US 2019/0315771 A1Published application

Novel 2-acylaminothiazole derivative and preparation method therefor and use thereof

AssigneeSichuan Kelun-Biotech Biopharmaceutical Co., Ltd.

InventorsJiaqiang CAI, Nan YU, Hong ZENG, Hongmei SONG, Yan QING, Shuai SONG, Hanwen DENG, Zujian TANG, Xiaofan DUAN, Haitao HUANG, Hong YE, Gang LIU, Lichun WANG, Jingyi WANG

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Abstract

The present invention relates to novel 2-acylaminothiazole derivatives. The present invention also relates to the preparation method for these novel 2-acylaminothiazole derivatives and intermediates thereof, and a pharmaceutical composition containing these compounds. Moreover, the present invention also relates to these novel 2-acylaminothiazole derivatives and the pharmaceutical composition containing the same for use in treating and/or preventing thrombopoietin receptor mediated diseases.

Claims47

Dependent claims

A compound represented by formula (I), or an isomer or racemate thereof, a salt thereof, an ester thereof, a solvate thereof, a chemically protected form thereof, a prodrug or metabolite thereof, a crystal form thereof, and a mixture thereof:

wherein m, n, q, and r are individually and separately selected from an integer of 0-4;
t is selected from an integer of 0-3;
X is N or C;
represents a single or double bond;
when X is N, is a single bond;
R1 is selected from hydrogen, optionally substituted C1-C12alkyl, optionally substituted C2-C12alkenyl, optionally substituted C2-C12alkynyl, optionally substituted C3-C12cycloalkyl, optionally substituted C5-C12cycloalkenyl, optionally substituted C5-C12polycycliccycloalkyl, optionally substituted C6-C12polycycliccycloalkenyl, optionally substituted C4-C12fused cycloalkyl, optionally substituted C6-C12fused cycloalkenyl, optionally substituted C6-C10aryl, optionally substituted C3-C10heterocyclyl, wherein the above “optionally substituted” in the definition of R1 refers to being unsubstituted or substituted by one or more identical or different groups selected from:
C1-C6alkyl, C1-C6alkyl substituted by one or more halogens, cyano, halogen, C1-C6alkoxy or C1-C6alkoxy substituted by one or more halogens;
R2 is selected from C6-C10aryl optionally substituted by R4, 5- or 6-membered heteroaryl optionally substituted by R4 and containing 1-3 identical or different heteroatoms selected from N, O and S, 8- to 10-membered heteroaryl optionally substituted by R4 and containing 1-4 identical or different heteroatoms selected from N, O and S;
R4 is selected from hydrogen, substituted or unsubstituted C1-C12alkyl, substituted or unsubstituted C3-C12cycloalkyl, halogen, cyano, nitro, substituted or unsubstituted C1-C12alkoxy, substituted or unsubstituted C2-C12alkoxyalkyl, carboxyl, carboxyl-substituted C2-C6alkenyl, ester group, ester group-substituted C2-C12alkenyl, R5R6N—, (C1-C12alkyl) C(═O)N(R5)—, R5R6NC(═O)—, R5SO, R5SO2, R5R6NSO2, wherein R5 and R6 are each independently selected from hydrogen, C1-C12alkyl and C3-C12cycloalkyl;
R3 is selected from an aryl or heteroaryl represented by formula (II), or, R3 is selected from a heteroaryl represented by formula (III):
wherein J, L, G, E and Y are each independently selected from N, O, S, CH or C,
wherein R7, R8 and R9 are each independently selected from hydrogen, halogen, OH, cyano, nitro, carboxyl, ester group, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C1-C4alkyl, substituted or unsubstituted C2-C4alkenyl, C1-C4alkoxy, R5R6N, substituted or unsubstituted 4-8 membered saturated heterocyclyl containing at least one atom selected from N, O, S and S(O)e, e is 1 or 2;
said “substituted” refers to being substituted by one or more identical or different groups selected from:
C1-C6alkyl, cyano, halogen, carboxyl, ester, phosphoric acid group, phosphate ester group.

