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

Abstract

The invention relates to 3-(carboxymethyl)-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) wherein ##STR00178## 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 polysubstituted; a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl moiety is optionally connected through —C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl moiety is optionally connected through —C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; R.sup.4 means —H; —C.sub.1-C.sub.6-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said —C.sub.1-C.sub.6-alkyl is optionally connected through —C(═O)—, —C(═O)O—, or —S(═O).sub.2—; a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C(═O)—, —C(═O)O—, —C(═O)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.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; 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, —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(═)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.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.

3. The compound according to claim 1, wherein R.sup.1 means —H; and R.sup.2 means —C.sub.1-C.sub.6-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.

4. 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.

5. 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.

6. 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—.

7. 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.

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

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

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

11. 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.

12. 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.

13. 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.

14. 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.

15. 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.

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

17. 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.

18. 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.

19. 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.

20. 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.

21. 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.

22. 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.

23. The compound according to claim 1, which has a structure according to any of general formulas (II-A) to (VIII-C): ##STR00179## ##STR00180## ##STR00181## ##STR00182## wherein in each case R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 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.

24. The compound according to claim 1, wherein the substructure ##STR00183## has a meaning selected from the group consisting of: ##STR00184## ##STR00185## ##STR00186## ##STR00187## ##STR00188## ##STR00189## ##STR00190## ##STR00191## ##STR00192## ##STR00193## ##STR00194## ##STR00195## ##STR00196##

25. The compound according to claim 1, wherein R.sup.1 means —H or —CH.sub.3; R.sup.2 means —CH.sub.3, —CH.sub.2CH.sub.3 or —CH.sub.2—C(H)(CH.sub.3).sub.2; R.sup.3 means -phenyl, -thienyl or -pyridinyl, in each case unsubstituted or monosubstituted with —F; R.sup.4 means —H; —C.sub.1-C.sub.6-alkyl, linear or branched, saturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, ═O, —N(CH.sub.3).sub.2 and —O—CH.sub.3; or -cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl, unsubstituted or monosubstituted with —F, —OH, —CN or —CH.sub.3, wherein said -cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl is connected through —CH.sub.2— or —CH.sub.2CH.sub.2—; -oxetanyl unsubstituted or monosubstituted with —F, —OH, —CN or —CH.sub.3, wherein said -oxetanyl is connected through —CH.sub.2— or —CH.sub.2CH.sub.2—; 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—CH.sub.3, —O—(CH.sub.2—CH.sub.2—O).sub.1-10—H, —O—(CH.sub.2CH.sub.2—O).sub.1-10—CH.sub.3, —C(═O)OH, —C(═O)OCH.sub.3, —C(═O)NH.sub.2, —C(═O)NHCH.sub.3, —C(═O)N(CH.sub.3).sub.2, —OH, —S(═O)CH.sub.3, —S(═O).sub.2CH.sub.3, unsubstituted —C(═O)-morpholinyl, —NH—C(═O)—CH.sub.3, —N(CH.sub.3).sub.2 and NH—S(═O).sub.2—CH.sub.3; -cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl, unsubstituted or monosubstituted with —F, —OH, —CN or —CH.sub.3, wherein said -cyclopropyl, -cyclobutyl, cyclopentyl or cyclohexyl is optionally connected through —CH.sub.2— or —CH.sub.2CH.sub.2—; -heterocyclobutyl, -heterocyclopentyl, or -heterocyclohexyl, 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, —CN, —O—CH.sub.3, —O—(CH.sub.2—CH.sub.2—O).sub.1-10—H, —O—(CH.sub.2CH.sub.2—O).sub.1-10—CH.sub.3, —C(═O)OH, —C(═O)OCH.sub.3, —C(═O)NH.sub.2, —C(═O)NHCH.sub.3, —C(═O)N(CH.sub.3).sub.2, ═O, —OH, —SCH.sub.3, —S(═O)CH.sub.3, —S(═O).sub.2CH.sub.3, unsubstituted —C(═O)-morpholinyl, —NH—C(═O)—CH.sub.3, —N(CH.sub.3).sub.2 and NH—S(═O).sub.2—CH.sub.3; wherein said -hetero-cyclobutyl, -heterocyclopentyl, or -heterocyclohexyl is optionally connected through —CH.sub.2— or —CH.sub.2CH.sub.2—; -oxazolyl, -isoxazolyl, -pyrazolyl, -pyridinyl, -pyridazinyl, -pyrazinyl, -thiazolyl, -thiadiazolyl, -imidazolyl, -pyrimidinyl, or 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine, 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, —CN, —OH, —CH.sub.3, —O—CH.sub.3, —C(═O)OH, —C(═O)OCH.sub.3, —C(═O)NH.sub.2, —C(═O)NHCH.sub.3, —C(═O)N(CH.sub.3).sub.2, S(═O)CH.sub.3, —S(═O).sub.2CH.sub.3 and —S—CH.sub.3, wherein said -oxazolyl, -isoxazolyl, -pyrazolyl, -pyridinyl, -pyridazinyl, -pyrazinyl, -thiazolyl, -thiadiazolyl, -imidazolyl, -pyrimidinyl, or 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine is optionally connected through —CH.sub.2—; or -phenyl, 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, —CH.sub.3, —O—CH.sub.3, —C(═O)OH, —C(═O)OCH.sub.3, —C(═O)NH.sub.2, —C(═O)NHCH.sub.3, —C(═O)N(CH.sub.3).sub.2, S(═O)CH.sub.3, —S(═O).sub.2CH.sub.3 and —S—CH.sub.3, wherein said -phenyl 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 -pyrrolidinyl, -piperidinyl, -piperazinyl, -morpholinyl, -thiomorpholinyl, -thiomorpholinyl dioxide or -(methylsulfonyl)piperazinyl, 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, —CH.sub.2—OH, —C(═O)NH.sub.2, and —S(═O).sub.2CH.sub.3, wherein said -pyrrolidinyl, -piperidinyl, -piperazinyl, -morpholinyl, -thiomorpholinyl, -thiomorpholinyl dioxide or -(methylsulfonyl)piperazinyl is optionally condensed with an imidazole moiety, 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.

26. The compound according to claim 1, which has a structure according to general formula (I′) ##STR00197## wherein R.sup.1 to R.sup.5, R.sup.9 to R.sup.20, and X are defined as in claim 1, or a physiologically acceptable salt thereof.

27. The compound according to claim 1, which has a structure according to general formula (IX) ##STR00198## wherein R.sup.C means —H or —OH; R.sup.3 means -phenyl or -3-fluorophenyl; R.sup.5 means —H, —CH.sub.3, —CH.sub.2CH.sub.2OH, or —CH.sub.2C(═O)NH.sub.2; R.sup.6 means —H or —CH.sub.3; or R.sup.5 and R.sup.6 together with the nitrogen atom to which they are attached form a ring and mean —(CH.sub.2).sub.5—, wherein said ring is unsubstituted or substituted with one or two substituents independently of one another selected from the group consisting of —CH.sub.3, —OH, —S(═O).sub.2CH.sub.3 and —C(═O)NH.sub.2; R.sup.9 and R.sup.10 independently of one another mean —H or —CH.sub.3; or a physiologically acceptable salt thereof.

28. The compound according to claim 1, which is selected from the group consisting of CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethyl]-acetamide; CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-pyridine-2-carboxylic acid methyl ester; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(1R)-2-hydroxy-1-methyl-ethyl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(1S)-2-hydroxy-1-methyl-ethyl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-N-(methylcarbamoyl-methyl)-acetamide; CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-nicotinic acid methyl ester; CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]-methyl-amino]-2-methyl-propionamide; CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N,2-dimethyl-propionamide; CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]-methyl-amino]-N,2-dimethyl-propionamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(dimethyl-carbamoyl)-methyl]-N-methyl-acetamide; CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-2-methyl-propionamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyridin-2-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyridin-2-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyridin-2-yl)-acetamide; CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-pyridine-2-carboxylic acid amide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(3-hydroxy-cyclobutyl)-methyl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(3-hydroxy-cyclobutyl)-methyl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(1-hydroxy-cyclopropyl)-methyl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(3-morpholin-4-yl-3-oxo-propyl)-acetamide; CIS-N-(1-Cyano-cyclopropyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(3-hydroxy-cyclopentyl)-methyl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[[(2R)-2-hydroxy-cyclohexyl]-methyl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethyl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(1-hydroxy-cyclohexyl)-methyl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethyl]-acetamide; CIS-N-(6-Cyano-pyridin-2-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide; CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-nicotinic acid methyl ester; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(3-methoxy-pyridin-2-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethyl]-acetamide; CIS-N-(4-Cyano-pyridin-2-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyrimidin-2-yl)-acetamide; CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-isonicotinic acid methyl ester; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-pyridin-4-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-fluoro-pyridin-3-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methyl-pyrimidin-5-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methyl-pyrimidin-2-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(3-fluoro-pyridin-2-yl)-acetamide; CIS-2-[1-Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(3-fluoro-pyridin-4-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyridin-3-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methyl-pyridin-3-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methyl-pyridin-3-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(3-methyl-pyridin-4-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methyl-pyridin-3-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-fluoro-pyridin-2-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methyl-pyridin-2-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methyl-pyridin-2-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(3-methyl-pyridin-2-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(3-methoxy-pyridin-4-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyridazin-3-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methylsulfonyl-pyridin-2-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyridin-2-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methylsulfonyl-pyridin-3-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyrazin-2-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyridin-2-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyrimidin-2-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxazol-5-yl-methyl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxazol-2-yl-methyl)-acetamide; CIS-1-(Cyclobutyl-methyl)-3-[2-[(3S,4S)-3,4-dihydroxy-piperidin-1-yl]-2-oxo-ethyl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-1-(Cyclobutyl-methyl)-3-[2-[(3S,4S)-3,4-dihydroxy-pyrrolidin-1-yl]-2-oxo-ethyl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-1-(Cyclobutyl-methyl)-3-[2-[(3S,4R)-3,4-dihydroxy-pyrrolidin-1-yl]-2-oxo-ethyl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-cyclopropyl-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-N-methyl-acetamide; CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-(3-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(1-hydroxy-cyclobutyl)-methyl]-acetamide; CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N,N-dimethyl-acetamide; CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-oxo-2-(5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-7-yl)-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-3-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N,N-dimethyl-propionamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethyl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyrimidin-5-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-pyrimidin-5-yl)-acetamide; CIS-N-(5-Cyano-pyridin-2-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide; CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-pyridine-4-carboxylic acid amide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyrimidin-4-yl)-acetamide; CIS-N-(2-Cyano-pyrimidin-5-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide; CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-pyridine-2-carboxylic acid amide; CIS-N-(3-Cyano-pyridin-2-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide; CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide; CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-pyridine-3-carboxylic acid amide; CIS-N-(4-Cyano-pyrimidin-2-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-([1,3,4]thiadiazol-2-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-thiazol-2-yl-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methyl-isoxazol-3-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-isoxazol-3-yl-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(1-methyl-1H-pyrazol-3-yl)-acetamide; CIS-N-(4-Cyano-5-methylsulfanyl-1H-pyrazol-3-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyrazin-2-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(pyridazin-4-yl-methyl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(2-hydroxyphenyl)-methyl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[1-methyl-1H-imidazol-4-yl)-methyl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(4-methyl-pyridin-3-yl)-methyl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(pyrimidin-2-yl-methyl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(pyridazin-3-yl-methyl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(pyrimidin-4-yl-methyl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(pyrazin-2-yl-methyl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxazol-4-yl-methyl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(2-methyl-pyridin-3-yl)-methyl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(2-methoxy-pyridin-3-yl)-methyl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(4-methoxy-pyridin-3-yl)-methyl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(6-methyl-pyridin-2-yl)-methyl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(6-methoxy-pyridin-2-yl)-methyl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(2-methoxyphenyl)-methyl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(o-tolyl-methyl)-acetamide; CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-pyridine-3-carboxylic acid amide; CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-pyridine-4-carboxylic acid amide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyrimidin-4-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-pyrimidin-4-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-hydroxy-pyrimidin-5-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-pyrimidin-5-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-hydroxy-pyridin-2-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(1,1-dioxo-thian-4-yl)-acetamide; CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-2-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide; CIS-2-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide; CIS-N-(5-Cyano-pyrimidin-4-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methylsulfanyl-pyridin-2-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyrimidin-2-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methylsulfanyl-pyridin-2-yl)-acetamide; CIS-2-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide; CIS-2-[[2-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-hydroxy-pyridin-2-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(2-methoxy-pyrimidin-5-yl)-methyl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(4-methoxy-pyrimidin-2-yl)-methyl]-acetamide; CIS-N-(2-Cyano-pyrimidin-4-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[6-(methylsulfinyl)-pyridin-2-yl]-acetamide; CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-2-methyl-propionamide; CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-acetamide; CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl]-acetamide; CIS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-N-(methylcarbamoyl-methyl)-acetamide; CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methylsulfonyl-ethyl)-acetamide; CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-5-yl-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methylsulfonyl-pyridin-2-yl)-acetamide; CIS-2-[8-Dimethylamino-1-[(dimethyl-carbamoyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide; CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]-methyl-amino]-2-methyl-propionamide; CIS-1-(Cyclobutyl-methyl)-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethyl]-acetamide; CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N,N-dimethyl-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-hydroxy-pyrimidin-2-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methylsulfonyl-pyridin-2-yl)-acetamide; CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-acetamide; CIS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide; CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-3-yl)-N-methyl-acetamide; CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[4-(methylsulfinyl)-pyridin-2-yl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(3-hydroxy-pyridin-2-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methylsulfonyl-ethyl)-acetamide; CIS-1-(Cyclobutyl-methyl)-3-[2-[(3S,4R)-3,4-dihydroxy-pyrrolidin-1-yl]-2-oxo-ethyl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide; CIS-2-[8-Dimethylamino-1-[(dimethyl-carbamoyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide; CIS-2-[8-Dimethylamino-1-[(dimethyl-carbamoyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide; CIS-2-[[2-[8-Dimethylamino-1-(2-methyl-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide; CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide; CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide; CIS-2-[[2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide; CIS-2-[8-Dimethylamino-1-(2-methyl-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide; CIS-1-(Cyclobutyl-methyl)-3-[2-[(3S,4R)-3,4-dihydroxy-pyrrolidin-1-yl]-2-oxo-ethyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-2-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide; CIS-2-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide; CIS-2-[[2-[8-Dimethylamino-1-[1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide; CIS-2-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide; CIS-2-[[2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide; CIS-2-[[2-(8-Dimethylamino-2-oxo-8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-3-yl)-acetyl]amino]-acetamide; CIS-2-[[2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide; CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide; CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(1,1-dioxo-thian-4-yl)-acetamide; CIS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide; CIS-2-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide; CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro [4.5]decan-3-yl]-acetyl]amino]-acetamide; CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N,2-dimethyl-propionamide; CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide; CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-N-(methylcarbamoyl-methyl)-acetamide; CIS-8-Dimethylamino-1-(3-methoxy-propyl)-3-[2-oxo-2-(3-oxo-piperazin-1-yl)-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-N-(Carbamoyl-methyl)-2-[8-dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide; CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(3-hydroxy-cyclobutyl)-methyl]-acetamide; CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(3-hydroxy-cyclobutyl)-methyl]-acetamide; CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(3-hydroxy-cyclopentyl)-methyl]-acetamide; CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridazin-4-yl-acetamide; CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyridin-2-yl)-acetamide; CIS-N-(2-Cyanoethyl)-2-[8-dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide; CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-5-yl-acetamide; CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyridin-2-yl)-acetamide; CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridin-3-yl-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-ethyl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethyl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide; CIS-(2S)-1-[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]-pyrrolidine-2-carboxylic acid amide; CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N,N-dimethyl-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-acetamide; CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide; CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-oxo-2-(3-oxo-piperazin-1-yl)-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(1,1-dioxo-thian-4-yl)-acetamide; CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-[2-(hydroxymethyl)-morpholin-4-yl]-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide; CIS-N-(Cyano-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide; CIS-N-(2-Acetylamino-ethyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methylsulfonyl-ethyl)-acetamide; CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[1,1-dioxo-thian-4-yl)-methyl]-acetamide; CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-(4-methylsulfonyl-piperazin-1-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-N-(2-Cyanoethyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-2-methyl-propyl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-morpholin-4-yl-2-oxo-ethyl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-(2-hydroxy-ethoxy)-ethyl]-acetamide; CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-(methanesulfonamido)-ethyl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(1-hydroxy-cyclopentyl)-methyl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(4-hydroxy-cyclohexyl)-methyl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-(2-methoxy-ethoxy)-ethyl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-(dimethylamino)ethyl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-[methyl-(2-methyl-propyl)-amino]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methyl-pyridin-2-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridazin-3-yl-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-5-yl-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridazin-4-yl-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyrimidin-4-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methyl-pyridin-4-yl)-acetamide; CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridin-4-yl-acetamide; CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-acetamide; CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-ethyl)-acetamide; CIS-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-acetamide; CIS-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-ethyl)-acetamide; CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyridin-2-yl)-acetamide; CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(pyrimidin-4-yl-methyl)-acetamide; CIS-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-2-one; CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridin-2-yl-acetamide; CIS-2-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide; CIS-2-[[2-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide; CIS-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide; CIS-3-[2-(1,1-Dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-methylamino-8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-2-one; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridin-2-yl-acetamide; CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-morpholin-4-yl-2-oxo-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide; CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(2-morpholin-4-yl-2-oxo-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methylsulfanyl-pyridin-2-yl)-acetamide; CIS-3-[2-(1,1-Dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-2-(8-Methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-acetamide; CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-acetamide; CIS-3-[2-(1,1-Dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-ethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; TRANS-3-[2-(1,1-Dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-ethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide; CIS-2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-acetamide; TRANS-2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-acetamide; CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-(2-hydroxy-ethyl)-N-methyl-acetamide; CIS-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione; CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-phenyl-acetamide; CIS-N-(Carbamoyl-methyl)-2-[1-(cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide; CIS-2-(8-Dimethylamino-2,4-dioxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-phenyl-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide; CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethyl]-acetamide; CIS-3-[2-(1,1-Dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-1-[(1-hydroxy-cyclobutyl)-methyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione; CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethyl]-acetamide; CIS-N-(Carbamoyl-methyl)-N-methyl-2-(8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-acetamide; CIS-N-(Carbamoyl-methyl)-2-(8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-methyl-acetamide; CIS-N-(Carbamoyl-methyl)-2-[8-dimethylamino-1-(oxetan-3-yl-methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide; CIS-N-(2-Hydroxy-ethyl)-N-methyl-2-(8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-acetamide; CIS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide; CIS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-N-methyl-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-acetic acid tert-butyl ester; CIS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-N-methyl-acetamide; CIS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methylsulfonyl-ethyl)-acetamide; CIS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide; CIS-1-[2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]-piperidine-4-carboxylic acid amide; CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-[2-(4-methylsulfonyl-piperidin-1-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide; TRANS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide; TRANS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide; CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-[2-(4-hydroxy-4-methyl-piperidin-1-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-8-(4-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide; TRANS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-(2-morpholin-4-yl-2-oxo-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; TRANS-8-Dimethylamino-3-(2-morpholin-4-yl-2-oxo-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-8-(4-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-N-methyl-acetamide; CIS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-8-(4-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide; CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[2-(4-hydroxy-4-methyl-piperidin-1-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-1-[2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]-piperidine-4-carboxylic acid amide; TRANS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide; TRANS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide; TRANS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[2-(4-methylsulfonyl-piperidin-1-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; TRANS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-acetamide; TRANS-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-8-(dimethylamino)-8-phenyl-1-(2,2,2-trifluoroethyl)-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one; CIS-8-(dimethylamino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1-(3,3,3-trifluoropropyl)-1,3-diazaspiro[4.5]decan-2-one and the physiologically acceptable salts thereof.

