WO2012011707A2 - Substituted pyridinone derivatives and methods for manufacturing the same - Google Patents
Substituted pyridinone derivatives and methods for manufacturing the same Download PDFInfo
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- WO2012011707A2 WO2012011707A2 PCT/KR2011/005268 KR2011005268W WO2012011707A2 WO 2012011707 A2 WO2012011707 A2 WO 2012011707A2 KR 2011005268 W KR2011005268 W KR 2011005268W WO 2012011707 A2 WO2012011707 A2 WO 2012011707A2
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- cycloalkyl
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- heterocyclyl
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- 0 CCC(C)C(N)=C(C)C=C(C=*(C(C)=C(C(*)=C1)N)C1=O)C#C Chemical compound CCC(C)C(N)=C(C)C=C(C=*(C(C)=C(C(*)=C1)N)C1=O)C#C 0.000 description 4
- AFRUCERNIGLMSW-UHFFFAOYSA-N BC(C)C(CC1)=CC=C1C#N Chemical compound BC(C)C(CC1)=CC=C1C#N AFRUCERNIGLMSW-UHFFFAOYSA-N 0.000 description 1
- GYCCSLIZUBCBLY-NVOKHFLUSA-N C/C(/CN(C=C(C(O)=C1)Cl)C1=O)=C\C(\OC)=C/C#C Chemical compound C/C(/CN(C=C(C(O)=C1)Cl)C1=O)=C\C(\OC)=C/C#C GYCCSLIZUBCBLY-NVOKHFLUSA-N 0.000 description 1
- OQROAMWCQMVJJC-UHFFFAOYSA-N C=C1NCCC(O)=C1 Chemical compound C=C1NCCC(O)=C1 OQROAMWCQMVJJC-UHFFFAOYSA-N 0.000 description 1
- WAHAHUZEKZMEEW-UHFFFAOYSA-N COC1=CCCC(CN(C=CC(O)=C2)C2=O)=C1 Chemical compound COC1=CCCC(CN(C=CC(O)=C2)C2=O)=C1 WAHAHUZEKZMEEW-UHFFFAOYSA-N 0.000 description 1
- QAKBJSPNKVMDCF-LWOQYNTDSA-N C[C@H](C(CC1)SC)N=C1Br Chemical compound C[C@H](C(CC1)SC)N=C1Br QAKBJSPNKVMDCF-LWOQYNTDSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/69—Two or more oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/70—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the present invention relates to a novel compound or a pharmaceutically acceptable salt thereof, a preparation method thereof, and the compound- containing pharmaceutical composition for treating a metabolic disorder.
- Diabetes mellitus is a serious disease suffered by 100 million or more people all over the world, and continues to threaten the health of people. Diabetes mellitus may be divided into two clinical syndromes, that is, type I diabetes mellitus and type II diabetes mellitus.
- Type I diabetes mellitus also known as insulin dependent diabetes mellitus (IDDM)
- IDDM insulin dependent diabetes mellitus
- Type II diabetes mellitus also known as noninsul in-dependent diabetes mellitus (NIDDM)
- NIDDM noninsul in-dependent diabetes mellitus
- Type II diabetes mellitus is characterized by people having an insulin secretion defect or insulin resistance, in other words, they have insufficient insulin or cannot effectively use insulin.
- diabetes mellitus patients a glucose level is accumulated within blood and urine, which causes excessive urination, thirst, hunger, fat or protein metabolism-related problems. Such diabetes mellitus may cause life threatening complications (e.g. sight loss, renal failure, and heart disease), and damage to the retina on the eye's inner surface, and increases risk of cataractsand glaucoma. Also, diabetes mellitus is related to a nerve damage of thelegs and feet, which reduces of the capacity to feel pain, and causes serious infections.
- GPR119 is a G-prote in-coupled receptor (GPCR) which is mainly expressed in the pancreas, small intestine, colon, and adipose tissue.
- GPCR G-prote in-coupled receptor
- a GPR119-expression profile is a target for treatment of obesity and diabetes mellitus and shows a latent availability of GPR119. It was proven that GPR119 activation stimulates cAMP, thereby inducing secretion of lucose-dependent GLP-1 and insulin (T. Soga et al., Biochemical and Biophysical Research Communication 326 (2005) 744-751).
- a GPR119 activator not only has an effect on a plasma glucose level, but also causes an acute decrease in ingestion in a rat after chronic administration, and reduces weight ([Overton, H.A. et al., "Deorphanizat ion of a G protein- coupled receptor for oleoylethanol amide and its use in the discovery of small-molecule hypophagic agent” Cell metabolism, 3:167-175 (2006)], and Patent Application W005/007647 and W005/007658).
- An activator of GPR119 may be used for treatment of diabetes mellitus, diabetes mellitus-related diseases, diabetes mel 1 itus-related microvessel complications, diabetes mellitus-related large vessel complications, cardiovascular disorders, metabolic syndrome and its constituent diseases, obesity, and other diseases.
- the present invention provides a novel compound or a pharmaceutically acceptable salt thereof, a preparation method thereof, and the compound- containing pharmaceutical composition for treating a metabolic disorder.
- X represents , aryl or heteroaryl, wherein aryl or heteroaryl may be substituted or unsubstituted with at least one selected from the group consisting of Ri a , Ri b , Ri c , Ri d and R le;
- each of Ri a , Rib, Ri c , Rid and R ie may be independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl , cycloalkyl, aryl, heterocyclyl, halo, -N3 ⁇ 4, -CN, -N0 2 , -C(O)0H, -0CF 3 , -0R U , -OH,
- each of alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl may be substituted or unsubstituted with at least one R6 and (b) alkyl may be substituted or unsubstituted with at least one R 7;
- Y represents S or 0
- K represents CH or N
- Z 2 represents C or N, provided that both of Zi and Z 2 are not N;
- 9> m represents 0 through 2;
- n 2 represents 0 through 2;
- n 3 represents 0 through 2;
- Pi represents aryl, heteroaryl, cycloalkyl or heterocycloalkyl, wherein each of aryl, heteroaryl, cycloalkyl and heterocycloalkyl may be substituted or unsubst ituted with at least one selected from the group consisting of Ri a ,
- each of alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl may be substituted or unsubst ituted with at least one 3 ⁇ 4 and (b) alkyl may be substituted or unsubst ituted with at least one R 7;
- R 2 represents alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl,
- R 3 is hydrogen, alkyl, alkoxy, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl , heterocyclyl or heterocyclylalkyl ;
- R4 represents substituted or unsubst ituted d- 3 alkylene, i represents integer from 0 to 2, wherein substituted C1-3 alkylene may be substituted with
- R 6i in each case is independently selected from the group consisting ofalkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl , heterocyclyl, heterocyclylalkyl , halo, -NH 2 , -CN,
- alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl may be substituted or unsubst ituted with 0 to 5 R 9a substituents;
- each of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl, and heterocyclyl may be substituted or unsubst ituted with 0 to 5 R 9a substituents;
- R 8 in each case, is independently selected from the group consisting of alkyl, aryl, cycloalkyl, heteroaryl, and heterocyclyl, wherein each of alkyl, aryl, cycloalkyl, heteroaryl, and heterocyclyl may be substituted or unsubst ituted with at least one Re a;
- 3i> 3 ⁇ 4 a in each case, is independently selected from the group consisting of alkyl, haloalkyl, aryl , alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl , heteroaryl, heteroarylalkyl , heterocyclyl , heterocyclylalkyl , halo, -NH 2 , -CN,
- R 9 in each case, is independently selected from the group consisting ofhydrogen, alkyl, alkoxy, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl, wherein each of alkyl, cycloalkyl, aryl, arylalkyl ,heteroaryl , heteroarylalkyl, heterocyclyl and heterocyclylalkyl may be substituted or unsubst ituted with 0 to 5 R 9A substituents;
- Rg a in each case, is independently selected from the group consisting ofalkyl , haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, -NH 2 , -CN,
- R 10 in each case, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl, wherein each of cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl may be substituted or unsubstituted with 0 to 3 R 10A substituents;
- ⁇ 35> Rioa in each case, is independently selected from the group consisting ofalkyl , haloalkyl , aryl, alkenyl , alkynyl, cycloalkyl, cycloalkylalkyl , heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, -NH 2 , -CN,
- R n in each case, is independently selected from the group consisting ofalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, and heterocyclylalkyl, wherein each of cycloalkyl, aryl, arylalkyl, heterocyclyl, and heterocyclylalkyl may be substituted or unsubstituted with 0 to 3 Ru a substituents;
- R lla in each case, is independently selected from the group consisting of alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, -NH 2 , -CN,
- Ri 2 in each case, is independently selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl and heterocyclylalkyl, wherein each of cycloalkyl , aryl , arylalkyl, heterocyclyl and heterocyclylalkyl may be substituted or unsubstituted with 0 to 3 Ri 0a substituents;
- R 14 in each case, is independently selected from the group consisting ofhydrogen, alkyl, cycloalkyl and aryl ;
- the present invention provides a compound and a pharmaceutically acceptable salt thereof, wherein the compound represented by Formula 1 is a compound represented by Formula 2 below or a compound represented by Formula 3 below.
- D represents NR3, S or 0;
- G represents S or 0;
- ⁇ 49> Represents alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl,
- R V is independently selected from the group consisting of hydrogen, alkyl, alkenyl , alkynyl, cycloalkyl, aryl, heterocyclyl, halo, -NH 2 , -CN,
- each of alkenyl , alkynyl, cycloalkyl, aryl , and heterocyclyl may be substituted or unsubst ituted with at least one R6 and (b) alkyl may be substituted or unsubst ituted with at least one R 7
- R" represents hydrogen, alkyl or halogen
- R3, Rg, R 7 and P3 are the same as defined above.
- the present invention provides a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound represented by Formula 1 is any one selected from the group consisting of fo 11owing compounds :
- Io I 3- ⁇ 5-ch1oro-4-[ 1-(4-methy1su1 fany1-benzoy1 )- iper idin-4-y1oxy]-2-oxo-2H- pyr idin-l-ylmethyl ⁇ -benzoni tr i lei
- ⁇ io4> 3-[5-ch1or0-4-( 1-i sobutyry1- iper idin-4-y1oxy)-2-oxo-2H-pyr idin-1-y1methy1 ]- benzonitri le;
- the compound represented by Formula 1 may be preferably any one selected from the group consisting of following compounds:
- ⁇ 1 1o> 4-[5-ch1oro-1-(4-cyano ⁇ 3-f 1uoro-pheny1 )-2-thioxo-1 , 2-dihydro-pyr idin-4- yloxy]-piperidine-l-carboxyl ic acid tert-butyl ester;
- ⁇ 112> 4-[5-ch1oro-1-(4-methanesu1 fony1-pheny1 )-2-1hioxo-1 , 2-dihydro-pyr idin-4- yloxy]-piper idine-l-carboxyl ic acid tert-butyl ester;
- ⁇ ii8> 4- ⁇ 5-chloro-4-[l-(5-ethyl-pyr imidin-2-yl)-piper idin-4-yloxy]-2-oxo ⁇ 2H- pyr i din-1-y1methy1 ⁇ -3-f 1uoro-benzoni tr i le ;
- a pharmaceutical composition for treating metabolic disorders which includes the inventive compound or a pharmaceutically acceptable salt thereof, as an active ingredient.
- the metabolic disorders include obesity, type I diabetes mellitus, type II diabetes mellitus, impaired glucose tolerance, insulin resistance, hyperglycemia, hyper 1 ipidemia, hypertriglyceridemia, hypercholesterolemia, dysl ipidemia, syndrome X, and the like.
- a and B represent halogen, and X, Y, Li, 3 ⁇ 4, r , Zi, Z 2 , Pi, P2 and Psare the same as defined above.
- FIG. 1 is a comparison graph of potency and efficacy according to concentrations of compounds.
- the aqueous layer was adjusted to pH 7 by using IN NaOH aqueous solution, and was extracted with 200mL of ethyl acetate.
- the organic layer was dried with anhydrous magnesium sulfate and vacuum-dried so as to provide a target compound.
- the compound obtained after the reaction was dissolved in 300ml of ethyl acetate, washed with 300ml of distilled water, and extracted twice with IN HC1 aqueous solution. The aqueous layer was washed twice with 300ml of ethyl acetate. The separated aqueous layer was adjusted to pH 10 by using saturatedsodium bicarbonate aqueous solution, and the organic layer was extracted twice with 300ml of ethyl acetate, dried with anhydrous magnesium sulfate, and vacuum-dried so as to provide a target compound.
- a target compound was obtained in the same manner as described in Preparation Example 3 except that instead of 5-chloro-4-hydroxy-lH-pyridi -2- thione, 4-amino-lH-pyr imidine-2-thione was used.
- a target compound was obtained in the same manner as described in Preparation Example 4 except that instead of 5 ⁇ chloro-4-hydroxy-lH-pyr idine- 2-thione, 4-hydroxy-lH-pyr idine-2-thione was used.
- Example 12 except that instead of 3-bromomethylbenzonitr i le, methyl 4- (bromomethyl)benzoate was used.
- a target compound was obtained in the same manner as described in Preparation Example 20 except that instead of 4-(bromomethyl )-3- f luorobenzonitr i le, 4-methoxybenzyl bromide was used.
- a target compound was obtained in the same manner as described in Preparation Example 20 except that instead of 4-(bromomethyl )-3- fluorobenzonitr i le, 3-methoxybenzyl bromide was used.
- a target compound was obtained in the same manner as described in Preparation Example 20 except that instead of 4-(bromomethyl )-3- f luorobenzonitr i le , 3-(trif luoromethoxy)benzyl bromide was used.
- a target compound was obtained in the same manner as described in Preparation Example 20 except that instead of 4-(bromomethyl )-3- f luorobenzonitr i le, 3-f luorobenzyl bromide was used.
- a target compound was obtained in the same manner as described in Preparation Example 20 except that instead of 4-(bromomethyl )-3- f luorobenzonitr i le, 3-(bromomethyl )benzonitri le was used.
- a target compound was obtained in the same manner as described in Preparation Example 20 except that instead of 4-(bromomethyl )-3- f luorobenzonitr i le, 4-(methylthio)benzyl bromide was used.
- ⁇ 2 1 > 3 ⁇ 4( 00MHz, CDCI3) 7.28-7.26(3H,m), 7.17-7.08(2H,m) , 5.98(lH,s), 5.01(2H,s)
- the separated organic layer was washed with 20ml of 1N-HC1 aqueous solution, then with 20ml of lN-Na0H aqueous solution, dried with anhydrous magnesium sulfate, and vacuum-dried.
- the obtained residue was purified with silica column so as to provide a target compound.
- Example 1 except that instead of 5-chloro-4-[l-(5-ethyl-pyr imidin-2-yl )- piper i din-4-y1 oxy] - ⁇ -pyr idine-2-1hione , 4-(5-ch1oro-2-1hioxo-1 , 2-dihydro- pyridin-4-yloxy)-piperidine-l-carboxylic acid tert-butyl ester was used.
- Example 3 except that instead of 5-chloro-4-[l-(5 ⁇ ethyl-pyr imidin-2-yl )- piper idin-4-y1oxy] - ⁇ -pyr idine-2-1hione , 4-(5-ch1oro ⁇ 2-1hioxo-1 , 2-dihydro- pyr idin-4-yloxy)-piperidine-l-carboxyl ic acid tert-butyl ester was used.
- Example 4 except that instead of 4-(5-chloro-2-thioxo-l,2-dihydro-pyridin- 4-yloxy)-piperidine-l-carboxyl ic acid tert-butyl ester, 4-(2-thioxo-l,2- dihydro-pyr imidin-4-ylamino)-piper idine-l-carboxyl ic acid tert-butyl ester was used.
- Example 1 except that instead of 2,4-dif luorobenzonitri le, methanesul fonic acid l-methanesulfonyl-piperidin-4-yl ester was used.
- Example 1 except that instead of 2,4-dif luorobenzonitri le, 6- chloronicotinonitri le was used.
- Example 1 except that instead of 2,4-dif luorobenzonitri le, 2-bromo ⁇ 5- methanesulfonyl-pyridine was used.
- the reaction mixture was dissolved in 100ml of ethyl acetate, and washed twice with 100ml of distilled water.
- the organic layer was dried with anhydrous magnesium sulfate, and vacuum-dried.
- the residue obtained after the vacuum-drying was purified with silica column so as to provide a target compound.
- Example 12 except that instead of l-(5-ethyl-pyrimidin-2-yl)-piperidin-4-ol , tert-butyl 4-hydroxy-l-piperidinecarboxylate was used. ⁇ 349> H(400MHz, CDCI3) 7.61-7.28(4H,m), 7.17-7.15(lH,m) , 5.95-5.94(2H,m) ,
- Example 13 except that instead of 3- ⁇ 4-[l-(5-ethyl-pyrimidin-2-yl)-piperidin- 4-y1oxy]-2-oxo-2H-pyr idin-1-y1methy1 ⁇ -benzonitrile, 4-[1-(3-cyano-benzy1 )-2- oxo-1 ,2-dihydro-pyr idin-4-y1oxy]-piper idine-1-carboxylie acid tert-butyl ester was used.
- Example 12 except that instead of l-(5-ethyl-pyr imidin-2-yl )-piper idin-4-ol , tert-butyl 4-(hydroxymethyl )-l-piper idinecarboxylate was used.
- Example 13 except that instead of 3- ⁇ 4-[l-(5-ethyl-pyr imidin-2-yl )-piper idin- 4-y1oxy]-2-oxo ⁇ 2H-pyr idin-1-y1methy1 ⁇ -benzonitrile, 4-[1-(3-cyano-benzy1 )-2- oxo-1 , 2-dihydro-pyr idin-4-y1oxymethy1 ]-piper idine-1-carboxy1 ic acid tert- butyl ester was used.
- Example 1 except that instead of 5-chloro-4-[l-(5-ethyl-pyrimidin-2-yl )- piper idin-4-y1oxy]-lH-pyr idine-2-thi one , 4-[ 1-(5-ethy1-pyr imidin-2-y1 )- piper idin-4-yloxy]-lH-pyridine-2-thione was used.
- Example 19 except that instead of l-(4-f luoro-benzyl)-4-hydroxy-lH-pyr idin-2- one, 4-hydroxy-l-(3-methoxy-benzyl )-lH-pyr idin-2-one was used.
- Example 19 except that instead of l-(4-f luoro-benzyl)-4-hydroxy-lH-pyridin-2- one , 4-[4-(4-hydroxy-2-oxo-2H-pyr idin-1-y1methy1 )-1hiazo1e-2-y1 ]-piper idine- 1-carboxylic acid tert-butyl ester was used
- Example 19 except that instead of l-(4-f luoro-benzyl)-4-hydroxy-lH-pyridin-2- one , 4-hydroxy-1-( 1-methanesu1 fony1- iperidin-4-y1methy1 )- ⁇ -pyr idin-2-one was used.
- Example 13 except that instead of 3- ⁇ 4-[l-(5-ethyl-pyrimidin-2-yl)-piper idin- 4-yloxy]-2-oxo-2H-pyr idin-l-ylmethyl ⁇ -benzonitr i le, 4-[l-(4-f luoro-benzyl )-2- oxo-1 , 2-dihydro-pyr idin-4-y1oxy]- iper idine-l-carboxylie ac id tert-buty1 ester was used.
- Example 13 except that instead of 3- ⁇ 4-[l-(5 ⁇ ethyl-pyr imidin-2-yl )-piper idin- 4-y1oxy]-2-oxo-2H-pyr idin-1-y1methy1 ⁇ ⁇ benzonitrile, 4-[ 1-(3-methoxy-benzy1 )- 2-oxo-1 ,2-dihydro-pyridin-4-yloxy]-piper idine-l-carboxyl ic acid tert-butyl ester was used.
- Example 19 except that instead of 1-(4-f luoro-benzyl )-4-hydroxy- ⁇ -pyr idin-2- one, 4-(4-hydroxy-2-oxo-2H-pyr idin-l-ylmethyl )-benzoic acid methyl ester was used .
- Example 19 except that instead of l-(4-fluoro-benzyl)-4-hydroxy-lH-pyridin-2- one, 3-fluoro-4-(4-hydroxy-2-oxo-2H-pyr idin-l-ylmethyl)-benzonitri le was used.
