1,3-DIAZA-SPIRO-[3.4]-OCTANE DERIVATIVES

Abstract

The invention relates to 1,3-diaza-spiro-[3.4]-octane derivatives, their preparation and use in medicine, particularly in various neurological disorders, including but not limited to pain, neurodegenerative disorders, neuroinflammatory disorders, neuropsychiatric disorders, substance abuse/dependence.

Claims

1. A compound according to general formula (I) ##STR00125## wherein R.sup.1 and R.sup.2 independently of one another mean H; C.sub.1-C.sub.6-alkyl, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of F, Cl, Br, I, OH, OCH.sub.3, CN and CO.sub.2CH.sub.3; a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of F, Cl, Br, I, OH, OCH.sub.3, CN and CO.sub.2CH.sub.3; wherein said 3-12-membered cycloalkyl moiety is optionally connected through C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted; or a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of F, Cl, Br, I, OH, OCH.sub.3, CN and CO.sub.2CH.sub.3; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted; or R.sup.1 and R.sup.2 together with the nitrogen atom to which they are attached form a ring and mean (CH.sub.2).sub.3-6; (CH.sub.2).sub.2O(CH.sub.2).sub.2; or (CH.sub.2).sub.2NR.sup.A(CH.sub.2).sub.2, wherein R.sup.A means H or C.sub.1-C.sub.6-alkyl, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of F, Cl, Br and I; R.sup.3 means C.sub.1-C.sub.6-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl moiety is optionally connected through C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl moiety is optionally connected through C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl moiety is optionally connected through C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; R.sup.4 means H; C.sub.1-C.sub.6-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said C.sub.1-C.sub.6-alkyl is optionally connected through C(O), C(O)O, or S(O).sub.2; a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl moiety is optionally connected through C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or wherein said 3-12-membered cycloalkyl moiety is optionally connected through C(O), C(O)O, C(O)OCH.sub.2, or S(O).sub.2; a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through C(O), C(O)O, C(O)OCH.sub.2, or S(O).sub.2; a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl moiety is optionally connected through C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or wherein said 6-14-membered aryl moiety is optionally connected through C(O), C(O)O, C(O)OCH.sub.2, or S(O).sub.2; or a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl moiety is optionally connected through C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or wherein said 5-14-membered heteroaryl moiety is optionally connected through C(O), C(O)O, C(O)OCH.sub.2, or S(O).sub.2; R.sup.5 means H; C.sub.1-C.sub.6-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said C.sub.1-C.sub.6-alkyl is optionally connected through C(O), C(O)O, or S(O).sub.2; a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl moiety is optionally connected through C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or wherein said 3-12-membered cycloalkyl moiety is optionally connected through C(O), C(O)O, C(O)OCH.sub.2, or S(O).sub.2; a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through C(O), C(O)O, C(O)OCH.sub.2, or S(O).sub.2; a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl moiety is optionally connected through C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or wherein said 6-14-membered aryl moiety is optionally connected through C(O), C(O)O, C(O)OCH.sub.2, or S(O); or a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl moiety is optionally connected through C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or wherein said 5-14-membered heteroaryl moiety is optionally connected through C(O), C(O)O, C(O)OCH.sub.2, or S(O).sub.2; R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, and R.sup.11 independently of one another mean H, F, Cl, Br, I, OH, or C.sub.1-C.sub.6-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or R.sup.6 and R.sup.7 together mean O; wherein mono- or polysubstituted means that one or more hydrogen atoms are replaced by substituents independently of one another selected from the group consisting of F, Cl, Br, I, CN, R.sup.12, C(O)R.sup.12, C(O)OR.sup.12, C(O)NR.sup.12R.sup.13, O(CH.sub.2CH.sub.2O).sub.1-30H, O(CH.sub.2CH.sub.2O).sub.1-30CH.sub.3, O, OR.sup.12, OC(O)R.sup.12, OC(O)OR.sup.12, OC(O)NR.sup.12R.sup.13, NO.sub.2, NR.sup.12R.sup.13, NR.sup.12(CH.sub.2).sub.1-6C(O)R.sup.13, NR.sup.12(CH.sub.2).sub.1-6C(O)OR.sup.13, NR.sup.14(CH.sub.2).sub.1-6C(O)NR.sup.12R.sup.13, NR.sup.12C(O)R.sup.13, NR.sup.12C(O)OR.sup.11, NR.sup.14C(O)NR.sup.12R.sup.13, NR.sup.12S(O).sub.2R.sup.13, SR.sup.12, S(O)R.sup.12, S(O).sub.2R.sup.12, S(O).sub.2OR.sup.2, and S(O).sub.2NR.sup.12R.sup.13; wherein R.sup.12, R.sup.13 and R.sup.14 independently of one another mean H; C.sub.1-C.sub.6-alkyl, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of F, Cl, Br, I, CN, O, OH, NH.sub.2, NHC.sub.1-C.sub.6-alkyl, N(C.sub.1-C.sub.6-alkyl).sub.2, C.sub.1-C.sub.6-alkyl, OC.sub.1-C.sub.6-alkyl, C(O)OH, C(O)OC.sub.1-C.sub.4-alkyl, C(O)NH.sub.2, C(O)NHC.sub.1-C.sub.6-alkyl, C(O)N(C.sub.1-C.sub.6-alkyl).sub.2, SC.sub.1-C.sub.6-alkyl, S(O)C.sub.1-C.sub.6-alkyl and S(O).sub.2C.sub.1-C.sub.6-alkyl; a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl moiety is optionally connected through C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of F, Cl, Br, I, CN, O, OH, NH.sub.2, NHC.sub.1-C.sub.6-alkyl, N(C.sub.1-C.sub.6-alkyl).sub.2, C.sub.1-C.sub.6-alkyl, OC.sub.1-C.sub.6-alkyl, C(O)OH, C(O)OC.sub.1-C.sub.4-alkyl, C(O)NH.sub.2, C(O)NHC.sub.1-C.sub.6-alkyl, C(O)N(C.sub.1-C.sub.6-alkyl).sub.2, S-C.sub.1-C.sub.6-alkyl, S(O)C.sub.1-C.sub.6-alkyl and S(O).sub.2C.sub.1-C.sub.6-alkyl; a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of F, Cl, Br, I, CN, O, OH, NH.sub.2, NHC.sub.1-C.sub.6-alkyl, N(C.sub.1-C.sub.6-alkyl).sub.2, C.sub.1-C.sub.6-alkyl, OC.sub.1-C.sub.6-alkyl, C(O)OH, C(O)OC.sub.1-C.sub.4-alkyl, C(O)NH.sub.2, C(O)NHC.sub.1-C.sub.6-alkyl, C(O)N(C.sub.1-C.sub.6-alkyl).sub.2, SC.sub.1-C.sub.6-alkyl, S(O)C.sub.1-C.sub.6-alkyl and S(O).sub.2C.sub.1-C.sub.6-alkyl; a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl moiety is optionally connected through C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of F, Cl, Br, I, CN, O, OH, NH.sub.2, NHC.sub.1-C.sub.6-alkyl, N(C.sub.1-C.sub.6-alkyl).sub.2, C.sub.1-C.sub.6-alkyl, OC.sub.1-C.sub.6-alkyl, C(O)OH, C(O)OC.sub.1-C.sub.4-alkyl, C(O)NH.sub.2, C(O)NHC.sub.1-C.sub.6-alkyl, C(O)N(C.sub.1-C.sub.6-alkyl).sub.2, SC.sub.1-C.sub.6-alkyl, S(O)C.sub.1-C.sub.6-alkyl and S(O).sub.2C.sub.1-C.sub.6-alkyl; or a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl moiety is optionally connected through C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of F, Cl, Br, I, CN, O, OH, NH.sub.2, NHC.sub.1-C.sub.6-alkyl, N(C.sub.1-C.sub.6-alkyl).sub.2, C.sub.1-C.sub.6-alkyl, OC.sub.1-C.sub.6-alkyl, C(O)OH, C(O)OC.sub.1-C.sub.4-alkyl, C(O)NH.sub.2, C(O)NHC.sub.1-C.sub.6-alkyl, C(O)N(C.sub.1-C.sub.6-alkyl).sub.2, SC.sub.1-C.sub.6-alkyl, S(O)C.sub.1-C.sub.6-alkyl and S(O).sub.2C.sub.1-C.sub.6-alkyl; or R.sup.12 and R.sup.13 within C(O)NR.sup.12R.sup.13, OC(O)NR.sup.12R.sup.13, NR.sup.12R.sup.13, NR.sup.14(CH.sub.2).sub.1-6C(O)NR.sup.12R.sup.13, NR.sup.14C(O)NR.sup.12R.sup.13, or S(O).sub.2NR.sup.12R.sup.13 together with the nitrogen atom to which they are attached form a ring and mean (CH.sub.2).sub.3-6; (CH.sub.2).sub.2O(CH.sub.2).sub.2; or (CH.sub.2).sub.2NR.sup.B(CH.sub.2).sub.2, wherein R.sup.B means H or C.sub.1-C.sub.6-alkyl, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of F, Cl, Br and I; or a physiologically acceptable salt thereof.

2. The compound according to claim 1, wherein R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, and R.sup.11 independently of one another mean H, F, OH, or C.sub.1-C.sub.6-alkyl; or R.sup.6 and R.sup.7 together mean O.

3. The compound according to claim 1, wherein R.sup.1 means H; and R.sup.2 means C.sub.1-C.sub.6-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; R.sup.1 means CH.sub.3; and R.sup.2 means C.sub.1-C.sub.6-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; R.sup.1 means H or CH.sub.3; and R.sup.2 means a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted; R.sup.1 means H or CH.sub.3; and R.sup.2 means a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted; wherein said 3-12-membered cycloalkyl moiety is connected through CH.sub.2, unsubstituted; or R.sup.1 and R.sup.2 together with the nitrogen atom to which they are attached form a ring and mean (CH.sub.2).sub.3-6.

4. The compound according to claim 1, wherein R.sup.3 means C.sub.1-C.sub.6-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.

5. The compound according to claim 1, wherein R.sup.3 means a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted, optionally connected through C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted.

6. The compound according to claim 1, wherein R.sup.3 means a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted.

7. The compound according to claim 1, wherein R.sup.3 means -phenyl, unsubstituted, mono-, di- or trisubstituted with F, Cl, Br, C.sub.1-C.sub.4-alkyl, CF.sub.3, CHF.sub.2, CH.sub.2F, CN, OH, OC.sub.1-C.sub.4-alkyl, OCF.sub.3 or OCH.sub.2OCH.sub.3; or -pyridinyl or thienyl, in each case unsubstituted, mono-, di- or trisubstituted with F, Cl, Br, C.sub.1-C.sub.4-alkyl, CF.sub.3, CHF.sub.2, CH.sub.2F, CN, OH, OC.sub.1-C.sub.4-alkyl, OCF.sub.3 or OCH.sub.2OCH.sub.3.

8. The compound according to according to claim 1, wherein R.sup.4 means H; C.sub.1-C.sub.6-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein the 3-12-membered cycloalkyl moiety is connected through C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is connected through C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.

9. The compound according to according to claim 1, wherein R.sup.4 means a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl moiety is connected through C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl moiety is connected through C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.

10. The compound according to claim 1, wherein, R.sup.5 means H.

11. The compound according to claim 1, wherein R.sup.5 means C.sub.1-C.sub.6-alkyl, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of F, Cl, Br, I, CN, OH, OC.sub.1-C.sub.4-alkyl, O(CH.sub.2CH.sub.2O).sub.1-30H, O(CH.sub.2CH.sub.2O).sub.1-30CH.sub.3, C(O)OH, C(O)OC.sub.1-C.sub.4-alkyl, C(O)NH.sub.2, C(O)NHC.sub.1-C.sub.4-alkyl, C(O)N(C.sub.1-C.sub.4-alkyl).sub.2, S(O)C.sub.1-C.sub.4-alkyl and S(O).sub.2C.sub.1-C.sub.4-alkyl.

12. The compound according to claim 1, wherein R.sup.5 means C.sub.1-C.sub.6-alkyl, linear or branched, saturated or unsaturated, monosubstituted with a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through CO.

13. The compound according to claim 1, wherein R.sup.5 means a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of F, Cl, Br, I, CN, OH, C.sub.1-C.sub.4-alkyl, OC.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkyl-OH, O(CH.sub.2CH.sub.2O).sub.1-30H, O(CH.sub.2CH.sub.2O).sub.1-30CH.sub.3, C(O)OH, C(O)C.sub.1-C.sub.4-alkyl, C(O)OC.sub.1-C.sub.4-alkyl, C(O)NH.sub.2, C(O)NHC.sub.1-C.sub.4-alkyl, C(O)N(C.sub.1-C.sub.4-alkyl).sub.2, NH.sub.2, NHC.sub.1-C.sub.4-alkyl, N(C.sub.1-C.sub.4-alkyl).sub.2, NHC(O)C.sub.1-C.sub.4-alkyl, N(C.sub.1-C.sub.4-alkyl)C(O)C.sub.1-C.sub.4-alkyl, S(O)C.sub.1-C.sub.4-alkyl and S(O).sub.2C.sub.1-C.sub.4-alkyl; wherein said 3-12-membered cycloalkyl moiety is optionally connected through C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted.

14. The compound according to claim 1, wherein R.sup.5 means a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of F, Cl, Br, I, CN, OH, C.sub.1-C.sub.4-alkyl, OC.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkyl-OH, O(CH.sub.2CH.sub.2O).sub.1-30H, O(CH.sub.2CH.sub.2O).sub.1-30CH.sub.3, C(O)OH, C(O)C.sub.1-C.sub.4-alkyl, C(O)OC.sub.1-C.sub.4-alkyl, C(O)NH.sub.2, C(O)NHC.sub.1-C.sub.4-alkyl, C(O)N(C.sub.1-C.sub.4-alkyl).sub.2, NH.sub.2, NHC.sub.1-C.sub.4-alkyl, N(C.sub.1-C.sub.4-alkyl).sub.2, NHC(O)C.sub.1-C.sub.4-alkyl, N(C.sub.1-C.sub.4-alkyl)C(O)C.sub.1-C.sub.4-alkyl, S(O)C.sub.1-C.sub.4-alkyl and S(O).sub.2C.sub.1-C.sub.4-alkyl; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted.

15. The compound according to claim 1, wherein R.sup.5 means -phenyl, unsubstituted, mono- or polysubstituted; wherein said phenyl is optionally connected through C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or wherein said phenyl is optionally connected through C(O), C(O)O, C(O)OCH.sub.2, or S(O).sub.2.

16. The compound according to claim 1, wherein R.sup.5 means a bicyclic 9-10-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted.

17. The compound according to claim 1, wherein R.sup.5 has a meaning selected from the group consisting of: ##STR00126## ##STR00127## ##STR00128## ##STR00129## ##STR00130##

18. The compound according to claim 1, wherein R.sup.1 means H or C.sub.3; R.sup.2 means C.sub.1-C.sub.6-alkyl, linear or branched, saturated, unsubstituted; -cyclopropyl; or -cyclopropylmethylene; or R.sup.1 and R.sup.2 together with the nitrogen atom to which they are attached form a ring and mean -azetidine or -pyrrolidine; R.sup.3 means -phenyl, -thienyl or -pyridinyl, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of F, Cl, Br, CN, C.sub.1-C.sub.4-alkyl, CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3, OCF.sub.3, OH, OC.sub.1-C.sub.4-alkyl, OCH.sub.3, C(O)NH.sub.2, C(O)NHCH.sub.3, C(O)N(CH.sub.3).sub.2, NH.sub.2, NHCH.sub.3, N(CH.sub.3).sub.2, NHC(O)CH.sub.3, CH.sub.2OH, SOCH.sub.3 and SO.sub.2CH.sub.3; or R.sup.4 means H; C.sub.1-C.sub.6-alkyl, linear or branched, saturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of F, Cl, Br, I, CN, OH, O, S(O).sub.2C.sub.1-C.sub.4-alkyl and OC.sub.1-C.sub.4-alkyl; 3-6-membered cycloalkyl, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of F, Cl, Br, I, CN, OH, and OC.sub.1-C.sub.4-alkyl, wherein said 3-6-membered cycloalkyl is connected through C.sub.1-C.sub.6-alkylene; 3-12-membered heterocycloalkyl, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of F, Cl, Br, I, CN, OH, and OC.sub.1-C.sub.4-alkyl; wherein said 3-12-membered heterocycloalkyl is optionally connected through C.sub.1-C.sub.6-alkylene-, unsubstituted or substituted with O; 6-14-membered aryl, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of F, Cl, Br, I, CN, OH, and OC.sub.1-C.sub.4-alkyl; wherein said 6-14-membered aryl is optionally connected through C.sub.1-C.sub.6-alkylene- or S(O).sub.2; R.sup.5 means H; C.sub.1-C.sub.6-alkyl, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of F, Cl, Br, I, CN, O, OH, OC.sub.1-C.sub.4-alkyl, O(CH.sub.2CH.sub.2O).sub.1-30H, O(CH.sub.2CH.sub.2O).sub.1-30CH.sub.3, C(O)OH, C(O)C.sub.1-C.sub.4-alkyl, C(O)OC.sub.1-C.sub.4-alkyl, C(O)NH.sub.2, C(O)NHC.sub.1-C.sub.4-alkyl, C(O)N(C.sub.1-C.sub.4-alkyl).sub.2, (CO)-heterocycloalkyl, S(O)C.sub.1-C.sub.4-alkyl, S(O).sub.2C.sub.1-C.sub.4-alkyl, NH.sub.2, NHC.sub.1-C.sub.4-alkyl, N(C.sub.1-C.sub.4-alkyl).sub.2, NHC(O)C.sub.1-C.sub.4-alkyl, NHS(O).sub.2C.sub.1-C.sub.4-alkyl; 3-12-membered heterocycloalkyl, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of F, Cl, Br, I, CN, O, OH, C.sub.1-C.sub.4-alkyl, NH.sub.2, NHC.sub.1-C.sub.4-alkyl, N(C.sub.1-C.sub.4-alkyl).sub.2, NHC(O)C.sub.1-C.sub.4-alkyl, NHS(O).sub.2C.sub.1-C.sub.4-alkyl, OC.sub.1-C.sub.4-alkyl, O(CH.sub.2CH.sub.2O).sub.1-30H, O(CH.sub.2CH.sub.2O).sub.1-30CH.sub.3, C(O)OH, C(O)OC.sub.1-C.sub.4-alkyl, C(O)C.sub.1-C.sub.4-alkyl, C(O)NH.sub.2, C(O)NHC.sub.1-C.sub.4-alkyl, C(O)N(C.sub.1-C.sub.4-alkyl).sub.2, S(O)C.sub.1-C.sub.4-alkyl, S(O).sub.2C.sub.1-C.sub.4-alkyl, -phenyl, C(O)-phenyl, C(O)-pyridyl, -pyridyl, -pyrimidinyl, and -pyridazinyl; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted; or wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through CO or CH.sub.2CO; -1,2-benzodioxole, -pyrazinyl, -pyridazinyl, -pyridinyl, -pyrimidinyl, -thienyl, -imidazolyl, -benzimidazolyl, -thiazolyl, -1,3,4-thiadiazolyl, -benzothiazolyl, -oxazolyl, -benzoxazolyl, -pyrazolyl, -quinolinyl, -isoquinolinyl, -quinazolinyl, -indolyl, -indolinyl, -benzo[c][1,2,5]oxadiazolyl, -imidazo[1,2-a]pyrazinyl, or -1H-pyrrolo[2,3-b]pyridinyl, in each case unsubstituted, mono- or polysubstituted; and R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, and R.sup.11 mean H; or R.sup.6 and R.sup.7 together mean O and R.sup.8, R.sup.9, R.sup.10, and R.sup.11 mean H.