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

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

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

32. 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

[0271] RT means room temperature (23±7° C.), M are indications of concentration in mol/l, aq. means aqueous, anhydr. means anhydrous, sat. means saturated, sol. means solution, “conc.” means concentrated.

[0272] Further Abbreviations: [0273] brine saturated aqueous sodium chloride solution [0274] CC column chromatography [0275] cHex cyclohexane [0276] DCM dichloromethane [0277] DIPEA N,N-diisopropylethylamine [0278] DMF N,N-dimethylformamide [0279] EDCl 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide [0280] Et ethyl [0281] ether diethyl ether [0282] EE ethyl acetate [0283] EtOAc ethyl acetate [0284] EtOH ethanol [0285] h hour(s) [0286] H.sub.2O water [0287] HATU O-(7-aza-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate [0288] LDA Lithium-di-isoproyl-amid [0289] Me methyl [0290] m/z mass-to-charge ratio [0291] MeOH methanol [0292] MeCN acetonitrile [0293] min minutes [0294] MS mass spectrometry [0295] NBS N-bromo-succinimide [0296] NEt.sub.3 triethylamine [0297] Pd.sub.2(dba).sub.3 tris(dibenzylideneacetone)dipalladium(0) [0298] PE petroleum ether (60-80° C.) [0299] RM reaction mixture [0300] RT room temperature [0301] T3P 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide [0302] tBME tert-butyl methyl ether [0303] THF tetrahydrofuran [0304] TFA trifluoroacetic acid [0305] v/v volume to volume [0306] w/w weight to weight [0307] XantPhos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[0308] The yields of the compounds prepared were not optimised. All temperatures are uncorrected.

[0309] All starting materials, which are not explicitly described, were either commercially available (the details of suppliers such as for example Acros, Aldrich, Bachem, Butt park, Enamine, Fluka, Lancaster, Maybridge, Merck, Sigma, TCI, Oakwood, etc. can be found in the Symyx® Available Chemicals Database of MDL, San Ramon, US or the SciFinder® Database of the ACS, Washington D.C., US, respectively, for example) or the synthesis thereof has already been described precisely in the specialist literature (experimental guidelines can be found in the Reaxys® Database of Elsevier, Amsterdam, NL or the SciFinder® Database of the ACS, Washington D.C., US, repspectively, for example) or can be prepared using the conventional methods known to the person skilled in the art.

[0310] The mixing ratios of solvents or eluents for chromatography are specified in v/v.

[0311] 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.

[0312] Remark Regarding Stereochemistry

[0313] 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:

##STR00026##

[0314] 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:

##STR00027##

[0315] Synthesis of Intermediates

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

[0316] ##STR00028##

Step 1: CIS-1-((1-(benzyloxy)cyclobutyl)methyl)-3-(3,4-dimethoxybenzyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

[0317] NaOH (1.42 g, 35.5 mmol) was added to a solution of CIS-3-(3,4-dimethoxybenzyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspirop.51decan-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 (4×300 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 (230-400mesh silica gel; 65-70% EtOAc in petroleum ether as eluent) to afford 2.5g (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

[0318] TFA (12mL) 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 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

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

[0319] ##STR00029##

Step 1: 1-((CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutanecarbonitrile

[0320] 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 (3×200mL). 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

[0321] TFA (100mL) 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

[0322] 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 2h. 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 (3×150 mL). 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.

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

[0323] ##STR00030##

[0324] 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 (3×300 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.

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

[0325] ##STR00031##

Step 1: 1-Cyclobutylmethyl-3-(4-methoxy-benzyl)-9,12-dioxa-1,3-diaza-dispiro[4.2.4.2]tetradecan-2-one

[0326] 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 (3×200 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-methoxy-benzyl)-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

[0327] 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 (3×50 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-methoxy-benzyl)-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

[0328] 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 4N 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 (3×30 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

[0329] 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, ˜2M 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 (4×30 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

[0330] A round bottom flask containing CIS-1-(cyclobutylmethyl)-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 (10 ml, ˜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—CHCl.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—CHCl.sub.3 (5:95); R.sub.f=0.25; [M+H].sup.+384.3

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

[0331] ##STR00032##

Step 1: Ethyl 5-cyano-2-oxo-5-(pyridin-2-yl)cyclohexanecarboxylate

[0332] 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 (2×500 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

[0333] 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.

[0334] 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 (3×300 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

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

[0335] ##STR00033##

Step 1: 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile

[0336] 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 (3×300 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

[0337] 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

[0338] A mixture of 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carboxamide (25.0 g, 95.41 mmol), sodium hypochlorite (5wt % 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 (3×500 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

[0339] 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 (4×200 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

[0340] 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 35wt % 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 (3×200 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

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

[0341] ##STR00034##

Step 1: 8-(Dimethylamino)-1,4-dioxaspiro[4.5]decane-8-carbonitrile

[0342] Dimethylamine hydrochloride (52 g, 0.645 mol) was added to the solution of 1,4-dioxaspiro[4.5]-decan-8-one (35g, 0.224 mmol) in MeOH (35 mL) at RT under argon atmosphere. The solution was stirred for 10 min and 40wt % 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 (2×200 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

[0343] 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 3M 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 (2×600 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

[0344] A solution of N,N-dimethyl-8-phenyl-1,4-dioxaspiro[4.5]decan-8-amine (32 g, 0.123 mol) in 6N 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 (2×150 mL).

[0345] The aqueous layer was basified to pH 10 with solid NaOH and extracted with ethyl acetate (2×200mL). 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

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

[0346] ##STR00035##

Step 1: 9,12-Dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}.2{circumflex over ( )}{5}]tetradecane-1,3-dione

[0347] KCN (93.8 g, 1441.6 mmol) and (NH.sub.4).sub.2CO.sub.3 (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[4.2.4{circumflex over ( )}{8}.2{{circumflex over ( )}5}]tetradecane-1,3-dione. The filtrate was extracted with DCM (2×1.5 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{circumflex over ( )}{8}.2{circumflex over ( )}{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{circumflex over ( )}{8}.2{circumflex over ( )}{5}]tetradecane-1,3-dione

[0348] 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 (1.0L) and the organic product was extracted with EtOAc (2×1.5L). 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{circumflex over ( )}{8}.2{circumflex over ( )}{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{circumflex over ( )}{8}.2{circumflex over ( )}{5}]tetradecan-3-one

[0349] AlCl.sub.3 (144.3 g, 1082.6 mmol) was added to a solution of LiAlH.sub.4 (2M 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-Methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}.2{circumflex over ( )}{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 (2×2.0 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{circumflex over ( )}{8}2{circumflex over ( )}{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

[0350] A solution of 2-[(4-methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}.2{circumflex over ( )}×{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 (2×2.0L). The aqueous layer was basified to pH 10 with 50% aq. NaOH and then extracted with DCM (2×2.0L). 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]-1,3-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.

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

[0351] ##STR00036##

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

[0352] 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

[0353] TFA (0.2mL) 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 (3×10 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 (Cyclobutyl-methyl)-8-dimethylamino-8-(3-hydroxyphenyl)-3-[(4-methoxyphenyl)-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

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

[0354] ##STR00037##

Step 1: 8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile

[0355] 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 40wt % 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 (2×2.0 L). 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

[0356] 3-Fluorophenylmagnesium bromide (1M 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 (2×200mL). 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×2 and 5 g×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

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

[0357] ##STR00038##

[0358] KOtBu (1M 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 (150mL) and the organic product was extracted with EtOAc (2×150 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×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

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

[0359] ##STR00039##

Step 1: 8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decane-2,4-dione

[0360] 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 18h. 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

[0361] LiAlH.sub.4 (2M 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

[0362] 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.

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

[0363] ##STR00040##

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

[0364] 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 (2M 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 (3×). 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

[0365] 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 (1mL) 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

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

[0366] ##STR00041##

[0367] CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-acetic acid00 (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 (3×5mL), 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

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

[0368] ##STR00042##

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

[0369] 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 (3×150 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-methoxybenzyl)-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

[0370] 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 2M 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

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

[0371] ##STR00043##

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

[0372] 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

[0373] 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-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-984).

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

[0374] ##STR00044##

Step 1: CIS-3-benzyl-1-(cyclobutylmethyl)-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

[0375] N-Iodosuccinimide (3.11 g, 13.92 mmol) was added to the solution of CIS-1-(Cyclobutyl-methyl)-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 (3×10 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 5N aq. NaOH to pH ˜10 and extracted with DCM (3×10 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-(ethyhmethyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

[0376] 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 (3×50 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)

[0377] 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 10min 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.4Cl, warmed to RT and stirred for 1 h. The organic product was extracted with DCM (3×50 mL). The combined organic layer was washed with water, brine and concentrated under reduced pressure to afford 1.30 g (72%) of CIS-1-(cyclobutylmethyl)-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

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

[0378] ##STR00045##

[0379] 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).

Synthesis of INT-988: CIS-8-(dimethylamino)-1-(2-(1-methoxycyclobutyl)ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

[0380] ##STR00046##

Step 1: CIS-8-(dimethylamino)-1-[2-(1-methoxycyclobutyl)ethyl]-3-[(4-methoxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

[0381] Sodium hydroxide (78.06 mg, 4.0 equiv.) was suspended in DMSO (3.5 mL), stirred for 10 minutes, 8-(dimethylamino)-3-[(4-methoxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-975) (192.0 mg, 1.0 equiv.) was added, the reaction mixture was stirred for 5 min followed by addition of 2-(1-methoxycyclobutyl)ethyl 4-methylbenzenesulfonate (416.2 mg, 3.0 equiv.) in DMSO (1.5 mL). The resulting mixture was stirred overnight at 50° C. The reaction mixture was quenched with water and extracted with DCM (3×20 mL). The combined organic phases were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue (283 mg yellow oil) was purified by column chromatography on silica gel (eluent DCM/EtOH 98/2 to 96/4) to give 8-(dimethylamino)-1-[2-(1-methoxycyclobutyl)ethyl]-3-[(4-methoxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one 163 mg (66%).

Step 2: CIS-8-(dimethylamino)-1-(2-(1-methoxycyclobutyl)ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-988)

[0382] In analogy to the method described for INT-982 step 2 CIS-8-(dimethylamino)-1-[2-(1-methoxycyclobutyl)ethyl]-3-[(4-methoxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one was converted into CIS-8-(dimethylamino)-1-(2-(1-methoxycyclobutyl)ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-988). Mass: m/z 386.3 (M+H).sup.+.

Synthesis of INT-992: CIS-2-[8-Dimethylamino-1-(2-methyl-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetic acid

[0383] ##STR00047##

[0384] CIS-8-Dimethylamino-1-(2-methyl-propyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-241) (0.9 g, 273 mmol) was added to a solution of NaH (60wt % in mineral oil, 1.64 g, 41.03 mmol) in DMF (20 mL) at RT. The reaction mixture was stirred at R.T. for 15 min, then cooled to 0° C. and ethyl 2-bromoacetate (4.56 g, 27.35 mmol) was added dropwise. The resulting mixture was stirred at RT for 2 days. The reaction completion was monitored by TLC. The reaction mixture was quenched with water and concentrated under reduced pressue. The residue was diluted with small amount of water and acidified by acetic acid. The resulting mixture was concentrated under reduced pressure again. The crude product was purified by silica gel flash chromatography using 230-400 mesh (25 vol % MeOH in DCM) to afford 1.1 g of CIS-2-[8-dimethylamino-1-(2-methyl-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetic acid (INT-992) as a solid. [M+H].sup.+388.3

Synthesis of INT-994: CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetic acid

[0385] ##STR00048##

Step 1: ethyl 2-(cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3 yl)acetate

[0386] KOtBu (1M in THF) (54.90 mL, 54.95 mmol) was added to a solution of CIS-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976) (10 g, 36.63 mmol) in THF (950 mL) under argon atmosphere at 0° C. and the reaction mixture was stirred for 15 min. A solution of ethyl bromoacetate (5.06 mL, 43.96 mmol) in THF (50 mL) was added. The reaction mixture was warmed up to RT and stirred for 48 h. The reaction completion was monitored by TLC. Solvent was evaporated under reduced pressure and the crude product was purified by column chromatography to yield the desired product in 2 fractions: fraction 1: 2.2 g ethyl 2-(cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate (68% pure according to LCMS) as an off-white solid and Fraction 2: 3.2 g of ethyl 2-(cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate (32% pure according to LCMS) as well as 1.1 g of unreacted starting material. Fraction 1 was used further without additional purification.

Step 2: 2-(cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetic acid

[0387] A mixture of ethyl-2-(CIS-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate (68% pure, 2.2 g, 6.128 mmol) and powdered NaOH (981 mg, 24.513 mmol) in toluene (40 mL) was stirred at 80° C. for 3 h under argon atmosphere. Ester hydrolysis was monitored by LCMS. Toluene was evaporated under reduced pressure and the resulting crude product (2.4 g) was further purified by reverse phase prep. HPLC to yield 0.93 g of 2-(CIS-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetic acid.

Step 3: 2-(cis-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetic acid

[0388] To a solution of 2-(CIS-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetic acid (1.5 g, 4.532 mmol) in toluene (45 mL) was added in one portion powdered NaOH (725.08 mg, 18.127 mmol) under argon atmosphere at RT. The reaction mixture was stirred at 80° C. for 4 h. Toluene was evaporated under reduced pressure to get the residue which was dissolved in DMSO (45 mL) under argon atmosphere. The solution was stirred at 55° C. for 1 h. To the reaction mixture was added dropwise a solution of 1-oxaspiro[2.3]hexane (1.144 g, 13.596 mmol) in DMSO (12 mL) via syring pump (flow rate 10 mL/h). The reaction mixture was stirred at 55° C. for 65 h. The reaction progress was monitored by LCMS. DMSO was evaporated in vacuo. The residue was dissolved in water (50 mL), cooled to 0° C. and pH was adjusted to 3-4 with acetic acid. The resulting mixture was concentrated under reduced pressure and the crude product was purified by column chromatography (elution with 8-10% MeOH in DCM) to yield 750 mg (78%) of 2-(cis-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetic acid (INT-994) as an off-white solid. [M+H].sup.+416.2

Synthesis of INT-998: CIS-2-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetic acid; 2,2,2-trifluoro-acetic acid salt

[0389] ##STR00049##

Step 1: CIS-tert-butyl 2-[8-(dimethylamino)-1-[(1-methylcyclobutyl)methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]acetate

[0390] CIS-8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-982) (2.8 g, 7.9 mmol) was dissolved in THF (110 mL) and the solution was cooled to 0° C. Lithium diisopropylamide solution in THF/heptane/ethylbenzene (2M, 16 mL) was added dropwise. The reaction mixture was stirred for 30 min and t-butyl-bromoacetate was added dropwise at the same temperature. The reaction mixture was concentrated in vacuo, water was added and the resulting mixture was extracted with DCM (3×250 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, concentrated in vacuo and the residue was purified by flash chromatography to yield CIS-tert-butyl 2-[8-(dimethylamino)-1-[(1-methylcyclobutyl)methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]acetate (1670 mg) as a white solid.

Step 2: CIS-2-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetic acid; 2,2,2-trifluoro-acetic acid salt

[0391] CIS-tert-butyl 2-[8-(dimethylamino)-1-[(1-methylcyclobutyl)methyl]-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]decan-3-yl]acetat (2250 mg, 4.8 mmol) was teated with TFA (18 mL) at RT. After stirring for 10 min, all volatiles were removed in vacuo. The residue was triturated with diethyl ether (30 mL) using ultrasonic bath, the solid rest was dried under reduced pressure to yield CIS-2-[8-dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetic acid; 2,2,2-trifluoro-acetic acid salt (INT-998) (2.2 g) as a brown solid. [M+H].sup.+413.3

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

[0392] ##STR00050##

Step 1 and step 2: ethyl-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-amine hydrochloride (INT-1004)

[0393] A mixture of 1,4-dioxa-spiro[4.5]decan-8-one (25.0 g, 160.25 mmol, 1.0 eq.) and 2M 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 2.5M 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 (2×750 mL), combined organic extracts were washed with water (3×350 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)

[0394] 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 1N aq. NaOH to pH ˜14 at 0° C. and extracted with DCM (2×750 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)

[0395] 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)

[0396] 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 (2×800 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 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)

[0397] 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 1 h 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-diaza-spiro[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.

Synthesis of INT-1019: CIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetic acid hydrochloride

[0398] ##STR00051##

Step 1: tert-butyl CIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate

[0399] The solution of CIS-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-799) (1.8 g, 5.042 mmol) in THF (40 mL) was cooled down to 0° C. and KOtBu (1 M in THF, 5.55 mL, 5.546 mmol) was added. The resulting mixture was stirred for 10 min followed by the dropwise addition of tert-butyl bromoacetate (1.081 g, 5.546 mmol). The ice bath was removed and the reaction mixture was stirred for 2 h, then quenched with sat. aq. NH.sub.4Cl (40 mL) and extracted with EtOAc (2×80 mL). The combined organic extracts were dried over anhydr. Na.sub.2SO.sub.4 and concentrated under reduced pressure. Crude product was purified by column chromatography (silica gel 100-200 mesh, 0-4% MeOH in DCM as eluent) to afford 1.7 g of tert-butyl CIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate as an off white solid.

