml).
The mixture was evaporated under reduced pressure and co-evaporated with toluene (twice).
To the residue in DMF(10 ml) was added O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (180 mg), HOBt (138 mg) and WSCD (318 mg) 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 (CHCl3 MeOH) to give crude product.
Crude product was purified by HPLC (Yamazene packed column, 26 mm×100 mm) to give 190 mg (44%) of (2E)-3-(5-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-2-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide as an oil.
MASS (ESI+): m/z=423.3(M+1).
1HNMR (400 MHz, 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 (1H, br.s), 5.01 (1H, br.s), 6.77 (1H, dd, J=8.4 and 2.8 Hz), 7.18 (1H, d, J=8.4 Hz), 7.25-7.40 (6H, m), 7.61 (1H, d, J=15.2 Hz), 7.98 (1H, s).
A mixture of ethyl (2Z)-3-(6-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoroacrylate and ethyl (2E)-3-(6-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoroacrylate (1:1, 1.15 g), di-tert-butyl dicarbonate (1.34 g, 6.1 mmol) and 4-dimethylaminopyridine (11 mg) in tetrahydrofuran (20 mL) 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 was purified by silica gel column chromatography (CHCl3/methanol=95/5) and preparative thin layer chromatography (CHCl3/methanol=15/1) to give ethyl (2Z)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoroacrylate (575 mg) as an oil.
1H-NMR (300 MHz, CDCl3) δ0.70-0.90 (2H, m), 1.04-1.30 (3H, m), 1.30-1.49 (12H, m), 1.49-1.78 (7H, m), 1.89-2.10 (1H, m), 2.10-2.30 (3H, m), 2.40-2.74 (3H, m), 2.84-2.99 (1H, m), 4.36 (2H, q, J=7.1 Hz), 4.89 (1H, br peak), 6.90 (1H, d, J=35.0 Hz), 7.32 (1H, d, J=9.0 Hz), 8.0 (1H, d, J=9.0 Hz), 8.60 (1H, d, J=2.2 Hz);
MS (ES+) m/z 476.
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 (1H, dd, J=11.7, 5.1 Hz), 3.61-3.79 (2H, m), 3.90-4.05 (1H, m), 4.23-4.36 (1H, m), 4.61 (1H, br d, J=6.6 Hz), 4.98 (1H, d, J=11.0 Hz), 5.03 (1H, br peak), 5.08 (1H, d, J=11.0 Hz), 6.70 (1H, br peak), 7.31-7.41 (3H, m), 7.41-7.50 (2H, m), 7.64 (1H, d, J=15.8 Hz), 7.80 (1H, s), 8.00 (1H, s), 8.36 (1H, br peak);
MS (ES+) m/z 468, 935.
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° C., 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-[(1E)-3-ethoxy-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)-1-piperidinecarboxylate (3.99 g, 89%).
1H-NMR (300 MHz, CDCl3) δ 1.33 (3H, t, J=7.1 Hz), 1.43 (9H, s), 1.50-1.82 (2H, m), 1.90-2.06 (1H, m), 3.09-3.36 (2H, m), 3.48-3.62 (1H, m), 3.71-3.90 (2H, m), 4.25 (2H, q, J=7.1 Hz), 4.76-4.90 (1H, m), 6.23 (1H, d, J=15.9 Hz), 6.43 (1H, d, J=8.8 Hz), 7.58 (1H, d, J=16.0 Hz), 7.64 (1H, dd, J=8.8, 2.3 Hz), 8.21 (1H, d, J=2.2 Hz);
MS (ES+) m/z 376.
To a solution of ethyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate (500 mg) in DMF (5 mL) was added (3R)-1-(4-chlorobenzoyl)-3-pyrrolidinamine (951 mg) and Et3N (1.15 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, 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-chlorobenzoyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate (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 (1H, m), 6.47-6.58 (1H, m), 7.46-7.61 (6H, m), 7.96-8.31 (3H, m).
MS (ES+) m/z 401 (M+1).
The following compounds were obtained in a similar manner to that of Preparation 439.
1H-NMR (300 MHz, CDCl3) δ1.32 (3H, t, J=7 Hz), 1.58-1.75 (1H, 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 (1H, m), 3.58-3.68 (2H, m), 4.25 (2H, q, J=7 Hz), 4.39-4.50 (1H, m), 5.20 (1H, d, J=7 Hz), 6.67 (1H, d, J=16 Hz), 7.01-7.12 (3H, m), 7.57 (1H, d, J=16 Hz), 7.87 (1H, d, J=1 Hz), 8.05 (1H, d, J=1 Hz).
MS (ES+) m/z 381 (M+1).
1H-NMR (300 MHz, CDCl3) δ1.32 (3H, t, J=7 Hz), 1.67-1.76 (1H, m), 2.33-2.51 (2H, m), 2.69-2.82 (2H, m), 2.63-3.01 (1H, m), 3.78 (2H, s), 4.25 (2H, q, J=7 Hz), 4.42-4.53 (1H, m), 5.25 (1H, d, J=8 Hz), 6.68 (1H, d, J=16 Hz), 7.16-7.28 (2H, m), 7.34-7.45 (2H, m), 7.57 (1H, d, J=16 Hz), 7.88 (1H, d, J=1 Hz), 8.05 (1H, d, J=1 Hz).
MS (ES+) m/z 385 (M−1).
1H-NMR (300 MHz, CDCl3) δ0.80 (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 (1H, m), 2.14-2.28 (3H, m), 2.50-2.70 (3H, m), 2.80-2.89 (1H, m), 4.28 (2H, q, J=7 Hz), 4.83-4.94 (1H, m), 6.46 (1H, d, J=16 Hz), 7.26-7.34 (1H, m), 7.66 (1H, d, J=16 Hz), 7.81 (1H, dd, J=2, 8 Hz), 8.56 (1H, d, J=2 Hz).
MS (ES+) m/z 446 (M+1).
1H-NMR (300 MHz, CDCl3) δ0.84 (6H, d, J=7 Hz), 1.35 (3H, t, J=7 Hz), 1.45 (9H, s), 1.58-1.72 (1H, m), 1.94-2.06 (1H, m), 2.10-2.27 (3H, m), 2.47-2.68 (3H, m), 2.86-2.94 (1H, m), 4.28 (2H, q, J=7 Hz), 4.86-4.94 (1H, m), 6.46 (1H, d, J=16 Hz), 7.32 (1H, d, J=8 Hz), 7.66 (1H, d, J=16 Hz), 7.81 (1H, dd, J=2, 8 Hz), 8.55 (1H, d, J=2 Hz).
MS (ES+) m/z 418 (M+1).
1H-NMR (300 MHz, CDCl3) δ1.32 (3H, t, J=7 Hz), 1.60-1.77 (1H, m), 2.22-2.97 (8H, m), 3.64-3.67 (2H, m), 4.24 (2H, q, J=7 Hz), 4.56-4.66 (1H, m), 5.00-5.06 (1H, m), 6.71 (1H, d, J=16 Hz), 7.25-7.35 (5H, m), 7.56 (1H, d, J=16 Hz), 7.95 (1H, s).
MS (ES+) m/z 367 (M+1).
1H-NMR (300 MHz, CDCl3) δ1.32 (3H, t, J=7 Hz), 1.64-1.77 (1H, m), 2.32-2.47 (2H, m), 2.63-2.75 (2H, m), 2.85-2.93 (1H, m), 3.61 (2H, s), 4.25 (2H, g, J=7 Hz), 4.43-4.52 (1H, m), 5.20 (1H, d, J=8 Hz), 6.68 (1H, d, J=16 Hz), 7.18-7.28 (3H, m), 7.33 (1H, s), 7.57 (1H, d, J=0.16 Hz), 7.89 (1H, d, J=1 Hz), 8.05 (1H, d, J=1 Hz).
MS (ES+) m/z 387 (M+1).
1) To a solution of ethyl (2E)-3-(5-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate (591 mg) in dioxane (15 mL) was added 1N sodium hydroxide (4.40 mL). After stirring at 60° C. for 2 hours, the reaction mixture was added H2O (15 mL) and neutralized with 1N hydrochloric acid (to pH 7). A resulting mixture was evaporated in vacuo.
2) To a mixture of above product, O-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)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide
1H-NMR (300 MHz, DMSO-d6) δ1.48-1.74 (6H, m), 1.82-2.31 (2H, m), 3.25-4.02 (6H, m), 4.31-4.50 (1H, m), 4.90 (1H, brs), 6.57-6.69 (1H, m), 7.33-8.19 (7H, m), 11.2 (1H, brs).
MS (ES+) m/z 472 (M+1).
The following compounds were obtained in a similar manner to that of Preparation 446.
1H-NMR (300 MHz, DMSO-d6) δ 1.48-1.74 (7H, m), 2.11-2.28 (1H, 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 (1H, m), 4.23-4.35 (1H, m), 4.89 (1H, brs), 6.59 (1H, d, J=16 Hz), 6.97-7.11 (3H, m), 7.37 (1H, d, J=16 Hz), 7.75 (1H, d, J=6 Hz), 7.97 (1H, s), 8.09 (1H, s).
MS (ES+) m/z 452 (M+1).
1H-NMR (300 MHz, DMSO-d6) δ 1.47-1.74 (7H, m), 2.18-2.31 (1H, m), 2.44-2.56 (2H, m), 2.69-2.89 (2H, m), 3.48-3.57 (1H, m), 3.65-3.77 (2H, m), 3.90-4.01 (1H, m), 4.27-4.39 (1H, m), 4.89 (1H, brs), 6.60 (1H, d, J=16 Hz), 7.24-7.54 (5H, m), 7.80 (1H, d, J=6 Hz), 7.98 (1H, s), 8.10 (1H, s), 11.2 (1H, brs).
MS (ES+) m/z 458 (M+1).
1H-NMR (300 MHz, DMSO-d6) δ1.46-1.74 (7H, m), 2.17-2.30 (1H, m), 2.38-2.48 (2H, m), 2.63-2.81 (2H, m), 3.48-3.57 (1H, m), 3.60 (2H, s), 3.89-4.01 (1H, m), 4.25-4.37 (1H, m), 4.89 (1H, brs), 6.60 (1H, d, J=16 Hz), 7.26-7.42 (5H, m), 7.79 (1H, d, J=6 Hz), 7.98 (1H, s), 8.10 (1H, s), 11.2 (1H, brs).
MS (ES+) m/z 458 (M+1).
To a mixture of tert-butyl (3R)-3-pyrrolidinylcarbamate (450 mg) and 3-methoxybenzaldehyde (352 uL) in CH2Cl2 (4.5 mL) was added sodium triacetoxyborohydride (922 mg), 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 Na2SO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give tert-butyl [(3R)-1-(3-methoxybenzyl)-3-pyrrolidinyl]carbamate (744 mg) as a off-white solid.
1H NMR (200 Mz, CDCl3) δ 1.43 (9H, s), 1.49-1.72 (1H, m), 2.16-2.46 (2H, m), 2.58-2.72 (2H, m), 2.80-2.98 (1H, m), 3.63 (2H, br. s), 3.82 (3H, s), 4.08-4.31 (1H, br), 4.90-5.14 (1H, br), 6.76-6.95 (3H, m), 7.24 (1H, t, J=8.1 Hz);
MS (ES+) m/z 307 (M+1).
The following compound was obtained in a similar manner to that of Preparation 450.
1H NMR (CDCl3, 200 MHz) d 1.44 (9H, s), 1.50-1.82 (1H, m), 2.12-2.42 (2H, m), 2.48-2.72 (2H, m), 2.72-2.89 (1H, m), 3.63 (2H, s), 4.08-4.31 (1H, br), 4.70-4.99 (1H, br), 7.36-7.68 (4H, m);
MS (ES+) 302 (M+1).
To a solution of tert-butyl [(3R)-1-(3-methoxybenzyl)-3-pyrrolidinyl]carbamate (739 mg) in ethyl acetate (3.7 mL) was added 4N HCl-ethyl acetate (6.0 mL), which was stirred at room temperature for 1.5 hours. The mixture was concentrated to give (3R)-1-(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+1).
The following compounds were obtained in a similar manner to that of Preparation 452.
1H NMR (DMSO-d6, 200 MHz) δ 1.89-2.34 (2H, m), 3.05-4.22 (5H, m), 4.41-4.71 (2H, m), 7.69 (1H, t, J=7.8 Hz), 7.89-8.23 (3H, m), 8.25-8.82 (2H, m);
MS (ES+) m/z 202 (M+1).
1H NMR (DMSO-d6, 200 MHz) (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 (1H, s), 8.39-8.85 (3H, m), 10.21 (1H, s), 11.10-11.67 (1H, m); MS (ES+) m/z 234 (M+1).
1H NMR (DMSO-d6, 200 MHz) δ 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 (1H, m);
MS (ES+) m/z 220 (M+1).
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), 6.93-7.51 (4H, m, J=q Hz), 8.34-8.94 (3H, m), 10.00 (1H, s), 11.16-11.98 (1H, m);
MS (ES+) m/z 270 (M+1).
To a mixture of ethyl (2E)-3-(5-chloro-2-pyrazin-yl)acrylate (278 mg) in 1,3-dimethyl-2-imidazolidinone (2.78 mL) was added (3R)-1-(3-methoxybenzyl)-3-pyrrolidinamine dihydrochloride (547.5 mg) and
K2CO3 (1.08 g), 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)-1-(3-methoxybenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate (367.5 mg) as a brown solid.
1H NMR (CDCl3, 200 MHz) δ1.32 (3H, t, J=7.1 Hz), 1.62-1.86 (1H; m), 2.28-2.50 (2H, m), 2.72 (2H, d, J=4.6 Hz), 2.89-3.04 (1H, m), 3.66 (2H, s), 3.81 (3H, s), 4.25 (2H, q, J=7.1 Hz), 4.39-4.58 (1H, m), 5.29-5.44 (1H, m), 6.68 (1H, d, J=15.5 Hz), 6.74-6.96 (3H, m), 7.25 (1H, t, J=7.9 Hz), 7.57 (1H, d, J=15.5 Hz), 7.89 (1H, d, J=1.2 Hz), 8.22 (1H, d, J=1.2 Hz);
MS (ES+) m/z 383 (M+1).
The following compounds were obtained in a similar manner to that of Preparation 457.
1H NMR 6 (DMSO-d6, 400 MHz) δ 1.24 (3H, t, J=7.0 Hz), 1.62-1.72 (1H, m), 2.18-2.30 (1H, m), 2.39-2.48 (2H, m), 2.64-2.73 (1H, m), 2.75-2.83 (1H, m), 3.66 (2H, s), 4.17 (2H, q, J=7.12 Hz), 4.34 (1H, br), 6.50 (1H, d, J=15.6 Hz), 7.50-7.58 (2H, m), 7.65-7.79 (3H, m), 7.92-7.79 (1H, m), 8.00 (1H, s), 8.21 (1H, s);
MS (ES+) m/z 378 (M+1).
1H NMR (DMSO-d6, 400 MHz) δ 1.24 (3H, t, J=7.2 Hz), 1.60-1.71 (1H, m), 2.02 (3H, s), 2.16-2.29 (1H, m), 2.31-2.53 (2H, m), 2.59-2.68 (1H, m), 2.75-2.83 (1H, m), 3.54 (2H, s), 4.16 (2H, q, J=7.1 Hz), 4.26-4.37 (1H, m), 6.49 (1H, d, J=15.5 Hz), 6.97 (1H, d, J=7.5 Hz), 7.21 (1H, t, J=7.8 Hz), 7.45 (1H, d, J=8.2 Hz), 7.49-7.57 (2H, m), 7.92 (1H, d, J=6.6 Hz), 7.99 (1H, s), 8.20 (1H, s), 9.89 (1H, s);
MS (ES+) m/z 410 (M+1).
1H NMR (DMSO-d6, 400 MHz) δ 1.24 (3H, t, J=7.2 Hz), 1.60-1.71 (1H, m), 2.17-2.28 (1H, m), 2.38-2.57 (2H, m), 2.63-2.78 (2H, m), 2.86 (6H, s), 3.49 (1H, d, J=12.9 Hz), 3.54 (1H, d, J=12.9 Hz), 4.16 (2H, q, J=7.12 Hz), 4.26-4.39 (1H, m), 6.49 (1H, d, J=15.6 Hz), 6.56-6.68 (3H, m), 7.10 (1H, t, J=7.8 Hz), 7.52 (1H, d, J=15.6 Hz), 7.90-7.97 (1H, m), 7.99 (1H, d, J=1.0 Hz), 8.20 (1H, d, J=1.1 Hz);
MS (ES+) m/z 396 (M+1).
1H NMR (DMSO-d6, 400 MHz) δ 1.24 (3H, t, J=7.0 Hz), 1.59-1.72 (1H, m), 2.16-2.29 (1H, m), 2.37-2.53 (2H, m), 2.61-2.70 (1H, m), 2.74-2.82 (1H, m), 2.94 (3H, s), 3.50-3.61 (2H, m), 4.16 (2H, q, J=7.1 Hz), 4.25-4.37 (1H, m), 6.49 (1H, d, J=15.4 Hz), 7.00-7.11 (2H, m), 7.16 (1H, s), 7.26 (1H, t, J=7.7 Hz), 7.53 (1H, d, J=15.6 Hz), 7.93 (1H, d, J=6.5 Hz), 7.99 (1H, d, J=1.0 Hz), 8.20 (1H, d, J=1.1 Hz), 9.20-9.70 (1H, br);
MS (ES+) 446 (M+1).
To a solution of ethyl (2E)-3-(5-{[(3R)-1-(3-methoxybenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate (362 mg) in methanol (2.9 mL) was added 1N NaOH aq. (947 uL), which was stirred at 55° C. for 45 minutes. The reaction mixture was added 1N HCl aq. (947 uL), and evaporated in vacuo to give (2E)-3-(5-{([(3R)-1-(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.
To a mixture of (2E)-3-(5-{[(3R)-1-(3-methoxybenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylic acid (crude of reaction), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (166.4 mg), and 1-hydroxybenzotriazole (191.9 mg) in DMF (3.4 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (251 uL), 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-(tetrahydro-2H-pyran-2-yloxy)acrylamide (312 mg) as a yellow amorphous.
1H NMR (200 MHz, DMSO-d6) δ1.42-1.83 (7H, m), 2.12-2.34 (1H, 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 (1H, m), 4.12-4.42 (1H, m), 4.89 (1H, br), 6.59 (1H, d, J=15.0 Hz), 6.73-6.96 (3H, m), 7.22 (1H, t, J=7.9 Hz), 7.37 (1H, d, J=15.3 Hz), 7.77 (1H, d, J=6.8 Hz), 7.97 (1H, s), 8.09 (1H, s), 11.17 (1H, br); MS (ES+) m/z 454 (M+1))
The following compounds were obtained in a similar manner to that of Preparation 471.
1H NMR (DMSO-d6, 400 MHz) δ 1.45-1.60 (3H, m), 1.60-1.80 (4H, m), 2.17-2.30 (1H, m), 2.39-2.48 (2H, m), 2.64-2.73 (1H, m), 2.74-2.83 (1H, m), 3.46-3.57 (1H, m), 3.66 (2H, s), 3.89-4.01 (1H, br), 4.23-4.39 (1H, br), 4.90 (sH, s), 6.69 (1H, d, J=15.1 Hz), 7.38 (1H, d, J=15.4 Hz), 7.54 (1H, t, J=7.7 Hz), 7.68 (1H, d, J=7.8 Hz), 7.73 (1H, d, J=7.7 Hz), 7.74-7.83 (2H, m), 7.98 (1H, s), 8.10 (1H, s), 11.18 (1H, s);
MS (ES+) m/z 449 (M+1).
1H NMR (DMSO-d6, 400 MHz) δ 1.45-1.77 (7H, m), 1.02 (3H, s), 2.16-2.29 (1H, m), 2.33-2.40 (1H, m), 2.41-2.53 (1H, m), 2.58-2.69 (1H, m), 2.75-2.84 (1H, m), 3.47-3.60 (3H, m), 3.88-4.02 (1H, m), 4.21-4.38 (1H, m), 4.89 (1H, s), 6.60 (1H, d, J=15.1 Hz), 6.97 (1H, d, J=7.6 Hz), 7.21 (1H, t, J=7.8 Hz), 7.37 (1H, d, J=15.2 Hz), 7.45 (1H, d, J=8.1 Hz), 7.54 (1H, s), 7.77 (1H, d, J=6.3 Hz), 7.96 (1H, s), 8.09 (1H, s), 9.90 (1H, s), 11.18 (1H, s);
MS (ES+) m/z 481 (M+1).
1H NMR (DMSO-d6, 400 MHz) δ 1.44-1.78 (7H, m), 2.15-2.28 (1H, m), 2.31-2.57 (2H, m), 2.61-2.71 (1H, m), 2.73-2.83 (1H, m), 2.94 (3H, s), 3.48-3.61 (3H, m), 3.88-4.00 (1H, m), 4.24-4.36 (1H, m), 4.89 (1H, s), 6.59 (1H, d, J=15.2 Hz), 7.01-7.11 (2H, m), 7.16 (1H, s), 7.26 (1H, t, J=7.8 Hz), 7.37 (1H, d, J=15.2 Hz), 7.77 (1H, d, J=6.3 Hz), 7.97 (1H, s), 8.09 (1H, s), 9.55-9.85 (1H, br), 11.07-11.29 (1H, br); MS (ES+) m/z 517 (M+1).
1H NMR (DMSO-d6, 400 MHz) δ 1.42-1.77 (7H, m), 2.13-2.28 (1H, 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 (1H, m), 4.24-4.34 (1H, m), 4.89 (1H, s), 6.54-6.67 (4H, m), 7.10 (1H, t, J=8.0 Hz), 1.36 (1H, d, J=15.2 Hz), 7.77 (1H, d, J=6.5 Hz), 7.97 (1H, s), 8.09 (1H, s), 11.18 (1H, s);
MS (ES+) m/z 467 (M+1).
1H NMR (DMSO-d6, 400 MHz) δ 1.44-1.77 (7H, m), 2.13-2.28 (1H, m), 2.40-2.55 (2H, m), 2.65-2.74 (1H, m), 2.74-2.81 (1H, m), 3.48-3.65 (3H, m), 3.77 (3H, s), 3.89-4.00 (1H, m), 4.25-4.36 (1H, m), 4.89 (1H, s), 6.59 (1H, d, J=15.1 Hz), 6.91 (1H, t, J=7.5 Hz), 6.96 (1H, d, J=8.2 Hz), 7.24 (1H, t, J=7.3 Hz), 7.31 (1H, d, J=7.4 Hz), 7.37 (1H, d, J=15.4 Hz), 7.77 (1H, d, J=6.3 Hz), 7.97 (1H, s), 8.09 (1H, s), 11.17 (1H, s);
MS (ES+) m/z 454 (M+1).
1H NMR (DMSO-d6, 400 MHz) δ1.41-1.79 (7H, m), 2.15-2.29 (1H, m), 2.33-2.48 (2H, m), 2.59-2.69 (1H, m), 2.73-2.81 (1H, m), 3.40-3.56 (3H, m), 3.87-4.00 (1H, m), 4.24-4.35 (1H, m), 4.83-4.93 (1H, m), 6.54-6.66 (2H, m), 6.66-6.77 (2H, m), 7.08 (1H, t, J=8.1 Hz), 7.37 (1H, d, J=15.2 Hz), 7.76 (1H, d, J=6.4 Hz), 7.97 (1N, s), 8.09 (1H, s), 9.29 (1H, s), 11.17 (1H, br);
MS (ES+) m/z 440 (M+1).
1H NMR (DMSO-d6, 400 MHz) δ 1.20-1.27 (6H, m), 1.47-1.76 (7H, m), 2.14-2.28 (1H, m), 2.37-2.47 (2H, m), 2.63-2.77 (2H, m), 3.47-3.61 (3H, m), 3.89-4.00 (1H, m), 4.25-4.35 (1H, m), 4.56 (1H, septet, J=6.0 Hz), 4.89 (1H, s), 6.59 (1H, d, J=15.2 Hz), 6.77 (1H, d, J=7.8 Hz), 6.82-6.87 (2H, m), 7.19 (1H, t, J=8.0 Hz), 7.37 (1H, d, J=15.2 Hz), 7.77 (1H, d, J=6.2 Hz), 7.97 (1H, s), 8.09 (1H, s), 11.17 (1H, s); MS (ES+) m/z 482.
1H NMR (DMSO-d6, 400 MHz) δ 1.44-1.79 (7H, m), 2.19-2.35 (1H, m), 2.44-2.56 (2H, m), 2.71-2.86 (2H, m), 3.12-3.60 (3H, m), 3.87-4.01 (1H, m), 4.27-4.39 (1H, m), 4.82-4.92 (1H, m), 6.62 (1H, d, J=15.2 Hz), 6.69-6.80 (3H, m), 7.00-7.14 (2H, m), 7.38 (1H, d, J=15.3 Hz), 7.77-7.87 (1H, m), 7.98 (1H, s), 8.10 (1H, s), 11.17 (1H, br);
MS (ES+) m/z 440 (M+1).
To a mixture of tert-butyl (3R)-3-pyrrolidinylcarbamate (450 mg), 1-(chloromethyl)-3-nitrobenzene (435 mg) in DMF (4.5 mL) was added N,N-diisopropylamine (463 uL), which was stirred at 75° C. 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)-1-(3-nitrobenzyl)-3-pyrrolidinyl]carbamate (, 757 mg) as a orange oil.
1H NMR (200 MHz, CDCl3) δ 1.44 (9H, s), 1.50-1.77 (1H, m), 2.17-2.96 (5H, m), 3.60-3.80 (2H, m), 4.19 (1H, br), 4.84 (1H, br), 7.49 (1H, t, J=7.9 Hz), 7.68 (1H, d, J=7.4 Hz), 7.99-8.24 (2H, m);
MS (ES+) 322 (M+1).
To a solution of tert-butyl [(3R)-1-(3-nitrobenzyl)-3-pyrrolidinyl]carbamate (750 mg) in ethanol (5.6 mL) and H2O (1.9 mL) was added NH4Cl (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)-1-(3-aminobenzyl)-3-pyrrolidinyl]carbamate (645 mg) as a brown oil.
1H NMR (CDCl3, 206 MHz) δ 1.43 (9H, s), 1.48-1.71 (1H, m), 2.12-2.43 (2H, m), 2.44-3.00 (3H, m), 3.51 (2H, s), 3.65 (2H, br), 4.17 (1H, br), 4.88 (1H, br), 6.53-6.73 (3H, m), 7.09 (1H, t, J=7.9 Hz); API-ES(posi) 292 (M+1).
To a solution of tert-butyl [(3R)-1-(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)-1-[3-(dimethylamino)benzyl]-3-pyrrolidinyl}carbamate (365 mg) as a white solid.
1H NMR (CDCl3, 200 MHz) δ 1.43 (9H, s), 1.50-1.76 (1H, m), 2.12-2.44 (2H, m), 2.47-2.70 (2H, m), 2.72-2.93 (1H, m), 2.95 (6H, s), 3.57 (2H, s), 4.17 (1H, br), 4.90 (1H, br), 6.58-6.74 (3H, m), 7.18 (1H, t, J=7.7 Hz);
MS (ES+) m/z 320 (M+1).
To a solution of tert-butyl [(3R)-1-(3-aminobenzyl)-3-pyrrolidinyl]carbamate (681 mg) in CH2Cl2 (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)-1-[3-(acetylamino)benzyl]-3-pyrrolidinyl}carbamate (944 mg) as a off-white amorphous.
1H NMR (CDCl3, 200 MHz) δ 1.42 (9H, s), 1.71-2.00 (1H, m), 2.18 (3H, s), 36-2.47 (1H, m), 2.58-2.75 (1H, m), 2.78-3.07 (2H, m), 3.07-3.36 (1H, m), 3.86 (2H, s), 4.34 (1H, br), 5.06 (1H, br), 7.10 (1H, d, J=7.5 Hz), 7.30 (1H, t, J=7.6 Hz), 7.56-7.69 (2H, m), 7.81 (1H, br);
MS (ES+) m/z 334 (M+1).
To tert-butyl [(3R)-1-(3-fluorobenzyl)-3-pyrrolidinyl]carbamate (3.0 g) was added 4NHCl/Dioxane (38 ml) at room temperature. The mixture was stirred for 2 hrs at the same temperature.
Evaporated and decanted with diisopropyl ether (three times).
Evaporated to give 2.85 g of (3R)-1-(3-fluorobenzyl)-3-pyrrolidinamine dihydrochloride as an amorphous.
MASS (ESI+): m/z=195.2 (M+1).
1HNMR (400 MHz, 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 (1H, m), 7.40-7.70 (3H, m), 8.67 and 8.84 (3H, br.s).
To a solution of tert-butyl [(3R)-1-(3-aminobenzyl)-3-pyrrolidinyl]carbamate (659 mg) in CH2Cl2 (6.6 mL) was added pyridine (274 uL) and methanesulfonyl chloride (193 uL), 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)-1-{3-[(methylsulfonyl)amino]benzyl}-3-pyrrolidinyl]carbamate (845 mg) as pale yellow amorphous.
1H NMR (CDCl3. 200 MHz) δ 1.43 (9H, s), 1.44-1.78 (1H, m), 2.16-2.46 (2H, m), 2.50-2.76 (2H, m), 2.78-2.95 (1H, m), 3.02 (3H, s), 3.62 (2H, s), 4.20 (1H, br), 4.93 (1H, br), 7.08-7.36 (4H, m);
MS (ES+) m/z 370.3 (M+1).
To a mixture of tert-butyl (3R)-3-pyrrolidinylcarbamate (2.0 g) and 2-fluorobenzaldehyde (1.4 g) was added NaBH(OAc)3 2.73 g (1.2 eq) under ice-cooling.
After 30 min, 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 Na2SO4.
Evaporated to give 3.21 g of tert-butyl [(3R)-1-(2-fluorobenzyl)-3-pyrrolidinyl]carbamate.
MASS (ESI+): m/z=295.3 (M+1).
1HNMR (400 MHz, CDCl3): δ 1.43 (9H, s), 1.5-1.7 (1H, m), 2.2-2.9 (5H, m), 3.67 (2H, s), 4.17 (1H, br.s), 4.87 (1H, br.s), 7.00-7.05 (1H, m), 7.08-7.12 (1H, m), 7.21-7.24 (1H, m), 7.33-7.37 (1H, m).
To tert-butyl [(3R)-1-(2-fluorobenzyl)-3-pyrrolidinyl]carbamate (3.0 g) was added 4NHCl/Dioxane (38 ml) at room temperature. The mixture was stirred for 2 hrs at the same temperature.
Evaporated and decanted with diisopropyl ether (three times).
Evaporated to give 3.74 g of (3R)-1-(2-fluorobenzyl)-3-pyrrolidinamine dihydrochloride.
MASS (ESI+): m/z=195.2 (M+1).
1HNMR (400 MHz, CDCl3): δ 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 (1H, m), 7.70-7.80 (1H, m), 8.63 and 8.76 (3H, br.s).
A mixture of (3R) 1-(3-fluorobenzyl)-3-pyrrolidinamine dihydrochloride (1.0 g), methyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate (1.74 g) and Na2CO3 (4.18 g) 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 CHCl3:MeOH=8:1) to give 1.68 g (94%) of methyl (2E)-3-(5-{[(3R)-1-(3-fluorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate as an oil.
MASS (ESI+): m/z=357.2 (M+1).
1HNMR (400 MHz, CDCl3): δ (1.70-1.80 (1H, m), 2.35-2.50 (2H, m), 2.65-2.75 (2H, m), 2.79 (3H, s), 2.90-3.00 (1H, m), 3.65 (2H, s), 4.50 (1H, br.s), 5.45 (1H, d, J=6.6 Hz), 6.68 (1H, d, J=15.6 Hz), 6.95-7.35 (4H, m), 7.58 (1H, d, J=15.6 Hz), 7.90 (1H, d, J=1.28 Hz), 8.03 (1H, d, J=1.28 Hz).
To a solution of methyl (2E)-3-(5-{[(3R)-1-(3-fluorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate (1.98 g) in methanol (42 ml) was added 1NNaOH (21 ml) at room temperature. After stirring for 2 hrs, 1N HCl (21 ml) was added. The mixture was evaporated under reduced pressure. To a residue was added DMF(40 ml), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (815 mg), HOBt (940 mg) and WSCD (1.25 g) 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 26×100 mm) to give 730 mg (30%) of (2E)-3-(5-{[(3R)-1-(3-fluorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide as an oil.
MASS (ESI+): m/z=442.3 (M+1).
MASS (ESI−): m/z=440.4 (M+1).
1HNMR (400 MHz, CDCl3): δ 1.51-2.03 (7H, m), 2.33-2.46 (2H, m), 2.71 (2H, d, J=4.8 Hz), 2.90-2.97 (1H, m), 3.65 (2H, s), 3.96 (1H, t, J=9.8 Hz), 4.44-4.53 (1H, m), 5.01 (1H, br.s.), 5.38 (1H, d, J=8.0 Hz), 6.96 (1H, dt, J=2.5 and 8.4 Hz), 7.04-7.12 (2H, m), 7.27 (1H, s), 7.25-7.31 (1H, m), 7.61 (1H, d, J=15.1 Hz), 7.87 (1H, s), 8.02 (1H, s).
A mixture of (3R)-1-(2-fluorobenzyl)-3-pyrrolidinamine dihydrochloride (1.0 g), methyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate (1.74 g) and Na2CO3 (4.18 g) 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 CHCl3:MeOH=8:1) to give 1.22 g (68%) of methyl (2E)-3-(5-{[(3R)-1-(2-fluorobenzyl)-3-pyrrolidinyl]amino) }-2-pyrazinyl)acrylate as an oil.
MASS (ESI+): m/z=357.2 (M+1).
1HNMR (400 MHz, CDCl3): δ 1.61-1.84 (1H, m), 2.25-3.00 (m, 5H), 3.79 (2H, s), 4.45-4.53 (1H, m), 5.45 (1H, d, J=6.6 Hz), 6.68 (1H, d, J=15.6 Hz), 7.00-7.45 (4H, m), 7.27 (2H, s), 7.57 (1H, d, J=15.6 Hz), 7.88 (1H, d, J=1.28 Hz), 8.03 (1H, d, J=1.28 Hz).
To a solution of methyl (2E)-3-(5-{[(3R)-1-(2-fluorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate (1.20 g) in methanol (34 ml) was added 1NNaOH (16.9 ml) at room temperature and stirred for 2 hrs. After then, the reaction mixture was neutralized with 1N HCl (16.9 ml).
The mixture was evaporated under reduced pressure and co-evaporated with toluene (twice).
To the residue in DMF(30 ml) was added O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (513 mg), HOBt (591 mg) and WSCD (784 mg) and the mixture was stirred overnight.
After 12 hours, water was added and extracted with CHCl3 (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)-1-(2-fluorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide.
Crude product was purified with HPLC (Yamazene packed column, 26 mm×100 nm) to give 540 mg (36%) of (2E)-3-(5-{[(3R)-1-(2-fluorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H pyran-2-yloxy)acrylamide as an oil.
MASS (ESI+): m/z 442.3, (M+1).
1HNMR (400 MHz): 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 (1H, m), 4.49 (1H, m), 5.01 (1H, br.s), 5.46 (1H, m), 7.05 (1H, ddd, J=1.0, 8.2 and 9.8 Hz), 7.12 (1H, dt, J=1.2 and 7.5 Hz), 7.22-7.30 (1H, m), 7.26 (2H, s), 7.38 (1H, dt, J=1.6 and 7.5 Hz), 7.61 (1H, d, J=14.1 Hz), 7.85 (1H, s), 8.02 (1H, s).
To a suspension of methyl (2E)-3-{5-[(3R)-3-pyrrolidinylamino]-2-pyrazinyl}acrylate 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)acrylate (193 mg) as a yellow amorphous.
1H NMR (DMSO-d6, 400 MHz) δ 1.59-1.70 (1H, m), 2.16-2.28 (1H, m), 2.40-2.53 (2H, m), 2.65-2.74 (1H, m), 2.74-2.81 (1H, m), 3.53-3.64 (2H, m), 3.69 (3H, s), 3.77 (3H, s), 4.26-4.38 (1H, m), 6.51 (1H, d, J=15.4 Hz), 6.91 (1H, t, J=7.4 Hz), 6.96 (1H, d, J=8.2 Hz), 7.22 (1H, t, J=8.2 Hz), 7.31 (1H, d, J=7.2 Hz), 7.55 (1H, d, J=15.6 Hz), 7.95 (1H, d, J=6.6 Hz), 8.00 (1H, s), 8.21 (1H, s); MS (ES+) m/z 369 (M+1).
The following compounds were obtained in a similar manner to that of Preparation 492.
1H NMR (DMSO-d6, 400 MHz) δ 1.60-1.71 (1H, m), 2.16-2.28 (1H, m), 2.32-2.47 (2H, m), 2.59-2.69 (1H, m), 2.73-2.81 (1H, m), 3.49 (2H, s), 3.69 (3H, s), 4.25-4.37 (1H, m), 6.51 (1H, d, J=15.4 Hz), 6.62 (1H, d, J=7.0 Hz), 6.67-6.79 (2H, m), 7.08 (1H, t, J=8.0 Hz), 7.55 (1H, d, J=15.4 Hz), 7.94 (1H, d, J=6.5 Hz), 8.00 (1H, s), 8.20 (1H, s), 9.28 (1H, s);
MS (ES+) m/z 355 (M+1).
1H NMR (DMSO-d6, 400 MHz) δ 1.18-1.31 (6H, m), 1.61-1.73 (1H, m), 2.16-2.29 (1H, m), 2.37-2.47 (2H, m), 2.61-2.79 (2H, m), 3.52 (1H, d, J=13.1 Hz), 3.57 (1H, d, J=13.2 Hz), 3.69 (3H, s), 4.23-4.38 (1H, m), 4.56 (1H, septet, J=6.0 Hz), 6.51 (1H, d, J=15.5 Hz), 6.77 (1H, dd, J=2.0, 8.0 Hz), 6.80-6.90 (2H, m), 7.19 (1H, t, J=8.0 Hz), 7.55 (1H, d, J=15.5 Hz), 7.94 (1H, d, J=6.7 Hz), 8.00 (1H, d, J=2.4 Hz), 8.20 (1H, s);
MS (ES+) m/z 397 (M+1).
1H NMR (DMSO-d6, 400 MHz) δ 1.66-1.79 (1H, m), 2.19-2.35 (1H, 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 (1H, m), 6.52 (1H, d, J=15.5 Hz), 6.67-6.79 (2H, m), 7.02-7.15 (2H, m), 7.56 (1H, d, J=15.5 Hz), 7.95-8.04 (2H, m), 8.21 (1H, d, J=1.1 Hz);
MS (ES+) m/z 355 (M+1).
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-1-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 Na2SO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give tert-butyl (3R)-3-({5-[(1E)-3-methoxy-3-oxo-1-propen-1-yl]-2-pyrazinyl}amino)-1-pyrrolidinecarboxylate (834 mg) as a off-white powder.
1H NMR (400 MHz, CDCl3) δ 1.47 (9H, s), 1.88-2.03 (1H, br), 2.20-2.33 (1H, m), 3.19-3.40 (1H, m), 3.41-3.58 (2H, m), 3.69-3.77 (1H, m), 3.80 (3H, s), 4.51 (1H, br), 5.08 (1H, br), 6.72 (1H, d, J=15.5 Hz), 7.60 (1H, d, J=15.6 Hz), 7.95 (1H, d, J=1.3 Hz), 8.08 (1H, s);
MS (ES+) m/z 371 (M+23).
To a solution of tert-butyl (3R)-3-({5-[(1E)-3-methoxy-3-oxo-1-propen-1-yl]-2-pyrazinyl}amino)-1-pyrrolidinecarboxylate (830 mg) in dioxane (8.3 mL) was added 4N HCl/dioxane (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, 400 MHz) δ 1.92-2.02 (1H, m), 2.16-2.28 (1H, m), 3.05-3.15 (1H, m), 3.21-3.49 (3H, m), 3.71 (3H, s), 4.43-4.52 (1H, br), 6.57 (1H, d, J=15.7 Hz), 7.60 (1H, d, J=15.6 Hz), 8.07 (1H, d, J=1.1 Hz), 8.23-8.39 (2H, m), 9.43 (2H, br);
MS (ES+) m/z 249 (M+1).
To a solution of ethyl (2E)-3-(6-{[(3R)-1-phenyl-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate (47 mg) in dioxane (1.4 mL) was added 1N sodium hydroxide (0.42 mL). After stirring at 60° C. for 2 hours, the reaction mixture was added H2O (7 mL) and acidified with 1N hydrochloric acid (to pH 4). A resulting precipitate was collected by filtration, and washed with water to give (2E)-3-(6-{[(3R)-1-phenyl-3-pyrrolidinyl]amino}-3-pyridinyl)acrylic acid hydrochloride (39 mg).
1H-NMR (300 MHz, DMSO-d6) δ 1.93-2.05 (1H, m), 2.23-2.36 (1H, m), 3.09-3.64 (4H, m), 4.54-4.62 (1H, m), 6.25 (1H, d, J=16 Hz), 6.51-6.63 (4H, m), 7.12-7.21 (2H, m), 7.44-7.51 (2H, m), 7.79 (1H, d, J=9 Hz), 8.24 (1H, brs), 12.1 (1H, brs).
MS (ES+) m/z 310 (M+1).
To a solution of ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(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 Na2SO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give ethyl (2E)-3-(6-{[(3R)-1-(4-aminophenyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate (186 mg).
1H-NMR (300 MHz, CDCl3) δ1.33 (3H, t, J=7 Hz), 1.97-2.08 (1H, m), 2.32-2.45 (1H, m), 3.19-3.61 (4H, m), 4.25 (2H, q, J=7 Hz), 4.53-4.64 (1H, m), 4.96-5.00 (1H, m), 6.23 (1H, d, J=16 Hz), 6.41 (1H, d, J=9 Hz), 6.49 (2H, d, J=9 Hz), 6.68 (2H, d, J=9 Hz), 7.58 (1H, d, J=16 Hz), 7.63 (1H, dd, J=2, 9 Hz), 8.22 (1H, d, J=2 Hz),
MS (ES+) m/z 353 (M+1).
To a mixture of ethyl (2E)-3-(6-{[(3R)-1-(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 4° C. The reaction mixture was stirred for 2 hours at 4° C. The resulting mixture was neutralized 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)-1-phenyl-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate (49.0 mg).
1H-NMR (300 MHz, CDCl3) δ1.33 (3H, t, J=7 Hz), 2.01-2.13 (1H, m), 2.34-2.47 (1H, m), 3.25-3.74 (4H, m), 4.25 (2H, q, J=7 Hz), 4.57-4.67 (1H, m), 4.91-4.97 (1H, m), 6.24 (1H, d, J=16 Hz), 6.42 (1H, d, J=9 Hz), 6.59 (2H, d, J=9 Hz), 6.69-6.76 (1H, m), 7.22-7.30 (2H, m), 7.58 (1H, d, J=16 Hz), 7.63 (1H, dd, J=2, 9 Hz), 8.23 (1H, d, J=2 Hz).
MS (ES+) m/z 338 (M+1).
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) δ1.34 (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 (1H, m), 6.44 (2H, d, J=9 Hz), 6.45 (1H, d, J=16 Hz), 7.32 (1H, d, J=8 Hz), 7.63 (1H, d, J=16 Hz), 7.83 (1H, dd, J=2, 8 Hz), 8.11 (2H, d, J=9 Hz), 8.50 (1H, d, J=2 Hz),
MS (ES+) m/z 483 (M+1).
1) To a mixture of 6-chloro-3-pyridazinecarbaldehyde (500 mg) and THF (10 mL) 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)-1-(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)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-3-pyridazinyl)acrylate (499 mg).
1H-NMR (300 MHz, CDCl3) δ 0.81-0.96 (2H, m), 1.22-1.28 (4H, m), 1.34 (3H, t, J1=7 Hz), 1.37-1.49 (1H, m), 1.62-1.83 (5H, m), 2.19-2.45 (4H, m), 2.59-2.72 (2H, m), 2.82-2.93 (1H, m), 4.27 (2H, q, J=7 Hz), 4.46-4.59 (1H, m), 5.29-5.35 (1H, m), 6.61 (1H, d, J=16 Hz), 6.62 (1H, d, J=9 Hz); 7.37 (1H, d, J=9 Hz), 7.79 (1H, d, J=16 Hz).
MS (ES+) m/z 359 (M+1).
To a mixture of ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate dihydrochloride (250 mg), 4-(chloromethyl)-1,2-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)-1-(3,4-dimethylbenzyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate (263 mg).
1H-NMR (300 MHz, CDCl3) δ 1.35 (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 (1H, m), 6.46 (1H, d, J=16 Hz), 6.93-7.06 (3H, m), 7.25-7.31 (1H, m), 7.66 (1H, d, J=16 Hz), 7.75-7.82 (1H, m), 8.53 (1H, d, J=2 Hz).
MS (ES+) m/z 480 (M+1).
To a solution of (2E)-3-(6-{[(3R)-1-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-dimethylformamide (1 mL) was added 1-(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)-1-phenyl-3-pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (43 mg).
1H-NMR (300 MHz, DMSO-d6) δ1.48-1.74 (6H, m), 1.92-2.04 (1H, m), 2.23-2.36 (1H, m), 3.09-3.64 (5H, m), 3.89-4.00 (1H, m), 4.52-4.63 (1H, m), 4.88 (1H, brs), 6.23 (1H, 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 (1H, m), 8.20 (1H, brs), 11.1 (1H, brs).
MS (ES+) m/z 409 (M+1).
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 10° C. After stirring for 1 hours at 10° C., 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, CDCl3) δ2.67 (3H, s), 2.86-2.95 (1H, m), 4.79 (2H, d, J=3 Hz), 8.25 (1H, s).
MS (ES+) m/z 159 (M+1).
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)acrylate (863 mg).
1H-NMR (300 MHz, CDCl3) δ1.35 (3H, t, J=7 Hz), 2.68 (3H, s), 4.29 (2H, q, J=7 Hz), 7.01 (1H, d, J=16 Hz), 7.63 (1H, d, J=16 Hz), 8.26 (1H, s).
MS (ES+) m/z 227 (M+1).
1) To a mixture of 6-chloro-3-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)-1-benzyl-3-pyrrolidinamine (556 mg) and Et3N (0.880 mL). After stirring for 5 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-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-3-pyridazinyl)acrylate (237 mg).
1H-NMR (300 MHz, CDCl3) δ1.33 (3H, t, J=7 Hz), 1.60-1.79 (1H, m), 2.25-2.94 (5H, m), 3.63-3.66 (2H, m), 4.27 (2H, q, J=7 Hz), 4.48-4.60 (1H, m), 5.17-5.23 (1H, m), 6.59 (1H, d, J=9 Hz), 6.61 (1H, d, J=16 Hz), 7.25-7.38 (6H, m), 7.78 (1H, d, J=16 Hz).
MS (ES+) m/z 353 (M+1).
To a mixture of ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate 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) δ1.35 (3H, t, J=7 Hz), 1.46 (9H, s), 1.98-2.10 (1H, m), 2.16-2.30 (1H, m), 2.63-2.73 (1H, m), 2.78-2.98 (4H, m), 3.08-3.16 (1H, m), 4.00-4.16 (2H, m), 4.28 (2H, q, J=7 Hz), 4.87-4.98 (1H, m), 6.44 (1H, d, J=16 Hz), 6.86-6.97 (3H, m), 7.24-7.34 (3H, m), 7.63 (1H, d, J=16 Hz), 7.78 (1H, dd, J=2, 8 Hz), 8.51 (1H, d, J=2 Hz).
MS (ES+) m/z 482 (M+1).
The following compound was obtained in a similar manner to that of Preparation 508.
1H-NMR (300 MHz, CDCl3) δ0.93 (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 (1H, m), 2.33-2.48 (1H, m), 2.60-3.50 (6H, m), 4.28 (2H, q, J=7 Hz), 4.95-5.08 (1H, m), 6.47 (1H, d, J=16 Hz), 7.33 (1H, d, J=8 Hz), 7.65 (1H, d, J=16 Hz), 7.81 (1H, dd, J=2, 8 Hz), 8.57 (1H, brs).
MS (ES+) m/z 418 (M+1).
1) To a solution of ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-isobutyl-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate (464 mg) in dioxane (11 mL) was added 1N sodium hydroxide (3.30 mL). After stirring at 60° C. for 2 hours, the reaction mixture was added H2O(55 mL) and acidified with 1N hydrochloric acid (to pH 4). A resulting mixture was evaporated in vacuo.
