MDM2 inhibitors

Abstract

A compound capable of being used as a tumor inhibitor, a preparation method therefor, and application thereof. The compound has a structure represented by general formula I; a stereoisomer, an enantiomer, a raceme, a cis/trans isomer, a tautomer, and an isotopic variant of the compound are comprised; the compound can be used separately or in combination with other drugs for treating tumors or inflammatory diseases, or for treating other disorders or diseases mediated by the activity of MDM2 and/or MDM4, and shows prominent curative activity. ##STR00001##

Claims

1. A compound of structural formula I: ##STR00243## wherein, R.sub.1 is linear or branched C.sub.1-C.sub.5 alkyl, C.sub.3-C.sub.5 cycloalkyl or ##STR00244## R.sub.2 is H or (C.sub.1-C.sub.6 alkyl), wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from alkoxy having 1 to 4 carbon atoms, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C.sub.1-C.sub.4)alkyl, —C(O)NR.sub.9R.sub.10, —NR.sub.9R.sub.10 and methanesulfonyl; R.sub.3 is a 5- or 6-membered aromatic ring or aromatic heterocycle comprising 1 or 2 heteroatoms independently selected from N, S, and O, which is unsubstituted or substituted by 1 to 3 substituents independently selected from H, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, —O—(C.sub.1-C.sub.6)alkyl, —O—(C.sub.3-C.sub.6)cycloalkyl, —S—(C.sub.1-C.sub.6)alkyl, halogen, haloalkyl, haloalkoxy, hydroxyalkoxy, —CN, —C(O)NR.sub.9R.sub.10, —C(O)-morpholin-4-yl, hydroxy-azetidin-1-yl-carbonyl, —CH.sub.2NR.sub.9R.sub.10, —CH.sub.2NR.sub.9—C(O)R.sub.10, methyl-imidazolyl-, —CH.sub.2C(O)NR.sub.9R.sub.10, —CH.sub.2C(O)OH, —C(O)OH, —CH.sub.2C(O)O—(C.sub.1-C.sub.4)alkyl, —N(R.sub.9)—C(O)—(C.sub.1-C.sub.4)alkyl, —NR.sub.9R.sub.10, —C(O)O—(C.sub.1-C.sub.4)alkyl, —CH.sub.2CN, tetrahydropyrrol-1-yl, azetidin-1-yl and azetidin-1-yl substituted with one or more —OH, or with —CH.sub.3 and —OH; wherein the alkyl or cycloalkyl is optionally substituted with 0 to 3 substituents independently selected from alkoxy having 1 to 4 carbon atoms, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C.sub.1-C.sub.4)alkyl, —C(O)NR.sub.9R.sub.10, —NR.sub.9R.sub.10 and methanesulfonyl; or R.sub.3 is selected from: ##STR00245## R.sub.5 is a 5- or 6-membered aromatic ring or aromatic heterocycle comprising 1 or 2 heteroatoms independently selected from N, S, and O, which is unsubstituted or substituted with 1 to 3 substituents independently selected from H, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, —O—(C.sub.1-C.sub.6)alkyl, —O—(C.sub.3-C.sub.6)cycloalkyl, —S—(C.sub.1-C.sub.6)alkyl, halogen, haloalkyl, haloalkoxy, hydroxyalkoxy, —CN, —C(O)NR.sub.9R.sub.10, —C(O)-morpholin-4-yl, hydroxy-azetidin-1-yl-carbonyl, —CH.sub.2NR.sub.9R.sub.10, —CH.sub.2NR.sub.9—C(O)R.sub.10, methyl-imidazolyl-, —CH.sub.2C(O)NR.sub.9R.sub.10, —CH.sub.2C(O)OH, —C(O)OH, —CH.sub.2C(O)O—(C.sub.1-C.sub.4)alkyl, —N(R.sub.9)—C(O)—(C.sub.1-C.sub.4)alkyl, —NR.sub.9R.sub.10, —C(O)OCH.sub.3, —CH.sub.2CN, tetrahydropyrrol-1-yl, azetidin-1-yl, and azetidin-1-yl substituted with one or more —OH, or with —CH.sub.3 and —OH; wherein the alkyl or cycloalkyl is optionally substituted with 0 to 3 substituents independently selected from alkoxy having 1 to 4 carbon atoms, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C.sub.1-C.sub.4)alkyl, —C(O)NR.sub.9R.sub.10, —NR.sub.9R.sub.10 and methanesulfonyl; or R.sub.5 is selected from: ##STR00246## R.sub.6 is selected from halogen, halomethyl, methyl and cyano; R.sub.7 is selected from H, (C.sub.1-C.sub.6) alkyl and halogen; wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from alkoxy having 1 to 4 carbon atoms, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C.sub.1-C.sub.4)alkyl, —C(O)NR.sub.9R.sub.10, —NR.sub.9R.sub.10 and methanesulfonyl; wherein: R.sub.8 is selected from —OH, —OCH.sub.3, —NH.sub.2, —NHMe, —NMe.sub.2, —NHCOMe, —NHCOH and methanesulfonyl; R.sub.9 is H or alkyl having 1 to 4 carbon atoms; R.sub.10 is H or (C.sub.1-C.sub.6) alkyl, wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from alkoxy having 1 to 4 carbon atoms, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C.sub.1-C.sub.4)alkyl and methanesulfonyl; wherein R.sub.11 is selected from —OCH.sub.3, —CH.sub.2CH.sub.3, —OH, halomethoxy and H; R.sub.12 is H or (C.sub.1-C.sub.6) alkyl, wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from alkoxy having 1 to 4 carbon atoms, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C.sub.1-C.sub.4)alkyl, —C(O)NR.sub.9R.sub.10, —NR.sub.9R.sub.10 and methanesulfonyl; R.sub.13 is halogen or alkyl having 1 to 4 carbon atoms; R.sub.14 is H or (C.sub.1-C.sub.6) alkyl, wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from alkoxy having 1 to 4 carbon atoms, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C.sub.1-C.sub.4)alkyl, —C(O)NR.sub.9R.sub.10, —NR.sub.9R.sub.10 and methanesulfonyl; R.sub.15 is selected from NH.sub.2, —C(O)OH, —NH(C(O)—CH.sub.3) and —C(O)—NH(CH.sub.3); R.sub.16 is selected from H, (C.sub.1-C.sub.6) alkyl and halogen; wherein the alkyl is optionally substituted by 0 to 3 substituents independently selected from alkoxy having 1 to 4 carbon atoms, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C.sub.1-C.sub.4)alkyl, —C(O)NR.sub.9R.sub.10, —NR.sub.9R.sub.10 and methanesulfonyl; and R.sub.17 is selected from —C(O)—NR.sub.9(R.sub.10), (C.sub.1-C.sub.6)alkyl, —C(O)(C.sub.1-C.sub.6)alkyl, and —C(O)O(C.sub.1-C.sub.6)alkyl; wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from alkoxy having 1 to 4 carbon atoms, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C.sub.1-C.sub.4)alkyl, —C(O)NR.sub.9R.sub.10, —NR.sub.9R.sub.10 and methanesulfonyl; and X.sub.1 is oxygen or sulfur; Y, X.sub.2, V and W are each independently carbon or nitrogen; wherein when Y is carbon, R.sub.4 is selected from H, hydroxyl, —O—(C.sub.1-C.sub.6)alkyl, —CN, halogen, (C.sub.1-C.sub.6)alkyl, —C(O)OH, —CH.sub.2C(O)OH, —CH.sub.2C(O)NR.sub.9R.sub.10, and —C(O)O—(C.sub.1-C.sub.6)alkyl, wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from alkoxy having 1 to 4 carbon atoms, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C.sub.1-C.sub.4)alkyl and methanesulfonyl; or a stereoisomer, an enantiomer, a diastereomer, a racemate, a mesomer, a cis/trans isomer, a tautomer, an isotopic variant of the compound of structural formula I, or any combination thereof; or a pharmaceutical salt thereof.

2. The compound according to claim 1, wherein R.sub.3 is a 5- or 6-membered aromatic ring or aromatic heterocycle comprising 1 or 2 heteroatoms independently selected from N, S, and O, which is unsubstituted or substituted with 1 to 3 substituents independently selected from H, (C.sub.1-C.sub.6)alkyl, —O—(C.sub.1-C.sub.6)alkyl, —S—(C.sub.1-C.sub.6)alkyl, halogen, haloalkyl, haloalkoxy, —CN, —C(O)NR.sub.9R.sub.10, —C(O)-morpholin-4-yl, hydroxy-azetidin-1-yl-carbonyl, —CH.sub.2NR.sub.9R.sub.10, —CH.sub.2NR.sub.9—C(O)R.sub.10, methyl-imidazolyl-, —CH.sub.2C(O)NR.sub.9R.sub.10, —CH.sub.2C(O)OH, —C(O)OH, —CH.sub.2C(O)O—(C.sub.1-C.sub.4)alkyl, —N(R.sub.9)—C(O)—(C.sub.1-C.sub.4)alkyl, —NR.sub.9R.sub.10, —C(O)O—(C.sub.1-C.sub.4)alkyl, —CH.sub.2CN, azetidin-1-yl and azetidin-1-yl substituted with one or more —OH, or with —CH.sub.3 and —OH; wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from alkoxy having 1 to 4 carbon atoms, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C.sub.1-C.sub.4)alkyl, —C(O)NR.sub.9R.sub.10, —NR.sub.9R.sub.10 and methanesulfonyl; and R.sub.5 is a 5- or 6-membered aromatic ring or aromatic heterocycle comprising 1 or 2 heteroatoms independently selected from N, S, and O, which is unsubstituted or substituted by 1 to 3 substituents independently selected from H, (C.sub.1-C.sub.6)alkyl, —O—(C.sub.1-C.sub.6)alkyl, —S—(C.sub.1-C.sub.6)alkyl, halogen, haloalkyl, haloalkoxy, —CN, —C(O)NR.sub.9R.sub.10, —C(O)-morpholin-4-yl, hydroxy-azetidin-1-yl-carbonyl, —CH.sub.2NR.sub.9R.sub.10, —CH.sub.2NR.sub.9—C(O)R.sub.10, —CH.sub.2CN, methyl-imidazolyl-, —CH.sub.2C(O)NR.sub.9R.sub.10, —CH.sub.2C(O)OH, —C(O)OH, —CH.sub.2C(O)O—(C.sub.1-C.sub.4)alkyl, —N(R.sub.9)—C(O)—(C.sub.1-C.sub.4)alkyl, —NR.sub.9R.sub.10, —C(O)OCH.sub.3, azetidin-1-yl and azetidin-1-yl substituted with one or more —OH or with —CH.sub.3 and —OH; wherein the alkyl is optionally substituted by 0 to 3 substituents independently selected from alkoxy having 1 to 4 carbon atoms, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C.sub.1-C.sub.4)alkyl, —C(O)NR.sub.9R.sub.10, —NR.sub.9R.sub.10 and methanesulfonyl.

3. The compound according to claim 2, wherein R.sub.1 is selected from methyl, ethyl, isopropyl, cyclopropyl, isobutyl, cyclobutyl, cyclopentyl, and ##STR00247## R.sub.2 is H or (C.sub.1-C.sub.6 alkyl), wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C.sub.1-C.sub.4)alkyl, —C(O)NR.sub.9R.sub.10, —NR.sub.9R.sub.10 and methanesulfonyl; R.sub.3 is a 5- or 6-membered aromatic ring or aromatic heterocycle comprising 1 or 2 heteroatoms independently selected from N, S, and O, which is unsubstituted or substituted with 1 to 3 substituents independently selected from H, (C.sub.1-C.sub.6)alkyl, —O—(C.sub.1-C.sub.6)alkyl, —S—(C.sub.1-C.sub.6)alkyl, halogen, —CF.sub.3, —CHF.sub.2, —CH.sub.2F, —OCF.sub.3, —OCHF.sub.2, —OCH.sub.2F, —OCH.sub.2CF.sub.3, —OCH.sub.2CHF.sub.2, —OCH.sub.2CH.sub.2F, —CN, —C(O)NR.sub.9R.sub.10, —C(O)-morpholin-4-yl, hydroxy-azetidin-1-yl-carbonyl, —CH.sub.2NR.sub.9R.sub.10, —CH.sub.2NR.sub.9—C(O)R.sub.10, methyl-imidazolyl-, —CH.sub.2C(O)NR.sub.9R.sub.10, —CH.sub.2C(O)OH, —C(O)OH, —CH.sub.2C(O)O—(C.sub.1-C.sub.4)alkyl, —N(R.sub.9)—C(O)—(C.sub.1-C.sub.4)alkyl, —NR.sub.9R.sub.10, —CH.sub.2NR.sub.9R.sub.10, —C(O)O—(C.sub.1-C.sub.4)alkyl, —CH.sub.2CN, azetidin-1-yl and azetidin-1-yl substituted with one or more —OH, or with —CH.sub.3 and —OH; wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C.sub.1-C.sub.4)alkyl, —C(O)NR.sub.9R.sub.10, —NR.sub.9R.sub.10 and methanesulfonyl; or R.sub.3 is selected from: ##STR00248## R.sub.5 is a 5- or 6-membered aromatic ring or aromatic heterocycle comprising 1 or 2 heteroatoms independently selected from N, S, and O, which is unsubstituted or substituted by 1 to 3 substituents independently selected from H, (C.sub.1-C.sub.6)alkyl, —O—(C.sub.1-C.sub.6)alkyl, —S—(C.sub.1-C.sub.6)alkyl, halogen, —CF.sub.3, —CHF.sub.2, —CH.sub.2F, —OCF.sub.3, —OCHF.sub.2, —OCH.sub.2F, —OCH.sub.2CF.sub.3, —OCH.sub.2CHF.sub.2, —OCH.sub.2CH.sub.2F, —CN, —C(O)NR.sub.9R.sub.10, —C(O)-morpholin-4-yl, hydroxy-azetidin-1-yl-carbonyl, —CH.sub.2NR.sub.9R.sub.10, —CH.sub.2NR.sub.9—C(O)R.sub.10, —CH.sub.2CN, methyl-imidazolyl-, —CH.sub.2C(O)NR.sub.9R.sub.10, —CH.sub.2C(O)OH, —C(O)OH, —CH.sub.2C(O)O—(C.sub.1-C.sub.4)alkyl, —N(R.sub.9)—C(O)—(C.sub.1-C.sub.4)alkyl, —NR.sub.9R.sub.10, —CH.sub.2NR.sub.9R.sub.10, —C(O)OCH.sub.3, —CH.sub.2CN, azetidin-1-yl and azetidin-1-yl substituted with one or more —OH or with —CH.sub.3 and —OH; wherein the alkyl is optionally substituted by 0 to 3 substituents independently selected from methoxy and ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C.sub.1-C.sub.4)alkyl, —C(O)NR.sub.9R.sub.10, —NR.sub.9R.sub.10 and methanesulfonyl; or R.sub.5 is selected from: ##STR00249## R.sub.6 is selected from chlorine, fluorine, bromine, trifluoromethyl, difluoromethyl, monofluoromethyl, methyl and cyano; R.sub.7 is selected from H, (C.sub.1-C.sub.6) alkyl and halogen; wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C.sub.1-C.sub.4)alkyl, —C(O)NR.sub.9R.sub.10, —NR.sub.9R.sub.10 and methanesulfonyl; R.sub.8 is selected from —OH, —OCH.sub.3, —NH.sub.2, —NHMe, —NMe.sub.2, —NHCOMe, —NHCOH or methanesulfonyl; R.sub.9 is H, methyl or ethyl; R.sub.10 is H or (C.sub.1-C.sub.6) alkyl, wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C.sub.1-C.sub.4)alkyl and methanesulfonyl; R.sub.11 is selected from —OCH.sub.3, —CH.sub.2CH.sub.3, —OH, —OCF.sub.3, —OCHF.sub.2, —OCH.sub.2F and H; R.sub.12 is H or (C.sub.1-C.sub.6) alkyl, wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C.sub.1-C.sub.4)alkyl, —C(O)NR.sub.9R.sub.10, —NR.sub.9R.sub.10 and methanesulfonyl; R.sub.13 is selected from halogen, methyl and ethyl; R.sub.14 is H or (C.sub.1-C.sub.6) alkyl, wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C.sub.1-C.sub.4)alkyl, —C(O)NR.sub.9R.sub.10, —NR.sub.9R.sub.10 and methanesulfonyl; R.sub.16 is selected from H, (C.sub.1-C.sub.6) alkyl and halogen; wherein the alkyl is optionally substituted by 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C.sub.1-C.sub.4)alkyl, —C(O)NR.sub.9R.sub.10, —NR.sub.9R.sub.10 and methanesulfonyl; and R.sub.17 is selected from —C(O)—NR.sub.9(R.sub.10), (C.sub.1-C.sub.6)alkyl, —C(O)(C.sub.1-C.sub.6)alkyl, and —C(O)O(C.sub.1-C.sub.6)alkyl; wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C.sub.1-C.sub.4)alkyl, —C(O)NR.sub.9R.sub.10, —NR.sub.9R.sub.10 and methanesulfonyl, and when present, R.sub.4 is selected from H, hydroxyl, —O—(C.sub.1-C.sub.6)alkyl, —CN, halogen, (C.sub.1-C.sub.6)alkyl, —C(O)OH, —CH.sub.2C(O)OH, —CH.sub.2C(O)NR.sub.9R.sub.10, or —C(O)O—(C.sub.1-C.sub.6)alkyl, wherein the alkyl is optionally substituted by 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C.sub.1-C.sub.4)alkyl or methanesulfonyl.

4. The compound according to claim 1, wherein R.sub.1 is selected from methyl, ethyl, isopropyl, cyclopropyl, isobutyl, cyclobutyl, cyclopentyl, ##STR00250## R.sub.2 is H or methyl; R.sub.3 is a 6-membered aromatic ring or aromatic heterocycle comprising 1 or 2 heteroatoms independently selected from N, S, and O, substituted with 1 to 3 substituents independently selected from H, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, —O—(C.sub.1-C.sub.6)alkyl, —S—(C.sub.1-C.sub.6)alkyl, —O—(C.sub.3-C.sub.6)cycloalkyl, halogen, —CF.sub.3, —CHF.sub.2, —OCHF.sub.2, —OCH.sub.2F, —OCH.sub.2CF.sub.3, —OCH.sub.2CHF.sub.2, —OCH.sub.2CH.sub.2F, hydroxyalkoxy, —CN, —C(O)NR.sub.9R.sub.10, —CH.sub.2NR.sub.9R.sub.10, —CH.sub.2NR.sub.9—C(O)R.sub.10, —CH.sub.2CN, —CH.sub.2C(O)NR.sub.9R.sub.10, —CH.sub.2C(O)OH, —C(O)OH, —CH.sub.2C(O)O—(C.sub.1-C.sub.4)alkyl, —N(R.sub.9)—C(O)—(C.sub.1-C.sub.4)alkyl, —NR.sub.9R.sub.10, —CH.sub.2NR.sub.9R.sub.10, —C(O)O—(C.sub.1-C.sub.4)alkyl, —CH.sub.2CN and tetrahydropyrrol-1-yl, wherein the alkyl or cycloalkyl is optionally substituted with 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C.sub.1-C.sub.4)alkyl, —C(O)NR.sub.9R.sub.10, —NR.sub.9R.sub.10 and methanesulfonyl; R.sub.5 is a 6-membered aromatic ring or aromatic heterocycle comprising 1 or 2 heteroatoms independently selected from N, S, and O, substituted with 1 to 3 substituents independently selected from H, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, —O—(C.sub.1-C.sub.6)alkyl, —S—(C.sub.1-C.sub.6)alkyl, —O—(C.sub.3-C.sub.6)cycloalkyl, halogen, —CF.sub.3, —CHF.sub.2, —CH.sub.2F, —OCF.sub.3, —OCHF.sub.2, —OCH.sub.2F, —OCH.sub.2CF.sub.3, —OCH.sub.2CHF.sub.2, —OCH.sub.2CH.sub.2F, hydroxyalkoxy, —CN, —C(O)NR.sub.9R.sub.10, —CH.sub.2NR.sub.9R.sub.10, —CH.sub.2NR.sub.9—C(O)R.sub.10, —CH.sub.2CN, —CH.sub.2C(O)NR.sub.9R.sub.10, —CH.sub.2C(O)OH, —C(O)OH, —CH.sub.2C(O)O—(C.sub.1-C.sub.4)alkyl, —N(R.sub.9)—C(O)—(C.sub.1-C.sub.4)alkyl, —NR.sub.9R.sub.10, —CH.sub.2NR.sub.9R.sub.10, —C(O)OCH.sub.3, —CH.sub.2CN and tetrahydropyrrol-1-yl, wherein the alkyl or cycloalkyl is optionally substituted with 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C.sub.1-C.sub.4)alkyl, —C(O)NR.sub.9R.sub.10, —NR.sub.9R.sub.10 and methanesulfonyl; R.sub.6 is chlorine or cyano; R.sub.7 is hydrogen; X.sub.1 is oxygen; X.sub.2, V and W are each carbon; and Y is nitrogen or carbon; wherein when Y is carbon, R.sub.4 is selected from H, hydroxyl, —O—(C.sub.1-C.sub.6)alkyl, —C(O)OH, —CH.sub.2C(O)OH, —CH.sub.2C(O)NR.sub.9R.sub.10 and —C(O)O—(C.sub.1-C.sub.6)alkyl, wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C.sub.1-C.sub.4) alkyl, —C(O)NR.sub.9R.sub.10, —NR.sub.9R.sub.10 and methanesulfonyl; wherein R.sub.9 is selected from H, methyl and ethyl; and R.sub.10 is H or (C.sub.1-C.sub.6)alkyl, wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C.sub.1-C.sub.4) alkyl and methanesulfonyl.

5. The compound according to claim 4, wherein R.sub.3 is a 6-membered aromatic ring or aromatic heterocycle comprising 1 or 2 heteroatoms independently selected from N, S, and O, substituted with 1 to 3 substituents independently selected from H, (C.sub.1-C.sub.6)alkyl, —O—(C.sub.1-C.sub.6)alkyl, halogen, —CF.sub.3, —CHF.sub.2, —CH.sub.2F, —OCF.sub.3, —OCHF.sub.2, —OCH.sub.2F, —CN, —C(O)NR.sub.9R.sub.10, —CH.sub.2NR.sub.9R.sub.10, —CH.sub.2NR.sub.9—C(O)R.sub.10, —CH.sub.2CN, —CH.sub.2C(O)NR.sub.9R.sub.10, —CH.sub.2C(O)OH, —C(O)OH, —CH.sub.2C(O)O—(C.sub.1-C.sub.4)alkyl, —N(R.sub.9)—C(O)—(C.sub.1-C.sub.4)alkyl, —NR.sub.9R.sub.10, —CH.sub.2NR.sub.9R.sub.10, —C(O)O—(C.sub.1-C.sub.4)alkyl and —CH.sub.2CN, wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C.sub.1-C.sub.4)alkyl, —C(O)NR.sub.9R.sub.10, —NR.sub.9R.sub.10 and methanesulfonyl; and R.sub.5 is a 6-membered aromatic ring or aromatic heterocycle comprising 1 or 2 heteroatoms independently selected from N, S, and O, substituted with 1 to 3 substituents independently selected from H, (C.sub.1-C.sub.6)alkyl, —O—(C.sub.1-C.sub.6)alkyl, halogen, —CF.sub.3, —CHF.sub.2, —CH.sub.2F, —OCF.sub.3, —OCHF.sub.2, —OCH.sub.2F, —CN, —C(O)NR.sub.9R.sub.10, —CH.sub.2NR.sub.9R.sub.10, —CH.sub.2NR.sub.9—C(O)R.sub.10, —CH.sub.2CN, —CH.sub.2C(O)NR.sub.9R.sub.10, —CH.sub.2C(O)OH, —C(O)OH, —CH.sub.2C(O)O—(C.sub.1-C.sub.4)alkyl, —N(R.sub.9)—C(O)—(C.sub.1-C.sub.4)alkyl, —NR.sub.9R.sub.10, —CH.sub.2NR.sub.9R.sub.10, —C(O)OCH.sub.3 and —CH.sub.2CN, wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C.sub.1-C.sub.4)alkyl, —C(O)NR.sub.9R.sub.10, —NR.sub.9R.sub.10 and methanesulfonyl.

6. The compound according to claim 5, wherein R.sub.3 is a 6-membered aromatic ring or aromatic heterocycle comprising 1 or 2 heteroatoms independently selected from N, S, and O, substituted with 1 to 3 substituents independently selected from H, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, methoxy, ethoxy, isopropoxy, —O-cyclopropyl, hydroxyethoxy, halogen, —CF.sub.3, —CHF.sub.2, —CH.sub.2F, —OCF.sub.3, —OCHF.sub.2, —OCH.sub.2F, —OCH.sub.2CF.sub.3, —OCH.sub.2CHF.sub.2, —OCH.sub.2CH.sub.2F, —CN, —C(O)NR.sub.9R.sub.10, —CH.sub.2NR.sub.9R.sub.10, —CH.sub.2NR.sub.9—C(O)R.sub.10, —CH.sub.2CN, —CH.sub.2C(O)NR.sub.9R.sub.10, —CH.sub.2C(O)OH, —C(O)OH, —CH.sub.2C(O)O—(C.sub.1-C.sub.4)alkyl, —N(R.sub.9)—C(O)—(C.sub.1-C.sub.4)alkyl, —NR.sub.9R.sub.10, —CH.sub.2NR.sub.9R.sub.10, —C(O)O—(C.sub.1-C.sub.4)alkyl and tetrahydropyrrol-1-yl; and R.sub.5 is a 6-membered aromatic ring or aromatic heterocycle comprising 1 or 2 heteroatoms independently selected from N, S, and O, substituted with 1 to 3 substituents independently selected from H, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, methoxy, ethoxy, isopropoxy, —O-cyclopropyl, hydroxyethoxy, halogen, —CF.sub.3, —CHF.sub.2, —CH.sub.2F, —OCF.sub.3, —OCHF.sub.2, —OCH.sub.2F, —OCH.sub.2CF.sub.3, —OCH.sub.2CHF.sub.2, —OCH.sub.2CH.sub.2F, —CN, —C(O)NR.sub.9R.sub.10, —CH.sub.2NR.sub.9R.sub.10, —CH.sub.2NR.sub.9—C(O)R.sub.10, —CH.sub.2CN, —CH.sub.2C(O)NR.sub.9R.sub.10, —CH.sub.2C(O)OH, —C(O)OH, —CH.sub.2C(O)O—(C.sub.1-C.sub.4)alkyl, —N(R.sub.9)—C(O)—(C.sub.1-C.sub.4)alkyl, —NR.sub.9R.sub.10, —CH.sub.2NR.sub.9R.sub.10, —C(O)OCH.sub.3 and tetrahydropyrrol-1-yl.

7. The compound according to claim 4, wherein Y is carbon or nitrogen; wherein when Y is nitrogen, R.sub.4 is absent; and wherein when Y is carbon, R.sub.4 is selected from H, hydroxyl, —O—(C.sub.1-C.sub.6)alkyl, —C(O)OH, —CH.sub.2C(O)OH, —CH.sub.2C(O)NR.sub.9R.sub.10 and —C(O)O—(C.sub.1-C.sub.6)alkyl, wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C.sub.1-C.sub.4)alkyl, —C(O)NR.sub.9R.sub.10, —NR.sub.9R.sub.10 and methanesulfonyl; R.sub.1 is selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl and cyclopentyl; R.sub.2 is H; R.sub.3 is a pyridine, pyridone, pyrimidine, pyrazine or pyridazine ring each substituted with 1 to 3 substituents independently selected from H, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, —S—(C.sub.1-C.sub.6)alkyl, —O—(C.sub.3-C.sub.6)cycloalkyl, halogen, —CF.sub.3, —CHF.sub.2, —CH.sub.2F, —OCF.sub.3, —OCHF.sub.2, —OCH.sub.2F, —OCH.sub.2CF.sub.3, —OCH.sub.2CHF.sub.2, —OCH.sub.2CH.sub.2F, hydroxyalkoxy, —CN, —C(O)NR.sub.9R.sub.10, —CH.sub.2NR.sub.9R.sub.10, —CH.sub.2NR.sub.9—C(O)R.sub.10, —C(O)OH, —CH.sub.2NR.sub.9R.sub.10, tetrahydropyrrol-1-yl and —NR.sub.9R.sub.10; wherein the alkyl or cycloalkyl is optionally substituted with 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C.sub.1-C.sub.4)alkyl, —C(O)NR.sub.9R.sub.10, —NR.sub.9R.sub.10 and methanesulfonyl; R.sub.5 is a pyridine, pyridone, pyrimidine, pyrazine or pyridazine ring each substituted with 1 to 3 substituents independently selected from H, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, —S—(C.sub.1-C.sub.6)alkyl, —O—(C.sub.3-C.sub.6)cycloalkyl, halogen, —CF.sub.3, —CHF.sub.2, —CH.sub.2F, —OCF.sub.3, —OCHF.sub.2, —OCH.sub.2F, —OCH.sub.2CF.sub.3, —OCH.sub.2CHF.sub.2, —OCH.sub.2CH.sub.2F, hydroxyalkoxy, —CN, —C(O)NR.sub.9R.sub.10, —CH.sub.2NR.sub.9R.sub.10, —CH.sub.2NR.sub.9—C(O)R.sub.10, —C(O)OH, —CH.sub.2NR.sub.9R.sub.10, tetrahydropyrrol-1-yl and —NR.sub.9R.sub.10; wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C.sub.1-C.sub.4)alkyl, —C(O)NR.sub.9R.sub.10, —NR.sub.9R.sub.10 and methanesulfonyl; R.sub.6 is chlorine; R.sub.7 is hydrogen; X.sub.1 is oxygen; and X.sub.2, V and W are each carbon; wherein R.sub.9 is selected from H, methyl and ethyl; and R.sub.10 is H or (C.sub.1-C.sub.6)alkyl, wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C.sub.1-C.sub.4)alkyl and methanesulfonyl.

8. The compound according to claim 7, wherein R.sub.3 is a pyridine, pyridone, pyrimidine, pyrazine or pyridazine ring each substituted with 1 to 3 substituents, the substituent independently selected from H, (C.sub.1-C.sub.6)alkyl, —S—(C.sub.1-C.sub.6)alkyl, halogen, —CF.sub.3, —CHF.sub.2, —CH.sub.2F, —OCF.sub.3, —OCHF.sub.2, —OCH.sub.2F, —CN, —C(O)NR.sub.9R.sub.10, —CH.sub.2NR.sub.9R.sub.10, —CH.sub.2NR.sub.9—C(O)R.sub.10, —C(O)OH, —CH.sub.2NR.sub.9R.sub.10 and —NR.sub.9R.sub.10; wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C.sub.1-C.sub.4)alkyl, —C(O)NR.sub.9R.sub.10, —NR.sub.9R.sub.10 and methanesulfonyl; R.sub.5 is a pyridine, pyridone, pyrimidine, pyrazine or pyridazine ring each substituted with 1 to 3 substituents independently selected from H, (C.sub.1-C.sub.6)alkyl, —O—(C.sub.1-C.sub.6)alkyl, —S—(C.sub.1-C.sub.6)alkyl, halogen, —CF.sub.3, —CHF.sub.2, —CH.sub.2F, —OCF.sub.3, —OCHF.sub.2, —OCH.sub.2F, —CN, —C(O)NR.sub.9R.sub.10, —CH.sub.2NR.sub.9R.sub.10, —CH.sub.2NR.sub.9—C(O)R.sub.10, —C(O)OH, —CH.sub.2NR.sub.9R.sub.10 and —NR.sub.9R.sub.10; wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C.sub.1-C.sub.4)alkyl, —C(O)NR.sub.9R.sub.10, —NR.sub.9R.sub.10, and methanesulfonyl; and R.sub.10 is selected from H, methyl, ethyl and 1-hydroxyethyl.

9. The compound according to claim 8, wherein R.sub.3 is a pyridine, pyridone, pyrimidine, pyrazine or pyridazine ring each substituted by 1 to 3 substituents independently selected from H, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, methoxy, ethoxy, isopropoxy, —O-cyclopropyl, hydroxyethoxy, halogen, —CF.sub.3, —CHF.sub.2, —CH.sub.2F, —OCF.sub.3, —OCHF.sub.2, —OCH.sub.2F, —OCH.sub.2CF.sub.3, —OCH.sub.2CHF.sub.2, —OCH.sub.2CH.sub.2F, —CN, —C(O)NR.sub.9R.sub.10, —CH.sub.2NR.sub.9R.sub.10, —CH.sub.2NR.sub.9—C(O)R.sub.10, —C(O)OH, —CH.sub.2NR.sub.9R.sub.10, tetrahydropyrrol-1-yl and —NR.sub.9R.sub.10; R.sub.5 is a pyridine, pyridone, pyrimidine, pyrazine or pyridazine ring each substituted with 1 to 3 substituents independently selected from H, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, methoxy, ethoxy, isopropoxy, —O-cyclopropyl, hydroxyethoxy, halogen, —CF.sub.3, —CHF.sub.2, —CH.sub.2F, —OCF.sub.3, —OCHF.sub.2, —OCH.sub.2F, —OCH.sub.2CF.sub.3, —OCH.sub.2CHF.sub.2, —OCH.sub.2CH.sub.2F, —CN, —C(O)NR.sub.9R.sub.10, —CH.sub.2NR.sub.9R.sub.10, —CH.sub.2NR.sub.9—C(O)R.sub.10, —C(O)OH, —CH.sub.2NR.sub.9R.sub.10, tetrahydropyrrol-1-yl and —NR.sub.9R.sub.10; and R.sub.10 is H, methyl or ethyl.

10. The compound according to claim 1, selected from: ##STR00251## ##STR00252## ##STR00253## ##STR00254## ##STR00255## ##STR00256## ##STR00257## ##STR00258## ##STR00259## ##STR00260## ##STR00261## ##STR00262## ##STR00263## ##STR00264## ##STR00265## ##STR00266## ##STR00267## ##STR00268## ##STR00269## ##STR00270## ##STR00271## ##STR00272## ##STR00273## ##STR00274## ##STR00275## ##STR00276## ##STR00277## ##STR00278## ##STR00279## ##STR00280## ##STR00281## ##STR00282## ##STR00283## ##STR00284## ##STR00285## ##STR00286## ##STR00287## ##STR00288## ##STR00289##

11. The compound according to claim 1, selected from: 6-chloro-5′-(3-chlorophenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione; 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,4-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione; 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4,6-dimethoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione; 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-(dimethylamino)-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione; 6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-isopropyl-2-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione; 6-chloro-5′-(5-chloro-2-fluorophenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione; 6-chloro-5′-(3-chloro-5-fluorophenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione; 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-isopropoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione; 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-ethoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione; 6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(6-ethoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione; 6-chloro-5′-(5-chloro-2-fluorophenyl)-2′-(6-ethoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione; 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-cyclopropyl-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione; 6-chloro-5′-(3-chlorophenyl)-2′-(4,6-dimethoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione; 6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(4,6-dimethoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione; 6-chloro-5′-(5-chloro-2-fluorophenyl)-2′-(4,6-dimethoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione; 6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(2-ethoxy-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione; 6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(2-(dimethylamino)-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione; 6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(6-isopropoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′ (5′ H)-dione; 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-(2-fluoroethoxy)-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′ (5′H)-dione; and 6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(2-cyclopropyl-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′ (5′H)-dione.

