3-(Carboxyethyl)-8-Amino-2-Oxo-1,3-Diaza-Spiro-[4.5]-Decane Derivatives

Abstract

The invention relates to 3-(carboxyethyl)-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives, their preparation and their use in medicine, particularly in the treatment of pain.

Claims

1. A compound according to general formula (I) ##STR00264## 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.2—O—(CH.sub.2).sub.2—; or —(CH.sub.2).sub.2—NR.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 poly substituted; 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 poly substituted; 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 poly substituted; 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)O—CH.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)O—CH.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)O—CH.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)O—CH.sub.2—, or —S(═O).sub.2—; X means —O—, —S— or —NR.sup.6—; R.sup.5 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 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; in case X means NR.sup.6, R.sup.6 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 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; or in case X means NR.sup.6, R.sup.5 and R.sup.6 together with the nitrogen atom to which they are attached form a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono-or polysubstituted; R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19, and R.sup.20 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.7 and R.sup.8 together with the carbon atom to which they are attached form a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein “mono- or polysubstituted” means that one or more hydrogen atoms are replaced by a substituent independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —R.sup.21, —C(═O)R.sup.21, —C(═O)OR.sup.21, —C(═O)NR.sup.21R.sup.22, —O—(CH.sub.2CH.sub.2—O).sub.1—30—H, —O—(CH.sub.2CH.sub.2—O).sub.1—30—CH.sub.3, ═O, —OR.sup.21, —OC(═O)R.sup.21, —OC(═O)OR.sup.21, —OC(═O)NR.sup.21R.sup.22, —NO.sub.2, —NR.sup.21R.sup.22, —NR.sup.21— (CH.sub.2).sub.1—6—C(═O)R.sup.22, —NR.sup.21—(CH.sub.2).sub.1—6—C(═O)OR.sup.22, —NR.sup.23—(CH.sub.2).sub.1—6—C(═O)NR.sup.21R.sup.22, —NR.sup.21C(═O)R.sup.22, —NR.sup.21C(═O)—OR.sup.22, —NR.sup.23C(═O)NR.sup.21R.sup.22, —NR.sup.21S(═O).sub.2R.sup.22, —SR.sup.21, —S(═O)R.sup.21, —S(═O).sub.2R.sup.21, —S(═O).sub.2OR.sup.21, and —S(═O).sub.2NR.sup.21R.sup.22; wherein R.sup.21, R.sup.22 and R.sup.23 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, —OH, —NH.sub.2, and —O—C.sub.1-C.sub.6-alkyl; a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted; 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, —OH, —NH.sub.2, -C.sub.1-C.sub.6-alkyl and —O—C.sub.1-C.sub.6-alkyl; a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted; 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, —OH, —NH.sub.2, -C.sub.1-C.sub.6-alkyl and -O-C.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, —OH, —NH.sub.2, -C.sub.1-C.sub.6-alkyl and —O—C.sub.1-C.sub.6-alkyl; 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, —OH, —NH.sub.2, -C.sub.1-C.sub.6-alkyl and —O—C.sub.1-C.sub.6-alkyl; or R.sup.21 and R.sup.22 within —C(═O)NR.sup.21R.sup.22, —OC(═O)NR.sup.21R.sup.22, -NR.sup.21R.sup.22, —NR.sup.23—(CH.sub.2).sub.1—6— C(═O)NR.sup.21R.sup.22, —NR.sup.23C(═O)NR.sup.21R.sup.22, or —S(═O).sub.2NR.sup.21R.sup.22 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.2—O—(CH.sub.2).sub.2—; or —(CH.sub.2).sub.2—NR.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.7 and R.sup.8 independently of one another mean —H or -C.sub.1-C.sub.6-alkyl.

3. The compound according to claim 1, wherein R.sup.7 and R.sup.8 together with the carbon atom to which they are attached form a ring selected from the group consisting of cyclopropyl, cyclobutyl or cyclopentyl, oxetanly, tetrahydrofuranyl or tetrahydropyranyl, in each case unsubstituted.

4. The compound according to claim 1, wherein R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19, and R.sup.20 independently of one another mean —H, —F, —OH, or -C.sub.1-C.sub.6-alkyl.

5. 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.

6. The compound according to claim 1, wherein 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.

7. The compound according to claim 1, wherein R.sup.1 means —H or —CH.sub.3; and wherein R.sup.2 means —CH.sub.2—cycloalkyl, —CH.sub.2—cyclobutyl, —CH.sub.2—cyclopentyl, —CH.sub.2—oxetanyl or —CH.sub.2—tetrahydrofuranyl.

8. The compound according to claim 1, wherein 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—.

9. 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.

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

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

12. The compound according to claim 1, wherein R.sup.4 means —H.

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

14. The compound according to claim 1, wherein R.sup.4 means 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.

15. The compound according to claim 1, wherein R.sup.4 means 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.

16. The compound 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.

17. The compound according to claim 1, wherein R.sup.4 means 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.

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

19. 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, mono- or polysubstituted.

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

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

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

23. The compound according to claim 1, wherein X means NR.sup.6 and R.sup.5 and R.sup.6 together with the nitrogen atom to which they are attached form a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted.

24. The compound according to claim 1, wherein X means NR.sup.6 and R.sup.6 means —H or -C.sub.1-C.sub.6-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.

25. The compound according to claim 1, which has a structure according to any of general formulas (II-A) to (VIII-C): ##STR00265## ##STR00266## ##STR00267## ##STR00268## ##STR00269## ##STR00270## ##STR00271## ##STR00272## ##STR00273## ##STR00274## ##STR00275## ##STR00276## ##STR00277## ##STR00278## ##STR00279## ##STR00280## ##STR00281## ##STR00282## ##STR00283## ##STR00284## ##STR00285## wherein in each case R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, and X are defined as in claim 1, R.sup.C means —H, —OH, —F, —CN or -C.sub.1-C.sub.4-alkyl; R.sup.D means —H or —F; or a physiologically acceptable salt thereof.

26. The compound according to claim 1, wherein the substructure ##STR00286## has a meaning selected from the group consisting of:. ##STR00287## ##STR00288## ##STR00289## ##STR00290## ##STR00291## ##STR00292## ##STR00293## ##STR00294## ##STR00295## ##STR00296## ##STR00297## ##STR00298## ##STR00299## ##STR00300## ##STR00301## ##STR00302## ##STR00303## ##STR00304## ##STR00305## ##STR00306## ##STR00307## ##STR00308## ##STR00309## ##STR00310## ##STR00311## ##STR00312## ##STR00313## ##STR00314## ##STR00315## ##STR00316## ##STR00317## ##STR00318## ##STR00319## ##STR00320## ##STR00321## ##STR00322## ##STR00323## ##STR00324## ##STR00325## ##STR00326## ##STR00327## ##STR00328## ##STR00329## ##STR00330## ##STR00331## ##STR00332##

27. The compound according to claim 1, wherein R.sup.1 means —H or —CH.sub.3; R.sup.2 means -C.sub.1-C.sub.6-alkyl, linear or branched, saturated, unsubstituted; 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, —CN, —CH.sub.3, —CH.sub.2CH.sub.3, —CH.sub.2F, —CHF.sub.2, —CF.sub.3, —OCF3, —OH, —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; 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, and —O—C.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 —O—C.sub.1-C.sub.4-alkyl, wherein said 3-6-membered cycloalkyl is connected through -C.sub.1-C.sub.6-alkylene; or 3-6-membered heterocycloalkyl, 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 —O—C.sub.1-C.sub.4-alkyl, wherein said 3-6-membered heterocycloalkyl is connected through -C.sub.1-C.sub.6-alkylene; X means —O— or —NR.sup.6—; 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—C.sub.1-C.sub.4-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.4-alkyl, —C(═O)N(C.sub.1-C.sub.4-alkyl).sub.2, —OH, —S(═O)C.sub.1-C.sub.4-alkyl and —S(═O).sub.2 C.sub.1-C.sub.4-alkyl; -cyclobutyl, unsubstituted or monosubstituted with —OH; wherein said -cyclobutyl is connected through —CH.sub.2—; -heterocyclobutyl, unsubstituted; or -oxazolyl, -pyridinyl, -pyridazinyl or -pyrimidinyl, 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, —I, —OH, —O—C.sub.1-C.sub.4-alkyl, —CN, and —S(═O).sub.2C.sub.1-C.sub.4-alkyl; wherein said -oxazolyl, -pyridinyl, -pyridazinyl or -pyrimidinyl is optionally connected through —CH.sub.2—; in case X means NR.sup.6, R.sup.6 means —H or —CH.sub.3; or in case X means NR.sup.6, R.sup.5 and R.sup.6 together with the nitrogen atom to which they are attached form a piperidine moiety, a pyrrolidine moiety, a morpholine moiety, a thiomorpholine moiety, a thiomorpholine dioxide moiety, or a piperazine moiety, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of ═O, —OH, and —C(═O)NH.sub.2; wherein said piperidine moiety, pyrrolidine moiety, morpholine moiety, thiomorpholine moiety, thiomorpholine dioxide moiety, or piperazine moiety is optionally condensed with an imidazole moiety, unsubstituted; R.sup.7 and R.sup.8 independently of one another mean —H or —CH.sub.3; or R.sup.7 and R.sup.8 together with the carbon atom to which they are attached form a ring selected from the group consisting of cyclopropyl, cyclobutyl, heterocyclobutyl and heterocyclohexyl, in each case unsubstituted; and R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19, and R.sup.20 mean —H.

28. The compound according to claim 1, which has a structure according to general formula (I′) ##STR00333## wherein R.sup.1 to R.sup.5, R.sup.7 to R.sup.20, and X are defined as in claim 1, or a physiologically acceptable salt thereof.

29. The compound according to claim 1, which has a structure according to general formula (IX) ##STR00334## wherein R.sup.7 means —H or —OH; R.sup.D means —H or —F; R.sup.5 means —H, —CH.sub.3, or —CH.sub.2CH.sub.2—OH; R.sup.6 means —H or —CH.sub.3; and R.sup.7 means —CH.sub.3 and R.sup.8 means —CH.sub.3; or R.sup.7 and R.sup.8 together with the carbon atom to which they are attached form a cyclopropyl ring; or a physiologically acceptable salt thereof.

30. The compound according to claim 1, which is selected from the group consisting of CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridazin-3-yl-propionamide; CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propionamide; CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-pyridin-4-yl)-propionamide; CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyridin-3-yl)-propionamide; CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(3-methoxy-pyridin-4-yl)-propionamide; CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyridazin-3-yl)-propionamide; CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methylsulfonyl-pyridin-2-yl)-propionamide; CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyridin-2-yl)-propionamide; CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methylsulfonyl-pyridin-3-yl)-propionamide; CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyrazin-2-yl)-propionamide; CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyridin-2-yl)-propionamide; CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxazol-5-yl-methyl)-propionamide; CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxazol-2-yl-methyl)-propionamide; CIS-1-(Cyclobutyl-methyl)-3-[3-[3,4-dihydroxy-piperidin-1-yl]-3-oxo-propyl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-1-(Cyclobutyl-methyl)-3-[3-[3,4-dihydroxy-pyrrolidin-1-yl]-3-oxo-propyl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-1-(Cyclobutyl-methyl)-3-[3-[(3S,4R)-3,4-dihydroxy-pyrrolidin-1-yl]-3-oxo-propyl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[3-(3-hydroxy-piperidin-1-yl)-3-oxo-propyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(1-hydroxy-cyclobutyl)-methyl]-propionamide; CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[3-oxo-3-(5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-7-yl)-propyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-3-[3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propanoylamino]-N,N-dimethyl-propionamide; CIS-N-(2-Cyano-pyrimidin-5-yl)-3-[8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propionamide; CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-2-yl-propionamide; CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-hydroxy-pyrimidin-2-yl)-propionamide; CIS-3-[8-Dimethylamino-1-[(1-hydroay-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyrimidin-2-yl)-propionamide; CIS-3-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide; CIS-3-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-propionamide; CIS-3-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propionamide; CIS-3-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-propionamide; CIS-3-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridazin-3-yl-propionamide; CIS-3-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-propionamide; CIS-3-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-propionamide; CIS-3-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-5-yl-propionamide; CIS-3-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide; CIS-3-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide; CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridin-3-yl-propionamide; CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridin-4-yl-propionamide; CIS-2-[3-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propanoylamino]-2-methyl-propionamide; CIS-3-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methylsulfonyl-ethyl)-propionamide; CIS-3-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-propionamide; CIS-8-Dimethylamino-1-(3-methoxy-propyl)-3-[3-oxo-3-(3-oxo-piperazin-1-yl)-propyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-(2R)-1-[3-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propanoyl]-pyrrolidine-2-carboxylic acid amide; CIS-N-(Carbamoyl-methyl)-3-[8-dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propionamide; CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridin-2-yl-propionamide; CIS-3-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide; CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide; CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propionamide; CIS-3-[1-(Cyclobutyl-methyl)-8-[methyl-(2-methyl-propyl)-amino]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-propionamide; CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-propionamide; CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-5-yl-propionamide; CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-propionamide; CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-ethyl)-propionamide; CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-propionamide; CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-propionamide; CIS-N-(Carbamoyl-methyl)-3-[1-(cyclobutyl-methyl)-8-dimethyl-amino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide; CIS-N-(Carbamoyl-methyl)-3-[1-(cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide; CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide; CIS-3-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-propionamide; CIS-3-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide; CIS-3-[8-(Ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro [4.5] decan-3-yl]-2,2-dimethyl-propionamide; CIS-3-[8-(Ethyl-methyl-amino)-1-methyl-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide; CIS-2,2-Dimethyl-3-(8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-propionamide; CIS-3-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethyl-propionamide; CIS-3-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethyl-propionamide; CIS-3-[1-(Cyclobutyl-methyl)-8-ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide; CIS-3-[8-Dimethylamino-1-(oxetan-3-yl-methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide; CIS-3-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide; CIS-3-[8-(Ethyl-methyl-amino)-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide; CIS-8-Dimethylamino-3-(2,2-dimethyl-3-morpholin-4-yl-3-oxo-propyl)-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-l,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-2,2-dimethyl-propionamide; CIS-3-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide; CIS-8-Dimethylamino-3-[3-(1,1-dioxo-[1,4]thiazinan-4-yl)-2,2-dimethyl-3-oxo-propyl]-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; TRANS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide TRANS-3-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethyl-propionamide; CIS-3-[1-(Cyclopropyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-N,N-dimethyl-propionamide; CIS-3-[1-(Cyclopropyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide; CIS-1-((1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)methyl)cyclopropanecarboxamide; CIS-3-((1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)methyl)oxetane-3-carboxamide; CIS-3-(1-(cyclopropylmethyl)-8-(methylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanamide; CIS-3-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)propanamide; CIS-3-(8-(dimethylamino)-1-((1-fluorocyclopropyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanamide and the physiologically acceptable salts thereof.

31. The compound according to claim 1 for use in the treatment of pain.

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

33. 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.

34. A method of treating a disorder selected from the group consisting of neurodegenerative disorders, neuroinflammatory disorders, neuropsychiatric disorders, and substance abuse/dependence, said method comprising administering to a patient in need thereof an effective amount therefor of at least one compound according to claim 1.

Description

EXAMPLES

[0277] “RT” means room temperature (23 ± 7° C.), “M” are indications of concentration in mol/l, ,,aq. “ means aqueous, ,,sat.” means saturated, “sol.” means solution, “conc.” means concentrated.

TABLE-US-00003 Further abbreviations: brine saturated aqueous sodium chloride solution CC column chromatography cHex cyclohexane DCM dichloromethane DIPEA N,N-diisopropylethylamine DMF N,N-dimethylformamide Et Ethyl ether diethyl ether EE ethyl acetate EtOAc ethyl acetate EtOH ethanol h hour(s) H.sub.2O water HATU O-(7-aza-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate LDA Lithium-di-isoproyl-amid Me Methyl m/z mass-to-charge ratio MeOH methanol MeCN acetonitrile min minutes MS mass spectrometry NBS N-bromo-succinimide NEt.sub.3 triethylamine Pd.sub.2(dba).sub.3 tris(dibenzylideneacetone)dipalladium(0) PE Petrol Ether (60-80° C.) RM reaction mixture RT room temperature T3P 2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide tBME tert-.butyl methyl ether THF tetrahydrofuran v/v volume to volume w/w weight to weight XantPhos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[0278] The yields of the compounds prepared were not optimised. All temperatures are uncorrected.

[0279] 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 DC, 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 DC, US, repspectively, for example) or can be prepared using the conventional methods known to the person skilled in the art.

[0280] The mixing ratios of solvents or eluents for chromatography are specified in v/v.

[0281] 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.

Remark Regarding Stereochemistry

[0282] CIS refers to the relative configuration of compounds described herein, in which both nitrogen atoms are drawn on the same face of the cyclohexane ring as described in the following exemplary structure. Two depictions are possible:

##STR00075##

##STR00076##

CIS configuration

[0283] TRANS refers to compounds, in which both nitrogen atoms are on opposite faces of the cyclohexane ring as described in the following exemplary structure. Two depictions are possible:

##STR00077##

##STR00078##

TRANS configuration

Synthesis of Intermediates

[0284] Synthesis of INT-799: CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

##STR00079##

Step 1: CIS-1-((1-(Benzyloxy)Cyclobutyl)Methyl)-3-(3,4-Dimethoxybenzyl)-8-(Dimethylamino)-8-Phenyl-1,3-Diazaspiro[4.5]Decan-2-One

[0285] NaOH (1.42 g, 35.5 mmol) was added to a solution of CIS-3-(3,4-dimethoxybenzyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-794) (3 g, 7.09 mmol) in DMSO (90 mL) under argon atmosphere and the reaction mixture was stirred at 80° C. for 30 min. ((1-(Bromomethyl)cyclobutoxy)methyl)benzene (5.4 g, 21.3 mmol) was added and stirring was continued for 2 days at 80° C. The reaction completion was monitored by TLC. The reaction mixture was diluted with water (500 mL) and extracted with diethyl ether (4x300 mL). The combined organic extracts were dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by column chromatography (230-400 mesh silica gel; 65-70% EtOAc in petroleum ether as eluent) to afford 2.5 g (59%) of CIS-1-((1-(benzyloxy)cyclobutyl)methyl)-3-(3,4-dimethoxybenzyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (TLC system: 10% MeOH in DCM; Rf: 0.8).