11 more elements

A compound, which is selected from:

1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(1-methyl-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)thiazol-2-yl]carbamoyl}pyridin-2-yl)piperidine-4-carboxylic acid;
1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(1-cyclobutyl-hexahydropyrrolo[3,4-b]-pyrrol-5(1H)-yl)-thiazol-2-yl]-carbamoyl}-pyridin-2-yl)-piperidine-4-carboxylic acid;
1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(1-cyclopentyl-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-thiazol-2-yl]-carbamoyl}-pyridin-2-yl)-piperidine-4-carboxylic acid;
1-[3-chloro-5-({4-(4-chlorothiophen-2-yl)-5-[1-(3-methylcyclopentyl)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]-thiazol-2-yl}-carbamoyl)-pyridin-2-yl]-piperidine-4-carboxylic acid;
1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(1-cyclohexyl-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-thiazol-2-yl]-carbamoyl}-pyridin-2-yl)-piperidine-4-carboxylic acid and a stereoisomer thereof;
1-[3-chloro-5-({4-(4-chlorothiophen-2-yl)-5-[1-(N-methyl-piperidin-4-yl)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]-thiazol-2-yl}-carbamoyl)-pyridin-2-yl]-piperidine-4-carboxylic acid;
1-[3-chloro-5-({4-(4-chlorothiophen-2-yl)-5-[1-(4H-tetrahydropyran-4-yl)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]-thiazol-2-yl}-carbamoyl)-pyridin-2-yl]-piperidine-4-carboxylic acid;
1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(1-cycloheptyl-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-thiazol-2-yl]-carbamoyl}-pyridin-2-yl)-piperidine-4-carboxylic acid;
1-[3-chloro-5-({4-(4-chlorothiophen-2-yl)-5-[1-(bicyclo[2.2.1]hept-2-yl)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]thiazol-2-yl}carbamoyl)pyridin-2-yl]piperidine-4-carboxylic acid;
1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(1-(1R,3R,5R,7R)-adamantanyl-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-thiazol-2-yl]-carbamoyl}-pyridin-2-yl)-piperidine-4-carboxylic acid;
1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(1-cyclopentyl-octahydropyrrolo[3,4-b]pyridin-6(1H)-yl)-thiazol-2-yl]-carbamoyl}-pyridin-2-yl)-piperidine-4-carboxylic acid;
1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(1-cyclohexyl-octahydropyrrolo[3,4-b]pyridin-6(1H)-yl)-thiazol-2-yl]-carbamoyl}-pyridin-2-yl)-piperidine-4-carboxylic acid;
1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(1-cyclohexyl-octahydro-1H-pyrrolo[3,2-c]pyridin-5(6H)-yl)-thiazol-2-yl]-carbamoyl}-pyridin-2-yl)-piperidine-4-carboxylic acid;
1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(1-cyclopentyl-octahydro-1H-pyrrolo[3,2-c]pyridin-5(6H)-yl)-thiazol-2-yl]-carbamoyl}-pyridin-2-yl)-piperidine-4-carboxylic acid;
3′-chloro-5′-[4-(4-chlorothiophen-2-yl)-5-(2,6-diazaspiro[3.3]heptan-2-yl)-thiazol-2-carbamoyl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridine-4-carboxylic acid;
3′-chloro-5′-[4-(4-chlorothiophen-2-yl)-5-(6-iso-propyl-2,6-diazaspiro[3.3]heptan-2-yl)-thiazol-2-carbamoyl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridine-4-carboxylic acid;
3′-chloro-5′-[4-(4-chlorothiophen-2-yl)-5-(6-cyclohexyl-2,6-diazaspiro[3.3]heptan-2-yl)-thiazol-2-carbamoyl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridine-4-carboxylic acid;
