Oxindole derivatives carrying a piperidyl-substituted azetidinyl substituent and use thereof for treating vasopressine-related diseases

Abstract

The present invention relates to novel substituted oxindole derivatives of formula (I) wherein the variables are as defined in the claims and description; to pharmaceutical compositions comprising them, and to their use for treatment of vasopressin-related disorders. ##STR00001##

Claims

1. A compound of formula (I) ##STR00017## wherein X.sup.1 is N or CH; X.sup.2 is CR.sup.1 or N; R.sup.1 and R.sup.2, independently of each other, are selected from the group consisting of hydrogen, halogen, cyano, C.sub.1-C.sub.3-alkyl, fluorinated C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-hydroxyalkyl, C.sub.1-C.sub.3-alkoxy and fluorinated C.sub.1-C.sub.3-alkoxy; R.sup.3 is selected from the group consisting of hydrogen, halogen, cyano, hydroxyl, C.sub.1-C.sub.3-alkyl, fluorinated C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-hydroxyalkyl, C.sub.1-C.sub.3-alkoxy and fluorinated C.sub.1-C.sub.3-alkoxy; R.sup.4 is C.sub.1-C.sub.3-alkoxy; R.sup.5 is selected from the group consisting of hydrogen and C.sub.1-C.sub.3-alkoxy; R.sup.6 is selected from the group consisting of cyano and halogen; R.sup.7 is selected from the group consisting of hydrogen, halogen and cyano; R.sup.8 is selected from the group consisting of hydrogen, cyano, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkoxy-C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.7-cycloalkyl, C.sub.3-C.sub.7-halocycloalkyl and phenyl which may carry 1, 2 or 3 substituents selected from the group consisting of halogen, hydroxyl, cyano, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy and C.sub.1-C.sub.4-haloalkoxy; R.sup.9 is selected from the group consisting of C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkoxy-C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy, C.sub.3-C.sub.7-cycloalkoxy, C.sub.3-C.sub.7-halocycloalkoxy, C.sub.1-C.sub.4-alkylthio, C.sub.1-C.sub.4-haloalkylthio, C.sub.1-C.sub.4-alkylsulfinyl, C.sub.1-C.sub.4-haloalkylsulfinyl, C.sub.1-C.sub.4-alkylsulfonyl, C.sub.1-C.sub.4-haloalkylsulfonyl, phenoxy, wherein the phenyl moiety may carry 1, 2 or 3 substituents selected from the group consisting of halogen, hydroxyl, cyano, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy and C.sub.1-C.sub.4-haloalkoxy; and a 3-, 4-, 5-, 6- or 7-membered saturated, partially unsaturated or maximally unsaturated heterocyclic ring containing 1, 2 or 3 heteroatoms or heteroatom groups selected from the group consisting of O, N, S, NO, SO and SO.sub.2 as ring members, wherein the heterocyclic ring may carry 1, 2 or 3 substituents selected from the group consisting of halogen, hydroxyl, cyano, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy and C.sub.1-C.sub.4-haloalkoxy; or R.sup.8 and R.sup.9, together with the nitrogen atom they are bound to, form a 3-, 4-, 5-, 6- or 7-membered saturated, partially unsaturated or maximally unsaturated heterocyclic ring, wherein the heterocyclic ring may contain 1 or 2 further heteroatoms or heteroatom groups selected from the group consisting of O, N, S, NO, SO and SO.sub.2 as ring members, and wherein the heterocyclic ring may carry 1 or 2 substituents R.sup.12 and/or 1 or 2 substituents R.sup.13; wherein in case that the heterocyclic ring does not contain 1 or 2 further heteroatoms or heteroatom groups as ring members, the heterocyclic ring carries 1 or 2 substituents R.sup.12 and optionally 1 or 2 substituents R.sup.13; R.sup.10 and R.sup.11, independently of each other and independently of each occurrence, are selected from the group consisting of halogen, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy and C.sub.1-C.sub.4-haloalkoxy, with the proviso that R.sup.10 and R.sup.11 are not halogen, C.sub.1-C.sub.4-alkoxy or C.sub.1-C.sub.4-haloalkoxy if they are bound to a carbon atom in -position to a nitrogen ring atom; or two non-geminal radicals R.sup.10 form together a group (CH.sub.2).sub.n, wherein n is 1, 2, 3 or 4, wherein 1 or 2 hydrogen atoms in this group may be replaced a methyl group; or two non-geminal radicals R.sup.11 form together a group (CH.sub.2).sub.n, wherein n is 1, 2, 3 or 4, wherein 1 or 2 hydrogen atoms in this group may be replaced a methyl group; each R.sup.12 is independently selected from the group consisting of halogen, hydroxyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy, C.sub.3-C.sub.7-cycloalkoxy, C.sub.3-C.sub.7-halocycloalkoxy, C.sub.1-C.sub.4-alkylthio, C.sub.1-C.sub.4-haloalkylthio, C.sub.1-C.sub.4-alkylsulfinyl, C.sub.1-C.sub.4-haloalkylsulfinyl, C.sub.1-C.sub.4-alkylsulfonyl, C.sub.1-C.sub.4-haloalkylsulfonyl, phenoxy, benzyloxy, wherein the phenyl moiety in the two last-mentioned radicals may carry 1, 2 or 3 substituents selected from the group consisting of halogen, hydroxyl, cyano, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy and C.sub.1-C.sub.4-haloalkoxy; and a 3-, 4-, 5-, 6- or 7-membered saturated, partially unsaturated or maximally unsaturated heterocyclic ring containing 1, 2 or 3 heteroatoms or heteroatom groups selected from the group consisting of O, N, S, NO, SO and SO.sub.2 as ring members, wherein the heterocyclic ring may carry 1, 2 or 3 substituents selected from the group consisting of halogen, hydroxyl, cyano, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy and C.sub.1-C.sub.4-haloalkoxy; or two radicals R.sup.12, together with the atom(s) they are bound to, form a 3-, 4-, 5-, 6- or 7-membered saturated, partially unsaturated or maximally unsaturated heterocyclic ring containing 1, 2 or 3 heteroatoms or heteroatom groups selected from the group consisting of O, N, S, NO, SO and SO.sub.2 as ring members, wherein the heterocyclic ring may carry 1, 2 or 3 substituents selected from the group consisting of halogen, hydroxyl, cyano, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy and C.sub.1-C.sub.4-haloalkoxy; each R.sup.13 is independently selected from the group consisting of halogen, hydroxyl, cyano, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkoxy-C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.7-cycloalkyl, C.sub.3-C.sub.7-halocycloalkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy, C.sub.3-C.sub.7-cycloalkoxy, C.sub.3-C.sub.7-halocycloalkoxy, C.sub.1-C.sub.4-alkylthio, C.sub.1-C.sub.4-haloalkylthio, C.sub.1-C.sub.4-alkylsulfinyl, C.sub.1-C.sub.4-haloalkylsulfinyl, C.sub.1-C.sub.4-alkylsulfonyl, C.sub.1-C.sub.4-haloalkylsulfonyl, C.sub.1-C.sub.4-alkylcarbonyl, C.sub.1-C.sub.4-haloalkylcarbonyl, phenyl, phenoxy and a 3-, 4-, 5-, 6- or 7-membered saturated, partially unsaturated or maximally unsaturated heterocyclic ring containing 1, 2 or 3 heteroatoms or heteroatom groups selected from the group consisting of O, N, S, NO, SO and SO.sub.2 as ring members, wherein the phenyl moieties or the heterocyclic ring may carry 1, 2 or 3 substituents selected from the group consisting of halogen, hydroxyl, cyano, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy and C.sub.1-C.sub.4-haloalkoxy; a is 0, 1 or 2; and b is 0, 1, 2, 3 or 4; or a N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof; or the above compound, wherein at least one of the atoms has been replaced by its stable, non-radioactive isotope.

2. The compound of claim 1, wherein at least one hydrogen atom has been replaced by a deuterium atom.

3. The compound of claim 1, wherein X.sup.2 is CR.sup.1 and R.sup.1, R.sup.2 and R.sup.3, independently of each other, are selected from the group consisting of hydrogen, halogen, C.sub.1-C.sub.3-alkyl, fluorinated C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy and fluorinated C.sub.1-C.sub.3-alkoxy.

4. The compound of claim 3, wherein R.sup.1, R.sup.2 and R.sup.3, independently of each other, are selected from the group consisting of hydrogen, fluorine and methoxy.

5. The compound of claim 4, wherein R.sup.1 is selected from the group consisting of hydrogen, fluorine and methoxy.

6. The compound of claim 4, wherein R.sup.2 is selected from the group consisting of hydrogen, fluorine and methoxy.

7. The compound of claim 4, wherein R.sup.3 is hydrogen or fluorine.

8. The compound of claim 1, wherein X.sup.2 is N and R.sup.2 and R.sup.3, independently of each other, are selected from the group consisting of hydrogen, halogen, C.sub.1-C.sub.3-alkyl, fluorinated C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy and fluorinated C.sub.1-C.sub.3-alkoxy.

9. The compound of claim 8, wherein R.sup.2 is selected from the group consisting of hydrogen, fluorine and methoxy.

10. The compound of claim 8, wherein R.sup.3 is selected from the group consisting of hydrogen, fluorine and methoxy.

11. The compound of claim 1, wherein R.sup.4 is selected from the group consisting of methoxy and ethoxy.

12. The compound of claim 1, wherein R.sup.5 is hydrogen or methoxy.

13. The compound of claim 1, wherein R.sup.6 is selected from the group consisting of cyano, fluorine and chlorine.

14. The compound of claim 1, wherein R.sup.7 is hydrogen or fluorine.

15. The compound of claim 1, wherein R.sup.8 is selected from the group consisting of hydrogen, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl, C.sub.3-C.sub.6-cycloalkyl and C.sub.3-C.sub.6-halocycloalkyl; R.sup.9 is selected from the group consisting of C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkoxy-C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy, C.sub.3-C.sub.6-cycloalkoxy, C.sub.3-C.sub.6-halocycloalkoxy, and a 3-, 4-, 5- or 6-membered saturated, partially unsaturated or maximally unsaturated heterocyclic ring containing 1 or 2 heteroatoms or heteroatom groups selected from the group consisting of O, N, S, NO, SO and SO.sub.2 as ring members, wherein the heterocyclic ring may carry 1, 2 or 3 substituents selected from the group consisting of halogen, hydroxyl, cyano, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy and C.sub.1-C.sub.4-haloalkoxy; or R.sup.8 and R.sup.9, together with the nitrogen atom they are bound to, form a 3-, 4-, 5- or 6-membered saturated, partially unsaturated or maximally unsaturated heterocyclic ring, wherein the heterocyclic ring may contain 1 or 2 further heteroatoms or heteroatom groups selected from the group consisting of O, N, S, NO, SO and SO.sub.2 as ring members, and wherein the heterocyclic ring may carry 1 or 2 substituents R.sup.12 and/or 1 substituent R.sup.13; wherein in case that the heterocyclic ring does not contain 1 or 2 further heteroatoms or heteroatom groups as ring members, the heterocyclic ring carries 1 or 2 substituents R.sup.12 and optionally 1 substituent R.sup.13; each R.sup.12 is independently selected from the group consisting of halogen, hydroxyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy, C.sub.3-C.sub.6-cycloalkoxy, C.sub.3-C.sub.6-halocycloalkoxy, and a 3-, 4-, 5- or 6-membered saturated, partially unsaturated or maximally unsaturated heterocyclic ring containing 1 or 2 heteroatoms or heteroatom groups selected from the group consisting of O, N, S, NO, SO and SO.sub.2 as ring members, wherein the heterocyclic ring may carry 1, 2 or 3 substituents selected from the group consisting of halogen, hydroxyl, cyano, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy and C.sub.1-C.sub.4-haloalkoxy; or two radicals R.sup.12, together with the atom(s) they are bound to, form a 3-, 4-, 5- or 6-membered saturated, partially unsaturated or maximally unsaturated heterocyclic ring containing 1 or 2 heteroatoms or heteroatom groups selected from the group consisting of O, N, S, NO, SO and SO.sub.2 as ring members, wherein the heterocyclic ring may carry 1, 2 or 3 substituents selected from the group consisting of halogen, hydroxyl, cyano, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy and C.sub.1-C.sub.4-haloalkoxy; and R.sup.13 is selected from the group consisting of halogen, hydroxyl, cyano, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkoxy-C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-halocycloalkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy, C.sub.3-C.sub.7-cycloalkoxy, C.sub.3-C.sub.7-halocycloalkoxy, C.sub.1-C.sub.4-alkylthio, C.sub.1-C.sub.4-haloalkylthio, C.sub.1-C.sub.4-alkylsulfinyl, C.sub.1-C.sub.4-haloalkylsulfinyl, C.sub.1-C.sub.4-alkylsulfonyl, C.sub.1-C.sub.4-haloalkylsulfonyl, C.sub.1-C.sub.4-alkylcarbonyl, C.sub.1-C.sub.4-haloalkylcarbonyl, phenyl, phenoxy and a 3-, 4-, 5- or 6-membered saturated, partially unsaturated or maximally unsaturated heterocyclic ring containing 1, 2 or 3 heteroatoms or heteroatom groups selected from the group consisting of O, N, S, NO, SO and SO.sub.2 as ring members, wherein the phenyl moieties or the heterocyclic ring may carry 1, 2 or 3 substituents selected from the group consisting of halogen, hydroxyl, cyano, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy and C.sub.1-C.sub.4-haloalkoxy.