Step 2: CIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetic acid hydrochloride

[0400] 4N HCl in dioxane (30 mL) was added to the solution of tert-butyl CIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate (1.7 g, 3.609 mmol) in 1,4 dioxane (10 mL). The resulting mixture was stirred at RT for 16 h and then concentrated under reduced pressure to afford 1.5 g of CIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetic acid hydrochloride (INT-1019) as a hygroscopic solid. TLC R.sub.f (10% MeOH in DCM)=0.2. LC-MS: m/z [M+H].sup.+=416.3.

Synthesis of INT-1020: sodium CIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2,4-dioxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate

[0401] ##STR00052##

Step 1: tert-butyl CIS-2-(8-(dimethylamino)-2,4-dioxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate

[0402] To the suspension of tert-butyl CIS-2-(8-(dimethylamino)-2,4-dioxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate (INT-1018) (0.5 g, 1.74 mmol) in DMF (11 mL) was added portionwise sodium hydride (60% in mineral oil, 70 mg, 1.74 mmol, 1 equiv.). The reaction mixture was stirred until the evolution of hydrogen was over and a clear solution was formed (ca. 40 min). Tert-butyl bromoacetate (257 μL, 1.74 mmol, 1 equiv.) was added, the reaction mixture was stirred at RT overnight, quenched with ca. 40 mL water and stirred for 2 h. The precipitate was filtered off, washed with water, hexane and dried under reduced pressure to give tert-butyl CIS-2-(8-(dimethylamino)-2,4-dioxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate (653 mg, 93%) which was used further without additional purification. LC-MS: m/z [M+H].sup.+=402.2.

Step 2: sodium CIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2,4-dioxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate (INT-1020)

[0403] Sodium hydroxide (135 mg, 3.37 mmol, 4 equiv.) was suspended in dimethyl sulfoxide (1.8 mL, 25.26 mmol, 30 equiv.) and the mixture was stirred at RT for 10 min Tert-butyl CIS-2-(8-(dimethylamino)-2,4-dioxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate (338 mg, 0.84 mmol, 1 equiv.) was added, the reaction mixture was stirred 5 min at RT and then heated up to 50° C. [1-[Tert-butyl(dimethyl)silyl]oxycyclobutyl]methyl 4-methylbenzenesulfonate (936 mg, 2.53 mmol, 3 equiv.) was added and the reaction mixture was stirred at 60° C. for 3 days. The resulting mixture was cooled down to RT, diluted with water (5 mL), extracted with EtOAc (1×10 mL) and the aqueous phase was concentrated under reduced pressure to give crude sodium CIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2,4-dioxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate (INT-1020) (473 mg) which was used in the next step without further purification. LC-MS: m/z [M+H].sup.+=452.2.

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

[0404] ##STR00053##

Step 1: 2-methyl-N-(1,4-dioxaspiro[4.5]decan-8-ylidene)propane-2-sulfinamide

[0405] 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 (3×100 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

[0406] Phenylmagnesium bromide (1M 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 (3×100 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

[0407] 2N solution of HCl 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)prop ane-2-sulfinamide (6.0g, 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

[0408] 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 16 h. 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 (3×30 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)

[0409] 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 (3×30 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

[0410] 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 (2×50 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

[0411] 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 (2×50 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

[0412] 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 μm, 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)

[0413] 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.

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

[0414] ##STR00054##

Step 1: CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one

[0415] 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

[0416] 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).

Synthesis of INT-1032: CIS-2-[1-(cyclobutylmethyl)-8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]acetic acid trifluoroacetate

[0417] ##STR00055##

[0418] In analogy to the method described for INT-998 step 2 2-[1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-acetic acid tert-butyl ester (SC_1346) was converted into 2-[1-(cyclobutylmethyl)-8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]acetic acid trifluoroacetate (INT-10322).

Synthesis of INT-1034: CIS-(8-methylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic acid

[0419] ##STR00056##

Step 1: CIS-[8-dimethylamino-2-oxo-8-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-diaza-spiro[4.5]dec-3-yl]-acetic acid tert-butyl ester

[0420] In analogy to the method described for INT-988 Step 1 CIS-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (INT-967) was converted into CIS-[8-dimethylamino-2-oxo-8-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-diaza-spiro[4.5]dec-3-yl]-acetic acid tert-butyl ester (INT-1033). LC-MS: m/z [M+H].sup.+=388.3

Step 2: CIS-[8-dimethylamino-2-oxo-8-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-diaza-spiro[4.5]dec-3-yl]-acetic acid tert-butyl ester

[0421] To a suspension of CIS-(8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic acid tert-butyl ester (INT-1033) (8.1 g, 20.90 mmol, 1.0 eq.) in DMF (300 mL) was added NaH (603 mg, 25.11 mmol, 1.2 eq.) at RT and the reaction mixture was stirred for 40 min Trimethylsilylethoxymethyl chloride (SEMCl) was added (4.06 ml, 23.02 mmol, 1.1 eq). The resulting mixture was stirred at RT for 16 h, then diluted with ice-water (100 mL) and extracted with ethyl acetate (2×500 mL). The combined organic layer was washed with water (150 mL), brine (200 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, 30% ethyl acetate/hexane) to yield CIS-[8-dimethylamino-2-oxo-8-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-diaza-spiro[4.5]dec-3-yl]-acetic acid tert-butyl ester (4.0 g, 7.736 mmol, 37%) as a light yellow dense sticky liquid. LC-MS: m/z [M+H].sup.+=518.3

Step 3: CIS-[8-methylamino-2-oxo-8-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-diaza-spiro[4.5]dec-3-yl]-acetic acid tert-butyl ester

[0422] In analogy to the method described for INT-986 Step 1 CIS-[8-dimethylamino-2-oxo-8-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-diaza-spiro[4.5]dec-3-yl]-acetic acid tert-butyl ester was converted into CIS-[8-methylamino-2-oxo-8-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-diaza-spiro[4.5]dec-3-yl]-acetic acid tert-butyl ester. LC-MS: m/z [M+H].sup.+=504.2

Step 4: CIS-(8-methylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic acid (INT-1034)

[0423] To a solution of CIS-[8-methylamino-2-oxo-8-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-diaza-spiro[4.5]dec-3-yl]-acetic acid tert-butyl ester (1.6 g, 3.180 mmol, 1.0 eq.) in MeOH (48 mL) was added 2N aq. HCl (48 mL) and the mixture was stirred at RT for 16 h. The reaction mixture concentrated under reduced pressure, diluted with MeOH (40 mL), basified with 1M aq. LiOH (pH ˜12) and stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure and acidified to pH ˜6 with aq. NaHSO.sub.4. The reaction mixture was extracted with 20% MeOH/DCM (5×200 ml). The combined organic layer was dried over anhydr. Na.sub.2SO.sub.4 and concentrated under reduced pressure to yield CIS-(8-methylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic acid (INT-1034) (850 mg, 0.681 mmol, 84%) as an off white solid. The product was used in the next step without further purification. LC-MS: m/z [M+H].sup.+=318.2

Synthesis of INT-1035: CIS-(8-dimethylamino-1-oxetan-3-ylmethyl-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic acid

[0424] ##STR00057##

Step 1: CIS -(8-dimethylamino-1-oxetan-3-ylmethyl-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic acid oxetan-3-ylmethyl ester

[0425] In analogy to the method described for INT-986 Step 1 CIS-(8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic acid tert-butyl ester (INT-1033) was converted into CIS-(8-dimethylamino-1-oxetan-3-ylmethyl-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic acid oxetan-3-ylmethyl ester.

Step 2: CIS-(8-dimethylamino-1-oxetan-3-ylmethyl-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic acid (INT-1035)

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

[0426] ##STR00058##

Step 1: 9,12-dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}.2{circumflex over ( )}{5}]tetradecan-3-one

[0427] 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{circumflex over ( )}{8}.2{circumflex over ( )}{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

[0428] In analogy to the method described for INT-1003 step 3 9,12-dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}.2{circumflex over ( )}{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)

[0429] 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.+.

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

[0430] ##STR00059##

[0431] 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 1M 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 1M 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 (3×). 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.+.

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

[0432] ##STR00060##

Step 1: TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione

[0433] 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)

[0434] 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.+.

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

[0435] ##STR00061##

Step 1: 1-amino-4-dimethylamino-4-phenyl-cyclohexanecarbonitrile

[0436] 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 (3×750 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

[0437] 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 (2×250 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

[0438] 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-diaza-spiro[4.5]decan-2-one (INT-1068 and INT-1069)

[0439] 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 (2×200 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-dimethyl amino-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 (100×4.6), 5 μ, 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).

[0440] To a solution of CIS-(8-dimethylamino-1-oxetan-3-ylmethyl-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic acid oxetan-3-ylmethyl ester (300 mg, 0.636 mmol, 1.0 eq.) in THF/H.sub.2O (8 mL, 1.5:1) was added LiOH (160 mg, 3.821 mmol, 6.0 eq.). The reaction mixture was stirred at RT for 16h, concentrated under reduced pressure, neutralized with aq. NaHSO.sub.4 to pH ˜6 and extracted with 5% MeOH/DCM (3×200 mL). the combined organic extract was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was triturated with 15% DCM-Hexane to yield CIS-(8-dimethylamino-1-oxetan-3-ylmethyl-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic acid (INT-1035) (210 mg, 0.523 mmol, 82%) as an off-white solid.

[0441] 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-00002 in analogy m/z Intermediate Chemical Name Chemical structure to method [M + H].sup.+ INT-241 CIS-8- (dimethylamino)-1- isobutyl-8-phenyl-1,3- diazaspiro[4.5]decan-2- one [00062] INT-982 330.3 INT-794 CIS-3-(3,4- dimethoxybenzyl)-8- (dimethylamino)-8- phenyl-1,3- diazaspiro[4.5]decan-2- one [00063] INT-975 424.3 INT-796 CIS-8-Dimethylamino- 3-[(4-methoxyphenyl)- methyl]-8-(3-methoxy- propyl)-1,3- diazaspiro[4.5]decan-2- one [00064] INT-974 390.3 INT-797 CIS-8-(Ethyl-methyl- amino)-8-phenyl-1,3- diazaspiro[4.5]decan-2- one [00065] INT-976 288.2 INT-949 CIS-8-Dimethylamino- 1-ethyl-8-phenyl-1,3- diazaspiro[4.5]decan-2- one [00066] INT-984 302.2 INT-950 CIS-1-(Cyclobutyl-1- methyl)-8- dimethylamino-8- phenyl-3-[phenyl- methyl-1,3- diazaspiro[4.5]decan-2- one [00067] INT-952 432.3 INT-954 4-Dimethylamino-4-(5- methyl-thiophen-2-yl)- cyclohexan-1-one [00068] INT-965 238.1 INT-955 4-Dimethylamino-4- thiophen-2-yl- cyclohexan-1-one [00069] INT-965 224.1 INT-956 1-(1-Methyl-1H- pyrazol-3-yl)-4-oxo- cyclohexane-1- carbonitrile [00070] INT-958 204.1 INT-957 4-Oxo-1-pyrazin-2-yl- cyclohexane-1- carbonitrile [00071] INT-958 202.1 INT-959 4-Dimethylamino-4-(1- methyl-1H-pyrazol-3- yl)-cyclohexan-1-one [00072] INT-961 222.2 INT-960 4-Dimethylamino-4- pyrazin-2-yl- cyclohexan-1-one [00073] INT-961 220.1 INT-962 4-Dimethylamino-4-(3- methoxyphenyl)- cyclohexan-1-one [00074] INT-965 248.2 INT-963 CIS-3-Benzyl-8- dimethylamino-8- phenyl-1,3- diazaspiro[4.5]decan-2- one [00075] INT-975 364.2 INT-964 4-(Ethyl-methyl- amino)-4-phenyl- cyclohexan-1-one [00076] INT-965 232.2 INT-967 CIS-8-Dimethylamino- 8-[4-(methoxymethyl- oxy)-phenyl]-3-[(4- methoxyphenyl)-methyl]- 1,3-diazaspiro[4.5] decan-2-one [00077] INT-974 454.3 INT-968 CIS-8-Dimethylamino- 8-[3-(methoxymethyl- oxy)-phenyl]-3-[(4- methoxyphenyl)-methyl]- 1,3-diazaspiro[4.5] decan-2-one [00078] 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 [00079] INT-971 478.3 INT-970 CIS-8-Dimethylamino- 8-(4-methoxyphenyl)- 3-[(4-methoxyphenyl)- methyl]-1,3- diazaspiro[4.5]decan-2- one [00080] SC_2017 424.3 INT-972 CIS-8-Dimethylamino- 8-(3-methoxyphenyl)- 3-[(4-methoxyphenyl)- methyl]-1,3- diazaspiro[4.5]decan-2- one [00081] SC_2017 424.3 INT-973 CIS-8-Dimethylamino- 8-(4-fluorophenyl)-3- [(4-methoxyphenyl)- methyl]-1,3- diazaspiro[4.5]decan-2- one [00082] INT-974 412.2 INT-979 CIS-8-Dimethylamino- 1-(3-methoxy-propyl)- 8-phenyl-1,3- diazaspiro[4.5]decan-2- one [00083] INT-984 346.2 INT-980 CIS-8-Dimethylamino- 1-(2-methoxy-ethyl)-8- phenyl-1,3- diazaspiro[4.5]decan-2- one [00084] INT-984 332.2 INT-981 CIS-8-Dimethylamino- 8-phenyl-1-propyl-1,3- diazaspiro[4.5]decan-2- one [00085] INT-984 316.2 INT-983 CIS-1-(Cyclopropyl- methyl)-8- dimethylamino-8- phenyl-1,3- diazaspiro[4.5]decan-2- one [00086] INT-984 328.2 INT-985 CIS-1-(Cyclobutyl- methyl)-8-(methyl- propyl-amino)-8- phenyl-1,3- diazaspiro[4.5]decan-2- one [00087] INT-986 370.3 INT-989 CIS-2-[1-[(1-Cyano- cyclobutyl)-methyl]-8- dimethylamino-2-oxo- 8-phenyl-1,3- diazaspiro[4.5]decan-3- yl]-acetic acid [00088] INT-992 425.2 INT-990 CIS-2-[8- Dimethylamino-1-(3- methoxy-propyl)-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3- yl]-acetic acid [00089] INT-992 404.2 INT-991 CIS-2-[1-(Cyclopropyl-1- methyl)-8- dimethylamino-2-oxo- 8-phenyl-1,3- diazaspiro[4.5]decan-3- yl]-acetic acid [00090] INT-992 386.2 INT-993 CIS-2-[1-(Cyclobutyl- methyl)-8- dimethylamino-2-oxo- 8-phenyl-1,3- diazaspiro[4.5]decan-3- yl]-acetic acid [00091] INT-992 400.3 INT-995 CIS-2-(8- Dimethylamino-2-oxo- 8-phenyl-1-propyl-1,3- diazaspiro[4.5]decan-3- yl)-acetic acid [00092] INT-992 374.2 INT-996 CIS-2-[8- Dimethylamino-1- [(dimethyl-carbamoyl)- methyl]-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3- yl]-acetic acid; 2,2,2- trifluoro-acetic acid salt [00093] INT-998 417.2 INT-997 CIS-2-[8- Dimethylamino-1-(2- methoxy-ethyl)-2-oxo- 8-phenyl-1,3- diazaspiro[4.5]decan-3- y]-acetic acid; 2,2,2- trifluoro-acetic acid [00094] INT-998 390.2 INT-999 CIS-2-[1-(Cyclobutyl- methyl)-8- dimethylamino-2-oxo- 8-phenyl-1,3- diazaspiro[4.5]decan-3- yl]-acetic acid; 2,2,2- trifluoro-acetic acid salt [00095] INT-998 400.3 INT-1000 4-benzyl-4- (dimethylamino)cyclo- hexanone [00096] INT-965 232.3 INT-1001 CIS-8-benzyl-8- (dimethylamino)-1,3- diazaspiro[4.5]decan-2- one [00097] INT-976 288.2 INT-1002 TRANS-8-benzyl-8- (dimethylamino)-1,3- diazaspiro[4.5]decan-2- one [00098] INT-976 288.2 INT-1009 CIS-8- (dimethylamino)-8- (thiophen-2-yl)-1,3- diazaspiro[4.5]decan-2- one [00099] INT-976 280.1 INT-1010 TRANS-8- (dimethylamino)-8- (thiophen-2-yl)-1,3- diazaspiro[4.5]decan-2- one [00100] INT-976 280.1 INT-1011 4-(dimethylamino)-4- (1-methyl-1H- benzo[d]imidazol-2- yl)cyclohexanone [00101] INT-965 272.2 INT-1012 CIS-8- (dimethylamino)-8-(1- methyl-1H- benzo[d]imidazol-2-yl)- 1,3-diazaspiro[4.5] decan-2-one [00102] INT-976 328.2 INT-1013 TRANS-8- (dimethylamino)-8-(1- methyl-1H- benzo[d]imidazol-2-yl)- 1,3-diazaspiro[4.5] decan-2-one [00103] INT-976 328.2 INT-1014 CIS-2-(8- (dimethylamino)-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3- yl)acetic acid trifluoroacetic salt [00104] steps 1 and 2 of INT- 994 332.2 INT-1015 CIS-2-(8-(ethylamino)- 2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3- yl)acetic acid trifluoroacetate salt [00105] steps 1 and 2 of INT- 994 332.2 INT-1016 TRANS-8- (ethylamino)-8-phenyl- 1,3- diazaspiro[4.5]decan-2- one [00106] INT-1008 274.2 INT-1017 TRANS-2-(8- (ethylamino)-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3- yl)acetic acid trifluoroacetate salt [00107] steps 1 and 2 of INT- 994 332.2 INT-1018 CIS-8- (dimethylamino)-8- phenyl-1,3- diazaspiro[4.5]decane- 2,4-dione [00108] INT-976 288.2 INT-1024 CIS-8- (dimethylamino)-8-(3- fluorophenyl)-1,3- diazaspiro[4.5]decan-2- one [00109] INT-977 (step 2) 292.2 INT-1025 CIS-8- (dimethylamino)-8-(4- fluorophenyl)-1,3- diazaspiro[4.5]decan-2- one [00110] 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 [00111] INT-1038 358.2 INT-1040 (CIS)-8- (dimethylamino)-8-(3- (trifluoromethyl)phenyl)- 1,3-diazaspiro[4.5]decan- 2-one [00112] INT-1038 342.2 INT-1041 (CIS)-8- (dimethylamino)-8-(3- methoxyphenyl)-1,3- diazaspiro[4.5]decan-2- one [00113] INT-1038 304.2 INT-1042 (CIS)-8-(5- chlorothiophen-2-yl)-8- (dimethylamino)-1,3- diazaspiro[4.5]decan-2- one [00114] INT-1038 314.1 INT-1043 (CIS)-8- (dimethylamino)-8-(3- fluoro-5- methylphenyl)-1,3- diazaspiro[4.5]decan-2- one [00115] INT-1038 306.2 INT-1044 (CIS)-8-(3- chlorophenyl)-8- (dimethylamino)-1,3- diazaspiro[4.5]decan-2- one [00116] INT-1038 308.2 INT-1047 (CIS)-8- (methyl(oxetan-3- ylmethyl)amino)-8- phenyl-1,3- diazaspiro[4.5]decan-2- one [00117] INT-1026 330.5 INT-1057 CIS-1- (cyclobutylmethyl)-8- (dimethylamino)-8-(4- fluorophenyl)-1,3- diazaspiro[4.5]decan-2- one [00118] INT-1031 360.3 INT-1058 CIS-2-(1- (cyclobutylmethyl)-8- (dimethylamino)-8-(4- fluorophenyl)-2-oxo- 1,3- diazaspiro[4.5]decan-3- yl)acetic acid trifluoroacetate [00119] INT-998 418.3 INT-1060 TRANS-2-(8- (dimethylamino)-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3- yl)acetic acid trifluoroacetate salt [00120] steps 1 and 2 of INT- 994 332.2 INT-1061 TRANS-1- (cyclopropyl-methyl)- 8-dimethylamino-8- phenyl-1,3- diazaspiro[4.5]decan-2- one [00121] INT-984 328.2 INT-1062 TRANS-2-[1- (cyclopropyl-methyl)- 8-dimethylamino-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3- yl]-acetic acid trifluoroacetic salt [00122] INT-998 386.2 INT-1063 CIS-1- (cyclopropylmethyl)-8- (dimethylamino)-8-(3- fluorophenyl)-1,3- diazaspiro[4.5]decan-2- one [00123] INT-1031 346.2 INT-1066 TRANS-1- (cyclobutylmethyl)-8- (dimethylamino)-8- phenyl-1,3- diazaspiro[4.5]decan-2- one [00124] INT-987 342.3 INT-1067 TRANS-2-[1- (cyclobutyl-methyl)-8- dimethylamino-2-oxo- 8-phenyl-1,3- diazaspiro[4.5]decan-3- yl]-acetic acid; 2,2,2- trifluoro-acetic acid salt [00125] INT-998 400.3 INT-1070 CIS-8- (dimethylamino)-8- phenyl-1-(3,3,3- trifluoropropyl)-1,3- diazaspiro[4.5]decan-2- one [00126] INT-1068 360.2 INT-1074 CIS-8- (dimethylamino)-8-(3- fluorophenyl)-1-((1- hydroxycyclobutyl) methyl)-1,3- diazaspiro[4.5]decan-2- one [00127] INT-1031 376.2 [00128]