2) To a mixture of above product, O-tetrahydro-2H-pyran-2-ylhydroxylamine (195 mg), and 1-hydroxybenzotriazole (225 mg) in N,N-dimethylformamide (6 mL) was added 1-(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)-1-isobutyl-3-pyrrolidinyl}amino}-2-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide
1H-NMR (300 MHz, DMSO-d6) δ0.71-0.79 (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 (1H, m), 3.49-3.58 (1H, m), 3.90-4.03 (1H, m), 4.67-4.78 (1H, m), 4.92 (1H, brs), 6.58 (1H, d, J=16 Hz), 7.34 (1H, d, J=8 Hz), 7.52 (1H, d, J=16 Hz), 8.00 (1H, d, J=8 Hz), 8.62 (1H, brs), 11.3 (1H, brs).
MS (ES+) m/z 489 (M+1).
The following compounds were obtained in a similar manner to that of Preparation 510.
1H-NMR (300 MHz, DMSO-d6) δ 1.08-1.29 (6H, m), 1.47-2.25 (13H, m), 2.39-2.53 (2H, m), 2.68-2.84, (2H, m), 3.49-3.57 (1H, m), 3.90-4.01 (1H, m), 4.22-4.33 (1H, m), 4.89 (1H, brs), 6.60 (1H, d, J=16 Hz), 7.38 (1H, d, J=16 Hz), 7.71-7.76 (1H, m), 7.97 (1H, brs), 8.11 (1H, brs), 11.2 (1H, brs).
MS (ES+) m/z 416 (M+1).
1H-NMR (300 MHz, DMSO-d6) δ 1.47-1.79 (7H, m), 2.08-2.21 (1H, m), 2.30-2.37 (1H, m), 2.44-2.63 (2H, m), 2.78-2.84 (1H, m), 3.47-3.61 (3H, m), 3.88-3.99 (1H, m), 4.27-4.37 (1H, m), 4.88 (1H, brs), 6.34 (1H, d, J=16 Hz), 7.20-7.34 (5H, m), 7.74-7.82 (1H, m), 8.51 (2H, s), 11.1 (1H, brs).
MS (ES+) m/z 424 (M+1).
1H-NMR (300 MHz, CDCl3) δ1.52-1.96 (7H, m), 2.34-2.52 (2H, m), 2.62-2.93 (3H, m), 3.58-3.68 (3H, m), 3.95-4.07 (1H, m), 4.34-4.50 (1H, m), 4.97-5.03 (1H, m), 6.60 (1H, d, J=9 Hz), 7.23-7.35 (7H, m), 7.67 (1H, d, J=16 Hz).
MS (ES+) m/z 424 (M+1).
1H-NMR (300 MHz, DMSO-d6) δ1.48-1.71 (6H, m), 1.79-1.92 (1H, m), 2.06-2.68 (7H, m), 2.81-2.93 (1H, m), 3.48-3.63 (3H, m), 3.88-3.99 (1H, m), 4.36-4.48 (1H, m), 4.90 (1H, brs), 6.63 (1H, d, J=16 Hz), 6.81 (1H, d, J=7 Hz), 7.20-7.39 (6H, m), 8.00 (1H, s), 11.2 (1H, brs).
MS (ES+) m/z 438 (M+1).
1H-NMR (300 MHz, DMSO-d6) δ0.76-0.92 (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 (1H, m), 2.73-2.81 (1H, m), 3.49-3.58 (1H, m), 3.91-4.03 (1H, m), 4.35-4.48 (1H, m), 4.92 (1H, brs), 6.62 (1H, A, J=16 Hz), 6.83 (1H, d, J=9 Hz), 7.33-7.55 (3H, m), 11.3 (1H, brs).
MS (ES+) m/z 430 (M+1).
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 1N sodium hydroxide (2.21 mL). After stirring at 60° C. for 2 hours, the reaction mixture was added H2O(37 mL) and acidified with 1N 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)-1-butyl-3-pyrrolidinyl]amino}-3-pyridinyl)acrylic acid dihydrochloride (214 mg).
1H-NMR (300 MHz, DMSO-d6) δ0.88 (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 (1H, d, J=16 Hz), 7.42 (1H, d, J=8 Hz), 7.62 (1H, d, J=16 Hz), 8.20 (1H, dd, J=2, 8 Hz), 8.70 (1H, d, J=2 Hz).
MS (ES+) m/z 390 (M+1).
The following compounds were obtained in a similar manner to that of Preparation 516.
1H-NMR (300 MHz, CDCl3) δ1.45 (9H, s), 2.23-2.89 (8H, m), 3.37-4.46 (6H, m), 5.10-5.24 (1H, m), 6.39 (1H, dd, J=2, 16 Hz), 7.16-7.40 (4H, m), 7.55 (1H, dd, J=2, 16 Hz), 7.78 (1H, dd, J=2, 8 Hz), 8.35-8.43 (1H, m).
MS (ES+) m/z 452 (M+1).
1H-NMR (300 MHz, DMSO-d6) δ0.80-0.92 (6H, m), 1.15-5.22 (14H, m), 1.42 (9H; s), 6.68 (1H, d, J=16 Hz), 7.42-7.51 (1H, m), 7.61-7.70 (1H, m), 8.20-8.28 (1H, m), 8.67-8.75 (1H, m).
MS (ES+) m/z 418 (M+1).
1H-NMR (300 MHz, DMSO-d6) δ1.40 (9H, s), 1.87-5.20 (11H, m), 6.63 (1H, d, J=16 Hz), 6.94-7.02 (3H, m), 7.28-7.35 (2H, m), 7.40-7.48 (1H, m), 7.60 (1H, d, J=16 Hz), 8.20 (1H, dd, J=2, 8 Hz), 8.67 (1H, d, J=2 Hz).
MS (ES+) m/z 454 (M+1).
To a mixture of (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(2-ethylbutyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylic acid dihydrochloride (303 mg), O-tetrahydro-2H-pyran-2-ylhydroxylamine (109 mg.), and 1-hydroxybenzotriazole (125 mg) in N,N-dimethylformamide (3.1 mL) was added 1-(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) δ0.74 (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 (1H, m), 3.90-4.02 (1H, m), 4.67-4.78 (1H, m), 4.92 (1H, brs), 6.58 (1H, d, J=16 Hz), 7.33 (1H, d, J=8 Hz), 7.53 (1H, d, J=16 Hz), 8.00 (1H, d, J=8 Hz), 8.63 (1H, brs).
MS (ES+) m/z 517 (M+1).
The following compounds were obtained in a similar manner to that of Preparation 520.
1H-NMR (300 MHz, DMSO-d6) δ1.35 (9H, s), 1.50-1.77 (6H, m), 1.88-2.23 (8H, m), 2.42-3.59 (7H, m), 3.91-4.03 (1H, m), 4.68-4.77 (1H, m), 4.91-4.95 (1H, m), 6.59 (1H, d, J=16 Hz), 6.85 (1H, d, J=8 Hz), 6.93 (1H, s), 7.00 (1H, d, J=8 Hz), 7.33 (1H, d, J=8 Hz), 7.54 (1H, d, J=16 Hz), 7.97-8.03 (1H, m), 8.61 (1H, brs), 11.3 (1H, brs).
MS (ES+) m/z 551 (M+1).
1H-NMR (300 MHz, CDCl3) δ0.91 (3H, t, J=7 Hz), 1.23-3.45 (12H, m), 1.46 (9H, s), 3.64-3.72 (1H, m), 3.93-4.04 (1H, m), 4.89-5.06 (2H, m), 6.30-7.34 (2H, m), 7.68 (1H, d, J=16 Hz), 7.78 (1H, dd, J=2, 8 Hz), 8.56 (1H, brs).
MS (ES+)-m/z 489 (M+1).
1H-NMR (300 MHz, CDCl3) δ1.45 (9H, s), 1.54-1.90 (6H, m), 1.98-2.10 (1H, m), 2.16-2.31 (1H, m), 2.65-2.98 (5H, m), 3.07-3.19 (1H, m), 3.63-3.74 (1H, 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 (1H, brs).
MS (ES+) m/z 553 (M+1).
The following compound was obtained in a similar manner to that of Preparation 309.
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 (1H, m), 2.58-2.76 (2H, m), 4.24-4.39 (3H, m), 6.37 (1H, br peak), 8.00 (1H, d, J=2.0 Hz), 8.66 (1H, d, J=2.0 Hz);
MS (ES+) m/z 380.
The following compound was obtained in a similar manner to that of Preparation 3.
1H-NMR (DMSO-d6): δ 1.25 (3H, t J=7.08 Hz), 1.51-1.71 (6H, m), 1.92-1.99 (2H, m), 4.16 (2H, q J=7.08 Hz), 4.32-4.43 (1H, m), 6.47 (1H, d J=15.84 Hz), 6.65 (1H, d J=7.24 Hz), 7.51 (1H, d J=15.84 Hz), 8.08 (1H, d J=1.96 Hz), 8.28 (1H, d J=1.96 Hz).
The following compound was obtained in a similar manner to that of Preparation 426.
1H-NMR (300 MHz, CDCl3) δ0.91-1.02 (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 (1H, m), 2.44-2.59 (2H, m), 2.61-2.74 (1H, m), 2.76-2.89 (1H, m), 2.96-3.10 (2H, m), 4.28 (2H, q, J=7.3 Hz), 4.76-4.91 (1H, m), 6.46 (1H, d, J=16.1 Hz), 7.28 (1H, d, J=8.8 Hz), 7.66 (1H, d, J=16.1 Hz), 7.80 (1H, dd, J=8.8, 2.6 Hz), 8.56 (1H, d, J=2.6 Hz);
MS (ES+) m/z 498(M+1).
The following compounds were obtained in a similar manner to that of Preparation 405, Preparation 414.
1H-NMR (300 MHz, DMSO-d6) δ0.90 (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 (1H, m), 3.89-4.04 (1H, m), 4.62-4.80 (1H, m), 4.92 (1H, br.s), 6.58 (1H, d, J=16.5 Hz), 7.33 (1H, d, J=8.4 Hz), 7.53 (1H, d, J=16.5 Hz), 7.99 (1H, br.d, J=8.4 Hz), 8.62 (1H, br.s);
MS (ES+) m/z 569(M+1).
1H-NMR (300 MHz, DMSO-d6) δ 1.21-2.01 (10H, m), 2.66-2.78 (0.6H, m), 3.01-4.03 (8H, m), 4.24-4.34 (0.4H, m), 4.90 (1H, br.s), 6.56-6.69 (1H, 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.
1H-NMR (300 MHz, CDCl3) δ1.32 (3H, t, J=7.0 Hz), 1.63-1.77 (1H, m), 2.31-2.46 (2H, m), 2.35 (3H, s), 2.62-2.75 (2H, m), 2.85-2.95 (1H, m), 3.60 (2H, br.s), 4.25 (2H, q, J=7.0 Hz), 4.39-4.54 (1H, m), 5.23 (1H, br.d, J=8.1 Hz), 6.67 (1H, d, J=15.8 Hz), 7.04-7.15 (3H, m), 7.18-7.25 (1H, m), 7.57 (1H, d, J=15.8 Hz), 7.87 (1H, br.s), 8.05 (1H, 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.
1H-NMR (300 MHz, DMSO-d6) δ1.44-1.77 (7H, m), 2.14-2.33 (1H, m), 2.28 (3H, s), 2.34-2.50 (2H, m), 2.58-2.70 (1H, m), 2.71-2.80 (1H, m), 3.47-3.57 (1H, m), 3.54 (2H, s), 3.87-4.03 (1H, m), 4.23-4.37 (1H, m), 4.89 (1H, br.s), 6.59 (1H, d, J=15.0 Hz), 7.01-7.14 (3H, m), 7.15-7.23 (1H, m), 7.37 (1H, d, J=15.0 Hz), 7.77 (1H, br.d), 7.97 (1H, br.s), 8.09 (1H, br.s); MS (ES+) m/z 438(M+1).
The following compound was obtained in a similar manner to that of Preparation 506.
1H-NMR (300 MHz, CDCl3) δ0.79-0.99 (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 (1H, m), 2.55-2.76 (2H, m), 4.22-4.33 (1H, m), 4.24 (2H, q, J=7.0 Hz), 6.19 (1H, d, J=15.8 Hz), 7.53 (1H, d, J=15.8 Hz), 7.66 (1H, d, J=1.8 Hz), 8.10 (1H, d, J=1.8 Hz); MS (ES+) m/z 406(M+1).
The following compound was obtained in a similar manner to that of Preparation 426.
1H-NMR (300 MHz, CDCl3) δ 0.90 (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 (1H, m), 4.29 (2H, q, J=7.0 Hz), 4.77-4.94 (1H, m), 6.47 (1H, d, J=16.1 Hz), 7.32 (1H, d, J=8.4 Hz), 7.67 (1H, d, J=16.1 Hz), 7.82 (1H, dd, J=8.4, 2.6 Hz), 8.56 (1H, d, J=2.6 Hz);
MS (ES+) m/z 550(M+1).
The following compound was obtained in a similar manner to that of Preparation 405, Preparation 414.
1H-NMR (300 MHz, DMSO-d6) δ 0.86 (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 (1H, m), 3.49-3.60 (1H, m), 3.87-4.06 (1H, m), 4.57-4.72 (1H, m), 4.89-4.96 (1H, m), 6.58 (1H, d, J=15.8 Hz), 7.34 (1H, d, J=8.4 Hz), 7.52 (1H, d, J=15.8 Hz), 7.97-8.05 (1H, m), 8.60-8.66 (1H, m).
The following compounds were obtained in a similar manner to that of Preparation 426.
1H-NMR (300 MHz, CDCl3) δ 0.74-0.90 (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 (1H, m), 1.93-2.09 (1H, m), 2.34-2.69 (4H, m), 2.87-2.98 (1H, m), 4.21 (2H, q, J=7.3 Hz), 4.58-4.73 (1H, m), 6.76 (1H, d, J=16.1 Hz), 7.35 (1H, d, J=8.8 Hz), 7.69 (1H, d, J=16.1 Hz), 8.19 (1H, dd, J=8.8, 2.6 Hz), 8.73 (1H, d, J=2.6 Hz);
MS (ES+) m/z 501(M+1).
1H-NMR (300 MHz, CDCl3) δ 1.35 (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 (1H, m), 2.11-2.35 (2H, m), 2.50-2.63 (1H, m), 2.69 (1H, t, J=8.4 Hz), 2.76-2.88 (1H, m), 3.15 (1H, 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 (1H, m), 6.46 (1H, d, J=16.1 Hz), 7.32 (1H, d, J=8.4 Hz), 7.66 (1H, d, J=16.1 Hz), 7.81 (1H, dd, J=8.4, 2.6 Hz), 8.54 (1H, d, J=2.6 Hz);
MS (ES+) m/z 446(M+1).
The following compound was obtained in a similar manner to that of Example 129.
1H-NMR (300 MHz, DMSO-d6) δ 0.83-2.13 (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.
1H-NMR (300 MHz, DMSO-d6) δ0.72-0.94 (2H, m), 1.01-1.31 (4H, m), 1.37-1.82 (15H, m), 2.03-2.61 (6H, m), 3.46-3.59 (1H, m), 4.11-4.25 (1H, m), 4.89 (1H, br.s), 6.26-6.46 (2H, m), 7.36 (1H, d, J=15.8 Hz), 7.87 (1H, br.s), 8.18-8.26 (1H, m); MS (ES+) m/z 477(M+1).
A mixture of tert-butyl (3R)-3-({3-chloro-5-[(1E)-3-ethoxy-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)-1-pyrrolidinecarboxylate (0.98 g) and 4N hydrogen chloride in dioxane solution (5 ml) in EtOH (10 ml) 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}acrylate dihydrochloride (0.9 g).ethyl (2E)-3-{5-chloro-6-[(3R)-3-pyrrolidinylamino]-3-pyridinyl}acrylate dihydrochloride
1H-NMR (DMSO-d6): δ 1.25 (3H, t J=7.08 Hz), 1.99-2.12 (2H, m), 3.19-3.45 (3H, m), 3.56-3.65 (1H, m), 4.16 (2H, q J=7.08 Hz), 4.52-4.57 (1H, m), 6.52 (1H, d J=15.94 Hz), 6.95 (1H, d J=6.52 Hz), 7.53 (1H, d J=15.94 Hz), 8.13 (1H, d J=1.90 Hz), 8.31 (1H, d J=1.90 Hz).
The following compound was obtained in a similar manner to that of Preparation 538.
1H-NMR (DMSO-d6): δ 1.25 (3H, t J=7.06 Hz), 2.04-2.05 (1H, m), 2.29-2-34 (1H, m), 3.24-3.29 (2H, m), 3.40-3.43 (1H, m), 3.45-3.52 (1H, m), 4.18 (2H, q J=7.06 Hz), 4.66 (1H, br.s), 6.59 (1H, d J=16.00 Hz), 7.11 (1H, d J=9.12 Hz), 7.65 (1H, d J=16.00 Hz), 8.27-8.32 (2H, m), 9.56 (1H, br.s), 9.69 (1H, br, s).
A solution of benzyl 4-methyl-2-(methylthio)-5-pyrimidinecarboxylate (6.0 g) and 1-benzyl-3-aminopyrrolidine (5.78 g) in dioxane (10 ml) was stirred at 130° C. for 15 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 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-pyrimidinecarboxylate (3.06 g).
1H-NMR (DMSO-d6): δ 1.71-1.81 (1H, m), 2.09-2.17 (1H, m), 2.47 (3H, s), 2.35-2.60 (3H, m), 2.79-2.81 (1H, m), 3.56 (2H, s), 4.39 (1H, m), 5.27 (2H, s), 7.22-7.47 (10H, m), 8.11-8.16 (1H; m), 8.70 & 8.75 (total 1H, each s).
A solution of benzyl 4-methyl-2-(methylsulfinyl)-5-pyrimidinecarboxylate (3.27 g), 1-benzyl-3-aminopyrrolidine (2.98 g) and N,N-diisopropylethylamine (1.75 g) in dioxane (15 ml) 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 MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on alumina eluting with AcOEt-n-hexane (5:5). 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-pyrimidinecarboxylate (3.9 g).
1H-NMR (DMSO-d6): δ 1.71-1.81 (1H, m), 2.09-2.17 (1H, m), 2.47 (3H, s), 2.35-2.60 (3H, m), 2.79-2.81 (1H, m), 3.56 (2H, s), 4.39 (1H, m), 5.27 (2H, s), 7.22-7.47 (10H, m), 8.11-8.16 (1H, m), 8.70 & 8.75 (total 1H, each s).
The following compounds were obtained in a similar manner to that of Preparation 541
1H-NMR (DMSO-d6): δ 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 (1H, m), 5.27 (2H, s), 7.23-7.44 (10H, m), 7.91-8.00 (1H, m), 8.68 & 8.77 (total 1H, each s).
benzyl 4-methyl-2-{[(3R)-1-(4-methylbenzyl)-3-pyrrolidinyl]amino}-5-pyrimidinecarboxylate
1H-NMR (DMSO-d6): δ 1.73-1.76 (1H, m), 2.13-2.60 (4H m), 2.27 (3H, s), 2.45 (3H, s), 2.74-2.89 (1H, m), 3.51 (2H, s), 4.37 (1H, m), 5.26 (2H, s), 7.08-7.20 (5H, m), 7.30-7.48 (4H, m), 8.10-8.15 (1H, m), 8.69 & 8.75 (total 1H, each s).
benzyl 2-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-4-methyl-5-pyrimidinecarboxylate
1H-NMR (DMSO-d6): δ 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 (1H, m), 4.37-4.51 (1H, m), 5.27 (2H, s), 7.22-7.70 (5H, m), 8.65-8.69 (1H, m), 8.69 & 8.77 (total 1H, each s).
A solution of benzyl 4-methyl-2-(methylthio)-5-pyrimidinecarboxylate (3.6 g) and m-chloroperbenzoic acid (P=75%) (2.72 g) in AcOEt (30 ml) 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 (3.2 g)
1H-NMR (DMSO-d6): δ 2.81 (3H, s), 2.90 (3H, s), 5.42 (2H, s) 7.23-7.55 (5H, m), 9.27 (1H, s).
A mixture of {2-[(1-benzyl-3-pyrrolidinyl)amino]-4-methyl-5-pyrimidinyl}methanol (1.75 g) and MnO2 (5.1 g) in AcOEt (30 ml) 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 (1.58 g).
1H-NMR (DMSO-d6): δ 1.72-1.78 (1H, m), 2.15-2.19 (1H, m), 2.36-2.61 (3H, m), 2.48 (3H, s), 2.80-2.88 (1H, m), 3.35 (2H, s), 4.39-4.47 (1H, m), 7.18-7.32 (5H, m), 8.34-8.43 (1H, m), 8.58 & 8.62 (total 1H, each s), 9.81 & 9.84 (total 1H, each s).
The following compounds were obtained in a similar manner to that of Preparation 546.
1H-NMR (DMSO-d6): δ 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 (1H, m), 7.19-7.37 (5H, m), 8.14-8.26 (1H, m), 8.18 & 8.26 (total 1H, each s), 9.81 & 9.84 (total 1H, each s).
1H-NMR (DMSO-d6): δ 1.74-1.77 (1H, m), 2.14-2.60 (4H, m), 2.27 (3H, s), 2.46 (3H, s), 2.77-2.86 (1H, m), 3.52 (2H, s), 4.41-4.48 (1H, m), 7.10 (2H, d J=8.02 Hz), 7.19 (2H, d J=8.02 Hz), 8.32-8.42 (1H, m), 8.58 & 8.61 (total 1H, each s), 9.81 & 8.93 (total 1H, each s).
1H-NMR (DMSO-d6): δ 0.78-0.84 (2H, m), 1.13-1.73 (10H, m), 2.00-2.57 (6H, m), 2.47 (3H, s), 2.79-2.82 (1H, m), 4.41-4.51 (1H, m), 8.28-8.34 (1H, m), 8.64 & 8.73 (total 1H, each s), 9.86 & 9.90 (total 1H, each s).
A solution of diethylphosphonoacetcacid ethyl ester (1.79 g) in THF (5 ml) was added dropwise to a mixture of 60% sodium hydride in oil (341 mg) in THF (60 mL) 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-pyrimidinecarbaldehyde (1.58 g) in THF (10 ml) 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-[(1-benzyl-3-pyrrolidinyl)amino]-4-methyl-5-pyrimidinyl}acrylate (1.7 g).
1H-NMR (DMSO-d6): δ 1.24 (3H, t J=7.06 Hz), 1.63-1.82 (1H, m), 2.04-2.30 (1H, m), 2.34 (3H, s), 2.38-2.57 (3H, m), 2.79-2.84 (1H, m), 3.56 (2H, s), 4.18 (2H, q J=7.06 Hz), 4.35 (1H, m), 6.40 (1H, d J=15.94 Hz), 7.18-7.32 (5H, m), 7.63 (1H, d J=15.94 Hz), 7.78-7.80 (1H, m), 8.63 (1H, s).
The following compounds were obtained in a similar manner to that of Preparation 550.
1H-NMR (DMSO-d6): δ 1.24 (3H, t J=7.06 Hz), 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 (1H, m), 4.18 (2H, q J=7.06 Hz), 6.39 (1H, d J=15.94 Hz), 7.19-7.36 (6H, m), 7.63 (1H, d J=15.94 Hz), 8.64 (1H, s).
1H-NMR (DMSO-d6): δ 1.24 (3H, t J=7.06 Hz), 1.67-1.80 (1H, 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 (1H, m), 3.51 (2H, s), 4.17 (2H, q J=7.06 Hz), 4.35 (1H, m), 6.39 (1H, d J=15.96 Hz), 7.10 (2H, d J=8.02 Hz), 7.18 (2H, d J=8.02 Hz), 7.63 (1H, d J=15.96 Hz), 7.76-7.79 (1H, m), 8.63 (1H, s).
1H-NMR (DMSO-d6): δ 0.77-0.83 (2H, m), 1.25 (3H, t J=7.08 Hz), 1.15-1.17 (4H, m), 1.23-1.26 (1H, 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 (1H, m), 4.17 (2H, q J=7.08 Hz), 4.33-4.34 (1H, m), 6.40 (1H, d J=15.96 Hz), 7.63 (1H, d J=15.96 Hz), 7.74 (1H, m), 8.65 (1H, s).
Lithium aluminium hydride (646 mg) was portionwise added to a solution of benzyl 2-[(1-benzyl-3-pyrrolidinyl)amino]-4-methyl-5-pyrimidinecarboxylate (4.56 g) in THF (60 ml) with stirring at 5-15° C. under atmospheric pressure of nitrogen, and the reaction mixture was stirred at 5-20° C. for 2 hours. The reaction mixture was cooled at 5° C. and H2O (0.7 ml), 15% NaOH solution (0.7 ml) and H2O (2.1 ml) 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
1H-NMR (DMSO-d6): δ 1.69-1.72 (1H, m), 2.12-2.36 (2H, m), 2.29 (3H, s), 2.47-2.59 (2H, m), 2.79-2.87 (1H, m), 3.52 (1H, d J=13.02 Hz), 3.59 (1H, d J=13.02 Hz), 4.29-4.32 (3H, m), 4.90 (1H, br.s), 7.07 (1H, d J=6.94 Hz), 7.12-7.32 (5H, m), 8.04 (1H, s).
The following compounds were obtained in a similar manner to that of Preparation 554.
1H-NMR (DMSO-d6): δ 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 (1H, m), 4.30 (2H, d J=5.16 Hz), 4.85 (1H, t J=5.16 Hz), 6.85 (1H, d J=7.96 Hz), 7.19-7.36 (5H, m), 8.02 (1H, s).
1H-NMR (DMSO-d6): δ 1.68-1.70 (1H, 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 (1H, m), 3.47 (1H, d J=12.90Hz), 3.55 (1H, d J=12.90 Hz), 4.31 (2H, s), 3.98-7.04 (1H, m), 7.02-7.20 (6H, m), 8.02 (1H, s).
1H-NMR (DMSO-d6): δ 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 (1H, m), 4.41-4.49 (1H, m), 4.49 (2H, s), 5.27 (1H, m), 6.91 (1H, d J=6.98 Hz), 8.03 (1H, s).
A solution of ethyl (2E)-3-{2-[(1-benzyl-3-pyrrolidinyl)amino]-4-methyl-5-pyrimidinyl}acrylate (750 mg) and 1N NaOH solution (4.1 ml) in MeOH (10 ml) and THF (10 ml) 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-[(1-benzyl-3-pyrrolidinyl)amino]-4-methyl-5-pyrimidinyl}acrylic acid (693 mg).
1H-NMR (DMSO-d6): δ 1.72-1.84 (1H, m), 2.13-2.30 (1H, m), 2.34 (3H, s), 2.34-2.87 (4H, m), 3.57 (2H, s), 4.27-4.33 (1H, m), 6.29 (1H, d J=15.90 Hz), 7.11-7.32 (6H, m), 7.41-7.62 (2H, m), 8.47 (1H, s).
The following compounds were obtained in a similar manner to that of Preparation 558.
1H-NMR (DMSO-d6): δ 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 (1H, d J=15.96 Hz), 7.38-7.54 (5H, m), 7.58 (1H, d J=15.96 Hz), 7.72 (1H, d J=7.20Hz), 8.61 (1H, s).
1H-NMR (DMSO-d6): δ 1.73-1.82 (1H, 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 (1H, m), 3.51-3.52 (2H, m), 4.31-4.34 (1H, m), 6.26 (1H, d J=15.68 Hz), 7.08-7.36 (5H, m), 7.47 (1H, d J=6.90Hz), 8.45 (1H, s).
1H-NMR (DMSO-d6): δ 0.78-0.90 (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 (1H, m), 4.20 (1H, m), 6.29 (1H, d J=15.86 Hz), 7.32 (1H, d J=15.86 Hz), 7.42-7.49 (1H, m), 8.49 (1H, s).
A mixture of A mixture of (2E)-3-{2-[(1-benzyl-3-pyrrolidinyl)amino]-4-methyl-5-pyrimidinyl}acrylic acid (693 mg), 0-(tetrahydro-2H-pyran-2-yl)hydroxylamine (264 mg), HOBt (290 mg) and EDCI (334 mg) in DMF (20 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 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-{2-[(1-benzyl-3-pyrrolidinyl)amino]-4-methyl-5-pyrimidinyl}-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (200 mg).
1H-NMR (DMSO-d6): δ 1.59-1.74 (7H, m), 1.99-2.59 (4H, m), 2.37 (3H, s), 2.79-2.87 (1H, m), 3.56 (2H, s), 3.98-4.05 (1H, m), 4.34 (1H, m), 4.89 (1H, s), 6.26 (1H, d J=15.98 Hz), 7.18-7.36 (5H, m), 7.46 (1H, d J=15.98 Hz), 7.64-7.69 (1H, m), 8.42 (1H, s), 11.13 (1H, s).
The following compounds were obtained in a similar manner to that of Preparation 562.
1H-NMR (DMSO-d6): δ 1.42-1.83 (10H, 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 (1H, m), 3.78-3.80 (1H, m), 3.95 (1H, m), 4.88 (1H, s), 6.25 (1H, d J=15.50 Hz), 7.23-7.72 (6H, m), 7.46 (1H, d J=15.50Hz), 8.42 (1H, s), 11.13 (1H, s).
1H-NMR (DMSO-d6): δ 1.65-1.99 (7H, m), 2.09-2.36 (4H, m), 2.27 (3H, s), 2.45 (3H, s), 2.76-2.84 (1H, m), 3.51-3.55 (3H, m), 3.98-7.02 (1H, m), 7.32 (1H, m), 4.88 (1H, s), 6.26 (1H, d J=15.62 Hz), 7.10 (2H, d J=8.04 Hz), 7.18 (2H, d J=8.04 Hz), 7.46 (1H, d J=15.62 Hz), 7.63 (1H, d J=6.52 Hz), 8.41 (1H, s), 11.12 (1H, s).
1H-NMR (DMSO-d6): δ 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 (1H, m), 3.93-3.99 (1H, m), 4.32 (1H, m), 4.89 (1H, s), 6.27 (1H, d J=15.52 Hz), 7.48 (1H, d J=15.52 Hz), 7.59 (1H, d J=6.72 Hz), 8.43 (1H, s), 11.13 (1H, br.s).
A mixture of ethyl 5,6-dichloronicotinate (5.0 g), tert-butyl
(3R)-3-amino-1-pyrrolidinecarboxylate (5.08 g) and K2CO3 (4.71 g) in DMF (40 ml) was stirred at 100° 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 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 (6.6 g).
1H-NMR (DMSO-d6): δ 1.26 (3H, t J=7.06 Hz), 1.40 (9H, s), 1.96-2.13 (2H, m), 3.18-3.45 (3H, m), 3.58-3.66 (1H, m), 4.27 (2H, q J=7.06 Hz), 4.58-4.62 (1H, m), 7.24 (1H, d J=6.64 Hz), 7.95 (1H, d J=1.96 Hz), 8.57 (1H, d J=1.96 Hz).
The following compounds were obtained in a similar manner to that of Preparation 566.
1H-NMR (DMSO-d6): δ 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 1H, each m), 1.18-4.33 (2H, m), 6.03 and 6.83(total 1H, each d, J=6.4 Hz), 7.90 and 7.97(total 1H, each d, J=2.0 Hz), 8.53 and 8.57(total 1H, each d, J=2.0 Hz).
1H-NMR (DMSO-d6): δ 1.26 (3H, t J=7.06 Hz), 1.56-1.73 (6H, m), 1.93-2.00 (2H, m), 4.26 (2H, q J=7.06 Hz), 4.37-4.48 (1H, m), 6.93 (1H, d J=7.34 Hz), 7.91 (1H, d J=1.98 Hz), 8.54 (1H, d J=1.98 Hz).
1H-NMR (DMSO-d6): δ 1.40 (9H, s), 1.80-1.89 (1H, m), 2.10-2.16 (1H, m), 3.11-3.16 (1H, m), 3.32-3.38 (2H, m), 3.42-3.56 (1H, m), 3.77 (3H, s), 4.43 (1H, m), 6.54 (1H, d J=8.86 Hz), 7.65 (1H, d J=6.34 Hz), 7.83 (1H, dd J=2.24 Hz, 8.86 Hz), 8.59 (1H, d J=2.24 Hz).
A solution of diisobutylaluminum hydride in hexane solution (0.93M) (138 ml) was added to dropwise a solution of ethyl 6-{[(3R)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]amino}-5-chloronicotinate (15.9 g) in THF (200 ml) with stirring at 0-15° 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 MeOH (10 ml) was added and the reaction mixture was stirred at ambient temperature for 20 minutes. The potassium sodium tartarate tetrahydrate (36.4 g) 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 in vacuo to give tert-butyl (3R)-3-{[3-chloro-5-(hydroxymethyl)-2-pyridinyl]amino}-1-pyrrolidinecarboxylate (5.85 g).
1H-NMR (DMSO-d6): δ 1.39 (9H, s), 1.90-2.14 (2H, m), 3.11-3.46 (3H, m), 3.56-3.65 (1H, m), 4.35 (2H, d J=5.56 Hz), 4.38-4.48 (1H, m), 5.09 (1H, t J=5.56 Hz), 6.38 (1H, d J=6.20Hz), 7.56 (1H, d J=1.90Hz), 7.95 (1H, d J=1.90Hz).
A mixture of tert-butyl (3R)-3-{[3-chloro-5-(hydroxymethyl)-2-pyridinyl]amino}-1-pyrrolidinecarboxylate (0.95 g) and MnO2 (3.02 g) in AcOEt (30 ml) 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 (0.95 g).
1H-NMR (DMSO-d6): δ 1.40 (9H, s), 1.99-2.15 (2H, m), 3.20-3.46 (3H, m), 3.56-3.67 (1H, m), 4.64-4.72 (1H, m), 7.49 (1H, d J=6.70Hz), 7.95 (1H, d J=1.90Hz), 8.57 (1H, d J=1.90Hz), 9.76 (1H, s).
The following compounds were obtained in a similar manner to that of Preparation 571.
1H-NMR (DMSO-d6): δ 1.53-1.73 (6H, m), 1.80-1.97 (2H, m), 4.40-4.57 (1H, m), 7.24 (1H, d J=7.32 Hz), 7.90 (1H, d J=1.88 Hz), 8.53 (1H, d J=1.88 Hz), 9.72 (1H, s).
1H-NMR (DMSO-d6): δ 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 1H, m), 6.25 & 7.14 (total 1H, each d J=6.40 Hz), 7.89 & 7.96 (total 1H, each d J=1.82 Hz), 8.52 & 8.57 (total 1H, each d J=1.82 Hz), 9.71 & 9.75 (total 1H, each s).
1H-NMR (DMSO-d6): δ 1.40 (9H, s), 1.82-1.88 (1H, m), 2.12-2.14 (1H, m), 3.13-3.18 (1H, m), 3.33-3.44 (2H, m), 3.56-3.63 (1H, m), 4.48 (1H, m), 6.61 (1H, d J=8.78 Hz), 7.56 (1H, dd J=2.18 Hz, 8.78 Hz), 8.53 (1H, d J=2.18 Hz), 9.70 (1H, s).
A solution of diethylphosphonoacetcacid ethyl ester (980 mg) in THF (5 ml)was added dropwise to a mixture of 60% sodium hydride in oil (187 mg) in THF (30 mL) 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]-1-pyrrolidinecarboxylate (0.95 g) in THF (10 ml) 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-[(1E)-3-ethoxy-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)-1-pyrrolidinecarboxylate (0.98 g)
1H-NMR (DMSO-d6): δ 1.25 (3H, t J=7.10 Hz), 1.40 (9H, s), 1.90-2.12 (2H, m), 3.19-3.45 (3H, m), 3.56-3.65 (1H, m), 4.16 (2H, q J=7.10 Hz), 4.57-4.60 (1H, m), 6.52 (1H, d J=15.96 Hz), 6.96 (1H, d J=6.50 Hz), 7.53 (1H, d J=15.96 Hz), 8.13 (1H, d J=1.82 Hz), 8.31 (1H, d J=1.82 Hz).
The following compounds were obtained in a similar manner to that of Preparation 575.
1H-NMR (DMSO-d6): δ 0.97 (9H, s), 1.01-2.00 (9H, m), 1.24 (3H, t J=7.06 Hz), 3.96-4.02 (1H, m), 4.16 (2H, q J=7.06 Hz), 5.78 & 6.53 (total 1H, each d J=6.58 Hz), 6.46 & 6.50 (total 1H, each d J=15.98 Hz), 7.50 & 7.52 (total 1H, each d J=15.98 Hz), 8.08 & 8.14 (total 1H, each d J=1.94 Hz), 8.25 & 8.30 (total 1H, each d J=1.94 Hz),
APCI-MS (m/z):395(M+H)+.
1H-NMR (DMSO-d6): δ 1.24 (3H, t J=7.06 Hz), 1.40 (9H, s), 1.80-1.86 (1H, m), 2.10-2.13 (1H, m), 3.05-3.16 (1H, m), 3.31-3.40 (2H, m), 3.53-3.58 (1H, m), 4.13 (2H, q, J=7.06 Hz), 4.39 (1H, m), 6.35 (1H, d J=15.86 Hz), 6.55 (1H, d J=8.84 Hz), 7.46 (1H, d J=6.78 Hz), 7.52 (1H, d J=15.86 Hz), 7.83 (1H, dd J=2.02 Hz, 8.84 Hz), 8.25 (1H, d J=2.02 Hz).
Lithium aluminium hydride (1.02 g) was added to a solution of methyl 6-{[(3R)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]amino}nicotinate (5.76 g) in THF (80 ml) with stirring at 5-15° C. 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 (1 ml), 15% NaOH solution (1 ml) and H2O (3 ml) 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 (1.82 g).
1H-NMR (DMSO-d6): δ 1.39 (9H, s), 1.76-1.99 (1H, m), 2.07-2.12 (1H, m), 3.06-3.13 (1H, m), 3.29-3.41 (2H, m), 3.42-3.57 (1H, m), 4.29 (2H, d J=5.52 Hz), 4.28-4.38 (1H, m), 4.91 (1H, t J=5.52 Hz), 6.47 (1H, d J=8.50Hz), 6.66 (1H, d J=5.80Hz), 7.35 (1H, dd J=2.02 Hz, 8.50 Hz), 7.90 (1H, d J=2.02 Hz).
The following compounds were obtained in a similar manner to that of Preparation 578.
1H-NMR (DMSO-d6): δ 1.44-1.68 (6H, m), 1.87-1.99 (2H, m), 4.20-4.37 (1H, m), 4.32 (2H, d J=5.72 Hz), 5.04 (1H, t J=5.72 Hz), 5.90 (1H, d J=7.12 Hz), 7.51 (1H, d J=1.94 Hz), 7.92 (1H, d J=1.94 Hz).
1H-NMR (DMSO-d6): δ 0.97 (9H, s), 0.97-1.56 (6H, m), 1.73-1.99 (3H, m), 3.78-3.82 (1H, m), 4.16-4.35 (2H, m), 5.01-5.10 (1H, m), 5.27 & 5.74 (total 1H, each d J=5.88 Hz), 7.50 & 7.56 (total 1H, each d J=1.92 Hz), 7.89 & 7.94 (total 1H, each d J=1.92 Hz).
A solution of ethyl (2E)-3-{5-chloro-6-[(3R)-3-pyrrolidinylamino]-3-pyridinyl}acrylate dihydrochloride (2.0 g) in H2O (10 ml) 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 (1.47 g).
1H-NMR (DMSO-d6): δ 1.25 (3H, t J=7.08 Hz), 1.99-2.09 (2H, m), 2.64-2.75 (2H, m), 2.87-3.01 (2H, m), 4.16 (2H, q J=7.08 Hz), 4.44-4.47 (1H, m), 6.49 (1H, d J=15.94 Hz), 6.72 (1H, d J=7.14 Hz), 7.52 (1H, d J=15.94 Hz), 8.09 (1H, d J=1.96 Hz), 8.28 (1H, d J=1.96 Hz).
A mixture of tert-butyl (3R)-3-({5-[(1E)-3-ethoxy-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)-1-pyrrolidinecarboxylate (600 mg) and 1N NaOH solution (3.3 ml) in MeOH (10 ml) and THF (10 ml) 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 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-{[(3R)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylic acid (0.45 g).
1H-NMR (DMSO-d6): δ 1.41 (9H, s), 1.84-1.87 (1H, m), 2.11-2.14 (1H, m), 3.10-3.19 (1H, m), 3.34-3.42 (2H, m), 3.55-3.58 (1H, m), 4.36-4.42 (1H, m), 6.29 (1H, d J=15.88 Hz), 6.62 (1H, d J=8.76 Hz), 7.48 (1H, d J=15.88 Hz), 7.64 (1H, m), 7.85 (1H, dd J=2.16 Hz, 8.76 Hz), 8.23 (1H, d J=2.16 Hz), 11.14 (1H, s).
A mixture of (2E)-3-(6-{[(3R)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylic acid (450 mg), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (174 mg), HOBt (191 mg) and EDCI (220 mg) in DMF (20 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 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-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridinyl)amino]-1-pyrrolidinecarboxylate (450 mg).
1H-NMR (DMSO-d6): δ 1.39 (9H, s), 1.69-2.00 (7H, m), 2.00-2.12 (1H, m), 3.09-3.15 (1H, m), 3.34-3.43 (3H, m), 3.50-3.55 (2H, m), 3.93-3.95 (1H, m), 4.37 (1H, m), 4.88 (1H, s), 6.24 (1H, d J=15.74 Hz), 6.55 (1H, d J=8.76 Hz), 7.30 (1H, d J=8.12 Hz), 7.37 (1H, d J=15.74 Hz), 7.63 (1H, d J=8.76 Hz), 8.17 (1H, s), 11.06 (1H, s).
A solution of ethyl (2E)-3-(5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate (330 mg) and 1N NaOH solution (1.5 ml) in MeOH (30 ml) 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-(5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylic acid (306 mg).
1H-NMR (DMSO-d6): δ 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 (1H, m), 4.39-4.45 (1H, m), 6.36 (1H, d J=15.88 Hz), 6.45 (1H, d J=7.08 Hz), 7.26 (1H, d J=15.88 Hz), 7.94 (1H, d J=1.76 Hz), 8.17 (1H, d J=1.76 Hz).
The following compounds were obtained in a similar manner to that of Preparation 584.
1H-NMR (DMSO-d6): δ 1.62-1.81 (9H, m), 2.30-2.52 (5H, m), 2.75-2.79 (1H, m), 4.38-4.45 (1H, m), 6.29 (1H, d J=15.84 Hz), 6.30 (1H, d J=7.20Hz), 7.07 (1H, d J=15.84 Hz), 7.84 (1H, d J=1.84 Hz), 8.10 (1H, d J=1.84 Hz).
1H-NMR (DMSO-d6): δ 1.61 (3H, s), 1.68 (3H, s), 1.68-1.79 (1H, m), 2.00-2.30 (1H, m), 2.42-2.82 (4H, m), 3.00 (2H, m), 4.44-4.49 (1H, m), 5.20-5.27 (1H, m), 6.37 (1H, d J=15.88 Hz), 6.50 (1H, d J=6.98 Hz), 7.17 (1H, d J=15.68 Hz), 7.96 (1H, d J=1.86 Hz), 8.18 (1H, d J=1.86 Hz).
1H-NMR (DMSO-d6): δ 1.80-1.87 (1H, m), 2.18-2.47 (1H, m), 2.47-2.57 (2H, m), 2.66-2.73 (1H, m), 2.85-2.90 (1H, m), 3.72 (2H, s), 4.48-4.51 (1H, m), 6.34 (1H, d J=15.90Hz), 6.46 (1H, d J=6.94 Hz), 7.13-7.28 (2H, m), 7.42-7.46 (1H, m), 7.72-7.76 (1H, m), 7.88 (1H, d J=1.80 Hz), 8.12 (1H, d J=1.80Hz), 8.47-8.50 (1H, m).
1H-NMR (DMSO-d6): δ 0.08-0.13 (2H, m), 0.40-0.49 (2H, m), 0.78-0.95 (1H, m), 1.70-1.90 (1H, m), 2.08-2.25 (1H, m), 2.31 (2H, d J=6.60Hz), 2.50-2.60 (2H, m), 2.73-2.90 (2H, m), 4.49-4.56 (1H, m), 6.38 (1H, d J=15.90Hz), 6.56 (1H, d J=7.06 Hz), 7.26 (1H, d J=15.90 Hz), 7.94 (1H, d J=1.84 Hz), 8.18 (1H, d J=1.84 Hz).
1H-NMR (DMSO-d6): δ 1.16-1.22 (2H, m), 1.45-2.30 (14H, m), 2.52-2.67 (1H, m), 2.79-2.84 (1H, m), 4.44-4.51 (1H, m), 6.39 (1H, d J=15.86 Hz), 6.55 (1H, d J=7.08 Hz), 7.34 (1H, d J=15.86 Hz), 7.99 (1H, d J=1.82 Hz), 8.20 (1H, d J=1.82 Hz).
A solution of ethyl (2E)-3-{5-chloro-6-[(3R)-3-pyrrolidinylamino]-3-pyridinyl}acrylate dihydrochloride (1.0 g), bromomethylcyclobutane (456 mg) and N,N-diisopropylethylamine (1.26 g) in DMF (30 ml) 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)-1-(cyclobutylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate (356 mg).
1H-NMR (DMSO-d6): δ 1.24 (3H, t J=7.08 Hz), 1.70-2.09 (9H, m), 2.46-2.52 (6H, m), 2.73-2.77 (1H, m), 4.16 (2H, q J=7.08 Hz), 4.43-4.50 (1H, m), 6.49 (1H, d J=15.96 Hz), 6.67 (1H, d J=7.00 Hz), 7.52 (1H, d J=15.96 Hz), 8.10 (1H, d J=1.92 Hz), 8.28 (1H, d J=1.92 Hz).
The following compound was obtained in a similar manner to that of Preparation 590.
1H-NMR (DMSO-d6): δ 1.24 (3H, t J=7.08 Hz), 1.61 (3H, s), 1.68 (3H, s), 1.78-1.81 (1H, m), 2.14-2.19 (1H, m), 2.43-2.52 (2H, m), 2.60-2.89 (2H, m), 3.02 (2H, d J=6.76 Hz), 3.39 (1H, m), 4.16 (2H, q J=7.08 Hz), 4.44-4.51 (1H, m), 5.20-5.26 (1H, m), 6.49 (1H, d J=15.94 Hz), 6.69 (1H, d J=6.94 Hz), 7.52 (1H, d J=15.94 Hz), 8.10 (1H, d J=1.94 Hz), 8.28 (1H, d J=1.94 Hz).
A mixture of ethyl (2E)-3-{5-chloro-6-[(3R)-3-pyrrolidinylamino]-3-pyridinyl}acrylate (0.73 g), m-tolualdehyde (356 mg) and sodium triacetoxyborohydride (1.57 g) in CH2Cl2 (30 ml) was stirred at 25-30° C. for 15 hours. The 10% K2CO3 solution (20 ml) 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)-1-(3-methylbenzyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate (820 mg).
1H-NMR (DMSO-d6): δ 1.24 (3H, t J=7.06 Hz), 1.86-1.99 (1H, m), 2.16-2.40 (1H, m), 2.40 (3H, s), 2.42-2.53 (2H, m), 2.62-2.66 (1H, m), 2.77-2.85 (1H, m), 3.54 (2H, s), 4.16 (2H, q J=7.06 Hz), 4.45-4.53 (1H, m), 6.49 (1H, d J=15.96 Hz), 6.72 (1H, d J=6.92 Hz), 7.02-7.24)4H, m), 7.51 (1H, d J=15.96 Hz), 8.10 (1H, d J=1.90Hz), 8.20 (1H, d J=1.90Hz).
The following compounds were obtained in a similar manner to that of Preparation 592.
1H-NMR (DMSO-d6): δ 0.80-0.92 (2H, m), 1.12-1.34 (4H, m), 1.24 (3H, t J=7.08 Hz), 1.63-1.78 (5H, m), 2.18-2.22 (2H, m), 2.37-2.52 (3H, m), 2.76-2.80 (1H, m), 3.16-3.22 (2H, m), 4.16 (2H, q J=7.08 Hz), 4.48-4.51 (1H, m), 6.49 (1H, d J=15.96 Hz), 6.95 (1H, d J=7.02 Hz), 7.52 (1H, d J=15.96 Hz), 8.10 (1H, d J=1.90Hz), 8.28 (1H, d J=1.90 Hz).
1H-NMR (DMSO-d6): δ 1.25 (3H, t J=7.08 Hz), 1.85-1.92 (1H, m), 2.18-2.22 (1H, m), 2.42-2.49 (2H, m), 2.61-2.68 (1H, m), 2.80-2.89 (1H, m), 3.62 (2H, s), 4.16 (2H, q J=7.08 Hz), 5.31-5.36 (1H, m), 6.49 (1H, d J=15.92 Hz), 6.74 (1H, d J=6.92 Hz), 7.01-7.17 (3H, m), 7.30-7.41 (1H, m), 7.52 (1H, d J=15.92 Hz), 8.10 (1H, d J=1.84 Hz), 8.27 (1H, d J=1.84 Hz).