- Example 12 except that instead of 3-(4-hydroxy-2-oxo-2H-pyridin-l- ylmethyl )-benzonitr i le , 4-(5-chloro ⁇ 4-hydroxy-2-oxo-2H-pyr idin-l-ylmethy1 )-3- f luoro-benzonitri le was used.
- Example 12 except that instead of 3-(4-hydroxy-2-oxo-2H-pyr idin-l-ylmethyl )- benzoni tr i le , 5-ch1or0-1-(6-ch1oro-pyr idin-3- 1methy1 )-4-hydroxy-lH-pyr idin-
- Example 12 except that instead of 3-(4-hydroxy-2-oxo-2H-pyr idin-l-ylmethyl )- benzoni tr i 1e , 5-ch1oro-4-hydroxy-1-(3-1r i f 1uoromethy1-benzy1 )- ⁇ -pyr idin-2- one was used.
- Example 12 except that instead of 3-(4-hydroxy-2-oxo-2H-pyr idin-l-ylmethyl )- benzoni tr i 1e , 5-ch1oro-4-hydroxy-1—(4—tr i f1uoromethy1-benzy1 )-lH-pyr idin-2- one was used.
- Example 12 except that instead of 3-(4-hydroxy-2-oxo-2H ⁇ pyridin-l-ylmethyl )- benzonitri le, 5-chloro-4-hydroxy-l-(4-methoxy-benzy1 )-IH-pyr idin-2-one was used.
- Example 12 except that instead of 3-(4-hydroxy-2-oxo-2H-pyridin-l-ylmethyl)- benzonitri le, 5-chloro-4-hydroxy-l-(3-methoxy-benzyl )-lH-pyr idin-2-one was used.
- Example 12 except that instead of 3-(4-hydroxy-2-oxo-2H-pyr idin-1- y1methy1 )-benzoni tr i 1e , 5-ch1oro-4-hydroxy-1-(3-tri f 1uoromethoxy-benzy1 )—IH- pyr idin—2—one was used.
- a target compound was obtained in the same manner as described in Example 12 except that instead of 3-(4-hydroxy-2-oxo-2H-pyridin-l-ylmethyl)- benzonitri le, 5-chloro-l-(4-f luoro-benzyl )-4-hydroxy-lH-pyridin-2-one was used.
- Example 12 except that instead of 3-(4-hydroxy-2-oxo-2H-pyr idin-l-ylmethyl )- benzonitri le, 4-(5-chloro-4-hydroxy-2-oxo-2H-pyridin-l-ylmethyl)-benzonitri le was used.
- Example 12 except that instead of 3-(4-hydroxy-2-oxo-2H-pyr idin-l-ylmethyl )- benzoni tr i 1e , 5-ch1oro-4-hydroxy-1-(4-isopropy1-benzy1 )- ⁇ -pyridin-2-one was used.
- Example 12 except that instead of 3-(4-hydroxy-2-oxo-2H-pyr idin-1- y1methy1 )-benzonitrile, 5-chloro-l-(3,4-di f 1uoro-benzy1 )-4-hydroxy-1H ⁇ pyr idin-2-one was used.
- Example 19 except that instead of l-(4-fluoro-benzyl)-4-hydroxy-lH-pyridin-2- one, 5-chloro-l-(3,4-di f luoro-benzoyl )-4-hydroxy-lH-pyridin-2-one was used.
- Example 12 except that instead of 3-(4-hydroxy-2-oxo-2H-pyridin-l-ylmethyl )- benzonitrile, 5-ch1oro-1-(3-f 1uoro-benzy1 )-4-hydroxy-lH-pyr idin-2-one was used.
- Example 12 except that instead of 3-(4-hydroxy-2-oxo-2H-pyridin-l-ylmethyl)- benzoni tr i 1e , 3-(5-ch1oro-4-hydroxy-2-oxo-2H-pyridin-1-y1methy1 )-benzoni tr i 1e was used.
- Example 19 except that instead of l-(4-f luoro-benzyl)-4-hydroxy-lH-pyridin-2- one, 3-(5-chloro-4-hydroxy-2-oxo-2H-pyr idin-l-ylmethyl )-benzonitri le was used.
- Example 12 except that instead of 3-(4-hydroxy-2-oxo-2H-pyridin-l-ylmethyl)- benzoni tr i 1e , 5-ch1oro-4-hydroxy-1-(4-methy1 su1 fany1-benzy1 )- ⁇ -pyr idin-2-one was used.
- a target compound was obtained in the same manner as described in Example 44 except that instead of 5-chloro-4-[l-(5-ethyl-pyrimidin-2-yl)- piper idin-4-y1oxy] -1-(4-methy1 su1 fany1-benzy1 )- ⁇ -pyr idin-2-one , 5-ch1oro-4- [ 1-(5-ethy1-pyr imidin-2-y1 )-piper i din ⁇ 4-y1oxy] -1-(4-methanesu1 f iny1-benzy1 )- lH-pyr idin-2-one was used.
- Example 12 except that instead of 3-(4-hydroxy-2-oxo-2H-pyr idin-l-ylmethyl )- benzoni t r i 1e , 5-ch1 oro-1-(2-f 1uoro-benzy1 )-4-hydroxy-lH-pyr idin-2-one was used.
- Example 19 except that instead of l-(4-fluoro-benzyl )-4-hydroxy-lH-pyr idin-2- one, 5-chloro-l-(3-f luoro-benzyl )-4-hydroxy-lH-pyridin-2-one was used.
- Example 48 except that instead of 4-(methylthio)benzoyl chloride, isobutyryl chloride was used.
- Example 12 except that instead of 3-(4-hydroxy-2-oxo-2H-pyr idin-l-ylmethyl )- benzoni tr i 1e , 5-ch1oro-l-[2-( -f1uoro-pheny1 )-ethy1 ]-4-hydroxy-lH-pyr idin-2- one was used.
- Example 12 except that instead of 3-(4-hydroxy-2-oxo-2H-pyridin-l-ylmethyl )- benzonitrile, 4-[1-(4-hydroxy-2-oxo-2H-pyr idin-1-y1 )-ethy1 ]-benzonitr i 1e was used.
- Example 55 Determination of compound activity based on cAMP stimulation
- ⁇ - ⁇ 5 cells In order to measure cAMP activity in a cell, in response to GPR119 agonist, ⁇ - ⁇ 5 cells (Korean cell line bank, beta cells derived from a hamster) were used. On a 96-well plate, 60,000 ⁇ - ⁇ 5 cells were plated per well. On the day after the plating, thecells were incubated together with GPR119 agonist with various concentrations for 1 hour at 37°C The compound was treated with 6 concentrations from 0.0032 to 10 umol. The cAMP activity was measured by using a cAMP dynamic kit from Cis Bio (Bedford, MA) under the instruction of the manufacturer.
- the cells were dissolved, and D2-labeled cAMP and crypt ate- labeled anti-cAMP antibody were used to measure cAMP level through a competitive immunoassay. Fluorescence was read by a Flex Station (Molecular Devices). Fluorescence resonance energy transfer (FRET) occurs between D2 and cryptate when D2 and cryptate come close to each other. FRET is measured as fluorescence ratio (665/620nm) . Non-labeled cAMP within a cell lysate competed with D2-labeled cAMP, against crypt ate- labeled antibody. The reduction of obtained FRET signal corresponds to cAMP level within cells. The compound activity was calculated by a change in FRET signals through DMSO control. The results are noted in Table 2 below.
- mice Male C57/6J mice (8 to 10 weeks old) were acclimated for at least 7 days. Then, only healthy individuals were used to carry out OGTT. After 12 to 15-hour fasting, the mice were divided into groups of 10 mice per group based on fasting glucose, and were administered with Vehicle (80% PEG, 10% tween 80, 10% ethanol) or test materials (Examples 1, 3, 12, 44, and 45) in an amount of 20mg/kg. Vehicle and test materials were orally administered (lOml/kg). After 30min from administration of Vehicle or test materials, glucose (3g/kg) was orally administered in an amount of 10 ml/kg.
- Vehicle 80% PEG, 10% tween 80, 10% ethanol
- test materials Examples 1, 3, 12, 44, and 45
- the glucose level was measured by using Accu-chek Go (Rosche diagnostic Co.), after -30, 0, 20, 40, 60 and 120 min from the administration of glucose, through puncture of caudal vein.
- 5 kinds of test materials (Examples 1, 3, 12, 44, and 45) showed an AUC (area under curve) reduction effect of about 30 to 60% in comparison to vehicle, respectively, as noted in Table 3.
- the results are noted in Table 3 below.
- An intrinsic activity indicates a maximum effect of a drug irrespective of an amount .
- FIG. 1 distinctively shows graphs on potency, efficacy, and intrinsic activity of an 0-compound having a carbonyl group and an S-compound having a thio-carbonyl group according to concentrations, in which the S ⁇ compound showed a good result of lOnM or less in view of potency and efficacy, and further showed a significantly high activity in view of the drug3 ⁇ 4 available intrinsic activity, compared to the 0-compound. Accordingly, the S-compound in a greater amount range can potentially show a more significantly maximum effect, compared to the 0-compound. This can increase the range of an effective dose, which is highly advantageous for treatment dose determination and stability acquirement.
Abstract
Disclosed are a novel compound or a pharmaceutically acceptable salt thereof, a preparation method thereof, and the compound-containing pharmaceutical composition for treating a metabolic disorder. Specifically, the disclosed compound is represented by [Formula 1]. The compound activates GPR119, and thus can be used for treating metabolic disorders, that is, diabetes mellitus, diabetes mellitus-related diseases, diabetes mellitus-related microvessel complications, diabetes mellitus-related large vessel complications, cardiovascular disorders, metabolic syndrome and its constituent diseases, obesity, and other diseases. In Formula 1, P1, P2, P3, P4, L1, R4, n4, X, Y, Z1 and Z2 are the same as defined above.
Description
[DESCRIPTION]
[Invent ion Tit le]
Substituted pyridinone derivatives and methods for manufacturing the same
[Technical Field]
<i> The present invention relates to a novel compound or a pharmaceutically acceptable salt thereof, a preparation method thereof, and the compound- containing pharmaceutical composition for treating a metabolic disorder.
[Background Art]
<2> Diabetes mellitus is a serious disease suffered by 100 million or more people all over the world, and continues to threaten the health of people. Diabetes mellitus may be divided into two clinical syndromes, that is, type I diabetes mellitus and type II diabetes mellitus. Type I diabetes mellitus, also known as insulin dependent diabetes mellitus (IDDM), is caused by an autoimmune process which destroys the insulin-producing pancreas beta cells, and requires regular administration of external insulin. Type II diabetes mellitus, also known as noninsul in-dependent diabetes mellitus (NIDDM), is caused by the loss of capability of adequately controlling blood glucose level. Type II diabetes mellitus is characterized by people having an insulin secretion defect or insulin resistance, in other words, they have insufficient insulin or cannot effectively use insulin.
<3> In diabetes mellitus patients, a glucose level is accumulated within blood and urine, which causes excessive urination, thirst, hunger, fat or protein metabolism-related problems. Such diabetes mellitus may cause life threatening complications (e.g. sight loss, renal failure, and heart disease), and damage to the retina on the eye's inner surface, and increases risk of cataractsand glaucoma. Also, diabetes mellitus is related to a nerve damage of thelegs and feet, which reduces of the capacity to feel pain, and causes serious infections.
<4> At present, treatments of diabetes mellitus include insulin, insulin secretagogue, glucose- lowering effectors, a peroxisom prol i ferators-act ivated receptor (PPAR) activators, etc. However, there are problems related to the
KR2011/005268
currently available treatments such as hypoglycemia, weight gain, a decrease in reactivity on treatment with the passing of time, gastro-intestinal tract problems, and edema.
<5> In order to introduce a novel and more effective treatment onto the market, research aiming at various areas has been conducted. One particular target is GPR119. GPR119 is a G-prote in-coupled receptor (GPCR) which is mainly expressed in the pancreas, small intestine, colon, and adipose tissue. A GPR119-expression profile is a target for treatment of obesity and diabetes mellitus and shows a latent availability of GPR119. It was proven that GPR119 activation stimulates cAMP, thereby inducing secretion of lucose-dependent GLP-1 and insulin (T. Soga et al., Biochemical and Biophysical Research Communication 326 (2005) 744-751). Also, it was proven that a GPR119 activator not only has an effect on a plasma glucose level, but also causes an acute decrease in ingestion in a rat after chronic administration, and reduces weight ([Overton, H.A. et al., "Deorphanizat ion of a G protein- coupled receptor for oleoylethanol amide and its use in the discovery of small-molecule hypophagic agent" Cell metabolism, 3:167-175 (2006)], and Patent Application W005/007647 and W005/007658).
<6> An activator of GPR119 may be used for treatment of diabetes mellitus, diabetes mellitus-related diseases, diabetes mel 1 itus-related microvessel complications, diabetes mellitus-related large vessel complications, cardiovascular disorders, metabolic syndrome and its constituent diseases, obesity, and other diseases.
[Disclosure]
[Technical Problem]
<7> The present invention provides a novel compound or a pharmaceutically acceptable salt thereof, a preparation method thereof, and the compound- containing pharmaceutical composition for treating a metabolic disorder.
[Technical Solution]
<s> In accordance with an aspect of the present invention, there is provided a compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof .
[Formula 1]
In Formula 1,
X represents
, aryl or heteroaryl, wherein aryl or heteroaryl may be substituted or unsubstituted with at least one selected from the group consisting of Ria, Rib, Ric, Rid and Rle;
each of Ria, Rib, Ric, Rid and Rie may be independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl , cycloalkyl, aryl, heterocyclyl, halo, -N¾, -CN, -N02, -C(O)0H,
-0CF3, -0RU, -OH,
-SH, -SRn, -S(0)3H, -P(0)3H2, -C(=0)NR9R9, -NR12R12, -S(0)2NR9R9, -NR9S(0)2CF3,
Y represents S or 0;
K represents CH or N;
Zi represents C or N;
Z2 represents C or N, provided that both of Zi and Z2 are not N;
Li represents CH2, N(R3) , COO) , 0, 0CR9R9, S, S(=0) or S(0)2
<|9> m represents 0 through 2;
<20> n2represents 0 through 2;
<2i> n3represents 0 through 2;
<22> Pi represents aryl, heteroaryl, cycloalkyl or heterocycloalkyl, wherein each of aryl, heteroaryl, cycloalkyl and heterocycloalkyl may be substituted or unsubst ituted with at least one selected from the group consisting of Ria,
<23> each of Rla, Rib, Ric, Rid and RJe may be independently selected from the group consisting of hydrogen, alkyl, alkenyl , alkynyl, cycloalkyl, aryl, heterocyclyl, halo, -NH2, ~CN, -N02, -C(=0)0H,
-0CF3, -0RU, -OH,
-SH, -SRii, -S(0)3H, -P(0)3H2, -C(=0)NR9R9, - R12Ri2, -S(0)2NR9R9, -NR9S(0)2CF3,
-C(=0)NR9S(0)2R9, -S(0)2NR9C(=0)0R9, -S(0)2NR9C(=0)NR9R9, -C(=0)NR9S(0)2CF3,
-NHC(-NRi4)NRi4Ri4, -S(=0)Rn, -S(0)2Rn, -NR9C(=0)OR8 and -NR9S(02)R8, wherein (a) each of alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl may be substituted or unsubst ituted with at least one ¾ and (b) alkyl may be substituted or unsubst ituted with at least one R7;
<24> R2represents alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl,
-S(0)2R5, -C(=0)NR3R5, -C(=0)R5 or -C(=0)0R5, wherein each of alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl may be substituted or unsubst ituted with at least one R6;
<25> R3is hydrogen, alkyl, alkoxy, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl , heterocyclyl or heterocyclylalkyl ;
<26> R4 represents substituted or unsubst ituted d-3alkylene, i represents integer from 0 to 2, wherein substituted C1-3 alkylene may be substituted with
Ci-6 alkyl or halogen (provided that Y=0, ¾=()), and Pi represents cycloalkyl or heterocycloalkyl;
<27> R5 represents alkyl, alkenyl, aryl, cycloalkyl, heteroaryl or heterocyclyl, wherein each of alkyl, alkenyl, aryl, cycloalkyl, heteroaryl and heterocyclyl may be substituted or unsubst ituted with at least one R6;
<28> R6i in each case, is independently selected from the group consisting ofalkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl , heterocyclyl, heterocyclylalkyl , halo, -NH2, -CN,
-N02, -C(=0)0H, -C(=0)0R10, -0CF3, -0Ri0, -OH, -SH, -SR10, -S(0)3H, -P(0)3¾,
-C(=0)NR9R9, -NR9R9, -S(0)2NR9R9, -NR9S(0)2CF3, -CO0)NR9S(0)2R9,
-S(0)2NR9C(=0)0R9, -S(0)2NR9C(=0)NR9R9, -C(=0)NR9S(0)2CF3, -C(=0)R10, -NR9C(=0)H,
=0, -NR9C(=0)0R8 and -NR9S(02)R8, wherein each of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl may be substituted or unsubst ituted with 0 to 5 R9a substituents;
<2<J> R7, in each case, is independently selected from the group consisting ofalkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, halo, -N¾, -CN, -N02, -C(=0)0H,
-0CF3, -(%<,, -OH,
-SH, -SR10, -S(0)3H, -P(0)3H2, -C(=0)NR9R9, -NR9R8, -S(0)2NR9R9, -NR9S(0)2CF3,
-C(=0)NR9S(0)2R9, -S(0)2NR9C(=0)0R9, -S(0)2NR9C(=0)NR9R9, -C(O)NR9S(0)2CF3,
-S(=0)Rio, -S(0)2Rio, =0, -NR9C(=0)0R8 and -NR9S(02)R8, wherein each of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl, and heterocyclyl may be substituted or unsubst ituted with 0 to 5 R9a substituents;
<30> R8, in each case, is independently selected from the group consisting of alkyl, aryl, cycloalkyl, heteroaryl, and heterocyclyl, wherein each of alkyl, aryl, cycloalkyl, heteroaryl, and heterocyclyl may be substituted or unsubst ituted with at least one Rea;
3i> ¾a, in each case, is independently selected from the group consisting of alkyl, haloalkyl, aryl , alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl , heteroaryl, heteroarylalkyl , heterocyclyl , heterocyclylalkyl , halo, -NH2, -CN,
-N02, -C(=0)0H,
-OCF3 , -OR14 , -OH, -SH, -SRM, -S(0)3H, -P(0)3H2)
-S(=0)Ri4, -S(0)ZRH,
and -NR14S(02)Ri4
<32> R9, in each case, is independently selected from the group consisting ofhydrogen, alkyl, alkoxy, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl, wherein each of alkyl, cycloalkyl, aryl, arylalkyl ,heteroaryl , heteroarylalkyl, heterocyclyl and heterocyclylalkyl may be substituted or unsubst ituted with 0 to 5 R9A substituents;
<33> Rga, in each case, is independently selected from the group consisting ofalkyl , haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, -NH2, -CN,
-NO2, -C(=O)0H, -C(=0)0Ri4, -0CF3, -0RM, -OH, -SH, -SRW, -S(0)3H, -P(0)3H2,
Ri4Ri4, -S(0)2NRi4Ri4, -NR14S(0)2CF3,
-C(=0)NRi4S(0)2CF3, -C(=0)R14,
-S(=0)Ri4, -S(0)2Ri4, -NR14C(=0)OR8, -NRi4S(02)Rg, =0 and arylalkyl;
<34> R10, in each case, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl, wherein each of cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl may be substituted or unsubstituted with 0 to 3 R10A
substituents;
<35> Rioa, in each case, is independently selected from the group consisting ofalkyl , haloalkyl , aryl, alkenyl , alkynyl, cycloalkyl, cycloalkylalkyl , heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, -NH2, -CN,
-NO2,
-OCF3, -OR14, -OH, -SH, -SRM, -S(0)3H, -P(0)3H2,
-S(=0)Ri4, -S(0)2R14, -NR14C(=0)0R8, -NRi4S(02)Rs and arylalkyl;
<36> Rn, in each case, is independently selected from the group consisting ofalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, and heterocyclylalkyl, wherein each of cycloalkyl, aryl, arylalkyl, heterocyclyl, and heterocyclylalkyl may be substituted or unsubstituted with 0 to 3 Rua substituents;
<37> Rlla, in each case, is independently selected from the group consisting of alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, -NH2, -CN,
-N02, -C(=0)0H. -C(=0)0Ri4, -0CF3, -0RM, -OH, -SH, -SR14, -S(0)3H, -P(0)3H2,
-C(=0)NR14Ri4, -NR14R14, -S(0)2NRi4Ri4, -NRi4S(0)2CF3, -C(O)NR14S(0)2R9,
-S(0)2NRi4C(=0)0R9, -S(0)2NR14C«l)NRi4Ri4, -C(=0)NR14S(0)2CF3, -C(=0)R14,
-S(=0)Ri4, -S(0)2Ri4,
-NRx4S(02)R8 and arylalkyl;
<38> Ri2, in each case, is independently selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl and heterocyclylalkyl, wherein each of cycloalkyl , aryl , arylalkyl, heterocyclyl and heterocyclylalkyl may be substituted or unsubstituted with 0 to 3 Ri0a substituents;
<39> R14 , in each case, is independently selected from the group consisting ofhydrogen, alkyl, cycloalkyl and aryl ;
<4o> each of P2 , P3 and P is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, halo, -CN, -C(=0)0H, -C(=0)ORio , -OCF3, -OR10 , -OH,
<4 i> Also, the present invention provides a compound and a pharmaceutically acceptable salt thereof, wherein the compound represented by Formula 1 is a compound represented by Formula 2 below or a compound represented by Formula 3 below.