[0442] Synthesis of Exemplary Compounds

Synthesis of SC_1051: CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyridin-2-yl)-acetamide

[0443] ##STR00129##

[0444] Into a dry reaction vessel were added successively 1 mL of a solution of CIS-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetic acid (INT-993) (0.1 M in DCM), 2 mL of a solution of 5-methoxy-pyridin-2-amine (0.2 M in DCM), 0.07 ml of triethylamine and 0.118 mL of a solution of T3P (1.7 M, 50% in EtOAc). The reaction mixture was stirred at RT overnight, then quenched with 3 mL aq. Na.sub.2CO.sub.3 (1 M) and stirred at RT for 1 h. The organic layer was separated and the aq. layer was extracted with DCM (2×). The combined organic layers were concentrated under reduced pressure and the resulting crude product was purified by HPLC to obtain CIS-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyridin-2-yl)-acetamide (SC_1051). [M+H].sup.+506.3

Synthesis of SC_1073: CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-pyridine-4-carboxylic acid amide

[0445] ##STR00130##

[0446] To a mixture of CIS-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetic acid trifluoroacetate (INT-999) (100 mg, 0.19 mmol) and 2-amino-N-methylisonicotinamide (118 mg, 0.78 mmol) in DCM (6 ml) were added HATU (148 mg, 0.39 mmol) and DIPEA (0.13 ml, 0.78 mmol) at RT and the reaction mixture was stirred at same temperature for 16 h. The reaction mixture was washed with 1M aq. Na.sub.2CO.sub.3 (1 mL) and 2M aq. NaOH (1 mL). The combined aqueous layers were extracted with DCM (3×5mL). The combined organic layers were washed with water (3 mL) and brine (3 ml), dried over magnesium sulfate, filtered and concentrated in vacuum. Column chromatography (silica gel, cHex/tBuOMe/1N methanolic ammonia 1:1:0.05) of the crude product provided CIS-2-[[2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-pyridine-4-carboxylic acid amide (SC_1073) (27 mg). [M+H].sup.+533.3

Synthesis of SC_1076: CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-pyridine-2-carboxylic acid amide

[0447] ##STR00131##

[0448] CIS-N-(6-Cyano-pyridin-2-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide (SC_1026) (30 mg, 0.06 mmol) was dissolved in DMSO (0.2 mL) and potassium carbonate (17 mg, 0.12 mmol) and hydrogen peroxide (30% in water, 0.12 mmol) were added at 0° C. The resulting mixture was stirred for 18 h, then water was added and the reaction mixture was extracted with DCM (3×5mL). The combined organic layers were dried over Na.sub.2SO.sub.4, concentrated in vacuo and the resulting crude product was purified by flash chromatography to yield CIS-6-[[2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-pyridine-2-carboxylic acid amide SC_1076 (14 mg) as a white solid. [M+H].sup.+519.3

Synthesis of SC_1110: CIS-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-pyrimidin-5-yl)-acetamide

[0449] ##STR00132##

[0450] A solution of CIS-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-pyrimidin-5-yl)-acetamide (SC_1070) (80 mg, 0.16 mmol) in DCM (12 mL) was cooled to 0° C. and treated with a boron tribromide solution (1M in DCM, 1.26 mL, 1.26 mmol). After stirring at RT for 16 h the reaction mixture was quenched with MeOH, diluted with water and extracted with DCM (3×). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The resulting crude product was purified by column chromatography (reversed phase silica gel C18, water/MeCN 100:0->20:80) to yield CIS-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-pyrimidin-5-yl)-acetamide (SC_1110) (17 mg). [M+H].sup.+493.3

Synthesis of SC_1128: CIS-N-(2-Cyano-pyrimidin-4-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide

[0451] ##STR00133##

[0452] CIS-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide (SC_1195) (50 mg, 0.1255 mmol), 4-bromopyrimidine-2-carbonitrile (0.1882 mmol), 4,5-XantPhos (0.0188 mmol), Cs.sub.2CO.sub.3 (0.2509 mmol) and Pd.sub.2(dba).sub.3 (0.0063 mmol) were dissolved in 1,4-dioxane (6 mL). The reaction mixture was degassed by three consecutive vacuum/nitrogen-refill cycles and then stirred at 90° C. for 18 h. Water (2 mL) was added and the resulting mixture was extracted with ethyl acetate (3x6 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, concentrated in vacuo and purified by flash chromatography to yield CIS-N-(2-cyano-pyrimidin-4-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide (SC_1128) (43 mg) as a white solid. [M+H].sup.+502.3

Synthesis of SC_1129: CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[6-(methylsulfinyl)-pyridin-2-yl]-acetamide

[0453] ##STR00134##

[0454] CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methylsulfanyl-pyridin-2-yl)-acetamide SC_1120 (30.0 mg) was dissolved in 1,1,1,3,3,3-hexafluoropropan-2-ol (0.303 mL) and hydrogen peroxide (30% in water, 12 μL) was added. The resulting mixture was stirred at 60° C. for 1 h. Then sat. aq. Na.sub.2S.sub.2O.sub.3 (2 mL) was added and the aqueous layer was extracted with DCM (3×5 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, concentrated in vacuo and purified by flash chromatography to yield CIS-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[6-(methylsulfinyl)-pyridin-2-yl]-acetamide (SC_1129) (8 mg) as a white solid. [M+H].sup.+538.3

Synthesis of SC_1136: CIS-2-[8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methylsulfonyl-ethyl)-acetamide

[0455] ##STR00135##

[0456] 50% Propylphosphonic anhydride (T3P) solution in EtOAc (0.766 mL, 1.204 mmol) was added to a solution of crude CIS-2-[8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetic acid (INT-994) (250 mg, 0.602 mmol), 2-(methylsulfonyl)ethanamine hydrochloride (115.4 mg, 0.723 mmol) and diisopropylethylamine (0.410 mL, 2.408 mmol) in DCM (15 mL) at 0° C. The reaction mixture was warmed to RT and stirred for 4 h. The reaction mixture was quenched with water and the organic product was extracted with DCM (3×20 mL). The combined organic layer was washed with sat. aq. NaHCO.sub.3 (10 mL), brine (10 mL) and dried over anhydr. Na.sub.2SO.sub.4 and concentrated under reduced pressure The crude product was purified by preparative HPLC to give 56 mg (25%) of CIS-2-[8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methylsulfonyl-ethyl)-acetamide (SC_1136) as an off-white solid. (TLC system: 10% MeOH in DCM Rf: 0.62). [M+H].sup.+521.3

Synthesis of SC_1138: CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methylsulfonyl-pyridin-2-yl)-acetamide

[0457] ##STR00136##

[0458] CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methylsulfanyl-pyridin-2-yl)-acetamide (SC_1120) (22 mg) was dissolved in a water/methanol (500 μL/500 μL) and oxone (39 mg) was added. The resulting mixture was stirred at RT for 18 h. Then 2N aq. NaOH (2 mL) was added and the aqueous layer was extracted with DCM (3×5mL). The combined organic layers were dried over Na.sub.2SO.sub.4, concentrated in vacuo and the residue was purified by flash chromatography to yield CIS-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methylsulfonyl-pyridin-2-yl)-acetamide (SC_1138) (14 mg) as a white solid. [M+H].sup.+554.3

Synthesis of SC_1149: CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide

[0459] ##STR00137##

[0460] CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-987) (0.2 g, 0.57 mmol) was added to a solution of NaH (60% in mineral oil) (0.15 g, 3.47 mmol) in DMF (5 mL) at RT and the reaction mixture was stirred at RT for 1 h. The reaction mixture was cooled to 0° C. and 2-bromo-N-methylacetamide (0.52 g, 3.47 mmol) in DMF (2 mL) was added dropwise. the resulting mixture was stirred for 30 min at 0° C. and then at RT for 16 h. The reaction completion was monitored by TLC. The reaction mixture was quenched with sat. aq. NH.sub.4Cl and the organic product was extracted with EtOAc (2×10 mL). The combined organic extracts were dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. Purified of the crude product by preparative TLC using 5% MeOH in DCM as a mobile phase gave 45 g (18%) of CIS -2-[8-dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide (SC_1149) as an off-white solid. (TLC system: 10% MeOH in DCM; Rf: 0.3). [M+H].sup.+417.3

Synthesis of SC_1303: CIS-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-acetamide

[0461] ##STR00138##

[0462] N-Iodosuccinimide (71.8 mg, 0.319 mmol) was added to a solution of CIS-2-[8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-acetamide (SC_1301) (100 mg, 0.213 mmol) in a mixture of acetonitrile and THF (1:1 v/v, 5 mL) at 0° C. and the resulting mixture was stirred at RT for 16 h. The reaction mixture was basified with 2N NaOH solution to pH ˜10 and the organic product was extracted with ethyl acetate (10 mL×3). The combined organic extracts were dried over anhydr. Na.sub.2SO.sub.4 and concentrated under reduced pressure. The resulting crude product was purified by preparative reverse phase HPLC to give 50 mg of the desired product as a formiate. The isolated product was diluted with water (5 mL) and basified with sat. aq. NaHCO.sub.3. The product was extracted with EtOAc (10 mL×2), combined organic layer was dried over anhydr. Na.sub.2SO.sub.4 and concentrated in vacuo to yield 42 mg (43%) of CIS-2-[1-[(1-hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-acetamide (SC_1303) as an off-white solid (TLC system: 5% MeOH in DCM; R.sub.f: 0.42.). [M+H].sup.+457.3

Synthesis of SC_1308: CIS-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-2-one

[0463] ##STR00139##

[0464] 50 wt % solution of T3P (2.32 g, 3.65 mmol) in EtOAc was added to a suspension of CIS-2-(8-dimethylamino-2-oxo-8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-3-yl)-acetic acid hydrochlorid (INT-995) (600 mg, 1.46 mmol), thiomorpholin-1,1-dioxide (237 mg, 1.76 mmol) and diisopropylethylamine (1.27 mL, 7.30 mmol) in THF (10 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 EtOAc (3×25mL). The combined organic extracts were washed with water, brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to give the crude compound. Purification by flash silica column chromatography using 4-5% methanol in DCM as eluent yielded 250 mg (34%) of CIS-8-dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-2-one (SC_1308) as a solid (TLC system: 10% MeOH in DCM R.sub.f: 0.30). [M+H].sup.+491.3

Synthesis of SC_1324: CIS-2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetamide

[0465] ##STR00140##

[0466] The suspension of TFA salt of CIS-(8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic acid (500 mg, 1.12 mmol, 1.0 eq.) in THF (40 ml) was cooled to 0° C. and DIPEA (0.78 ml, 4.48 mmol, 4.0 eq.), 1-hydroxy-1H-benzotriazole ammonium salt (287 mg, 1.68 mmol, 1.5 eq.) and EDCl (321 mg, 1.68 mmol, 1.5 eq.) were sequentially added. The resulting mixture was stirred at RT for 16 h and then concentrated under reduced pressure. Crude product was purified by column chromatography (neutral alumina; 0.5% NH.sub.3 in 20% MeOH/DCM) to yield CIS-2-(8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetamide (SC_1324) (250 mg, 0.75 mmol, 67%) as an off-white solid. [M+H].sup.+331.2

Synthesis of SC_1332: CIS-2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-phenylacetamide

[0467] ##STR00141##

[0468] KOtBu (1M in THF) (1.4 mL, 1.37 mmol) was added to the solution of CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (250 mg, 0.915 mmol) in THF (15 mL) under argon atmosphere at 0° C. and the reaction mixture was stirred for 30 min 2-Bromo-N-phenylacetamide (312 mg, 1.46 mmol) was added, the ice bath was removed and the reaction mixture was stirred for 4 h. Sat. aq. NH.sub.4Cl (10 mL) was added and the resulting mixture was extracted with EtOAc (2×50 mL). The combined organic extracts were dried over anhydr. Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC to give 60 mg (16%) of CIS-2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-phenylacetamide (SC_1332) as a white solid. .sup.1H NMR (CDCl.sub.3): δ 8.32 (br s, 1H), 7.50-7.48 (d, 2H), 7.39-7.36 (m, 2H), 7.33-7.26 (m, 5H), 7.12-7.08 (t, 1H), 5.90 (br s, 1H), 3.90 (s, 2H), 3.25 (s, 2H), 2.12 (m, 4H), 1.99 (s, 6H), 1.94-1.91 (m, 2H),1.58-1.53 (m, 2H). [M+H].sup.+407.2

Synthesis of SC-1346: CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-acetic acid tert-butyl ester

[0469] ##STR00142##

[0470] KOtBu (187 mg, 1.67 mmol) was added to a solution of CIS-1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-1,3-di azaspiro[4.5]decan-2-one (INT-1031) (400 mg, 1.1 mmol) in dry THF (9 mL) at 0° C. The mixture was stirred for 15 min at this temperature and t-butyl-bromoacetate (0.246 mL, 1.67 mmol) was added subsequently. After stirring for 1 h at 0° C., the reaction was quenched with water, diluted with EtOAc and stirred for 5 min at RT. The layers were separated and the aqueous layer was extracted two times with ethyl acetate. The combined organic extracts were dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica, 0.5 M NH.sub.3 in MeOH/DCM gradient) to yield 395 mg (75%) of CIS-2-[1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-acetic acid tert-butyl ester (SC_1346) as a white solid. .sup.1H NMR (600 MHz, DMSO) δ 7.43-7.36 (m, 1H), 7.17 (d, 1H), 7.13 (dt, 1H), 7.09 (td, 1H), 3.75 (d, 2H), 3.21 (s, 2H), 3.05 (d, 2H), 2.67-2.61 (m, 2H), 2.08-2.00 (m, 2H), 1.99 (d, 7H), 1.98-1.93 (m, 2H), 1.83-1.75 (m, 2H), 1.75-1.65 (m, 2H), 1.39 (d, 8H), 1.38-1.29 (m, 5H). [M+H].sup.+474.3

of SC-1357: TRANS-1-(cyclopropylmethyl)-8-(dimethylamino)-3-(2-morpholino-2-oxoethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

[0471] ##STR00143##

[0472] To a solution of TRANS-2-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetic acid trifluoroacetate (300 mg, 0.6 mmol, 1.0 eq.) in DCM (10 mL) were added DIPEA (0.62 mL, 3.6 mmol, 6.0 eq.) and HATU (296 mg, 0.78 mmol, 1.3 eq.) followed by morpholine (102 mg, 1.08 mmol, 1.8 eq.) at 0° C. The reaction mixture was stirred at RT for 16 h, then quenched with water (25 mL) and extracted with DCM (50 mL×2). Combined organic layer was washed with brine (25 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The resulting crude product was purified by prep HPLC to get TRANS-1-cyclopropylmethyl-8-dimethylamino-3-(2-morpholin-4-yl-2-oxo-ethyl)-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (SC-1357) (55 mg, 0.12 mmol, 20%) as a white solid. .sup.1HNMR (DMSO-d.sub.6, 400 MHz), δ (ppm)=7.44-7.29 (m, 5H), 3.96 (s, 2H), 3.56 (bs, 4H), 3.42-3.40 (m, 4H), 3.29 (s, 2H), 2.67 (bs, 2H), 2.55-2.54 (d, 2H, J=6.36 Hz), 1.92 (s, 6H), 1.56-0.144 (m, 6H), 0.51-0.48 (m, 1H), 0.16-0.14 (m, 2H), (−0.26)-(−0.27) (m, 2H). [M+H].sup.+455.1

Synthesis of INT-1363: TRANS-2-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetamide

[0473] ##STR00144##

Step 1: tert-butyl TRANS-2-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate

[0474] In analogy to the method described for INT-1019 step 1 TRANS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1061) was converted into tert-butyl TRANS-2-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate. LC-MS: m/z [M+H].sup.+=442.3

Step 2: TRANS-2-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetamide (INT-1363)

[0475] A mixture of TRANS-(1-cyclopropylmethyl-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic acid tert-butyl ester (250 mg, 0.56 mmol, 1.0 eq.) and 7M NH.sub.3 in MeOH (5 mL) was heated in sealed tube at 90° C. for 16 h, then cooled down to RT and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel basified with aq. NH.sub.3; 10% MeOH in DCM) to yield 2-(1-cyclopropylmethyl-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetamide (77 mg,0.2 mmol, 35%) as a white solid. LC-MS: m/z [M+1].sup.+=385.2 (MW calc. 384.52); .sup.1H NMR at 100° C. (DMSO-d6, 400 MHz), δ (ppm)=7.40-7.29 (m, 5H), 6.76 (bs, 2H), 3.68 (s, 2H), 3.33 (s, 2H), 2.61-2.60 (m, 4H), 2.00 (s, 6H), 1.61-0.153 (m, 6H), 0.58-0.56 (m, 1H), 0.22-0.20 (m, 2H), (−0.16)-(−0.18) (m, 2H).