Step 2: CIS-8-Dimethylamino-1-[(1-Hydroxy-Cyclobutyl)-Methyl]-8-Phenyl-1,3-Diazaspiro[4.5] Decan-2-One

[0286] TFA (12 mL) was added to CIS-1-((1-(benzyloxy)cyclobutyl)methyl)-3-(3,4-dimethoxybenzyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (2.5 g, 4.18 mmol) at 0° C. and the resulting mixture was stirred at 70° C. for 6 h. The reaction completion was monitored by LCMS. The reaction mixture was concentrated under reduced pressure. To the residue sat. aq. NaHCO.sub.3 was added (until pH 10) and the organic product was extracted with DCM (3×150 mL). The combined organic extracts were dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by column chromatography (230-400 mesh silica gel; 5% MeOH in DCM as eluent) to afford 500 mg (33%) of CIS-8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-799) (TLC system: 10% MeOH in DCM; Rf: 0.5). [M+H].sup.+ 358.2

[0287] Synthesis of INT-897: CIS-3-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionic acid

##STR00080##

Step 1: CIS-3-(1-(Cyclobutylmethyl)-8-(Dimethylamino)-2-Oxo-8-Phenyl-1,3-Diazaspiro[4.5] Decan-3-yl)-2,2-Dimethylpropanenitrile

[0288] KOtBu (1.7 g, 15.23 mmol) was added to a suspension of CIS-1-(cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-987) (1.3 g, 3.80 mmol) in DMSO (20 mL) at RT. 3-Bromo-2,2-dimethylpropanenitrile (3.7 g, 28.84 mmol) was added and the reaction mixture was stirred for 16 h at 130° C. The reaction mixture was quenched with cold water (25 mL) and the organic product was extracted with EtOAc (2x20 mL). The combined organic extracts were dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to give 1.6 g of CIS-3-(1-(cyclobutylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanenitrile as a brown semi-solid. (TLC system: 10% MeOH in DCM; Rf: 0.6). The product was used in the next step without further purification.

Step 2: CIS-3-[1-(Cyclobutyl-Methyl)-8-Dimethylamino-2-Oxo-8-Phenyl-1,3-Diazaspiro[4.5]Decan-3-yl]-2,2-Dimethyl-Propionic Acid

[0289] 12 N aq. HCl (16 mL) was added to CIS-3-(1-(cyclobutylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanenitrile (1.6 g, 3.78 mmol) and the resulting solution was refluxed for 16 h. The reaction mixture was concentrated under reduced pressure. To the residue toluene was added and the resulting mixture was concentrated under reduced pressure again. The residue was washed with acetone (10 mL), diethyl ether (10 mL) and DCM (10 mL) to give 1.2 g of CIS-3-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionic acid (INT-897) as a solid. (TLC system: 10% MeOH in DCM R.sub.f: 0.3.) [M+H].sup.+ 442.3

[0290] Synthesis of INT-898: CIS-3-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propionic acid; 2,2,2-trifluoro-acetic acid salt

##STR00081##

Step 1: CIS-Tert-Butyl-3-(8-(Dimethylamino)-2-Oxo-8-Phenyl-1,3-Diazaspiro[4.5]Decan-3-yl)Propanoate

[0291] KOtBu (1 M in THF) (13.74 mL, 13.74 mmol) was added to a solution of CIS-1-(cyclobutylmethyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-987) (2.5 g, 9.16 mmol) in 1,4-dioxane (240 mL) under argon atmosphere and the reaction mixture was stirred for 15 minutes. Tert-butyl acrylate (1.60 mL, 10.99 mmol) in 1,4-dioxane (10 mL) was added. The reaction mixture was stirred for 1 h at RT, then quenched with sat. aq. NH.sub.4Cl (60 mL) and the organic product was extracted with EtOAc (2×100 mL). The combined organic layer was dried over anhydr. Na.sub.2SO.sub.4 and concentrated in vacuo. The crude product was purified by column chromatography (using 100-200 mesh silica gel and 0-10 vol% MeOH in DCM as eluent) to afford 1.2 g (32%) of tert-butyl CIS-3-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)propanoate as pale yellow solid (TLC system: 10% MeOH in DCM; Rf: 0.4).

Step 2: CIS-3-[1-(Cyclobutyl-Methyl)-8-Dimethylamino-2-Oxo-8-Phenyl-1,3-Diazaspiro[4.5]Decan-3-yl]-Propionic Acid; 2,2,2-Trifluoro-Acetic Acid Salt

[0292] CIS-tert-butyl-3-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)propanoate (44 mg) was treated with TFA (360 .Math.L) at RT for 30 min. All volatiles were removed in vacuo. The residue was taken up in toluene and concentrated under reduced pressure (3x) to yield 3-(cis-1-(cyclobutylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl) propanoic acid as the trifluoroacetic acid salt (INT-898) (54 mg). [M+H].sup.+ 414.3

[0293] Synthesis of INT-899: CIS-3-[8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propionic acid

##STR00082##

Step 1: CIS-Tert-Butyl 3-(8-(Dimethylamino)-2-Oxo-8-Phenyl-1,3-Diazaspiro[4.5]Decan-3-yl)Propanoate

[0294] In analogy to the method described for INT-898 step 1 CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976) was converted into CIS-tert-butyl 3-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)propanoate.

Step 2: CIS-3-[8-Dimethylamino-1-[(1-Hydroxy-Cyclobutyl)-Methyl]-2-Oxo-8-Phenyl-1,3-Diazaspiro[4.5]Decan-3-yl]-Propionic Acid

[0295] A mixture of CIS-tert-butyl 3-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)propanoate (2.2 g, 5.486 mmol) and powdered NaOH (877 mg, 21.95 mmol) in toluene (40 mL) was stirred at 80° C. for 5 h under argon atmosphere. Toluene was evaporated in vacuo. The resulting off-white solid was dissolved in DMSO (40 mL) under argon atmosphere at RT and powdered NaOH (877 mg, 21.945 mmol) was added in one portion. The reaction mixture was stirred at 55° C. for 1h. (1-(tert-butyldimethylsilyloxy)cyclobutyl)methyl 4-methylbenzenesulfonate (2.029 g, 5.486 mmol) was added dropwise over 5 min. The reaction mixture was stirred for for 1.5 h at 55° C. and a new portion of (1-(tert-butyldimethylsilyloxy)cyclobutyl)methyl 4-methylbenzenesulfonate (2.029 g, 5.486 mmol) was added dropwise over 5 min. Stirring was continued at 55° C. for 18h. (1-(tert-butyldimethylsilyloxy)cyclobutyl)methyl 4-methylbenzenesulfonate (2.029 g, 5.486 mmol) was added dropwise over 5 min and stirring was continued for 65 h at at 55° C. The reaction progress was monitored by LCMS. DMSO was evaporated in vacuo. The resulting crude product was dissolved in water (50 mL), the solution was cooled to 0° C. and neutralized with acetic acid. The excess water was evaporated in vacuo and the residue was purified by column chromatography (using 100-200 mesh silica gel and 0-10 vol% MeOH in DCM as an eluent) to get 450 mg of CIS-3-[8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro [4.5] decan-3-yl]-propionic acid (INT-899) contaminated with 4-methylbenzene-sulfonic acid (44% pure by LCMS) as a pale yellow solid. This material was used for following reactions without additional purification. [M+H].sup.+ 430.3

[0296] Synthesis of INT-951: CIS-1-[(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-methyl]-cyclobutane-1-carbonitrile

##STR00083##

Step 1: 1-((CIS-8-(Dimethylamino)-3-(4-Methoxybenzyl)-2-Oxo-8-Phenyl-1,3-Diazaspiro[4.5] Decan-1-yl)Methyl)Cyclobutanecarbonitrile

[0297] NaH (50% in mineral oil) (2.44 g, 50.89 mmol) was added to a solution of CIS-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro [4.5]decan-2-one (INT-975) (5 g, 12.72 mmol) in DMF (100 mL) at 0° C. portionwise over 10 min. 1-(Bromomethyl)cyclobutanecarbonitrile (4.4 g, 25.44 mmol) was added dropwise over 10 minutes at 0° C. The reaction mixture was allowed to stir at RT for 3 h, then quenched with water and the organic product was extracted with ethyl acetate (3x200 mL). The combined organic extracts were dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford 5 g (crude) of 1-((CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutane-carbonitrile as gummy brown liquid. The material was used for the next step without further purification.

Step 2: 1-((CIS-8-(Dimethylamino)-2-Oxo-8-Phenyl-1,3-Diazaspiro[4.5]Decan-1-yl)Methyl) Cyclobutanecarboxamide

[0298] TFA (100 mL) was added to 1-((CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutanecarbonitrile (5 g, 10.28 mmol) at 0° C. and the reaction mixture at mixture was stirred at RT for 2 days. The reaction mixture was concentrated in vacuo. To the residue sat. aq. NaHCO.sub.3 was added (until pH 10) and the organic product was extracted with dichloromethane (3×150mL). The combined organic extracts were dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford 3.5 g (crude) of 1-((CIS-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl) cyclobutanecarboxamide. The material was used for the next step without further purification.

Step 3: 1-((cis-8-(Dimethylamino)-2-Oxo-8-Phenyl-1,3-Diazaspiro[4.5]Decan-1-yl)Methyl)Cyclobutane Carbonitrile

[0299] Thionyl chloride (35 mL) was added to 1-((cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutanecarboxamide (3.5 g, 9.11 mmol) at RT and the resulting mixture was stirred at reflux for 2 h. The reaction mixture was concentrated in vacuo. To the residue sat. aq. NaHCO.sub.3 was added (until pH 10) and the organic product was extracted with dichloromethane (3×150mL). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by column chromatography to afford 1.3 g (34% after three steps) of CIS-1-[(8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-methyl]-cyclobutane-1-carbonitrile (INT-951). [M+H].sup.+ 367.2.

[0300] Synthesis of INT-952: CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one

##STR00084##

[0301] To a solution of CIS-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro [4.5]decan-2-one (INT-975) (10 g, 25 mmol) in THF (500 mL) was added KOtBu (7.1 g, 63 mmol) at 50° C. The reaction mixture was heated up to reflux, cyclobutylmethylbromide (11.3 g, 76 mmol) was added in one portion, and stirring was continued at reflux for 12 h. KOtBu (7.1 g) and cyclobutylmethylbromide (11.3 g) were added again. The reaction mixture was allowed to stir another 2 h at reflux, then cooled to RT, diluted with water (150 mL) and the layers partitioned. The aqueous layer was extracted with EtOAc (3x300 mL). The combined organic layers were dried over Na.sub.2SO.sub.4 and then concentrated in vacuo. The residue was filtered through a plug of silica gel using a DCM/MeOH (19/1 v/v) mixture. The filtrate was concentrated in vacuo and the resulting solid was recrystallized from hot ethanol to yield 7.8 g of CIS-1-(cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one (INT-952). [M+H].sup.+ 461.3.

[0302] Synthesis of INT-953: CIS-1-(Cyclobutyl-methyl)-8-(methyl-(2-methyl-propyl)-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

##STR00085##

Step 1: 1-Cyclobutylmethyl-3-(4-Methoxy-Benzyl)-9,12-Dioxa-1,3-Diaza-Dispiro[4.2.4.2]Tetradecan-2-One

[0303] To a stirred solution of 3-(4-methoxy-benzyl)-9,12-dioxa-1,3-diaza-dispiro[4.2.4.2]tetradecan-2-one (4 g, 12.04 mmol) in anhydrous DMF (60 ml) was added NaH (1.38 g, 60% dispersion in oil, 36.14 mmol) at RT. The reaction mixture was stirred for 10 min, bromomethylcyclobutane (3 ml, 26.5 mmol) was added dropwise and stirring was continued for 50 h. TLC analysis showed complete consumption of the starting material. The reaction mixture was quenched with sat. aq. NH.sub.4Cl (50 ml) and extracted with EtOAc (3x200 ml). The combined organic phase was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The resulting residue was purified column chromatography (neutral aluminum oxide, EtOAc - petroleum ether (2:8)) to give 1-cyclobutylmethyl-3-(4-methoxybenzyl)-9,12-dioxa-1,3-diaza-dispiro[4.2.4.2]tetradecan-2-one (2.4 g, 50%, white solid). TLC system: EtOAc - pet ether (6:4); R.sub.f= 0.48.

Step 2: 1-Cyclobutylmethyl-3-(4-Methoxy-Benzyl)-1,3-Diaza-Spiro[4.5]Decane-2,8-Dione

[0304] To a stirred solution of 1-cyclobutylmethyl-3-(4-methoxy-benzyl)-9,12-dioxa-1,3-diaza-dispiro[4.2.4.2]tetradecan-2-one (1 g, 2.5 mmol) in MeOH (7 ml) was added 10% aq. HCl (8 ml) at 0° C. The reaction mixture was warmed up to RT and stirred for 16 h. TLC analysis showed complete consumption of the starting material. The reaction mixture was quenched with sat. aq. NaHCO.sub.3 (30 ml) and extracted with EtOAc (3x50 ml). The combined organic phase was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, 230-400 mesh, EtOAc - pet ether (1:3).fwdarw.(3:7)) to give 1-cyclobutylmethyl-3-(4-methoxybenzyl)-1,3-diaza-spiro[4.5]decane-2,8-dione (650 mg, 73%, colorless viscous oil). TLC system: EtOAc - pet ether (6:4); R.sub.f= 0.40.

Step 3: 1-(Cyclobutylmethyl)-8-(Isobutyl(Methyl)Amino)-3-(4-Methoxybenzyl)-2-Oxo-1,3-Diazaspiro[4.5] Decane-8-Carbonitrile

[0305] To a stirred solution of N-isobutyl-N-methylamine (1.34 ml, 11.23 mmol) and MeOH/H.sub.2O (8 ml, 1:1, v/v) was added 4 N aq. HCl (1.5 ml) and the reaction mixture was stirred for 10 min at 0° C. (ice bath). A solution of 1-cyclobutylmethyl-3-(4-methoxy-benzyl)-1,3-diaza-spiro[4.5]decane-2,8-dione (1 g, 2.80 mmol) in MeOH (7 ml) and KCN (548 mg, 8.42 mmol) were added and the reaction mixture was stirred at 45° C. for 20 h. TLC analysis showed complete consumption of the starting material. The reaction mixture was diluted with water (30 ml), extracted with EtOAc (3x30 ml), the combined organic phase was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to give 1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile (1.3 g, viscous yellow oil). TLC system: EtOAc - pet ether (1:1); R.sub.f= 0.45. The product was used for the next step without additional purification.

Step 4: CIS-1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

[0306] A round bottom flask containing 1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile (1.3 g, 2.81 mmol) was cooled in an ice bath (~0° C.) and a solution of phenylmagnesium bromide (26 ml, ~2 M in THF) was added slowly at 0° C.-5° C. The ice bath was removed and the reaction mixture was stirred for 30 min, then diluted with sat. aq. NH.sub.4Cl (25 ml) and extracted with EtOAc (4x30 ml). The combined organic phase was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to give pale yellow viscous oil. This residue was purified by column chromatography (silica gel, 230-400 mesh, eluent: EtOAc - pet ether (15:85).fwdarw. (2:4)) to give CIS-1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (135 mg, 10%, white solid). TLC system: EtOAc - pet ether (1:1); R.sub.f= 0.6

Step 5: CIS-1-(Cyclobutyl-Methyl)-8-(Methyl-(2-Methyl-Propyl)-Amino)-8-Phenyl-1,3-Diazaspiro[4.5]Decan-2-one

[0307] A round bottom flask containing CIS-1-(cyclobutylinethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (130 mg, 0.25 mmol) was cooled in an ice bath and a mixture of TFA/CH.sub.2Cl.sub.2 (2.6 ml, 1:1, v/v) was added slowly at 0° C.-5° C. The reaction mixture was warmed to RT and stirred for 20 h, then quenched with methanolic NH.sub.3 (10ml, ~10% in MeOH) and concentrated under reduced pressure to give pale yellow viscous oil. This residue was purified twice by column chromatography (silica gel, 230-400 mesh, eluent: MeOH - CHC1.sub.3 (1:99) .fwdarw. (2:98)) to give CIS-1-(cyclobutyl-methyl)-8-(methyl-(2-methyl-propyl)-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-953) (65 mg, 66%, white solid). TLC system: MeOH - CHC1.sub.3 (5:95); R.sub.f= 0.25; [M+H].sup.+ 384.3

[0308] Synthesis of INT-958: 4-Oxo-1-pyridin-2-yl-cyclohexane-1-carbonitrile

##STR00086##

Step 1: Ethyl 5-Cyano-2-Oxo-5-(Pyridin-2-yl)Cyclohexanecarboxylate

[0309] KOtBu (57.0 g, 508.4 mmol) was added to the solution of 2-(pyridin-2-yl)acetonitrile (50.0 g, 423.7 mmol) and ethyl acrylate (89.0 g, 889.8 mmol) in THF (500 mL) at 0° C. and stirred for 16 h at RT. The reaction mixture was quenched with sat. aq. NH.sub.4Cl and extracted with EtOAc (2x500 mL). The combined organic layer was washed with brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford 68.0 g (60%; crude) of ethyl 5-cyano-2-oxo-5-(pyridin-2-yl)cyclohexanecarboxylate as a brown liquid (TLC system: 50% ethyl acetate in petroleum ether ; Rf: 0.65).

Step 2: 4-Oxo-1-Pyridin-2-yl-Cyclohexane-1-Carbonitrile

[0310] A solution of ethyl 5-cyano-2-oxo-5-(pyridin-2-yl)cyclohexanecarboxylate (68.0 g, 250.0 mmol) was added to a mixture of conc. aq. HCl and glacial acetic acid (170 mL/510 mL) at 0° C. The reaction mixture was heated to 100° C. for 16 h. All volatiles were evaporated under reduced pressure. The residue was diluted with sat. aq. NaHCO.sub.3 and extracted with ethyl acetate (3x300 mL). The combined organic layer was washed with brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford 44.0 g (88%) of 4-oxo-1-pyridin-2-yl-cyclohexane-1-carbonitrile INT-958 as a brown solid (TLC system: 50% ethyl acetate in pet ether; Rf: 0.45). [M+H].sup.+ 201.1

[0311] Synthesis of INT-961: 4-Dimethylamino-4-pyridin-2-yl-cyclohexan-1-one

##STR00087##

Step 1: 8-(Pyridin-2-yl)-1,4-Dioxaspiro[4.5]Decane-8-Carbonitrile

[0312] A solution of 4-oxo-1-pyridin-2-yl-cyclohexane-1-carbonitrile (INT-958) (44.0 g, 220.0 mmol), ethylene glycol (27.0 g, 440.0 mmol) and PTSA (4.2 g, 22.0 mmol) in toluene (450 mL) was heated to 120° C. for 16 h using Dean Stark apparatus. All volatiles were evaporated under reduced pressure. The residue was diluted with sat. aq. NaHCO.sub.3 and extracted with ethyl acetate (3x300 mL). The combined organic layer was washed with brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford 45.0 g (85%) of 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile as a light brown solid (TLC system: 50% ethyl acetate in petroleum ether; Rf: 0.55).