12. The compound according to claim 1, wherein the compound is in the S configuration.

13. A method of synthesizing a compound according to claim 1, wherein Y is N, the method comprising: ##STR00290## ##STR00291## (1) subjecting compound 1 and compound 2 to a substitution and rearrangement reaction to synthesize compound 3; (2) subjecting compound 3 and compound 4 to a cyclization reaction to construct an imidazole ring to obtain compound 5; (3) brominating compound 5 with N-bromosuccinimide to obtain compound 6; (4) subjecting compound 6 and compound 7 to low-temperature lithiation with lithium diisopropylamide to obtain compound 8; (5) subjecting compound 8 and compound 9 to an ammonolysis reaction to obtain compound 10; (6) subjecting compound 10 to an acidification and dehydration reaction to obtain compound 11; and (7) subjecting compound 11 and an aryl or heteroaryl borate or boronic acid to a Suzuki coupling reaction to obtain a compound according to claim 1, wherein Y is N.

14. A method of synthesizing a compound according to claim 1, wherein Y is C, the method comprising: ##STR00292## ##STR00293## (1) subjecting compound 1 and compound 2 to a substitution reaction to synthesize compound 3; (2) brominating compound 3 with N-bromosuccinimide to obtain compound 4; (3) subjecting compound 4 and compound 5 to low-temperature lithiation with lithium diisopropylamide to obtain compound 6; (4) subjecting compound 6 and compound 7 to an ammonolysis reaction to obtain compound 8; (5) subjecting compound 8 to an acidification and dehydration reaction to obtain compound 9; and (6) subjecting compound 9 and an aryl or heteroaryl boronic acid to a Suzuki coupling reaction to obtain a compound according to claim 1, wherein Y is C.

15. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable excipient.

16. The pharmaceutical composition of claim 15, further comprising one or more therapeutically active agents.

17. The pharmaceutical composition of claim 16, wherein the therapeutically active agent is an anti-proliferative agent.

18. A method for inducing apoptosis in tumor cells in a subject in need of treatment thereof, the method comprising administering to such subject an effective amount of an MDM2 inhibitor selected from a compound according to claim 1.

19. A method for inhibiting tumor cell growth in a subject in need of treatment thereof, the method comprising administering to such subject an effective amount of an MDM2 inhibitor selected from a compound according to claim 1.

Description

SPECIFIC MODES FOR CARRYING OUT THE EMBODIMENTS

(1) The following Examples are used to illustrate the present invention, but not to limit the scope of the present invention.

(2) All raw materials used in the present invention are known commercial products.

(3) In the present invention, “Mdm2” refers to a protein encoded by the murine double minute 2 gene. “Mdm2” includes Mdm2 protein encoded by the full-length Mdm2 gene, Mdm2 protein encoded by mutated Mdm2 gene (including deletion mutants, substitution mutants, and addition mutants) and the like. In the present invention, “Mdm2” also includes homologs derived from different animal species, such as human Mdm2 homolog (HDM2).

(4) The abbreviations and their meanings in the Examples of the present invention are as follows:

(5) NBS: N-bromosuccinimide

(6) EA: ethyl acetate

(7) PE: petroleum ether

(8) THF: tetrahydrofuran

(9) LDA: lithium diisopropylamide

(10) Pd(PPh.sub.3).sub.4: tetrakis(triphenylphosphine)palladium

Example 1

6-chloro-5′-(3-chlorophenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(11) ##STR00050##

Step 1: Preparation of Ethyl (E)-2-cyano-3-(dimethylamino)acrylate

(12) ##STR00051##

(13) Under nitrogen atmosphere, ethyl isocyanoacetate (500.0 g, 4.425 mol) and 1000 mL of ethanol were added to a 2000 mL three-necked flask, and cooled to −5° C., 1,1-diethoxy-N,N-dimethylmethanamine (845.6 g, 5.752 mol) was added dropwise. During the dropwise addition, the reaction solution was maintained at about 0° C., and then naturally raised to room temperature, stirred overnight, and concentrated under vacuum. The crude product was dissolved in 5 L of tert-butyl methyl ether, and the resultant mixture was added with 1 Kg of silica gel, stirred for 30 min and filtered. The filtrate was washed with 500 mL of tert-butyl methyl ether for 5 times, and concentrated under vacuum to obtain 678.2 g of ethyl (R)-2-cyano-3-(dimethylamino)acrylate (yield 91.25%, yellow oil). MS (ESI): mass calcd. For C.sub.8H.sub.12N.sub.2O.sub.2 168.2, m/z found 169.3 [M+H].sup.+.

Step 2: Preparation of Ethyl 1-isopropyl-1H-imidazole-4-carboxylate

(14) ##STR00052##

(15) Under nitrogen atmosphere, ethyl (E)-2-cyano-3-(dimethylamino)acrylate (120.0 g, 0.714 mol), 100 mL of N-butanol and propyl-2-amine (126.4 g, 2.14 mol) were added to a 500 ml three-necked flask. The mixture was heated to 70° C. for overnight reaction and concentrated under vacuum. The resultant mixture was added with 1000 mL of ethyl acetate, and washed with 500 mL of saturated sodium chloride aqueous solution for three times. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 119.3 g of ethyl 1-isopropyl-1H-imidazole-4-carboxylate (yield 91.76%, brown oil). MS (ESI): mass calcd. For C.sub.9H.sub.14N.sub.2O.sub.2 182.2, m/z found 183.4 [M+H].sup.+.

Step 3: Preparation of Ethyl 2-bromo-1-isopropyl-1H-imidazole-4-carboxylate

(16) ##STR00053##

(17) Under nitrogen atmosphere, ethyl 1-isopropyl-1H-imidazole-4-carboxylate (60.0 g, 0.328 mol) and 500 mL of tetrahydrofuran were added to a 1000 mL three-necked flask, and cooled to 0° C., and NBS (87.0 g, 0.492 mol) was added in batches. The resultant was naturally raised to room temperature for overnight reaction, concentrated under vacuum, added with 500 mL of ethyl acetate, washed with 500 mL of saturated sodium carbonate aqueous solution for three times, then washed once with 45 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and separated by column chromatography (EA:PE=1:10 to 1:2) to obtain 21.2 g of ethyl 2-bromo-1-isopropyl-H-imidazole-4-carboxylate (yield 24.7%, yellow oil). MS (ESI): mass calcd. for C.sub.9H.sub.13BrN.sub.2O.sub.2 260.0, m/z found 261.5 [M+H].sup.+.

Step 4: Preparation of Ethyl 2-bromo-5-(6-chloro-3-hydroxy-2-oxoindolin 3-yl)-1-isopropyl-1H-imidazole-4-carboxylate

(18) ##STR00054##

(19) Under nitrogen atmosphere, ethyl 2-bromo-1-isopropyl-1H-imidazole-4-carboxylate (5.0 g, 19.15 mmol) and 10 mL of anhydrous THF were added to a 50 mL three-necked flask, and cooled to −78° C. LDA (40 ml, 2 M) was slowly added dropwise, and the resultant mixture was maintained at −78° C. to react for 1.5 h. Then an anhydrous tetrahydrofuran solution (100 ml) of 6-chlorodihydroindole-2,3-dione (3.46 g, 19.15 mmol) was slowly added dropwise. After the dropwise addition was completed, the mixture was maintained at −78° C. to react for 2 h, followed by quenching with 100 ml of saturated ammonium chloride aqueous solution, and extraction with 200 mL of ethyl acetate for three times. The organic layers were combined, washed once with 45 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and separated by column chromatography (EA:PE=1:10 to 1:2) to obtain 1.4 g of ethyl 2-bromo-5-(6-chloro-3-hydroxy-2-oxoindolin 3-yl)-1-isopropyl-1H-imidazole-4-carboxylate (yield 17.0%, yellow solid) as a yellow solid. MS (ESI): mass calcd. For C.sub.17H.sub.17BrClN.sub.3O.sub.4 441.0, m/z found 442.0 [M+H].sup.+.

Step 5: Preparation of 2-bromo-5-(6-chloro-3-hydroxy-2-oxoindolin-3-yl)-N-(3-chlorobenzene)-1-isopropyl-1H-imidazole-4-amide

(20) ##STR00055##

(21) Under nitrogen atmosphere, 3-chloroaniline (503.3 mg, 2.94 mmol) and 5 mL of anhydrous toluene were added to a 25 mL three-necked flask, and cooled to 0° C. AlMe.sub.3 (1.2 ml, 25% w/w) was slowly added dropwise to the reaction solution, then 5 mL of anhydrous toluene solution of ethyl 2-bromo-5-(6-chloro-3-hydroxy-2-oxoindolin-3-yl)-1-isopropyl-1H-imidazole-4-carboxylate (600 mg, 1.36 mmol) was slowly added dropwise into the reaction solution. The resultant mixture was raised to 90° C. for overnight reaction, then naturally lowered to room temperature, and added with 50 mL of ice water and 15 mL of saturated aqueous solution of sodium potassium tartrate, extracted with 100 mL of dichloromethane for two times. The organic layers were combined, washed once with 50 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and separated by column chromatography to obtain 401.2 mg of 2-bromo-5-(6-chloro-3-hydroxy-2-oxoindolin-3-yl)-N-(3-chlorobenzene)-1-isopropyl-1H-imidazole-4-amide (yield 56.47%, yellow solid). MS (ESI): mass calcd. For C.sub.21H.sub.17BrCl.sub.2N.sub.4O.sub.3 522.0, m/z found 523.4 [M+H].sup.+.

Step 6: Preparation of 2′-bromo-6-chloro-5′-(3-chlorophenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(22) ##STR00056##

(23) 2-bromo-5-(6-chloro-3-hydroxy-2-oxoindolin-3-yl)-N-(3-chlorobenzene)-1-isopropyl-1H-imidazole-4-amide (400.0 mg, 0.766 mmol) and acetic acid (5 mL) were added to a 25 mL three-necked flask, concentrated sulfuric acid (0.75 g, 7.66 mmol) was added in batches, and the temperature was raised to 110° C. for reaction overnight, then the temperature was naturally lowered to room temperature, and 20 mL of ice water was added. The pH value was adjusted to 7.0 with saturated sodium carbonate aqueous solution, followed by extraction with 200 mL of dichloromethane for two times. The organic layers were combined, washed once with 50 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated under vacuum and separated by column chromatography (EA:PE=1:5 to 1:1) to obtain 130.2 mg of 2′-bromo-6-chloro-5′-(3-chlorophenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (33.67% yield, yellow solid). MS (ESI): mass calcd. For C.sub.21H.sub.15BrCl.sub.2N.sub.4O.sub.2 504.0, m/z found 505.3 [M+H].sup.+.

Step 7: Preparation of 6-chloro-5′-(3-chlorophenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(24) ##STR00057##

(25) Under nitrogen atmosphere, 2′-bromo-6-chloro-5′-(3-chlorophenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (90.0 mg, 0.178 mmol), (2,4-dimethoxypyrimidin-5-yl)boronic acid (33.0 mg, 0.178 mmol), Pd(PPh.sub.3).sub.4 (20.7 mg, 0.0178 mmol), anhydrous Na.sub.2CO.sub.3 (57.0 mg, 0.535 mmol), 1,4-dioxane (4 mL) and water (1 ml) were added into a microwave reaction flask, and then the temperature was raised to 100° C. to perform a microwave reaction for 1 h. The reaction solution was cooled to room temperature and filtered, and 10 mL of water was added, followed by extraction with 10 mL of dichloromethane for three times. The organic layers were combined, washed once with 10 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, separated by column chromatography, and supercritical high-pressure preparative chromatography to obtain 7.8 mg of (S)-6-chloro-5′-(3-chlorophenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-1); and 8.8 mg of (R)-6-chloro-5′-(3-chlorophenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-1). MS (ESI): mass calcd. for C.sub.27H.sub.22Cl.sub.2N.sub.6O.sub.4 564.1, m/z found 565.3 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.54 (brs, 1H), 8.51 (s, 1H), 7.48 (d, 1H, J=8.0 Hz), 7.38-7.32 (m, 2H), 7.15-7.12 (m, 2H), 7.01-6.97 (m, 1H), 6.96-6.95 (m, 1H), 4.19-4.12 (m, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 1.12 (d, 3H, J=6.8 Hz), 0.64 (d, 3H, J=6.8 Hz).

Example 2

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(26) ##STR00058##

(27) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 23.1 mg of(S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-2); and 24.0 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-2).

(28) MS (ESI): mass calcd. for C.sub.28H.sub.24Cl.sub.2N.sub.6O.sub.4 578.1, m/z found 579.1[M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.62 (brs, 1H), 8.53 (m, 1H), 7.51-7.41 (m, 4H), 6.98-6.89 (m, 2H), 4.16-4.13 (m, 1H), 3.99 (s, 3H), 3.95 (s, 3H), 2.22 (s, 3H), 1.10 (d, 3H, J=4.8 Hz), 0.67 (d, 3H, J=4.8 Hz).

Example 3

6-chloro-5′-(3-chloro-4-fluorophenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(29) ##STR00059##

(30) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 24.1 mg of (S)-6-chloro-5′-(3-chloro-4-fluorophenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-3), and 35.8 mg of (R)-6-chloro-5′-(3-chloro-4-fluorophenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-3). MS (ESI): mass calcd. for C.sub.27H.sub.21Cl.sub.2FN.sub.6O.sub.4 582.1, m/z found 583.3 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.55 (brs, 1H), 8.51 (s, 1H), 7.51 (d, 1H, J=8.0 Hz), 7.43-7.39 (m, 1H), 7.27 (dd, 1H, J=9.2 Hz, J.sup.2=2.4 Hz), 7.16-7.03 (m, 1H), 7.02-6.99 (m, 1H), 4.19-4.12 (m, 1H), 3.99 (s, 3H), 3.95 (s, 3H), 1.12 (d, 3H, J=6.8 Hz), 0.65 (d, 3H, J=6.8 Hz).

Example 4

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-fluoro-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(31) ##STR00060##

(32) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 20.5 mg of(S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-fluoro-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-4); and 22.3 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-fluoro-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-4). MS (ESI): mass calcd. for C.sub.29H.sub.23Cl.sub.2FN.sub.4O.sub.3 564.1, m/z found 565.3 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.47 (brs, 1H), 7.55-7.49 (m, 2H), 7.48-7.00 (m, 5H), 6.96-6.93 (m, 2H), 4.06-4.02 (m, 1H), 3.81 (s, 3H), 2.32 (s, 3H), 1.06 (d, 3H, J=5.2 Hz), 0.63 (d, 3H, J=5.2 Hz).

Example 5

6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(33) ##STR00061##

(34) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 15.0 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-5); and 13.3 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-5). MS (ESI): mass calcd. for C.sub.29H.sub.24Cl.sub.2N.sub.4O.sub.3 546.1, m/z found 547.3 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.52 (brs, 1H), 7.57-7.42 (m, 3H), 7.33-7.08 (m, 6H), 7.06-7.00 (m, 1H), 4.08-4.04 (m, 1H), 3.79 (s, 3H), 2.22 (s, 3H), 1.14 (d, 3H, J=5.2 Hz), 0.64 (d, 3H, J=5.2 Hz).

Example 6

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(5-fluoro-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(35) ##STR00062##

(36) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 17.0 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(5-fluoro-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-6); and 18.5 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(5-fluoro-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-6). MS (ESI): mass calcd. for C.sub.29H.sub.23Cl.sub.2FN.sub.4O.sub.3 564.1, m/z found 565.4 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.61 (brs, 1H), 7.54-7.00 (m, 8H), 6.97-6.96 (m, 1H), 4.07-4.04 (m, 1H), 3.78 (s, 3H), 2.49 (s, 3H), 1.08 (d, 3H, J=6.4 Hz), 0.65 (d, 3H, J=6.4 Hz).

Example 7

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-ethylphenyl)-3′-isopropylisopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(37) ##STR00063##

(38) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 26.3 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-ethylphenyl)-3′-isopropylisopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-7), and 21.5 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-ethylphenyl)-3′-isopropylisopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-7). MS (ESI): mass calcd. for C.sub.30H.sub.26Cl.sub.2N.sub.4O.sub.2 544.1, m/z found 545.2 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.70 (brs, 1H), 7.60-6.95 (m, 10H), 6.97-6.96 (m, 1H), 4.07-4.04 (m, 1H), 2.45 (s, 3H), 1.11-1.07 (m, 8H), 0.67 (d, 3H, J=4.8 Hz).

Example 8

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,6-dimethoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(39) ##STR00064##

(40) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 22.5 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,6-dimethoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-8), and 31.2 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,6-dimethoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-8). MS (ESI): mass calcd. for C.sub.29H.sub.25Cl.sub.2N.sub.5O.sub.4 577.13, m/z found 578.2[M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 7.82-7.80 (m, 1H), 7.79-7.04 (m, 6H), 6.56 (d, 2H, J=8.0 Hz), 4.13-4.10 (m, 1H), 3.94 (s, 3H), 3.91 (s, 3H), 2.21 (s, 3H), 1.08 (d, 3H, J=6.4 Hz), 0.66 (d, 3H, J=6.4 Hz).

Example 9

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,4-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(41) ##STR00065##

(42) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 19.5 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,4-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-9), and 18.3 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,4-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-9). MS (ESI): mass calcd. for C.sub.30H.sub.26Cl.sub.2N.sub.4O.sub.4 576.1 m/z found 577.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.58 (brs, 1H), 7.55-6.67 (m, 9H), 4.08-4.04 (m, 1H), 3.84 (s, 3H), 3.78 (s, 3H), 2.20 (s, 3H), 1.06 (d, 3H, J=4.0 Hz). 0.62 (d, 3H, J=4.0 Hz).

Example 10

6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(3-methoxypyridin-4-yl)-3′H-spiro[dihydroindole-34′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(43) ##STR00066##

(44) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 25.8 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(3-methoxypyridin-4-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-10), and 28.0 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(3-methoxypyridin-4-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-10). MS (ESI): mass calcd. for C.sub.28H.sub.23Cl.sub.2N.sub.5O.sub.3 547.1, m/z found 548.4 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.79 (brs, 1H), 8.61 (s, 1H), 8.40 (d, 1H, J=4.8 Hz), 7.62-7.45 (m, 2H), 7.33-6.98 (m, 5H), 4.11-4.10 (m, 1H), 4.08 (s, 3H), 2.22 (s, 3H), 1.10 (d, 3H, J=6.8 Hz), 0.66 (d, 3H, J=6.8 Hz).

Example 11

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4,6-dimethoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(45) ##STR00067##

(46) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 18.6 mg of(S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4,6-dimethoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-11), and 17.2 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4,6-dimethoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-11). MS (ESI): mass calcd. for C.sub.29H.sub.25Cl.sub.2N.sub.5O.sub.4 577.1, m/z found 578.2 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.61 (brs, 1H), 8.13 (d, 1H, J=4.8 Hz), 7.55 (d, 1H, J=8.4 Hz), 7.43-7.22 (m, 3H), 7.16-6.96 (m, 2H), 6.59 (d, 1H, J=1.6 Hz), 4.10-4.04 (m, 1H), 3.92 (s, 3H), 3.84 (s, 3H), 2.22 (s, 3H), 1.08 (d, 3H, J=6.4 Hz), 0.69 (d, 3H, J=6.4 Hz).

Example 12

4-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-3-methoxybenzonitrile

(47) ##STR00068##

(48) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 27.1 mg of (S)-4-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-3-methoxybenzonitrile (S-12), and 23.5 mg of (R)-4-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-3-methoxybenzonitrile (R-12). MS (ESI): mass calcd. for C.sub.27H.sub.22Cl.sub.2N.sub.6O.sub.4 564.1, m/z found 565.3[M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 7.73 (s, 1H), 7.68-7.62 (m, 1H), 7.60-7.46 (m, 2H), 7.16-7.09 (m, 2H), 7.01-6.97 (m, 2H), 4.06-4.03 (m, 1H), 3.87 (s, 3H), 2.22 (s, 3H), 1.07 (d, 3H, J=6.4 Hz), 0.64 (d, 3H, J=6.4 Hz).

Example 13

3-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-4-methoxybenzonitrile

(49) ##STR00069##

(50) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 10.1 mg of (S)-3-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-4-methoxybenzonitrile (S-13), and 13.7 mg of (R)-3-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-4-methoxybenzonitrile (R-13). MS (ESI): mass calcd. for C.sub.30H.sub.23Cl.sub.2N.sub.5O.sub.3 571.1, m/z found 572.4 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 8.06-8.04 (m, 2H), 7.97-6.97 (m, 7H), 4.05-4.02 (m, 1H), 3.89 (s, 3H), 2.22 (s, 3H), 1.08 (d, 3H, J=6.4 Hz), 0.65 (d, 3H, J=6.4 Hz).

Example 14

6-chloro-5′-(3-chloro-2-fluorophenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(51) ##STR00070##

(52) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 54.9 mg of (S)-6-chloro-5′-(3-chloro-2-fluorophenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-14), and 50.8 mg of (R)-6-chloro-5′-(3-chloro-2-fluorophenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-14). MS (ESI): mass calcd. for C.sub.27H.sub.21Cl.sub.2FN.sub.6O.sub.4 582.1, m/z found 583.5 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.52 (brs, 1H), 8.54 (s, 1H), 7.59 (t, 1H, J=6.8 Hz), 7.34 (d, 1H, J=7.6 Hz), 7.23-7.14 (m, 2H), 7.03-6.98 (m, 2H), 4.20-4.13 (m, 1H), 3.99 (s, 3H), 3.95 (s, 3H), 1.12 (d, 3H, J=6.8 Hz), 0.66 (d, 3H, J=6.8 Hz).

Example 15

6-chloro-5′-(5-chloro-2-ethylphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(53) ##STR00071##

(54) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 17.5 mg of (S)-6-chloro-5′-(5-chloro-2-ethylphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-15), and 54.6 mg of (R)-6-chloro-5′-(5-chloro-2-ethylphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-15). MS (ESI): mass calcd. for C.sub.29H.sub.26Cl.sub.2N.sub.6O.sub.4 592.1, m/z found 593.2 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.38 (brs, 1H), 8.53 (d, 1H, J=6.8 Hz), 7.58-7.09 (m, 5H), 7.07-6.95 (m, 1H), 4.17-4.14 (m, 1H), 3.99 (s, 3H), 3.95 (s, 3H), 2.57-2.48 (m, 2H), 1.14-1.02 (m, 6H), 0.67 (d, 3H, J=6.0 Hz).

Example 16

6-chloro-5′-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(55) ##STR00072##

(56) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 6.3 mg of (S)-6-chloro-5′-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-16), and 8.1 mg of (R)-6-chloro-5′-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-16). MS (ESI): mass calcd. for C.sub.26H.sub.21Cl.sub.2N.sub.7O.sub.5 581.1, m/z found 582.1[M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.30 (brs, 1H), 8.51 (s, 1H), 7.97 (d, 1H, J=2.4 Hz), 7.31 (d, 1H, J=2.4), 7.21 (d, 1H, J=8.0), 7.04 (d, 1H, J=8.0), 6.99 (s, 1H), 4.13-4.08 (m, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 1.35 (s, 3H), 1.11 (d, 3H, J=6.8 Hz), 0.62 (d, 3H, J=8.0).

Example 17

6-chloro-5′-(5-chloro-2-methoxyphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(57) ##STR00073##

(58) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 15.1 mg of (S)-6-chloro-5′-(5-chloro-2-methoxyphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-17), and 14.6 mg of (R)-6-chloro-5′-(5-chloro-2-methoxyphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-17). MS (ESI): mass calcd. for C.sub.28H.sub.24Cl.sub.2N.sub.6O.sub.5 594.1, m/z found 595.2[M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 8.49 (s, 1H), 7.30-7.28 (m, 1H), 7.10 (s, 1H), 7.43-7.22 (m, 3H), 7.98-6.96 (m, 2H), 6.75-6.74 (m, 2H), 4.08-4.03 (m, 1H), 3.98 (s, 3H), 3.94 (s, 3H), 3.63 (s, 3H), 1.12 (d, 3H, J=6.4 Hz), 0.65 (d, 3H, J=6.4 Hz).

Example 18

6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-methoxypyridin-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(59) ##STR00074##

(60) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 23.7 mg of(S)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-methoxypyridin-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-18), and 30.9 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-methoxypyridin-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-18). MS (ESI): mass calcd. for C.sub.28H.sub.23Cl.sub.2N.sub.5O.sub.3 547.1, m/z found 548.3 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 8.64 (d, 1H, J=5.6 Hz), 8.50 (d, 1H, J=6.0 Hz), 7.56-6.94 (m, 7H), 4.07-4.04 (m, 1H), 3.89 (s, 3H), 2.20 (s, 3H), 1.09 (d, 3H, J=7.2 Hz), 0.66 (d, 3H, J=7.2 Hz).

Example 19

6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-isopropyl-5-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(61) ##STR00075##

(62) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 24.3 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-isopropyl-5-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-19), and 24.6 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-isopropyl-5-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-19). MS (ESI): mass calcd. for C.sub.32H.sub.30Cl.sub.2N.sub.4O.sub.3 588.2, m/z found 589.2 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ, 7.59-6.89 (m, 9H), 4.06-4.03 (m, 1H), 3.83 (s, 3H), 2.63-2.59 (m, 1H), 2.22 (s, 3H), 1.23-1.15 (m, 6H), 0.83 (d, 3H, J=6.8 Hz), 0.65 (d.3H, J=6.8 Hz).

Example 20

6-chloro-5′-(3-chloro-4-methylphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(63) ##STR00076##

(64) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 24.0 mg of(S)-6-chloro-5′-(3-chloro-4-methylphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-20), and 27.9 mg of (R)-6-chloro-5′-(3-chloro-4-methylphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-20). MS (ESI): mass calcd. for C.sub.28H.sub.24Cl.sub.2N.sub.6O.sub.4 578.1, m/z found 579.4 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 8.51 (s, 1H), 7.96 (brs, 1H), 7.94 (d, 1H, J=4.8 Hz), 7.47 (d, 1H, J=8.0 Hz), 7.30 (d, 1H, J=8.0 Hz), 7.15 (dd, 1H, J.sup.1=8.0 Hz, J.sup.2=1.6 Hz), 7.08-7.01 (m, 1H), 6.87 (d, 1H, J=8.0 Hz), 4.18-4.13 (m, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 2.26 (s, 3H), 1.11 (d, 3H, J=6.8 Hz), 0.65 (d, 3H, J=6.8 Hz).

Example 21

3-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-4-methoxy-N-methylbenzamide

(65) ##STR00077##

(66) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 26.4 mg of (S)-3-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-4-methoxy-N-methylbenzamide (S-21), and 30.3 mg of (R)-3-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-4-methoxy-N-methylbenzamide (R-21). MS (ESI): mass calcd. for C.sub.31H.sub.27Cl.sub.2N.sub.5O.sub.4, 603.1 m/z found 604.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 8.46 (d, 1H, J=4.0 Hz), 8.08-8.06 (m, 1H), 7.96 (s, 1H), 7.55-6.99 (m, 6H), 4.08-4.04 (m, 1H), 3.86 (s, 3H), 2.77 (d, 3H, J=4.0 Hz), 2.23 (s, 3H), 1.07 (d, 3H, J=6.0 Hz), 0.65 (d, 3H, J=6.0 Hz).

Example 22

3-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-4-methoxy-N,N-dimethylbenzamide

(67) ##STR00078##

(68) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 26.9 mg of (S)-3-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-4-methoxy-N,N-dimethylbenzamide (S-22), and 29.5 mg of (R)-3-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-4-methoxy-N,N-dimethylbenzamide (R-22). MS (ESI): mass calcd. for C.sub.31H.sub.27Cl.sub.2N.sub.5O.sub.4, 617.1 m/z found 618.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 7.66-6.97 (m, 9H), 4.09-4.06 (m, 1H), 3.85 (s, 3H), 2.98 (s, 6H), 2.22 (s, 3H), 1.08 (s, 3H), 0.65 (s, 3H).

Example 23

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-(dimethylamino)-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(69) ##STR00079##

(70) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 23.2 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-(dimethylamino)-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-23), and 22.3 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-(dimethylamino)-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-23). MS (ESI): mass calcd. for C.sub.31H.sub.29Cl.sub.2N.sub.5O.sub.3 589.2, m/z found 590.2 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.50 (brs, 1H), 7.51-6.38 (m, 9H), 4.12-4.09 (m, 1H), 3.77 (s, 3H), 3.00 (s, 6H), 2.22 (s, 3H), 1.06 (d, 3H, J=6.8 Hz), 0.62 (d, 3H, J=6.8 Hz).

Example 24

6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-methoxy-4-methylphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(71) ##STR00080##

(72) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 36.0 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-methoxy-4-methylphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-24), and 26.2 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-methoxy-4-methylphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-24). MS (ESI): mass calcd. for C.sub.30H.sub.26Cl.sub.2N.sub.4O.sub.3 560.1, m/z found 561.1[M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 7.54-6.91 (m, 9H), 4.08-4.04 (m, 1H), 3.77 (s, 3H), 2.39 (s, 3H), 2.22 (s, 3H), 1.06 (d, 3H, J=6.0 Hz), 0.63 (d, 3H, J=6.0 Hz).

Example 25

6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-methoxy-4-(methylamine)phenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(73) ##STR00081##

(74) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 9.0 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-methoxy-4-(methylamine)phenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-25), and 11.6 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-methoxy-4-(methylamine)phenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-25). MS (ESI): mass calcd. for C.sub.30H.sub.27Cl.sub.2N.sub.5O.sub.3 575.2, m/z found 576.2 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.69 (brs, 1H), 7.55-6.22 (m, 9H), 4.13-4.09 (m, 1H), 3.72 (s, 3H), 2.74 (s, 3H), 2.22 (s, 3H) 1.05 (d, 3H, J=5.2 Hz), 0.60 (d, 3H, J=5.2 Hz).

Example 26

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-ethyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(75) ##STR00082##

(76) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 26.2 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-ethyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-26), and 28.3 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-ethyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-26). MS (ESI): mass calcd. for C.sub.27H.sub.22Cl.sub.2N.sub.6O.sub.4 564.1, m/z found 565.1[M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 8.54 (d, 1H, J=6.0 Hz), 7.64-6.95 (m, 6H), 3.99 (s, 3H), 3.95 (s, 3H), 3.58-3.50 (m, 1H), 2.25 (s, 3H), 1.17 (d, 3H, J=6.0 Hz), 0.85 (d, 3H, J=6.0 Hz).

Example 27

6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-methoxypyrimidin-5-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(77) ##STR00083##

(78) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 2.2 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-methoxypyrimidin-5-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-27), and 3.6 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-methoxypyrimidin-5-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-27). MS (ESI): mass calcd. for C.sub.27H.sub.22Cl.sub.2N.sub.6O.sub.3 548.1, m/z found 549.4 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.19 (brs, 1H), 8.99 (s, 1H), 8.76 (d, 1H, J=7.2 Hz), 7.57-6.98 (m, 6H), 4.19-4.12 (m, 1H), 4.00 (s, 3H), 2.22 (s, 3H), 1.11 (d, 3H, J=6.8 Hz), 0.68 (d, 3H, J=6.8 Hz).

Example 28

6-chloro-5′-(5-chloro-2-methylphenyl)-3′-cyclopropane-2′-(2,4-dimethoxypyrimidin-5-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(79) ##STR00084##

(80) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 10.2 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-cyclopropane-2′-(2,4-dimethoxypyrimidin-5-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-28), and 11.0 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-cyclopropane-2′-(2,4-dimethoxypyrimidin-5-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-28). MS (ESI): mass calcd. for C.sub.28H.sub.22Cl.sub.2N.sub.6O.sub.4 576.1, m/z found 577.1[M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.58 (brs, 1H), 8.55 (d, 1H, J=4.0 Hz), 7.56-6.97 (m, 6H), 3.99 (s, 3H), 3.96 (s, 3H), 3.01-3.00 (m, 1H), 2.23 (s, 3H), 0.85-0.47 (m, 4H).

Example 29

3-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-4-methoxybenzamide

(81) ##STR00085##

(82) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 6.1 mg of (S)-3-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-4-methoxybenzamide (S-29), and 6.6 mg of (R)-3-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-4-methoxybenzamide (R-29). MS (ESI): mass calcd. for C.sub.30H.sub.25Cl.sub.2N.sub.5O.sub.4 589.1, m/z found 590.4 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 8.08 (d, 1H, J=6.8 Hz), 7.98 (brs, 2H), 7.37-6.52 (m, 8H), 4.02-3.96 (m, 1H), 3.84 (s, 3H), 2.26 (s, 3H), 1.10 (d, 3H, J=7.2 Hz), 0.66 (d, 3H, J=7.2 Hz).

Example 30

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-(difluoromethoxy)phenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(83) ##STR00086##

(84) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 36.0 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-(difluoromethoxy)phenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-30), and 36.8 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-(difluoromethoxy)phenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-30). MS (ESI): mass calcd. for C.sub.29H.sub.22Cl.sub.2F.sub.2N.sub.4O.sub.3 582.1, m/z found 583.4 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.55 (brs, 1H), 7.69-6.96 (m, 10H), 4.08-4.07 (m, 1H), 2.22 (s, 3H), 1.08 (d, 3H, J=6.0 Hz), 0.67 (d, 3H, J=6.4 Hz).

Example 31

6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-(trifluoromethoxy)phenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(85) ##STR00087##

(86) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 19.9 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-(trifluoromethoxy)phenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-31), and 18.9 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-(trifluoromethoxy)phenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-31). MS (ESI): mass calcd. for C.sub.29H.sub.21Cl.sub.2F.sub.3N.sub.4O.sub.3 600.1, m/z found 601.4 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.54 (brs, 1H), 7.77-6.96 (m, 10H), 4.10-4.03 (m, 1H), 2.22 (s, 3H), 1.09 (d, 3H, J=7.2 Hz), 0.70 (d, 3H, J=6.4 Hz).