19. The compound according to claim 1 claim 1, which is selected from the group consisting of 2-(2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)acetamide 2-(dimethylamino)-7-(2-(1,1-dioxidothiomorpholino)-2-oxoethyl)-2-phenyl-5,7-diazaspiro-[3.4]-octan-6-one 5-(2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)-4-methoxy-pyrimidine-2-carbonitrile 5-(cyclobutylmethyl)-2-(dimethylamino)-7-(2-(1,1-dioxidothiomorpholino)-2-oxoethyl)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one 2-(5-(cyclobutylmethyl)-2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)acetamide 5-(5-(cyclobutylmethyl)-2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)-4-methoxypyrimidine-2-carbonitrile 2-(dimethylamino)-7-(4-methyl-2-morpholin-4-ylpyrimidin-5-yl)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one 7-(6-(azetidin-1-yl)-4-methylpyridin-3-yl)-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one 5-(2-(dimethylamino)-2-(3-fluorophenyl)-6-oxo-5,7-diazaspiro[3.4]octan-7-yl)-4-methylpicolino-nitrile 5-(5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-6-oxo-5,7-diazaspiro[3.4]octan-7-yl)-4-methyl-picolinonitrile 6-(5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-6-oxo-5,7-diazaspiro[3.4]octan-7-yl)-5-methyl-nicotinonitrile 2-(dimethylamino)-2-(3-fluorophenyl)-7-(5-(trifluoromethoxy)pyridin-2-yl)-5,7-diazaspiro[3.4]-octan-6-one 5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-7-(5-(trifluoromethoxy)pyridin-2-yl)-5,7-diazaspiro[3.4]octan-6-one 2-(dimethylamino)-7-(4-methyl-6-morpholinopyridin-3-yl)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one 2-(dimethylamino)-7-(6-(2-hydroxypropan-2-yl)-4-methylpyridin-3-yl)-2-phenyl-5,7-diazaspiro-[3.4]octan-6-one 2-(dimethylamino)-7-(4-(2-hydroxypropan-2-yl)-2-methylphenyl)-2-phenyl-5,7-diazaspiro[3.4]-octan-6-one 7-(6-(difluoromethyl)-4-methylpyridin-3-yl)-2-(dimethylamino)-2-(3-fluorophenyl)-5,7-diazaspiro-[3.4]octan-6-one 2-(dimethylamino)-5-((3-fluorooxetan-3-yl)methyl)-2-(3-fluorophenyl)-7-(5-(trifluoromethoxy)-pyridin-2-yl)-5,7-diazaspiro[3.4]octan-6-one 5-(cyclopropylmethyl)-7-(6-(difluoromethyl)-4-methylpyridin-3-yl)-2-(dimethylamino)-2-(3-fluoro-phenyl)-5,7-diazaspiro[3.4]octan-6-one 2-(dimethylamino)-7-(2-morpholinopyrimidin-5-yl)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one 2-(dimethylamino)-5-((1-fluorocyclopropyl)methyl)-2-(3-fluorophenyl)-7-(5-(trifluoromethoxy)-pyridin-2-yl)-5,7-diazaspiro[3.4]octan-6-one 2-(dimethylamino)-2-(3-fluorophenyl)-5-((1-hydroxycyclobutyl)methyl)-7-(5-(trifluoromethoxy)-pyridin-2-yl)-5,7-diazaspiro[3.4]octan-6-one 5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-7-(4-(2-hydroxypropan-2-yl)phenyl)-5,7-diazaspiro[3.4]octan-6-one 2-(dimethylamino)-5-((3-fluorooxetan-3-yl)methyl)-2-phenyl-7-(5-(trifluoromethoxy)pyridin-2-yl)-5,7-diazaspiro[3.4]octan-6-one 5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-7-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,7-diazaspiro[3.4]octan-6-one 5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-7-(2-(methylsulfonyl)ethyl)-5,7-diazaspiro[3.4]octan-6-one 5-(cyclopropylmethyl)-2-(dimethylamino)-2-phenyl-7-(5-(trifluoromethoxy)pyridin-2-yl)-5,7-diazaspiro[3.4]octan-6-one 5-(cyclopropylmethyl)-2-(dimethylamino)-7-((3-fluorooxetan-3-yl)methyl)-2-(3-fluorophenyl)-5,7-diazaspiro[3.4]octan-6-one 5-(cyclopropylmethyl)-7-(6-cyclopropylpyridin-3-yl)-2-(dimethylamino)-2-phenyl-5,7-diazaspiro-[3.4]octan-6-one 7-(6-cyclopropyl-4-methylpyridin-3-yl)-5-(cyclopropylmethyl)-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one 7-(6-cyclopropyl-4-methylpyridin-3-yl)-2-(dimethylamino)-5-((3-fluorooxetan-3-yl)methyl)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one 5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-7-(2-methoxy-2-methylpropyl)-5,7-diazaspiro[3.4]octan-6-one 2-(dimethylamino)-2-phenyl-7-(2-pyridin-4-ylpyrimidin-5-yl)-5,7-diazaspiro[3.4]octan-6-one 5-(cyclopropylmethyl)-2-(dimethylamino)-2-phenyl-7-[5-(trifluoromethyl)pyridin-3-yl]-5,7-diazaspiro[3.4]octan-6-one 5-[5-(cyclopropylmethyl)-2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl]-3-(trifluoromethyl)pyridine-2-carbonitrile 2-(dimethylamino)-2-(3-fluorophenyl)-7-(4-morpholinobenzyl)-5,7-diazaspiro[3.4]octan-6-one 5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-7-[(1-hydroxycyclobutyl)methyl]-5,7-diazaspiro[3.4]octan-6-one 5-(cyclopropylmethyl)-2-(dimethylamino)-2-phenyl-7-(2-pyridin-4-ylpyrimidin-5-yl)-5,7-diaza-spiro[3.4]octan-6-one 3-(5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-6-oxo-5,7-diazaspiro[3.4]octan-7-yl)propanenitrile 3-[5-(cyclopropylmethyl)-2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl]-propanenitrile 5-(cyclopropylmethyl)-2-(dimethylamino)-7-[(1-hydroxycyclobutyl)methyl]-2-phenyl-5,7-diaza-spiro[3.4]octan-6-one 5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-7-[2-(oxetan-3-yl)ethyl]-5,7-diaza-spiro[3.4]octan-6-one cis-2-(2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)acetamide cis-2-(dimethylamino)-7-(2-(1,1-dioxidothiomorpholino)-2-oxoethyl)-2-phenyl-5,7-diazaspiro-[3.4]octan-6-one cis-5-(2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)-4-methoxy-pyrimidine-2-carbonitrile trans-2-(dimethylamino)-7-(2-(1,1-dioxidothiomorpholino)-2-oxoethyl)-2-phenyl-5,7-diazaspiro-[3.4]octan-6-one trans-5-(2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)-4-methoxy-pyrimidine-2-carbonitrile cis-5-(cyclobutylmethyl)-2-(dimethylamino)-7-(2-(1,1-dioxidothiomorpholino)-2-oxo-ethyl)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one trans-5-(cyclobutylmethyl)-2-(dimethylamino)-7-(2-(1,1-dioxidothiomorpholino)-2-oxoethyl)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one cis-2-(5-(cyclobutylmethyl)-2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl-)acetamide trans-2-(5-(cyclobutylmethyl)-2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]-octan-7-yl)-acetamide cis-5-(5-(cyclobutylmethyl)-2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)-4-methoxypyrimidine-2-carbonitrile trans-5-(5-(cyclobutylmethyl)-2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]-octan-7-yl)-4-methoxypyrimidine-2-carbonitrile cis-2-(dimethylamino)-7-(4-methyl-2-morpholin-4-ylpyrimidin-5-yl)-2-phenyl-5,7-diazaspiro-[3.4]octan-6-one cis-7-(6-(azetidin-1-yl)-4-methylpyridin-3-yl)-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one cis-5-(2-(dimethylamino)-2-(3-fluorophenyl)-6-oxo-5,7-diazaspiro[3.4]octan-7-yl)-4-methyl-picolinonitrile cis-5-(5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-6-oxo-5,7-diazaspiro[3.4]octan-7-yl)-4-methylpicolinonitrile cis-6-(5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-6-oxo-5,7-diazaspiro[3.4]octan-7-yl)-5-methylnicotinonitrile cis-2-(dimethylamino)-2-(3-fluorophenyl)-7-(5-(trifluoromethoxy)pyridin-2-yl)-5,7-diazaspiro[3.4]-octan-6-one cis-5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-7-(5-(trifluoromethoxy)pyridin-2-yl)-5,7-diazaspiro[3.4]octan-6-one cis-2-(dimethylamino)-7-(4-methyl-6-morpholinopyridin-3-yl)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one cis-2-(dimethylamino)-7-(6-(2-hydroxypropan-2-yl)-4-methylpyridin-3-yl)-2-phenyl-5,7-diazaspiro-[3.4]octan-6-one cis-2-(dimethylamino)-7-(4-(2-hydroxypropan-2-yl)-2-methylphenyl)-2-phenyl-5,7-diazaspiro-[3.4]octan-6-one cis-7-(6-(difluoromethyl)-4-methylpyridin-3-yl)-2-(dimethylamino)-2-(3-fluorophenyl)-5,7-diaza-spiro[3.4]octan-6-one cis-2-(dimethylamino)-5-((3-fluorooxetan-3-yl)methyl)-2-(3-fluorophenyl)-7-(5-(trifluoromethoxy)-pyridin-2-yl)-5,7-diazaspiro[3.4]octan-6-one cis-5-(cyclopropylmethyl)-7-(6-(difluoromethyl)-4-methylpyridin-3-yl)-2-(dimethylamino)-2-(3-fluorophenyl)-5,7-diazaspiro[3.4]octan-6-one cis-2-(dimethylamino)-7-(2-morpholinopyrimidin-5-yl)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one cis-2-(dimethylamino)-5-((1-fluorocyclopropyl)methyl)-2-(3-fluorophenyl)-7-(5-(trifluoromethoxy)-pyridin-2-yl)-5,7-diazaspiro[3.4]octan-6-one cis-2-(dimethylamino)-2-(3-fluorophenyl)-5-((1-hydroxycyclobutyl)methyl)-7-(5-(trifluoromethoxy)-pyridin-2-yl)-5,7-diazaspiro[3.4]octan-6-one cis-5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-7-(4-(2-hydroxypropan-2-yl)-phenyl)-5,7-diazaspiro[3.4]octan-6-one cis-2-(dimethylamino)-5-((3-fluorooxetan-3-yl)methyl)-2-phenyl-7-(5-(trifluoromethoxy)pyridin-2-yl)-5,7-diazaspiro[3.4]octan-6-one cis-5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-7-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,7-diazaspiro[3.4]octan-6-one cis-5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-7-(2-(methylsulfonyl)ethyl)-5,7-diazaspiro[3.4]octan-6-one cis-5-(cyclopropylmethyl)-2-(dimethylamino)-2-phenyl-7-(5-(trifluoromethoxy)pyridin-2-yl)-5,7-diazaspiro[3.4]octan-6-one cis-5-(cyclopropylmethyl)-2-(dimethylamino)-7-((3-fluorooxetan-3-yl)methyl)-2-(3-fluorophenyl)-5,7-diazaspiro[3.4]octan-6-one cis-5-(cyclopropylmethyl)-7-(6-cyclopropylpyridin-3-yl)-2-(dimethylamino)-2-phenyl-5,7-diaza-spiro[3.4]octan-6-one cis-7-(6-cyclopropyl-4-methylpyridin-3-yl)-5-(cyclopropylmethyl)-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one cis-7-(6-cyclopropyl-4-methylpyridin-3-yl)-2-(dimethylamino)-5-((3-fluorooxetan-3-yl)methyl)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one cis-5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-7-(2-methoxy-2-methylpropyl)-5,7-diazaspiro[3.4]octan-6-one cis-2-(dimethylamino)-2-phenyl-7-(2-pyridin-4-ylpyrimidin-5-yl)-5,7-diazaspiro[3.4]octan-6-one cis-5-(cyclopropylmethyl)-2-(dimethylamino)-2-phenyl-7-[5-(trifluoromethyl)pyridin-3-yl]-5,7-diazaspiro[3.4]octan-6-one cis-5-[5-(cyclopropylmethyl)-2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl]-3-(trifluoromethyl)pyridine-2-carbonitrile cis-2-(dimethylamino)-2-(3-fluorophenyl)-7-(4-morpholinobenzyl)-5,7-diazaspiro[3.4]octan-6-one cis-5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-7-[(1-hydroxycyclobutyl)methyl]-5,7-diazaspiro[3.4]octan-6-one cis-5-(cyclopropylmethyl)-2-(dimethylamino)-2-phenyl-7-(2-pyridin-4-ylpyrimidin-5-yl)-5,7-diazaspiro[3.4]octan-6-one cis-3-(5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-6-oxo-5,7-diazaspiro[3.4]octan-7-yl)propanenitrile cis-3-[5-(cyclopropylmethyl)-2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl]-propanenitrile cis-5-(cyclopropylmethyl)-2-(dimethylamino)-7-[(1-hydroxycyclobutyl)methyl]-2-phenyl-5,7-diaza-spiro[3.4]octan-6-one cis-5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-7-[2-(oxetan-3-yl)ethyl]-5,7-diaza-spiro[3.4]octan-6-one and the physiologically acceptable salts thereof.

20. A medicament comprising a compound according to claim 1.

21. A method of treating pain in a subject in need thereof, said method comprising administering to said subject an effective amount therefor of at least one compound according to claim 1.

Description

EXAMPLES

[0333] The following examples further illustrate the invention but are not to be construed as limiting its scope.

[0334] RT means room temperature (237 C.), M are indications of concentration in mol/l, aq. means aqueous, sat. means saturated, sol. means solution, conc. means concentrated.

Further Abbreviations

[0335] brine saturated aqueous sodium chloride solution [0336] Boc.sub.2O di-tert-butyl dicarbonate [0337] Bu butyl [0338] DCM dichloromethane [0339] DIPEA N,N-diisopropylethylamine [0340] DMSO dimethylsulfoxide [0341] DMF N,N-dimethylformamide [0342] Pd.sub.2(dba).sub.3 tris(dibenzylideneacetone)dipalladium(0) [0343] Et ethyl [0344] ether diethyl ether [0345] EtOAc ethyl acetate [0346] EtOH ethanol [0347] h hour(s) [0348] HATU O-(7-aza-benzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate [0349] LDA lithium diisoproylamide [0350] Me methyl [0351] m/z mass-to-chargeratio [0352] MeOH methanol [0353] MeCN acetonitrile [0354] min minutes [0355] MS mass spectrometry [0356] NBS N-bromosuccinimide [0357] NIS N-iodosuccinimide [0358] NEt.sub.3 triethylamine [0359] TFA trifluoroacetic acid [0360] T3P 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide [0361] THF tetrahydrofurane [0362] v/v volume to volume [0363] w/w weight to weight [0364] Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[0365] The yields of the compounds prepared were not optimised. All temperatures are uncorrected.

[0366] All starting materials, which are not explicitly described, were either commercially available (the details of suppliers such as for example Acros, Aldrich, Bachem, Butt park, Enamine, Fluka, Lancaster, Maybridge, Merck, Sigma, TCI, Oakwood, etc. can be found in the Symyx Available Chemicals Database of MDL, San Ramon, US or the SciFinder Database of the ACS, Washington D.C., US, respectively, for example) or the synthesis thereof has already been described precisely in the specialist literature (experimental guidelines can be found in the Reaxys Database of Elsevier, Amsterdam, NL or the SciFinder Database of the ACS, Washington D.C., US, respectively, for example) or can be prepared using the conventional methods known to the person skilled in the art.

[0367] The mixing ratios of solvents or eluents for chromatography are specified in v/v.

[0368] All the intermediate products and exemplary compounds were analytically characterised by mass spectrometry (MS, m/z for [M+H].sup.+). In addition .sup.1H-NMR and .sup.13C spectroscopy was carried out for all the exemplary compounds and selected intermediate products.

Synthetic Procedures for the Preparation of Intermediates

General Scheme for the Synthesis of INT-7 and INT-8

[0369] ##STR00013## ##STR00014##

3-(Benzyloxy)-1-(dimethylamino)cyclobutanecarbonitrile (INT-1)

[0370] ##STR00015##

[0371] This reaction was carried out under N.sub.2 in a 5 L 3-neck round bottom flask. To 3-(benzyloxy)cyclobutan-1-one (88 g, 499 mmol) was added MeOH (88 mL), followed by Me.sub.2NH.HCl (116 g, 1423 mmol). After stirring at RT for 10 min, 40% aqueous Me.sub.2NH (626 mL, 4939 mmol) was added followed by NaCN (26.9 g, 549 mmol). The reaction mixture was stirred at RT overnight. The reaction mixture was diluted with sat aq NaHCO.sub.3 (400 mL) and water (400 mL) and extracted with EtOAc (4800 mL). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered, and the filtrate was concentrated under reduced pressure. The residue was co-evaporated twice with THF affording 3-(benzyloxy)-1-(dimethylamino)cyclobutanecarbonitrile (INT-1) (122.9 g (80% pure), 427 mmol, 85%) as a brown oil which was used in the next step without further purification. LCMS: calculated for [M+H].sup.+=231.2, found 231.1.

3-(Benzyloxy)-N,N-dimethyl-1-phenylcyclobutanamine (INT-2

[0372] ##STR00016##

[0373] This reaction was carried out under N.sub.2. The reaction flask was dried (heat-gun) before use. 3 M PhMgBr in Et.sub.2O (1.423 L, 4269 mmol) was cooled to 10 C. A solution of 3-(benzyloxy)-1-(dimethylamino)cyclobutanecarbonitrile (INT-1) (122.9 g (80% pure), 427 mmol) in dry THF (1.0 L) was added dropwise over ca. 70 min at 10 C. and stirring at 10 C. to 0 C. was continued for 3 h after complete addition of the starting material. Upon cooling on ice bath, the reaction mixture was carefully quenched by the dropwise addition of a solution of 660 g of NH.sub.4Cl (12.3 mol) in H.sub.2O (2.6 L). After complete addition, EtOAc (1.7 L) was added, the mixture was stirred for 30 min and the layers were separated. EtOAc (1.7 L) was added to the aqueous phase and the mixture was stirred for 30 min and left standing overnight. Layers were separated. EtOAc (1.7 L) was added to the aqueous phase, the mixture was stirred for 30 min and the layers were separated. EtOAc (1.7 L) was added to the aqueous phase and the mixture was stirred for 30 min and the layers were separated. All organic layers were combined and evaporated under reduced pressure. The product was purified by column chromatography (1.2 kg silica, heptane/EtOAc, 9:1.fwdarw.1:1.fwdarw.1:2 .fwdarw.0:1), to give 58.15 g (207 mmol, 48.4%) of 3-(benzyloxy)-N,N-dimethyl-1-phenylcyclobutanamine (INT-2). LCMS: calculated for [M+H].sup.+=282.2, found 282.2.