Step 2: 8-(Pyridin-2-yl)-1,4-Dioxaspiro[4.5]Decane-8-Carboxamide

[0313] Potassium carbonate (50.0 g, 368.84 mmol) and 30% aq. H.sub.2O.sub.2 (210.0 mL, 1844.2 mmol) were added to the solution of 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (45.0 g, 184.42 mmol) in DMSO (450 mL) at 0° C. and the resulting mixture was stirred at RT for 14 h. The reaction mixture was diluted with water (1.5 L) and stirred for 1 h. The precipitated solid was separated by filtration, washed with water, petroleum ether and dried under reduced pressure to get 32.0 g (66%) of 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carboxamide as a white solid. (TLC system: 10% MeOH in DCM R.sub.f: 0.35).

Step 3: Methyl 8-(Pyridin-2-yl)-1,4-Dioxaspiro[4.5]Decan-8-Ylcarbamate

[0314] A mixture of 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carboxamide (25.0 g, 95.41 mmol), sodium hypochlorite (5 wt% aq. solution, 700 mL, 477.09 mmol) and KF-Al.sub.2O.sub.3 (125.0 g) in methanol (500 mL) was heated to 80° C. for 16 h. The reaction mixture was filtered through celite and the solid residue was washed with methanol. The combined filtrate was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate (3x500 mL). The combined organic layer was washed with brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford 18.0 g (66%) of methyl 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-ylcarbamate as a light brown solid. (TLC system: 5% MeOH in DCM R.sub.f: 0.52.)

Step 4: 8-(Pyridin-2-yl)-1,4-Dioxaspiro[4.5]Decan-8-Amine

[0315] A suspension of methyl 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-ylcarbamate (18.0 g, 61.64 mmol) in 10 wt% aq. NaOH (200 mL) was heated to 100° C. for 24 h. The reaction mixture was filtered through celite pad, the solid residue was washed with water and the combined filtrate was extracted with EtOAc (4x200 mL). The combined organic layer washed with brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford 12.5 g (88%) of 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-amine as a light brown semi-solid. (TLC system: 5% MeOH in DCM R.sub.f: 0.22.).

Step 5: 4-Dimethylamino-4-Pyridin-2-yl-Cyclohexan-1-One

[0316] Sodium cyanoborohydride (13.7 g, 0.213 mol) was added portionwise to a solution of 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-amine (12.5 g, 53.418 mmol) and 35 wt% aq. formaldehyde (45 mL, 0.534 mol) in acetonitrile (130 mL) at 0° C. The reaction mixture was warmed up to room temperature and stirred for 16 h. The reaction mixture was quenched with sat. aq. NH.sub.4Cl and concentrated under reduced pressure. The residue was dissolved in water and extracted with EtOAc (3x200 mL). The combined organic layer was washed with brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford 10.5 g (72%) of 4-dimethylamino-4-pyridin-2-yl-cyclohexan-1-one (INT-961) as a light brown solid. (TLC system: 5% MeOH in DCM R.sub.f: 0.32.). [M+H].sup.+ 219.1

[0317] Synthesis of INT-965: 4-Dimethylamino-4-phenyl-cyclohexan-1-one

##STR00088##

Step 1: 8-(Dimethylamino)-1,4-Dioxaspiro 4.5] Decane-8-Carbonitrile

[0318] Dimethylamine hydrochloride (52 g, 0.645 mol) was added to the solution of 1,4-dioxaspiro-[4.5]-decan-8-one (35 g, 0.224 mmol) in MeOH (35 mL) at RT under argon atmosphere. The solution was stirred for 10 min and 40 wt% aq. dimethylamine (280 mL, 2.5 mol) and KCN (32 g, 0.492 mol) were sequentially added. The reaction mixture was stirred for 48 h at RT, then diluted with water (100 mL) and extracted with EtOAc (2x200 mL). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford 44 g of 8-(dimethylamino)-1,4-dioxaspiro-[4.5]-decane-8-carbonitrile (93%) as a white solid.

Step 2: N,N-Dimethyl-8-Phenyl-1,4-Dioxaspiro [4.5] Decan-8-Amine

[0319] 8-(Dimethylamino)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (35 g, 0.167 mol) in THF (350 mL) was added to the solution of 3 M phenylmagnesium bromide in diethyl ether (556 mL, 1.67 mol) dropwise at -10° C. under argon atmosphere. The reaction mixture was stirred for 4 h at -10° C. to 0° C. and then at RT for 18 h. The reaction completion was monitored by TLC. The reaction mixture was cooled to 0° C., diluted with sat. aq. NH.sub.4Cl (1 L) and extracted with EtOAc (2x600 mL). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford 60 g of, N N-dimethyl-8-phenyl-1, 4-dioxaspiro-[4.5]-decan-8-amine as a liquid.

Step 3: 4-(Dimethylamino)-4-Phenylcyclohexanone

[0320] A solution of N,N-dimethyl-8-phenyl-1,4-dioxaspiro[4.5]decan-8-amine (32 g, 0.123 mol) in 6 N aq. HCl (320 mL) was stirred at 0° C. for 2 h and then at RT for 18 h. The reaction completion was monitored by TLC. The reaction mixture was extracted with DCM (2x150 mL). The aqueous layer was basified to pH 10 with solid NaOH and extracted with ethyl acetate (2x200 mL). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The solid residue was washed with hexane and dried in vacuo to afford 7 g of 4-dimethylamino-4-phenyl-cyclohexan-1-one (INT-965) (25% over 2 steps) as a brown solid. [M+H].sup.+ 218.1

[0321] Synthesis of INT-966: 3-[(4-Methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decane-2,8-dione

##STR00089##

Step 1: 9,12-Dioxa-2,4-Diazadispiro[4.2.4^{8}.2^{5}]Tetradecane-1,3-Dione

[0322] KCN (93.8 g, 1441.6 mmol) and (NH.sub.4).sub.2CO3 (271.8 g, 1729.9 mmol) were added to the solution of 1,4-dioxaspiro[4.5]decan-8-one (150 g, 961 mmol) in MeOH:H.sub.2O (1:1 v/v) (1.92 L) at RT under argon atmosphere. The reaction mixture was stirred at 60° C. for 16 h. The reaction completion was monitored by TLC. The reaction mixture was cooled to 0° C., the precipitated solid was filtered off and dried in vacuo to afford 120 g (55%) of 9,12-dioxa-2,4-diazadispiro[42.4^{8}.2^{5}]tetradecane-1,3-dione. The filtrate was extracted with DCM (2x1.5 L). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford additional 30 g (14%) of 9,12-dioxa-2,4-diazadispiro[4.2.4^{8}.2^{5}]tetradecane-1,3-dione (TLC system: 10% Methanol in DCM; Rf: 0.4).

Step 2: 2-[(4-Methoxyphenyl)-Methyl]-9,12-Dioxa-2,4-Diazadispiro[4.2.4^{8}.2^{5}] Tetradecane-1,3-Dione

[0323] Cs.sub.2CO.sub.3 (258.7 g, 796.1 mmol) was added to the solution of 73a (150 g, 663.4 mmol) in MeCN (1.5 L) under argon atmosphere and the reaction mixture was stirred for 30 min. A solution of p-methoxybenzyl bromide (96 mL, 663.4 mmol) was added. The reaction mixture was stirred at RT for 48 h. The reaction completion was monitored by TLC. The reaction mixture was quenched with sat. aq. NH.sub.4Cl (1.0 L) and the organic product was extracted with EtOAc (2x1.5 L). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was washed with diethyl ether and pentane and dried under reduced pressure to afford 151 g (65%) of 2-[(4-Methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4^{8}.2^{5}]tetradecane-1,3-dione as an off white solid (TLC system: 10% MeOH in DCM; Rf: 0.6).

Step 3: 2-[(4-Methoxyphenyl)-Methyl]-9,12-Dioxa-2,4-Diazadispiro[4.2.4^{8}.2^{5}] Tetradecan-3-One

[0324] AlCl.sub.3 (144.3 g, 1082.6 mmol) was added to a solution of LiAlH.sub.4 (2 M in THF) (433 mL, 866.10 mmol) in THF (4.5 L) at 0° C. under argon atmosphere and the resulting mixture was stirred at RT for 1 h. 2-[(4-Methoayphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4^{8}.2^{5}]tetradecane-1,3-dione (150 g, 433.05 mmol) was added at 0° C. The reaction mixture was stirred at RT for 16 h. The reaction completion was monitored by TLC. The reaction mixture was cooled to 0° C., quenched with sat. aq. NaHCO.sub.3 (500 mL) and filtered through celite pad. The filtrate was extracted with EtOAc (2x2.0 L). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo to afford 120 g (84%) of 2-[(4-methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4^{8}.2^{5}]tetradecan-3-one as an off-white solid. (TLC system: 10% MeOH in DCM, Rf: 0.5).

Step 4: 3-[(4-Methoxyphenyl)-Methyl]-1,3-Diazaspiro[4.5]Decane-2,8-Dione

[0325] A solution of 2-[(4-methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4^{8}.2^{5}] tetradecan-3-one (120 g, 361.03 mmol) in 6N aq. HCl (2.4 L) was stirred at 0° C. for 2 h and then at RT for 18 h. The reaction completion was monitored by TLC. The reaction mixture was extracted with DCM (2x2.0L). The aqueous layer was basified to pH 10 with 50% aq. NaOH and then extracted with DCM (2 x 2.0L). Combined organic extracts were dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The solid residue was washed with hexane and dried in vacuo to afford 90 g of 3-[(4-Methoxyphenyl)-methyl]-l,3-diazaspiro[4.5]decane-2,8-dione (INT-966) as an off-white solid (TLC system: 10% MeOH in DCM; Rf: 0.4) [M+H].sup.+ 289.11.

[0326] Synthesis of INT-971: CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-hydroxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one

##STR00090##

Step 1: CIS-8-(Dimethylamino)-1-Isobutyl-3-(4-Methoxybenzyl)-8-Phenyl-1,3-Diazaspiro[4.5] Decan-2-One

[0327] In analogy to the method described for INT-951 step 1 CIS-8-Dimethylamino-8-[3-(methoxymethyloxy)-phenyl]-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one (INT-968) was converted into CIS-1-(cyclobutylmethyl)-8-(dimethylamino)-3-(4-methoxybenzyl)-8-(3-(methoxymethoxy)phenyl)-1,3-diazaspiro[4.5]decan-2-one.

Step 2: CIS-1-(Cyclobutyl-Methyl)-8-Dimethylamino-8-(3-Hydroxyphenyl)-3-[(4-Methoxyphenyl)-Methyl]-1,3-Diazaspiro[4.5]Decan-2-One

[0328] TFA (0.2 mL) was added to the solution of CIS-1-(cyclobutylmethyl)-8-(dimethylamino)-3-(4-methoxybenzyl)-8-(3-methoxyphenyl)-1,3-diazaspiro[4.5]decan-2-one (300 mg, 0.57 mmol) in DCM (1.5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 3 h. The reaction completion was monitored by TLC. The reaction mixture was quenched with sat. aq. NaHCO.sub.3 and the organic product was extracted with DCM (3x10 mL). The combined organic extracts were dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. Purification of the residue by preparative TLC (3% MeOH in DCM as mobile phase) yielded 50 mg (18%) of CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-hydroayphenyl)-3-[(4-methoayphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one (INT-971) as an off white solid. (TLC system: 10% MeOH in DCM; Rf: 0.20) [M+H].sup.+ 478.3

[0329] Synthesis of INT-974: CIS-8-Dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one

##STR00091##

Step 1: 8-(Dimethylamino)-3-(4-Methoxybenzyl)-2-Oxo-1,3-Diazaspiro[4.5]Decane-8-Carbonitrile

[0330] Dimethylamine hydrochloride (76.4 g, 936.4 mmol) was added to a solution of 3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decane-2,8-dione (INT-966) (90 g, 312.13 mmol) in MeOH (180 mL) at RT under argon atmosphere. The solution was stirred for 15 min and 40 wt% aq. dimethylamine (780 mL) and KCN (48.76 g, 749.11 mmol) were sequentially added. The reaction mixture was stirred for 48 h and the completion of the reaction was monitored by NMR. The reaction mixture was diluted with water (1.0 L) and the organic product was extracted with ethyl acetate (2x2.0L). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford 90 g (85%) of 8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile as an off white solid (TLC system: TLC system: 10% MeOH in DCM; Rf: 0.35, 0.30).

Step 2: CIS-8-Dimethylamino-8-(3-Fluorophenyl)-3-[(4-Methoxyphenyl)-Methyl]-1,3-Diazaspiro[4.5]Decan-2-One

[0331] 3-Fluorophenylmagnesium bromide (1 M in THF) (220 mL, 219.17 mmol) was added dropwise to a solution of 8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile (15 g, 43.83 mmol) in THF (300 mL) at 0° C. under argon atmosphere. The reaction mixture was stirred for 16 h at RT. The reaction completion was monitored by TLC. The reaction mixture was cooled to 0° C., quenched with sat. aq. NH.sub.4Cl (200 mL) and the organic product was extracted with EtOAc (2x200 mL). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The reaction was carried out in 4 batches (15 g x 2 and 5 g x 2) and the batches were combined for purification. Purification of the crude product by flash column chromatography on silica gel (230-400 mesh) (2 times) (0-20% methanol in DCM) eluent and subsequently by washing with pentane yielded 5.6 g (11%) of CIS-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one (INT-974) as an off-white solid. (TLC system: 5% MeOH in DCM in presence of ammonia; Rf: 0.1). [M+H].sup.+ 412.2

[0332] Synthesis of INT-975: CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5] decan-2-one

##STR00092##

[0333] KOtBu (1 M in THF) (29.30 mL, 29.30 mmol) was added to the solution of CIS-8-Dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 (8.0 g, 29.30 mmol) in THF (160 mL) under argon atmosphere and the reaction mixture was stirred for 30 min. 4-Methoxybenzyl bromide (4.23 mL, 29.30 mmol) was added and stirring was continued at RT for 4 h. The reaction completion was monitored by TLC. The reaction mixture was diluted with sat. aq. NH.sub.4Cl (150 mL) and the organic product was extracted with EtOAc (2x150 mL). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo. The reaction was carried out in 2 batches (8 g x 2) and the batches were combined for purification. Purification of the crude product by flash column chromatography on silica gel (0-10% methanol in DCM) and subsequently by washing with pentane yielded 11 g (47%) of CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-975) as a white solid. [M+H].sup.+ 394.2

[0334] Synthesis of INT-976: CIS-8-Dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

##STR00093##

Step 1: 8-(Dimethylamino)-8-Phenyl-1,3-Diazaspiro[4,5]Decane-2,4-Dione

[0335] In a sealed tube 4-dimethylamino-4-phenyl-cyclohexan-1-one (INT-965) (2 g, 9.22 mmol) was suspended in 40 mL EtOH/H.sub.2O (1:1 v/v) at RT under argon atmosphere. (NH.sub.4).sub.2CO.sub.3 (3.62 g, 23.04 mmol) and KCN (0.6 g, 9.22 mmol) were added. The reaction mixture was stirred at 60° C. for 18 h. The reaction mixture was cooled to 0° C. and diluted with ice-water and filtered through a glass filter. The solid residue was dried under reduced pressure to afford 8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decane-2,4-dione (1.8 g, 86%) as an off white crystalline solid (TLC: 80% EtOAc in hexane; Rf : 0.25).

Step 2: 8-(Dimethylamino)-8-Phenyl-1,3-Diazaspiro[4,5]Decan-2-One

[0336] LiAlH.sub.4 (2 M in THF) (70 mL, 139.4 mmol) was added to the solution of 8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decane-2,4-dione (10 g, 34.8 mmol) in THF/Et.sub.2O (2:1 v/v) (400 mL) at 0° C. under argon atmosphere. The reaction mixture was stirred for 4 h at 60° C. The reaction completion was monitored by TLC. The reaction mixture was cooled to 0° C., quenched with saturated Na.sub.2SO.sub.4 solution (100 mL) and filtered through Celite pad. The filtrate was dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo to afford 5.7 g (59%) of 8-(dimethylamino)-8-phenyl-1, 3-diazaspiro [4, 5] decan-2-one as an off white solid. (TLC system: 10% MeOH in DCM, Rf: 0.3).

Step 3: CIS-8-Dimethylamino-8-Phenyl-1,3-Diazaspiro[4.5]Decan-2-One

[0337] A mixture of CIS- and TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decan-2-one (8 g, 29.30 mmol) was purified by preparative chiral SFC (column: Chiralcel AS-H, 60% CO.sub.2, 40% (0.5% DEA in MeOH)) to get 5 g of CIS-8-Dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976) as a white solid. [M+H].sup.+ 274.2.

[0338] Synthesis of INT-977: CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-acetic acid; 2,2,2-trifluoro-acetic acid salt

##STR00094##

Step 1: CIS-2-[8-Dimethylamino-3-[(4-Methoxyphenyl)-Methyl]-2-Oxo-8-Phenyl-1,3-Diazaspiro[4.5] Decan-1-yl]-Acetic Acid Tert-Butyl Ester

[0339] A solution of CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro [4.5]decan-2-one (INT-975) (5.0 g, 12.7 mmol) in THF (18 mL) was cooled to 0° C. and treated with LDA solution (2 M in THF/heptane/ether, 25.4 mL, 50.8 mmol). The resulting mixture was was allowed to warm up to RT over 30 min. The solution was then cooled to 0° C. again and tert-butyl-bromoacetate (5.63 mL, 38.1 mmol) was added. The reaction mixture was stirred at RT for 16 h, quenched with water and extracted with DCM (3x). The combinded organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated inder reduced pressure. Purification of the residue by column chromatography on silica gel provided CIS-2-[8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-acetic acid tert-butyl ester (4.4 g).