1H-NMR (DMSO-d6): δ 1.24 (3H, t J=7.06 Hz), 1.84-1.91 (1H, m), 2.10-2.23 (1H, m), 2.49-2.58 (2H, m), 2.70-2.74 (1H, m), 2.86-2.95 (1H, m), 3.73 (2H, s), 4.16 (2H, q J=7.06 Hz), 4.52-4.59 (1H, m), 6.49 (1H, d J=15.90Hz), 6.75 (1H, d J=6.92 Hz), 7.22-7.28 (1H, m), 7.42-7.48 (1H, m), 7.52 (1H, d J=15.90Hz), 7.72-7.76 (1H, m), 8.10 (1H, d J=1.92 Hz), 8.27 (1H, d J=1.92 Hz), 8.47-8.50 (1H, m).
1H-NMR (DMSO-d6): δ 0.34-0.11 (2H, m), 0.39-0.48 (2H, m), 0.70-0.92 (1H, m), 1.24 (3H, t J=7.06 Hz), 1.70-1.90 (1H, m), 2.05-2.26 (1H, m), 2.26 (2H, d J=6.64 Hz), 2.46-2.67 (2H, m), 2.67-2.71 (1H, m), 2.80-2.88 (1H, m), 4.16 (1H, d J=7.06 Hz), 6.49 (1H, d J=15.90Hz), 6.70 (1H, d J=6.98 Hz), 7.52 (1H, d J=15.90Hz), 8.10 (1H, d J=1.90Hz), 8.28 (1H, d J=1.90Hz).
1H-NMR (DMSO-d6): δ 1.06-1.28 (2H, m), 1.24 (3H, t J=7.06 Hz), 1.47-2.50 (14H, m), 2.55-2.69 (1H, m), 2.70-2.82 (1H, m), 4.16 (2H, q J=7.06 Hz), 6.49 (1H, d J=15.92 Hz), 6.66 (1H, d J=7.02 Hz), 7.52 (1H, d J=15.92 Hz), 8.10 (1H, d J=1.92 Hz), 8.28 (1H, d J=1.92 Hz).
A solution of ethyl (2E)-3-(5-chloro-6-{[(3R)-1-(3-methylbenzyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate (820 mg) and 1N NaOH solution (4.1 ml) in MeOH (20 ml) 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 aqueous 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)-1-(3-methylbenzyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylic acid (410 mg).
1H-NMR (DMSO-d6): δ 1.76-1.90 (1H, m), 2.17-2.29 (1H, m), 2.49 (3H, s), 2.49-2.61 (2H, m), 2.74-2.77 (1H, m), 2.87-2.95 (1H, m), 3.60 (2H, s), 4.46-4.58 (1H, m), 6.39 (1H, d J=15.92 Hz), 6.75 (1H, d J=6.88 Hz), 7.05-7.25 (4H, m), 7.45 (1H, d J=15.92 Hz), 8.07 (1H, d J=1.82 Hz), 8.24 (1H, d J=1.82 Hz).
The following compounds were obtained in a similar manner to that of Preparation 598.
1H-NMR (DMSO-d6): δ 1.54-1.71 (6H, m), 1.90-2.00 (2H, m), 4.32-4.46 (1H, m), 6.38 (1H, d J=15.84 Hz), 6.60 (1H, d J=7.26 Hz), 7.47 (1H, d J=15.84 Hz), 8.04 (1H, d J=1.96 Hz), 8.25 (1H, d J=1.96 Hz).
1H-NMR (DMSO-d6): δ 0.97 (9H, s), 1.02-1.99 (9H, m), 3.85-3.98 & 4.20 (total 1H, each m), 5.78 & 6.50 (total 1H, each d J=6.58 Hz), 6.36 & 6.58 (total 1H, each d J=15.96 Hz), 7.45 & 7.47 (total 1H, each d J=15.96 Hz), 8.03 & 8.11 (total 1H, each d J=1.90Hz), 8.23 & 8.28 (total 1H, each d J=1.90Hz).
1H-NMR (DMSO-d6): δ 1.76-1.93 (1H, m), 2.19-2.26 (1H, m), 2.50-2.63 (2H, m), 2.77-2.80 (1H, m), 2.91-2.99 (1H, m), 3.73 (2H, s), 4.53-4.61 (1H, m), 6.41 (1H, d J=15.94 Hz), 6.78 (1H, d J=6.90Hz), 6.88-7.22 (3H, m), 7.33-7.40 (1H, m), 7.47 (1H, d J=15.94 Hz), 8.07 (1H, d J=1.84 Hz), 8.25 (1H, d J=1.84 Hz).
1H-NMR (DMSO-d6): δ 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 (1H, m), 6.42 (1H, d J=15.90Hz), 6.87-6.98 (1H, m), 7.48 (1H, d J=15.90Hz), 8.10 (1H, d J=1.92 Hz), 8.28 (1H, d J=1.92 Hz), 12.21 (1H, br.s).
1H-NMR (DMSO-d6): δ 1.90-2.06 (2H, m), 2.39 (3H, s), 3.09-3.52 (4H, m), 4.28-4.37 (1H, m), 6.42 (11H, d J=15.90Hz), 6.61 (1H, d J=5.92 Hz), 7.36 (2H, d J=8.14 Hz), 7.47 (1H, d J=15.90 Hz), 7.64 (2H, d J=8.14 Hz), 8.06 (1H, d J=1.90Hz), 8.24 (1H, d J=1.90Hz), 12.23 (1H, br.s).
1H-NMR (DMSO-d6): δ 1.72-1.74 (1H, m), 1.91-2.02 (1H, m), 2.39 (3H, s), 3.03-3.10 (1H, m), 3.19-3.45 (3H, m), 4.18-4.26 (1H, m), 6.26 (1H, d J=15.82 Hz), 6.41 (1H, d J=8.82 Hz), 7.28 (1H, m), 7.38 (2H, d J=8.06 Hz), 7.46 (1H, d J=15.82 Hz), 7.65 (2H, d J=8.06 Hz), 7.78 (1H, dd J=2.04 Hz, 8.82 Hz), 8.18 (1H, d J=2.04 Hz).
1H-NMR (DMSO-d6): δ 1.36-1.49 (6H, m), 1.71-1.91 (1H, m), 1.99-2.13 (1H, m), 3.12-3.17 (4H, m), 3.34-3.47 (3H, m), 3.57-3.66 (1H, m), 4.30-4.36 (1H, m), 6.25 (1H, d J=15.92 Hz), 6.55 (1H, d J=8.86 Hz), 7.38 (1H, d J=6.16 Hz), 7.46 (1H, d J=15.92 Hz), 7.79 (1H, dd J=2.08 Hz, 8.86 Hz), 8.21 (1H, d J=2.08 Hz), 12.06 (1H, s).
1H-NMR (DMSO-d6): δ 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 (1H, m), 4.46-4.56 (1H, m), 6.41 (1H, d J=15.98 Hz), 6.69 (1H, d J=6.40Hz), 7.47 (1H, d J=15.98 Hz), 8.09 (1H, d J=1.84 Hz), 8.28 (1H, d J=1.84 Hz).
1H-NMR (DMSO-d6): δ 1.49-1.77 (8H, m), 1.90-2.30 (2H, m), 2.70-2.86 (1H, m), 3.28-3.67 (3H, m), 3.68-3.84 (1H, m), 4.49-4.68 (1H, m), 6.42 (1H, d J=15.96 Hz), 6.87-6.98 (1H, m), 7.48 (1H, d J=15.96 Hz), 8.10 (1H, d J=1.76 Hz), 8.29 (1H, d J=1.78 Hz), 12.15 (1H, br.s).
1H-NMR (DMSO-d6): δ 1.72-2.18 (9H, m), 3.21-3.71 (4H, m), 4.48-4.64 (1H, m), 6.41 (1H, d J=15.94 Hz), 6.85-6.97 (1H, m), 7.44 (1H, d J=15.94 Hz), 8.11 (1H, s), 8.29 (1H, s), 12.21 (1H, br.s).
1H-NMR (DMSO-d6): δ 2.12-2.18 (2H, m), 3.38-3.66 (4H, m), 4.54-4.69 (1H, m), 6.36-6.47 (1H, m), 6.88-7.07 (1H, m), 7.40-7.59 (5H, m), 8.09 & 8.12 (total 1H, each s), 8.22—& 8.31 (total 1H, each s).
1H-NMR (DMSO-d6): δ 2.06-2.31 (2H, m), 3.55-3.70 (3H, m), 3.84-3.93 (1H, m), 4.67-4.77 (1H, m), 6.42 (1H, d J=15.90Hz), 6.49-6.59 (1H, m), 7.00 (1H, d J=6.42 Hz), 7.49 (1H, d J=15.90Hz), 8.10 (1H, d J=1.90Hz), 8.31-8.46 (3H, m), 12.17 (1H, br, s).
1H-NMR (DMSO-d6): δ 2.09-2.21 (2H, m), 3.34-3.76 (4H, m), 4.54-4.68 (1H, m), 6.39 & 6.43 (total 1H, each d J=15.96 Hz), 6.98 & 7.04 (total 1H, each d J=6.32 Hz), 7.21 (2H, m), 7.44 & 7.49 (total 1H, each d J=15.96 Hz), 7.56-7.65 (2H, m), 8.08 & 8.11 (total 1H, each s), 8.22 & 8.31 (total 1H, each s), 12.26 (1H, br.s).
1H-NMR (DMSO-d6): δ 2.09-2.21 (2H, m), 2.32 & 2.35 (total 1H, each s), 3.36-3.74 (4H, m), 4.52-4.69 (1H, m), 6.39 & 6.43 (total 1H, each d J=15.92 Hz), 6.97 & 7.03 (total 1H, each d J=6.52 Hz), 7.29-7.36 (4H, m), 7.43 & 7.49 (total 1H, d each d J=15.92 Hz), 8.08 & 8.12 (total 1H, each d J=1.40Hz), 8.23 & 8.31 (total 1H, each d J=1.40Hz), 12.20 (1H, br.s).
1H-NMR (DMSO-d6): δ 2.09-2.19 (2H, m), 3.35-3.73 (4H, m), 4.55-4.70 (1H, m), 6.40 & 6.43 (total 1H, each d J=15.96 Hz), 6.93 & 7.00 (total 1H, each d J=6.26 Hz), 7.36-7.57 (5H, m), 8.08 & 8.12 (total 1H, each d J=1.70Hz), 8.23 & 8.31 (total 1H, each d J=1.70 Hz), 12.19 (1H, br.s).
1H-NMR (DMSO-d6): δ 2.07-2.18 (2H, m), 3.09-3.56 (3H, m), 3.83-3.86 (1H, m), 4.57-4.67 (1H, m), 6.40 & 6.43 (total 1H, each d J=15.96 Hz), 6.93 & 7.00 (total 1H, each d J=6.40 Hz), 7.36-7.57 (5H, m), 8.08 & 8.11 (total 1H, each d J=1.86 Hz), 8.22 & 8.31 (total 1H, each d J=1.86 Hz), 12.19 (1H, br.s).
A mixture of A mixture of (2E)-3-(5-chloro-6-{[(3R)-1-(3-methylbenzyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylic acid (410 mg), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (142 mg), HOBt (156 mg) and EDCI (180 mg) in DMF (15 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 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 (400 mg).
1H-NMR (DMSO-d6): δ 1.23-1.84 (7H, m), 2.09-2.29 (1H, m), 2.29 (3H, s), 2.37-2.53 (2H, m), 2.63-2.65 (1H, m), 2.74-2.89 (1H, m), 3.55 (2H, s), 3.30-3.57 (2H, m), 3.94-4.01 (1H, m), 4.44-4.55 (1H, m), 4.89 (1H, s), 6.32 (1H, d J=15.64 Hz), 6.61 (1H, d J=6.88 Hz), 7.02-7.23 (4H, m), 7.36 (1H, d J=15.64 Hz), 7.84 (1H, s), 7.20 (1H, s), 11.07 (1H, s).
The following compounds were obtained in a similar manner to that of Preparation 615.
1H-NMR (DMSO-d6): δ 1.53-1.84 (12H, m), 1.89-1.99 (2H, m), 3.49-3.55 (1H, m), 3.93-4.05 (1H, m), 4.30-4.41 (1H, m), 4.89 (1H, s), 6.31 (1H, d J=15.76 Hz), 6.54 (1H, d J=7.26 Hz), 7.36 (1H, d J=15.76 Hz), 7.82 (1H, s), 8.21 (1H, s), 11.07 (1H, s).
1H-NMR (DMSO-d6): δ 0.85 (9H, s), 1.00-2.00 (15H, m), 3.49-3.55 (1H, m), 3.86-4.20 (2H, m), 4.89 (1H, s), 5.70 & 6.43 (total 1H, each d J=6.58 Hz), 6.34-6.41 (1H, m), 7.32-7.40 (1H, m), 7.82 & 7.87 (total 1H, each s), 8.19 & 8.23 (total 1H, each s), 11.07 (1H, s).
A mixture of (2E)-3-(5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylic acid (306 mg), 0-(tetrahydro-2H-pyran-2-yl)hydroxylamine (108 mg) HOBt (119 mg) and EDCI (137 mg) in DMF (15 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 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-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (100 mg).
1H-NMR (DMSO-d6): δ 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 (1H, m), 3.95-4.02 (1H, m), 4.48-4.56 (1H, m), 4.89 (1H, s), 6.32 (1H, d J=15.76 Hz), 6.59 (1H, d J=5.04 Hz), 7.36 (1H, d J=15.76 Hz), 7.85 (1H, s), 8.21 (1H, s), 11.08 (1H, s).
The following compounds were obtained in a similar manner to that of Preparation 618.
1H-NMR (DMSO-d6): δ 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 (1H, m), 4.39-4.46 (1H, m), 4.89 (1H, s), 6.32 (1H, d J=15.80Hz), 6.58 (1H, d J=7.00 Hz), 7.36 (1H, d J=15.80Hz), 7.84 (1H, d J=1.60Hz), 8.21 (1H, d J=1.60 Hz), 11.07 (1H, br.s).
1H-NMR (DMSO-d6): δ 1.14-1.91 (7H, m), 1.63 (3H, s), 1.69 (3H, s), 2.09-2.16 (1H, m), 2.49-2.57 (2H, m), 2.73-2.92 (2H, m), 2.92-3.10 (2H, m), 3.49-3.51 (1H, m), 3.95 (1H, m), 4.48-4.52 (1H, m), 4.89 (1H, s), 5.24-5.27 (1H, m), 6.33 (1H, d J=15.74 Hz), 6.65 (1H, d J=6.90Hz), 7.36 (1H, d J=15.74 Hz), 7.86 (1H, s), 8.21 (1H, s), 11.08 (1H, s).
The following compounds were obtained in a similar manner to that of Preparation 615.
1H-NMR (DMSO-d6): δ 1.22-2.00 (7H, m), 2.18-2.20 (1H, m), 2.41-2.52 (2H, m), 2.61-2.68 (1H, m), 2.81-2.90 (1H, m), 3.50-3.55 (2H, m), 3.55 (2H, m), 3.94-4.05 (1H, m), 4.47-4.57 (1H, m), 4.90 (1H, s), 6.33 (1H, d J=15.66 Hz), 6.65 (1H, d J=6.88 Hz), 7.01-7.18 (3H, m), 7.30-7.41 (2H, m), 7.85 (1H, s), 8.20 (1H, s), 10.96 (1H, s).
1H-NMR (DMSO-d6): δ 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 (1H, m), 4.30-4.33 (1H, m), 4.89 (1H, s), 6.35 (1H, d J=15.92 Hz), 6.56 (1H, d J=5.78 Hz), 7.36 (2H, d J=8.14 Hz), 7.48 (1H d J=15.92 Hz), 7.64 (2H, d J=8.14 Hz), 7.84 (1H, s), 8.20 (1H, s), 11.10 (1H, br.s).
1H-NMR (DMSO-d6): δ 1.14-1.29 (6H, m), 1.53-1.69 (10H, m), 1.96-2.14 (3H, m), 3.23-3.96 (6H, m), 4.51-4.68 (1H, m), 4.89 (1H, s), 6.35 (1H, d J=15.90Hz), 6.84-6.92 (1H, m), 7.38 (1H, d J=15.90Hz), 7.88 (1H, s), 8.25 (1H, s), 11.10 (1H, s).
1H-NMR (DMSO-d6): δ 1.52-1.77 (7H, m), 1.99-2.02 (1H, m), 2.39 (3H, s), 3.02-3.09 (1H, m), 3.20-3.55 (4H, m), 3.98-4.01 (1H, m), 4.20-4.23 (1H, m), 4.88 (1H, s), 6.24 (1H, d J=15.48 Hz), 6.40 (1H, d J=8.76 Hz), 7.13 (1H, d J=5.74 Hz), 7.36 (1H, d J=15.48 Hz), 7.38 (2H, d J=8.18 Hz), 7.61 (1H, d J=8.76 Hz), 7.65 (2H, d J=8.18 Hz), 8.18 (1H, s), 11.07 (1H, s).
1H-NMR (DMSO-d6): δ 1.23-1.84 (13H, m), 2.07-2.09 (1H, m), 3.11 (4H, m), 3.35-3.66 (4H, m), 3.93-3.95 (1H, m), 4.30-4.35 (1H, m), 4.88 (1H, s), 6.24 (1H, d J=15.44 Hz), 6.55 (1H, d J=8.80Hz), 7.28 (1H, d J=6.24 Hz), 7.37 (1H, d J=15.44 Hz), 7.63 (1H, d J=8.80Hz), 8.17 (1H, s), 11.06 (1H, s).
1H-NMR (DMSO-d6): δ 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 (1H, m), 4.44-4.48 (1H, m), 4.90 (1H, s), 6.35 (1H, d J=15.78 Hz), 6.81 (1H, d J=6.58 Hz), 7.38 (1H, d J=15.78 Hz), 7.96 (1H, s), 8.24 (1H, s), 11.08 (1H, br.s).
1H-NMR (DMSO-d6): δ 1.53-1.69 (14H, m), 1.99-2.12 (2H, m), 2.73-2.89 (1H, m), 3.28-4.00 (6H, m), 4.51-4.70 (1H, m), 4.89 (1H, s), 6.35 (1H, d J=15.84 Hz), 6.85-6.92 (1H, m), 7.38 (1H, d J=15.84 Hz), 7.88 (1H, s), 8.25 (1H, s), 11.09 (1H, br.s).
1H-NMR (DMSO-d6): δ 1.53-2.18 (15H, m), 3.25-3.71 (4H, m), 3.93-3.95 (1H, m), 4.50-4.60 (1H, m), 4.89 (1H, s), 6.35 (1H, d J=15.98 Hz), 6.84-6.91 (1H, m), 7.38 (1H, d J=15.98 Hz), 7.95 (1H, s), 8:24 (1H, s), 11.08 (1H, br.s).
The following compounds were obtained in a similar manner to that of Preparation 618.
1H-NMR (DMSO-d6): δ 1.53-1.99 (8H, m), 2.00-2.18 (1H, m), 2.47-2.58 (2H, m), 2.69-2.73 (1H, m), 2.86-2.94 (1H, m), 3.34 (2H, s), 3.49-3.50 (1H, m), 3.98-4.05 (1H, m), 4.50-4.56 (1H, m), 4.89 (1H, s), 6.36 (1H, d J=15.90 Hz), 6.96 (1H, d J=6.90 Hz), 7.22-7.28 (1H, m), 7.41-7.45 (1H, m), 7.72-7.85 (2H, m), 7.96 (1H, s), 8.26 (1H, s), 8.46-8.50 (1H, m), 11.07 (1H, br.s).
The following compound was obtained in a similar manner to that of Preparation 615.
1H-NMR (DMSO-d6): δ 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 (1H, s), 6.28-6.36 (1H, m), 6.91-6.97 (1H, m), 7.31-7.60 (5H, m), 7.86-7.96 (1H, m), 8.11-8.27 (1H, m), 11.09 (1H, s).
The following compounds were obtained in a similar manner to that of Preparation 618.
1H-NMR (DMSO-d6): δ 0.04-0.11 (2H, m), 0.39-0.48 (2H, m), 0.70-0.90 (1H, m), 1.53-1.90 (7H, m), 2.09-2.24 (1H, m), 2.26 (2H, d J=6.62 Hz), 2.46-2.52 (2H, m), 2.68-2.71 (1H, m), 2.80-2.88 (1H, m), 3.34-3.49 (1H, m), 3.93-3.96 (1H, m), 4.47-4.58 (1H, m), 4.89 (1H, s), 6.33 (1H, d J=15.78 Hz), 6.59 (1H, d J=6.98 Hz), 7.37 (1H, d J=15.78 Hz), 7.85 (1H, s), 8.22 (1H, s), 11.07 (1H, br.s).
1H-NMR (DMSO-d6): δ 1.16-1.21 (2H, m), 1.49-2.52 (20H, m), 2.52-2.69 (1H, m), 2.70-2.90 (1H, m), 3.49-3.55 (1H, m), 3.94-3.99 (1H, m), 4.41-4.47 (1H, m), 4.89 (1H, s), 6.34 (1H, d J=15.78 Hz), 6.55 (1H, d J=7.04 Hz), 7.33 (1H, d J=15.78 Hz), 7.85 (1H, s), 8.21 (1H, s), 11.07 (1H, br.s).
The following compounds were obtained in a similar manner to that of Preparation 615.
1H-NMR (DMSO-d6): δ 1.54 (3H, br.s), 1.69 (1H, br.s), 1.74-2.09 (1H, m), 2.15-2.17 (1H, m), 3.35-3.55 (3H, m), 3.67-3.69 (1H, m), 3.86-3.96 (2H, m), 4.66-4.71 (1H, m), 4.89 (1H, s), 6.35 (1H, d J=15.78 Hz), 6.58-6.60 (1H, m), 6.95 (1H, d J=6.40Hz), 7.88 (1H, s), 8.27 (1H, s), 8.32-8.33 (2H, m), 11.11 (1H, s).
1H-NMR (DMSO-d6): δ 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 (1H, m), 4.90 (1H, s), 6.30-6.34 (1H, m), 6.93 & 6.99 (total 1H, each d J=6.06 Hz), 7.27-7.41 (3H, m), 7.58-7.64 (2H, m), 7.86 & 7.89 (total 1H, each s), 8.18 & 8.27 (total 1H, each s), 11.10 (1H, s).
1H-NMR (DMSO-d6): δ 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 (1H, m), 4.89 (1H, s), 6.30-6.37 (1H, m), 6.91 & 6.98 (total 1H, each d J=6.12 Hz), 7.24-7.47 (5H, m), 7.85 & 7.89 (total 1H, each s), 8.17 & 8.27 (total 1H, each s), 11.10 (1H, s).
1H-NMR (DMSO-d6): δ 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 (1H, m), 4.89 (1H, s), 6.30-6.34 (1H, m), 6.93 & 7.02 (total 1H, each d J=6.10 Hz), 7.33-7.58 (5H, m), 7.85 & 7.89 (total 1H, each s), 8.19 & 8.27 (total 1H, each s), 11.10 (1H, s).
1H-NMR (DMSO-d6): δ 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 (1H, m), 4.90 (1H, s), 6.34 (1H, m), 6.87-6.94 (1H, m), 7.37-7.53 (5H, m), 7.86 & 7.90 (total 1H, each s), 8.17 & 8.27 (total 1H, each s), 11.11 (1H, s).
A solution of ethyl (2E)-3-{5-chloro-6-[(3R)-3-pyrrolidinylamino]-3-pyridinyl}acrylate dihydrochloride (560 mg), p-toluenesulfonyl chloride (318 mg) and Et3N (0.7 ml) in DMF (15 ml) 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]acrylate (490 mg).
1H-NMR (DMSO-d6): δ 1.25 (3H, t J=7.12 Hz), 1.98-2.05 (2H, m), 2.38 (3H, s), 3.14-3.17 (1H, m), 3.23-3.34 (2H, m), 3.45-3.49 (1H, m), 4.16 (2H, q J=7.12 Hz), 4.32-4.33 (1H, m), 6.53 (1H, d J=15.96 Hz), 6.65 (1H, d J=5.92 Hz), 7.36 (2H, d J=8.12 Hz), 7.54 (1H, d J=15.96 Hz), 7.62 (2H, d J=8.12 Hz), 8.11 (1H, d J=1.96 Hz), 8.27 (1H, d J=1.96 Hz).
The following compound was obtained in a similar manner to that of Preparation 638.
1H-NMR (DMSO-d6): δ 1.24 (3H, t=7.06 Hz), 1.68-1.82 (1H, m), 1.92-2.22 (1H, m), 2.39 (3H, s), 3.04-3.11 (1H, m), 3.21-3.45 (3H, m), 4.18 (2H, q J=7.06 Hz), 6.34 (1H, d J=15.90 Hz), 6.39 (1H, d J=8.76 Hz), 7.23 (1H, d J=5.86 Hz), 7.38 (2H, d J=8.08 Hz), 7.52 (1H, d J=15.90Hz), 7.65 (2H, d J=8.08 Hz), 7.79 (1H, dd J=2.08 Hz, 8.78 Hz), 8.21 (1H, d J=2.08 Hz).
A solution of ethyl (2E)-3-{5-chloro-6-[(3R)-3-pyrrolidinylamino]-3-pyridinyl}acrylate dihydrochloride (610 mg), cyclohexanecarbonyl chloride (267 mg) and Et3N (0.76 ml) in DMF (15 ml) 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)-1-(cyclohexylcarbonyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate (630 mg).
1H-NMR (DMSO-d6): δ 1.21-1.31 (6H, m), 1.25 (3H, t J=7.08 Hz), 1.63-1.69 (5H, m), 1.93-2.10 (2H, m), 3.28-3.84 (4H, m), 4.15 (2H, q J=7.08 Hz), 4.67-4.68 (1H, m), 6.52 (1H, d J=15.98 Hz), 6.95-7.19 (1H, m), 7.53 (1H, d J=15.98 Hz), 8.14 (1H, d J=1.86 Hz), 8.32 (1H, d J=1.86 Hz).
The following compounds were obtained in a similar manner to that of Preparation 640
1H-NMR (DMSO-d6): δ 1.24 (3H, t J=7.06 Hz), 1.49 (6H, br.s), 1.70-1.89 (1H, m), 2.00-2.16 (1H, m), 3.15 (4H, br, s), 3.15-3.46 (3H, m), 3.58-3.66 (1H, m), 4.18 (2H, q J=7.06 Hz), 4.34-4.40 (1H, m), 6.34 (1H, d J=15.82 Hz), 6.55 (1H, d J=8.84 Hz), 7.39 (1H, d J=6.28 Hz), 7.52 (1H, d J=15.82 Hz), 7.81 (1H, dd J=2.14H, 8.84 Hz), 8.24 (11, d J=2.14 Hz).
1H-NMR (DMSO-d6): δ 1.24 (3H, t J=7.08 Hz), 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 (1H, m), 4.16 (2H, q J=7.08 Hz), 4.46-4.56 (1H, m), 6.51 (1H, d J=15.90Hz), 6.91 (1H, d J=6.62 Hz), 7.53 (1H, d J=15.90Hz), 8.13 (1H, d J=1.90Hz), 8.31 (1H, d J=1.90Hz).
1H-NMR (DMSO-d6): δ 1.25 (3H, t J=7.06 Hz), 1.97-2.18 (9H, m), 3.21-3.60 (3H, m), 3.60-3.72 (1H, m), 4.16 (2H, q J=7.06 Hz), 4.52-4.62 (1H, m), 6.52 (1H, d J=15.86 Hz), 6.89-7.01 (1H, m), 7.53 (1H, d J=15.86 Hz), 8.13 (1H, s), 8.32 (1H, s).
1H-NMR (DMSO-d6): δ 1.25 (3H, t J=7.06 Hz), 1.49-1.77 (8H, m), 1.90-2.20 (2H, m), 2.70-2.86 (1H, m), 3.30-3.51 (3H, m), 3.98-4.02 (1H, m), 4.16 (2H, q J=7.06 Hz), 4.53-4.69 (1H, m), 6.52 (1H, d J=15.96 Hz), 6.94-7.02 (1H, m), 7.54 (1H, d J=15.96 Hz), 8.13-8.15 (1H, m), 8.31-8.33 (1H, m).
A solution of ethyl (2E)-3-{5-chloro-6-[(3R)-3-pyrrolidinylamino]-3-pyridinyl}acrylate dihydrochloride (500 mg), 4-chlorobenzoyl chloride (249 mg) and Et3N (0.624 ml) in DMF (20 ml) 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 washed with IPE and n-hexane to give ethyl (2E)-3-(5-chloro-6-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate (570 mg).
1H-NMR (DMSO-d6): δ 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 (1H, m), 7.00-7.07 (1H, m), 7.46-7.60 (5H, m), 8.11-8.18 (1H, m), 8.25 & 8.34 (total 1H, each s).
The following compounds were obtained in a similar manner to that of Preparation 645.
1H-NMR (DMSO-d6): δ 1.24 (3H, t J=7.08 Hz), 2.00-2.16 (2H, m), 3.35-3.78 (4H, m), 4.15 (2H, q J=7.08 Hz), 4.56-4.70 (1H, m), 6.50 & 6.54 (total 1H, each d J=15.88 Hz), 7.03 & 7.04 (total 1H, each d J=6.32 Hz), 7.23-7.28 (2H, m), 7.48-7.63 (3H, m), 8.12 & 8.16 (total 1H, each d J=1.72 Hz), 8.26 & 8.34 (total 1H, each d J=1.72 Hz).
1H-NMR (DMSO-d6): δ 1.24 (3H, t J=7.08 Hz), 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=7.08 Hz), 4.53-4.70 (1H, m), 6.50 & 6.54 (total 1H, each d J=15.86 Hz), 7.01 & 7.08 (total 1H, each d J=6.56 Hz), 7.24-7.33 (4H, m), 7.49 & 7.54 (total 1H, each d J=15.86 Hz), 8.12 & 8.16 (total 1H, each d J=1.76 Hz), 8.25 & 8.34 (total 1H, each d J=1.76 Hz).
1H-NMR (DMSO-d6): δ 1.24 (3H, t J=7.06 Hz), 1.99-2.30 (2H, m), 3.34-3.58 (3H, m), 3.58-3.74 (1H, m), 4.15 (2H, q J=7.06 Hz), 4.56-4.70 (1H, m), 6.50 & 6.53 (total 1H, each d J=15.92 Hz), 7.03 & 7.04 (total 1H, each d J=6.32 Hz), 7.47-7.58 (5H, m), 8.12 & 8.16 (total 1H, each d J=1.92 Hz), 8.26 & 8.34 (total 1H, each d J=1.92 Hz).
1H-NMR (DMSO-d6): δ 1.24 (3H, t J=7.06 Hz), 2.09-2.17 (2H, m), 3.13-3.43 (2H, m), 3.40-3.55 (1H, m), 3.70-3.76 (1H, m), 4.15 (2H, q J=7.06 Hz), 4.56-4.70 (1H, m), 6.50 & 6.54 (total 1H, each d J=16.00 Hz), 6.97 & 6.99 (total 1H, each d J=6.52 Hz), 7.38-7.52 (5H, m), 8.12 & 8.16 (total 1H, each d J=2.00 Hz), 8.25 & 8.34 (total 1H, each d J=2.00 Hz).
A solution of ethyl (2E)-3-{5-chloro-6-[(3R)-3-pyrrolidinylamino]-3-pyridinyl}acrylate dihydrochloride (700 mg), 2-chloropyrimidine (283 mg) and N,N-diisopropylethylamine (1.09 ml) in DMF (20 ml) 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)-1-(2-pyrimidinyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate (−560 mg).
1H-NMR (DMSO-d6): δ 1.25 (3H, t J=7.12 Hz), 2.16-2.27 (2H, m), 3.35-3.56 (2H, m), 3.67-3.70 (1H, m), 3.84-3.93 (1H, m), 4.17 (2H, q J=7.12 Hz), 4.65-4.71 (1H, m), 6.52 (1H, d J=16.12 Hz), 6.60 (1H, d J=4.48 Hz), 7.04 (1H, d J=6.42 Hz), 7.54 (1H, d J=16.14 Hz), 8.32-8.35 (3H, m).
To a mixture of ethyl (dimethoxyphosphoryl)(fluoro)acetate (2.08 g) and magnesium bromide (1.9 g) in THF (20 ml) was added dropwise to a Et3N (1.32 ml) with stirring at 0-15° C. 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-9-pyridinyl)amino]-1-pyrrolidinecarboxylate (2.0 g) in THF (10 ml) solution was added the above mixture and resultant mixture was stirred at 0-15° C. 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-[(1Z)-3-ethoxy-2-fluoro-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)-1-pyrrolidinecarboxylate (2.34 g)
1H-NMR (CDCl3): δ 1.37 (3H, t J=7.08 Hz), 1.40 (9H, s), 1.96 (1H, m), 2.24-2.33 (1H, m), 3.21-3.35 (1H, m), 3.48-3.55 (2H, m), 3.76-3.81 (1H, m), 4.34 (2H, q J=7.08 Hz), 4.66-4.67 (1H, m), 5.30-5.32 (1H, m); 6.78 (1H, d J=35.36 Hz), 7.90 (1H, d J=1.64 Hz), 8.15 (1H, d J=1.64 Hz).
A mixture of tert-butyl (3R)-3-({3-chloro-5-[(1Z)-3-ethoxy-2-fluoro-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)-1-pyrrolidinecarboxylate (2.34 g) and 4N hydrogen chloride in dioxane solution (11 ml) in EtOH (10 ml) was stirred at ambient temperature for 4 hours. IPE (100 ml) 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 (1.95 g).
1H-NMR (DMSO-d6): δ 1.29 (3H, t J=7.10 Hz), 2.03-2.04 (1H, m), 2.22-2.26 (1H, m), 3.19-3.25 (2H, m), 3.35-3.57 (2H, m), 4.28 (2H, q J=7.10 Hz), 4.73-4.86 (1H, m), 7403 (1H, d J=37.48 Hz), 7.97 (1H, d J=1.82 Hz), 8.38 (1H, d J=1.82 Hz), 9.65 (2H, br.s).
A mixture of ethyl (2Z)-3-{5-chloro-6-[(3R)-3-pyrrolidinylamino]-3-pyridinyl}-2-fluoroacrylate dihydrochloride (720 mg), cyclopentanone (188 mg), sodium triacetoxyborohydride (1.18 g) and Et3N (0.52 ml) in CHCl3 (20 ml) was stirred at 25-30° C. for 15 hours. The 10% K2CO3 solution (2 ml) 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)-1-cyclopentyl-3-pyrrolidinyl]amino)-3-pyridinyl)-2-fluoroacrylate (710 mg).
1H-NMR (CDCl3): δ 1.37 (3H, t J=7.16 Hz), 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 (1H, m), 4.33 (2H, q J=7.16 Hz), 4.64-4.68 (1H, m), 5.61-5.63 (1H, m), 6.76 (1H, d J=35.52 Hz), 7.87 (1H, d J=1.84 Hz), 8.15 (1H, d J=1.84 Hz).
The following compounds were obtained in a similar manner to that of Preparation 653.
1H-NMR (CDCl3): 1.21-1.28 (4H, m), 1.37 (3H, t J=7.16 Hz), 1.73-1.77 (4H, m), 1.93 (2H, m), 2.17 (1H, m), 2.42-2.45 (2H, m), 2.78-2.85 (2H, m), 3.00 (1H, m), 4.33 (2H, q J=7.16 Hz), 4.62-4.66 (1H, m), 5.61-5.63 (1H, m), 6.76 (1H, d J=35.52 Hz), 7.87 (1H, d J=1.84 Hz), 8.15 (1H, d J=1.84 Hz).
1H-NMR (CDCl3): δ 0.88-0.91 (2H, m), 1.19-1.21 (3H, m), 1.37 (3H, t J=7.16 Hz), 1.40-1.60 (1H, m), 1.68-1.73 (6H, m), 2.27-2.34 (4H, m), 2.65-2.66 (2H, m), 2.89 (1H, m), 4.33 (2H, q J=7.16 Hz), 4.62-4.67 (1H, m), 5.63-5.65 (1H, m), 6.77 (1H, d J=35.52 Hz), 7.87 (1H, d J=1.76 Hz), 8.17 (1H, d J=1.76 Hz).
A mixture of ethyl (2Z)-3-(5-chloro-6-{[(3R)-1-cyclopentyl-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoroacrylate (710 mg) and 1N NaOH solution (3.8 ml) in MeOH (20 ml) was stirred at 75-80° C. for 2 hours. To the reaction mixture was added 1N HCl solution (3.8 ml) 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 dried to give (2Z)-3-(5-chloro-6-{[(3R)-1-cyclopentyl-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoroacrylic acid (658 mg).
1H-NMR (DMSO-d6): δ 1.75-2.12 (9H, m), 2.35-2.52 (2H, m), 2.99-3.81 (4H, m), 4.78-4.91 (1H, m), 6.67 (1H, d J=37.52 Hz), 7.09 (1H, d J=7.34 Hz), 7.86 (1H, d J=1.64 Hz), 8.24 (1H, d J=11.64 Hz).
The following compounds were obtained in a similar manner to that of Preparation 656.
1H-NMR (DMSO-d6): δ 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 (1H, m), 6.66 (1H, d J=37.56 Hz), 7.09 (1H, d J=7.33 Hz), 7.86 (1H, d J=1.28 Hz), 8.23 (1H, d J=1.28 Hz).
1H-NMR (DMSO-d6): δ 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 (1H, m), 3.40 (1H, m), 4.76-4.79 (1H, m), 6.69 (1H, d J=37.54 Hz), 7.06 (1H, d J=7.21 Hz), 7.87 (1H, d J=1.68 Hz), 8.24 (1H, d J=1.68 Hz).
1H-NMR (DMSO-d6): δ 1.99-2.11 (1H, m), 2.30-2.41 (1H, m), 3.11-3.52 (4H, m), 4.30 (2H, s), 4.71-4.81 (1H, m), 6.82 (1H, d J-37.42 Hz), 7.11-7.29 (3H, m), 7.40-7.47 (2H, m), 7.60-7.62 (1H, m), 7.90 (1H, s), 8.28 (1H, s).
1H-NMR (DMSO-d6): δ 1.83-1.89 (1H, m), 2.26-2.36 (1H, m), 2.75-3.28 (4H, m), 3.96-4.09 (2H, m), 4.46-4.49 (1H, m), 6.57 (1H, d J=8.88 Hz), 6.75 (1H, d J=37.98 Hz), 7.14-7.51 (6H, m), 7.74 (1H, dd J=1.92 Hz, 8.88 Hz), 8.23 (1H, d J=1.92 Hz).
A mixture of (2Z)-3-(5-chloro-6-{[(3R)-1-cyclopentyl-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoroacrylic acid (658 mg), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (229 mg), HOBt (264 mg) and EDCI (303 mg) in DMF (15 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 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)-1-cyclopentyl-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoro-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (620 mg).
1H-NMR (DMSO-d6): δ 1.37-1.72 (12H, m), 2.09-2.20 (1H, m), 2.73 (1H, m), 2.89 (1H, m), 3.36 (6H, m), 3.50-3.52 (1H, m), 4.05-4.07 (1H, m), 4.48-4.50 (1H, m), 4.97 (1H, s), 6.66 (1H, d J=7.00 Hz), 7.85 (1H, d J=1.88 Hz), 8.28-8.32 (1H, m).
The following compounds were obtained in a similar manner to that of Preparation 661.
1H-NMR (DMSO-d6): δ 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 (1H, m), 2.88-2.92 (1H, m), 3.36 (4H, m), 3.36 (4H, m), 3.50-3.53 (1H, m), 4.03-4.08 (1H, m), 4.46-4.50 (1H, m), 4.97 (1H, s), 6.50 (1H, d J=6.96 Hz), 6.78 (1H, d J=39.72 Hz), 7.85 (1H, d J=1.88 Hz), 8.29-8.32 (1H, m).
1H-NMR (DMSO-d6): δ 0.81-0.84 (2H, m), 1.15-1.17 (3H, m), 1.53-1.57 (1H, 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 (1H, m), 3.50-3.53 (1H, m), 4.07-4.08 (1H, m), 4.49-4.51 (1H, m), 4.98 (1H, s), 6.62 (1H, d J=7.04 Hz), 6.79 (1H, d J=69.72 Hz), 7.85 (1H, d J=1.88 Hz), 8.29 (1H, d J=1.88 Hz).
1H-NMR (DMSO-d6): δ 1.54 (3H, m), 1.70 (3H, s), 1.81-1.84 (1H, m), 2.10-2.22 (1H, m), 2.37-2.40 (2H, m), 2.64-2.65 (1H, m), 2.81-2.85 (1H, m), 3.50-3.52 (1H, m), 3.59 (2H, s), 4.02-4.07 (1H, m), 4.49-4.52 (1H, m), 4.98 (1H, s), 6.68 (1H, d J=6.96 Hz), 6.78 (1H, d J=39.68 Hz), 7.21-7.26 (1H, m), 7.28-7.34 (1H, m), 7.85 (1H, d J=1.88 Hz), 8.31 (1H, d J=1.88 Hz).
1H-NMR (DMSO-d6): δ 1.63 (3H, s), 1.64-1.69 (4H, m), 2.20 (1H, m), 2.35-2.45 (2H, m), 2.63-2.64 (1H, m), 2.75-2.79 (1H, m), 3.49-3.51 (1H, m), 3.57 (2H, d J=4.76 Hz), 4.03-4.06 (1H, m), 4.32 (1H, m), 4.96 (1H, s), 6.53 (1H, d J=8.90Hz), 6.69 (1H, d J=40.40 Hz), 7.21-7.26 (2H, m), 7.28-7.33 (4H, m), 7.67 (1H, dd J=2.20Hz, 8.90 Hz), 8.19 (1H, d J=2.20Hz), 11.66 (1-H, s).
To a mixture of ethyl (dimethoxyphosphoryl)(fluoro)acetate (1.46 g) and magnesium bromide (1.33 g) in THF (20 ml) was added dropwise to a Et3N (0.92 ml) with stirring at 0-15° C. under atmospheric pressure of nitrogen, and the reaction mixture was stirred at same condition for an hour. A solution of 6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-chloronicotinaldehyde (1.36 g) in THF (10 ml) solution was added the above mixture and resultant mixture was stirred at 0-15° C. 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 ethyl (2Z)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-chloro-3-pyridinyl)-2-fluoroacrylate (1.42 g).
1H-NMR (CDCl3): δ1.36 (3H, t J=7.16 Hz), 1.33-1.39 (1H, m), 1.68-1.73 (1H, m), 2.38-2.40 (1H, m), 2.66-2.67 (1H, m), 1.73-2.74 (1H, m), 2.89 (1H, m), 3.65 (2H, s), 4.33 (2H, q J=7.16 Hz), 5.69 (1H, d J=7.70 Hz), 6.75 (1H, d J=35.52 Hz), 7.23-7.34 (5H, m), 7.86 (1H, d J=1.84 Hz), 8.15 (1H, d J=1.84 Hz).
The following compound was obtained in a similar manner to that of Preparation 666.
1H-NMR (CDCl3): δ 1.36 (3H, t J=7.14 Hz), 1.71-1.72 (1H, m), 2.33-2.45 (2H, m), 2.57-2.88 (3H, m), 3.64 (2H, s), 4.29 (2H, q J=7.14 Hz), 5.19 (1H, d J=7.84 Hz), 6.37 (1H, d J=8.80Hz), 6.79 (1H, d J=36.28 Hz), 7.2-7.33 (5H, m), 7.81 (1H, dd J=2.10 Hz, 8.80 Hz), 8.22 (1H, d J=2.10 Hz).
To a stirred suspension of ethyl (2E)-3-{5-[(3R)-3-piperidinylamino]-2-pyrazinyl}acrylate dihydrochloride (300 mg) in dichloromethane (6 mL) was added N,N-diisopropylethylamine (348 mg) and phenylacetyl chloride (139 mg) in dichloromethane (1 mL) 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)-1-(phenylacetyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylate (225 mg) as a pale brown viscous oil.
1H-NMR (300 MHz, CDCl3) δ1.33 (3H, t, J=7.3 Hz), 1.35-1.50 (1H, 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 (1H, m); MS (ES+) m/z 395.
A mixture of 5,6-dichloronicotinic acid (356 mg), iodoethane (318 mg) and potassium carbonate (308 mg) in N,N-dimethylformamide (3 mL) was heated at eighty degree for fourteen hours. The mixture was allowed to cool to ambient temperature and to this was added (3R)-1-(cyclohexylmethyl)-3-piperidinamine dihydrochloride (549 mg) and potassium carbonate (898 mg) and heated at eighty degree for thirty eight hours. The mixture was allowed to cool to ambient temperature and was added water. The mixture was extracted with ethyl acetate (100 mL) 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).1-(cyclohexylmethyl)-3-piperidinyl]amino}nicotinate (154 mg) as a pale yellow amorphous solid.
1H-NMR (300 MHz, CDCl3)(0.79-0.98 (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 (1H, m), 2.59-2.75 (2H, m), 4.33 (2H, q, J=7.3 Hz), 4.36-4.48 (1H, m), 6.36 (1H, br.s), 8.00 (1H, d, J=1.8 Hz), 8.66 (1H, d, J=1.8 Hz).
To a stirred solution of ethyl 5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}nicotinate (321 mg) in tetrahydrofuran (6 mL) was added lithium aluminumhydride (80.2 mg)-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 1:1(v/v) to afford (5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-3-pyridinyl)methanol (210 mg) as a colorless oil.
1H-NMR (300 MHz, CDCl3) δ 0.77-0.98 (2H, m), 1.08-1.34 (4H, m), 1.39-1.89 (9H, m), 2.03-2.21 (3H, m), 2.34-2.48 (1H, m), 2.52-2.71 (2H, m), 4.17-4.29 (1H, m), 4.52 (2H, s), 5.87 (1H, br.s), 7.51 (1H, d, J=2.2 Hz), 7.96 (1H, d, J=2.2 Hz); MS (ES+) m/z 338(M+1).
To a stirred solution of ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(2,2,6,6-tetramethyl-4-piperidinyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate (265 mg, 0.529 mmol) in methanol (5 mL) was added hydroxylamine hydrochloride (184 mg, 2.65 mmol) at ambient temperature. To this mixture was added 1N potassium methoxide in methanol (5.29 mL, 5.29 mmol) dropwise in an ice bath and the resulting mixture was stirred at ambient temperature for three hours. To the mixture was added 1N 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-[(1E)-3-(hydroxyamino)-3-oxo-1-propen-1-yl]-2-pyridinyl}[(3R)-1-(2,2,6,6-tetramethyl-4-piperidinyl)-3-pyrrolidinyl]carbamate (103 mg) 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 (1H, m), 4.57-4.72 (1H, m), 6.54 (1H, d, J=16.1 Hz), 7.32 (1H, d, J=8.4 Hz), 7.48 (1H, d, J=16.1 Hz), 7.99 (1H, dd, J=8.4, 2.2 Hz), 8.60 (1H, 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.
1H-NMR (300 MHz, DMSO-d6) δ1.13-1.36 (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 (1H, m), 3.19-3.33 (2H, m), 3.70-3.83 (2H, m), 4.61-4.78 (1H, m), 6.54 (1H, d, J=15.8 Hz), 7.34 (1H, d, J=8.4 Hz), 7.49 (1H, d, J=15.8 Hz), 7.99 (1H, br.d, J=8.8 Hz), 8.61 (1H, br.s); MS (ES+) m/z 433(M+1).
The following compound was obtained in a similar manner to that of Preparation 871.
1H-NMR (300 MHz, CDCl3) δ1.37 (3H, t, J=7 Hz), 4.03 (2H, s), 4.34 (2H, q, J=7 Hz), 6.93 (1H, s), 7.14-7.38 (8H, m), 7.88 (1H, d, J=8 Hz), 8.08 (1H, d, J=2 Hz), 8.69 (1H, d, J=2 Hz); MS (ES+) m/z 367.
To a mixture of ethyl 5-chloro-6-(2,3-dihydro-1H-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° C. 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-1H-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-1H-inden-2-ylamino)nicotinate (209 mg) as a pale yellow solid.
1H-NMR (300 MHz, DMSO-d6) δ 1.28 (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 (1H, m), 6.52 (1H, d, J=9 Hz), 7.11-7.19 (2H, m), 7.20-7.29 (2H, m), 7.72 (1H, d, J=6.5 Hz), 7.81 (1H, dd, J=9, 2.5 Hz), 8.60 (1H, d, J=2.5 Hz); MS (ES+) M/z 283.
tert-Butyl [(1R)-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 o 0° C., 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) δ 0.86-1.04 (2H, m), 1.10-1.29 (3H, m), 1.45 (3×3H, s), 1.51-1.91 (7H, m), 2.65 (1H, m), 3.03-3.41 (4H, m), 4.17 (1H, m), 5.14 (1H, m); MS (ES+) m/z 297.