16. The compound of claim 15, wherein R.sup.8 is selected from the group consisting of hydrogen, C.sub.1-C.sub.4-alkyl, fluorinated C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkyl and fluorinated C.sub.3-C.sub.6-cycloalkyl; R.sup.9 is selected from the group consisting of C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl, fluorinated C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy, fluorinated C.sub.1-C.sub.4-alkoxy, and a 3-, 4-, 5- or 6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms or heteroatom groups selected from the group consisting of O, N, S, NO, SO and SO.sub.2 as ring members, wherein the heterocyclic ring may carry 1, 2 or 3 substituents selected from the group consisting of halogen, hydroxyl, cyano, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy and C.sub.1-C.sub.4-haloalkoxy; or R.sup.8 and R.sup.9, together with the nitrogen atom they are bound to, form a 3-, 4-, 5- or 6-membered saturated heterocyclic ring, wherein the heterocyclic ring may contain 1 or 2 further heteroatoms or heteroatom groups selected from the group consisting of O, N, S, NO, SO and SO.sub.2 as ring members, and wherein the heterocyclic ring may carry 1 or 2 substituents and/or 1 substituent R.sup.13; wherein in case that the heterocyclic ring does not contain 1 or 2 further heteroatoms or heteroatom groups as ring members, the heterocyclic ring carries 1 or 2 substituents R.sup.12 and optionally 1 substituent R.sup.13; each R.sup.12 is independently selected from the group consisting of halogen, hydroxyl, C.sub.1-C.sub.4-alkoxy, fluorinated C.sub.1-C.sub.4-alkoxy, and a 3-, 4-, 5- or 6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms or heteroatom groups selected from the group consisting of O, N, S, NO, SO and SO.sub.2 as ring members, wherein the heterocyclic ring may carry 1, 2 or 3 substituents selected from the group consisting of halogen, hydroxyl, cyano, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy and C.sub.1-C.sub.4-haloalkoxy; or two radicals R.sup.12, together with the atom(s) they are bound to, form a 3-, 4-, 5- or 6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms or heteroatom groups selected from the group consisting of O, N, S, NO, SO and SO.sub.2 as ring members, wherein the heterocyclic ring may carry 1, 2 or 3 substituents selected from the group consisting of halogen, hydroxyl, cyano, C.sub.1-C.sub.4-alkoxy and C.sub.1-C.sub.4-haloalkoxy; and R.sup.13 is selected from the group consisting of halogen, hydroxyl, cyano, fluorinated C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl, fluorinated C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkyl, fluorinated C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.4-alkoxy, fluorinated C.sub.1-C.sub.4-alkoxy, and a 3-, 4-, 5- or 6-membered saturated, partially unsaturated or maximally unsaturated heterocyclic ring containing 1 or 2 heteroatoms or heteroatom groups selected from the group consisting of O, N, S, NO, SO and SO.sub.2 as ring members, wherein the heterocyclic ring may carry 1, 2 or 3 substituents selected from the group consisting of halogen, hydroxyl, cyano, C.sub.1-C.sub.4-alkoxy and C.sub.1-C.sub.4-haloalkoxy.

17. The compound of claim 16, wherein R.sup.8 is selected from the group consisting of hydrogen, C.sub.1-C.sub.4-alkyl and C.sub.3-C.sub.6-cycloalkyl; R.sup.9 is selected from the group consisting of C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl, fluorinated C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy, fluorinated C.sub.1-C.sub.4-alkoxy, and a 3-, 4-, 5- or 6-membered saturated heterocyclic ring containing 1 oxygen atom as ring member; or R.sup.8 and R.sup.9, together with the nitrogen atom they are bound to form a 3-, 4-, 5- or 6-membered saturated heterocyclic ring, wherein the heterocyclic ring contains 1 further oxygen atom as ring member, and wherein the heterocyclic ring may carry 1 or 2 substituents R.sup.12; or form a 3-, 4-, 5- or 6-membered saturated heterocyclic ring which carries 1 or 2 substituents R.sup.12; and each R.sup.12 is independently selected from the group consisting of halogen, hydroxyl, C.sub.1-C.sub.4-alkoxy, and a 3-, 4-, 5- or 6-membered saturated heterocyclic ring containing 1 oxygen atom as ring member; or two radicals R.sup.12 bound to the same carbon ring atom, together with this carbon atom they are bound to, form a 3-, 4-, 5- or 6-membered saturated heterocyclic ring containing 1 oxygen atom as ring member.

18. The compound of claim 17, wherein the saturated heterocyclic ring formed by R.sup.8 and R.sup.9 together with the nitrogen atom they are bound to is selected from the group consisting of azetidin-1-yl carrying in the 3-position (relative to the 1-position of the nitrogen ring atom) 1 or 2 substituents isoxazolidin-2-yl, piperidin-1-yl carrying in the 4-position (relative to the 1-position of the nitrogen ring atom) 1 or 2 substituents R.sup.12; and morpholin-1-yl.

19. The compound of claim 17, wherein two radicals R.sup.12 bound to the same carbon ring atom together form a group CH.sub.2OCH.sub.2 (i.e. together with the carbon atom they are bound to form a spiro-bound oxetan-3-yl ring).

20. The compound of claim 1, wherein each R.sup.10 is independently selected from the group consisting of halogen and C.sub.1-C.sub.4-alkyl with the proviso that R.sup.10 is not halogen if it is bound to a carbon atom in -position to a nitrogen ring atom.

21. The compound of claim 1, wherein each R.sup.11 is independently selected from the group consisting of halogen and C.sub.1-C.sub.4-alkyl with the proviso that R.sup.11 is not halogen if it is bound to a carbon atom in -position to a nitrogen ring atom; or two non-geminal radicals R.sup.11 form together a group CH.sub.2.

22. The compound of claim 1, wherein X.sup.1 is N.

23. The compound of claim 1, wherein X.sup.1 is CH.

24. The compound of claim 1, wherein X.sup.2 is CR.sup.1.

25. The compound of claim 1, wherein X.sup.2 is N.

26. The compound of claim 1, wherein a is 0 or 1.

27. The compound of claim 1, wherein b is 0, 1 or 2.

28. A compound selected from the group consisting of (S)N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-morpholinopiperidin-1-yl)azetidine-1-carboxamide; (S)N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-(methyl(oxetan-3-yl)amino)piperidin-1-yl)azetidine-1-carboxamide; (S)N-(5-Cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-morpholinopiperidin-1-yl)azetidine-1-carboxamide; (S)N-(5-Cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-(methyl(oxetan-3-yl)amino)piperidin-1-yl)azetidine-1-carboxamide; (S)N-(5-Cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-(ethyl(oxetan-3-yl)amino)piperidin-1-yl)azetidine-1-carboxamide; (S)-3-(4-(2-Oxa-7-Azaspiro[3.5]nonan-7-yl)piperidin-1-yl)-N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)azetidine-1-carboxamide; N-[(3S)-5-Cyano-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-ethoxy-3-pyridyl)-2-oxo-indolin-3-yl]-3-[4-[cyclopropyl(oxetan-3-yl)amino]-1-piperidyl]azetidine-1-carboxamide; (S)N-(1-((2,4-Dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-5,6-difluoro-2-oxoindolin-3-yl)-3-(4-morpholinopiperidin-1-yl)azetidine-1-carboxamide; (S)N-(5-Cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxoindolin-3-yl)-3-(4-morpholinopiperidin-1-yl)azetidine-1-carboxamide; (S)N-(5-Cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxoindolin-3-yl)-3-(4-(methyl(oxetan-3-yl)amino)piperidin-1-yl)azetidine-1-carboxamide; N-[(3S)-1-[(2,4-Dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-5,6-difluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]-3-{4-[methyl(oxetan-3-yl)amino]piperidin-1-yl}azetidine-1-carboxamide; (S)N-(5-Cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-(cyclopropyl(oxetan-3-yl)amino)piperidin-1-yl)azetidine-1-carboxamide; (S)N-(5-Chloro-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-morpholinopiperidin-1-yl)azetidine-1-carboxamide; (S)N-(5-Chloro-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-(methyl(oxetan-3-yl)amino)piperidin-1-yl)azetidine-1-carboxamide; (S)N-(5-Cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-((2-methoxyethyl)(methyl)amino)piperidin-1-yl)azetidine-1-carboxamide; (S)N-(5-Cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-(methoxy(methyl)amino)piperidin-1-yl)azetidine-1-carboxamide; (S)N-(5-Cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-(isoxazolidin-2-yl)piperidin-1-yl)azetidine-1-carboxamide; (S)N-(5-Cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-(3-(oxetan-3-yl)azetidin-1-yl)piperidin-1-yl)azetidine-1-carboxamide; (S)-3-(4-(2-Oxa-6-azaspiro[3.3]heptan-6-yl)piperidin-1-yl)-N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)azetidine-1-carboxamide; (S)N-(5-Cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-(oxetan-3-ylamino)piperidin-1-yl)azetidine-1-carboxamide; (S)N-(5-Cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-(methyl(tetrahydro-2H-pyran-4-yl)amino)piperidin-1-yl)azetidine-1-carboxamide; (S)N-(5-Cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-(oxetan-3-yl(propyl)amino)piperidin-1-yl)azetidine-1-carboxamide; (S)N-(5-Cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-(ethyl(oxetan-3-yl)amino)piperidin-1-yl)azetidine-1-carboxamide; (S)N-(5-Cyano-3-(2-ethoxypyridin-3-yl)-1-((5-fluoro-2,4-dimethoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)-3-(4-morpholinopiperidin-1-yl)azetidine-1-carboxamide; (S)N-(5-Cyano-3-(2-ethoxypyridin-3-yl)-1-((4-methoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)-3-(4-morpholinopiperidin-1-yl)azetidine-1-carboxamide; (S)N-(5-Cyano-1-((2,4-difluorophenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-morpholinopiperidin-1-yl)azetidine-1-carboxamide; (S)N-(5-cyano-3-(2-ethoxypyridin-3-yl)-1-((2-fluoro-4-methoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)-3-(4-morpholinopiperidin-1-yl)azetidine-1-carboxamide; (S)N-(5-cyano-3-(2-ethoxypyridin-3-yl)-1-((4-fluoro-2-methoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)-3-(4-morpholinopiperidin-1-yl)azetidine-1-carboxamide; (S)N-(5-Cyano-1-((2-methoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-(methyl(oxetan-3-yl)amino)piperidin-1-yl)azetidine-1-carboxamide; (S)N-(5-Cyano-1-((4-fluoro-2-methoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-(methyl(oxetan-3-yl)amino)piperidin-1-yl)azetidine-1-carboxamide; (S)N-(5-Cyano-1-((4-fluorophenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-(methyl(oxetan-3-yl)amino)piperidin-1-yl)azetidine-1-carboxamide; (S)N-(5-Cyano-1-((2-fluoro-4-methoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-(methyl(oxetan-3-yl)amino)piperidin-1-yl)azetidine-1-carboxamide; (S)N-(5-Cyano-1-((2,4-difluorophenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-(methyl(oxetan-3-yl)amino)piperidin-1-yl)azetidine-1-carboxamide; (S)N-(5-Cyano-1-((5-fluoro-2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-(methyl(oxetan-3-yl)amino)piperidin-1-yl)azetidine-1-carboxamide; (S)N-(5-cyano-1-((4-methoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-(methyl(oxetan-3-yl)amino)piperidin-1-yl)azetidine-1-carboxamide; (S)N-(5-Cyano-3-(2-ethoxypyridin-3-yl)-1-((5-methoxypyridin-2-yl)sulfonyl)-2-oxoindolin-3-yl)-3-(4-morpholinopiperidin-1-yl)azetidine-1-carboxamide; (S)N-(5-Cyano-3-(2-ethoxypyridin-3-yl)-1-((2-methoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)-3-(4-morpholinopiperidin-1-yl)azetidine-1-carboxamide; (S)N-(5-Cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-(isopropyl(oxetan-3-yl)amino)piperidin-1-yl)azetidine-1-carboxamide; (S)N-(5-Cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-(3,3-difluoroazetidin-1-yl)piperidin-1-yl)azetidine-1-carboxamide; (S)N-(5-Cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4,4-difluoro-[1,4-bipiperidin]-1-yl)azetidine-1-carboxamide; (S)N-(5-Cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-((3-methoxyazetidin-1-yl)piperidin-1-yl)azetidine-1-carboxamide; (S)N-(5-Cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-methoxy-[1,4-bipiperidin]-1-yl)azetidine-1-carboxamide; (S)N-(5-Cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-(3-hydroxyazetidin-1-yl)piperidin-1-yl)azetidine-1-carboxamide; (S)N-(5-Cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-hydroxy-[1,4-bipiperidin]-1-yl)azetidine-1-carboxamide; (S)N-(5-Cyano-3-(2, 5-dimethoxyphenyl)-1-((2,4-dimethoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)-3-(4-morpholinopiperidin-1-yl)azetidine-1-carboxamide; and (S)N-(5-Cyano-3-(2, 5-dimethoxyphenyl)-1-((2,4-dimethoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)-3-(4-(methyl(oxetan-3-yl)amino)piperidin-1-yl)azetidine-1-carboxamide; or a N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof; or the above compound, wherein at least one of the atoms has been replaced by its stable, non-radioactive isotope.

29. A pharmaceutical composition comprising a compound of claim 1 or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

Description

EXPERIMENTAL SECTION

(1) Abbreviations Used:

(2) Et.sub.3N: Triethylamine

(3) THF: Tetrahydrofuran

(4) DMF: N,N-Dimethylformamide

(5) DMSO: Dimethyl sulfoxide

(6) TFA: Trifluoroacetic acid

(7) RT room temperature

(8) p: pseudo (for example pt pseudo triplet)

(9) b: broad (for example bs broad singlet)

(10) s: singlet

(11) d: doublet

(12) t: triplet

(13) m: multiplet

(14) dd: doublet of doublets

(15) dt: doublet of triplets

(16) tt: triplet of triplets

(17) I. Preparation of the Starting Compounds

1.) (S)N-(5-Cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-oxoazetidine-1-carboxamide

(18) To a solution of (S)-phenyl (5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)carbamate (425 mg, 0,691 mmol) and azetidin-3-one hydrochloride (80 mg, 0,744 mmol) in DMF (6 ml) Et3N (1 ml, 7.17 mmol) was added and the mixture stirred over night at room temperature. Subsequently 40 ml of water and 10 ml NaHCO.sub.3-solution were added and the mixture extracted twice with ethyl acetate. The combined organic layers were washed 3 with brine, dried over MgSO.sub.4, filtered off and evaporated to give 430 mg of a yellow solid.

(19) Flash chromatography (silica gel/gradient from 0 to 5% methanol in dichloromethane) yielded 330 mg of the title compound as white solid.

(20) ESI-MS [M+H.sup.+]=592.2

2.) (S)N-(5-Cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-oxoazetidine-1-carboxamide

(21) To a solution of (S)-phenyl (5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)carbamate (1 g, 1,665 mmol) and azetidin-3-one hydrochloride (220 mg, 2,046 mmol) in 10 ml of DMF Et.sub.3N (1.5 ml, 10.76 mmol) was added and the mixture stirred over night at room temperature. 70 ml of water and 10 ml of 10% NaHCO.sub.3-solution were added, the mixture extracted twice with ethyl acetate, the combined organic layers washed twice with brine, dried over MgSO.sub.4, filtered and concentrated to leave 1.3 g of the crude product as yellow oil. Flash chromatography (silica gel/gradient from 0 to 5% methanol in dichloromethane) yielded 610 mg of the title compound as an off-white solid.

(22) ESI-MS [M+H.sup.+]=578.1

3.) (S)N-(5-Cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-oxopiperidin-1-yl)azetidine-1-carboxamide

(23) To a solution of (S)-phenyl (5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)carbamate (1.3 g, 2,009 mmol) and 1-(3-azetidinyl)-4-piperidinone (0.37 g, 2,399 mmol) in DMF (9 ml) Et.sub.3N (2 ml, 14.35 mmol) was added and the mixture stirred over night at room temperature. Water (80 ml) was added, stirring continued for 30 min, the precipitated solid filtered off, subsequently washed with water and n-pentane, and dried under vacuum to give 705 mg of a solid. The aqueous layers were re-extracted twice with ethyl acetate, the combined organic layers washed with brine, dried over MgSO.sub.4, filtered and evaporated to leave 360 mg of yellow oil. Flash chromatography (silica gel/gradient from 0 to 5% methanol in dichloromethane) of the combined crude product yielded 500 mg of the title compound as white solid.

(24) ESI-MS [M+H.sup.+]=675.2.

(25) Following the procedures as described for intermediates 1 and 2 and using the appropriate starting material were prepared:

4.) (S)N-(1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-5,6-difluoro-2-oxoindolin-3-yl)-3-oxoazetidine-1-carboxamide

(26) ESI-MS [M+H.sup.+]=603.1.

5.) (S)N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxoindolin-3-yl)-3-oxoazetidine-1-carboxamide

(27) ESI-MS [M+H.sup.+]=610.1.

6.) (S)N-(5-chloro-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-oxoazetidine-1-carboxamide

(28) ESI-MS [M+H.sup.+]=602.1.

7.) (S)N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-oxopiperidin-1-yl)azetidine-1-carboxamide

(29) ESI-MS [M+H.sup.+]=661.2.

8.) (S)N-(5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-morpholinopiperidin-1-yl)azetidine-1-carboxamide

(30) a) To a solution of (S)-3-amino-3-(2-ethoxypyridin-3-yl)-2-oxoindoline-5-carbonitrile (9 g, 30.6 mmol) in dichloromethane (150 ml) at 5 C. were added subsequently pyridine (20 ml) and then dropwise phenyl chloroformate (4.5 ml, 35.8 mmol), and stirring was continued for 1.5 hr. Dichloromethane (220 ml) and water (60 ml) were added, the mixture was stirred for 20 min, the organic layer washed subsequently with water and brine, dried over MgSO.sub.4, filtered and concentrated to give 18.7 g of a brown oil. Flash chromatography of the crude product (silica gel/gradient from 0 to 30% methanol in dichloromethane) yielded 12.1 g of the title compound as amorphous solid; ESI-MS [M+H.sup.+]=415.0.

(31) b) To a solution of (S)-phenyl (5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)carbamate (2.6 g, 5.65 mmol) and 4-(1-(azetidin-3-yl)piperidin-4-yl)morpholine3TFA (3.3 g, 5.82 mmol) in acetonitrile (80 ml) at 5 C. Et.sub.3N (5.5 ml, 39.5 mmol) was added and then stirred over night at room temperature. The mixture then was concentrated, treated with 100 ml of ice water, digested 3 with dichloromethane, the combined organic layers washed with brine, dried over MgSO.sub.4, filtered and evaporated to give 3.0 g of a yellow oil. Flash chromatography of the crude product (silica gel/gradient from 0 to 50% methanol in dichloromethane) yielded 1.2 g of the title compound as amorphous solid; ESI-MS [M+H+]=546.2.

9.) (S)N(C-cyano-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-(methyl(oxetan-3-yl)amino)piperidin-1-yl)azetidine-1-carboxamide

(32) Synthesis according to procedure as described for intermediate 8.

(33) ESI-MS [M+H.sup.+]=532.2.

10.) (S)-Phenyl (5-Cyano-3-(2,5-dimethoxyphenyl)-1-((2,4-dimethoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)carbamate

(34) To a solution of (S)-3-amino-3-(2,5-dimethoxyphenyl)-2-oxoindoline-5-carbonitrile (425 mg, 1,374 mmol) DMF (10 ml) at 5 C. first sodium hydride (60%: 77 mg, 1,924 mmol) and after stirring for 20 min 2,4-dimethoxybenzenesulfonyl chloride (358 mg, 1,511 mmol) was added, and stirring continued for 30 min. Then 40 ml of water and 10 ml of 10% NaHCO.sub.3-solution were added, extracted twice with ethyl acetate, the combined organic layers washed with brine, dried over MgSO.sub.4, filtered and evaporated to give 730 mg of a yellow solid.

(35) The crude product was dissolved in dichloromethane (20 ml), pyridine (0,834 ml, 10.32 mmol) and phenyl chloroformate (0,194 ml, 1,547 mmol) were added at 5 C. and stirred 1 for h at 5 C. The mixture was diluted with 120 ml of water, the organic layer washed 3 with water, dried over MgSO.sub.4, filtered and evaporated to leave 966 mg of a yellow solid, which was treated with 50 ml of methyl-tert-butylether/diisopropylether 1:5 to give 630 mg of the title compound as white solid.

(36) ESI-MS [M+H+]=630.0

11) N-Methyl-N-(oxetan-3-yl)piperidin-4-amine2TFA

(37) To a solution of 1-Boc-4-methylaminopiperidine (500 mg, 2,333 mmol) in THF (10 ml) 3-oxetanone (235 mg, 3.27 mmol) was added and the mixture stirred over night at room temperature. Then subsequently sodium cyanoborohydride (176 mg, 2.80 mmol) and acetic acid (0.27 ml, 4.72 mmol) were added and stirring continued for 3 days at room temperature. The mixture was concentrated under vacuum, the obtained residue diluted with 20 ml of and 10 ml of 10% NaHCO.sub.3-solution, extracted 2 with dichloromethane, the combined organic layers dried over MgSO.sub.4, filtered off and evaporated to leave 700 mg of the crude product. Flash chromatography (silica gel/gradient from 0 to 10% methanol in dichloromethane) gave 230 mg of a clear oil, which was treated with TFA (2 ml, 26.0 mmol) for 1 hr. The mixture was concentrated, diluted with 20 ml of methyl-tert-butylether, the precipitate filtered off, washed with 10 ml of methyl-tert-butyl ether and dried to yield 340 mg of the title compound as white solid;

(38) ESI-MS [M+H+]=171.2.

12) N-Ethyl-N-(oxetan-3-yl)piperidin-4-amine2TFA

(39) To a solution of 1-Boc-4-piperidinone (0.6 g, 3.01 mmol) and N-ethyloxetan-3-amine (0.38 g, 3.76 mmol) in methanol (5 ml) were added zinc chloride (1,231 g, 9.03 mmol), and then after 10 min stirring sodium cyanoborohydride (0,473 g, 7.53 mmol), and the mixture stirred over night at room temperature. For work-up 2 ml of 10% NaHCO.sub.3-solution were added, the mixture concentrated, diluted with 80 ml of water, extracted 3 with ethyl acetate, the combined organic layers washed twice with brine, dried over MgSO.sub.4, filtered and evaporated to give 730 mg of a clear oil. The Boc-protected amine was treated with 2 ml of TFA for 1 hr, concentrated, and the obtained residue digested with 20 ml methyl-tert-butylether. Filtering off the precipitate, washing and drying gave 690 mg of the title compound as white solid.

(40) ESI-MS [M+H.sup.+]=185.2.

13) N-Cyclopropyl-N-(oxetan-3-yl)piperidin-4-amine2TFA

(41) To a solution of 1-tert-butoxycarbonyl-4-(cyclopropylamino)piperidine (2 g, 8.32 mmol) and 3-oxetanone (0,840 g, 11.65 mmol) in methanol (25 ml) subsequently zinc chloride (2,155 g, 15.81 mmol)and after stirring for 10 minsodium cyanoborohydride (0,994 g, 15.81 mmol) were added and the mixture was stirred over night. 20 ml of a 10% NaHCO.sub.3-solution were added to the reaction mixture and concentrated under vacuum. After addition of 60 ml of water, 10 ml of 10% NaHCO.sub.3-solution and 30 ml of dichloromethane the formed solid was filtered off, washed with 10 ml of water and 10 ml of dichloromethane, the aqueous layer digested again with dichloromethane, and the combined organic layers then washed with water, dried over MgSO.sub.4, filtered and evaporated to leave 2.29 g of a yellow oil. Hash chromatography (silica gel/gradient from 0 to 15% methanol in dichloromethane) yielded 1.57 g of a clear oil, which was dissolved in dichloromethane (1 ml) and treated with TFA (4 ml) for 15 min. The mixture was concentrated, 40 ml of methyl-tert-butylether added and stirred for 2 hr. The precipitate was filtered off, washed and dried to give 1.9 g of the title compound as white solid.

(42) ESI-MS [M+H.sup.+]=197.2

14) 1-(Azetidin-3-yl)-N-methyl-N-(oxetan-3-yl)piperidin-4-amine3TFA

(43) a. To a solution of 1-Boc-4-methylaminopiperidine (5.5 g, 25.7 mmol) and 3-oxetanone (3 g, 41.6 mmol) in methanol (50 ml) and THF (40 ml) subsequently were added zinc chlorideand after stirring for 10 minsodium cyanoborohydride (2.3 g, 36.6 mmol), and the mixture stirred over night at room temperature. The mixture was concentrated, 30 ml of 10% NaHCO.sub.3-solution, 100 ml of water and 70 ml of dichloromethane added, filtered, and the aqueous layer digested with dichloromethane. The combined organic layers were washed with brine, dried over MgSO.sub.4, filtered and evaporated to leave 6.78 g of a pale yellow oil. The crude product was treated with TFA (15 ml) in dichloromethane (40 ml) at 5 C. over night, the mixture concentrated, diluted with 150 ml of methyl-tert-butylether, stirred for 2 hr, the precipitated solid was filtered off, washed again with 50 ml methyl-tert-butylether and dried to give 9.63 g of the amine 2TFA salt as white solid.

(44) c. Reductive amination tert-butyl 3-oxoazetidine-1-carboxylate (3 g, 17.52 mmol) with N-methyl-N-(oxetan-3-yl)piperidin-4-amine2TFA (8 g, 20.09 mmol) following the procedure as described for step a and followed by BOC-cleavage using TFA gave 19.5 g of a yellow oil, which was treated with 150 ml of methyl-tert-butylether for 2 hr, the precipitated solid filtered off, washed and dried to give 8.5 g of the title compound as white solid.

(45) ESI-MS [M+H+]=171.2

15) 4-(1-(Azetidin-3-yl)piperidin-4-yl)morpholine3TFA

(46) Reductive amination of 1-Boc-azetidinone (5 g, 29.2 mmol) and 4-(piperidin-4-yl)-morpholine (5.97 g, 35.0 mmol) as described for intermediate 13 and subsequent cleavage of Boc yielded 12.1 g of the title compound as white solid.

(47) ESI-MS [M+H+]=226.2

(48) II. Preparation of the Compounds of the Formula I

(49) Enantiomers of the compounds I were prepared by using enantiomerically pure starting compounds.

Example 1

(S)N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-morpholinopiperidin-1-yl)azetidine-1-carboxamide

(50) (compound of formula I.1, wherein R.sup.1 is methoxy, R.sup.2 is methoxy, R.sup.3 is H, R.sup.6 is CN, R.sup.7 is H, and R.sup.8 and R.sup.9, together with the nitrogen atom they are bound to, form morpholin-4-yl)

(51) (S)N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-oxoazetidine-1-carboxamide (400 mg, 0,676 mmol) and 4-(piperidin-4-yl)-morpholine (400 mg, 2.35 mmol) were stirred in THF (15 ml) over night at room temperature. Sodium cyanoborohydride (70 mg, 1,114 mmol) and acetic acid (250 l, 4.37 mmol) were added and the mixture was stirred for 2 hr. Subsequently 40 ml of water and 10 ml of a 10% NaHCO.sub.3-solution were added, extracted twice with ethyl acetate, the combined organic layers washed with brine, dried over MgSO.sub.4, filtered off and evaporated to give 620 mg as white solid. Flash chromatography of the crude product (silica gel/gradient from 0 to 10% methanol in dichloromethane) yielded 336 mg of the title compound as white solid.

(52) ESI-MS [M+H.sup.+]=746.3

(53) .sup.1H-NMR (600 MHz DMSO), [ppm]: 8.14 (dd, 1H), 7.88 (dd, 1H), 7.83 (m, 3H), 7.66 (s, 1H), 7.55 (s, 1H), 7.05 (dd, 1H), 6.70 (dd, 1H), 6.65 (d, 1H), 4.08 (q, 2H), 3.86 (s, 3H), 3.79 (m broad, 2H), 3.65-3.50 (m, 6H), 3.46 (s, 3H), 2.95 (m, 1H), 2.71 (m, 2H), 2.39 (m, 4H), 2.08 (m, 1H), 1.71 (4H), 1.34 (m, 2H), 0.95 (t, 3H).

Example 2

(S)N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-(methyl(oxetan-3-yl)amino)piperidin-1-yl)azetidine-1-carboxamide

(54) (compound of formula I.1, wherein R.sup.1 is methoxy, R.sup.2 is methoxy, R.sup.3 is H, R.sup.6 is CN, R.sup.7 is H, R.sup.8 is methyl, and R.sup.9 is oxetan-3-yl)

(55) To a solution of (S)N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-oxoazetidine-1-carboxamide (250 mg, 0,423 mmol) and N-methyl-N-(oxetan-3-yl)piperidin-4-amine TFA-salt (200 mg, 0,502 mmol) in methanol (5 ml) zinc chloride (115 mg, 0,844 mmol) was added and stirred for 10 min. Sodium cyanoborohydride (55 mg, 0,875 mmol) was added and the mixture stirred over night. Then 2 ml of 10% NaHCO.sub.3-solution were added, the mixture was concentrated under vacuum, 60 ml of water and 20 ml of dichloromethane were added, and the solid was filtered off and washed with 10 ml of water and 10 ml of dichloromethane. The aqueous layer was separated and extracted with dichloromethane, and the combined organic layers were washed with water, dried over MgSO.sub.4, filtered and concentrated to give 350 mg of a clear oil. Flash chromatography of the crude product (silica gel/gradient from 0 to 10% methanol in dichloromethane) afforded 123 mg of the title compound as white solid.