Step 2: Cis- 2-(8-Dimethylamino-2-Oxo-8-Phenyl-1,3-Diazaspiro[4.5]Decan-1-yl)-Acetic Acid Trifluoroacetic Acid Salt

[0340] CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5] decan-1-yl]-acetic acid tert-butyl ester (200 mg, 0.4 mmol) was dissolved in TFA (5 mL) and heated to reflux overnight. After cooling to RT all volatiles are removed in vacuo. The residue was taken up in THF (1 mL) and added dropwise to diethyl ether (20 mL). The resulting precipitate was filtered off and dried under reduced pressure to give CIS-2-(8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-acetic acid; 2,2,2-trifluoro-acetic acid salt (INT-977) (119 mg) as a white solid. [M+H].sup.+ 332.2

[0341] Synthesis of INT-978: CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-N,N-dimethyl-acetamide

##STR00095##

[0342] CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-acetic acid (INT-977) trifluoroacetic acid salt (119 mg, 0.35 mmol) was dissolved in DCM (5 mL). Triethylamine (0.21 mL, 1.6 mmol), dimethylamine (0.54 mL, 1.1 mmol) and T3P (0.63 mL, 1.1 mmol) were sequentially added. The reaction mixture was stirred at RT overnight, then diluted with 1 M aq. Na.sub.2CO.sub.3 (5 mL). The aqueous layer was extracted with DCM (3x5 mL), the combined organic layers were dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to yield CIS-2-(8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-N,N-dimethyl-acetamide (INT-978) (39 mg) as a white solid. [M+H].sup.+ 359.2

[0343] Synthesis of INT-982: CIS-8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

##STR00096##

Step 1: CIS-8-(Dimethylamino)-3-(4-Methoxybenzyl)-1-((1-Methylcyclobutyl)Methyl)-8-Phenyl-1,3-Diazaspiro[4.5]Decan-2-One

[0344] A solution of NaOH (2.85 g, 71.2 mmol) in DMSO (25 mL) was stirred at RT for 10 min. CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5] decan-2-one (INT-975) (7.00 g, 17.8 mmol) was added and stirring was continued for 15 min. 1-(Bromo-methyl)-1-methyl-cyclobutane (8.7 g, 53.4 mmol) was added at 0° C. The reaction mixture was heated to 60° C. for 16 h. After cooling down to RT, water (100 mL) was added and the mixture was extracted with DCM (3x150 mL). The combined organic layers were washed with water (70 mL), brine (100 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. Purification of the residueby column chromatography on silica gel provided CIS-8-(dimethylamino)-3-(4-methoaybenzyl)-1-((1-methylcyclobutyl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (6.5 g) as a light yellow solid.

Step 2: CIS-8-Dimethylamino-1-[(1-Methyl-Cyclobutyl)-Methyl]-8-Phenyl-1,3-Diazaspiro[4.5]Decan-2-One

[0345] To the solution of CIS-8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro [4.5]decan-2-one (6.66 g, 14.0 mmol) in DCM (65 mL) was added TFA (65 mL) and the resulting mixture was stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was taken up in DCM (100 mL) and water (60 mL) and basified with 2 M aq. NaOH to pH 10. The organic layer was separated and washed with brine (40 mL), dried over MgSO.sub.4, filtered and concentrated under reduced pressure. Crystallization of the residue from EtOAc provided CIS-8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5] decan-2-one (INT-982) (3.41 g) as an off-white solid. [M+H].sup.+ 356.3

[0346] Synthesis of INT-984: CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

##STR00097##

Step 1: CIS-8-(Dimethylamino)-1-Isobutyl-3-(4-Methoxybenzyl)-8-Phenyl-1,3-Diazaspiro[4.5] Decan-2-One

[0347] In analogy to the method described for INT-951 step 1 CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-975) was converted into CIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro [4.5]decan-2-one.

Step2: CIS-1-(Cyclobutyl-Methyl)-8-(Ethyl-Methyl-Amino)-8-Phenyl-1,3-Diazaspiro[4.5]Decan-2-One

[0348] In analogy to the method described for INT-982 step 2 CIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one was converted into CIS-1-(Cyclobutylmethyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-984).

[0349] Synthesis of INT-986: CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

##STR00098##

Step 1: CIS-3-Benzyl-1-(Cyclobutylmethyl)-8-(Methylamino)-8-Phenyl-1,3-Diazaspiro[4.5]Decan-2-One

[0350] N-Iodosuccinimide (3.11 g, 13.92 mmol) was added to the solution of CIS-1-(Cyclobutylmethyl)-8-dimethylamino-8-phenyl-3-[phenyl-methyl]-1,3-diazaspiro[4.5]decan-2-one (INT-950) (4 g, 9.28 mmol) in a mixture of acetonitrile and THF (1:1 v/v, 80 mL) and the resulting mixture was stirred at RT for 16 h. The reaction mixture was basified with 2N aq. NaOH to pH~10 and the organic product was extracted with DCM (3x10 mL). The combined organic extracts were dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was stirred vigorously with a mixture of 10 wt% aq. citric acid (5 mL) and DCM (10 mL) at RT for 10 min. The reaction mixture was basified with 5 N aq. NaOH to pH~10 and extracted with DCM (3x10 mL). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo to give 3.5 g (crude) of CIS-3-benzyl-1-(cyclobutylmethyl)-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one as semi solid (TLC system: 10% MeOH in DCM; R.sub.f: 0.60.).

Step 2: CIS-3-Benzyl-1-(Cyclobutylmethyl)-8-(Ethyl(methyl)Amino)-8-Phenyl-1,3-Diazaspiro [4.5]Decan-2-One

[0351] Sodium cyanoborohydride (1.56 g, 25.17 mmol, 3 equiv.) was added to the solution of CIS-3-benzyl-1-(cyclobutylmethyl)-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (3.5 g, 8.39 mmol), acetaldehyde (738 mg, 16.78 mmol, 2 equiv.) and acetic acid (0.5 mL) in methanol (20 mL). The reaction mixture was stirred at RT for 3 h, then quenched with sat. aq. NaHCO.sub.3 and the organic product was extracted with DCM (3x50 mL). The combined organic extracts were dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (230-400 mesh) (20-25% ethyl acetate in petroleum ether) yielded 2.3 g (62%) of CIS-3-benzyl-1-(cyclobutylmethyl)-8-(ethyl(methyl)amino)-8-phenyl-1,3-diazaspiro [4.5]decan-2-one as a solid. (TLC system: 50% EtOAc in Pet. Ether; R.sub.f: 0.65).

Step 3: CIS-1-(Cyclobutyl-Methyl)-8-(Ethyl-Methyl-Amino)-8-Phenyl-1,3-Diazaspiro[4.5]Decan-2-One (INT-986)

[0352] Sodium metal (1.18 g, 51.68 mmol, 10 equiv.) was added to liquid ammonia (~25 mL) at -78° C. The resulting mixture was stirred for 10 min at -78° C. A solution of CIS-3-benzyl-1-(cyclobutylmethyl)-8-(ethyl(methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (2.3 g, 5.16 mmol) in THF (25 mL) was added at -78° C. The reaction mixture was stirred for 15 min, then quenched with sat. aq. NH.sub.4C1, warmed to RT and stirred for 1 h. The organic product was extracted with DCM (3x50 mL). The combined organic layer was washed with water, brine and concentrated under reduced pressure to afford 1.30 g (72%) of CIS-1-(cyclobutylinethyl)-8-(ethyl(methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-986) as an off-white solid. (TLC system: 10% MeOH in DCM R.sub.f: 0.15.). [M+H].sup.+ 356.3

[0353] Synthesis of INT-987: CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

##STR00099##

[0354] In analogy to the method as described for INT-982 step 2 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one (INT-952) was converted into CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-987).

[0355] Synthesis of INT-1008: CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one

##STR00100##

Step 1 and Step 2: Ethyl-(8-Phenyl-1,4-Dioxa-Spiro[4.5]Dec-8-yl)-Amine Hydrochloride (INT-1004)

[0356] A mixture of 1,4-dioxa-spiro[4.5]decan-8-one (25.0 g, 160.25 mmol, 1.0 eq.) and 2 M solution of EtNH.sub.2 in THF (200 ml, 2.5 eq. 400.64 mmol) in EtOH (30 mL) was stirred at RT for 48 h. The reaction mixture was concentrated under argon atmosphere. The residue was diluted with ether (60 mL) and added to the freshly prepared PhLi solution [prepared by addition of 2.5 M n-BuLi in THF (70.5 mL, 1.1 eq. 176.27 mmol) to a solution of bromobenzene (27.675 g, 1.1 eq. 176.275 mmol) in ether (100 mL) at -30° C. and stirred at RT for 1 h] at RT. The reaction mixture was stirred at RT for 1.5 h, then cooled down to 0° C. and quenched with sat. aq. NH.sub.4Cl (100 mL). The resulting mixture was extracted with EtOAc (2x750 mL), combined organic extracts were washed with water (3x350 mL), brine (300 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude product was dissolved in ethylmethyl ketone (100 mL) and TMSCl (37.5 mL) was added at 0° C. The reaction mixture was stirred at RT for 16 h, the precipitate formed was filtered off and washed with acetone and THF to give ethyl-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-amine hydrochloride as an off-white solid. This reaction was done in 2 batches of 25 g scale and the yield is given for 2 combined batches. Yield: 18% (17.1 g, 57.575 mmol). LCMS: m/z 262.2 (M+H).sup.+.

Step 3: 4-Ethylamino-4-Phenyl-Cyclohexanone (INT-1005)

[0357] To a solution of ethyl-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-amine hydrochloride (10.1 g, 34.0 mmol, 1 eq.) in water (37.5 mL) was added conc. HCl (62.5 mL) at 0° C. and the reaction mixture was stirred at RT for 16 h. The reaction mixture was basified with 1 N aq. NaOH to pH ~14 at 0° C. and extracted with DCM (2x750 mL). Organic layer was washed with water (400 mL), brine (400 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to yield 4-ethylamino-4-phenyl-cyclohexanone which was used in the next step without further purification. This reaction was carried out in another batch of 15.1 g scale and yield is given for 2 combined batches. Yield: 92 % (17.0 g, 78.34 mmol).

Step 4: Mixture of CIS- and TRANS-8-Ethylamino-8-Phenyl-1,3-Diaza-Spiro[4.5]Decane-2,4-Dione (INT-1006 and INT-1007)

[0358] To a solution of 4-ethylamino-4-phenyl-cyclohexanone (17 g, 78.341 mmol, 1.0 eq.) in EtOH (250 mL) and water (200 mL) was added (NH.sub.4).sub.2CO.sub.3 (18.8 g, 195.85 mmol, 2.5 eq.) and the reaction mixture was stirred at RT for 15 min. KCN (5.09 g, 78.341 mmol, 1.0 eq.) was and the resulting mixture was stirred at 60° C. for 18 h. The reaction mixture was cooled to RT, the precipitate was filtered off, washed with water (250 mL), EtOH (300 mL), hexane (200 mL) and dried under reduced pressure to yield CIS- and TRANS- mixture 8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (13.0 g, 45.29 mmol, 58%) as a white solid. Yield: 58 % (13 g, 45.296 mmol). LC-MS: m/z [M+1].sup.+ = 288.2.

Step 5: CIS-8-Ethylamino-8-Phenyl-1,3-Diaza-Spiro[4.5]Decane-2,4-Dione (INT-1006)

[0359] To a solution of cis and trans mixture of 8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (12 g) in MeOH/DCM (1:1 v/v, 960 mL) was added a solution of L-tartaric acid in MeOH (25 mL). The resulting mixture was stirred at RT for 2 h and then kept in refrigerator for 16 h. The solid material was filtered off and washed with MeOH/DCM (1:5, 50 ml) to get 8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione tartrate (7.5 g) as a white solid. The solid was suspended in sat. aq. NaHCO.sub.3 (pH~8) and the resulting mixture was extracted with 25% MeOH-DCM (2 x 800 ml). Combined organic extracts were washed with water (300 ml), brine (300 ml) and dried over anhydrous Na.sub.2SO.sub.4. The solvent was evaporated under reduced pressure and the residue was triturated with 20 % DCM-hexane to afford CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione as a white solid. This step was done in 2 batches (12 g & 2.4 g) and yield is given for 2 combined batches. Yield: 31.2 % (5.0 g, 17.421 mmol). LC-MS: m/z [M+1].sup.+ = 288.0.

Step 6: CIS-8-Ethylamino-8-Phenyl-1,3-Diaza-Spiro[4.5]Decan-2-One (INT-1008)

[0360] To a slurry of LiAlH.sub.4 (793 mg, 20.905 mmol, 3.0 eq.) in THF (15 mL) was added a suspension of cis-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (2.0 g, 6.968 mmol, 1.0 eq.) in THF (60 mL) at 0° C. and the reaction mixture was stirred at 65° C. for 16 h. The resulting mixture was cooled to 0° C., quenched with sat. aq. Na.sub.2SO.sub.4 (20 ml), stirred at RT for 1h and filtered through celite. The celite layer was washed with 15% MeOH-DCM (500 ml). The combined filtrate was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The resulting crude product was triturated with 15% DCM-Hexane to afford CIS-8-ethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1008) (1.6 g, 5.86 mmol, 84%) as a white solid. Yield: 84 % (1.6 g, 5.86 mmol). LC-MS: m/z [M+H].sup.+ = 274.2.

[0361] Synthesis of INT-1026: CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

##STR00101##

Step 1: 2-Methyl-N-(1,4-Dioxaspiro[4.5]Decan-8-Ylidene)Propane-2-Sulfinamide

[0362] Titanium ethoxide (58.45 g, 256.4 mmol) was added to a solution of 1,4-dioxaspiro[4.5]decan-8-one (20 g, 128.20 mmol) and 2-methylpropane-2-sulfinamide (15.51 g, 128.20 mmol) in THF (200 mL) at RT and the reaction mixture was stirred at RT for 18 h. The reaction mixture was cooled to 0° C. and quenched by dropwise addition of sat. aq. NaHCO.sub.3 (500 mL) over a period of 30 min. The organic product was extracted with EtOAc (3x100 mL). The combined organic extracts were dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo to afford 10 g (crude) of 2-methyl-N-(1,4-dioxaspiro[4.5]decan-8-ylidene)propane-2-sulfinamide as a white solid (TLC system: 30% Ethyl acetate in hexane; Rf: 0.30).

Step 2: 2-Methyl-N-(8-Phenyl-1,4-Dioxaspiro[4.5]Decan-8-yl)Propane-2-Sulfinamide

[0363] Phenylmagnesium bromide (1 M in THF, 116 mL, 116 mmol) was added dropwise to a solution of 2-methyl-N-(1,4-dioxaspiro[4.5]decan-8-ylidene)propane-2-sulfinamide (10 g, 38.61 mmol) in THF (500 mL) at -10° C. under argon atmosphere. The reaction mixture was stirred for 2 h at -10° C. to 0° C. The reaction completion was monitored by TLC. The reaction mixture was quenched with sat. aq. NH.sub.4Cl (50 mL) at 0° C. and the organic product was extracted with EtOAc (3x100 mL). The combined organic extracts were dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel 230-400 mesh; 40-60% ethyl acetate in hexane) to yield 6.0 g (46%) of 2-methyl-N-(8-phenyl-1,4-dioxaspiro[4.5]decan-8-yl)propane-2-sulfinamide as a liquid (TLC system: 70% Ethyl acetate in hexane; Rf: 0.30).

Step 3: 8-Phenyl-1,4-Dioxaspiro[4.5]Decan-8-Amine Hydrochloride

[0364] 2N solution of HC1 in diethyl ether (17.80 mL, 35.60 mmol) was added to a solution of 2-methyl-N-(8-phenyl-1,4-dioxaspiro[4.5]decan-8-yl)propane-2-sulfinamide (6.0 g, 17.80 mmol) in DCM (60 mL) at 0° C. The reaction mixture was stirred at RT for 2 h. The reaction mixture was concentrated in vacuo. The residue was washed with diethyl ether to yield 3 g (crude) of 8-phenyl-1,4-dioxaspiro[4.5]decan-8-amine hydrochloride as a brown solid (TLC system: 5% MeOH in DCM; Rf: 0.10).

Step 4: 8-Phenyl-N-((Tetrahydrofuran-3-yl)Methyl)-1,4-Dioxaspiro[4.5]dEcan-8-Amine

[0365] Sodium cyanoborohydride (2.17 g, 33.45 mmol) was added to a solution of 8-phenyl-1,4-dioxaspiro[4.5]decan-8-amine hydrochloride (3.0 g, 11.15 mmol) and tetrahydrofuran-3-carbaldehyde (4.46 mL, 22.30 mmol) and acetic acid (0.05 mL) in methanol (30 mL) at 0° C. The reaction mixture was stirred at RT for 16h. The reaction mixture was concentrated in vacuo at 30° C. and to the residue sat. aq. NaHCO.sub.3 was added. The organic product was extracted with DCM (3x30 mL). The combined organic extracts were dried over anhydrous Na.sub.2SO.sub.4 and solvent was concentrated under reduced pressure to get 3 g (crude) of 8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amine as a semi-solid (TLC system: 10% MeOH in DCM; Rf: 0.22).

Step 5: N-Methyl-8-Phenyl-N-((Tetrahydrofuran-3-yl)Methyl)-1,4-Dioxaspiro[4.5]Decan-8-Amine)

[0366] Sodium cyanoborohydride (1.76 g, 28.39 mmol) was added to a solution of 8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amine (3.0 g, 9.46 mmol), 37% formaldehyde in water (7.70 mL, 94.60 mmol) and acetic acid (0.05 mL) in methanol (30 mL) at 0° C. The reaction mixture was stirred at RT for 16 h. The reaction mixture was concentrated in vacuo and to the residue sat. aq. NaHCO.sub.3 was added. The organic product was extracted with DCM (3x30 mL). The combined organic extracts were dried over anhydrous Na.sub.2SO.sub.4 and solvent was concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel 230-400 mesh; 5-6% MeOH in DCM) to yield 2.50 g (83%) of N-methyl-8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amine as a semi solid (TLC system: 10% MeOH in DCM; Rf: 0.25).

Step 6: 4-(Methyl((Tetrahydrofuran-3-yl)Methyl)amino)-4-Phenylcyclohexanone

[0367] 5% sulfuric acid in water (25 mL) was added to N-methyl-8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amine (2.50 g, 7.55 mmol) at 0° C. and the resulting mixture was stirred at RT for 24 h. The reaction mixture was quenched with sat. aq. NaHCO.sub.3 and the organic product was extracted with DCM (2x50 mL). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo to afford 2.0 g (crude) of 4-(methyl((tetrahydrofuran-3-yl)methyl)amino)-4-phenylcyclohexanone as a thick liquid (TLC system: 10% MeOH in DCM, Rf: 0.20).