To an ice-cooled solution of ethyl (2E)-3-(5-{[(3R)-1-benzyl-3-pyrrolidinyl](tert-butoxycarbonyl)amino}-2-pyrazinyl)acrylate (4.63 g) in dichloromethane (7.8 ml) were added anisole (4.7 ml) and trifluoroacetic acid (15.6 ml), 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 (50 g) 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 (3.05 g, 85%) was obtained as slightly yellowish powder.
MASS(API-ES); 353 (M+H),
1H-NMR (200 MHz), (DMSO-d6, δ): 1.24 (3H, t, J=7.1 Hz), 1.50-1.80 (1H, m), 2.10-2.35 (1H, m), 2.36-2.55 (2H, m), 2.60-2.85 (2H, m), 3.50-3.66 (2H, m), 4.16 (2H, q, J=7.1 Hz) 4.25-4.45 (1H, m), 6.49 (1H, d, J=15 Hz), 7.15-7.40 (5H, m), 7.53 (1H, d, J=15 Hz), 7.93 (1H, d, J=6.6 Hz), 8.00 (1H, s), 8.20 (1H, s).
The following compound was obtained in a similar manner to that of Preparation 676.
MASS(API-ES); 371 (M+H)+,
1H-NMR (200 MHz), (CDCl3, δ): 1.20-1.50 (3H, m), 1.60-1.90 (1H, m), 2.25-2.50 (2H, m), 2.60-2.80 (2H, m), 2.85-3.03 (1H, m), 3.67 (2H, s), 4.33 (2H, q, J=7.2 Hz), 4.37-4.65 (1H, m), 5.24 (0.5H, d, J=7.6 Hz), 5.37 (0.5H, d, J=7.6 Hz), 6.78 (0.5H, d, J=22 Hz), 6.98 (0.5H, d, J=37 Hz), 7.20-7.40 (5H, m), 7.83 (0.5H, d, J=1.1 Hz), 7.89 (0.5H, d, J=1.1 Hz), 8.47 (0.5H, d, J=1.1 Hz), 8.56 (0.5H, d, J=1.1 Hz).
To a mixture of ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate 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)-1-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 (1H, m), 2.95 (1H, m), 3.41 (1H, m), 3.65 (1H, m), 3.96 (1H, m), 4.28 (2H, g, J=7 Hz), 5.09 (1H, m), 6.46 (1H, d, J=16 Hz), 7.30 (1H, d, J=9 Hz), 7.64 (1H, d, J=16 Hz), 7.81 (1H, d, J=9 Hz), 8.48 (1H, s); MS (ES+) m/z 444.
The following compounds were obtained in a similar manner to that of Preparation 678.
1H-NMR (300 MHz, CDCl3) δ 1.21-1.72 (11H, m), 1.35 (3H, t, J=7 Hz), 1.45 (9H, s), 1.73-1.88 (2H, m), 1.99, (1H, m), 2.18 (1H, m), 2.35 (1H, m), 2.60 (1H, m), 2.75 (1H, m), 3.10 (1H, m), 4.28 (2H, q, J=7 Hz), 4.86 (1H, m), 6.46 (1H, d, J=16 Hz), 7.31 (1H, d, J=8.5 Hz), 7.65 (1H, d, J=16 Hz), 7.81 (1H, d, J=8.5, 2.5 Hz), 8.54 (1H, dr J=2-5 Hz); MS (ES+) m/z 458.
1H-NMR (300 MHz, CDCl3) δ 1.20-1.86 (8H, m), 1.35 (3H, t, J=7 Hz), 1.46 (9H, s), 2.01 (1H, m), 2.21 (1H, m), 2.42-2.57 (2H, m), 2.63 (1H, m), 2.83 (1H, m), 3.14 (1H, m), 4.28 (2H, q. J=7 Hz), 4.90 (1H, m), 6.46 (1H, d, J=16 Hz), 7.32 (1H, d, J=8.5 Hz), 7.65 (1H, d, J=16 Hz), 7.81 (1H, dd, J=8.5, 2 Hz), 8.54 (1H, d, J=2 Hz); MS (ES+) m/z 430.
0.94 M solution of diisobutylaluminum hydride in hexane (2.73 ml) was added dropwise to a solution of ethyl 6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-fluoronicotinate (294 mg) in THF (1 ml) 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 (0.727 ml) below 5° C., then the mixture was stirred at 25° C. for 30 minutes. Na2SO4(2.87 g) was added to the solution, and the mixture was stirred at 25° C. for 15 minutes. The reaction mixture was filtrated, the filtrate was evaporated in vacuo. Toluene (15 ml) was added to the residue, and the mixture was evaporated in vacuo.
The resulting residue and activated MnO2 (744 mg) in ethyl acetate (20 ml) were stirred at 75° C. for 1 hour. After removal of the insoluble material by filtration, the filtrate was evaporated in vacuo to give 6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-fluoronicotinaldehyde (250 mg, 98%) as syrup. The compound was used in the next step reaction without purification.
To an ice-cooled solution of ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(cyclohexylcarbonyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate (355 mg) in dichloromethane (2 ml) was added anisole (1.0 ml) end trifluoroacetic acid (2.0 ml), 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 (6 ml) and methanol (2.5 ml), and 1 mol/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 1 mol/L hydrochloric acid. The organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure to give (2E)-3-(6-{[(3R)-1-(cyclohexylcarbonyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylic acid (250 mg, 97%) as powder.
MASS(API-ES); 344 (M+H)+Free
1H-NMR (200 MHz), (DMSO-d6, δ): 1.05-1.77 (10H, m), 1.78-2.47 (3H, m), 3.10-3.90 (4H, m), 4.24-4.57 (1H, m), 6.25 (1H, d, J=16 Hz), 6.54 (1H, dd, J=2.2 Hz, J=8.8 Hz), 7.30-7.45 (1H, m), 7.46 (1H, d, J=16 Hz), 7.79 (1H, d, J=8.8 Hz), 8.22 (1H, d, J=2.2 Hz).
To a stirred solution of 6-(2,3-dihydro-1H-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-1H-inden-2-ylamino)-3-pyridinyl]acrylic acid (190 mg) as a pale yellow powder.
1H-NMR (300 MHz, DMSO-d6) δ 2.83 (2H, dd, J=16, 6 Hz), 3.29 (2H, dd, J=16, 7 Hz), 4.64 (1H, m), 6.24 (1H, d, J=16 Hz), 6.52 (1H, d, J=9 Hz), 7.10-7.29 (4H, m), 7.4-7.52 (2H, m), 7.77 (1H, dd, J=9, 2.2 Hz), 8.23 (1H, d, J=2.2 Hz), 12.06 (1H, br); MS (ES+) m/z 281.
The following compounds were obtained in a similar manner to that of Preparation 683.
1H-NMR (300 MHz, CDCl3) δ 1.50 (1H, m), 1.68-2.06 (4H, m), 2.33 (1H, m), 3.87 (1 μl, m), 4.49 (1H, m), 4.67 (2H, s), 5.21 (1H, d, J=7 Hz), 6.23 (1H, d, J=16 Hz), 7.23-7.38 (5H, m), 7.65 (1H, d, J=16 Hz), 7.68 (1H, d, J=1.8 Hz), 8.18 (1H, d, J=1.8 Hz); MS (ES+) m/z 373.
1H-NMR (300 MHz, CDCl3) δ 1.26 (1H, m), 1.40 (1H, m), 2.14 (1H, ddd, J=9, 6, 3 Hz), 3.09 (1H, m), 5.65 (1H, d, J=3 Hz), 6.25 (1H, d, J=15.7 Hz), 7.17-7.36 (5H, m), 7.64 (1H, d, J=15.7 Hz), 7.70 (1H, d, J=2 Hz), 8.24 (1H, d, J=2 Hz); MS (ES+) m/z 315.
1H-NMR (300 MHz, DMSO-d6) δ 3.92 (2H, s), 6.44 (1H, br), 7.07-7.30 (8H, m), 7.39 (1H, br), 7.45 (1H, d, J=8 Hz), 8.08-8.25 (3H, m); MS (ES+) m/z 365.
1H-NMR (300 MHz, DMSO-d6) δ 1.10-1.86 (10H, m), 2.41 (1H, m), 6.49 (1H, d, J=16 Hz), 7.11-7.30 (3H, m), 7.48 (1H, d, J=16 Hz), 7.77 (1H, d, J=7.5 Hz), 8.24 (1H, d, J=1 Hz), 8.26 (1H, d, J=1 Hz), 8.36 (1H, s), 9.93 (1H, s), 12.28 (1H, br-s); MS (ES+) m/z 400.
1H-NMR (300 MHz, DMSO-d6) δ 1.13-1.48 (5H, m), 1.58-1.84 (5H, m), 2.33 (1H, m), 6.51 (1H, d, J=16 Hz), 7.16-7.34 (3H, m), 7.52 (1H, d, J=16 Hz), 7.95 (1H, s), 8.25 (1H, d, J=2 Hz), 8.33 (1H, d, J=2 Hz), 8.70 (1H, s), 9.80 (1H, s); MS (ES+) m/z 400.
A mixture of ethyl (2E)-3-{5-chloro-6-[(3R)-3-pyrrolidinylamino]-3-pyridinyl}acrylate dihydrochloride (2.0 g), trans-4-{[(tert-butoxycarbonyl)amino]methyl}cyclohexanecarboxylate (1.68 g), HOBt (880 mg) and WSCD (1.26 g) in dichloromethane (40 ml) and Et3N (1.51 ml) (2.0 eq) 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 2.85 g (98%) of ethyl (2E)-3-[6-({(3R)-[(trans-4-{[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-3-pyrrolidinyl}amino)-5-chloro-3-pyridinyl]acrylate.
MASS (ESI+): m/z=557.2 (M+Na).
11NMR (400 MHz, CDCl3): δ 0.8-2.4 (12H, m), 1.43 and 1.44 (9H, s), 1.33 (3H, t, J=7.1 Hz), 2.8-4 (6H, m), 4.24 (1H, t, J=7.1 Hz), 4.25 (1H, t, J=7.1 Hz), 4.53-4.8 (2H, m), 5.26 (1H, dd, J=6.4, 20 Hz), 6.25 (1H, dd, J=6.6, 16 Hz), 7.54 (1H, dd, J=4.6, 16 Hz), 7.69 (1H, dd, J=2, 7.9 Hz), 8.15 (1H, dd, J=2, 7.6 Hz).
4NHCl/Dioxane (14 ml) was added to ethyl (2E)-3-[6-({(3R)-1-[(trans-4-{[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-3-pyrrolidinyl}amino)-5-chloro-3-pyridinyl]acrylate (3.0 g) under ice cooling.
After 2 hours, IPE was added to this reaction mixture.
The mixture was decanted and dioxane and IPE was separated. Residue was evaporated under reduced pressure to give 2.80 g (98%) of ethyl (2E)-3-{6-[((3R)-1-{[trans-4-(aminomethyl)cyclohexyl]carbonyl}-3-pyrrolidinyl)amino]-5-chloro-3-pyridinyl}acrylate dihydrochloride as an amorphous.
MASS (ESI+): m/z=435.2 (M+1).
1HNMR (400 MHz, CDCl3): δ 0.90-2.80 (12H, m), 1.24 (3H, t, J=7.1 Hz), 2.94-3.88 (6H, m), 4.16 (2H, q, J=7.1 Hz), 4.54 and 4.68 (1H, br.s), 6.53 (1H, dd, J=3.2, 15.9 Hz), 7.54 (1H, dd, J=2.6, 15.9 Hz), 7.9-8.02 (2H, m), 8.17 (1H, dd, J=1.9, 5.8 Hz), 8.33 (1H, dd, J=1.9, 4.8 Hz).
A mixture of ethyl (2E)-3-{6-[((3R)-1-{[trans-4-(aminomethyl)cyclohexyl]carbonyl}-3-pyrrolidinyl)amino]-5-chloro-3-pyridinyl}acrylate dihydrochloride (1.0 g), Formaldehyde (1.0 ml), NaBH(OAc)3 (1.25 g) and triethylamine (2.0 eq. 398 mg, 0.55 ml) in dichloromethane (20 ml) 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 660 mg (72%) of ethyl (2E)-3-(5-chloro-6-{[(3R)-1-({trans-4-[(dimethylamino)methyl]cyclohexyl}carbonyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate.
MASS (ESI+): m/z=463.3 (M+1).
1HNMR (400 MHz): δ 0.80-2.45 (14H, m), 1.33 (3H; t, J=7.2 Hz), 1.33 (3H, t, J=7.1 Hz), 2.23 and 2.24 (6H, s), 3.36-4.01 (4H, m), 4.25 (1H, q, J=7.2 Hz), 4.26 (1H, q, J=7.1 Hz), 4.6-4.75 (1H, m), 5.26 (1H, dd, J=6.5, 21.2 Hz), 6.25 (1H, dd, J=6, 15.9 Hz), 7.54 (1H, dd, J=4, 15.9 Hz), 7.69 (1H, dd, J=2, 7.7 Hz), 8.15 (1H, dd, J=2, 6.3 Hz).
A mixture of I (610 mg) and 1NNaOH (5 ml) in THF (20 ml) and MeOH (20 ml) was stirred at 60° C. for 3 hrs.
1N HCl (5 ml) was added.
The mixture was evaporated under reduced pressure.
Toluene was added and evaporated again to give 600 mg (quant.) of (2E)-3-(5-chloro-6-{[(3R)-1-({trans-4-[(dimethylamino)methyl]cyclohexyl}carbonyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylic acid.
This product was used for next transformation.
MASS (ESI−): m/z=433.3 (M−1).
A mixture of (2E)-3-(5-chloro-6-{[(3R)-1-({trans-4-[(dimethylamino)methyl]cyclohexyl}carbonyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylic acid (600 mg), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (194 mg), HOBt (242 mg) and WSCD (321 mg) in DMF (40 ml) 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 530 mg (72%) of (2E)-3-(5-chloro-6-{[(3R)-1-({trans-4-[(dimethylamino)methyl]cyclohexyl)carbonyl}-3-pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide.
MASS (ESI+): m/z=534.2 (M+1).
1HNMR (400 MHz, CDCl3): δ 0.82-2.44 (20H, m), 2.23 and 2.24 (6H, s), 3.32-4.05 (6H, m), 4.60-4.75 (1H, m), 5.01 (1H, br.s), 5.23 (1H, dd, J=6.5, 20.6 Hz), 7.56 (1H, d, J=5.2 Hz), 7.6 (1H, d, J=5.2 Hz), 7.66 (1H, d, J=8.8 Hz), 8.16 (H, d, J=8.8 Hz).
A diisobutylaluminum hydride in toluene solution (4.6 mL) was dropwise added to a solution of ethyl ethyl 5-chloro-6-{[(1S,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° C. for 1 hour. A methanol (1 mL) was added to a reaction mixture at 0° C. 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-{[(1S,2R)-2-phenylcyclopropyl]amino}-3-pyridinyl)methanol (398 mg).
1H-NMR (300 MHz, CDCl3) δ 1.24 (1H, m), 1.37 (1H, m), 1.62 (1H, t, J=5 Hz), 2.10 (1H, m), 3.03 (1H, m), 4.56 (1H, d, J=5 Hz), 5.37 (1H, s), 7.16-7.34 (6H, m), 7.54 (1H, d, J=2 Hz), 8.07 (1H, d, J=2 Hz); MS (ES+) m/z 275.
The following compounds were obtained in a similar manner to that of Preparation 694.
1H-NMR (300 MHz, CDCl3) δ 1.18-1.38 (3H, m), 1.42-1.59 (2H, m), 1.68 (1H, m), 1.74-1.97 (4H, m), 2.28 (1H, m), 3.68 (1H, t, J=5.5 Hz), 4.54 (2H, d, J=5.5 Hz), 7.13 (1H, ddd, J=7.7, 7.7, 1.5 Hz), 7.21 (1H, ddd, J=7.7, 7.7, 1.5 Hz), 7.44 (1H, dd, J=7.7, 1.5 Hz), 7.48 (1H, s), 7.65-7.72 (2H, m), 7.99 (1H, d, J=1.8 Hz), 8.37 (1H, s); MS (ES+) m/z 360.
1H-NMR (300 MHz, CDCl3) δ1.60 (1H, t, J=5.5 Hz), 4.03 (2H, s), 4.56 (2H, d, J=5.5 Hz), 6.65 (1H, s), 7.08-7.36 (8H, m), 7.59 (1H, d, J=2 Hz), 7.92 (1H, d, J=8 Hz), 8.02 (1H, d, J=2 Hz); MS (ES+) m/z 325.
A mixture of ethyl (2E)-3-{5-chloro-6-[(3R)-3-pyrrolidinylamino]-3-pyridinyl}acrylate dihydrochloride (600 mg), cyclohexylacetic acid (255 mg), HOBt (264 mg) and WSCD (379 mg) in dichloromethane (20 ml) 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 630 mg (92%) of ethyl (2E)-3-(5-chloro-6-{[(3R)-1-(cyclohexylacetyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate.
MASS (ESI+): m/z=442.3 (M+Na).
1HNMR (400 MHz, CDCl3): δ 0.85-1.38 (3H, m), 1.33 (3H, t, J=7.1 Hz), 1.6-2.4 (12H, m), 3.35-3.95 (4H, m), 4.25 (1H, q, J=7.1 Hz), 4.26 (1H, q, J=7.1 Hz), 4.61-4.75 (1H, m), 5.26 (1H, dd, J=6.4, 15.5 Hz), 6.25 (1H, dd, J=5.2, 16 Hz), 7.54 (1H, dd, J=3.3, 15.9 Hz), 7.69 (1H, dd, J=2.1, 6.4 Hz), 8.15 (1H, dd, J=2, 4.7 Hz).
A mixture of ethyl (2E)-3-(5-chloro-6-{[(3R)-1-(cyclohexylacetyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate (600 mg) and 1N NaOH (6 ml) in THF (20 ml) and MeOH (20 ml) was stirred at 50° C. for 2 hrs.
1N HCl (6 ml) was added.
Evaporated under reduced pressure.
Added toluene and evaporated to give 550 mg of crude (2E)-3-(5-chloro-6-{[(3R)-1-(cyclohexylacetyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylic acid.
This product was used for next transformation.
MASS (ESI−): m/z=390.2 (M−1).
To a solution of ethyl 6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-2-chloro-5-fluoronicotinate (500 mg) in ethanol (20 mL) were added ammonium formate (584 mg) and 10% Pd/C (300 mg) at 25° C. and the mixture was heated to reflux with stirring for 1 hour. After cooling, the catalyst in the reaction mixture was removed by filtration. The filtrate was evaporated in vacuo. To the residue were added CH2Cl2(30 ml), ethanol (7 mL), and benzaldehyde (140 mg) at 25° C. After stirring for 5 minutes, sodium triacetoxyborohydride (280 mg) was 3 hours, 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 (11 g) 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 (302 mg, 66%) was obtained as colorless syrup.
MASS(API-ES); 344 (M+H)+
1H-NMR (200 MHz), (DMSO-d6, δ): 1.28 (3H, t, J=7.1 Hz), 1.70-1.95 (1H, m), 2.05-2.30 (1H, m), 2.35-2.70 (3H, m), 2.80-2.90 (1H, m), 3.58 (2H, s), 4×24 (2H, q, J=7.1 Hz), 4.40-4.60 (1H, m), 7.15-7.35 (5H, m), 7.54 (1H, d, J=6.3 Hz), 7.64 (1H, dd, J=1.9 Hz, J=12 Hz), 8.41 (1H, d, J=1.9 Hz).
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) δ 1.20-1.39 (3H, m), 1.44-1.62 (2H, m), 1.70 (1H, m), 1.77-2.00 (4H, m), 2.20 (1H, m), 3.68 (2H, s), 6.42 (1H, dd, J=8, 2 Hz), 6.64 (1H, dd, J=8, 2 Hz), 7.06 (1H, dd, J=8, 8 Hz), 7.07 (1H, br), 7.23 (1H, s); MS (ES+) m/z 219.
The following compound was obtained in a similar manner to that of Preparation 700.
1H-NMR (300 MHz, CDCl3) δ 1.20-2.06 (10H, m), 2.31 (1H, m), 3.83 (2H, br-s), 6.74-6.86 (2H, m), 7.05 (1H, m), 7.10-7.23 (2H, m); MS (ES+) m/z 219.
0.94 M solution of diisobutylaluminum hydride in hexane (4.82 ml) was added dropwise to a solution of methyl 5-{[(3R)-1-benzyl-3-pyrrolidinyl](tert-butoxycarbonyl)amino}-2-pyrazinecarboxylate (1.01 g) in THF (20 ml) 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 (1.28 ml) at the same temperature, then the mixture was stirred at 25° C. for 40 minutes. THF (14 ml) and MgSO4(4.36 G) 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 (1.07 g), and the mixture was stirred at 25° C. for 16 hr. 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 (51 g) 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 (584 mg, 53%) was obtained as slightly yellowish oil.
MASS(API-ES); 453 (M+H)+
1H-NMR (200 MHz), (DMSO-d6, δ): 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=13 Hz), 4.24 (2H, q, J=7.1 Hz), 4.66-4.88 (1H, m), 6.94 (1H, d, J=16 Hz), 7.03-7.33 (5H, m), 7.76 (1H, d, J=16 Hz), 8.67 (1H, d, J=1.0 Hz), 8.80 (1H, d, J=1.0 Hz).
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)-(−)-1-benzyl-3-aminopyrrolidine (1.42 g), and cesium carbonate (3.28 g), and the mixture was heated at 80° C. 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)-1-benzyl-3-pyrrolidinyl]-6-chloro-2-pyrazinamide (1.00 g) as a yellow solid.
1H-NMR (300 MHz, CDCl3) δ 1.67 (1H, m), 2.30-2.44 (2H, m), 2.64 (1H, dd, J=10, 4 Hz), 2.68 (1H, dd, J=10, 5.5 Hz), 2.89 (1H, m), 3.62 (1H, d, J=13 Hz), 3.66 (1H, d, J=13 Hz), 4.38 (1H, m), 5.09 (1H, d, J=8 Hz), 7.22-7.38 (5H, m), 7.71 (1H, s), 7.77 (—H, s); MS (ES+) m/z 289.
The following compounds were obtained in a similar manner to that of Preparation 703.
1H-NMR (300 MHz, CDCl3) δ 1.34 (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 (1H, d, J=15.5 Hz), 7.04 (1H, ddd, J=7.5, 7.5, 1.5 Hz), 7.11-7.20 (2H, m), 7.63 (1H, d, J=15.5 Hz), 8.19-8.24 (3H, m), 8.28 (1H, dd, J=7.5, 1.5 Hz); MS (ES+) m/z 353.
1H-NMR (300 MHz, CDCl3) δ 1.18-1.38 (5H, m), 1.33 (3H, t, J=7 Hz), 1.42 (1H, m), 1.65 (1H, m), 1.72-1.91 (4H, m), 2.20 (1H, m), 4.24 (2H, q, J=7 Hz), 6.08 (1H, s), 6.27 (1H, d, J=15.7 Hz), 6.75 (2H, d, J=8.5 Hz), 7.12-7.22 (2H, m), 7.31 (1H, m), 7.38 (2H, d, J=8.5 Hz), 7.53 (1H, s), 7.61 (1H, d, J=15.7 Hz), 7.82 (1H, m); MS (ES+) m/z 393.
0.94 M solution of diisobutylaluminum hydride in hexane (5.79 ml) was added dropwise to a solution of methyl 5-{[(3R)-1-benzyl-3-pyrrolidinyl] (tert-butoxycarbonyl)amino}-2-pyrazinecarboxylate (1.18 g) in THF (25 ml) 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 (1.54 ml) at the same temperature, then the mixture was stirred at 25° C. for 40 minutes. THF (15 ml), MgSO4(7G) and Na2SO4(15 g)were added to the solution, and the mixture was stirred at 25° C. for 15 minutes. The reaction mixture was filtered, the filtrate was Filtrate(A).
On the other hand, to an ice-cooled solution of ethyl (dimethoxyphosphoryl)(fluoro)acetate (970 mg) in THF (21 ml) was added MgBr2(885 mg), and triethylamine (0.614 ml), then the mixture was stirred at 50° C. for 2 hours. 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 (20 g) using a mixed solvent of hexane and ethyl acetate(2:1 to 1:1). The fractions containing the objective compound were collected and evaporated under reduced pressure. Title compound (674 mg, 50%) was obtained as oil.
MASS(API-ES); 471 (M+H)+
A mixture of N-[(3R)-1-benzyl-3-pyrrolidinyl]-6-chloro-2-pyrazinamide (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)-1-benzyl-3-pyrrolidinyl](6-chloro-2-pyrazinyl)carbamate (925 mg) as a pale yellow oil.
1H-NMR (300 MHz, CDCl3) δ1.44 (9H, s), 1.90-2.11 (2H, m), 2.26 (1H, m), 2.58-2.78 (3H, m), 2.88 (1H, m), 3.53 (1H, d, J=13 Hz), 3.62 (1H, d, J=13 Hz), 4.92 (1H, m), 7.17-7.36 (5H, m), 8.35 (1H, s), 8.51 (1H, s);
MS (ES+) m/z 389.
The following compound was obtained in a similar manner to that of Preparation 336.
1H-NMR (300 MHz, DMSO-d6) δ1.20-1.78 (14H, m), 1.38 (9H, s), 1.82-2.15 (2H, m), 2.20-2.53 (4H, m), 3.54 (1H, m), 3.96 (1H, m), 4.72 (1H, m), 4.92 (1H, m), 6.58 (1H, d, J=16 Hz), 7.36 (1H, d, J=7 Hz), 7.53 (1H, d, J=16 Hz), 8.01 (1H, dd, J=7, 2 Hz), 8.63 (1H, d, J=2 Hz), 11.32 (1H, br-s); MS (ES+) m/z 501.
To a stirred solution of 1-(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 1-(2-nitrobenzyl)pyrrolidine (1.92 g) as a pale yellow oil.
1H-NMR (300 MHz, CDCl3) δ1.71-1.83 (4H, m), 2.46-2.57 (4H, m), 3.93 (2H, s), 7.37 (1H, ddd, J=8, 7.5, 1.5 Hz), 7.55 (1H, ddd, J=8, 7.5, 1.5 Hz), 7.69 (1H, br-d, J=8 Hz), 7.85 (1H, dd, J=8, 1.5 Hz); MS (ES−) m/z 205.
A mixture of (2E)-3-(5-chloro-6-{[(3R)-1-(cyclohexylacetyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylic acid (550 mg), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (198 mg), HOBt (247 mg) and WSCD (218 mg) in DMF (40 ml) 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 680 mg (99%) of (2E)-3-(5-chloro-6-{[(3R)-1-(cyclohexylacetyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide.
MASS (ESI+): m/z=513.3 (M+Na).
1HNMR (400 MHz, CDCl3): δ (0.85-1.35 (5H, m), 1.55-2.41 (15H, m), 3.35-4.05 (6H, m), 4.60-4.73 (1H, m), 4.99 (1H, br.s), 5.19-5.28 (1H, m), 4.61-4.75 (1H, m), 7.56-7.70 (2H, m), 8.02 (1H, s), 8.16 (1H, s), 8.48-8.52 (1H, m).
To an ice-cooled suspension of sodium hydride (38.5 mg) in THF (10 ml) was added ethyl (dimethoxyphosphoryl)acetate (206 mg), and the mixture was stirred at 24° C. for 40 minutes. To the mixture was added 6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-fluoronicotinaldehyde (250 mg) at 24° C., 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 (8.29) 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 (111 mg, 36%) was obtained as oil.
MASS(API-ES); 370 (M+H)+
1H-NMR (200 MHz), (DMSO-d6, δ): 1.23 (3H, t, J=7.0 Hz), 1.45-2.70 (5H, m), 2.80-2.90 (1H, m), 3.57 (2H, s), 4.15 (2H, q, J=7.0 Hz), 4.35-4.60 (s H, m), 6.41 (1H, d, J=16 Hz), 7.15-7.40 (6H, m), 7.53 (1H, d, J=16 Hz), 7.84 (1H, dd, J=1.1 Hz, J=13 Hz), 8.08 (1H, d, J=1.1 Hz).
0.94 M solution of diisobutylaluminum hydride in hexane (38.3 ml) was added dropwise to a solution of methyl 5-{[(3R)-1-benzyl-3-pyrrolidinyl](tert-butoxycarbonyl)amino}-2-pyrazinecarboxylate (8.42 g) in THP (170 ml) 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 (10.2 ml) at the same temperature, then the mixture was stirred at 25° C. for 40 minutes. THF (60 ml) and MgSO4(34.1 G) 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 (938 mg) in THF (90 ml) was added ethyl (dimethoxyphosphoryl)acetate (5.26 g), and the mixture was stirred at 25° C. for 1 hr. To the mixture was added Filtrate (A) at 25° C., 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 (116 g) using a mixed solvent of hexane and ethyl acetate(5:1 to 1:1). The fractions containing the objective compound were collected and evaporated under reduced pressure. Title compound (6.74 g, 73%) was obtained as slightly yellowish oil.
MASS(API-ES); 453 (M+H)+,
1H-NMR (200 MHz), (DMSO-d6, δ): 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=13 Hz), 4.24 (2H, q, J=7.1 Hz), 4.65-4.90 (1H, m), 6.94 (1H, d, J=16 Hz), 7.00-7.30 (5H, m), 7.76 (1H, d, J=16 Hz), 8.67 (1H, d, J=1.0 Hz) 8.80 (1H, d, J=1.0 Hz).
To a solution of ethyl 6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-2-chloro-5-fluoronicotinate (1.43 g) in ethanol (30 mL) were added ammonium formate (1.67 g) and 10% Pd/C (600 mg) at 25° C. and the mixture was heated to reflux with stirring for 30 minutes. After cooling, the catalyst in the reaction mixture was removed by filtration. The filtrate was evaporated in vacuo. To the residue were added CH2Cl2(15 ml), ethanol (3 mL), di-tert-butyl dicarbonate (830 mg), and N,N-diisopropylethylamine (0.66 ml) at 25° C. After stirring for 5 minutes, sodium triacetoxyborohydride (280 mg) was added to the mixture. The reaction mixture was stirred at 25° C. for 2 hours, 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 (34 g) 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 (1.088 g, 81%) was obtained as colorless syrup.
MASS(API-ES); 354 (M+H)+,
1H-NMR (200 MHz), (DMSO-d6, δ): 1.29 (3H, t, J=7.1 Hz), 1.39 (9H, s), 1.80-2.30 (2H, m), 3.10-3.70 (4H, m), 4.26 (2H, q, J=7.1 Hz), 4.45-4.65 (1H, m), 7.67 (1H, d, J=6.8 Hz), 7.69 (1H, dd, J=1.7 Hz, J=12 Hz), 8.46 (1H, d, J=1.7 Hz).
Tert-butyl (3R)-3-{[3-fluoro-5-(hydroxymethyl)-2-pyridinyl]amino}-1-pyrrolidinecarboxylate (990 mg) and activated MnO2 (2.76 g) in ethyl acetate (20 ml) 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 (159 mg) in THF (20 ml) was added ethyl (dimethoxyphosphoryl)acetate (855 mg), and the mixture was stirred at 24° C. for 60 minutes. To the mixture was added syrup (A) at 24° C., 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 (19 g) using a mixed solvent of hexane and ethyl acetate(5:1 to 3:2). The fractions containing the objective compound were collected and evaporated under reduced pressure. Title compound (1.09 g, 90%) was obtained as colorless oil.
MASS(API-ES): 380 (M+H)+,
1H-NMR (200 MHz), (DMSO-d6, δ): 1.24 (3H, t, J=7.3 Hz), 1.39 (9H, s), 1.80-2.30 (2H, m), 3.10-3.70 (4H, m), 4.16 (2H, q, J=7.1 Hz), 4.35-4.65 (1H, m), 6.46 (1H, d, J=16 Hz), 7.42 (NH, d, J=5.9 Hz), 7.56 (1H, dd, J=1.8 Hz, J=16 Hz), 7.89 (1H, dd, J=1.5 Hz, J=13 Hz), 8.14 (1H, d, J=1.5 Hz).
To a stirred solution of tert-butyl [(3R)-1-benzyl-3-pyrrolidinyl](6-chloro-2-pyrazinyl)carbamate (910 mg) in DMF (15 mL) was added ethyl acrylate (1.27 mL), palladium(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 Na2SO4, 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)acrylate (755 mg) as a pale yellow foam.
1H-NMR (300 MHz. CDCl3) δ 1.36 (3H, t. J=7 Hz), 1.45 (9H, s), 2.12 (1H, m), 2.27 (1H, m), 2.58-2.70 (2H, m), 2.77 (1H, dd, J=9, 7 Hz), 2.94 (1H, dd, J=9, 8 Hz), 3.54 (1H, d, J=13 Hz), 3.63 (1H, d, J=13 Hz), 4.30 (2H, q, J=7 Hz), 4.95 (1H, m), 6.96 (1H, d, J=15.5 Hz), 7.04-7.49 (5H, m), 7.64 (1H, d, J=15.5 Hz), 8.38 (1H, s), 8.54 (1H, s); MS (ES+) m/z 453.
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 [(1R)-1-{[(cyclohexylmethyl)amino]carbonyl}-3-(methylthio)propyl]carbamate (5.65 g).
1H-NMR (300 MHz, CDCl3) δ 0.84-1.00 (2H, m), 1.08-1.32 (3H, m), 1.45 (3×3H, s), 1.45 (1H, m), 1.60-1.77 (5H, m), 1.92 (1H, m), 2.09 (1H, m), 2.11 (3H, s), 2.45-2.65 (2H, m), 3.02-3.18 (2H, m), 4.21 (1H, m), 5.14 (1H, m), 6.22 (1H, br-t, J=6 Hz); MS (ES+) m/z 345.
1) A solution of methyl 5-chloro-2-pyrazinecarboxylate (10 g) in THF (100 ml) was cooled under −5° C. by NaCl-ice bath.
To this solution was added dropwise DIBAL (60 ml) for 15 min under −8-0° C.
After stirring for 30 min under 0° C., the reaction mixture was quenched with EtOH (17 ml).
2) To a solution of ethyl (dimethoxyphosphoryl)acetate (14.2 g) in THF (100 ml) was added portionwise NaH under ice-cooling.
The reaction mixture was allowed stirred at 30° C. for 1 hr.
To a solution of 1) was added dropwise 2) under ° C.
After stirring for 1 hr, 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 3.15 g of ethyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate.
Combined unpure fractions was chromatographed to give additional 1.6 g of ethyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate.
1HNMR (400 MHz, CDCl3): δ 1.35 (3H, t, J=7.1 Hz), 4.30 (2H, q, J=7.1 Hz), 7.00 (1H, d, J=15.7 Hz), 7.66 (1H, d, J=15.7 Hz), 8.43 (1H, d, J=1.3 Hz), 8.60 (1H, d, J=1.3 Hz).
To an ice-cooled solution of tert-butyl (3R)-3-({5-[(1E)-3-ethoxy-3-oxo-1-propen-1-yl]-3-fluoro-2-pyridinyl}amino)-1-pyrrolidinecarboxylate (11.6 g) in EtOH (70 ml) was added solution of 4N HCl in dioxane (76.4 ml). 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 (7.1 g, 83%) as colorless powder.
MASS(API-ES); 280 (M+H)+,
1H-NMR (200 MHz), (DMSO-d6, δ): 1.23 (3H, t, J=7.1 Hz), 1.50-2.20 (2H, m), 2.60-3.03 (4H, m), 3.18 (1H, br), 4.16 (2H, q, J=7.1 Hz), 4.30-4.50 (1H, m), 6.42 (1H, d, J=16 Hz), 7.19 (1H, d, J=6.4 Hz), 7.55 (1H, dd, J=2.0 Hz, J=16 Hz), 7.84 (1H, dd, J=1.8 Hz, J=13 Hz), 8.11 (1H, d, J=1.8 Hz)
To a mixed solution of 1-(2,2-dimethoxyethyl)-1H-pyrazole (705 mg) in dioxane (3 mL) and water (3 ml) were added 4N-HCl in 1,4-dioxane solution (3.01 ml) at 25° C. and the mixture was heated at 60° C. with stirring for 40 minutes. 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(6 ml), ethyl (2E)-3-{5-fluoro-6-[(3R)-3-pyrrolidinylamino]-3-pyridinyl}acrylate (420 mg) at 25° C. After stirring for 5 minutes, sodium triacetoxyborohydride (637 mg) was added to the mixture. The reaction mixture was stirred at 25° C. for 5 hours, 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 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 (165 mg, 29%) was obtained as colorless oil.
MASS(API-ES); 374 (M+H)+
1H-NMR (200 MHz), (DMSO-d6, δ): 1.23 (3H, t, J=7.0 Hz), 1.67-1.92 (1H, m), 2.00-2.25 (1H, m), 2.40-2.95 (6H, m), 3.95-4.28 (4H, m), 4.34-4.58 (1H, m), 6.20 (1H, t, J=2.0 Hz), 6.43 (1H, d, J=16 Hz), 7.23 (1H, d, J=6.4 Hz), 7.40 (1H, d, J=2.0 Hz), 7.55 (1H, dd, J=1.8 Hz, J=16 Hz), 7.74 (1H, d, J=2.0 Hz), 7.85 (1H, dd, J=1.6 Hz, J=13 Hz), 8.10 (1H, d, J=1.6 Hz).
The following compound was obtained in a similar manner to that of Preparation 336.
1H-NMR (300 MHz, DMSO-d6) δ1.08-1.42 (5H, m), 1.46-1.78 (11H, m), 2.33 (1H, m), 3.52 (1H, m), 3.95 (1H, m), 4.88 (1H, m), 6.26 (1H, d, J=16 Hz), 6.80 (2H, d, J=8.5 Hz), 7.02-7.19 (2H, m), 7.28 (1H, dd, J=7.5, 1 Hz), 7.33-7.44 (3H, m), 7.59 (1H, dd, J=7.5, 1 Hz), 7.71 (1H, s), 9.23 (1H, s), 11.07 (1H, s); MS (ES−) m/z 462.
The following compound was obtained in a similar manner to that of Preparation 382.
1H-NMR (300 MHz, CDCl3) δ4.04 (2H, s), 7.09 (1H, s), 7.12-7.41 (8H, m), 7.85 (1H, d, J=8 Hz), 7.99 (1H, d, J=2 Hz), 8.45 (1H, d, J=2 Hz), 9.80 (1H, s); MS (ES+) m/z 323.
The following compound was obtained in a similar manner to that of Preparation 379.
MASS(API-ES); 378 (M+H)+,
1H-NMR (200 MHz), (DMSO-d6, δ): 1.28 (3H, t, J=7.1 Hz), 1.70-1.95 (1H, m), 2.05-2.30 (1H, m), 2.35-2.75 (3H, m), 2.80-2.90 (1H, m), 3.50-3.70 (2H, m), 4.23 (2H, q, J=7.1 Hz), 4.30-4.55 (1H, m), 7.15-7.40 (5H, m), 7.77 (1H, d, J=11Hz), 7.89 (1H, d, J=6.4 Hz).
The following compound was obtained in a similar manner to that of Preparation 336.
1H-NMR (300 MHz, CDCl3) δ 1.47 (3×3H, s), 1.56-1.95 (6H, m), 2.06-2.32 (2H, m), 2.56-2.84 (7H, m), 3.08 (1H, dd, J=8, 8 Hz), 3.68 (1H, m), 3.97 (1H, m), 4.92-5.10 (2H, m), 6.46 (1H, br), 7.13-7.33 (5H, m), 7.63 (1H, d, J=15.5 Hz), 8.78 (2×1H, s); MS (ES+) m/z 538.
The following compounds were obtained in a similar manner to that of Preparation 414.
1H-NMR (300 D-% DMSO-d6) δ 1.42-1.76 (12H, m), 2.71-2.83 (4H, m), 3.52 (1H, m), 3.96 (1H, m), 4.91 (1H, m), 6.74 (1H, d, J=15.5 Hz), 7.03-7.10 (2H, m), 7.14 (1H, m), 7.48 (1H, d, J=15.5 Hz), 7.92 (1H, dd, J=6, 3.5 Hz), 8.27 (1H, s), 8.32 (1H, s), 8.78 (1H, s), 11.26 (1H, s); MS (ES+) m/z 424.
The following compound was obtained in a similar manner to that of Preparation 375.
MASS(API-ES); 390 (M+H)+
1H-NMR (200 MHz), (DMSO-d6, δ): 1.05-1.79 (10H, m), 1.24 (3H, t, J=7.1 Hz), 1.80-2.55 (3H, m), 3.15-3.90 (4H, m), 4.16 (2H, q, J=7.1 Hz), 4.35-4.75 (1H, m), 6.46 (1H, d, J=16 Hz), 7.38-7.50 (1H, m), 7.56 (1H, d, J=16 Hz), 7.90 (1H, d, J=13 Hz), 8.15 (1H, s).
The following compound was obtained in a similar manner to that of Preparation 450.
1H-NMR (300 MHz. CDCl3) δ1.46 (9H, s), 1.63 (1H, m), 2.20-2.47 (1H, m), 2.56-2.76 (2H, m), 2.79-2.96 (3H, m), 2.97-3.11 (3H, m), 4.20 (1H, m), 4.86 (1H, 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.
1H-NMR (300 MHz, DMSO-d6) δ2.00-2.40 (1H, m), 3.05-4.32 (11H, 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.
1H-NMR (300 MHz, CDCl3) δ 1.33 (3H, t, J=7 Hz), 1.75 (1H, m), 2.35-2.50 (2H, m), 2.75 (1H, dd, J=10, 6 Hz), 2.79 (1H, dd, J=10, 3 Hz), 2.83-3.19 (6H, m), 4.25 (2H, q, J=7 Hz), 4.51 (1H, m), 5.25 (1H, d, J=8 Hz), 6.69 (1H, d, J=15.5 Hz), 7.10-7.23 (4H, m), 7.58 (1H, d, J=15.5 Hz), 7.90 (1H, d, J=1 Hz), 8.07 (1H, d, J=1 Hz); MS (ES+) m/z 379.
The following compound was obtained in a similar manner to that of Preparation 397.
MASS(API-ES); 461 (M+H)+,
1H-NMR (200 MHz), (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 (1H, m), 4.89 (1H, s), 6.29 (1H, d, J=16 Hz), 7.25-7.38 (1H, m), 7.41 (1H, d, J=16 Hz), 7.62 (1H, d, J=12 Hz), 8.09 (1H, s
The following compound was obtained in a similar manner to that of Preparation 311.
MASS(API-ES); 406 (M+H)+,
1H-NMR (200 MHz), (DMSO-d6, δ): 1.24 (3H, t, J=7.1 Hz), 1.65-1.90 (1H, m), 2.00-2.30 (1H, m), 2.35-2.73 (3H, m), 2.80-2.95 (1H, m), 3.69 (2H, s), 4.15 (2H, q, J=7.1 Hz), 4.30-4.55 (1H, m), 6.42 (1H, d, J=16 Hz), 7.00-7.20 (2H, m), 7.25-7.50 (2H, m), 7.53 (1H, dd, J=1.9 Hz, J=16 Hz), 7.84 (1H, dd, J=1.7 Hz, J=13 Hz), 8.09 (1H, d, J=1.7 Hz).
The following compound was obtained in a similar manner to that of Preparation 414.
1H-NMR (300 MHz, CDCl3) δ 1.52-1.94 (7H, m), 2.36-2.50 (2H, m), 2.74 (1H, dd, J=10, 6 Hz), 2.78-3.17 (7H, m), 3.65 (1H, m), 3.96 (1H, m), 4.51 (1H, m), 5.02 (1H, m), 5.33 (1H, d, J=7 Hz), 6.70 (1H, br), 7.12-7.22 (4H, m), 7.63 (1H, d, J=15.5 Hz), 7.88 (1H, s), 8.05 (1H, s); MS (ES+) m/z 450.
The following compound was obtained in a similar manner to that of Preparation 405.
1H-NMR (300 MHz, DMSO-d6) δ1.68 (1H, m), 2.25 (1H, m), 2.44-2.56 (1H, m), 2.71-2.90 (4H, m), 2.94-3.60 (4H, m), 4.35 (1H, m), 6.46 (1H, d, J=15.3 Hz), 7.07-7.22 (4H, m), 7.48 (1H, d, J=15.3 Hz), 7.92 (1H, d, J=6.5 Hz), 8.00 (1H, d, J=1 Hz), 8.20 (1H, d, J=1 Hz); MS (ES+) m/z 351.
The following compound was obtained in a similar manner to that of Preparation 414.
1H-NMR (300 MHz, DMSO-d6) δ1.00-2.15 (18H, m), 2.30-3.20 (5H, m), 3.54 (1H, m), 3.96 (1H, m), 4.72 (1H, m), 4.92 (1H, m), 6.59 (1H, d, J=16 Hz), 7.36 (1H, d, J=8 Hz), 7.53 (1H, d, J=16 Hz), 8.01 (1H, d, J=8 Hz), 8.63 (1H, s), 11.31 (1H, br-s); MS (ES+) m/z 515.
The following compound was obtained in a similar manner to that of Preparation 397.
MASS(API-ES); 477 (M+H)+,
1H-NMR (200 MHz), (DMSO-d6, δ): 1.40-1.90 (7H, m), 2.00-2.28 (1H, m), 2.30-2.75 (3H, m), 2.80-3.00 (1H, m), 3.40-3.60 (1H, m) 3.69 (2H, s), 3.80-4.05 (1H, m), 4.25-4.60 (1H, m), 4.88 (1H, s), 6.25 (1H, d, J=15 Hz), 7.00-7.25 (3H, m), 7.30-7.75 (3H, m), 8.03 (1H, s).
The following compounds were obtained in a similar manner to that of Preparation 336.
MASS(API-ES); 441 (M+H)+,
1H-NMR (200 MHz), (DMSO-d6, δ): 1.40-1.95 (7H, m), 2.05-2.30 (1H, m), 2.32-2.70 (3H, m), 2.80-2.90 (1H, m), 3.40-3.65 (3H, m), 3.80-4.10 (1H, m), 4.30-4.60 (1H, m), 4.88 (1H, s), 6.25 (1H, d, J=15 Hz), 7.15 (1H d, J=6.5 Hz), 7.18-7.45 (6H, m), 7.56 (1H, d, J=12 Hz), 8.02 (1H, s
1H-NMR (300 MHz, DMSO-d6) δ 0.54-0.72 (2H, m), 1.00-1.78 (151H, m), 1.33 (3×3H, s), 1.94-2.14 (4H, m), 2.25 (1H, m), 2.37-2.58 (2H, m), 2.68 (1H, m), 3.54 (1H, m), 3.96 (1H, m), 4.76 (1H, m), 4.93 (1H, m), 6.70 (1H, d, J=16 Hz), 7.51 (1H, d, J=16 Hz), 9.01 (2×1H, s), 11.41 (1H, s); MS (ES+) m/z 530.
The following compound was obtained in a similar manner to that of Preparation 810.
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 (1H, m), 4.14 (2H, q, J=7.4 Hz), 6.29 (1H, d, J=15.9 Hz), 6.48 (1H, d, J=7.8 Hz), 7.09-7.18 (3H, m), 7.30-7.37 (2H, m), 7.48 (1H, d, J=15.9 Hz), 7.76 (1H, dd, J=1.9, 8.0 Hz), 8.20 (1H, d, J=1.9 Hz),
Mass (ESI): 384(M+H)+.
The following compound was obtained in a similar manner to that of Preparation 198.
1H NMR (DMSO-d6, δ): 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 (1H, m), 4.14 (2H, q, J=7.4 Hz), 6.30 (1H, d, J=15.9 Hz), 6.49 (1H, d, J=8.8 Hz), 7.12 (1H, d, J=7.2 Hz), 7.49 (1H, d, J=15.9 Hz), 7.76 (1H, dd, J=2.2, 8.8 Hz), 8.20 (1H, d, J=2.2 Hz),
Mass (ESI): 372(M+H)+.
The following compounds were obtained in a similar manner to that of Preparation 862.
Mass (ESI): 356(M+H)+.
Mass (ESI): 344(M+H)+.
The following compounds were obtained in a similar manner to that of Preparation 62.
MASS(API-ES); 455 (M+H)+.
MASS(API-ES); 443 (M+H)+.
The following compound was obtained in a similar manner to that of Preparation 375.