[0476] 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-00003 in analogy m/z Example Chemical Name Reactant I Reactant II to method [M + H].sup.+ SC_1001 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2,5,8,11,14,17,20- SC_1308 721.5 8-dimethylamino-2-oxo-8- heptaoxadocosan- phenyl-1,3- 22-amine diazaspiro[4.5]decan-3-yl]-N- [2-[2-[2-[2-[2-[2-(2-methoxy- ethoxy)-ethoxy]-ethoxy]- ethoxy]-ethoxy]-ethoxy]-ethyl]- acetamide SC_1002 CIS-6-[[2-[1-(Cyclobutyl- INT 993 methyl SC_1308 534.3 methyl)-8-dimethylamino-2- 6-aminopicolinate oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-pyridine-2- carboxylic acid methyl ester SC_1003 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 (R)-2-aminopropan-1-ol SC_1308 457.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(1R)-2-hydroxy-1-methyl- ethyl]-acetamide SC_1004 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 (S)-2-aminopropan-1-ol SC_1308 457.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(1S)-2-hydroxy-1-methyl- ethyl]-acetamide SC_1005 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 N-methyl-2- SC_1308 484.3 8-dimethylamino-2-oxo-8- (methylamino)acetamide phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- methyl-N-(methylcarbamoyl- methyl)-acetamide SC_1006 CIS-6-[[2-[1-(Cyclobutyl- INT 993 methyl 6-aminonicotinate SC_1308 534.3 methyl)-8-dimethylamino-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-nicotinic acid methyl ester SC_1007 CIS-2-[[2-[1-(Cyclobutyl- INT 993 2-methyl-2- SC_1308 498.3 methyl)-8-dimethylamino-2- (methylamino)propanamide oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]-methyl-amino]-2- methyl-propionamide SC_1008 CIS-2-[[2-[1-(Cyclobutyl- INT 993 2-amino-N,2- SC_1308 498.3 methyl)-8-dimethylamino-2- dimethylpropanamide oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-N,2-dimethyl- propionamide SC_1009 CIS-2-[[2-[1-(Cyclobutyl- INT 993 N,2-dimethyl-2- SC_1308 512.4 methyl)-8-dimethylamino-2- (methylamino)propanamide oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]-methyl-amino]-N,2- dimethyl-propionamide SC_1010 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 N,N-dimethyl-2- SC_1308 498.3 8-dimethylamino-2-oxo-8- (methylamino)acetamide phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(dimethyl-carbamoyl)-methyl]- N-methyl-acetamide SC_1011 CIS-2-[[2-[1-(Cyclobutyl- INT 993 2-amino-2- SC_1308 484.3 methyl)-8-dimethylamino-2- methylpropanamide oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-2-methyl- propionamide SC_1012 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 5-methoxypyridin- SC_1308 506.3 8-dimethylamino-2-oxo-8- 2-amine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (5-methoxy-pyridin-2-yl)- acetamide SC_1013 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 6-methoxypyridin- SC_1308 506.3 8-dimethylamino-2-oxo-8- 2-amine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (6-methoxy-pyridin-2-yl)- acetamide SC_1014 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 4-methoxypyridin- SC_1308 506.3 8-dimethylamino-2-oxo-8- 2-amine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (4-methoxy-pyridin-2-yl)- acetamide SC_1015 CIS-6-[[2-[1-(Cyclobutyl- INT 999 6-amino-N- SC_1073 533.3 methyl)-8-dimethylamino-2- methylpicolinamide oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-N-methyl- pyridine-2-carboxylic acid amide SC_1016 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 cis-3- SC_1308 483.3 8-dimethylamino-2-oxo-8- (aminomethyl)cyclobutanol phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(3-hydroxy-cyclobutyl)- methyl]-acetamide SC_1017 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 trans-3- SC_1308 483.3 8-dimethylamino-2-oxo-8- (aminomethyl)cyclobutanol phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(3-hydroxy-cyclobutyl)- methyl]-acetamide SC_1018 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 1- SC_1308 469.3 8-dimethylamino-2-oxo-8- (aminomethyl)cyclopropanol phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(1-hydroxy-cyclopropyl)- methyl]-acetamide SC_1019 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 3-amino-1- SC_1308 540.3 8-dimethylamino-2-oxo-8- morpholinopropan-1-one phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (3-morpholin-4-yl-3-oxo- propyl)-acetamide SC_1020 CIS-N-(1-Cyano-cyclopropyl)- INT 993 1- SC_1308 464.3 2-[1-(cyclobutyl-methyl)-8- aminocyclopropanecarbonitrile dimethylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- acetamide SC_1021 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 3- SC_1308 497.3 8-dimethylamino-2-oxo-8- (aminomethyl)cyclopentanol phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(3-hydroxy-cyclopentyl)- methyl]-acetamide SC_1022 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 (1R)-2- SC_1308 511.4 8-dimethylamino-2-oxo-8- (aminomethyl)cyclohexanol diazaspiro[4.5]decan-3-yl]-N- [2-[2-[2-[2-[2-(2-methoxy- ethoxy)-ethoxy]-ethoxy]- ethoxy]-ethoxy]-ethyl]- acetamide SC_1030 CIS-N-(4-Cyano-pyridin-2-yl)- INT 993 2-aminoisonicotinonitrile SC_1308 501.3 2-[1-(cyclobutyl-methyl)-8- dimethylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- acetamide SC_1031 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 5-methoxypyrimidin-2- SC_1308 507.3 8-dimethylamino-2-oxo-8- amine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (5-methoxy-pyrimidin-2-yl)- acetamide SC_1032 CIS-2-[[2-[1-(Cyclobutyl- INT 993 methyl 2-aminoisonicotinate SC_1308 534.3 methyl)-8-dimethylamino-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-isonicotinic acid methyl ester SC_1033 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2-methoxypyridin-4-amine SC_1051 506.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (2-methoxy-pyridin-4-yl)- acetamide SC_1034 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 6-fluoropyridin-3-amine SC_1051 494.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (6-fluoro-pyridin-3-yl)- acetamide SC_1035 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2-methylpyrimidin-5-amine SC_1051 491.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (2-methyl-pyrimidin-5-yl)- acetamide SC_1036 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 5-methylpyrimidin-2-amine SC_1051 491.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (5-methyl-pyrimidin-2-yl)- acetamide SC_1037 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 3-fluoropyridin-2-amine SC_1051 494.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (3-fluoro-pyridin-2-yl)- acetamide SC_1038 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 3-fluoropyridin-4-amine SC_1051 494.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (3-fluoro-pyridin-4-yl)- acetamide SC_1039 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 6-methoxypyridin-3-amine SC_1051 506.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (6-methoxy-pyridin-3-yl)- acetamide SC_1040 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2-methylpyridin-3-amine SC_1051 490.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (2-methyl-pyridin-3-yl)- acetamide SC_1041 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 4-methylpyridin-3-amine SC_1051 490.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (4-methyl-pyridin-3-yl)- acetamide SC_1042 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 3-methylpyridin-4-amine SC_1051 490.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (3-methyl-pyridin-4-yl)- acetamide SC_1043 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 6-methylpyridin-3-amine SC_1051 490.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (6-methyl-pyridin-3-yl)- acetamide SC_1044 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 5-fluoropyridin-2-amine SC_1051 494.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (5-fluoro-pyridin-2-yl)- acetamide SC_1045 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 5-methylpyridin-2-amine SC_1051 490.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (5-methyl-pyridin-2-yl)- acetamide SC_1046 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 4-methylpyridin-2-amine SC_1051 490.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (4-methyl-pyridin-2-yl)- acetamide SC_1047 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 3-methylpyridin-2-amine SC_1051 490.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (3-methyl-pyridin-2-yl)- acetamide SC_1048 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 3-methoxypyridin-4-amine SC_1051 506.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (3-methoxy-pyridin-4-yl)- acetamide SC_1049 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 6-methoxypyridazin-3- SC_1051 507.3 8-dimethylamino-2-oxo-8- amine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (6-methoxy-pyridazin-3-yl)- acetamide SC_1050 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 5-(methylsulfonyl)pyridin- SC_1051 554.3 8-dimethylamino-2-oxo-8- 2-amine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (5-methylsulfonyl-pyridin-2-yl)- acetamide SC_1052 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 6-(methylsulfonyl)pyridin- SC_1051 554.3 8-dimethylamino-2-oxo-8- 3-amine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (6-methylsulfonyl-pyridin-3-yl)- acetamide SC_1053 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 6-methoxypyrazin-2-amine SC_1051 507.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (6-methoxy-pyrazin-2-yl)- acetamide SC_1054 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 4-methoxypyridin-2-amine SC_1051 506.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (4-methoxy-pyridin-2-yl)- acetamide SC_1055 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 4-methoxypyrimidin-2- SC_1051 507.3 8-dimethylamino-2-oxo-8- amine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (4-methoxy-pyrimidin-2-yl)- acetamide SC_1056 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 oxazol-5-ylmethanamine SC_1051 480.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (oxazol-5-yl-methyl)-acetamide SC_1057 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 oxazol-2-ylmethanamine SC_1051 480.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (oxazol-2-yl-methyl)-acetamide SC_1058 CIS-1-(Cyclobutyl-methyl)-3- INT 993 (3S,4S)-piperidine-3,4-diol SC_1051 499.3 [2-[(3S,4S)-3,4-dihydroxy- piperidin-1-yl]-2-oxo-ethyl]-8- dimethylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_1059 CIS-1-(Cyclobutyl-methyl)-3- INT 993 (3S,4S)-pyrrolidine-3,4-diol SC_1051 485.3 [2-[(3S,4S)-3,4-dihydroxy- pyrrolidin-1-yl]-2-oxo-ethyl]-8- dimethylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_1060 CIS-1-(Cyclobutyl-methyl)-3- INT 993 (3S,4R)-pyrrolidine-3,4-diol SC_1051 485.3 [2-[(3S,4R)-3,4-dihydroxy- pyrrolidin-1-yl]-2-oxo-ethyl]-8- dimethylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_1061 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 cyclopropanamine SC_1051 439.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- cyclopropyl-acetamide SC_1062 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2-(methylamino)ethanol SC_1051 457.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (2-hydroxy-ethyl)-N-methyl- acetamide SC_1063 CIS-1-(Cyclobutyl-methyl)-8- INT 993 piperidin-3-ol SC_1051 483.3 dimethylamino-3-[2-(3- hydroxy-piperidin-1-yl)-2-oxo- ethyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_1064 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 1- SC_1051 483.3 8-dimethylamino-2-oxo-8- (aminomethyl)cyclobutanol phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(1-hydroxy-cyclobutyl)- methyl]-acetamide SC_1065 CIS-2-[[2-[1-(Cyclobutyl- INT 993 2-amino-N,N- SC_1051 484.3 methyl)-8-dimethylamino-2- dimethylacetamide oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-N,N-dimethyl- acetamide SC_1066 CIS-1-(Cyclobutyl-methyl)-8- INT 993 5,6,7,8-tetrahydro- SC_1051 506.3 dimethylamino-3-[2-oxo-2- [1,2,4]triazolo[1,5- (5,6,7,8-tetrahydro- a]pyrazine [1,2,4]triazolo[1,5-a]pyrazin-7- yl)-ethyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_1067 CIS-3-[[2-[1-(Cyclobutyl- INT 993 3-amino-N,N- SC_1051 498.3 methyl)-8-dimethylamino-2- dimethylpropanamide oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-N,N-dimethyl- propionamide SC_1068 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2,5,8,11,14,17,20,23-octa- SC_1308 765.5 8-dimethylamino-2-oxo-8- oxapentacosan-25-amine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [2-[2-[2-[2-[2-[2-[2-(2- methoxy-ethoxy)-ethoxy]- ethoxy]-ethoxy]-ethoxy]- ethoxy]-ethoxy]-ethyl]- acetamide SC_1069 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 4-methoxypyrimidin-5- SC_1308 507.3 8-dimethylamino-2-oxo-8- amine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (4-methoxy-pyrimidin-5-yl)- acetamide SC_1070 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2-methoxypyrimidin-5- SC_1308 507.3 8-dimethylamino-2-oxo-8- amine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (2-methoxy-pyrimidin-5-yl)- acetamide SC_1072 CIS-N-(5-Cyano-pyridin-2-yl)- INT 993 6-aminonicotinonitrile SC_1308 501.3 2-[1-(cyclobutyl-methyl)-8- dimethylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- acetamide SC_1074 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 5-methoxypyrimidin-4- SC_1308 507.3 8-dimethylamino-2-oxo-8- amine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (5-methoxy-pyrimidin-4-yl)- acetamide SC_1075 CIS-N-(2-Cyano-pyrimidin-5- INT 993 5-aminopyrimidine-2- SC_1308 502.3 yl)-2-[1-(cyclobutyl-methyl)-8- carbonitrile dimethylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- acetamide SC_1077 CIS-N-(3-Cyano-pyridin-2-yl)- INT 993 2-aminonicotinonitrile SC_1308 501.3 2-[1-(cyclobutyl-methyl)-8- dimethylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- acetamide SC_1078 CIS-2-[[2-[1-(Cyclobutyl- INT 993 2-aminoacetamide SC_1308 456.3 methyl)-8-dimethylamino-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-acetamide SC_1079 CIS-6-[[2-[1-(Cyclobutyl- SC 1072 — SC_1076 519.3 methyl)-8-dimethylamino-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-pyridine-3- carboxylic acid amide SC_1080 CIS-N-(4-Cyano-pyrimidin-2- INT 993 2-aminopyrimidine-4- SC_1308 502.3 yl)-2-[1-(cyclobutyl-methyl)-8- carbonitrile dimethylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- acetamide SC_1081 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 1,3,4-thiadiazol-2-amine SC_1051 483.2 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- ([1,3,4]thiadiazol-2-yl)- acetamide SC_1082 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 thiazol-2-amine SC_1051 482.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- thiazol-2-yl-acetamide SC_1083 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 5-methylisoxazol-3-amine SC_1051 480.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (5-methyl-isoxazol-3-yl)- acetamide SC_1084 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 isoxazol-3-amine SC_1051 466.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- isoxazol-3-yl-acetamide SC_1085 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 1-methyl-1H-pyrazol-3- SC_1051 479.3 8-dimethylamino-2-oxo-8- amine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (1-methyl-1H-pyrazol-3-yl)- acetamide SC_1086 CIS-N-(4-Cyano-5- INT 993 3-amino-5-(methylthio)-1H- SC_1051 536.3 methylsulfanyl-1H-pyrazol-3- pyrazole-4-carbonitrile yl)-2-[1-(cyclobutyl-methyl)-8- dimethylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- acetamide SC_1087 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 5-methoxypyrazin-2-amine SC_1051 507.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (5-methoxy-pyrazin-2-yl)- acetamide SC_1088 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 pyridazin-4-ylmethanamine SC_1051 491.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (pyridazin-4-yl-methyl)- acetamide SC_1089 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2-(aminomethyl)phenol SC_1051 505.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(2-hydroxyphenyl)-methyl]- acetamide SC_1090 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 (1-methyl-1H-imidazol-4- SC_1051 493.3 8-dimethylamino-2-oxo-8- yl)methanamine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(1-methyl-1H-imidazol-4-yl)- methyl]-acetamide SC_1091 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 (4-methylpyridin-3- SC_1051 504.3 8-dimethylamino-2-oxo-8- yl)methanamine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(4-methyl-pyridin-3-yl)- methyl]-acetamide SC_1092 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 pyrimidin-2-ylmethanamine SC_1051 491.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (pyrimidin-2-yl-methyl)- acetamide SC_1093 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 pyridazin-3-ylmethanamine SC_1051 491.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (pyridazin-3-yl-methyl)-acetamide SC_1094 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 pyrimidin-4-ylmethanamine SC_1051 491.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (pyrimidin-4-yl-methyl)- acetamide SC_1095 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 pyrazin-2-ylmethanamine SC_1051 491.3 8-dimediylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (pyrazin-2-yl-methyl)-acetamide SC_1096 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 oxazol-4-ylmedianamine SC_1051 480.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (oxazol-4-yl-methyl)-acetamide SC_1097 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 (2-methylpyridin-3- SC_1051 504.3 8-dimethylamino-2-oxo-8- yl)methanamine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(2-methyl-pyridin-3-yl)- methyl]-acetamide SC_1098 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 (2-methoxypyridin-3- SC_1051 520.3 8-dimethylamino-2-oxo-8- yl)methanamine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(2-methoxy-pyridin-3-yl)- methyl]-acetamide SC_1099 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 (4-methoxypyridin-3- SC_1051 520.3 8-dimethylamino-2-oxo-8- yl)methanamine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(4-methoxy-pyridin-3-yl)- methyl]-acetamide SC_1100 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 (6-methylpyridin-2- SC_1051 504.3 8-dimethylamino-2-oxo-8- yl)methanamine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(6-methyl-pyridin-2-yl)- methyl]-acetamide SC_1101 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 (6-methoxypyridin-2- SC_1051 520.3 8-dimethylamino-2-oxo-8- yl)methanamine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(6-methoxy-pyridin-2-yl)- methyl]-acetamide SC_1102 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 (2- SC_1051 519.3 8-dimethylamino-2-oxo-8- methoxyphenyl)methanamine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(2-methoxyphenyl)-methyl]- acetamide SC_1103 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 o-tolylmethanamine SC_1051 503.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (o-tolyl-methyl)-acetamide SC_1104 CIS-6-[[2-[1-(Cyclobutyl- INT 999 6-amino-N- SC_1073 533.3 methyl)-8-dimethylamino-2- methylnicotinamide oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-N-methyl- pyridine-3-carboxylic acid amide SC_1105 CIS-2-[[2-[1-(Cyclobutyl- SC 1030 — SC_1076 519.3 methyl)-8-dimethylamino-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-pyridine-4- carboxylic acid amide SC_1106 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 6-methoxypyrimidin-4- SC_1308 507.3 8-dimethylamino-2-oxo-8- amine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (6-methoxy-pyrimidin-4-yl)- acetamide SC_1107 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2-methoxypyrimidin-4- SC_1308 507.3 8-dimethylamino-2-oxo-8- amine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (2-methoxy-pyrimidin-4-yl)- acetamide SC_1109 CIS-2-[1-(Cyclobutyl-methyl)- SC 1069 SC_1110 493.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (4-hydroxy-pyrimidin-5-yl)- acetamide SC_1111 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 6-aminopyridin-3-ol SC_1308 492.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (5-hydroxy-pyridin-2-yl)- acetamide SC_1112 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 4-aminotetrahydro-2H- SC_1308 531.3 8-dimethylamino-2-oxo-8- thiopyran 1,1-dioxide phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (1,1-dioxo-thian-4-yl)- acetamide SC_1113 CIS-1-(Cyclobutyl-methyl)-8- INT 993 thiomorpholine 1,1-dioxide SC_1308 517.3 dimethylamino-3-[2-(1,1-dioxo- [1,4]thiazinan-4-yl)-2-oxo- ethyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_1114 CIS-2-[8-Dimethylamino-1-(2- INT 997 pyrimidin-4-amine SC_1308 467.3 methoxy-ethyl)-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- N-pyrimidin-4-yl-acetamide SC_1115 CIS-2-[8-Dimethylamino-1-(2- INT 997 methylamine SC_1308 403.3 methoxy-ethyl)-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- N-methyl-acetamide SC_1117 CIS-N-(5-Cyano-pyrimidin-4- INT 993 4-aminopyrimidine-5- SC_1308 502.3 yl)-2-[1-(cyclobutyl-methyl)-8- carbonitrile dimethylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- acetamide SC_1118 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 5-(methylthio)pyridin-2- SC_1308 522.3 8-dimethylamino-2-oxo-8- amine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (5-methylsulfanyl-pyridin-2-yl)- acetamide SC_1119 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 4-methoxypyrimidin-2- SC_1308 507.3 8-dimethylamino-2-oxo-8- amine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (4-methoxy-pyrimidin-2-yl)- acetamide SC_1120 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 6-(methylthio)pyridin-2- SC_1308 522.3 8-dimethylamino-2-oxo-8- amine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (6-methylsulfanyl-pyridin-2-yl)- acetamide SC_1121 CIS-2-[8-Dimethylamino-1-(2- INT 997 2-aminoethanol SC_1308 433.3 methoxy-ethyl)-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- N-(2-hydroxy-ethyl)-acetamide SC_1122 CIS-2-[[2-[8-Dimethylamino-1- INT 997 2-aminoacetamide SC_1308 446.3 (2-methoxy-ethyl)-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-acetamide SC_1123 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 methylamine SC_1308 413.