<42> [Formula 2]
<44> [Formula 3]
<46> In Formulas 2 and 3,
<47> D represents NR3, S or 0;
<48> G represents S or 0;
<49> Represents alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl,
-S(0)2R5, -C(=0)NR3R5, -C(=0)R5 or -C(=0)0R5, wherein each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl may be substituted or unsubst ituted with at least one Re
<50> R V is independently selected from the group consisting of hydrogen, alkyl, alkenyl , alkynyl, cycloalkyl, aryl, heterocyclyl, halo, -NH2 , -CN,
-NQz ,
, -0CF3, -0Rn, -OH , -SH , -SRn , -S(0)3H , -P(0)3H2 ,
-C(=0)NR9R9, -NR12R12> -S(0)2NR9R9, -NR9S(0)2CF3, -C(=0)NR9S(0)2R9,
-S(0)2NR9C(=0)0R9( -S(0)2NR9C(=0)NR9R9, -C(=0)NR9S(0)2CF3, -C(=0)Ru, -NR9C(=0)H,
-S(=0)Rii, -S(0)2Rn, -NR9C(=0)0R8 and -NR9S(02)R8, wherein (a) each of alkenyl , alkynyl, cycloalkyl, aryl , and heterocyclyl may be substituted or unsubst ituted with at least one R6 and (b) alkyl may be substituted or unsubst ituted with at least one R7
<5i> R" represents hydrogen, alkyl or halogen; and
<52> R3, Rg, R7 and P3 are the same as defined above.
<53> Further, the present invention provides a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound represented by Formula 1 is any one selected from the group consisting of fo 11owing compounds :
<54> 4-{5-ch1oro-4-[ 1-(5-ethy1-pyr imidin-2-y1 )-piper idin-4-y1oxy]-2-thi oxo-2H- pyr idin-l-yl }-2-f luoro-benzonitri lei
<55> 4-[5-ch1oro-1-(4-cyano-3-f 1uoro-pheny1 )-2-thioxo-1 , 2-dihydro-pyr idin-4- yloxy]-piper idine-l-carboxyl ic acid tert-butyl ester;
<56> 5-ch1oro-4-[ 1-( 5-ethy1-pyr imidin-2-y1 )-piper idin-4-y1oxy]-1-(4- methanesu1 fony1-pheny1 )-lH-pyr idin-2—thione ;
<57> 4-[5-ch1oro-1-(4-methanesu1 fony1-pheny1 )-2-thioxo-1 , 2-dihydro-pyr idin-4- yloxy]-piper idine-l-carboxyl ic acid tert-butyl ester;
<58> 4-(l-tert-butoxycarbonyl-piper idin-4-yloxy)-5-chloro-2-thioxo-3' ,4' ,5' ,6'- tetrahydro-2H,2'H-[l,4' ]bipyr idinyl-Γ -carboxy1 ic acid tert-butyl ester;
<59> 4-[ 1-(4-methanesu1 fony1 -pheny1 )-2-1hioxo-1 , 2-dihydro-pyr imi din-4-y1 amino]- piper idine-l-carboxyl ic acid tert-butyl ester;
<60> 3~bromo-5-ch1oro-4- [ 1-(5-ethy1-pyr imidin-2-y1 )- iper idin-4-y1oxy]-1-(4- methanesu1 fony1-pheny1 )-ΙΗ-pyr i dine-2-thione ;
<61> 5-ch1or0-5 ' -ch1oromethy1-4- [ 1-(5-ethy1-pyr imidin-2-y1 )-piperidin-4-y1oxy]-
[1,2' ]bipyr idinyl-2-thione;
<62> 5-ch1oro-4-[ 1-(5-eth 1-pyr imidin-2-y1 )- iper i din-4-y1oxy]-1 ' -methanesu1 fony1-
Γ ,2' ,3' ,4' ,5' ,6'-hexahydro-[l,4']bipyridinyl-2-thione;
<63> 5-ch1oro-4-[ 1-(5-ethy1-pyr imidi n-2-y1 )-piper idin-4-y1oxy]-2-thi oxo~2H-
[1,2' ]bipyridinyl-5'-carbonitr i le;
<64> 5-ch1oro-4-[ 1-(5-ethy1-pyr imid i n-2-y1 )-piper i d in-4-y1oxy]-5' -methanesu1 fony1 -
[1,2' ]bipyr idinyl-2-thione;
<65> 3-{4-[ 1-(5-eth 1-pyr imidin~2-y1 )-pi per i din-4-y1oxy] -2-oxo-2H-pyr idin-1- ylmethyl }-benzonitr i le',
<66> 3-{4-[ 1-(5-ethy1-pyr imidin-2-y1 )- i per i din-4-y1oxy]-2-1hi oxo~2H-pyr idin-1- ylmethyl }-benzonitr i le;
<f7> 4- [ 1-(3-cyano-benzy1 )-2-oxo-1 , 2-di hydro-pyr idin-4-y1oxy]-piper idine-1- carboxylic acid tert-butyl ester;
<68> 4- [ 1-(3-cyano-benzy1 )-2-1hi oxo-1 , 2-dihydro-pyr i din-4-y1oxy] -pi per i dine-1- carboxylic acid tert-butyl ester;
<69> 4- [ 1-(3-cyano-benzy1 )-2-oxo-1 , 2-dihydro-pyr idin-4-y1oxymethy1 ] -piper idine-1- carboxylic acid tert-butyl ester;
<70> 4- [ 1-(3-cyano-benzy1 )-2-thioxo-1 ,2-dihydro-pyr i din-4-y1oxymethy1 ]-piper idine~
1-carboxylic acid tert-butyl ester;
<7 i> 4-{4-[l-(5-ethyl-pyrimidin-2-yI )-piper idin~4-y1oxy]-2-1hioxo-2H-pyr i d in-1- yl }-2-f luoro-benzonitr i le;
<72> 4-[ 1-(4-f 1uoro-benzy1 )-2-oxo-1 , 2-dihydro-pyr idin-4-y1oxy]-piper idine-1- carboxylic acid tert-butyl ester;
<73> 4- [ l-(3-methoxy-benzy1 )-2-oxo-1 , 2-di hydro-pyr i din-4-y1oxy] -piper i di ne-1- carboxylic acid tert-butyl ester;
<74> 4-(4-{4-[ 1-( tert-butoxycarbony1 )-p i per i din-4-y1oxy]-2-oxo-2H-pyr idin-1- ylmethyl }-thiazole-2-yl )-piper idine-l-carboxyl ic acid tert-butyl ester;
<75> 4- [ 1-( 1-methanesu1 fony1-piper idi n-4-y1methy1 )-2-oxo-1 , 2-di hydro-pyr idi n-4- yloxy]-piper idine-l-carboxyl ic acid tert-butyl ester;
<76> 4-[l-(4-f luoro-benzyl )-2-thioxo-l,2-dihydro-pyr idi n-4-yloxy]-pi per idine-l- carboxyl ic acid tert-butyl ester;
<77> 4-[ 1-(3-methoxy-benzy1 )-2-1hioxo-1 , 2-d ihydro-pyr idi n-4-y1oxy] -pi per idi ne-1- carboxylic acid tert-butyl ester;
<78> 4- [ 1-(4-methoxycarbony1-benzy1 )-2-oxo-1 , 2-d ihydro-pyr i din-4-y1oxy] -
piperidine-l-carboxyl ic acid tert-butyl ester;
<79> 4-[ 1-(4-cyano-2-fluoro-benzyl)-2-oxo-l,2-dihydro-pyr i din-4-y1oxy] -piper idine-
1-carboxylic acid tert-butyl ester;
<80> 4-{5-ch1oro-4-[ 1-(5-ethy1-pyr imidin-2-y1 )- iper idin-4-y1oxy]-2-oxo~2H- pyr idin-l-ylmethyl }-3-f luoro-benzonitr i le;
<81> 5-ch1oro-1-(6-ch1oro-pyr idin-3-y1methy1 )-4-[ 1-(5-ethy1-pyr imidin-2-y1 )- piper idin-4-y1oxy] -lH-pyr i din-2-one ;
<82> 5-ch1oro-4-[ 1-(5-ethy1-pyr imidin-2-y1 )- iper idin-4-y1oxy]-1-(3- tr i f 1uoromethy1-benzy1 )-ΙΗ-pyr i din-2-one ;
<83> 5-ch1oro-4-[ 1-(5-ethy1-pyr imidin-2-y1 )-piper idin-4-y1oxy]-1-( - tr i f 1uoromethy1-benzy1 )-ΙΗ-pyr i din-2-one ;
<84> 5-ch1oro~4-[ 1-(5-ethy1-pyr imidin-2-y1 )- iper idin~4-y1oxy]-1-(4-methoxy- benzy1 )-lH-pyr i din-2-one ;
<85> 5-ch1oro-4-[ 1-(5-ethy1-pyr imidin-2-y1 )- iper idin-4-y1oxy]-1-(3-methoxy- benzy1 )-ΙΗ-pyr idin-2-one ;
<86> 5-ch1oro-4-[ 1-(5-ethy1-pyr imidin-2-y1 )-piper idin-4-y1oxy]-1-(3- tr i f 1uoromethoxy-benzy1 )-lH-pyr idin-2-one ;
<87> 5-ch1oro-4-[ 1-(5-ethy1-pyr imidin-2-y1 )- iper idin-4-y1oxy]-1-(4-f 1uoro- benzy1 )-lH-pyr i din-2-one '.
<88> 4-{5-ch1oro-4-[ 1-(5-ethy1-pyr imidin-2-y1 )-piper idin-4-y1oxy]-2-oxo~2H- pyr idin-l-ylmethyl }-benzonitri le;
<89> 5-chloro-4-[l-(5-ethyl -pyr imidin-2-yl)-piperidin-4-yloxy]-l-(4-isopropyl- benzy1 )-lH-pyr i din-2-one ;
<90> 5-chloro-1-(3 , -di f 1uoro-benzy1 )-4-[ 1-(5-ethy1-pyr imidin-2-y1 )-piper idin-4- y1oxy]-lH-pyr idin-2-one ;
< 1> 4- [5-ch1oro-1-(3 , 4-di f 1uoro-benzoy1 )-2-oxo-1 ,2-dihydro-pyr i din-4-y1 oxy]- piper idine-l-carboxyl ic acid tert-butyl ester;
<92> 5-ch1oro-4-[ 1-(5-ethy1-pyr imidin-2-y1 )-piper idin-4-y1oxy]-1-(3-f 1uoro- benzy1 )-lH-pyr idin-2-one ;
<93> 3-{5-ch1oro-4-[ 1-(5-ethy1-pyr imidin-2-y1 )-piper i din-4-y1oxy]-2-oxo~2H- pyr i din-1-y1methy1 }-benzoni tr i 1e ;
<94> 4- [5-ch1oro-1-(3-cyano-benzy1 )-2-oxo-1 , 2-dihydro-pyr idin-4-y1oxy]-piper idine-
1-carboxylic acid tert-butyl ester;
<95> 4- [5-ch1oro-1-(3-cyano-benzy1 )-2-oxo-1 , 2-dihydro-pyr idin-4-y1oxy]- iper idium chloride;
<%> 5-ch1oro~4- [ 1-(5-ethy1-pyr imidin-2-y1 )-piper idin-4-y1oxy]-1-(4- methy1 su1 fany1-benzy1 )-ΙΗ-pyr idin-2-one ;
<97> 5-ch1 oro-4- [ 1-(5-ethy1-pyr imidin-2-y1 )-piper idin-4-y1oxy]-1-(4- methanesulf inyl-benzyl )-lH-pyr idin-2-one;
<98> 5-ch1oro-4-[ 1-(5-ethy1-pyr imidin-2-y1 )- iper idin-4-y1oxy]-1-( - methanesu1 fony1-benzy1 )-ΙΗ-pyr i din-2-one ;
<99> 5-ch1oro~4- [ 1-(5-ethy1-pyr imidin-2-y1 )-piper idin-4-y1oxy]-1-(2-f 1uoro- benzy1 )-lH-pyr idin-2-one ;
<loo> 5-ch1oro-4-[ 1-(5-ethy1-pyr imidin-2-y1 )-piper idin-4-y1oxy]-1-(3-f 1uoro-4- methy1 su1 fany1-benzy1 )-ΙΗ-pyr idin-2-one ;
< Io I > 3-{5-ch1oro-4-[ 1-(4-methy1su1 fany1-benzoy1 )- iper idin-4-y1oxy]-2-oxo-2H- pyr idin-l-ylmethyl }-benzoni tr i lei
< 102> 3- [4-( 1-benzoxazo1e-2-y1- iper idin-4-y1oxy)-5-ch1oro-2-oxo-2H-pyr idin—1- ylmethyl ]-benzonitr i le;
< 103> 4-[5-ch1oro-1-(3-f 1uoro-benzy1 )-2-oxo-1 , 2-dihydro-pyr idin-4-y1oxy] - piper idine-l-carboxyl ic acid tert-butyl ester;
<io4> 3-[5-ch1or0-4-( 1-i sobutyry1- iper idin-4-y1oxy)-2-oxo-2H-pyr idin-1-y1methy1 ]- benzonitri le;
< 105> 5-chloro-4-[l-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxy]-l-[2-(4- f luoro- pheny1 )-ethy1 ]-lH-pyr idin-2-one ;
< 106> 3-{4-[ 1-(5-bromo-pyr imidin-2-y1 )-piper idin-4-y1oxy]-5-ch1oro-2-oxo-2H- pyr idin-l-ylmethyl }-benzoni tr i le; and
< 107> 4-( l-{4-[ 1-(5-ethy1 -pyr imidin-2-y1 )-piper idin-4-y1oxy]-2-oxo-2H-pyr idin-1- yl }-ethyl)-benzonitr i le.
<io8> Herein, the compound represented by Formula 1 may be preferably any one selected from the group consisting of following compounds:
< 109> 4-{5-ch1oro-4- [ l-(5-ethy1-pyr imidin-2-y1 )-piper idin-4-y1oxy]-2-thioxo-2H- pyridin-l-yl }-2-f luoro-benzonitri le;
< 1 1o> 4-[5-ch1oro-1-(4-cyano~3-f 1uoro-pheny1 )-2-thioxo-1 , 2-dihydro-pyr idin-4-
yloxy]-piperidine-l-carboxyl ic acid tert-butyl ester;
<iii> 5-chloro-4-[l-(5-ethyl-pyr imidin-2-y1 )- iper idin-4-y1oxy]-1-(4- methanesu1 fony1-pheny1 )-lH-pyr idin-2-thione ;
<112> 4-[5-ch1oro-1-(4-methanesu1 fony1-pheny1 )-2-1hioxo-1 , 2-dihydro-pyr idin-4- yloxy]-piper idine-l-carboxyl ic acid tert-butyl ester;
<i i3> 5-chloro-4-[l-(5-ethyl-pyr imidin-2-yl)-piper idin-4-yloxy]-5'-methanesul fonyl- [1,2' ]bipyr idinyl-2-thione;
<n 4> 3-{4-[ 1-(5-ethy1-pyr imi din-2-y1 )-pi per idin-4-y1oxy]-2-oxo~2H-pyr idin—1—
ylmethyl }-benzoni tr i le ;
<115> 4-[ 1-(3-cyano-benzy1 )-2-oxo-1 , 2-dihydro-pyr i din-4-y1oxy]-piper idine-1- carboxylic acid tert-butyl ester;
< 116> 4-{4-[ 1-(5-ethy1-pyr imidin-2-y1 )- i er i din-4-y1oxy]-2-thioxo-2H-pyr idin-1- yl }-2-f luoro-benzonitr i le!
<117> 4- [ 1-(4-cyano~2-f 1uoro-benzy1 )-2-oxo-1 , 2-dihydro-pyr idin-4-y1oxy]- iper idine-
1-carboxylic acid tert-butyl ester;
<ii8> 4-{5-chloro-4-[l-(5-ethyl-pyr imidin-2-yl)-piper idin-4-yloxy]-2-oxo~2H- pyr i din-1-y1methy1 }-3-f 1uoro-benzoni tr i le ;
<11 > 4-{5-ch1oro-4-[ 1-(5-eth 1-pyr imidin-2-y1 )- iper idin-4-y1oxy]~2-oxo-2H- pyr idin-l-ylmethyl }-benzonitri le;
<120> 3—{5-ch1or0-4-[ 1-(5-ethy1-pyr imi din-2-y1 )- i per idin-4-y1oxy]-2-oxo~2H- pyr i din-1-y1methy1 }~benzoni tr i 1 e ;
<121> 4-[5-ch1oro-1-(3-cyano-benzy1 )-2-oxo-1 , 2-dihydro-pyr idin-4-y1oxy]-piper idine-
1-carboxylic acid tert-butyl ester;
< 122> 5-ch1oro-4-[ 1-(5~ethy1-pyr imidin-2-y1 )- iper idin-4-y1oxy]-1-(4- methylsul fanyl-benzyl )-lH-pyr idin-2-one;
< 123> 5-ch1oro-4-[ 1-(5-ethy1-pyr imidin-2-y1 )- iper idin-4-y1oxy]-1-(4- methanesu1 f iny1-benzy1 )-ΙΗ-pyr idin-2-one ;
< 124> 5-ch1 oro-4- [ 1-(5-ethy1-pyr imidin-2-y1 )-piper idin-4-y1oxy]-1-(4- methanesul fony1 -benzyl )-lH-pyr idin-2-one ;
< 125> 5-ch1oro-4- [ 1-(5-ethy1-pyr imidin-2-y1 )- iper idin-4-y1oxy]-1-(3-f 1uoro~4- methy1 su1 fan 1-benzy1 )-lH-pyr idin-2-one ;
<126> 3-[5-ch1oro-4-( 1-i sobutyry1 -piper idin-4-y1oxy)-2-oxo-2H-pyr idin-l-y1methy1 ]-
benzonitri le! and
3-{ 4- [ 1- ( 5-br omo-pyr i m i d i n-2-y 1 ) - i per i d i n-4-y 1 oxy ] -5-ch 1 or o-2-oxo~2H- pyr i d i n- 1-y 1 me t hy 1 }-benzon i t r i 1 e .
In accordance with another aspect of the present invention, there is provided a pharmaceutical composition for treating metabolic disorders, which includes the inventive compound or a pharmaceutically acceptable salt thereof, as an active ingredient.
Herein, for example, the metabolic disorders include obesity, type I diabetes mellitus, type II diabetes mellitus, impaired glucose tolerance, insulin resistance, hyperglycemia, hyper 1 ipidemia, hypertriglyceridemia, hypercholesterolemia, dysl ipidemia, syndrome X, and the like.
In accordance with afurther aspect of the present invention, there is provided a method for preparing the compound represented by Formula 1 by reacting a compound represented by Formula 4 below with a compound represented by Formula 5 below:
Formula 4]
[Formula 5]
In the Formulas above,
A and B represent halogen, and X, Y, Li, ¾, r , Zi, Z2, Pi, P2 and Psare the same as defined above.