3-(Dimethylamino)-3-phenylcyclobutanol (INT-3)

[0374] ##STR00017##

[0375] This reaction was carried out under N.sub.2. At 0 C., 1 M BCl.sub.3 in DCM (349 mL, 349 mmol) was added dropwise over ca. 45 min to a solution of 3-(benzyloxy)-N,N-dimethyl-1-phenylcyclobutanamine (INT-2) (65.39 g, 232 mmol) in DCM (650 mL). Stirring at 0 C. was continued for 30 min. More 1 M BCl.sub.3 in DCM (349 mL, 349 mmol) was added dropwise over 45 min and stirring was continued at 0 C. for 1 h. MeOH (ca. 200 mL) was added dropwise at 0 C. and the solvent was removed under reduced pressure at 30 C. The crude product was concentrated again from MeOH (3). The crude product was dissolved in DCM (200 mL) and MeOH (200 mL). Silica (200 g) was added and the solvent was removed under reduced pressure. The product was purified by column chromatography (silica, DCM/(7M NH.sub.3 in MeOH), 1:0.fwdarw.98:2.fwdarw.95:5.fwdarw.93:7.fwdarw.9:1), to obtain 3-(dimethylamino)-3-phenylcyclobutanol (INT-3) (37.53 g, 196 mmol, 84%). LCMS: calculated for [M+H].sup.+=192.1, found 192.2.

3-(Methylamino)-3-phenylcyclobutanol (INT-4)

[0376] ##STR00018##

[0377] To 3-(dimethylamino)-3-phenylcyclobutanol (INT-3) (44.44 g, 232 mmol) was added dry MeCN (2.25 L) and the resulting suspension was stirred at RT overnight to dissolve most of the starting material. N-iodosuccinimide (57.5 g, 256 mmol) was added portionwise over ca. 10 min and the reaction mixture was stirred at RT for 2 h. More N-iodosuccinimide (15.68 g, 69.7 mmol) was added portionwise over ca. 5 min and stirring at RT was continued for 2.5 h. The solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica, DCM/(7M NH.sub.3 in MeOH), 1:0.fwdarw.98:2.fwdarw.95:5.fwdarw.9:1) to give a reasonably pure batch of 3-(methylamino)-3-phenylcyclobutanol (INT-4) (8.19 g (73% pure), 33.7 mmol, 14.5%) and a very impure batch of INT-4 (78 g (ca. 9% pure)). The very impure batch was purified further by column chromatography (silica, DCM/MeOH/Et.sub.3N, 90:9:1) to give another batch of INT-4 (27.7 g (23% pure), 35.9 mmol, 15.5%). Total yield: 30%. LCMS: calculated for [M+H].sup.+=178.1, found 178.2.

Tert-Butyl (3-hydroxy-1-phenylcyclobutyl)(methyl)carbamate (INT-5)

[0378] ##STR00019##

[0379] To a solution of 3-(methylamino)-3-phenylcyclobutanol (INT-4) (8.15 g (73% pure), 33.6 mmol) and Et.sub.3N (23.39 mL, 168 mmol) in DCM (50 mL) was added Boc.sub.2O (8.06 g, 36.9 mmol) and the reaction mixture was stirred at RT overnight. More Boc.sub.2O (8.06 g, 36.9 mmol) was added and stirring at RT was continued for 6 h. The solvent was removed under reduced pressure. The product was purified by column chromatography (1 kg silica, DCM/MeOH, 1:0.fwdarw.98:2), to afford a pure batch of tert-butyl (3-hydroxy-1-phenylcyclobutyl)(methyl)carbamate (INT-5) (5.89 g, 21.2 mmol, 63.3%) and an impure batch of INT-5 (2.36 g (71% pure), 6.04 mmol, 18.0%). Total yield: 81%. LCMS: calculated for [M+H.sup.tBu].sup.+=222.1, found 222.1.

Tert-Butyl methyl(3-oxo-1-phenylcyclobutyl)carbamate (INT-6)

[0380] ##STR00020##

[0381] To a solution of tert-butyl (3-hydroxy-1-phenylcyclobutyl)(methyl)carbamate (INT-5) (5.89 g, 21.24 mmol) in DCM (90 mL) was added Et.sub.3N (17.76 mL, 127 mmol) and DMSO (12.06 mL, 170 mmol) followed by pyridine SO.sub.3 (10.14 g, 63.7 mmol). The reaction mixture was stirred at RT overnight. Sat. aq. NH.sub.4Cl (50 mL) and water (50 mL) was added. Layers were separated and the aqueous layer was extracted with DCM (60 mL). Organic layers were combined, washed with sat. aq. NaHCO.sub.3 (100 mL), dried over Na.sub.2SO.sub.4 and evaporated under reduced pressure. The crude product was purified by flash chromatography (120 g silica, gradient heptane/EtOAc, 95:5.fwdarw.3:2). The resulting product was concentrated from EtOH to afford tert-butyl methyl(3-oxo-1-phenylcyclobutyl)carbamate (INT-6) (4.50 g, 16.34 mmol, 77%). LCMS: calculated for [M+H.sup.tBu].sup.+=220.1, found 220.1.

Tert-Butyl cis-(6,8-dioxo-2-phenyl-5,7-diazaspiro[3.4]octan-2-yl)(methyl)carbamate (INT-7) and Tert-Butyl trans-(6,8-dioxo-2-phenyl-5,7-diazaspiro[3.4]octan-2-yl)(methyl)-carbamate (INT-8)

[0382] ##STR00021##

[0383] This reaction was carried out in a closed system (500 mL glass Parr system). To a mixture of (NH.sub.4).sub.2CO.sub.3 (13.09 g, 136 mmol) and KCN (1.774 g, 27.2 mmol) was added a solution of tert-butyl methyl(3-oxo-1-phenylcyclobutyl)carbamate (INT-6) (7.5 g, 27.2 mmol) in EtOH (60 mL). H.sub.2O (60 mL) was added and the reaction mixture was stirred at 70 C. overnight. The white suspension was allowed to cool to RT. Crushed ice (60 mL) was added and the obtained mixture was filtered over a sintered glass filter (P3). The flask was rinsed with a mixture of EtOH/H.sub.2O (50 mL, 1/1, v/v), which was also filtered. To the combined filtrate was added aq. sat. NaHCO.sub.3 (300 mL) and the mixture was extracted with DCM (3300 mL). The combined organic layers were dried (Na.sub.2SO.sub.4) and concentrated. Purification by flash chromatography (220 g silica, gradient heptane/EtOAc, 3:2.fwdarw.0:1) followed by co-evaporation with Et.sub.2O (230 mL) afforded tert-butyl trans-(6,8-dioxo-2-phenyl-5,7-diazaspiro[3.4]octan-2-yl)(methyl)carbamate (INT-8) (5.53 g, 16.01 mmol, 59%). LCMS: calculated for [MH].sup.=344.2, found 344.2. The residue on the glass filter was washed with a mixture of EtOH/H.sub.2O (120 mL, 1/1, v/v) and was dried on the filter by vacuum under a N.sub.2 stream to yield tert-butyl cis-(6,8-dioxo-2-phenyl-5,7-diazaspiro[3.4]octan-2-yl)(methyl)carbamate (INT-7) (3.05 g, 8.83 mmol, 32%). LCMS: calculated for [MH].sup.=344.2, found 344.2.

General Scheme for the Synthesis of INT-13

[0384] ##STR00022## ##STR00023##

Tert-Butyl cis-(7-(4-methoxybenzyl)-6,8-dioxo-2-phenyl-5,7-diazaspiro[3.4]-octan-2-yl)(methyl)carbamate (INT-9)

[0385] ##STR00024##

[0386] Dry glassware and argon atmosphere were used. To a suspension of tert-butyl cis-(6,8-dioxo-2-phenyl-5,7-diazaspiro[3.4]octan-2-yl)(methyl)carbamate (INT-7) (0.3 g, 0.869 mmol) and 4-methoxybenzyl chloride (0.124 mL, 0.912 mmol) in anhydrous DMF (15 mL) was added K.sub.2CO.sub.3 (0.126 g, 0.912 mmol) and the mixture was stirred at RT overnight. Additional K.sub.2CO.sub.3 (0.012 g, 0.087 mmol) and 4-methoxybenzyl chloride (0.012 mL, 0.087 mmol) were added and the mixture was stirred at RT for another 4 h. The reaction mixture was partitioned between brine (200 mL) and EtOAc (100 mL). The water layer was extracted with EtOAc (3100 mL). Combined organic layers were washed with brine (3100 mL) and dried over Na.sub.2SO.sub.4(s). In vacuo concentration gave a colourless oil as crude product. This experiment was repeated in the same way using 1.62 g (4.68 mmol) of tert-butyl cis-(6,8-dioxo-2-phenyl-5,7-diazaspiro[3.4]octan-2-yl)(methyl)carbamate (INT-7). The obtained crude products were combined for purification by flash chromatography (120 g silica, gradient heptane/EtOAc, 20:1.fwdarw.3:7) and afforded tert-butyl cis-(7-(4-methoxybenzyl)-6,8-dioxo-2-phenyl-5,7-diazaspiro[3.4]-octan-2-yl)(methyl)carbamate (INT-9) (2.09 g, 4.489 mmol, 81%). LCMS: calculated for [M+H].sup.+=466.5, found 466.3.

Tert-Butyl cis-(5-(cyclobutylmethyl)-7-(4-methoxybenzyl)-6,8-dioxo-2-phenyl-5,7-diazaspiro[3.4]octan-2-yl)(methyl)carbamate (INT-10)

[0387] ##STR00025##

[0388] Dry glassware and argon atmosphere were used. To a solution of tert-butyl cis-(7-(4-methoxybenzyl)-6,8-dioxo-2-phenyl-5,7-diazaspiro[3.4]-octan-2-yl)(methyl)carbamate (INT-9) (200 mg, 0.430 mmol) in anhydrous DMF (8 mL) was added 60% NaH in mineral oil (34.4 mg, 0.859 mmol) and the mixture was stirred at RT until gas evolution ceased. Then, (bromomethyl)cyclobutane (0.191 mL, 1.718 mmol) was added and stirring was continued at RT for 4 h. The reaction mixture was cooled in an ice-bath and carefully quenched with water (2 mL) and diluted with brine (100 mL) and EtOAc (20 mL). Layers were partitioned and the water layer was extracted with EtOAc (320 mL). Combined organic layers were washed with brine and dried over Na.sub.2SO.sub.4(s). Filtration followed by in vacuo filtrate concentration gave a colorless oil as crude product. This experiment was repeated in the same way using 1.81 g (3.89 mmol) of tert-butyl cis-(7-(4-methoxybenzyl)-6,8-dioxo-2-phenyl-5,7-diazaspiro[3.4]-octan-2-yl)(methyl)carbamate (INT-9). However, quenching was performed with MeOH (1 mL) instead of water. The obtained crude products were combined for purification by flash chromatography (120 g silica, gradient heptane/EtOAc, 9:1.fwdarw.1:1), which afforded tert-butyl cis-(5-(cyclobutylmethyl)-7-(4-methoxybenzyl)-6,8-dioxo-2-phenyl-5,7-diazaspiro[3.4]octan-2-yl)(methyl)carbamate (INT-10) (1.92 g, 3.587 mmol, 83%) as a white foamy solid. LCMS: calculated for [M+H].sup.+=534.7, found 534.4.

Cis-5-(cyclobutylmethyl)-2-(methylamino)-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione (INT-11)

[0389] ##STR00026##

[0390] Dry glassware and an inert atmosphere (Ar(g)) were used. To a solution of tert-butyl cis-(5-(cyclobutylmethyl)-7-(4-methoxybenzyl)-6,8-dioxo-2-phenyl-5,7-diazaspiro[3.4]octan-2-yl)(methyl)carbamate (INT-10 (2.022 g, 3.79 mmol) in extra dry anisole (60 mL) was added AlCl.sub.3 (2.53 g, 18.94 mmol) and the resulting colourless solution was stirred at 75 C. for 1.5 h. Then after cooling down to RT, additional AlCl.sub.3 (2.53 g, 18.94 mmol) was added and stirring at 75 C. was continued overnight. The reaction mixture was cooled down to RT and quenched by adding the reaction mixture to sat. aq. Na.sub.2CO.sub.3 (400 mL). Brine (150 mL) and EtOAc (400 mL) were added and the layers were separated. The aqueous phase was extracted with EtOAc (3100 mL). The combined organic layers were washed with brine (200 mL) and dried over Na.sub.2SO.sub.4(s). Filtration followed by in vacuo filtrate concentration gave a brown oil as crude product. The obtained crude product was loaded onto silica and purified by flash chromatography (120 g silica, gradient heptane/EtOAc, 3:1.fwdarw.3:7) which afforded cis-5-(cyclobutylmethyl)-2-(methylamino)-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione (INT-11) (998 mg, 3.185 mmol, 84%) as a yellowish solid. LCMS: calculated for [M+H].sup.+=314.4, found 314.2. .sup.1H-NMR (400 MHz, CDCl.sub.3) 7.62 (bs, 1H), 7.36 (t, J=7.5 Hz, 2H), 7.30-7.19 (m, 3H), 3.80 (d, J=7.4 Hz, 2H), 3.07 (d, J=14.2 Hz, 2H), 2.85 (m, 1H), 2.56 (d, J=14.2 Hz, 2H), 2.07 (m, 5H), 1.89 (m, 4H).

Cis-5-(cyclobutylmethyl)-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]-octane-6,8-dione (INT-12) 1

[0391] ##STR00027##

[0392] To a solution of cis-5-(cyclobutylmethyl)-2-(methylamino)-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione (INT-11) (200 mg, 0.638 mmol) in 2-propanol (10 mL) was added slowly formic acid (0.240 mL, 6.38 mmol) and the mixture was stirred at 65 C. At the same temperature, 37% aqueous formaldehyde (0.480 mL, 6.38 mmol) was added at once and stirring was continued at the same temperature overnight. The reaction mixture was cooled down to RT and the reaction was carefully quenched with sat. aq. NaHCO.sub.3. The mixture was then diluted with brine and DCM. Layers were separated using a phase separator and the aqueous phase was extracted with DCM (215 mL). The combined organic layers were concentrated under reduced pressure to afford the crude product as a brownish sticky oil. The crude product was subjected to a purification by flash column chromatography (12 g silica, gradient DCM/MeOH, 199:1.fwdarw.97:3) affording a more pure product. Subsequently, this material was subjected to a second purification by preparative HPLC (HPLC instrument type: Agilent Technologies 1200 preparative LC; column: Waters XSelect CSH (C18, 15025 mm, 10p); flow: 43 mL/min; column temp: RT; eluent A: 99% acetonitrile+1% 10 mM ammonium bicarbonate in water pH=9.0, eluent B: 10 mM ammonium bicarbonate in water pH=9.0; lin. gradient: t=0 min 20% A, t=2.5 min 20% A, t=11 min 60% A, t=13 min 100% A, t=17 min 100% A; detection: DAD (210 nm)) to obtain cis-5-(cyclobutylmethyl)-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]-octane-6,8-dione (INT-12) as a white solid (98 mg, 0.30 mmol, 47%). LCMS: calculated for [M+H].sup.+=328.4, found 328.2. .sup.1H-NMR (400 MHz, CDCl.sub.3) 7.35 (m, 3H), 7.28 (m, 1H), 7.05-7.03 (m, 2H), 3.71 (d, J=7.4 Hz, 2H), 3.02 (d, J=14.0 Hz, 2H), 2.86-2.78 (m, 1H), 2.71 (d, J=14.0 Hz, 2H), 2.12-2.06 (m, 2H), 1.94 (s, 6H), 1.94-1.77 (m, 4H).

Cis-5-(cyclobutylmethyl)-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]-octan-6-one (INT-13)

[0393] ##STR00028##

[0394] Oven dried glassware and an inert atmosphere were used. To an ice-bath cooled solution of AlCl.sub.3 (586 mg, 4.40 mmol) in dry THF (8 mL) was carefully and dropwise added 2.4 M LiAlH.sub.4 in THF (1.374 mL, 3.30 mmol) and the reaction mixture was stirred at RT for 30 min. Then, the mixture was re-cooled in an ice-bath and a solution of cis-5-(cyclobutylmethyl)-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]-octane-6,8-dione (INT-12) (360 mg, 1.099 mmol) in dry THF (14 mL) was added dropwise. The mixture was stirred at the same temperature for 1 h and at RT for 3 h. The reaction mixture was cooled in an ice bath and the reaction was carefully quenched by the dropwise addition of water (20 mL). Aqueous 1 M NaOH (30 mL) and DCM (25 mL) were added and the layers were separated using a phase separator. The water layer was extracted with DCM (410 mL). In vacuo concentration of the combined organic layers gave the crude product as a white solid. The obtained crude product was purified by flash chromatography (40 g silica, gradient DCM/MeOH, 199:1.fwdarw.93:7) and afforded cis-5-(cyclobutylmethyl)-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]-octan-6-one (INT-13) (311 mg, 0.992 mmol, 90%). LCMS: calculated for [M+H].sup.+=314.4, found 314.3. .sup.1H NMR (400 MHz, CDCl.sub.3) : 7.37 (m, 2H), 7.33-7.27 (m, 1H), 7.25-7.18 (m, 2H), 4.12 (s, 1H), 3.29 (d, J=7.3 Hz, 2H), 2.85 (d, J=1.2 Hz, 2H), 2.72-2.59 (m, 3H), 2.58-2.49 (m, 2H), 2.03 (m, 2H), 1.94 (s, 6H), 1.90-1.76 (m, 4H).

Cis-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one (INT-14)

[0395] ##STR00029##

[0396] To a cooled (0 C.) suspension of tert-butyl cis-(6,8-dioxo-2-phenyl-5,7-diazaspiro[3.4]octan-2-yl)(methyl)carbamate (INT-7) (250 mg, 0.724 mmol) in dry THF (2.5 mL) was dropwise added 2.4 M LiAlH.sub.4 in THF (1.206 mL, 2.90 mmol). The mixture was stirred under reflux for 2 d. After cooling to RT, the mixture was diluted with THF (5 mL) and carefully quenched with Na.sub.2SO.sub.4 10H.sub.2O. The mixture was diluted further with THF (15 mL) and stirred at RT for ca. 1 h. The mixture was filtered over a layer of Na.sub.2SO.sub.4 and rinsed with THF (10 mL) and DCM (25 mL). The combined filtrate was concentrated to dryness. The residue of the filtration was then stirred in MeOH/THF (1:1, v/v, 40 mL), filtered and the filtrate was combined with the first batch of crude product and concentrated to dryness. The product was triturated with hot DMSO. After filtration, the residue was washed with a small amount of Et.sub.2O and dried under reduced pressure with a flow of N.sub.2 to give cis-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one (INT-14) (94.2 mg, 0.384 mmol, 53%). LCMS: calculated for [2M+Na].sup.+=513, found 513.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.38 (m, 2H), 7.28 (m, 3H), 6.70 (s, 1H), 5.98 (s, 1H), 2.77-2.65 (m, 4H), 2.33 (d, J=11.4 Hz, 2H), 1.81 (s, 6H).