Example 32

6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-isopropyl-2-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(87) ##STR00088##

(88) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 27.7 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-isopropyl-2-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-32), and 33.9 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-isopropyl-2-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-32). MS (ESI): mass calcd. for C.sub.32H.sub.30Cl.sub.2N.sub.4O.sub.3 588.2, m/z found 589.2 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.71 (brs, 1H), 7.56-6.48 (m, 9H), 4.08-4.05 (m, 1H), 3.79 (s, 3H), 3.01-2.94 (m, 1H), 2.22 (s, 3H) 1.27-1.23 (m, 6H), 1.07 (d, 3H, J=6.8 Hz), 0.63 (d, 3H, J=6.8 Hz).

Example 33

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-ethyl-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(89) ##STR00089##

(90) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 21.8 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-ethyl-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-33), and 20.5 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-ethyl-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-33). MS (ESI): mass calcd. for C.sub.31H.sub.28Cl.sub.2N.sub.4O.sub.3 574.2, m/z found 575.2 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.70 (brs, 1H), 7.55-6.50 (m, 9H), 4.08-4.04 (m, 1H), 3.78 (s, 3H), 2.72-2.50 (m, 2H), 2.22 (s, 3H), 1.27-1.06 (m, 3H), 1.06 (d, 3H, J=6.4 Hz), 0.63 (d, 3H, J=6.4 Hz).

Example 34

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-isopropoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(91) ##STR00090##

(92) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 18.8 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-isopropoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-34), and 21.1 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-isopropoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-34). MS (ESI): mass calcd. for C.sub.31H.sub.28Cl.sub.2N.sub.4O.sub.3 574.2, m/z found 575.4 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.67 (brs, 1H), 7.54-6.95 (m, 10H), 4.65-4.62 (m, 1H), 4.12-4.08 (m, 1H), 2.22 (s, 3H), 1.18 (m, 6H), 1.07 (d, 3H, J=7.2 Hz), 0.65 (d, 3H, J=6.4 Hz).

Example 35

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-ethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(93) ##STR00091##

(94) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 15.9 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-ethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-35), and 23.0 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-ethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-35). MS (ESI): mass calcd. for C.sub.30H.sub.26Cl.sub.2N.sub.4O.sub.3 560.1, m/z found 561.5 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.68 (brs, 1H), 7.55-6.95 (m, 10H), 4.09-4.08 (m, 3H), 2.22 (s, 3H), 1.24 (t, 3H, J=6.0 Hz), 1.07 (d, 3H, J=6.8 Hz), 0.65 (d, 3H, J=6.8 Hz).

Example 36

6-chloro-5′-(3-chlorophenyl)-2′-(2,4-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(95) ##STR00092##

(96) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 29.1 mg of (S)-6-chloro-5′-(3-chlorophenyl)-2′-(2,4-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-36), and 36.6 mg of (R)-6-chloro-5′-(3-chlorophenyl)-2′-(2,4-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-36). MS (ESI): mass calcd. for C.sub.29H.sub.24C.sub.12N.sub.4O.sub.4 562.1, m/z found 563.1[M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 7.47-7.45 (m, 1H), 7.38-7.36 (m, 3H), 7.13-7.12 (m, 2H), 7.02 (s, 1H), 6.97 (d, 1H, J=7.2 Hz), 6.72-6.67 (m, 2H), 4.11-4.00 (m, 1H), 3.84 (s, 3H), 3.77 (s, 3H), 1.10 (d, 3H, J=5.2 Hz), 0.60 (d, 3H, J=5.2 Hz).

Example 37

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(5-ethyl-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(97) ##STR00093##

(98) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 21.5 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(5-ethyl-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-37), and 32.4 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(5-ethyl-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-37). MS (ESI): mass calcd. for C.sub.31H.sub.28Cl.sub.2N.sub.4O.sub.3 574.1, m/z found 575.2 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 7.70-6.98 (m, 9H), 4.08-4.05 (m, 1H), 3.76 (s, 3H), 2.64-2.60 (m, 2H), 2.22 (s, 3H), 1.23-1.17 (m, 3H), 1.07 (d, 3H, J=5.2 Hz), 0.63 (d, 3H, J=5.2 Hz).

Example 38

6-chloro-5′-(3-chlorophenyl)-2′-(5-ethyl-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(99) ##STR00094##

(100) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 18.1 mg of (S)-6-chloro-5′-(3-chlorophenyl)-2′-(5-ethyl-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-38), and 23.1 mg of (R)-6-chloro-5′-(3-chlorophenyl)-2′-(5-ethyl-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-38). MS (ESI): mass calcd. for C.sub.30H.sub.26Cl.sub.2N.sub.4O.sub.3 560.1, m/z found 561.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.52 (brs, 1H), 7.48 (d, 1H, J=8.0 Hz), 7.39-7.32 (m, 3H), 7.15-7.10 (m, 3H), 7.01 (s, 1H), 6.98-6.96 (d, 1H, J=7.2 Hz), 4.10-4.04 (m, 1H), 3.75 (s, 3H), 2.64 (q, 2H, J=7.2 Hz), 1.24 (t, 3H, J=7.2 Hz), 1.10 (d, 3H, J=5.2 Hz), 0.61 (d, 3H, J=5.2 Hz).

Example 39

6-chloro-5′-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2′-(2,4-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(101) ##STR00095##

(102) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 8.0 mg of (S)-6-chloro-5′-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2′-(2,4-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-39), and 12.7 mg of (R)-6-chloro-5′-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2′-(2,4-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-39). MS (ESI): mass calcd. for C.sub.29H.sub.24C.sub.12N.sub.4O.sub.4 593.1, m/z found 594.3 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.44 (brs, 1H), 7.96 (d, 1H, J=2.4 Hz), 7.33-7.31 (m, 2H), 7.22 (d, 1H, J=8.0 Hz), 7.04 (d, 1H, J=8.0 Hz), 6.98 (s, 1H), 6.70-6.66 (m, 2H), 4.07-4.01 (m, 1H), 3.84 (s, 3H), 3.77 (s, 3H), 2.98 (m, 1H), 1.08 (d, 3H, J=6.4 Hz), 0.58 (d, 3H, J=6.4 Hz).

Example 40

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,5-dimethoxypyridin-4-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(103) ##STR00096##

(104) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 20.2 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,5-dimethoxypyridin-4-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-40), and 28.2 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,5-dimethoxypyridin-4-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-40). MS (ESI): mass calcd. for C.sub.29H.sub.25Cl.sub.2N.sub.5O.sub.4 577.1, m/z found 578.3 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.62 (brs, 1H), 8.10 (s, 1H), 7.56-6.95 (m, 7H), 4.11-4.10 (m, 1H), 3.86 (s, 3H), 3.83 (s, 3H), 2.21 (s, 3H), 1.10 (d, 3H, J=6.4 Hz), 0.66 (d, 3H, J=6.4 Hz).

Example 41

6-chloro-5′-(5-chloro-2-methylphenyl)-3′-cyclobutyl-2′-(2,4-dimethoxypyrimidin-5-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(105) ##STR00097##

(106) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 23.5 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-cyclobutyl-2′-(2,4-dimethoxypyrimidin-5-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-41), and 23.3 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-cyclobutyl-2′-(2,4-dimethoxypyrimidin-5-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-41). MS (ESI): mass calcd. for C.sub.29H.sub.24Cl.sub.2N.sub.6O.sub.4 590.1, m/z found 591.1 [M+H].sup.+. .sup.1H-NMR (300 MHz, DMSO-d.sub.6) δ 11.38 (brs, 1H), 8.49 (d, 1H, J=5.4 Hz), 7.56-7.47 (m, 1H), 7.45-6.45 (m, 5H), 4.47-4.43 (m, 1H), 3.98-3.94 (m, 6H), 2.21 (s, 3H), 2.01-1.71 (m, 3H), 1.61-1.31 (m, 2H), 1.30-1.29 (m, 1H).

Example 42

6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(107) ##STR00098##

(108) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 8.3 mg of (S)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-42), and 8.9 mg of (R)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-42). MS (ESI): mass calcd. for C.sub.27H.sub.23Cl.sub.2N.sub.7O.sub.4 579.1, m/z found 580.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 8.53-8.46 (m, 2H), 7.61-6.96 (m, 4H), 4.17-4.13 (m, 1H), 3.98 (s, 3H), 3.94 (s, 3H), 2.40 (s, 1H), 0.84 (d, 3H, J=6.8 Hz), 0.66 (d, 3H, J=6.8 Hz).

Example 43

6-chloro-5′-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-3′-isopropyl-2′-(2-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(109) ##STR00099##

(110) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 26.2 mg of (S)-6-chloro-5′-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-3′-isopropyl-2′-(2-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-43), and 28.2 mg of (R)-6-chloro-5′-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-3′-isopropyl-2′-(2-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-43). MS (ESI): mass calcd. for C.sub.28H.sub.23Cl.sub.2N.sub.5O.sub.4 563.1, m/z found 564.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 7.95 (d, 1H, J=2.4 Hz), 7.56 (t, 1H, J=7.2 Hz), 7.41 (d, 1H, J=7.2 Hz), 7.31 (d, 1H, J=2.4 Hz), 7.23-7.08 (m, 3H), 6.93 (s, 1H), 4.04-4.01 (m, 1H), 3.98 (s, 3H), 1.10 (d, 3H, J=5.4 Hz), 0.60 (d, 3H, J=5.4 Hz).

Example 44

6-chloro-5′-(5-chloro-2-fluorophenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(111) ##STR00100##

(112) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 15.4 mg of (S)-6-chloro-5′-(5-chloro-2-fluorophenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-44), and 19.7 mg of (R)-6-chloro-5′-(5-chloro-2-fluorophenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-44). MS (ESI): mass calcd. for C.sub.27H.sub.21Cl.sub.2FN.sub.6O.sub.4 582.1, m/z found 583.2 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 8.53 (s, 1H), 7.48-7.47 (m, 1H), 7.46-7.36 (m, 2H), 7.21-7.11 (m, 1H), 7.10-7.06 (m, 1H), 7.05-7.01 (m, 1H), 4.20-4.15 (m, 1H), 3.99 (s, 3H), 3.95 (s, 3H), 1.17 (d, 3H, J=6.8 Hz), 0.66 (d, 3H, J=6.8 Hz).

Example 45

6-chloro-5′-(3-chloro-5-fluorophenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(113) ##STR00101##

(114) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 28.1 mg of (S)-6-chloro-5′-(3-chloro-5-fluorophenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-45), and 29.8 mg of (R)-6-chloro-5′-(3-chloro-5-fluorophenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-45). MS (ESI): mass calcd. for C.sub.27H.sub.21Cl.sub.2FN.sub.6O.sub.4 582.1, m/z found 583.2 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 8.51 (s, 1H), 7.49-7.39 (m, 2H), 7.38-7.14 (m, 2H), 7.07-6.85 (m, 2H), 4.19-4.14 (m, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 1.12 (d, 3H, J=6.8 Hz), 0.64 (d, 3H, J=6.8 Hz).

Example 46

6-chloro-5′-(5-chloro-2-methylphenyl)-3′-cyclopropyl-2′-(2,4-dimethoxypyrimidin-5-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(115) ##STR00102##

(116) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 5.0 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-cyclopropyl-2′-(2,4-dimethoxypyrimidin-5-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-46), and 10.5 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-cyclopropyl-2′-(2,4-dimethoxypyrimidin-5-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-46). MS (ESI): mass calcd. for C.sub.30H.sub.26Cl.sub.2N.sub.6O.sub.4, 604.1 m/z found 605.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 8.51 (d, 1H, J=6.8 Hz), 7.50-6.48 (m, 7H), 4.32-4.27 (m, 1H), 3.99 (s, 3H), 3.95 (s, 3H), 2.21 (s, 3H), 1.92-1.91 (m, 1H), 1.69-1.67 (m, 1H), 1.37-1.23 (m, 4H), 0.91-0.80 (m, 2H).

Example 47

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-((dimethylamino)methyl)-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(117) ##STR00103##

(118) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 9.7 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-((dimethylamino)methyl)-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-47), and 9.4 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-((dimethylamino)methyl)-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-47). MS (ESI): mass calcd. for C.sub.32H.sub.31Cl.sub.2N.sub.5O.sub.3 603.2, m/z found 604.4 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 7.42-6.73 (m, 9H), 4.07-3.98 (m, 1H), 3.77 (s, 3H), 2.14 (s, 6H), 2.08 (s, 2H), 1.08 (d, 3H, J=6.8 Hz), 0.63 (d, 3H, J=6.8 Hz).

Example 48

6-chloro-5′-(3-chloro-4-methoxyphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(119) ##STR00104##

(120) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 32.4 mg of (S)-6-chloro-5′-(3-chloro-4-methoxyphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-48), and 34.4 mg of (R)-6-chloro-5′-(3-chloro-4-methoxyphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-48). MS (ESI): mass calcd. for C.sub.28H.sub.24Cl.sub.2N.sub.6O.sub.5 594.1, m/z found 595.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.57 (brs, 1H), 8.51 (s, 1H), 7.48 (d, 1H, J=8.0 Hz), 7.14-7.07 (m, 3H), 6.97-6.92 (m, 2H), 4.16-4.11 (m, 1H), 3.99 (s, 3H), 3.95 (s, 3H), 3.81 (s, 3H), 1.11 (d, 3H, J=6.4 Hz), 0.65 (d, 3H, J=6.4 Hz).

Example 49

2′-(4-amino-2-methoxyphenyl)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(121) ##STR00105##

(122) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 5.4 mg of (S)-2′-(4-amino-2-methoxyphenyl)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-49), and 17.1 mg of (R)-2′-(4-amino-2-methoxyphenyl)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-49). MS (ESI): mass calcd. for C.sub.29H.sub.25Cl.sub.2N.sub.5O.sub.3, 561.1 m/z found 562.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 7.44-7.15 (m, 4H), 7.02-6.85 (m, 3H), 6.30 (s, 1H), 6.25 (d, 1H, J=8.0 Hz), 5.55 (brs, 2H), 4.24-4.06 (m, 1H), 3.67 (s, 3H), 2.22 (s, 3H), 1.06 (d, 1H, J=6.4 Hz), 0.61 (d, 1H, J=6.4 Hz).

Example 50

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-1′-isopropyl-1′H-spiro[dihydroindole-3,6′-pyrrolo[3,4-b]pyrrole]-2,4′(5′H)-dione

(123) ##STR00106##

Step 1: Preparation of Methyl 1-isopropyl-1H-pyrrole-3-carboxylate

(124) ##STR00107##

(125) Under nitrogen atmosphere, methyl 1H-pyrrole-3-carboxylate (25 g, 0.1998 mol) and 30 mL of anhydrous tetrahydrofuran were added to a 500 mL three-necked flask, and cooled to 0° C., NaH (7.19 g, 0.2997 mol) was added in batches, and the resultant mixture was maintained at 0° C. to react for 30 min, slowly and dropwise added with 2-bromopropane (49.2 g, 0.3996 mol), then naturally warmed to room temperature, and reacted overnight. The temperature was reduced to 0° C., and 20 mL of water was added dropwise for quenching, the resultant was concentrated under reduced pressure, added with 500 mL of ethyl acetate, and washed with 500 mL of saturated sodium carbonate aqueous solution for three times. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and separated by column chromatography (EA:PE=20% to 25%) to obtain 21.1 g of methyl 1-isopropyl-1H-pyrrole-3-carboxylate (yield 63.2%, yellow oil). MS (ESI): mass calcd. for C.sub.9H.sub.13NO.sub.2 167.1, m/z found 168.2[M+H].sup.+.

Step 2 Preparation of Methyl 5-bromo-1-isopropyl-1H-pyrrole-3-carboxylate

(126) ##STR00108##

(127) Under nitrogen atmosphere, methyl 1-isopropyl-1H-pyrrole-3-carboxylate (5.0 g, 0.02994 mol) and 30 mL of anhydrous tetrahydrofuran were added to a 100 mL three-necked flask, and cooled to 0° C., and NBS (5.06 g, 0.0284 mol) was added in batches, the resultant was naturally warmed to room temperature to react overnight, concentrated under vacuum, added with 50 mL of ethyl acetate, then washed with 50 mL of saturated sodium carbonate aqueous solution for three times, the organic layer was dried over anhydrous sodium sulfate, and separated by column chromatography (EA:PE=5% to 25%) to obtain 5.8 g of methyl 5-bromo-1-isopropyl-1H-pyrrole-3-carboxylate (93% yield, yellow oil). MS (ESI): mass calcd. for C.sub.9H.sub.12BrNO.sub.2 245.0, m/z found 246.1[M+H].sup.+.

Step 3: Preparation of Methyl 5-bromo-2-(6-chloro-3-hydroxy-2-oxoindolin-3-yl)-1-isopropyl-1H-pyrrole-3-carboxylate

(128) ##STR00109##

(129) Under nitrogen atmosphere, methyl 5-bromo-1-isopropyl-1H-pyrrole-3-carboxylate (4.8 g, 0.0196 mol) and 20 mL of anhydrous tetrahydrofuran were added to a 100 mL three-necked flask, and cooled to −78° C. LDA (39.2 ml, 2 M) was slowly added dropwise, and the resultant was maintained at −50° C. to react for 1.5 h after completion of the dropwise addition. Then 6-chloroindolin-2,3-dione (3.546 g, 19.6 mmol) was dissolved in 10 mL of anhydrous tetrahydrofuran, and slowly added dropwise into the reaction flask, the resultant was maintained at −50° C. to react for 1 h. 10 mL of saturated ammonium chloride aqueous solution was added dropwise to the reaction flask, the resultant was concentrated under vacuum, added with 100 mL of ethyl acetat and washed once with 50 mL of saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated and separated by column chromatography (EA:PE=1:10 to 1:2) to obtain 1.2 g of methyl 5-bromo-2-(6-chloro-3-hydroxy-2-oxoindolin-3-yl)-1-isopropyl-1H-pyrrole-3-carboxylate (yield 20%, yellow solid). MS (ESI): mass calcd. For C.sub.17H.sub.16BrClN.sub.2O.sub.4 426.0, m/z found 409.0 [M+H−18].sup.+.

Step 4: Preparation of 5-bromo-N-(5-chloro-2-methylphenyl)-2-(6-chloro-3-hydroxy-2-oxoindolin-3-yl)-1-isopropyl-1H-pyrrole-3-amide

(130) ##STR00110##

(131) Under nitrogen atmosphere, 5-chloro-2-methylaniline (450 mg, 3.169 mmol) and anhydrous toluene (5 mL) were added to a 50 mL reaction flask, the temperature was reduced to 0° C., and AlMe.sub.3 (1.826 g, 25% w/w) was slowly added. Then, methyl 5-bromo-2-(6-chloro-3-hydroxy-2-oxoindolin-3-yl)-1-isopropyl-1H-pyrrole-3-carboxylate (675 mg, 1.585 mmol) was dissolved in 5 mL of toluene, and slowly added dropwise into the reaction flask. The resultant mixture was warmed to 90° C. to react overnight, then cooled to room temperature, added with 20 mL of ice water and 15 mL of saturated aqueous solution of sodium potassium tartrate, then extracted with 50 mL of dichloromethane for two times. The organic phases were combined, washed once with 30 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by a preparative plate to obtain 795 mg of 5-bromo-N-(5-chloro-2-methylphenyl)-2-(6-chloro-3-hydroxy-2-oxoindolin-3-yl)-1-isopropyl-1H-pyrrole-3-amide (94% yield, yellow solid). MS (ESI): mass calcd. For C.sub.23H.sub.20BrCl.sub.2N.sub.3O.sub.3 535.0, m/z found 518.0 [M+H−18].sup.+.

Step 5: Preparation of 2′-bromo-6-chloro-5′-(5-chloro-2-methylphenyl)-1′-isopropyl-1′H-spiro[dihydroindole-3,6′-pyrrolo[3,4-b]pyrrole]-2,4′(5′H)-dione

(132) ##STR00111##

(133) 5-bromo-N-(5-chloro-2-methylphenyl)-2-(6-chloro-3-hydroxy-2-oxoindolin-3-yl)-1-isopropyl-1H-pyrrole-3-amide (1155 mg, 2.155 mmol), H.sub.2SO.sub.4 (2.112 g, 21.55 mmol) and acetic acid (10 mL) were added to a 50 mL reaction flask, and the temperature was raised to 110° C. for overnight reaction, then the temperature was naturally lowered to room temperature, and 20 mL of ice water was added. The pH value was adjusted to about 7 with saturated sodium carbonate aqueous solution, and the resultant was extracted with 50 mL of dichloromethane for two times. The organic layers were combined, washed once with 20 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (EA:PE=25%) to obtain 150 mg of 2′-bromo-6-chloro-5′-(5-chloro-2-methylphenyl)-1′-isopropyl-1′H-spiro[dihydroindole-3,6′-pyrrolo[3,4-b]pyrrole]-2,4′(5′H)-dione (13.5% yield, yellow solid). MS (ESI): mass calcd. for C.sub.23HisBrC.sub.2N.sub.32 517.0, m/z found 518.0 [M+H].sup.+.

Step 6: Preparation of 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-1′-isopropyl-1′H-spiro[dihydroindole-3,6′-pyrrolo[3,4-b]pyrrole]-2,4′(5′H)-dione

(134) ##STR00112##

(135) Under nitrogen atmosphere, 2′-bromo-6-chloro-5′-(5-chloro-2-methylphenyl)-1′-isopropyl-1′H-spiro[dihydroindole-3,6′-pyrrolo[3,4-b]pyrrole]-2,4′(5′H)-dione (100 mg, 0.1934 mmol), (2,4-dimethoxypyrimidin-5-yl)boronic acid (36 mg, 0.1934 mmol), Pd(PPh.sub.3).sub.4 (45 mg, 0.0387 mmol), Na.sub.2CO.sub.3 (62 mg, 0.5802 mmol), dioxane (4 mL) and H.sub.2O (1 ml) were added into a microwave reaction flask, and the temperature was raised to 100° C. to perform a microwave reaction for 1 h. The resultant was cooled to room temperature, filtered, added with 10 mL of water, and extracted with 10 mL of dichloromethane for three times. The organic layers were combined, washed once with 10 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by a preparative plate, and then subjected to supercritical high-pressure preparative liquid phase separation to obtain 6.2 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-1′-isopropyl-1′H-spiro[dihydroindole-3,6′-pyrrolo[3,4-b]pyrrole]-2,4′(5′H)-dione (S-50); and 7.8 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-1′-isopropyl-1′H-spiro[dihydroindole-3,6′-pyrrolo[3,4-b]pyrrole]-2,4′(5′H)-dione (R-50). MS (ESI): mass calcd. for C.sub.29H.sub.25Cl.sub.2N.sub.5O.sub.4 577.1, m/z found 578.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 9.51 (d, 1H, J=8.0 Hz), 7.62-6.55 (m, 8H), 4.07 (s, 3H), 3.94 (s, 3H), 3.62-3.48 (m, 1H), 2.25 (s, 3H), 1.29 (d, 3H, J=6.4 Hz), 1.09 (d, 3H, J=6.4 Hz).

Example 51

6-chloro-5′-(3-chloro-5-methylphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(136) ##STR00113##

(137) Title compounds were obtained by steps similar to those described in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 18.9 mg of (S)-6-chloro-5′-(3-chloro-5-methylphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-51), and 18.4 mg of (R)-6-chloro-5′-(3-chloro-5-methylphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-51). MS (ESI): mass calcd. for: C.sub.28H.sub.24Cl.sub.2N.sub.6O.sub.4, 579.4 m/z found 580.2 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.60 (brs, 1H), 8.51 (s, 1H), 7.46 (d, 1H, J=8.0 Hz), 7.18-7.13 (m, 2H), 7.02 (s, 1H), 6.89 (s, 1H), 6.80 (s, 1H), 4.18-4.11 (m, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 2.20 (s, 3H), 1.12 (d, 3H, J=6.8 Hz), 0.64 (d, 3H, J=6.8 Hz).

Example 52

6-chloro-5′-(5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2′-(2,4-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(138) ##STR00114##

(139) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 17.2 mg of (S)-6-chloro-5′-(5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2′-(2,4-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-52), and 14.7 mg of (R)-6-chloro-5′-(5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2′-(2,4-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-52). MS (ESI): mass calcd. for C.sub.29H.sub.25Cl.sub.2N.sub.5O.sub.5 593.1, m/z found 594.3[M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.51 (s, 1H), 7.55-7.51 (m, 2H), 7.49-7.27 (m, 2H), 7.18-7.14 (m, 1H), 7.02 (s, 1H), 6.71-6.66 (m, 2H), 4.07-4.02 (m, 1H), 3.84 (s, 3H), 3.77 (s, 3H), 3.32 (s, 3H), 1.07 (d, 3H, J=6.8 Hz), 0.62 (d, 3H, J=6.8 Hz).

Example 53

6-chloro-5′-(5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3′-isopropyl-2′-(2-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(140) ##STR00115##

(141) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 18.3 mg of (S)-6-chloro-5′-(5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3′-isopropyl-2′-(2-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-53), and 18.2 mg of (R)-6-chloro-5′-(5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3′-isopropyl-2′-(2-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-53). MS (ESI): mass calcd. for C.sub.28H.sub.23Cl.sub.2N.sub.5O.sub.4 564.1, m/z found 565.3[M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.49 (brs, 1H), 7.57-7.52 (m, 3H), 7.52-7.48 (m, 2H), 7.21-7.19 (m, 2H), 7.16-7.12 (m, 1H), 7.10-7.02 (m, 1H), 4.07-4.02 (m, 1H), 3.78 (s, 3H), 3.49 (s, 3H), 1.08 (d, 3H, J=6.8 Hz), 0.62 (d, 3H, J=6.8 Hz).

Example 54

4-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-3-methoxy-N-methylbenzamide

(142) ##STR00116##

(143) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 7.5 mg of (S)-4-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-3-methoxy-N-methylbenzamide (S-54), and 8.8 mg of (R)-4-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-3-methoxy-N-methylbenzamide (R-54). MS (ESI): mass calcd. for C.sub.31H.sub.27Cl.sub.2N.sub.5O.sub.4, 603.1 m/z found 604.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 8.59 (d, 1H, J=4.4 Hz), 7.59-6.94 (m, 9H), 4.08-4.04 (m, 1H), 3.85 (s, 3H), 2.83 (d, 3H, J=4.4 Hz), 2.23 (s, 3H), 1.08 (d, 3H, J=5.2 Hz). 0.64 (d, 3H, J=5.2 Hz).

Example 55

6-chloro-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-5′-(m-tolyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(144) ##STR00117##

(145) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 52.7 mg of (S)-6-chloro-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-5′-(m-tolyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-55), and 58.7 mg of (R)-6-chloro-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-5′-(m-tolyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-55). MS (ESI): mass calcd. for C.sub.28H.sub.25Cl.sub.1N.sub.6O.sub.4 544.2, m/z found 545.2 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 8.51 (s, 1H), 7.42 (d, 1H, J=8.0 Hz), 7.20-6.99 (m, 3H), 6.96 (s, 1H), 6.84 (s, 1H), 6.97 (d, 1H, J=8.0 Hz), 4.18-4.11 (m, 1H), 3.99 (s, 3H), 3.95 (s, 3H), 2.20 (s, 3H), 1.10 (d, 3H, J=6.8 Hz), 0.65 (d, 3H, J=6.8 Hz).

Example 56

6-chloro-2′-(2,4-dimethoxypyrimidin-5-yl)-5′-(2,5-dimethylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(146) ##STR00118##

(147) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 42.4 mg of (S)-6-chloro-2′-(2,4-dimethoxypyrimidin-5-yl)-5′-(2,5-dimethylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-56), and 48.7 mg of (R)-6-chloro-2′-(2,4-dimethoxypyrimidin-5-yl)-5′-(2,5-dimethylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-56). MS (ESI): mass calcd. for C.sub.29H.sub.27ClN.sub.6O.sub.4 558.1, m/z found 559.3 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.54 (brs, 1H), 8.54 (d, 1H, J=7.6 Hz), 7.62-7.37 (m, 1H), 7.25-7.23 (m, 1H), 7.06-6.93 (m, 4H), 4.16-4.13 (m, 1H), 3.99 (s, 3H), 3.96 (s, 3H), 2.22 (s, 3H), 2.03 (s, 3H), 1.09 (d, 3H, J=6.8 Hz), 0.64 (d, 3H, J=6.8 Hz).

Example 57

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-fluoro-6-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(148) ##STR00119##

(149) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 19.9 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-fluoro-6-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-57), and 17.9 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-fluoro-6-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-57). MS (ESI): mass calcd. for C.sub.29H.sub.23Cl.sub.2FN.sub.4O.sub.3 564.1, m/z found 565.1[M+H].sup.+. .sup.1H-NMR (300 MHz, DMSO-d.sub.6) δ 11.12 (brs, 1H), 7.62-6.97 (m, 9H), 4.01-3.98 (m, 1H), 3.82 (s, 3H), 2.23 (s, 3H), 1.07-1.02 (m, 3H), 0.70-0.63 (m, 3H).

Example 58

6-chloro-5′-(3-chloro-5-methoxyphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(150) ##STR00120##

(151) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 26.3 mg of (S)-6-chloro-5′-(3-chloro-5-methoxyphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-58), and 29.9 mg of (R)-6-chloro-5′-(3-chloro-5-methoxyphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-58). MS (ESI): mass calcd. for C.sub.28H.sub.24Cl.sub.2N.sub.6O.sub.5 594.1, m/z found 595.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.65 (brs, 1H), 8.51 (s, 1H), 7.47 (d, 1H, J=8.4 Hz), 7.16 (d, 1H, J=8.0 Hz), 7.05 (d, 1H, J=1.6 Hz), 6.95 (s, 1H), 6.72 (s, 1H), 6.52 (s, 1H), 4.16-4.13 (m, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 3.67 (s, 3H), 1.12 (d, 3H, J=6.4 Hz), 0.64 (d, 3H, J=6.4 Hz).

Example 59

6-chloro-5′-(3-chloro-4-fluorophenyl)-3′-isopropyl-2′-(4-methoxypyridin-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(152) ##STR00121##

(153) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 17.9 mg of (S)-6-chloro-5′-(3-chloro-4-fluorophenyl)-3′-isopropyl-2′-(4-methoxypyridin-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-59), and 22.5 mg of (R)-6-chloro-5′-(3-chloro-4-fluorophenyl)-3′-isopropyl-2′-(4-methoxypyridin-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-59). MS (ESI): mass calcd. for: C.sub.27H.sub.20Cl.sub.2FN.sub.5O.sub.3, 551.1 m/z found 552.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 8.64 (d, 1H, J=6.4 Hz), 8.48 (brs, 1H), 7.54 (d, 1H, J=8.0 Hz), 7.44-7.42 (m, 1H), 7.40-7.14 (m, 4H), 7.08-6.97 (m, 2H), 4.09-4.03 (m, 1H), 3.88 (s, 3H), 1.11 (d, 3H, J=6.4 Hz), 0.64 (d, 3H, J=6.4 Hz).

Example 60

2-chloro-4-(6-chloro-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-2,6′-dioxo-3′,6′-dihydro-5′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-5′-yl)benzamide

(154) ##STR00122##

(155) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 14.0 mg of (S)-2-chloro-4-(6-chloro-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-2,6′-dioxo-3′,6′-dihydro-5′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-5′-yl)benzamide (S-60), and 16.3 mg of (R)-2-chloro-4-(6-chloro-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-2,6′-dioxo-3′,6′-dihydro-5′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-5′-yl)benzamide (R-60). MS (ESI): mass calcd. for C.sub.28H.sub.23Cl.sub.2N.sub.7O.sub.5 607.1, m/z found 608.1 [M+H].sup.+. H-NMR (400 MHz, DMSO-d.sub.6) δ 11.69 (brs, 1H), 8.51 (s, 1H), 7.91 (s, 1H), 7.59 (s, 1H), 7.50 (d, 1H, J=7.2 Hz), 7.40 (d, 1H, J=8.0 Hz), 7.16-7.14 (m, 2H), 7.06-6.99 (m, 2H), 4.17-4.14 (m, 1H), 3.99 (s, 3H), 3.95 (s, 3H), 1.13 (d, 3H, J=6.4 Hz), 0.63 (d, 3H, J=6.4 Hz).

Example 61

6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(2,4-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(156) ##STR00123##

(157) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 29.9 mg of (S)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(2,4-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-61), and 26.3 mg of (R)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(2,4-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-61). MS (ESI): mass calcd. for C.sub.29H.sub.25Cl.sub.2N.sub.5O.sub.4 577.1, m/z found 578.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.49 (s, 1H), 8.50 (d, 1H, J=8.4 Hz), 7.62 (d, 1H, J=8.4 Hz), 7.54 (d, 1H, J=9.2 Hz), 7.36-7.33 (m, 1H), 7.27 (d, 1H, J=8.0 Hz), 7.04-7.00 (m, 1H), 6.73-6.79 (m, 2H), 4.10 (t, 1H, J=6.8 Hz), 3.84 (s, 3H), 3.79 (s, 3H), 2.42-2.27 (m, 3H), 1.07 (d, 3H, J=4.8 Hz), 0.638 (d, 3H, J=4.8 Hz).

Example 62

6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-methoxy-5-methylphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(158) ##STR00124##

(159) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 40.0 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-methoxy-5-methylphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-62), and 44.0 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-methoxy-5-methylphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-62). MS (ESI): mass calcd. for C.sub.30H.sub.26Cl.sub.2N.sub.4O.sub.3, 560.1 m/z found 561.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.72 (brs, 1H), 7.55-6.97 (m, 10H), 4.09-4.05 (m, 1H), 3.75 (s, 3H), 2.30 (s, 3H), 2.22 (s, 3H), 1.07 (d, 3H, J=5.6 Hz), 0.63 (d, 3H, J=5.6 Hz).

Example 63

6-chloro-5′-(3-chloro-4-methoxyphenyl)-3′-isopropyl-2′-(2-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(160) ##STR00125##

(161) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 22.9 mg of (S)-6-chloro-5′-(3-chloro-4-methoxyphenyl)-3′-isopropyl-2′-(2-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-63), and 22.9 mg of (R)-6-chloro-5′-(3-chloro-4-methoxyphenyl)-3′-isopropyl-2′-(2-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-63). MS (ESI): mass calcd. for C.sub.29H.sub.24Cl.sub.2N.sub.4O.sub.4, 563.4 m/z found 564.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 7.57-6.91 (m, 10H), 4.08-4.00 (m, 1H), 3.81 (s, 3H), 3.78 (s, 3H), 1.08 (m, 3H), 0.75-0.70 (m, 3H).