1-(5-{[5-(2,5-diazabicyclo[2.2.1]heptan-2-yl)-4-(4-chlorothiophen-2-yl)thiazol-2-yl]carbamoyl}-3-chloropyridin-2-yl)piperidine-4-carboxylic acid;
1-(3-chloro-5 {[4-(4-chlorothiophen-2-yl)-5-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)thiazol-2-yl]carbamoyl}pyridin-2-yl)piperidine-4-carboxylic acid;
1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(5-iso-propyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-thiazol-2-yl]-carbamoyl}-pyridin-2-yl)-piperidine-4-carboxylic acid;
1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(5-cyclobutyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-thiazol-2-yl]-carbamoyl}-pyridin-2-yl)-piperidine-4-carboxylic acid;
1-(3-chloro-5 {[4-(4-chlorothiophen-2-yl)-5-(5-cyclopentyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-thiazol-2-yl]-carbamoyl}-pyridin-2-yl)-piperidine-4-carboxylic acid;
1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(5-cyclohexyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-thiazol-2-yl]-carbamoyl}-pyridin-2-yl)-piperidine-4-carboxylic acid;
3′-chloro-5′-[4-(4-chlorothiophen-2-yl)-5-(2,5-diazabicyclo[2.2.2]octan-2-yl)-thiazol-2-carbamoyl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridine-4-carboxylic acid;
3′-chloro-5′-[4-(4-chlorothiophen-2-yl)-5-(5-methyl-2,5-diazabicyclo[2.2.2]octan-2-yl)-thiazol-2-carbamoyl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridine-4-carboxylic acid;
3′-chloro-5′-[4-(4-chlorothiophen-2-yl)-5-(5-iso-propyl-2,5-diazabicyclo[2.2.2]octan-2-yl)-thiazol-2-carbamoyl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridine-4-carboxylic acid;
3′-chloro-5′-[4-(4-chlorothiophen-2-yl)-5-(5-cyclobutyl-2,5-diazabicyclo[2.2.2]octan-2-yl)-thiazol-2-carbamoyl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridine-4-carboxylic acid;
3′-chloro-5′-[4-(4-chlorothiophen-2-yl)-5-(5-cyclopentyl-2,5-diazabicyclo[2.2.2]octan-2-yl)-thiazol-2-carbamoyl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridine-4-carboxylic acid;
3′-chloro-5′-[4-(4-chlorothiophen-2-yl)-5-(5-cyclohexyl-2,5-diazabicyclo[2.2.2]octan-2-yl)-thiazol-2-carbamoyl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridine-4-carboxylic acid;
3′-chloro-5′-[4-(4-chlorothiophen-2-yl)-5-(5-cyclohexyl-octahydropyrrolo[3,4-c]pyridin-2-yl)-thiazol-2-carbamoyl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridine-4-carboxylic acid;
3′-chloro-5′-[4-(4-chlorothiophen-2-yl)-5-(5-cyclopentyl-octahydropyrrol[3,4-c]pyridin-2-yl)-thiazol-2-carbamoyl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridine-4-carboxylic acid;
3′-chloro-5′-[4-(4-chlorothiophen-2-yl)-5-(5-cyclohexyl-hexahydropyrrolo[3,4-b]pyrrol-1-yl)-thiazol-2-carbamoyl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridine-4-carboxylic acid;
1-(3-chloro-5-{[4-(4-chloropyridin-2-yl)-5-(2-cyclohexyl-hexahydropyrrolo[3,4-c]pyrrol-5-yl)-thiazol-2-yl]-carbamoyl}-pyridin-2-yl)-pyridin-4-carboxylic acid;
3′-chloro-5′-[5-(1-cyclohexyl-hexahydropyrrolo[3,4-b]pyrrol-5-yl)-4-(3-trifluoromethylphenyl)-thiazol-2-carbamoyl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridine-4-carboxylic acid;
(E)-3-{2,6-dichloro-4-[5-(1-cyclohexyl-hexahydropyrrolo[3,4-b]pyrrol-5-yl)-4-(3-trifluoromethylphenyl)-thiazol-2-carbamoyl]-phenyl}-2-methyl-acrylic acid;