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- methyl-acetamide SC_1124 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2-aminoethanol SC_1308 443.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (2-hydroxy-ethyl)-acetamide SC_1125 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 6-aminopyridin-2-ol SC_1308 492.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (6-hydroxy-pyridin-2-yl)- acetamide SC_1126 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 (2-methoxypyrimidin-5- SC_1308 521.3 8-dimethylamino-2-oxo-8- yl)methanamine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(2-methoxy-pyrimidin-5-yl)- methyl]-acetamide SC_1127 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 (4-methoxypyrimidin-2- SC_1308 521.3 8-dimethylamino-2-oxo-8- yl)methanamine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(4-methoxy-pyrimidin-2-yl)- methyl]-acetamide SC_1130 CIS-2-[[2-[1-(Cyclobutyl- SC 1011 2-amino-2- SC_1303 470.3 methyl)-8-methylamino-2-oxo- methylpropanamide 8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-2-methyl- propionamidc SC_1131 CIS-2-[[2-[1-(Cyclobutyl- SC 1222 — SC_1303 456.3 methyl)-8-methylamino-2-oxo- 8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-N-methyl- acetamide SC_1132 CIS-2-[[2-[1-(Cyclobutyl- SC 1078 — SC_1303 442.3 methyl)-8-methylamino-2-oxo- 8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-acetamide SC_1133 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2-(2-(2- SC_1308 545.4 8-dimethylamino-2-oxo-8- methoxyethoxy)ethoxy)- phenyl-1,3- ethanamine diazaspiro[4.5]decan-3-yl]-N- [2-[2-(2-methoxy-ethoxy)- ethoxy]-ethyl]-acetamide SC_1134 CIS-N-(Carbamoyl-methyl)-2- SC 1146 2-(methylamino)acetamide SC_1303 456.3 [1-(cyclobutyl-methyl)-8- methylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- N-methyl-acetamide SC_1135 CIS-2-[1-(Cyclobutyl-methyl)- SC 1005 N-methyl-2- SC_1303 470.3 8-methylamino-2-oxo-8-phenyl- (methylamino)acetamide 1,3-diazaspiro[4.5]decan-3-yl]- N-methyl-N-(methylcarbamoyl- methyl)-acetamide SC_1137 CIS-2-[8-Dimethylamino-1-[(1- INT 994 pyrimidin-5-amine SC_1136 493.3 hydroxy-cyclobutyl)-methyl]-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- pyrimidin-5-yl-acetamide SC_1139 CIS-2-[8-Dimethylamino-1- INT 996 2-aminoethanol SC_1308 460.3 [(dimethyl-carbamoyl)-methyl]- 2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (2-hydroxy-ethyl)-acetamide SC_1140 CIS-2-[[2-[1-(Cyclobutyl- SC 1007 — SC_1303 484.3 methyl)-8-methylamino-2-oxo- 8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]-methyl-amino]-2- methyl-propionamide SC_1141 CIS-1-(Cyclobutyl-methyl)-3- SC 1214 — SC_1303 503.3 [2-(1,1-dioxo-[1,4]thiazinan-4- yl)-2-oxo-ethyl]-8- methylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_1142 CIS-2-[1-(Cyclobutyl-methyl)- SC 1199 — SC_1303 707.5 8-methylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- N-[2-[2-[2-[2-[2-[2-(2-methoxy- ethoxy)-ethoxy]-ethoxy]- ethoxy]-ethoxy]-ethoxy]-ethyl]- acetamide SC_1143 CIS-2-[[2-[1-(Cyclobutyl- SC 1065 — SC_1303 470.3 methyl)-8-methylamino-2-oxo- 8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-N,N-dimethyl- acetamide SC_1144 CIS-2-[1-(Cyclobutyl-methyl)- SC 1070 — SC_1110 493.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (5-hydroxy-pyrimidin-2-yl)- acetamide SC_1145 CIS-2-[1-(Cyclobutyl-methyl)- SC 1321 — SC_1138 554.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (4-methylsulfonyl-pyridin-2-yl)- acetamide SC_1146 CIS-2-[[2-[1-(Cyclobutyl- INT 993 2-amino-N- SC_1308 470.3 methyl)-8-dimethylamino-2- methylacetamide oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-N-methyl- acetamide SC_1147 CIS-N-(Carbamoyl-methyl)-2- INT 993 2-(methylamino)acetamide SC_1308 470.3 [1-(cyclobutyl-methyl)-8- dimethylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- N-methyl-acetamide SC_1148 CIS-2-(8-Dimethylamino-2- INT 995 methylamine SC_1136 387.3 oxo-8-phenyl-1-propyl-1,3- diazaspiro[4.5]decan-3-yl)-N- methyl-acetamide SC_1150 CIS-2-[1-(Cyclobutyl-methyl)- SC 1321 — SC_1129 538.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [4-(methylsulfinyl)-pyridin-2- yl]-acetamide SC_1151 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2-aminopyridin-3-ol SC_1308 492.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (3-hydroxy-pyridin-2-yl)- acetamide SC_1152 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2- SC_1308 505.3 8-dimethylamino-2-oxo-8- (methylsulfonyl)ethanamine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (2-methylsulfonyl-ethyl)- acetamide SC_1154 CIS-1-(Cyclobutyl-methyl)-3- INT 993 (3S,4R)-pyrrolidine-3,4-diol SC_1308 485.3 [2-[(3S,4R)-3,4-dihydroxy- pyrrolidin-1-yl]-2-oxo-ethyl]-8- dimethylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_1155 CIS-2-[1-(Cyclobutyl-methyl)- SC 1198 — SC_1303 429.3 8-methylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- N-(2-hydroxy-ethyl)-acetamide SC_1156 CIS-2-[8-Dimethylamino-1- INT 996 pyrimidin-4-amine SC_1308 494.3 [(dimethyl-carbamoyl)-methyl]- 2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- pyrimidin-4-yl-acetamide SC_1157 CIS-2-[8-Dimethylamino-1- INT 996 methylamine SC_1308 430.3 [(dimethyl-carbamoyl)-methyl]- 2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- methyl-acetamide SC_1158 CIS-2-[[2-[8-Dimethylamino-1- INT 992 2-aminoacetamide SC_1136 444.3 (2-methyl-propyl)-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-acetamide SC_1159 CIS-2-[8-Dimethylamino-1-[(1- INT 994 NH.sub.4Cl SC_1136 415.3 hydroxy-cyclobutyl)-methyl]-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetamide SC_1160 CIS-2-[8-Dimethylamino-1-[(1- INT 994 methylamine SC_1136 429.3 hydroxy-cyclobutyl)-methyl]-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- methyl-acetamide SC_1161 CIS-2-[[2-[8-Dimethylamino-1- INT 987 N-(2-amino-2-oxoethyl)-2- SC_1149 460.3 (3-methoxy-propyl)-2-oxo-8- bromoacetamide phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-acetamide SC_1162 CIS-2-[8-Dimethylamino-1-(2- INT 984 2-bromo-N- SC_1149 401.3 methyl-propyl)-2-oxo-8-phenyl- methylacetamide 1,3-diazaspiro[4.5]decan-3-yl]- N-methyl-acetamide SC_1163 CIS-1-(Cyclobutyl-methyl)-3- SC 1154 — SC_1303 471.3 [2-[(3S,4R)-3,4-dihydroxy- pyrrolidin-1-yl]-2-oxo-ethyl]-8- methylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_1164 CIS-2-[8-Dimethylamino-1-[(1- INT 998 methylamine SC_1308 427.3 methyl-cyclobutyl)-methyl]-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- methyl-acetamide SC_1165 CIS-2-[8-Dimethylamino-1-[(1- INT 998 pyrimidin-4-amine SC_1308 491.3 methyl-cyclobutyl)-methyl]-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- pyrimidin-4-yl-acetamide SC_1166 CIS-2-[[2-[8-Dimethylamino-1- INT 998 2-aminoacetamide SC_1308 470.3 [(1-methyl-cyclobutyl)-methyl]- 2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-acetamide SC_1167 CIS-2-[8-Dimethylamino-1-[(1- INT 998 2-aminoethanol SC_1308 457.3 methyl-cyclobutyl)-methyl]-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (2-hydroxy-ethyl)-acetamide SC_1168 CIS-2-[[2-[1-(Cyclopropyl- INT 983 N-(2-amino-2-oxoethyl)-2- SC_1149 442.3 methyl)-8-dimethylamino-2- bromoacetamide oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-acetamide SC_1169 CIS-2-[1-(Cyclobutyl-methyl)- INT 986 2-bromo-N- SC_1149 427.3 8-(ethyl-methyl-amino)-2-oxo- methylacetamide 8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- methyl-acetamide SC_1171 CIS-2-[[2-(8-Dimethylamino-2- INT 995 2-aminoacetamide SC_1308 430.3 oxo-8-phenyl-1-propyl-1,3- diazaspiro[4.5]decan-3-yl)- acetyl]amino]-acetamide SC_1172 CIS-2-[[2-[8-Dimethylamino-1- INT 994 2-aminoacetamide SC_1308 472.3 [(1-hydroxy-cyclobutyl)- methyl]-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-acetamide SC_1173 CIS-2-[8-Dimethylamino-1-[(1- INT 994 2-aminoethanol SC_1308 459.3 hydroxy-cyclobutyl)-methyl]-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (2-hydroxy-ethyl)-acetamide SC_1174 CIS-2-[8-Dimethylamino-1-[(1- INT 994 4-aminotetrahydro-2H- SC_1308 547.3 hydroxy-cyclobutyl)-methyl]-2- thiopyran 1,1-dioxide oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (1,1-dioxo-thian-4-yl)- acetamide SC_1175 CIS-2-[1-(Cyclopropyl-methyl)- INT 983 2-bromo-N- SC_1149 399.3 8-dimethylamino-2-oxo-8- methylacetamide phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- methyl-acetamide SC_1176 CIS-2-[1-[(1-Cyano- INT 951 2-bromo-N- SC_1149 438.3 cyclobutyl)-methyl]-8- methylacetamide dimethylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- N-methyl-acetamide SC_1177 CIS-2-[1-(Cyclobutyl-methyl)- INT 998 2-aminoethanol SC_1308 457.3 8-(ethyl-methyl-amino)-2-oxo- 8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (2-hydroxy-ethyl)-acetamide SC_1178 CIS-2-[[2-[1-(Cyclobutyl- INT 998 2-aminoacetamide SC_1308 470.3 methyl)-8-(ethyl-methyl- amino)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-acetamide SC_1179 CIS-2-[[2-[1-(Cyclobutyl- SC 1008 — SC_1303 484.3 methyl)-8-methylamino-2-oxo- 8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-N,2-dimethyl- propionamide SC_1180 CIS-2-[8-Dimethylamino-1-(3- INT 990 2-aminoethanol SC_1308 447.3 methoxy-propyl)-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (2-hydroxy-ethyl)-acetamide SC_1181 CIS-2-[8-Dimethylamino-1-(3- INT 990 N-methyl-2- SC_1308 488.3 methoxy-propyl)-2-oxo-8- (methylamino)acetamide phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- methyl-N-(methylcarbamoyl- methyl)-acetamide SC_1182 CIS-8-Dimethylamino-1-(3- INT 990 piperazin-2-one SC_1308 486.3 methoxy-propyl)-3-[2-oxo-2-(3- oxo-piperazin-1-yl)-ethyl]-8- phenyl-1,3- diazaspiro[4.5]decan-2-one SC_1183 CIS-N-(Carbamoyl-methyl)-2- INT 990 2-(methylamino)acetamide SC_1308 474.3 [8-dimethylamino-1-(3- methoxy-propyl)-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- methyl-acetamide SC_1184 CIS-2-[8-Dimethylamino-1-(3- INT 990 cis-3- SC_1073 487.3 methoxy-propyl)-2-oxo-8- (aminomethyl)cyclobutanol phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- |(3-hydroxy-cyclobutyl)- methyl]-acetamide SC_1185 CIS-2-[8-Dimethylamino-1-(3- INT 990 trans-3- SC_1073 487.3 methoxy-propyl)-2-oxo-8- (aminomethyl)cyclobutanol phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(3-hydroxy-cyclobutyl)- methyl]-acetamide SC_1186 CIS-2-[8-Dimethylamino-1-(3- INT 990 3- SC_1073 501.3 methoxy-propyl)-2-oxo-8- (aminomethyl)cyclopentanol phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(3-hydroxy-cyclopentyl)- methyl]-acetamide SC_1187 CIS-2-[8-Dimethylamino-1-(3- INT 990 pyridazin-4-amine SC_1308 481.3 methoxy-propyl)-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- pyridazin-4-yl-acetamide SC_1188 CIS-2-[8-Dimethylamino-1-(3- INT 990 6-methoxypyridin-2-amine SC_1308 510.3 methoxy-propyl)-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (6-methoxy-pyridin-2-yl)- acetamide SC_1189 CIS-N-(2-Cyanoethyl)-2-[8- INT 990 3-aminopropanenitrile SC_1308 456.3 dimethylamino-1-(3-methoxy- propyl)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetamide SC_1190 CIS-2-[8-Dimethylamino-1-(3- INT 990 pyrimidin-5-amine SC_1308 481.3 methoxy-propyl)-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- pyrimidin-5-yl-acetamide SC_1191 CIS-2-[8-Dimethylamino-1-(3- INT 990 pyrimidin-4-amine SC_1308 481.3 methoxy-propyl)-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- pyrimidin-4-yl-acetamide SC_1192 CIS-2-[1-(Cyclobutyl-methyl)- INT 999 6-methoxypyridin-2-amine SC_1073 520.3 8-(ethyl-methyl-amino)-2-oxo- 8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (6-methoxy-pyridin-2-yl)- acetamide SC_1193 CIS-2-[8-Dimediylamino-1-[(1- INT 995 pyridin-3-amine SC_1308 492.3 hydroxy-cyclobutyl)-methyl]-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- pyridin-3-yl-acetamide SC_1195 CIS-2-[1-(Cyclobutyl-methyl)- INT 999 NH.sub.4Cl SC_1073 399.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetamide SC_1196 CIS-2-[1-(Cyclobutyl-methyl)- INT 999 pyrimidin-4-amine SC_1073 477.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- pyrimidin-4-yl-acetamide SC_1197 CIS-2-[1-(Cyclobutyl-methyl)- INT 999 2-methoxyethanamine SC_1073 457.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (2-methoxy-ethyl)-acetamide SC_1198 CIS-2-[1-(Cyclobutyl-methyl)- INT 999 2-aminoethanol SC_1073 443.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (2-hydroxy-ethyl)-acetamide SC_1199 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2,5,8,11,14,17,20- SC_1308 721.5 8-dimethylamino-2-oxo-8- heptaoxadocosan-22-amine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [2-[2-[2-[2-[2-[2-(2-methoxy- ethoxy)-ethoxy]-ethoxy]- ethoxy]-ethoxy]-ethoxy]-ethyl]- acetamide SC_1201 CIS-2-[1-(Cyclobutyl-methyl)- SC 1229 — SC_1303 399.3 8-methylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- N-methyl-acetamide SC_1203 CIS-(2S)-1-[2-[1-(Cyclobutyl- INT 993 (S)-pyrrolidine-2- SC_1308 496.3 methyl)-8-dimethylamino-2- carboxamide oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]-pyrrolidine-2-carboxylie acid amide SC_1204 CIS-2-[[2-[1-(Cyclobutyl- INT 993 2-amino-N,N- SC_1308 484.3 methyl)-8-dimethylamino-2- dimethylacetamide oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-N.N-dimethyl- acetamide SC_1205 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 oxetan-3-amine SC_1308 455.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (oxetan-3-yl)-acetamide SC_1206 CIS-2-[[2-[1-(Cyclobutyl- INT 993 2-aminoacetamide SC_1308 456.3 methyl)-8-dimethylamino-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-acetamide SC_1207 CIS-1-(Cyclobutyl-methyl)-8- INT 999 piperazin-2-one SC-1073 482.3 dimethylamino-3-[2-oxo-2-(3- oxo-piperazin-1-yl)-ethyl]-8- phenyl-1,3- diazaspiro[4.5]decan-2-one SC_1208 CIS-2-[1-(Cyclobutyl-methyl)- INT 999 4-aminotetrahydro-2H- SC_1073 531.3 8-dimethylamino-2-oxo-8- thiopyran 1,1-dioxide phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (1,1-dioxo-thian-4-yl)- acetamide SC_1209 CIS-1-(Cyclobutyl-methyl)-8- INT 999 morpholin-2-ylmethanol SC_1073 499.3 dimethylamino-3-[2-[2- (hydroxymethyl)-morpholin-4- yl]-2-oxo-ethyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_1210 CIS-N-(Carbamoyl-methyl)-2- INT 993 2-(methylamino)acetamide SC_1308 470.3 [1-(cyclobutyl-methyl)-8- dimethylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- N-methyl-acetamide SC_1211 CIS-N-(Cyano-methyl)-2-[1- INT 993 2-aminoacetonitrile SC_1308 438.3 (cyclobutyl-methyl)-8- dimethylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- acetamide SC_1212 CIS-N-(2-Acetylamino-ethyl)-2- INT 993 N-(2-aminoethyl)acetamide SC_1308 484.3 [1-(cyclobutyl-methyl)-8- dimethylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- acetamide SC_1213 CIS-2-[1-(Cyclobutyl-methyl)- INT 999 2-(methylsulfonyl)ethan- SC_1073 505.3 8-dimethylamino-2-oxo-8- amine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (2-methylsulfonyl-ethyl)- acetamide SC_1214 CIS-1-(Cyclobutyl-methyl)-8- INT 999 thiomorpholine 1,1-dioxide SC_1073 517.3 dimethylamino-3-[2-(1,1-dioxo- [1,4]thiazinan-4-yl)-2-oxo- ethyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_1215 CIS-2-[1-(Cyclobutyl-methyl)- INT 999 4-(aminomethyl)tetra- SC_1073 545.3 8-dimethylamino-2-oxo-8- hydro-2H-thiopyran 1,1- phenyl-1,3- dioxide diazaspiro[4.5]decan-3-yl]-N- [(1,1-dioxo-thian-4-yl)-methyl]- acetamide SC_1216 CIS-1-(Cyclobutyl-methyl)-8- INT 999 1-(methylsulfonyl)- SC_1073 546.3 dimethylamino-3-[2-(4- piperazine methylsulfonyl-piperazin-1-yl)- 2-oxo-ethyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_1217 CIS-N-(2-Cyanoethyl)-2-[1- INT 993 3-aminopropanenitrile SC_1308 452.3 (cyclobutyl-methyl)-8- dimethylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- acetamide SC_1218 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 1-amino-2-methylpropan-2- SC_1308 471.3 8-dimethylamino-2-oxo-8- ol phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (2-hydroxy-2-methyl-propyl)- acetamide SC_1219 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2-amino-1- SC_1308 526.3 8-dimethylamino-2-oxo-8- morpholinoethanone phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (2-morpholin-4-yl-2-oxo-ethyl)- acetamide SC_1220 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2-(2-aminoethoxy)ethanol SC_1308 487.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [2-(2-hydroxy-ethoxy)-ethyl]- acetamide SC_1222 CIS-2-[[2-[1-(Cyclobutyl- INT 993 2-amino-N- SC_1308 470.3 methyl)-8-dimethylamino-2- methylacetamide oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-N-methyl- acetamide SC_1223 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 N-(2-aminoethyl)- SC_1308 520.3 8-dimethylamino-2-oxo-8- methanesulfonamide phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [2-(methanesulfonamido)- ethyl]-acetamide SC_1224 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 1-(aminomethyl)- SC_1308 497.3 8-dimethylamino-2-oxo-8- cyclopentanol phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(1-hydroxy-cyclopentyl)- methyl]-acetamide SC_1225 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 4- SC_1308 511.4 8-dimethylamino-2-oxo-8- (aminomethyl)cyclohexanol phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(4-hydroxy-cyclohexyl)- methyl]-acetamide SC_1226 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2-(2-methoxyethoxy)- SC_1308 501.3 8-dimethylamino-2-oxo-8- ethanamine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [2-(2-methoxy-ethoxy)-ethyl]- acetamide SC_1227 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 N.sup.1,N.sup.1-dimethylethane-1,2- SC_1308 470.3 8-dimethylamino-2-oxo-8- diamine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [2-(dimethylamino)ethyl]- acetamide SC_1228 CIS-2-[1-(Cyclobutyl-methyl)- INT 953 2-bromo-N- SC_1149 455.3 8-[methyl-(2-methyl-propyl)- methylacetamide amino]-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- methyl-acetamide SC_1229 CIS-2-[1-(Cyclobutyl-methyl)- INT 999 methylamine SC_1073 413.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- methyl-acetamide SC_1230 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 pyrimidin-4-amine SC_1051 477.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- pyrimidin-4-yl-acetamide SC_1231 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 6-methylpyridin-2-amine SC_1051 490.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (6-methyl-pyridin-2-yl)- acetamide SC_1232 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 pyridazin-3-amine SC_1051 477.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- pyridazin-3-yl-acetamide SC_1233 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 pyrimidin-5-amine SC_1051 477.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- pyrimidin-5-yl-acetamide SC_1234 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 pyridazin-4-amine SC_1051 477.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- pyridazin-4-yl-acetamide SC_1235 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 6-methoxypyrimidin-4- SC_1051 507.3 8-dimethylamino-2-oxo-8- amine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (6-methoxy-pyrimidin-4-yl)- acetamide SC_1236 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2-methylpyridin-4-amine SC_1051 490.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (2-methyl-pyridin-4-yl)- acetamide SC_1300 CIS-2-[8-Dimethylamino-1-[(1- INT 994 pyridin-4-amine SC_1308 492.3 hydroxy-cyclobutyl)-methyl]-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- pyridin-4-yl-acetamide SC_1301 CIS-2-[8-Dimethylamino-1-[(1- INT 994 oxetan-3-amine SC_1308 471.3 hydroxy-cyclobutyl)-methyl]-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (oxetan-3-yl)-acetamide SC_1302 CIS-2-[8-Dimethylamino-1-[(1- INT 994 2-methoxyethanamine SC_1308 473.3 hydroxy-cyclobutyl)-methyl]-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (2-methoxy-ethyl)-acetamide SC_1304 CIS-2-[1-[(1-Hydroxy- SC 1301 — SC_1303 459.3 cyclobutyl)-methyl]-8- methylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- N-(2-methoxy-ethyl)-acetamide SC_1305 CIS-2-[8-Dimethylamino-1-(3- SC 1302 — SC_1308 510.3 methoxy-propyl)-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (4-methoxy-pyridin-2-yl)- acetamide SC_1306 CIS-2-[8-Dimethylamino-1-(3- INT 990 pyrimidin-4-ylmethanamine SC_1073 495.3 methoxy-propyl)-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (pyrimidin-4-yl-methyl)- acetamide SC_1309 CIS-2-[8-Dimethylamino-1-[(1- SC 1159 — SC_1128 492.3 hydroxy-cyclobutyl)-methyl]-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- pyridin-2-yl-acetamide SC_1310 CIS-2-[1-[(1-Cyano- INT 989 NH.sub.4Cl SC_1308 424.3 cyclobutyl)-methyl]-8- dimethylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- acetamide SC_1311 CIS-2-[[2-[1-[(1-Cyano- INT 989 2-aminoacetamide SC_1308 481.3 cyclobutyl)-methyl]-8- dimethylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- acetyl]amino]-acetamide SC_1312 CIS-2-[1-[(1-Hydroxy- SC 1160 — SC_1303 415.3 cyclobutyl)-methyl]-8- methylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- N-methyl-acetamide SC_1313 CIS-3-[2-(1,1-Dioxo- SC 1308 — SC_1303 477.2 [1,4]thiazinan-4-yl)-2-oxo- ethyl]-8-methylamino-8-phenyl- 1-propyl-1,3- diazaspiro[4.5]decan-2-one SC_1317 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 pyridin-2-amine SC_1051 476.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- pyridin-2-yl-acetamide SC_1318 CIS-8-Dimethylamino-1-[(1- INT 994 morpholine SC_1136 485.3 hydroxy-cyclobutyl)-methyl]-3- (2-morpholin-4-yl-2-oxo-ethyl)- 8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_1319 CIS-2-[1-[(1-Hydroxy- SC 1159 — SC_1303 401.2 cyclobutyl)-methyl]-8- methylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- acetamide SC_1320 CIS-1-(Cyclobutyl-methyl)-8- INT 993 morpholine SC_1308 469.3 dimethylamino-3-(2-morpholin- 4-yl-2-oxo-ethyl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_1321 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 4-(methylthio)pyridin-2- SC_1073 522.3 8-dimethylamino-2-oxo-8- amine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (4-methylsulfanyl-pyridin-2-yl)- acetamide