Example 64

6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(162) ##STR00126##

(163) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 73.9 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-64), and 79.7 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-64). MS (ESI): mass calcd. for C.sub.29H.sub.24Cl.sub.2N.sub.4O.sub.3 546.1, m/z found 547.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.73 (brs, 1H), 7.58-6.45 (m, 10H), 4.46-4.43 (m, 1H), 3.83 (s, 3H), 2.21 (s, 3H), 1.11-1.09 (d, 3H, J=6.4 Hz), 0.75 (d, 3H, J=6.4 Hz).

Example 65

2-chloro-4-(6-chloro-2′-(4,6-dimethoxypyridin-3-yl)-3′-isopropyl-2,6′-dioxo-3′,6′-dihydro-5′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-5′-yl)benzamide

(164) ##STR00127##

(165) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 7.3 mg of (S)-2-chloro-4-(6-chloro-2′-(4,6-dimethoxypyridin-3-yl)-3′-isopropyl-2,6′-dioxo-3′,6′-dihydro-5′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-5′-yl)benzamide (S-65), and 10.3 mg of (R)-2-chloro-4-(6-chloro-2′-(4,6-dimethoxypyridin-3-yl)-3′-isopropyl-2,6′-dioxo-3′,6′-dihydro-5′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-5′-yl)benzamide (R-65). MS (ESI): mass calcd. for C.sub.29H.sub.24Cl.sub.2N.sub.6O.sub.5 606.1, m/z found 607.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.63 (brs, 1H), 8.11 (s, 1H), 7.91 (s, 1H), 7.59 (s, 1H), 7.51 (d, 1H, J=8.0 Hz), 7.41 (d, 1H, J=8.4 Hz), 7.16-7.14 (m, 2H), 7.04-7.01 (m, 1H), 7.01-6.99 (m, 1H), 6.59 (s, 1H), 4.07-4.03 (m, 1H), 3.91 (s, 3H), 3.83 (s, 3H), 1.11 (d, 3H, J=6.0 Hz), 0.61 (d, 3H, J=6.0 Hz).

Example 66

2′-(4-amino-2-methoxyphenyl)-6-chloro-5′-(5-chloro-2-fluorophenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(166) ##STR00128##

(167) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 12.7 mg of (S)-2′-(4-amino-2-methoxyphenyl)-6-chloro-5′-(5-chloro-2-fluorophenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-66), and 10.1 mg of (R)-2′-(4-amino-2-methoxyphenyl)-6-chloro-5′-(5-chloro-2-fluorophenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-66). MS (ESI): mass calcd. for C.sub.28H.sub.22Cl.sub.2FN.sub.5O.sub.3 565.1, m/z found 566.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 7.70-7.00 (m, 7H), 6.31 (s, 1H), 6.23 (d, 1H, J=9.2 Hz), 5.59 (brs, 2H), 4.12-4.07 (m, 1H), 3.67 (s, 3H), 1.07 (d, 3H, J=5.6 Hz), 0.60 (d, 3H, J=5.6 Hz).

Example 67

2′-(4-amino-2-methoxyphenyl)-6-chloro-5′-(3-chloro-5-fluorophenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(168) ##STR00129##

(169) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 21.3 mg of (S)-2′-(4-amino-2-methoxyphenyl)-6-chloro-5′-(3-chloro-5-fluorophenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-67), and 18.8 mg of (R)-2′-(4-amino-2-methoxyphenyl)-6-chloro-5′-(3-chloro-5-fluorophenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-67). MS (ESI): mass calcd. for C.sub.28H.sub.22Cl.sub.2FN.sub.5O.sub.3 565.1, m/z found 566.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 7.35-7.28 (m, 2H), 7.02-6.92 (m, 5H), 6.29 (s, 1H), 6.24 (d, 1H, J=8.0 Hz), 5.57 (brs, 2H), 4.10-4.04 (m, 1H), 3.65 (s, 3H), 1.09 (d, 3H, J=6.4 Hz), 0.57 (d, 3H, J=6.4 Hz).

Example 68

4-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-3-methoxy-N,N-dimethylbenzamide

(170) ##STR00130##

(171) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 13.4 mg of (S)-4-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-3-methoxy-N,N-dimethylbenzamide (S-68), and 17.1 mg of (R)-4-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-3-methoxy-N,N-dimethylbenzamide (R-68). MS (ESI): mass calcd. for C.sub.32H.sub.29Cl.sub.2N.sub.5O.sub.4, 617.2 m/z found 618.2 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.73 (brs, 1H), 7.58-6.97 (m, 9H), 4.10-4.07 (m, 1H), 3.82 (s, 3H), 3.01 (s, 3H), 2.96 (s, 3H), 2.22 (s, 3H), 1.08 (d, 3H, J=6.4 Hz), 0.65 (d, 3H, J=6.4 Hz).

Example 69

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-isopropoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(172) ##STR00131##

(173) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 9.6 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-isopropoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-69), and 28.9 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-isopropoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-69). MS (ESI): mass calcd. for C.sub.31H.sub.29Cl.sub.2N.sub.5O.sub.4, 605.2 m/z found 606.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.54 (brs, 1H), 8.10 (d, J=4.4 Hz, 1H), 7.56-6.96 (m, 7H), 5.36-5.30 (m, 1H), 4.08-4.05 (m, 1H), 3.83 (s, 3H), 2.21 (s, 3H), 1.33 (d, J=6.4 Hz, 6H), 1.08 (d, J=5.2 Hz, 3H), 0.64 (d, J=5.2 Hz, 3H).

Example 70

2-(3-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-4-methoxyphenyl)-N,N-dimethylacetamide

(174) ##STR00132##

(175) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 25.9 mg of (S)-2-(3-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-4-methoxyphenyl)-N,N-dimethylacetamide (S-70), and 30.7 mg of (R)-2-(3-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-4-methoxyphenyl)-N,N-dimethylacetamide (R-70). MS (ESI): mass calcd. for C.sub.33H.sub.31Cl.sub.2N.sub.5O.sub.4 631.2, m/z found 632.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.72 (brs, 1H), 7.57-6.96 (m, 9H), 4.09-4.06 (m, 1H), 3.78 (s, 3H), 3.69 (s, 2H), 3.01 (s, 3H), 2.83 (s, 3H), 2.22 (s, 3H), 1.07 (s, 3H), 0.36 (s, 3H).

Example 71

2′-(4-amino-2-methoxyphenyl)-6-chloro-5′-(3-chloro-4-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(176) ##STR00133##

(177) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 17.1 mg of (S)-2′-(4-amino-2-methoxyphenyl)-6-chloro-5′-(3-chloro-4-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-71), and 16.1 mg of (R)-2′-(4-amino-2-methoxyphenyl)-6-chloro-5′-(3-chloro-4-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-71). MS (ESI): mass calcd. for C.sub.29H.sub.25Cl.sub.2N.sub.5O.sub.4, 577.1 m/z found 578.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 7.20-6.20 (m, 9H), 5.49 (s, 2H), 3.98 (m, 1H), 3.78 (s, 3H), 3.64 (s, 3H), 1.11-1.05 (m, 3H), 0.60-0.59 (m, 3H).

Example 72

(178) 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-ethoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(179) ##STR00134##

(180) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 20.2 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-ethoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-72), and 23.2 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-ethoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-72). MS (ESI): mass calcd. for C.sub.30H.sub.27Cl.sub.2N.sub.5O.sub.4 591.1, m/z found 592.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.73 (brs, 1H), 8.10 (s, 1H), 7.56-7.44 (m, 1H), 7.31-6.48 (m, 6H), 4.40 (brs, 2H), 4.06-4.02 (m, 1H), 3.84 (s, 3H), 2.21 (s, 3H), 1.36 (t, 3H, J=7.6 Hz), 1.08 (d, 3H, J=6.4 Hz), 0.64 (d, 3H, J=6.4 Hz).

Example 73

2′-(4-amino-2-methoxyphenyl)-6-chloro-5′-(3-chloro-4-fluorophenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(181) ##STR00135##

(182) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 24.7 mg of (S)-2′-(4-amino-2-methoxyphenyl)-6-chloro-5′-(3-chloro-4-fluorophenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-73), and 28.7 mg of (R)-2′-(4-amino-2-methoxyphenyl)-6-chloro-5′-(3-chloro-4-fluorophenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-73). MS (ESI): mass calcd. for C.sub.28H.sub.22Cl.sub.2FN.sub.5O.sub.3 565.1, m/z found 566.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 7.39-7.34 (m, 1H), 7.27-7.21 (m, 2H), 7.03-6.90 (m, 4H), 6.29 (s, 1H), 6.24 (d, 1H, J=8.0 Hz), 5.56 (brs, 2H), 4.08-4.05 (m, 1H), 3.65 (s, 3H), 1.08 (s, 3H), 0.59 (s, 3H).

Example 74

2′-(4-amino-2-methoxy-5-methylphenyl)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(183) ##STR00136##

(184) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 25.0 mg of (S)-2′-(4-amino-2-methoxy-5-methylphenyl)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-74), and 26.6 mg of (R)-2′-(4-amino-2-methoxy-5-methylphenyl)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-74). MS (ESI): mass calcd. for C.sub.30H.sub.27Cl.sub.2N.sub.5O.sub.3 575.1, m/z found 576.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.68 (brs, 1H), 7.51-6.93 (m, 8H), 5.33 (brs, 2H), 4.12-4.10 (m, 1H), 3.66 (s, 3H), 2.21 (s, 3H), 2.01 (s, 3H), 1.05 (d, 3H, J=6.4 Hz), 0.61 (d, 3H, J=6.4 Hz).

Example 75

2′-(4-amino-5-fluoro-2-methoxyphenyl)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(185) ##STR00137##

(186) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 7.8 mg of (S)-2′-(4-amino-5-fluoro-2-methoxyphenyl)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-75), and 12.7 mg of (R)-2′-(4-amino-5-fluoro-2-methoxyphenyl)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-75). MS (ESI): mass calcd. for C.sub.29H.sub.24Cl.sub.2FN.sub.5O.sub.3 579.1, m/z found 580.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.54 (brs, 1H), 7.49-6.46 (m, 8H), 5.65 (brs, 2H), 4.13-4.11 (m, 1H), 3.67 (s, 3H), 2.21 (s, 3H), 1.06 (s, 3H, J=6.0 Hz), 0.62 (d, 3H, J=6.0 Hz).

Example 76

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(3-fluoro-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(187) ##STR00138##

(188) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 22.0 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(3-fluoro-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-76), and 25.1 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(3-fluoro-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-76). MS (ESI): mass calcd. for C.sub.29H.sub.23Cl.sub.2FN.sub.4O.sub.3 564.1, m/z found 565.3 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.51 (brs, 1H), 7.57-6.95 (m, 9H), 4.11-4.10 (m, 1H), 3.77 (s, 3H), 2.22 (s, 3H), 1.08 (d, 3H, J=6.0 Hz), 0.66 (d, 3H, J=6.0 Hz).

Example 77

4-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-3-methoxybenzamide

(189) ##STR00139##

(190) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 23.6 mg of (S)-4-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-3-methoxybenzamide (S-77), and 21.5 mg of (R)-4-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-3-methoxybenzamide (R-77). MS (ESI): mass calcd. for C.sub.30H.sub.25Cl.sub.2N.sub.5O.sub.4, 589.1 m/z found 590.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.76 (brs, 1H), 8.14 (brs, 2H), 7.64-6.98 (m, 9H), 4.08-4.06 (m, 1H), 3.85 (s, 3H), 2.22 (s, 3H), 1.07 (d, 3H, J=4.8 Hz), 0.64 (d, 3H, J=4.8 Hz).

Example 78

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-dimethylamino)-5-fluoro-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(191) ##STR00140##

(192) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 19.7 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-dimethylamino)-5-fluoro-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-78), and 28.3 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-dimethylamino)-5-fluoro-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-78). MS (ESI): mass calcd. for C.sub.31H.sub.28Cl.sub.2FN.sub.5O.sub.3 607.2, m/z found 608.2 [M+H].sup.+. H-NMR (400 MHz, DMSO-d.sub.6) δ 11.54 (brs, 1H), 7.52-6.57 (m, 9H), 4.12-4.10 (m, 1H), 3.78 (s, 3H), 2.91 (s, 6H), 2.21 (s, 3H), 1.06 (d, 3H, J=4.0 Hz), 0.63 (d, 3H, J=4.0 Hz).

Example 79

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,6-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(193) ##STR00141##

(194) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 23.7 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,6-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-79), and 24.7 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,6-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-79). MS (ESI): mass calcd. for C.sub.30H.sub.26Cl.sub.2N.sub.4O.sub.4 576.1, m/z found 577.2 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.70 (brs, 1H), 7.51-6.78 (m, 9H), 3.90-3.83 (m, 1H), 3.75 (s, 3H), 3.71 (s, 3H), 2.24 (s, 3H), 1.02 (d, 3H, J=6.8 Hz), 0.61 (d, 3H, J=6.8 Hz).

Example 80

6-chloro-5′-(5-chloro-2-fluorophenyl)-2′-(2,4-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(195) ##STR00142##

(196) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 32.0 mg of (S)-6-chloro-5′-(5-chloro-2-fluorophenyl)-2′-(2,4-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-80), and 35.4 mg of (R)-6-chloro-5′-(5-chloro-2-fluorophenyl)-2′-(2,4-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-80). MS (ESI): mass calcd. for C.sub.29H.sub.23Cl.sub.2FN.sub.4O.sub.4 580.1, m/z found 581.2 [M+H].sup.+. 1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.85 (brs, 1H), 7.48-6.66 (m, 9H), 4.09-4.03 (m, 1H), 3.84 (s, 3H), 3.77 (s, 3H), 1.04 (d, 3H, J=6.0 Hz), 0.61 (d, 3H, J=6.0 Hz).

Example 81

6-chloro-5′-(5-chloro-2-fluorophenyl)-2′-(4-(dimethylamino)-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(197) ##STR00143##

(198) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 26.0 mg of (S)-6-chloro-5′-(5-chloro-2-fluorophenyl)-2′-(4-(dimethylamino)-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-81), and 19.5 mg of (R)-6-chloro-5′-(5-chloro-2-fluorophenyl)-2′-(4-(dimethylamino)-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-81). MS (ESI): mass calcd. for C.sub.30H.sub.26Cl.sub.2FN.sub.5O.sub.3 593.13, m/z found 594.2 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.52 (brs, 1H), 7.46-7.05 (m, 6H), 6.98 (s, 1H), 6.40 (d, 1H, J=8.4 Hz), 6.35 (s, 1H), 4.12-4.08 (m, 1H), 3.76 (s, 3H), 2.99 (s, 6H), 1.08 (d, 3H, J=5.6 Hz), 0.61 (d, 3H, J=5.6 Hz).

Example 82

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-(dimethylamino)-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(199) ##STR00144##

(200) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 13.7 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-(dimethylamino)-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-82), and 13.6 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-(dimethylamino)-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-82). MS (ESI): mass calcd. for C.sub.29H.sub.27Cl.sub.2N.sub.7O.sub.3 591.15, m/z found 592.2 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 8.25 (d, 1H, J=4.4 Hz), 7.55-6.97 (m, 6H), 4.15-4.12 (m, 1H), 3.90 (s, 3H), 3.19 (s, 6H), 2.20 (s, 3H), 1.08 (d, 3H, J=6.4 Hz), 0.66 (d, 3H, J=6.4 Hz).

Example 83

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,4-dimethoxy-5-methylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(201) ##STR00145##

(202) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 48.6 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,4-dimethoxy-5-methylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-83), and 30.5 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,4-dimethoxy-5-methylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-83). MS (ESI): mass calcd. for C.sub.31H.sub.28Cl.sub.2N.sub.4O.sub.4 590.19, m/z found 591.2 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.52 (brs, 1H), 7.47-7.04 (m, 6H), 6.98 (d, 1H, J=1.6 Hz), 6.40 (d, 1H, J=8.4 Hz), 6.35 (s, 1H), 4.12-4.08 (m, 1H), 3.76 (s, 3H), 2.99 (s, 6H), 2.22 (s, 3H), 1.08 (d, 3H, J=6.4 Hz), 0.61 (d, 3H, J=6.4 Hz).

Example 84

3-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-4-methoxybenzoic acid

(203) ##STR00146##

(204) 80 mg of the title compound was obtained by steps similar to those in Example 1. MS (ESI): mass calcd. for C.sub.30H.sub.24Cl.sub.2N.sub.4O.sub.5, 590.11 m/z found 591.1 [M+H].sup.+. H-NMR (400 MHz, DMSO-d.sub.6) δ 11.35 (brs, 1H), 8.12 (d, 1H, J=8.0 Hz), 7.96 (s, 1H), 7.60-6.97 (m, 7H), 4.07-4.06 (m, 1H), 3.87 (s, 3H), 2.23 (s, 3H), 1.17 (d, 3H, J=7.2 Hz), 0.62 (d, 3H, J=7.2 Hz).

Example 85

6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-methoxy-4-(trifluoromethyl)phenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(205) ##STR00147##

(206) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 10.1 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-methoxy-4-(trifluoromethyl)phenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-85), and 9.7 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-methoxy-4-(trifluoromethyl)phenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-85). MS (ESI): mass calcd. for C.sub.30H.sub.23Cl.sub.2F.sub.3N.sub.4O.sub.3 614.11, m/z found 615.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 7.71-6.98 (m, 9H), 4.08-4.06 (m, 1H), 3.89 (s, 3H), 2.22 (s, 3H), 1.18 (d, 3H, J=4.0 Hz), 0.64 (d, 3H, J=4.0 Hz).

Example 86

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-cyclopropyl-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(207) ##STR00148##

(208) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 18.7 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-cyclopropyl-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-86), and 21.2 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-cyclopropyl-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-86). MS (ESI): mass calcd. for C.sub.32H.sub.28Cl.sub.2N.sub.4O.sub.3 586.15 m/z found 587.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.57 (brs, 1H), 7.53-6.47 (m, 9H), 4.07-4.03 (m, 1H), 3.78 (s, 3H), 2.21 (s, 3H), 2.01-2.00 (m, 1H), 1.16 (d, 3H, J=6.4 Hz), 1.05-1.00 (m, 4H), 0.64 (d, 3H, J=6.4 Hz).

Example 87

6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-methoxy-4-(trifluoromethoxy)phenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(209) ##STR00149##

(210) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 45.1 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-methoxy-4-(trifluoromethoxy)phenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-87), and 44.6 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-methoxy-4-(trifluoromethoxy)phenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-87). MS (ESI): mass calcd. for C.sub.30H.sub.23Cl.sub.2F.sub.3N.sub.4O.sub.4, 630.10 m/z found 631.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.74 (brs, 1H), 7.60-6.48 (m, 9H), 4.07-4.02 (m, 1H), 3.84 (s, 3H), 2.22 (s, 3H), 1.14 (d, 3H, J=4.8 Hz), 0.64 (d, 3H, J=4.8 Hz).

Example 88

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-ethoxy-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(211) ##STR00150##

(212) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 36.2 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-ethoxy-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-88), and 42.5 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-ethoxy-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-88). MS (ESI): mass calcd. for C.sub.31H.sub.28Cl.sub.2N.sub.4O.sub.4 590.15 m/z found 591.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.54 (brs, 1H), 7.54-6.95 (m, 9H), 4.14-4.04 (m, 3H), 3.77 (s, 3H), 2.22 (s, 3H), 1.36 (t, 3H, J=6.8 Hz), 1.05 (d, 3H, J=5.2 Hz), 0.62 (d, 3H, J=5.2 Hz).

Example 89

6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-3′-isopropyl-2′-(4-isopropyl-2-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(213) ##STR00151##

(214) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 43.2 mg of (S)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-3′-isopropyl-2′-(4-isopropyl-2-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-89), and 32.4 mg of (R)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-3′-isopropyl-2′-(4-isopropyl-2-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-89). MS (ESI): mass calcd. for C.sub.31H.sub.29Cl.sub.2N.sub.5O.sub.3 589.16, m/z found 590.2 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.69 (brs, 1H), 8.50 (d, 1H, J=8.0 Hz), 7.64-7.00 (m, 7H), 4.09-4.06 (m, 1H), 3.79 (s, 3H), 3.01-2.94 (m, 1H), 2.42 (s, 3H), 1.35 (d, 3H, J=7.6 Hz), 1.27 (d, 3H, J=7.6 Hz), 1.07 (d, 3H, J=4.0 Hz), 0.64 (d, 3H, J=4.0 Hz).

Example 90

2′-(2-amino-4-methoxypyrimidin-5-yl)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(215) ##STR00152##

(216) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 19.0 mg of (S)-2′-(2-amino-4-methoxypyrimidin-5-yl)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-90), and 17.4 mg of (R)-2′-(2-amino-4-methoxypyrimidin-5-yl)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-90). MS (ESI): mass calcd. for C.sub.27H.sub.23Cl.sub.2N.sub.7O.sub.3 563.12, m/z found 564.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.57 (brs, 1H), 8.14 (d, 1H, J=4.8 Hz), 7.54-6.96 (m, 8H), 4.18-4.13 (m, 1H), 3.84 (s, 3H), 2.20 (s, 3H), 1.08 (d, 3H, J=4.4 Hz), 0.67 (d, 3H, J=4.4 Hz).

Example 91

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-(dimethylamino)-2-methoxy-5-methylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(217) ##STR00153##

(218) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 29.2 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-(dimethylamino)-2-methoxy-5-methylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-91), and 17.8 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-(dimethylamino)-2-methoxy-5-methylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-91). MS (ESI): mass calcd. for C.sub.32H.sub.31Cl.sub.2N.sub.5O.sub.3 603.18, m/z found 604.2 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.51 (brs, 1H), 7.53-6.47 (m, 8H), 4.11-4.08 (m, 1H), 3.77 (s, 3H), 2.73 (s, 6H), 2.22 (s, 3H), 2.07 (s, 3H), 1.06 (d, 3H, J=4.4 Hz), 0.62 (d, 3H, J=4.4 Hz).

Example 92

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(5-fluoro-2,4-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(219) ##STR00154##

(220) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 29.1 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(5-fluoro-2,4-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-92), and 33.8 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(5-fluoro-2,4-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-92). MS (ESI): mass calcd. for C.sub.30H.sub.25Cl.sub.2FN.sub.4O.sub.4 594.13, m/z found 595.2 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.75 (brs, 1H), 7.53-6.47 (m, 8H), 4.10-4.07 (m, 1H), 3.96 (s, 3H), 3.82 (s, 3H), 2.21 (s, 3H), 1.07 (d, 3H, J=4.4 Hz), 0.63 (d, 3H, J=4.4 Hz).

Example 93

6-chloro-5′-(3-chlorophenyl)-3′-isopropyl-2′-(4-isopropyl-2-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(221) ##STR00155##

(222) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 125.0 mg of (S)-6-chloro-5′-(3-chlorophenyl)-3′-isopropyl-2′-(4-isopropyl-2-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-93), and 132.7 mg of (R)-6-chloro-5′-(3-chlorophenyl)-3′-isopropyl-2′-(4-isopropyl-2-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-93). MS (ESI): mass calcd. for C.sub.31H.sub.28Cl.sub.2N.sub.4O.sub.3 574.15, m/z found 575.2 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.58 (brs, 1H), 7.49 (d, 1H, J=8.0 Hz), 7.38-6.95 (m, 9H), 4.09-4.02 (m, 1H), 3.78 (s, 3H), 3.01-2.94 (m, 1H), 1.27 (d, 6H, J=7.2 Hz), 1.09 (d, 3H, J=6.4 Hz), 0.59 (d, 3H, J=6.4 Hz).

Example 94

6-chloro-5′-(5-chloro-2-fluorophenyl)-2′-(4-ethoxy-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(223) ##STR00156##

(224) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 7.8 mg of (S)-6-chloro-5′-(5-chloro-2-fluorophenyl)-2′-(4-ethoxy-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-94), and 15.2 mg of (R)-6-chloro-5′-(5-chloro-2-fluorophenyl)-2′-(4-ethoxy-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-94). MS (ESI): mass calcd. for C.sub.30H.sub.25Cl.sub.2FN.sub.4O.sub.4 594.12, m/z found 595.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.01 (brs, 1H), 7.48-6.64 (m, 9H), 4.14-4.04 (m, 3H), 3.76 (s, 3H), 1.37-1.18 (m, 3H), 1.04 (d, 3H, J=6.4 Hz), 0.62 (d, 3H, J=6.4 Hz).

Example 95

6-chloro-5′-(3-chlorophenyl)-2′-(6-isopropoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(225) ##STR00157##

(226) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 100.8 mg of (S)-6-chloro-5′-(3-chlorophenyl)-2′-(6-isopropoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-95), and 108.8 mg of (R)-6-chloro-5′-(3-chlorophenyl)-2′-(6-isopropoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-95). MS (ESI): mass calcd. for C.sub.30H.sub.27Cl.sub.2N.sub.5O.sub.4 591.14, m/z found 592.1[M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.53 (brs, 1H), 8.08 (s, 1H), 7.48 (d, 1H, J=8.4 Hz), 7.38 (d, 1H, J=8.0 Hz), 7.34 (d, 1H, J=8.4 Hz), 7.14 (d, 2H, J=9.2 Hz), 7.00 (d, 1H, J=1.6 Hz), 6.97 (d, 1H, J=7.2 Hz), 6.51 (s, 1H), 5.36-5.29 (m, 1H), 4.11-4.04 (m, 1H), 3.82 (s, 1H), 1.33 (d, 6H, J=6.0 Hz), 1.11 (d, 3H, J=6.4 Hz), 0.61 (d, 3H, J=6.4 Hz).

Example 96

6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(6-ethoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(227) ##STR00158##

(228) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 27.1 mg of (S)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(6-ethoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-96), and 29.6 mg of (R)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(6-ethoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-96). MS (ESI): mass calcd. for C.sub.29H.sub.26Cl.sub.2N.sub.6O.sub.4 592, m/z found 593.1[M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.80 (brs, 1H), 8.50 (d, 1H, J=8.0 Hz), 8.12 (d, 1H, J=4.8 Hz), 7.64-7.00 (m, 4H), 6.58 (s, 1H), 4.40 (q, 2H, J=7.2 Hz), 4.09-4.04 (m, 1H), 3.84 (s, 3H), 2.27 (s, 3H), 1.36 (t, 3H, J=7.2 Hz), 1.08 (d, 3H, J=6.8 Hz), 0.65 (d, 3H, J=4.0 Hz).

Example 97

6-chloro-5′-(5-chloro-2-fluorophenyl)-2′-(2-ethoxy-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(229) ##STR00159##

(230) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 0.8 mg of (S)-6-chloro-5′-(5-chloro-2-fluorophenyl)-2′-(2-ethoxy-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-97), and 3.3 mg of (R)-6-chloro-5′-(5-chloro-2-fluorophenyl)-2′-(2-ethoxy-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-97). MS (ESI): mass calcd. for C.sub.28H.sub.23Cl.sub.2FN.sub.6O.sub.4 596.11, m/z found 597.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.59 (brs, 1H), 8.51 (s, 1H), 7.48-7.00 (m, 6H), 4.46 (q, 2H, J=6.8 Hz), 4.10-4.07 (m, 1H), 3.94 (s, 3H), 1.39 (t, 3H, J=6.8 Hz), 1.11 (d, 3H, J=6.4 Hz), 0.66 (d, 3H, J=6.4 Hz).

Example 98

6-chloro-5′-(5-chloro-2-fluorophenyl)-2′-(6-ethoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(231) ##STR00160##

(232) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 17.5 mg of(S)-6-chloro-5′-(5-chloro-2-fluorophenyl)-2′-(6-ethoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-98), and 20.7 mg of (R)-6-chloro-5′-(5-chloro-2-fluorophenyl)-2′-(6-ethoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-98). MS (ESI): mass calcd. for C.sub.29H.sub.24Cl.sub.2FN.sub.5O.sub.4 595.11, m/z found 596.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.60 (brs, 1H), 8.11 (s, 1H), 7.48-7.00 (m, 6H), 6.57 (s, 1H), 4.40 (q, 2H, J=6.8 Hz), 4.08-4.04 (m, 1H), 3.83 (s, 3H), 1.35 (t, 3H, J=6.8 Hz), 1.08 (d, 3H, J=6.4 Hz), 0.64 (d, 3H, J=6.4 Hz).

Example 99

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-(ethyl(methyl)amino)-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(233) ##STR00161##

(234) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 42.0 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-(ethyl(methyl)amino)-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-99), and 41.2 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-(ethyl(methyl)amino)-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-99). MS (ESI): mass calcd. for C.sub.32H.sub.31Cl.sub.2N.sub.5O.sub.3 603, m/z found 604.2[M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.69 (brs, 1H), 7.54-6.96 (m, 7H), 6.46-6.32 (m, 2H), 4.11-4.10 (m, 1H), 3.76 (s, 3H), 3.47-3.45 (m, 2H), 2.95 (s, 3H), 2.21 (s, 3H), 1.11-1.07 (m, 6H), 0.62 (d, 3H, J=6.4 Hz).

Example 100

6-chloro-5′-(3-chlorophenyl)-2′-(4-ethoxy-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(235) ##STR00162##

(236) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 19.1 mg of (S)-6-chloro-5′-(3-chlorophenyl)-2′-(4-ethoxy-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-100), and 21.3 mg of (R)-6-chloro-5′-(3-chlorophenyl)-2′-(4-ethoxy-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-100). MS (ESI): mass calcd. for C.sub.30H.sub.26Cl.sub.2N.sub.4O.sub.4 576.13, m/z found 577.2 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.56 (brs, 1H), 7.45 (d, 1H, J=8.0 Hz), 7.37-6.94 (m, 7H), 6.69 (s, 1H), 6.66 (d, 1H, J=8.4 Hz), 7.00-6.94 (m, 2H), 4.14-4.03 (m, 3H), 3.76 (s, 3H), 1.37 (t, 3H, J=6.8 Hz), 1.04 (d, 3H, J=6.4 Hz), 0.60 (d, 3H, J=6.4 Hz).

Example 101

2′-(4-(tert-butyl)-2-methoxyphenyl)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(237) ##STR00163##

(238) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 17.1 mg of (S)-2′-(4-(tert-butyl)-2-methoxyphenyl)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-101), and 17.2 mg of (R)-2′-(4-(tert-butyl)-2-methoxyphenyl)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-101). MS (ESI): mass calcd. for C.sub.33H.sub.32Cl.sub.2N.sub.4O.sub.3 602.2, m/z found 603.4 [M+H].sup.+. H-NMR (400 MHz, DMSO-d.sub.6) δ 7.56-6.48 (m, 9H), 4.08-4.07 (m, 1H), 3.81 (s, 3H), 2.22 (s, 3H), 1.35 (s, 9H), 1.07 (d, 3H, J=5.2 Hz), 0.62 (d, 3H, J=5.2 Hz).

Example 102

6-chloro-5′-(3-chlorophenyl)-2′-(6-ethoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(239) ##STR00164##

(240) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 53.4 mg of (S)-6-chloro-5′-(3-chlorophenyl)-2′-(6-ethoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-102), and 55.0 mg of (R)-6-chloro-5′-(3-chlorophenyl)-2′-(6-ethoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-102). MS (ESI): mass calcd. for C.sub.29H.sub.25Cl.sub.2N.sub.5O.sub.4 577.13, m/z found 578.4 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.54 (brs, 1H), 8.09 (s, 1H), 7.48 (d, 1H, J=8.0 Hz), 7.38 (d, 1H, J=8.4 Hz), 7.34 (s, 1H), 7.14-7.12 (m, 2H), 7.00 (s, 1H), 6.97 (d, 1H, J=7.2 Hz), 6.57 (s, 1H), 4.40 (q, 2H, J=6.8 Hz), 4.07-4.02 (m, 1H), 3.83 (s, 3H), 1.35 (t, 3H, J=6.8 Hz), 1.10 (d, 3H, J=6.4 Hz), 0.62 (d, 3H, J=6.4 Hz).

Example 103

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-cyclopropyl-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(241) ##STR00165##

(242) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 39.5 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-cyclopropyl-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-103), and 32.7 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-cyclopropyl-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-103). MS (ESI): mass calcd. for C.sub.31H.sub.27Cl.sub.2N.sub.5O.sub.3 587, m/z found 588.4 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.72 (brs, 1H), 8.30 (d, 1H, J=4.0 Hz), 7.57-6.97 (m, 7H), 4.08-4.06 (m, 2H), 3.88 (s, 3H), 2.21 (s, 3H), 2.07-1.98 (m, 4H), 1.08 (d, 3H, J=6.0 Hz), 0.66 (d, 3H, J=6.0 Hz).

Example 104

6-chloro-5′-(3-chlorophenyl)-2′-(4-(dimethylamino)-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(243) ##STR00166##

(244) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 80.2 mg of (S)-6-chloro-5′-(3-chlorophenyl)-2′-(4-(dimethylamino)-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-104), and 70.0 mg of (R)-6-chloro-5′-(3-chlorophenyl)-2′-(4-(dimethylamino)-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-104). MS (ESI): mass calcd. for C.sub.30H.sub.27C.sub.12N.sub.5O.sub.3 575.15, m/z found 576.6[M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.50 (brs, 1H), 7.45 (d, 1H, J=8.0 Hz), 7.37-7.30 (m, 2H), 7.17-7.11 (m, 3H), 7.00-6.94 (m, 2H), 6.40-6.35 (m, 2H), 4.13-4.06 (m, 1H), 4.06 (s, 3H), 3.76 (s, 3H), 2.99 (s, 6H), 1.09 (d, 3H, J=6.0 Hz), 0.60 (d, 3H, J=6.0 Hz).

Example 105

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-(diethylamino)-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(245) ##STR00167##

(246) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 11.6 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-(diethylamino)-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-105), and 16.3 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-(diethylamino)-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-105). MS (ESI): mass calcd. for C.sub.33H.sub.33Cl.sub.2N.sub.5O.sub.3 617.19, m/z found 618.5 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.68 (brs, 1H), 7.54-6.94 (m, 7H), 6.46-6.27 (m, 2H), 4.14-4.11 (m, 1H), 3.75 (s, 3H), 3.42-3.40 (m, 4H), 2.21 (s, 3H), 1.16-1.12 (m, 6H), 1.06 (d, 3H, J=5.2 Hz), 0.62 (d, 3H, J=5.2 Hz).