MASS(API-ES); 472 (M+H)+Free
1H-NMR (200 MHz), (DMSO-d6, δ): 1.10-1.80 (22H, m), 1.85-2.40 (3H, m), 3.00-3.90 (4H, m), 4.21 (2H, q, J=7.1 Hz), 4.61-4.97 (1H, m), 6.78 (1H, d, J=16 Hz), 7.38 (1H, dd, J=3.4 Hz, J=8.6 Hz), 7.69 (1H, d, J=16 Hz), 8.22 (1H, d, J=8.6 Hz), 8.73 (1H, d, J=3.4 Hz).
The following compound was obtained in a similar manner to that of Preparation 397.
MASS(API-ES); 443 (M+H)+Free
1H-NMR (200 MHz), (DMSO-d6, δ): 1.03-2.57 (19H, m), 3.10-4.08 (6H, m), 4.20-4.60 (1H, m), 4.88 (1H, s), 6.23 (1H, d, J=15 Hz), 6.55 (1H, dd, J=3.2 Hz, J=8.8 Hz), 7.28 (1H, d, J=6.7 Hz), 7.37 (1H, d, J=15 Hz), 7.63 (1H, d, J=8.8 Hz), 8.18 (1H, s
The following compounds were obtained in a similar manner to that of Preparation 871.
1-NMR (300 MHz, CDCl3) δ1.37 (3H, t, J=7 Hz), 1.51 (1H, m), 1.67-2.03 (4H, m), 2.33 (1H, m), 3.87 (1H, m), 4.34 (2H, q, J=7 Hz), 4.52 (1H, m), 4.67 (1H, d, J=12.7 Hz), 4.69 (1H, d, J=12.7 Hz), 5.27 (1H, d, J=7 Hz), 7.22-7.38 (5H, m), 8.01 (1H, d, J=2.2 Hz), 8.71 (1H, d, J=2.2 Hz); MS (ES+) m/z 375.
The following compound was obtained in a similar manner to that of Preparation 361.
1H-NMR (300 MHz, CDCl3) δ2.88 (2H, dd, J=16, 4.5 Hz), 3.39 (2H, dd, J=16, 7 Hz), 4.54 (2H, s), 4.60 (1H, m), 4.82 (1H, br-d, J=6 Hz), 6.43 (1H, d, J=9 Hz), 7.14-7.30 (4H, m), 7.49 (1H, dd, J=8.5, 2.5 Hz), 8.06 (1H, d, J=2.5 Hz); MS (ES+) m/z 241.
The following compound was obtained in a similar manner to that of Preparation 382.
1H-NMR (300 MHz, CDCl3) δ2.93 (2H, dd, J=16, 4.5 Hz), 3.43 (2H, dd, J=16, 7 Hz), 4.75 (1H, br), 5.42 (1H, br), 6.45 (1H, d, J=8.8 Hz), 7.16-7.30 (4H, m), 7.90 (1H, dd, J=8.8, 2.2 Hz), 8.52 (1H, d, J=2.2 Hz), 9.78 (1H, s); MS (ES+) m/z 239.
The following compound was obtained in a similar manner to that of Preparation 414.
1H-NMR (300 MHz, DMSO-d6) δ1.45-1.78 (6H, m), 2.83 (2H, dd, J=16, 5.5 Hz), 3.29 (1H, dd, J=16, 7 Hz), 3.53 (1H, m), 3.95 (1H, m), 4.64 (1H, m), 4.88 (1H, m), 6.22 (1H, br-d, J=16 Hz), 6.54 (1H, d, J=8.5 Hz), 7.11-7.28 (4H, m), 7.31-7.45 (2H, m), 7.61 (1H, br-d, J=8.5 Hz), 8.19 (1H, s), 11.16 (1H, br); MS (ES+) m/z 380.
The following compound was obtained in a similar manner to that of Preparation 405.
1H-NMR (300 MHz, DMSO-d6) δ2.40 (3H, s), 6.33 (1H, d, J=16 Hz), 6.67 (1H, d, J=7.5 Hz), 6.69 (1H, d, J=7.5 Hz), 7.49 (1H, dd, J=7.5, 7.5 Hz), 7.51 (1H, d, J=16 Hz), 7.57 (2H, d, J=8.5 Hz), 7.77 (2H, d, J=8.5 Hz), 9.29 (1H, s), 12.13 (1H, br); MS (ES+) m/z 255.
The following compound was obtained in a similar manner to that of Preparation 414.
1H-NMR (300 MHz, DMSO-d6) δ1.46-1.76 (6H, m), 2.39 (3H, s), 3.53 (1H, m), 3.96 (1H, m), 4.90 (1H, m), 6.33 (1H, br-d, J=16 Hz), 6.66 (1H, d, J=7 Hz), 6.68 (1H, d, J=7 Hz), 7.37-7.54 (4H, m), 7.77 (2×1H, d, J=8.5 Hz), 9.25 (1H, s), 11.12 (1H, s); MS (ES+) m/z 354.
The following compound was obtained in a similar manner to that of Preparation 361.
1H-NMR (300 MHz, CDCl3)(1.49 (1H, m), 1.68-2.02 (4H, m), 2.31 (1H, m), 3.87 (1H, m), 4.44 (1H, m), 4.54 (2H, s), 4.66 (1H, d, J=12 Hz), 4.69 (1H, d, J=12 Hz), 4.89 (1H, d, J=7.5 Hz), 7.23-7.42 (4H, m), 7.51 (1H, d, J=2 Hz), 8.02 (1H, d, J=2 Hz); MS (ES+) m/z 333.
The following compound was obtained in a similar manner to that of Preparation 382.
1H-NMR (300 MHz, CDCl3) δ1.53 (1H, m), 1.68-2.06 (4H, m), 2.34 (1H, m), 3.89 (1H, m), 4.56 (1H, m), 4.67 (2H, s), 5.50 (1H, d, J=7 Hz), 7.22-7.38 (5H, m), 7.93 (1H, d, J=2 Hz), 8.47 (1H, d, J=2 Hz), 9.78 (1H, s); MS (ES+) m/z 331.
The following compound was obtained in a similar manner to that of Preparation 414.
1H-NMR (300 MHz, DMSO-d6) δ1.45-1.78 (10H, m), 1.87-2.12 (2H, m), 3.53 (1H, m), 3.90-4.02 (2H, m), 4.45 (1H, m), 4.54 (2H, s), 4.89 (1H, m), 6.33 (1H, br-d, J=16 Hz), 6.74 (1H, d, J=7.7 Hz), 7.22-7.37 (5H, m), 7.37 (1H, d, J=16 Hz), 7.84 (1H, s), 8.24 (1H, s), 11.08 (1H, s); MS (ES+) m/z 472.
The following compound was obtained in a similar manner to that of Preparation 336.
1H-NMR (300 MHz, DMSO-d6) δ1.13-1.78 (20H, m), 1.89 (1H, m), 2.03 (1H, m), 2.25 (1H, m), 2.62 (1H, m), 2.81 (1H, m), 3.54 (1H, m), 3.95 (1H, m), 4.68 (1H, m), 4.92 (1H, m), 6.58 (1H, d, J=15 Hz), 7.34 (1H, d, J=8 Hz), 7.52 (1H, d, J=15 Hz), 8.00 (1H, d, J=8, 2 Hz), 8.62 (1H, d, J=2 Hz), 11.32 (1H, br-s); MS (ES+) m/z 529.
The following compound was obtained in a similar manner to that of Preparation 486.
1HNMR (400 MHz, CDCl3): δ 1.44 (9H, s), 1.54-1.66 (1H, m), 2.20-2.35 (2H, m), 2.51-2.64 (2H, m), 2.74-2.84 (1H, m), 3.56, 3.61 (2H, q, Jab=13.2 Hz), 4.18 (1H, br.s), 4.92 (1H, br.s), 7.11 (1H, dt, J=2.7, 8.3 Hz), 7.02-7.09 (2H, m), 7.23-7.29 (1H, m),
MASS (ESI): m/z=295.3 (M+1).
The following compound was obtained in a similar manner to that of Preparation 871.
1H-NMR (300 MHz, CDCl3) δ1.26 (1H, m), 1.37 (3H, t, J=7 Hz), 1.39 (1H, m), 2.13 (1H, m), 3.10 (1H, m), 4.34 (2H, q, J=7 Hz), 5.70 (1H, br), 7.17-7.35 (5H, m), 8.04 (1H, d, J=2 Hz), 8.77 (1H, d, J=2 Hz); MS (ES+) m/z 317.
The following compound was obtained in a similar manner to that of Preparation 382.
1H-NMR (300 MHz, CDCl3) δ1.29 (1H, m), 1.44 (1H, m), 2.17 (1H, ddd, J=9, 6, 3 Hz), 3.15 (1H, m), 5.91 (1H, br-s), 7.19-7.36 (5H, m), 7.96 (1H, d, J=1.8 Hz), 8.53 (1H, d, J=1.8 Hz), 9.81 (1H, s); MS (ES+) m/z 273.
The following compound was obtained in a similar manner to that of Preparation 414.
1H-NMR (300 MHz, DMSO-d6) δ 1.24 (1H, m), 1.42 (1H, m), 1.46-1.77 (6H, m), 2.06 (1H, m), 3.03 (1H, m), 3.52 (1H, m), 3.95 (1H, m), 4.88 (1H, m), 6.33 (1H, d, J=16 Hz), 7.13-7.22 (3H, m), 7.24-7.32 (3H, m), 7.36 (1H, d, J=16 Hz), 7.85 (1H, br-s), 8.22 (1H, br-s), 11.09 (1H, br-s);
MS (ES+) m/z 414.
The following compound was obtained in a similar manner to that of Preparation 871.
1H-NMR (300 MHz, CDCl3) δ1.20-1.42 (3H, m), 1.39 (3H, t, J=7 Hz), 1.48-1.64 (2H, m), 1.72 (1H, m), 1.80-1.90 (2H, m), 1.92-2.02 (2H, m), 2.24 (1H, m), 4.36 (2H, q, J=7 Hz), 7.15-7.36 (4H, m), 7.46 (1H, m), 8.09 (1H, s), 8.16 (1H, d, J=2 Hz), 8.79 (1H, d, J=2 Hz); MS (ES+) m/z 402.
The following compound was obtained in a similar manner to that of Preparation 414.
1H-NMR (300 MHz, DMSO-d6) δ 1.46-1.78 (6H, m), 3.53 (1H, m), 3.92 (2H, s), 3.95 (1H, m), 4.89 (1H, m), 6.36 (1H, d, J=16 Hz), 7.07-7.30 (8H, m), 7.37 (1H, d, J=16 Hz), 7.44 (1H, d, J=8 Hz), 7.95 (1H, s), 8.13 (1H, s), 8.23 (1H, s), 11.13 (1H, s); MS (ES+) m/z 464.
The following compound was obtained in a similar manner to that of Preparation 361.
1H-NMR (300 MHz, CDCl3) 1.20-1.40 (3H, m), 1.45-1.75 (3H, m), 1.76-2.01 (4H, m), 2.22 (1H, m), 4.59 (2H, s), 7.03 (1H, s), 7.13 (1H, d, J=8 Hz), 7.22-7.32 (2H, m), 7.39 (1H, d, J=8 Hz), 7.65 (1H, d, J=2 Hz), 8.04 (1H, s), 8.09 (1H, d, J=2 Hz); MS (ES+) m/z 360.
The following compound was obtained in a similar manner to that of Preparation 414.
1H-NMR (300 MHz, DMSO-d6) δ1.12-1.34 (3H, m), 1.36-1.86 (13H, m), 2.41 (1H, m), 3.53 (1H, m), 3.96 (1H, m), 4.89 (1H, m), 6.40 (1H, d, J=16 Hz), 7.14 (1H, dd, J=7.5, 7.5 Hz), 7.21-7.29 (2H, m), 7.40 (1H, d, J=16 Hz), 7.78 (1H, d, J=7.5 Hz), 8.02 (1H, s), 8.22 (1H, s), 8.32 (1H, s), 9.92 (1H, s), 11.16 (1H, s); MS (ES+) m/z 499.
The following compound was obtained in a similar manner to that of Preparation 871.
1H-NMR (300 MHz, CDCl3) δ1.20-1.40 (3H, m), 1:37 (3H, t, J=7 Hz), 1.43-1.59 (2H, m), 1.69 (1H, m), 1.75-1.99 (4H, m), 2.27 (1H, m), 4.35 (2H, q, J=7 Hz), 7.19 (1H, ddd, J=7.7, 7.7, 1.5 Hz), 7.24-7.37 (2H, m), 7.58 (1H, s), 7.70 (1H, dd, J=7.7, 1.5 Hz), 7.95 (1H, s), 8.15 (1H, d, J=1.7 Hz), 8.67 (1H, d, J=1.7 Hz); MS (ES+) m/z 402.
The following compounds were obtained in a similar manner to that of Preparation 382.
1H-NMR (300 MHz, CDCl3) δ 1.18-1.38 (3H, m), 1.42-1.64 (2H, m), 1.70 (1H, m), 1.76-1.88 (2H, m), 1.90-2.00 (2H, m), 2.30 (1H, m), 7.17-7.36 (5H, m), 7.50 (1H, s), 7.77 (1H, d, J=7.5 Hz), 8.05 (1H, d, J=1.5 Hz), 8.34 (1H, s), 8.44 (1H, d, J=1.5 Hz), 9.81 (1H, s); MS (ES+) m/z
1H-NMR (300 MHz, CDCl3) δ1.22-1.41 (3H, m), 1.48-1.64 (2H, m), 1.72 (1H, m), 1.79-1.91 (2H, m), 1.92-2.02 (2H, m), 2.25 (1H, m), 7.17 (1H, d, J=8 Hz), 7.23 (1H, s), 7.33 (1H, dd, J=8, 8 Hz), 7.44-7.54 (2H, m), 8.07 (1H, d, J=2 Hz), 8.14 (1H, s), 8.56 (1H, d, J=2 Hz), 9.85 (1H, s); MS (ES+) m/z 358.
The following compound was obtained in a similar manner to that of Preparation 414.
1H-NMR (300 MHz, DMSO-d6) δ1.13-1.85 (16H, m), 2.33 (1H, m), 3.53 (1H, m), 3.96 (1H, m), 4.90 (1H, m), 6.43 (1H, d, J=16 Hz), 7.16-7.34 (4H, m), 7.43 (1H, d, J=16 Hz), 7.95 (1H, s), 8.03 (1H, s), 8.29 (1H, s), 8.66 (1H, s), 9.79 (1H, s), 11.19 (1H, s); MS (ES+) m/z 499.
The following compound was obtained in a similar manner to that of Preparation 405.
1H-NMR (300 MHz, DMSO-d6) δ 1.50 (2H, m), 1.56-1.68 (4H, m), 2.76-2.88 (4H, m), 6.58 (1H, d, J=15.5 Hz), 7.04-7.14 (2H, m), 7.17 (1H, m), 7.56 (1H, d, J=15.5 Hz), 7.90 (1H, m), 8.33-8.38 (2H, m), 8.92 (1H, br-s);
MS (ES+) m/z 325.
The following compound was obtained in a similar manner to that of Preparation 366.
MASS(API-ES); 280 (M+H)+Free
1H-NMR (200 MHz), (DMSO-d6, δ): 1.24 (3H, t, J=7.1 Hz), 1.90-2.35 (2H, m), 3.05-3.60 (4H, m), 4.17 (2H, q, J=7.1 Hz), 4.55-4.75 (1H, m), 6.50 (1H, d, J=16 Hz), 7.58 (1H, dd, J=1.8 Hz, J=16 Hz), 7.65 (1H, br), 7.97 (1H, dd, J=1.6 Hz, J=13 Hz), 8.17 (1H, d, J=1.6 Hz), 9.47 (2H, br).
The following compound was obtained in a similar manner to that of Preparation 452.
1H-NMR (300 MHz, DMSO-d6) δ2.21 (1H, m), 2.44 (1H, m), 3.55 (1H, m), 3.66 (1H, m), 3.76-3.94 (2H, m), 4.04 (1H, m), 4.91 (2H, s), 7.69 (1H, m), 7.73 (1H, d, J=8.5 Hz), 7.86 (1H, ddd, J=7, 7, 1.5 Hz), 8.03-8.13 (2H, m), 8.52 (1H, 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.
1H-NMR (300 MHz, CDCl3) δ1.32 (3H, t, J=7 Hz), 1.76 (1H, m), 2.42 (1H, m), 2.54 (1H, m), 2.75-2.88 (2H, m), 3.03 (1H, m), 3.98 (1H, d, J=13.5 Hz), 4.02 (1H, d, J=13.5 Hz), 4.25 (2H, q, J=7 Hz), 4.51 (1H, m), 5.39 (1H, d, J=8 Hz), 6.68 (1H, d, J=15.5 Hz), 7.49-7.62 (3H, m), 7.71 (1H, ddd, J=7, 7, 1.5 Hz), 7.81 (1H, dd, J=8, 1.5 Hz), 7.89 (1H, d, J=1 Hz), 8.04 (1H, d, J=1 Hz), 8.08 (1H, d, J=8 Hz), 8.15 (1H, d, J=8 Hz);
MS (ES+) m/z 404.
The following compound was obtained in a similar manner to that of Preparation 390.
MASS(API-ES); 356 (M+H)+
The following compound was obtained in a similar manner to that of Preparation 452.
1H-NMR (300 MHz, DMSO-d6) δ2.00-2.65 (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 (1H, 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.
1H-NMR (300 MHz, CDCl3) δ1.44 (9H, s), 2.25 (1H, m), 2.51 (1H, m), 2.77 (1H, m), 3.02 (1H, m), 3.14-3.40 (4H, m), 3.64 (1H, m), 3.90 (1H, m), 4.63 (1H, m), 6.45 (1H, 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.
1H-NMR (300 MHz, CDCl3) δ 1.32 (3H, t, J=7 Hz), 1.69 (1H, m), 2.29-2.45 (2H, m), 2.38 (3H, s), 2.66 (1H, dd, J=10, 3 Hz), 2.70 (1H, dd, J=10, 6 Hz), 2.91 (1H, m), 3.62 (2H, s), 4.25 (2H, q, J=7 Hz), 4.45 (1H, m), 5.19 (1H, d, J=8 Hz), 6.68 (1H, d, J=15.5 Hz), 7.11-7.20 (3H, m), 7.26 (1H, m), 7.56 (1H, d, J=15.5 Hz), 7.87 (1H, d, J=1 Hz), 8.05 (1H, d, J=1 Hz); MS (ES+) m/z 367.
The following compound was obtained in a similar manner to that of Preparation 397.
MASS(API-ES); 455 (M+H)+.
1H-NMR (200 MHz), (DMSO-d6, δ): 1.40-1.95 (7H, m), 2.00-2.30 (1H, m), 2.45-2.80 (7H, m), 2.85-3.00 (1H, m), 3.40-3.65 (1H, m), 3.80-4.10 (1H, m), 4.35-4.60 (1H, m), 4.89 (1H, s), 6.27 (1H, d, J=16 Hz), 7.05-7.35 (6H, m), 7.39 (1H, d, J=16 Hz), 7.58 (1H, d, J=12 Hz), 8.05 (1H, s).
The following compound was obtained in a similar manner to that of Preparation 439.
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 (1H, m), 1.58-1.84 (5H, m), 2.18-2.38 (4H, m), 2.61 (2H, d, J=5 Hz), 2.83 (1H, m), 4.25 (2H, q, J=7 Hz), 4.53 (1H, m), 5.75 (1H, d, J=8 Hz), 6.30 (1H, d, J=16 Hz), 7.48 (1H, d, J=16 Hz), 8.44 (2×1H, s); MS (ES+) m/z 359.
The following compound was obtained in a similar manner to that of Preparation 480.
1H-NMR (300 MHz, CDCl3) δ1.35 (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 (1H, m), 2.10-2.36 (2.5H, m), 2.49-2.68 (2H, m), 2.88 (0.5H, m), 3.19 (1H, q, J=6.6 Hz), 4.12 (1H, m), 4.82 (1H, 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.
1H-NMR (300 MHz, DMSO-d6) δ 1.29 (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 (1H, m), 2.65-2.83 (2H, m), 3.20-3.42 (1H, m), 3.52 (1H, m), 3.95 (1H, m), 4.27 (1H, m), 4.89 (2H, m), 6.60 (1H, d, J=15 Hz), 7.19-7.37 (5H, m), 7.36 (1H, d, J=15 Hz), 7.73 (0.5H, d, J=6 Hz), 7.76 (0.5H, d, J=6 Hz), 7.97 (1H, s), 8.08 (0.5H, s), 8.09 (0.5H, s), 11.18 (1H, br-s); MS (ES+) m/z 438.
The following compounds were obtained in a similar manner to that of Preparation 452.
1H-NMR (300 MHz, CDCl3) δ1.37 (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 (1H, m), 2.54 (1H, dd, J=7, 7 Hz), 2.62 (0.5H, dd, J=9.5, 6.5 Hz), 2.67-2.82 (1H, m), 3.20 (1H, q, J=6.6 Hz), 3.46 (1H, m), 7.18-7.36 (5H, m); MS (ES+) m/z 191.
1H-NMR (300 MHz, CDCl3) δ1.42-1.66 (3H, m), 2.21 (1H, dddd, J=13, 8.5, 8.5, 5.5 Hz), 2.37 (1H, dd, J=9.5, 4.5 Hz), 2.53 (1H, ddd, J=8.5, 8.5, 6.5 Hz), 2.60-2.86 (4H, m), 3.53 (1H, m), 7.15-7.33 (5H, m); MS (ES+) m/z 191.
1H-NMR (300 MHz, CDCl3) δ1.35 (2H, br), 1.52 (1H, m), 2.24 (1H, dddd, J=13, 8.5, 8.5, 5 Hz), 2.36 (1H, dd, J=9.5, 5 Hz), 2.59 (1H, ddd, J=8.5, 8.5, 6 Hz), 2.77 (1H, ddd, J=8.5, 8.5, 6 Hz), 2.82-2.97 (3H, m), 2.98-3.14 (3H, m), 3.57 (1H, 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.
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 (1H, m), 6.68 (0.7H, d, J=16 Hz), 6.70 (0.3H, d, J=16 Hz), 7.43 (1H, d, J=8.5 Hz), 7.63 (0.7H, d, J=16 Hz), 7.64 (0.3H, d, J=16 Hz), 8.23 (1H, m), 8.73 (1H, m), 11.48 (1H, br); MS (ES+) m/z 416.
The following compound was obtained in a similar manner to that of Preparation 452.
1H-NMR (300 MHz, CDCl3) δ0.86-1.06 (2H, m), 1.10-1.30 (3H, m), 1.52-1.80 (9H, m), 2.42 (1H, m), 3.08 (1H, dd, J=14, 7 Hz), 3.15 (1H, dd, J=14, 7 Hz), 3.23-3.35 (2H, m), 3.53 (1H, dd, J=10, 8.5 Hz); MS (ES+) m/z 197.
The following compound was obtained in a similar manner to that of Preparation 414.
1H-NMR (300 MHz, DMSO-d6) δ0.73-0.93 (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 (1H, m), 2.72 (1H, m), 3.52 (1H, m), 3.95 (1H, m), 4.29 (1H, m), 4.89 (1H, m), 6.60 (1H, d, J=15.2 Hz), 7.38 (1H, d, J=15.2 Hz), 7.73 (1H, d, J=6.6 Hz), 7.98 (1H, s), 8.11 (1H, s), 11.18 (1H, s); MS (ES+) m/z 430.
The following compound was obtained in a similar manner to that of Preparation 480.
1H-NMR (300 MHz, CDCl3) δ1.43 (9H, s), 1.67 (1H, m), 2.16-2.33 (2H, m), 2.52 (1H, m), 2.59 (1H, dd, J=9.5, 6 Hz), 2.79 (1H, m), 3.56 (2H, s), 4.16 (1H, m), 4.80 (1H, m), 7.10-7.20 (3H, m), 7.25 (1H, m); MS (ES+) m/z 291.
The following compound was obtained in a similar manner to that of Preparation 336.
1H-NMR (300 MHz, DMSO-d6) δ 0.80-0.96 (2H, m), 1.10-1.30 (3H, m), 1.45-1.76 (12H, m), 1.84 (1H, m), 2.44 (1H, m), 2.97-3.12 (2H, m), 3.27-3.39 (2H, m), 3.52 (1H, m), 3.95 (1H, m), 4.64 (1H, m), 4.90 (1H, m), 6.64 (1H, d, J=15.5 Hz), 7.41 (1H, d, J=15.5 Hz), 7.88 (1H, d, J=7.5 Hz), 8.06 (1H, s), 8.10 (1H, s), 11.21 (1H, s); MS (ES+) m/z 444.
The following compound was obtained in a similar manner to that of Preparation 390.
MASS(API-ES); 362 (M+H)+.
1H-NMR (200 MHz), (DMSO-d6, δ): 1.05-1.79 (10H, m), 1.80-2.55 (3H, m), 3.15-3.90 (4H, m), 4.40-4.70 (1H, m), 6.36 (1H, d, J=16 Hz), 7.35-7.45 (1H, m), 7.51 (1H, d, J=16 Hz), 7.86 (1H, dd, J=1.8 Hz, J=12 Hz), 8.12 (1H, d, J=1.8 Hz).
The following compound was obtained in a similar manner to that of Preparation 336.
1H-NM (300 MHz, DMSO-d6) δ1.46-1.77 (7H, m), 2.26 (1H, m), 2.46-2.60 (2H, m), 2.77 (1H, m), 2.89 (1H, dd, J=9.5, 7 Hz), 3.52 (1H, m), 3.90 (2H, s), 3.95 (1H, m), 4.35 (1H; m), 4.89 (1H, m), 6.59 (1H, d, J=15 Hz), 7.37 (1H, d, J=15 Hz), 7.57 (1H, m), 7.65 (1H, d, J=8.5 Hz), 7.73 (1H, m), 7.81 (1H, d, J=7 Hz), 7.93-8.02 (3H, m), 8.09 (1H, s), 8.33 (1H, d, J=8.5 Hz), 11.18 (1H, s); MS (ES+) m/z 475.
The following compound was obtained in a similar manner to that of Preparation 859.
1H-NMR (300 MHz, CDCl3) δ1.35 (3H, t, J=7 Hz), 1.47 (3×3H, s), 2.07-2.33 (2H, m), 2.56-2.83 (7H, m), 3.08 (1H, dd, J=8, 8 Hz), 4.29 (2H, q, J=7 Hz), 5.00 (1H, m), 6.54 (1H, d, J=16 Hz), 7.14-7.33 (5H, m), 7.59 (1H, d, J=16 Hz), 8.79 (2×1H, s); MS (ES+) m/z 467.
The following compound was obtained in a similar manner to that of Preparation 436.
MASS(API-ES); 413 (M+H)+
1H-NMR (200 MHz), (DMSO-d6, δ): 1.39 (10H, s), 1.95-2.30 (2H, m), 2.40-2.85 (3H, m), 3.45, 3.53 (2H, ABq, J=13 Hz), 3.93 (3H, s), 4.70-4.95 (1H, m), 7.05-7.30 (5H, m), 8.79 (1H, d, J=1.3 Hz), 9.00 (1H, d, J=1.3 Hz).
The following compound was obtained in a similar manner to that of Preparation 379.
MASS(API-ES); 313 (M+H)+
1H-NMR (200 MHz), (DMSO-d6, δ): 1.55-1.80 (1H, m), 2.10-2.55 (3H, m), 2.60-2.85 (2H, m), 3.59 (2H, s), 3.78 (3H, s), 4.25-4.45 (1H, m), 7.20-7.35 (5H, m), 7.96 (1H, d, J=1.0 Hz), 8.16 (1H, d, J=6.7 Hz), 8.56 (1H, d, J=1.0 Hz).
The following compound was obtained in a similar manner to that of Preparation 439.
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 (1H, m), 2.85 (1H, m), 3.16 (1H, dd, J=14, 7 Hz), 3.22 (1H, dd, J=14, 7 Hz), 3.30-3.50 (2H, m), 4.25 (2H, q, J=7 Hz), 4.47 (1H, m), 5.75 (1H, d, J=4 Hz), 6.72 (1H, d, J=15.5 Hz), 7.57 (1H, d, J=15.5 Hz), 8.01 (1H, d, J=1 Hz), 8.05 (1H, d, J=1 Hz); MS (ES+) m/z 373.
The following compound was obtained in a similar manner to that of Preparation 480.
1H-NMR (300 MHz, CDCl3) δ1.44 (9H, s), 1.64 (1H, m), 2.29 (1H, m), 2.48 (1H, m), 2.62 (1H, m), 2.78 (1H, dd, J=9.5, 6.5 Hz), 2.89 (1H, m), 3.95 (2H, s), 4.21 (1H, m), 4.96 (1H, br-d, J=8 Hz), 7.52 (1H, m), 7.56 (1H, d, J=8.5 Hz), 7.70 (1H, m), 7.81 (1H, dd, J=8, 1.5 Hz), 8.08 (1H, d, J=8 Hz), 8.13 (1H, d, J=8.5 Hz); MS (ES+) m/z 328.
The following compound was obtained in a similar manner to that of Preparation 336.
1H-NMR (300 MHz, DMSO-d6) δ1.42-1.78 (7H, m), 2.24 (1H, m), 2.32 (3H, s), 2.36-2.53 (2H, m), 2.66 (1H, m), 2.79 (1H, m), 3.52 (1H, m), 3.55 (2H, s), 3.95 (1H, m), 4.30 (1H, m), 4.89 (1H, m), 6.60 (1H, d, J=15 Hz), 7.09-7.18 (3H, m), 7.26 (1H, m), 7.37 (1H, d, J=15 Hz), 7.76 (1H, d, J=6.5 Hz), 7.97 (1H, s), 8.09 (1H, s), 11.18 (1H, s); MS (ES+) m/z 438.
The following compound was obtained in a similar manner to that of Preparation 450.
1H-NMR (300 MHz, CDCl3) δ1.41 (3H, t, J=7 Hz), 1.43 (3×3H, s), 1.61 (1H, m), 2.16-2.39 (2H, m), 2.48-2.67 (2H, m), 2.81 (1H, m), 3.56 (2H, s), 4.02 (2H, q, J=7 Hz), 4.18 (1H, m), 4.96 (1H, m), 6.84 (2×1H, d, J=8.5 Hz), 7.21 (2×1H, d, J=8.5 Hz); MS (ES+) m/z 321.
The following compound was obtained in a similar manner to that of Preparation 452.
1H-NMR (300 MHz, CDCl3) δ1.41 (3H, t, J=7 Hz), 1.44-1.58 (3H, m), 2.19 (1H, dddd, J=13, 8.5, 8, 6 Hz), 2.27 (1H, dd, J=9, 4.5 Hz), 2.46 (1H, ddd, J=8.5, 8.5, 6 Hz), 2.68 (1H, ddd, J=8.5, 8.5, 6 Hz), 2.71 (1H, dd, J=9, 5.5 Hz), 3.49 (1H, m), 3.51 (1H, d, J=12.5 Hz), 3.56 (1H, d, J=12.5 Hz), 4.02 (2H, q, J=7 Hz), 6.84 (2×1H, d, J=8.7 Hz), 7.21 (2×1H, d, J=8.7 Hz); MS (ES+) m/z 221.
The following compound was obtained in a similar manner to that of Preparation 439.
1H-NMR (300 MHz, CDCl3) δ1.32 (3H, t, J=7 Hz), 1.41 (3H, t, J=7 Hz), 1.68 (1H, m), 2.28-2.44 (2H, m), 2.60-2.70 (2H, m), 2.88 (1H, m), 3.55 (1H, d, J=13 Hz), 3.59 (1H, d, J=13 Hz), 4.02 (2H, q, J=7 Hz), 4.25 (2H, q, J=7 Hz), 4.45 (1H, m), 5.24 (1H, d, J=7.5 Hz), 6.68 (1H, d, J=15.5 Hz), 6.85 (2×1H, d, J=8.5 Hz), 7.21 (2×1H, d, J=8.5 Hz), 7.56 (1H, d, J=15.5 Hz), 7.86 (1H, d, J=1 Hz), 8.04 (1H, d, J=1 Hz); MS (ES+) m/z 397.
The following compound was obtained in a similar manner to that of Preparation 336.
1H-NMR (300 MHz, DMSO-d6) δ1.31 (3H, t, J=7 Hz), 1.44-1.76 (7H, m), 2.21 (1H, m), 2.31-2.45 (2H, m), 2.63 (1H, m), 2.73 (1H, dd, J=9.5, 7 Hz), 3.33 (1H, m), 3.50 (2H, s), 3.53 (1H, m), 3.96 (1H, m), 3.98 (2H, q, J=7 Hz), 4.29 (1H, m), 4.89 (1H, m), 6.60 (1H, d, J=16 Hz), 6.85 (2×1H, d, J=8.5 Hz), 7.19 (2×1H, d, J=8.5 Hz), 7.37 (1H, d, J=15.5 Hz), 7.76 (1H, d, J=6.5 Hz), 7.96 (1H, s), 8.09 (1H, s), 11.09 (1H, s);
MS (ES+) m/z 468.
The following compound was obtained in a similar manner to that of Preparation 380.
MASS(API-ES); 312 (M+H)+
1H-NMR (200 MHz), (DMSO-d6, δ): 1.30-1.50 (9H, m), 1.65-2.25 (2H, m), 3.05-3.70 (4H,), 4.34 (2H, d, J=5.6 Hz), 4.30-4.50 (1H, m), 5.07 (1H, t, J=5.6 Hz), 6.68 (1H, d, J=6.1 Hz), 7.30 (1H, dd, J=1.7 Hz, J=12 Hz), 7.79 (1H, d, J=1.7 Hz).
The following compound was obtained in a similar manner to that of Preparation 405.
1H-NMR (300 MHz, CDCl3) δ1.48 (9H, s), 2.38-2.57 (2H, m), 3.22-3.47 (3H, m), 3.97 (1H, m), 4.10 (1H, d, J=12.5 Hz), 4.42 (1H, d, J=12.5 Hz), 5.20 (1H, m), 7.26 (1H, d, J=15.5 Hz), 7.36-7.45 (3H, m), 7.49 (1H, d, J=15.5 Hz), 7.49-7.58 (2H, m), 8.28 (1H, s), 8.60 (1H, s); MS (ES+) m/z 425.
The following compound was obtained in a similar manner to that of Preparation 414.
1H-NMR (300 MHz, DMSO-d6) δ1.35 (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 (1H, m), 4.78 (1H, m), 4.95 (1H, m), 6.97 (1H, d, J=15.5 Hz), 7.04 (2×1H, d, J=7 Hz), 7.14-7.28 (3H, m), 7.61 (1H, d, J=15.5 Hz), 8.58 (1H, s), 8.71 (1H, s), 11.51 (1H, br-s); MS (ES+) m/z 524.
The following compound was obtained in a similar manner to that of Preparation 439.
1H-NMR (300 MHz, CDCl3) δ 1.33 (3H, t, J=7 Hz), 1.72 (1H, m), 2.30-2.48 (2H, m), 2.64-2.86 (6H, m), 2.95 (1H, m), 4.25 (2H, q, J=7 Hz), 4.56 (1H, m), 5.73 (1H, d, J=7 Hz), 6.30 (1H, d, J=16 Hz), 7.14-7.34 (5H, m), 7.49 (1H, d, J=16 Hz), 8.45 (2×1H, s); MS (ES+) m/z 367.
The following compounds were obtained in a similar manner to that of Preparation 336.
MASS(API-ES); 442 (M+H)+,
1H-NMR (200 MHz), (CDCl3, δ): 1.50-2.00 (7H, m), 2.30-2.60 (2H, m), 2.70-3.10 (3H, m), 3.30-3.70 (1H, m), 3.72 (2H, s), 3.95-4.20 (1H, m), 4.40-4.60 (1H, m), 5.00-5.10 (1H, m), 6.89 (1H, d, J=39 Hz), 7.20-7.45 (5H, m), 7.89 (1H, d, J=1.3 Hz), 8.35 (1H, d, J=1.3 Hz).
MASS(API-ES); 442 (M+H)+,
1H-NMR (200 MHz), (CDCl3, δ): 1.50-2.00 (7H, m), 2.10-2.55 (2H, m), 2.65-2.85 (2H, m), 2.90-3.10 (1H, m), 3.60-3.80 (1H, m), 3.71 (2H, s), 3.95-4.15 (1H, m), 4.40-4.60 (1H, m), 5.07 (1H, s), 5.69 (1H, d, J=7.7 Hz), 6.60 (1H, d, J=25 Hz), 7.20-7.43 (5H, m), 7.77 (1H, d, J=1.0 Hz), 8.04 (1H, d, J=1.0 Hz).
The following compound was obtained in a similar manner to that of Preparation 311.
MASS(API-ES); 384 (M+H)+,
1H-NMR (400 MHz), (DMSO-d6, δ): 1.23 (3H, t, J=7.0 Hz), 1.70-1.90 (1H, m), 2.00-2.25 (1H, m), 2.30-2.83 (7H, m), 2.85-2.95 (1H, m), 4.16 (2H, q, J=7.0 Hz), 4.35-4.55 (1H, m), 6.43 (1H, d, J=16 Hz), 7.00-7.30 (6H, m), 7.55 (1H, dd, J=2.0 Hz, J=16 Hz), 7.85 (1H, dd, J=1.8 Hz, J=13 Hz), 8.11 (1H, d, J=1.8 Hz).
The following compound was obtained in a similar manner to that of Preparation 390.
MASS(API-ES); 346 (M+H)+.
The following compound was obtained in a similar manner to that of Preparation 397.
MASS(API-ES); 445 (M+H)+,
1H-NMR (200 MHz), (DMSO-d6, δ): 1.40-1.88 (7H, m), 2.00-2.25 (1H, m), 2.38-2.95 (6H, m), 3.43-3.62 (1H, m), 3.83-4.05 (1H, m), 4.20 (2H, t, J=6.6 Hz), 4.32-4.55 (1H, m), 4.88 (1H, s), 6.20 (1H, t, J=1.7 Hz), 6.26 (1H, d, J=16 Hz), 7.10 (1H, d, J=6.2 Hz), 7.39 (1H, d, J=16 Hz), 7.40 (1H, d, J=1.7 Hz), 7.57 (1H, d, J=12 Hz), 7.74 (1H, d, J=1.7 Hz), 8.04 (1H, s).
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 (1.35 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-pyrimidinyl)acrylate (494 mg) as a yellow powder.
1H-NMR (300 MHz, CDCl3) δ1.35 (3H, t, J=7 Hz), 4.30 (2H, q, J=7 Hz), 6.59 (1H, d, J=16 Hz), 7.58 (1H, d, J=16 Hz), 8.76 (2×1H, s); MS ( ) m/z not detected.
The following compound was obtained in a similar manner to that of Preparation 439.
1H-NMR (300 MHz, CDCl3) δ 1.32 (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 (1H, m), 2.26-2.40 (2H, m), 2.46 (0.5H, dd, J=10, 3 Hz), 2.56-2.72 (1.5H, m), 2.79 (0.5H, dd, J=10, 3 Hz), 3.04 (1H, m), 3.26 (1H, q, J=6.6 Hz), 4.24 (1H, q, J=7 Hz), 4.25 (11H, q, J=7 Hz), 4.42 (1H, 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=1 Hz), 7.90 (0.5H, d, J=1 Hz), 8.03 (0.5H, d, J=1 Hz), 8.06 (0.5H, d, J=1 Hz); MS (ES+) m/z 367.
The following compound was obtained in a similar manner to that of Preparation 390.
MASS(API-ES); 378 (M+H)+,
1H-NMR (200 MHz), (DMSO-d6, δ): 1.60-2.25 (2H, m), 2.30-2.70 (3H, m), 2.80-3.00 (1H, m), 3.69 (2H, s), 4.30-4.55 (1H, m), 6.31 (1H, d, J=16 Hz), 7.00-7.44 (4H, m), 7.45 (1H, d, J=16 Hz), 7.80 (1H, d, J=13 Hz), 8.05 (1H, s).
The following compound was obtained in a similar manner to that of Preparation 198.
1H NMR (DMSO-d6, δ): 1.24 (3H, t, J=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), 7.50 (1H, d, J=16.0 Hz), 7.73-7.81 (1H, m), 8.10 (1H, d, J=1.9 Hz), 8.27 (1H, d, J=1.9 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.
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), 3.91-4.10 (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), 7.50 (1H, d, J=15.9 Hz), 8.10 (1H, d, J=1.9 Hz), 8.27 (1H, d, J=1.9 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.
1H NMR (DMSO-d6, δ): 1.50-1.84 (10H, 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), 6.30 (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), 8.20 (1H, s), 8.49 (1H, d, J=4.2 Hz), 11.07 (1H, brs),
Mass (APCI): 472(M+H)+.
1H NMR (DMSO-d6, δ): 1.45-1.90(10H, 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), 6.30 (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.
1H-NMR (300 MHz, DMSO-d6) δ1.24 (3H, t, J=7 Hz), 1.89 (1H, m), 2.21 (1H, m), 3.04 (1H, m), 3.16-3.50 (4H, m), 4.14 (2H, q, J=7 Hz), 6.30 (1H, d, J=16 Hz), 6.62 (2H, d, J=8.5 Hz), 7.49 (2H, d, J=8.5 Hz), 7.50 (1H, 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.
1H-NMR (300 MHz, CDCl3) δ 0.80-0.97 (2H, m), 1.10-1.31 (3H, m), 1.32 (3H, t, J=7 Hz), 1.44 (1H, m), 1.58-1.84 (4H, m), 2.18-2.42 (4H, m), 2.56 (1H, dd, J=9.5, 3 Hz), 2.68 (1H, dd, J=9.5, 6.5 Hz), 2.78 (1H, m), 4.01 (1H, m), 4.24 (2H, q, J=7 Hz), 4.30 (1H, m), 6.21 (1H, d, J=15.8 Hz), 6.56 (2×1H, d, J=8.5 Hz), 7.36 (2H, d, J=8.5 Hz), 7.59 (1H, d, J=15.8 Hz); MS (ES+) m/z 357.
The following compound was obtained in a similar manner to that of Preparation 434.
1H-NMR (300 MHz, CDCl3) δ 1.10-2.12 (11H, m), 1.33 (3H, t, J=7 Hz), 2.18-2.42 (2H, m), 3.42 (1H, m), 3.55-3.70 (2H, m), 3.84 (1H, m), 4.06 (1H, m), 4.18 (1H, m), 4.24 (1H, q, J=7 Hz), 4.25 (1H, q, J=7 Hz), 6.23 (0.5H, d, J=15.8 Hz), 6.24 (0.5H, d, J=15.5 Hz), 6.58 (1H, d, J=7.7 Hz), 6.59 (1H, d, J=7.7 Hz), 7.38 (1H, d, J=7.7 Hz), 7.40 (1H, 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.
1H NMR (DMSO-d6, δ): 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 (1H, m), 4.15 (2H, q, J=7.4 Hz), 6.48 (1H, d, J=15.9 Hz), 6.59 (1H, d, J=7.8 Hz), 7.50 (1H, d, J=15.9 Hz), 8.09 (1H, d, J=1.9 Hz), 8.27 (1H, d, J=1.9 Hz),
Mass (ESI): 406(M+H)+.
The following compound was obtained in a similar manner to that of Preparation 405.
1H-NMR (300 MHz, CDCl3) δ1.16-2.43 (13H, m), 3.36-3.70 (3H, m), 3.83 (1H, m), 4.04-4.24 (1H, m), 6.24 (0.5H, d, J=15.8 Hz), 6.26 (0.5H, d, J=15.8 Hz), 6.59 (1H, d, J=8 Hz), 6.61 (1H, d, J=8 Hz), 7.40 (1H, d, J=8 Hz), 7.43 (1H, 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.
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 (1H, m), 6.19 (1H, br), 6.40 (1H, m), 6.61 (1H, d, J=8.5 Hz), 6.64 (1H, d, J=8.5 Hz), 7.28-7.41 (3H, m), 10.99 (1H, s); MS ( ) m/z not detected.
The following compounds were obtained in a similar manner to that of Preparation 62.
1H NMR (DMSO-d6): δ 1.50-1.90 (11H, 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 (1H, s), 6.30 (1H, d, J=15.9 Hz), 6.52 (1H, d, J=7.8 Hz), 7.02-7.16 (3H, m), 7.32-7.42 (2H, m), 7.84 (1H, s), 8.20 (1H, s), 11.07 (1H, brs),
Mass (ESI): 489(M+H)+.
1H NMR (DMSO-d6): δ 1.53-1.85 (18H, m), 1.93-2.20 (2H, m), 2.87-3.07 (4H, m), 3.49-0.355 (1H, m), 3.80-4.10 (2H, m), 4.87 (1H, s), 5.17-5.24 (1H, m), 6.31 (1H, d, J=15.9 Hz), 6.55 (1H, d, J=7.8 Hz), 7.35 (1H, d, J=15.9 Hz), 7.84 (1H, s), 8.20 (1H, s), 11.08 (1H, brs),
Mass (ESI): 449(M+H)+.
1H NMR (DMSO-d6, δ): 0.78-0.90 (2H, m), 1.14-1.30 (3H, m), 1.46-2.08 (20H, m), 2.78-2.83 (2H, m), 3.49-3.55 (1H, m), 3.80-4.05 (2H, m), 4.88 (1H, s), 6.30 (1H, d, J=15.9 Hz), 6.49 (1H, d, J=7.8 Hz), 7.35 (1H, d, J=15.9 Hz), 7.83 (1H, s), 8.20 (1H, s), 11.07 (1H, brs).
Mass (ESI): 477(M+H)+.
The following compound was obtained in a similar manner to that of Preparation 370.
1H-NMR (300 MHz, CDCl3) δ1.38 (3H, t, J=7 Hz), 2.36 (3H, s), 4.35 (2H, q, J=7 Hz), 6.75 (1H, d, J=9 Hz), 6.89 (1H, br-s), 7.15-7.26 (4H, m), 8.03 (1H, dd, J=9, 2.5 Hz), 8.82 (1H, d, J=2.5 Hz); MS (ES+) m/z 257.
The following compound was obtained in a similar manner to that of Preparation 361.
1H-NMR (300 MHz, CDCl3) δ 2.33 (3H, s), 4.58 (2H, s), 6.54 (1H, br-s), 6.82 (1H, d, J=8.5 Hz), 7.11-7.22 (4H, m), 7.52 (1H; dd, J=8.5, 2.5 Hz), 8.14 (1H, d, J=2.5 Hz); MS (ES+) m/z 215.
The following compound was obtained in a similar manner to that of Preparation 382.
1H-NMR (300 MHz, CDCl3) δ 2.37 (3H, s), 6.79 (1H, d, J=8.5 Hz), 7.15 (1H, br-s), 7.18-7.30 (4H, m), 7.94 (1H, dd, J=8.5, 2 Hz), 8.60 (1H, d, J=2 Hz), 9.83 (1H, s); MS (ES+) m/z 213.
The following compound was obtained in a similar manner to that of Preparation 683.
1H-NMR (300 MHz, DMSO-d6) δ 2.25 (3H, s), 6.35 (1H, d, J=16 Hz), 6.81 (1H, d, J=8.5 Hz), 7.10 (2×1H, d, J=8.5 Hz), 7.51 (1H, d, J=16 Hz), 7.58 (2H, d, J=8.5 Hz), 7.93 (1H, dd, J=8.5, 2 Hz), 8.35 (1H, d, J=2 Hz), 9.33 (1H, s); MS (ES+) m/z 255.
The following compound was obtained in a similar manner to that of Preparation 414.
1H-NMR (300 MHz, DMSO-d6) δ 1.45-1.78 (6H, m), 2.25 (3H, s), 3.53 (1H, m), 3.96 (1H, m), 4.89 (1H, m), 6.32 (1H, d, J=16 Hz), 6.83 (1H, d, J=8.8 Hz), 7.10 (2H, d, J=8.5 Hz), 7.42 (1H, d, J=16 Hz), 7.57 (2H, d, J=8.5 Hz), 7.76 (1H, br-d, J=8.8 Hz), 8.30 (1H, d, J=1.5 Hz), 9.29 (1H, s), 11.13 (1H, br-s); MS (ES+) m/z 354.
The following compound was obtained in a similar manner to that of Preparation 674.
1H-NMR (300 MHz, CDCl3) δ1.39 (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 (1H, d, J=8.8 Hz), 6.89-7.06 (3H, m), 7.28 (1H, s), 8.03 (1H, dd, J=7.5, 2 Hz), 8.07 (1H, dd, J=8.8, 2.2 Hz), 8.89 (1H, d, J=2.2 Hz); MS (ES+) m/z 287.
The following compound was obtained in a similar manner to that of Preparation 361.
1H-NMR (300 MHz, CDCl3) δ1.45 (3H, t, J=7, Hz), 1.71 (1H, br), 4.11 (2H, q, J=7 Hz), 4.60 (2H, s), 6.86-6.99 (4H, m), 7.05 (1H, s), 7.56 (1H, dd, J=8.5, 2.5 Hz), 7.97 (1H, m), 8.20 (1H, d, J=2.5 Hz); MS (ES+) m/z 245.