[Advantageous Effects]
Although several exemplary embodiments of the present invention have
been described for illustrative purposes, those skilled in the art will appreciate that various modifications, additions and substitutions are possible, without departing from the scope and spirit of the invention as disclosed in the accompanying claims.
[Description of Drawings]
<I38> The foregoing and other objects, features and advantages of the present invention will become more apparent from the following detailed description when taken in conjunction with the accompanying drawing in which:
<I39> FIG. 1 is a comparison graph of potency and efficacy according to concentrations of compounds.
[Best Mode]
<I4()> Hereinafter, the present invention will be described in detail with reference to Preparation Examples and Examples below. However, Preparation Examples and Examples as described below are only for illustrative purposes and are not intended to limit the scope of the invention.
<I41> All reagents used in Examples were bought from Sigma-Aldr ich, Fluka, and TCI, and H NMR Spectra was recorded by using tetramethyl si lane as an internal standard material and Bruker Biospin AVANCE II 400.
<142> Preparation Example l:Synthesis of l-(5-methyl-pyrimidin-2-yl )- din-4- l
<144> Under a nitrogen atmosphere, in a 500ml flask, 9.6g of 4- hydroxypiper idine and 250ml of 2:1 acetonitr i le/dist i 1 led water-solution were placed, stirred and dissolved. Then, 19.5ml of di isopropylethylamine and 11.2g of 2-chloro-5-ethylpyr imidine were added thereto, followed by heating and reflux for 2.5 days or more. The temperature was lowered to a room temperature, and the resultant product was dissolved in 200ml of IN HC1 aqueous solution, and washed with 200ml of ethyl acetate. The aqueous layer was adjusted to pH 7 by using IN NaOH aqueous solution, and was extracted with 200mL of ethyl acetate. The organic layer was dried with anhydrous
magnesium sulfate and vacuum-dried so as to provide a target compound.
<i45> H NMR (400MHz, CDC13): 8.18(2H, s), 4.37-4,48(2H, m), 3.91-4.0K 1H, m) ,
3.22-3.3K2H, m), 2.42-2.5K2H, m) , 1.49-1.99(4H, m) , 1.17-1.2K3H, m).
<I46> Preparation Example 2:Synthesis of 5-chloro-4-hydroxy-lH-pyr idin-2- thione
<i48> Under a nitrogen atmosphere, in a 500ml flask, 16g of 5-chloro-4- hydroxy-lH-pyr idin-2-one and 200ml of Ν,Ν-dimethylformamide were placed, and stirred and dissolved. Then, 8.9g of Lawesson^s reagent was added thereto, followed by heating and reflux for 12 hours or more. Then, the mixture obtained after the reaction was extracted with 200ml of distilled water and 200ml of ethyl acetate. The separated organic layer was washed with 200ml of brine, dried with anhydrous magnesium sulfate, concentrated, and purified with silica column chromatography so as to provide a target compound.
<I49> H NMR (400MHz, DMS0-d6) : 7.61-7.82UH, m) , 7.01-7.03(1H, m).
<i50> Preparation Example 3:Synthesis of 4-(5-chloro-2-thioxo-l,2-dihydro- pyr idin-4-yloxy)-piperidine-l-carboxyl ic acid tert-butyl ester
<15l>
<i52> Under a nitrogen atmosphere, in a 500ml flask, 15g of 5-chloro-4- hydroxy-lH-pyr idin-2-thione and 300ml of N,N-dimethyl formamide were placed, and stirred and dissolved. 40g of tr iphenylphosphine and 22.5g of 4-hydroxy- piper idine-l-carboxyl ic acid tert-butyl ester were added thereto, and then, at 0°C 30.5ml of diisopropyl azadi carboxylate was slowly dropped by using a dropping funnel. The resultant mixture was stirred at room temperature for 12 hours or more. The compound obtained after the reaction was dissolved in
300ml of ethyl acetate, washed with 300ml of distilled water, and extracted twice with IN HC1 aqueous solution. The aqueous layer was washed twice with 300ml of ethyl acetate. The separated aqueous layer was adjusted to pH 10 by using saturatedsodium bicarbonate aqueous solution, and the organic layer was extracted twice with 300ml of ethyl acetate, dried with anhydrous magnesium sulfate, and vacuum-dried so as to provide a target compound.
< I 53> H NMR (400MHz, CDC13): 7.35(1H, s), 7.24UH, s), 4.58-4.6K1H, m),
3.47-3.66 (4H, m) , 1.84-1.95(4H, m), 1.6K9H, s).
< 154> Preparation Example 4:Synthesis of 5-chloro-4-[l-(5-ethyl-pyr imidin-2- y1 )-pip r i din~4-y1oxy]-lH-pyr idin-2-thi one
< I 55>
< 1 5(» A target compound was obtained in the same manner as described in
Preparation Example 3 except that instead of 4-hydroxy-piper idine-1- carboxylic acid tert-butyl ester, l-(5-ethyl-pyrimidin-2-yl )-piper idin-4-ol was used.
< 1 57> H NMR (400MHz, CDC13): 8.2K2H, s), 7.46UH, s), 7.27(1H, s), 4.57-
4.65C1H, m), 3.69-4.04(4H, m) , 2.36-2.48(2H, m) , 1.87-1.95(4H, m), 1.18- 1.23(3H, m).
< 1 58> Preparation Example 5:Synthesis of 4-amino-lH-pyr imidin-2-thione
< 1 60> A target compound was obtained in the same manner as described in
Preparation Example 2 except that instead of 5-chloro-4-hydroxy~lH-pyr idin-2- one, 4-amino-lH-pyrimidin-2-one was used.
<161 > H NMR (400MHz, DMS0-d6): 8.29(1H, m), 7.21-7.23(1H, m). < I 62> Preparation Example 6: Synthesis of 4-(2-thioxo-l,2-dihydro-pyr imidin-
no)-piper idine-l-carboxyl ic acid tert-butyl ester
A target compound was obtained in the same manner as described in Preparation Example 3 except that instead of 5-chloro-4-hydroxy-lH-pyridi -2- thione, 4-amino-lH-pyr imidine-2-thione was used.
H NMR (400MHz, CDC13): 8.05(1H. d), 7.22(1H, d), 4.72-4.8K1H, m) ,
3.69-3.84 (4H, m) , 1.83-2.08(4H, m), 1.59(9H, s).
Preparation Example 7:Synthesis of methanesulfonic acid 1- methanesu1 fony1-piper idin-4-y1 ester
Under a nitrogen atmosphere, in a 250ml flask, 5g of 4- hydroxypiper idine and 100ml of MC were placed, and stirred and dissolved. 17.5mL of triethylamine and 12.5mL of methanesulfonyl chloride were added thereto, and the mixture was reacted at room temperature for 6 hours. Then, 100ml of distilled water was slowly added to the compound obtained after the reaction, and the compound wasextracted with 100ml of ethyl acetate. The extract was washed with 100ml of brine, dried with anhydrous magnesium sulfate, concentrated, and purified with silica column chromatography so as to provide a target compound.
H NMR (400MHz, CDC13): 4.11-4.13(2H, d), 3.87-3.9K2H, m), 3.05(3H, s),
2.8K3H, s), 2.66-2.73(2H, m) , 1.91-1.93C3H, m) , 1.41-1.50(2H, m).
Preparation Example 8: Synthesis of 2-bromo-5-methylsulfanyl-pyr idine
Under a nitrogen atmosphere, in a 500ml flask, 12g of 2,5-dibromo- pyridine and 250ml of ether were placed. At -78°C 34ml of n-butyl lithium
(1.52M in n-hexane) was added thereto, and after 1 hour, 4.9ml of dimethyldisulf ide was dropped. After 12-hours of stirring at room temperature, distilled water was slowly dropped at 0°C and the resultant mixture was extracted with 200ml of ethyl acetate. The extract was washed with 200ml of 1N-HC1, and the organic layer was dried with anhydrous magnesium sulfate, and vacuum-dried, so as to provide a target compound.
<173> ¾ NMR (400MHz, CDC13): 8.25C1H, s), 7.38-7.44(2H, m), 2.5K3H, s).
<174> Preparation Example 9:Synthesis of 2-bromo-5-methanesulfonyl -pyridine
<i76> Under a nitrogen atmosphere, in a 500ml flask, 5g of 5-methylthio~2- bromopyr idine was added in THF 200mL/dist i 1 led water 40mL, and stirred. At 0 °C 40g of oxone was added thereto, followed by stirring at room temperature for 3 hours. Then, the reaction mixture was filtered, and the filtrate was extracted with 200ml of distilled water and 200ml of ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, and vacuum-dried so as to provide a target compound.
<i77> ¾ NMR (400MHz, CDC13): 8.93(1H, s), 8.06-8.09UH, d), 7.73-7.75UH, d) ,
3.14C3H, s).
<I78> Preparation Example 10:Synthesis of 4-hydroxy-lH-pyr idine-2-thione
<i80> A target compound was obtained in the same manner as described in
Preparation Example 2 except that instead of 5-chloro-4-hydroxy-lH-pyr idin-2- one, 4-hydroxy-lH-pyridin-2-one was used.
<i8i> H NMR (400MHz, DMS0-d6) : 7.53(1H, d), 7.22(1H, s), 5.97UH, d) ,
<i82> Preparation Example 11'· Synthesis of 4-[ l-(5-ethyl-pyr imidin-2- y1 )-piper idin-4-y1oxy]-lH-pyr idine-2~thione
A target compound was obtained in the same manner as described in Preparation Example 4 except that instead of 5~chloro-4-hydroxy-lH-pyr idine- 2-thione, 4-hydroxy-lH-pyr idine-2-thione was used.
¾ NMR (400MHz, CDC13): 8.19C2H, s), 7.42(1H, d) , 7.23(1H, s), 6.05QH, d), 4.55-4.56C1H, m) , 3.61-4.56 (4H, m), 2.46-2.49(2H, m) , 1.81-2.08(4H, m), 1.22-1.28C3H, m) .
Preparation Example 12:Synthesis of 3-(4-hydroxy-2-oxo-2H-pyr idin-1- ylmethyl )-benzonitr i le
Under a nitrogen atmosphere, in a 50ml flask, 300mg of 4-hydroxy-2(lH)- pyridone and 20ml of Ν,Ν-dimethylformamide were placed, and stirred and dissolved. Then, 108mg of sodium hydride and 530mg of 3- bromomethylbenzonitr i le were added thereto, followed by stirring at room temperature for 5 hours or more. The reaction mixture was dissolved in 100ml ofethyl acetate, and washed twice with 100ml of distilled water. The organic layer was dried with anhydrous magnesium sulfate and vacuum-dried. The residue obtained after the vacuum-drying was purified with silica column so as to provide a target compound.
¾ NMR (400MHz, DMS0-d6) 7.78(lH,d), 7.76-7.65(2H,m) , 7.63-7.52(2H,m) ,
5.92(lH,d), 5.61(lH,s) 5.10(2H,s)
Preparation Example 13:Synthesis of l-(4-f luoro-benzyl )-4-hydroxy-lH- pyr idine-2-one
<1 2> A target compound was obtained in the same manner as described in Preparation Example 12 except that instead of 3-bromomethylbenzonitri le, 4- fluorobenzyl bromide was used.
<I93> H NMR (400MHz, CDC13): 7.31(2H,d) 7.15(lH.d), 7.06(2H,t) 5.7(lH,d),
5.5(lH,d), 4.9(2H,S)
<194> Preparation Example 14:Synthesis of 4-hydroxy-l-(3-methoxy-benzyl )-lH- pyridine-2-one
< 196> A target compound was obtained in the same manner as described in
Preparation Example 12 except that instead of 3-bromomethylbenzonitrile, 3- methoxybenzyl bromide was used.
<I 7> H NMR (400MHz, CDC13): 7.28(lH,m), 7.14(lH,d), 6.88-6.82(3H,m) ,
5.78(lH,d), 5.64(lH,s),4.92(2H,s)
<I 8> Preparation Example 15-Synthesis of 4-[4-(4-hydroxy-2-oxo-2H-pyridin-1- ylmethyl)-thiazole-2-yl]-piperidine-l-carboxyl ic acid tert-butyl ester
<199>
<200> A target compound was obtained in the same manner as described in
Preparation Example 12 except that instead of 3-bromomethylbenzonitrile, 4- (4-chloromethyl-thiazole-2-yl )-piperidine-l-carboxyl ic acid tert-butyl ester was used.
<20l ¾(400MHz, CDCls) 7.41(lH,d), 7.15(lH,s),5.81(lH,d) , 5.61(lH,s),
5.2(2H.s), 4.30-4.10(lH,s)3.20-3.10(lH,m), 3.0-2.8(2H,m) , 2.15-2.07(2H,m) , 1.80-1.56(2H,m), 1.52(9H,s)
<202> Preparation Example 16:Synthesis of methanesul fonic acid 1- methanesulfonyl-piperidin-4-ylmethyl ester
OMs
sN
<2 3>
<204> Under a nitrogen atmosphere, in a 50ml flask, 500mg of 4- piper idinemethaneol and 30ml of tetrahydrofuran were placed, and stirred and dissolved. 0.91ml of t iethylamine and 0.17ml of methanesul fonyl chloride were added thereto, followed by stirring at room temperature for 10 hours or more. 30ml of disti 1 ledwater was added thereto, and tetrahydrofuran was removed through vacuum distillation. Then, the solid was filtered, washed with 50ml of distilled water, and dried so as to provide a target compound.
<205> ¾(400MHz, CDC13) 4.11(2H,d), 3.89(2H,d), 3.05(3H,s), 2.81(3H,s),
2.69(2H,t), 1.92(3H,d), 1.47-1.40(2H,m)
<206> Preparation Example 17:Synthesis of 4-hydroxy-l-(l-methanesulfonyl- p i per i d i n-4-y 1 met hy 1 ) - lH-pyr i d i n-2-one
<207>
<208> A target compound was obtained in the same manner as described in
Preparation Example 12 except that instead of 3-bromomethylbenzonitr i le, methanesulfonic acid 1-methanesulfonyl-piper idin-4-ylmethyl ester was used.
<209> oOMHz, CDC13) 7.06(lH,d), 5.7(lH,d) ,5.52(lH,s) , 4.82(2H,d),
3.67(2H,d), 2.78(3H,s), 2.62(2H,t), 2.14-2.04(lH,m) , 1.65(2H,m), 1.42- 1.37(2H,m)
<2I0> Preparation Example 18:Synthesis of 4-(4-hydroxy-2-oxo-2H-pyr idin-1- lmethyl )-benzoic acid methyl ester
<212> A target compound was obtained in the same manner as described in Preparation
Example 12 except that instead of 3-bromomethylbenzonitr i le, methyl 4-
(bromomethyl)benzoate was used.
<213> Η(400ΜΗζ, CDCls) 7.82(2H,d), 7.24(2H,d), 7.15(lH,d), 5.7(lH,d), 5.52(lH,s), 5.05(2H,s), 3.62(3H,s)
<2I4> Preparation Example 19: Synthesis of 3-f luoro-4-(4-hydroxy-2-oxo-2H-pyr idin- -ylmethyl)-benzonitri le
<216> A target compound was obtained in the same manner as described in
Preparation Example 12 except that instead of 3-bromomethylbenzonitri le, 4- (bromomethyl )-3-f luorobenzonitr i le was used.
<217> ¾(400MHz, CDCI3) 7.46(lH,t), 7.35-7.30(2H,m) , 7.18(lH,d), 5.7(lH,d),
5.52(lH,s), 4.98(2H,s)
<2I8> Preparation Example 20:Synthesis of 4-(5-chloro-4-hydroxy-2-oxo-2H- pyr i din- -y1methy1 )-3-f 1uoro-benzoni tr i 1e
<219>
<220> Under a nitrogen atmosphere, in a 50ml flask, 300mg of 5-chloro-4- hydroxy-2(lH)-pyr idinone and 20ml of Ν,Ν-dimethylformamide were placed, and stirred and dissolved. Then, 82mg of sodium hydride and 441mg of 4- (bromomethyl )-3-f luorobenzonitr ile were added thereto, followed by stirring at room temperature for 5 hours or more. The reaction mixture was dissolved in 100ml of ethyl acetate, and washed twice with 100ml of distilled water. The organic layer was dried with anhydrous magnesium sulfate and vacuum- dried. The residue obtained after the vacuum-drying was purified with silica column so as to provide a target compound.
<221> H(400MHz, CDCI3) 7.46(lH,t), 7.35-7.30(2H,m) , 7.18(lH,d), 5.52(lH,s), 4.98(2H,s)
<222> Preparation Example 21: Synthesis of 5-chloro-l-(6-chloro-pyr idin-3- y1methy -4-hydroxy-IH-pyr i din-2-one
<223>
<224> A target compound was obtained in the same manner as described in
Preparation Example 20 except that instead of 4-(bromomethyl )-3- f luorobenzonitr i le, 2-chloro-5-(chloromethyl )pyr idine was used.
<225> ¾( 00MHz, CDC13) 8.21(lH,s), 7.62(lH,d), 7.28-7.23(2H,m) , 5.72(lH,s),
<226> Preparation Example 22:Synthesis of 5-chloro-4-hydroxy-l-(3- -benzyl )-lH-pyr idin-2-one
<228> A target compound was obtained in the same manner as described in
Preparation Example 20 except that instead of 4-(bromomethyl )-3- f luorobenzonitr i le, 3-(trif luoromethyl )benzyl bromide was used.
<229> H(400MHz, CDC13) 7.41-7.28(4H,m), 7.12(lH,s), 5.48(lH,s), 4,91(2H,s) <230> Preparation Example 23: Synthesis of 5-chloro-4-hydroxy-l-(4- t r i f 1uoromethy1-benzy1 )-IH-pyr i din-2-one
<232> A target compound was obtained in the same manner as described in
Preparation Example 20 except that instead of 4-(bromomethyl )-3- f luorobenzonitr ile, 4-( tr if luoromethyl )benzyl bromide was used.
<233> ¾(400MHz, CDC13) 7.44(2H,d), 7.22(2H,d), 6.98(lH,s), 5.87(lH,s),
4.98(2H,s)
Preparation Example 24:Synthesis of 5-chloro-4-hydroxy-l-(4-methoxy- benzy1 )-ΙΗ-pyr idin-2-one
A target compound was obtained in the same manner as described in Preparation Example 20 except that instead of 4-(bromomethyl )-3- f luorobenzonitr i le, 4-methoxybenzyl bromide was used.
¾(400MHz, CDC13) 7.18(2H,d), 7.11(lH,s), 6.73(2H,d), 5.87(lH,s),
4.98(2H,s), 3.67(3H,s)
Preparation Example 25: Synthesis of 5-chloro-4-hydroxy-l-(3-methoxy- benzy1 )-ΙΗ-pyr idin-2-one
A target compound was obtained in the same manner as described in Preparation Example 20 except that instead of 4-(bromomethyl )-3- fluorobenzonitr i le, 3-methoxybenzyl bromide was used.
H(400MHz, CDCI3) 7.28(lH,s), 7.16(lH,s), 6.98-6.87(3H,m) , 4.78(2H,s), 3,84(3H,s)
Preparation Example 26 Synthesis of 5-chloro-4-hydroxy-l-(3- tr i f 1uoromethoxy-benzy1 )-lH-pyr idin-2-one
A target compound was obtained in the same manner as described in Preparation Example 20 except that instead of 4-(bromomethyl )-3-
f luorobenzonitr i le , 3-(trif luoromethoxy)benzyl bromide was used.
H OOMHz, CDCls) 7.42-7.40(lH,m), 7.28-7.18(3H,m) , 6.92(lH,s),
5.88(lH,s), 4.78(2H,s)
Preparation Example 27:Synthesis of 5-chloro-l-(4-f luoro-benzyD^- hydroxy-lH-pyr idin-2-one
<248> A target compound was obtained in the same manner as described in
Preparation Example 20 except that instead of 4-(bromomethyl )-3- f luorobenzonitri le, 4-f luorobenzyl bromide was used.