Example 106

6-chloro-5′-(3-chlorophenyl)-2′-(6-cyclopropyl-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(247) ##STR00168##

(248) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 47.4 mg of (S)-6-chloro-5′-(3-chlorophenyl)-2′-(6-cyclopropyl-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-106), and 57.5 mg of (R)-6-chloro-5′-(3-chlorophenyl)-2′-(6-cyclopropyl-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-106). MS (ESI): mass calcd. for C.sub.30H.sub.25Cl.sub.2N.sub.5O.sub.3 573, m/z found 574.3[M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.56 (brs, 1H), 8.33 (s, 1H), 7.49 (d, 1H, J=8.0 Hz), 7.36-6.95 (m, 8H), 4.08-4.06 (m, 1H), 3.89 (s, 3H), 2.15-2.00 (m, 1H), 1.05 (d, 3H, J=6.0 Hz), 1.03-0.98 (m, 4H), 0.62 (d, 3H, J=6.0 Hz).

Example 107

6-chloro-5′-(3-chlorophenyl)-2′-(4-ethyl-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(249) ##STR00169##

(250) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 49.1 mg of (S)-6-chloro-5′-(3-chlorophenyl)-2′-(4-ethyl-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-107), and 39.8 mg of (R)-6-chloro-5′-(3-chlorophenyl)-2′-(4-ethyl-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-107). MS (ESI): mass calcd. for C.sub.30H.sub.26Cl.sub.2N.sub.4O.sub.3 560.13, m/z found 561.3 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.48 (brs, 1H), 7.48 (d, 1H, J=8.0 Hz), 7.37-6.94 (m, 9H), 4.09-4.02 (m, 1H), 3.77 (s, 3H), 2.72 (q, 2H, J=7.6 Hz), 1.26 (t, 3H, J=7.6 Hz), 1.04 (d, 3H, J=6.0 Hz), 0.61 (d, 3H, J=6.0 Hz).

Example 108

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-cyclopropyl-2,6-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(251) ##STR00170##

(252) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 28.4 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-cyclopropyl-2,6-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-108), and 29.9 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-cyclopropyl-2,6-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-108). MS (ESI): mass calcd. for C.sub.33H.sub.30Cl.sub.2N.sub.4O.sub.4 616.16, m/z found 617.4 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.66 (brs, 1H), 7.45-6.48 (m, 8H), 3.89-3.88 (m, 1H), 3.73 (s, 3H), 3.70 (s, 3H), 2.23 (s, 3H), 2.07-2.00 (m, 1H), 1.01-0.99 (m, 5H), 0.84-0.83 (m, 2H), 0.60 (d, 3H, J=6.8 Hz).

Example 109

6-chloro-5′-(3-chlorophenyl)-3′-isopropyl-2′-(2-methoxy-4-methylphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(253) ##STR00171##

(254) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 34.0 mg of (S)-6-chloro-5′-(3-chlorophenyl)-3′-isopropyl-2′-(2-methoxy-4-methylphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-[108]109), and 43.5 mg of (R)-6-chloro-5′-(3-chlorophenyl)-3′-isopropyl-2′-(2-methoxy-4-methylphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-[108]109). MS (ESI): mass calcd. For C.sub.29H.sub.24Cl.sub.2N.sub.4O.sub.3 546.12, m/z found 547.4[M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.53 (brs, 1H), 7.47-6.90 (m, 10H), 4.07-4.02 (m, 1H), 3.76 (s, 3H), 2.39 (s, 3H), 1.04 (d, 3H, J=6.0 Hz), 0.59 (d, 3H, J=6.0 Hz).

Example 110

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-cyclopropoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(255) ##STR00172##

(256) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 13.6 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-cyclopropoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-[109]110), and 13.1 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-cyclopropoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-[109]110). MS (ESI): mass calcd. For C.sub.31H.sub.27Cl.sub.2N.sub.5O.sub.4 603.14, m/z found 604.3 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.73 (brs, 1H), 8.16-6.48 (m, 8H), 4.31-4.30 (m, 1H), 4.07-4.06 (m, 1H), 3.84 (s, 3H), 2.22 (s, 3H), 1.08 (d, 3H, J=5.6 Hz), 0.82-0.80 (m, 2H), 0.79-0.71 (m, 2H), 0.65 (d, 3H, J=5.6 Hz).

Example 111

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-(dimethylamino)-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(257) ##STR00173##

(258) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 44.9 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-(dimethylamino)-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-[110]111), and 47.3 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-(dimethylamino)-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′ (5′H)-dione (R-[110]111). MS (ESI): mass calcd. For C.sub.29H.sub.27Cl.sub.2N.sub.7O.sub.3 591, m/z found 592.4 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.52 (brs, 1H), 7.98-6.21 (m, 8H), 4.11-4.07 (m, 1H), 3.84 (s, 3H), 3.10 (s, 6H), 2.22 (s, 3H), 1.07 (d, 3H, J=6.0 Hz), 0.63 (d, 3H, J=6.0 Hz)

Example 112

6-chloro-5′-(3-chlorophenyl)-2′-(2-(dimethylamino)-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′ H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′ (5′ H)-dione

(259) ##STR00174##

(260) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 50.9 mg of (S)-6-chloro-5′-(3-chlorophenyl)-2′-(2-(dimethylamino)-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-[111]112), and 46.6 mg of (R)-6-chloro-5′-(3-chlorophenyl)-2′-(2-(dimethylamino)-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-[111]112). MS (ESI): mass calcd. For C.sub.28H.sub.25Cl.sub.2N.sub.7O.sub.3 577.13, m/z found 578.3 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.52 (brs, 1H), 8.23 (s, 1H), 7.65-6.94 (m, 7H), 4.16-4.09 (m, 1H), 3.89 (s, 3H), 3.19 (s, 6H), 1.11 (d, 3H, J=6.8 Hz), 0.64 (d, 3H, J=6.4 Hz).

Example 113

6-chloro-5′-(3-chlorophenyl)-2′-(6-(dimethylamino)-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(261) ##STR00175##

(262) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 45.0 mg of (S)-6-chloro-5′-(3-chlorophenyl)-2′-(6-(dimethylamino)-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-[112]113), and 34.4 mg of (R)-6-chloro-5′-(3-chlorophenyl)-2′-(6-(dimethylamino)-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-[112]113). MS (ESI): mass calcd. For C.sub.29H.sub.26Cl.sub.2N.sub.6O.sub.3 576, m/z found 577.4 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.60 (brs, 1H), 8.06 (s, 1H), 7.44-6.96 (m, 7H), 6.39 (s, 1H), 4.12-4.05 (m, 1H), 3.92 (s, 3H), 3.20 (s, 6H), 1.12 (d, 3H, J=6.8 Hz), 0.63 (d, 3H, J=6.4 Hz).

Example 114

6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-methoxy-2-(10zetidine10e-1-yl)pyrimidin-5-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′ (5′ H)-dione

(263) ##STR00176##

(264) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 10.1 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-methoxy-2-(pyrrolidine-1-yl)pyrimidin-5-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-[113]114), and 13.5 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-methoxy-2-(10zetidine10e-1-yl)pyrimidin-5-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-[113]114). MS (ESI): mass calcd. For C.sub.31H.sub.29Cl.sub.2N.sub.7O.sub.3 617.17, m/z found 618.2[M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.63 (brs, 1H), 8.24 (d, 1H, J=4.4 Hz), 7.54-6.47 (m, 6H), 4.13-4.12 (m, 1H), 3.90 (s, 3H), 3.69-3.56 (m, 4H), 2.21 (s, 3H), 2.06-1.95 (m, 4H), 1.09 (d, 3H, J=5.2 Hz), 0.66 (d, 3H, J=6.0 Hz).

Example 115

6-chloro-5′-(3-chlorophenyl)-2′-(4,6-dimethoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(265) ##STR00177##

(266) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 171.8 mg of (S)-6-chloro-5′-(3-chlorophenyl)-2′-(4,6-dimethoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-[114]115), and 137.4 mg of (R)-6-chloro-5′-(3-chlorophenyl)-2′-(4,6-dimethoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-[114]115). MS (ESI): mass calcd. For C.sub.28H.sub.23Cl.sub.2N.sub.5O.sub.4 563.11, m/z found 564.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.57 (brs, 1H), 8.11 (s, 1H), 7.48-6.95 (m, 7H), 6.58 (s, 1H), 4.09-4.02 (m, 1H), 3.92 (s, 3H), 3.83 (s, 3H), 1.04 (d, 3H, J=3.6 Hz), 0.63 (d, 3H, J=6.4 Hz).

Example 116

6-chloro-5′-(3-chlorophenyl)-2′-(4-cyclopropyl-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(267) ##STR00178##

(268) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 9.2 mg of (S)-6-chloro-5′-(3-chlorophenyl)-2′-(4-cyclopropyl-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-[115]116), and 9.2 mg of (R)-6-chloro-5′-(3-chlorophenyl)-2′-(4-cyclopropyl-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-[115]116). MS (ESI): mass calcd. For C.sub.31H.sub.26Cl.sub.2N.sub.4O.sub.3 572.14, m/z found 573.2 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.06 (brs, 1H), 7.46-6.77 (m, 10H), 4.07-4.01 (m, 1H), 3.77 (s, 3H), 2.01-1.99 (m, 1H), 1.24-0.79 (m, 7H), 0.60 (d, 3H, J=4.4 Hz).

Example 117

2′-(2-(12zetidine-1-yl)-4-methoxypyrimidin-5-yl)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(269) ##STR00179##

(270) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 42.3 mg of (S)-2′-(2-(12zetidine-1-yl)-4-methoxypyrimidin-5-yl)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-[116]117), and 41.8 mg of (R)-2′-(2-(12zetidine-1-yl)-4-methoxypyrimidin-5-yl)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′ H)-dione (R-[116]117). MS (ESI): mass calcd. For C.sub.30H.sub.27Cl.sub.2N.sub.7O.sub.3 603.15, m/z found 604.4 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.27 (brs, 1H), 8.22 (d, 1H, J=4.8 Hz) 7.54-6.47 (m, 6H), 4.14 (t, 4H, J=7.2 Hz), 3.87 (s, 3H), 2.36-2.32 (m, 2H), 2.22 (s, 3H), 1.08 (d, 3H, J=5.2 Hz), 0.66 (d, 3H, J=5.6 Hz).

Example 118

(271) 6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-methoxy-2-methylpyrimidin-5-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′ (5′H)-dione

(272) ##STR00180##

(273) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 61.9 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-methoxy-2-methylpyrimidin-5-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-[117]118), and 62.0 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-methoxy-2-methylpyrimidin-5-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-[117]118). MS (ESI): mass calcd. For C.sub.28H.sub.24Cl.sub.2N.sub.6O.sub.3 562, m/z found 563.4[M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.73 (brs, 1H), 8.62 (d, 1H, J=6.4 Hz), 7.57-6.48 (m, 6H), 4.15-4.12 (m, 1H), 3.96 (s, 3H), 2.63 (s, 3H), 2.22 (s, 3H), 1.09 (d, 3H, J=6.4 Hz), 0.66 (d, 3H, J=6.4 Hz).

Example 119

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-(ethyl(methyl)amino)-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(274) ##STR00181##

(275) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 40.7 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-(ethyl(methyl)amino)-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-[118]119), and 24.5 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-(ethyl(methyl)amino)-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-[118]119). MS (ESI): mass calcd. For C.sub.30H.sub.29Cl.sub.2N.sub.7O.sub.3 605.17, m/z found 606.4[M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.61 (brs, 1H), 8.24 (d, 1H, J=4.0 Hz), 7.55-6.47 (m, 6H), 4.16-4.15 (m, 1H), 3.89 (s, 3H), 3.69-3.68 (m, 2H), 3.15 (s, 3H), 2.21 (s, 3H), 1.23-1.16 (m, 3H), 1.09 (d, 3H, J=5.2 Hz), 0.66 (d, 3H, J=5.2 Hz).

Example 120

6-chloro-5′-(3-chlorophenyl)-3′-isopropyl-2′-(2-methoxy-4-(trifluoromethoxy)phenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(276) ##STR00182##

(277) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 115.1 mg of (S)-6-chloro-5′-(3-chlorophenyl)-3′-isopropyl-2′-(2-methoxy-4-(trifluoromethoxy)phenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-[119]120), and 44.0 mg of (R)-6-chloro-5′-(3-chlorophenyl)-3′-isopropyl-2′-(2-methoxy-4-(trifluoromethoxy)phenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-[119]120). MS (ESI): mass calcd. For Chemical Formula: C.sub.29H.sub.21Cl.sub.2F.sub.3N.sub.4O.sub.4, Exact Mass: 616.09, m/z found 617.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.51 (brs, 1H), 7.57-7.47 (m, 2H), 7.38-7.34 (m, 2H), 7.21 (s, 1H), 7.14-7.09 (m, 3H), 7.00-6.96 (m, 2H), 4.06-4.03 (m, 1H), 3.88 (s, 3H), 1.10 (d, 3H, J=4.4 Hz), 0.62 (d, 3H, J=4.4 Hz).

Example 121

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-cyclopropyl-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(278) ##STR00183##

(279) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 9.9 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-cyclopropyl-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-[120]121), and 9.4 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-cyclopropyl-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′ (5′H)-dione (R-[120]121). MS (ESI): mass calcd. For C.sub.30H.sub.26Cl.sub.2N.sub.6O.sub.3 588.14, m/z found 589.4[M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.76 (brs, 1H), 8.54 (d, 1H, J=6.4 Hz), 7.56-6.98 (m, 7H), 4.15-4.14 (m, 1H), 3.94 (s, 3H), 2.21 (s, 3H), 2.07-1.99 (m, 1H), 1.35-1.08 (m, 7H), 0.66 (d, 3H, J=6.0 Hz).

Example 122

6-chloro-5′-(3-chlorophenyl)-2′-(2-cyclopropyl-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(280) ##STR00184##

(281) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 13.1 mg of (S)-6-chloro-5′-(3-chlorophenyl)-2′-(2-cyclopropyl-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-[121]122), and 13.3 mg of (R)-6-chloro-5′-(3-chlorophenyl)-2′-(2-cyclopropyl-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-[121]122). MS (ESI): mass calcd. For C.sub.29H.sub.24Cl.sub.2N.sub.6O.sub.3 574.13, m/z found 575.4[M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.55 (brs, 1H), 8.52 (s, 1H), 7.48 (d, 1H, J=8.0 Hz), 7.38-7.34 (m, 2H), 7.15-7.12 (m, 2H), 7.01-0.95 (m, 2H), 4.14-4.11 (m, 1H), 3.93 (s, 3H), 2.22-1.19 (m, 1H), 1.12-1.10 (m, 6H), 0.64 (d, 3H, J=6.4 Hz).

Example 123

6-chloro-5′-(3-chlorophenyl)-2′-(2-ethoxy-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(282) ##STR00185##

(283) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 38.8 mg of (S)-6-chloro-5′-(3-chlorophenyl)-2′-(2-ethoxy-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-[122]123), and 38.7 mg of (R)-6-chloro-5′-(3-chlorophenyl)-2′-(2-ethoxy-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-[122]123). MS (ESI): mass calcd. For C.sub.28H.sub.24Cl.sub.2N.sub.6O.sub.4 578.12, m/z found 579.3 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.33 (brs, 1H), 8.49 (s, 1H), 7.48 (d, 1H, J=8.4 Hz), 7.38-7.34 (m, 2H), 7.15-7.11 (m, 2H), 7.01 (s, 1H), 6.97-6.95 (m, 1H), 4.46 (q, 2H, J=7.2 Hz), 4.19-4.14 (m, 1H), 3.93 (s, 3H), 1.39 (t, 3H, J=7.2 Hz), 1.12 (d, 3H, J=6.8 Hz), 0.65 (d, 3H, J=6.4 Hz).

Example 124

6-chloro-5′-(3-chlorophenyl)-2′-(2-isopropoxy-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′ (5′H)-dione

(284) ##STR00186##

(285) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 43.9 mg of (S)-6-chloro-5′-(3-chlorophenyl)-2′-(2-isopropoxy-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-[123]124), and 45.7 mg of (R)-6-chloro-5′-(3-chlorophenyl)-2′-(2-isopropoxy-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-[123]124). MS (ESI): mass calcd. For C.sub.29H.sub.26Cl.sub.2N.sub.6O.sub.4 592.14, m/z found 593.4 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.58 (brs, 1H), 8.48 (s, 1H), 7.48-6.96 (m, 7H), 5.32-5.26 (m, 1H), 4.20-4.14 (m, 1H), 2.31 (s, 3H), 1.38 (d, 6H, J=6.0 Hz), 1.13 (d, 3H, J=6.8 Hz), 0.65 (d, 3H, J=6.8 Hz).

Example 125

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-(dimethylamino)-5-ethyl-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(286) ##STR00187##

(287) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 53.23 mg of 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-(dimethylamino)-5-ethyl-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione. MS (ESI): mass calcd. for C.sub.33H.sub.33Cl.sub.2N.sub.5O.sub.3 617.20, m/z found 618.4 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.47 (brs, 1H), 7.95-6.47 (m, 8H), 4.11-4.08 (m, 1H), 3.78 (s, 3H), 2.74 (s, 6H), 2.66-2.61 (m, 2H), 2.22 (s, 3H), 1.238-1.071 (m, 6H), 0.68 (d, 3H, J=6.4 Hz).

Example 126

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-isopropoxy-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(288) ##STR00188##

(289) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 28.9 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-isopropoxy-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-126), and 35.5 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-isopropoxy-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-126). MS (ESI): mass calcd. for C.sub.30H.sub.28Cl.sub.2N.sub.6O.sub.4 606.15, m/z found 607.4 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.76 (brs, 1H), 8.50 (d, 1H, J=6.4 Hz), 7.57-6.49 (m, 6H), 5.32-5.26 (m, 1H), 4.20-4.16 (m, 1H), 3.94 (s, 3H), 2.22 (s, 3H), 1.38 (d, 6H, J=6.0 Hz), 1.09 (d, 3H, J=4.4 Hz), 0.67 (d, 3H, J=6.0 Hz).

Example 127

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-ethoxy-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-prrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(290) ##STR00189##

(291) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 27.9 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-ethoxy-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-127), and 32.0 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-ethoxy-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-127). MS (ESI): mass calcd. for C.sub.29H.sub.26Cl.sub.2N.sub.6O.sub.4 592.14, m/z found 593.4 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.75 (brs, 1H), 8.52 (d, 1H, J=6.8 Hz), 7.567-6.486 (m, 6H), 4.46 (q, 2H, J=7.2 Hz), 4.18-4.09 (m, 1H), 3.94 (s, 3H), 2.21 (s, 3H), 1.39 (t, 3H, J=7.2 Hz), 1.09 (d, 3H, J=4.8 Hz), 0.67 (d, 3H, J=6.0 Hz).

Example 128

4-(6-chloro-5′-(3-chlorophenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-3-methoxybenzonitrile

(292) ##STR00190##

(293) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 35.3 mg of (S)-4-(6-chloro-5′-(3-chlorophenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-3-methoxybenzonitrile (S-128), and 34.5 mg of (R)-4-(6-chloro-5′-(3-chlorophenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-3-methoxybenzonitrile (R-128). MS (ESI): mass calcd. for C.sub.29H.sub.21Cl.sub.2N.sub.5O.sub.3 557.10, m/z found 558.3 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.43 (brs, 1H), 7.73-6.96 (m, 10H), 4.06-4.04 (m, 1H), 3.86 (s, 3H), 1.04 (d, 3H, J=5.6 Hz), 0.61 (d, 3H, J=5.6 Hz).

Example 129

6-chloro-5′-(3-chlorophenyl)-3′-isopropyl-2′-(2-methoxy-4-(trifluoromethyl)phenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(294) ##STR00191##

(295) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 40.2 mg of (S)-6-chloro-5′-(3-chlorophenyl)-3′-isopropyl-2′-(2-methoxy-4-(trifluoromethyl)phenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-129), and 44.7 mg of (R)-6-chloro-5′-(3-chlorophenyl)-3′-isopropyl-2′-(2-methoxy-4-(trifluoromethyl)phenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-129). MS (ESI): mass calcd. for C.sub.29H.sub.21Cl.sub.2F.sub.3N.sub.4O.sub.3 600.1, m/z found 601.3 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.56 (brs, 1H), 7.68-6.95 (m, 10H), 4.07-4.04 (m, 1H), 3.88 (s, 3H), 1.10 (d, 3H, J=6.0 Hz), 0.62 (d, 3H, J=6.0 Hz).

Example 130

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-fluoro-4,6-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(296) ##STR00192##

(297) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 42.7 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-fluoro-4,6-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-130), and 30.0 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-fluoro-4,6-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-130). MS (ESI): mass calcd. for C.sub.30H.sub.25Cl.sub.2FN.sub.4O.sub.4 594.12, m/z found 595.3 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.75 (brs, 1H), 7.44-6.60 (m, 8H), 4.00 (s, 1H), 3.86-3.77 (m, 6H), 3.86 (s, 3H), 3.81 (d, 3H, J=2.8 Hz), 2.22 (s, 3H), 1.23-1.01 (m, 3H), 0.69-0.61 (m, 3H).

Example 131

6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(4,6-dimethoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(298) ##STR00193##

(299) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 45.5 mg of (S)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(4,6-dimethoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-131), and 50.5 mg of (R)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(4,6-dimethoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-131). MS (ESI): mass calcd. for C.sub.28H.sub.24Cl.sub.2N.sub.6O.sub.4 578, m/z found 579.3[M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.80 (brs, 1H), 8.50 (d, 1H, J=1.6 Hz), 8.48 (d, 1H, J=2.0 Hz), 8.14-7.00 (m, 4H), 6.60 (s, 1H), 4.09-4.06 (m, 1H), 3.92 (s, 3H), 3.84 (s, 3H), 2.27 (s, 3H), 1.08 (d, 3H, J=4.0 Hz), 0.65 (d, 3H, J=4.0 Hz).

Example 132

5-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-4-methoxypyridylmethylcyanide

(300) ##STR00194##

(301) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 4.9 mg of (S)-5-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-4-methoxypyridylmethylcyanide (S-132), and 5.4 mg of (R)-5-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-4-methoxypyridylmethylcyanide (R-132). MS (ESI): mass calcd. for C.sub.29H.sub.22Cl.sub.2N.sub.6O.sub.3 572.11, m/z found 573.4 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.36 (brs, 1H), 8.69 (d, 1H, J=6.8 Hz), 8.06 (s, 1H), 7.57-6.99 (m, 6H), 4.12-4.10 (m, 1H), 3.97 (s, 3H), 2.21 (s, 3H), 1.08 (d, 3H, J=7.6 Hz), 0.65 (d, 3H, J=7.6 Hz).

Example 133

6-chloro-5′-(5-chloro-2-fluorophenyl)-2′-(4,6-dimethoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(302) ##STR00195##

(303) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 63.3 mg of (S)-6-chloro-5′-(5-chloro-2-fluorophenyl)-2′-(4,6-dimethoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-133), and 66.9 mg of (R)-6-chloro-5′-(5-chloro-2-fluorophenyl)-2′-(4,6-dimethoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-133). MS (ESI): mass calcd. for Chemical Formula: C.sub.28H.sub.22Cl.sub.2FN.sub.5O.sub.4 581.10, m/z found 582.4 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.57 (brs, 1H), 8.13 (s, 1H), 7.48 (d, 1H, J=7.2 Hz), 7.36-7.32 (m, 2H), 7.15 (d, 1H, J=8.0 Hz), 7.06 (d, 1H, J=3.6 Hz), 7.05 (s, 1H), 6.59 (s, 1H), 4.09-4.05 (m, 1H), 3.92 (s, 3H), 3.84 (s, 3H), 1.10 (d, 3H, J=6.4 Hz), 0.64 (d, 3H, J=6.4 Hz).

Example 134

6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(2-ethoxy-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(304) ##STR00196##

(305) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 38.8 mg of (S)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(2-ethoxy-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-134), and 40.0 mg of (R)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(2-ethoxy-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-134). MS (ESI): mass calcd. for C.sub.28H.sub.25Cl.sub.2N.sub.7O.sub.4 593, m/z found 594.4[M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.79 (brs, 1H), 8.52-8.48 (m, 2H), 7.64-7.00 (m, 4H), 4.47 (q, 2H, J=6.8 Hz), 4.21-4.18 (m, 1H), 3.99 (s, 3H), 2.27 (s, 3H), 1.39 (t, 3H, J=6.8 Hz), 1.09 (d, 3H, J=6.4 Hz), 0.68 (d, 3H, J=6.4 Hz).

Example 135

6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(2-(dimethylamino)-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(306) ##STR00197##

(307) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 50.6 mg of (S)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(2-(dimethylamino)-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-135), and 50.9 mg of (R)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(2-(dimethylamino)-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-135). MS (ESI): mass calcd. for C.sub.28H.sub.26Cl.sub.2N.sub.8O.sub.3 592, m/z found 593.4 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.77 (brs, 1H), 8.50 (d, 1H, J=7.2 Hz), 8.26 (d, 1H, J=5.2 Hz), 7.62-6.99 (m, 4H), 4.17-4.14 (m, 1H), 3.90 (s, 3H), 3.19 (s, 6H), 2.26 (s, 3H), 1.09 (d, 3H, J=6.4 Hz), 0.68 (d, 3H, J=6.4 Hz).

Example 136

6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(2-isopropoxy-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(308) ##STR00198##

(309) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 33.0 mg of (S)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(2-isopropoxy-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-136), and 30.5 mg of (R)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(2-isopropoxy-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-136). MS (ESI): mass calcd. for C.sub.30H.sub.28Cl.sub.2N.sub.6O.sub.4 606 m/z found 607.4[M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.79 (brs, 1H), 8.51 (m, 2H), 7.63-7.00 (m, 4H), 5.32-5.28 (m, 1H), 4.22-4.16 (m, 1H), 3.94 (s, 3H), 2.27 (s, 3H), 1.37 (d, 6H, J=6.4 Hz), 1.09 (d, 3H, J=6.4 Hz), 0.68 (d, 3H, J=6.4 Hz).

Example 137

6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(6-isopropoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(310) ##STR00199##

(311) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 30.9 mg of (S)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(6-isopropoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-137), and 32.3 mg of (R)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(6-isopropoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-137). MS (ESI): mass calcd. for C.sub.30H.sub.28Cl.sub.2N.sub.6O.sub.4 606, m/z found 607.4 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.77 (brs, 1H), 8.50 (d, 1H, J=6.8 Hz), 8.11 (d, 3H, J=6.4 Hz), 7.64-7.00 (m, 4H), 6.52 (s, 1H), 5.35-5.32 (m, 1H), 4.10-4.07 (m, 1H), 3.83 (s, 3H), 2.27 (s, 3H), 1.33 (d, 6H, J=6.0 Hz), 1.08 (d, 3H, J=6.4 Hz), 0.66 (d, 3H, J=6.4 Hz).

Example 138

6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-methoxy-6-(trifluoromethyl)pyridin-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(312) ##STR00200##

(313) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 42.6 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-methoxy-6-(trifluoromethyl)pyridin-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-138), and 40.9 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-methoxy-6-(trifluoromethyl)pyridin-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-138). MS (ESI): mass calcd. for C.sub.29H.sub.22Cl.sub.2F.sub.3N.sub.5O.sub.3 615.10, m/z found 616.3 [M+H].sup.+. H-NMR (400 MHz, DMSO-d.sub.6) δ 11.75 (brs, 1H), 8.72 (d, 1H, J=6.8 Hz), 7.74 (s, 1H), 7.59-6.49 (m, 6H), 4.20-4.11 (m, 1H), 4.02 (s, 3H), 2.22 (s, 3H), 1.18 (d, 3H, J=6.4 Hz), 0.66 (d, 3H, J=6.4 Hz).

Example 139

6-chloro-5′-(3-chloro-5-fluorophenyl)-2′-(6-ethoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(314) ##STR00201##

(315) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 45.7 mg of(S)-6-chloro-5′-(3-chloro-5-fluorophenyl)-2′-(6-ethoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-139), and 42.1 mg of (R)-6-chloro-5′-(3-chloro-5-fluorophenyl)-2′-(6-ethoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-139). MS (ESI): mass calcd. for Chemical Formula: C.sub.29H.sub.24Cl.sub.2FN.sub.5O.sub.4 Exact Mass: 595.12, m/z found 596.5 [M+H].sup.+. H-NMR (400 MHz, DMSO-d.sub.6) δ 11.58 (brs, 1H), 8.08 (s, 1H), 7.49 (d, 1H, J=8.0 Hz), 7.38 (d, 1H, J=8.4 Hz), 7.16 (d, 1H, J=7.6 Hz), 7.06 (s, 1H), 6.96 (s, 1H), 6.92 (d, 1H, J=9.6 Hz), 6.56 (s, 1H), 4.40 (q, 2H, J=6.8 Hz), 4.07-4.02 (m, 1H), 3.83 (s, 3H), 1.35 (t, 3H, J=6.8 Hz), 1.11 (d, 3H, J=5.6 Hz), 0.62 (d, 3H, J=6.0 Hz).

Example 140

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-(2-fluoroethoxy)-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(316) ##STR00202##

(317) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 36.1 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-(2-fluoroethoxy)-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-140), and 31.5 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-(2-fluoroethoxy)-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-140). MS (ESI): mass calcd. for C.sub.29H.sub.25Cl.sub.2FN.sub.6O.sub.4 610.13, m/z found 611.4 [M+H].sup.+. H-NMR (400 MHz, DMSO-d.sub.6): δ 11.50 (brs, 1H), 8.539 (d, J=7.2 Hz, 1H), 7.57-6.48 (m, 6H), 4.86-4.61 (m, 4H), 4.19-4.16 (m, 1H), 3.96 (s, 3H), 2.145 (s, 3H), 1.09 (d, J=4.8 Hz, 3H), 0.66 (d, J=6.0 Hz, 3H).

Example 141

6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-methoxy-2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(318) ##STR00203##

(319) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 36.4 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-methoxy-2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-141), and 43.1 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-methoxy-2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-141). MS (ESI): mass calcd. for C.sub.28H.sub.21Cl.sub.2F.sub.3N.sub.6O.sub.4 646.11, m/z found 649.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.45 (brs, 1H), 8.60 (d, J=7.6 Hz, 1H), 7.56-6.49 (m, 6H), 5.15-5.01 (m, 2H), 4.21-4.15 (m, 1H), 3.99 (s, 3H), 2.07 (s, 3H), 1.08 (d, J=6.4 Hz, 3H), 0.66 (d, J=6.4 Hz, 3H).

Example 142

6-chloro-5′-(3-chlorophenyl)-3′-isopropyl-2′-(4-methoxy-6-(trifluoromethyl)pyridin-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(320) ##STR00204##

(321) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 20.9 mg of (S)-6-chloro-5′-(3-chlorophenyl)-3′-isopropyl-2′-(4-methoxy-6-(trifluoromethyl)pyridin-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-142), and 21.6 mg of (R)-6-chloro-5′-(3-chlorophenyl)-3′-isopropyl-2′-(4-methoxy-6-(trifluoromethyl)pyridin-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-142). MS (ESI): mass calcd. for C.sub.28H.sub.20Cl.sub.2F.sub.3N.sub.5O.sub.3 601.08, m/z found 602.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.56 (brs, 1H), 8.69 (s, 1H), 7.73 (s, 1H), 7.51 (d, 1H, J=8.8 Hz), 7.39-7.35 (m, 2H), 7.16-7.01 (m, 2H), 6.98-6.97 (m, 2H), 4.13-4.08 (m, 1H), 4.01 (s, 3H), 1.12 (d, 3H, J=6.4 Hz), 0.64 (d, 3H, J=6.4 Hz).

Example 143

6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(6-cyclopropyl-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(322) ##STR00205##

(323) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 23.6 mg of (S)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(6-cyclopropyl-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-143), and 23.8 mg of (R)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(6-cyclopropyl-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-143). MS (ESI): mass calcd. for C.sub.30H.sub.26Cl.sub.2N.sub.6O.sub.3 588, m/z found 589.2 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.76 (brs, 1H), 8.50 (d, 1H, J=8.0 Hz), 8.30 (d, 1H, J=3.6 Hz), 7.64-6.99 (m, 5H), 4.09-4.05 (m, 1H), 3.88 (s, 3H), 2.27 (s, 3H), 2.19-2.17 (m, 1H), 1.08 (d, 3H, J=6.4 Hz), 1.02-1.00 (m, 4H), 0.65 (d, 3H, J=4.0 Hz).

Example 144

6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-3′-isopropyl-2′-(2-methoxy-4-(trifluoromethyl)phenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(324) ##STR00206##

(325) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 40.9 mg of (S)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-3′-isopropyl-2′-(2-methoxy-4-(trifluoromethyl)phenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-144), and 47.4 mg of (R)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-3′-isopropyl-2′-(2-methoxy-4-(trifluoromethyl)phenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-144). MS (ESI): mass calcd. for C.sub.29H.sub.22Cl.sub.2F.sub.3N.sub.5O.sub.3 615, m/z found 616.4[M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.79 (brs, 1H), 8.51 (d, 1H, J=7.6 Hz), 7.71-7.00 (m, 7H), 4.10-4.07 (m, 1H), 3.90 (s, 3H), 2.28 (s, 3H), 1.07 (d, 3H, J=5.2 Hz), 0.66 (d, 3H, J=5.6 Hz).

Example 145

6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(4-cyclopropyl-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(326) ##STR00207##

(327) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 23.3 mg of (S)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(4-cyclopropyl-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-145), and 21.9 mg of (R)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(4-cyclopropyl-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-145). MS (ESI): mass calcd. for C.sub.31H.sub.27Cl.sub.2N.sub.5O.sub.3 587, m/z found 588.2 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.71 (brs, 1H), 8.50 (d, 1H, J=7.6 Hz), 7.62-6.78 (m, 7H), 4.09-4.06 (m, 1H), 3.78 (s, 3H), 2.27 (s, 3H), 2.01-1.99 (m, 1H), 1.06-1.01 (m, 5H), 0.85-0.80 (m, 2H), 0.62 (d, 3H, J=5.6 Hz).

Example 146

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-ethoxy-2-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(328) ##STR00208##

(329) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 17.2 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-ethoxy-2-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-146), and 21.7 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-ethoxy-2-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-146). MS (ESI): mass calcd. for C.sub.30H.sub.27Cl.sub.2N.sub.5O.sub.4 591.14, m/z found 592.2 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.55 (brs, 1H), 7.81-6.48 (m, 8H), 4.42 (q, 2H, J=7.2 Hz), 4.13-4.11 (m, 1H), 3.88 (s, 3H), 2.22 (s, 3H), 1.38 (t, 3H, J=7.2 Hz), 1.08 (d, 3H, J=6.4 Hz), 0.66 (d, 3H, J=6.8 Hz).