Step 7: 8-(Methyl((Tetrahydrofuran-3-yl)Methyl)amino)-8-Phenyl-1,3-Diazaspiro[4.5] Decane-2,4-Dione

[0368] 4-(methyl((tetrahydrofuran-3-yl)methyl)amino)-4-phenylcyclohexanone (1.50 g, 5.22 mmol) was suspended in 30 mL of EtOH:H.sub.2O (1:1 v/v) at RT under argon atmosphere. (NH.sub.4).sub.2CO.sub.3 (1.9 g, 13.05 mmol) and KCN (0.34 g, 5.22 mmol) were added. The reaction mixture was heated to 70° C. for 16 h. The reaction mixture was diluted with ice-water and the organic product was extracted with DCM (2x50 mL). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo to give 1.0 g (crude) of 8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione as a solid (TLC system: 70% Ethyl acetate in hexane; Rf: 0.18).

Step 8: CIS-8-(Methyl((Tetrahydrofuran-3-yl)Methyl)amino)-8-Phenyl-1,3-Diazaspiro[4.5]Decane-2,4-Dione

[0369] Diastereomeric mixture of 8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione (1.0 g) was separated by reverse phase preparative HPLC to afford 400 mg of isomer 1 (CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione) and 60 mg of isomer 2 (TRANS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione) and 300 mg of mixture of both isomers. Reverse phase preparative HPLC conditions: mobile phase: 10 mM ammonium bicarbonate in H.sub.2O/acetonitrile, column: X-BRIDGE-C18 (150*30), 5 .Math.m, gradient (T/B%): 0/35, 8/55, 8.1/98, 10/98, 10.1/35, 13/35, flow rate: 25 ml/min, diluent: mobile phase+ THF.

Step 9: CIS-8-(Methyl((Tetrahydrofuran-3-yl)Methyl)amino)-8-Phenyl-1,3-Diazaspiro[4.5]Decan-2-One (INT-1026)

[0370] LiAlH.sub.4 (1 M in THF) (4.48 mL, 4.48 mmol) was added to a solution of CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione (isomer-1) (0.4 g, 1.12 mmol) in THF:Et.sub.2O (2:1 v/v, 15 mL) at 0° C. under argon atmosphere The reaction mixture was stirred at 65° C. for 16 h. The mixture was cooled to 0° C., quenched with sat. aq. Na.sub.2SO.sub.4 (1000 mL) and filtered through celite pad. The filtrate was dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel 230-400 mesh; 5-6% MeOH in DCM) to yield 0.3 g (78%) of CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1026) as an off white solid. (TLC system: 10% MeOH in DCM, Rf: 0.2). LC-MS: m/z [M+1].sup.+ = 344.2.

[0371] Synthesis of INT-1031: CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-1,3-diazaspiro[4.5] decan-2-one

##STR00102##

Step 1: CIS-1-(Cyclobutyl-Methyl)-8-Dimethylamino-8-(3-Fluorophenyl)-3-[(4-Methoxyphenyl)-Methyl]-1,3-Diazaspiro[4.5]Decan-2-One

[0372] In analogy to the method described for INT-952 CIS-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one (INT-974) was converted into CIS-1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5] decan-2-one.

Step 2: CIS-1-(Cyclobutyl-Methyl)-8-Dimethylamino-8-(3-Fluorophenyl)-1,3-Diazaspiro[4.5] Decan-2-One

[0373] In analogy to the method described for INT-982 step 2 1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one was converted into 1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one (INT-1031).

[0374] Synthesis of INT-1037: 8-(dimethylamino)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile

##STR00103##

Step 1: 9,12-Dioxa-2,4-Diazadispiro[4.2.4^{8}.2^{5}]Tetradecan-3-One

[0375] Lithiumaluminiumhydride (2.2 equiv., 292 mmol) was suspended in THF (400 mL) and the suspension was cooled to 0° C. 8-(Dimethylamino)-8-(m-tolyl)-1,3-diazaspiro[4.5]decan-2-one (B, 75 mg, 0.261 mmol) (step 1 of INT-965) was added portionwise at 0° C. The reaction mixture was stirred 1.5 h at 0° C., then overnight at RT and then 2 h at 40° C. The reaction mixture was cooled down to 0° C., quenched carefully with sat. aq. Na.sub.2SO.sub.4, EtOAc (400 mL) was added and the resulting mixture was stirred for 2 h and then left without stirring for 2 h at RT. The precipitate was filtered off and washed with EtOAc and MeOH. The resulting solid residue was suspended in methanol and stirred at RT overnight. The precipitate was filtered off and disposed. The filtrate was concentrated under reduced pressure, the residue was suspended thoroughly in water (50 mL) at 40° C., the precipitate was filtered off and dried under reduced pressure to yield 9,12-dioxa-2,4-diazadispiro[4.2.4^{8}.2^{5}]tetradecan-3-one (11.4 g, 41%). Mass: m/z 213.2 (M+H).sup.+.

Step 2: 1,3-Diazaspiro[4.5]Decane-2,8-Dione

[0376] In analogy to the method described for INT-1003 step 3 9,12-dioxa-2,4-diazadispiro[4.2.4^{8}.2^{5}]tetradecan-3-one was treated with conc. aq. HCl to be converted into 1,3-diazaspiro[4.5]decane-2,8-dione. Mass: m/z 169.1 (M+H).sup.+.

Step 3: 8-(Dimethylamino)-2-Oxo-1,3-Diazaspiro[4.5]Decane-8-Carbonitrile (INT-1037)

[0377] In analogy to the method described for INT-965 step 1 1,3-diazaspiro[4.5]decane-2,8-dione was treated with dimethyl amine and potassium cyanide to be converted into 8-(dimethylamino)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile (INT-1037). Mass: m/z 223.2 (M+H).sup.+.

[0378] Synthesis of INT-1038: CIS-8-(dimethylamino)-8-(m-tolyl)-1,3-diazaspiro[4.5]decan-2-one

##STR00104##

[0379] To the suspension of 8-(dimethylamino)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile (200 mg, 0.90 mmol) in THF (4 mL) at RT was added dropwise 1 M bromo(m-tolyl)magnesium in THF (4 equiv., 3.6 mmol, 3.6 mL) and the reaction mixture was stirred for 1 h at RT. Additional portion of 1 M bromo(m-tolyl)magnesium in THF (1 equiv., 0.8 mL) was added. The reaction mixture was stirred at RT overnight, then quenched with methanol/water. Solid NH.sub.4Cl and DCM were added to the resulting mixture and the precipitate was filtered off. The organic phase of the filtrate was separated and the aqueous phase was extracted with DCM (3x). The combined organic phases were dried over anhydr. Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (DCM/MeOH, 100/0 to 65/35) to yield CIS-8-(dimethylamino)-8-(m-tolyl)-1,3-diazaspiro[4.5]decan-2-one (INT-1038) (81 mg, 31%). Mass: m/z 288.2 (M+H).sup.+.

[0380] Synthesis of INT-1059: TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

##STR00105##

Step 1: TRANS-8-(Dimethylamino)-8-Phenyl-1,3-Diazaspiro[4.5]Decane-2,4-Dione

[0381] To a stirred solution of 4-dimethylamino-4-phenyl-cyclohexanone (250.0 g, 1.15 mol, 1.0 eq.) in EtOH (2.5 L) and water (2.1 L) was added (NH.sub.4).sub.2CO.sub.3 (276.2 g, 2.87 mol, 2.5 eq.) and the reaction mixture was stirred at RT for 15 min. KCN (74.92 g, 1.15 mol, 1.0 eq.) was added. The reaction mixture was stirred at 60° C. for 18 h and then filtered in hot condition to get white solid which was washed with water (2.5 L), ethanol (1 L) and hexane (2.5 L). The resulting solid was dried under reduced pressure to get CIS-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (223 g, 0.776 mol, 65%) as a white solid. The filtrate was collected from multiple batches (~450 g) which contained a mixture of cis and trans isomers. The filtrate was concentrated under reduced pressure and solid obtained was filtered and washed with water (1 L) and hexane (1 L). Solid material was dried under reduced pressure to get ~100 g of a mixture of cis and trans (major) isomers. Crude material was partially dissolved in hot MeOH (600 mL) and cooled to RT, filtered through sintered funnel, washed with MeOH (200 mL) followed by ether (150 mL) and dried to get TRANS-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (50 g, 0.174 mmol, ~9-10%).

Step 2: TRANS-8-(Dimethylamino)-8-Phenyl-1,3-Diazaspiro[4.5]Decan-2-One (INT-1059)

[0382] In analogy to the method described for INT-976 step 2 TRANS-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione was treated with LiAlH.sub.4 to be converted into TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1059). Mass: m/z 274.2 (M+H).sup.+.

[0383] Synthesis of INT-1068 and INT-1069: CIS- and TRANS-8-(dimethylamino)-8-phenyl-1-(2,2,2-trifluoroethyl)-1,3-diazaspiro[4.5]decan-2-one

##STR00106##

Step 1: 1-Amino-4-Dimethylamino-4-Phenyl-Cyclohexanecarbonitrile

[0384] To a stirred solution of 4-dimethylamino-4-phenyl-cyclohexanone (50 g, 230.096 mmol) in MeOH (400 mL) was added NH.sub.4Cl (24.6 g, 460.8 mmol) followed by NH.sub.4OH (400 mL) at RT and the reaction mixture was stirred for 15 min. NaCN (22.5 g, 460.83 mmol) was added and the resulting mixture was stirred for 16 h at RT. The reaction mixture was extracted with DCM (3x750 mL). Combined organic layer was washed with water (750 mL), brine (750 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was triturated with DCM/hexane to get crude 1-amino-4-dimethylamino-4-phenyl-cyclohexanecarbonitrile (50 g, 90%) as an off white solid which was used in next step without further purification. LC-MS: m/z [M+H].sup.+ = 244.2 (MW calc. 244.09).

Step 2: N-(1-Cyano-4-Dimethylamino-4-Phenyl-Cyclohexyl)-2,2,2-Trifluoroacetamide

[0385] To a solution of 1-amino-4-dimethylamino-4-phenyl-cyclohexanecarbonitrile (5.0 g, 20.57 mmol, 1.0 eq.) in THF (100 ml) were added DIPEA (10.72 ml, 61.71 mmol, 3.0 eq), trifluoroacetic acid (1.89 ml, 24.69 mmol, 1.2 eq) and T3P (18.2 ml, 30.85 mmol, 1.5 eq) at 0° C. The reaction mixture was stirred at RT for 16 h, then diluted with water (100 ml) and extracted with 10 % MeOH in DCM (2x250 mL). Combined organic layer was washed with brine (100 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to get crude N-(1-cyano-4-dimethylamino-4-phenyl-cyclohexyl)-2,2,2-trifluoroacetamide as a light yellow sticky material which was used in the next step without further purification. LC-MS: m/z [M+1].sup.+ = 339.9 (MW calc. 339.36).

Step 3: 1-Aminomethyl-N′,N′-Dimethyl-4-Phenyl-N-(2,2,2-Trifluoroethyl)Cyclohexane-1,4-Diamine

[0386] To suspension of LiAlH.sub.4 (4.03 g, 106.19 mmol, 6.0 eq.) in dry THF (40 mL) was added N-(1-cyano-4-dimethylamino-4-phenyl-cyclohexyl)-2,2,2-trifluoro-acetamide (6.0 g, 17.69 mmol, 1.0 eq.) in dry THF (100 mL) dropwise at 0° C. The reaction mixture was stirred at RT for 16 h, then quenched with sat. aq. Na.sub.2SO.sub.4 at 0° C., excess THF was added and the resulting mixture was stirred at RT for 2 h. The resulting suspension was filtered through celite and the filter cake was washed with 10% MeOH in DCM (150 mL). Combined filtrate was concentrated under reduced pressure to yield crude 1-aminomethyl-N′,N′-dimethyl-4-phenyl-N-(2,2,2-trifluoro-ethyl)-cyclohexane-1,4-diamine (4.2 g, crude) as a light yellow sticky material which was directly used in the next step without further purification. LC-MS: m/z [M+1].sup.+ = 330.0 (MW calc. 329.40).

Step 4: CIS- and TRANS-8-Dimethylamino-8-Phenyl-1-(2,2,2-Trifluoro-Ethyl)-1,3-DiazaSpiro[4.5]Decan-2-One (INT-1068 and INT-1069)

[0387] To a solution of 1-aminomethyl-N′,N′-dimethyl-4-phenyl-N-(2,2,2-trifluoro-ethyl)-cyclohexane-1,4-diamine (4.2 g, 12.76 mmol, 1.0 eq.) in toluene (60 ml) was added KOH (4.29 g, 76.56 mmol, 6.0 eq.) in water (120 ml) at 0° C. followed by addition of COCl.sub.2 (15.6 ml, 44.66 mmol, 3.5 eq., 20% in toluene) at 0° C. and stirred at RT for 16 h. Reaction mixture was basified with sat NaHCO.sub.3 solution and extracted with DCM (2 x 200 ml). Combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to get crude product which was purified by prep HPLC to get CIS-8-dimethylamino-8-phenyl-1-(2,2,2-trifluoro-ethyl)-1,3-diaza-spiro[4.5]decan-2-one (INT-1068) (1.5 g) (major isomer, polar spot on TLC) and TRANS-8-dimethylamino-8-phenyl-1-(2,2,2-trifluoro-ethyl)-1,3-diaza-spiro[4.5]decan-2-one (INT-1069) as minor isomer (non-polar spot on TLC) (120 mg, 92.93% by HPLC) as off-white solids. CIS-isomer: LC-MS: m/z [M+1].sup.+ =356.2 (MW calc.= 355.40). HPLC: 98.53%, Column: Xbridge C-18 (100 x4.6), 5.Math., Diluent: MeOH, Mobile phase: A) 0.05% TFA in water; B) ACN flow rate: 1 ml/min, R.sub.t = 5.17 min. .sup.1HNMR (DMSO-d.sub.6, 400 MHz), δ (ppm) = 7.43-7.27 (m, 5H), 6.84 (s, 1H), 3.30-3.25 (m, 4H), 2.66-2.63 (d, 2H, J = 12.72 Hz), 1.89 (s, 6H), 1.58-1.51 (m, 2H), 1.46-1.43 (m, 2H), 1.33-1.23 (m, 2H).

[0388] Synthesis of INT-1075: CIS-3-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanoic acid

##STR00107##

[0389] A mixture of CIS-3-[8-dimethylamino-1-(1-hydroxy-cyclobutylmethyl)-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl]-2,2-dimethyl-propionitrile (INT-790) (2.8 g, 6.39 mmol,1.0 eq.) and NaOH (1.02 g, 25.57 mmol, 4.0 eq.) in ethylene glycol/water (3:1; 20 mL) was stirred at 110° C. for 36 h. The reaction mixture was acidified with aq. NaHSO.sub.4, the precipitate was filtered off and purified by column chromatography (silica gel; 8% MeOH/DCM) to yield CIS-3-[8-dimethylamino-1-(1-hydroxy-cyclobutylmethyl)-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl]-2,2-dimethyl-propionic acid (1.0 g, 2.188 mmol, 34%) as an off-white solid. LC-MS): m/z [M+1].sup.+ = 458.0 (MW calc.=457.61).