Tert-Butyl cis-2-(2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)acetate (INT-15)

[0397] ##STR00030##

[0398] To a suspension of cis-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one (INT-14) (260 mg, 1.06 mmol) in dry DMF (26 mL), a solution of 1.65 M solution of KOtBu in THF (0.642 mL, 1.06 mmol) was added dropwise under a N.sub.2 atmosphere. After 10 min a solution of tert-butyl bromoacetate (0.188 mL, 1.27 mmol) in DMF (5 mL) was added dropwise and the solution was stirred at RT for 30 min. Solid NH.sub.4Cl (193 mg, 3.60 mmol) was added and after 20 min the suspension was filtered. The residue was rinsed with MeCN (30 mL) and the combined filtrates were concentrated. The residue was loaded on silica using MeOH/DCM. Purification by flash chromatography (40 g silica, gradient DCM/(7 M NH.sub.3 in MeOH), 99:1 to 9:1) afforded tert-butyl cis-2-(2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)acetate (INT-15) (142 mg, 0.40 mmol, 37%). LCMS: calculated for [M+H]+=360.5, found 360.3.

Cis-2-(2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)acetic Acid (INT-16)

[0399] ##STR00031##

[0400] To a solution of tert-butyl cis-2-(2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)acetate (INT-15) (141 mg, 0.392 mmol) in DCM (3 mL) was added TFA (3.02 mL, 39.2 mmol) and the mixture was stirred at RT. After 2 h the mixture was concentrated and the crude product was concentrated again from DCM solution (2, 10 mL each) to yield crude cis-2-(2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)acetic acid (INT-16) (240 mg) which was used in the next step without further purification. LCMS: calculated for [M+H]+=304.2, found 304.2.

Tert-Butyl cis-2-(5-(cyclobutylmethyl)-2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro-[3.4]octan-7-yl)acetate (INT-25)

[0401] ##STR00032##

[0402] Oven dried glassware and an inert atmosphere Ar(g) were used. To a solution of cis-5-(cyclobutylmethyl)-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]-octan-6-one (INT-13) (20 mg, 0.064 mmol) in a mixture of dry DMF (1 mL)/dry THF (1 mL) at RT was added 60% NaH in mineral oil (3.32 mg, 0.083 mmol). After 15 min gas evolution had ceased and a solution of tert-butyl bromoacetate (0.014 mL, 0.096 mmol) in dry DMF (1 mL) was added dropwise and the mixture was stirred at RT for 4 h. The reaction was quenched carefully by adding a mixture of brine/water (10 mL, 1/1, v/v). Then, the mixture was diluted with EtOAc (4 mL). The layers were separated and the water layer was extracted with EtOAc (34 mL). Combined organic layers were concentrated in vacuo (bath temperature 40 C.) to afford the crude product as a colorless sticky oil. This experiment was repeated in the same way on larger scale: cis-5-(cyclobutylmethyl)-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]-octan-6-one (INT-13) (100 mg, 0.319 mmol). The crude products were combined and subjected to flash chromatography (12 g silica, gradient DCM/MeOH, 199:1.fwdarw.193:7) to afford tert-butyl cis-2-(5-(cyclobutylmethyl)-2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro-[3.4]octan-7-yl)acetate (INT-25) as a white solid (135 mg (94% pure), 0.297 mmol, 78%). LCMS: calculated for [M+H].sup.+=428.6, found 428.3.

General Scheme for the Synthesis of INT-34

[0403] ##STR00033##

1-(3-fluorophenyl)-3,3-dimethoxycyclobutanecarbonitrile (INT-27)

[0404] ##STR00034##

[0405] A suspension of NaH (110 g, 4580.1 mmol) in DMF (1.6 Lit) was cooled to 0 C., prior to the dropwise addition of 2-(3-fluorophenyl)acetonitrile (206 g, 1526.7 mmol) over 2 h. Reaction mixture was brought to rt and stirred for 45 min. To this mixture was added 1,3-dibromo-2,2-dimethoxypropane (200 g, 763.3 mmol) in one portion at RT and stirring was continued at RT for 16 h, before heating at 80 C. for 3 h. The reaction mixture was cooled to 0 C. and quenched with crushed ice water (500 mL) and diluted with water (2.5 L), extracted with ethyl acetate (22 L). The combined organic layer was washed with brine solution (33 L), dried over Na.sub.2SO.sub.4, filtered and the filtrate was concentrated. The crude compound was purified by silica gel column chromatography (100-200 mesh), eluting with 2-3% ethyl acetate in pet-ether to afford 114 g (63%) of 1-(3-fluorophenyl)-3,3-dimethoxycyclobutanecarbonitrile (INT-27) as a colorless liquid (TLC system: 15% ethyl acetate in pet ether; Rf: 0.4).

1-(3-fluorophenyl)-3,3-dimethoxycyclobutanecarboxamide (INT-28)

[0406] ##STR00035##

[0407] 30% H.sub.2O.sub.2 solution (109.9 mL, 970.2 mmol) was added drop wise to a mixture of K.sub.2CO.sub.3 (20 g, 145.5 mmol) and 1-(3-fluorophenyl)-3,3-dimethoxycyclobutanecarbonitrile (INT-27) (114 g, 485.1 mmol) in DMSO (1.14 L) at 40 C. and the reaction mixture was heated at 80 C. for 3 h. The reaction completion was monitored by TLC. The reaction mass was quenched with ice cold water (1 L) and ), extracted with ethyl acetate (32 L), washed with brine solution (33 L), dried over Na.sub.2SO.sub.4, filtered and the filtrate was concentrated to afford 117 g of 1-(3-fluorophenyl)-3,3-dimethoxycyclobutanecarboxamide (INT-28) (95%) as an off white solid. (TLC system: 70% ethyl acetate in pet ether; Rf: 0.6). LCMS: calculated for [M+H]+=254.12, found 254.1.

1-(3-fluorophenyl)-3-oxocyclobutanecarboxamide (INT-29)

[0408] ##STR00036##

[0409] To a solution of 1-(3-fluorophenyl)-3,3-dimethoxycyclobutanecarboxamide (INT-28) (1.8 g, 7.11 mmol) in acetone (18 mL) was added 6 N HCl (14 mL) at 0 C. and the resulting mixture was stirred at RT for 2 h. The reaction completion was monitored by TLC. The reaction mixture was neutralized with 20% NaOH solution up to pH 6 at 0-10 C., and extracted with ethyl acetate, dried over Na.sub.2SO.sub.4, filtered and the filtrate was concentrated to afford 1.4 g of 1-(3-fluorophenyl)-3-oxocyclobutanecarboxamide (INT-29) (95%) as a pink solid. (TLC system: 70% ethyl acetate in pet ether; Rf: 0.7). LCMS: calculated for [M+H]+=208.08, found 207.9.

2-(3-fluorophenyl)-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxamide (INT-30)

[0410] ##STR00037##

[0411] To a suspension of 1-(3-fluorophenyl)-3-oxocyclobutanecarboxamide (INT-29) (81 g, 391.30 mmol) in 1620 mL of EtOH:H.sub.2O (1:1 v/v) were added KCN (35.6 g, 1533.9 mmol) and (NH.sub.4).sub.2CO.sub.3 (172 g, 1095.6 mmol) at room temperature. The reaction mixture was heated at 70 C. for 16 h. The reaction mixture was cooled to RT, diluted with water (810 mL), neutralized with 6 N HCl up to pH 6 and solid thus precipitated was filtered and dried to afford 52 g (47.9%) of 2-(3-fluorophenyl)-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxamide (INT-30) as an off-white solid (3:1 mixture of stereoisomers) (TLC: 10% methanol in dichloromethane; Rf: 0.25-0.40). LCMS: calculated for [M+H]+=278.1, found 277.9.

2-amino-2-(3-fluorophenyl)-5,7-diazaspiro[3.4]octane-6,8-dione (INT-31)

[0412] ##STR00038##

[0413] Bis(trifluoroacetoxy)iodo]benzene (93 g, 217.39 mmol) was added to a solution of 2-(3-fluorophenyl)-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxamide (INT-30) (50 g, 181.15 mmol) in a mixture of acetonitrile and water (3:1, 2.0 L) at RT. The reaction mixture was stirred at RT for 16 h. The reaction completion was monitored by TLC. Reaction mixture was neutralized with aq NaHCO.sub.3 solution till pH 6, extracted with ethyl acetate, dried over Na.sub.2SO.sub.4, filtered and the filtrate was concentrated to afford 40 g of 2-amino-2-(3-fluorophenyl)-5,7-diazaspiro[3.4]octane-6,8-dione (INT-31) (88%) as an off-white solid (1:1 mixture of stereoisomers). (TLC: 10% methanol in dichloromethane; Rf: 0.30-035). LCMS: calculated for [M+H]+=250.1, found 250.0.

2-(dimethylamino)-2-(3-fluorophenyl)-5,7-diazaspiro[3.4]octane-6,8-dione (INT-32)

[0414] ##STR00039##

[0415] To a solution of 2-amino-2-(3-fluorophenyl)-5,7-diazaspiro[3.4]octane-6,8-dione (INT-31)(18 g, 72.28 mmol) in THF (540 L) under argon were added DIPEA (25 mL, 144.57 mmol), MeI (18 mL, 289.15 mmol) and the reaction mixture was stirred at RT for 16 h. The reaction completion was monitored by LC-MS. The reaction mixture was concentrated under vacuum and triturated with water (200 mL) and the resulting solid was filtered to afford 12 g (59%) of 2-(dimethylamino)-2-(3-fluorophenyl)-5,7-diazaspiro[3.4]octane-6,8-dione (INT-32) as an off-white solid (3:5 mixture of stereoisomers). LCMS: calculated for [M+H]+=278.13, found 278.0.

Cis-2-(dimethylamino)-2-(3-fluorophenyl)-5,7-diazaspiro[3.4]octane-6,8-dione (INT-33)

[0416] ##STR00040##

[0417] 2-(Dimethylamino)-2-(3-fluorophenyl)-5,7-diazaspiro[3.4]octane-6,8-dione (INT-32)(12 g) was purified by chiral SFC to get 6.2 g of cis-2-(dimethylamino)-2-(3-fluorophenyl)-5,7-diazaspiro[3.4]octane-6,8-dione (INT-33) as an off-white solid (LC-MS peak-2). Preparative SFC Conditions: column: Chiralpak IG (30250 mm), 5; % co-solvent: 30.0% (100% Methanol); % CO.sub.2: 70.0%; total flow: 90.0 g/min; back pressure: 90.0 bar; UV: 214 nm; stack time: 10.3 min; load/inj: 103.0 mg; injection solvent: methanol+acetonitrile+THF (2:2:1); No. of injections: 140; instrument details: Make/Model: SFC-200-002. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.50 (s, 1H), 8.32 (s, 1H), 7.42-7.33 (m, 1H), 7.12-7.08 (m, 1H), 6.97-6.89 (m, 2H), 2.86 (d, 2H), 2.51 (d, 2H), 1.88 (s, 6H).

Cis-2-(dimethylamino)-2-(3-fluorophenyl)-5,7-diazaspiro[3.4]octan-6-one (INT-34)

[0418] ##STR00041##

[0419] LiAlH.sub.4 (1 M in THF) (82 mL, 82.31 mmol) was added to a solution of cis-2-(dimethylamino)-2-(3-fluorophenyl)-5,7-diazaspiro[3.4]octane-6,8-dione (INT-33) (5.7 g, 20.57 mmol) in THF (228 mL) at 0 C. under argon. The reaction mixture was stirred at 80 C. for 16 h. The reaction completion was monitored by TLC. The reaction mixture was cooled to 0 C., quenched with saturated Na.sub.2SO.sub.4 solution and diluted with 10% methanol in DCM and filtered through celite bed. The filtrate was washed with 10% methanol in DCM and the filtrate was concentrated under reduced pressure to afford crude compound. The crude compound was triturated with methanol and diethyl ether successively to get 6 g (LC-MS 82%) of desired compound, which was in turn triturated with ethyl acetate to furnish 5.7 g (LC-MS 94%) of compound. Another trituration with methanol gave 5.4 g (98%, LC-MS 97%) of cis-2-(dimethylamino)-2-(3-fluorophenyl)-5,7-diazaspiro[3.4]octan-6-one (INT-34) as an off-white solid. (TLC system: 10% MeOH in DCM, Rf: 0.28). .sup.1H NMR (DMSO-d.sub.6): 7.44-7.38 (m, 1H), 7.13-7.09 (m, 3H), 6.69 (s, 1H), 5.99 (s, 1H), 2.72-2.69 (m, 4H), 2.32 (dd, J=2.4 Hz, 9.6 Hz, 2H), 1.82 (s, 6H). LCMS: calculated for [M+H]+=264.15, found 264.15.

General Scheme for the Synthesis of INT-38 and INT-39

[0420] ##STR00042##

2-(Dimethylamino)-2-(3-fluorophenyl)-7-(4-methoxybenzyl)-5,7-diazaspiro[3.4]octane-6,8-dione (INT-36)

[0421] ##STR00043##

[0422] Cs.sub.2CO.sub.3 (3.3 g, 10.37 mmol) was added to a solution of 2-(dimethylamino)-2-(3-fluorophenyl)-5,7-diazaspiro[3.4]octane-6,8-dione (INT-36) (2.5 g, 9.02 mmol) in acetonitrile (300 mL) under argon and stirred for 15 min at RT, prior to the addition of 4-methoxybenzyl bromide (1.42 mL, 9.92 mmol). The reaction mixture was stirred for 16 h at RT. The reaction completion was monitored by TLC. The reaction was repeated on the same scale and the reaction mixtures from both batches were combined and quenched with saturated NH.sub.4Cl solution (100 mL) and extracted with ethyl acetate (2100 mL). The organic layer was washed with brine solution, dried over Na.sub.2SO.sub.4, filtered and the filtrate was concentrated to give crude compound. The crude product was purified by neutral alumina column chromatography, eluting with 0.5-1.0% methanol in DCM to afford 4.3 g (60%) of 2-(dimethylamino)-2-(3-fluorophenyl)-7-(4-methoxybenzyl)-5,7-diazaspiro[3.4]octane-6,8-dione (INT-36) as an off-white solid (1:1 mixture of stereoisomers) (TLC system: 10% MeOH in dichloromethane, Rf: 0.5 and 0.6). LCMS: calculated for [M+H]+=398.19, found 397.9.

2-(dimethylamino)-2-(3-fluorophenyl)-7-(4-methoxybenzyl)-5,7-diazaspiro[3.4]octan-6-one (INT-37)

[0423] ##STR00044##

[0424] AlCl.sub.3 (5.6 g, 42.11 mmol) was dissolved in THF (300 mL) at 0 C. under argon, prior to the addition of LiAlH.sub.4 (1 M in THF) (44 mL, 44.33 mmol) and the solution was stirred at RT for 1 h. To this mixture was dropwise added a solution 2-(dimethylamino)-2-(3-fluorophenyl)-7-(4-methoxybenzyl)-5,7-diazaspiro[3.4]octane-6,8-dione (INT-36) (4.4 g, 11.08 mmol) in THF (100 mL) at 0 C. under argon over 1 h. After addition, the reaction mixture was stirred at 80 C. for 16 h. The reaction completion was monitored by LC-MS. The reaction mixture was cooled to 0 C., quenched with sat. aq. NaHCO.sub.3 and diluted with 10% methanol in DCM and filtered through celite bed. The filtrate was washed with 10% methanol in dichloromethane and the filtrate was concentrated under reduced pressure to afford crude compound. The crude compound was triturated with n-pentane to furnish 4.2 g (98%) of (2-(dimethylamino)-2-(3-fluorophenyl)-7-(4-methoxybenzyl)-5,7-diazaspiro[3.4]octan-6-one (INT-37) as an off-white solid (1:1 mixture of stereoisomers). LCMS: calculated for [M+H]+=384.21, found 384.2.

Cis-2-(dimethylamino)-2-(3-fluorophenyl)-7-(4-methoxybenzyl)-5,7-diazaspiro[3.4]octan-6-one (INT-38) and trans-2-(dimethylamino)-2-(3-fluorophenyl)-7-(4-methoxybenzyl)-5,7-diazaspiro[3.4]octan-6-one (INT-39)

[0425] ##STR00045##

[0426] The diastereomeric mixture of (2-(dimethylamino)-2-(3-fluorophenyl)-7-(4-methoxybenzyl)-5,7-diazaspiro[3.4]octan-6-one (INT-37) (7.9 g) was separated by chiral SFC to afford 2.2 g of cis-2-(dimethylamino)-2-(3-fluorophenyl)-7-(4-methoxybenzyl)-5,7-diazaspiro[3.4]octan-6-one (INT-38) as an off-white solid (HPLC peak-1) and 2.4 g of trans-2-(dimethylamino)-2-(3-fluorophenyl)-7-(4-methoxybenzyl)-5,7-diazaspiro[3.4]octan-6-one (INT-39) as an off-white solid (HPLC peak-2). Preparative SFC Conditions: column: Chiralpak AD-H (30250 mm), 5; % co-solvent: 30.0% (100% Methanol); % CO.sub.2: 70.0%; total flow: 90.0 g/min; back pressure: 90.0 bar; UV: 214 nm; stack time: 6.3 min; load/inj: 74.0 mg; injection solvent: 200 mL methanol; No. of injections: 70; instrument details: Make/Model: SFC-200-003.

[0427] Cis-2-(dimethylamino)-2-(3-fluorophenyl)-7-(4-methoxybenzyl)-5,7-diazaspiro[3.4]octan-6-one (INT-38): .sup.1H NMR (DMSO-d.sub.6): 7.38 (br s, 1H), 7.07 (br s, 2H), 7.01-6.97 (m, 3H), 6.83 (d, J=6.8 Hz, 2H), 4.04 (s, 2H), 3.70 (s, 3H), 2.66 (br s, 4H), 2.36 (br s, 2H), 1.82 (br s, 6H).

[0428] Trans-2-(dimethylamino)-2-(3-fluorophenyl)-7-(4-methoxybenzyl)-5,7-diazaspiro[3.4]octan-6-one (INT-39): .sup.1H NMR (DMSO-d.sub.6): 7.37-7.34 (m, 1H), 7.16 (d, J=6.8 Hz, 2H), 7.08-7.05 (m, 1H), 6.91 (d, J=6.8 Hz, 2H), 6.83 (d, J=6.4 Hz, 2H), 6.77 (s, 1H), 4.16 (s, 2H), 3.74 (s, 3H), 3.34 (s, 2H), 2.56 (d, J=1.0 Hz, 2H), 2.26 (d, J=10.0 Hz, 2H), 1.88 (s, 6H).

General Scheme for the Synthesis of INT-43

[0429] ##STR00046##

Cis-5-(cyclopropylmethyl)-2-(dimethylamino)-7-(4-methoxybenzyl)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one (INT-42)

[0430] ##STR00047##

[0431] To a solution of cis-2-dimethylamino-7-(4-methoxy-benzyl)-2-phenyl-5,7-diaza-spiro[3.4]octan-6-one (INT-40) (3.0 g, 8.22 mmol, 1.0 eq.) in dry DMF (160 ml) was added 60% NaH (657 mg, 16.438 mmol, 2 eq.) at 0 C. and the resulting mixture was stirred for 30 min followed by addition of bromomethyl-cyclopropane (1.9 ml, 20.54 mmol, 2.5 eq.) at 0 C. The reaction mixture was stirred at RT for 16 h. The reaction mixture was quenched with ice-cold water (20 ml) and extracted with ethyl acetate (1 L). The organic layer was washed with ice-cold water (3100 ml), brine (250 ml) and dried over sodium sulfate. Organic layer was concentrated under reduced pressure to get crude product which was purified by column chromatography (silica gel; 1.5% MeOH/DCM) to yield cis-5-cyclopropylmethyl-2-dimethylamino-7-(4-methoxy-benzyl)-2-phenyl-5,7-diaza-spiro[3.4]octan-6-one (INT-42) as colourless sticky liquid. LCMS: calculated for [M+H]+=420.4, found 420.1.