(56) ESI-MS [M+H.sup.+]=746.3.

(57) .sup.1H-NMR (600 MHz DMSO), [ppm]: 8.14 (dd, 1H), 7.88 (dd, 1H), 7.83 (m, 3H), 7.66 (s, 1H), 7.55 (s, 1H), 7.05 (dd, 1H), 6.70 (dd, 1H), 6.66 (d, 1H), 4.46 (m, 4H), 4.07 (q, 2H), 3.85 (s, 3H), 3.78 (m broad, 3H), 3.55 (m broad, 2H), 3.46 (s, 3H), 2.93 (m, 1H), 2.71 (m, 2H), 2.20 (m, 1H), 2.08 (s, 3H), 1.67 (m, 2H), 1.51 (m, 2H), 1.36 (m, 2H), 0.95 (t, 3H).

Example 3

(S)N-(5-Cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-morpholinopiperidin-1-yl)azetidine-1-carboxamide

(58) (compound of formula I.6, wherein R.sup.1 is methoxy, R.sup.2 is methoxy, R.sup.3 is H, R.sup.6 is CN, R.sup.7 is H, and R.sup.8 and R.sup.9, together with the nitrogen atom they are bound to, form morpholin-4-yl)

(59) To a solution of (S)N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-oxoazetidine-1-carboxamide (80 mg, 0,139 mmol) and 4-(piperidin-4-yl)-morpholine (50 mg, 0,294 mmol) in ethanol (5 ml) and THF (5 ml) titanium isopropoxide (2000, 0,672 mmol) was added, the mixture then stirred over night at room temperature and then for 50 min. at 60 C. The mixture was then cooled to 25 C., sodium cyanoborohydride (25 mg, 0,398 mmol) was added and stirring continued for 30 min. For work-up 2 ml of water and 2 ml of 10% NaHCO.sub.3-solution were added, the mixture concentrated under vacuum, the obtained residue di-diluted with 20 ml of water and 20 ml dichloromethane, filtered over celite, washed with 20 ml of dichloromethane, the organic layer separated and dried over MgSO.sub.4, to leave 80 mg of a yellow solid. Flash chromatography of the crude product (silica gel/gradient from 0 to 10% methanol in dichloromethane) afforded 17.7 mg of the title compound as white solid.

(60) ESI-MS [M+H.sup.+]=732.3.

(61) .sup.1H-NMR (600 MHz DMSO), [ppm]: 8.15 (dd, 1H), 7.91 (d, 1H), 7.86 (d, 1H), 7.80 (dd, 1H), 7.78 (dd, 1H), 7.70 (m, 1H), 7.64 (s broad, 1H), 7.06 (dd, 1H), 6.72 (dd, 1H), 6.68 (dd, 1H), 3.87 (s, 3H), 3.70 (s, 3H), 3.65-3.55 (m, 6H), 3.51 (s, 3H), 2.96 (m, 1H), 2.74 (m, 2H), 2.55-2.40 (m, overlapped with DMSO), 2.1 (m, 1H), 1.75 (m, 4H), 1.37 (m, 2H).

Example 4

(S)N-(5-Cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-(methyl(oxetan-3-yl)amino)piperidin-1-yl)azetidine-1-carboxamide

(62) (compound of formula I.6, wherein R.sup.1 is methoxy, R.sup.2 is methoxy, R.sup.3 is H, R.sup.6 is CN, R.sup.7 is H, R.sup.8 is methyl, and R.sup.9 is oxetan-3-yl)

(63) To a solution of (S)N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-oxoazetidine-1-carboxamide (225 mg, 0,390 mmol) and N-methyl-N-(oxetan-3-yl)piperidin-4-amine TFA-salt (220 mg, 0,552 mmol) in methanol (3 ml) and THF (6 ml) zinc chloride (200 mg, 1,468 mmol) was added and the mixture stirred for 10 min. The sodium cyanoborohydride (100 mg, 1,591 mmol) was added and stirring continued over night at room temperature. Then 6 ml of 10% NaHCO.sub.3-solution were added, concentrated under vacuum, 50 ml of water and 20 ml of ethyl acetate, the aqueous layer extracted again with ethyl acetate, and the combined organic layers washed twice with brine, dried over MgSO.sub.4, filtered and evaporated to leave 235 mg of a yellow solid. Flash chromatography of the crude product (silica gel/gradient from 0 to 10% methanol in dichloromethane) afforded 108 mg of the title compound as white solid.

(64) ESI-MS [M+H.sup.+]=732.3.

(65) .sup.1H-NMR (600 MHz DMSO), [ppm]: 8.15 (dd, 1H), 7.90 (d, 1H), 7.82 (d, 1H), 7.81 (dd, 1H), 7.79 (dd, 1H), 7.70 (m, 1H), 7.58 (s broad, 1H), 7.06 (dd, 1H), 6.72 (dd, 1H), 6.68 (dd, 1H), 4.46 (m, 4H), 3.86 (s, 3H), 3.80-3.70 (m broad, 3H), 3.65 (s, 3H), 3.60-3.52 (m broad, 2H), 3.50 (s, 3H), 2.92 (m, 1H), 2.71 (d, 2H), 2.19 (m, 2H), 2.19 (m, 1H), 1.67 (m, 2H), 1.51 (m, 2H), 1.36 (m, 2H).

(66) The following compounds were obtained according to the procedures described for examples 1-4 using the appropriate starting materials.

Example 5

(S)N-(5-Cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-(ethyl(oxetan-3-yl)amino)piperidin-1-yl)azetidine-1-carboxamide

(67) (compound of formula I.1, wherein R.sup.1 is methoxy, R.sup.2 is methoxy, R.sup.3 is H, R.sup.6 is CN, R.sup.7 is H, R.sup.8 is ethyl, and R.sup.9 is oxetan-3-yl)

(68) ESI-MS [M+H+]=760.6.

(69) .sup.1H-NMR (600 MHz DMSO), [ppm]: 8.14 (dd, 1H), 7.88 (d, 1H), 7.86-7.80 (m, 3H), 7.66 (s, 1H), 7.55 (s, 1H), 7.05 (dd, 1H), 6.70 (dd, 1H), 6.66 (d, 1H), 4.47 (dt, 4H), 4.15-3.99 (m, 3H), 3.86 (s, 1H), 3.77 (m broad, 1H), 3.54 (m broad, 1H), 3.46 (s, 3H), 2.93 (m, 1H), 2.70 (t, 2H), 2.58 (m, 2H), 2.37 (m, 1H), 1.68 (m, 2H), 1.51 (m, 2H), 1.29 (m, 2H), 0.94 (dt, 6H).

Example 6

(S)-3-(4-(2-Oxa-7-Azaspiro[3.5]nonan-7-yl)piperidin-1-yl)-N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)azetidine-1-carboxamide

(70) (compound of formula I.1, wherein R.sup.1 is methoxy, R.sup.2 is methoxy, R.sup.3 is H, R.sup.6 is CN, R.sup.7 is H, and R.sup.8 and R.sup.9, together with the nitrogen atom they are bound to, form 2-oxa-7-aza-spiro[3.5]non-7-yl)

(71) ESI-MS [M+H+]=786.30.

(72) .sup.1H-NMR (600 MHz DMSO), [ppm]: 8.13 (dd, 1H), 7.88 (d, 1H), 7.84-7.80 (m, 3H), 7.66 (s, 1H), 7.54 (s, 1H), 7.05 (dd, 1H), 6.70 (dd, 1H), 6.66 (d, 1H), 4.24 (s, 4H), 4.09 (q, 2H), 3.86 (s, 3H), 3.80 and 3.62 (each m broad, 2H), 3.46 (s, 3H), 2.93 (m, 1H), 2.71 (m, 2H), 2.40-2.30 (m, 4H), 2.15 (m, 1H), 1.85-1.65 (m, 8H), 1.38 (m, 2H), 0.95 (t, 3H).

Example 7

N-[(3S)-5-Cyano-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-ethoxy-3-pyridyl)-2-oxoindolin-3-yl]-3-[4-[cyclopropyl(oxetan-3-yl)amino]-1-piperidyl]azetidine-1-carboxamide

(73) (compound of formula I.1, wherein R.sup.1 is methoxy, R.sup.2 is methoxy, R.sup.3 is H, R.sup.6 is CN, R.sup.7 is H, R.sup.8 is cyclopropyl, and R.sup.9 is oxetan-3-yl)

(74) ESI-MS [M+H+]=772.3.

(75) .sup.1H-NMR (600 MHz DMSO), [ppm]: 8.14 (dd, 1H), 7.89 (d, 1H), 7.83 (dd, 3H), 7.66 (s, 1H), 7.55 (s, 1H), 7.05 (dd, 1H), 6.71 (dd, 1H), 6.66 (d, 1H), 4.67 (m, 2H), 4.43 (m, 2H), 4.18 (m, 1H), 4.09 (q, 2H), 3.86 (s, 3H), 3.73 (m broad, 2H), 3.60 (m broad, 2H), 3.46 (s, 3H), 2.93 (m, 1H), 2.72 (t, 2H), 2.48 (m, overlapped with DMSO), 1.94 (m, 1H), 1.67 (m, 2H), 1.56 (m, 2H), 1.45 (m, 2H), 0.95 (t, 3H), 0.50 (m, 2H), 0.30 (m, 2H).

Example 8

(S)N-(1-((2,4-Dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-5,6-difluoro-2-oxoindolin-3-yl)-3-(4-morpholinopiperidin-1-yl)azetidine-1-carboxamide

(76) (compound of formula I.1, wherein R.sup.1 is methoxy, R.sup.2 is methoxy, R.sup.3 is H, R.sup.6 is F, R.sup.7 is F, and R.sup.8 and R.sup.9, together with the nitrogen atom they are bound to, form morpholin-4-yl)

(77) ESI-MS [M+H+]=757.3.

(78) .sup.1H-NMR (600 MHz DMSO), [ppm]: 8.13 (dd, 1H), 7.89 (d, 1H), 7.74 (dd, 1H), 7.62 (dd, 1H), 7.48 (s, 1H), 7.34 (m, 1H), 7.02 (dd, 1H), 6.70 (dd, 1H), 6.67 (d, 1H), 4.11 (q, 2H), 3.86 (s, 3H), 3.80-3.70 (m broad, 2H), 3.67-3.52 (m, 6H), 3.50 (s, 3H), 2.94 (m, 1H), 2.70 (m, 2H), 2.42 (m, 4H), 2.08 (m, 1H), 1.71 (m, 4H), 1.35 (m, 2H), 1.01 (t, 3H).

Example 9

(79) (S)N-(5-Cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxoindolin-3-yl)-3-(4-morpholinopiperidin-1-yl)azetidine-1-carboxamide (compound of formula I.1, wherein R.sup.1 is methoxy, R.sup.2 is methoxy, R.sup.3 is H, R.sup.6 is CN, R.sup.7 is F, and R.sup.8 and R.sup.9, together with the nitrogen atom they are bound to, form morpholin-4-yl)

(80) ESI-MS [M+H+]=764.3.

(81) .sup.1H-NMR (600 MHz DMSO), [ppm]: 8.15 (dd, 1H), 7.89 (s, 1H), 7.88 (s, 1H), 7.71 (d, 1H), 7.68 (d, 1H), 7.56 (s, 1H), 7.07 (dd, 1H), 6.71 (dd, 1H), 6.67 (d, 1H), 4.10 (q, 2H), 3.86 (s, 3H), 3.84-3.70 (m broad, 2H), 3.68-3.53 (m, 6H), 3.52 (s, 3H), 2.94 (m, 1H), 2.71 (m, 2H), 2.42 (m, 4H), 2.08 (m, 1H), 1.72 (m, 4H), 1.34 (m, 2H), 0.99 (t, 3H).

Example 10

(S)N-(5-Cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxoindolin-3-yl)-3-(4-(methyl(oxetan-3-yl)amino)piperidin-1-yl)azetidine-1-carboxamide

(82) (compound of formula I.1, wherein R.sup.1 is methoxy, R.sup.2 is methoxy, R.sup.3 is H, R.sup.6 is CN, R.sup.7 is F, R.sup.8 is methyl, and R.sup.9 is oxetan-3-yl)

(83) ESI-MS [M+H+]=764.3.

(84) .sup.1H-NMR (600 MHz DMSO), [ppm]: 8.15 (dd, 1H), 7.88 (m, 1H), 7.69 (dd, 1H), 7.56 (s, 1H), 7.07 (dd, 1H), 6.71 (dd, 1H), 6.67 (d, 1H), 4.53-4.38 (m, 4H), 4.09 (q, 2H), 3.84 (m broad, 2H), 3.58 (m broad, 2H), 3.51 (s, 3H), 2.93 (m, 1H), 2.71 (m, 2H), 2.19 (m, 1H), 1.67 (m, 2H), 1.51 (m, 2H), 1.36 (m, 2H), 0.99 (t, 3H).

Example 11

N-[(3S)-1-[(2,4-Dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-5,6-difluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]-3-{4-[methyl(oxetan-3-yl)amino]piperidin-1-yl}azetidine-1-carboxamide

(85) (compound of formula I.1, wherein R.sup.1 is methoxy, R.sup.2 is methoxy, R.sup.3 is H, R.sup.6 is F, R.sup.7 is F, R.sup.8 is methyl, and R.sup.9 is oxetan-3-yl)

(86) ESI-MS [M+H+]=757.3.

(87) .sup.1H-NMR (600 MHz DMSO), [ppm]: 8.13 (dd, 1H), 7.89 (d, 1H), 7.73 (dd, 1H), 7.62 (dd, 1H), 7.48 (s, 1H), 7.34 (m, 1H), 7.02 (dd, 1H), 6.71 (dd 1H), 6.67 (d, 1H), 4.46 (m, 4H), 4.10 (q, 2H), 3.85 (s, 3H), 3.75 (m broad, 3H), 3.55 (m broad, 2H), 3.50 (s, 3H), 2.93 (m, 1H), 2.71 (m, 2H), 2.19 (m, 1H), 2.11 (s, 3H), 1.67 (m, 2H), 1.51 (m, 2H), 1.36 (m, 2H), 1.01 (t, 3H).