(E)-3-(2,6-dichloro-4-{[4-(4-chlorothiophen-2-yl)-5-(1-cyclohexyl-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-thiazol-2-yl]-carbamoyl}-phenyl)-2-methylacrylic acid;
(E)-3-(2,6-dichloro-4-{[4-(4-chlorothiophen-2-yl)-5-(1-cyclobutyl-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-thiazol-2-yl]-carbamoyl}-phenyl)-2-methylacrylic acid;
(E)-3-[4-({5-[1-(3,3-difluorocyclobutyl)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]-4-(4-chlorothiophen-2-yl)-thiazol-2-yl}-carbamoyl)-2,6-dichlorophenyl]-2-methylacrylic acid;
(E)-3-[4-({5-[1-(3-fluorocyclobutyl)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]-4-(4-chlorothiophen-2-yl)-thiazol-2-yl}-carbamoyl)-2,6-dichlorophenyl]-2-methylacrylic acid;
(E)-3-(2,6-dichloro-4-{[4-(4-chlorothiophen-2-yl)-5-(1-cyclopentyl-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-thiazol-2-yl]-carbamoyl}-phenyl)-2-methylacrylic acid;
(E)-3-[4-({5-[1-(3-methylcyclopentyl)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]-4-(4-chlorothiophen-2-yl)-thiazol-2-yl}-carbamoyl)-2,6-dichlorophenyl]-2-methylacrylic acid;
(E)-3-[4-({5-[1-(N-methyl-piperidin-4-yl)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]-4-(4-chlorothiophen-2-yl)-thiazol-2-yl}-carbamoyl)-2,6-dichlorophenyl]-2-methylacrylic acid;
(E)-3-[4-({5-[1-(4H-tetrahydropyran-4-yl)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]-4-(4-chlorothiophen-2-yl)-thiazol-2-yl}-carbamoyl)-2,6-dichlorophenyl]-2-methylacrylic acid;
(E)-3-(4-{[5-(1-cycloheptyl-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-4-(4-chlorothiophen-2-yl)-thiazol-2-yl]-carbamoyl}-2,6-dichlorophenyl)-2-methylacrylic acid;
(E)-3-[4-({5-[1-(bicyclo[2.2.1]hept-2-yl)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]-4-(4-chlorothiophen-2-yl)-thiazol-2-yl}-carbamoyl)-2,6-dichlorophenyl]-2-methylacrylic acid;
(E)-3-{4-[(5-{1-[(1R,3R,5R,7R)-adamantan-2-yl]hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl}-4-(4-chlorothiophen-2-yl)thiazol-2-yl)carbamoyl]-2,6-dichlorophenyl}-2-methylacrylic acid;
(E)-3-{2,6-dichloro-4-[4-(4-chlorothiophen-2-yl)-5-(5-cyclohexyl-2,5-diazabicyclo[2.2.2]octan-2-yl)-thiazol-2-carbamoyl]-phenyl}-2-methyl-acrylic acid;
(E)-3-(2,6-dichloro-4-((4-(4-chlorothiophen-2-yl)-5-(5-cyclohexylhexahydro-1H-pyrrolo[3,2-c]pyridin-2(3H)-yl)thiazol-2-yl)carbamoyl)phenyl)-2-methylacrylic acid;
3′-chloro-5′-[5-(1-cyclohexyl-hexahydropyrrolo[3,4-b]pyrrol-5-yl)-4-(2-fluoro-3-trifluoromethylphenyl)-thiazol-2-carbamoyl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridine-4-carboxylic acid;
3-{2,6-dichloro-4-[5-(1-cyclohexyl-hexahydropyrrolo[3,4-b]pyrrol-5-yl)-4-(2-fluoro-3-trifluoromethylphenyl)-thiazol-2-carbamoyl]-phenyl}-2-methyl-acrylic acid;
(E)-3-{4-[(5-{(3aR,6aR)-1-[(1R,3R,5R,7R)-adamantan-2-yl]hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl}-4-(4-chlorothiophen-2-yl)thiazol-2-yl)carbamoyl]-2,6-dichlorophenyl}-2-methylacrylic acid;
(E)-3-{4-[(5-{(3aS,6aS)-1-[(1S,3S,5S,7S)-adamantan-2-yl]hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl}-4-(4-chlorothiophen-2-yl)thiazol-2-yl)carbamoyl]-2,6-dichlorophenyl}-2-methylacrylic acid;
or an isomer or racemate thereof, a salt thereof, an ester thereof, a solvate thereof, a chemically protected form thereof, a prodrug or metabolite thereof, a crystal form thereof, and a mixture thereof.