[0390] 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-00004 Intermediate Chemical Name Chemical Structure in analogy to method m/z [M+H].sup.+ INT-790 CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionitrile [00108] INT-897 Step 1 439.3 INT-791 CIS-3-[1-(Cyclobutylmethyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionitrile [00109] INT-897 Step 1 437.3 INT-792 CIS-3-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl] -2,2-dimethyl-propionitrile [00110] INT-897 Step 1 413.3 INT-793 CIS-3-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionitrile [00111] INT-897 Step 1 427.3 INT-794 CIS-3-(3,4-dimethoxybenzyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one [00112] INT-975 424.3 INT-796 CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-(3-methoxypropyl)-1,3-diazaspiro[4.5]decan-2-one [00113] INT-974 390.3 INT-797 CIS-8-(Ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one [00114] INT-976 288.2 INT-894 CIS-3-[1-(Cyclobutylmethyl)-8-[methyl-(2-methyl-propyl)-amino]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propionic acid; 2,2,2-trifluoro-acetic acid salt [00115] INT-898 456.3 INT-895 CIS-3-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propionic acid; 2,2,2-trifluoro-acetic acid salt [00116] INT-898 404.2 INT-896 CIS-3-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propionic acid; 2,2,2-trifluoro-acetic acid salt [00117] INT-898 418.3 INT-949 CIS-8-Dimethylamino-1-ethyl-8-phenyl-1,3-diazaspiro[4.5]decan-2-one [00118] INT-984 302.2 INT-950 CIS-1-(Cyclobutylmethyl)-8-dimethylamino-8-phenyl-3-[phenylmethyl]-1,3-diazaspiro[4.5]decan-2-one [00119] INT-952 432.3 INT-954 4-Dimethylamino-4-(5-methyl-thiophen-2-yl)-cyclohexan-1-one [00120] INT-965 238.1 INT-955 4-Dimethylamino-4-thiophen-2-yl-cyclohexan-1-one [00121] INT-965 224.1 INT-956 1-(1-Methyl-1H-pyrazol-3-yl)-4-oxo-cyclohexane-1-carbonitrile [00122] INT-95 8 204.1 INT-957 4-Oxo-1-pyrazin-2-yl-cyclohexane-1-carbonitrile [00123] INT-95 8 202.1 INT-959 4-Dimethylamino-4-(1-methyl-1H-pyrazol-3-yl)-cyclohexan-1-one [00124] INT-961 222.2 INT-960 4-Dimethylamino-4-pyrazin-2-yl-cyclohexan-1-one [00125] INT-961 220.1 INT-962 4-Dimethylamino-4-(3-methoxyphenyl)-cyclohexan-1-one [00126] INT-965 248.2 INT-963 CIS-3-Benzyl-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan- [00127] INT-975 364.2 2-one INT-964 4-(Ethyl-methyl-amino)-4-phenyl-cyclohexan-1-one [00128] INT-965 232.2 INT-967 CIS-8-Dimethylamino-8-[4-(methoxymethyloxy)-phenyl]-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one [00129] INT-974 454.3 INT-968 CIS-8-Dimethylamino-8-[3-(methoxymethyloxy)-phenyl]-3-[(4-methoxyphenyl)-methyl] -1,3-diazaspiro[4.5]decan-2-one [00130] INT-974 454.3 INT-969 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(4-hydroxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one [00131] INT-971 478.3 INT-970 CIS-8-Dimethylamino-8-(4-methoxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one [00132] SC_2017 424.3 INT-972 CIS-8-Dimethylamino-8-(3-methoxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro [4.5]decan-2-one [00133] SC_2017 424.3 INT-973 CIS-8-Dimethylamino-8-(4-fluorophenyl)-3-[(4-methoxyphenyl)-methyl] -1,3-diazaspiro[4.5]decan-2-one [00134] INT-974 412.2 INT-979 CIS-8-Dimethylamino-1-(3-methoxy-propyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one [00135] INT-984 346.2 INT-980 CIS-8-Dimethylamino-1-(2-methoxy-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one [00136] INT-984 332.2 INT-981 CIS-8-Dimethylamino-8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-2-one [00137] INT-984 316.2 INT-983 CIS-1-(Cyclopropylmethyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one [00138] INT-984 328.2 INT-985 CIS-1-(Cyclobutylmethyl)-8-(methyl-propyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one [00139] INT-986 370.3 INT-993 4-benzyl-4-(dimethylamino)cyclohexa none [00140] INT-965 232.3 INT-994 CIS-8-benzyl-8-(dimethylamino)-1,3-diazaspiro[4.5]decan-2-one [00141] INT-976 288.2 INT-995 TRANS-8-benzyl-8-(dimethylamino)-1,3-diazaspiro[4.5]decan-2-one [00142] INT-976 288.2 INT-997 CIS-8-(dimethylamino)-8-(thiophen-2-yl)-1,3-diazaspiro[4.5]decan-2-one [00143] INT-976 280.1 INT-998 TRANS-8-(dimethylamino)-8-(thiophen-2-yl)-1,3-diazaspiro[4.5]decan-2-one [00144] INT-976 280.1 INT-999 4-(dimethylamino)-4-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclohexanone [00145] INT-965 272.2 INT-1000 CIS-8-(dimethylamino)-8-(1-methyl-1H-benzo[d]imidazol-2-yl)-1,3-diazaspiro[4.5]decan-2-one [00146] INT-976 328.2 INT-1001 TRANS-8-(dimethylamino)-8-(1-methyl-1H-benzo[d]imidazol-2-yl)-1,3-diazaspiro[4.5]decan-2-one [00147] INT-976 328.2 INT-1009 TRANS-8-ethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one [00148] INT-1008 274.2 INT-1013 CIS-3-(1-(cyclobutylmethyl)-2-oxo-8-phenyl-8-(propylamino)-1,3-diazaspiro[4.5]decan-3-yl)-2,2- [00149] SC_5068 437.3 dimethylpropanenitrile INT-1024 CIS-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one [00150] INT-977 (step 2) 292.2 INT-1025 CIS-8-(dimethylamino)-8-(4-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one [00151] INT-974, INT-977 (step 2) 292.2 INT-1039 CIS-8-(dimethylamino)-8-(3-(trifluoromethoxy)phenyl)-1,3 -diazaspiro [4.5] decan-2-one [00152] INT-1038 358.2 INT-1040 (CIS)-8-(dimethylamino)-8-(3-(trifluoromethyl)phenyl)-1,3 -diazaspiro [4.5] decan-2-one [00153] INT-1038 342.2 INT-1041 (CIS)-8-(dimethylamino)-8-(3-methoxyphenyl)-1,3-diazaspiro[4.5]decan-2-one [00154] INT-1038 304.2 INT-1042 (CIS)-8-(5-chlorothiophen-2-yl)-8-(dimethylamino)-1,3 -diazaspiro [4.5] decan-2-one [00155] INT-1038 314.1 INT-1043 (CIS)-8-(dimethylamino)-8-(3-fluoro-5-methylphenyl)-1,3-diazaspiro[4.5]decan-2-one [00156] INT-1038 306.2 INT-1044 (CIS)-8-(3-chlorophenyl)-8-(dimethylamino)-1,3-diazaspiro[4.5]decan-2-one [00157] INT-1038 308.2 INT-1047 (CIS)-8-(methyl(oxetan-3-ylmethyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one [00158] INT-1026 330.5 INT-1061 TRANS-1-(cyclopropylmethyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one [00159] INT-984 328.2 INT-1063 CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one [00160] INT-1031 346.2 INT-1066 TRANS-1-(cyclobutylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one [00161] INT-987 342.3 INT-1070 CIS-8-(dimethylamino)-8-phenyl-1-(3,3,3-trifluoropropyl)-1,3-diazaspiro[4.5]decan-2-one [00162] INT-1068 360.2 INT-1074 CIS-8-(dimethylamino)-8-(3-fluorophenyl)-1-((1-hydroxycyclobutyl)methyl) -1,3-diazaspiro[4.5]decan-2-one [00163] INT-1031 376.2

Synthesis of Exemplary Compounds

[0391] Synthesis of SC_5003: CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-pyridin-4-yl)-propionamide

##STR00164##

[0392] Into a dry tube were added successively 1 mL of a solution of CIS-3-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propionic acid trifluoroacetate (INT-898) (0.1 M in DCM), 2 mL of a solution of 2-methoxypyridin-4-amine (0.2 M in DCM), 0.07 mL of triethylamine and 0.118 mL T3P (1.7 M, 50% in ethyl acetate). The reaction mixture was stirred at RT overnight, quenched with 3 mL 1 M aq. Na.sub.2CO.sub.3 and stirred at RT for 1 h. The organic layer was separated and the aqueous layer was extracted with DCM (2x). The combined organic layers were concentrated under reduced pressure and the product was purified by HPLC to obtain CIS-3-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methoxy- pyridin-4-yl)-propionamide (SC_5003). [M+H].sup.+ 520.3

[0393] Synthesis of SC_5022: CIS-N-(2-cyano-pyrimidin-5-yl)-3-[8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propionamide

##STR00165##

[0394] CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propionamide (SC_5002) (0.270 g, 0.631 mmol) was dissolved in 1,4 dioxane (30 mL) at RT and purged with nitrogen. To the reaction mixture were added 5-bromopyrimidine-2-carbonitrile (0.173 g, 0.946 mmol), C.sub.S2CO.sub.3 (0.410 g, 1.262 mmol), Xanthphos (0.055 g, 0.095 mmol), Pd.sub.2(dba).sub.3 (0.029 g, 0.032 mmol) and the resulting suspension was again purged with nitrogen for 15 minutes. The reaction mixture was stirred at 90° C. for 18 h, then cooled to RT and diluted with EtOAc (60 mL). The insoluble solid was filtered off and the clear filtrate was concentrated under reduced pressure. The crude product was purified preparative TLC using 3% MeOH in DCM as a mobile phase to afford 52 mg (15%) of CIS-N-(2-cyano-pyrimidin-5-yl)-3-[8-dimethylamino-1-[(1-hydroay-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propionamide (SC_5022) as an off-white solid (TLC system: 10% MeOH in DCM; Rf: 0.56). [M+H].sup.+ 532.3

[0395] Synthesis of SC_5031: CIS-3-[8-dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-propionamide

##STR00166##

[0396] 50% Propylphosphonic anhydride (T3P) solution in ethyl acetate (0.766 mL, 1.204 mmol) was added to a solution of crude CIS-3-[8-dimethylamino-1-(3-methoay-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propionic acid trifluoroacetate (INT-896) (100 mg, 0.193 mmol), 2-aminoethanol (0.035 mL, 0.580 mmol) and diisopropylethylamine (0.167 mL, 0.966 mmol) in DCM (4 mL) at 0° C. The reaction mixture was warmed to RT and stirred for 4 h and then quenched with water. The organic product was extracted with DCM (3x20 mL). The combined organic layer was washed with sat. aq. NaHCO.sub.3 (10 mL), brine (10 mL), dried over anhydr. Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 31 mg of CIS-3-[8-dimethylamino-l-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro [4.5]decan-3-yl]-N-(2-hydroxyethyl)propionamide (SC_5031) as an off-white solid. [M+H].sup.+ 447.3

[0397] Synthesis of SC_5034: CIS-3-[8-dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide

##STR00167##

[0398] 30% aq. H.sub.2O.sub.2 (0.2 mL, 0.74 mmol) was added to a suspension of CIS-3-[8-dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethylpropionitrile (INT-793) (80 mg, 0.187 mmol) and K.sub.2CO.sub.3 (52 mg, 0.37 mmol) in DMSO at 10-15° C. The resulting reaction mixture was warmed to RT and stirred for 18 h. The reaction mixture was quenched with water and the organic product was extracted with EtOAc (3x10 mL). The combined organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The resulting crude product was purified by preparative TLC (2% MeOH in DCM) to yield 30 mg of CIS-3-[8-dimethylamino-l-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide (SC_5034) (25%) as an off-white solid. (TLC system: 10% MeOH in DCM R.sub.f: 0.40). [M+H].sup.+ 445.3

[0399] Synthesis of SC_5055: CIS-3-[8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-propionamide

##STR00168##

[0400] 50% Propylphosphonic anhydride (T3P) solution in DMF (1.1 mL, 1.748 mmol) was added to a mixture of crude CIS-3-[8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5] decan-3-yl]-propionic acid (INT-899) (300 mg, 0.699 mmol, crude, contaminated with 4-methylbenzene-sulfonic acid), oxetan-3-amine hydrochloride (91 mg, 0.839 mmol) and diisopropylethylamine (0.51 mL, 2.797 mmol) in DMF (6 mL) at 0° C. The reaction mixture was warmed to RT and stirred for 6h, then quenched with water and the organic product was extracted with EtOAc (3x20mL). The combined organic layer was washed with sat. aq. NaHCO.sub.3 (10 mL), brine (10 mL), dried over anhydr. Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude product was purified by preparative TLC by using 3% methanol in DCM as a mobile phase to yield 140 mg (41%) of CIS-3-[8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-propionamide (SC_5055) as an off-white solid. (TLC system: 10% MeOH in DCM Rf: 0.55). [M+H].sup.+ 485.3

[0401] Synthesis of SC_5056: CIS-N-(carbamoyl-methyl)-3-[1-(cyclobutyl-methyl)-8-dimethyl-amino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide

##STR00169##

[0402] 50% propylphosphonic anhydride (T3P) solution in DMF (3.99 mL, 6.27 mmol) was added to a solution of CIS-3-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5] decan-3-yl]-2,2-dimethyl-propionic acid (INT-897) (1.2 g, 2.51 mmol), 2-aminoacetamide hydrochloride (0.41 g, 3.76 mmol) and diisopropylethylamine (2.63 mL, 15.06 mmol) in DMF (15 mL) at 0° C. The reaction mixture was warmed to RT and stirred for 16 h. The reaction mixture was quenched with water, the organic product was extracted with DCM (3x15 mL). The combined organic extracts were washed with brine, dried over anhydr. Na.sub.2SO.sub.4 and concentrated under reduced pressure. The resulting crude product was purified by reverse phase preparative HPLC to give 105 mg of CIS-N-(carbamoyl-methyl)-3-[1-(cyclobutyl-methyl)-8-dimethyl-amino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide (SC_5056) as an off-white solid. (TLC system: 10% MeOH in DCM R.sub.f: 0.4). [M+H].sup.+ 442.3

[0403] Synthesis of SC_5059: CIS-3-[1-[(1-hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-propionamide

##STR00170##

[0404] N-Iodosuccinimide (104.6 mg, 0.465 mmol) was added to a solution of CIS-3-[8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-propionamide (SC_5055) (150 mg, 0.309 mmol) in a mixture of acetonitrile and THF (1:1 v/v, 8 mL) at 0° C. and the resulting mixture was stirred for 16 h at RT. The reaction mixture was basified with 2 N aq. NaOH to pH~10 and the organic product was extracted with EtOAc (3x30 mL). The combined organic extracts were dried over anhydr. Na.sub.2SO.sub.4 and concentrated in vacuo. The resulting crude product was purified by preparative reverse phase HPLC to give 70 mg of the desired product as a formic acid salt. The isolated product was diluted with water (8 mL) and basified with solid NaHCO.sub.3. The resulting mixture was extracted with ethyl acetate (2x30 mL), the combined organic layer was dried over anhydr. Na.sub.2SO.sub.4 and concentrated in vacuo to yield 60 mg (41%) of CIS-3-[1-[(1-hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-propionamide (SC_5059) as an off-white solid (TLC system: 5% MeOH in DCM; R.sub.f: 0.44.). [M+H].sup.+ 471.3

[0405] Synthesis of SC_5063: CIS-2,2-dimethyl-3-(8-(methylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5] decan-3-yl)propanenitrile

##STR00171##

##STR00172##

Step 1: CIS-3-(8-(Dimethylamino)-1-(Methoxymethyl)-2-Oxo-8-Phenyl-1,3-Diazaspiro[4.5] Decan-3-yl)-2,2-Dimethylpropanenitrile

[0406] To a solution of CIS-3-(8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-2,2-dimethyl-propionitrile (SC_5062) (1.8 g, 5.08 mmol, 1.0 eq.) in THF (20 ml) was added NaH (95%, 366 mg, 15.25 mmol, 3.0 eq.) at 0° C. and the reaction mixture was stirred for 20 min at RT. A solution of methoxymethyl chloride (0.57 ml, 7.62 mmol, 1.5 eq.) in THF (5 ml) was added at 0° C. and the resulting mixture was stirred at RT for 16 h. The reaction mixture was diluted with water (20 ml) and extracted with EtOAc (2x50 ml). The combined organic layers were washed with water (50 ml) and brine (50 ml), dried over anhydr. Na.sub.2SO.sub.4 and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (neutral alumina; 0.2% MeOH/DCM) to yield CIS-3-(8-(dimethylamino)-1-(methoxymethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanenitrile (700 mg, 1.75 mmol, 34%) as an off-white sticky solid.. LC-MS: m/z [M+H].sup.+ = 399.3 (MW calc. = 398.54).

Step 2: CIS-3-(1-(Methoxymethyl)-8-(Methylamino)-2-Oxo-8-Phenyl-1,3-Diazaspiro[4.5]Decan-3-yl)-2,2-Dimethylpropanenitrile

[0407] To a solution of CIS-3-(8-(dimethylamino)-1-(methoxymethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanenitrile (700 mg, 1.75 mmol, 1.0 eq.) in acetonitrile (20 ml) and THF (10 ml) was added N-iodosuccinimide (590 mg, 2.63 mmol, 1.5 eq.) at 0° C. and the mixture was stirred at RT for 3 h. The reaction mixture was diluted with water (20 ml) and 1 N aq. NaOH (5 ml) and extracted with DCM (2x30 ml). The combined organic layers were washed with brine (40 ml), dried over anhydr. Na.sub.2SO.sub.4 and concentrated under reduced pressure to give CIS-3-(1-(methoxymethyl)-8-(methylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanenitrile (350 mg, 0.911 mmol, 52 %) which was used directly for next step without further purification. LC-MS: m/z [M+H]+ = 385.2 (MW calc. = 384.52).

Step 3: CIS-2,2-Dimethyl-3-(8-(Methylamino)-2-Oxo-8-Phenyl-1,3-Diazaspiro[4.5]Decan-3-yl)Propanenitrile (SC_5063)

[0408] To a solution of CIS-3-(1-(methoxymethyl)-8-(methylamino)-2-oxo-8-phenyl-l=1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanenitrile (400 mg, 1.04 mmol, 1.0 eq.) in MeOH (10 ml) was added 2 M aq. HCl (30 ml) at 0° C. and the mixture was stirred at RT for 16 h. The reaction mixture was basified with 2 M aq. NaOH and extracted with DCM (2x25 ml). The combined organic layers were washed with brine (30 ml), dried over anhydr. Na.sub.2SO.sub.4 and concentrated under reduced pressure to give CIS-2,2-dimethyl-3-(8-(methylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)propanenitrile (SC_5063) (300 mg, 0.882 mmol, 84 %) which was 95.72% pure according to HPLC. LC-MS: m/z [M+H]+ = 341.27 (MW calc. = 340.46). .sup.1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 7.42-7.19 (m, 5H), 6.78 (bs, 1H), 3.36 (s, 2H), 3.18 (s, 2H), 1.96-1.85 (m, 7H), 1.66 (bs, 2H), 1.46-1.43 (m, 2H), 1.25 (s, 6H).

[0409] Synthesis of SC_5074: CIS-3-(8-(ethyl(methyl)amino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanamide

##STR00173##

Step 1: CIS-3-(8-(Ethyl(methyl)amino)-1-((1-Hydroxycyclobutyl)Methyl)-2-Oxo-8-Phenyl-1,3-Diazaspiro[4.5]Decan-3-yl)-2,2-Dimethylpropanenitrile

[0410] To a solution of CIS-3-(8-(ethyl(methyl)amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanenitrile (SC_5061) (250 mg, 0.679 mmol, 1.0 eq.) in DMSO (10 ml) was added NaOH (108 mg, 2.716 mmol, 4.0 eq.) at RT and the reaction mixture was stirred at 60° C. for 30 min. A solution of 1-oxa-spiro[2.3]hexane (142 mg, 1.69 mmol, 2.5 eq.) in DMSO (1 ml) was added at RT. The reaction mixture was stirred at 55° C. for 16h, then diluted with water (100 ml) and extracted with ethyl acetate (60 ml). The organic layer was washed with water (50 ml) and brine (50 ml), dried over anhydr. Na.sub.2SO.sub.4 and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (neutral alumina; 30% ethyl acetate/hexane) to yield CIS-3-(8-(ethyl(methyl)amino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanenitrile (120 mg, 0.265 mmol, 39 %) as an off-white solid. LC-MS: m/z [M+1]+ = 453.1 (MW calc. 452.63).

Step 2: CIS-3-(8-(Ethyl(methyl)Amino)-1-((1-Hydroxycyclobutyl)Methyl)-2-Oxo-8-Phenyl-1,3-Diazaspiro[4.5]Decan-3-yl)-2,2-Dimethylpropanamide (SC_5074)

[0411] In analogy to the method described for SC_5034 CIS-3-(8-(ethyl(methyl)amino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanenitrile was treated with 30% aq. H.sub.2O.sub.2 in the presence of DMSO and potassium carbonate to be converted into CIS-3-(8-(ethyl(methyl)amino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanamide (SC_5074). Yield: 44% (55 mg, 0.117 mmol). LC-MS: m/z [M+H]+ = 471.1 (MW calc. = 470.65). .sup.1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 7.34-722 (m, 5H), 7.16 (s, 1H), 6.95 (s, 1H), 6.11 (s, 1H), 3.25 (s, 2H), 3.16 (s, 2H), 3.09 (s, 2H), 2.68-2.65 (m, 2H), 2.20-1.99 (m, 6H), 1.95-1.87 (m, 5H), 1.63-1.61 (m, 1H), 1.43-1.23 (m, 6H), 1.02 (s, 6H), 0.99 (t, 3H, J = 6.94 Hz).