Example 12

(S)N-(5-Cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-(cyclopropyl(oxetan-3-yl)amino)piperidin-1-yl)azetidine-1-carboxamide

(88) (compound of formula I.6, wherein R.sup.1 is methoxy, R.sup.2 is methoxy, R.sup.3 is H, R.sup.6 is CN, R.sup.7 is H, R.sup.8 is cyclopropyl, and R.sup.9 is oxetan-3-yl)

(89) ESI-MS [M+H+]=758.3.

(90) .sup.1H-NMR (600 MHz DMSO), [ppm]: 8.15 (dd, 1H), 7.90 (d, 1H), 7.86 (d, 1H), 7.81 (m, 2H), 7.70 (d, 1H), 7.59 (s, 1H), 7.06 (dd, 1H), 6.72 (dd, 1H), 6.68 (d, 1H), 4.67 (m 2H), 4.43 (m 2H), 4.18 (1H), 3.87 s, 3H), 3.77 (m broad, 2H), 3.65 (s, 3H), 3.58 (m broad, 2H), 3.52 (s, 3H), 2.94 (m, 1H), 2.71 (m, 2H), 2.61 (m, 2H), 2.39 (m, 1H), 1.68 (m, 2H), 1.52 (m, 2H), 1.29 (m, 2H), 0.93 (t, 3H).

Example 13

(S)N-(5-Chloro-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-morpholinopiperidin-1-yl)azetidine-1-carboxamide

(91) (compound of formula I.1, wherein R.sup.1 is methoxy, R.sup.2 is methoxy, R.sup.3 is H, R.sup.6 is Cl, R.sup.7 is H, and R.sup.8 and R.sup.9, together with the nitrogen atom they are bound to, form morpholin-4-yl)

(92) ESI-MS [M+H+]=756.3.

(93) .sup.1H-NMR (600 MHz DMSO), [ppm]: 8.12 (dd, 1H), 7.88 (d, 1H), 7.69 (dd, 1H), 7.66 (d, 1H), 7.49 (s, 1H), 7.38 (dd, 1H), 7.33 (d, 1H), 7.01 (dd, 1H), 6.70 (dd, 1H), 6.66 (d, 1H), 4.11 (q, 2H), 3.86 (s, 3H), 3.79 (m broad, 2H), 3.68-3.50 (m, 6H), 3.47 (s, 3H), 2.95 (m, 1H), 2.73 (m, 2H), 2.09 (m, 1H), 1.72 (m, 4H), 1.35 (m, 2H), 1.0 (t, 3H).

Example 14

(S)N-(5-Chloro-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-(methyl(oxetan-3-yl)amino)piperidin-1-yl)azetidine-1-carboxamide

(94) (compound of formula I.1, wherein R.sup.1 is methoxy, R.sup.2 is methoxy, R.sup.3 is H, R.sup.6 is Cl, R.sup.7 is H, R.sup.8 is methyl, and R.sup.9 is oxetan-3-yl)

(95) ESI-MS [M+H+]=756.3.

(96) .sup.1H-NMR (600 MHz DMSO), [ppm]: 8.12 (dd, 1H), 7.88 (d, 1H), 7.69 (d, 1H), 7.66 (d, 1H), 7.49 (s, 1H), 7.38 (dd, 1H), 7.33 (d, 1H), 7.01 (dd, 1H), 6.70 (dd, 1H), 6.66 (d, 1H), 4.45 (m, 4H), 4.11 (q, 2H), 3.88 (s, 3H), 3.80 (m broad, 2H), 3.57 (m broad, 3H), 3.46 (s, 3H), 2.92 (m, 1H), 2.71 (m, 2H), 2.20 (m, 1H), 2.08 (s, 3H), 1.67 (m, 2H), 1.51 (m, 2H), 1.36 (m, 2H), 1.00 (t, 3H).

Example 15

(S)N-(5-Cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-((2-methoxyethyl)(methyl)amino)piperidin-1-yl)azetidine-1-carboxamide

(97) (compound of formula I.1, wherein R.sup.1 is methoxy, R.sup.2 is methoxy, R.sup.3 is H, R.sup.6 is CN, R.sup.7 is H, R.sup.8 is methyl and R.sup.9 is 2-methoxyethyl)

(98) To a solution of (S)N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-oxopiperidin-1-yl)azetidine-1-carboxamide (60 mg, 0,089 mmol) and N-(2-methoxyethyl)methylamine (10 mg, 0,112 mmol) in a 1:1 mixture of methanol and THF (3 ml) first zinc chloride (20 mg, 0,147 mmol), and after stirring for 10 min, sodium cyanoborohydride (15 mg, 0,239 mmol) was added and stirring continued over night. For work-up 5 ml of 10% NaHCO3-solution were added, the mixture concentrated, diluted with 50 ml of water and 20 ml of ethyl acetate, separated and the aqueous layer re-extracted with ethyl acetate. The combined organic layers then were washed with brine, dried over MgSO4, filtered and evaporated to leave 70 mg of a white solid. Flash chromatography of the crude product (silica gel/gradient from 0 to 10% methanol in dichloromethane) yielded 45 mg of the title compound as white solid.

(99) ESI-MS [M+H+]=748.3.

(100) .sup.1H-NMR (600 MHz DMSO), [ppm]: 8.14 (dd, 1H), 7.88 (d, 1H), 7.83 (m, 3H), 7.66 (s, 1H), 7.55 (s, 1H), 7.05 (dd, 1H), 6.70 (dd, 1H), 6.66 (d, 1H), 4.09 (q, 2H), 3.86 (s, 3H), 3.77 (m broad, 2H), 3.58 (m broad, 2H), 3.46 (s, 3H), 3.22 (s, 3H), 2.94 (m, 1H), 2.72 (m, 2H), 2.52 (m overlapped with DMSO), 2.28 (m, 1H), 2.17 (s, 3H), 1.70 (m, 2H), 1.63 (m, 2H), 1.38 (m, 2H), 0.95 (t, 3H).

Example 16

(S)N-(5-Cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-(methoxy(methyl)amino)piperidin-1-yl)azetidine-1-carboxamide

(101) (compound of formula I.1, wherein R.sup.1 is methoxy, R.sup.2 is methoxy, R.sup.3 is H, R.sup.6 is CN, R.sup.7 is H, R.sup.8 is methyl, and R.sup.9 is methoxy)

(102) ESI-MS [M+H+]=720.3

Example 17

(S)N-(5-Cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-(isoxazolidin-2-yl)piperidin-1-yl)azetidine-1-carboxamide

(103) (compound of formula I.1, wherein R.sup.1 is methoxy, R.sup.2 is methoxy, R.sup.3 is H, R.sup.6 is CN, R.sup.7 is H, and R.sup.8 and R.sup.9, together with the nitrogen atom they are bound to, form isoxazolidin-2-yl)

(104) ESI-MS [M+H+]=732.3

(105) .sup.1H-NMR (600 MHz DMSO), [ppm]: 8.14 (dd, 1H), 7.89 (d, 1H), 7.83 (m, 3H), 7.67 (s, 1H), 7.54 (s, 1H), 7.05 (dd, 1H), 6.70 (dd, 1H), 6.66 (d, 1H), 4.09 (q, 2H), 3.86 (s, 3H), 3.76 (m, 3H), 3.62 (m, 3H), 3.47 (s, 3H), 3.03 (m, 1H), 2.96 (m, 1H), 2.65 (m, 2H), 2.55 (m, 1H), 2.36 (m, 1H), 2.13 (m, 2H), 2.13 (m, 1H), 1.92 (m, 1H), 1.77 (m, 2H), 1.64 (m, 1H), 1.35 (m, 2H), 0.94 (t, 3H).

Example 18

(S)N-(5-Cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-(3-(oxetan-3-yl)azetidin-1-yl)piperidin-1-yl)azetidine-1-carboxamide

(106) (compound of formula I.1, wherein R.sup.1 is methoxy, R.sup.2 is methoxy, R.sup.3 is H, R.sup.6 is CN, R.sup.7 is H, and R.sup.8 and R.sup.9, together with the nitrogen atom they are bound to, form 3-(oxetan-3-yl)-azetidin-1-yl)

(107) ESI-MS [M+H+]=772.3

(108) .sup.1H-NMR (600 MHz DMSO), [ppm]: 8.13 (dd, 1H), 7.88 (d, 1H), 7.84 (m, 3H), 7.66 (s, 1H), 7.54 (s, 1H), 7.05 (dd, 1H), 6.70 (dd, 1H), 6.66 (d, 1H), 4.63 (dd, 2H), 4.27 (dd, 2H), 4.09 (q, 2H), 3.86 (s, 3H), 3.72 (m broad, 2H), 3.53 (m broad, 2H), 3.46 (s, 3H), 3.22 (m, 2H), 3.11 (m, 1H), 2.95 (m, 1H), 2.76 (m, 2H), 2.62 (m, 1H), 2.53 (m overlapped with DMSO), 1.96 (m, 1H), 1.79 (m, 2H), 1.57 (m, 2H), 1.10 (m, 2H), 0.95 (t, 3H).

Example 19

(S)-3-(4-(2-Oxa-6-azaspiro[3.3]heptan-6-yl)piperidin-1-yl)-N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)azetidine-1-carboxamide

(109) (compound of formula I.1, wherein R.sup.1 is methoxy, R.sup.2 is methoxy, R.sup.3 is H, R.sup.6 is CN, R.sup.7 is H, and R.sup.8 and R.sup.9, together with the nitrogen atom they are bound to, form 2-oxa-6-aza-spiro[3.3]hept-6-yl)

(110) ESI-MS [M+H+]=758.3

(111) .sup.1H-NMR (600 MHz DMSO), [ppm]: 8.13 (dd, 1H), 7.88 (d, 1H), 7.83 (m, 3H), 7.66 (s, 1H), 7.53 (s, 1H), 7.05 (dd, 1H), 6.70 (dd, 1H), 6.65 (d, 1H), 4.57 (s, 4H), 4.08 (q, 2H), 3.85 (s, 3H), 3.78 (m broad, 2H), 3.58 (m broad, 2H), 3.46 (s, 3H), 3.19 (s, 3H), 2.94 (m, 1H), 2.54 (overlapped with DMSO), 1.86 (m, 1H), 1.75 (m, 2H), 1.54 (m, 2H), 1.09 (m, 2H), 0.94 (t, 3H).

Example 20

(S)N-(5-Cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-(oxetan-3-ylamino)piperidin-1-yl)azetidine-1-carboxamide

(112) (compound of formula I.6, wherein R.sup.1 is methoxy, R.sup.2 is methoxy, R.sup.3 is H, R.sup.6 is CN, R.sup.7 is H, R.sup.8 is hydrogen, and R.sup.9 is oxetan-3-yl)

(113) ESI-MS [M+H+]=718.3

(114) .sup.1H-NMR (600 MHz DMSO), [ppm]: 8.15 (dd, 1H), 7.91 (d, 1H), 7.86 (d, 1H), 7.82 (d, 1H), 7.80 (dd, 1H), 7.70 (d, 1H), 7.57 (s, 1H), 7.06 (dd, 1H), 6.71 (dd, 1H), 6.68 (d, 1H), 4.60 (m, 2H), 4.28 (m, 2H), 3.91 (m, 1H), 3.85 (s, 3H), 3.75 (m broad, 2H), 3.65 (s, 3H), 3.59 (m broad, 3H), 3.53 (s, 3H), 2.93 (m, 1H), 2.61 (m, 2H), 2.30 (m, 1H), 1.72 (m, 2H), 1.60 (m, 2H), 1.17 (m, 2H).

Example 21

(S)N-(5-Cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-(methyl(tetrahydro-2H-pyran-4-yl)amino)piperidin-1-yl)azetidine-1-carboxamide

(115) (compound of formula I.6, wherein R.sup.1 is methoxy, R.sup.2 is methoxy, R.sup.3 is H, R.sup.6 is CN, R.sup.7 is H, R.sup.8 is methyl, and R.sup.9 is tetrahydropyran-4-yl)

(116) ESI-MS [M+H+]=760.3

(117) .sup.1H-NMR (600 MHz DMSO), [ppm]: 8.15 (dd, 1H), 7.91 (d, 1H), 7.86 (d, 1H), 7.82 (d, 1H), 7.80 (m, 2H), 7.70 (d, 1H), 7.58 (s, 1H), 7.06 (dd, 1H), 6.72 (dd, 1H), 6.68 (d, 1H), 3.85 (s, 3H), 3.80 (m, 3H), 3.75 (m, 2H), 3.65 (s, 3H), 3.60 (m, 2H), 3.51 (s, 3H), 3.27 (m, 2H), 2.93 (m, 1H), 2.74-2.64 (m, 3H), 1.72 (m, 2H), 1.58 (m, 4H), 1.43 (m, 4H).

Example 22

(S)N-(5-Cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-(oxetan-3-yl(propyl)amino)piperidin-1-yl)azetidine-1-carboxamide

(118) (compound of formula I.6, wherein R.sup.1 is methoxy, R.sup.2 is methoxy, R.sup.3 is H, R.sup.6 is CN, R.sup.7 is H, R.sup.8 is propyl, and R.sup.9 is oxetan-3-yl)

(119) ESI-MS [M+H+]=760.3

(120) .sup.1H-NMR (600 MHz DMSO), [ppm]: 8.13 (dd, 1H), 7.89 (d, 1H), 7.73 (dd, 1H), 7.62 (dd, 1H), 7.48 (s, 1H), 7.34 (m, 1H), 7.02 (dd, 1H), 6.70 (dd, 1H), 6.67 (d, 1H), 4.46 (m, 4H), 4.11 (q, 2H), 3.86 (s, 3H), 3.78 (m broad, 2H), 3.57 (m broad, 2H), 3.50 (s, 3H), 2.93 (m, 1H), 2.71 (m, 2H), 2.54 (m, overlapped with DMSO), 2.19 (m, 1H), 2.08 (s, 3H), 1.67 (m, 2H), 1.51 (m, 2H), 1.36 (m, 2H), 1.01 (t, 3H).