50 more elements

A compound, which is selected from:

tert-butyl 5-[2-amino-4-(4-chlorothiophen-2-yl)-thiazol-5-yl]-hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate;
tert-butyl 5-[4-(4-chlorothiophen-2-yl)-2-(5,6-dichloro-pyridin-3-carbonylamino)-thiazol-5-yl]-hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate;
tert-butyl 5-[2-{5-chloro-6-[4-(ethoxycarbonyl)-piperidin-1-yl]-nicotinamido}-4-(4-chlorothiophen-2-yl)-thiazol-5-yl]-hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate;
ethyl 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-thiazol-2-yl]-carbamoyl}-pyridin-2-yl)-piperidine-4-carboxylate;
ethyl 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(1-methyl-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-thiazol-2-yl]-carbamoyl}-pyridin-2-yl)-piperidine-4-carboxylate;
tert-butyl 6-[2-amino-4-(4-chlorothiophen-2-yl)thiazol-5-yl]octahydro-H-pyrrolo[3,4-b]pyridine carboxylate;
tert-butyl 6-(4-(4-chlorothiophen-2-yl)-2-(5,6-dichloronicotinamido)thiazol-5-yl)octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate;
tert-butyl 6-(2-{5-chloro-6-[4-(ethoxycarbonyl)piperidin-1-yl]-nicotinamido}-4-(4-chlorothiophen-2-yl)-thiazol-5-yl)-octahydro-H-pyrrolo[3,4-b]pyridin-carboxylate;
ethyl 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(octahydropyrrolo[3,4-b]pyridin-6(1H)-yl)-thiazol-2-yl]-carbamoyl}pyridin-2-yl)-piperidine-4-carboxylate;
ethyl 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(1-cyclopentyl-octahydropyrrolo[3,4-b]pyridin-6(1H)-yl)-thiazol-2-yl]-carbamoyl}-pyridin-2-yl)-piperidine-4-carboxylate;
tert-butyl 5-[2-amino-4-(4-chlorothiophen-2-yl)thiazol-5-yl]-octahydro-1H-pyrrolo[3,2-c]pyridin-1-carboxylate;
tert-butyl 5-[4-(4-chlorothiophen-2-yl)-2-(5,6-dichloronicotinamide)-thiazol-5-yl]-octahydro-1H-pyrrolo[3,2-c]pyridin-1-carboxylate;
tert-butyl 5-[2-{5-chloro-6-[4-(ethoxycarbonyl)-piperidin-1-yl]-nicotinamido}-4-(4-chlorothiophen-2-yl)-thiazol-5-yl]-octahydro-1H-pyrrolo[3,2-c]pyridin-1-carboxylate;
ethyl 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(octahydro-1H-pyrrol[3,2-c]-pyridin-5(6H)-yl)-thiazol-2-yl]-carbamoyl}-pyridin-2-yl)-piperidine-4-carboxylate;
ethyl 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(1-cyclohexyloctahydro-1H-pyrrolo[3,2-c]pyridin-5(6H)-yl)-thiazol-2-yl]-aminoformamide}-pyridin-2-yl)-piperidine-4-carboxylate;
tert-butyl 6-[2-amino-4-(4-chloro-thiophen-2-yl)-thiazol-5-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate;
tert-butyl 6-(4-(4-chlorothiophen-2-yl)-2-(5,6-dichloronicotinamido)thiazol-5-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate;
ethyl 5′-[5-(6-tert-butyloxycarbonyl-2,6-diazaspiro[3.3]heptan-2-yl-4-(4-chloro-thiophen-2-yl)-thiazol-2-carbamoyl]-3′-chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridine-4-carboxylate;
ethyl 3′-chloro-5′-[4-(4-chloro-thiophen-2-yl)-5-(2,6-diazaspiro[3.3]heptan-2-yl)-thiazol-2-carbamoyl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridine-4-carboxylate;