The following compound was obtained in a similar manner to that of Preparation 414.
1H-NMR (300 MHz, DMSO-d6) δ 1.35 (3H, t, J=7 Hz), 1.46-1.78 (6H, m), 3.53 (1H, m), 3.96 (1H, m), 4.10 (2H, q, J=7 Hz), 4.89 (1H, m), 6.33 (1H, d, J=16 Hz), 6.87-7.07 (4H, m), 7.42 (1H, d, J=16 Hz), 7.77 (1H, m), 8.08 (1H, dd, J=8, 1 Hz), 8.29 (1H, d, J=2 Hz), 8.37 (1H, s), 11.13 (1H, s); MS (ES+) m/z 384.
The following compound was obtained in a similar manner to that of Preparation 382.
1H-NMR (300 MHz, CDCl3) δ 1.46 (3H, t, J=7 Hz), 4.13 (2H, q, J=7 Hz), 6.88 (1H, d, J=8.8 Hz), 6.91-7.11 (3H, m), 7.43 (1H, s), 7.97 (1H, dd, J=8.8, 2.2 Hz), 8.09 (1H, dd, J=7.7, 1.8 Hz), 8.66 (1H, d, J=2.2 Hz), 9.86 (1H, s); MS (ES+) m/z 243.
The following compound was obtained in a similar manner to that of Preparation 683.
1H-NMR (300 MHz, DMSO-d6) δ1.35 (3H, t, J=7 Hz), 4.10 (2H, q, J=7 Hz), 6.37 (1H, d, J=16 Hz), 6.86-7.07 (4H, m), 7.50 (1H, d, J=16 Hz), 7.93 (1H, dd, J=8.8, 2.2 Hz), 8.09 (1H, dd, J=8, 1.4 Hz), 8.33 (1H, d, J=2.2 Hz), 8.42 (1H, s); MS (ES+) m/z 285.
The following compound was obtained in a similar manner to that of Preparation 405.
1H-NMR (300 MHz, DMSO-d6) δ 0.82-1.03 (2H, m), 1.04-1.32 (3H, m), 1.54-2.02 (7H, m), 2.24-2.46 (1H, m), 2.83-3.45 (5H, m), 3.56-4.34 (2H, m), 6.21 (1H, d, J=16 Hz), 6.61 (2H, d, J=8.5 Hz), 6.69 (1H, m), 7.46 (2H, d, J=8.5 Hz), 7.46 (1H, d, J=16 Hz), 10.29 (1H, br), 12.00 (1H, s); MS (ES+) m/z 329.
The following compound was obtained in a similar manner to that of Preparation 363.
1H-NMR (300 MHz, CDCl3) δ 0.78-0.96 (2H, m), 1.06-1.40 (5H, m), 1.40-1.84 (11H, m), 2.00-2.25 (3H, m), 2.38-2.64 (3H, m), 3.96 (1H, br peak), 4.25 (2H, q, J=7.1 Hz), 5.49 (1H, br peak), 6.21 (1H, d, J=15.9 Hz), 6.39 (1H, d, J=8.8 Hz), 7.57 (1H, d, J=15.9 Hz), 7.61 (1H, dd, J=8.7, 2.4 Hz), 8.19 (1H, d, J=2.2 Hz).
The following compound was obtained in a similar manner to that of Preparation 414.
1H-NMR (300 MHz, DMSO-d6) δ 0.74-0.91 (2H, m), 1.04-1.30 (3H, m), 1.40 (1H, m), 1.46-1.81 (12H, m), 2.11-2.29 (3H, m), 2.33 (1H, dd, J=9, 4.5 Hz), 2.42 (1H, m), 2.56 (1H, m), 2.75 (1H, dd, J=9, 7 Hz), 3.53 (1H, m), 3.82-4.01 (2H, m), 4.87 (1H, m), 6.16 (1H, br-d, J=16 Hz), 6.29 (1H, d, J=6.5 Hz), 6.56 (2H, d, J=8.8 Hz), 7.26-7.38 (3H, m), 10.97 (1H, s); MS (ES+) m/z 428.
The following compound was obtained in a similar manner to that of Preparation 361.
1H-NMR (300 MHz, CDCl3) δ1.62 (1H, t, J=4 Hz), 1.88 (1H, m), 2.72 (1H, m), 2.84-3.10 (2H, m), 4.57 (2H, d, J=4 Hz), 5.25 (1H, br-d, J=8 Hz), 5.70 (1H, ddd, J=8, 7.5, 7.5 Hz), 7.17-7.37 (4H, m), 7.57 (1H, d, J=2 Hz), 8.05 (1H, d, J=2 Hz); MS (ES+) m/z 275.
The following compound was obtained in a similar manner to that of Preparation 382.
1H-NMR (300 MHz, CDCl3) δ1.94 (1H, m), 2.74 (1H, m), 2.85-3.13 (2H, m), 5.76-5.92 (2H, m), 7.18-7.38 (4H, m), 7.98 (1H, d, J=2 Hz), 8.51 (1H, d, J=2 Hz), 9.80 (1H, s); MS (ES+) m/z 273.
The following compound was obtained in a similar manner to that of Preparation 683
1H-NMR (300 MHz, CDCl3) δ1.92 (1H, m), 2.74 (1H, m), 2.86-3.12 (2H, m), 5.58 (1H, d, J=8 Hz), 5.76 (1H, ddd, J=8, 7.5, 7.5 Hz), 6.26 (1H, d, J=15.7 Hz), 7.19-7.40 (4H, m), 7.66 (1H, d, J=15.7 Hz), 7.73 (1H, d, J=1.8 Hz), 8.22 (1H, d, J=1.8 Hz); MS (ES+) m/z 315.
The following compound was obtained in a similar manner to that of Preparation 414.
1H-NMR (300 MHz, DMSO-d6) δ1.44-1.76 (1H, m), 2.08 (1H, m), 2.76-3.15 (3H, m), 3.53 (1H, m), 3.95 (1H, m), 4.90 (1H, m), 5.78 (1H, ddd, J=8, 7.5, 7.5 Hz), 6.35 (1H, d, J=16 Hz), 7.06 (1H, d, J=8.5 Hz), 7.13-7.32 (5H, m), 7.40 (1H, d, J=16 Hz), 7.90 (1H, s), 8.26 (1H, s), 11.11 (1H, br-s); MS (ES+) m/z 414.
The following compound was obtained in a similar manner to that of Preparation 390.
MASS(API-ES); 341 (M+H)+.
1H-NMR (200 MHz), (DMSO-d6, δ): 1.55-1.86 (1H, m), 2.07-2.73 (4H, m), 2.77-2.93 (1H, m), 3.57, 3.64 (2H, ABq, J=13 Hz), 3.90-4.10 (1H, m), 5.99 (1H, d, J=5.2 Hz), 6.26 (1H, d, J=16 Hz), 6.67 (1H, t, J=8.8 Hz), 7.10-7.37 (7H, m), 7.43 (1H, d, J=16 Hz).
The following compound was obtained in a similar manner to that of Preparation 397.
MASS(API-ES); 440 (M+H)+,
1H-NMR (200 MHz), (DMSO-d6, δ): 1.39-1.89 (7H, m), 2.07-2.33 (1H, m), 2.36-2.70 (3H, m), 2.75-2.93 (1H, m), 3.44-3.70 (3H, m), 3.83-4.12 (2H, m), 4.88 (1H, s), 5.90 (1H, d, J=5.3 Hz), 6.23 (1H, d, J=16 Hz), 6.69 (1H, t, J=8.9 Hz), 7.11-7.44 (8H, n).
The following compound was obtained in a similar manner to that of Preparation 198.
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), 7.50 (1H, d, J=15.9 Hz), 8.10 (1H, d, J=1.9 Hz), 8.27 (1H, d, J=1.99 Hz),
Mass (APCI): 418(M+H)+.
The following compounds were obtained in a similar manner to that of Preparation 62.
1H NMR (DMSO-d6, δ): 1.45-1.90(10H, 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), 6.30 (1H, d, J=15.9 Hz), 6.52 (1H, d, J=7.9 Hz), 7.25-7.41 (5H, m), 7.84 (1H, s), 8.20 (1H, s), 11.07 (1H, brs),
Mass (APCI): 505(M+H)+.
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), 6.30 (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.
1H NMR (DMSO-d6, δ): 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 (1H, m), 4.16 (2H, q, J=7.4 Hz), 5.15-5.22 (1H, m), 6.47 (1H, d, J=15.9 Hz), 6.62 (1H, d, J=7.9 Hz), 7.50 (1H, d, J=15.9 Hz), 8.10 (1H, d, J=1.9 Hz), 8.27 (1H, d, J=1.9 Hz),
Mass (ESI): 378(M+H)+.
The following compound was obtained in a similar manner to that of Preparation 414.
1H-NMR (300 MHz, CDCl3) δ1.50-1.95 (10H, m), 2.50-2.62 (4H, m), 3.67 (1H, m), 3.71 (2H, s), 3.97 (1H, m), 5.00 (1H, m), 6.30 (1H, br), 6.97 (1H, ddd, J=7.5, 7.5, 1 Hz), 7.15 (1H, dd, J=7.5, 1 Hz), 7.31 (1H, dd, J=7.5, 7.5 Hz), 7.64 (1H, d, j=15.5 Hz), 7.74 (1H, d, J=2 Hz), 8.24 (1H, d, J=2 Hz), 8.34 (1H, d, J=7.5 Hz), 8.36 (1H, br), 10.95 (1H, s); MS ( ) m/z not detected.
The following compound was obtained in a similar manner to that of Preparation 62.
1H NMR (DMSO-d6, δ): 1.53-1.84 (10H, 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), 6.30 (1H, d, J=15.9 Hz), 6.52 (1H, d, J=7.9 Hz), 7.32-7.39 (2H, m), 7.68-7.72 (1H, m), 7.84 (1H, s), 8.20 (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.
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), 7.50 (1H, d, J=15.9 Hz), 8.09 (1H, d, J=1.9 Hz), 8.27 (1H, d. J=1.9 Hz),
Mass (APCI): 418(M+H)+.
The following compound was obtained in a similar manner to that of Preparation 62.
1H NMR (DMSO-d6, δ): 1.53-1.85 (10H, m), 2.03-2.14 (2H, m), 2.77-2.83 (2H, m), 3.50-3.54 (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), 8.20 (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.
1H NMR (DMSO-d6, δ): 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), 7.50 (1H, d, J=15.9 Hz), 7.68-7.73 (1H, m), 8.09 (1H, d, J=1.9 Hz), 8.27 (1H, d, J=1.9 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.
1H-NMR (300 MHz, DMSO-d6) δ 1.72-1.86 (4H, m), 2.44-2.58 (4H, m), 3.73 (2H, s), 6.52 (1H, d, J=16 Hz), 6.98 (1H, dd, J=7.5, 7.5 Hz), 7.23 (1H, d, J=7.5 Hz), 7.29 (1H, dd, J=7.5, 7.5 Hz), 7.52 (1H, d, J=7.5 Hz), 8.28 (1H, d, J=2 Hz), 8.33 (1H, d, J=7.5 Hz), 8.39 (1H, d, J=2 Hz), 10.97 (1H, s); MS (ES+) m/z 358.
The following compound was obtained in a similar manner to that of Preparation 361.
1H-NMR (300 MHz, CDCl3) δ1.77-1.88 (4H, m), 2.50-2.60 (4H, m), 3.70 (2H, s), 4.59 (2H, s), 6.92 (1H, ddd, J=7.5, 7.5, 1.5 Hz), 7.14 (1H, dd, J=7.5, 1.5 Hz), 7.30 (1H, m), 7.64 (1H, d, J=2 Hz), 8.07 (1H, d, J=2 Hz), 8.32 (1H, d, J=7.5 Hz), 10.56 (1H, s); MS (ES+) m/z 318.
The following compound was obtained in a similar manner to that of Preparation 382.
1H-NMR (300 MHz, CDCl3) 1.76-1.91 (4H, m), 2.49-2.62 (4H, m), 3.74 (2H, s), 7.04 (1H, ddd, J=7.5, 7.5, 1.5 Hz), 7.18 (1H, d, J=7.5 Hz), 7.35 (1H, ddd, J=7.5, 7.5, 1.5 Hz), 8.03 (1H, d, J=2 Hz), 8.38 (1H, d, J=7.5 Hz), 8.52 (1H, d, J=2 Hz), 9.82 (1H, s), 11.39 (1H, br-s); MS-(ES+) m/z 316.
The following compound was obtained in a similar manner to that of Preparation 714.
MASS(API-ES); 369 (M+H)+
1H-NMR (200 MHz), (DMSO-d6, δ): 1.23 (3H, t, J=7.1 Hz), 1.63-1.87 (1H, m), 2.08-2.33 (1H, m), 2.37-2.70 (3H, m), 2.75-2.90 (1H, m), 3.55, 3.62 (2H, ABq, J=13 Hz), 3.88-4.11 (1H, m), 4.15 (2H, q, J=7.1 Hz), 6.02 (1H, d, J=5.1 Hz), 6.34 (1H, d, J=16 Hz), 6.67 (1H, t, J=8.8 Hz), 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.
MASS(API-ES); 301 (M+H)+,
1H-NMR (200 MHz), (DMSO-d6, δ): 1.52-1.86 (1H, m), 2.05-2.31 (1H, m), 2.32-2.69 (3H, m), 2.71-2.88 (1H, m), 3.46-3.68 (2H, m), 3.81-4.05 (1H, m), 4.32 (2H, d, J=5.6 Hz), 4.98 (1H, t, J=5.6 Hz), 5.15 (1H, d, J=5.7 Hz), 6.62 (1H, t, J=8.7 Hz), 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.
MASS(API-ES); 329 (M+H)+
1H-NMR (200 MHz), (DMSO-d6, δ): 1.64-1.94 (1H, m), 2.06-2.35 (1H, m), 2.38-2.95 (4H, m), 3.55, 3.63 (2H, ABq, J=13 Hz), 3.76 (3H, s), 3.92-4.14 (1H, m), 6.30 (1H, d, J=6.8 Hz), 6.74 (1H, t, J=8.7 Hz) 7.16-7.38 (5H, m), 7.49 (1H, dd, J=1.9 Hz, J=13 Hz), 7.60 (1H, dd, J=1.9 Hz, J=8.7 Hz).
The following compounds were obtained in a similar manner to that of Preparation 703.
1H-NMR (300 MHz, CDCl3) δ 1.33 (3H, t, J=7 Hz), 1.47(9H, s), 1.92 (1H, m), 2.20 (1H, m), 3.26 (1H, m), 3.38-3.56 (2H, m), 3.71 (1H, m), 4.00-4.12 (2H, m), 4.24 (2H, q, J=7 Hz), 6.23 (1H, d, J=16 Hz), 6.57 (2H, d, J=8.5, Hz), 7.38 (2H, d, J=8.5 Hz), 7.60 (1H, d, J=16 Hz).
1H-NMR (300 MHz, CDCl3) δ 1.34 (3H, t, J=7 Hz), 2.47 (3H, s), 4.26 (2H, q, J=7 Hz), 6.34 (1H, d, J=15.7 Hz), 6.64 (1H, s), 6.68 (1H, d, J=7.5 Hz), 6.76 (1H, d, J=7.5 Hz), 7.37 (2H, d, J=9 Hz), 7.45 (1H, dd, J=7.5, 7.5 Hz), 7.48 (2H, d, J=9 Hz), 7.64 (1H, d, J=15.7 Hz); MS (ES+) m/z 283.
To a stirred solution of ethyl (2E)-3-(2-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-5-pyrimidinyl)acrylate (384 mg) in acetonitrile (5 mL) 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 80° C. 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 (300 MHz, CDCl3) δ 0.66-0.86 (2H, m), 1.04-1.72 (9H, m), 1.35 (3×3H, t, J=7 Hz), 1.46 (9H, s), 2.06-2.30 (4H, m), 2.54 (2H, t, J=7 Hz), 2.70 (1H, dd, J=9, 7 Hz), 2.84 (1H, dd, J=9, 8 Hz), 4.29 (2H, q, J=7 Hz), 4.96 (1H, m), 6.54 (1H, d, J=16 Hz), 7.59 (H, d, J=16 Hz), 8.80 (2×1H, s); MS (ES+) m/z 459
To a solution of ethyl (2E)-3-[5-chloro-6-(4-piperidinylamino)-3-pyridinyl]acrylate dihydrochloride (500 mg) in DMF (5 ml) was added 1-chloro-3-(chloromethyl)benzene (0.173 ml) and N,N-diisopropylethylamine (0.91 ml), the mixture was stirred at 70° C. for 7 hour. The mixed solution was poured into a mixture of water (30 ml) and AcOEt (30 ml). 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-{[1-(3-chlorobenzyl)-4-piperidinyl]amino}-3-pyridinyl)acrylate (261 mg, 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), 7.50 (1H, d, J=15.9 Hz), 8.09 (1H, d, J=1.9 Hz), 8.27 (1H, d, J=1.9 Hz).
Mass (APCI): 434(M+H)+.
The following compound was obtained in a similar manner to that of Preparation 860.
1H NMR (DMSO-d6, δ): 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), 3.90-4.15 (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), 7.50 (1H, d, J=15.9 Hz), 8.10 (1H, d, J=1.9 Hz), 8.28 (1H, d, J=1.9 Hz).
Mass (APCI): 434(M+H)+.
To a solution of ethyl (2E)-3-(5-chloro-6-{[1-(4-pyridinylmethyl)-4-piperidinyl]amino}-3-pyridinyl)acrylate (308 mg) in THF (3 ml) and MeOH (3 ml) was added 1N NaOHaq (2.3 ml), the mixture was stirred at 80° C. for 1 hour. The pH of the mixture was adjusted to ca.4.5 with 1N HClaq. The solution was evaporated under reduced pressure to give crude (2E)-3-(5-chloro-6-{[1-(4-pyridinylmethyl)-4-piperidinyl]amino}-3-pyridinyl)acrylic acid (469 mg, 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.
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)+.
1H NMR (DMSO-d6, δ): 1.80-2.10 (4H, m), 2.60-3.20 (4H, m), 3.16 (2H, s), 6.40 (1H, d, J=15.9 Hz), 6.79 (1H, brs), 7.23-7.71 (5H, m), 8.07 (1H, d, J=1.9 Hz), 8.25 (1H, d, J=1.9 Hz),
Mass (ESI): 390(M+H)+.
1NMR (DMSO-d6, δ): 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 (1H, d, J=7.9 Hz), 7.28 (1H, d, J=15.7 Hz), 7.35-7.39 (1H, 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)+.
1H NMR (DMSO-d6, δ): 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=1.9 Hz), 8.62 (1H, d, J=1.9 Hz),
Mass (APCI): 406(M+H)+.
1H (DR (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 (1H, m), 5.58 (1H, d, J=15.9 Hz), 6.85 (1H, d, J=15.9 Hz), 7.01-7.17 (4H, m), 7.30-7.41 (1H, m), 7.44 (1H, d, J=1.9 Hz),
Mass (ESI): 390(M+H)+.
Mass (APCI): 378(M+H)+.
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 (1H, m), 5.16-5.23 (1H, m), 6.37 (1H, d, J=15.9 Hz), 6.55 (1H, d, J=7.9 Hz), 7.40 (1H, d, J=15.9 Hz), 8.03 (1H d, J=1.9 Hz), 8.22 (1H, d, J=1.9 Hz),
Mass (ESI): 350(M+H)+.
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 (1H, 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=1.9 Hz), 8.23 (1H, d, J=1.9 Hz),
Mass (APCI): 406(M+H)+.
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 10° C. 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-1H-inden-2-ylamino)nicotinate (420 mg) as a pale tan solid.
1H-NMR (300 MHz, CDCl3) δ 1.37 (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 (1H, m), 5.59 (1H, br-d, J=3 Hz), 7.17-7.25 (4H, m), 8.02 (1H, d, J=2 Hz), 8.73 (1H, d, J=2 Hz); MS (ES+) m/z 317.
The following compounds were obtained in a similar manner to that of Preparation 871.
1H-NMR (300 MHz, CDCl3) δ1.38 (3H, t, J=7 Hz), 2.35 (3H, s), 4.35 (2H, Hz), 8.14 (1H, d, J=2 Hz), 8.75 (1H, d, J=2 Hz); MS (ES+) m/z 291.
1H-NMR (300 MHz, CDCl3) 1.39 (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 (1H, m), 6.98-7.05 (2H, m), 8.15 (1H, d, J=2 Hz), 8.27 (1H, br-s), 8.66 (1H, m), 8.82 (11H, d, J=2 Hz); MS (ES+) m/z 321.
1H-NMR (300 MHz, CDCl3)(1.38 (3H, t, J=7 Hz), 1.92 (1H, m), 2.74 (1H, m), 2.87-3.12 (2H, m), 4.35 (2H, q, J=7 Hz), 5.63 (1H, br-d, J=8 Hz), 5.80 (1H, ddd, J=8, 7.5, 7.5 Hz), 7.19-7.36 (4H, m), 8.06 (1H, d, J=2 Hz), 8.75 (1H, d, J=2 Hz); MS (ES+) m/z 317.
1H-NMR (300 MHz, CDCl3) δ1.39 (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, J=7 Hz), 6.99 (1H, ddd, J=7.5, 7.5, 1.5 Hz), 7.16 (1H, dd, J=7.5, 1.5 Hz), 7.32 (1H, ddd, J=7.5, 7.5, 1.5 Hz), 8.12 (1H, d, J=2 Hz), 8.36 (1H, dd, J=7.5, 1.5 Hz), 8.76 (1H, d, J=2 Hz), 11.07 (1H, s); MS (ES+) m/z 360.
A mixture of ethyl 1-(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 reaction 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-(1-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 (1H, br-d, J=8 Hz), 7.09 (1H, br-dd, J=8, 8 Hz); MS (ES+) m/z 177.
To a solution of 5,6-dichloronicotinic acid (7.0, 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)-1-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/1-4˜1-3) to give ethyl 6-{[(3R)-1-benzyl-3-piperidinyl]amino}-5-chloronicotinate (6.75 g, 52%) as a powder.
1H-NMR (300 MHz, CDCl3) δ1.36 (3H, t, J=7.1 Hz), 1.51-1.69 (2H, m), 1.69-1.88 (2H, m), 2.18-2.33 (1H, m), 2.41-2.54, (1H, m), 2.54-2.67 (1H, m), 2.67-2.79 (1H, m), 3.45 (1H, d, J=13 Hz), 3.61 (1H, d, J=13 Hz), 4.32 (2H, q, J=7.1 Hz), 6.24 (1H, br peak), 7.21-7.41 (5H, m), 8.00 (1H, d, J=2 Hz), 8.65 (1H, d, J=2 Hz); MS (ES+) m/z 374.
A solution of 10% HCl-MeOH solution (0.75 ml) was added to a mixture of (2E)-3-{6-[(1-benzyl-3-pyrrolidinyl)amino]-3-pyridyl}-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (170 mg) in MeOH 3 ml) 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-[(1-benzyl-3-pyrrolidinyl)amino]-3-pyridyl}-N-hydroxyacrylamide dihydrochloride (107 mg)
NMR (DMSO-d6, δ): 2.04-2.40 (2H, m), 3.18-3.83 (4H, m), 4.43-4.58 (2H, m), 4.80 (1H, m), 6.42 (1H, d, J=15.80 Hz), 7.04 (1H, d, J=9.20 Hz), 7.25 (1H, d, J=9.20H), 7.40-7.46 (4H, m), 7.65-7.70 (2H, m), 8.01-8.10 (1H, m), 8.18 (1H, s), 11043-11.78 (1H m)
The following compounds were obtained according to a similar manner to that of Example 1.
NMR (DMSO-d6, δ): 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 (1H, m), 6.38-6.50 (1H, m), 7.03-7.19 (1H, m), 7.38-7.47 (4H, m), 7.64-7.69 (2H, m), 7.98-8.07 (1H, m), 8.26 (1H, s)
NMR (DMSO-d6, δ): 1.99-2.50 (2H, m), 3.25-3.83 (4H, m), 4.43, 4.55 (2H, ABq, J=5.38 Hz), 4.77 (1H, m), 6.36-6.45 (1H, m), 6.99 (0.5H, d, J=9.00 Hz), 7.19 (0.5H d, J=9.00 Hz), 7.74-7.46 (4H, m), 7.63-7.66 (2H, m), 7.98-8.06 (1H, m), 8.18 (1H, s)
NMR (DMSO-d6, δ): 2.06-2.62 (2H, m), 3.26-3.83 (4H, m), 4.44, 4.56 (2H, ABq, J=5.48 Hz), 4.79 (1H, m), 6.42 (1H, d, J=15.72 Hz), 7.02 (0.5H, d, J=9.16 Hz), 7.22 (0.5H, d, J=9.16 Hz), 7.40-7.46 (4H, i), 7.64-7.70 (2H, m), 8.00-8.08 (1H, m), 8.18 (1H, s)
NMR (DMSO-d6, δ): 1.91-2.16 (1H, m), 2.30-2.40 (1H, m), 3.08-3.68 (4H, m), 4.41 (2H, d, J=5.56 Hz), 4.70-4.89 (1H, m), 6.38 (1H, d, J=15.82 Hz), 7.34 (1H, d, J=15.82 Hz), 7.30-7.46 (3H, m), 7.62-7.66 (2H, m), 7.91 (1H; s), 8.21 (1H, s)
NMR (DMSO-d6, δ): 1.95-2.16 (2H, m), 3.06-3.70 (4H, m), 4.41 (2H, d, J=5.50 Hz), 4.70-4.89 (1H, m), 6.39 (1H, d, J=15.82 Hz), 7.35 (1H, d, J=15.82 Hz), 7.39-7.51 (4H, m), 7.62-7.66 (2H, m), 7.91 (1H, s), 8.21 (1H, s)
NMR (DMSO-d6, δ): 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 (1H, m), 6.40 (1H, dd, J=3.0 Hz, J=16 Hz), 6.90-7.21 (3H, m), 7.35-7.62 (3H, m), 7.95-8.08 (1H, m), 8.18 (1H, s), 8.70-10.40 (1H, m), 11.10-11.60 (1H,
MASS(API-ES); 369 (M+H)+Free
NMR (DMSO-d6, δ): 1.95-2.90 (2H, m), 3.10-3.90 (4H, m), 4.40-4.90 (3H, m), 6.40 (1H, dd, J=2.5 Hz, J=16 Hz), 6.90-7.35 (3H, m), 7.42 (1H, dd, J=2.5 Hz, J=16 Hz), 7.60-7.80 (2H, m), 7.90-8.10 (1H, m), 8.18 (1H, s), 8.70-10.40 (1H, m), 11.30-11.80 (1H, m)
MASS(API-ES); 357 (M+H)+Free
NMR (DMSO-d6, δ): 1.90-2.80 (2H, m), 3.10-3.90 (4H, m), 4.35-4.85 (3H, m), 6.40 (1H, dd, J=2.0 Hz, J=16 Hz), 6.95-7.25 (1H, m), 7.44 (1H, dd, J=2.0 Hz, J=16 Hz), 7.48-7.60 (2H, m), 7.64-7.80 (2H, m), 7.95-8.10 (1H, m), 8.18 (1H, s), 8.80-10.40 (1H, m), 11.40-11.80 (1H, m)
MASS(API-ES); 373 (M+H)+, 375 (M+H+2)+Free
MASS(API-ES); 353 (M+H)+Free
NMR (DMSO-d6, δ): 1.95-2.75 (2H, m), 2.32 (3H, s), 3.10-3.90 (4H, m), 4.25-4.90 (3H, m), 6.40 (1H, dd, J=2.8 Hz, J=16 Hz), 6.95-7.30 (3H, m), 7.43 (1H, dd, J=2.5 Hz, J=16 Hz), 7.47-7.60 (2H, m), 7.95-8.10 (1H, m), 8.18 (1H, s), 8.80-10.30 (1H, m), 11.20-11.70 (1H, m)
NMR (DMSO-d6, δ): 0.30-0.70 (4H, m), 1.00-1.30 (1H, m), 1.95-2.80 (2H, m), 3.00-4.10 (6H, m), 4.55-4.90 (1H, m), 6.44 (1H, d, J=16 Hz), 7.05-7.30 (1H, m), 7.45 (1H, d, J=16 Hz), 8.07 (1H, d, J=9.3 Hz), 8.20 (1H, s), 9.20-10.60 (1H, m), 11.00-11.40 (1H, m)
MASS(API-ES); 303 (M+H)+Free
NMR (DMSO-d6, δ): 1.90-2.40 (2H, m), 3.20-4.00 (4H, m), 4.40-4.80 (1H, m), 6.25-6.42 (1H, m), 7.04 (1H, br), 7.25-7.60 (6H, m), 7.85-8.00 (1H, m), 8.10-8.30 (1H, m)
MASS(API-ES); 387 (M+H)+Free, 389
NMR (DMSO-d6, δ): 0.60-0.80 (4H, m), 1.60-1.85 (1H, m), 1.90-2.40 (2H, m), 3.20-4.10 (4H, m), 4.45-5.00 (1H, m), 6.35 (1H, d, J=16 Hz), 7.01 (1H, br), 7.35 (1H, d, J=16 Hz), 7.91 (1H, s), 8.23 (1H, s)
MASS(API-ES); 351 (M+H)+Free
NMR (DMSO-d6, δ): 1.30-1.60 (2H, m), 1.85-2.10 (2H, m), 2.90-4.50 (5H, m), 6.40 (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)
NMR (DMSO-d6, 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)+
NMR (DMSO-d6, δ): 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, 37=16.0 Hz), 7.10 (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)+
NMR (DMSO-d6, δ): 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), 7.10 (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)+
NMR (DMSO-d6, 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), 6.40 (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), 9.30 (1H, brs)
Mass (ESI): 432(M+H)+
NMR (DMSO-d6, δ): 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), 10.81 (1H, brs)
Mass (ESI): 416(M+H)+
NMR (DMSO-d6, δ): 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), 6.40 (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 (1H, s)
Mass (ESI): 396(M+H)+
NMR (DMSO-d6, δ): 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)+
NMR (DMSO-d6, δ): 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), 8.20 (1H, s)
NMR (DMSO-d6, δ): 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)
1H NMR (DMSO-d6, δ): 1.45-2.10 (4H, m), 2.70-3.30 (2H, m), 3.40-3.70 (1H, m), 6.35 (1H, d, J=16.0 Hz), 6.89 (1H, brs), 7.31-7.57 (5H, m), 7.95 (1H, s), 8.20 (1H, s)
NMR (DMSO-d6, δ): 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)
(2E)-3-(5-Chloro-6-{[1-(4-phenoxybenzoyl)-4-piperidyl]amino}-3-pyridyl)-N-hydroxyacrylamide hydrochloride
NMR (DMSO-d6, δ): 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, d, J=16.0 Hz), 7.01-7.48 (11H, m), 7.97 (1H, s), 8.20 (1H, s)
Mass (ESI): 493(M+H)+
NMR (DMSO-d6, δ): 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)+
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), 7.90 (1H, s), 8.18 (1H, s), 11.04 (1H, brs)
Mass (APCI): 406(M+H)+
A solution of 10% HCl-MeOH solution (0.5 ml) was added to a mixture of (2E)-3-{6-[(1-benzyl-4-piperidyl)amino]-3-pyridyl}-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (180 mg) in MeOH (5 ml) 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-[(1-benzyl-4-piperidyl)amino]-3-pyridyl}-N-hydroxyacrylamide dihydrochloride (120 mg)
1H-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 (1H, s), 7.08 (1H, d, J=18.8 Hz), 7.47 (5H, s), 7.58-7.72 (2H, m), 8.04 (1H, d, J=18.8 Hz), 8.13 (1H, s), 9.33 (1H, br.s), 11.2 (2H, br.s).
The following compounds were obtained according to a similar manner to that of Example 29.
NMR (DMSO-d6, δ): 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 (1H, d, J=15.82 Hz), 6.89-6.97 (1H, m), 7.15-7.27 (3H, m), 7.42-7.50 (3H, m), 8.08 (1H, d, J=9.56 Hz), 8.28 (1H, s), 8.63 (1H, s), 9.40 (1H, m)
NMR (DMSO-d6, δ): 1.91-2.18 (6H, m), 2.95-3.01 (2H, m), 4.33-4.35 (1H, m), 6.41 (1H, d, J=15.86 Hz), 7.08 (1H, d, J=9.38 Hz), 7.44 (1H, d, J=15.86 Hz), 7.54 (2H, d, J=8.42 Hz), 7.71 (2H, d, J=8.42 Hz), 8.03-8.14 (2H, m), 11.37 (1H, m)
NMR (DMSO-d6, δ): 1.50-1.80 (1H, m), 2.10-2.90 (5 Hz, m), 3.45-3.70 (2H, m), 4.20-4.45 (1H, m), 6.16 (1H, d, J=16 Hz), 6.51 (1H, d, J=8.8 Hz), 7.10-7.40 (7H, m), 7.57 (1H, dd, J=1.5 Hz, J=8.8 Hz), 8.10 (1H, d, J=1.5 Hz), 8.91 (1H, br), 10.57 (1H, br)
MASS(API-ES); 339 (M+H)+
To a suspension of (2E)-3-(6-{[(3R)-1-(4-tert-butylbenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (270 mg) was suspended in methanol (1 mL) and to this suspension was added hydrogen chloride in methanol solution(10%, 3 mL). 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)-1-(4-tert-butylbenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-hydroxyacrylamide dihydrochloride (228 mg) 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 (1H, m), 6.33-6.45 (1H, m), 6.90-7.21 (1H, m), 7.36-7.51 (3H, m), 7.54-7.63 (2H, m), 7.89-8.09 (1H, m), 8.18 (1H, s)
MS (ES+) m/z 395.32(free, M+1)
10% Metallic hydrogen chloride (1.4 mL) was added to the solution of (2E)-3-(2-{[1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-1,3-thiazol-4-yl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (0.6 g) in MeOH (12 ml) 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 (0.42 g)
NMR (DMSO-d6, δ): 1.89-2.33 (2H, m), 3.31-3.71 (3H, m), 3.72-3.87 (1H, m), 4.30-4.49 (1H, m), 4.63 and 4.50(total 1H, each d, J=15.3 Hz), 7.06 and 7.11(total 1H, each s), 7.18 and 7.22(total 1H, 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.
1H-NMR (DMSO-d6): δ 1.30-1.84 (4H, m), 2.89-3.46 (4H, m), 3.82-4.15 (1H, m), 4.30 (2H, s), 6.52 (1H, d, J=15.4 Hz), 7.09 (1H, s), 7.21 (1H, d, J=15.4 Hz), 7.39-7.51 (3H, m), 7.59-7.72 (2H, m), 8.99 (1H, br.s), 11.21 (1H, s),
(+)ESI-MS: 359 (M+1).
NMR (DMSO-d6, δ): 1.37-1.66 (2H, m), 1.87-2.15 (2H, m), 3.04-3.30 (2H, m), 3.48-3.75 (1H, 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)
(+)ESI-MS:407(M+H)+
To a stirred solution of tert-butyl [(3R)-1-(diphenylmethyl)-3-pyrrolidinyl](5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-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 (3 ml) and methanol (1 ml). To this solution was added 4N-hydrogen chloride in dioxane (3 ml) 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)-1-(diphenylmethyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-hydroxyacrylamide dihydrochloride (63 mg) as a pale yellow powder.
NMR (CDCl3, δ): 1.36 (3H, t, J=7 Hz), 1.42 (3×3H, s), 2.02-2.30 (2H, m), 2.42-2.61 (2H, m), 2.64 (1H, dd, J=9.5, 7 Hz), 2.78 (1H, dd, J=9.5, 8 Hz), 4.17 (1H, s), 4.29 (2H, q, J=7 Hz), 4.91 (1H, m), 6.49 (1H, d, J=16 Hz), 7.08-7.38 (11H, m), 7.69 (1H, d, J=16 Hz), 7.83 (1H, dd, J=8.5, 2 Hz), 8.57 (1H, d, J=2 Hz)
MS (ES+) m/z 528.
To a solution of (2E)-3-{6-[(1-benzyl-4-piperidyl)amino]-5-chloro-3-pyridyl}-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide(168 mg) in EtOH(2 ml) was treated with 10% HCl in MeOH (1.76 ml) and was stirred at 25° C. for 1 hour. The precipitate was collected, washed with EtOH, dried under reduced pressure to give (2E)-3-{6-[(1-benzyl-4-piperidyl)amino]-5-chloro-3-pyridyl}-N-hydroxyacrylamide dihydrochloride (137 mg).
NMR (DMSO-d6, δ): 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.
NMR (DMSO-d6, δ): 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)+
NMR (DMSO-d6, δ): 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).
Mass (ESI): 415(M+H)+
To a solution of (2E)-3-(5-chloro-6-{[1-(4-methylbenzyl)-4-piperidyl]amino}-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (470 mg) in EtOH(2 ml) was treated with 2N HCl in EtOH (2.42 ml) and was stirred at 25° C. 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 (308 mg).
NMR (DMSO-d6, δ): 1.90-2.20 (4H, m), 2.34 (3H, s), 2.90-2.45 (4H, m), 4.10-4.25 (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)+
The following compounds were obtained according to a similar manner to that of Example 41.
NMR (DMSO-d6, δ): 1.90-2.20 (4H, m), 2.90-2.45 (4H, m), 3.79 (3H, s), 4.10-4.25(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 Hz), 7.94 (1H, s), 8.18 (1H, s), 10.98 (1H, brs) Mass (ESI): 417(M+H)+
NMR (DMSO-d6, 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 (1H, m), 3.40-3.60 (1H, m), 4.10-4.30 (1H, m), 6.40 (1H, d, J=16.0 Hz), 7.35 (1H, d, J=16.0 Hz), 7.95 (1H, s), 8.20 (1H, s), 10.26 (1H, brs)
Mass (ESI): 353(M+H)+
NMR (DMSO-d6, δ): 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), 4.10-4.40 (1H, m), 6.41 (1H, d, J=16.0 Hz), 7.36 (1H, d, J=16.0 Hz), 7.98 (1H, s), 8.20 (1H, s), 10.86 (1H, brs)
Mass (ESI): 351(M+H)+
NMR (DMSO-d6, δ): 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), 6.40 (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)
NMR (DMSO-d6, δ): 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), 8.20 (1H, s)
NMR (DMSO-d6, §): 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), 6.40 (1H, d, J=16.0 Hz), 6.99 (2H, d, J=8.8 Hz), 7.15-7.40 (1H, m), 7.34 (1H, d, J=16.0 Hz), 7.53-7.89 (2H, m), 7.92 (1H, s), 8.21 (1H, s)
To [(3R)-1-(3-methoxybenzyl)-3-pyrrolidinyl](5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-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, δ): 2.13 (1H, br), 2.34 (0.5H, br), 2.59 (0.5H, br), 3.22-3.83 (4H, br), 3.79 (3H, s), 4.41 (1H, m), 4.51 (1H, 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 (1H, m), 8.18 (1H, s)
MS (ES+) m/z 369 (M+1)
The following compounds were obtained according to a similar manner to that of Example 48.
NMR (DMSO-d6, δ): 1.97-2.62 (2H, m), 3.30-4.10 (5H, m), 4.55-4.73 (2H, m), 6.35 (1H, d, J=16 Hz), 6.88-7.01 (1H, m), 7.41 (1H, d, J=16 Hz), 7.48-7.57 (3H, m), 7.89-8.03 (4H, m), 8.16-8.23 (1H, m)
MS (ES+) m/z 422 (M+1)
NMR (DMSO-d6, δ): 2.02-4.73 (9H, m), 6.32 (1H, d, J=16 Hz), 7.40 (1H, d, J=16 Hz), 7.55-7.82 (11H, m), 8.18-8.21 (1H, m)
MS (ES+) m/z 443 (M+1).
NMR (DMSO-d6, δ): 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 (1H, m), 6.79-7.09 (2H, m), 7.29-7.50 (3H, m), 7.87-7.99 (1H, m), 8.17-8.21 (1H, s)
MS (ES+) m/z 381 (M+1)
NMR (DMSO-d6, δ): 1.61-4.44 (9H, m), 6.17 (1H, d, J=16 Hz), 6.52 (1H, d, J=8 Hz), 7.19-7.36 (4H, m), 7.52-7.64 (3H, m), 8.10-8.15 (1H, m)
MS (ES+) m/z 379 (M+1)
NMR (DMSO-d6, δ): 1.72-4.53 (9H, m), 6.20 (1H, d, J=16 Hz), 6.54 (1H, d, J=8 Hz), 6.95-8.16 (8H, m)
MS (ES+) m/z 379 (M+1)
(2E)-N-Hydroxy-3-(6-{[(3R)-1-(3-phenylpropyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylamide dihydrochloride
NMR (DMSO-d6, δ): 2.00 (2H, m), 2.06 (1H, 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 (1H, br), 4.69 (1H, br), 6.38 (1H, 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 (1H, d, J=16.1 Hz), 7.99 (1H, m), 8.21 (1H, s)
MS (ES+) m/z 367 (M+1)
NMR (DMSO-d6, δ): 2.12 (1H, br), 2.37 (1H, br), 2.96 (6H, s), 3.18-4.00 (4H, br), 4.30 (1H, br), 4.40 (1H, 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 (1H, m), 7.48 (2H, m), 8.03 (1H, m), 8.20 (1H, s)
MS (ES+) m/z 382 (M+1)
NMR (DMSO-d6, δ): 2.11 (1H, br), 2.39 (1H, br), 3.11-3.71 (4H, br), 3.82 (1.5H, s), 3.87 (1.5H, s), 4.39 (1H, br), 4.45 (1H, br), 4.59 (0.5H, br), 4.71 (0.5H, br), 6.36 (1H, d, J=16.1 Hz), 6.93 (1H, m), 7.02 (1H, m), 7.12 (1H, dd, J=8.4, 4.5 Hz), 7.43 (2H, m), 7.57 (1H, m), 7.96 (1H, m), 8.18 (1H, s)
MS (ES+) m/z 369 (M+1)
To a solution of tert-butyl [(3R)-1-(3-fluorobenzyl)-3-pyrrolidinyl](5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-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, δ): 2.08 (1H, m), 2.34 (1H, m), 3.23-3.81 (4H, m), 4.45 (1H, m), 4.54 (1H, 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 (1H, m), >7.41 (1H, m), 7.48-7.60 (3H, m), 7.95 (1H, m), 8.18 (1H, s),
MS (ES+) m/z 357 (M+1)
The following compounds were obtained according to a similar manner to that of Example 57.
NMR (DMSO-d6, δ): 1.98-2.76 (2H, m), 3.17-4.25 (4H, m), 4.50-4.79 (3H, m), 6.29-6.45 (1H, m), 6.87-7.18 (1H, m), 7.36-7.48 (1H, m), 7.81-8.08 (5H, m), 8.19 (1H, brs)
MS (ES+) m/z 407.33(free, M+1)
NMR (DMSO-d6, δ): 1.92-2.80 (2H, m), 3.14-4.23 (4H, m), 4.43-4.78 (3H, m), 6.30-6.46 (1H, m), 6.86-7.16 (1H, m), 7.37-7.53 (3H, m), 7.76-7.86 (2H, m), 7.88-8.08 (1H, m), 8.19 (1H, s)
MS (ES+) m/z 423.25(free, M+1)
NMR (DMSO-d6, 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 (1H, m), 6.36 (1H, d, J=15.8 Hz), 6.88-7.10 (1H, m), 7.43 (1H, d, J=15.8 Hz), 7.91-8.01 (1H, m), 8.20 (1H, s)
MS (ES+) m/z 345.41 (free, M+1)
NMR (DMSO-d6, δ): 1.45-1.66 (4H, m), 1.90-2.20 (5H, m), 2.30-2.63 (1H, m), 2.99-3.90 (6H, m), 4.52-4.81 (1H, m), 5.94-6.04 (1H, m), 6.38 (1H, d, J=15.8 Hz), 6.93-7.17 (1H, m), 7.43 (1H, d, J=15.8 Hz), 7.91-8.09 (1H, m), 8.21 (1H, brs)
MS (ES+) m/z 343.50(free, M+1)
NMR (DMSO-d6, δ): 2.12 (1H, br), 2.37 (1H, br), 2.60 (1H, br), 3.25 (1H, br), 3.45 (1H, br), 3.66 (1H, br), 3.91 (1H, br), 4.50 (1H, br), 4.56 (1H, d, J=5.1 Hz), 4.59 (0.5H, br), 4.70 (0.5H, br), 6.35 (1H, d, J=16.1 Hz), 6.91 (0.5H, br), 6.98 (0.5H, br), 7.30 (1H, d, J=7.3 Hz), 7.35 (1H, d, J=9.1 Hz), 7.41 (1H, d, J=16.1 Hz), 7.52 (1H, m), 7.78 (1H, m), 7.94 (1H, m), 8.19 (1H, s)
MS (ES+) m/z 357 (M+1)
NMR (DMSO-d6, δ): 2.21 (1H, br), 2.51 (1H, br), 3.61 (2H, br), 3.76 (1H, br), 3.95 (1H, br), 4.72 (1H, br), 4.93 (2H, s), 6.38 (1H, d, J=15.8 Hz), 7.08 (1H, d, J=9.5 Hz), 7.43 (1H, d, J=15.8 Hz), 7.69 (1H, m), 7.71 (1H, d, J=8.4 Hz), 7.84 (1H, m), 8.04 (2H, m), 8.20 (1H, s), 8.50 (1H, d, J=8.1 Hz)
MS (ES+) m/z 390 (M+1)
NMR (DMSO-d6, δ): 2.10 (1H, br), 2.63 (1H, br), 3.35 (1H, br), 3.49 (1H, br), 3.69 (1H, br), 3.90 (1H, br), 4.58 (1H, br), 4.72 (1H, br), 4.80 (1H, br), 6.35 (1H, d, J=16.1 Hz), 6.91 (0.5H, br), 7.03 (0.5H, br), 7.41 (1H, d, J=16.1 Hz), 7.76 (1H, t, J=7.7 Hz), 7.93 (2H, m), 8.08 (1H, d, J=7.7 Hz), 8.14 (1H, d, J=8.1 Hz), 8.19 (1H, s), 8.79 (1H, d, J=6.6 Hz), 9.23 (1H, d, J=8.1 Hz)
MS (ES+) m/z 390 (M+1)
NMR (DMSO-d6, δ): 2.07 (1H, br), 2.31 (1H, br), 2.45 (3H, s), 3.23 (1H, br), 3.37 (1H, br), 3.52 (1H, br), 3.81 (1H, br), 4.56 (1H, d, J=4.4 Hz), 4.57 (0.5H, br), 4.64 (1H, d, J=5.1 Hz), 4.67 (0.5H, br), 6.35 (1H, d, J=16.1 Hz), 6.80 (1H, br), 6.90 (0.5H, br), 6.98 (0.5H, br), 7.19 (1H, m), 7.42 (1H, d, J=16.1 Hz), 7.93 (1H, m), 8.19 (1H, s)
MS (ES+) m/z 359 (M+1)
(2E)-N-Hydroxy-3-[6-({(3R)-1-[(5-methyl-2-furyl)methyl]-3-pyrrolidinyl}amino)-3-pyridyl]acrylamide dihydrochloride
NMR (DMSO-d6, δ): 2.09 (2H, br.), 2.26 (1.5H, s), 2.29 (1.5H, s), 3.26 (1H, br.), 3.53 (2H, br.), 3.86 (1H, br.), 4.44 (1H, s), 4.53 (1H, s), 4.64 (1H, br.d), 6.15 (1H, m), 6.39 (1H, d, J=15.8 Hz), 6.60 (1H, s), 7.04 (1H, m), 7.43 (1H, d, J=15.4 Hz), 8.00 (1H, br.), 8.20 (1H, s)
MS (ES+) m/z 343 (M+1)
NMR (DMSO-d6, δ): 2.23 (2H, br.), 3.00 (6H, s), 3.07 (1H, br.), 3.43 (2H, br.), 3.71 (1H, br.), 3.97 (1H, br.), 4.07 (1H, br.), 4.65 (0.5H, br.), 4.77 (0.5H, br.), 6.27 (1H, br.), 6.42 (1H, d, J=15.8 Hz), 6.80 (1H, d, J=15.4 Hz), 7.09 (2H, br.), 7.22 (1H, d, J=8.4 Hz), 7.44 (3H, m), 8.07 (1H, m), 8.19 (1H, s)
MS (ES+) m/z 408 (M+1)
NMR (DMSO-d6, δ): 1.06 (4.5H, s), 1.07 (4.5H, s), 2.08 (1H, m), 2.45 (1H, m), 3.16 (1H, m), 3.25 (1H, m), 3.39-3.92 (4H, br), 4.12 (1H, m), 4.59 (0.5H, br), 4.71 (0.5H, br), 6.35 (1H, d, J=16.1 Hz), 6.94 (1H, br.d), 7.42 (1H, d, J=16.1 Hz), 7.94 (1H, br.d), 8.21 (1H, br)
MS (ES+) m/z 319 (M+1)
To a solution of (2E)-3-(4-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}phenyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (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)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}phenyl)-N-hydroxyacrylamide hydrochloride (64.1 mg) as colorless powder.