[0412] Synthesis of SC_5075: CIS-3-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanenitrile

##STR00174##

[0413] CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-984) (50 mg, 0.15 mmol) was added to a suspension of NaH (60% in mineral oil, 18 mg, 0.45 mmol) in DMF (5 mL) at 0° C. and the reaction mixture was stirred at RT for 5 min. 2-Cyano-2-methylpropyl 4-methylbenzenesulfonate (113 mg, 0.45 mmol) was added at 0° C. and stirring was continued 120° C. for 16 h. The reaction mixture was quenched with cold water and the organic product was extracted with DCM (3x20 mL). The combined organic extracts were dried over anhydr. Na.sub.2SO.sub.4 and concentrated under reduced pressure. The above described reaction was repeated with 300 mg of CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-984). Both reaction batches were combined and purified by column chromatography (silica gel 100-200 mesh, 0-10% MeOH in DCM) to yield the product which was further purified by reverse phase preparative HPLC to afford 41 mg (16%) of CIS-3-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanenitrile (SC_5075) as an off-white solid. (TLC system: 10% MeOH in DCM; Rf: 0.40). .sup.1H NMR (DMSO-d6): δ 7.37-7.23 (m, 5H), 3.38 (s, 2H), 3.22 (s, 2H), 2.94 (d, 2H), 2.71-2.68 (m, 2H), 2.18 (t, 2H), 1.97 (s, 6H), 1.42-1.30 (m, 4H), 1.26 (s, 6H), 0.93-0.92 (m, 1H), 0.48-0.44 (m, 2H), 0.28-0.24 (m, 2H). [M+H].sup.+ 471.3

[0414] Synthesis of SC_5079: CIS-8-(dimethylamino)-3-(3-(1,1-dioxidothiomorpholino)-2,2-dimethyl-3-oxopropyl)-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

##STR00175##

Step 1: CIS-3-(2,2-Dimethyl-3-Oxo-3-Thiomorpholinopropyl)-8-(Dimethylamino)-1-((1-Hydroxycyclobutyl)Methyl)-8-Phenyl-1 ,3-Diazaspiro [4.5] Decan-2-One

[0415] To a solution of CIS-3-[8-dimethylamino-1-(1-hydroxy-cyclobutylmethyl)-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl]-2,2-dimethyl-propionic acid (INT-1075) (250 mg, 0.55 mmol, 1.0 eq) in DCM (20 mL) were added DIPEA (0.29 mL, 1.65 mmol, 3.0 eq.), HATU (209 mg, 0.55 mmol, 1.0 eq.) and thiomorpholine (83 .Math.L, 0.82 mmol, 1.5 eq.) at 0° C. The reaction mixture was stirred at RT for 16 h, diluted with DCM (100 mL), washed with water (50 mL), sat. aq. NaHCO.sub.3 (50 mL) and brine (50 mL). Organic layer was dried over sodium sulfate and concentrated under reduced pressure to get crude product which was purified by column chromatography (silica gel; 3% MeOH in DCM) to yield CIS-8-dimethylamino-3-(2,2-dimethyl-3-oxo-3-thiomorpholin-4-yl-propyl)-1-(1-hydroxy-cyclobutylmethyl)-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (220 mg, 0.40 mmol, 73%) as an off-white solid. LC-MS: m/z [M+1].sup.+ =543.3 (MW calc.=542.78).

Step 2: CIS-8-(Dimethylamino)-3-(3-(1,1-Dioxidothiomorpholino)-2,2-Dimethyl-3-Oxopropyl)-1-((1-Hydroxycyclobutyl)Methyl)-8-Phenyl-1,3-Diazaspiro[4.5]Decan-2-One (SC_5079)

[0416] To a solution of CIS-8-dimethylamino-3-(2,2-dimethyl-3-oxo-3-thiomorpholin-4-yl-propyl)-1-(1-hydroxy-cyclobutylmethyl)-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (270 mg, 0.5 mmol, 1.0 eq) in acetone/THF/H.sub.2O (40 mL, 6/1/1 v/v/v) was added oxone (615 mg, 1.0 mmol, 2.0 eq.) at 0° C. The reaction mixture was stirred at RT for 16 h, quenched with sat. aq. Na.sub.2SO.sub.3, diluted with EtOAc (150 mL) and washed with sat. aq. NaHCO.sub.3 (75 mL). Organic layer was dried over sodium sulfate and concentrated under reduced pressure to get crude product which was purified by column chromatography (silica gel; 4%MeOH in DCM) to yield CIS-8-dimethylamino-3-[3-(1,1-dioxo-1l6-thiomorpholin-4-yl)-2,2-dimethyl-3-oxo-propyl]-1-(1-hydroxy-cyclobutylmethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_5079) (100 mg, 0.17 mmol, 34%) as a white solid. .sup.1HNMR (DMSO-d.sub.6, 400 MHz), δ (ppm) = 7.37-7.25 (m, 5H), 5.91 (s, 1H), 3.92 (bs, 4H), 3.28 (bs, 4H), 3.13 (bs, 4H), 3.07 (s, 2H), 2.64 (d, 2H, J = 13.44 Hz), 2.07-2.00 (m, 4H), 1.96 (s, 6H), 1.87-1.85 (m, 2H), 1.61-1.64 (m, 1H), 1.40-1.30 (m, 5H), 1.19 (s, 6H). LC-MS: m/z [M+1].sup.+ =575.1 (MW calc.=574.78).

[0417] Synthesis of SC_5083: CIS-3-(1-(cyclopropylmethyl)-8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl)-N,N-dimethylpropanamide

##STR00176##

Step 1: Sodium CIS-3-(1-(Cyclopropylmethyl)-8-(Dimethylamino)-8-(3-Fluorophenyl)-2-Oxo-1,3-Diazaspiro[4.5]Decan-3-yl)Propanoate

[0418] To a solution of CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one (INT-1063) (100 mg, 0.29 mmol) in dry THF (2.4 mL) cooled to 0° C. was added potassium tert-butoxide (1.5 equiv., 0.43 mmol, 49 mg). The reaction mixture was stired for 15 min at 0° C. and methyl 3-bromopropionate (1.2 equiv., 0.35 mmol, 38 .Math.L) was added dropwise. The reaction mixture was stirred at RT for 16 h and new portions of methyl 3-bromopropionate (1.2 equiv., 0.35 mmol, 38 .Math.L) and potassium tert-butoxide (1.5 equiv., 0.43 mmol, 49 mg) were added. The reaction mixture was stirred for 3 h at RT, quenched with sat. aq. NaHCO.sub.3 and then extracted with DCM (2x). To the combined organic phase 2 mL of 2 M aq. NaOH were added, the resulting mixture was vigorously stirred overnight at RT and then concentrated under reduced pressure to yield crude sodium CIS-3-(1-(cyclopropylmethyl)-8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl)propanoate (60 mg, 50 %) which was used in the next step without further purification. LC-MS: m/z [M+1].sup.+ = 418.3 (MW calc. 417.3)

Step 2: CIS-3-(1-(Cyclopropylmethyl)-8-(Dimethylamino)-8-(3-Fluorophenyl)-2-Oxo-1,3-Diazaspiro[4.5]Decan-3-yl)-N,N-Dimethylpropanamide (SC_5083)

[0419] To a solution of sodium CIS-3-[1-(cyclopropylmethyl)-8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]propanoate (60 mg, 0.144 mmol, 60 mg) and N-methylmethanamine (8 equiv., 1.15 mmol, 2 M in THF, 0.57 mL) in DCM (1 mL) was added propylphosphonic anhydride solution ≥50 wt. % in EtOAc (2 equiv., 0.29 mmol, 0.17 mL). The reaction mixture was stirred at RT overnight, then quenched with sat. aq. NaHCO.sub.3 (2 mL) and diluted with EtOAc. The organic phase was separated and the aqueous phase extracted with EtOAc. The combined organic layers were dried over anhydr. Na.sub.2SO.sub.4 and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography (eluent gradient DCM/MeOH) to yield CIS-3-(1-(cyclopropylmethyl)-8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl)-N,N-dimethylpropanamide (SC_5083) (25 mg, 39%). LC-MS: m/z [M+H].sup.+ = 445.3 (MW calc. = 444.29). .sup.1H NMR (600 MHz, DMSO) δ 7.40 (td, 1H), 7.21 - 7.05 (m, 3H), 3.27 (t, 2H), 3.18 (s, 2H), 2.95 (s, 3H), 2.91 (d, 2H), 2.79 (s, 3H), 2.67 - 2.55 (m, 2H), 2.47 (t, 2H), 2.13 (ddd, 2H), 1.99 (s, 6H), 1.43 - 1.21 (m, 4H), 0.92 (ddt, 1H), 0.49 - 0.41 (m, 2H), 0.30 - 0.21 (m, 2H).