Example 23

(S)N-(5-Cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-(ethyl(oxetan-3-yl)amino)piperidin-1-yl)azetidine-1-carboxamide

(121) (compound of formula I.6, wherein R.sup.1 is methoxy, R.sup.2 is methoxy, R.sup.3 is H, R.sup.6 is CN, R.sup.7 is H, R.sup.8 is ethyl, and R.sup.9 is oxetan-3-yl)

(122) ESI-MS [M+H+]=746.3

(123) .sup.1H NMR (600 MHz, DMSO) 8.15 (dd, 1H), 7.90 (d, 1H), 7.86 (d, 1H), 7.80 (m, 2H), 7.69 (d, 1H), 7.58 (s, 1H), 7.06 (dd, 1H), 6.72 (dd, 1H), 6.68 (d, 1H), 4.47 (dt, 4H), 4.04 (m, 1H), 3.87 (s, 3H), 3.85 (m broad, 2H), 3.65 (m, 3H), 3.56 (m broad, 2H), 3.53 (s, 3H), 2.94 (m, 1H), 2.71 (m, 2H), 2.60 (m, 2H), 2.39 (m, 1H), 1.68 (m, 2H), 1.52 (m, 2H), 1.29 (m, 2H), 0.93 (t, 3H).

Example 24

(S)N-(5-Cyano-3-(2-ethoxypyridin-3-yl)-1-((5-fluoro-2,4-dimethoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)-3-(4-morpholinopiperidin-1-yl)azetidine-1-carboxamide

(124) (compound of formula I.1, wherein R.sup.1 is methoxy, R.sup.2 is methoxy, R.sup.3 is 5-F (relative to the 2- and 4-positions of R.sup.1 and R.sup.2), R.sup.6 is CN, R.sup.7 is H, and R.sup.8 and R.sup.9, together with the nitrogen atom they are bound to, form morpholin-4-yl)

(125) a. To a solution of (S)-3-amino-3-(2-ethoxypyridin-3-yl)-2-oxoindoline-5-carbonitrile (1.0 g, 3.40 mmol) in DMF (12 ml) at 5 C. sodium hydride (55%: 0.22 g, 5.04 mmol) was added. After stirring for 20 min 5-fluoro-2,4-dimethoxybenzene-1-sulfonyl chloride (1.0 g, 3.93 mmol) was added and stirring continued for 1 hr at 5 C. After completion of the reaction 30 ml of water were added dropwise, the mixture digested 3 with dichloromethane, the combined organic layers washed with brine, dried over MgSO.sub.4, filtered and concentrated to leave a brown oil, which was purified by flash chromatography (silica gel/gradient from 0 to 15% methanol in dichloromethane) to yield 1.5 g; ESI-MS [M+H+]=513.2.

(126) b. To a solution of (S)-3-amino-3-(2-ethoxypyridin-3-yl)-1-((5-fluoro-2,4-dimethoxyphenyl)sulfonyl)-2-oxoindoline-5-carbonitrile (1.5 g, 2.63 mmol) in dichloromethane (50 ml) at 5 C. were added dropwise pyridine (2.3 ml, 28.4 mmol) and phenylchloroformate (0.8 ml, 6.37 mmol), and the mixture stirred over night at room temperature. The mixture was diluted with dichloromethane, digested twice with water, the organic layer washed subsequently with 10% NaHCO3-solution and brine, dried over MgSO4, filtered and concentrated to give 2.1 g of a yellow oil, which was further purified by flash chromatography (silica gel/gradient from 0 to 15% methanol in dichloromethane) to give 0.7 g of a yellow amorphous solid; ESI-MS [M+H+]=633.9.

(127) c. To a solution of (S)-phenyl (5-cyano-3-(2-ethoxypyridin-3-yl)-1-((5-fluoro-2,4-dimethoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)carbamate (80 mg, 0,126 mmol) and 4-(1-(azetidin-3-yl)piperidin-4-yl)morpholine3TFA (70 mg, 0,123 mmol) in DMF (3 ml) at 5 C. Et3N (120 l, 0,861 mmol) was added and then stirred for 4 h at room temperature. The mixture was concentrated, diluted with dichloromethane, washed with water and brine, dried over MgSO.sub.4, filtered and evaporated to leave 210 mg of a brown oil. Flash chromatography (silica gel/gradient from 0 to 20% methanol in dichloromethane) yielded 52 mg of the title compound as white solid.

(128) ESI-MS [M+H+]=764.3.

(129) .sup.1H NMR (600 MHz, DMSO) 8.13 (dd, 1H), 7.89 (d, 1H), 7.74 (dd, 1H), 7.62 (dd, 1H), 7.48 (s, 1H), 7.34 (m, 1H), 7.02 (dd, 1H), 6.70 (dd, 1H), 6.67 (d, 1H), 4.11 (q, 2H), 3.86 (s, 3H), 3.75 (m broad, 2H), 3.70-3.55 (m, 6H), 3.50 (s, 3H), 2.94 (m, 1H), 2.71 (m, 2H), 2.42 (m, 4H), 2.08 (m, 1H), 1.71 (m, 4H), 1.34 (m, 2H), 1.01 (t, 3H).

Example 25

(S)N-(5-Cyano-3-(2-ethoxypyridin-3-yl)-1-((4-methoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)-3-(4-morpholinopiperidin-1-yl)azetidine-1-carboxamide

(130) (compound of formula I.1, wherein R.sup.1 is H, R.sup.2 is methoxy, R.sup.3 is H, R.sup.6 is CN, R.sup.7 is H, and R.sup.8 and R.sup.9, together with the nitrogen atom they are bound to, form morpholin-4-yl)

(131) Prepared according to the procedure described for EXAMPLE 25:

(132) ESI-MS [M+H+]=716.3.

Example 26

(S)N-(5-Cyano-1-((2,4-difluorophenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-morpholinopiperidin-1-yl)azetidine-1-carboxamide

(133) (compound of formula I. 1, wherein R.sup.1 is F, R.sup.2 is F, R.sup.3 is H, R.sup.6 is CN, R.sup.7 is H, and R.sup.8 and R.sup.9, together with the nitrogen atom they are bound to, form morpholin-4-yl)

(134) To a solution of (S)N-(5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-morpholinopiperidin-1-yl)azetidine-1-carboxamide (200 mg, 0,367 mmol) in THF (3 ml) at 5 C. potassium tert-butoxide (60 mg, 0,535 mmol) and after 30 min 2,4-diflurobenzenesulfonylchloride (90 mg, 0,423 mmol) were added, and the mixture stirred over night at room temperature. The mixture was diluted with 20 ml of water, digested 3 with dichloromethane, and the combined organic layers washed with brine, dried over MgSO4, filtered and concentrated to give 300 mg of a clear oil. Flash chromatography (silica gel/gradient from 0 to 20% methanol in dichloromethane) yielded 115 mg of the title compound as white solid.

(135) ESI-MS [M+H+]=716.3.

(136) .sup.1H NMR (600 MHz, DMSO) 8.30 (dd, 1H), 8.10 (m, 2H), 7.88 (m, 2H), 7.57 (s, 2H), 7.50 (m, 1H), 7.34 (m, 1H), 7.12 (dd, 1H), 4.09 (q, 2H), 3.80-3.50 (m, 7H), 2.93 (m, 1H), 2.71 (m, 2H), 2.39 (m, 4H), 2.08 (m, 1H), 1.71 (m, 4H), 1.4 (m, 2H), 0.98 (t, 3H).

(137) The following compounds were prepared according to the procedure as described for EXAMPLE 27

Example 27

(S)N-(5-cyano-3-(2-ethoxypyridin-3-yl)-1-((2-fluoro-4-methoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)-3-(4-morpholinopiperidin-1-yl)azetidine-1-carboxamide

(138) (compound of formula I.1, wherein R.sup.1 is F, R.sup.2 is methoxy, R.sup.3 is H, R.sup.6 is CN, R.sup.7 is H, and R.sup.8 and R.sup.9, together with the nitrogen atom they are bound to, form morpholin-4-yl)

(139) ESI-MS [M+H+]=734.3.

(140) .sup.1H NMR (600 MHz, DMSO) 8.14 (dd, 1H), 8.01 (dd, 1H), 7.94 (t, 1H), 7.85 (m, 2H), 7.61 (s, 1H), 7.58 (s, 1H), 7.10 (dd, 1H), 7.05 (dd, 1H), 6.98 (dd, 1H), 4.05 (m, 2H), 3.86 (s, 3H), 3.75 (m broad, 2H), 3.60-3.50 (m, 5H), 2.93 (m, 1H), 2.71 (m, 2H), 2.39 (m, 4H), 2.09 (m, 1H), 1.72 (m, 4H), 1.35 (m, 2H), 0.93 (t, 3H).

Example 28

(S)N-(5-cyano-3-(2-ethoxypyridin-3-yl)-1-((4-fluoro-2-methoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)-3-(4-morpholinopiperidin-1-yl)azetidine-1-carboxamide

(141) (compound of formula I.1, wherein R.sup.1 is methoxy, R.sup.2 is F, R.sup.3 is H, R.sup.6 is CN, R.sup.7 is H, and R.sup.8 and R.sup.9, together with the nitrogen atom they are bound to, form morpholin-4-yl)

(142) ESI-MS [M+H+]=734.3.

(143) 1H NMR (600 MHz, DMSO) 8.14 (dd, 1H), 8.01 (dd, 1H), 7.94 (dd, 1H), 7.86 (m, 2H), 7.64 (s, 1H), 7.56 (s, 1H), 7.15 (dd, 1H), 7.09 (dd, 1H), 6.98 (td, 1H), 4.10 (m, 2H), 3.74 (m broad, 2H), 3.62-3.50 (m, 6H), 3.49 (s, 3H), 2.94 (m, 1H), 2.71 (m, 2H), 2.39 (m, 4H), 2.08 (m, 1H), 1.71 (m, 4H), 1.34 (m, 2H), 0.98 (t, 3H).

Example 29

(S)N-(5-Cyano-1-((2-methoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-(methyl(oxetan-3-yl)amino)piperidin-1-yl)azetidine-1-carboxamide

(144) (compound of formula I.6, wherein R.sup.1 is methoxy, R.sup.2 is H, R.sup.3 is H, R.sup.6 is CN, R.sup.7 is H, R.sup.8 is methyl, and R.sup.9 is oxetan-3-yl)

(145) ESI-MS [M+H+]=702.2.

(146) .sup.1H NMR (600 MHz, DMSO) 8.13 (dd, 1H), 7.98 (d, 1H), 7.87 (d, 1H), 7.82 (m, 2H), 7.71 (m, 2H), 7.69 (s, 1H), 7.24 (d, 1H), 7.16 (m, 1H), 7.06 (m, 1H), 4.44 (m, 4H), 3.84 (q, 2H), 3.75 (m broad, 2H), 3.63 (s, 3H), 3.54 (s, 3H, overlapped with m broad, 2H), 2.92 (m, 1H), 2.69 (m, 2H), 2.19 (m, 1H), 1.66 (m, 2H), 1.49 (m, 2H), 1.37 (m, 2H).

Example 30

(S)N-(5-Cyano-1-((4-fluoro-2-methoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-(methyl(oxetan-3-yl)amino)piperidin-1-yl)azetidine-1-carboxamide

(147) (compound of formula I.6, wherein R.sup.1 is methoxy, R.sup.2 is F, R.sup.3 is H, R.sup.6 is CN, R.sup.7 is H, R.sup.8 is methyl, and R.sup.9 is oxetan-3-yl)

(148) ESI-MS [M+H+]=720.2.

(149) .sup.1H NMR (600 MHz, DMSO) 8.16 (dd, 1H), 8.04 (dd, 1H), 7.91 (dd, 1H), 7.87 (d, 1H), 7.83 (dd, 1H), 7.69 (d, 1H), 7.60 (s, 3H), 7.17 (dd, 1H), 7.10 (dd, 1H), 7.00 (td, 1H), 4.45 (m, 4H), 3.83-3.50 (m broad, 5H) overlapped with 3.65 (s, 3H), 2.92 (m, 1H), 2.71 (m, 2H), 2.19 (m, 1H), 1.66 (m, 2H), 1.50 (m, 2H), 1.36 (m, 2H).

Example 31

(S)N-(5-Cyano-1-((4-fluorophenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-(methyl(oxetan-3-yl)amino)piperidin-1-yl)azetidine-1-carboxamide

(150) (compound of formula I.6, wherein R.sup.1 is H, R.sup.2 is F, R.sup.3 is H, R.sup.6 is CN, R.sup.7 is H, R.sup.8 is methyl and R.sup.9 is oxetan-3-yl)

(151) ESI-MS [M+H+]=690.2.

(152) .sup.1H NMR (600 MHz, DMSO) 8.16 (m, 3H), 8.05 (dd, 1H), 7.88 (d, 1H), 7.83 (dd, 1H), 7.65 (d, 2H), 7.53 (m, 2H), 7.13 (dd, 1H), 4.45 (m, 4H), 3.92-3.47 (m, 5H), 3.42 (s, 3H), 2.93 (m, 1H), 2.72 (m, 2H), 2.20 (m, 1H), 2.06 (s, 3H), 1.67 (m, 2H), 1.51 (m, 2H), 1.36 (m, 2H).

Example 32

(S)N-(5-Cyano-1-((2-fluoro-4-methoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-(methyl(oxetan-3-yl)amino)piperidin-1-yl)azetidine-1-carboxamide

(153) (compound of formula I.6, wherein R.sup.1 is F, R.sup.2 is methoxy, R.sup.3 is H, R.sup.6 is CN, R.sup.7 is H, R.sup.8 is methyl, and R.sup.9 is oxetan-3-yl)

(154) ESI-MS [M+H+]=720.3.

(155) .sup.1H NMR (600 MHz, DMSO) 8.16 (dd, 1H), 8.0 (m, 1H), 7.98 (m, 1H), 7.85 (m, 2H), 7.67 (s, 1H), 7.62 (s, 1H), 7.11 (m 2H), 7.0 (dd, 1H), 4.46 (m, 4H), 3.87 (s, 3H), 3.79-3.60 (m, 5H), 3.57 (s, 3H), 2.92 (m, 1H), 2.71 (m, 2H), 2.20 (m, 1H), 2.10 (s, 3H), 1.67 (m, 2H), 1.51 (m, 2H), 1.36 (m, 2H).

Example 33

(S)N-(5-Cyano-1-((2,4-difluorophenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-(methyl(oxetan-3-yl)amino)piperidin-1-yl)azetidine-1-carboxamide

(156) (compound of formula I.6, wherein R.sup.1 is F, R.sup.2 is F, R.sup.3 is H, R.sup.6 is CN, R.sup.7 is H, R.sup.8 is methyl, and R.sup.9 is oxetan-3-yl)

(157) ESI-MS [M+H+]=708.2.