NMR (DMSO-d6, δ): 1.89 (1H, m), 2.18 (1H, m), 3.24 (0.5H, m), 3.45 (0.5H, m), 3.59 (1H, m), 3.67 (1H, m), 3.78 (1H, 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 (1H, d, J=8.4 Hz), 6.70 (1H, d, J=8.8 Hz), 7.26-7.36 (3H, m), 7.47-7.59 (5H, m)
To a solution of (2E)-3-(6-{[(3R)-1-(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)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-hydroxyacrylamide hydrochloride (1.18 g) as colorless powder.
NMR (DMSO-d6, δ): 2.02 (1H, br), 2.25 (1H, br), 3.34-3.64 (4H, br), 3.85 (1H, 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 (1H, m), 8.14 (0.5H, s), 8.23 (0.5H, s)
MS (ES+) m/z 387 (M+1)
The following compounds were obtained according to a similar manner to that of Example 70.
NMR (DMSO-d6, δ): 2.02 (1H, br), 2.25 (1H, br), 3.34-3.64 (4H, br), 3.85 (1H, 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 (1H, m), 8.14 (0.5H, s), 8.23 (0.5H, s)
MS (ES+) m/z 387 (M+1)
To a solution of (2E)-3-(4-{[(3R)-1-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)-1-benzyl-3-pyrrolidinyl]amino}phenyl)-N-hydroxyacrylamide hydrochloride (257.4 mg) as colorless powder.
NMR (DMSO-d6, δ): 1.94 (1H, 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 (1H, d, J=5.9 Hz), 4.44 (1H, d, J=5.9 Hz), 6.20 (—H, d, J=16.1 Hz), 6.61-1H, d, J=8.8 Hz), 6.63 (1H, d, J=8.8 Hz), 7.33 (2H, m), 7.44 (3H, m), 7.64 (2H, m)
MS (ES+) m/z 338 (M+1)
To a solution of (2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-methyl-3-pyridyl)-N-(tetrahydro-2H-pyran-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)-1-benzyl-3-pyrrolidinyl]amino}-5-methyl-3-pyridyl)-N-hydroxyacrylamide dihydrochloride (202.1 mg) as colorless powder.
NMR (DMSO-d6, δ): 2.16 (1H, m), 2.28 (3H, s), 2.65 (1H, m), 3.22 (1H, m), 3.48 (2H, m, 3.58 (1H, m), 4.44 (1H, d, J=5.6 Hz), 4.49 (1H, d, J=5.8 Hz), 4.98 (1H, br), 6.39 (1H, d, J=16.1 Hz), 7.41 (1H, d, J=16.1 Hz), 7.45 (3H, m), 7.63 (2H, m), 7.88 (1H, be), 8.09 (1H, s)
MS (ES+) m/z 353 (M+1)
To a solution of (2E)-3-(5-{[(3R)-1-(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)-1-(4-chlorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamide dihydrochloride (1.40 g).
1H-NMR (300 MHz, DMSO-d6) δ 1.93-2.38 (2H, m), 3.00-3.79 (4H, m), 4.37-4.63 (3H, m), 6.63 (1H, d, J=15 Hz), 7.39 (1H, 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+1)
The following compounds were obtained in a similar manner to that of Example 74.
1H-NMR (300 MHz, DMSO-d6) δ 0.81-1.03 (2H, m), 1.04-1.35 (3H, m), 1.35-2.20 (10H, m), 2.56-2.76 (1H, m), 2.76-3.13 (3H, m), 3.16-3.65 (2H, m), 4.03-4.75 (1H, m), 6.63 (1H, d, J=15.0 Hz), 7.40 (1H, d, J=15.0 Hz), 7.76-7.89 (0.6H, m), 8.03 (1H, s), 8.05-8.35 (0.4H, m), 8.15 (1H, s), 9.80-10.02 (1H, br.s)
MS (ES+) m/z 360(M+1, free)
1H-NMR (300 MHz, DMSO-d6)(1.31-1.53 (1H, m), 1.74-2.16 (3H, m), 2.56-2.78 (1H, m), 2.78-3.05 (1H, m), 3.23-3.40 (1H, m), 3.40-3.54 (1H, m), 4.20-4.45 (3H, m), 6.61 (1H, d, J=15 Hz), 7.36 (1H, d, J=15 Hz), 7.42-7.54 (3H, m), 7.54-7.70 (2H, m), 7.70-7.94 (1H, m), 8.00 (1H, s), 8.10 (1H, s)
MS (ES+) m/z 354
1H-NMR (300 MHz, CD3OD)d 1.10-1.30 (1H, m), 1.30-1.77 (6H, m), 1.85-2.06 (3H, m), 2.06-2.30 (3H, m), 2.85 (1H, t, J=11 Hz), 2.99-3.15 (1H, m), 3.15-3.33 (2H, m), 3.45-3.58 (1H, m), 3.67-3.86 (1H, m), 4.28-4.44 (1H, m), 6.76 (1H, d, J=15 Hz), 7.53 (1H, d, J=15 Hz), 8.11-8.24 (2H, m)
MS (ES+) m/z 346
1H-NMR (300 MHz, DMSO-d6) δ 1.30-1.52 (1H, m), 1.70-2.15 (4H, m), 2.33 (3H, s), 2.54-2.71 (1H, m), 2.71-2.99 (1H, m), 3.21-3.36 (1H, m), 3.36-3.50 (1H, m), 4.23-4.44 (2H, m), 6.61 (1H, d, J=15 Hz), 7.10 (1H, s), 7.25 (2H, d, J=8 Hz), 7.30 (1H, s), 7.36 (1H, d, J=15 Hz), 7.41-7.55 (3H, m), 7.80 (1H, br peak), 7.93-8.06 (1H, m), 8.10 (1H, s)
MS (ES+) m/z 368
1H-NMR (300 MHz, DMSO-d6) δ1.34-1.56 (1H, m), 1.70-2.11 (4H, m), 2.56-2.75 (1H, m), 2.75-2.93 (1H, m), 3.20-3.38 (1H, m), 3.38-3.55 (1H, m), 4.22-4.45 (2H, m), 6.62 (1H, d, J=15 Hz), 7.40 (1H, d, J=15 Hz), 7.49-7.58 (2H, m), 7.58-7.70 (2H, m), 7.70-7.82 (1H, m), 7.95-8.06 (1H, m), 8.11 (1H, s)
MS (ES+) m/z 388
1H-NMR (300 Mhz, DMSO-d6) δ 1.39-1.52 (3H, m), 1.52-2.04 (9H, m), 2.56-2.78 (1H, m), 2.78-3.10 (1H, m), 3.20-4.50 (4H, m), 6.63 (1H, d, J=15 Hz), 7.13 (1H, s), 7.30 (1H, s), 7.39 (1H, d, J=15 Hz), 7.47 (1H, s), 7.85 (1H, br peak), 7.98-8.10 (1H, m), 8.10-8.21 (1H, m)
MS (ES+) m/z 332
1H-NMR (300 MHz, DMSO-d6) δ 1.16-1.35 (2H, m), 1.35-1.69 (4H, m), 1.69-2.07 (5H, m), 2.18-2.36 (1H, m), 2.56-2.75 (1H, m), 2.75-2.96 (1H, m), 2.96-3.19 (2H, m), 3.19-4.20 (3H, m), 4.20-4.42 (1H, m), 6.63 (1H, d, J=15 Hz), 7.11 (1H, s), 7.28 (1H, s), 7.40 (1H, d, J=15 Hz), 7.45 (1H, s), 7.76-7.91 (1H, m), 8.01-8.11 (1H, m), 8.15 (1H, s)
MS (ES+) m/z 346
1H-NMR (300 MHz, DMSO-d6) δ 1.95-2.36 (2n, m), 2.99-3.78 (4H, m), 4.33-4.62 (3H, m), 6.62 (1H, dd, J=2, 15 Hz), 7.38 (1H, 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+1)
1H-NMR (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 (1H, dd, J=2, 15 Hz), 7.22-7.28 (2H, m), 7.39 (1H, d, J=15 Hz), 7.46-7.52 (2H, m), 8.00-8.15 (2H, m)
MS (ES+) m/z 354 (M+1)
1H-NMR (300 MHz, DMSO-d6) δ 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 (1H, m), 2.33 (1H, m), 2.92-3.85 (6H, m), 4.55 (1H, m), 6.63 (1H, d, J=15.3 Hz), 7.40 (1H, d, J=15.3 Hz), 8.05 (1H, d, J=8.4 Hz), 8.11-8.32 (3H, m), 10.44 (1H, br-s)
MS (ES+) m/z 346
To a stirred solution of (2E)-3-(5-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamide (300 mg) in 95% ethanol (3 mL) was added 4-methylbenzenesulfonic acid hydrate (168 mg) at ambient temperature. After stirring at the same temperature for one hour, additional 95% ethanol(1.5 mL) was added to the mixture. The precipitate was collected after two hours to afford (2E)-3-(5-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamide 4-methylbenzenesulfonate (253 mg) as a pale brown solid.
1H-NMR (300 MHz, CD3OD) δ 2.07-2.26 (1H, m), 2.36 (3H, s), 2.43-2.65 (1H, m), 3.24-3.49 (2H, m), 3.54-3.82 (2H, m), 4.38 (1H, d, J=12.8 Hz), 4.46 (13H, d, J=12.0 Hz), 4.51-4.65 (1H, m), 6.68 (1H, 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 (1H, s), 8.05 (1H, s)
To a solution of (2E)-3-(5-{[(3R)-1-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 combined organic layer was dried over Na2SO4, filtered, and evaporated in vacuo to give (2E)-3-(5-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamide (796 mg).
1H-NMR (300 MHz, DMSO-d6) δ 1.58-1.72 (1H, m), 2.16-2.29 (1H, m), 2.36-2.48 (2H, m), 2.61-2.80 (2H, m), 3.58 (2H, s), 4.24-4.36 (1H, m), 6.56 (1H, d, J=15 Hz), 7.20-7.38 (6H, m), 7.73 (1H, d, J=7 Hz), 7.97 (1H, s), 8.07 (1H, s), 8.97 (1H, brs), 10.70 (1H, brs)
MS (ES+) m/z 340 (M+1)
The following compound was obtained in similar manners to those of Examples 74 and 86.
1H-NMR (300 MHz, DMSO-d) δ 1.55-1.72 (1H, m), 2.12-2.29 (1H, m), 2.27 (3H, s), 2.32-2.49 (2H, m), 2.57-2.78 (2H, m), 3.51 (1H, d, J=13.2 Hz), 3.55 (1H, d, J=13.2 Hz), 4.21-4.36 (1H, m), 6.56 (1H, d, J=15.0 Hz), 7.11 (2H, d, J=8.1 Hz), 7.19 (2H, d, J=8.1 Hz), 7.33 (1H, d, J=15.0 Hz), 7.71 (1H, d, J=6.2 Hz), 7.96 (1H, s), 8.06 (1H, s)
To a solution of (2E)-3-(5-{[(3R)-1-(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)-1-(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 (1H, 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+1).
To a mixture of (2E)-3-(5-{[(3R)-1-(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)-1-(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 (1H, m), 6.56-6.66 (1H, m), 7.31-7.61 (5H, m), 7.98-8.17 (2H, m).
MS (ES+) m/z 388 (M+1).
The following compounds were obtained in a similar manner to that of Example 89.
1H-NMR (300 MHz, DMSO-d6) δ1.94-2.45 (2H, m), 3.10-4.66 (7H, m), 6.63 (1H, d, J=16 Hz), 7.40 (1H, d, J=16 Hz), 7.45-7.63 (3H, m), 7.85-8.18 (4H, m), 11.1 (1H, brs).
MS (ES+) m/z 374 (M+1),
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 (1H, d, J=16 Hz), 7.39 (1H, d, J=16 Hz), 7.44-7.63 (3H, m), 7.77 (1H, s), 8.00-8.29 (3H, m), 11.4 (1H, brs).
MS (ES+) m/z 374 (M+1).
To a solution of tert-butyl [(3R)-1-(cyclopentylmethyl)-3-pyrrolidinyl](5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridinyl)carbamate (179 mg, 0.35 mmol) 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 (1 mL). To the reaction mixture was added 4N HCl in dioxane (4 mL) and stirred for 1 hr 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)-1-(cyclopentylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-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 (1H, m), 6.36 (1H, d, J=15.7 Hz), 6.88-7.08 (1H, m), 7.43 (1H, d, J=15.8 Hz), 7.91-8.01 (1H, m), 8.12 (1H, s);
The following compounds were obtained in a similar manner to that of Example 92.
1H-NMR (300 MHz, DMSO-d6) δ1.15-1.34 (2H, m), 1.34-1.71 (7H, m), 1.71-1.99 (3H, m), 1.99-2.19 (1H, m), 2.25-2.65 (1H, m), 3.02-3.24 (3H, m), 3.24-3.92 (3H, m), 3.92-4.11 (1H, m), 4.53-7.76 (1H, m), 6.36 (1H, d, J=15.8 Hz), 6.87-7.06 (1H, m), 7.43 (1H, d, J=15.8 Hz), 7.92-8.03 (1H, m), 8.20 (1H, s), 10.27 (1H, br peak); MS (ES+) m/z 359.
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 (1H, m), 2.25-2.65 (1H, m), 2.97-4.09 (6H, m), 4.52-4.76 (1H, m), 6.73-7.00 (2H, m), 7.08 (1H, s), 7.25 (1H, s), 7.42 (1H, s), 7.95 (1H, d, J=8.6 Hz), 8.25 (1H, MS (ES+) m/z 363.
1H-NMR (300 MHz, DMSO-d6) δ1.55-1.75 (16H, m), 1.90-2.03 (3H, m), 2.03-2.16 (1H, m), 2.95-4.20 (3H, m), 4.53-4.80 (1H, m), 6.38 (1H, d, J=15.4 Hz), 6.89-7.12 (1H, m), 7.44 (1H, d, J=15.4 Hz), 8.00 (1H, d, J=9.5 Hz), 8.21 (1H, s).
To the solution of (2E)-3-(5-{[(3R)-1-(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 ethanolic 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)-1-(2-phenylethyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylamide dihydrochloride (2.3 g, 74%) as an amorphous powder.
1H-NMR (300 MHz, DMSO-d6) δ1.40-1.61 (1H, m), 1.74-2.21 (3H, m), 2.60-2.80 (1H, m), 2.80-3.01 (1H, m), 3.01-3.14 (2H, m), 3.21-3.38 (2H, m), 3.38-3.75 (2H, m), 4.23-4.42 (1H, m), 6.64 (1H, d, J=15.2 Hz), 7.20-7.48 (6H, m), 7.84 (1H, br peak), 8.00-8.12 (1H, m), 8.12-8.26 (1H, m); MS (ES+) m/z 368.
The following compounds were obtained in a similar manner to that of Example 96.
1H-NMR (300 MHz, DMSO-d6) δ1.30-1.66 (1H, m), 1.66-2.17 (3H, m), 2.60-4.00 (4H, m), 4.16-4.60 (3H, m), 6.21-6.44 (1H, m), 6.55-7.10 (2H, m), 7.32-7.67 (6H, m), 7.79-8.01 (1H, m), 8.11-8.38 (1H, m); MS (ES+) m/z 353.
1H-NMR (300 MHz, DMSO-d6) δ0.80-1.04 (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 (1H, m), 3.00-3.20 (3H, m), 3.94-4.10 (1H, m), 4.51-4.73 (1H, m), 6.87-7.04 (2H, m), 7.85 (1H, d, J=9.0 Hz), 8.03 (1H, s); MS (ES+) m/z 359.
1H-NMR (300 Mhz, DMSO-d6) δ0.86-1.05 (2H, m), 1.05-1.35 (3H, m), 1.35-2.15 (10H, m), 2.65-3.10 (3H, m), 3.20-4.00 (3H, m), 4.30-4.62 (1H, m), 6.37 (1H, d, J=16.1 Hz), 6.90-7.11 (1H, m), 7.35-7.51 (1H, m), 7.90-8.10 (1H, m), 8.15-8.30 (1H, m);
1H-NMR (300 MHz, DMSO-d6) δ1.00-1.69 (8H, m), 1.75-2.15 (7H, m), 2.58-3.90 (4H, m), 4.25-4.55 (1H, m), 6.26-6.41 (1H, m), 6.80-7.05 (1H, m), 7.35-7.50 (1H, m), 7.85-8.06 (1H, m), 8.21 (1H, s); MS (ES+) m/z 345.
1H-NMR (300 MHz, DMSO-d6) δ1.31-1.66 (1H, 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 (1H, d, J=15.7 Hz), 6.85-7.10 (1H, m), 7.41 (1H, 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 (1H, m), 8.19 (1H, s);
MS (ES+) m/z 387.
1H-NMR (300 MHz, DMSO-d6) δ1.41-1.64 (3H, m), 1.64-2.18 (10H, m), 2.72-4.00 (4H, m), 4.21-4.60 (1H, m), 6.30-6.44 (1H, m), 6.94-7.11 (1H, m), 7.36-7.50 (1H, m), 7.94-8.08 (1H, m), 8.15-8.25 (1H, m);
MS (ES+) m/z 331.
1H-NMR (300 MHz, DMSO-d6) δ1.31-1.65 (1H, 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 (1H, d, J=15.9 Hz), 6.91-7.16 (1H, m), 7.27 (2H, d, J=7.7 Hz), 7.35-7.59 (3H, m), 7.95-8.12 (1H, m), 8.20 (1H, br s).
1H-NMR (300 MHz, DMSO-d6) δ1.90-2.20 (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 (1H, m), 8.24 (1H, s);
MS (ES+) m/z 371.
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 (1H, t, J=9.9 Hz), 8.22 (1H, s);
MS (ES+) m/z 391.
1H-NMR (300 MHz, DMSO-d6) δ 0.96-1.94 (12H, m), 1.94-2.14 (1H, m), 2.38-2.67 (1H, m), 2.94-4.15 (6H, m), 6.39 (1H, d, J=16.0 Hz), 6.95-7.20 (1H, m), 7.45 (1H, d, J=16.3 Hz), 7.92-8.14 (1H, m), 8.20 (1H, br s);
MS (ES+) m/z 373.
1H-NMR (300 MHz, DMSO-d6) δ1.37-2.14 (5H, m), 3.04-4.20 (4H, m), 6.41 (1H, d, J=15.9 Hz), 6.95-7.95 (7H, m), 7.95-8.38 (1H, m);
MS (ES+) m/z 401.
1H-NMR (300 MHz, DMSO-d6) δ0.85-1.07 (2H, m), 1.07-1.36 (3H, m), 1.36-2.15 (10H, m), 2.65-3.10 (3H, m), 3.20-4.10 (3H, m), 4.30-4.65 (1H, m), 6.39 (1H, d, J=16.1 Hz), 6.94-7.12 (1H, m), 7.34-7.51 (1H, m), 7.91-8.09 (1H, m), 8.15-8.30 (1H, m).
1H-NMR (300 MHz, DMSO-d6) δ1.34-1.54 (1H, 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 (1H, d, J=15.2 Hz), 7.38 (1H, d, J=15.2 Hz), 7.45-7.65 (3H, m), 7.70-7.84 (2H, m), 7.96-8.06 (1H, m), 8.06-8.16 (1H, m);
MS (ES+) m/z 388.
1H-NMR (300 MHz, DMSO-d6) δ1.30-1.54 (1H, m), 1.70-2.15 (4H, m), 2.55-2.75 (1H, m), 2.75-2.94 (1H, m), 3.22-3.36 (1H, m), 3.36-3.53 (1H, m), 4.17-4.45 (2H, m), 6.62 (1H, d, J=15.2 Hz), 7.25-7.45 (3H, m), 7.65-7.85 (3H, m), 7.96-8.19 (2H, m);
MS (ES+) m/z 372.
1H-NMR (300 MHz, DMSO-d6) δ1.31-1.60 (1H, m), 1.72-2.19 (4H, m), 2.56-3.25 (2H, m), 3.25-3.58 (2H, m), 4.18-4.40 (1H, m), 4.52-4.65 (2H, m), 6.62 (1H, d, J=15.2 Hz), 7.09-7.19 (1H, m), 7.34-7.46 (2H, m), 7.65-7.88 (2H, m), 7.96-8.20 (2H, m);
MS (ES+) m/z 360.
1H-NMR (300 MHz, DMSO-d6) δ 1.40-1.65 (1H, m), 1.80-2.05 (3H, m), 2.86-3.03 (1H, m), 3.03-3.20 (1H, m), 3.28-3.45 (1H, m), 3.45-3.57 (1H, m), 4.25-4.38 (1H, m), 4.51 (2H, s), 6.61 (1H, d, J=15.3 Hz), 7.40 (1H, d, J=15.2 Hz), 7.50 (1H, dd, J=7.0, 5.4 Hz), 7.66 (1H, d, J=7.7 Hz), 7.85 (1H, br peak), 7.90-7.98 (1H, m), 8.02 (1H, s), 8.10 (1H, s), 8.65 (1H, d, J=4.6 Hz);
MS (ES+) m/z 355.
1H-NMR (300 MHz, DMSO-d6) δ1.34-1.59 (1H, m), 1.74-2.19 (3H, m), 2.61-2.84 (1H, m), 2.84-3.01 (1H, m), 3.25-3.46 (1H, m), 3.46-3.60 (1H, m), 4.30-4.50 (1H, m), 4.50-4.70 (2H, m), 6.62 (1H, d, J=15.3 Hz), 7.39 (1H, d, J=15.2 Hz), 7.30 (1H, br peak), 8.01 (1H, s), 8.07-8.22 (3H, m), 8.94 (2H, d, J=5.9 Hz);
MS (ES+) m/z 355.
1H-NMR (300 MHz, DMSO-d6) δ1.35-2.15 (4H, m), 2.56-3.80 (4H, m), 4.45-4.70 (3H, m), 6.61 (1H, d, J=15.2 Hz), 7.39 (1H, d, J=15.2 Hz), 7.80 (1H, br peak), 7.90-7.98 (1H, m), 8.01 (1H, s), 8.13 (1H, s), 8.55-8.72 (1H, m), 8.90 (1H, d, J=5.0 Hz), 9.02-9.12 (1H, m), 11.59 (1H, br peak);
MS (ES+) m/z 355.
1H-NMR (300 MHz, DMSO-d6) δ1.31-1.54 (1H, 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 (1H, d, J=15.5 Hz), 7.30-7.45 (2H, m), 7.59-7.70 (1H, m), 7.70-85 (2H, m), 7.96-8.08 (1H, m), 8.08-8.17 (1H, m);
MS (ES+) m/z 360.
1H-NMR (300 MHz, DMSO-d6) δ1.87-2.16 (1H, m), 2.16-2.60 (1H, m), 2.96-3.11 (1H, m), 3.11-4.10 (3H, m), 4.32-4.51 (2H, m), 4.57 (1H, br peak), 6.63 (1H, d, J=15.2 Hz), 7.22 (2H, t-like, J=8.8 Hz), 7.39 (1H, d, J=15.2 Hz), 7.67 (2H, t-like, J=6.7 Hz), 7.90-8.16 (2H, m), 8.21 (1H, br peak); MS (ES+) m/z 358.
1H-NMR (300 MHz, DMSO-d6) δ1.11-1.31 (2H, m), 1.31-1.69 (8H, m), 1.69-1.84 (2H, m), 1.84-2.06 (3H, m), 2.56-2.78 (1H, m), 2.78-3.09 (3H, m), 3.09-4.00 (4H, m), 4.30 (1H, br peak), 6.62 (1H, d, J=15.4 Hz), 7.40 (1H, d, J=15.4 Hz), 7.73-7.85 (1H, m), 7.98-8.10 (1H, m), 8.15 (1H, s), 9.52 (1H, br peak);
MS (ES+) m/z 374.
1H-NMR (300 MHz, DMSO-d6) δ1.30-2.25 (16H, m), 2.57-3.50 (5H, m), 4.24-4.40 (1H, m), 6.64 (1H, d, J=15.2 Hz), 7.40 (1H, d, J=15.2 Hz), 7.75 (1H, br peak), 7.98-8.10 (1H, m), 8.10-8.17 (1H, m);
MS (ES+) m/z 360.
1H-NMR (300 MHz, DMSO-d6) δ1.94-2.16 (1H, m), 2.16-2.70 (1H, m), 2.96-3.14 (2H, m), 3.14-4.10 (6H, m), 4.41-4.61 (1H, m), 6.64 (1H, d, J=15.2 Hz), 7.23-7.50 (5H, m), 8.05 (1H, s), 8.11-8.24 (1H, m);
MS (ES+) m/z 354.
1H-NMR (300 MHz, DMSO-d6) δ1.45-1.72 (2H, m), 1.76-1.94 (1H, m), 1.94-2.10 (1H, m), 3.20-3.44 (2H, m), 3.88-4.04 (1H, m), 4.15-4.26 (1H, m), 4.42 (1H, dd, J=12.6, 3.4 Hz), 6.60 (1H, d, J=15.3 Hz), 6.68 (1H, t, J=4.8 Hz), 7.38 (1H, d, J=15.2 Hz), 7.80 (1H, br peak), 8.04 (1H, s), 8.13 (1H, s), 8.40 (1H, d, J=4.8 Hz);
MS (ES+) m/z 342.
1H-NMR (300 MHz, DMSO-d6) δ1.44-1.64 (1H, m), 1.76-2.20 (3H, m), 2.68-3.17 (2H, m), 3.17-3.41 (4H, m), 3.41-3.54 (1H, m), 3.54-3.65 (1H, m), 4.05-4.24 (1H, m), 4.24-4.41 (1H, m), 6.58-6.69 (1H, m), 7.14-7.31 (4H, m), 7.40 (1H, d, J=15.4 Hz), 7.99-8.11 (1H, m), 8.18 (1H, s);
MS (ES+) m/z 380.
1H-NMR (300 MHz, DMSO-d6) δ1.01-1.35 (3H, m), 1.35-1.54 (2H, m), 1.54-1.69 (1H, m), 1.72-1.89 (2H, m), 1.94-2.36 (4H, m), 3.02-4.10 (5H, m), 4.50-4.70 (1H, m), 6.75-7.07 (2H, m), 7.94-8.08 (1H, m), 8.26 (1H, s); MS (ES+) m/z 349.
To a solution of (2E)-3-(5-{[(3R)-1-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)-1-cyclohexyl-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamide dihydrochloride (252 mg).
1H-NMR (300 MHz, DMSO-d6) δ1.01-4:59 (18H, m), 6.63 (1H, d, J=16 Hz), 7.40 (1H, d, J=16 Hz), 8.01-8.19 (2H, m).
MS (ES+) m/z 332 (M+1).
The following compounds were obtained in a similar manner to that of Example 123.
1H-NMR (300 MHz, DMSO-d6) δ1.93-4.67 (9H, m), 6.37 (1H, d, J=16 Hz), 7.32 (1H, d, J=16 Hz), 7.41-7.65 (5H, m), 8.56 (2H, s).
MS (ES+) m/z 340 (M+1).
1H-NMR (300 MHz, DMSO-d6) δ2.01-4.83 (12H, m), 6.6 (1H, d, J=16 Hz), 7.18-7.27 (1H, m), 7.37 (1H, d, J=16 Hz), 7.42-7.51 (3H, m), 7.59-7.68 (2H, m), 8.03 (1H, s).
MS (ES+) m/z 354 (M+1).
1H-NMR (300 MHz, DMSO-d6) δ 2.02-4.76 (9H, m), 6.74-6.83 (1H, m), 7.28-7.69 (7H, m), 7.84-7.97 (1H, m), 10.2 (1H, brs), 11.4 (1H, brs).
MS (ES+) m/z 340 (M+1).
1H-NMR (300 MHz, DMSO-d6) δ2.04-2.16 (1H, m), 2.33-2.46 (1H, m), 3.29-4.65 (5H, m), 6.42 (1H, d, J=16 Hz), 6.56-6.68 (3H, m), 7.12-7.24 (3H, m), 7.49 (1H, d, J=16 Hz), 8.06-8.13 (1H, m), 8.23 (1H, brs).
MS (ES+) m/z 323 (M−1).
1H-NMR (300 MHz, DMSO-d6) δ0.88-1.02 (2H, m), 1.09-4.79 (18H, m), 6.76-6.85 (1H, m), 7.35-7.56 (2H, m), 7.89-7.98 (1H, m), 10.6 (1H, brs).
MS (ES+) m/z 346 (M+1).
2M ethanolic hydrogen chloride (2.0 mL) was added to the solution of (2Z)-3-(5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-3-pyridinyl)-2-fluoro-N-(tetrahydro-2H-pyran-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)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-3-pyridinyl)-2-fluoro-N-hydroxyacrylamide dihydrochloride (0.28 g),
(+)ESI-MS:411(M+H)+.
The following compounds were obtained in a similar manner to that of Example 129.
1H-NMR (DMSO-d6): δ 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 1H, each d, J=each 15.2 Hz), 7.09 (1H, s), 7.20 (1H, d, J=15.2 Hz),
(+)ESI-MS:351(M+H)+.
1H-NMR (DMSO-d6): δ 1.48-2.09 (4H, m), 2.66-3.42 (4H, m), 4.31-4.47 (2H, m), 4.62 and 4.75(total 1H, each s), 6.78 and 6.81(total 1H, 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 1H, each d, J=each 1.9 Hz), 8.26 and 8.28(total 1H, each d, J each 1.9 Hz), 11.34 and 11.66(total 1H, each s),
(+)ESI-MS:405(M+H)+.
(+)ESI-MS:383(M+H)+.
(+)ESI-MS:397(M+H)+.
(+)ESI-MS:371(M+H)+.
(2Z)-3-(6-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-3-pyridinyl)-2-fluoro-N-hydroxyacrylamide dihydrochloride
1H-NMR (DMSO-d6): δ 0.89-1.02 (2H, m), 1.06-1.30 (3H, m), 1.44-2.16 (10H, m), 2.75-3.67 (6H, m), 4.41 and 4.67(total 1H, each s), 6.87 and 6.89(total 1H, each d, J=each 39.2 Hz), 7.04-7.14 (1H, m), 8.01-8.11 (1H, m), 8.20-8.29 (1H, m),
(+)ESI-MS:377(M+H)+.
1H-NMR (DMSO-d6): δ 1.45-2.15 (12H, m), 2.79-3.09 (2H, m), 3.34-3.66 (3H, m), 4.31 and 4.67(total 1H, each s), 6.88 and 6.89(total 1H, 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)+.
(2Z)-3-(6-{[(3R)-1-cyclohexyl-3-piperidinyl]amino}-3-pyridinyl)-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 1H, each s), 6.89 and 6.90 (total 1H, 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 1H, each s)
(+)ESI-MS:363(M+H)+.
A mixture of (2E)-3-(5-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-2-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (185 mg) and 2NHCl/EtOH (9 ml, 20 eq.) was stirred at room temperature for 3 hours. After then, IPE (50 ml) was added and stirred. Precipitate was filtered, washed with IPE, and dried to give 486 mg (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+1).
1HNMR (400 MHz, DMSO-d6): δ 1.90-2.10 (2H, m), 2.25-2.60 (2H, m), 3.10-3.40 (2H, m), 4.31 (1H, br.s), 4.42 (2H, d, J=6.0 Hz), 6.74 (1H, d, J=13.9 Hz), 7.44 (5H, s), 7.64, (2H, m), 7.80 (1H, m), 8.07 (d, 13.9 Hz).
To a solution of (2E)-3-(5-{[(3R)-1-(3-methoxybenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (240 mg) in ethanol (3.6 mL) was added 2NHCl-EtOH (1.1 mL), which was stirred at room temperature for 1 hour. To the resultant was added ethyl acetate (9.6 mL), 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 (223 mg) as a yellow powder.
1H NMR (400 MHz, DMSO-d6) δ1.94-2.58 (2H, m), 2.96-5.02 (10H, m), 6.63 (1H, dd, J=2.6, 15.2 Hz), 6.99 (1H, d, J=8.2 Hz), 7.15 (1H, d, J=6.4 Hz), 7.26-7.45 (3H, m), 8.00-8.34 (3H, m), 11.32 (1H, br);
MS (ES+) m/z 370 (M+1)
The following compounds were obtained in a similar manner to that of Example 139.
1H NMR (DMSO-d6, 400 MHz) δ 1.19-2.40 (2H, m), 3.01-3.82 (4H, m), 3.95-5.05 (3H, m), 6.29 (1H, dd, J=2.5, 15.3 Hz), 7.39 (1H, d, J=15.3 Hz), 7.67 (1H, dt, J=1.8, 7.8 Hz), 7.93 (1H, d, J=7.9 Hz), 7.96-8.11 (3H, m), 8.11-8.38 (2H, m), 11.45-11.64 (1H, m);
MS (ES+) 365 (M+1).
1H NMR (DMSO-d6, 400Mz) δ 1.92-2.39 (5H, m), 2.97-3.79 (4H, m), 3.81-4.68 (3H, m), 6.63 (1H, dd, J=2.9, 15.4 Hz), 7.23-7.45 (3H, m), 7.53 (1H, d, J=7.3 Hz), 7.85 (1H, d, J=9.0 Hz), 7.97-8.33 (3H, m), 10.18 (1H, s), 11.04 (1H, br);
MS (ES+) m/z 397 (M+1).
1H NMR (DMSO-d6, 400 MHz) δ 1.92-2.84 (2H, m), 2.88-4.80 (13H, m), 6.65 (1H, d, J=15.3 Hz), 6.83-7.55 (5H, m), 7.94-8.36 (3H, m), 11.32 (1H, br);
MS (ES+) m/z 383 (M+1).
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 (1H, dd, J=2.8, 15.2 Hz), 7.21 (1H, dd, J=2.0, 7.2 Hz), 7.32-7.47 (4H, m), 7.98-8.41 (3H, m), 9.98 (1H, s), 11.30 (1H, br); MS (ES+) m/z 433 (M+1).
1H NMR (DMSO-d6, 400 MHz) (1.94-2.43 (2H, m), 2.93-5.02 (10H, m), 6.60 (1H, dd, J=3.3, 15.3 Hz), 6.96-7.07 (1H, m), 7.11 (1H, t, J=9.0 Hz), 7.33-7.49 (2H, m), 7.50-7.61 (1H, m), 7.99-8.37 (3H, m), 10.72 (1H, br);
MS (ES+) m/z 369 (M+1).
1H NMR (DMSO-d6, 400 MHz) δ 1.92-2.59 (2H, m), 3.01-4.73 (7H, m), 6.63 (1H, d, J=15.3 Hz), 6.81-6.93 (1H, m), 6.78 (1H, t, J=8.2 Hz), 7.26 (1H, t, J=7.5 Hz), 7.39 (1H, d, J=15.3 Hz), 7.42-7.51 (1H, m), 8.00-8.30 (2H, m), 10.22-10.69 (2H, m);
MS (ES+) m/z 356 (M+1).
1H NMR (DMSO-d6, 400 MHz) δ 1.93-2.40 (2H, m), 2.99-3.80 (4H, m), 4.17-5.38 (3H, m), 6.63 (1H, dd, J=2.4, 15.2 Hz), 6.84 (1H, d, J=7.9 Hz), 6.93-7.08 (2H, m), 7.22 (1H, dt, J=2.1, 7.8 Hz), 7.38 (1H, d, J=15.3 Hz), 7.98-8.45 (3H, m), 11.16 (1H, br),
MS (ES+) m/z 356 (M+1).
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 (1H, dd, J=2.9, 15.3 Hz), 6.95 (1H, dd, J=2.1, 8.1 Hz), 7.11 (1H, d, J=7.0 Hz), 7.21-7.49 (3H, m), 7.98-8.45 (3H, m), 11.35 (1H, br);
MS (ES+) m/z 398 (M+1).
A mixture of (2E)-3-(5-{[(3R)-1-(2-fluorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (600 mg) and 2N HCl/Ethanol (13.6 ml, 20 eq) was stirred at room temperature for 2 hours. After then, ethyl acetate (10 ml) and IPE (50 ml) was added and stirred. Precipitate was filtered, washed with IPE, and dried under reduced pressure to give 486 mg (83%) of (2E)-3-(5-{[(3R)-1-(2-fluorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamide dihydrochloride as a powder.
MASS (ESI+): m/z=358.3(M+1).
1HNMR (400 MHz, DMSO-d6,): δ 1.96-2.37 (2H, m), 3.05-3.85 (4H, m), 4.47 (1H, d, J=5.5 Hz), 4.51 (1H, d, J=5.5 Hz), 4.59 (m, 1H), 6.63 (1H, dd, J=2.6 Hz and 15.1 Hz), 7.28-7.39 (2H, m), 7.39 (1H, d, J=15.1 Hz), 7.49-7.56 (1H, m), 7.72-7.79 (1H, m) 8.02 (1H, d, J=8.3 Hz), 8.14 (1H, s), 11.12 (1H, br.s.).
A mixture of (2E)-3-(5-{[(3R)-1-(3-fluorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (700 mg) and 2N HCl/Ethanol (16.4 ml) was stirred for 2 hrs.
EtOAc (10 ml) and IPE (50 ml) was added and stirred. After 1 hr, precipitate was filtered and dried to give 565 mg of (2E)-3-(5-{[(3R)-1-(3-fluorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamide dihydrochloride as a powder.
MASS (ESI+): m/z=358.3 (M+1).
1HNMR (400 MHz, CDCl3): δ 1.96-2.56 (2H, m), 3.03-3.80 (4H, m), 4.43 (1H, d, J=5.7 Hz), 4.49 (1H, d, J=5.7 Hz), 4.60 (m, 1H), 6.63 (1H, dd, J=2.2 Hz and 15.3 Hz), 7.25-7.32 (1H, m), 7.39 (1H, d, J=15.3 Hz), 7.46-7.54 (2H, m), 7.59 (1H, d, J=10.0 Hz), 8.03, 8.10 (1H, s), 8.14 (1H, s), 11.48-11.73 (1H, m.
i) To a solution of tert-butyl [(3R)-1-(2-ethylbutyl)-3-pyrrolidinyl](5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-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)-1-(2-ethylbutyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamide dihydrochloride (92.0 mg).
1H-NMR (300 MHz, DMSO-d6) δ 0.85 (6H, t, J=7 Hz), 1.28-1.52 (4H, m), 1.58-1.72 (1H, m), 2.02-2.15 (1H, m), 2.32-2.67 (2H, m), 3.06-4.78 (6H, m), 6.37 (1H, d, J=16 Hz), 6.91-7.08 (1H, m), 7.43 (1H, d, J=16 Hz), 7.94-8.02 (1H, m), 8.21 (1H, brs), 10.4 (1H, brs).
MS (ES+) m/z 333 (M+1).
The following compounds were obtained in a similar manner to that of Example 150.
1H-NMR (300 MHz, DMSO-d6) δ 1.87-4.62 (15H, m), 6.23 (1H, d, J=16 Hz), 6.57 (1H, d, J=8 Hz), 7.15-7.69 (5H, m), 8.15 (1H, brs), 8.93 (1H, brs), 10.7 (1H, brs), 11.0 (1H, brs).
MS (ES+) m/z 367 (M+1).
1H-NMR (300 MHz, DMSO-d6) δ2.01-4.75 (11H, m), 6.33-6.42 (1H, m), 6.96-7.07 (4H, m), 7.29-7.47 (3H, m), 7.92-8.01 (1H, m), 8.21 (1H, brs).
MS (ES+) m/z 369 (M+1).
1H-NMR (300 MHz, DMSO-d6) δ0.91 (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 (1H, d, J=16 Hz), 6.90-7.07 (1H, m), 7.43 (1H, d, J=16 Hz), 7.93-8.02 (1H, m), 8.21 (1H, brs).
MS (ES+) m/z 305 (M+1).
1H-NMR (300 MHz, DMSO-d6) δ1.00 (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 (1H, d, J=16 Hz), 6.90-7.08 (1H, m), 7.43 (1H, d, J=16 Hz), 7.93-8.02 (1H, m), 8.21 (1H, brs), 10.4 (1H, brs).
MS (ES+) m/z 305 (M+1).
To a solution of ethyl (2E)-3-(5-{[(3R)-1-(benzyloxy)-6-oxo-3-piperidinyl]amino}-2-pyrazinyl)acrylate (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, 1M sodium methanolate in methanol (5 mL) was added dropwise to the mixture over 1 h, the reaction mixture was stirred at 0° C. for 2 hrs and at ambient temperature for 4 hrs. The reaction mixture was adjusted to PH 6.0 with 1 mol/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)-1-(benzyloxy)-6-oxo-3-piperidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamide (15 mg, 8%) as a powder.
1H-NMR (300 MHz, CD3OD) δ 1.78-1.98 (1H, m), 1.98-2.15 (1H, m), 2.44-2.74 (2H, m), 3.40 (1H, dd, J=11.4, 5.9 Hz), 3.76 (1H, dd, J=11.4, 4.0 Hz), 4-31 (1H, br peak), 4.93 (2H, s), 6.66 (1H, d, J=15.4 Hz), 7.20-7.33 (3H, m), 7.33-7.43 (2H, m), 7.48 (1H, d, J=15.4 Hz), 7.94 (1H, s), 8.03 (1H, s);
MS (ES+) m/z 384.
The following compounds were obtained in a similar manner to that of Example 129.
1H-NMR (300 MHz, CD3OD) δ1.19-2.21 (4H, m), 3.12-3.49 (2H, m), 3.70-4.01 (4H, m), 4.24-4.35 (1H, m), 6.76-6.90 (1H, m), 7.09-7.41 (5H, m), 7.48-7.58 (1H, 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).
1H-NMR (300 MHz, DMSO-d6) δ1.90-2.15 (1H, 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 (1H, m), 7.21-7.46 (5H, m), 8.00-8.35 (3H, m);
MS (ES+) m/z 354(M+1, free).
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 (1H, m), 6.86-7.27 (1H, m), 7.39-7.52 (1H, m), 7.91-8.12 (1H, m), 8.14-8.35 (2H, m), 9.51-9.78 (1H, m);
MS (ES+) m/z 388(M+1, free).
1H-NMR (300 MHz, DMSO-d6) δ1.61-1.86 (2H, m), 1.87-2.41 (8H, m), 3.06-4.21 (5H, m), 4.49-4.73 (1H, m), 6.36 (1H, d, J=16.1 Hz), 6.84-7.09 (1H, m), 7.43 (1H, d, J=16.1 Hz), 7.89-8.05 (1H, m), 8.21 (1H, s);
MS (ES+) m/z 333(M+1, free).
1H-NMR (300 MHz, DMSO-d6) δ0.84-1.05 (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 (1H, d, J=15.8 Hz), 6.87 (1H, br.d, J=6.6 Hz), 7.36 (1H, d, J=15.8 Hz), 7.90 (1H, br.s), 8.22 (1H, br.s);
MS (ES+) m/z 393(free, M+1).
A solution of 2N HCl-EtOH solution (1.2 ml) was added to a mixture of (2E)-3-{2-[(1-benzyl-3-pyrrolidinyl)amino]-4-methyl-5-pyrimidinyl}-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (200 mg) in EtOH (5 ml) and stirred at 20-25° C. for 2 hours. IPE (30 ml) 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-[(1-benzyl-3-pyrrolidinyl)amino]-4-methyl-5-pyrimidinyl}-N-hydroxyacrylamide dihydrochloride (90 mg).
1H-NMR (DMSO-d6): δ 1.70-20.7 (1H, m), 2.10-2.42 (1H, m), 2.42 (3H, s), 3.10-3.77 (4H, m), 4.42 (2H, s), 4.57-4.70 (1H, m), 6.34 (1H, d J=15.80 Hz), 7.39-7.46 (4H, m), 7.62-7.65 (2H, m), 8.49 (1H, s), 11.40-11.58 (1H, m).
The following compounds were obtained in a similar manner to that of Example 161.
1H-NMR (DMSO-d6): δ 1.86-2.13 (4H, m), 2.46 (3H, s), 2.78-3.49 (4H, m), 4.03 (1H, m), 4.29 (2H, d J=4.42 Hz), 6.37 (1H, d J=15.82 Hz), 7.41 (1H, d J=15.82 Hz), 7.44-7.47 (3H, m), 7.65-7.68 (2H, m), 8.15-8.25 (1H, m), 8.50 & 8.53 (total 1H, each s).
1H-NMR (DMSO-d6): δ 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 (1H, m), 6.33 (1H, d J=15.78 Hz), 7.25 (2H d J=7.12 Hz), 7.39-7.62 (3H, m), 8.48 (1H, s).
1H-NMR (DMSO-d6): δ 0.90-1.26 (6H, m), 1.65-2.09 (6H, m), 2.10-2.30 (1H, m), 2.43 (3H, s), 2.98-3.88 (5H, m), 3.88-3.91 (1H, m), 4.59-4.70 (1H, m), 6.34 (1H, d J=15.78 Hz), 7.43 (1H, d J=15.78 Hz), 8.01-8.10 (1H, m), 8.49 (1H, s), 10.54-10.64 (1H, m).
A solution of tert-butyl (3R)-3-[(5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridinyl)amino]-1-pyrrolidinecarboxylate (450 mg) and pyridinium p-toluenesulfonate (261 mg) in EtOH (10 ml) 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 PH10 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 MgSO4. The solvent was evaporated in vacuo and the residue was washed with IPE to give tert-butyl (3R)-3-({5-[(1E)-3-(hydroxyamino)-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)-1-pyrrolidinecarboxylate (118 mg).
1H-NMR (DMSO-d6): 1.39 (9H, s), 1.69-1.84 (1H, m), 1.99-2.12 (1H, m), 3.09-3.14 (1H, m), 3.34-3.43 (2H, m), 3.52-3.66 (1H, m), 4.01-4.05 (1H, m), 6.19 (1H, d J=15.88 Hz), 6.50 (1H, d J=8.38 Hz), 7.26 (1H, d J=6.62 Hz), 7.34 (1H, d J=15.88 Hz), 7.61 (1H, d J=8.38 Hz), 8.16 (1H, s), 8.91 (1H, s), 10.59 (1H, s).
A solution of 2NHCl-EtOH solution (2.3 ml) was added to a mixture of (2E)-3-(5-chloro-6-{[(3R)-1-(3-methylbenzyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (440 mg) in EtOH (5 ml) and stirred at 20-25° C. for 2 hours.
IPE (20 ml) 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 dihydrochloride (375 mg).
1H-NMR (DMSO-d6): δ 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 1H, each br, s), 6.39 (1H, d J=15.80Hz), 7.22-7.45 (5H, m), 7.83 (1H, s), 8.21 (1H, s).
The following compounds were obtained in a similar manner to that of Example 166.
1H-NMR (DMSO-d6): δ 1.78-2.09 (8H, m), 2.73 (1H, m), 304-3.80 (6H, m), 4.46-4.52 (1H, m), 6.29 (1H, d J=15.60Hz), 7.16-7.20 (1H, m), 7.24 (1H, d J=15.60Hz), 7.91 (1H, s), 8.23 (1H, s).
1H-NMR (DMSO-d6): δ 1.37-1.73 (6H, m), 1.92-2.09 (2H, m), 4.33-4.39 (1H, m), 6.40 (1H, d J=15.80Hz), 7.37 (1H, d J=15.80Hz), 8.03 (1H, s), 8.19 (1H, s).
1H-NMR (DMSO-d6): δ 0.97 (9H, s), 0.97-1.45 (6H, m), 1.45-1.96 (3H, m), 3.84-3.89 & 4.21 (total 1H, each m), 6.36 & 6.37 (total 1H, each d J=15.66 Hz), 7.36 (1H, d J=15.66 Hz), 7.96 & 8.02 (total 1H, each s), 8.17 & 8.21 (total 1H, each s).
1H-NMR (DMSO-d6): δ 0.91-1.27 (6H, m), 1.65-1.89 (5H, m), 2.09-2.10 (1H, m), 2.98-3.91 (6H, m), 4.79-4.91 (1H, m), 6.37 (1H, d J=15.78 Hz), 7.35 (1H, d J=15.78 Hz), 7.91 (1H, s), 8.22 (1H, s), 10.64 (1H, br.s).
1H-NMR (DMSO-d6): δ 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 (1H, m), 5.30-5.34 (1H, m), 6.36 (1H, d J=15.68 Hz), 7.05-7.15 (1H, m), 7.35 (1H, d J=15.68 Hz), 7.91 (1H, s), 8.24 (1H, s).