<249> HUOOMHz, CDCI3) 7.9(lH,s), 7.20-7.28(2H,m) , 7.18-7.05(2H,m) ,
5.99(lH,s), 4.98(2H,s)
<250> Preparation Example 28:Synthesis of 4-(5-chloro-4-hydroxy-2-oxo-2H- pyr idin-l-ylmethyl)-benzoni tr i le
<252> A target compound was obtained in the same manner as described in
Preparation Example 20 except that instead of 4-(bromomethyl )-3- f luorobenzonitr i le, 4-(bromomethyl)benzonitri le was used.
<253> H(400MHz, CDCls) 7.42(2H,d), 7.22(2h,d), 7.02(lH,s), 5.97(lH,s),
4.87(2H,s)
<254> Preparation Example 29:Synthesis of 5-chloro-4-hydroxy-l-(4-isopropyl- benzy1 )-ΙΗ-pyr idin-2-one
<256> A target compound was obtained in the same manner as described in
Preparation Example 20 except that instead of 4-(bromomethyl )-3- f luorobenzonitr i le, 4-isopropyl benzyl bromide was used.
<257> ¾(400MHz, CDCls) 7.12(2H,d), 7.02(lH,s), 6.00(lH,s), 4.78(2H,s), 2.87-
2.82(lH,m), 1.21-1.19(6H,d)
<258> Preparation Example 30: Synthesis of 5-ch1 oro~l-(3,4-dif luoro-benzyl )-4- hydroxy-lH-pyr i din-2-one
<260> A target compound was obtained in the same manner as described in
Preparation Example 20 except that instead of 4-(bromomethyl )-3- f luorobenzonitr i le, 3,4-dif luorobenzyl bromide was used.
<26 l H(400MHz, CDCI3) 7.23-7. lK4H.ni), 5.98(lH,s), 4.85(2H,s) <262> Preparation Example 31: Synthesis of 5-chloro-l-(3,4-dif luoro-benzoyl )- 4-hydrox -ΙΗ-pyr idin-2-one
<263>
<264> A target compound was obtained in the same manner as described in
Preparation Example 20 except that instead of 4-(bromomethyl )-3- f luorobenzonitr i le, 3,4-dif luorobenzoyl chloride was used.
<265> ¾(400MHz, CDCI3) 7.88-7.84(2h,m), 7.33-7.31(lH,m), 6.34(lH,s) <266> Preparation Example 32:Synthesis of 5-chloro-l-(3-f luoro-benzyl )-4-
hydroxy-IH-pyr i din-2-one
A target compound was obtained in the same manner as described in Preparation Example 20 except that instead of 4-(bromomethyl )-3- f luorobenzonitr i le, 3-f luorobenzyl bromide was used.
¾(400MHz, CDC13) 7.34-7.28(lH,m), 7.10-7.01(4H,m) , 5.88(lH,s), 4.96(2H,s)
Preparation Example 33:Synthesis of 3-(5-chloro-4-hydroxy-2-oxo-2H- pyr i din-1-y1methy1 )-benzoni tr i 1 e
A target compound was obtained in the same manner as described in Preparation Example 20 except that instead of 4-(bromomethyl )-3- f luorobenzonitr i le, 3-(bromomethyl )benzonitri le was used.
H(400MHz, CDCI3) 7.34-7.28(lH,m), 7.10-7.01(4H,m) , 5.92(lH,s), 4.96(2H,s)
Preparation Example 34:Synthesis of 5-chloro-4-hydroxy-l-(4- methy1 su1 fany1-benzy1 )-IH-pyr idin-2-one
A target compound was obtained in the same manner as described in Preparation Example 20 except that instead of 4-(bromomethyl )-3- f luorobenzonitr i le, 4-(methylthio)benzyl bromide was used.
¾(400MHz, CDCI3) 7.9(lH,s), 7.20-7.28(2H,m) , 7.18-7.05(2H,m) ,
5.99(lH,s), 4.98(2H,s)
<278> Preparation Example 35:Synthesis of 5-chloro-l-(2-f luoro-benzyl )-4- hydroxy-lH-pyr i din-2-one
<279>
<280> A target compound was obtained in the same manner as described in
Preparation Example 20 except that instead of 4-(bromometh l )-3- f luorobenzonitr i le, 2-f luorobenzyl bromide was used.
<2 1 > ¾( 00MHz, CDCI3) 7.28-7.26(3H,m), 7.17-7.08(2H,m) , 5.98(lH,s), 5.01(2H,s)
<282> Preparation Example 36:Synthesis of 5-chloro-l-[2-(4-f luoro-phenyl )- eth l ]-4-hydroxy-lH- yr idin-2-one
<284> A target compound was obtained in the same manner as described in
Preparation Example 20 except that instead of 4-(bromomethyl )-3- f luorobenzonitr i le, 4-f luorophenethyl bromide was used.
<285> ¾( 00MHz, CDCI3) 7.18-7.13(2H,m), 7.04-7.01(2H,m) , 6.98(lH,s),
5.98(lH,s), 3.99-3.78(2H,m), 3.03-3..00(2H,m)
<286> Preparation Example 37:Synthesis of 4-(l-bromo-ethyl)-benzonitri le
<287>
<288> Underatmosphere, in a 500ml flask, 2-acetylbenzonitr i le was placed, and dissolved in methanol, followed by stirring. After the dissolution, at 0°C 2.6g of sodiumborohydr ide was added thereto, followed by stirring at room temperature for 24 hours. Then, lOg of triphenyl phosphine and llg of
carbotetra bromide were added thereto, followed by stirring at room temperature for 24 hours. The reaction mixture was extracted with 500ml of ethyl acetate. The separated organic layer was washed with 20ml of 1N-HC1 aqueous solution, then with 20ml of lN-Na0H aqueous solution, dried with anhydrous magnesium sulfate, and vacuum-dried. The obtained residue was purified with silica column so as to provide a target compound.
<289> ¾ NMR (400MHz, CDC13): 7.67 (2H, d), 7.54 (2H, d), 5.18 (1H, q), 2.06
(3H, d)
<290> Preparation Example 38:
<292> A target compound was obtained in the same manner as described in
Preparation Example 20 except that instead of 4-(bromomethyl )-3- f Iuorobenzonitr i le, 4-(l-bromo-ethyl)-benzonitri le was used.
<293> H NMR (400MHz, CDC13): 7.73 (2H, d), 7.45 (2H, d), 7.21 (1H, s), 6.37
(1H, m), 6.07 (1H, s), 1.83 (3H, d)
[Mode for Invention]
<294> Example 1
<295> Synthesis of 4-{5-chloro-4-[l-(5-ethyl-pyrimidin-2-yl)-piperidin-4- y1oxy]-2-1hioxo-2H-pyr idin-1-y1 }-2-f 1uoro-benzoni tr i 1e
<296> Under a nitrogen atmosphere, in a 100ml flask, lg of 5-chloro-4-[l-(5- ethyl-pyrimidin-2-yl)-piperidin-4-yloxy]-lH-pyridine-2-thione and 50ml of Ν,Ν-dimethylformamide were placed, and stirred and dissolved. At 0°C , 240mg of sodium hydride was slowly dropped, followed by stirring 1 hour or more, and 465mg of 2, -dif Iuorobenzonitr i le was added thereto, followed by heating and reflux for 12 hours or more. Then, at 0°C 100ml of distilled water was slowly added to the compound obtained after the reaction, and the compound wasextracted with 100ml of ethyl acetate. The extract was washed with 100ml of brine, dried with anhydrous magnesium sulfate, concentrated, and purified
with silica column chromatography so as to provide a target compound.
<297> H N R (400MHz, CDC13) : 8.22(2H, s), 7.81-7.86(1H, m) , 7.59UH, s),
7.44-7.47(lH, m) , 7.31-7.34(1H, m) , 7.25QH, s), 4.71-4.8K1H, m) , 3.81- 4.15C4H, m), 2.48-2.53(2H, m) , 1.94-2.09(4H, m) , 1.21-1.25(3H, m) .
<298> Example 2
<299> Synthesis of 4-[5-chloro-l-(4-cyano-3-f luoro-phenyl )-2-thioxo-l ,2- dihydro-pyridin-4-yloxy]-piperidine-l-carboxylic acid tert-butyl ester
<3oo> A target compound was obtained in the same manner as described in
Example 1 except that instead of 5-chloro-4-[l-(5-ethyl-pyr imidin-2-yl )- piper i din-4-y1 oxy] -ΙΗ-pyr idine-2-1hione , 4-(5-ch1oro-2-1hioxo-1 , 2-dihydro- pyridin-4-yloxy)-piperidine-l-carboxylic acid tert-butyl ester was used.
<30 i > H NMR (400MHz, CDC13): 7.81-7.86UH, m), 7.59(1H, s), 7.35-7.41UH, m) ,
7.31-7.34(1H, m) , 7.25(1H, s), 4.71-4.81(1H, m) , 3.51-3.64 (4H, m) , 1.94- 2.09(4H, m), 1.66(9H, s).
<302> Example 3
<303> Synthesis of 5-chloro-4-[l-(5-ethyl-pyr imidin-2-yl)-piper idin-4-yloxy]-
1-(4-methanesu1 fony1-pheny1 )-lH-pyr idine-2-thione
<304> A target compound was obtained in the same manner as described in
Example 1 except that instead of 2,4-dif luorobenzonitri le, l-fluoro-4-
(methylsul fonyl )benzene was used.
<305> H NMR (400MHz, CDC13): 8.22(2H, s), 8.15(2H, d) , 7.63(1H, s), 7.6K2H, d), 7.29(1H, s), 4.71-4.8K1H, m) , 3.81-4.15(4H, m) , 2.48-2.53(2H, m), 1.94- 2.09(4H, m), 1.21-1.25(3H, m) .
<306> Example 4
<307> Synthesis of 4-[5-chloro-l-(4-methanesulfonyl-phenyl)-2-thioxo-l,2- dihydro-pyr idin-4-yloxy]-piper idine-l-carboxyl ic acid tert-butyl ester
<308> A target compound was obtained in the same manner as described in
Example 3 except that instead of 5-chloro-4-[l-(5~ethyl-pyr imidin-2-yl )- piper idin-4-y1oxy] -ΙΗ-pyr idine-2-1hione , 4-(5-ch1oro~2-1hioxo-1 , 2-dihydro- pyr idin-4-yloxy)-piperidine-l-carboxyl ic acid tert-butyl ester was used.
<309> ¾ NMR (400MHz, CDC13): 8.13C2H, d), 7.6K1H, s), 7.59(2H, d), 7.25UH, s), 4.71-4.8K1H, m), 3.51-3.64 (4H, m), 3.15C3H, s), 1.94-2.09(4H, m) , 1.66C9H, s).
<3 io> Example 5
<3ii> Synthesis of 4-(l-tert-butoxycarbonyl-piperidin-4-yloxy)-5-chloro-2- thioxo-3' ,4' ,5' ,6'-tetrahydro-2H,2*H-[l,4' jbipyr idinyl-l'-carbox l ic acid tert-butyl ester
<3i2> Under a nitrogen atmosphere, in a 100ml flask, lg of 4-(5-chloro~2- thioxo-1 , 2-dihydro-pyr idin-4-y1oxy)- iper idine-1-carboxylie ac id tert-buty1 ester and 50ml of N,N-dimethylformamide were placed, and stirred and dissolved. At 0°C 240mg of sodium hydride was slowly dropped, followed by stirring 1 hour or more, and 650mg of t-butyl-4-hydroxy-l- piperidinecarboxylate was added thereto, followed by heating and reflux for 12 hours or more. Then, at 0°C 100ml of distilled water was slowly added to the compound obtained after the reaction, and the compound wasextracted with 100ml of ethyl acetate. The extract was washed with 100ml of brine, dried with anhydrous magnesium sulfate, concentrated, and purified with silica column chromatography so as to provide a target compound.
<3B> H NMR (400MHz, CDC13): 8.99UH, m) , 7.24(1H, s), 5.15-5.23UH, m) ,
4.59-4.67UH, m), 3.21-3.89 (8H, m), 1.65-2.11(8H, m) , 1.49U8H, s).
<3i4> Example 6
<3i5> Synthesis of 4-[l-(4-methanesulfonyl-phenyl)-2-thioxo-l,2-dihydro- pyrimidin-4-ylamino]-piperidine-l-carboxylic acid tert-butyl ester
<3i6> A target compound was obtained in the same manner as described in
Example 4 except that instead of 4-(5-chloro-2-thioxo-l,2-dihydro-pyridin- 4-yloxy)-piperidine-l-carboxyl ic acid tert-butyl ester, 4-(2-thioxo-l,2- dihydro-pyr imidin-4-ylamino)-piper idine-l-carboxyl ic acid tert-butyl ester was used.
<3i7> H NMR (400MHz, CDC13): 8.18(1H, d), 7.87-7.93(4H, m) , 7.24(1H, d),
5.01-5.08(1H, m), 3.53-3.78 (4H, m), 3.16(3H, s), 1.92-2.05(4H, m) , 1.63(9H,
s).
<3i8> Example 7
<3i9> Synthesis of 3-bromo-5-chloro-4-[l-(5-ethyl-pyrimidin-2-yl)-piperidin-
4-y1oxy]-1-(4-methanesu1 fony1-pheny1 )-IH-pyr idine-2-1hi one
<32o> Undera nitrogen atmosphere, in a 50ml flask, lOOmg of 5-chloro-4-[l-(5- ethy1-pyr imidin-2-y1 )-piper idin-4-y1oxy]-1-(4-methanesu1 fony1-pheny1 )-1H- pyr idine-2-thione and 20ml of MC were stirred and dissolved. At room temperature, 0.03ml of N-bromosuccinimide was added thereto, followed by heating and reflux. Then, 20ml of distilled water was added to the compound obtained after the reaction, andthe compound wasextracted with 20ml of ethyl acetate. By using saturated sodium bicarbonate aqueous solution, an organic layer was extracted with 20ml of ethyl acetate, dried with anhydrous magnesium sulfate, concentrated and purified with silica column chromatography so as to provide a target compound.
<32i> H NMR (400MHz, CDC13): 8.22(2H, s), 8.81-8.13(2H, d), 7.64-7.69(2H, d),
7.5K1H, s), 4.91-4.99UH, m), 3.48-4.49(4H, m), 3.15C3H, s), 2.48-2.53(2H, m), 1.94-2.19(4H, m), 1.21-1.25(3H, m).
<322> Example 8
<323> Synthesis of 5-chloro-5'-chloromethyl-4-[l-(5-ethyl-pyrimidin-2-yl)- piper idin-4-yloxy]-[l ,2' ]bipyr idinyl-2-thione
<324> A target compound was obtained in the same manner as described in
Example 1 except that instead of 2,4-dif luorobenzonitri le, 2-chloro-5-
(chloromethyl )pyr idine was used.
<325> H NMR (400MHz, CDC13): 8.5K1H, s), 8.2K2H, s), 8.02(1H, s), 7.75-
7.78UH, d), 7.31-7.34(1H, d) , 7.25(1H, s), 5.36(2H, s), 4.71-4.8K1H, m) , 3.81-4.15(4H, m), 2.48-2.53C2H, m) , 1.94-2.09C4H, m), 1.21-1.25(3H, m) . <326> Example 9
<327> Synthesis of 5-chloro-4-[l-(5-ethyl-pyr imidin-2-yl )-piper idin-4-yloxy]- l'-methanesulfonyl-l' ,2' ,3' ,4' ,5' ,6' -hexahydro-[l,4' ]bipyr idinyl-2-thione
<328> A target compound was obtained in the same manner as described in
Example 1 except that instead of 2,4-dif luorobenzonitri le, methanesul fonic
acid l-methanesulfonyl-piperidin-4-yl ester was used.
<329> H NMR (400MHz, CDC13): 8.22(2H, s) , 7.99UH, s), 7.26UH, s), 5.17-
5.24(1H, m), 4.71-4.8K1H, m), 3.81-4.15(4H, m) , 3.21-3.59(4H, m), 2.83(3H, s), 2.48-2.53(2H, m) , 1.94-2.18(4H, m) , 1.86-1.98(4H, m), 1.21-1.25C3H, m) . <33Q> Example 10
<33 i > Synthesis of 5-chloro-4-[l-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxy]-
2-thioxo-2H-[l,2' ]bipyridinyl-5'-carbonitr i le
<332> A target compound was obtained in the same manner as described in
Example 1 except that instead of 2,4-dif luorobenzonitri le, 6- chloronicotinonitri le was used.
<333> H NMR (400MHz, CDC13): 8.82UH, s), 8.37-8.39( 1H, d) , 8.27(1H, s),
8.22(2H, s), 8.08-8.1K1H, d), 7.26(1H, s), 4.71-4.8K1H, m), 3.81-4.15(4H, m), 2.48-2.53(2H, m) , 1.94-2.09(4H, m) , 1.21-1.25(3H, m).
<334> Example 11
<335> Synthesis of 5-chloro-4-[l-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxy]-
5'-methanesulfonyl-[l,2' Jbipyr idinyl-2-thione
<336> A target compound was obtained in the same manner as described in
Example 1 except that instead of 2,4-dif luorobenzonitri le, 2-bromo~5- methanesulfonyl-pyridine was used.
<337> lH NMR (400MHz, CDC13): 9.07(1H, s), 8.33-8.4K2H, m) , 8.26UH, s),
8.2K2H, s), 7.26(1H, s), 4.71-4.81UH, m) , 3.81-4.15(4H, m) , 2.48-2.53(2H, m), 1.94-2.09C4H, m) , 1.21-1.25C3H, m) .
<338> Example 12
<339> Synthesis of 3-{4-[l-(5-ethyl-pyr imidin-2-yl )-piperidin-4-yloxy]-2-oxo-
2H-pyr idin-l-ylmethyl }-benzonitri le
<340> Undera nitrogen atmosphere, in a 50ml flask, 473mg of 3-(4-hydroxy-2- oxo-2H-pyr idin-l-ylmethyl )-benzoni tr i le and 30ml of N,N-dimethylformamide were placed, and stirred and dissolved. 290mg of l-(5-ethyl-pyr imidin-2-yl )- piperidin-4-ol , 550mg of triphenylphosphine, and 0.4ml of diisopropyl azodi carboxylate were added thereto, followed by stirring at room temperature
for 10 hours or more. The reaction mixture was dissolved in 100ml of ethyl acetate, and washed twice with 100ml of distilled water. The organic layer was dried with anhydrous magnesium sulfate, and vacuum-dried. The residue obtained after the vacuum-drying was purified with silica column so as to provide a target compound.
<34 i > H(400MHz, CDC13) 8.20(2H,s), 7.62-7.56(3H,m) , 7.49-7.45(lH,m) , 7.17-
7.15(lH,d), 6.06-5.95(2H,m), 6.00-5.95(2H,m) , 5.10(2H,s), 4.57-4.51(lH,m) , 4.22-4.16(2H,m), 3.66-3.60(2H,m) ,2.50-2.46(2H,m) , 2.10-2.03(2H,m) , 1.86- 1.78(2H,m), 1.23-1.19(3H,m)
<342> Example 13
< 43> Synthesis of 3-{4-[l-(5-ethyl-pyrimidin-2-yl)-piper idin-4-yloxy]-2- thi oxo-2H-pyr idin-1-y1methy1 }-benzoni tr i 1e
<344> Under a nitrogen atmosphere, in a 50ml flask, 300mg of 3-{4-[l-(5- ethy1-pyr imidin-2-y1 )- iper idine~4-y1oxy]-2-oxo-2H-pyr idin-l-y1methy1 }- benzonitrile and 20ml of toluene were placed, and stirred and dissolved. Then, 160 mg of Lawesson's reagent was added thereto, followed by heating and reflux for 12 hours or more. Then, the mixture obtained after the reaction was extracted with 100ml of distilled water and 100ml of ethyl acetate. The separated organic layer was washed with 100ml of brine, dried with anhydrous magnesium sulfate, concentrated, and purified with silica column so as to provide a target compound.
<345> H(400MHz, CDC13) 8.20(2H,s), 7.63-7.61(2H,d) , 7.57(lH,s), 7.51-
7.49(2H,m), 7.28(lH,s), 6.38-6.35(lH,m) , 5.83(2H,s), 4.66-4.65(lH,m) , 4.24- 4.19(2H,m), 3.63-3.58(2H,m) , 2.52-2.46(2H,m) , 2.07-2.06(2H,m) , 1.84- 1.78(2H,m), 1.28-1.19(3H,m)
<346> Example 14
<347> Synthesis of 4-[l-(3-cyano-benzyl)-2-oxo-l,2-dihydro-pyridin-4-yloxy]- piper idin-l-carboxyl ic acid tert-butyl ester
<348> A target compound was obtained in the same manner as described in
Example 12 except that instead of l-(5-ethyl-pyrimidin-2-yl)-piperidin-4-ol , tert-butyl 4-hydroxy-l-piperidinecarboxylate was used.