(158) .sup.1H NMR (600 MHz, DMSO) 8.17 (dd, 1H), 8.14 (m, 1H), 8.06 (dd, 1H), 7.86 (m, 2H), 7.68 (s, 1H), 7.65 (s, 1H), 7.60 (m, 1H), 7.37 (m, 1H), 7.14 (dd, 1H), 4.46 (m, 4H), 3.90-3.55 (m, 5H), overlapped with 3.60 (s, 3H), 2.932 (m, 1H), 2.70 (m, 2H), 2.19 (m, 1H), 2.19 (s, 3H), 1.67 (m, 2H), 1.51 (m, 2H), 1.35 (m, 2H).

Example 34

(S)N-(5-Cyano-1-((5-fluoro-2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-(methyl(oxetan-3-yl)amino)piperidin-1-yl)azetidine-1-carboxamide

(159) (compound of formula I.6, wherein R.sup.1 is methoxy, R.sup.2 is methoxy, R.sup.3 is 5-F (relative to the 2- and 4-positions of R.sup.1 and R.sup.2), R.sup.6 is CN, R.sup.7 is H, R.sup.8 is methyl, and R.sup.9 is oxetan-3-yl)

(160) ESI-MS [M+H+]=750.3.

(161) .sup.1H NMR (600 MHz, DMSO) 8.16 (dd, 1H), 7.87 (m, 2H), 7.82 (dd, 1H), 7.75 (dd, 1H), 7.70 (d, 1H), 7.62 (s, 1H), 7.09 (dd, 1H), 6.92 (d, 1H), 4.46 (m, 4H), 3.96 (s, 3H), 3.85 (m broad, 2H), 3.66 and 3.58 (each s, 3H) overlapped with 3.70-3.50 (m, 3H), 2.93 (m, 1H), 2.71 (m, 2H), 2.20 (m, 1H), 2.15 (s, 3H), 1.67 (m, 2H), 1.51 (m, 2H), 1.36 (m, 2H).

Example 35

(S)N-(5-cyano-1-((4-methoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-(methyl(oxetan-3-yl)amino)piperidin-1-yl)azetidine-1-carboxamide

(162) (compound of formula I.6, wherein R.sup.1 is H, R.sup.2 is methoxy, R.sup.3 is H, R.sup.6 is CN, R.sup.7 is H, R.sup.8 is methyl, and R.sup.9 is oxetan-3-yl)

(163) ESI-MS [M+H+]=702.3.

(164) .sup.1H NMR (600 MHz, DMSO) 8.14 (dd, 1H), 8.00 (dd, 1H), 7.85 (d, 1H), 7.82 (dd, 1H), 7.63 (m, 2H), 7.18 (m, 2H), 7.10 (dd, 1H), 4.45 (m, 4H), 3.86 (s, 3H), 3.75-3.65 (m, 3H), 3.59 (m broad, 2H), 2.93 (m, 1H), 2.72 (m, 2H), 2.20 (m, 1H), 2.09 (s, 3H), 1.68 (m, 2H), 1.52 (m, 2H), 1.37 (m, 2H).

Example 36

(S)N-(5-Cyano-3-(2-ethoxypyridin-3-yl)-1-((5-methoxypyridin-2-yl)sulfonyl)-2-oxoindolin-3-yl)-3-(4-morpholinopiperidin-1-yl)azetidine-1-carboxamideTFA

(165) (compound of formula I.21, wherein R.sup.2 is methoxy, R.sup.3 is H, R.sup.6 is CN, R.sup.7 is H, and R.sup.8 and R.sup.9, together with the nitrogen atom they are bound to, form morpholin-4-yl)

(166) ESI-MS [M+H+]=717.3.

Example 37

(S)N-(5-Cyano-3-(2-ethoxypyridin-3-yl)-1-((2-methoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)-3-(4-morpholinopiperidin-1-yl)azetidine-1-carboxamide

(167) (compound of formula I.1, wherein R.sup.1 is methoxy, R.sup.2 is H, R.sup.3 is H, R.sup.6 is CN, R.sup.7 is H, and R.sup.8 and R.sup.9, together with the nitrogen atom they are bound to, form morpholin-4-yl)

(168) ESI-MS [M+H+]=716.3

(169) .sup.1H NMR (600 MHz, DMSO) 8.14 (dd, 1H), 7.97 (dd, 1H), 7.85 (m, 3H), 7.71 (m, 1H), 7.67 (s, 1H), 7.56 (s, 1H), 7.20 (d, 1H), 7.14 (m, 1H), 7.06 (dd, 1H), 4.08 (q, 2H), 3.81 (m broad, 2H), 3.75-3.50 (m, 5H), 3.49 (s, 1H), 2.93 (m, 1H), 2.70 (m, 2H), 2.40 (m, 4H), 2.08 (m, 1H), 1.71 (m, 4H), 1.34 (m, 2H), 0.94 (t, 3H).

Example 38

(S)N-(5-Cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-(isopropyl(oxetan-3-yl)amino)piperidin-1-yl)azetidine-1-carboxamide

(170) (compound of formula I.6, wherein R.sup.1 is methoxy, R.sup.2 is methoxy, R.sup.3 is H, R.sup.6 is CN, R.sup.7 is H, R.sup.8 is isopropyl, and R.sup.9 is oxetan-3-yl)

(171) ESI-MS [M+H+]=760.3

(172) .sup.1H NMR (600 MHz, DMSO) 8.15 (dd, 1H), 7.91 (d, 1H), 7.86 (d, 1H), 7.81 (m, 2H), 7.69 (d, 1H), 7.58 (s, 1H), 7.06 (dd, 1H), 6.72 (dd, 1H), 6.68 (d, 1H), 4.47 (m, 4H), 4.23 (m, 1H), 3.87 (s, 4H), 3.75 (m broad, 2H), 3.65 (s, 3H), 3.58 (m broad, 2H) 3.53 (s, 3H), 3.03 (m, 1H), 2.93 (m, 1H), 2.71 (m, 2H), 2.59 (m, 1H), 1.74 (m, 2H), 1.42 (m, 4H), 0.94 (d, 3H), 0.93 (d, 3H).

Example 39

(S)N-(5-Cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-(3,3-difluoroazetidin-1-yl)piperidin-1-yl)azetidine-1-carboxamide

(173) (compound of formula I.1, wherein R.sup.1 is methoxy, R.sup.2 is methoxy, R.sup.3 is H, R.sup.6 is CN, R.sup.7 is H, and R.sup.8 and R.sup.9, together with the nitrogen atom they are bound to, form 3,3-difluoroazetidin-1-yl)

(174) ESI-MS [M+H+]=752.3

(175) .sup.1H NMR (600 MHz, DMSO) 8.13 (dd, 1H), 7.88 (d, 1H), 7.86-7.80 (m, 3H), 7.66 (s, 1H), 7.54 (s, 1H), 7.05 (dd, 1H), 6.70 (dd, 1H), 6.66 (d, 1H), 4.09 (q, 2H), 3.86 (s, 4H), 3.78 (m broad, 2H), 3.66-3.53 (m, 6H), 3.52 (s, 3H), 2.98 (m, 1H), 2.57 (m, 2H), 2.16 (d, 1H), 1.83 (d, 2H), 1.62 (d, 2H), 1.19 (m, 2H), 0.95 (t, 3H).

Example 40

(S)N-(5-Cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4,4-difluoro-[1,4-bipiperidin]-1-yl)azetidine-1-carboxamide

(176) (compound of formula I.1, wherein R.sup.1 is methoxy, R.sup.2 is methoxy, R.sup.3 is H, R.sup.6 is CN, R.sup.7 is H, and R.sup.8 and R.sup.9, together with the nitrogen atom they are bound to, form 4,4-difluoropiperidin-1-yl)

(177) ESI-MS [M+H+]=780.3

(178) .sup.1H NMR (600 MHz, DMSO) 8.14 (dd, 1H), 7.88 (d, 1H), 7.83 (m, 3H), 7.66 (s, 1H), 7.55 (s, 1H), 7.05 (dd, 1H), 6.70 (dd, 1H), 6.66 (d, 1H), 4.09 (q, 2H), 3.86 (s, 3H), 3.73 (m broad, 2H), 3.58 (m broad, 2H), 3.46 (s, 3H), 2.95 (m, 1H), 2.73 (m, 2H), 2.55 (m, 4H), 2.32 (m, 1H), 1.90 (m, 4H), 1.68 (m, 4H), 1.42 (m, 2H), 0.95 (t, 3H).

Example 41

(S)N-(5-Cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-(3-methoxyazetidin-1-yl)piperidin-1-yl)azetidine-1-carboxamide

(179) (compound of formula I.1, wherein R.sup.1 is methoxy, R.sup.2 is methoxy, R.sup.3 is H, R.sup.6 is CN, R.sup.7 is H, and R.sup.8 and R.sup.9, together with the nitrogen atom they are bound to, form 3-methoxyazetidin-1-yl)

(180) ESI-MS [M+H+]=746.3

(181) .sup.1H NMR (600 MHz, DMSO) 8.13 (dd, 1H), 7.88 (d, 1H), 7.83 (m, 3H), 7.66 (s, 1H), 7.54 (s, 1H), 7.05 (dd, 1H), 6.70 (dd, 1H), 6.66 (d, 1H), 4.07 (q, 2H), 3.89 (m, 1H), 3.86 (s, 3H), 3.76 (m broad, 2H), 3.58 (m broad, 2H), 3.46 (s, 3H), 3.42 (m, 2H), 3.13 (s, 3H), 2.95 (m, 1H), 2.69 (m, 2H), 2.51 (m, overlapped with DMSO, 2H), 1.94 (m, 1H), 1.79 (m, 2H), 1.59 (d, 2H), 1.14 (m, 2H), 0.95 (t, 3H).

Example 42

(S)N-(5-Cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-methoxy-[1,4-bipiperidin]-1-yl)azetidine-1-carboxamide

(182) (compound of formula I.1, wherein R.sup.1 is methoxy, R.sup.2 is methoxy, R.sup.3 is H, R.sup.6 is CN, R.sup.7 is H, and R.sup.8 and R.sup.9, together with the nitrogen atom they are bound to, form 4-methoxypiperidin-1-yl)

(183) ESI-MS [M+H+]=774.3

(184) .sup.1H NMR (600 MHz, DMSO) 8.14 (dd, 1H), 7.88 (d, 1H), 7.83 (m, 3H), 7.66 (s, 1H), 7.54 (s, 1H), 7.05 (dd, 1H), 6.70 (dd, 1H), 6.66 (d, 1H), 4.09 (q, 2H), 3.86 (s, 3H), 3.76 (m broad, 2H), 3.58 (m broad, 2H), 3.46 (s, 3H), 3.20 (s, 3H), 3.10 (m, 1H), 2.93 (m, 1H), 2.70 (m, 4H), 2.17 (m, 3H), 1.80 (m, 2H), 1.68 (m, 4H), 1.37 (m, 4H), 0.95 (t, 3H).

Example 43

(S)N-(5-Cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-(3-hydroxyazetidin-1-yl)piperidin-1-yl)azetidine-1-carboxamide

(185) (compound of formula I.1, wherein R.sup.1 is methoxy, R.sup.2 is methoxy, R.sup.3 is H, R.sup.6 is CN, R.sup.7 is H, and R.sup.8 and R.sup.9, together with the nitrogen atom they are bound to, form 3-hydroxyazetidin-1-yl)

(186) ESI-MS [M+H+]=732.3

(187) .sup.1H NMR (600 MHz, DMSO) 8.13 (dd, 1H), 7.87 (d, J=11.1 Hz, 1H), 7.83 (m, 3H), 7.66 (s, 1H), 7.53 (s, 1H), 7.05 (dd, 1H), 6.70 (dd, 1H), 6.66 (d, 1H), 5.23 (d, 1H), 4.09 (q, 2H), 3.86 (s, 3H), 3.76 (m broad, 2H), 3.58 (m broad, 2H), 3.45 (s, 3H), 3.41 (m, 3H), 2.95 (m, 1H), 2.60 (m, 2H), 2.52 (m overlapped with DMSO), 1.91 (m, 1H), 1.78 (s, 2H), 1.58 (m, 2H), 1.11 (m, 2H), 0.95 (t, 3H).

Example 44

(S)N-(5-Cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-hydroxy-[1,4-bipiperidin]-1-yl)azetidine-1-carboxamide

(188) (compound of formula I.1, wherein R.sup.1 is methoxy, R.sup.2 is methoxy, R.sup.3 is H, R.sup.6 is CN, R.sup.7 is H, and R.sup.8 and R.sup.9, together with the nitrogen atom they are bound to, form 4-hydroxypiperidin-1-yl)

(189) ESI-MS [M+H+]=760.3

(190) .sup.1H NMR (600 MHz, DMSO) 8.13 (dd, 1H), 7.88 (d, 1H), 7.83 (m, 3H), 7.66 (s, 1H), 7.54 (s, 1H), 7.05 (dd, 1H), 6.70 (dd, 1H), 6.66 (d, 1H), 4.51 (d, 1H), 4.08 (q, 2H), 3.86 (s, 3H), 3.73 (m broad, 2H), 3.54 (m broad, 2H), 3.46 (s, 3H), 3.40 (m, overlapped with DMSO), 2.93 (m, 1H), 2.71 (m, 4H), 2.14 (m, 3H), 1.67 (m, 6H), 1.33 (m, 4H), 0.95 (t, 3H).

Example 45

(S)N-(5-Cyano-3-(2,5-dimethoxyphenyl)-1-((2,4-dimethoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)-3-(4-morpholinopiperidin-1-yl)azetidine-1-carboxamide

(191) (compound of formula I.16, wherein R.sup.1 is methoxy, R.sup.2 is methoxy, R.sup.3 is H, R.sup.6 is CN, R.sup.7 is H, and R.sup.8 and R.sup.9, together with the nitrogen atom they are bound to, form morpholin-4-yl)

(192) ESI-MS [M+H+]=761.2

(193) .sup.1H NMR (600 MHz, DMSO) 7.90 (d, 1H), 7.84 (d, 1H), 7.77 (dd, 1H), 7.69 (d, 1H), 7.48 (s, 1H), 7.07 (d, 1H), 6.95-6.86 (m, 2H), 6.70 (dd, 1H), 6.66 (d, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 3.70-3.55 (m, 11H), 3.50 (s, 3H), 2.90 (m, 1H), 2.70 (m, 2H), 2.40 (m, 4H), 2.07 (m, 1H), 1.70 (m, 4H), 1.35 (m, 2H).