Cis-5-cyclopropylmethyl-2-dimethylamino-2-phenyl-5,7-diaza-spiro[3.4]octan-6-one (INT-43)

[0432] ##STR00048##

[0433] To a stirred solution of cis-5-cyclopropylmethyl-2-dimethylamino-7-(4-methoxy-benzyl)-2-phenyl-5,7-diaza-spiro[3.4]octan-6-one (INT-42) (2.0 g) in DCM (12 ml) was added TFA (12 ml) drop-wise at 0 C. The reaction mixture was stirred at RT for 16 h and then concentrated under reduced pressure to get crude product which was purified by column chromatography (silica gel neutralized by aqueous NH.sub.3; 4% MeOH/DCM) to yield cis-5-cyclopropylmethyl-2-dimethylamino-2-phenyl-5,7-diaza-spiro[3.4]octan-6-one (INT-43) as a white solid. Note: This step was done with another 1.0 g and 2.0 g batches. Combined yield: 60% (2.15 g, 7.18 mmol). LCMS: calculated for [M+H]+=300.3, found 300.2.

[0434] For further intermediates the synthesis in analogy to previously described methods is given in the following table. The syntheses of the building blocks and intermediates have either been described previously within this application or can be performed in analogy to the herein described methods or by methods known to the person, skilled in the art. Such a person will also know which building blocks and intermediates need to be chosen for synthesis of each exemplary compound.

TABLE-US-00001 in analogy to m/z Intermediate Chemical Name Chemical Structure method [M + H].sup.+ INT-17 tert-butyl trans-(7- (4-methoxybenzyl)- 6,8-dioxo-2-phenyl- 5,7-diazaspiro[3.4] octan-2-yl)(methyl) carbamate [00049] INT-9 466.2 INT-18 tert-butyl trans-(5- (cyclobutylmethyl)- 7-(4-methoxybenzyl)- 6,8-dioxo-2-phenyl- 5,7-diazaspiro[3.4] octan-2-yl)(methyl) carbamate [00050] INT-10 534.3 INT-19 trans-5- (cyclobutylmethyl)- 2-(methylamino)-2- phenyl-5,7-diazaspiro [3.4]octane-6,8-dione [00051] INT-11 314.2 INT-20 trans-5- (cyclobutylmethyl)-2- (dimethylamino)-2- phenyl-5,7-diazaspiro [3.4]octane-6,8-dione [00052] INT-12 328.2 INT-21 trans-5- (cyclobutylmethyl)- 2-(dimethylamino)- 2-phenyl-5,7- diazaspiro[3.4]octan- 6-one [00053] INT-13 314.2 INT-22 trans-2- (dimethylamino)- 2-phenyl-5,7- diazaspiro[3.4] octan-6-one [00054] INT-14 246.2 INT-23 trans-2-(2- (dimethylamino)- 6-oxo-2-phenyl-5, 7-diazaspiro[3.4] octan-7-yl)acetic acid tert-butyl ester [00055] INT-15 360.2 INT-24 trans-2-(2- (dimethylamino)- 6-oxo-2-phenyl- 5,7-diazaspiro[3.4] octan-7-yl)acetic acid [00056] INT-16 304.2 INT-26 cis-2-(5- (cyclobutylmethyl)- 2-(dimethylamino)- 6-oxo-2-phenyl- 5,7-diazaspiro[3.4] octan-7-yl)acetic acid [00057] INT-16 372.2 INT-35 trans-2- (dimethylamino)-2- (3-fluorophenyl)-5, 7-diazaspiro[3.4] octan-6-one [00058] INT-34 264.15 INT-40 Cis-2- (dimethylamino)- 7-(4-methoxybenzyl)- 2-phenyl-5,7- diazaspiro[3.4]octan- 6-one [00059] INT-38 366.2 INT-41 Trans-2- (dimethylamino)-7- (4-methoxybenzyl)- 2-phenyl-5,7- diazaspiro[3.4] octan-6-one [00060] INT-39 366.2 INT-44 Cis-5- (cyclopropylmethyl)- 2-(dimethylamino)-2- (3-fluorophenyl)-7- (4-methoxybenzyl)-5,7- diazaspiro[3.4]octan- 6-one [00061] INT-42 438.3 INT-45 Cis--5- (cyclopropylmethyl)- 2-(dimethylamino)-2- (3-fluorophenyl)-5, 7-diazaspiro[3.4] octan-6-one [00062] INT-43 318.2

Synthesis of Exemplary Compounds

Cis-2-(2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)acetamide (SC-1)

[0435] ##STR00063##

[0436] To a solution of crude cis-2-(2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)acetic acid (INT-16) (120 mg, max. 0.196 mmol) in DCM (3.5 mL) were added Et.sub.3N (0.137 mL, 0.98 mmol) and NH.sub.4Cl (41.9 mg, 0.784 mmol) under a N.sub.2 atmosphere. HATU (112 mg, 0.294 mmol) was added and the mixture was stirred at RT overnight. The mixture was diluted with MeOH (5 mL) and filtered off. The residue was rinsed with MeOH (10 mL) and the combined filtrates were concentrated. The residue was purified by basic preparative LC (HPLC instrument type: Agilent Technologies 1200 preparative LC; column: Waters XSelect CSH (C18, 15025 mm, 10p); flow: 43 mL/min; column temp: RT; eluent A: 99% acetonitrile+1% 10 mM ammonium bicarbonate in water pH=9.0, eluent B: 10 mM ammonium bicarbonate in water pH=9.0; lin. gradient: t=0 min 5% A, t=2.5 min 5% A, t=11 min 50% A, t=13 min 100% A, t=17 min 100% A; detection: DAD (210 nm)). The product-containing fractions were concentrated to dryness and co-evaporated with MeCN (2, 5 mL each) and Et.sub.2O (2, 5 mL each) to yield cis-2-(2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)acetamide (SC-1) (42 mg, 0.139 mmol). LCMS: calculated for [M+H].sup.+=303.2, found 303.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.43-7.34 (m, 2H), 7.33-7.17 (m, 4H), 6.98 (s, 1H), 6.89 (s, 1H), 3.45 (s, 2H), 2.85 (s, 2H), 2.75 (d, J=11.9 Hz, 2H), 2.36 (d, J=11.9 Hz, 2H), 1.81 (s, 6H).

Cis-2-(dimethylamino)-7-(2-(1,1-dioxidothiomorpholino)-2-oxoethyl)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one (SC-2)

[0437] ##STR00064##

[0438] To a solution of cis-2-(2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)acetic acid (INT-16) (120 mg, max. 0.196 mmol) in DCM (3.5 mL) were added Et.sub.3N (0.109 mL, 0.784 mmol) and thiomorpholine 1,1-dioxide (106 mg, 0.784 mmol) under a N.sub.2 atmosphere. HATU (112 mg, 0.294 mmol) was added and the mixture was stirred at RT overnight. The mixture was diluted with MeOH (5 mL) and filtered off. The residue was rinsed with MeOH (10 mL) and the combined filtrates were concentrated. The residue was purified by basic preparative LC (HPLC instrument type: Agilent Technologies 1200 preparative LC; column: Waters XSelect CSH (C18, 15025 mm, 10p); flow: 43 mL/min; column temp: RT; eluent A: 99% acetonitrile+1% 10 mM ammonium bicarbonate in water pH=9.0, eluent B: 10 mM ammonium bicarbonate in water pH=9.0; lin. gradient: t=0 min 5% A, t=2.5 min 5% A, t=11 min 50% A, t=13 min 100% A, t=17 min 100% A; detection: DAD (210 nm)). The product-containing fractions were concentrated to dryness and co-evaporated with MeCN (2, 5 mL each) and Et.sub.2O (2, 5 mL each) to yield cis-2-(dimethylamino)-7-(2-(1,1-dioxidothiomorpholino)-2-oxoethyl)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one (SC-2) (52 mg, 0.124 mmol). LCMS: calculated for [M+H].sup.+=421.2, found 421.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.38 (t, J=7.5 Hz, 2H), 7.32-7.22 (m, 3H), 6.99 (s, 1H), 3.86 (s, 2H), 3.79-3.66 (m, 4H), 3.18 (s, 2H), 3.02 (s, 2H), 2.88 (s, 2H), 2.76 (d, J=11.9 Hz, 2H), 2.37 (d, J=11.9 Hz, 2H), 1.80 (s, 6H).

Cis-5-(2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)-4-methoxypyrimidine-2-carbonitrile (SC-3)

[0439] ##STR00065##

[0440] This reaction was carried out under Ar. A mixture of cis-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one (INT-14) (83 mg, 0.338 mmol), 5-bromo-4-methoxypyrimidine-2-carbonitrile (80 mg, 0.372 mmol), Cs.sub.2CO.sub.3 (331 mg, 1.015 mmol) and XantPhos (9.79 mg, 0.017 mmol) in dry 1,4-dioxane (8 mL) was flushed with Ar for 5 min. Pd.sub.2(dba).sub.3 (31.0 mg, 0.034 mmol) was added and the reaction mixture was stirred at 110 C. overnight. The reaction mixture was combined with a reaction mixture obtained from another experiment which started from cis-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one (INT-14) (41 mg, 0.167 mmol) using the described procedure. H.sub.2O (10 mL) was added and the aqueous layer was extracted with DCM (310 mL) and DCM/7 M NH.sub.3 in MeOH, 9:1 (310 mL). Organic layers were combined, dried (Na.sub.2SO.sub.4) and evaporated under reduced pressure. The product was subjected to flash chromatography (28 g silica, gradient DCM/(7 M NH.sub.3 in MeOH), 1:0 to 95:5). TLC-impure fractions were combined and subjected to flash chromatography again (28 g silica, gradient DCM/(7 M NH3 in MeOH), 97:3 to 95:5), to result in impure product which was triturated with MeOH (22 mL). This batch of product was combined with the TLC-pure batch of the first flash column. The resulting batch was triturated with MeOH (ca. 2 mL). The residue was dried in vacuo, to give cis-5-(2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)-4-methoxypyrimidine-2-carbonitrile (SC-3) (87 mg, 0.23 mmol, 46%). LCMS: calculated for [M+H]+=379.2, found 379.2. .sup.1H NMR (400 MHz, CDCl.sub.3) 8.88 (s, 1H), 7.37 (t, J=7.3 Hz, 2H), 7.30 (t, J=7.3 Hz, 1H), 7.09 (d, J=7.2 Hz, 2H), 6.01 (s, 1H), 4.00 (s, 3H), 3.76 (s, 2H), 2.71 (d, J=12.4 Hz, 2H), 2.63 (d, J=12.4 Hz, 2H), 2.05 (s, 6H).

Cis-5-(cyclobutylmethyl)-2-(dimethylamino)-7-(2-(1,1-dioxidothiomorpholino)-2-oxoethyl)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one (SC-6)

[0441] ##STR00066##

Step 1: 2-bromo-1-(1,1-dioxidothiomorpholino)ethanone

[0442] A solution of thiomorpholine 1,1-dioxide (1.0 g, 7.40 mmol) in DCM (30 mL) was added dropwise over 20 min to a cooled (0 C.) and argon flushed mixture of 2-bromoacetyl bromide (970 L, 11.10 mmol) and K.sub.3PO.sub.4 (3.93 g, 18.5 mmol) in DCM (20 mL) and the mixture was stirred at RT overnight. The reaction mixture was diluted with DCM (50 mL) and quenched with aq. 0.5 M HCl (10 mL). Water (50 mL) and brine (50 mL) were added and the layers were separated. The aqueous layer was extracted with DCM (50 mL) and the combined organic layers were washed with aq. 10% KHCO.sub.3 (100 mL) and brine (50 mL), dried over Na.sub.2SO.sub.4(s) and concentrated to dryness. The residue was triturated with Et.sub.2O (50 mL) for 30 min. The solid material was filtered off, washed with some Et.sub.2O and dried under reduced pressure to afford 2-bromo-1-(1,1-dioxidothiomorpholino)ethanone (1.20 g, 4.69 mmol, 63%). LCMS: calculated for [M+H].sup.+=256.1/258.1, found 256.0/258.0.

Step 2: cis-5-(cyclobutylmethyl)-2-(dimethylamino)-7-(2-(1,1-dioxidothiomorpholino)-2-oxoethyl)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one (SC-6)

[0443] Oven dried glassware and an inert atmosphere (Ar(g)) were used. To a solution of cis-5-(cyclobutylmethyl)-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one (INT-13) (40 mg, 0.128 mmol) in a mixture of dry DMF (2 mL) and dry THF (2 mL) was added 60% NaH in mineral oil (10.21 mg, 0.255 mmol) and the mixture was stirred at RT. After 15 min gas evolution had ceased and a solution of 2-bromo-1-(1,1-dioxidothiomorpholino)ethanone (49.0 mg, 0.191 mmol) in dry DMF (2 mL) was added dropwise. The mixture was stirred at RT for 1 h. A mixture of brine/water (10 mL, 1/1, v/v) was carefully added and the mixture was diluted with DCM (10 mL). The layers were separated using a phase separator. The water layer was extracted with DCM (45 mL). Organic layers were combined and concentrated in vacuo (bath temperature 55 C.). The residue was concentrated consequently from the solution in toluene, EtOAc and DCM to obtain a colourless sticky oil. The obtained crude product was purified by flash chromatography (4 g silica, gradient DCM/MeOH, 199:1 to 95:5) which afforded cis-5-(cyclobutylmethyl)-2-(dimethylamino)-7-(2-(1,1-dioxidothiomorpholino)-2-oxoethyl)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one (SC-6) (47 mg, 0.096 mmol, 75%) as a white solid. LCMS: calculated for [M+H]+=489.6, found 489.3. .sup.1H NMR (400 MHz, CDCl.sub.3) 7.38 (t, J=7.4 Hz, 2H), 7.31 (d, J=7.2 Hz, 1H), 7.21 (d, J=7.2 Hz, 2H), 3.98 (broad d, 4H), 3.89 (s, 2H), 3.32 (d, J=7.3 Hz, 2H), 2.99 (broad s, 4H), 2.93 (s, 2H), 2.70-2.53 (m, 5H), 2.04 (m, 2H), 1.92 (s, 6H), 1.81 (m, 4H).

Trans-2-(5-(cyclobutylmethyl)-2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)acetamide (SC-9)

[0444] ##STR00067##

[0445] To an ice-bath cooled suspension of trans-5-(cyclobutylmethyl)-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one (INT-21) (378 mg, 1.21 mmol) in dry DMF (10 mL) under an argon atmosphere was added dry THF (10 mL) to give a clear solution. 60% NaH in mineral oil (72.4 mg, 1.81 mmol) was added and the mixture was stirred at RT. After 20 min a solution of 2-chloroacetamide (201 L, 1.81 mmol) in dry THF (10 mL) was added dropwise and the mixture was stirred at RT overnight. More 60% NaH in mineral oil (193 mg, 4.82 mmol) was added and the mixture was stirred at RT for 1 h, then 2-chloroacetamide (201 L, 1.81 mmol) was added. The mixture was stirred at RT for 3 h, quenched with water (50 mL) and extracted with EtOAc (275 mL). The combined organic layers were washed with brine (2100 mL), dried over Na.sub.2SO.sub.4(s) and concentrated to dryness. The crude material was purified by preparative LC (HPLC instrument type: Agilent Technologies 1200 preparative LC; column: Waters XSelect CSH (C18, 15025 mm, 10p); flow: 43 mL/min; column temp: RT; eluent A: 99% acetonitrile+1% 10 mM ammonium bicarbonate in water pH=9.0, eluent B: 10 mM ammonium bicarbonate in water pH=9.0; lin. gradient: t=0 min 20% A, t=2.5 min 20% A, t=11 min 60% A, t=13 min 100% A, t=17 min 100% A; detection: DAD (210 nm)). Product-containing fractions were pooled, concentrated to dryness. The resulting product was concentrated again from the solution in Et.sub.2O (25 mL) to afford trans-2-(5-(cyclobutylmethyl)-2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)acetamide (SC-9) (89 mg, 0.241 mmol, 20%). LCMS: calculated for [M+H].sup.+=371.50, found: 371.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.37 (t, J=7.5 Hz, 2H), 7.31 (s, 1H), 7.26 (t, J=7.2 Hz, 1H), 7.08 (d, J=7.6 Hz, 2H), 6.99 (s, 1H), 3.65 (s, 2H), 3.59 (s, 2H), 2.88 (d, J=7.2 Hz, 2H), 2.58-2.46 (m, 2H), 2.41 (d, J=12.8 Hz, 2H), 2.32 (dq, J=14.9, 7.4 Hz, 1H), 1.92 (s, 6H), 1.86-1.76 (m, 2H), 1.68 (tt, J=19.5, 10.3 Hz, 2H), 1.51 (p, J=8.4 Hz, 2H).

Cis-2-(Dimethylamino)-7-(4-methyl-2-morpholinopyrimidin-5-yl)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one (SC-12)

[0446] ##STR00068##

[0447] K.sub.2CO.sub.3 (338 mg, 2.448 mmol) was added to a solution of cis-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one (INT-14) (200 mg, 0.816 mmol) and 4-(5-bromo-4-methylpyrimidin-2-yl)morpholine (314 mg, 1.224 mmol) in 1,4-dioxane (20 mL) at RT under argon atmosphere. To this reaction mixture, N,N-dimethylethylenediamine (71.8 mg, 0.816 mmol) followed by CuI (155 mg, 0.816 mmol) were added and degassed with argon for 15 minutes. The resulting reaction mixture was then maintained at 120 C. for 16 h. The reaction progress was checked by LC-MS.

Following the above condition, another 200 mg of (2s,4s)-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one was treated with 4-(5-bromo-4-methylpyrimidin-2-yl)morpholine. Both these lots were mixed, quenched with water (30 mL) and extracted with ethyl acetate (230 mL). The combined organic layer was concentrated under reduced pressure. The crude product was purified by prep-HPLC to afford 37 mg (5%) of cis-2-(dimethylamino)-7-(4-methyl-2-morpholinopyrimidin-5-yl)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one (SC-12) as an off-white solid (TLC system: 10% MeOH in dichloromethane; Rf: 0.5). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.04 (s, 1H), 7.38-7.26 (m, 6H), 3.65-3.60 (m, 8H), 3.10 (s, 2H), 2.86-2.82 (m, 2H), 2.46-2.41 (m, 2H), 2.10 (s, 3H), 1.83 (s, 6H). Mass: m/z 423.2 (M+H) ion present.