Example 147

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-(2,2-difluoroethoxy)-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(330) ##STR00209##

(331) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 52.3 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-(2,2-difluoroethoxy)-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-147), and 48.2 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-(2,2-difluoroethoxy)-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-147). MS (ESI): mass calcd. for C.sub.29H.sub.24Cl.sub.2F.sub.2N.sub.6O.sub.4 628.12, m/z found 629.1 [M+H].sup.+. H-NMR (400 MHz, DMSO-d.sub.6) δ 8.58 (d, 1H, J=7.2 Hz), 7.56-6.46 (m, 7H), 4.74-4.66 (m, 2H), 4.17-4.10 (m, 1H), 3.98 (s, 3H), 2.21 (s, 3H), 2.01-1.98 (m, 1H), 1.09 (d, 3H, J=6.8 Hz), 0.68 (d, 3H, J=7.2 Hz).

Example 148

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-(2-hydroxyethoxy)-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(332) ##STR00210##

(333) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 43.3 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-(2-hydroxyethoxy)-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-148), and 43.7 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-(2-hydroxyethoxy)-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-148). MS (ESI): mass calcd. for C.sub.31H.sub.28Cl.sub.2N.sub.4O.sub.5 606.14, m/z found 607.2 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 7.55-6.48 (m, 10H), 4.89 (t, J=5.2 Hz, 1H), 4.10-4.05 (m, 3H), 3.78-3.74 (m, 5H), 2.07 (s, 3H), 1.06 (d, J=5.6 Hz, 3H), 0.63 (d, J=5.6 Hz, 3H).

Example 149

6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(6-isopropyl-2-methoxypyridin-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(334) ##STR00211##

(335) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 16.3 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(6-isopropyl-2-methoxypyridin-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-149), and 17.0 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(6-isopropyl-2-methoxypyridin-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-149). MS (ESI): mass calcd. for C.sub.29H.sub.31Cl.sub.2N.sub.5O.sub.3 589.16, m/z found 589.5[M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.72 (brs, 1H), 7.84-7.81 (m, 1H), 7.57 (d, 1H, J=8.0 Hz), 7.47 (d, 1H, J=8.0 Hz), 7.33-6.97 (m, 4H), 6.49 (s, 1H), 4.10-4.07 (m, 1H), 3.89 (s, 3H), 3.04-3.01 (m, 1H), 2.22 (s, 3H), 1.29 (d, 6H, J=6.8 Hz), 1.10 (d, 1H, J=6.8 Hz), 0.66 (d, 1H, J=6.8 Hz).

Example 150

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-(difluoromethoxy)-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(336) ##STR00212##

(337) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 42.1 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-(difluoromethoxy)-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-150), and 46.0 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-(difluoromethoxy)-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-150). MS (ESI): mass calcd. for C.sub.29H.sub.23Cl.sub.2F.sub.2N.sub.5O.sub.4 613.11, m/z found 614.5 [M+H].sup.+. H-NMR (400 MHz, DMSO-d.sub.6) δ 11.65 (brs, 1H), 8.25-6.48 (m, 8H), 4.09-4.07 (m, 1H), 3.91 (s, 3H), 2.22 (s, 3H), 1.08 (d, 3H, J=6.4 Hz), 0.66 (d, 3H, J=6.4 Hz).

Example 151

4-chloro-2-(6-chloro-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-2,6′-dioxo-3′,6′-dihydro-5′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-5′-yl)benzonitrile

(338) ##STR00213##

(339) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 119.4 mg of (S)-4-chloro-2-(6-chloro-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-2,6′-dioxo-3′,6′-dihydro-5′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-5′-yl)benzonitrile (S-151), and 105.8 mg of (R)-4-chloro-2-(6-chloro-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-2,6′-dioxo-3′,6′-dihydro-5′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-5′-yl)benzonitrile (R-151). MS (ESI): mass calcd. for C.sub.28H.sub.21Cl.sub.2N.sub.7O.sub.4 589.10, m/z found 590.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.81 (brs, 1H), 8.56 (s, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.86 (d, J=1.6 Hz, 1H), 7.56-7.53 (m, 1H), 7.25 (d, J=8.4 Hz, 1H), 7.16 (d, J=1.6 Hz, 1H), 7.09-7.07 (m, 1H), 4.24-4.17 (m, 1H), 4.00 (s, 3H), 3.95 (s, 3H), 1.21 (d, J=6.4 Hz, 3H), 0.63 (d, J=6.4 Hz, 3H).

Example 152

6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-3′-isopropyl-2′-(4-methoxy-6-(trifluoromethyl)pyridine-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(340) ##STR00214##

(341) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 41.8 mg of (S)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-3′-isopropyl-2′-(4-methoxy-6-(trifluoromethyl)pyridine-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-152), and 45.3 mg of (R)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-3′-isopropyl-2′-(4-methoxy-6-(trifluoromethyl)pyridine-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-152). MS (ESI): mass calcd. for C.sub.28H.sub.21Cl.sub.2F.sub.3N.sub.6O.sub.3 616 m/z found 617.1[M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.57 (brs, 1H), 8.72 (d, 1H, J=7.2 Hz), 8.51 (d, 1H, J=6.4 Hz), 7.74 (s, 1H), 7.66-7.01 (m, 5H), 4.16-4.11 (m, 1H), 4.02 (s, 3H), 2.27 (s, 3H), 1.10 (d, 3H, J=6.8 Hz), 0.67 (d, 3H, J=6.4 Hz).

Example 153

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-(2,2-difluoroethoxy)-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(342) ##STR00215##

(343) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 45.1 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-(2,2-difluoroethoxy)-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-153), and 46.6 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-(2,2-difluoroethoxy)-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-153). MS (ESI): mass calcd. for C.sub.30H.sub.25Cl.sub.2F.sub.2N.sub.5O.sub.4 627.12, m/z found 628.2[M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.73 (brs, 1H), 8.16 (d, 1H, J=5.2 Hz), 7.57-6.42 (m, 7H), 4.68-4.61 (m, 2H), 4.08-4.04 (m, 1H), 3.87 (s, 3H), 2.22 (s, 3H), 1.08 (d, 3H, J=6.4 Hz), 0.65 (d, 3H, J=6.4 Hz).

Example 154

6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-methoxy-6-methylpyridin-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(344) ##STR00216##

(345) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 39.3 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-methoxy-6-methylpyridin-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-154), and 39.5 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-methoxy-6-methylpyridin-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-154). MS (ESI): mass calcd. for C.sub.29H.sub.25Cl.sub.2N.sub.5O.sub.3 561.13, m/z found 562.2 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.73 (brs, 1H), 8.35 (d, 1H, J=4.4 Hz), 7.57-6.48 (m, 7H), 4.07-4.03 (m, 1H), 3.87 (s, 3H), 2.22 (s, 3H), 1.08 (d, 3H, J=6.8 Hz), 0.64 (d, 3H, J=6.4 Hz).

Example 155

6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(6-(dimethylamino)-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(346) ##STR00217##

(347) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 9.1 mg of (S)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(6-(dimethylamino)-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-155), and 9.9 mg of (R)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(6-(dimethylamino)-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-155). MS (ESI): mass calcd. for C.sub.29H.sub.27C.sub.12N.sub.7O.sub.3 591.16, m/z found 594.2 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.79 (brs, 1H), 8.50 (s, 1H), 8.49 (d, 1H, J=5.6 Hz), 7.99-6.99 (m, 4H), 6.22 (s, 1H), 4.11-4.08 (m, 1H), 3.84 (s, 3H), 3.11 (s, 6H), 2.27 (s, 3H), 1.08 (d, 3H, J=6.4 Hz), 0.65 (d, 3H, J=4.0 Hz).

Example 156

6-chloro-5′-(5-chloro-2-isopropylphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(348) ##STR00218##

(349) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 50.95 mg of 6-chloro-5′-(5-chloro-2-isopropylphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione. MS (ESI): mass calcd. for C.sub.30H.sub.28Cl.sub.2N.sub.6O.sub.4 606.15, m/z found 607.2 [M+H].sup.+. H-NMR (400 MHz, DMSO-d.sub.6) δ 8.53 (d, 1H, J=6.0 Hz), 7.65-7.07 (m, 6H), 4.13-4.06 (m, 1H), 3.99 (d, 3H, J=13.6 Hz), 3.96 (d, 3H, J=13.6 Hz), 3.17-3.16 (m, 1H), 1.15-1.03 (m, 9H), 0.63 (d, 3H, J=5.6 Hz).

Example 157

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-(dimethylamino)-2-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(350) ##STR00219##

(351) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 16.2 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-(dimethylamino)-2-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-157), and 17.6 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-(dimethylamino)-2-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-157). MS (ESI): mass calcd. for C.sub.30H.sub.28Cl.sub.2N.sub.6O.sub.3 590.16, m/z found 591.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.60 (brs, 1H), 7.58-6.29 (m, 8H), 4.21-4.14 (m, 1H), 3.83 (s, 3H), 3.09 (s, 6H), 2.14 (s, 3H), 1.07 (d, J=6.8 Hz, 3H), 0.64 (d, J=6.8 Hz, 3H).

Example 158

2-chloro-4-(6-chloro-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-2,6′-dioxo-3′,6′-dihydro-5′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-5′-yl)benzonitrile

(352) ##STR00220##

(353) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 119.4 mg of (S)-2-chloro-4-(6-chloro-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-2,6′-dioxo-3′,6′-dihydro-5′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-5′-yl)benzonitrile (S-158), and 105.8 mg of (R)-2-chloro-4-(6-chloro-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-2,6′-dioxo-3′,6′-dihydro-5′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-5′-yl)benzonitrile (R-158). MS (ESI): mass calcd. for C.sub.28H.sub.21Cl.sub.2N.sub.7O.sub.4 589.10, m/z found 590.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.81 (brs, 1H), 8.52 (s, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.54 (d, J=2.4 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.17-7.09 (m, 3H), 4.20-4.13 (m, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 1.13 (d, J=6.8 Hz, 3H), 0.61 (d, J=6.8 Hz, 3H).

Example 159

6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(2-cyclopropyl-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(354) ##STR00221##

(355) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 55.9 mg of (S)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(2-cyclopropyl-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-159), and 55.7 mg of (R)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(2-cyclopropyl-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-159). MS (ESI): mass calcd. for C.sub.30H.sub.26Cl.sub.2N.sub.6O.sub.3 589.14, m/z found 590.2 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.65 (brs, 1H), 8.56-7.00 (m, 6H), 4.17-4.14 (m, 1H), 3.94 (s, 3H), 2.27 (s, 3H), 2.20-2.19 (m, 1H), 1.13-1.07 (m, 7H), 0.68 (d, 3H, J=6.8 Hz).

Example 160

3-chloro-5-(6-chloro-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-2,6′-dioxo-3′,6′-dihydro-5′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-5′-yl)benzonitrile

(356) ##STR00222##

(357) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 20.4 mg of (S)-3-chloro-5-(6-chloro-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-2,6′-dioxo-3′,6′-dihydro-5′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-5′-yl)benzonitrile (S-160), and 23.3 mg of (R)-3-chloro-5-(6-chloro-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-2,6′-dioxo-3′,6′-dihydro-5′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-5′-yl)benzonitrile (R-160). MS (ESI): mass calcd. for C.sub.28H.sub.21Cl.sub.2N.sub.7O.sub.4 589.10, m/z found 590.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.71 (brs, 1H), 8.52 (s, 1H), 7.98 (s, 1H), 7.51-7.45 (m, 3H), 7.18-7.16 (m, 1H), 7.08 (s, 1H), 4.17-4.16 (m, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 1.12 (d, 3H, J=5.2 Hz), 0.64 (d, 3H, J=4.8 Hz).

Example 161

6-chloro-5′-(3-chloro-4-(trifluoromethoxy)phenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(358) ##STR00223##

(359) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 20.4 mg of (S)-6-chloro-5′-(3-chloro-4-(trifluoromethoxy)phenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-161), and 23.3 mg of (R)-6-chloro-5′-(3-chloro-4-(trifluoromethoxy)phenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-161). MS (ESI): mass calcd. for C.sub.28H.sub.21Cl.sub.2F.sub.3N.sub.6O.sub.5 648.09, m/z found 649.1 [M+H].sup.+. H-NMR (400 MHz, DMSO-d.sub.6) δ 11.63 (brs, 1H), 8.52 (s, 1H), 7.61-7.50 (m, 2H), 7.38 (d, J=2.4 Hz, 1H), 7.18-7.05 (m, 3H), 4.20-4.13 (m, 1H), 3.99 (s, 3H), 3.95 (s, 3H), 1.11 (d, J=6.8 Hz, 3H), 0.64 (d, J=6.8 Hz, 3H).

Example 162

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-((2-hydroxyethyl)(methyl)amino)-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(360) ##STR00224##

(361) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 16.7 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-((2-hydroxyethyl)(methyl) amino)-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-162), and 16.7 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-((2-hydroxyethyl)(methyl)amino)-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-162). MS (ESI): mass calcd. for C.sub.32H.sub.31Cl.sub.2N.sub.5O.sub.4, 619.18 m/z found 620.2 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.80 (brs, 1H), 7.51-6.34 (m, 9H), 4.72 (t, 1H, J=5.0 Hz), 4.13-4.10 (m, 1H), 3.76 (s, 3H), 3.60-3.57 (m, 2H), 3.49-3.47 (m, 2H), 3.02 (s, 3H), 2.22 (s, 3H), 1.05 (d, 3H, J=6.0 Hz), 0.62 (d, 3H, J=5.6 Hz).

Example 163

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-(2-fluoroethoxy)-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(362) ##STR00225##

(363) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 12.4 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-(2-fluoroethoxy)-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-163), and 12.4 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-(2-fluoroethoxy)-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-163). MS (ESI): mass calcd. for C.sub.30H.sub.26Cl.sub.2FN.sub.5O.sub.4 609.13, m/z found 610.1[M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.73 (brs, 1H), 8.13 (d, 1H, J=4.8 Hz), 7.54-6.91 (m, 6H), 6.67 (s, 1H), 4.83-4.54 (m, 4H), 4.07-4.06 (m, 1H), 3.86 (s, 3H), 2.21 (s, 3H), 1.08 (d, 3H, J=6.0 Hz), 0.65 (d, 3H, J=6.0 Hz).

Example 164

(364) 6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(6-isopropyl-4-methoxypyridin-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(365) ##STR00226##

(366) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 14.4 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(6-isopropyl-4-methoxypyridin-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-164), and 14.5 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(6-isopropyl-4-methoxypyridin-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-164). MS (ESI): mass calcd. for C.sub.31H.sub.29Cl.sub.2N.sub.5O.sub.3, 589.16 m/z found 590.2 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.5 (brs, 1H), 8.43 (d, 1H, J=4.8 Hz), 7.59-6.49 (m, 7H), 4.11-4.02 (m, 1H), 3.91 (s, 3H), 3.12-3.09 (m, 1H), 2.22 (s, 3H), 1.30-1.29 (m, 6H), 1.07 (d, 3H, J=6.8 Hz), 0.65 (d, 3H, J=6.8 Hz).

Example 165

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,4-dimethoxyphenyl)-3′-(1-hydroxypropan-2-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(367) ##STR00227##

(368) Steps similar to those in Example 1 were performed to obtain 20.0 mg of the title compound 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,4-dimethoxyphenyl)-3′-(1-hydroxypropan-2-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione. MS (ESI): mass calcd. for C.sub.30H.sub.26Cl.sub.2N.sub.4O.sub.5 592.13, m/z found 593.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 10.80 (brs, 1H), 9.35 (s, 1H), 7.59-6.71 (m, 9H), 4.33-4.29 (m, 2H), 3.93-3.85 (m, 7H), 2.07 (s, 3H), 1.18 (d, J=6.0 Hz, 3H).

Example 166

6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-3′-isopropyl-2′-(6-isopropyl-4-methoxypyridin-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(369) ##STR00228##

(370) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 31.8 mg of (S)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-3′-isopropyl-2′-(6-isopropyl-4-methoxypyridin-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-166), and 33.1 mg of (R)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-3′-isopropyl-2′-(6-isopropyl-4-methoxypyridin-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-166). MS (ESI): mass calcd. for C.sub.30H.sub.28Cl.sub.2N.sub.6O.sub.3, 590.16 m/z found 591.2 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.59 (brs, 1H), 8.51-8.41 (m, 2H), 7.67-7.01 (m, 5H), 4.12-4.05 (m, 1H), 3.90 (s, 3H), 3.11-3.06 (m, 1H), 2.50 (s, 3H), 1.30 (d, 6H, J=6.8 Hz), 1.09 (d, 3H, J=6.4 Hz), 0.66 (d, 3H, J=4.0 Hz).

Example 167

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-(1-hydroxymethylpropane-2-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(371) ##STR00229##

(372) Steps similar to those in Example 1 were performed to obtain 50.6 mg of the title compound 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-(1-hydroxymethylpropan-2-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione. MS (ESI): mass calcd. for C.sub.28H.sub.24Cl.sub.2N.sub.6O.sub.5 594.12, m/z found 595.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 10.80 (brs, 1H), 9.43 (s, 1H), 8.66 (s, 1H), 7.50 (s, 1H), 7.50-6.88 (m, 5H), 4.40-4.31 (m, 2H), 4.02 (s, 6H), 3.93 (d, J=12.0 Hz), 2.05 (s, 3H), 1.24 (s, 3H).

Example 168

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4,6-dimethoxypyridin-3-yl)-3′-(1-hydroxypropan-2-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(373) ##STR00230##

(374) Steps similar to those in Example 1 were performed to obtain 101.2 mg of the title compound 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4,6-dimethoxypyridin-3-yl)-3′-(1-hydroxypropan-2-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione. MS (ESI): mass calcd. for C.sub.29H.sub.25Cl.sub.2N.sub.5O.sub.5 593.12, m/z found 594.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 10.83 (brs, 1H), 9.42 (s, 1H), 8.25 (s, 1H), 7.53 (d, J=2.4 Hz, 1H), 7.28-6.88 (m, 6H), 6.64 (s, 1H), 4.34-4.30 (m, 2H), 3.94-3.91 (m, 7H), 2.06 (s, 3H), 1.21 (d, 6.8 Hz, 3H).

Example 169

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-ethoxy-4-methoxypyridin-3-yl)-3′-(1-hydroxypropan-2-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(375) ##STR00231##

(376) Steps similar to those in Example 1 were performed to obtain 151.1 mg of the title compound 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-ethoxy-4-methoxypyridin-3-yl)-3′-(1-hydroxypropan-2-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione. MS (ESI): mass calcd. for C.sub.27H.sub.22Cl.sub.2N.sub.6O.sub.3 607.14, m/z found 608.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 10.83 (brs, 1H), 9.41 (s, 1H), 8.23 (s, 1H), 7.53 (d, J=2.4 Hz, 1H), 7.28-6.89 (m, 5H), 6.62 (s, 1H), 4.42-4.30 (m, 4H), 3.93-3.90 (m, 4H), 2.06 (s, 3H), 1.36 (t, J=6.8 Hz, 3H), 1.21 (d, J=6.8 Hz, 3H).

Example 170

6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(2-(2-fluoroethoxy)-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(377) ##STR00232##

(378) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 25.2 mg of (S)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(2-(2-fluoroethoxy)-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-170), and 25.9 mg of (R)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(2-(2-fluoroethoxy)-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-170). MS (ESI): mass calcd. for C.sub.28H.sub.24Cl.sub.2FN.sub.7O.sub.4 611.12, m/z found 612.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.65 (brs, 1H), 8.56-8.49 (m, 2H), 7.64-7.00 (m, 4H), 4.87-4.85 (m, 1H), 4.75-4.73 (m, 1H), 4.69-4.67 (m, 1H), 4.61-4.59 (m, 1H), 4.19-4.18 (m, 1H), 3.96 (s, 3H), 2.27 (s, 3H), 1.09 (d, 3H, J=6.8 Hz), 0.68 (d, 3H, J=5.6 Hz).

Example 171

6-chloro-5′-(3-chlorophenyl)-2′-(2-(2-fluoroethoxy)-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(379) ##STR00233##

(380) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 5.3 mg of (S)-6-chloro-5′-(3-chlorophenyl)-2′-(2-(2-fluoroethoxy)-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-171), and 4.3 mg of (R)-6-chloro-5′-(3-chlorophenyl)-2′-(2-(2-fluoroethoxy)-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-171). MS (ESI): mass calcd. for C.sub.28H.sub.23Cl.sub.2FN.sub.6O.sub.4, 596.11 m/z found 597.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.59 (brs, 1H), 8.52 (s, 1H), 7.49 (d, 1H, J=8.0 Hz), 7.38-7.35 (m, 2H), 7.15-7.12 (m, 2H), 7.01 (d, 1H, J=2.0 Hz), 6.98-6.95 (m, 1H), 4.87-4.59 (m, 4H), 4.18-4.15 (m, 1H), 3.95 (s, 3H), 1.12 (d, 3H, J=6.8 Hz), 0.65 (d, 3H, J=6.8 Hz).

Example 172

6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-isopropyl-4-methoxypyrimidin-5-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(381) ##STR00234##

(382) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 19.6 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-isopropyl-4-methoxypyrimidin-5-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-172), and 18.1 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-isopropyl-4-methoxypyrimidin-5-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-172). MS (ESI): mass calcd. for C.sub.30H.sub.28Cl.sub.2N.sub.6O.sub.3 590.19, m/z found 591.1[M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.78 (brs, 1H), 8.67 (d, 1H, J=6.4 Hz), 8.29-6.48 (m, 6H), 4.08-4.06 (m, 1H), 3.98 (s, 3H), 3.14-3.11 (m, 1H), 2.22 (s, 3H), 1.34 (d, 6H, J=6.8 Hz), 1.10 (d, 3H, J=6.4 Hz), 0.68 (d, 3H, J=6.8 Hz).

Example 173

6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(6-(2-fluoroethoxy)-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(383) ##STR00235##

(384) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 20.1 mg of (S)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(6-(2-fluoroethoxy)-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-173), and 19.6 mg of (R)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(6-(2-fluoroethoxy)-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-173). MS (ESI): mass calcd. for C.sub.29H.sub.25Cl.sub.2FN.sub.6O.sub.4 610.12, m/z found 611.2 [M+H].sup.+. H-NMR (400 MHz, DMSO-d.sub.6) δ 11.81 (brs, 1H), 8.51 (dd, 1H, J.sup.1=8.4 Hz, J.sup.2=2.4 Hz), 8.14 (d, 1H, J=5.6 Hz), 7.62-7.00 (m, 4H), 6.69 (s, 3H), 4.84-4.82 (m, 1H), 4.72-4.70 (m, 1H), 4.63-4.61 (m, 1H), 4.55-4.54 (m, 1H), 4.09-4.07 (m, 1H), 3.86 (s, 3H), 2.27 (s, 3H), 1.08 (d, 3H, J=6.4 Hz), 0.65 (d, 3H, J=6.4 Hz).

Example 174

6-chloro-5′-(3-chloro-5-fluorophenyl)-2′-(2-cyclopropyl-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(385) ##STR00236##

(386) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 37.8 mg of (S)-6-chloro-5′-(3-chloro-5-fluorophenyl)-2′-(2-cyclopropyl-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-174), and 39.0 mg of (R)-6-chloro-5′-(3-chloro-5-fluorophenyl)-2′-(2-cyclopropyl-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-174). MS (ESI): mass calcd. for C.sub.29H.sub.23Cl.sub.2FN.sub.6O.sub.3 592.12, m/z found 593.1 [M+H].sup.+. H-NMR (400 MHz, DMSO-d.sub.6) δ 11.75 (brs, 1H), 8.53 (s, 1H), 7.50 (d, 1H, J=8.0 Hz), 7.41-6.89 (m, 5H), 4.17-4.10 (m, 1H), 3.93 (s, 3H), 2.23-2.17 (m, 1H), 1.12-1.11 (m, 7H), 0.65 (d, 3H, J=6.8 Hz).

Example 175

6-chloro-5′-(3-chloro-5-fluorophenyl)-2′-(4,6-dimethoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(387) ##STR00237##

(388) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 45.2 mg of (S)-6-chloro-5′-(3-chloro-5-fluorophenyl)-2′-(4,6-dimethoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-175), and 44.9 mg of (R)-6-chloro-5′-(3-chloro-5-fluorophenyl)-2′-(4,6-dimethoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-175). MS (ESI): mass calcd. for C.sub.28H.sub.22Cl.sub.2FN.sub.5O.sub.4 581.10, m/z found 582.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.69 (brs, 1H), 8.11 (s, 1H), 7.50 (d, 1H, J=8.4 Hz), 7.48-6.90 (m, 5H), 6.60 (s, 1H), 4.09-4.02 (m, 1H), 3.91 (s, 3H), 3.83 (s, 3H), 1.11 (d, 3H, J=6.4 Hz), 0.61 (d, 3H, J=6.0 Hz).

Example 176

6-chloro-5′-(3-chloro-5-fluorophenyl)-2′-(6-cyclopropyl-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(389) ##STR00238##

(390) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 40.3 mg of (S)-6-chloro-5′-(3-chloro-5-fluorophenyl)-2′-(6-cyclopropyl-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-176), and 40.6 mg of (R)-6-chloro-5′-(3-chloro-5-fluorophenyl)-2′-(6-cyclopropyl-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-176). MS (ESI): mass calcd. for C.sub.30H.sub.24Cl.sub.2FN.sub.5O.sub.3 591.12, m/z found 592.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.69 (brs, 1H), 8.27 (s, 1H), 7.51 (d, 1H, J=8.4 Hz), 7.40-6.80 (m, 6H), 4.09-4.04 (m, 1H), 3.87 (s, 3H), 2.21-2.07 (m, 1H), 1.11 (d, 3H, J=6.4 Hz), 1.10-0.99 (m, 4H), 0.60 (d, 3H, J=6.4 Hz).

Example 177

6-chloro-5′-(3-chlorophenyl)-2′-(6-(2-fluoroethoxy)-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(391) ##STR00239##

(392) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 5.3 mg of (S)-6-chloro-5′-(3-chlorophenyl)-2′-(6-(2-fluoroethoxy)-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-177), and 4.3 mg of (R)-6-chloro-5′-(3-chlorophenyl)-2′-(6-(2-fluoroethoxy)-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-177). MS (ESI): mass calcd. for C.sub.29H.sub.24Cl.sub.2FN.sub.5O.sub.4 595.12, m/z found 596.2 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.56 (brs, 1H), 8.11 (s, 1H), 7.49-6.95 (m, 7H), 6.68 (s, 1H), 4.83-4.53 (m, 4H), 4.09-4.02 (m, 1H), 1.11 (d, 3H, J=6.4 Hz), 0.62 (d, 3H, J=6.4 Hz).

Example 178

6-chloro-5′-(3-chlorophenyl)-2′-(4,6-dimethoxypyridin-3-yl)-3′-(1-hydroxypropan-2-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(393) ##STR00240##

(394) Steps similar to those in Example 1 were performed to obtain 120.1 mg of the title compound 6-chloro-5′-(3-chlorophenyl)-2′-(4,6-dimethoxypyridin-3-yl)-3′-(1-hydroxypropan-2-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione. MS (ESI): mass calcd. for C.sub.28H.sub.23Cl.sub.2N.sub.5O.sub.5 579.11, m/z found 580.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 10.88 (brs, 1H), 10.06 (s, 1H), 8.24 (s, 1H), 7.80 (s, 1H), 7.79-6.92 (m, 6H), 6.63 (s, 1H), 4.32-4.29 (m, 2H), 3.94 (s, 6H), 3.92-3.89 (m, 1H), 1.22 (d, 3H, J=6.8 Hz).

Example 179

5-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-4-methoxypyrimidine-2-methylcyanide

(395) ##STR00241##

(396) Steps similar to those in Example 1 were performed to obtain 4.3 mg of the title compound 5-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-4-methoxypyrimidine-2-methylcyanide. MS (ESI): mass calcd. for C.sub.28H.sub.21Cl.sub.2N.sub.7O.sub.3 Exact Mass: 573.11, m/z found 574.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.81 (brs, 1H), 8.96 (d, J=8.4 Hz, 1H), 7.59-6.50 (m, 6H), 4.27-4.22 (m, 1H), 4.05 (s, 3H), 2.21 (s, 3H), 1.10 (d, J=6.8 Hz, 3H), 0.67 (d, J=6.4 Hz, 3H).

Example 180

6-chloro-5′-(3-chloro-5-fluorophenyl)-2′-(2-ethoxy-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

(397) ##STR00242##

(398) Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 44.3 mg of (S)-6-chloro-5′-(3-chloro-5-fluorophenyl)-2′-(2-ethoxy-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-180), and 45.1 mg of (R)-6-chloro-5′-(3-chloro-5-fluorophenyl)-2′-(2-ethoxy-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-180). MS (ESI): mass calcd. for C.sub.28H.sub.23Cl.sub.2FN.sub.6O.sub.4 596.11, m/z found 597.1 [M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.69 (brs, 1H), 8.50 (d, J=3.2 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.41-6.90 (m, 5H), 4.47 (q, J=6.8 Hz, 2H), 4.21-4.14 (m, 1H), 3.97 (s, 3H), 1.27 (t, J=6.4 Hz, 2H), 1.13 (d, J=6.8 Hz, 3H), 0.64 (d, J=6.4 Hz, 3H).

(399) In order to verify the activity of the MDM2 inhibitors according to the present invention, the present invention further provides several representative Experimental Examples.

Experimental Example 1 Determination of the Inhibitory Activities of the Compounds OF THE PRESENT INVENTION ON MDM2 BY A BIOLOGICAL ASSAY METHOD

(400) Experimental purpose: To determine the inhibitory activities of the compounds of the present invention on MDM2.

(401) The present experiment uses the following assay methods/instruments/reagents:

(402) TABLE-US-00001 Type Name (Product code) Manufacturer Plate shaker MTS2/4 IKA Microplate reader M1000pro TECAN Centrifuge Avanti J-26XP Beckman Coulter GST-MDM2 (70 μM) In-house purification Biotin-P53 (100 μM) GL Biochem Anti-GST-Tb(100×) 61GSTTLA Cisbio SA-XL665(16.67 μM) 610SAXLA Cisbio BSA B2064 Sigma AEBSF 76307 Sigma DTT 43816 Sigma PBS 20012-027 Cisbio
Experiment Subjects:

(403) Positive control group: Compound HDM201, disclosed in patent No. 201380016617.6; synthesized in laboratory.

(404) Experimental groups S-1 to R-180, corresponding to the compounds prepared in Examples 1-180, respectively.

(405) Experiment Procedure:

(406) Solution Preparation:

(407) Buffer: 1×PBS+0.1% BSA+5 mM DTT; MDM2 Buffer: Buffer+1 mM AEBSF

(408) GST-MDM2: The final concentration is 4 nM, and it is required to formulate a 20 nM (5×) solution. A mother liquor is diluted by 3500 folds, wherein the mother liquor is 10-fold diluted first, and then 350-fold diluted.

(409) Biotin-P53: The final concentration is 37 nM, and it is required to formulate a 185 nM (5×) solution. A mother liquor is diluted by 540.5 folds.

(410) SA-XL665: The final concentration is 4.625 nM, and it is required to formulated a 1805 nM (4×) solution. A mother liquor is diluted by 901 folds.

(411) Anti-GST-Tb: The final concentration is 2×, and a mother liquor is diluted by 50 folds.

(412) MIX: GST-MDM2, Biotin-P53, SA-XL665 and Anti-GST-Tb were mixed according to a ratio of 4:4:5:5.

(413) Sample: Preparation of a sample (10 mM in DMSO) solution: a. 3 μL sample+7 μL DMSO+20 μL DMSO were formulated to give an initial concentration of 1 mM and mixed well; b. in plate 1, twelve 5-fold serial dilutions (sequentially prepared by adding 10 μL of the last sample to 40 μL DMSO) were prepared and mixed well, individually; c. plate 2 was taken, 45 μL of Buffer was added to each well, and 5 μL of dilution at each concentration was taken from plate 1 and added to the corresponding well in plate 2 (the concentration in well 1 was 100 μM), and mixed well.

(414) Experimental Steps:

(415) 1. 18 μL of MIX was added to a 384-well plate, and centrifugation was performed at 4500 rpm for 5 min.

(416) 2. 2 μL of sample was added correspondingly to each well, the resultant was centrifuged at 25° C. and 4500 rpm for 5 min, and shaked at 25° C. for 90 min on a shaker.

(417) Readings were obtained from the Microplate reader, and data was processed by Graphpad Prism 6.0.