1H-NMR (DMSO-d6): δ 1.71-2.52 (2H, m), 3.06-4.71 (4H, m, 4.44 (2H, d J=5.58 Hz), 4.70-4.89 (1H, m), 6.37 (1H, d J=15.80Hz), 7.23-7.90 (5H, m), 7.94 (1H, d J=1.88 Hz), 8.21 (1H, d J=1.88 Hz).
1H-NMR (DMSO-d6): δ 1.95-2.09 (2H, m), 2.39 (3H, s), 3.11-3.45 (3H, m), 3.44-3.53 (1H, m), 4.30-4.36 (1H, m), 6.35 (1H, d J=15.76 Hz), 7.34 (1H, d J=15.76 Hz), 7.37 (2H, d J=8.16 Hz), 7.64 (2H, d J=8.16 Hz), 7.86 (1H, d J=1.36 Hz), 8.18 (1H, d J=1.36 Hz).
1H-NMR (DMSO-d6): δ 1.24-1.33 (6H, m), 1.66-2.52 (5H, m), 3.26-3.88 (4H, m), 4.51-4.67 (1H, m), 6.38 (1H, d J=15.68 Hz), 7.36 (1H, d J=15.68 Hz), 7.94 (1H, s), 8.23 (1H, s).
1H-NMR (DMSO-d6): δ 1.85-1.91 (1H, m), 2.07-2.14 (1H, m), 2.38 (3H, s), 3.12-3.49 (4H, m), 4.33 (1H, br.s), 6.41 (1H, d J=15.82 Hz), 6.92 (1H, d J=9.18 Hz), 7.38 (2H, d J=8.24 Hz), 7.44 (1H, d J=15.82 Hz), 7.67 (2H, d J=8.24 Hz), 8.02 (1H, d J=9.18 Hz), 8.15 (1H, s), 9.10 (1H, m).
H-NMR (DMSO-d6): δ 1.50 (6H, br.s), 1.89-1.92 (1H, m), 2.18-2.22 (1H, m), 3.14 (4H, br.s), 3.14-3.54 (3H, m), 3.64-3.73 (1H, m), 4.76 (1H, br.s), 6.44 (1H, d J=15.84 Hz), 7.20 (1H, d J=9.36 Hz), 7.46 (1H, d J=15.84 Hz), 8.09 (1H, d J=9.36 Hz), 8.18 (1H, s), 9.61 (1H, m).
1H-NMR (DMSO-d6): δ 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 (1H, m), 4.47-4.54 (1H, m), 6.36 (1H, d J=15.76 Hz), 7.35 (1H, d J=15.76 Hz), 7.93 (1H, s), 8.21 (1H, s).
1H-NMR (DMSO-d6): δ 1.51-1.76 (8H, m), 1.90-2.30 (2H, m), 2.70-2.88 (1H, m), 3.28-3.68 (3H, m), 3.88-3.90 (1H, m), 4.50-4.69 (1H, m), 6.36 (1H, d J=15.78 Hz), 7.35 (1H, d J=15.78 Hz), 7.92 (1H, s), 8.23 (1H, s).
1H-NMR (DMSO-d6): δ 1.76-2.18 (9H, m), 3.26-3.68 (4H, m), 4.49-4.65 (1H, m), 6.35 (1H, d J=15.78 Hz), 7.35 (1H, d J=15.78 Hz), 7.90 (1H, s), 8.22 (1H, s).
1H-NMR (DMSO-d6): δ 1.92-2.17 (1H, m), 2.18-2.35 (1H, m), 3.39-3.77 (4H, m), 4.66 (2H, s), 4.83 (1H, m), 6.41 (1H, d J=15.78 Hz), 7.54-7.60 (1H, m), 7.77-7.81 ( ) 1H, m), 7.92-7.09 (2H, m), 8.23 (1H, s), 8.70-8.73 (1H, m).
1H-NMR (DMSO-d6): δ 1.97-2.22 (2H, m), 3.39-3.85 (4H, m), 4.52-4.66 (1H, m), 6.28-6.40 (1H, m), 7.29-7.39 (1H, m), 7.40-7.69 (5H, m), 7.88-7.96 (1H, m), 8.16-8.25 (1H, m).
1H-NMR (DMSO-d6): δ 0.04-0.45 (2H, m), 0.56-0.65 (2H, m), 1.02-1.16 (1H, m), 2.08-2.13 (1H, m), 2.49-2.56 (1H, m), 2.02-3.93 (6H, m), 4.51-4.88 (1H, m), 6.39 (1H, d J=15.78 Hz), 7.35 (1H, d J=15.78 Hz), 7.91 (1H, s), 8.24 (1H, s), 11.12 (1H, br.s).
1H-NMR (DMSO-d6): δ 1.65-1.89 (5H, m), 2.06-2.13 (1H, m), 2.20-2.40 (1H, m), 2.98-3.92 (6H, m), 4.75-4.90 (1H, m), 6.37 (1H, d J=15.78 Hz), 7.35 (1H, d J=15.78 Hz), 7.91 (1H, s), 8.22 (1H, s).
1H-NMR (DMSO-d6): δ 2.18-2.39 (2H, m), 3.66-3.84 (3H, m), 3.95-4.04 (1H, m), 4.76-4.79 (1H, m), 6.39 (1H, d J=15.76 Hz), 6.92-6.98 (1H, m), 7.36 (1H, d J=15.76 Hz), 7.92 (1H, s), 8.26 (1H, s), 8.60-8.63 (2H, m).
1H-NMR (DMSO-d6): δ 2.09-2.22 (2H, m), 3.39-3.84 (4H, m), 4.55-4.67 (1H, m), 6.31 & 6.35 (total 1H, each d J=15.68 Hz), 7.00 (1H, m), 7.21-7.40 (3H, m), 7.56-7.63 (2H, m), 7.87 & 7.91 (total 1H, each s), 8.16 & 8.24 (total 1H, each s).
1H-NMR (DMSO-d6): δ 2.09-2.32 (2H, m), 2.32 & 2.35 (total 3H, each s), 3.40-3.75 (4H, m), 4.53-4.66 (1H, m), 6.32 & 6.35 (total 1H, each d J=15.76 Hz), 6.98 (1H, m), 7.29-7.73 (5H, m), 7.88 & 7.92 (total 1H, each s), 8.15 & 8.24 (total 1H, each s).
1H-NMR (DMSO-d6): δ 2.03-2.23 (2H, m), 3.43-3.76 (4H, m), 4.53-4.67 (1H, m), 6.33 & 6.36 (total 1H, each d J=15.74 Hz), 7.05 (1H, m), 7.27 & 7.36 (total 1H, each d J=15.74 Hz), 7.45-7.58 (4H, m), 7.89 & 7.92 (total 1H, each s), 8.16 & 8.25(total 1H, each s).
1H-NMR (DMSO-d6): δ 2.08-2.21 (2H, m), 3.15-3.22 (2H, m), 3.27-3.87 (2H, m), 4.55-4.65 (1H, m), 6.33 & 6.37 (total 1H, each d J=15.86 Hz), 6.93 (1H, m), 7.27-7.55 (5H, m), 7.88 & 7.93 (total 1H, each s), 8.15 & 8.25 (total 1H, each s).
To a stirred solution of tert-butyl (5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridinyl){(3R)-1-[(2,6,6-trimethyl-1-cyclohexen-1-yl)methyl]-3-pyrrolidinyl}carbamate (80 mg) in methanol (1 mL) was added 4N hydrogen chloride in methanol (3 mL) 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 (1 mL). To this solution was added 4N hydrogen chloride in dioxane (3 mL) 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-1-cyclohexen-1-yl)methyl]-3-pyrrolidinyl}amino)-3-pyridinyl]acrylamide dihydrochloride (40 mg) as a pale tan amorphous solid.
1H-NMR (300 MHz, DMSO-d6) δ1.10 (3H, s), 1.11 (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 (1H, m), 6.39 (1H, d, J=16.1 Hz), 6.92-7.23 (1H, m), 7.39-7.54 (1H, m), 7.96-8.15 (1H, m), 8.16-8.27 (1H, m); MS (ES+) m/z 385(free, M+1).
The following compound was obtained in a similar manner to that of Example 189.
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 (1H, m), 2.46-3.62 (2H, m), 4.50-4.74 (1H, m), 6.37 (1H, d, J=15.4 Hz), 6.88-7.15 (1H, m), 7.44 (1H, d, J=15.4 Hz), 7.92-8.06 (1H, m), 8.19-8.26 (1H, m); MS (ES+) m/z 387(M+1, free).
A solution of 2NHCl-EtOH solution (3.4 ml) was added to a mixture of (2Z)-3-(5-chloro-6-{[(3R)-1-cyclopentyl-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoro-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (620 mg) in EtOH (5 ml) and stirred at 20-25° C. for 2 hours. IPE (20 ml) 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]amino}-3-pyridinyl)-2-fluoro-N-hydroxyacrylamide dihydrochloride (500 mg).
1H-NMR (DMSO-d6): δ 1.52-1.55 (2H, m), 1.75-1.76 (4H, m), 1.97-2.09 (3H, m), 3.04-3.12 (1H, m), 3.20-3.81 (4H, m), 4.73 & 4.89 (total 1H, each m), 6.79 (1H, dd J=3.08 Hz, 39.72 Hz), 7.27 (1H, m), 7.90 (1H, d J=1.80Hz), 8.30-8.32 (1H, m), 11.52 (1H, m).
The following compounds were obtained in a similar manner to that of Example 191.
1H-NMR (DMSO-d6): δ 1.04-1.25 (3H, m), 1.45-1.48 (2H, m), 1.58-1.62 (1H, m), 1.78-1.80 (2H, m), 2.04-2.10 (3H, m), 2.20-2.51 (1H, m), 3.10-3.15 (2H, m), 3.26-3.46 (2H, m), 3.64 & 3.78 (total 1H, each m), 4.74 & 4.86 (total 1H, each m), 6.79 (1H, dd J=2.48 Hz, 39.72 Hz), 7.20-7.30 (1H, m), 7.90 (1H, d J=1.56 Hz), 8.30-8.32 (1H, m), 11.29-11.36 (1H, m).
1H-NMR (DMSO-d6): δ 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 (1H, m), 2.30-2.50 (1H, m), 2.99-3.11 (3H, m), 3.20-3.42 (1H, m), 3.52-3.60 (1H, m), 3.75 & 3.90-3.92 (total 1H, each m), 4.77 & 4.91 (total 1H, each m), 6.79 (1H, dd J=1.80Hz, 39.74 Hz), 7.21 & 7.41 (total 1H, each m), 7.90 (1H, d J=1.88 Hz), 8.30-8.32 (1H, m), 10.71-10.72 (1H, m).
1H-NMR (DMSO-d6): δ 2.05-2.07 (1H, m), 2.30-2.37 & 2.48-2.54 (total 1H, each m), 3.13-3.18 (1H, m), 3.32-3.68 (3H, m), 4.40 (2H, d J=5.64 Hz), 4.71 & 4.90 (total 1H, each m), 6.78 (1H, dd J=3.20Hz, 39.70 Hz), 7.27 (1H, m), 7.44-7.48 (3H, m), 7.63-7.66 (2H, m), 7.89-7.91 (1H, m), 8.29 (1H, m), 11.56-11.57 (1H, m).
1H-NMR (DMSO-d6): δ 2.09-2.19 (1H, m), 2.32 & 2.62 (total 1H, each in), 3.24-3.47 (2H, m), 3.57-3.82 (2H, m), 4.44 & 4.55 (total 2H, each d J=5.68 Hz), 4.64 & 4.80 (total 1H, each m), 6.88 (1H, dd J=5.12 Hz, 39.08 Hz), 7.00 & 7.20 (total 1H, each d J=9.24 Hz), 7.44-7.47 (3H, m), 7.65-7.70 (2H, m), 8.03-8.09 (1H, m), 8.22 (1H, s), 11.52 & 11.65 (total 1H, each br, s).
A mixture of (2E)-3-(5-chloro-6-{[(3R)-1-({trans-4-[(dimethylamino) methyl]cyclohexyl}-carbonyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (530 mg) and 2N HCl/Ethanol (5 ml) was stirred for 3 hrs. EtOAc (10 ml) and IPE (50 ml) was added and stirred. After 1 hour, precipitate was filtered and dried to give 462 mg (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+1).
1HNMR (400 MHz, DMSO-d6): δ 0.90-2.80 (14H, m), 2.51 (6H, b.s), 3.2-3.8 (4H, m), 4.52 and 4.66 (1H, br.s), 6.35 (1H, dd, J=4.9, 15.8 Hz), 6.84-6.98 (1H, m), 7.34 (1H, d, J=15.8 Hz), 7.89 (1H, dd, J=1.8, 4.4 Hz), 8.23 (1H, dd, J=1.8, 4.4 Hz).
A mixture of (2E)-3-(5-chloro-6-{[(3R)-1-(cyclohexylacetyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (680 mg) and 2N HCl/Ethanol (13.8 ml) was stirred for 2 hrs. EtOAc (10 ml) and IPE (50 ml) was added and stirred. After 1 hr, precipitate was filtered and dried to give 387 mg (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+1).
1HNMR (400 MHz, CDCl3): δ 0.82-2.27 (15H, m), 3.20-3.80 (4H, m), 4.51 (1H, m), 4.61 (1H, m), 6.34 (1H, d, J=15.8 Hz), 7.34 (1H, d, J=15.8 Hz), 7.90 (1H, s), 8.23 (1H, s).
To a solution of (2E)-3-(5-fluoro-6-{[(3R)-1-(2-octyn-1-yl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (155 mg) in methanol (3.5 ml) was added 4-methylbenzenesulfonic acid hydrate (122 mg) 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 (178 mg, 73%) was obtained as colorless powder.
MASS(API-ES); 375 (M+H)+Free 1H-NMR (200 MHz), (DMSO-d6, δ): 0.84 (3H, t, J=6.8 Hz), 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 (1H, br), 6.32 (1H, d, J=16 Hz), 7.12 (4H, d, J=7.9 Hz), 7.39 (1H, d, J=16 Hz), 7.49 (4H, d, J=7.9 Hz), 7.70 (1H, d, J=13 Hz), 8.08 (1H, s), 10.30 (1H, br).
The following compound was obtained in a similar manner to that of Example 198.
MASS(API-ES); 381 (M+H)+Free,
1H-NMR (200 MHz), (DMSO-d6, δ): 2.00-2.65 (2H, m), 2.29 (6H, s), 3.10-4.20 (4H, m), 4.48 (2H, br), 4.69 (1H, br), 6.32 (1H, d, J=16 Hz), 7.12 (4H, d, J=7.8 Hz), 7.30-7.55 (11H, m), 7.60-7.80 (1H, m), 8.09 (1H, s), 10.51 (1H, br).
The following compounds were obtained in a similar manner to that of Example 41.
MASS(ESI); 339 (M+H)+.
1H-NMR (300 MHz, DMSO-d6) δ 1.63 (1.5H, d. J=6 Hz), 1.65 (1.5H, d, J=6 Hz), 1.84-2.14 (1H, m), 2.30-2.53 (1H, 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 (1H, br); MS (ES+) m/z 354.
1H-NMR (300 MHz, DMSO-d6) δ1.59 (2H, m), 1.76-1.91 (4H, m), 3.16-3.30 (4H, m), 6.74 (1H, d, J=15.5 Hz), 7.21-7.38 (2H, m), 7.46 (1H, d, J=15.5 Hz), 7.54 (1H, m), 7.85 (1H, dd, J=7.5, 1.5 Hz), 8.26 (1H, s), 8.39 (1H, s); MS (ES+) m/z 340.
The following compound(s) was(were) obtained in a similar manner to that of Example 92.
1H-NMR (300 MHz, DMSO-d6) δ0.85-1.32 (5H, m), 1.54-1.90 (6H, m), 2.05 (1H, m), 2.22-2.54 (1H, m), 2.93-3.30 (3H, m), 3.34-4.72 (7H, m), 6.40 (1H, d, J=16 Hz), 7.32 (1H, d, J=16 Hz), 8.06 (1H, m), 8.59 (2×1H, s), 10.41 (1H, m); MS (ES+) m/z 346.
The following compound was obtained in a similar manner to that of Example 89.
MASS(API-ES); 357 (M+H)+Free
1H-NMR (200 MHz), (DMSO-d6, δ): 1.90-2.60 (2H, m), 2.95-3.85 (4H, m), 4.35-4.50 (2H, m), 4.55-4.75 (1H, m), 4.77 (2H, br), 6.31 (1H, d, J=16 Hz), 7.30-7.80 (8H, m), 8.06 (1H, s), 11.31 (1H, br).
The following compounds were obtained in a similar manner to that of Example 89.
MASS(API-ES); 407 (M+H)+Free
1H-NMR (200 MHz), (DMSO-d6, δ): 1.95-2.60 (2H, m), 3.15-4.20 (4H, m), 4.31 (2H, t, J=16 Hz), 4.50-4.85 (1H, m), 6.33 (1H, d, J=16 Hz), 7.39 (1H, d, J=16 Hz), 7.50-7.80 (7H, m), 8.08 (1H, s), 11.28 (1H, br).
MASS(API-ES); 359 (M+H)+Free,
1H-NMR (200 MHz), (DMSO-d6, δ): 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 (1H, m), 6.40 (1H, d, J=16 Hz), 7.10 (1H, d, J=9.2 Hz), 7.45 (1H, d, J=16 Hz), 8.04 (1H, d, J=9.2 Hz), 8.20 (1H, s), 9.30 (1H, br), 10.90 (1H, br).
The following compound was obtained in a similar manner to that of Example 41.
1H-NMR (200 MHz, DMSO-d6): δ 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 (1H, d, J=15.8 Hz), 7.14 (1H, d, J=9.3 Hz), 7.43 (1H, d, J=15.8 Hz), 8.03-8.18 (2H, m), 10.28 (1H, brs), 10.29 (1H, brs).
The following compound was obtained in a similar manner to that of Example 89.
MASS(API-ES); 353 (M+H)+Free
1H-NMR (200 MHz), (DMSO-d6, δ): 1.80-2.40 (2H, m), 3.30-3.95 (4H, m), 4.40-4.70 (1H, m), 6.40 (0.5H, d, J=16 Hz), 6.44 (0.5H, d, J=16 Hz), 7.12 (0.5H, d, J=9.2 Hz), 7.23 (0.5H, d, J=9.2 Hz), 7.30-7.70 (6H, m), 8.00-8.40 (2H, m), 9.48 (0.5H, br), 9.71 (0.5H, br), 10.90 (1H, br).
The following compound was obtained in a similar manner to that of Example 41.
1H NMR (DMSO-d6, δ): 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 (1H, m), 5.37-5.44 (1H, m), 6.39 (1H, d, J=15.9 Hz), 7.35 (1H, d, J=15.9 Hz), 7.94 (1H, s), 8.19 (1H, s).
Mass (APCI): 371(M+H)+.
The following compound was obtained in a similar manner to that of Example 129
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 (1H, m), 6.40 (1H, d, J=15.8 Hz), 7.05 (1H, d, J=10 Hz), 7.16-7.24 (2H, m), 7.25-7.33 (2H, m), 7.46 (1H, d, J=15.8 Hz), 8.04 (1H, d, J=10 Hz), 8.20 (1H, s), 9.38 (1H, br), 10.82 (1H, br); MS (ES+) m/z 296.
The following compounds were obtained in a similar manner to that of Example 41
1H-NMR (200 MHz, DMSO-d6) δ: 1.90-1.90 (2H, m), 2.00-2.40 (5H, m), 2.90-3.90 (5H, m), 4.69-4.86 (1H, m), 6.40 (1H, d, J=15.8 Hz), 7.22 (1H, brs), 7.50 (1H, d, J=15.8 Hz), 7.92 (1H, s), 8.23 (1H, s), 11.86 (1H, brs),
MASS(ESI); 337 (M+H)+.
1H-NMR (200 MHz, DMSO-d6) δ: 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 (1H, m), 6.37 (1H, d, J=15.8 Hz), 7.18 (1H, brs), 7.35 (1H, d, J=15.8 Hz), 7.91 (1H, s), 8.23 (1H, s), 141.39 (1H, brs),
MASS(ESI); 351 (M+H)+.
The following compound was obtained in a similar manner to that of Example 129.
1H-NMR (300 MHz, DMSO-d6) δ2.50 (3H, s), 6.43 (1H, d, J=16 Hz), 6.88 (1H, d, J=7.5 Hz), 7.01 (1H, d, J=7.5 Hz), 7.45 (1H, d, J=16 Hz), 7.53 (2H, d, J=8.5 Hz), 7.59 (2H, d, J=8.5 Hz), 7.83 (1H, dd, J=7.5, 7.5 Hz), 10.12 (1H, br); MS (ES+) m/z 270.
The following compound was obtained in a similar manner to that of Example 41.
1H-NMR (200 MHz, DMSO-d6) δ: 2.06 (4H, m), 2.71 (3H, d, J=4.6 Hz), 3.04-3.49 (4H, m), 4.09-4.40 (1H, m), 6.40 (1H, d, J=15.8 Hz), 7.35 (1H, d, J=15.8 Hz), 7.95 (1H, s), 8.20 (1H, s), 10.88 (1H, brs),
MASS(ESI); 311 (M+H)+.
The following compound was obtained in a similar manner to that of Example 129.
1H-NMR (300 MHz, DMSO-d6) δ 1.48-1.78 (4H, m), 1.82-2.13 (2H, m), 4.00 (1H, m), 4.30-4.60 (1H, m), 4.54 (2H, s), 6.32 (1H, d, J=16 Hz), 6.86 (1H, br), 7.20-7.38 (6H, m), 7.88 (1H, s), 8.21 (1H, s); MS (ES+) m/z 388.
The following compound was obtained in a similar manner to that of Example 92.
1H-NMR (300 MHz, DMSO-d6) δ 1.34-1.82 (10H, m), 1.94-2.16 (3H, m), 2.30 (1H, m), 3.08-4.20 (5H, m), 4.57 (1H, m), 4.66 (1H, m), 6.38 (1H, d, J=15.5 Hz), 7.00 (1H, m), 7.44 (1H, d, J=15.5 Hz), 7.98 (1′H, m), 8.21 (1H, s), 10.26 (1H, br-s), 11.11 (1H, br); MS (ES+) m/z 345.
The following compounds were obtained in a similar manner to that of Example 41.
1H-NMR (200 MHz, DMSO-d6) δ: 1.09-1.62 (7H, m), 1.78-2.07 (7H, m), 2.84-3.46 (5H, m), 6.38 (1H, d, J=15.8 Hz), 6.77 (1H, d, J=7.6 Hz), 7.34 (1H, d, J=15.8 Hz), 7.90 (1H, s), 8.23 (1H, s), 10.44 (1H, brs).
MASS(ESI); 379 (M+H)+.
1H-NMR (200 MHz, DMSO-d6) δ: 1.56-1.99 (14H, m), 2.79-2.96 (1H, m), 3.32-3.54 (3H, m), 6.38 (1H, d, J=15.8 Hz), 6.84 (1H, d, J=7.6 Hz), 7.34 (1H, d, J=15.8 Hz), 7.90 (1H, s), 8.22 (1H, s), 10.71 (1H, brs),
MASS(ESI); 365 (M+H)+.
The following compound was obtained in a similar manner to that of Example 89.
MASS(API-ES); 358 (M+H)+Free
1H-NMR (200 MHz), (DMSO-d6, δ): 1.90-2.60 (2H, m), 2.95-3.85 (4H, m), 4.35-4.70 (3H, m), 5.70 (2H, br), 6.69 (1H, d, J=25 Hz), 7.40-7.50 (3H, m), 7.60-7.70 (2H, m), 7.99 (0.5H, d, J=1.1 Hz), 8.06 (0.5H, d, J=1.1 Hz), 8.33 (1H, s), 11.43 (1H, br).
The following compounds were obtained in a similar manner to that of Example 129.
1H-NMR (300 MHz, DMSO-d6) δ0.78-0.97 (2H, m), 1.07-1.28 (3H, m), 1.51-1.74 (6H, m), 1.85 (1H, m), 2.44 (1H, m), 2.96-3.12 (2H, m), 3.25-3.40 (2H, m), 4.63 (1H, t, J=9 Hz), 6.61 (1H, d, J=15.5 Hz), 7.37 (1H, d, J=15.5 Hz), 7.90 (1H, br), 8.07 (1H, s), 8.08 (1H, s); MS (ES+) m/z 360.
1H-NMR (300 MHz, DMSO-d6) δ1.13-1.54 (5H, m), 1.64 (1H, m), 1.69-1.86 (4H, m), 2.42 (1H, m), 6.37 (1H, d, J=16 Hz), 7.14 (1H, ddd, J=7.5, 7.5, 1.5 Hz), 7.21-7.30 (2H, m), 7.36 (1H, d, J=16 Hz), 7.78 (1H, d, J=7.5 Hz), 8.02 (1H, d, J=1 Hz), 8.20 (1H, d, J=1 Hz), 8.32 (1H, s), 9.95 (1H, s); MS (ES+) m/z 415.
1H-NMR (300 MHz, DMSO-d6) δ 1.07-1.43 (5H, m), 1.55-1.78 (5H, m), 2.34 (1H, m), 6.23 (1H, d, J=16 Hz), 6.81 (2H, d, J=8 Hz), 7.05 (1H, dd, J=7.5, 7.5 Hz), 7.12 (1H, dd, J=7.5, 7.5 Hz), 7.28 (1H, d, J=7.5 Hz), 7.34 (1H, d, J=16 Hz), 7.37 (2H, d, J=8 Hz), 7.59 (1H, d, J=7.5 Hz), 7.72 (1H, br), 9.25 (1H, s), 10.60 (1H, br); MS (ES+) m/z 380.
1H-NMR (300 MHz, DMSO-d6) δ 1.12-1.49 (5H, m), 1.59-1.84 (5H, m), 2.34 (1H, m), 6.40 (1H, d, J=16 Hz), 7.16-7.34 (3H, m), 7.39 (1H, d, J=16 Hz), 7.95 (1H, s), 8.03 (1H, s), 8.27 (1H, s), 8.65 (1H, s), 9.81 (1H, s); MS (ES+) m/z 415.
The following compound was obtained in a similar manner to that of Example 89.
cyclopentyl (3R)-3-({3-chloro-5-[(1E)-3-(hydroxyamino)-3-oxo-1-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 (1H, m), 4.54 (1H, m), 4.99 (1H, brs), 6.23 (1H, d, J=15.8 Hz), 6.91 (1H, brs), 7.34 (1H, d, J=15.8 Hz), 7.89 (1H, s), 8.22 (1H, s),
MASS(ESI); 395 (M+H)+.
The following compound was obtained in a similar manner to that of Example 41.
1H-NMR (200 MHz, DMSO-d6) δ: 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 (1H, brs), 6.37 (1H, d, J=15.8 Hz), 6.86 (1H, brs), 7.34 (1H, d, J=15.8 Hz), 7.45-7.48 (3H, m), 7.61-7.72 (2H, m), 7.88 (1H, s), 8.18 (1H, s), 11.15-11.52 (1H, brs),
MASS(ESI); 387 (M+H)+.
The following compound was obtained in a similar manner to that of Example 89.
MASS(API-ES); 363 (M+H)+Free
1H-NMR (200 MHz), (DMSO-d6, δ): 0.80-1.40 (5H, m), 1.55-1.90 (6H, m), 1.95-2.60 (2H, m), 2.90-4.10 (6H, m), 4.55-4.80 (1H, m), 4.82 (2H, br), 6.33 (1H, d, J=16 Hz), 7.39 (1H, d, J=16 Hz), 7.60 (1H, br), 7.69 (1H, d, J=12 Hz), 8.07 (1H, s), 10.53 (1H, br).
The following compounds were obtained in a similar manner to that of Example 41.
1H-NMR (200 MHz, DMSO-d6) δ: 1.58-1.77 (7H, m), 1.98-2.13 (2H, m), 3.24-3.66 (4H, m), 4.54 (1H, m), 4.97 (1H, m), 6.34 (1H, d, J=15.8 Hz), 6.92 (1H, brs), 7.34 (1H, d, J=15.8 Hz), 7.89 (1H, s), 8.23 (1H, s),
MASS(ESI); 351 (M+H)+.
1H-NMR (200 MHz, DMSO-d6) δ: 1.02-1.91 (14H, m), 2.62-3.07 (3H, m), 3.80-4.25 (3H, m), 6.38 (1H, d, J=15.8 Hz), 6.69 (1H, brs), 7.36 (1H, d, J=15.8 Hz), 7.93 (1H, s), 8.19 (1H, s), MASS(ESI); 407 (M+H)+.
The following compound was obtained in a similar manner to that of Example 89.
MASS(API-ES); 377 (M+H)+Free,
1H-NMR (200 MHz), (DMSO-d6, δ): 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 (1H, m), 5.40 (1H, br), 6.33 (1H, d, J=16 Hz), 7.40 (1H, d, J=16 Hz), 7.75 (1H, d, J=13 Hz), 7.80 (1H, br), 8.08 (1H, s).
The following compound was obtained in a similar manner to that of Example 92.
1H-NMR (300 MHz, DMSO-d6) δ1.43-1.62 (2H, m), 1.64-1.84 (4H, m), 1.90-2.16 (3H, m), 2.29 (1H, m), 3.10-4.05 (5H, m), 4.58 (1H, m), 4.70 (1H, m), 6.38 (1H, d, J=16 Hz), 7.02 (1H, m), 7.44 (1H, d, J=16 Hz), 8.00 (1H, m), 8.21 (1H, s), 10-26 (1H, s), 11.16-11.44 (1H, br); MS (ES+) m/z 317.
The following compound was obtained in a similar manner to that of Example 129.
1H-NMR (300 MHz, CD3OD) δ2.10-2.32 (1H, m), 2.40-2.75 (1H, m), 2.47 (1.7H, s), 2.49 (1.3H, s), 3.23-3.45 (1H, 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 (1H, d, J=15.5 Hz), 6.74 (1H, 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.
MASS(API-ES); 356 (M+H)+Free
1H-NMR (200 MHz), (DMSO-d6, δ): 1.90-2.70 (2H, m), 3.00-3.90 (4H, m), 4.00-4.50 (3H, m), 6.26 (1H, d, J=16 Hz), 6.60-6.90 (1H, m), 7.20-7.39 (3H, m), 7.40-7.50 (3H, m), 7.58-7.70 (2H, m), 11.10-11.50 (1H, m).
MASS(API-ES); 393 (M+H)+Free,
1H-NMR (200 MHz), (DMSO-d6, δ): 1.95-2.70 (2H, m), 3.10-4.00 (4H, m), 4.40-4.90 (3H, m), 6.31 (1H, d, J=16 Hz), 7.20-7.80 (6H, m), 8.07 (1H, s), 11.22 (1H, br).
MASS(API-ES); 364 (M+H)+Free,
1H-NMR (200MHz), (DMSO-d6, δ): 2.00-2.60 (2H, m), 3.10-4.00 (4H, m), 4.55-5.00 (3H, m), 6.34 (1H, d, J=16 Hz), 7.38 (1H, d, J=16 Hz), 7.56 (1H, br), 7.69 (1H, d, J=13 Hz), 7.90-8.00 (2H, m), 8.07 (1H, s), 11.58 (1H, br).
MASS(API-ES); 371 (M+H)+Free,
1H-NMR (200 MHz), (DMSO-d6, δ): 1.95-2.60 (2H, m), 3.00-4.40 (8H, m), 4.50-4.90 (1H, m), 6.32 (1H, d, J=16 Hz), 7.20-7.50 (6H, m), 7.52 (1H, br), 7.69 (1H, d, J=12 Hz), 8.06 (0.5H, s), 8.09 (0.5H, s), 11.00-11.30 (1H, m).
MASS(API-ES); 392 (M+H)+Free,
1H-NMR (200 MHz), (DMSO-d6, δ): 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 (1H, m), 6.35 (1H, d, J=16 Hz), 7.39 (1H, d, J=16 Hz), 7.58 (1H, br), 7.69 (1H, d, J=13 Hz), 8.08 (1H, s), 9.65 (1H, br).
MASS(API-ES); 392 (M+H)+Free,
1H-NMR (200 MHz), (DMSO-d6, δ): 2.00-2.70 (2H, m), 3.10-4.05 (4H, m), 4.60-5.00 (3H, m), 6.35 (1H, d, J=16 Hz), 7.38 (1H, d, J=16 Hz), 7.72 (1H, d, J=12 Hz), 7.75 (1H, br), 8.00-8.10 (2H, m), 8.66 (1H, d, J=5.0 Hz), 8.79 (1H, s), 11.80-12.10 (1H, m).
The following compound was obtained in a similar manner to that of Example 129.
1H-NMR (300 MHz, DMSO-d6) δ2.12 (1H, m), 2.44 (1H, m), 3.35-4.00 (4H, m), 4.59 (1H, m), 4.87 (2H, s), 6.64 (1H, d, J=15 Hz), 7.38 (1H, d, J=15 Hz), 7.65-7.76 (2H, m), 7.84 (1H, ddd, J=7, 7, 1.5 Hz), 8.02-8.38 (6H, m), 8.50 (1H, d, J=8.5 Hz), 11.16 (1H, br-s); MS (ES+) m/z 391.
The following compound was obtained in a similar manner to that of Example 92.
1H-NMR (300 MHz, DMSO-d6) δ1.02-1.52 (6H, m), 1.60 (1H, m), 1.73-1.86 (2H, m), 1.94-2.14 (2H, m), 2.27 (1H, m), 3.04-4.05 (5H, m), 4.58 (1H, m), 6.34 (1H, d, J=16 Hz), 6.90 (1H, m), 7.42 (1H, d, J=16 Hz), 8.21 (1H, s); MS (ES+) m/z 331.
The following compound was obtained in a similar manner to that of Example 89.
MASS(API-ES); 414 (M+H)+Free,
1H-NMR (400 MHz), (DMSO-d6, δ): 2.00-2.65 (2H, m), 3.20-4.10 (4H, m), 4.60-5.10 (3H, m), 6.32 (1H, d, J=16 Hz), 7.38 (1H, d, J=16 Hz), 7.50-7.75 (4H, m), 8.00-8.30 (3H, m), 11.50-11.90 (1H, m).
The following compounds were obtained in a similar manner to that of Example 41.
1H-NMR (400 MHz, DMSO-d6) δ: 1.52 (1H, brs), 1.93-2.06 (3H, m), 2.92-3.55 (4H, m), 4.34 (1H, brs), 4.50 (2H, s), 6.39 (1H, d, J=15.8 Hz), 7.04 (1H, brs), 7.39-7.52 (3H, m), 7.57-7.60 (1H, m), 7.97-8.02 (2H, m), 8.19 (1H, brs), 10.95 (1H, brs),
MASS(ESI); 387 (M+H)+.
1H-NMR (400 MHz, DMSO-d6) δ: 1.46 (1H, brs), 1.81-2.08 (3H, m), 2.89-3.52 (4H, m), 4.34 (1H, brs), 4.39-4.42 (1H, m), 6.42 (1H, d, J=15.8 Hz), 7.08-7.10 (1H, m), 7.42 (1H, d, J=15.8 Hz), 7.47-7.55 (3H, m), 7.62 (1H, d, J=6.8 Hz), 7.79 (1H, s), 8.06 (1H, brs), 8.20 (1H, s), 11.08-11.22 (1H, m),
MASS(ESI); 387 (M+H)+.
MASS(ESI); 323 (M+H)+.
The following compounds were obtained, in a similar manner to that of Example 129.
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 (1H, d, J=15 Hz), 7.18-7.32 (5H, m), 7.40 (1H, d, J=15 Hz), 8.04 (0.5H, s), 8.06 (0.5H, s), 8.17 (1H, s), 11.63 (1H, br); MS (ES+) m/z 366.
1H-NMR (300 MHz, DMSO-d6) δ3.93 (2H, s), 6.35 (1H, d, J=16 Hz), 7.07-7.32 (9H, m), 7.33 (1H, d, J=16 Hz), 7.45 (1H, d, J=8 Hz), 7.98 (1H, d, J=1.5 Hz), 8.09 (1H, d, J=1.5 Hz), 8.31 (1H, s); MS (ES+) m/z 380.
1H-NMR (300 MHz, DMSO-d6) δ 1.32 (3H, t, J=7 Hz), 2.00 (1H, m), 2.21-2.53 (11, 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 (1H, d, J=9 Hz), 6.98 (1H, d, J=9 Hz), 7.38 (1H, d, J=15.5 Hz), 7.49 (1H, d, J=9 Hz), 7.50 (1H, d, J=9 Hz), 7.98 (0.5H, br), 8.02 (0.5H, s), 8.04 (0.5H, s), 8.14 (1H, s), 8.16 (0.5H, br), 10.87 (1H, br); MS (ES+) m/z 384.
The following compounds were obtained in a similar manner to that of Example 92.
1H-NMR (300 MHz, DMSO-d6) δ1.92-2.17 (1H, m), 2.24-2.58 (1H, 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 (1H, d, J=15.5 Hz), 7.40-7.52 (3H, m), 7.60-7.71 (2H, m), 7.75 (0.5H, m), 7.92 (1H, s), 7.95 (0.5w, 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.
1H-NMR (300 MHz, DMSO-d6) δ1.95-2.16 (1H, m), 2.19-2.54 (1H, m), 2.96-4.00 (8H, m), 4.58 (1H, m), 6.40 (1H, d, J=16 Hz), 7.23-7.42 (7H, m), 7.99 (0.5H, br), 8.13 (0.5H, br), 8.58 (1H, s), 8.59 (1H, s), 10.89 (0.5H, br), 11.11 (0.5H, br); MS (ES+) m/z 354.
The following compounds were obtained in a similar manner to that of Example 89.
MASS(API-ES); 358 (M+H)+Free,
1H-NMR (200 MHz), (DMSO-d6, δ): 1.90-2.60 (2H, m), 2.95-3.90 (4H, m), 4.35-4.70 (3H, m), 6.21 (2H, br), 6.70 (1H, d, J=39 Hz), 7.40-7.50 (3H, m), 7.60-7.70 (2H, m), 8.04 (0.5H, d, J=1.1 Hz), 8.10 (0.5H, d, J=11.1 Hz), 8.32 (1H, s), 11.46 (1H, br).
MASS(API-ES); 331 (M+H)+Free,
1H-NMR (200 MHz), (DMSO-d6, δ): 2.00-2.60 (2H, m), 3.05-4.10 (4H, m), 3.87 (2H, dt, J=3.8 Hz, J=13 Hz), 4.50-4.90 (1H, m), 6.33 (1H, d, J=16 Hz), 6.57 (1H, tt, J=3.8 Hz, J=54 Hz), 7.39 (1H, d, J=16 Hz), 7.60 (1H, br), 7.69 (1H, d, J=13 Hz), 8.08 (1H, s).
MASS(API-ES); 361 (M+H)+Free,
1H-NMR (200 MHz), (DMSO-d6, δ): 1.90-2.60 (2H, m), 2.85-3.90 (6H, m), 4.60 (2H, t, J=6.4 Hz), 4.65 (1H, br), 6.25-6.40 (2H, m), 7.38 (1H, d, J=16 Hz), 7.54 (1H, d, J=1.6 Hz), 7.69 (1H, d, J=13 Hz), 7.85 (1H, d, J=2.2 Hz), 8.06 (1H, s), 11.20-11.60 (1H, m).
The following compound was obtained in a similar manner to that of Example 129.
1H-NMR (300 MHz, DMSO-d6) δ1.26 (1H, m), 1.41 (1H, m), 2.12 (1H, m), 3.02 (1H, m), 6.34 (1H, d, J=16 Hz), 7.13-7.22 (3H, m), 7.24-7.38 (3H, m), 7.51 (1H, br), 7.92 (1H, s), 8.21 (1H, s); MS (ES−) m/z 328.
The following compound was obtained in a similar manner to that of Example 41.
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 (1H, m), 5.75 (1H, d, J=15.8 Hz), 7.20 (1H, brs), 7.35 (1H, d, J=15.8 Hz), 7.91 (1H, s), 8.22 (1H, s), 11.32 (1H, brs).
The following compound was obtained in a similar manner to that of Example 89.
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 (1H, brs), 6.33 (1H, d, J=15.8 Hz), 6.85 (1H, brs), 7.34 (1H, d, J=15.8 Hz), 7.88, (1H, s), 8.22 (1H, s).
MASS(ESI); 383 (M+H)+.
The following compounds were obtained in a similar manner to that of Example 41.
1H NMR (DMSO-d6, δ): 2.00-2.20 (4H, m), 3.00-3.46 (4H, m), 4.10-4.20 (1H, m), 4.30-4.46 (2H, m), 6.39 (1H, d, J=15.9 Hz), 7.26-7.58 (4H, m), 7.66 (1H, d, J=8.3 Hz), 7.95 (1H, s), 8.18-8.22 (1H, m),
Mass (APCI): 405(M+H)+
1H NMR (DMSO-d6, δ): 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), 10.97 (1H, brs),
Mass (APCI): 388(M+H)+.
1H NMR (DMSO-d6, δ): 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), 11.80 (1H, brs),
Mass (ESI): 388(M+H)+.
1H NMR (DMSO-d6, δ): 2.00-2.30 (4H, m), 3.10-3.60 (4H, m), 4.10-4.30 (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)+.
1H NMR (DMSO-d6, δ): 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), 11.30 (1H, brs),
Mass (ESI): 421(M+H)+.
1H NMR (DMSO-d6, δ): 2.00-2.25 (4H, m), 3.10-3.50 (4H, m), 4.10-4.30 (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), 11.20 (1H, brs),
Mass (ESI): 421(M+H)+.
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 (1H, m), 6.40 (1H, d, J=15.9 Hz), 7.35 (1H, d, J=15.9 Hz), 8.20 (1H, s), 8.30 (1H, s), 10.30 (1H, brs),
Mass (APCI): 393(M+H)+.
Mass (APCI): 405(M+H)+.
1H NMR (DMSO-d6, δ): 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 (1H, m), 5.37-5.44 (1H, m), 6.39 (1H, d, J=15.9 Hz), 7.35 (1H, d, J=15.9 Hz), 7.94 (1H, s), 8.19 (1H, s),
Mass (APCI): 365(M+H)+.
The following compounds were obtained in a similar manner to that of Example 129.
1H-NMR (300 MHz, DMSO-d6) δ1.10-1.40 (5H, m), 1.54-1.95 (6H, m), 2.02-2.45 (2H, m), 3.25-4.15 (5H, m), 6.15 (1H, br-d, J=16 Hz), 6.34 (1H, m), 6.56-6.70 (2H, m), 7.26-7.40 (3H, m), 8.86 (1H, s), 10.53 (1H, s);
MS (ES+) m/z 358.
H-NMR (300 MHz, DMSO-d6) δ 2.31 (3H, s), 6.38 (1H, d, J=16 Hz), 7.06 (1H, d, J=9 Hz), 7.22 (2H, d, J=8 Hz), 7.38-7.50 (3H, m), 8.00 (m, br-d, J=8 Hz), 8.23 (1H, d, J=1.5 Hz), 10.27 (1H, br-s); MS (ES+) m/z 270.
1H-NMR (300 MHz, DMSO-d6) δ1.21 (3H, t, J=7 Hz), 4.10 (2H, q, J=7 Hz), 6.44 (1H, d, J=15.8 Hz), 7.03 (1H, dd, J=7.5, 7.5 Hz), 7.17 (1H, d, J=8 Hz), 7.21 (1H, d, J=9.5 Hz), 7.30 (1H, dd, J=7.5, 7.5 Hz), 7.46 (1H, d, J=15.8 Hz), 7.53 (1H, br-d, J=7.5 Hz), 8.13 (1H, br-d, J=9.5 Hz), 8.21 (1H, d, J=1.5 Hz), 10.38 (1H, br), 10.82 (1H, br); MS (ES+) m/z 300.
1H-NMR (300 MHz, DMSO-d6) δ2.09 (1H, m), 2.77-3.06 (3H, m), 5.78 (1H, m), 6.35 (1H, d, J=16 Hz), 7.12-7.32 (5H, m), 7.37 (1H, d, J=16 Hz), 7.94 (1H, s), 8.24 (1H, s); MS (ES+) m/z 330.
The following compound was obtained in a similar manner to that of Example 96.
1H-NMR (300 MHz, DMSO-d6) δ 1.39-1.49 (1H, m), 1.70-2.06 (3H, m), 2.70-2.94 (1H, m), 2.94-3.21 (1H, m), 3.30-3.61 (2H, m), 4.21-4.41 (1H, m), 4.41-4.56 (2H, m), 6.62 (1H, d, J=15.2 Hz), 7.37 (1H, d, J=15.2 Hz), 7.44-7.55 (2H, m), 7.55-7.65 (1H, m), 7.72-7.87 (1H, m), 7.87-7.99 (1H, m), 7.99-8.06 (1H, m), 8.11 (1H, s); MS (ES+) m/z 388.
The following compound was obtained in a similar manner to that of Example 129.
1H-NMR (300 MHz, DMSO-d6) δ 0.84-1.03 (2H, m), 1.08-1.32 (3H, m), 1.54-1.76 (4H, m), 1.79-2.02 (3H, m), 2.22-2.50 (1H, m), 2.82-3.14 (3H, m), 3.40 (1H, m), 3.60 (1H, m), 3.87-4.40 (2H, m), 6.20 (1H, d, J=16 Hz), 6.62 (2H, d, J=8 Hz), 7.26-7.42 (3H, m), 10.46 (1H, s); MS (ES+) m/z 344.
The following compounds were obtained in a similar manner to that of Example 41.
1H-NMR (200 MHz, DMSO-d6) δ: 1.30-1.60 (1H, 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 (1H, d, J=16.1 Hz), 7.37 (1H, d, J=16.1 Hz), 7.41-7.47 (4H, m), 7.61-7.75 (3H, m), 8.03 (1H, s), 11.20 (1H, brs),
MASS(ESI); 371 (M+H)+.
1H-NMR (200 MHz, DMSO-d6) δ: 0.92-1.27 (5H, m), 1.52-2.02 (10H, m), 2.73-3.00 (3H, m), 3.20-3.57 (2H, m), 4.55-4.60 (2H, m), 6.34 (1H, d, J=16.1 Hz), 7.34-7.43 (2H, m), 7.64-7.76 (1H, m), 8.67 (1H, s), 10.11 (1H, brs),
MASS(ESI); 377 (M+H)+.
1H-NMR (200 MHz, DMSO-d6) δ: 1.35-1.60 (1H, 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 (1H, d, J=16.0 Hz), 7.20 (1H, d, J=16.0 Hz), 7.44-7.47 (3H, m), 7.59-7.64 (2H, m), 8.15 (1H, d, J=8.0 Hz), 8.55 (2H, s), 11.07 (1H, brs),
MASS(ESI); 354 (M+H)+.
1H-NMR (200 MHz, DMSO-d6) δ: 0.92-1.28 (5H, m), 1.64-2.10 (10H, m), 2.70-3.16 (3H, m), 3.32-3.57 (2H, m), 4.44 (2H, brs), 6.47 (1H, d, J=16.0 Hz), 7.33 (1H, d, J=16.0 Hz), 8.03 (1H, brs), 8.62 (2H, s), 10.40 (1H, brs),
MASS(ESI); 360 (M+H)+.
The following compound was obtained in a similar manner to that of Example 129.
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 (1H, d, J=16 Hz), 7.30-7.52 (4H, m), 7.78 (1H, d, J=7.5 Hz), 8.02 (1H, s), 8.10 (1H, s), 8.81 (1H, s), 10.96 (1H, br-s); MS (ES+) m/z 373.
1N-NaOH (4.7 mL) was added to the solution of (2E)-N-hydroxy-3-(5-{[(3R)-1-(2-phenylethyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylamide dihydrochloride (1.0 g) in water (20 mL) 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)-1-(2-phenylethyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylamide (0.71 g).
1H-NMR (CD3OD): δ 1.77-1.89 (1H, m), 2.33-2.46 (1H, m), 2.71-2.91 (6H, m), 2.94-3.04 (1H, m), 3.10-3.17 (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.
(2E)-3-(5-{[(3R)-1-(2-chlorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamide
A solution of acetic acid (3.2 μL) in acetonitrile (29.2 μL) was added to the mixture of (2E)-N-hydroxy-3-(5-{[(3R)-1-(2-phenylethyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylamide (20 mg) in THF (0.1 mL) and acetonitrile (0.1 mL) and the mixture was stirred at ambient temperature for 5 minutes. To the mixture was added AcOEt (1.5 mL) and isolated precipitate was collected by filtration to give (2E)-N-hydroxy-3-(5-{[(3R)-1-(2-phenylethyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylamide acetate (18 mg).
1H-NMR (DMSO-d6): δ 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), 8.10 (1H, s), 10.71 (1H, br-s)
The following compounds can be obtained in a similar manner to that of Example 290.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2004904487 | Aug 2004 | AU | national |
| 2004907228 | Dec 2004 | AU | national |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 11199453 | Aug 2005 | US |
| Child | 12264363 | US |