<349> H(400MHz, CDCI3) 7.61-7.28(4H,m), 7.17-7.15(lH,m) , 5.95-5.94(2H,m) ,
5.11(2H,s), 5.11(2H,s), 4.48-4.44(lH,m), 3.75-3.69(2H,m) , 3.36-3.30(2H,m) , 2.06-1.94(2H,m), 1.78-1.73(2H,m), 1.47(9H,s)
<350> Example 15
<35 i > Synthesis of 4-[1-(3-cyano-benzy1)-2-thioxo-l,2-dihydro-pyr idin-4- yloxy]-piperidine-l-carboxyl ic acid tert-butyl ester
<352> A target compound was obtained in the same manner as described in
Example 13 except that instead of 3-{4-[l-(5-ethyl-pyrimidin-2-yl)-piperidin- 4-y1oxy]-2-oxo-2H-pyr idin-1-y1methy1 }-benzonitrile, 4-[1-(3-cyano-benzy1 )-2- oxo-1 ,2-dihydro-pyr idin-4-y1oxy]-piper idine-1-carboxylie acid tert-butyl ester was used.
<353> ¾(400MHz, CDCI3) 7.60-7.45(5H,m), 7.22-7.21(2H,d) , 6.35-6.32(lH,m) ,
5.80(2H,s), 4.57-4.53(lH,m), 3.73-3.70(2H,m) , 3.33-3.27(2H,m) , 2.04- 1.95(2H,m), 1.76-1.72(2H,m), 1.48(9H,ra)
<354> Example 16
<355> Synthesis of 4-[l-(3-cyano-benzyl)-2-oxo-l,2-dihydro-pyridin-4- yloxymethyl ]-piper idine-l-carboxyl ic acid tert-butyl ester
<356> A target compound was obtained in the same manner as described in
Example 12 except that instead of l-(5-ethyl-pyr imidin-2-yl )-piper idin-4-ol , tert-butyl 4-(hydroxymethyl )-l-piper idinecarboxylate was used.
<357> 1H(400MHz, CDCI3) 7.61-7.45(3H,m), 7.15-7.13(lH,d) , 5.97-5.92(2H,m) ,
5.1K2H. S ) , 4.21-4.76(lH,m), 3.80-3.79(2H,d) , 2.80-2.72(2H,m) , 19.7- 1.96(lH,m), 1.80-1.77(2H,m), 1.42(9H,s), 1.33-1.24(2H,m)
<358> Example 17
<359> Synthesis of 4-[l-(3-cyano-benzyl)-2-thioxo-l,2-dihydro-pyridin-4- yloxymethyl ]-piper idine-l-carboxyl ic acid tert-butyl ester
<360> A target compound was obtained in the same manner as described in
Example 13 except that instead of 3-{4-[l-(5-ethyl-pyr imidin-2-yl )-piper idin- 4-y1oxy]-2-oxo~2H-pyr idin-1-y1methy1 }-benzonitrile, 4-[1-(3-cyano-benzy1 )-2- oxo-1 , 2-dihydro-pyr idin-4-y1oxymethy1 ]-piper idine-1-carboxy1 ic acid tert-
butyl ester was used.
<36 i> H(400MHz, CDC13) 7.62-7.46(5H,m), 7.22(lH,d), 6.36-6.34(lH,m) ,
5.82(2H,s), 4.19-4.17(2H,m), 3.88(2H,d), 2.77-2.37(2H,m) , 2.04-1.96(lH,m) , 1.79-1.76(2H,m), 1.48(9H,s), 1.21-1.22(2H,m)
<362> Exam le 18
<363> Synthesis of 4-{4-[l-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxy]-2- thioxo-2H-pyridin-l-yl }-2-f luoro-benzonitr i le
<364> A target compound was obtained in the same manner as described in
Example 1 except that instead of 5-chloro-4-[l-(5-ethyl-pyrimidin-2-yl )- piper idin-4-y1oxy]-lH-pyr idine-2-thi one , 4-[ 1-(5-ethy1-pyr imidin-2-y1 )- piper idin-4-yloxy]-lH-pyridine-2-thione was used.
<365> ¾ NMR (400MHz, CDC13) : 8.2K2H, s), 7.79-7.83C1H, m) , 7.41-7.43(1H, d), 7.32-7.34(2H, m) , 7.25UH, s), 6.43-6.46UH, d) , 4.71-4.8K1H, m) , 3.81- 4.15(4H, m), 2.48-2.53(2H, m) , 1.94-2.09(4H, m), 1.21-1.25C3H, m) .
<366> Example 19
<367> Synthesis of 4-[l-(4-f luoro-benzyl)-2-oxo-l,2-dihydro-pyridin-4-yloxy]- piper idine-l-carboxyl ic acid tert-butyl ester
<368> Under a nitrogen atmosphere, in a 50ml flask, 250mg of l-(4-fluoro- benzyl )-4-hydroxy-lH-pyridin-2-one, and 30ml of Ν,Ν-dimethylformamide were placed, and stirred and dissolved. 230mg of 4-hydroxy-l- piper idinecarboxylate, 450mg of tr iphenylphosphine, and 0.34mL of diisopropyl azodi carboxylate were added thereto, followed by stirring at room temperature for 10 hours or more. The reaction mixture was dissolved in 100ml of ethyl acetate, and washed twice with 100ml of distilled water. The organic layer was dried with anhydrous magnesium sulfate, and vacuum-dried. The residue obtained after the vacuum-drying was purified with silica column so as to provide a target compound.
<36 > ¾(400MHz, CDCI3) 7.31(2H,d) 7.15(lH,d), 7.06(2H,t), 5.94(lH,d)
5.90(lH,d), 5.06(2H,s), 4.46-4.42(lH,m), 3.72-3.69(2H,m) , 3.35-3.28(2H,m) , 1.97-1.93(2H,m), 1.93-1.75(2H,m), 1.32(9H,s)
<370> Example 20
<37 i > Synthesis of 4-[l-(3-methoxy-benzyl)-2-oxo-l,2-dihydro-pyridin-4- yloxy]-piper idine-l-carboxyl ic acid tert-butyl ester
<3 2> A target compound was obtained in the same manner as described in
Example 19 except that instead of l-(4-f luoro-benzyl)-4-hydroxy-lH-pyr idin-2- one, 4-hydroxy-l-(3-methoxy-benzyl )-lH-pyr idin-2-one was used.
<373> H(400MHz, CDC13) 7.28(lH,s), 7.14(lH,d), 6.87-6.83(3H,m) , 5.94(lH,s),
5.88(lH,d), 5.07(2H,s), 4.46-4.42(lH,s), 3.80(3H,s), 3.75-3.65(2H,m) , 3.35- 3.29(2H,m), 1.98-1.94(2H,m), 1.95-1.94(2H,m), 1.50(9H,s)
<374> Example 21
<375> Synthesis of 4-(4-{4-[l-(tert-butoxycarbonyl)-piperidin-4-yloxy]-2-oxo-
2H-pyridin-l-ylmethyl }-thiazole-2-yl )-piper idine-l-carboxyl ic acid tert-butyl ester
<376> A target compound was obtained in the same manner as described in
Example 19 except that instead of l-(4-f luoro-benzyl)-4-hydroxy-lH-pyridin-2- one , 4-[4-(4-hydroxy-2-oxo-2H-pyr idin-1-y1methy1 )-1hiazo1e-2-y1 ]-piper idine- 1-carboxylic acid tert-butyl ester was used
<377> H(400MHz. CDC13) 7.48(lHd), 7.15(lH,s), 5.92-5.93(2H,m) , 5.14(2H,s),
4.49-4.38(lH,m), 4.30-4.12(2H,m) , 3.81-3.65(2H,m) , 3.40-3.28(2H,m) , 3.18- 3.07(lH,m), 2.98-2.87(2H,m), 2.21-2.13(2H.m) , 2.01-1.87(2H,m) , 1.76- 1.65(4H,m), 1.48(18H,s)
<378> Example 22
<379> Synthesis of 4-[l-(l-methanesulfonyl-piperidin-4-ylmethyl)-2-oxo-l,2- dihydro-pyr idin-4-yloxy]-piper idine-l-carboxyl ic acid tert-butyl ester
<380> A target compound was obtained in the same manner as described in
Example 19 except that instead of l-(4-f luoro-benzyl)-4-hydroxy-lH-pyridin-2- one , 4-hydroxy-1-( 1-methanesu1 fony1- iperidin-4-y1methy1 )-ΙΗ-pyr idin-2-one was used.
<38 i > Η(400ΜΗζ, CDCI3) 7.28(lH,d), 5.88-5.87(2H,m) , 4.44-4.42(lH,m), 3.84-
3.87(2H,m) , 3.77-3.3.75(2H,d) , 3.70-3.69(2H,m) , 3.35-3.29(2H,m) , 2.68(3H,s),
2.67-2.61(2H,m), 2.10-2.00(lH,m) , 1.97-1.93(2H,m) , 1.92-1.73(4H,m) , 1.48(9H,s)
<382> Example 23
<3X3> Synthesis of 4-[l-(4-f luoro-benzyl)-2-thioxo-l,2-dihydro-pyridin-4- yloxy]-piperidine-l-carboxylic acid tert-butyl ester
<384> A target compound was obtained in the same manner as described in
Example 13 except that instead of 3-{4-[l-(5-ethyl-pyrimidin-2-yl)-piper idin- 4-yloxy]-2-oxo-2H-pyr idin-l-ylmethyl }-benzonitr i le, 4-[l-(4-f luoro-benzyl )-2- oxo-1 , 2-dihydro-pyr idin-4-y1oxy]- iper idine-l-carboxylie ac id tert-buty1 ester was used.
<385> H(400MHz, CDCls) 7.47-7.45(lH,d), 7.37-7.33(2H,m) , 7.24-7.23(lH,d) ,
7.08-7.04(2H,m), 6.30-6.27(lH,m), 5.76(2H,,s), 4.57-4.51(lH,m) , 3.72- 3.71(2H,m), 3.32-3.26(2H,m) , 1.99-1.94(2H,m) , 1.75-1.71(2H,m) , 1.46(9H,s)
<38d> Example 24
<387> Synthesis of 4-[l-(3-methoxy-benzyl)-2-thioxo-l,2-dihydro-pyridin-4- yloxy]-piper idine-l-carboxyl ic acid tert-butyl ester
<388> A target compound was obtained in the same manner as described in
Example 13 except that instead of 3-{4-[l-(5~ethyl-pyr imidin-2-yl )-piper idin- 4-y1oxy]-2-oxo-2H-pyr idin-1-y1methy1 }~benzonitrile, 4-[ 1-(3-methoxy-benzy1 )- 2-oxo-1 ,2-dihydro-pyridin-4-yloxy]-piper idine-l-carboxyl ic acid tert-butyl ester was used.
<389> ¾( 00MHz, CDCI3) 7.45-7.44(lH,d), 7.31-7.27(lH,m), 7.24(lH,d), 6.90-
6.86(3H,m), 6.28-6.25(lH,m) , 5.75(2H,s), 4.57-4.52(lH,m) , 3.81(3H,s), 3.74- 3.71(2H,m), 3.32-3.26(2H,m) , 1.99-1.94(2H,m) , 1.75-1.72(2H,m), 1.47(9H,s)
<390> Example 25
<39 i > Synthesis of 4-[l-(4-methoxycarbonyl-benzyl)-2-oxo-l,2-dihydro-pyridin-
4-yloxy]-piperidine~l-carboxyl ic acid tert-butyl ester
<392> A target compound was obtained in the same manner as described in
Example 19 except that instead of 1-(4-f luoro-benzyl )-4-hydroxy-ΙΗ-pyr idin-2- one, 4-(4-hydroxy-2-oxo-2H-pyr idin-l-ylmethyl )-benzoic acid methyl ester was used .
<393> ¾(400MHz, CDCls) 8.03(2H,d), 7.35(2H,d), 7.15(lH,d), 5,95(lH,s),
5.91(lH,d), 1.15, 2H,s), 4.5-4.4(lH,m), 3.92(3H,s), 3.76-3.66(2H,M) , 3.38- 3.26(2H,m), 2.23-1.92(2H,m), 1.81-1.69(2H,m) , 1.48(9H,s)
<394> Example 26
<395> Synthesis of 4-[l-(4-cyano-2-f luoro-benzyl)-2-oxo-l,2-dihydro-pyr idin-
4-yloxy]-piper idine-l-carboxyl ic acid tert-butyl ester
<396> A target compound was obtained in the same manner as described in
Example 19 except that instead of l-(4-fluoro-benzyl)-4-hydroxy-lH-pyridin-2- one, 3-fluoro-4-(4-hydroxy-2-oxo-2H-pyr idin-l-ylmethyl)-benzonitri le was used.
<397> H(400MHz, CDC13) 7.56(lH,t), 7.57-7.37(2H,m) , 7.26-7.24(lH,d), 5.96-
5.93(2H,m), 5.14(2H,s), 4.45-4.41(lH,m) , 3.71-3.67(2H,m) , 3.35-3.29(2H,m) , 1.97-1.95(2H,m), 1.94-1.92(2H,m), 1.49(9H,s)
<398> Example 27
<399> Synthesis of 4-{5-chloro-4-[l-(5-ethyl-pyrimidin-2-yl)-piperidin-4- y1oxy]-2-oxo-2H-pyr idin-1-y1methy1 }-3-f 1uoro-benzoni tr i 1e
<400> A target compound was obtained in the same manner as described in
Example 12 except that instead of 3-(4-hydroxy-2-oxo-2H-pyridin-l- ylmethyl )-benzonitr i le , 4-(5-chloro~4-hydroxy-2-oxo-2H-pyr idin-l-ylmethy1 )-3- f luoro-benzonitri le was used.
<40 i> H(400MHz, CDC13) 8.32(2H,s), 7.61(lH,t), 7.49-7.41(3H,m) , 6.00(lH,s),
5.14(2H,s), 4.70-4.68(lH,m), 4.-20-4.12(2H,m) , 4.01-3.96(2H,m), 2.59- 2.53(2H,m), 2.05-2.04(4H,m) , 1.27-1.23(3H,m)
<402> Example 28
<403> Synthesis of 5-chloro-l-(6-chloro-pyr idin-3-ylmethyl)-4-[l-(5-ethyl- pyr imidin-2-y1 )- iper idin-4-y1oxy]-ΙΗ-pyr idin-2-one
<404> A target compound was obtained in the same manner as described in
Example 12 except that instead of 3-(4-hydroxy-2-oxo-2H-pyr idin-l-ylmethyl )- benzoni tr i le , 5-ch1or0-1-(6-ch1oro-pyr idin-3- 1methy1 )-4-hydroxy-lH-pyr idin-
2~one was used.
<405> ¾(400MHz, CDCI3) 8.40-8.29(lH,d), 8.20(2H,s), 7.72-7-70( 1H,m) ,
7.35(lH,s), 7.33(lH,s), 6.02(lH,s), 5.06(2H,s), 4.63-4.61(lH,m), 4.08- 4.02(2H,m), 3.85-3.79(2H,m) , 2.52-2.46(2H,m) , 2.06-2.01(2H,m) , 1.94- 1.86(2H,m), 1.24-1.19(3H,m)
<406> Example 29
<407> Synthesis of 5-chloro-4-[l-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxy]-
1—(3—tr i f1uoromethy1-benzy1 )-ΙΗ-pyridin-2-one
<408> A target compound was obtained in the same manner as described in
Example 12 except that instead of 3-(4-hydroxy-2-oxo-2H-pyr idin-l-ylmethyl )- benzoni tr i 1e , 5-ch1oro-4-hydroxy-1-(3-1r i f 1uoromethy1-benzy1 )-ΙΗ-pyr idin-2- one was used.
<409> 1H(400MHz, CDCI3) 8.20(2H,s), 7.61-7.58(2H,m) , 7.52-7.50(2H,m) ,
7.32(lH,s), 6.05(lH,s), 5.13(2H,s), 4.64-4.37(lH,m) , 4.10-4.03(2H,m) , 3.84- 3.78(2H,m), 2.52-2.46(2H,m) , 2.07-2.02(2H,m) , 1.94-1.90(2H,m) , 1.24- 1.19(3H,m)
<4io> Example 30
<4ii> Synthesis of 5-chloro-4-[l-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxy]- l-(4-tri fluoromethyl-benzyl )-lH-pyr idin-2-one
<4i2> A target compound was obtained in the same manner as described in
Example 12 except that instead of 3-(4-hydroxy-2-oxo-2H-pyr idin-l-ylmethyl )- benzoni tr i 1e , 5-ch1oro-4-hydroxy-1—(4—tr i f1uoromethy1-benzy1 )-lH-pyr idin-2- one was used.
<4i3> HUOOMHz, CDCI3) 8.20(2H,s), 7.63(2H,d), 7.43(2H,d), 7.31(lH,s),
6.04(lH,s), 5.13(2H,s), 4.65-4.61(lH,m) , 4.09-4.02(2H,m) , 3.85-3.79(2H,m) , 2.52-2.46(2H,m), 2.07-2.01(2H,m), 1.95-1.88(2H.m), 1.23-1.19(3H,m)
<4i4> Example 31
<4i5> Synthesis of 5-chloro-4-[l-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxy]-
1-( -methoxy-benzy1 )-ΙΗ-pyr idin-2~one
<4i6> A target compound was obtained in the same manner as described in
Example 12 except that instead of 3-(4-hydroxy-2-oxo-2H~pyridin-l-ylmethyl )-
benzonitri le, 5-chloro-4-hydroxy-l-(4-methoxy-benzy1 )-IH-pyr idin-2-one was used.
<4i7> H(400MHz, CDC13) 8.20(2H,s), 7.28-7.26(3H,m) , 6.92(2H,d), 6.03(lH,s),
5.02(2H,s), 4.63-4.60(lH,m), 4.08-4.01(2H,m) , 3.85-3.78(5H,m) , 2.51- 2.46(2H,m), 2.06-2.00(2H,m) , 1.93-1.86(2H,m) , 1.23-1.18(3H,m)
<4ifi> Example 32
<4i')> Synthesis of 5-chloro-4-[l-(5-ethyl-pyr imidin-2-yl)-piperidin-4-yloxy]-
1-(3-methoxy-benzy1 )-IH-pyr idin-2-one
<42o> A target compound was obtained in the same manner as described in
Example 12 except that instead of 3-(4-hydroxy-2-oxo-2H-pyridin-l-ylmethyl)- benzonitri le, 5-chloro-4-hydroxy-l-(3-methoxy-benzyl )-lH-pyr idin-2-one was used.
<42i> H(400MHz, CDC13) 8.20(2H,s), 7.30-7.28(2H,m) , 6.90-6.85(3H,m) ,
6.04(lH,s), 5.06(2H,s), 4.64-4.60(lH,m) , 4.09-4.02(2H,m) , 3.84-3.78(5H,m) , 2.52-2.46(2H(m), 2.52-2.46(2H,m) , 2.06-2.02(2H,m) , 1.29-1.19(3H,m)
<422> Example 33
<423> Synthesis of 5-chloro-4-[l-(5-ethyl-pyr imidin-2-yl)-piperidin-4-yloxy]-
1-(3-1r i f1uoromethoxy-benzy1 )-ΙΗ-pyr idin-2-one
<424> A target compound was obtained in the same manner as described in
Example 12 except that instead of 3-(4-hydroxy-2-oxo-2H-pyr idin-1- y1methy1 )-benzoni tr i 1e , 5-ch1oro-4-hydroxy-1-(3-tri f 1uoromethoxy-benzy1 )—IH- pyr idin—2—one was used.