Example 46

(S)N-(5-Cyano-3-(2,5-dimethoxyphenyl)-1-((2,4-dimethoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)-3-(4-(methyl(oxetan-3-yl)amino)piperidin-1-yl)azetidine-1-carboxamide

(194) (compound of formula I.16, wherein R.sup.1 is methoxy, R.sup.2 is methoxy, R.sup.3 is H, R.sup.6 is CN, R.sup.7 is H, R.sup.8 is methyl, and R.sup.9 is oxetan-3-yl)

(195) ESI-MS [M+H+]=761.3

(196) .sup.1H NMR (600 MHz, DMSO) 7.90 (d, 1H), 7.84 (d, 1H), 7.77 (dd, 1H), 7.68 (d, 1H), 7.48 (s, 1H), 7.07 (d, 1H), 6.96-6.87 (m, 2H), 6.69 (m, 1H), 6.66 (d, 1H), 4.53-4.41 (m, 4H), 3.90-3.81 (m, 5H), 3.74 (s, 3H), 3.64-3.56 (m, 3H), 3.53 (s, 3H), 3.49 (s, 3H), 2.91 (m, 1H), 2.70 (m, 2H), 2.19 (m, 1H), 2.08 (s, 3H), 1.66 (m, 2H), 1.50 (m, 2H), 1.35 (m, 2H).

(197) III. Determination of the Biological Activity

(198) 1. Vasopressin V1b Receptor Binding Assay:

(199) Substances:

(200) The test substances were dissolved in a concentration of 5 mM in 100% DMSO and further diluted to 510.sup.4M to 510.sup.9 M. These serial DMSO predilutions were diluted 1:10 with assay buffer. The substance concentration was further diluted 1:5 in the assay mixture resulting in 2% DMSO in the mixture. All dilutions were performed in a Biomek NX automation workstation (Beckman)

(201) Membrane Preparation:

(202) CHO-K1 cells with stably expressed human vasopressin V1b receptor (clone 3H2) were harvested and homogenized in 50 mM Tris-HCl and in the presence of protease inhibitors (Roche complete Mini #1836170) using a Polytron homogenizer at intermediate setting for 210 seconds, and subsequently centrifuged at 40 000g for 1 h. The membrane pellet was again homogenized and centrifuged as described and subsequently taken up in 50 mM Tris-HCl, pH 7.4, homogenized and stored in aliquots frozen in liquid nitrogen at 190 C.

(203) Binding Assay:

(204) The binding assay was carried out by the method based on that of Tahara et al. (Tahara A et al., Brit. J. Pharmacol. 125, 1463-1470 (1998)).

(205) The incubation buffer was: 50 mM Tris, 10 mM MgCl.sub.2, 0.1% BSA, pH 7.4.

(206) In the assay mixture (2000), membranes (26 g protein in incubation buffer) from CHO-K1 cells with stably expressed human V1b receptors (cell line hV1b_3H2_CHO) were incubated with 1.5 nM .sup.3H-AVP (8-Arg-vasopressin, PerkinElmer, NET 800) in incubation buffer (50 mM Tris, 10 mM MgCl.sub.2, 0.1% BSA, pH 7.4) (total binding) or additionally with increasing concentrations of test substance (displacement experiment). The nonspecific binding was determined with 1 M AVP (Fluka 94836). All determinations were carried out as duplicate determinations. After incubation (60 minutes at room temperature), the free radioligand was filtered off by vacuum filtration (Tomtec Mach III) through Wathman GF/B glass fiber filter plates (UniFilter, PerkinElmer 6005177). The liquid scintillation measurement took place in a Microbeta TriLux 12 (Wallac).

(207) Analysis:

(208) The binding parameters were calculated by nonlinear regression in SAS. The algorithms of the program operate in analogy to the LIGAND analysis program (Munson P T and Rodbard D, Analytical Biochem. 107, 220-239 (1980)). The Kd of .sup.3H-AVP for the recombinant human V1b receptors is 0.4 nM and was used to determine the Ki.

(209) 2. Vasopressin V1a Receptor Binding Assay:

(210) Substances:

(211) The test substances were dissolved in a concentration of 5 mM M in DMSO. Further dilution of these DMSO solutions took place as described for V1b.

(212) Membrane Preparation:

(213) CHO-K1 cells with stably expressed human vasopressin V1a receptor (clone 5) were harvested and homogenized in 50 mM Tris-HCl and in the presence of protease inhibitors (Roche complete Mini #1836170) using a Polytron homogenizer at intermediate setting for 210 seconds, and subsequently centrifuged at 40 000g for 1 h. The membrane pellet was again homogenized in a High-Pressure-Homogenizer, Polytec 50K at 1500 PSI (Heinemann, Germany) and subsequently taken up in 50 mM Tris-HCl, pH 7.4, homogenized and stored in aliquots frozen in liquid nitrogen at 190 C.

(214) Binding Assay:

(215) The binding assay was carried out by the method based on that of Tahara et al. (Tahara A et al., Brit. J. Pharmacol. 125, 1463-1470 (1998)).

(216) The incubation buffer was: 50 mM Tris, 10 mM MgCl.sub.2, 0.1% BSA, pH 7.4.

(217) In the assay mixture (200 l), membranes (40 g protein in incubation buffer) from CHO-K1 cells with stably expressed human V1a receptors (cell line hV1a_5_CHO) were incubated with 0.04 nM .sup.125I-AVP (8-Arg-vasopressin, PerkinElmer NEX 128) in incubation buffer (50 mM Tris, 10 mM MgCl.sub.2, 0.1% BSA, pH 7.4) (total binding) or additionally with increasing concentrations of test substance (displacement experiment). The nonspecific binding was determined with 1 M AVP (Fluka 94836). Duplicate determinations were carried out.

(218) After incubation (60 minutes at room temperature), the samples were processed as described for V1b.

(219) Analysis:

(220) The binding parameters were calculated by nonlinear regression in SAS. The algorithms of the program operate in analogy to the LIGAND analysis program (Munson P J and Rodbard D, Analytical Biochem. 107, 220-239 (1980)). The Kd of .sup.125I-AVP for the recombinant hV1a receptors was determined in saturation experiments. A Kd of 1.33 nM was used to determine the Ki.

(221) 3. Oxytocin Receptor Binding Assay

(222) Substances:

(223) The substances were dissolved in a concentration of 5 mM in DMSO and diluted further as described for V1b.

(224) Membrane Preparation:

(225) Confluent HEK-293 cells with transiently expressing recombinant human oxytocin receptors were harvested and centrifuged at 750g at room temperature for 5 minutes. The pellet was taken up in ice-cold lysis buffer (50 mM Tris-HCl, 10% glycerol, pH 7.4 and Roche complete protease inhibitor) and thereby subjected to an osmotic shock at 4 C. for 20 minutes. Lysed cells were then centrifuged at 750g at 4 C. for 20 minutes, the pellet was taken up in incubation buffer (50 mM Tris, 10 mM MgCl.sub.2, 0.1% BSA, pH 7.4), and aliquots corresponding to 10.sup.7 cells/ml were prepared. The aliquots were frozen at 80 C. until use.

(226) Binding Assay:

(227) On the day of the experiment, the cell lysate was thawed, homogenized, and diluted with incubation buffer (50 mM Tris, 10 mM MgCl.sub.2, 0.1% BSA, pH 7.4) to the desired concentration. The reaction mixture of 0.200 ml was composed of cell lysate corresponding to 510.sup.4 cells (HEK-293 cells expressing transiently human OT receptors) and 1 nM 3H-oxytocin (PerkinElmer NET858) in the presence of test substance (displacement experiment) or incubation buffer only (total binding). The nonspecific binding was determined in the presence of 1 M oxytocin (Bachem AG, H2510). Determinations were carried out in duplicates. After 60 minutes incubation at room temperature, bound and free radioligand were separated by filtration under vacuum on GF/B UniFilter plates (Perkin Elmer #6005177) pre-incubated with 0.3% PEI. The bound radioactivity was determined by liquid scintillation measurement in a Microbeta (Perkin Elmer) plate counter.

(228) Analysis:

(229) The binding parameters were calculated by nonlinear regression analysis (SAS) in analogy to the LIGAND program of Munson and Rodbard (Analytical Biochem 1980; 107: 220-239). The Kd of .sup.3H-oxytocin for the recombinant hOT receptors was 7.6 nM and was used to calculate the Ki from competition binding experiments.

(230) 4. Determination of the Microsomal Half-Life:

(231) The metabolic stability of the compounds of the invention was determined in the following assay.

(232) The test substances were incubated in a concentration of 0.5 M as follows: 0.5 M test substance are preincubated together with liver microsomes from different species (from rat, human or other species) (0.25 mg of microsomal protein/ml) in 0.05 M potassium phosphate buffer of pH 7.4 in microtiter plates at 37 C. for 5 min. The reaction is started by adding NADPH (1 mg/mL). After 0, 5, 10, 15, 20 and 30 min, 50 l aliquots are removed, and the reaction is immediately stopped and cooled with the same volume of acetonitrile. The samples are frozen until analyzed. The remaining concentration of undegraded test substance is determined by MSMS. The half-life (T) is determined from the gradient of the signal of test substance/unit time plot, it being possible to calculate the half-life of the test substance, assuming first order kinetics, from the decrease in the concentration of the compound with time. The microsomal clearance (mCl) is calculated from mCl=ln 2/T/(content of microsomal protein in mg/ml)1000 [ml/min/mg] (modified from references: Di, The Society for Biomoleculur Screening, 2003, 453-462; Obach, D M D, 1999 vol 27. N 11, 1350-1359).

(233) 5. Methods for In Vitro Determination of the Cytochrome P450 (CYP) Inhibition

(234) Luminescent Substrates for 2C9 and 3A4:

(235) 0.4 mg/ml human liver microsomes are preincubated with the test substances to be investigated (0-20 M), the CYP-specific substrates, in 0.05 M potassium phosphate buffer of pH 7.4 at 37 C. for 10 min. The Cyp-specific substrate for CYP 2C9 is lucifer-luciferin H, and for CYP 3A4 is luciferin BE. The reaction is started by adding NADPH. After incubation at RT for 30 min, the luciferin detection reagent is added, and the resulting luminescence signal is measured (modified from reference: Promega, Technical Bulletin P450-GLO Assays).

(236) Midazolam CYP 3A4 Time-Dependent Inhibition

(237) The assay consists of 2 parts. Firstly, the test substance is preincubated with the liver microsomes (with NADPH=preincubation, then addition of the substrate; in the second part the substrate and the test substance are added simultaneously=coincubation.

(238) Preincubation:

(239) 0.05 mg/ml microsomal protein (human liver microsomes) are preincubated with 0-10 M (or 50 M) test substance in 50 mM potassium phosphate buffer for 5 min. The reaction is started with NADPH. After 30 min 4 M midazolam (final concentration) are added, and incubation is continued for 10 min. 75 l of the reaction solution are removed after 10 min, and stopped with 150 l of acetonitrile solution.

(240) Coincubation:

(241) 0.05 mg/ml microsomal protein (human liver microsomes) are preincubated with 4 m midazolam (final concentration) and 0-10 M (or 50 0\4) test substance in 50 mM potassium phosphate buffer for 5 min. The reaction is started with NADPH. 75 l of the reaction solution are removed after 10 min and stopped with 150 l of acetonitrile solution. The samples are frozen until the MSMS analysis (modified from references: Obdach, Journal of Pharmacology & Experimental Therapeutics, Vol 316, 1, 336-348, 2006; Walsky, Drug Metabolism and Disposition Vol 32, 6, 647-660, 2004).

(242) 6. Method for Determining the Solubility in Water (in Mg/Ml)

(243) The solubility in water of the compounds of the invention can be determined for example by the so-called shake flask method (as specified in ASTM International: E 1148-02, Standard test methods for measurement of aqueous solubility, Book of Standards Volume 11.05.). This entails an excess of the solid compound being put into a buffer solution with a particular pH (for example phosphate buffer of pH 7.4), and the resulting mixture being shaken or stirred until equilibrium has been set up (typically 24 or 48 hours, sometimes even up to 7 days). The undissolved solid is then removed by filtration or centrifugation, and the concentration of the dissolved compound is determined by UV spectroscopy or high pressure liquid chromatography (HPLC) by means of an appropriate calibration plot.

(244) 7. Results

(245) The results of the receptor binding investigations are expressed as receptor binding constants [K.sub.i(V1b)] or selectivities [K.sub.i(V1a)/K.sub.i(V1b)]. The results of the investigation of the metabolic stability are indicated as microsomal clearance (mCl).

(246) The compounds of the invention show very high affinities for the V1b receptor in these assays (maximally 100 nM, or maximally 10 nM, frequently <1 nM). The compounds also show high selectivities vis--vis the V1a receptor and a good metabolic stability, measured as microsomal clearance.

(247) The results are listed in table C. The numbers of the compounds refer to the synthesis examples.

(248) TABLE-US-00003 TABLE C Example K.sub.i(h-V1b)* [nM] K.sub.i(h-V1a)/Ki(h-V1b) 1 +++ +++ 2 +++ +++ 3 +++ +++ 4 ++ +++ 5 ++ +++ 6 ++ +++ 8 +++ ++ 9 +++ ++ 10 +++ +++ 11 ++ ++ 13 +++ +++ 14 +++ ++ 15 ++ +++ 17 + +++ 18 +++ +++ 19 +++ +++ 20 ++ + 21 +++ + 23 ++ ++ 24 ++ +++ 25 +++ ++ 26 ++ +++ 27 +++ +++ 28 ++ +++ 29 ++ + 30 ++ + 31 ++ + 32 ++ + 33 + + 35 ++ ++ 36 ++ + 37 ++ +++ 38 + + 39 + +++ 40 +++ +++ 41 ++ +++ 42 ++ +++ 43 ++ +++ 44 +++ +++ 45 +++ + 46 +++ ++ * h = human Key: K.sub.i(h-V1b) K.sub.i(h-V1a)/K.sub.i(h-V1b) + >10-100 nM 10-<25 ++ 1-10 nM 25-75 +++ <1 nM >75