ethyl 3′-chloro-5′-[4-(4-chlorothiophen-2-yl)-5-(6-iso-propyl-2,6-diazaspiro[3.3]heptan-2-yl)-thiazol-2-carbamoyl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridine-4-carboxylate;
tert-butyl 5-[2-amino-4-(4-chlorothiophen-2-yl)-thiazol-5-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate;
tert-butyl 5-(2-amino-4-(4-chlorothiophen-2-yl)-thiazol-5-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate;
tert-butyl 5-[4-(4-chlorothiophen-2-yl)-2-(5,6-dichloropyridin-3-formamide)-thiazol-5-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate;
tert-butyl 5-(2-{5-chloro-6-[4-(ethoxycarbonyl)piperidin-1-yl]nicotinamido}-4-(4-chlorothiophen-2-yl)thiazol-5-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate;
1-[5-({5-[5-(2-tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-4-(4-chlorothiophen-2-yl)-thiazol-2-yl}carbamoyl)-3-chloropyridin-2-yl]piperidine-4-carboxylic acid;
ethyl 1-(5-{[5-(-2,5-diazabicyclo[2.2.1]heptan-2-yl)-4-(4-chlorothiophen-2-yl)-thiazol-2-yl]-carbamoyl}-3-chloropyridin-2-yl)-piperidine-4-carboxylate;
ethyl 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)thiazol-2-yl]carbamoyl}pyridin-2-yl)piperidine-4-carboxylate;
tert-butyl 5-[2-amino-4-(4-chloro-thiophen-2-yl)-thiazol-5-yl]-2,5-diazabicyclo[2.2.2]octane-2-carboxylate;
tert-butyl 5-(4-(4-chloro-thiophen-2-yl)-2-((5,6-dichloro-pyridin-3-carbonyl)-amino)-thiazol-5-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate;
ethyl 5′-[5-(5-tert-butyloxycarbonyl-2,5-diazabicyclo[2.2.2]octan-2-yl)-4-(4-chloro-thiophen-2-yl)-thiazol-2-carbamoyl]-3′-chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridine-4-carboxylate;
ethyl 5′-[5-(2,5-diazabicyclo[2.2.2]octan-2-yl)-4-(4-chloro-thiophen-2-yl)-thiazol-2-carbamoyl]-3′-chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridine-4-carboxylate;
ethyl 3′-chloro-5′-[4-(4-chlorothiophen-2-yl)-5-(5-methyl-2,5-diazabicyclo[2.2.2]octan-2-yl)-thiazol-2-carbamoyl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridine-4-carboxylate;
tert-butyl 2-[2-amino-4-(4-chloro-thiophen-2-yl)-thiazol-5-yl]-octahydropyrrolo[3,4-c]pyridin-5-carboxylate;
tert-butyl 2-(4-(4-chlorothiophen-2-yl)-2-(5,6-dichloronicotinamido)thiazol-5-yl)hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylate;
ethyl 5′-[5-(5-tert-butyloxycarbonyl-octahydropyrrolo[3,4-c]pyridin-2-yl)-4-(4-chloro-thiophen-2-yl)-thiazol-2-carbamoyl]-3′-chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridine-4-carboxylate;
ethyl 3′-chloro-5′-[4-(4-chloro-thiophen-2-yl)-5-(octahydropyrrolo[3,4-c]pyridin-2-yl)-thiazol-2-carbamoyl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridine-4-carboxylate;
ethyl 3′-chloro-5′-[4-(4-chloro-thiophen-2-yl)-5-(5-cyclohexyl-octahydropyrrolo[3,4-c]pyridin-2-yl)-thiazol-2-carbamoyl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridine-4-carboxylate;