(418) $\begin{array}{c}\mathrm{Inhibition}\mathrm{rate}\mathrm{at}\mathrm{each}\\ \mathrm{concentration}\mathrm{point}\left(\mathrm{inh}\%\right)\end{array}=\frac{\begin{array}{c}\mathrm{fluorescence}\mathrm{value}\mathrm{at}\\ \mathrm{zero}\mathrm{point}\mathrm{concentration}\end{array}-\begin{array}{c}\mathrm{fluorescence}\mathrm{value}\mathrm{at}\\ \mathrm{each}\mathrm{concentration}\mathrm{point}\end{array}}{\mathrm{fluorescence}\mathrm{value}\mathrm{at}\mathrm{zero}\mathrm{concentration}}\times 100\%$

(419) TABLE-US-00002 TABLE 1 Test results of inhibitory activities of the compounds of the present invention on MDM2 (IC.sub.50: nM) Inhibition test of Experimental MDM2-P53, IC.sub.50 (nM) MDM2-PS3 .sub.50 (nM) HDM201 2.50 S-1 2.21 R-1 617.89 S-2 1.13 R-2 117.50 S-3 4.92 R-3 1194.23 S-4 3.37 R-4 132.48 S-5 3.22 R-5 109.29 S-6 2.21 R-6 42.26 S-7 73.24 R-7 35972.70 S-8 3.29 R-8 329.21 S-9 2.38 R-9 332.39 S-10 2.77 R-10 116.59 S-11 1.58 R-11 257.20 S-12 3.55 R-12 367.64 S-13 2.55 R-13 120.80 S-14 1.34 R-14 460.77 S-15 1.62 R-15 107.21 S-16 3.39 R-16 570.33 S-17 3.75 R-17 49.37 S-18 1.43 R-18 158.09 S-19 34.6 R-19 NA S-20 4.39 R-20 256.30 S-21 1.34 R-21 222.76 S-22 1.10 R-22 626.74 S-23 2.80 R-23 174.99 S-24 4.40 R-24 391.92 S-25. 2.52 R-25 51.85 S-26 2.37 R-26 235.74 S-27 3.45 R-27 924.43 S-28 54.32 R-28 3109.44 S-29 1.01 R-29 93.57 S-30 3.31 S-31 60.11 R-31 1403.96 S-32 3.89 R-32 1100.34 S-33 2.47 R-33 591.54 S-34 139.47 R-34 NA S-35 23.40 R-35 NA S-36 4.67 R-66 464.19 S-37 22.01 R-37 3111.09 S-38 12.01 R-38 1115.99 S-39 3.93 R-39 1847.84 S-40 3.85 R-40 322.24 S-41 149.29 R-41 7317.32 S-42 1.51 R-42 364.49 S-43 3.28 R-43 129.78 S-44 1.18 R-44 51.11 S-45 1.72 R-45 170.63 S-46 236.27 R-46 2332.41 S-47 4.16 R-47 209.81 S-48 1.46 R-48 195.57 S-49 1.72 R-49 71.38 S-50 85.52 R-50 20410.23 S-51 4.36 R-51 547.30 S-52 0.87 R-52 540.41 S-53 0.84 R-53 3768.80 S-54 2.25 R-54 1961.81 S-55 4.25 R-55 437.30 S-56 5.19 R-56 154.99 S-57 3.04 R-57 426.50 S-58 11.42 R-58 1429.18 S-50 2.29 R-59 689.37 S-60 4.81 R..60 1072.13 S-61 1.31 R-61 135.68 S-62 1.61 R-62 252.45 S-63 1.16 R-63 537.10 S-64 11.83 R-64 1023.67 S-65 4.04 R-65 497.90 S-66 1.50 R-66 85.88 S-67 1.22 R-67 354.64 S-68 2.32 R-68 656.97 S-69 1.78 R-69 635.65 S-70 0.94 R-70 111.12 S-71 2.96 R-71 100.03 S-72 0.90 R-72 213.52 S-73 1.10 R-73 142.35 S-74 0.98 R-74 93.42 S-75 0.97 R-75 122.38 S-76 4.23 R-76 579.08 S-77 1.86 R-77 139.30 S-78 1.42 R-78 222.23 S-79 1.89 R-79 285.33 S-80 2.56 R-80 362.85 S-81 1.23 R-81 53.27 S-82 1.16 R-82 394.36 S-83 2.23 R-83 87.64 84 3.78 S-85 3.30 R-85 493.70 S-86 2.59 R-86 142.00 S-87 3.31 R-87 473.20 S-88 2.34 R-88 399.20 S-89 4.32 R-89 568.90 S-90 1.38 R-90 309.80 S-91 3.56 R-91 460.90 S-92 1.72 R-92 377.83 S-93 3.89 R-93 658.14 S-94 4.72 R-94 840.35 S-95 1.92 R-95 1668.15 S-96 1.04 R-96 150.65 S-97 3.94 R-97 5.73 S-98 1.27 R-98 1034.32 S-99 2.56 R-99 115.26 S-100 3.14 R-100 632.69 S-101 9.86 R-101 1999.88 S-102 2.01 R-102 412.91 S-103 1.81 R-103 180.98 S-104 2.26 R-104 146.16 S-105 11.20 R-105 342.96 S-106 2.59 R-106 481.33 S-107 4.55 R-107 535.69 S-108 8.87 R-108 690.54 S-109 2.34 R-109 380.99 S-110 1.60 R-110 704.44 S-111 1.52 R-111 110.36 S-112 1.15 R-112 103.77 S-113 1.25 R-113 50.54 S-114 3.20 R-114 261.25 S-115 1.30 R-115 268.55 S-116 4.18 R-116 689.19 S-117 2.15 R-117 232.73 S-118 3.51 R-118 436.15 S-119 2.39 R-119 851.01 S-120 9.01 R-120 4778.08 S-121 3.35 R-121 300.14 S-122 2.76 R-122 794.09 S-123 2.11 R-123 115.65 S-124 2.91 R-124 1314.68 125 20.79 S-126 1.52 R-126 193.43 S-127 2.76 R-127 91.04 S-128 1.09 R-128 612.42 S-129 3.84 R-129 149.30 S-130 5.59 R-130 568.03 S-131 1.17 R-131 119.79 S-132 3.60 R-132 1320.63 S-133 1.41 R-133 1109.64 S-134 2.60 R-134 322.16 S-135 1.36 R-135 422.57 S-136 2.35 R-136 1800.00 S-137 1.65 R-137 421.88 S-138 1.04 R-138 132.36 S-139 1.36 R-139 341.78 S-140 1.06 R-140 147.08 S-141 3.42 R-141 762.36 S-142 1.45 R-142 137.08 S-143 1.10 R-143 214.30 S-144 3.84 R-144 119.22 S-145 2.05 R-145 749.40 S-146 5.44 R-146 6712.03 S-147 5.89 R-147 118.69 S-148 1.58 R-148 200.92 S-149 18.49 R-149 2282.00 S-150 1.93 R-150 377.20 S-151 1410.00 R-151 5373.00 S-152 0.78 R-152 134.00 S-153 0.49 R-153 31.11 S-154 0.90 R-154 31.11 S-155 0.95 R-155 96.44 156 11.23 S-157 3.81 R-157 369.60 S-158 4.07 R-158 2203.00 S-159 2.80 R-159 467.60 S-160 5.91 R-160 5713.00 S-161 8.09 R-161 126.30 S-162 2.07 R-162 119.90 S-163 1.36 R-163 166.34 S-164 0.94 R-164 591.56 165 NA S-166 1.88 R-166 957.19 167 NA 168 NA 169 NA S-170 1.86 R-170 234.96 S-171 2.86 R-171 8830.80 S-172 4.15 R-172 408.32 S-173 1.39 R-173 528.45 S-174 4.12 R-174 515.23 S-175 1.96 R-175 522.39 S-176 1.76 R-176 320.63 S-177 2.37 R-177 108.63 178 NA 179 4.27 S-180 4.60 R-180 679.20 NA: data not available
Experimental Results:

(420) The experimental results in Table 1 above demonstrate that:

(421) 1) The compounds of the present invention, such as the compounds prepared in Examples 1-180, have an inhibitory effect on MDM2, especially compounds with S-configuration therein have a significant inhibitory effect on MDM2.

(422) 2) Some compounds of the present invention have a better inhibitory effect on MDM2 than the positive control compound HDM201, for example, the activities of the compounds with S-configuration in Examples 2, 11, 14, 15, 18, 21, 22, 29, 42, 44, 45, 48, 49, 52, 53, 61, 62, 63, 66, 67, 69, 70, 72, 73, 74, 75, 77, 78, 79, 81, 82, 90, 92, 95, 96, 98, 102, 103, 110, 111, 112, 113, 115, 126, 128, 131, 133, 135, 137, 138, 139, 140, 142, 143, 148, 150, 152, 153, 154, 155, 163, 164, 166, 170, 173, 175 and 176 are better than that of the positive control compound HDM201.

Experimental Example 2 Determination of the Inhibition of the Mdm2 Inhibitors According to the Present Invention on the Proliferation of Human Osteosarcoma Cell Line SJSA-1 (the Same Test Subjects as Experimental Example 1)

(423) 2.1 Experimental materials: human osteosarcoma cell line SJSA-1 (Nanjing Kebai Biotechnology Co., Ltd.), DAPI (5 mg/mL, Beyotime, c1002), 4% paraformaldehyde (Ding Guo Biotech., AR-0211), 96-well plate with black transparent bottom (PE, 6005182), In Cell Analyzer 2200 (GE Healthcare).

(424) 2.2 Experiment Preparation:

(425) 2.2.1 Preparation of a culture medium for human osteosarcoma cell line SJSA-1: RPMI1640+10% FBS+1% penicillin/streptomycin

(426) 2.2.2 Preparation of a test compound solution:

(427) a. the test compound solution with a certain concentration was taken, and diluted with the culture medium to obtain a compound solution with a final concentration of 20 μM;

(428) b. 200 μL of a culture medium containing 0.2% DMSO (dimethyl sulfoxide) was added into H.sub.2-H.sub.10 of a 96-well plate; 300 μl of the above solution was added into H.sub.1; and

(429) c. 100 μL was taken out from well H.sub.1, added into H.sub.2, and mixed well; then 100 μl of the resultant solution was taken and added into H.sub.3, and dilution was carried out in sequence until H.sub.9 to obtain the 3-fold serial dilution of the test compound.

(430) 2.3 Experimental Process:

(431) 2.3.1 SJSA-1 cells were inoculated into a 96-well cell plate with black transparent bottom at 4000 cells/100 μl/well, and cultured overnight at 37° C.;

(432) 2.3.2 The above samples were added at 100 μl/well to a culture plate inoculated with cells, gently patted to mix well, and incubated at 37° C. for 72 h;

(433) 2.3.3 Fixation: the cell plate was taken out, the culture medium was removed, and 50 μL of 4% paraformaldehyde solution was added to each well to fix for 10 min;

(434) 2.3.4 50 μl of 0.1 M glycine was added to neutralize for 10 min;

(435) 2.3.5 Washing was performed with 1×PBS (phosphate buffer solution pH7.2) twice;

(436) 2.3.6 Permeabilization: 50 μL of 0.2% TritonX-100 (Triton) was added per well, and permeabilization was carried out at room temperature for 10 min;

(437) 2.3.7 Washing was performed with 1×PBS (phosphate buffer solution pH7.2) twice;

(438) 2.3.8 5 mg/mL DAPI stock solution was diluted at a ratio of 1:5000 (final concentration of 1 g/ml), and staining was performed at room temperature for 20 min;

(439) 2.3.9 Washing was performed with 1×PBS (phosphate buffer solution pH7.2) for three times; and

(440) 2.3.10 Scanning and analysis were performed by In cell analyzer.

(441) 2.4 Data Processing:

(442) The inhibition rate of each compound at each concentration point was calculated according to the following formula, and curve fitting was performed by GraphPad Prism 6.0 software to obtain the IC.sub.50 value.

(443) $\begin{array}{c}\mathrm{Cell}\mathrm{relative}\\ \mathrm{inhibition}\mathrm{rate}\left(\%\right)\end{array}=\frac{\begin{array}{c}\mathrm{fluorescence}\mathrm{value}\\ \mathrm{of}\mathrm{control}\mathrm{group}\end{array}-\begin{array}{c}\mathrm{fluorescence}\mathrm{value}\mathrm{of}\\ \mathrm{expreimental}\mathrm{group}\end{array}}{\mathrm{fluorescence}\mathrm{value}\mathrm{of}\mathrm{control}\mathrm{group}}\times 100\%$

(444) TABLE-US-00003 TABLE 2 Inhibitory activities of the compounds of the present invention on proliferation of human osteosarcoma cell line SJSA-1 Compounds IC.sub.50 (nM) HDM201 91.31 S-1 39.62 R-1 16660.88 S-2 7.40 R-2 2772.00 S-3 173.71 R-3 16271.55 S-4 7.92 R-4 2188.17 S-5 25.44 R-5 1595.07 S-6 6.20 R-6 1766.00 S-7 1271.50 R-7 NA S-8 10.33 R-8 2293.00 S-9 7.39 R-9 2817.23 S-10 124.27 R-10 2169.08 S-11 1.67 R-11 1508.07 S-12 5.27 R-12 2441.56 S-13 5.95 R-13 1124.55 S-14 63.47 R-14 5378.16 S-15 10.87 R-15 840.33 S-16 3557.71 R-16 20057.44 S-17 201.10 R-17 1311.66 S-18 13.91 R-18 1615.66 S-19 352.22 R-19 NA S-20 48.08 R-20 4005.08 S-21 62.19 R-21 5232.02 S-22 7.46 R-22 6954.13 S-23 1.24 R-23 353.78 S-24 4.17 R-24 872.23 S-25 8.83 R-25 265.16 S-26 22.23 R-26 3646.55 S-27 119.33 R-27 NA S-28 1289.92 R-28 NA S-29 196.37 R-29 10856.23 S-30 58.10 R-30 NA S-31 1584.88 R-31 3575.10 S-32 10.09 R-32 8197.15 S-33 9.70 R-33 4885.16 S-34 618.96 R-34 NA S-35 257.65 R-35 NA S-36 72.27 R-36 3176.49 S-37 14.16 R-17 2439.34 S-38 14.74 R-38 NA S-39 1183.40 R-39 NA S-40 14.08 R-40 3086.90 S-41 1205.42 R-41 NA S-42 5.60 R-42 4555.29 S-43 563.67 R-43 NA S-44 11.95 R-44 1332.43 S-45 6.20 R-45 4307.06 S-46 5981.97 R-46 NA S-47 14.02 R-47 3851.55 S-48 16 84 R-48 3630.98 S-49 5.92 R-49 1486.41 S-50 1315.42 R-50 8427.52 S-51 62.56 R-51 9516.69 S-52 466.77 R-52 22436.03 S-53 213.39 R-53 77439.40 S-54 468.31 R-54 NA S-55 117.29 R-55 9939.33 S-36 83.85 R-56 3481.69 S-57 11.78 R-57 3958.52 S-58 50.75 R-58 5892.75 S-59 262.70 R-59 NA S-60 NA R-60 NA S-61 5.50 R-61 135.68 S-62 10.54 R-62 4357.85 S-63 77.62 R-63 NA S-64 725.96 R-64 NA S-65 NA R-65 NA S-66 39.59 R-66 3861.83 S-67 20.76 R-67 8492.33 S-68 1702.99 R-68 NA S-69 2.29 R-69 6584.81 S-70 73.64 R-70 4205.60 S-71 291.56 R-71 7017.36 S-72 5.90 R-72 3480.88 S-73 250.87 R-73 NA S-74 7.85 R-74 1839.65 S-75 9.84 R-75 3040.51 S-76 308.66 R-76 NA S-77 535.23 R-77 NA S- 78 7.88 R-78 1363.64 8-79 72.44 R-79 NA S-80 16.85 R-80 NA S-81 82.79 R-81 1603.25 S-82 7.43 R-82 NA S-83 6.21 R-83 588.54 84 2606.15 S-85 40.18 R-85 2187.76 S-86 21.18 R-86 NA S-87 11.12 R-87 7345.13 S-88 77.27 R-88 NA S-89 43.25 R-89 NA S-90 254.68 R-90 NA S-91 14.42 R-91 993.12 S-92 19.86 R-92 4875.28 R-91 NA S-94 309.03 R-94 NA S-95 49.55 R-95 NA S-96 25.29 R-96 NA S-97 167.49 R-97 395.80 S-98 56.10 R-98 NA S-99 34.20 R-99 1472.31 S-100 1210.60 R-100 NA S-101 48.53 R-101 NA S-102 57.41 R-102 NA S-103 40.46 R-103 2426.61 S-104 266.07 R-104 6886.52 S-105 243.22 R-105 NA S-106 33.50 R-106 NA S-107 114.82 R-107 3235.93 S-108 28.77 R-108 NA S-109 54.58 R-109 8203.52 S-110 77.98 R-110 NA S-111 13.03 R-111 561.05 S-112 90.57 R-112 NA S-113 26.73 R-113 2172.70 S-114 10.12 R-114 1870.68 S-115 3357.38 R-115 26.92 S-116 212.81 R-117 NA S-117 14.42 R-117 NA S-118 107.15 R-118 NA S-119 20.00 R-119 NA S-120 363.92 R-120 NA S-121 66.99 R-121 NA S-122 117.21 R-122 NA S-123 321.37 R-123 NA S-124 129.41 R-124 NA 125 60.26 S-126 79.62 R-126 1592.21 S-127 83.18 R-127 1570.36 S-128 144.88 R-128 NA S-129 146.22 R-129 NA S-130 NA R-130 NA S-131 46.34 R-131 NA S-132 163.68 R-132 NA S-133 99.77 R-133 NA S-134 82.22 R-134 NA S-135 96.16 R-135 NA S-136 108.39 R-136 NA S-137 65.92 R-137 NA S-138 75.68 R-138 NA S-139 50.70 R-139 NA S-140 81.47 R-140 862.98 S-141 73.62 R-141 NA S-142 137.72 R-142 NA S-143 24.89 R-143 6223.00 S-144 100.92 R-144 2449.06 S-145 28.25 R-145 NA S-146 67.76 R-146 NA S-147 271.02 R-147 5741.16 S-148 71.78 R-148 NA S-149 153.46 R-149 NA S-150 80.53 R-150 5701.63 S-151 NA R-151 NA S-152 79.80 R-152 NA S-153 21.99 R-153 NA S-154 22.03 R-154 NA S-155 14.59 R-155 1524.05 156 NA S-157 16.67 R-157 1798.87 S-158 549.54 R.158 NA S-159 34.20 R-159 5333.35 S-160 350.75 R-160 NA S-161 557.18 R-161 NA S-162 14.93 R-162 781.63 S-163 125.60 R-163 NA S-164 16.79 R-164 NA 165 NA S-166 38.11 R-166 NA 167 NA 168 NA 169 NA S-170 130.62 R-170 NA S-171 379.31 R-171 NA S-172 53.33 R-172 NA S-173 216.77 R-173 NA S-174 93.50 R-174 NA S-175 49.20 R-175 NA S-176 28.84 R-176 NA S-177 420.72 R-177 4246.20 178 NA 179 52.72 S-180 56.75 R-180 2172.70 NA: data not available

(445) Experimental Results:

(446) The experimental results of Table 2 above demonstrate that:

(447) 1) The compounds of the present invention, such as the compounds prepared in Examples 1-180, have an inhibitory effect on the human osteosarcoma cell line SJSA-1, and especially the compounds with S-configuration therein have a significant inhibitory effect on the human osteosarcoma cell line SJSA-1.

(448) 2) Some compounds of the present invention have a better inhibitory effect on the human osteosarcoma cell line SJSA-1 than the positive control compound HDM201, for example, the inhibitory effects on the human osteosarcoma cell line SJSA-1 of the compounds with S-configuration in Examples 2, 4, 6, 9, 11, 12, 13, 15, 22, 23, 24, 25, 32, 33, 42, 45, 49, 61, 69, 72, 74, 75, 78, 82, 83, 86, 89, 91, 92, 96, 98, 99, 101, 102, 103, 106, 108, 110, 113, 114, 115, 119, 121, 126, 127, 131, 137, 138, 139, 141, 143, 145, 146, 153, 154, 155, 157, 159, 162, 164, 166, 172, and 176 are better than that of the positive control compound HDM201.

Experimental Example 3 Determination of the Pharmacokinetics of the Mdm2 Inhibitors of the Present Invention in Mice

(449) 3.1 Experimental Summary

(450) ICR mice were used as the test animals, and the concentrations of the drugs in plasma of mice at different time points after intravenous administration and intragastric administration of the representative compounds were measured by a LC/MS/MS method, so as to study the pharmacokinetic behavior of the compounds of the present invention in mice and evaluate the pharmacokinetic characteristics thereof.

(451) 3.2 Experimental Scheme

(452) 3.2.1 Test Drugs:

(453) Some compounds prepared in Examples 1-180 of the present invention.

(454) The control drug HDM201 was prepared by the method disclosed in patent No. CN104203952A.

(455) 3.2.2 Test Animals:

(456) Healthy adult ICR mice, male, 6-9 weeks old, weighing 20-30 g, purchased from Shanghai Xipuer-Bikai Laboratory Animal Co., Ltd., Animal Production License No.: SCXK (HU) 2013-0016

(457) 3.2.3 Preparation of Test Drugs

(458) Intragastric or intravenous administration: an appropriate amount of sample was weighed, dissolved in 5% DMSO+40% PEG400+55% (10% HP-β-CD in Saline) to prepare a 0.5 mg/ml solution for intragastric or intravenous administration.

(459) 3.2.4 Administration of Test Drugs

(460) Intravenous administration: for each test compound, 3 male ICR mice were administered intravenously at a dose of 2 mg/kg and an administration volume of 1 ml/kg after fasting overnight.

(461) Intragastric administration: for each test compound, 3 male ICR mice were administered intragastrically at a dose of 5 mg/kg and an administration volume of 5 ml/kg after fasting overnight.

(462) 3.3 Experimental Operation

(463) Before administration and 0.083 h, 0.167 h, 0.25 h, 0.33 h, 0.5 h, 1 h, 2 h, 4 h, 8 h and 24 h after administration, approximately 0.2 mL blood was collected via jugular vein puncture, the obtained blood was anticoagulated with heparin sodium, and placed on ice after collection, and the blood was centrifuged to separate plasma (centrifugation conditions: 8000 rpm, 6 min, and 4° C.). The collected plasma was stored at −80° C. before analysis. The plasma sample was analyzed by LC-MS/MS, and the sample was pretreated by protein precipitation method. The linear range of sample analysis was 1 to 2000 ng/ml. The lowest quantification limit was 1 ng/mL. WinNonlin (Pharsight, USA) was used to calculate the following pharmacokinetic parameters: area under the curve AUC.sub.(0-t), area under the curve AUC.sub.(0-∞), half-life t.sub.1/2, retention time MRT.sub.(0-∞), blood drug concentration C.sub.max, time taken to reach the peak blood drug concentration T.sub.max, bioavailability F, apparent volume of distribution V.sub.z, and clearance rate CL.

(464) 3.4 Results of Pharmacokinetic Data

(465) TABLE-US-00004 TABLE 3 Pharmacokinetic parameters of ICR mice after intravenous and oral administration of HDM201 IV- 2 mg/kg Animal t.sub.1/2 T.sub.max C.sub.max AUC.sub.(0-t) AUC.sub.(0-∞) MRT.sub.(0-t) MRT.sub.(0-∞) Vz CL number h h ng/mL h*ng/mL h*ng/mL h h mL/kg mL/h/kg 101 0.67 0.08 585.03 622.13 713.62 0.66 0.96 2717.30 2802.63 102 0.53 0.08 605.51 573.66 619.30 0.59 0.75 2456.27 3229.47 103 0.67 0.08 459.85 520.23 600.29 0.68 0.98 3231.81 3331.71 Mean 0.62 0.083 550.13 572.01 644.40 0.64 0.90 2801.79 3121.27 SD 0.08 0.000 78.85 50.97 60.69 0.04 0.13 394.61 280.65 PO- 5 mg/kg Animal t.sub.1/2 T.sub.max C.sub.max AUC.sub.(0-t) AUC.sub.(0-∞) MRT.sub.(0-t) MRT.sub.(0-∞) F* number h h ng/mL h*ng/mL h*ng/mL h h % 201 1.34 0.50 408.75 1058.75 1078.76 1.94 2.09 202 0.74 0.50 584.08 797.19 818.45 1.04 1.15 203 1.24 0.50 715.01 1522.78 1539.76 1.82 1.91 Mean 1.11 0.50 569.28 1126.24 1145.66 1.60 1.72 78.76 SD 0.32 0.00 153.66 367.47 365.28 0.49 0.50 ${\hspace{0.17em}}^{*}F=\frac{{\mathrm{AUC}}_{\left(0-t\right)\left(\mathrm{PO}\right)}\times {\mathrm{Dose}}_{\left(\mathrm{IV}\right)}}{{\mathrm{AUC}}_{\left(0-t\right)\left(\mathrm{IV}\right)}\times {\mathrm{Dose}}_{\left(\mathrm{PO}\right)}}\times 100\%$

(466) TABLE-US-00005 TABLE 4 Pharmacokinetic parameters of ICR mice after intravenous and oral administration of compound S-1 IV- 2 mg/kg Animal t.sub.1/2 T.sub.max C.sub.max AUC.sub.(0-t) AUC.sub.(0-∞) MRT.sub.(0-t) MRT.sub.(0-∞) Vz CL number h h ng/mL h*ng/mL h*ng/mL h h mL/kg mL/h/kg 301 1.21 0.08 307.80 532.69 548.82 1.33 1.52 6380.69 3644.18 302 1.00 0.08 329.89 725.28 736.92 1.31 1.41 3917.79 2713.99 303 0.98 0.08 336.17 843.53 855.63 1.34 1.43 3308.82 2337.47 Mean 1.07 0.083 324.62 700.50 713.79 1.33 1.45 4535.77 2898.55 SD 0.13 0.000 14.90 156.90 154.71 0.01 0.06 1626.50 672.62 PO- 5 mg/kg Animal t.sub.1/2 T.sub.max C.sub.max AUC.sub.(0-t) AUC.sub.(0-∞) MRT.sub.(0-t) MRT.sub.(0-∞) F* number h h ng/mL h*ng/mL h*ng/mL h h % 401 1.03 1.00 629.23 1822.90 1834.25 1.94 1.99 402 1.98 1.00 471.21 1944.41 2088.41 2.60 3.17 403 1.92 1.00 92.81 241.17 330.15 1.79 3.13 Mean 1.64 1.00 397.75 1336.16 1417.60 2.11 2.76 76.30 SD 0.54 0.00 275.65 950.23 950.30 0.43 0.67 ${\hspace{0.17em}}^{*}F=\frac{{\mathrm{AUC}}_{\left(0-t\right)\left(\mathrm{PO}\right)}\times {\mathrm{Dose}}_{\left(\mathrm{IV}\right)}}{{\mathrm{AUC}}_{\left(0-t\right)\left(\mathrm{IV}\right)}\times {\mathrm{Dose}}_{\left(\mathrm{PO}\right)}}\times 100\%\hspace{0.17em}$

(467) TABLE-US-00006 TABLE 5 Pharmacokinetic parameters of ICR mice after intravenous and oral administration of compound S-2 IV- 2 mg/kg Animal t.sub.1/2 T.sub.max C.sub.max AUC.sub.(0-t) AUC.sub.(0-∞) MRT.sub.(0-t) MRT.sub.(0-∞) Vz CL number h h ng/mL h*ng/mL h*ng/mL h h mL/kg mL/h/kg 501 1.11 0.08 492.38 1362.57 1392.31 1.51 1.64 2291.83 1436.46 502 0.84 0.50 477.30 1554.01 1564.61 1.47 1.51 1552.17 1278.27 503 0.93 1.00 456.11 1477.86 1494.93 1.47 1.54 1804.36 1337.86 Mean 0.96 0.528 475.26 1464.81 1483.95 1.48 1.56 1882.79 1350.86 SD 0.13 0.459 18.22 96.38 86.68 0.02 0.07 376.01 79.90 PO- 5 mg/kg Animal t.sub.1/2 T.sub.max C.sub.max AUC.sub.(0-t) AUC.sub.(0-∞) MRT.sub.(0-t) MRT.sub.(0-∞) F* number h h ng/mL h*ng/mL h*ng/mL h h % 601 1.45 2.00 655.97 3165.38 3254.89 2.89 3.09 602 1.83 1.00 729.77 3883.23 4100.77 2.87 3.28 603 1.50 2.00 804.59 4136.52 4259.08 2.76 2.97 Mean 1.59 1.67 730.11 3728.38 3871.58 2.84 3.12 101.81 SD 0.21 0.58 74.31 503.75 539.90 0.07 0.16 ${\hspace{0.17em}}^{*}F=\frac{{\mathrm{AUC}}_{\left(0-t\right)\left(\mathrm{PO}\right)}\times {\mathrm{Dose}}_{\left(\mathrm{IV}\right)}}{{\mathrm{AUC}}_{\left(0-t\right)\left(\mathrm{IV}\right)}\times {\mathrm{Dose}}_{\left(\mathrm{PO}\right)}}\times 100\%$

(468) TABLE-US-00007 TABLE 6 Pharmacokinetic parameters of ICR mice after intravenous and oral administration of compound S-9 IV- 2 mg/kg Animal t.sub.1/2 T.sub.max C.sub.max AUC.sub.(0-t) AUC.sub.(0-∞) MRT.sub.(0-t) MRT.sub.(0-∞) Vz CL number h h ng/mL h*ng/mL h*ng/mL h h mL/kg mL/h/kg 701 1.26 0.08 1403.26 3334.44 3452.37 1.47 1.68 1055.16 579.31 702 1.40 0.08 1274.58 3650.23 3830.08 1.58 1.88 1054.38 522.18 703 1.16 0.08 1643.99 4107.04 4214.93 1.47 1.63 793.38 474.50 Mean 1.27 0.083 1440.61 3697.23 3832.46 1.51 1.73 967.64 525.33 SD 0.12 0.000 187.52 388.44 381.29 0.06 0.13 150.91 52.48 PO- 5 mg/kg Animal t.sub.1/2 T.sub.max C.sub.max AUC.sub.(0-t) AUC.sub.(0-∞) MRT.sub.(0-t) MRT.sub.(0-∞) F* number h h ng/mL h*ng/mL h*ng/mL h h % 801 1.57 2.00 1366.47 6319.30 6555.06 2.65 2.92 802 1.44 1.00 2009.05 8692.39 8911.44 2.60 2.78 803 1.22 1.00 1914.07 6976.33 7048.92 2.68 2.75 Mean 1.41 1.33 1763.20 7329.34 7505.14 2.64 2.82 79.30 SD 0.18 0.58 346.84 1225.29 1242.67 0.04 0.09 ${\hspace{0.17em}}^{*}F=\frac{{\mathrm{AUC}}_{\left(0-t\right)\left(\mathrm{PO}\right)}\times {\mathrm{Dose}}_{\left(\mathrm{IV}\right)}}{{\mathrm{AUC}}_{\left(0-t\right)\left(\mathrm{IV}\right)}\times {\mathrm{Dose}}_{\left(\mathrm{PO}\right)}}\times 100\%$

(469) TABLE-US-00008 TABLE 7 Pharmacokinetic parameters of ICR mice after intravenous and oral administration of compound S-11 IV- 2 mg/kg Animal t.sub.1/2 T.sub.max C.sub.max AUC.sub.(0-t) AUC.sub.(0-∞) MRT.sub.(0-t) MRT.sub.(0-∞) V.sub.Z CL number h h ng/mL h*ng/mL h*ng/mL h h L/kg mL/min/kg 101 1.15 0.50 1376.51 3578.38 3680.24 1.43 1.61 0.91 9.06 102 2.09 0.50 1519.69 4225.58 4820.40 1.81 2.70 1.25 6.92 103 1.15 0.50 1302.60 3169.84 3250.24 1.40 1.55 1.02 10.26 Mean 1.46 0.500 1399.60 3657.93 3916.96 1.55 1.95 1.06 8.74 SD 0.54 0.000 110.37 532.35 811.41 0.23 0.65 0.17 1.69 PO-5 mg/kg Animal t.sub.1/2 T.sub.max C.sub.max AUC.sub.(0-t) AUC.sub.(0-∞) MRT.sub.(0-t) MRT.sub.(0-∞) F* number h h ng/mL h*ng/mL h*ng/mL h h % 201 2.18 1.00 1645.73 8018.78 8771.68 2.96 3.66 202 1.55 1.00 1573.02 8536.56 8816.41 2.87 3.11 203 1.33 2.00 2144.69 11568.40 11784.98 2.92 3.05 Mean 1.69 1.33 1787.81 9374.58 9791.02 2.92 3.27 102.51 SD 0.44 0.58 311.20 1917.46 1726.96 0.04 0.34

(470) TABLE-US-00009 TABLE 8 Some pharmacokinetic parameters of ICR mice after intravenous and oral administration of S-23 IV- 2 mg/kg Animal t.sub.1/2 T.sub.max C.sub.max AUC.sub.(0-t) AUC.sub.(0-∞) MRT.sub.(0-t) MRT.sub.(0-∞) Vz CL number h h ng/mL h*ng/mL h*ng/mL h h L/kg mL/min/kg 101 1.57 0.08 3640.21 6625.30 7084.65 1.55 1.99 0.64 4.71 102 1.86 0.08 3779.72 9462.95 10504.31 1.78 2.46 0.51 3.17 103 1.33 0.08 3040.32 6172.76 6427.71 1.50 1.75 0.60 5.19 Mean 1.59 0.083 3486.75 7420.34 8005.55 1.61 2.07 0.58 4.35 SD 0.26 0.000 392.86 1783.37 2188.77 0.15 0.36 0.07 1.05 PO- 5 mg/kg t.sub.1/2 T.sub.max C.sub.max AUC.sub.(0-t) AUC.sub.(0-∞) MRT.sub.(0-t) MRT.sub.(0-∞) F* h h ng/mL h*ng/mL h*ng/mL h h % 201 1.15 1.00 2050.29 7235.20 7315.60 2.35 2.43 202 0.98 1.00 3316.65 9122.66 9163.57 2.02 2.05 203 1.52 0.50 2730.39 7675.41 7881.03 2.08 2.29 Animal 1.22 0.83 2699.11 8011.09 8120.07 2.15 2.26 43.18 number 0.27 0.79 633.76 987.49 946.89 0.18 0.19 ${\hspace{0.17em}}^{*}F=\frac{{\mathrm{AUC}}_{\left(0-t\right)\left(\mathrm{PO}\right)}\times {\mathrm{Dose}}_{\left(\mathrm{IV}\right)}}{{\mathrm{AUC}}_{\left(0-t\right)\left(\mathrm{IV}\right)}\times {\mathrm{Dose}}_{\left(\mathrm{PO}\right)}}\times 100\%$

(471) TABLE-US-00010 TABLE 9 Pharmacokinetic parameters of ICR mice after intravenous and oral administration of S-32 IV- 2 mg/kg Animal t.sub.1/2 T.sub.max C.sub.max AUC.sub.(0-t) AUC.sub.(0-∞) MRT.sub.(0-t) MRT.sub.(0-∞) Vz CL number h h ng/mL h*ng/mL h*ng/mL h h mL/kg mL/h/kg 901 1.23 0.25 2766.01 4699.29 4854.66 1.32 1.53 730.20 411.98 902 1.44 0.50 2451.28 7199.84 7627.51 1.61 1.97 542.87 262.21 903 1.26 0.08 1902.13 3859.04 4004.98 1.29 1.53 908.33 499.38 Mean 1.31 0.278 2373.14 5252.72 5495.32 1.41 1.68 727.14 391.19 SD 0.11 0.210 437.21 1737.80 1894.44 0.17 0.25 182.75 119.94 PO- 5 mg/kg Animal t.sub.1/2 T.sub.max C.sub.max AUC.sub.(0-t) AUC.sub.(0-∞) MRT.sub.(0-t) MRT.sub.(0-∞) F* number h h ng/mL h*ng/mL h*ng/mL h h % 1001 2.89 1.00 1578.70 6017.39 7102.68 2.79 4.22 1002 1.51 1.00 3356.31 10704.89 11027.74 2.24 2.48 1003 2.07 1.00 2518.33 8458.06 9168.53 2.48 3.14 Mean 2.16 1.00 2484.45 8393.45 9099.65 2.50 3.28 63.92 SD 0.69 0.00 889.29 2344.42 1963.44 0.27 0.88 ${\hspace{0.17em}}^{*}F=\frac{{\mathrm{AUC}}_{\left(0-t\right)\left(\mathrm{PO}\right)}\times {\mathrm{Dose}}_{\left(\mathrm{IV}\right)}}{{\mathrm{AUC}}_{\left(0-t\right)\left(\mathrm{IV}\right)}\times {\mathrm{Dose}}_{\left(\mathrm{PO}\right)}}\times 100\%$