Cis-7-(6-(azetidin-1-yl)-4-methylpyridin-3-yl)-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one (SC-13)

[0448] ##STR00069##

Step 1: 2-(Azetidin-1-yl)-5-bromo-4-methylpyridine

[0449] Cs.sub.2CO.sub.3 (3.4 g, 10.526 mmol) was added to a stirred solution of 2,5-dibromo-4-methylpyridine (1.0 g, 5.263 mmol) and azetidine hydrochloride (0.5 g, 5.263 mmol) in DMSO (10 mL) at RT. The resulting reaction mixture was heated to 90 C. and maintained under stirring for 20 h. The reaction completion was monitored by TLC To the reaction mixture, water (30 mL) was added and extracted with ethyl acetate (230 mL). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford 0.8 g (66%) of 2-(azetidin-1-yl)-5-bromo-4-methylpyridine as a pale yellow solid. (TLC system: 30% ethyl acetate in pet-ether; Rf: 0.7).

Step 2: Cis-7-(6-(azetidin-1-yl)-4-methylpyridin-3-yl)-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one (SC-13)

[0450] In analogy to the method described for SC-12 cis-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one (INT-14) (200 mg, 0.816 mmol) was reacted with 2-(azetidin-1-yl)-5-bromo-4-methylpyridine (278 mg, 1.224 mmol) to be converted into cis-7-(6-(azetidin-1-yl)-4-methylpyridin-3-yl)-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one (SC-13) (35 mg, 11%). .sup.1H NMR (400 MHz, zDMSO-d.sub.6): 7.69 (s, 1H), 7.38-7.33 (m, 2H), 7.31-7.23 (m, 3H), 7.14 (s, 1H), 6.14 (s, 1H), 3.86-3.81 (m, 4H), 3.05 (s, 2H), 2.86-2.82 (m, 2H), 2.45-2.41 (m, 2H), 2.29-2.21 (m, 2H), 1.98 (s, 3H), 1.83 (s, 6H). Mass: m/z 392.2 (M+H) ion present.

Cis-5-(5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-6-oxo-5,7-diazaspiro[3.4]octan-7-yl)-4-methylpicolinonitrile (SC-15)

[0451] ##STR00070##

Step 1: cis-5-(2-(dimethylamino)-2-(3-fluorophenyl)-6-oxo-5,7-diazaspiro[3.4]octan-7-yl)-4-methylpicolinonitrile (SC-14)

[0452] In analogy to the method described for SC-3 cis-2-(dimethylamino)-2-(3-fluorophenyl)-5,7-diazaspiro[3.4]octan-6-one (INT-34) (120 mg, 0.456 mmol) was reacted with 5-bromo-4-methyl-pyridine-2-carbonitrile (197 mg, 0.592 mmol) to be converted into cis-5-(5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-6-oxo-5,7-diazaspiro[3.4]octan-7-yl)-4-methylpicolinonitrile (SC-14) (133 mg, 77%). .sup.1H NMR (600 MHz, DMSO-d.sub.6): 8.46 (s, 1H), 7.89 (s, 1H), 7.66 (s, 1H), 7.41 (td, J=7.8, 6.0 Hz, 1H), 7.16-7.07 (m, 3H), 2.92-2.86 (m, 2H), 2.51-2.45 (m, 2H), 2.19 (s, 3H), 1.86 (s, 6H). Mass: m/z 380.2 (M+H) ion present.

Step 2: cis-5-(5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-6-oxo-5,7-diazaspiro[3.4]octan-7-yl)-4-methylpicolinonitrile (SC-15)

[0453] To a solution of cis-5-(5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-6-oxo-5,7-diazaspiro[3.4]octan-7-yl)-4-methylpicolinonitrile (SC-14) (60 mg, 0.158 mmol) in dry DMF (1.2 mL) under nitrogen atmosphere was added 60% NaH in mineral oil (9.5 mg, 0.237 mmol) and the mixture was stirred at RT. After 5 min a solution of bromomethylcyclopropane (23 L, 0.237 mmol) was added. The reaction mixture was stirred at RT for 1.5 h, quenched with sat. aq. NH.sub.4Cl (5 mL) and extracted with DCM (210 mL). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4(s) and concentrated to dryness. The crude material (75 mg) was purified by flash chromatography on silica gel (eluent DCM/MeOH gradient 0% to 6% methanol) to yield 40 mg (58%) cis-5-(5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-6-oxo-5,7-diazaspiro[3.4]octan-7-yl)-4-methylpicolinonitrile (SC-15) as white solid. .sup.1H NMR (600 MHz, DMSO-d.sub.6): 8.47 (s, 1H), 7.90 (s, 1H), 7.42 (td, J=8.8, 8.3, 6.3 Hz, 1H), 7.16-7.08 (m, 3H), 3.43 (s, 2H), 3.23 (d, J=6.6 Hz, 2H), 2.85-2.79 (m, 2H), 2.71-2.65 (m, 2H), 2.18 (s, 3H), 1.88 (s, 6H), 1.13-1.03 (m, 1H), 0.56-0.47 (m, 2H), 0.39-0.31 (m, 2H). Mass: m/z 434.2 (M+H) ion present.

Cis-7-(6-(difluoromethyl)-4-methylpyridin-3-yl)-2-(dimethylamino)-2-(3-fluorophenyl)-5,7-diazaspiro[3.4]octan-6-one (SC-22)

[0454] ##STR00071##

Step 1: 5-bromo-2-(difluoromethyl)-4-methylpyridine

[0455] To the solution of 5-bromo-4-methyl-pyridine-2-carbaldehyde (200 mg, 1.00 mmol) in DCM (7.7 mL) at 78 C. (diethylamino)sulfurtrifluoride (242 mg, 0.198 mL, 1.50 mmol) was added under nitrogen atmosphere. The reaction mixture was allowed to warm up to RT over 4 h and stirred at RT overnight. The reaction mixture was quenched with 2 M aq. NaOH and extracted with DCM (3). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4(s) and concentrated at 100 mbar. The resulting crude product (220 mg) was used directly in the next step.

Step 2: cis-7-(6-(difluoromethyl)-4-methylpyridin-3-yl)-2-(dimethylamino)-2-(3-fluorophenyl)-5,7-diazaspiro[3.4]octan-6-one (SC-22)

[0456] In analogy to the method described for SC-3 cis-2-(dimethylamino)-2-(3-fluorophenyl)-5,7-diazaspiro[3.4]octan-6-one (INT-34) (200 mg, 0.760 mmol) was reacted with 5-bromo-2-(difluoromethyl)-4-methylpyridine (219 mg, 0.987 mmol) to be converted into cis-7-(6-(difluoromethyl)-4-methylpyridin-3-yl)-2-(dimethylamino)-2-(3-fluorophenyl)-5,7-diazaspiro[3.4]octan-6-one (SC-22) (110 mg, 36%). .sup.1H NMR (600 MHz, DMSO-d.sub.6): 8.38 (s, 1H), 7.54 (s, 1H), 7.51 (s, 1H), 7.41 (td, J=8.0, 6.1 Hz, 1H), 7.23-7.03 (m, 3H), 6.85 (t, J=55.0 Hz, 1H), 3.34 (s, 2H), 2.99-2.80 (m, 2H), 2.57-2.39 (m, 2H), 2.20 (s, 3H), 1.86 (s, 6H). Mass: m/z 405.2 (M+H) ion present.

Cis-5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-7-(2-(methylsulfonyl)ethyl)-5,7-diazaspiro[3.4]octan-6-one (SC-31)

[0457] ##STR00072##

[0458] To the solution of cis-5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl-5,7-diazaspiro[3.4]octan-6-one (INT-45) (80 mg, 0.252 mmol) in THF (2.1 mL) was added 1M potassium tert-butylate in THF (0.378 mL, 0.378 mmol). The resulting mixture was stirred 0.5 h at RT, cooled to 0 C. and the solution of 1-bromo-2-methylsulfonyl-ethane (71 mg, 0.378 mmol) in THF (1 mL) was added dropwise. The reaction mixture was stirred for 1 h, quenched with water and extracted with ethyl acetate (3). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4(s) and concentrated to dryness. Crude product (108 mg) was further purified by column chromatography on silica gel (gradient 0 to 5% EtOH in DCM) to yield 53 mg of semi-pure product which was further purified by reversed phase HPLC to yield 28 mg (26%) of cis-5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-7-(2-(methylsulfonyl)ethyl)-5,7-diazaspiro[3.4]octan-6-one (SC-31) as a white solid. .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.45 (td, J=8.0, 6.2 Hz, 1H), 7.18-7.08 (m, 3H), 3.39 (s, 2H), 3.19 (t, J=6.9 Hz, 2H), 3.10 (d, J=6.6 Hz, 2H), 2.94 (s, 2H), 2.91 (s, 3H), 2.68-2.62 (m, 2H), 2.60-2.54 (m, 2H), 1.85 (s, 6H), 1.06-0.93 (m, 1H), 0.51-0.43 (m, 2H), 0.34-0.26 (m, 2H). Mass: m/z 424.2 (M+H) ion present.

Cis-5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-7-(2-methoxy-2-methylpropyl)-5,7-diazaspiro[3.4]octan-6-one (SC-37)

[0459] ##STR00073##

[0460] Anhydrous NaOH powder (50.4 mg, 1.26 mmol) was suspended in anhydrous DMSO (5.25 mL) under nitrogen atmosphere and the resulting mixture was stirred 40 min at RT. Cis-5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-5,7-diazaspiro[3.4]octan-6-one (INT-45) (100 mg, 0.315 mmol) and 1-bromo-2-methoxy-2-methylpropane (79 mg, 0.473 mmol) were added. The resulting mixture was stirred 22 h at 90 C. and a new portion of 1-bromo-2-methoxy-2-methylpropane (26.3 mg, 0.158 mmol) was added. The reaction mixture was stirred for 4 h, quenched with brine (30 mL) and extracted with ethyl acetate (3). The combined organic layers were dried over Na.sub.2SO.sub.4(s) and concentrated to dryness. Crude product (152 mg) was purified by column chromatography on silica gel (gradient 1 to 5% EtOH in DCM) to yield 78 mg (61%) of cis-5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-7-(2-methoxy-2-methylpropyl)-5,7-diazaspiro[3.4]octan-6-one (SC-37). .sup.1H NMR (600 MHz, DMSO-d.sub.6): 7.48-7.41 (m, 1H), 7.17-7.11 (m, 3H), 3.08 (d, J=6.5 Hz, 2H), 2.93 (s, 2H), 2.91 (s, 2H), 2.90 (s, 3H), 2.64-2.59 (m, 2H), 2.56-2.50 (m, 3H), 1.86 (s, 6H), 1.04-0.97 (m, 1H), 0.96 (s, 6H), 0.49-0.42 (m, 2H), 0.31-0.24 (m, 2H). Mass: m/z 404.3 (M+H) ion present.

Cis-2-(dimethylamino)-2-(3-fluorophenyl)-7-(4-morpholinobenzyl)-5,7-diazaspiro[3.4]octan-6-one (SC-41)

[0461] ##STR00074##

[0462] To the solution of cis-2-(dimethylamino)-2-(3-fluorophenyl)-5,7-diazaspiro[3.4]octan-6-one (INT-34) (100 mg, 0.380 mmol) in dioxane (15.2 mL) was added potassium tert-butylate (93.8 mg, 0.836 mmol) and the resulting mixture was stirred 10 min at RT. 4-[4-(Chloromethyl)phenyl]morpholine hydrochloride (104 mg, 0.418 mmol) was added and the reaction mixture was stirred at RT for 3 h. A new portion of potassium tert-butylate (42.6 mg, 0.380 mmol) was added. The reaction mixture was stirred further 19 h at RT and concentrated to dryness. The solid residue was taken up in water (10 mL)/ethyl acetate (20 mL), organic phase separated and aqueous phase extracted with ethyl acetate (20 mL). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4(s) and concentrated to dryness. Crude product (158 mg) was further purified by column chromatography on silica gel (gradient 0 to 7% (0.5M NH.sub.3 in MeOH) in DCM) to yield 46 mg of semi-pure product which was further purified by reversed phase HPLC to yield 27 mg (16%) of cis-2-(dimethylamino)-2-(3-fluorophenyl)-7-(4-morpholinobenzyl)-5,7-diazaspiro[3.4]octan-6-one (SC-41) as a white solid. .sup.1H NMR (600 MHz, DMSO-d.sub.6): 7.38 (td, J=7.6, 5.9 Hz, 1H), 7.12-7.03 (m, 3H), 6.95 (d, J=8.3 Hz, 3H), 6.87-6.81 (m, 2H), 4.02 (s, 2H), 3.74-3.69 (m, 4H), 3.08-3.03 (m, 4H), 2.70-2.65 (m, 4H), 2.39-2.33 (m, 2H), 1.81 (s, 6H). Mass: m/z 439.3 (M+H) ion present.

Cis-3-(5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-6-oxo-5,7-diazaspiro[3.4]octan-7-yl)propanenitrile (SC-44)

[0463] ##STR00075##

[0464] To the solution of cis-5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-5,7-diazaspiro[3.4]octan-6-one (INT-45) (130 mg, 0.410 mmol) in DMSO (1.7 mL) was added potassium tert-butylate (68.9 mg, 0.614 mmol) at RT under nitrogen atmosphere. The resulting mixture was stirred 15 min at RT. 3-Bromopropionitrile (51 L, 0.614 mmol) in DMSO (1.7 mL) was added dropwise and the reaction mixture was stirred at RT for 18 h. A new portion of 3-bromopropionitrile (17 L, 0.205 mmol) was added. The reaction mixture was stirred further 6 h at RT, quenched with brine (30 mL) and extracted with ethyl acetate (3). The combined organic layers were dried over Na.sub.2SO.sub.4(s) and concentrated to dryness. Crude product (208 mg) was further purified by column chromatography on silica gel (gradient 2 to 5% EtOH in DCM) to yield 105 mg (87%) of cis-3-(5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-6-oxo-5,7-diazaspiro[3.4]octan-7-yl)propanenitrile (SC-44) as a white solid. .sup.1H NMR (600 MHz, DMSO-d.sub.6+TFA): 7.68-7.54 (m, 3H), 7.41 (td, J=8.5, 2.5 Hz, 1H), 3.24 (d, J=6.7 Hz, 2H), 3.21 (t, J=6.5 Hz, 2H), 3.07-3.02 (m, 2H), 3.01-2.96 (m, 2H), 2.85 (s, 2H), 2.56-2.52 (m, 8H), 1.12-0.99 (m, 1H), 0.47-0.39 (m, 2H), 0.38-0.30 (m, 2H). Mass: m/z 371.2 (M+H) ion present.

[0465] The following compounds were prepared in analogy and by combining previously described methods:

TABLE-US-00002 Example Chemical name Chemical structure Reactant I SC-4 trans-2-(dimethylamino)-7- (2-(1,1- dioxidothiomorpholino)-2- oxoethyl)-2-phenyl-5,7- diazaspiro[3.4]octan-6-one [00076] INT-24 SC-5 trans-5-(2- (dimethylamino)-6-oxo-2- phenyl-5,7- diazaspiro[3.4]octan-7-yl)- 4-methoxypyrimidine-2- carbonitrile [00077] INT-22 SC-7 trans-5-(cyclobutylmethyl)- 2-(dimethylamino)-7-(2- (1,1- dioxidothiomorpholino)-2- oxoethyl)-2-phenyl-5,7- diazaspiro[3.4]octan-6-one [00078] INT-21 SC-8 cis-2-(5- (cyclobutylmethyl)-2- (dimethylamino)-6-oxo-2- phenyl-5,7- diazaspiro[3.4]octan-7- yl)acetamide [00079] INT-26 SC-10 cis-5-(5- (cyclobutylmethyl)-2- (dimethylamino)-6-oxo-2- phenyl-5,7- diazaspiro[3.4]octan-7-yl)- 4-methoxypyrimidine-2- carbonitrile [00080] INT-13 SC-11 trans-5-(5- (cyclobutylmethyl)-2- (dimethylamino)-6-oxo-2- phenyl-5,7- diazaspiro[3.4]octan-7-yl)- 4-methoxypyrimidine-2- carbonitrile [00081] INT-21 SC-16 Cis-6-(5- (cyclopropylmethyl)-2- (dimethylamino)-2-(3- fluorophenyl)-6-oxo-5,7- diazaspiro[3.4]octan-7-yl)- 5-methylnicotinonitrile [00082] INT-34 SC-17 Cis-2-(dimethylamino)-2- (3-fluorophenyl)-7-(5- (trifluoromehoy)pyridin- 2-yl)-5,7- diazaspiro[3.4]octan-6-one [00083] INT-34 SC-18 Cis-5-(cyclopropylmethyl)- 2-(dimethylamino)-2-(3- fluorophenyl)-7-(5- (trifluoromethoxy)pyridin- 2-yl)-5,7- diazaspiro[3.4]octan-6-one [00084] SC-17 SC-19 Cis-2-(dimethylamino)-7- (4-methyl-6- morpholinopyridin-3-yl)-2- phenyl-5,7- diazaspiro[3.4]octan-6-one [00085] INT-14 (step 2) SC-20 Cis-2-(dimethylamino)-7- (6-(2-hydroxypropan-2-yl)- 4-methylpyridin-3-yl)-2- phenyl-5,7- diazaspiro[3.4]octan-6-one [00086] INT-14 SC-21 Cis-2-(dimethylamino)-7- (4-(2-hydroxypropan-2-yl)- 2-methylphenyl)-2-phenyl- 5,7-diazaspiro[3.4]octan-6- one [00087] INT-14 SC-23 Cis- -2-(dimethylamino)-5- ((3-fluorooxetan-3- yl)methyl)-2-(3- fluorophenyl)-7-(5- (trifluoromethoxy)pyridin- 2-yl)-5,7- diazaspiro[3.4]octan-6-one [00088] SC-17 SC-24 Cis-5-(cyclopropylmethyl)- 7-(6-(difluoromethyl)-4- methylpyridin-3-yl)-2- (dimethylamino)-2-(3- fluorophenyl)-5,7- diazaspiro[3.4]octan-6-one [00089] SC-22 SC-25 Cis-2-(dimethylamino)-7- (2-morpholinopyrimidin-5- yl)-2-phenyl-5,7- diazaspiro[3.4]octan-6-one [00090] INT-14 SC-26 Cis-2-(dimethylamino)-5- ((1- fluorocyclopropyl)methyl)- 2-(3-fluorophenyl)-7-(5- (trifluoromethoxy)pyridin- 2-yl)-5,7- diazaspiro[3.4]octan-6-one [00091] SC-17 SC-27 Cis-2-(dimethylamino)-2- (3-fluorophenyl)-5-((1- hydroxycyclobutyl) methyl) -7-(5- (trifluoromethoxy)pyridin- 2-yl)-5,7- diazaspiro[3.4] octan-6-one [00092] SC-17 SC-28 Cis-5-(cyclopropylmethyl)- 2-(dimethylamino)-2-(3- fluorophenyl)-7-(4-(2- hydroxypropan-2- yl)phenyl)-5,7- diazaspiro[3.4]octan-6-one [00093] INT-34 SC-29 Cis-2-(dimethylamino)-5- ((3-fluorooxetan-3- yl)methyl)-2-phenyl-7-(5- (trifluoromethoxy)pyridin- 2-yl)-5,7- diazaspiro[3.4]octan-6-one [00094] INT-14 SC-30 Cis-5-(cyclopropylmethyl)- 2-(dimethylamino)-2-(3- fluorophenyl)-7-((6- (trifluoromethyl)pyridin-3- yl)methyl)-5,7- diazaspiro[3.4]octan-6-one [00095] INT 45 SC-32 Cis-5-(cyclopropylmethyl)- 2-(dimethylamino)-2- phenyl-7-(5- (trifluoromethoxy)pyridin- 2-yl)-5,7- diazaspiro[3.4]octan-6-one [00096] INT-14 SC-33 Cis-5-(cyclopropylmethyl)- 2-(dimethylamino)-7-((3- fluorooxetan-3-yl)methyl)- 2-(3-fluorophenyl)-5,7- diazaspiro[3.4]octan-6-one [00097] INT-45 SC-34 Cis-5-(cyclopropylmethyl)- 7-(6-cyclopropylpyridin-3- yl)-2-(dimethylamino)-2- phenyl-5,7- diazaspiro[3.4]octan-6-one [00098] INT-14 SC-35 Cis-7-(6-cyclopropyl-4- methylpyridin-3-yl)-5- (cyclopropylmethyl)-2- (dimethylamino)-2-phenyl- 5,7-diazaspiro[3.4]octan-6- one [00099] INT-14 SC-36 Cis-7-(6-cyclopropyl-4- methylpyridin-3-yl)-2- (dimethylamino)-5-((3- fluorooxetan-3-yl)methyl)- 2-phenyl-5,7- diazaspiro[3.4]octan-6-one [00100] INT-14 SC-38 Cis-2-(dimethylamino)-2- phenyl-7-(2-pyridin-4- ylpyrimidin-5-yl)-5,7- diazaspiro[3.4]octan-6-one [00101] INT-14 SC-39 Cis-5-(cyclopropylmethyl)- 2-(dimethylamino)-2- phenyl-7-[5- (trifluoromethyl)pyridin-3- yl]-5,7- diazaspiro[3.4]octan-6-one [00102] INT-43 SC-40 Cis-5-[5- (cyclopropylmethyl)-2- (dimethylamino)-6-oxo-2- phenyl-5,7- diazaspiro[3.4]octan-7-yl]- 3- (trifluoromethyl)pyridine- 2-carbonitrile [00103] INT-43 SC-42 Cis-5-(cyclopropylmethyl)- 2-(dimethylamino)-2-(3- fluorophenyl)-7-[(1- hydroxycyclobutyl)methyl]- 5,7-diazaspiro[3.4]octan- 6-one [00104] INT-45 SC-43 Cis-5-(cyclopropylmethyl)- 2-(dimethylamino)-2- phenyl-7-(2-pyridin-4- ylpyrimidin-5-yl)-5,7- diazaspiro[3.4]octan-6-one [00105] SC-38 SC-45 Cis-3-[5- (cyclopropylmethyl)-2- (dimethylamino)-6-oxo-2- phenyl-5,7- diazaspiro[3.4]octan-7- yl]propanenitrile [00106] INT-43 SC-46 Cis-5-(cyclopropylmethyl)- 2-(dimethylamino)-7-[(1- hydroxycyclobutyl)methyl]- 2-phenyl-5,7- diazaspiro[3.4]octan-6-one [00107] INT-43 SC-47 Cis-5-(cyclopropylmethyl)- 2-(dimethylamino)-2-(3- fluorophenyl)-7[2-(oxetan- 3-yl)ethyl]-5,7- diazaspiro[3.4]octan-6-one [00108] INT-45 in analogy m/z Example Reactant II to method .sup.1H NMR data (M + H).sup.+ SC-4 thiomorpholine 1,1-dioxide SC-2 .sup.1H NMR (400 MHz, DMSO-d6) 7.34 (t, J = 7.5 Hz, 2H), 7.24 (t, J = 7.3 Hz, 1H), 7.03 (d, J = 7.3 Hz, 2H), 6.77 (s, 1H), 4.01 (s, 2H), 3.90-3.77 (m, 4H), 3.63 (s, 2H), 3.28 (s, 2H), 3.11 (s, 2H), 2.65 (d, J = 12.3 Hz, 2H), 2.29 (d, J = 12.2 Hz, 2H), 1.93 (s, 6H). 421.2 SC-5 5-bromo-4- methoxypyrimidine- 2-carbonitrile SC-3 .sup.1H NMR (400 MHz, DMSO-d6) 8.79 (s, 1H), 7.71 (s, 1H), 7.36 (t, J = 7.5 Hz, 2H), 7.26 (t, J = 7.3 Hz, 1H), 7.05 (d, J = 7.1 Hz, 2H), 4.13 (s, 2H), 4.06 (s, 3H), 2.75 (dd, J = 10.1, 2.6 Hz, 2H), 2.42-2.34 (m, 2H), 1.95 (s, 6H). 379.2 SC-7 2-bromo-1-(1,1- dioxidothiomor- pholino) ethanone SC-6 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) 7.37 (t, J = 7.5 Hz, 2H), 7.26 (t, J = 7.3 Hz, 1H), 7.08 (d, J = 7.3 Hz, 2H), 4.06 (s, 2H), 3.84 (s, 4H), 3.62 (s, 2H), 3.28 (m, 2H), 3.11 (m, 2H), 2.89 (d, J = 7.2 Hz, 2H), 2.55 (m, 2H), 2.41 (d, J = 12.8 Hz, 2H), 2.33 (m, 1H), 1.92 (s, 6H), 1.86-1.76 (m, 2H), 1.68 (m, 2H), 1.53 (m, 2H). 489.3 SC-8 ammonium chloride SC-1 .sup.1H-NMR (400 MHz, CDCl3) 7.38 (m, 2H), 7.35-7.29 (m, 1H), 7.23-7.17 (m, 2H), 6.25 (bs, 1H), 5.21 (bs, 1H), 3.64 (s, 2H), 3.33 (d, J = 7.3 Hz, 2H), 2.85 (s, 2H), 2.69-2.51 (m, 5H), 2.04 (m, 2H), 1.94 (s, 6H), 1.89-1.73 (m, 4H). 371.3 SC-10 5-bromo-4- methoxypyrimidine-2- carbonitrile SC-3 .sup.1H NMR (400 MHz, CDCl.sub.3) 8.85 (s, 1H), 7.41 (m, 2H), 7.33 (t, J = 7.3 Hz, 1H), 7.24 (m, 2H) 3.85 (s, 3H), 3.42 (d, J = 7.3 Hz, 2H), 3.36 (s, 2H), 2.78-2.70 (m, 2H), 2.67 (m, 1H), 2.63- 2.59 (m, 2H), 2.12-2.03 (m, 2H), 1.97 (s, 6H), 1.85 (m, 4H). 447.3 SC-11 5-bromo-4- methoxypyrimidine-2- carbonitrile SC-3 .sup.1H NMR (400 MHz, CDCl.sub.3) 8.87 (s, 1H), 7.39 (t, J = 7.4 Hz, 2H), 7.30 (t, J = 7.3 Hz, 1H), 7.11-7.00 (m, 2H), 4.16 (s, 2H), 4.10 (s, 3H), 3.07 (d, J = 7.2 Hz, 2H), 2.65-2.54 (m, 4H), 2.46 (m, 1H), 2.02 (s, 6H), 1.92 (ddt, J = 11.3, 8.2, 3.4 Hz, 2H), 1.76 (tdd, J = 14.6, 8.6, 2.7 hz, 2H), 1.68-1.58 (m, 2H). 447.3 SC-16 6-bromo-5- methyl- pyridine-3- carbonitrile (step 1); bromomethylcyclopropane (step 2) SC-15 .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.56 (d, J = 2.2 Hz, 1H), 8.13- 8.09 (m, 1H), 7.44 (td, J = 8.0, 6.2 Hz, 1H), 7.14 (ddd, J = 16.1, 7.8, 2.7 Hz, 3H), 3.45 (s, 2H), 3.22 (d, J = 6.7 Hz, 2H), 2.89- 2.83 (m, 2H), 2.69-2.62 (m, 2H), 2.24 (s, 3H), 1.88 (s, 6H), 1.10-1.03 (m, 1H), 0.54-0.46 (m, 2H), 0.38-0.29 (m, 2H). 434.2 SC-17 2-bromo-5- (trifluoromethoxy) pyridine SC-3 .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.25-8.18 (m, 2H), 7.93 (s, 1H), 7.76 (dd, J = 9.5, 3.0 Hz, 1H), 7.47 (td, J = 7.9, 6.2 Hz, 1H), 7.22-7.13 (m, 3H), 3.50 (s, 2H), 2.91-2.85 (m, 2H), 2.49-2.43 (m, 2H), 1.84 (s, 6H). 425.2 SC-18 bromomethylcyclopropane SC-15 (step 2) .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.26-8.18 (m, 2H), 7.79 (ddd, J = 9.3, 2.9, 1.1 Hz, 1H), 7.48 (td, J = 8.0, 6.3 Hz, 1H), 7.23-7.14 (m, 3H), 3.54 (s, 2H), 3.25 (d, J = 6.6 Hz, 2H), 2.84-2.77 (m, 2H), 2.69-2.63 (m, 2H), 1.87 (s, 6H), 1.15- 1.00 (m, 1H), 0.56-0.48 (m, 2H), 0.41-0.33 (m, 2H). 479.2 SC-19 5-bromo-2- fluoro-4- methylpyridine, morpholine (step 1) SC-13 .sup.1H NMR (DMSO-d.sub.6): 7.78 (s, 1H), 7.39-7.31 (m, 2H), 7.32- 7.27 (m, 2H), 7.26-7.24 (m, 1H), 7.19 (s, 1H), 6.62 (s, 1H), 3.65-3.62 (m, 4H), 3.38-3.36 (m, 4H), 3.07 (s, 2H), 2.85-81 (m, 2H), 2.45-2.41 (m, 2H), 2.01 (s, 3H), 1.84 (s, 6H). 422.3 SC-20 2-(5-bromo-4- methylpyridin- 2-yl)propan-2-ol SC-12 .sup.1H NMR (DMSO-d.sub.6): 8.13 (s, 1H), 7.44 (s, 1H), 7.37-7.24 (m, 6H), 5.13 (bs, 1H), 3.17(s, 2H), 2.87 (d, 2H), 2.46 (d, 2H), 2.10 (s, 3H), 1.84 (s, 6H), 1.36 (s, 6H). 395.3 SC-21 2-(4-bromo-3- methylphenyl) propan-2-ol SC-12 .sup.1H NMR (DMSO-d.sub.6): 7.37- 7.32 (m, 2H), 7.31-7.28 (m, 2H), 7.27-7.22 (m, 2H), 7.18-7.11 (m, 2H), 6.95-6.92 (m, 1H), 4.91 (s, 1H), 3.08 (s, 2H), 2.86-2.84 (m, 2H), 2.45-2.43 (m, 2H), 2.06 (s, 3H), 1.84 (s, 6H), 1.35 (s, 6H). 394.2 SC-23 (3-fluorooxetan- 3-yl)methyl 4- methylbenzenesulfonate SC-15 (step 2) .sup.1H-NMR (600 MHz, DMSO-d.sub.6) 8.26 (d, J = 2.9 Hz, 1H), 8.20 (d, J = 9.3 Hz, 1H), 7.87-7.77 (m, 1H), 7.47 (td, J = 7.8, 6.0 Hz, 1H), 7.24-7.12 (m, 3H), 4.86-4.74 (m, 2H), 4.64 (dd, J = 20.8, 8.1 Hz, 2H), 3.91 (d, J = 21.4 Hz, 2H), 3.54 (s, 2H), 2.84- 2.75 (m, 2H), 2.63-2.51 (m, 2H), 1.84 (s, 6H). 513.2 SC-24 bromomethylcyclopropane SC-15 (step 2) .sup.1H-NMR (600 MHz, DMSO-d.sub.6) 8.40 (s, 1H), 7.56 (s, 1H), 7.45- 7.36 (m, 1H), 7.23-7.03 (m, 3H), 6.87 (t, J = 55.0 Hz, 1H), 3.22 (d, J = 6.6 Hz, 2H), 2.98- 2.74 (m, 2H), 2.82-2.60 (m, 2H), 2.20 (s, 3H), 1.89 (s, 6H), 1.16-1.04 (m, 1H), 0.53 (dtd, J = 8.3, 4.1, 1.9 Hz, 2H), 0.34 (dd, J = 4.8, 1.7 Hz, 2H). 459.2 SC-25 4-(5-bromopyrimidin-2- yl)morpholine SC-12 .sup.1H NMR (DMSO-d.sub.6): 8.31 (s, 2H), 7.54 (s, 1H), 7.40-7.37 (m, 2H), 7.31-7.28 (m, 3H), 3.62- 3.60 (m, 4H), 3.57-3.55 (m, 4H), 3.29 (s, 2H), 2.85-2.82 (m, 2H), 2.48-2.44 (m, 2H), 1.83 (s, 6H). 409.3 SC-26 (1- fluorocyclopropyl) methyl 4- methylbenzenesulfonate SC-15 (step 2) .sup.1H-NMR (600 MHz, DMSO-d.sub.6): 8.26 (d, J = 2.9 Hz, 1H), 8.20 (d, J = 9.3 Hz, 1H), 7.81 (ddd, J = 9.3, 2.9, 1.1 Hz, 1H), 7.48 (td, J = 7.7, 6.0 Hz, 1H), 7.19 (dd, J = 9.9, 8.0 Hz, 3H), 3.79 (d, J = 20.6 Hz, 2H), 3.58 (s, 2H), 2.86- 2.77 (m, 2H), 2.77-2.66 (m, 2H), 1.87 (s, 6H), 1.10-1.00 (m, 2H), 0.98-0.86 (m, 2H). 497.2 SC-27 [1-[tert- butyl(dimethyl) silyl] oxycyclobutyl] methyl 4- methylbenzenesulfonate SC-15 (step 2) .sup.1H NMR (600 MHz, DMSO-d.sub.6): 8.25 (d, J = 2.9 Hz, 1H), 8.21 (d, J = 9.3 Hz, 1H), 7.82-7.76 (m, 1H), 7.47 (td, J = 8.0, 6.3 Hz, 1H), 7.17 (dddt, J = 10.5, 5.7, 4.3, 1.9 Hz, 3H), 3.50 (s, 2H), 3.44 (s, 2H), 2.79-2.69 (m, 4H), 2.16 (tt, J = 8.7, 3.1 Hz, 2H), 1.91 (qd, J = 9.4, 2.7 Hz, 2H), 1.84 (s, 6H), 1.72- 1.62 (m, 1H), 1.60-1.51 (m, 1H). 509.2 SC-28 2-(4-bromo-3- methylphenyl) propan-2-ol (step 1); bromomethylcyclopropane (step 2) SC-15 .sup.1H-NMR (600 MHz, DMSO-d.sub.6) 7.46 (td, J = 8.1, 6.2 Hz, 1H), 7.34-7.28 (m, 2H), 7.22-7.19 (m, 2H), 7.19-7.12 (m, 3H), 4.88 (d, J = 0.8 Hz, 1H), 3.36 (s, 2H), 3.22 (d, J = 6.6 Hz, 2H), 2.80-2.72 (m, 2H), 2.69-2.63 (m, 2H), 1.88 (s, 6H), 1.36 (s, 6H), 1.08 (ddt, J = 9.7, 8.0, 3.1 Hz, 1H), 0.54-0.46 (m, 2H), 0.38-0.30 (m, 2H). 452.3 SC-29 2-bromo-5- (trifluoromethoxy) pyridine (step 1); (3- fluorooxetan-3- yl)methyl 4- methylbenzenesulfonate (step 2) SC-15 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 8.25 (d, J = 2.9 Hz, 1H), 8.19 (d, J = 9.2 Hz, 1H), 7.82 (dd, J = 9.2, 2.9 Hz, 1H), 7.43 (t, J = 7.5 Hz, 2H), 7.40-7.29 (m, 3H), 4.80 (ddd, J = 21.7, 7.9, 1.3 Hz, 2H), 4.64 (dd, J = 20.8, 8.1 Hz, 2H), 3.91 (d, J = 21.3 Hz, 2H), 3.51 (s, 2H), 2.84-2.74 (m, 2H), 2.63-2.51 (m, 2H), 1.83 (s, 6H). 495.2 SC-30 5-(Chloromethyl)- 2-(trifluoromethyl) pyridine SC-15 (step 2) .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.53 (d, J = 1.9 Hz, 1H), 7.88- 7.77 (m, 2H), 7.39 (q, J = 7.6, 7.1 Hz, 1H), 7.14-7.04 (m, 3H), 4.31 (s, 2H), 3.14 (d, J = 6.5 Hz, 2H), 2.82 (s, 2H), 2.67- 2.54 (m, 4H), 1.83 (s, 6H), 1.10- 0.99 (m, 1H), 0.54-0.43 (m, 2H), 0.37-0.26 (m, 2H). 477.2 SC-32 2-bromo-5- (trifluoromethoxy) pyridine (step 1); bromomethylcyclopropane (step 2) SC-15 .sup.1H-NMR (600 MHz, DMSO-d.sub.6) 8.24-8.19 (m, 2H), 7.81- 7.76 (m, 1H), 7.44 (t, J = 7.6 Hz, 2H), 7.38-7.32 (m, 3H), 3.51 (s, 2H), 3.25 (d, J = 6.7 Hz, 2H), 2.84-2.78 (m, 2H), 2.69- 2.64 (m, 2H), 1.85 (s, 6H), 1.10 (ddt, J = 9.7, 8.1, 3.2 Hz, 1H), 0.53 (dt, J = 10.3, 2.9 Hz, 2H), 0.41-0.33 (m, 2H). 461.2 SC-33 (3-fluorooxetan-3-yl)methyl)- (3- fluorooxetan- 3-yl)methyl 4- methylbenzenesulfonate SC-15 (step 2) .sup.1H-NMR (600 MHz, DMSO-d.sub.6) 7.44 (q, J = 7.4 Hz, 1H), 7.19- 7.07 (m, 3H), 4.48 (ddd, J = 44.0, 20.0, 7.9 Hz, 4H), 3.49 (d, J = 23.3 Hz, 2H), 3.11 (d, J = 6.6 Hz, 2H), 2.90 (s, 2H), 2.68- 2.60 (m, 2H), 2.60-2.52 (m, 2H), 1.85 (s, 6H), 1.08-0.95 (m, 1H), 0.53-0.41 (m, 2H), 0.36-0.24 (m, 2H). 406.2 SC-34 5-Bromo-2- cyclopropylpyridine (step 1); bromomethylcyclopropane (step 2) SC-15 .sup.1H NMR (600 MHz, DMSO-d.sub.6 8.26 (d, J = 2.6 Hz, 1H), 7.60 (dt, J = 8.5, 2.1 Hz, 1H), 7.42 (t, J = 7.6 Hz, 2H), 7.36-7.28 (m, 3H), 7.14 (d, J = 8.6 Hz, 1H), 3.36 (s, 2H), 3.25 (d, J = 6.7 Hz, 2H), 2.82-2.76 (m, 2H), 2.71- 2.65 (m, 2H), 2.02-1.94 (m, 1H), 1.87 (s, 6H), 1.17-1.02 (m, 1H), 0.88-0.82 (m, 2H), 0.78 (dq, J = 6.8, 4.1, 3.6 Hz, 2H), 0.51 (dt, J = 8.3, 3.0 Hz, 2H), 0.39-0.31 (m, 2H). 417.3 SC-35 5-bromo-2- cyclopropyl-4- methylpyridine (step 1), bromomethylcyclopropane (step 2) SC-12 for step 1; SC-15 (step 2) for step 2 .sup.1H-NMR (600 MHz, DMSO-d.sub.6) 8.05 (s, 1H), 7.37 (t, J = 7.6 Hz, 2H), 7.33-7.26 (m, 2H), 7.29-7.24 (m, 1H), 7.10 (d, J = 1.1 Hz, 1H), 3.20 (d, J = 6.5 Hz, 2H), 3.17 (s, 2H), 2.82-2.76 (m, 2H), 2.69-2.63 (m, 2H), 2.05 (s, 3H), 1.99 (tt, J = 8.2, 4.8 Hz, 1H), 1.87 (s, 6H), 1.08 (ddt, J = 9.7, 8.0, 3.2 Hz, 1H), 0.87 (dt, J = 8.1, 3.0 Hz, 2H), 0.83- 0.80 (m, 2H), 0.54-0.47 (m, 2H), 0.37-0.30 (m, 2H). 431.3 SC-36 5-bromo-2- cyclopropyl-4- methylpyridine (step 1), (3- fluorooxetan-3- yl)methyl 4- methylbenzenesulfonate (step 2) SC-12 for step 1; SC-15 (step 2) for step 2 .sup.1H-NMR (600 MHz, DMSO-d.sub.6) 8.07 (s, 1H), 7.37 (t, J = 7.6 Hz, 2H), 7.33-7.22 (m, 3H), 7.12 (s, 1H), 4.82-4.70 (m, 2H), 4.63 (dd, J = 20.6, 8.0 Hz, 2H), 3.85 (d, J = 22.0 Hz, 2H), 3.19 (s, 2H), 2.84-2.74 (m, 2H), 2.64-2.55 (m, 2H), 2.05 (s, 3H), 2.00 (tt, J = 8.2, 4.8 Hz, 1H), 1.85 (s, 6H), 0.92-0.86 (m, 2H), 0.84-0.79 (m, 2H). 465.3 SC-38 5-bromo-2-(4- pyridyl) pyrimidine SC-12 .sup.1H-NMR (600 MHz, DMSO-d.sub.6 +TFA): 10.59 (s, 1H), 9.01- 8.96 (m, 3H), 8.72 (d, J = 6.9 Hz, 2H), 8.08 (s, 1H), 7.69 (dd, J = 6.6, 2.9 Hz, 2H), 7.57 (dd, J = 5.0, 1.8 Hz, 3H), 3.30-3.24 (m, 2H), 3.10-3.05 (m, 2H), 2.52 (s, 6H). 401.2 SC-39 3-Bromo-5- trifluoromethylpyridine SC-12 .sup.1H-NMR (600 MHz, DMSO-d.sub.6) 8.67 (d, J = 2.5 Hz, 1H), 8.52 (d, J = 2.0 Hz, 1H), 8.25 (t, J = 2.3 Hz, 1H), 7.43 (t, J = 7.5 Hz, 2H), 7.34 (t, J = 7.3 Hz, 1H), 7.32-7.27 (m, 2H), 3.59 (s, 2H), 3.32 (d, J = 6.7 Hz, 2H), 2.85-2.80 (m, 2H), 2.77-2.71 (m, 2H), 1.88 (s, 6H), 1.18- 1.09 (m, 1H), 0.53 (dt, J = 8.2, 3.0 Hz, 2H), 0.41-0.34 (m, 2H). 445.2 SC-40 5-Bromo-2- cyano-3- (trifluoromethyl) pyridine SC-12 .sup.1H-NMR (600 MHz, DMSO-d.sub.6): 8.81 (d, J = 2.4 Hz, 1H), 8.43 (d, J = 2.5 Hz, 1H), 7.43 (t, J = 7.6 Hz, 2H), 7.37-7.31 (m, 1H), 7.30-7.25 (m, 2H), 3.71 (s, 2H), 3.37 (d, J = 6.7 Hz, 2H), 2.83 (d, J = 13.7 Hz, 2H), 2.78 (d, J = 13.5 Hz, 2H), 1.88 (s, 6H), 1.20-1.11 (m, 1H), 0.54 (dt, J = 8.2, 3.0 Hz, 2H), 0.43- 0.33 (m, 2H). 470.2 SC-42 [1-[tert- butyl(dimethyl) silyl] oxycyclobutyl] methyl 4- methylbenzenesulfonate SC-37 .sup.1H-NMR (600 MHz, DMSO-d.sub.6): 7.46 (q, J = 7.3 Hz, 1H), 7.17 (s, 3H), 3.11 (d, J = 6.5 Hz, 2H), 3.02 (s, 2H), 2.99 (s, 2H), 2.77- 2.57 (m, 4H), 2.01-1.86 (br s, 6H), 1.86-1.74 (m, 4H), 1.59- 1.51 (m, 1H), 1.42-1.32 (m, 1H), 1.06-0.98 (m, 1H), 0.50- 0.43 (m, 2H), 0.33-0.26 (m, 2H). 402.3 SC-43 bromomethylcyclopropane SC-15 (step 2) .sup.1H-NMR (600 MHz, DMSO-d.sub.6) 8.94 (s, 2H), 8.72-8.68 (m, 2H), 8.17-8.13 (m, 2H), 7.44 (t, J = 7.5 Hz, 2H), 7.35 (t, J = 7.4 Hz, 1H), 7.31 (d, J = 7.5 Hz, 2H), 3.60 (s, 2H), 2.84 (d, J = 13.7 Hz, 2H), 2.76 (d, J = 13.6 Hz, 2H), 1.88 (s, 6H), 1.20- 1.08 (m, 1H), 0.58-0.50 (m, 2H), 0.43-0.35 (m, 2H). One CH.sub.2 signal overlaps with residual water peak (observed in HSQC: (3.3; 44.8)). 455.3 SC-45 3- Bromopropionitrile SC-44 .sup.1H-NMR (600 MHz, DMSO-d.sub.6) 7.40 (t, J = 7.6 Hz, 2H), 7.34- 7.27 (m, 3H), 3.21 (t, J = 6.6 Hz, 2H), 3.12 (d, J = 6.6 Hz, 2H), 2.92 (s, 2H), 2.67 (d, J = 13.2 Hz, 2H), 2.60 (d, J = 13.1 Hz, 2H), 2.56 (t, J = 6.5 Hz, 2H), 1.84 (s, 6H), 1.06-0.99 (m, 1H), 0.52-0.44 (m, 2H), 0.34-0.27 (m, 2H). 353.2 SC-46 [1-[tert- butyl(dimethyl) silyl] oxycyclobutyl] methyl 4- methylbenzenesulfonate SC-37 .sup.1H NMR (600 MHz, DMSO-d.sub.6): 7.39 (t, J = 7.6 Hz, 2H), 7.32- 7.25 (m, 3H), 3.10 (d, J = 6.6 Hz, 2H), 3.01 (s, 2H), 2.98 (s, 2H), 2.65-2.59 (m, 2H), 2.59- 2.53 (m, 2H), 1.86-1.80 (m, 8H), 1.77 (qd, J = 9.4, 2.5 Hz, 2H), 1.59-1.52 (m, 1H), 1.36 (dp, J = 11.3, 8.9 Hz, 1H), 1.06- 0.98 (m, 1H), 0.47 (dt, J = 10.1, 2.9 Hz, 2H), 0.33-0.26 (m, 2H). 384.3 SC-47 2-(oxetan-3- yl)ethyl 4- methylbenzenesulfonate SC-44 .sup.1H NMR (600 MHz, DMSO-d.sub.6): 7.49-7.41 (m, 1H), 7.18- 7.11 (m, 3H), 4.54 (dd, J = 7.8, 5.8 Hz, 2H), 4.17 (t, J = 6.1 Hz, 2H), 3.08 (d, J = 6.5 Hz, 2H), 2.89 (t, J = 6.9 Hz, 2H), 2.82 (s, 2H), 2.85-2.76 (m, 1H), 2.67- 2.61 (m, 2H), 2.59-2.53 (m, 2H), 1.85 (s, 6H), 1.62 (q, J = 7.2 Hz, 2H), 1.04-0.97 (m, 1H), 0.47 (dt, J = 10.4, 3.0 Hz, 2H), 0.31-0.25 (m, 2H). 402.3