tert-butyl 1-[2-amino-4-(4-chloro-thiophen-2-yl)-thiazol-5-yl]-hexahydropyrrolo[3,4-b]pyrrole-5-carboxylate;
tert-butyl-1-(4-(4-chlorothiophen-2-yl)-2-(5,6-dichloronicotinamido)thiazol-5-yl)hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate;
ethyl 5′-[5-(5-tert-butyloxycarbonyl-hexahydropyrrolo[3,4-b]pyrrol-1-yl)-4-(4-chloro-thiophen-2-yl)-thiazol-2-carbamoyl]-3′-chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridine-4-carboxylate;
ethyl 3′-chloro-5′-[4-(4-chloro-thiophen-2-yl)-5-(hexahydropyrrolo[3,4-b]pyrrol-1-yl)-thiazol-2-carbamoyl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridine-4-carboxylate;
ethyl 3′-chloro-5′-[4-(4-chloro-thiophen-2-yl)-5-(5-cyclohexyl-hexahydropyrrolo[3,4-b]pyrrol-1-yl)-thiazol-2-carbamoyl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridine-4-carboxylate;
tert-butyl 5-[2-amino-4-(4-chlorothiophen-2-yl)-thiazol-5-yl]hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;
tert-butyl 5-[4-(4-chlorothiophen-2-yl)-2-(5,6-dichloropyridin-3-formamide)-thiazol-5-yl]hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;
tert-butyl 5-{2-[5-chloro-6-(4-ethoxycarbonyl-piperidin-1-yl)nicotinamide]-4-(4-chlorothiophen-2-yl)thiazol-5-yl}hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;
ethyl 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-thiazol-2-yl]-carbamoyl}-pyridin-2-yl)-piperidine-4-carboxylate;
ethyl 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(5-cyclohexyl-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-thiazol-2-yl]carbamoyl}-pyridin-2-yl)-piperidine-4-carboxylate;
tert-butyl 5-[2-amino-4-(3-trifluoromethylphenyl)-thiazol-5-yl]-hexahydropyrrolo[3,4-b]pyrrole-1-carboxylate;
tert-butyl 5-[2-[(5,6-dichloro-pyridin-3-carbonyl)-amino]-4-(3-trifluoromethylphenyl)-thiazol-5-yl]-hexahydropyrrolo[3,4-b]pyrrole-1-carboxylate;
ethyl 5′-[5-(1-tert-butyloxycarbonyl-hexahydropyrrolo[3,4-b]pyrrol-5-yl)-4-(3-trifluoromethylphenyl)-thiazol-2-carbamoyl]-3′-chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridine-4-carboxylate;
ethyl 3′-chloro-5′-[5-(hexahydropyrrolo[3,4-b]pyrrol-5-yl)-4-(3-trifluoromethylphenyl)-thiazol-2-carbamoyl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridine-4-carboxylate;
ethyl 3′-chloro-5′-[5-(1-cyclohexyl-hexahydropyrrolo[3,4-b]pyrrol-5-yl)-4-(3-trifluoromethylphenyl)-thiazol-2-carbamoyl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridine-4-carboxylate;
tert-butyl (E)-5-[2-[3,5-dichloro-4-(2-ethoxycarbonyl-propenyl)-benzoylamino]-4-(3-trifluoromethyl-phenyl)-thiazol-5-yl]-hexahydropyrrolo[3,4-b]pyrrole-1-carboxylate;
(E)-3-{2,6-dichloro-4-[5-(hexahydropyrrolo[3,4-b]pyrrol-5-yl)-4-(3-trifluoromethylphenyl)-thiazol-2-carbamoyl]-phenyl}-2-methyl-acrylic acid ethyl ester;
(E)-3-{2,6-dichloro-4-[5-(1-cyclohexyl-hexahydropyrrolo[3,4-b]pyrrol-5-yl)-4-(3-trifluoromethylphenyl)-thiazol-2-carbamoyl]-phenyl}-2-methyl-acrylic acid ethyl ester;