<425> ¾(400MHz, CDCI3) 8.20 (2H,s), 7.43-7.30(lH,m) , 7.28(lH,s), 7.25-
7.17(2H,m), 6.05(lH,s), 5.09(2H,s), 4.65-4.62(lH,m), 4.09-4.03(2H,m) , 3.84- 3.78(2H,m), 2.52-2.46(2H,m) , 2.07-2.02(2H,m) , 1.95-1.86(2H,m) , 1.24- 1.19(3H,m)
<426> Example 34
<427> Synthesis of 5-chloro-4-[l-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxy]-
1-(4-f 1uoro-benzy1 )-IH-pyr idin-2-one
<428> A target compound was obtained in the same manner as described in
Example 12 except that instead of 3-(4-hydroxy-2-oxo-2H-pyridin-l-ylmethyl)- benzonitri le, 5-chloro-l-(4-f luoro-benzyl )-4-hydroxy-lH-pyridin-2-one was used.
<429> ¾(400MHz, DMSO-de) 8.26(2H,s), 8.14(lh,s), 7.40-7.36(2H,m) , 7.20-
7.15(2H,m), 6.14(lH,s), 5.00(2H,s), 4.82-4.80(lH,m) , 4.06-4.01(2H,m) , 3.63- 3.57(2H,m), 2.46-2.40(2H,M) , 1.96-1.93(2H,m) , 1.64-1.59(2H,m), 1.15- l.ll(3H,m)
<43o> Example 35
<43 i> Synthesis of 4-{5-chloro-4-[l-(5-ethyl-pyrimidin-2-yl)-piperidin-4- y1oxy]-2-oxo-2H-pyr idin-1-y1methy1 }-benzonitr i 1e
<432> A target compound was obtained in the same manner as described in
Example 12 except that instead of 3-(4-hydroxy-2-oxo-2H-pyr idin-l-ylmethyl )- benzonitri le, 4-(5-chloro-4-hydroxy-2-oxo-2H-pyridin-l-ylmethyl)-benzonitri le was used.
<433> H(400MHz, CDC13) 8.20(2H,s), 7.68(2H,d), 7.42(2H,d), 7.31(lH,s),
6.04(lH,s), 5.1392H. S ) , 4.65-4.6291H,m) , 4.09-4.03(2H,m) , 3.85-3.79(2H,m) , 2.52-2.46(2H,m), 2.07-2.02(2H,m) , 1.95-1.87(2H,m) , 1.23-1.19(3H,m)
<434> Example 36
<435> Synthesis of 5-chloro-4-[l-(5-ethyl-pyr imidin-2-yl)-piperidin-4-yloxy]-
1-(4-isopropy1-benzy1 )-ΙΗ-pyr idin-2-one
<436> A target compound was obtained in the same manner as described in
Example 12 except that instead of 3-(4-hydroxy-2-oxo-2H-pyr idin-l-ylmethyl )- benzoni tr i 1e , 5-ch1oro-4-hydroxy-1-(4-isopropy1-benzy1 )-ΙΗ-pyridin-2-one was used.
<437> H(400MHz, CDCI3) 8.2(2H,s), 7.29-7.24(3H,m) , 6.03(lH,s), 5.05(2H,s),
4.68-4.62(lH,m), 4.07-4.03(2H,m) , 3.82-3.79(2H,m) , 2.93-2.90(lH,m), 2.51- 2.46(2H,m), 2.03-2.01(2H,m), 1.94-1.91(2H,m), 1.29-1.19(9H,m)
<438> Example 37
<439> Synthesis of 5-chloro-l-(3,4-difluoro-benzyl )-4-[l-(5-ethyl-pyr imidin-
2-y1 )-piper idin-4-y1oxy]-lH-pyr idin-2-one
<440> A target compound was obtained in the same manner as described in
Example 12 except that instead of 3-(4-hydroxy-2-oxo-2H-pyr idin-1- y1methy1 )-benzonitrile, 5-chloro-l-(3,4-di f 1uoro-benzy1 )-4-hydroxy-1H~ pyr idin-2-one was used.
<44i> ¾( 00MHz, CDC13) 8.02(2H,sO, 7.29(lH,s), 7.19-7.17(2H,m) , 7.13-
7.07(lH,m), 6.03(lH,s), 5.02(2H,s), 4.63-4.61(lH,m), 4.09-4.02(2H,m) , 3.85- 3.78(2H,m), 2.52-2.46(2H,m) , 2.06-2.01(2H,m) , 1.95-1.88(2H,m) , 1.24- 1.19(3H,m)
<442> Example 38
<443> Synthesis of 4-[5-chloro-l-(3,4-dif luoro-benzoyl )-2-oxo-l,2-dihydro- pyridin-4-yloxy]-piperidine-l-carboxylic acid tert-butyl ester
<444> A target compound was obtained in the same manner as described in
Example 19 except that instead of l-(4-fluoro-benzyl)-4-hydroxy-lH-pyridin-2- one, 5-chloro-l-(3,4-di f luoro-benzoyl )-4-hydroxy-lH-pyridin-2-one was used.
<445> ¾(400MHz, CDCI3) 8.3K2H. S ) , 8.07-8.01(2H,m) , 7.36-7.28(lH,m) ,
6.74(lH,s), 4.71-4.69(lH,m), 3.68-3.61(2H,m), 3.55-3.47(2H,m) , 1.97- 1.88(4H,m), 1.49(9H,s)
<446> Example 39
<447> Synthesis of 5-chloro-4-[l-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxy]-
1-(3-f 1uoro-benzy1 )-ΙΗ-pyr idin-2-one
<448> A target compound was obtained in the same manner as described in
Example 12 except that instead of 3-(4-hydroxy-2-oxo-2H-pyridin-l-ylmethyl )- benzonitrile, 5-ch1oro-1-(3-f 1uoro-benzy1 )-4-hydroxy-lH-pyr idin-2-one was used.
<449> ¾(400MHz, CDCI3) 8.20(2H,s), 7.37-7.29(2H,m) , 7.10-7.01(3H,m) ,
6.04(lH,s), 5.08(2H,s), 4.65-4.61(lH,m) , 4.09-40.3(2H,m) , 3.85-3.79(2H,m) , 2.52-2.46(2H,m), 2.07-2.02(2H,m) , 1.95-1.87(2H.m), 1.24-1.19(3H,m)
<450> Example 40
<4?i> Synthesis of 3-{5-chloro-4-[l-(5-ethyl-pyrimidin-2-yl )-piper idin-4- y1oxy]-2-oxo-2H-pyr idin-1-y1methy1 }-benzonitrile
<452> A target compound was obtained in the same manner as described in
Example 12 except that instead of 3-(4-hydroxy-2-oxo-2H-pyridin-l-ylmethyl)- benzoni tr i 1e , 3-(5-ch1oro-4-hydroxy-2-oxo-2H-pyridin-1-y1methy1 )-benzoni tr i 1e was used.
<453> HUOOMHz, CDC13) 8.20(2H,s), 7.64~-7.48(4H,m), 7.35(lH,s), 6.05(lH,s),
5.10(lH,s), 4.65-4.64(lH,m), 4.63-4.04(2H,m) , 3.84-3.79(2H,m) , 2.52- 2.46(2H,m), 2.08-2.03(2H,m) , 2.02-1.91(2H,m), 1.23-1.19(3H,m)
<454> Exam le 41
<455> Synthesis of 4-[5-chloro-l-(3-cyano-benzyl)-2-oxo-l,2-dihydro-pyridin-
4-yloxy]-piper idine-l-carboxyl ic acid tert-butyl ester
<456> A target compound was obtained in the same manner as described in
Example 19 except that instead of l-(4-f luoro-benzyl)-4-hydroxy-lH-pyridin-2- one, 3-(5-chloro-4-hydroxy-2-oxo-2H-pyr idin-l-ylmethyl )-benzonitri le was used.
<457> H(400MHz, CDCI3) (7.68-7.47(4H,m), 7.32(lH,s), 6.00(lH,s),
5.09(2H,s) ,4.57-4.55(lH,s), 3.65-3.59(2H,m) , 3.50-3.47(2H,m) , 1.94- 1.84(2H,m), 1.48(9H,s)
<458> Exam le 42
<459> Synthesis of 4-[5-chloro-l-(3-cyano-benzyl)-2-oxo-l,2-dihydro-pyridin-
4-yloxy]-piper idium chloride
<460> Under a nitrogen atmosphere, in a 50ml flask, l.Og of HD-G-504 and 21mL of dichloromethane/methanol (5/2) solution were placed, and stirred and dissolved. HC1 in 1,4-dioxane (2.4 mL) was added thereto, followed by stirring at room temperature for 1 hour or more. Then 20ml of diethyl ether was added to thereaction mixture , followed by stirring for 30min. Then, the produced solid was filtered, washed with 50ml of diethyl ether, and dried to provide a target compound.
<46 i> H(400MHz, CDCI3) 9.03(2H,s), 8.22(lH,s), 7.78-7.76(2H,m) , 7.66-
7.55(2H,m), 6.18(lH,s), 5.06(2H,s), 4.79-4.77(lH,m) , 3.16-3.08(4H,m) , 2.13- 2.10(2H,m), 1.91-1.85(2H,m)
<462> Example 43
<463> Synthesis of 5-chloro-4-[l-(5-ethyl-pyr imidin-2-yl)-piperidin-4-yloxy]-
1-( -methy1 su1 fany1-benzy1 )-lH-pyr i din-2-one
<464> A target compound was obtained in the same manner as described in
Example 12 except that instead of 3-(4-hydroxy-2-oxo-2H-pyridin-l-ylmethyl)- benzoni tr i 1e , 5-ch1oro-4-hydroxy-1-(4-methy1 su1 fany1-benzy1 )-ΙΗ-pyr idin-2-one was used.
<465> HUOOMHz, CDC13) 8.20(2H,s), 7.28-7.25(5H,m) , 6.03(lH,s), 5.03(2H,s),
4.62-4.60(lH,m), 4.08-4.02(2H,m) , 3.84-3.78(2H,m) , 2.52-2.46(5H,m) , 2.06- 2.01(2H,m), 1.94-1.87(2H,m), 1.23-1.19(3H,m)
<466> Example 44
<467> Synthesis of 5-chloro-4-[l-(5-ethyl-pyr imidin-2-yl)-piper idin-4-yloxy]-
1-(4-methanesu1 f iny1-benzy1 )-ΙΗ-pyr idin-2-one
<468> Under a nitrogen atmosphere, in a 50ml flask, 250mg of 5-chloro-4-[l-
(5-ethy1-pyr imidin-2-y1 )-piper i din-4-y1oxy] -1-(4-methy1 su1 fany1-benzy1 )-1H- pyr idin-2-one and 30ml of dichloromethane were placed, and stirred and dissolved. 137mg of 3-chloroperbenzoic acid was added thereto, followed by stirring at roomtemperature for 2 hours or more. The reaction mixture was vacuum-dried. The residue was dissolved in 100ml of ethyl acetate, and washed twice with 100ml of distilled water. The organic layer was dried with anhydrous magnesium sulfate, and vacuum-dried. The residue obtained after the vacuum-drying was purified with silica column so as to provide a target compound.
<469> H(400MHz, CDCI3) 8.20(2H,s), 7.67-7.65(2H,d) , 7.49-7.47(2H,d) ,
7.33(lH,s), 6.05(lH,s), 5.14(2H,s), 4.64-4.61(lH,s), 4.09-4.03(2H,m) , 3.84- 3.78(2H,m), 2.73(3H,s), 2.52-2.46(2H,m) , 2.07-2.02(2H,m) , 1.94-1.87(2H,m) , 1.27-1.19(3H,m)
<470> Example 45
<47 i > Synthesis of 5-chloro-4-[l-(5-ethyl-pyrimidin-2-yl)-piper idin-4-yloxy]-
1-(4-methanesu 1 fonyl-benzyl )-lH-pyr idin-2-one
<4 2> A target compound was obtained in the same manner as described in
Example 44 except that instead of 5-chloro-4-[l-(5-ethyl-pyrimidin-2-yl)- piper idin-4-y1oxy] -1-(4-methy1 su1 fany1-benzy1 )-ΙΗ-pyr idin-2-one , 5-ch1oro-4- [ 1-(5-ethy1-pyr imidin-2-y1 )-piper i din~4-y1oxy] -1-(4-methanesu1 f iny1-benzy1 )- lH-pyr idin-2-one was used.
<473> H(400MHz, CDC13) 8.20(2H,s), 7.96-7.94(2H,d) , 7.52-7.50(2H,d) ,
7.34(lH,s), 6.05(lH,s), 5.16(2H,s), 4.65-4.62(lH,m), 4.15-4.03(2H,m) , 3.85- 3.79(2H,m), 3.06(3H,s), 2.52-2.46(2H,m) , 2.07-2.02(2H,m) , 1.95-1.89(2H,m) , 1.26-1.19(3H,m)
<474> Example 46
<475> Synthesis of 5-chloro-4-[l-(5-ethyl-pyr imidin-2-yl)-piperidin-4-yloxy]-
1-(2-f 1uoro-benzy1 )-ΙΗ-pyr i din-2-one
<476> A target compound was obtained in the same manner as described in
Example 12 except that instead of 3-(4-hydroxy-2-oxo-2H-pyr idin-l-ylmethyl )- benzoni t r i 1e , 5-ch1 oro-1-(2-f 1uoro-benzy1 )-4-hydroxy-lH-pyr idin-2-one was used.
<477> H(400MHz, CDC13) 8.20(2H,s), 7.47-7.36(2H,m) , 7.35-7.32(lH,m), 7.17-
7.08(2H,m), 6.00(lH,s), 5.13(2H,s), 4.62-4.59( 1H ,m) , 4.06-4.01(2H,m) , 3.84- 3.78(2H,m), 2.51-2.46(2H,m) , 2.05-2.00(2H,m) , 1.92-1.85(2H,m) , 1.23- 1.19(3H,m)
<478> Example 47
<479> Synthesis of 5-chloro-4-[l-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxy]-
1-(3-f 1uoro-4-methy1 su1 fany1-benzy1 )-lH-pyr i din-2-one
<480> Undera nitrogen atmosphere, in a 50ml flask, 300mg of 5-chloro-l-(3,4- di f 1uoro-benzy1 )-4- [ 1-(5-ethy1-pyr imidin-2- 1 )- iper idin-4-y1oxy]-lH-pyr idin-
2-one and 20ml of dimethyl sulfoxide were placed, and stirred and dissolved. 92mg of sodium thiomethoxide and 425mg of cesium carbonate were added thereto, followed by stirring at 50°C for 10 hours or more. The reaction mixture was dissolved in 100ml of ethyl acetate, and washed twice with 100ml of distilled water. The organic layer was dried with anhydrous magnesiumsulfate, and vacuum-dried. The residue obtained after the vacuum- drying was purified with silica column so as to provide a target compound.
<48 i> H(400MHz, CDCls) 8.20(2H,s), 7.28-7.19(2H,m) , 7.10-7.00(2H,s) ,
6.03(lH,s), 5.03(2H,s), 4.67-4.60(lH,m) , 4.07-4.02(2H,m) , 3.83-3.78(2H,m) , 2.52-2.46(5H,m), 2.06-2.01(2H,m) , 1.92-1.88(2H,m) , 1.23-1.19(3H,m)
<482> Example 48
<4«3> Synthesis of 3-{5-chloro-4-[l-(4-methylsul fanyl-benzoyl )-piperidin-4- y1oxy]-2~oxo-2H-pyr idin-1-y1methy1 }-benzoni tr i 1 e
< 8 > Under a nitrogen atmosphere, in a 50ml flask, llOmg of 4-[5-chloro-l-
(3-cyano-benzy1 )-2-oxo-1 , 2-dihydro-pyr i din-4-y1 oxy]-piper i diniurn ch1or i de and 24mL of acetonitri le/H^ (5/3) solution were placed, and stirred and dissolved. O.lmL of tr iethylamine and 53mg of 4-(methylthio)benzoyl chloride were added thereto, followed by stirring at room temperature for 1 hour or more. The reaction mixture was dissolved in 100ml of ethyl acetate, and washed twice with 100ml of distilled water. The organic layer was dried with anhydrous magnesium sulfate, and vacuum-dried. The residue obtained after the vacuum-drying was purified with silica column so as to provide a target compound .
<485> H(400MHz, CDCI3) 7.64-7.47(4H,m), 7.38-7.33(3H,m) , 7.29-7.27(2H,m) ,
6.00(lH,s), 5.09(2H,s), 4.72-4.62(lH,m), 4.01-3.42(4H,m) , 2.52(3H,s), 2.20- 1.81(4H,m)
<486> Example 49
<487> Synthesis of 3-[4-(l-benzoxazole-2-yl-piperidin-4-yloxy)-5-chloro-2- oxo-2H-pyr i din-1-y1methy1]-benzoni tr i 1e
<488> A target compound was obtained in the same manner as described in
Example 48 except that instead of 4-(methylthio)benzoyl chloride, 2-chloro-
1,3-benzoxazole was used.
<48 > 1H(400MHz, CDCI3) 7.65-7.48(4H,m), 7.39-7.29(3H,m) , 7.21-7.17(lH,m) ,
7.08-7.03(lH,m), 6.04(lH,s), 5.10(2H,s), 4.70-4.69(lH,m) , 3.88-3.85(4H,m) , 2.12-2.03(4H,m)
<490> Example 50
<49i > Synthesis of 4-[5-chloro-l-(3-f luoro-benzyl)-2-oxo-l,2-dihydro-pyridin-
4-yloxy]-piper idine-l-carboxyl ic acid tert-butyl ester
<492> A target compound was obtained in the same manner as described in
Example 19 except that instead of l-(4-fluoro-benzyl )-4-hydroxy-lH-pyr idin-2- one, 5-chloro-l-(3-f luoro-benzyl )-4-hydroxy-lH-pyridin-2-one was used.
<493> H(400MHz, CDC13) 7.37-7.31(lH,m), 7.29(lH.s), 7.09-6.99(3H,m) ,
5.99(lH,s), 5.07(2H,s), 4.57-4.54(lH,s) , 3.65-3.58(2H,m) , 3.52-3.47(2H,m) , 1.94-1.83(4H,m), 1.48(9H,s)
<494> Example 51
<49.i> Synthesis of 3-[5-chloro-4-(l-isobutyryl-piper idin-4-yloxy)-2-oxo-2H- pyr idin-l-ylmethyl ]-benzonitri le
<4%> A target compound was obtained in the same manner as described in
Example 48 except that instead of 4-(methylthio)benzoyl chloride, isobutyryl chloride was used.
<497> ¾( 00MHz, CDCI3) 7.64-7.62(lH,d), 7.58-7.56(2H,m) , 7.51-7.47( lH.ro) ,
7.33(lH,s), 6.01(lH,s), 5.31(2H,s), 5.15-5.04(2H,m) , 4.64-4.62(lH,m), 3.85- 3.54(4H,m), 2.04-1.87(4H,m) , 1.21-1.08(6H,d)
<498> Example 52
<499> Synthesis of 5-chloro-4-[l-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxy]-
1-[2-(4-f1uoro-pheny1 )-ethy1 ]-lH-pyridin-2-one
<sno> A target compound was obtained in the same manner as described in
Example 12 except that instead of 3-(4-hydroxy-2-oxo-2H-pyr idin-l-ylmethyl )- benzoni tr i 1e , 5-ch1oro-l-[2-( -f1uoro-pheny1 )-ethy1 ]-4-hydroxy-lH-pyr idin-2- one was used.
<50i> H(400MHz, CDC I3) 8.20(2H,s), 7.17-7.13(2H,m), 7.04-7.00(3H,m) ,
6.01(lH,s), 4.62-4.60(lH,m), 4.10-4.04(4H,m), 3.83-3.77(2H,m) , 3.03- 3.00(2H,m), 2.52-2.46(2H,m), 2.07-2.02(2H,m) , 1.94-1.86(2H,m) , 1.24- 1.19(3H,m)
<502> Example 53
<503> Synthesis of 3-{4-[l-(5-bromo-pyrimidin-2-yl)-piperidin-4-yloxy]-5- ch1oro~2-oxo-2H-pyr idin-1-y1methy1 }-benzoni tri 1e
<504> A target compound was obtained in the same manner as described in Example 48 except that instead of 4-(methylthio)benzoyl chloride, 5-bromo-2- chloropyr imidine was used.