[0466] Names and structures of exemplified compounds:

##STR00109## ##STR00110## ##STR00111## ##STR00112## ##STR00113## ##STR00114## ##STR00115## ##STR00116## ##STR00117## ##STR00118## ##STR00119## ##STR00120## ##STR00121## ##STR00122## ##STR00123## ##STR00124##

[0467] Pharmacological Investigations

[0468] Functional investigation on the human mu-opioid receptor (hMOP), human kappa-opioid receptor (hKOP), human delta-opioid receptor (hDOP), and human nociceptin/orphanin FQ peptide receptor (hNOP)

[0469] Human Mu-Opioid Peptide (hMOP) Receptor Binding Assay

[0470] The hMOP receptor binding assay was performed as homogeneous SPA-assay (scintillation proximity assay) using the assay buffer 50 mM TRIS-HCl (pH 7.4) supplemented with 0.052 mg/ml bovine serum albumin (Sigma-Aldrich Co. St. Louis. Mo.). The final assay volume (250 l/well) included 1 nM of [N-allyl-2.3-.sup.3H]naloxone as ligand (PerkinElmer Life Sciences. Inc. Boston. Mass. USA) and either test compound in dilution series or 25 M unlabelled naloxone for determination of unspecific binding. The test compound was diluted with 25% DMSO in H.sub.2O to yield a final 0.5% DMSO concentration which also served as a respective vehicle control. The assay was started by adding wheat germ agglutinin coated SPA beads (GE Healthcare UK Ltd. Buckinghamshire. UK) which had been preloaded with hMOP receptor membranes (PerkinElmer Life Sciences. Inc. Boston. Mass. USA). After incubation for 90 minutes at RT and centrifugation for 20 minutes at 500 rpm the signal rate was measured by means of a 1450 Microbeta Trilux -counter (PerkinElmer Life Sciences/Wallac. Turku. Finland). Half-maximal inhibitory concentration (IC50) values reflecting 50% displacement of [.sup.3H]naloxone-specific receptor binding were calculated by nonlinear regression analysis and Ki values were calculated by using the Cheng-Prusoff equation. (Cheng and Prusoff 1973).

[0471] Human Kappa-Opioid Peptide (hKOP) Receptor Binding Assay

[0472] The hKOP receptor binding assay is run as homogeneous SPA-assay (scintillation proximity assay) using the assay buffer 50 mM TRIS-HCl (pH 7.4) supplemented with 0.076 mg BSA/ml. The final assay volume of 250 l per well includes 2 nM of [.sup.3H]U69,593 as ligand, and either test compound in dilution series or 100 M unlabelled naloxone for determination of unspecific binding. The test compound is diluted with 25% DMSO in H.sub.2O to yield a final 0.5% DMSO concentration which serves as respective vehicle control, as well. The assays are started by the addition of wheat germ agglutinin coated SPA beads (1 mg SPA beads/250 l final assay volume per well) which has been preloaded for 15 minutes at room temperature with hKOP receptor membranes (14.8 g/250 l final assay volume per well). After short mixing on a mini-shaker, the microtiter plates are covered with a lid and the assay plates are incubated for 90 minutes at room temperature. After this incubation, the microtiter plates are sealed with a topseal and centrifuged for 20 minutes at 500 rpm. The signal rate is measured after a short delay of 5 minutes by means of a 1450 Microbeta Trilux -counter (PerkinElmer Life Sciences/Wallac, Turku, Finland). Half-maximal inhibitory concentration (IC50) values reflecting 50% displacement of [.sup.3H]U69.593-specific receptor binding are calculated by nonlinear regression analysis and K.sub.i values are calculated by using the Cheng-Prusoff equation, (Cheng and Prusoff, 1973).

[0473] Human Delta-Opioid Peptide (hDOP) Receptor Binding Assay

[0474] The hDOP receptor binding assay is performed as homogeneous SPA-assay using the assay buffer 50 mM TRIS-HCl, 5 mM MgCl.sub.2 (pH 7.4). The final assay volume (250 l/well) includes 1 nM of [Tyrosyl-3,5-.sup.3H]2-D-Ala-deltorphin II as ligand, and either test compound in dilution series or 10 M unlabelled naloxone for determination of unspecific binding. The test compound is diluted with 25% DMSO in H.sub.2O to yield a final 0.5% DMSO concentration which serves as respective vehicle control, as well. The assays are started by the addition of wheat germ agglutinin coated SPA beads (1 mg SPA beads/250 l final assay volume per well) which has been preloaded for 15 minutes at room temperature with hDOP receptor membranes (15.2 g/250 l final assay volume per well). After short mixing on a mini-shaker, the microtiter plates are covered with a lid and the assay plates are incubated for 120 minutes at room temperature and centrifuged for 20 minutes at 500 rpm. The signal rate is measured by means of a 1450 Microbeta Trilux -counter (PerkinElmer Life Sciences/Wallac, Turku, Finland). Half-maximal inhibitory concentration (IC50) values reflecting 50% displacement of [Tyrosyl-3,5-.sup.3H]2-D-Ala-deltorphin II-specific receptor binding are calculated by nonlinear regression analysis and K.sub.i values are calculated by using the Cheng-Prusoff equation, (Cheng and Prusoff, 1973).

[0475] Human Nociceptin/Orphanin FQ Peptide (hNOP) Receptor Binding Assay

[0476] The hNOP receptor binding assay was performed as homogeneous SPA-assay (scintillation proximity assay) using the assay buffer 50 mM TRIS-HCl, 10 mM MgCl.sub.2, 1 mM EDTA (pH 7.4). The final assay volume (250 l/well) included 0.5 nM of [leucyl-.sup.3H]nociceptin as ligand (PerkinElmer Life Sciences. Inc. Boston. Mass. USA) and either test compound in dilution series or 1 M unlabelled nociceptin for determination of unspecific binding. The test compound was diluted with 25% DMSO in H.sub.2O to yield a final 0.5% DMSO concentration which also served as a respective vehicle control. The assay was started by adding wheat germ agglutinin coated SPA beads (GE Healthcare UK Ltd. Buckinghamshire. UK) which had been preloaded with hNOP receptor membranes (PerkinElmer Life Sciences. Inc. Boston. Mass. USA). After incubation for 60 minutes at RT and centrifugation for 20 minutes at 500 rpm the signal rate was measured by means of a 1450 Microbeta Trilux -counter (PerkinElmer Life Sciences/Wallac. Turku. Finland). Half-maximal inhibitory concentration (IC50) values reflecting 50% displacement of [.sup.3H]nociceptin-specific receptor binding were calculated by nonlinear regression analysis and Ki values were calculated by using the Cheng-Prusoff equation. (Cheng and Prusoff. 1973).

TABLE-US-00003 hNOP Ki [nM] or % hMOP Ki [nM] or % Example inhibition at 1 M inhibition at 1 M SC-1 200 19% SC-2 850 12% SC-3 370 3605 SC-4 860 15 SC-5 800 99 SC-6 1 285 SC-7 230 2 SC-8 3 100 SC-9 380 48 SC-10 2 157 SC-11 99 3 SC-12 630 13% SC-13 860 18% SC-15 13 1330 SC-16 31 1315 SC-18 55 805 SC-19 1810 5890 SC-20 1165 5840 SC-21 775 3580 SC-22 380 11% SC-23 25 545 SC-24 23 1185 SC-26 91 1015 SC-27 12 335 SC-28 46 78 SC-29 16 65 SC-31 15 150 SC-32 36 100 SC-33 23 115 SC-34 17 50 SC-35 19 185 SC-36 10 330 SC-37 37 44 SC-39 5 48 SC-40 6 102 SC-41 21 465 SC-42 21 125 SC-43 31 83 SC-44 15 110 SC-45 25 37 SC-46 29 48 SC-47 9 44

[0477] Protocol for [.sup.5S]GTPS Functional NOP/MOP/KOP/DOP Assays

[0478] Cell membrane preparations of CHO-K1 cells transfected with the human MOP receptor (Art.-No. RBHOMM) or the human DOP receptor (Art.-No. RBHODM), and HEK293 cells transfected with the human NOP receptor (Art.-No. RBHORLM) or the human KOP receptor (Art.-No. 6110558) are available from PerkinElmer (Waltham, Mass.). Membranes from CHO-K1 cells transfected with the human nociceptin/orphanin FQ peptide (hNOP) receptor (Art.-No. 93-0264C2, DiscoveRx Corporation, Freemont, Calif.) are also used. [S]GTPS (Art.-No. NEG030H; Lot-No. #0112, #0913, #1113 calibrated to 46.25 TBq/mmol) is available from PerkinElmer (Waltham, Mass.).

[0479] The [.sup.35S]GTPS assays are carried out essentially as described by Gillen et al (2000). They are run as homogeneous scintillation proximity (SPA) assays in microtiter luminescence plates, where each well contains 1.5 mg of WGA-coated SPA-beads. To test the agonistic activity of test compounds on recombinant hNOP, hMOP, hDOP, and hKOP receptor expressing cell membranes from CHO-K1 or HEK293 cells, 10 or 5 g membrane protein per assay are incubated with 0.4 nM [.sup.3S]GTPS and serial concentrations of receptor-specific agonists in buffer containing 20 mM HEPES pH 7.4, 100 mM NaCl, 10 mM MgCl2, 1 mM EDTA, 1 mM dithiothreitol, 1.28 mM NaN.sub.3, and 10 M GDP for 45 min at room temperature. The microtiter plates are then centrifuged for 10 min at 830 g to sediment the SPA beads. The microtiter plates are sealed and the bound radioactivity [cpm] is determined after a delay of 15 min by means of a 1450 Microbeta Trilux (PerkinElmer, Waltham, Mass.).

[0480] The unstimulated basal binding activity (UBS.sub.obs [cpm]) is determined from 12 unstimulated incubates and is set as 100% basal binding. For determination of the potency and the efficacy, the arithmetic mean of the observed total [.sup.35S]GTPS binding (TB.sub.obs [cpm]) of all incubates (duplicates) stimulated by the receptor-specific agonists (i.e. N/OFQ, SNC80, DAMGO, or U69,593) are transformed in percent total binding (TB.sub.obs [%]) relative to the basal binding activity (i.e. 100% binding). The potency (EC.sub.50) of the respective agonist and its maximal achievable total [.sup.35S]GTPS binding (TB.sub.calc [%]) above its calculated basal binding (UBS.sub.calc [%]) are determined from its transformed data (TB.sub.obs [%]) by means of nonlinear regression analysis with XLfit for each individual concentration series. Then the difference between the calculated unstimulated [.sup.35S]GTPS binding (UBS.sub.calc [%]) and the maximal achievable total [.sup.3S]GTPS binding (TB.sub.calc [%]) by each tested agonist is determined (i.e. B1.sub.calc [%]). This difference (B1.sub.calc [%]) as a measure of the maximal achievable enhancement of [.sup.3S]GTPS binding by a given agonist is used to calculate the relative efficacy of test compounds versus the maximal achievable enhancement by a receptor-specific full agonist, e.g. N/OFQ (B1.sub.calc-N/OFQ [%]) which is set as 100% relative efficacy for the hNOP receptor. Likewise, the percentage efficacies of test compounds at the hDOP, hMOP, or hKOP receptor are determined versus the calculated maximal enhancement of [.sup.35S]GTPS binding by the full agonists SNC80 (B1.sub.calc-SNC80 [%]), DAMGO (B1.sub.calc-DAMGO [%]) and U69,593 (B1.sub.calc-U69,593 [%]) which are set as 100% relative efficacy at each receptor, respectively.