(472) TABLE-US-00011 TABLE 10 Some pharmacokinetic parameters of ICR mice after intravenous and oral administration of S-44 IV- 2 mg/kg Animal t.sub.1/2 T.sub.max C.sub.max AUC.sub.(0-t) AUC.sub.(0-∞) MRT.sub.(0-t) MRT.sub.(0-∞) Vz CL number h h ng/mL h*ng/mL h*ng/mL h h L/kg mL/min/kg 301 1.91 0.08 951.21 2987.84 3364.67 1.77 2.56 1.64 9.91 302 1.79 0.08 872.25 2506.41 2766.34 1.71 2.35 1.86 12.05 303 1.92 0.08 826.58 2703.63 3052.47 1.82 2.61 1.82 10.92 Mean 1.87 0.083 883.35 2732.63 3061.16 1.77 2.51 1.77 10.96 SD 0.08 0.000 63.05 242.03 299.26 0.05 0.14 0.12 1.07 PO- 5 mg/kg Animal t.sub.1/2 T.sub.max C.sub.max AUC.sub.(0-t) AUC.sub.(0-∞) MRT.sub.(0-t) MRT.sub.(0-∞) F* number h h ng/mL h*ng/mL h*ng/mL h h % 401 2.56 1.00 1357.96 7904.41 8959.71 3.17 4.17 402 1.77 1.00 1097.85 5161.46 5447.83 2.81 3.22 403 1.65 2.00 1204.30 6287.89 6556.64 3.08 3.38 Mean 2.00 1.33 1220.04 6451.26 6988.07 3.02 3.59 94.43 SD 0.49 0.58 130.77 1378.76 1795.24 0.19 0.51 ${\hspace{0.17em}}^{*}F=\frac{{\mathrm{AUC}}_{\left(0-t\right)\left(\mathrm{PO}\right)}\times {\mathrm{Dose}}_{\left(\mathrm{IV}\right)}}{{\mathrm{AUC}}_{\left(0-t\right)\left(\mathrm{IV}\right)}\times {\mathrm{Dose}}_{\left(\mathrm{PO}\right)}}\times 100\%$

(473) TABLE-US-00012 TABLE 11 Some pharmacokinetic parameters of ICR mice after intravenous and oral administration of S-45 IV-2 mg/kg Animal t.sub.1/2 T.sub.max C.sub.max AUC.sub.(0-t) AUC.sub.(0-∞) MRT.sub.(0-t) MRT.sub.(0-∞) V.sub.Z CL number h h ng/mL h*ng/mL h*ng/mL h h L/kg mL/min/kg 301 1.01 0.25 779.74 1865.23 1895.22 1.36 1.45 1.54 17.59 302 1.00 0.08 882.75 2072.07 2103.04 1.35 1.44 1.37 15.85 303 1.05 0.08 765.75 1793.27 1825.35 1.34 1.45 1.65 18.26 Mean 1.02 0.139 809.41 19110.19 1941.20 1.35 1.45 1.52 17.23 SD 0.02 0.096 63.90 144.74 144.44 0.01 0.01 0.14 1.24 PO-5 mg/kg Animal t.sub.1/2 T.sub.max C.sub.max AUC.sub.(0-t) AUC.sub.(0-∞) MRT.sub.(0-t) MRT.sub.(0-∞) F* number h h ng/mL h*ng/mL h*ng/mL h h % 401 2.17 0.50 1590.61 5862.67 6346.49 2.56 3.21 402 1.54 1.00 1355.63 5315.63 5471.40 2.53 2.75 403 1.87 1.00 1169.32 4196.04 4431.71 2.56 2.99 Mean 1.86 0.83 1371.85 5124.78 5416.53 2.55 2.99 107.31 SD 0.32 0.29 211.11 849.55 958.57 0.02 0.23

(474) TABLE-US-00013 TABLE 12 Some pharmacokinetic parameters of ICR mice after intravenous and oral administration of S-61 IV- 2 mg/kg Animal t.sub.1/2 T.sub.max C.sub.max AUC.sub.(0-t) AUC.sub.(0-∞) MRT.sub.(0-t) MRT.sub.(0-∞) Vz CL number h h ng/mL h*ng/mL h*ng/mL h h L/kg mL/min/kg 301 1.09 0.08 2994.43 4640.74 4724.28 1.21 1.32 0.67 7.06 302 1.00 0.08 3249.64 3583.88 3626.86 0.99 1.07 0.80 9.19 303 1.15 0.08 3244.96 5346.76 5483.62 1.26 1.42 0.60 6.08 Mean 1.08 0.083 3163.00 4523.79 4611.59 1.15 1.27 0.69 7.44 SD 0.07 0.000 146.02 887.24 933.50 0.14 0.18 0.10 1.59 PO- 5 mg/kg Animal t.sub.1/2 T.sub.max C.sub.max AUC.sub.(0-t) AUC.sub.(0-∞) MRT.sub.(0-t) MRT.sub.(0-∞) F* number h h ng/mL h*ng/mL h*ng/mL h h % 401 3.58 0.25 2434.93 2462.65 2768.24 1.57 2.85 402 2.71 0.50 2489.40 4960.30 5500.70 2.03 3.00 403 2.98 0.25 1772.67 3162.34 3530.81 1.91 3.00 Mean 3.09 0.33 2232.33 3528.43 3933.25 1.84 2.95 31.20 SD 0.44 0.14 399.01 1288.44 1409.98 0.24 0.09 0${\hspace{0.17em}}^{*}F=\frac{{\mathrm{AUC}}_{\left(0-t\right)\left(\mathrm{PO}\right)}\times {\mathrm{Dose}}_{\left(\mathrm{IV}\right)}}{{\mathrm{AUC}}_{\left(0-t\right)\left(\mathrm{IV}\right)}\times {\mathrm{Dose}}_{\left(\mathrm{PO}\right)}}\times 100\%$

(475) TABLE-US-00014 TABLE 13 Some pharmacokinetic parameters of ICR mice after intravenous and oral administration of S-69 IV-2 mg/kg Animal t.sub.1/2 T.sub.max C.sub.max AUC.sub.(0-t) AUC.sub.(0-∞) MRT.sub.(0-t) MRT.sub.(0-∞) Vz CL number h h ng/mL h*ng/mL h*ng/mL h h L/kg mL/min/kg 301 2.83 0.08 6038.43 52203.96 52314.11 4.30 4.35 0.16 0.64 302 2.88 0.50 5977.53 53093.43 53217.23 4.38 4.44 0.16 0.63 303 4.02 0.08 5141.60 50006.21 50659.35 4.62 4.95 0.23 0.66 Mean 3.24 0.222 5719.19 51767.87 52061.56 4.43 4.58 0.18 0.64 SD 0.67 0.241 501.13 1589.14 1297.22 0.17 0.32 0.04 0.02 PO-5 mg/kg Animal t.sub.1/2 T.sub.max C.sub.max AUC.sub.(0-t) AUC.sub.(0-∞) MRT.sub.(0-t) MRT.sub.(0-∞) F* number h h ng/mL h*ng/mL h*ng/mL h h % 401 2.24 2.00 7627.20 69211.96 69264.13 4.92 4.94 402 2.28 2.00 10867.97 106563.84 106654.00 5.03 5.04 403 2.03 2.00 11828.43 85266.27 85298.58 4.46 4.47 Mean 2.18 2.00 10107.87 87014.02 87072.23 4.80 4.82 67.23 SD 0.13 0.00 2201.34 18737.18 18757.93 0.30 0.31

(476) TABLE-US-00015 TABLE 14 Some pharmacokinetic parameters of ICR mice after intravenous and oral administration of S-72 IV-2 mg/kg Animal t.sub.1/2 T.sub.max C.sub.max AUC.sub.(0-t) AUC.sub.(0-∞) MRT.sub.(0-t) MRT.sub.(0-∞) Vz CL number h h ng/mL h*ng/mL h*ng/mL h h L/kg mL/min/kg 301 2.16 1.00 3686.88 14847.37 17305.95 1.96 2.98 0.36 1.93 302 1.39 0.08 4634.53 11456.75 11918.88 1.53 1.78 0.34 2.80 303 1.23 0.08 4839.23 11802.83 12174.58 1.52 1.71 0.29 2.74 Mean 1.59 0.389 4386.88 12702.32 13799.80 1.67 2.16 0.33 2.49 SD 0.50 0.529 614.80 1865.71 3039.10 0.25 0.71 0.03 0.49 PO-5 mg/kg Animal t.sub.1/2 T.sub.max C.sub.max AUC.sub.(0-t) AUC.sub.(0-∞) MRT.sub.(0-t) MRT.sub.(0-∞) F* number h h ng/mL h*ng/mL h*ng/mL h h % 401 2.54 0.50 7867.58 51286.19 51351.03 3.95 3.98 402 1.13 0.50 7160.86 23996.12 24161.28 2.18 2.23 403 1.47 1.00 6289.71 26941.23 27586.31 2.66 2.84 Mean 1.72 0.67 7106.05 34074.52 34366.20 2.93 3.01 107.30 SD 0.73 0.29 790.36 14978.31 14808.64 0.91 0.89

(477) TABLE-US-00016 TABLE 15 Some pharmacokinetic parameters of ICR mice after intravenous and oral administration of S-96 IV-2 mg/kg Animal t.sub.1/2 T.sub.max C.sub.max AUC.sub.(0-t) AUC.sub.(0-∞) MRT.sub.(0-t) MRT.sub.(0-∞) Vz CL number h h ng/mL h*ng/mL h*ng/mL h h L/kg mL/min/kg 301 3.36 0.08 3438.41 6719.85 6815.93 2.62 2.99 1.42 4.89 302 0.93 0.08 2982.34 3109.78 3157.25 0.90 1.00 0.85 10.56 303 1.07 0.08 3353.43 3206.41 3250.65 0.90 0.99 0.95 10.25 Mean 1.79 0.083 3258.06 4345.35 4407.95 1.47 1.66 1.07 8.57 SD 1.37 0.000 242.53 2056.95 2085.90 1.00 1.16 0.31 3.19 PO-5 mg/kg Animal t.sub.1/2 T.sub.max C.sub.max AUC.sub.(0-t) AUC.sub.(0-∞) MRT.sub.(0-t) MRT.sub.(0-∞) F* number h h ng/mL h*ng/mL h*ng/mL h h % 401 1.69 0.25 3921.65 6327.28 6705.00 1.66 2.15 402 2.06 0.50 2400.19 6993.90 7471.54 2.42 2.97 403 2.58 0.50 5236.64 13010.63 15115.19 2.30 3.61 Mean 2.11 0.42 3852.83 8777.27 9763.91 2.13 2.91 80.80 SD 0.44 0.14 1419.48 3681.32 4650.17 0.41 0.73

(478) TABLE-US-00017 TABLE 16 Some pharmacokinetic parameters of ICR mice after intravenous and oral administration of S-98 IV-2 mg/kg Animal t.sub.1/2 T.sub.max C.sub.max AUC.sub.(0-t) AUC.sub.(0-∞) MRT.sub.(0-t) MRT.sub.(0-∞) Vz CL number h h ng/mL h*ng/mL h*ng/mL h h L/kg mL/min/kg 301 1.93 0.08 3405.07 11177.15 12596.27 1.82 2.60 0.44 2.65 302 1.43 0.08 3672.74 10025.81 10533.19 1.55 1.86 0.39 3.16 303 1.17 0.08 3789.06 8869.53 9108.92 1.43 1.60 0.37 3.66 Mean 1.51 0.083 3622.29 10024.16 10746.13 1.60 2.02 0.40 3.16 SD 0.39 0.000 196.90 1153.81 1753.40 0.20 0.52 0.04 0.51 PO-5 mg/kg Animal t.sub.1/2 T.sub.max C.sub.max AUC.sub.(0-t) AUC.sub.(0-∞) MRT.sub.(0-t) MRT.sub.(0-∞) F* number h h ng/mL h*ng/mL h*ng/mL h h % 401 2.31 4.00 3835.13 37288.31 37324.50 5.36 5.38 402 2.12 2.00 3420.72 18064.52 19691.36 3.17 3.82 403 2.30 2.00 2943.86 23330.62 23352.18 4.72 4.74 Mean 2.24 2.67 3399.90 26227.82 26789.35 4.41 4.65 104.66 SD 0.11 1.15 446.00 9933.98 9305.51 1.12 0.78

(479) TABLE-US-00018 TABLE 17 Some pharmacokinetic parameters of ICR mice after intravenous and oral administration of S-103 IV-2 mg/kg Animal t.sub.1/2 T.sub.max C.sub.max AUC.sub.(0-t) AUC.sub.(0-∞) MRT.sub.(0-t) MRT.sub.(0-∞) Vz CL number h h ng/mL h*ng/mL h*ng/mL h h L/kg mL/min/kg 301 4.11 1.00 1333.49 5508.40 8771.81 2.33 5.91 1.35 3.80 302 2.89 1.00 1332.61 10460.62 10483.52 4.16 4.21 0.79 3.18 303 2.71 1.00 1045.99 4009.87 5119.53 2.05 3.75 1.53 6.51 Mean 3.24 1.000 1237.36 6659.63 8124.95 2.85 4.62 1.22 4.50 SD 0.77 0.000 165.73 3375.95 2739.88 1.15 1.13 0.38 1.77 PO-5 mg/kg Animal t.sub.1/2 T.sub.max C.sub.max AUC.sub.(0-t) AUC.sub.(0-∞) MRT.sub.(0-t) MRT.sub.(0-∞) F* number h h ng/mL h*ng/mL h*ng/mL h h % 401 1.84 2.00 2382.42 10967.55 11688.42 3.08 3.54 402 1.72 4.00 2344.01 13078.28 14231.55 3.36 3.93 403 2.23 4.00 3008.06 19872.62 19888.79 4.45 4.47 Mean 1.93 3.33 2578.16 14639.49 15269.59 3.63 3.98 87.93 SD 0.27 1.15 372.80 4653.29 4197.58 0.73 0.46

(480) TABLE-US-00019 TABLE 18 Some pharmacokinetic parameters of ICR mice after intravenous and oral administration of S-115 IV-2 mg/kg Animal t.sub.1/2 T.sub.max C.sub.max AUC.sub.(0-t) AUC.sub.(0-∞) MRT.sub.(0-t) MRT.sub.(0-∞) Vz CL number h h ng/mL h*ng/mL h*ng/mL h h L/kg mL/min/kg 301 0.90 0.08 4136.98 2987.42 3011.30 0.82 0.87 0.87 11.07 302 0.90 0.08 2997.99 2575.46 2591.81 0.90 0.94 1.00 12.86 303 0.80 0.08 2549.96 2278.66 2289.66 0.79 0.82 1.01 14.56 Mean 0.87 0.083 3228.31 2613.85 2630.92 0.84 0.88 0.96 12.83 SD 0.06 0.000 818.20 355.93 362.40 0.05 0.06 0.08 1.74 PO-5 mg/kg Animal t.sub.1/2 T.sub.max C.sub.max AUC.sub.(0-t) AUC.sub.(0-∞) MRT.sub.(0-t) MRT.sub.(0-∞) F* number h h ng/mL h*ng/mL h*ng/mL h h % 401 1.07 0.50 2135.46 3655.37 3672.50 1.37 1.41 402 1.19 1.00 834.66 2355.30 2377.88 2.13 2.20 403 1.12 4.00 601.29 2985.59 3066.25 3.22 3.39 Mean 1.12 1.83 1190.47 2998.75 3038.87 2.24 2.33 45.89 SD 0.06 1.89 826.66 650.14 647.74 0.93 1.00

(481) TABLE-US-00020 TABLE 19 Some pharmacokinetic parameters of ICR mice after intravenous and oral administration of S-121 IV-2 mg/kg Animal t.sub.1/2 T.sub.max C.sub.max AUC.sub.(0-t) AUC.sub.(0-∞) MRT.sub.(0-t) MRT.sub.(0-∞) Vz CL number h h ng/mL h*ng/mL h*ng/mL h h L/kg mL/min/kg 301 5.50 0.08 3887.60 24572.30 25488.79 5.26 6.22 0.62 1.31 302 5.25 0.08 3346.18 28379.48 29352.82 5.15 6.03 0.52 1.14 303 5.09 0.08 3576.94 26953.62 27749.72 5.04 5.79 0.53 1.20 Mean 5.28 0.083 3603.57 26635.14 27530.44 5.15 6.01 0.56 1.21 SD 0.21 0.000 271.69 1923.47 1941.33 0.11 0.21 0.06 0.09 PO-5 mg/kg Animal t.sub.1/2 T.sub.max C.sub.max AUC.sub.(0-t) AUC.sub.(0-∞) MRT.sub.(0-t) MRT.sub.(0-∞) F* number h h ng/mL h*ng/mL h*ng/mL h h % 401 3.09 2.00 4920.31 40051.63 40259.72 4.96 5.08 402 3.34 4.00 4835.52 43063.09 43407.01 5.27 5.45 403 3.14 4.00 4714.57 40782.54 41032.91 5.40 5.54 Mean 3.19 3.33 4823.47 41299.09 41566.55 5.21 5.36 62.02 SD 0.13 1.15 103.40 1570.77 1640.10 0.23 0.24

(482) TABLE-US-00021 TABLE 20 Some pharmacokinetic parameters of ICR mice after intravenous and oral administration of S-131 IV-2 mg/kg Animal t.sub.1/2 T.sub.max C.sub.max AUC.sub.(0-t) AUC.sub.(0-∞) MRT.sub.(0-t) MRT.sub.(0-∞) Vz CL number h h ng/mL h*ng/mL h*ng/mL h h L/kg mL/min/kg 301 0.90 0.08 1997.01 1776.79 1788.59 0.94 0.98 1.45 18.64 302 0.76 0.08 1776.22 1261.09 1264.23 0.71 0.73 1.73 26.37 303 0.98 0.08 2021.33 1579.23 1594.10 0.90 0.96 1.78 20.91 Mean 0.88 0.083 1931.52 1539.04 1548.98 0.85 0.89 1.65 21.97 SD 0.11 0.000 135.04 260.19 265.08 0.12 0.14 0.18 3.97 PO-5 mg/kg Animal t.sub.1/2 T.sub.max C.sub.max AUC.sub.(0-t) AUC.sub.(0-∞) MRT.sub.(0-t) MRT.sub.(0-∞) F* number h h ng/mL h*ng/mL h*ng/mL h h % 401 1.03 1.00 1438.00 3743.48 3765.68 1.90 1.95 402 1.28 1.00 1853.01 5902.77 6003.28 2.27 2.40 403 1.47 1.00 1794.96 6839.45 7052.50 2.45 2.68 Mean 1.26 1.00 1695.32 5495.23 5607.15 2.21 2.34 142.82 SD 0.22 0.00 224.73 1587.71 1678.83 0.28 0.37

(483) TABLE-US-00022 TABLE 21 Some pharmacokinetic parameters of ICR mice after intravenous and oral administration of S-133 IV-2 mg/kg Animal t.sub.1/2 T.sub.max C.sub.max AUC.sub.(0-t) AUC.sub.(0-∞) MRT.sub.(0-t) MRT.sub.(0-∞) Vz CL number h h ng/mL h*ng/mL h*ng/mL h h L/kg mL/min/kg 301 1.22 0.08 2055.95 2904.29 3022.24 1.20 1.45 1.16 11.03 302 1.07 0.08 2980.85 4602.71 4699.55 1.18 1.31 0.66 7.09 303 1.13 0.08 2521.09 3187.22 3247.82 1.05 1.17 1.01 10.26 Mean 1.14 0.083 2519.30 3564.74 3656.54 1.14 1.31 0.94 9.46 SD 0.08 0.000 462.45 909.97 910.29 0.08 0.14 0.26 2.09 PO-5 mg/kg Animal t.sub.1/2 T.sub.max C.sub.max AUC.sub.(0-t) AUC.sub.(0-∞) MRT.sub.(0-t) MRT.sub.(0-∞) F* number h h ng/mL h*ng/mL h*ng/mL h h % 401 1.15 1.00 1569.92 6074.68 6148.80 2.34 2.43 402 1.05 1.00 1489.30 4282.62 4314.80 2.17 2.22 403 1.04 1.00 2195.02 5953.82 5994.87 2.05 2.10 Mean 1.08 1.00 1751.41 5437.04 5486.16 2.19 2.25 61.01 SD 0.06 0.00 386.28 1001.58 1017.34 0.15 0.17

(484) TABLE-US-00023 TABLE 22 Some pharmacokinetic parameters of ICR mice after intravenous and oral administration of S-134 IV-2 mg/kg Animal t.sub.1/2 T.sub.max C.sub.max AUC.sub.(0-t) AUC.sub.(0-∞) MRT.sub.(0-t) MRT.sub.(0-∞) Vz CL number h h ng/mL h*ng/mL h*ng/mL h h L/kg mL/min/kg 301 1.47 0.08 3408.57 6534.27 6880.52 1.50 1.83 0.61 4.84 302 0.93 0.08 3518.10 5015.80 5060.18 1.17 1.23 0.53 6.59 303 1.07 0.25 4224.01 7289.25 7419.12 1.28 1.39 0.42 4.49 Mean 1.15 0.14 3716.89 6279.77 6453.27 1.32 1.48 0.52 5.31 SD 0.28 0.10 442.58 1159.90 1236.14 0.17 0.31 0.10 1.12 PO-5 mg/kg Animal t.sub.1/2 T.sub.max C.sub.max AUC.sub.(0-t) AUC.sub.(0-∞) MRT.sub.(0-t) MRT.sub.(0-∞) F* number h h ng/mL h*ng/mL h*ng/mL h h % 401 1.38 0.50 3905.15 9716.82 9926.06 2.04 2.21 402 1.54 0.25 3059.53 7889.97 8123.13 2.04 2.28 403 1.43 0.50 1591.65 4859.23 4978.41 2.21 2.40 Mean 1.45 0.42 2852.11 7488.67 7675.87 2.10 2.29 47.70 SD 0.08 0.14 1170.61 2453.53 2503.96 0.10 0.10

(485) TABLE-US-00024 TABLE 23 Some pharmacokinetic parameters of ICR mice after intravenous and oral administration of S-135 IV-2 mg/kg Animal t.sub.1/2 T.sub.max C.sub.max AUC.sub.(0-t) AUC.sub.(0-∞) MRT.sub.(0-t) MRT.sub.(0-∞) Vz CL number h h ng/mL h*ng/mL h*ng/mL h h L/kg mL/min/kg 301 2.03 0.08 3314.60 6495.01 7378.29 1.70 2.57 0.80 4.52 302 1.65 0.08 3896.05 7270.82 7835.48 1.60 2.09 0.61 4.25 303 1.78 0.08 3518.53 7341.09 7977.92 1.66 2.21 0.64 4.18 Mean 1.82 0.083 3576.39 7035.64 7730.56 1.65 2.29 0.68 4.32 SD 0.19 0.000 295.01 469.51 313.28 0.05 0.25 0.10 0.18 PO-5 mg/kg Animal t.sub.1/2 T.sub.max C.sub.max AUC.sub.(0-t) AUC.sub.(0-∞) MRT.sub.(0-t) MRT.sub.(0-∞) F* number h h ng/mL h*ng/mL h*ng/mL h h % 401 1.87 1.00 2159.84 9385.38 9974.62 2.64 3.12 402 1.27 1.00 2014.04 7012.03 7126.47 2.19 2.32 403 1.34 1.00 2249.28 9412.84 9616.11 2.43 2.59 Mean 1.49 1.00 2141.05 8603.42 8905.73 2.42 2.67 48.91 SD 0.33 0.00 118.74 1378.25 1551.28 0.22 0.41

(486) TABLE-US-00025 TABLE 24 Some pharmacokinetic parameters of ICR mice after intravenous and oral administration of S-137 IV-2 mg/kg Animal t.sub.1/2 T.sub.max C.sub.max AUC.sub.(0-t) AUC.sub.(0-∞) MRT.sub.(0-t) MRT.sub.(0-∞) Vz CL number h h ng/mL h*ng/mL h*ng/mL h h L/kg mL/min/kg 301 1.57 0.08 5653.28 10168.14 10938.18 1.50 1.97 0.41 3.05 302 1.68 0.08 5261.76 8963.80 9736.77 1.51 2.06 0.50 3.42 303 2.79 0.08 5945.51 15555.08 15581.80 2.84 2.88 0.52 2.14 Mean 2.01 0.083 5620.19 11562.34 12085.58 1.95 2.30 0.48 2.87 SD 0.67 0.000 343.08 3509.85 3086.83 0.77 0.50 0.05 0.66 PO-5 mg/kg Animal t.sub.1/2 T.sub.max C.sub.max AUC.sub.(0-t) AUC.sub.(0-∞) MRT.sub.(0-t) MRT.sub.(0-∞) F* number h h ng/mL h*ng/mL h*ng/mL h h % 401 1.85 0.50 5883.71 15390.44 16193.31 2.28 2.70 402 1.98 0.50 5542.83 16097.34 17159.38 2.31 2.84 403 1.69 0.50 6791.01 14779.57 15367.65 2.03 2.35 Mean 1.84 0.50 6072.52 15422.45 16240.12 2.21 2.63 53.35 SD 0.15 0.00 645.15 659.47 896.78 0.16 0.25

(487) TABLE-US-00026 TABLE 25 Some pharmacokinetic parameters of ICR mice after intravenous and oral administration of S-138 IV-2 mg/kg Animal t.sub.1/2 T.sub.max C.sub.max AUC.sub.(0-t) AUC.sub.(0-∞) MRT.sub.(0-t) MRT.sub.(0-∞) Vz CL number h h ng/mL h*ng/mL h*ng/mL h h L/kg mL/min/kg 301 3.81 0.08 1828.27 6387.52 6445.45 4.19 4.42 1.70 5.17 302 4.03 0.08 2169.08 6061.48 6126.90 4.04 4.32 1.90 5.44 303 4.29 0.08 2002.99 3427.99 5237.36 2.03 5.54 2.37 6.36 Mean 4.04 0.083 2000.11 5292.33 5936.57 3.42 4.76 1.99 5.66 SD 0.24 0.000 170.42 1622.77 626.13 1.21 0.68 0.34 0.63 PO-5 mg/kg Animal t.sub.1/2 T.sub.max C.sub.max AUC.sub.(0-t) AUC.sub.(0-∞) MRT.sub.(0-t) MRT.sub.(0-∞) F* number h h ng/mL h*ng/mL h*ng/mL h h % 401 2.69 4.00 1239.88 7428.81 9151.03 3.56 5.12 402 2.74 2.00 1475.55 7494.57 8818.35 3.19 4.51 403 2.74 1.00 1466.48 8147.05 9514.89 3.27 4.52 Mean 2.72 2.33 1393.97 7690.15 9161.42 3.34 4.72 58.12 SD 0.02 1.53 133.53 397.06 348.38 0.19 0.35

(488) TABLE-US-00027 TABLE 26 Some pharmacokinetic parameters of ICR mice after intravenous and oral administration of S-140 IV-2 mg/kg Animal t.sub.1/2 T.sub.max C.sub.max AUC.sub.(0-t) AUC.sub.(0-t) MRT.sub.(0-t) MRT.sub.(0-t) Vz CL number h h ng/mL h*ng/mL h*ng/mL h h L/kg mL/min/kg 301 2.67 0.08 5215.16 11628.12 14758.73 1.94 3.62 0.52 2.26 302 1.70 0.08 4542.99 9144.58 9903.12 1.58 2.11 0.50 3.37 303 4.19 0.08 6627.89 19456.40 19918.23 3.73 4.34 0.61 1.67 Mean 2.86 0.083 5462.01 13409.70 14860.03 2.42 3.36 0.54 2.43 SD 1.25 0.000 1064.14 5381.82 5008.33 1.15 1.14 0.06 0.86 PO-5 mg/kg Animal t.sub.1/2 T.sub.max C.sub.max AUC.sub.(0-t) AUC.sub.(0-∞) MRT.sub.(0-t) MRT.sub.(0-∞) F* number h h ng/mL h*ng/mL h*ng/mL h h % 401 2.19 2.00 4254.74 22556.48 24737.64 2.97 3.69 402 1.54 2.00 5947.01 26053.96 26994.24 2.67 2.93 403 2.38 1.00 4972.85 23914.34 26699.24 2.97 3.85 Mean 2.04 1.67 5058.20 24174.92 26143.71 2.87 3.49 72.11 SD 0.44 0.58 849.36 1763.24 1226.59 0.18 0.49

(489) TABLE-US-00028 TABLE 27 Some pharmacokinetic parameters of ICR mice after intravenous and oral administration of S-159 IV-2 mg/kg Animal t.sub.1/2 T.sub.max C.sub.max AUC.sub.(0-t) AUC.sub.(0-∞) MRT.sub.(0-t) MRT.sub.(0-∞) Vz CL number h h ng/mL h*ng/mL h*ng/mL h h L/kg mL/min/kg 301 1.86 0.08 2457.53 4501.92 4960.27 1.52 2.19 1.08 13.44 302 1.22 0.08 2540.90 3595.54 3718.50 1.23 1.45 0.95 17.93 303 1.75 0.08 2591.90 4456.51 4834.16 1.45 2.00 1.05 13.79 Mean 1.61 0.083 2530.11 4184.66 4504.31 1.40 1.88 1.02 15.05 SD 0.34 0.000 67.83 510.70 683.45 0.15 0.38 0.07 2.50 PO-5 mg/kg Animal t.sub.1/2 T.sub.max C.sub.max AUC.sub.(0-t) AUC.sub.(0-∞) MRT.sub.(0-t) MRT.sub.(0-∞) F* number h h ng/mL h*ng/mL h*ng/mL h h % 401 1.03 1.00 1438.00 3743.48 3765.68 1.90 1.95 402 1.28 1.00 1853.01 5902.77 6003.28 2.27 2.40 403 1.47 1.00 1794.96 6839.45 7052.50 2.45 2.68 Mean 1.26 1.00 1695.32 5495.23 5607.15 2.21 2.34 52.53 SD 0.22 0.00 224.73 1587.71 1678.83 0.28 0.37

(490) Experimental results: the experimental results in tables 3 to 27 above show that: after oral intragastric administration at a dose of 5 mg/kg, the bioavailability of HDM201 is 78.76%, and the AUC.sub.0-t is 1126.24 h*ng/ml; after oral intragastric administration at a dose of 5 mg/kg, the representative compound S-1 of the present invention has an AUC.sub.0-t of 1336.16 h*ng/mL, and a half-life of 1.64 hr, which are better than the corresponding parameters of HDM201; the compound S-2 has a bioavailability of 101.81%, an AUC.sub.0-t of 3728.38 h*ng/mL, and a half-life of 1.59 hr, which are better than the corresponding parameters of HDM201; the compound S-9 has an AUC.sub.0-t of 7329.34 h*ng/mL, which is better than the corresponding parameter of HDM201; the compound S-11 has a bioavailability of 102.51%, an AUC.sub.0-t of 9374.58 h*ng/mL, and a half-life of 1.69 hr, which are better than the corresponding parameters of HDM201; the compound S-23 has an AUC.sub.0-t of 8011.09 h*ng/mL, which is better than the corresponding parameter of HDM201; the compound S-32 has an AUC.sub.0-t of 8393.45 h*ng/mL, and a half-life of 2.16 hr, which are better than the corresponding parameters of HDM201; the compound S-44 has a bioavailability of 94.43%, an AUC.sub.0-t of 6451.26 h*ng/mL, and a half-life of 2.00 hr, which are better than the corresponding parameters of HDM201; the compound S-45 has a bioavailability of 107.31%, an AUC.sub.0-t of 5124.78 h*ng/mL, and a half-life of 1.86 hr, which are better than the corresponding parameters of HDM201; the compound S-61 has an AUC.sub.0-t of 3528.43 h*ng/mL, and a half-life of 3.09 hr, which are better than the corresponding parameters of HDM201; the compound S-69 has an AUC.sub.0-t of 87014.02 h*ng/mL, and a half-life of 2.18 hr, which are better than the corresponding parameters of HDM201; the compound S-72 has a bioavailability of 107.30%, an AUC.sub.0-t of 34074.52 h*ng/mL, and a half-life of 1.72 hr, which are better than the corresponding parameters of HDM201; the compound S-96 has an AUC.sub.0-t of 8777.27 h*ng/mL, and a half-life of 2.11 hr, which are better than the corresponding parameters of HDM201; the compound S-98 has a bioavailability of 104.66%, an AUC.sub.0-t of 26227.82 h*ng/mL, and a half-life of 2.24 hr, which are better than the corresponding parameters of HDM201; the compound S-103 has an AUC.sub.0-t of 14639.49 h*ng/mL, and a half-life of 1.93 hr, which are better than the corresponding parameters of HDM201; the compound S-115 has an AUC.sub.0-t of 2998.75 h*ng/mL, which is better than the corresponding parameter of HDM201; the compound S-121 has an AUC.sub.0-t of 41299.09 h*ng/mL, and a half-life of 3.19 hr, which are better than the corresponding parameters of HDM201; the compound S-131 has an AUC.sub.0-t of 5495.23 h*ng/mL, and a half-life of 1.26 hr, which are significantly better than the corresponding parameters of HDM201; the compound S-133 has an AUC.sub.0-t of 5437.04 h*ng/mL, which is better than the corresponding parameter of HDM201; the compound S-134 has an AUC.sub.0-t of 7488.67 h*ng/mL, and a half-life of 1.45 hr, which are better than the corresponding parameters of HDM201; the compound S-135 has an AUC.sub.0-t of 8603.42 h*ng/mL, which is better than the corresponding parameter of HDM201; the compound S-137 has an AUC.sub.0-t of 15422.45 h*ng/mL, and a half-life of 1.84 hr, which are better than the corresponding parameters of HDM201; the compound S-138 has an AUC.sub.0-t of 7690.15 h*ng/mL, and a half-life of 2.72 hr, which are better than the corresponding parameters of HDM201; the compound S-140 has an AUC.sub.0-t of 24174.92 h*ng/mL, and a half-life of 2.04 hr, which are better than the corresponding parameters of HDM201; and the compound S-159 has an AUC.sub.0-t of 5495.23 h*ng/mL, which is better than the corresponding parameter of HDM201.

(491) The above contents show and describe the basic principles, main features and advantages of the present invention. A person skilled in the art should understand that the present invention is not limited by the above-mentioned Examples. The above-mentioned Examples and the description only describe the principles of the present invention. It is obvious to a person skilled in the art that there will be various variations and improvements in the present invention, without departing from the spirit and scope of the present invention, and these variations and improvements fall within the claimed protection scope of the present invention. The claimed protection scope of the present invention is defined by the appended claims and their equivalents.