<5U5> H(400MHz, CDC13) 8.31(2H,s), 7.64-7.48(4H,m) , 7.33(lH,s), 6.04(lH,s),
5.10(2H,s), 4.66-4.64(lH,s), 4.02-3.87(4H,m) , 2.06-1.90(4H,4)
<506> Example 54
<507> Synthesis of 4-( l-{ -[1-(5-ethy1-pyr imidin-2-y1 )-piper idin-4-y1oxy]-2- oxo-2H- r idin-l-yl }-ethyl )-benzonitri le
<508>
<509> A target compound was obtained in the same manner as described in
Example 12 except that instead of 3-(4-hydroxy-2-oxo-2H-pyridin-l-ylmethyl )- benzonitrile, 4-[1-(4-hydroxy-2-oxo-2H-pyr idin-1-y1 )-ethy1 ]-benzonitr i 1e was used.
<510> H N R (400MHz, CDCI3) : 8.2K2H, s), 7.68-7.7K2H, d), 7.41-7.43C2H, d), 7.13C1H, s), 6.34-6.36UH, m) , 6.03(1H, s), 4.63-4.64(lH, m), 3.79- 4.07(4H, m), 2.46-2.52(2H, m) , 1.87-2.09(4H, m) , 1.76(2H, d) , 1.2K3H, m) .
<511> Structural formulas of the compounds obtained from Examples 1 to 54 are noted in Table 1.
Example 55: Determination of compound activity based on cAMP stimulation
In order to measure cAMP activity in a cell, in response to GPR119 agonist, ΗΙΤ-ΊΊ5 cells (Korean cell line bank, beta cells derived from a hamster) were used. On a 96-well plate, 60,000 ΗΙΤ-ΊΊ5 cells were plated per well. On the day after the plating, thecells were incubated together with GPR119 agonist with various concentrations for 1 hour at 37°C The compound was treated with 6 concentrations from 0.0032 to 10 umol. The cAMP activity
was measured by using a cAMP dynamic kit from Cis Bio (Bedford, MA) under the instruction of the manufacturer. The cells were dissolved, and D2-labeled cAMP and crypt ate- labeled anti-cAMP antibody were used to measure cAMP level through a competitive immunoassay. Fluorescence was read by a Flex Station (Molecular Devices). Fluorescence resonance energy transfer (FRET) occurs between D2 and cryptate when D2 and cryptate come close to each other. FRET is measured as fluorescence ratio (665/620nm) . Non-labeled cAMP within a cell lysate competed with D2-labeled cAMP, against crypt ate- labeled antibody. The reduction of obtained FRET signal corresponds to cAMP level within cells. The compound activity was calculated by a change in FRET signals through DMSO control. The results are noted in Table 2 below.
[Table 2]
Exam le EC50 (nM)
1 5
2 30
3 10
4 45
12 21
13 51
15 110
27 27
28 100
32 40
37 3.2
39 3.2
40 3.2
41 30
44 3.2
47 23
49 40
<52i> Example 56:0ral Glucose Tolerance Test (OGTT)
<522> Male C57/6J mice (8 to 10 weeks old) were acclimated for at least 7 days. Then, only healthy individuals were used to carry out OGTT. After 12 to 15-hour fasting, the mice were divided into groups of 10 mice per group based on fasting glucose, and were administered with Vehicle (80% PEG, 10% tween 80, 10% ethanol) or test materials (Examples 1, 3, 12, 44, and 45) in an amount of 20mg/kg. Vehicle and test materials were orally administered (lOml/kg). After 30min from administration of Vehicle or test materials, glucose (3g/kg) was orally administered in an amount of 10 ml/kg. The glucose level was measured by using Accu-chek Go (Rosche diagnostic Co.), after -30,
0, 20, 40, 60 and 120 min from the administration of glucose, through puncture of caudal vein. Asa result of the test, 5 kinds of test materials (Examples 1, 3, 12, 44, and 45) showed an AUC (area under curve) reduction effect of about 30 to 60% in comparison to vehicle, respectively, as noted in Table 3. The results are noted in Table 3 below.
<523> [Table 3]
<524> Test materials % AUC of vehicle
Example 1 54.9 %
Example 3 62.7 %
Example 12 31.3 %
Example 44 33.3 %
Example 45 31.3 %
<644> Example 57
<525> The estimation of an activator is determined in two views of potency and efficacy.
<526> An intrinsic activity indicates a maximum effect of a drug irrespective of an amount .
<527> For Examples 12 to 15 (10 uM) , a CYP3A4 inhibition ratio was measured as 95 to 100%.
<528> Meanwhile, FIG. 1 distinctively shows graphs on potency, efficacy, and intrinsic activity of an 0-compound having a carbonyl group and an S-compound having a thio-carbonyl group according to concentrations, in which the S~ compound showed a good result of lOnM or less in view of potency and efficacy, and further showed a significantly high activity in view of the drug¾ available intrinsic activity, compared to the 0-compound. Accordingly, the S-compound in a greater amount range can potentially show a more significantly maximum effect, compared to the 0-compound. This can increase the range of an effective dose, which is highly advantageous for treatment dose determination and stability acquirement.
<529> Also, in measurement of a CYP inhibition ratio (lOuM) by an S-compound and an 0-compound, as a result of the measurement on 3A4 (the most major
type), the O-compound showed an inhibition ratio of 82%, while the S-compound showed an inhibition ratio of 100%. It can be found that the S-compound can show a prior result in view of cell-based metabolic activity.
[Industrial Applicability]
Although several exemplary embodiments of the present invention have been described for illustrative purposes, those skilled in the art will appreciate that various modifications, additions and substitutions are possible, without departing from the scope and spirit of the invention as disclosed in the accompanying claims.
Claims
[Claim 1]
<532> A compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof:
<533> [Formula 1]
<535> in Formula 1,
<536> X represents 
, aryl or heteroaryl, wherein aryl or heteroaryl is substituted or unsubstituted with at least one selected from the group consisting of Rla, Rlb, Rlc, Rid and Rie;
<537> each of Ria, Rib, Rlc, id and Rle is independently selected from the group consisting of hydrogen, alkyl , alkenyl, alkynyl , cycloalkyl, aryl, heterocyclyl, halo, -N¾, -CN, -N¾, -C(=0)0H, 
-0CF3, -ORn, -OH,
-SH, -SRn, -S(0)3H, -P(0)3H2, -C(=0)NR9R9, -NR12R12, -S(0)2NR9R9, -NR9S(0)2CF3,
-C(=0)NR9S(0)2R9) -S(0)2NR9C(=0)0R9, -S(0)2NR9C(=0)NR9R9, -C(O)NR9S(0)2CF3, 
<538> Y represents S or 0;
<53< > K represents CH or N; <540> Zi represents C or N;
<54 i> Z2 represents C or N, provided that both of Zi and Z2 are not N;
<542> Li represents CH2, N(R3) , C(=0), 0, OCR9R9, S, S(=0) or S(0)2
<543> m represents 0 through 2;
<544> n2represents 0 through 2;
<545> n3 represents 0 through 2;
<546> Pi represents aryl , heteroaryl , cycloalkyl or heterocycloalkyl , wherein each of aryl, heteroaryl, cycloalkyl and heterocycloalkyl is substituted or unsubst ituted with at least one selected from the group consisting of Ria , Rib , 
<547> each of Rla , Rlb , Rlc , Rld and Rie is independently selected from the group consisting of hydrogen, alkyl, alkenyl , alkynyl , cycloalkyl, aryl, heterocyclyl, halo, -NH2, -CN, -N02, -C(=0)0H, -C(=0)0RM, -0CF3, -0Rn, -OH,
-SH, -SR11 , -S(0)3H, -P(0)3H2, -C(=0)NR9R9, -NR12Ri2, -S(0)2NR9R9, -NR9S(0)2CF3,
-C(=0)NR9S(0)2R9, -S(0)2NR9C(=0)0R9, -S(0)2NR9C(O)NR9R9, -C(=0)NR9S(0)2CF3, 
<548> R2represents alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl,
-S(0)2R5, 
or -C(=0)0R5, wherein each of alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is substituted or unsubstituted with at least one Re;
<?49> R3is hydrogen, alkyl, alkoxy, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl , heterocyclyl or heterocyc lyl alkyl ; <550> R4 represents substituted or unsubst ituted Ci-3alkylene, oj represents an integer from 0 to 2, wherein substituted C1-3 alkylene is substituted with d-6 alkyl or halogen (provided that Y=0, 
and Pi represents cycloalkyl or heterocycloalkyl ;
<?5i> R5 represents alkyl, alkenyl, aryl, cycloalkyl, heteroaryl or heterocyclyl, wherein each of alkyl, alkenyl, aryl, cycloalkyl, heteroaryl and heterocyclyl is substituted or unsubst ituted with at least one R6;
552> R6i in each case, is independently selected from the group consisting of alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl , heteroaryl, heteroaryl alkyl , heterocyclyl, heterocyc lyl alkyl , halo, -NH2, -CN,
-NO2, -C(=0)0H, 
-0CF3, -0R10, -OH, -SH, -SR10, -S(0)3H, -P(0)3H2,
-C(=0)NR9R9, -NR9R9 , -S(0)2NR9R9, -NR9S(0)2CF3, -C(=0)NR9S(0)2R9,
-S(0)2NR9C(=0)0R9, -S(0)2NR9C(=0)NR9R9, -C(=0)NR9S(0)2CF3, -C(=0)R10, -NR9C(=0)H, 
-S(0)2Ri0,
-0, -NR9C(=0)0R8 and -NR9S(02)R8, wherein each of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl , heterocyclyl and heterocyclylalkyl is substituted or unsubst ituted with 0 to 5 R9a substituents;
<553> R7, in each case, is independently selected from the group consisting ofalkyl, haloalkyl,. aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, halo, -NH2, -CN, -N02, -C(=0)0H, -C(=0)0R10, -0CF3, -0RM, -OH,
-SH, -SR10, -S(0)3H, -P(0)3H2, -C(0)NR9R9, -NR9R9, -S(0)2NR9R9, -NR9S(0)2CF3,
-C(=0)NR9S(0)2R9, -S(0)2NR9C(=0)0R9, -S(0)2NR9C(=0)NR9R9, -C(=0)NR9S(0)2CF3, 
<555> R8a, in each case, is independently selected from the group consisting ofalkyl, haloalkyl, aryl, alkenyl, alkynyl , cycloalkyl, cycloalkylalkyl , heteroaryl, heteroarylalkyl , heterocyclyl, heterocyclylalkyl , halo, -NH2, -CN,
-NO2 , -C(=0)0H, 
-OCF3, -OR14 , -OH, -SH, -SRM , -S(0)3H, -P(0)3H2,
-C(=0)NR14Ri4, -NR14Ri4, -S(0)2NR14R14, -NRi4S(0)2CF3, -CO0)NR14S(0)2Ri4,
-S(0)2NR14C(-0)0Ri4, 
, 
-S( 
and -NR14S(02)R14
<556> R9, in each case, is independently selected from the group consisting ofhydrogen, alkyl, alkoxy, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl, wherein each of alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl is substituted or unsubst ituted with 0 to 5 R9a substituentsi
<557> R9a, in each case, is independently selected from the group consisting ofalkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, -NH2, -CN,
-NO2 , -CO0)0H, -C( =0)0Ri4 , -0CF3, -0R14 , -OH, -SH, ~SR14 , -S(0)3H, -P(0)3H2,
-C(-0)NR14Ri4, -NR14R14, -S(0)2NRMR14, -NR14S(0)2CF3, 
<558> R10, in each case, is independently selected from the group consisting ofalkyl , alkenyl, alkynyl, cycloalkyl, aryl , arylalkyl, heteroaryl , heteroarylalkyl , heterocyclyl and heterocyclylalkyl , wherein each of cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl is substituted or unsubstituted with 0 to 3 Ri0a substituents;
<559> R10A, in each case, is independently selected from the group consisting ofalkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl , heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, -NH2, ~CN,
-N0a, -C(=0)QH, -C(=0)0Ru, "0CF3, -0RM, -OH, -SH, -SRU, -S(0)3H, -P(0)3H2, 
-NR1 R14. -S(0)2NR14Ri4, -NRi4S(0)2CF3, -C(-0)NR14S(0)2R9, 
-S(0)2R14, -NRi4C(=0)0R8, -NRi4S(02)R8 and arylalkyl;
<560> Ru, in each case, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, and heterocyclylalkyl, wherein each of cycloalkyl, aryl, arylalkyl, heterocyclyl, and heterocyclylalkyl is substituted or unsubstituted with 0 to 3 Rna substituents;
<56i> Rlla, in each case, is independently selected from the group consisting of alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, -NH2, -CN,
-NO2, -C(=0)0H, 
-0CF3, -ORM, -OH, -SH, -SRM, -S(0)3H, -P(0)3H2, 
- R14R14, -S(0)2NRi4Ri4, -NR14S(0)2CF3,
-S(0)2NRi4C(=0)0R9, -S(0)2NR14C(=0)NR14RM, -C(=0)NR14S(0)2CF3, -C(=0)RM,
(=0)RI4, -C(=NR14)NRi4Ri4,
<562> R12, in each case, is independently selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl , arylalkyl, heterocyclyl and heterocyclylalkyl, wherein each of cycloalkyl, aryl, arylalkyl, heterocyclyl and heterocyclylalkyl is substituted or unsubstituted with 0 to 3 Rioa substituents;
<563> Ri4, in each case, is independently selected from the group consisting ofhydrogen, alkyl, cycloalkyl and aryl; and
<564> each of P2, P3 and P4 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, halo, -CN, -C(=0)0H, 
[Claim 2]
<565> A compound or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein the compound represented by Formula 1 is a compound represented by Formula 2 below or a compound represented by Formula 3 below,
<566> [Formula 2]
<57o> in Formulas 2 and 3,
<57i> D represents NR3, S or 0;
<572> G represents S or 0;
<573> Rx represents alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl,
-S(0)2R5, -ίΧ=0)Ν¾¾, -C(=0)Rs or -C(=0)0R5, wherein each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is substituted or unsubstituted with at least one !¾;
<574> R N is independently selected from the group consisting of hydrogen, alkyl , alkenyl , alkynyl, cycloalkyl, aryl, heterocyclyl , halo, -NH2, _CN,
-NO2, -C(=0)0H, 
-OCF3 , -ORn, -OH, -SH, -SRn, -S(0)3H, -P(0)3H2>
-C(=0)NR9R9, -NR12R12, -S(0)2NR9R9, -NR9S(0)2CF3, -C(=0)NR9S(0)2R9,
-S(0)2NR9C(=0)0R9, -S(0)2NR9C(=0)NR9R9, -C(=0)NR9S(0)2CF3, -C(=0)Ru, -NR9C(=0)H, 
-S(=0)Rn, -S(0)2Rn, -NR9C(=0)ORs and -NR9S(02)R8, wherein (a) each of alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl is substituted or unsubstituted with at least one R6 and (b) alkyl is substituted or unsubstituted with at least one R7;
<575> R'NV represents hydrogen, alkyl or halogen; and
<ί 6 R3, R6, R7 and P3 are the same as defined in claim 1.
[Claim 3]
<577> A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein the compound represented by Formula 1 is any one selected from the group consisting of following compounds:
a
CI
CI
CI
O 0 CI
c*
CI
<58l>
[Claim 4]
<582> A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein the compound represented by Formula 1 is any one selected from the group consisting of following compounds: 
CI
δ ct
CI 
CI
<584>
[Claim 5]
<585> A pharmaceutical composition for treating a metabolic disorder, which
comprises the compound or the pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 4, as an active ingredient.
[Claim 6]
<586> A pharmaceutical composition as claimed in claim 5, wherein the metabolic disorder is any one selected from the group consisting ofobesity, type I diabetes mellitus, type II diabetes mellitus, impaired glucose tolerance, insulin resistance, hyperglycemia, hyper 1 ipidemia, hypertriglyceridemia, hypercholesterolemia, dysl ipidemia, and syndrome X.
[Claim 7] <5«7> A method for preparing the compound as claimed in claim 1 by reacting a compound represented by Formula 4 below with a compound represented by Formula 5 below:
<588> F rmula 4] 
<590> [F rmula 5]
<592> inthe Formulas 5 and 6,
<593> A and B represent halogen, and X, Y, L1( Rj, ¾, Z1? Z2, Pi, P2 and P3are the same as defined in claim 1.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020100071674A KR20120011357A (en) | 2010-07-23 | 2010-07-23 | Substituted pyridinone derivatives and methods for manufacturing the same |
| KR10-2010-0071674 | 2010-07-23 |
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| Publication Number | Publication Date |
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| WO2012011707A2 true WO2012011707A2 (en) | 2012-01-26 |
| WO2012011707A3 WO2012011707A3 (en) | 2012-05-31 |
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ID=45497277
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/KR2011/005268 WO2012011707A2 (en) | 2010-07-23 | 2011-07-18 | Substituted pyridinone derivatives and methods for manufacturing the same |
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| Country | Link |
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| KR (1) | KR20120011357A (en) |
| WO (1) | WO2012011707A2 (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012170867A1 (en) | 2011-06-09 | 2012-12-13 | Rhizen Pharmaceuticals Sa | Novel compounds as modulators of gpr-119 |
| WO2014011926A1 (en) | 2012-07-11 | 2014-01-16 | Elcelyx Therapeutics, Inc. | Compositions comprising statins, biguanides and further agents for reducing cardiometabolic risk |
| WO2014052619A1 (en) * | 2012-09-27 | 2014-04-03 | Irm Llc | Piperidine derivatives and compositions as modulators of gpr119 activity |
| US9902712B2 (en) | 2013-12-19 | 2018-02-27 | Sunshine Lake Pharma Co., Ltd. | Nitrogenous heterocyclic derivatives and their application in drugs |
| CN108503575A (en) * | 2012-10-02 | 2018-09-07 | 英特穆恩公司 | Anti-fibrosis pyridinone |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090018055A1 (en) * | 2007-05-04 | 2009-01-15 | Bristol-Myers Squibb Company | [6,5]-bicyclic gpr119 g protein-coupled receptor agonists |
| US20090286812A1 (en) * | 2008-05-19 | 2009-11-19 | Shawn David Erickson | GPR119 Receptor Agonists |
-
2010
- 2010-07-23 KR KR1020100071674A patent/KR20120011357A/en not_active Application Discontinuation
-
2011
- 2011-07-18 WO PCT/KR2011/005268 patent/WO2012011707A2/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090018055A1 (en) * | 2007-05-04 | 2009-01-15 | Bristol-Myers Squibb Company | [6,5]-bicyclic gpr119 g protein-coupled receptor agonists |
| US20090286812A1 (en) * | 2008-05-19 | 2009-11-19 | Shawn David Erickson | GPR119 Receptor Agonists |
Non-Patent Citations (1)
| Title |
|---|
| HA OVERTON ET AL.: 'GPR119, a novel G protein receptor target for the treatment of type 2 diabetes and obesity' BRITISH JOURNAL OF PHARMACOLOGY vol. 153, 2008, pages S76 - S81 * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012170867A1 (en) | 2011-06-09 | 2012-12-13 | Rhizen Pharmaceuticals Sa | Novel compounds as modulators of gpr-119 |
| WO2014011926A1 (en) | 2012-07-11 | 2014-01-16 | Elcelyx Therapeutics, Inc. | Compositions comprising statins, biguanides and further agents for reducing cardiometabolic risk |
| WO2014052619A1 (en) * | 2012-09-27 | 2014-04-03 | Irm Llc | Piperidine derivatives and compositions as modulators of gpr119 activity |
| CN108503575A (en) * | 2012-10-02 | 2018-09-07 | 英特穆恩公司 | Anti-fibrosis pyridinone |
| US10376497B2 (en) | 2012-10-02 | 2019-08-13 | Intermune, Inc. | Anti-fibrotic pyridinones |
| EA034171B1 (en) * | 2012-10-02 | 2020-01-14 | Интермьюн, Инк. | Anti-fibrotic pyridinones |
| US10898474B2 (en) | 2012-10-02 | 2021-01-26 | Intermune, Inc. | Anti-fibrotic pyridinones |
| US9902712B2 (en) | 2013-12-19 | 2018-02-27 | Sunshine Lake Pharma Co., Ltd. | Nitrogenous heterocyclic derivatives and their application in drugs |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20120011357A (en) | 2012-02-08 |
| WO2012011707A3 (en) | 2012-05-31 |
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