[0420] For further exemplary compounds the last synthesis step 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-00005 Example Chemical Name Reactant I Reactant II in analogy to method m/z [M+H].sup.+ SC_5001 CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro [4.5] decan-3-yl]-N-pyridazin-3-yl-propionamide INT 899 pyridazin-3 -amine SC_5055 507.3 SC_5002 CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro [4.5] decan-3-yl]-propionamide INT 899 NH.sub.4Cl SC_5055 429.3 SC_5004 CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyridin-3-yl)-propionamide INT 998 6-methoxypyridin-3-amine SC_5003 520.3 SC_5005 CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5] decan-3-yl]-N-(3 -methoxy-pyridin-4-yl)-propionamide INT 998 3-methoxypyridin-4-amine SC_5003 520.3 SC_5006 CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5] decan-3-yl]-N-(6-methoxy-pyridazin-3-yl)-propionamide INT 998 6-methoxypyridazi n-3-amine SC_5003 521.3 SC_5007 CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5] decan-3-yl]-N-(5-methylsulfonyl-pyridin-2-yl)-propionamide INT 998 5-(methylsulfonyl) pyridin-2-amine SC_5003 568.3 SC_5008 CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyridin-2-yl)-propionamide INT 998 5-methoxypyridin-2-amine SC_5003 520.3 SC_5009 CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro [4.5]decan-3-yl]-N-(6-methylsulfonyl-pyridin-3-yl)-propionamide INT 998 6-(methylsulfonyl) pyridin-3-amine SC_5003 568.3 SC_5010 CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5] decan-3-yl]-N-(6-methoxy-pyrazin-2-yl)-propionamide INT 998 6-methoxypyrazin-2-amine SC_5003 521.3 SC_5011 CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyridin-2-yl)-propionamide INT 998 4-methoxypyridin-2-amine SC_5003 520.3 SC_5012 CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxazol-5-yl-methyl)-propionamide INT 998 oxazol-5-ylmethanamine SC_5003 494.3 SC_5013 CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxazol-2-yl-methyl)-propionamide INT 998 oxazol-2-ylmethanamine SC_5003 494.3 SC_5014 CIS-1-(Cyclobutyl-methyl)-3-[3-[3,4-dihydroxy-piperidin-1-yl]-3-oxo-propyl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT 998 piperidine-3,4-diol SC_5003 513.3 SC_5015 CIS-1-(Cyclobutyl-methyl)-3-[3-[3,4-dihydroxy-pyrrolidin-1-yl] -3 -oxo-propyl] -8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT 998 pyrrolidine-3,4-diol SC_5003 499.3 SC_5016 CIS-1-(Cyclobutyl-methyl)-3-[3-[(3S,4R)-3,4-dihydroxy-pyrrolidin-1-yl]-3 -oxo-propyl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT 998 (3S,4R)-pyrrolidine-3,4-diol SC_5003 499.3 SC_5017 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[3-(3-hydroxy-piperidin-1-yl)-3-oxo-propyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT 998 piperidin-3-ol SC_5003 497.3 SC_5018 CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(1-hydroxy-cyclobutyl)-methyl]-propionamide INT 998 1-(aminomethyl)cy clobutanol SC_5003 497.3 SC_5019 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[3-oxo-3-(5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-7-yl)-propyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT 998 5,6,7,8-tetrahydro-[1,2,4]triazolo[1, 5-a]pyrazine SC_5003 520.3 SC_5020 CIS-3-[3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- INT 998 3-amino-N,N-dimethylpropana SC_5003 512.4 diazaspiro[4.5]decan-3-yl]-propanoylamino]-N,N-dimethyl-propionamide mide SC_5023 CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-2-yl-propionamide SC_5002 2-bromopyrimidine SC_5022 507.3 SC_5024 CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1.3 -diazaspiro[4.5]decan-3-yl]-N-(4-hydroxy-pyrimidin-2-yl)-propionamide INT-899 2-aminopyrimidin-4(3H)-one SC_5055 523.3 SC_5025 CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyrimidin-2-yl)-propionamide SC_5002 2-bromo-4-methoxypyrimidi ne SC_5022 537.3 SC_5026 CIS-3-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide SC_5046 --- SC_5059 427.3 SC_5027 CIS-3-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-propionamide SC_5054 --- SC_5059 459.3 SC_5028 CIS-3-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propionamide SC_5002 --- SC_5059 415.3 SC_5029 CIS-3-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-propionamide SC_5052 --- SC_5059 429.3 SC_5030 CIS-3-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridazin-3-yl-propionamide SC_5001 --- SC_5059 493.3 SC_5032 CIS-3-[8-Dimethylamino-1-(2-methoxyethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-propionamide INT 896 methylamine SC_5031 417.3 SC_5033 CIS-3-[8-Dimethylamino-1-(2-methoxyethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-5-yl-propionamide INT 896 pyrimidin-5-amine SC_5031 481.3 SC_5035 CIS-3-[8-Dimethylamino-1-(2-methoxyethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide INT-792 --- SC_5034 431.3 SC_5036 CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridin-3-yl-propionamide INT 899 pyridin-3-amine SC_5055 506.3 SC_5037 CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridin-4-yl-propionamide INT 899 pyridin-4-amine SC_5055 506.3 SC_5038 CIS-2-[3-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propanoylamino]-2-methyl-propionamide INT 896 2-amino-2-methylpropanami de SC_5031 502.3 SC_5039 CIS-3-[8-Dimethylamino-1-(3-methoxypropyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methylsulfonyl-ethyl)-propionamide INT 896 2-(methylsulfonyl) ethanamine SC_5031 523.3 SC_5040 CIS-3-[8-Dimethylamino-1-(3-methoxypropyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxyethyl)-propionamide INT 896 2-aminoethanol SC_5031 461.3 SC_5041 CIS-8-Dimethylamino-1-(3-methoxypropyl)-3-[3-oxo-3-(3-oxo-piperazin-1-yl)-propyl]-8-phenyl-1,3-diazaspiro [4.5] decan-2-one INT 896 piperazin-2-one SC_5031 500.3 SC_5042 CIS-(2R)-1-[3-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propanoyl]-pyrrolidine-2-carboxylic acid amide INT 896 (R)-pyrrolidine-2-carboxamide SC_5031 514.3 SC_5043 CIS-N-(Carbamoyl-methyl)-3-[8-dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3- INT 896 2-aminoacetamide SC_5031 474.3 yl]-propionamide SC_5044 CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridin-2-yl-propionamide INT 899 pyridin-2-amine SC_5055 506.3 SC_5045 CIS-3-[1-(Cyclobutyl-methyl)-8-(ethylmethyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide INT-791 --- SC_5034 455.3 SC_5046 CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide INT-897 product step 1 --- SC_5034 441.3 SC_5047 CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propionamide INT-898 NH.sub.4Cl SC_5031 413.3 SC_5048 CIS-3-[1-(Cyclobutyl-methyl)-8-[methyl-(2-methyl-propyl)-amino]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-propionamide INT 894 methylamine SC_5031 469.4 SC_5049 CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-propionamide INT 898 methylamine SC_5031 427.3 SC_5051 CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-5-yl-propionamide INT 899 pyrimidin-5-amine SC_5055 507.3 SC_5052 CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-propionamide INT 899 methylamine SC_5055 443.3 SC_5053 CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl] -2-oxo-8-phenyl-1,3 -diazaspiro[4.5]decan-3-yl]-N-(2-methoxyethyl)-propionamide INT 899 2-methoxyethanam ine SC_5055 487.3 SC_5054 CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro [4.5] decan-3-yl]-N-(2-hydroxy- INT 899 2-aminoethanol SC_5055 473.3 ethyl)-propionamide SC_5057 CIS-N-(Carbamoyl-methyl)-3-[1-(cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide SC_5056 --- SC_5059 484.3 SC_5058 CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3 -diazaspiro [4.5] decan-3-yl]-2,2-dimethyl-propionamide INT-790 --- SC_5034 457.3 SC_5060 CIS-3-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionamide SC_5058 --- SC_5059 443.3 Example Chemical name Reactant I Reactant II in analogy to method .sup.1H NMR data m/z (M+H).sup.+ SC_5061* CIS-3-[8-(Ethylmethyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan -3-yl]-2,2-dimethyl-propionitrile INT-797 3-bromo-2,2-dimethyl-propionitrile step 1 of INT-897 1HNMR (DMSO-d6, 400 MHz, at 100 0C), δ (ppm) = 7.34-7.21 (m, 5H), 6.70 (bs, 1H), 3.28 (s, 2H), 3.19 (s, 2H), 2.32-2.24 (m, 4H), 2.06 (s, 3H), 1.87-1.82 (m, 4H), 1.45-1.37 (bs, 2H), 1.27 (s, 6H), 0.93 (t, 3H, 6.8 Hz). 369.2 SC_5062* CIS-3-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan -3-yl)-2,2-dimethyl-propionitrile INT-976 3-bromo-2,2-dimethyl-propionitrile step 1 of INT-897 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 7.35-7.24 (m, 5H), 7.03 (bs, 1H), 3.25 (s, 2H), 3.15 (s, 2H), 2.32 (bs, 2H), 1.92 (s, 6H), 1.82 (bs, 4H), 1.38 (bs, 2H), 1.24 (s, 6H). 355.2 SC_5064 CIS-3-[8-(Ethylmethyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan SC_5061 SC_5034 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 7.33-7.22 (m, 5H), 7.14 (bs, 1H), 6.83-6.79 (m, 387.5 -3-yl]-2,2-dimethyl-propionamide 2H), 3.07 (s, 2H), 3.01 (s, 2H), 2.32 (bs, 2H), 2.11 (bs, 2H), 1.96 (s, 3H), 1.78-1.69 (m, 4H), 1.31 (bs, 2H), 0.99 (s, 6H), 0.90 (t, 3H, J = 6.66 Hz). SC_5065* CIS-3-[8-(Ethylmethyl-amino)-1-methyl-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan -3-yl]-2,2-dimethyl-propionitrile SC_5061 methyl iodide step 1 of INT-953 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 7.34-722 (m, 5H), 3.38 (s, 2H), 3.21 (s, 2H), 2.71-2.64 (m, 5H), 2.19-2.16 (m, 4H), 1.96 (s, 3H), 1.37-1.30 (m, 4H), 1.25 (s, 6H), 0.98 (t, 3H, J = 6.48 Hz). 383.2 SC_5066 CIS-3-[8-(Ethylmethyl-amino)-1-methyl-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan -3-yl]-2,2-dimethyl-propionamide SC_5065 SC_5034 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 7.34-723 (m, 5H), 7.15 (s, 1H), 6.90 (s, 1H), 3.13 (s, 4H), 2.67-2.60 (m, 5H), 2.12-2.09 (m, 4H), 1.95 (s, 3H), 1.33-1.25 (m, 4H), 1.01-0.97 (m, 9H). 401.2 SC_5067 CIS-2,2-Dimethyl-3-(8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan -3-yl)-propionamide SC_5063 SC_5034 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 7.42 (d, 2H, J = 8), 7.33-7.29 (t, 2H,J = 8), 7.19-7.15 (m, 2H), 6.90 (s,1H), 6.51 (bs, 1H), 3.12-3.09 (m, 4H), 1.90-1.83 (m,7H), 1.74-1.69 (m, 2H),1.41-1.38 (d, 2H, J=12), 1.01 (s, 6H) 358.48 SC_5068* CIS-3-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan -3-yl)-2,2-dimethyl-propionitrile INT-1008 3-bromo-2,2-dimethyl-propionitrile step 1 of INT-897 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 7.42 (d, 12H, J = 7.32 Hz), 7.30 (t, 2H, J = 7.20 Hz), 7.17 (t, 1H, J = 7.12 Hz), 6.78 (s, 1H), 3.35 (s, 2H), 3.17 (s, 2H), 2.05 (m, 7H), 1.67-1.43 (m, 4H), 1.25 (s, 6H), 0.91 (t, 3H, J = 6.78 Hz). 355.1 SC_5069 CIS-3-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan -3-yl)-2,2-dimethyl-propionamide SC_5068 SC_5034 1HNMR (DMSO-d6, 400 MHz, at 100 0C), δ (ppm) = 7.45 (d, 2H, J = 6.52 Hz), 7.32 (t, 2H, J = 7.2 Hz), 7.21 (t, 1H, J = 6.66 Hz), 6.64 (bs, 2H), 6.18 (s, 1H), 3.16 (s, 4H), 2.19 (bs, 2H), 1.91-1.79 (m, 6H), 1.44 (bs, 2H), 1.07 (s, 6H), 0.95 (t, 3H, J = 6.62 Hz). 373.0 SC_5070 CIS-3-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan -3-yl)-2,2-dimethyl-propionamide SC_5062 SC_5034 1H NMR (600 MHz, DMSO) δ 7.39 - 7.29 (m, 4H), 7.29 - 7.22 (m, 1H), 7.14 (s, 1H), 6.81 (s, 1H), 6.76 (s, 1H), 3.09 (s, 2H), 3.03 (s, 2H), 2.40 - 2.21 (m, 2H), 1.93 (s, 6H), 1.82 - 1.74 (m, 2H), 1.74-1.61 (m, 2H), 1.37 -1.29 (m, 2H), 1.01 (s, 6H). 373.3 SC_5071 CIS-3-[1-(Cyclobutylmethyl)-8-ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan -3-yl]-2,2-dimethyl-propionamide SC_5068 cyclobutylmet hylbromide step 1 of INT-953 (for step 1), SC_5034 (for step 2) 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 7.42 (d, 2H, J = 7.48 Hz), 7.30 (t, 2H, J = 7.32 Hz), 7.19-7.14 (m, 2H), 6.94 (s, 1H), 3.12 (s, 4H), 3.05 (d, 2H, J = 7.08 Hz), 2.14-2.03 (m, 4H), 1.95-1.88 (m, 4H), 1.79-1.66 (m, 4H), 1.53-1.25 (m, 4H), 1.01 (s, 6H), 0.95 (t, 3H). 441.0 SC_5072 CIS-3-[8-Dimethylamino-1-(oxetan-3-yl-methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan -3-yl]-2,2-dimethyl-propionamide SC_5062 toluene-4-sulfonic acid oxetan-3-ylmethyl ester step 1 of INT-953 (for step 1), SC_5034 (for step 2) 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 7.37-7.24 (m, 5H), 7.14 (s, 1H), 6.92 (s, 1H), 4.62-4.58 (m, 2H), 4.35 (t, 2H, J = 6.02 Hz), 3.29 (d, 2H, J = 7.28 Hz), 3.14-3.08 (m, 5H), 2.68-2.65 (m, 2H), 2.01-1.95 (m, 8H), 1.33-1.22 (m, 4H), 1.00 (s, 6H). 443.3 SC_5073 CIS-3-[1-(Cyclopropylmethyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan -3-yl]-2,2-dimethyl-propionamide SC_5075 SC_5034 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 7.35-7.25 (m, 5H), 7.15 (s, 1H), 6.90 (s, 1H), 3.13 (s, 4H), 2.90 (d, 2H, J = 6.32 Hz), 2.68-2.65 (m, 2H), 2.15-2.09 (m 2H), 1.98 (s, 6H), 1.36-1.23 (m, 4H), 1.01(s, 6H), 0.91 (m, 1H), 0.44 (d, 2H, J = 6.84 Hz), 0.24 (d, 2H, J = 4.08 Hz). 427.4 SC_5076 CIS-8-Dimethylamino-3-(2,2-dimethyl-3-morpholin-4-yl-3-oxo-propyl)-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan -2-one INT-1075 morpholine SC_5031 527.5 SC_5077 CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan -3-yl]-N-(2-hydroxy-ethyl)-2,2-dimethyl-propionamide INT-1075 2-aminoethanol SC_5031 1HNMR (DMSO-d6, 400 MHz at 100 0C), δ (ppm) = 7.33-7.18 (m, 6H), 5.66 (bs, 1H), 4.19 (bs, 1H), 3.40 (bs, 2H), 3.25-3.22 (m, 4H), 3.13 (bs, 4H), 2.62-2.59 (m, 2H), 2.10-2.05 (m, 9H), 1.91-1.89 (m, 2H), 1.70-1.66 (m, 2H), 1.41-1.28 (m, 4H), 1.09 (s, 6H). 501.2 SC_5078 CIS-3-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan -3-yl]-2,2-dimethyl-propionamide SC_5062 toluene-4-sulfonic acid 1-cyano-cyclobutylmet hyl ester step 1 of INT-953 (for step 1), SC_5034 (for step 2) .sup.1HNMR (DMSO-d.sub.6, 400 MHz), δ (ppm) = 7.37-7.31 (m, 4H ), 7.27-7.23 (m, 1H ), 7.14 (s, 1H), 6.93 (s,1H), 3.32 (s, 2H), 3.17 (s, 4 H), 2.69-2.65 (d, 2H), 2.45-2.38 (m, 2H), 2.35-2.28 (m, 2H), 2.0-1.95 (m, 10H), 1.41-1.38 (d, 2H), 1.30-1.23 (t, 2H), 1.02 ( s, 6H). 466.2 SC_5080* TRANS-3-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan -3-yl]-2,2-dimethyl-propionitrile INT-1059 3-bromo-2,2-dimethyl-propionitrile (step 1), cyclopropylm ethylbromide (step 2) step 1 of INT-897 (for step 1), step 1 of INT-953 (for step 2) 1HNMR at 20oC (DMSO-d6, 400 MHz), δ (ppm) = 7.44-7.28 (m, 5H), 3.46 (s, 2H), 3.23 (s, 2H), 2.72-2.66 (m, 2H), 2.57-2.55 (m, 2H), 1.91 (s, 6H), 1.55-1.45 (m, 6H), 1.27 (s, 6H), 0.51 (bs, 1H), 0.19-0.14 (m, 2H), (-0.22)-(-0.26) (m, 2H). 409.2 SC_5081 TRANS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan -3-yl]-2,2-dimethyl-propionamide INT-1059 3-bromo-2,2-dimethyl-propionitrile (step 1), 1-oxaspiro[2.3]h exane (step 2) step 1 of INT-897 (for step 1), SC_5074 (for steps 2 and 3) 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 7.43-7.27 (m, 5H), 7.21 (bs, 1H), 7.05 (bs, 1H), 5.75 (s, 1H), 3.17 (s, 2H), 2.67-2.65 (bs, 2H), 2.55 (s, 2H), 1.91 (s, 6H), 1.73-1.68 (m, 4H), 1.48-1.34 (m, 7H), 1.04 (s, 6H), 0.90-0.83 (m, 1H). 457.2 SC_5082 TRANS-3-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan -3-yl)-2,2-dimethyl-propionamide INT-1061 3-bromo-2,2-dimethyl-propionitrile (step 1) step 1 of INT-897 (for step 1), SC_5034 (for step 2) 1HNMR at 100oC (DMSO-d6, 400 MHz), δ (ppm) = 7.37-7.25 (m, 5H), 6.68 (bs, 2H), 6.30 (bs, 1H), 3.22 (s, 2H), 3.17 (s, 2H), 2.16 (bs, 2H), 1.99 (bs, 8H), 1.70-1.68 (m, 2H), 1.43-1.38 (m, 2H), 1.09 (s, 6H). 373.3 SC_5084 CIS-3-[1-(Cyclopropyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo- INT-1031 2-cyano-2-methylpropyl 4-methylbenzen esulfonate SC_5075 (step 1), SC_5034 (step 2) 1H NMR (DMSO-d6): δ 7.41-7.36 (m, 1H), 7.18-7.07 (m, 4H), 6.89 (br, s, 1H), 3.14 (s, 4H), 2.90 (d, 2H), 2.64 445.3 1,3-diazaspiro[4.5]decan -3-yl]-2,2-dimethyl-propionamide (step 1) (d, 2H), 2.11 (t, 2H), 1.98 (s, 6H), 1.34 (d, 2H), 1.27 (t, 2H), 1.02 (s, 6H), 0.93-0.88 (m, 1H), 0.47-0.42 (m, 2H), 0.26-0.22 (m, 2H). SC_5085 CIS-1-((1-(cyclopropylmethyl) -8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan -3-yl)methyl)cycloprop anecarboxamide INT-983 (1-cyanocyclopro pyl)methyl 4-methylbenzen esulfonate (step 1) step 1 of INT-897 (for step 1), SC_5034 (for step 2) 425.3 SC_5086 CIS-3-((1-(cyclopropylmethyl) -8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan -3-yl)methyl)oxetane-3-carboxamide INT-983 (3-cyanooxetan-3-yl)methyl 4-methylbenzen esulfonate (step 1) step 1 of INT-897 (for step 1), SC_5034 (for step 2) 441.3 SC_5087 CIS-3-(1-(cyclopropylmethyl) -8-(methylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan -3-yl)-2,2-dimethylpropanamid e SC_5073 step 2 of SC_5063 413.3 SC_5088 CIS-3-(1-(cyclopropylmethyl) -8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan -3-yl)propanamide INT-983 3-bromopropane nitrile step 1 of INT-897 (for step 1), SC_5034 (for step 2) SC_5089 CIS-3-(8-(dimethylamino)-1-((1-fluorocyclopropyl)m ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan -3-yl)-2,2-dimethylpropanamid e INT-976 3-bromo-2,2-dimethyl-propionitrile (step 1), (1-fluorocyclopr opyl)methyl 4-methylbenzen esulfonate (step 2), H2O2 nitrile hydrolysis (step 3) step 1 of INT-897 (for step 1), step 1 of INT-953 (for step 2), SC_5034 (for step 3) (* comparative examples)

[0421] The chemical structures of the example compounds are shown in the following table.

TABLE-US-00006 [00177] [00178] [00179] [00180] [00181] [00182] [00183] [00184] [00185] [00186] [00187] [00188] [00189] [00190] [00191] [00192] [00193] [00194] [00195] [00196] [00197] [00198] [00199] [00200] [00201] [00202] [00203] [00204] [00205] [00206] [00207] [00208] [00209] [00210] [00211] [00212] [00213] [00214] [00215] [00216] [00217] [00218] [00219] [00220] [00221] [00222] [00223] [00224] [00225] [00226] [00227] [00228] [00229] [00230] [00231] [00232] [00233] [00234]

TABLE-US-00007 [00235] [00236] [00237] [00238] [00239] [00240] [00241] [00242] [00243] [00244] [00245] [00246] [00247] [00248] [00249] [00250] [00251] [00252] [00253] [00254] [00255] [00256] [00257] [00258] [00259] [00260] [00261] [00262] [00263] C_5088 C_5089 (*comparative examples)

Pharmacological Investigations

[0422] 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)

Human Mu-Opioid Peptide (hMOP) Receptor Binding Assay

[0423] 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 .Math.l/well) included 1 nM of [N-ally1-2.3.sup.-3H]naloxone as ligand (PerkinElmer Life Sciences. Inc. Boston. MA. USA). and either test compound in dilution series or 25 .Math.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. MA. 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 ß-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).

Human Kappa-Opioid Peptide (hKOP) Receptor Binding Assay

[0424] 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 .Math.l per well includes 2 nM of [.sup.3H]U69,593 as ligand, and either test compound in dilution series or 100 .Math.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 .Math.l final assay volume per well) which has been preloaded for 15 minutes at room temperature with hKOP receptor membranes (14.8 .Math.g/250 .Math.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 ß-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).

Human Delta-Opioid Peptide (hDOP) Receptor Binding Assay

[0425] 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 .Math.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 .Math.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 .Math.l final assay volume per well) which has been preloaded for 15 minutes at room temperature with hDOP receptor membranes (15.2 .Math.g/250 .Math.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 ß-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).

Human Nociceptin/orphanin FQ Peptide (hNOP) Receptor Binding Assay

[0426] 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 .Math.l/well) included 0.5 nM of [leucyl-.sup.3H]nociceptin as ligand (PerkinElmer Life Sciences. Inc. Boston. MA. USA). and either test compound in dilution series or 1 .Math.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 hMOP receptor membranes (PerkinElmer Life Sciences. Inc. Boston. MA. 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 ß-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-00008 Example hNOP Ki [nM] hMOP Ki [nM] SC_5001 4 410 SC_5002 12.2 118 SC_5003 2.6 44.5 SC_5004 1.1 10 SC_5005 1.2 46.5 SC_5006 1.9 24.5 SC_5007 2.1 66 SC_5008 1 25 SC_5009 1.8 43.5 SC_5010 2.2 19 SC_5011 2.6 51.5 SC_5012 5.8 28 SC_5013 3.6 8.2 SC_5014 6.6 33 SC_5015 10.6 24.5 SC_5016 11.4 31 SC_5017 2.6 7.6 SC_5018 3.2 1.7 SC_5019 3 49 SC_5020 8.1 47.5 SC_5022 3.1 99.5 SC_5023 14.5 245 SC_5024 9.4 160 SC_5025 22.5 130 SC_5026 17.5 555 SC_5027 215 1195 SC_5028 140 895 SC_5029 205 1635 SC_5030 20 810 Example hNOP Ki [nM] hMOP Ki [nM] SC_5031 195 510 SC_5032 220 1130 SC_5033 48.5 1030 SC_5034 130 1185 SC_5035 230 815 SC_5036 4.2 140 SC_5037 8 40 SC_5038 72.5 175 SC_5039 130.5 130 SC_5040 115.5 395 SC_5041 63.5 445 SC_5042 70.5 190 SC_5043 101 210 SC_5044 5.6 160.5 SC_5045 19 910 SC_5046 1 113.4 SC_5047 5.8 69 SC_5048 1195 4146.7 SC_5049 1.5 11.3 SC_5051 3.6 320 SC_5052 12 250 SC_5053 16.5 58.5 SC_5054 18.5 160 SC_5055 11.5 74 SC_5056 7.4 64 SC_5057 75.5 124 SC_5058 19.5 545 SC_5059 111.5 88.5 SC_5060 285 1300 Example hNOP Ki [nM] hMOP Ki [nM] SC_5064 3%@1.Math.M (DOP 20%) 3%@1.Math.M SC_5066 0%@1.Math.M (DOP 22%) 7%@1.Math.M SC_5067 1300 11%@1.Math.M SC_5069 1%@1.Math.M (KOP 50%) 7%@1.Math.M SC_5070 245 7340 SC_5071 625 2845 SC_5072 150 4675 SC_5073 23 480 SC_5074 260 2615 SC_5076 7 670 SC_5077 15 485 SC_5078 0.5 180 SC_5079 12 510 SC_5081 815 4025 SC_5082 340 790 SC_5083 22 610 SC_5084 12 2475

Protocol for [.SUP.35.S]GTPγS Functional NOP/MOP/KOP/DOP Assays

[0427] 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, MA). Membranes from CHO-K1 cells transfected with the human nociceptin/orphanin FQ peptide (hNOP) receptor (Art.-No. 93-0264C2, DiscoveRx Corporation, Freemont, CA) are also used. [.sup.35S]GTPγS (Art.-No. NEG030H; Lot-No. #0112, #0913, #1113 calibrated to 46.25 TBq/mmol) is available from PerkinElmer (Waltham, MA).

[0428] The [.sup.35S]GTPγS 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 .Math.g membrane protein per assay are incubated with 0.4 nM [.sup.35S]GTPγS 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 .Math.M GDP for 45 min at room temperature. The microtiter plates are then centrifuged for 10 min at 830 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, MA).

[0429] 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]GTPγS 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]GTPγS 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]GTPγS binding (UBS.sub.calc [%]) and the maximal achievable total [.sup.35S]GTPγS 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.35S]GTPγS 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]GTPγS 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.

[0430] The foregoing description and examples have been set forth merely to illustrate the invention and are not intended to be limiting. Since modifications of the described embodiments incorporating the spirit and substance of the invention may occur to persons skilled in the art, the invention should be construed broadly to include all variations within the scope of the appended claims and equivalents thereof.