tert-butyl (E)-5-{4-(4-chlorothiophen-2-yl)-2-[3,5-dichloro-4-(3-ethoxy-2-methyl-3-oxo-propenyl)-benzoylamino]-thiazol-5-yl}-hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate;
(E)-3-(2,6-dichloro-4-{[5-(4-chlorothiophen-2-yl)-4-(hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-thiazol-2-yl]-carbamoyl}-phenyl)-2-methylacrylic acid ethyl ester;
(E)-3-(2,6-dichloro-4-{[4-(4-chlorothiophen-2-yl)-5-(1-cyclohexyl-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-thiazol-2-yl]-carbamoyl}-phenyl)-2-methylacrylic acid ethyl ester;
tert-butyl (3aR,6aR)-5-[2-amino-4-(4-chlorothiophen-2-yl)-thiazol-5-yl]-hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate;
tert-butyl (E)-(3 aR,6aR)-5-{4-(4-chlorothiophen-2-yl)-2-[3,5-dichloro-4-(3-ethoxy-2-methyl-3-oxo-1-propenyl)-benzoylamino]thiazol-5-yl}hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate;
(E)-(3 aR,6aR)-3-(2,6-dichloro-4-{[4-(4-chlorothiophen-2-yl)-5-(hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-thiazol-2-yl]-carbamoyl}-phenyl)-2-methylacrylic acid ethyl ester;
(E)-3-{4-[(5-{(3aR,6aR)-1-[(1R,3R,5R,7R)-adamantan-2-yl]hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl}-4-(4-chlorothiophen-2-yl)-thiazol-2-yl)-carbamoyl]-2,6-dichlorophenyl}-2-methylacrylic acid ethyl ester;
tert-butyl (3 aS,6aS)-5-[2-amino-4-(4-chlorothiophen-2-yl)-thiazol-5-yl]-hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate;
(E)-(3 aS,6aS)-5-{4-(4-chlorothiophen-2-yl)-2-[3,5-dichloro-4-(3-ethoxy-2-methyl-3-oxo-tert-butyl 1-propenyl)-benzoylamino]thiazol-5-yl}hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate;
(E)-(3aS,6aS)-3-(2,6-dichloro-4-{[4-(4-chlorothiophen-2-yl)-5-(hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-thiazol-2-yl]-carbamoyl}-phenyl)-2-methylacrylic acid ethyl ester;
(E)-3-{4-[(5-{(3aS,6aS)-1-[(1S,3S,5S,7S)-adamantan-2-yl]hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl}-4-(4-chlorothiophen-2-yl)-thiazol-2-yl)-carbamoyl]-2,6-dichlorophenyl}-2-methylacrylic acid ethyl ester;
or an isomer or racemate thereof, a salt thereof, an ester thereof, a solvate thereof, a chemically protected form thereof, a prodrug or metabolite thereof, a crystal form thereof, and a mixture thereof.

64 more elements

Dependencies are inferred from the claim text.

Facts

Application: 16/317,127Filed 31 Aug 2017
Priority: CN 201610810656.98 Sep 2016
Published: 17 Oct 2019
Term ends: Not estimatedThe source records don’t support an estimate.

Classification10 codes

A61P 7/04
Drugs for disorders of the blood or the extracellular fluid: antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
C07D 513/04
In which the condensed system contains two hetero rings: ortho-condensed systems
A61P 7/02
Drugs for disorders of the blood or the extracellular fluid: antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
C07D 471/04
In which the condensed system contains two hetero rings: ortho-condensed systems

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