TABLE-US-00004 in analogy .sup.1H NMR m/z Example Chemical name Reactant I Reactant II to method data (M + H).sup.+ SC_1322 CIS-3-[2-(1,1- INT-1014 thiomorpholin- SC_1308 .sup.1HNMR (DMSO-d6, 400 435.3 Dioxo- 1,1-dioxide (for step 1), MHz), δ (ppm) = 7.40 (d, [1,4]thiazinan-4- SC_1303 2H, J = 7.2 Hz), yl)-2-oxo-ethyl]- (for step 2) 7.31 (t, 2H, J = 7.44 Hz), 8-methylamino-8- 7.18 (t, 1H, J = 6.78 Hz), phenyl-1,3- 6.61 (bs, 1H), 3.98 (s, diazaspiro[4.5]decan- 2H), 3.82 (bs, 4H), 2-one 3.21 (bs, 4H), 3.09 (s, 2H), 1.95 (t, 2H, J = 11.74 Hz), 1.85 (bs, 5H), 1.65 (bs, 2H), 1.48 (bs, 2H). SC_1323 CIS-2-(8- SC_1324 SC_1303 .sup.1HNMR (DMSO-d6, 317.2 Methylamino-2- 400 MHz), δ (ppm) = oxo-8-phenyl-1,3- 7.41 (d, diazaspiro[4.5]decan- 2H, J = 7.60 Hz), 7.30 (t, 3-yl)-acetamide 2H, J = 7.60 Hz), 7.23 (s, 1H), 7.18 (t, 1H, J = 7.08 Hz), 6.95 (s, 1H), 6.58 (s, 1H), 3.58 (s, 2H), 3.21 (s, 2H), 1.96 − 1.80 (m, 7H), 1.69 − 1.66 (m, 2H), 1.47 (d, 2H, J = 11.76 Hz). SC_1324 CIS-2-(8- INT-1014 procedure — 331.2 Dimethylamino-2- described oxo-8-phenyl-1,3- diazaspiro[4.5]decan- 3-yl)-acetamide SC_1325 CIS-3-[2-(1,1- INT-1015 thiomorpholin- SC_1308 .sup.1HNMR (DMSO-d6, 400 449.4 Dioxo- 1,1-dioxide (for step 1), MHz), δ (ppm) = 7.42 (d, [1,4]thiazinan-4 SC_1303 2H, J = 7.2 Hz), 7.29 (t, 2H, yl)-2-oxo-ethyl]- (for step 2) J = 7.2 Hz), 7.17 (t, 1H), 8-ethylamino-8- 6.61 (s, 1H), 5.75 (s, 1H), phenyl-1,3- 3.98 (s, 2H), 3.82 (s, 4H), diazaspiro[4.5]decan- 3.21 (s, 4H), 3.09 (s, 2H), 2-one 2.07 − 1.93 (m, 4H), 1.87 − 1.83 (m, 2H), 1.69 − 1.66 (m, 2H), 1.48 − 1.45 (m, 2H), 0.92 (t, 3H, J = 6.8 Hz). SC_1326 TRANS-3-[2- INT-1017 thiomorpholin- SC_1308 .sup.1HNMR (DMSO-d6, 400 449.2 (1,1-Dioxo- 1,1-dioxide (for step 1), MHz), δ (ppm) = 7.50 (d, [1,4]thiazinan-4- SC_1303 2H, J = 7.4 Hz), 7.30 (t 2H, yl)-2-oxo-ethyl]- (for step 2) J = 7.2 Hz), 7.18 − 7.15 (m, 8-ethylamino-8- 2H), 4.00 (s, 2H), 3.84 (bs, phenyl-1,3- 4H), 3.24 (s, 2H), 3.19 (s, diazaspiro[4.5]decan- 2H), 3.11 (s, 2H), 2.07 − 2-one 1.44 (m, 11H), 0.91 (t, 3H, J = 6.6 Hz). SC_1327 CIS-2-[1- INT-998 methylamine SC_1308 .sup.1H NMR (DMSO-d6, δ 399.3 (Cyclobutyl- (step 1) (for step 1), 7.71 − 7.70 (m, 1H), 7.43 methyl)-8- SC_1303 (d, 2H), 7.30 (t, 2H), 7.18 (t, methylamino-2- (for step 2) 1H), 3.64 (s, 2H), 3.21 (s, oxo-8-phenyl-1,3- 2H), 3.08 (d, 2H), 2.57 − diazaspiro[4.5]decan- 2.54 (m, 4H), 2.25 (m, 1H), 3-yl]-N- 2.11-2.06 (m, 2H), 1.97 − methyl-acetamide 1.82 (m, 7H), 1.80 − 1.67 (m, 4H), 1.59 (m, 2H), 1.36 − 1.35 (m, 2H). SC_1328 CIS-2-(8- INT-1015 SC_1324 .sup.1HNMR (DMSO-d6, 400 331.1 Ethylamino-2- MHz) δ (ppm) = 7.43 (d, oxo-8-phenyl-1,3- 2H, J = 7.6 Hz), 7.29 (t, 2H, diazaspiro[4.5]decan- J = 7.2 Hz), 7.22 (s, 1H), 3-yl)-acetamide 7.17 (t, 1H, J = 6.8 Hz), 6.95 (s, 1H), 6.58 (s, 1H), 3.58 (s, 2H), 3.20 (s, 2H), 2.07 − 2.05 (m, 2H), 1.93 (t, 2H, J = 11.2), 1.85 − 1.82 (m, 2H), 1.69 − 1.67 (m, 2H,), 1.48 − 1.45 (m, 2H), 0.92 (t, 3H, J = 6.8 Hz). SC_1329 TRANS-2-(8- INT-1017 SC_1324 .sup.1HNMR (DMSO-d6, 400 331.2 Ethylamino-2- MHz) δ (ppm) = 7.49 (d, oxo-8-phenyl-1,3- 2H, J = 7.56 Hz), 7.29 (t, diazaspiro[4.5]decan- 2H, J = 7.66 Hz), 7.24 (s, 3-yl)-acetamide 1H), 7.16 (t, 1H), 7.24 Hz), 7.11 (bs, 1H), 6.98 (bs, 1H), 3.59 (s, 2H), 3.17 (s, 2H), 2.09 − 1.95 (m, 4H). SC_1330 CIS-2-(8- INT-1014 2- SC_1308 .sup.1HNMR (DMSO-d6, 400 389.2 Dimethylamino-2- (methylamino)- MHz at 100 0C.), δ (ppm) = oxo-8-phenyl-1,3- ethanol 7.34 − 7.23 (m, 5H), 6.41 diazaspiro[4.5]decan- (s, 1H), 4.4 (bs, 1H), 3.89 3-yl)-N-(2- (s, 2H), 3.53 − 3.52 (m, 2H), hydroxy-ethyl)-N- 3.34 (t, 2H, J = 5.56 Hz), methyl-acetamide 3.13 (s, 2H), 2.89 (s, 2H), 2.31 − 2.27 (m, 2H), 2.01 (s, 6H), 1.89 − 1.78 (m, 4H), 1.46 − 1.41 (m, 2H). SC_1331 CIS-8- INT-1020 1,4-thiazinane SC_1308 .sup.1H NMR (600 MHz, 547.3 Dimethylamino-3- 1,1-dioxide DMSO) δ 7.35 (qd, 4H), [2-(1,1-dioxo- 7.26 (tt, 1H), 4.40 (s, 2H), [1,4]thiazinan-4- 3.89 (dt, 4H), 3.26 (t, 2H), yl)-2-oxo-ethyl]- 3.11 (d, 2H), 2.64 − 2.58 1-[(1-hydroxy- (m, 2H), 2.45 (td, 2H), 2.14 cyclobutyl)- (tt, 2H), 2.03 (td, 2H), 1.98 methyl]-8-phenyl- (s, 6H), 1.97 − 1.88 (m, 1,3- 2H), 1.70 − 1.63 (m, 1H), diazaspiro[4.5]decane- 1.58 − 1.47 (m, 3H). 2,4-dione SC_1332 CIS-2-(8- INT-976 procedure .sup.1H NMR (CDCl3): δ 8.32 407.2 Dimethylamino-2- described (br s, 1H), 7.50 − 7.48 (d, oxo-8-phenyl-1,3- 2H), 7.39 − 7.36 (m, 2H), diazaspiro[4.5]decan- 7.33 − 7.26 (m, 5H), 7.12 − 3-yl)-N-phenyl- 7.08 (t, 1H), 5.90 (br s, 1H), acetamide 3.90 (s, 2H), 3.25 (s, 2H), 2.12 (m, 4H), 1.99 (s, 6H), 1.94 − 1.91 (m, 2H), 1.58 − 1.53 (m, 2H). SC_1333 CIS-N- INT-991 2- SC_1308 .sup.1HNMR (DMSO-d6, 400 388.3 (Carbamoyl- methylamino- MHz at 100 0C.), δ (ppm) = methyl)-2-[1- acetamide•HCl 7.34 − 7.23 (m, 5H), 6.85 (bs, (cyclopropyl- 2H), 3.94 (s, 2H), 3.88 (s, methyl)-8- 2H), 3.26 (s, 2H), 3.00 − 2.99 dimethylamino-2- (m, 2H), 2.95 (s, 3H), 2.61 oxo-8-phenyl-1,3- (d, 2H, J = 13.2 Hz), 2.22 (t, diazaspiro[4.5]decan- 2H, J = 12 Hz), 2.06 (s, 6H), 3-yl]-N-methyl- 1.47 − 1.38 (m, 4H), 0.98 (m, acetamide 1H), 0.48 (d, 2H, J = 7.6 Hz), 0.28 (d, 2H, 4.8 Hz). SC_1334 CIS-2-(8- INT-1018 2-Bromo-N- SC_1332 .sup.1H NMR (DMSO-d6): δ 421.2 Dimethylamino- phenylacetamide 10.19 (s, 1H), 8.80 (br s, 2,4-dioxo-8- 1H), 7.52 − 7.520 (d, 2H), phenyl-1,3- 7.42 − 7.34 (m, 4H), 7.31 − diazaspiro[4.5]decan- 7.27 (m, 3H), 7.06 − 7.02 3-yl)-N-phenyl- (t, 1H), 4.11 (s, 2H), 2.49 − acetamide 2.45 (m, 2H), 2.03 − 1.93 (m, 8H), 1.71 − 1.68 (m, 2H), 1.60 − 1.54 (m, 2H). SC_1335 CIS-2-[1- INT-998 NH.sub.4Cl SC_1308 .sup.1H NMR (DMSO-d6): δ 399.3 (Cyclobutyl- 7.36 − 7.22 (m, 6H), 6.93 (br methyl)-8- s, 1H), 3.61 (s, 2H), 3.18 (s, dimethylamino-2- 2H), 3.04 (d, 2H), 2.66 − 2.63 oxo-8-phenyl-1,3- (m, 2H), 2.54 − 2.52 (m, 1H), diazaspiro[4.5]decan- 2.07 − 1.93 (m, 10H), 1.81 − 3-yl]-acetamide 1.67 (m, 4H), 1.39 − 1.29 (m, 4H). SC_1336 CIS-2-[8- INT-1019 2,5,8,11- SC_1308 .sup.1H NMR (DMSO-d6): δ 605.3 Dimethylamino-1- tetraoxatridecan- 7.37 − 7.33 (m, 2H), 7.28 − [(1-hydroxy- 13-amine 7.26 (m, 3H), 6.67 (t, 1H), cyclobutyl)- 6.31 (br, s, 1H), 3.83 (s, methyl]-2-oxo-8- 2H), 3.65 − 3.59 (m, 10H), phenyl-1,3- 3.55 − 3.52 (m, 4H), 3.46 − diazaspiro[4.5]decan- 3.42 (m, 2H), 3.37 (s, 5H), 3-yl]-N-[2-[2- 3.29 (s, 2H), 2.68 − 2.65 (m, [2-(2-methoxy- 2H), 2.20 − 2.06 (m, 12H), ethoxy)-ethoxy]- 1.78 − 1.71 (m, 1H), 1.59 − ethoxy]-ethyl]- 1.56 (m, 2H), 1.48 − 1.37 acetamide (m, 3H). SC_1337 CIS-3-[2-(1,1- SC_1331 SC_1303 .sup.1H NMR (600 MHz, 533.3 Dioxo- DMSO) δ 7.46 (d, 2H), 7.33 [1,4]thiazinan-4- (t, 2H), 7.21 (t, 1H), 4.42 (s, yl)-2-oxo-ethyl]- 2H), 3.90 (dt, 4H), 3.49 (s, 1-[(1-hydroxy- 2H), 3.28 (t, 2H), 3.12 (t, cyclobutyl)- 2H), 2.47 (dd, 2H), 2.35 − methyl]-8- 2.25 (m, 2H), 2.15 − 2.08 methylamino-8- (m, 2H), 1.98 − 1.89 (m, phenyl-1,3- 6H), 1.84 (d, 2H), 1.71 − diazaspiro[4.5]decane- 1.63 (m, 1H), 1.58 − 1.48 2,4-dione (m, 3H). SC_1338 CIS-2-(8- INT-976 2-bromo-N- SC_1332 .sup.1H NMR (DMSO-d6): δ 521.3 Dimethylamino-2- (2,5,8,11- 7.78 (t, 1H), 7.37 − 7.23 (m, oxo-8-phenyl-1,3- tetraoxatridecan- 5H), 6.89 (br s, 1H), 3.60 diazaspiro[4.5]decan- 13-yl)acetamide (s, 2H), 3.49 − 3.47 (m, 10H), 3-yl)-N-[2-[2- 3.43 − 3.37 (m, 4H), 3.22 − [2-(2-methoxy- 3.17 (m, 5H), 3.08 (s, 2H), ethoxy)-ethoxy]- 2.30 (br m, 2H), 1.92 − 1.74 ethoxy]-ethyl]- (m, 10H), 1.38 (br m, 2H). acetamide SC_1339 CIS-N- INT-1034 2- SC_1308 .sup.1HNMR (DMSO-d6, 400 388.3 (Carbamoyl- methylamino- MHz at 100 0C.), δ (ppm) = methyl)-N- acetamide•HCl 7.43 (d, 2H, J = 7.52 Hz), methyl-2-(8- 7.31 (t, 2H, J = 7.44 Hz), methylamino-2- 7.18 (t, 1H, J = 7.20 Hz), oxo-8-phenyl-1,3- 6.8 (bs, 2H), 3.88 (s, 4H), diazaspiro[4.5]decan- 3.25 (s, 2H), 2.95 (3H, 3-yl)-acetamide merged with DMSO water), 1.97 − 1.85 (m, 7H), 1.77 − 1.50 (m, 4H). SC_1340 CIS-N- INT-1014 2-methylamino- SC_1308 .sup.1HNMR (DMSO-d6, 400 402.1 (Carbamoyl- acetamide•HCl MHz at 100 0C.), δ (ppm) = methyl)-2-(8- 7.33 − 7.23 (m, 5H), 6.84 (bs, dimethylamino-2- 2H), 6.45 (s, 1H), 3.87 (s, oxo-8-phenyl-1,3- 4H), 3.13 (s, 2H), 2.95 (3H, diazaspiro[4.5]decan- merged with DMSO water), 3-yl)-N- 2.32 − 2.27 (m, 2H), 2.01 (s, methyl-acetamide 6H),1.88 − 1.77 (m, 4H), 1.46 − 1.41 (m, 2H). SC_1341 CIS-N- INT-1035 2- SC_1308 .sup.1HNMR (DMSO-d6, 400 472.3 (Carbamoyl- methylamino- MHz at 100 0C.), δ (ppm) = methyl)-2-[8- acetamide•HCl 7.33 − 7.24 (m, 5H), 6.8 (bs, dimethylamino-1- 2H), 4.63 (t, 2H, J = 5.6 (oxetan-3-yl- Hz), 4.39 (s, 2H), 3.93 − 3.87 methyl)-2-oxo-8- (m, 4H), 3.36 (d, 2H, J = 6.8 phenyl-1,3- Hz), 3.24 (m, 3H), 2.95 (s, diazaspiro[4.5]decan- 3H), 2.66 − 2.60 (m, 2H), 3-yl]-N- 2.06 − 2.03 (m, 8H), 1.44 − methyl-acetamide 1.37 (m, 4H). SC_1342 CIS-N-(2- INT-1034 2- SC_1308 .sup.1HNMR (DMSO-d6, 400 375.0 Hydroxy-ethyl)- (methylamino)- MHz at 100 0C.), δ (ppm) = N-methyl-2-(8- ethanol 7.41 (d, 2H, J = 7.48 Hz), methylamino-2- 7.31 (t, 2H, J = 7.60 Hz), oxo-8-phenyl-1,3- 7.18 (t, 1H), J = 7.18 Hz), diazaspiro[4.5]decan- 6.24 (s, 1H), 4.58 − 4.36 (m, 3-yl)-acetamide 1H), 3.92 (bs, 2H), 3.52 (bs, 2H), 3.34 (t, 2H, J = 5.72 Hz), 3.24 (s, 2H), 2.96 − 2.84 (m, 3H), 1.97 − 1.84 (m, 7H), 1.74 − 1.49 (m, 4H). SC_1343 CIS-2-[1- INT-991 ammonium SC_1308 .sup.1H NMR (DMSO d6): δ 385.3 (Cyclopropyl- chloride 7.34 − 7.25 (m, 6H), 6.96 (s, methyl)-8- 1H), 3.63 (s, 2H), 3.22 (m, dimethylamino-2- 2H), 2.93 (d, 2H), 2.67 − 2.64 oxo-8-phenyl-1,3- (m, 2H), 2.16 (t, 2H), 1.97 diazaspiro[4.5]decan- (s, 6H), 1.43 − 1.31 (m, 4H), 3-yl]-acetamide 0.93 (m, 1H), 0.46 − 0.45 (m, 2H), 0.26 (m, 2H). SC_1344 CIS-2-[1- INT-991 2- SC_1308 .sup.1H NMR (DMSO d6): δ 429.3 (Cyclopropyl- aminoethanol 7.77 − 7.75 (m, 1H), 7.36 − methyl)-8- 7.33 (m, 4H), 7.26 − 7.23 (m, dimethylamino-2- 1H), 4.65 − 4.63 (m, 1H), oxo-8-phenyl-1,3- 3.67 (s, 2H), 3.39 − 3.35 (m, diazaspiro[4.5]decan- 2H), 3.21 (s, 2H), 3.12 − 3.09 3-yl]-N-(2-hydroxy- (m, 2H), 2.94 − 2.93 (m, 2H), ethyl)-acetamide 2.67 − 2.64 (m, 2H), 2.19 − 2.14 (t, 2H), 1.97 (s, 6H), 1.42 − 1.31 (m, 4H), 0.93 − 0.92 (s, 1H), 0.48 − 0.44 (m, 2H), 0.27 − 0.25 (m, 2H). SC_1345 CIS-2-[1- INT-1032 2- SC_1308 .sup.1H NMR (600 MHz, 475.3 (Cyclobutyl- (methylamino)- DMSO) δ 7.39 (td, 1H), methyl)-8- ethanol 7.16 (dd, 1H), 7.13 (dt, 2H), dimethylamino-8- 7.08 (td, 1H), 3.99 (s, 1H), (3-fluorophenyl)- 3.91 (s, 1H), 3.52 (q, 1H), 2-oxo-1,3- 3.45 (d, 1H), 3.40 − 3.36 diazaspiro[4.5]decan- (m, 0H), 3.34 − 3.28 (m, 3-yl]-N-(2- 2H), 3.19 (d, 2H), 3.05 (dd, hydroxy-ethyl)-N- 2H), 2.96 (s, 2H), 2.80 (s, methyl-acetamide 2H), 2.66 − 2.60 (m, 3H), 2.07 − 1.93 (m, 3H), 1.99 (s, 7H), 1.85 − 1.74 (m, 2H), 1.75 − 1.65 (m, 3H), 1.40 − 1.28 (m, 5H). SC_1346 CIS-2-[1- INT-1031 tert-butyl- procedure .sup.1H NMR (600 MHz, 474.3 (Cyclobutyl- bromo acetate described DMSO) δ 7.43 − 7.36 (m, methyl)-8- 1H), 7.17 (d, 1H), 7.13 (dt, dimethylamino-8- 1H), 7.09 (td, 1H), 3.75 (d, (3-fluorophenyl)- 2H), 3.21 (s, 2H), 3.05 (d, 2-oxo-1,3- 2H), 2.67 − 2.61 (m, 2H), diazaspiro[4.5]decan- 2.08 − 2.00 (m, 2H), 1.99 3-yl]-acetic (d, 7H), 1.98 − 1.93 (m, acid tert-butyl 2H), 1.83 − 1.75 (m, 2H), ester 1.75 − 1.65 (m, 2H), 1.39 (d, 8H), 1.38 − 1.29 (m, 5H). SC_1347 CIS-2-[1- INT-991 2- SC_1308 .sup.1H NMR (DMSO): δ 7.36 − 444.3 (Cyclopropyl- (methylamino)- 7.32 (m, 4H), 7.26 − 7.23 (m, methyl)-8- ethanol 1H), 4.83 − 4.63 (m, 1H), dimethylamino-2- 3.99 − 3.91 (m, 2H), 3.50 − oxo-8-phenyl-1,3- 3.44 (m, 2H), 3.32 − 3.28 (m, diazaspiro[4.5]decan- 2H), 3.22 − 3.20 (m, 2H), 3-yl]-N-(2- 2.95 − 2.92 (m, 3H), 2.79 (s, hydroxy-ethyl)-N- 2H), 2.67 − 2.65 (m, 2H), methyl-acetamide 2.20 − 2.15 (m, 2H), 1.97(s, 6H), 1.42 − 1.30 (m, 4H), 0.93 − 0.90 (s, 1H), 0.47 − 0.43 (m, 2H), 0.27 − 0.25 (m, 2H). SC_1348 CIS-2-[1- INT-991 2- SC_1308 .sup.1H NMR (DMSO): δ 8.05 − 491.3 (Cyclopropyl- (methyl 8.02 (m, 1H), 7.37 − 7.32 (m, methyl)-8- sulfonyl)ethan- 4H), 7.26 − 7.22 (m, 1H), dimethylamino-2- amine 3.67 (s, 2H), 3.49 − 3.44 (m, oxo-8-phenyl-1,3- 2H), 3.25 − 3.21 (m, 4H), diazaspiro[4.5]decan- 2.98 − 2.93 (m, 5H), 2.67 − 3-yl]-N-(2- 2.64 (m, 2H), 2.19 − 2.13 (m, methylsulfonyl- 2H), 1.97 (s, 6H), 1.45 − 1.31 ethyl)-acetamide (m, 4H), 0.95 − 0.91 (s, 1H), 0.48 − 0.44 (m, 2H), 0.28 − 0.24 (m, 2H). SC_1349 CIS-N- INT-1032 2- SC_1308 1H NMR (600 MHz, 488.3 (Carbamoyl- methylamino- DMSO) δ 7.39 (td, 1H), methyl)-2-[1- acetamide 7.31 (s, 1H), 7.19 − 7.05 (cyclobutyl- hydrochloride (m, 3H), 6.99 (s, 1H), methyl)-8- 4.00 − 3.78 (m, 4H), 3.18 dimethylamino-8- (d, 2H), 3.07 − 3.02 (m, 2H), (3-fluorophenyl)- 2.94 (s, 2H), 2.76 (s, 1H), 2-oxo-1,3- 2.66 − 2.59 (m, 2H), 2.06 − diazaspiro[4.5]decan- 1.93 (m, 9H), 1.84 − 1.73 3-yl]-N- (m, 2H), 1.70 (dt, 2H), methyl-acetamide 1.43 − 1.28 (m, 4H) (mixture of amide rotamers) SC_1350 CIS-1-[2-[8- INT-1019 piperidine-4- SC_1308 1H NMR (DMSO d6): δ 526.4 Dimethylamino-1- carboxamide 7.37 − 7.25 (m, 6H), 6.77 (s, [(1-hydroxy- 1H), 6.02 (s, 1H), 4.26 − 4.23 cyclobutyl)- (m, 1H), 4.02 − 3.91 (m, 2H), methyl]-2-oxo-8- 3.79 − 3.75 (m, 1H), 3.31 (m, phenyl-1,3- 2H), 3.10 (s, 2H), 3.00 − 2.93 diazaspiro[4.5]decan- (t, 1H), 2.68 − 2.65 (m, 2H), 3-yl]-acetyl]- 2.60 − 2.58 (m, 2H), 2.32 − piperidine-4- 2.27 (m, 2H), 2.06 − 2.03 (m, carboxylic acid 4H), 1.91 − 1.83 (m, 8H), amide 1.67 − 1.61 (m, 2H), 1.49 − 1.40 (m, 2H), 1.36 − 1.30 (m, 4H). SC_1351 CIS-8- INT-1019 4- SC_1308 1H NMR (DMSO d6): δ 561.3 Dimethylamino-1- (methyl- 7.37 − 7.23 (m, 5H), 6.00 (s, [(1-hydroxy- sulfonyl)piper- 1H), 4.45 − 4.41 (m, 1H), cyclobutyl)- idine 4.08 − 3.91 (m, 3H), 3.17 (s, methyl]-3-[2-(4- 3H), 3.10 − 2.99 (m, 2H), methylsulfonyl- 2.92 (s, 3H), 2.73 − 2.65 (m, piperidin-1-yl)-2- 3H), 2.06 − 1.83 (m, 15H), oxo-ethyl]-8- 1.64 − 1.46 (m, 4H), 1.40 − phenyl-1,3- 1.30 (m, 4H). diazaspiro[4.5]decan- 2-one SC_1352 CIS-2-[1- INT-1032 2- SC_1308 1H NMR (600 MHz, 461.3 (Cyclobutyl- aminoethanol DMSO) δ 7.73 (t, 1H), 7.39 methyl)-8- (td, 1H), 7.19 − 7.05 (m, dimethylamino-8- 3H), 4.66 (t, 1H), 3.67 (s, (3-fluorophenyl)- 2H), 3.43 − 3.35 (m, 2H), 2-oxo-1,3- 3.18 (s, 2H), 3.11 (q, 2H), diazaspiro[4.5]decan- 3.05 (d, 2H), 2.65 − 2.58 3-yl]-N-(2- (m, 2H), 2.55 − 2.45 (m, hydroxy-ethyl)- 1H), 2.07 − 1.93 (m, 10H), acetamide 1.84 − 1.73 (m, 2H), 1.74 − 1.64 (m, 2H), 1.41 − 1.29 (m, 4H). SC_1353 TRANS-2-[1- INT-1067 2- SC_1357 1HNMR at 100oC. (DMSO- 443.1 (Cyclobutyl- aminoethanol d6, 400 MHz), δ (ppm) = methyl)-8- 7.44 − 7.38 (m, 5H), 7.29 (t, dimethylamino-2- 1H, J = 6.48 Hz), 4.29 (bs, oxo-8-phenyl-1,3- 1H), 3.69 (s, 2H), 3.48 − 3.44 diazaspiro[4.5]decan- (m, 2H), 3.28 (s, 2H), 3.21 − 3-yl]-N-(2- 3.17 (m, 2H), 2.69 − 2.67 (m, hydroxy-ethyl)- 2H), 2.58 − 2.55 (d, 2H, J = acetamide 11.6 Hz), 2.19 − 2.12 (m, 1H), 1.98 (s, 6H), 1.82 − 1.74 (m, 2H), 1.71 − 1.60 (m, 4H), 1.58 − 1.46 (m, 6H). SC_1354 TRANS-N- INT-1067 2- SC_1357 1HNMR at 100oC. (DMSO- 470.4 (Carbamoyl- methylamino- d6, 400 MHz), δ (ppm) = methyl)-2-[1- acetamide 7.40 − 7.28 (m, 5H), 6.87 (bs, (cyclobutyl- hydrochloride 2H), 3.94 − 3.90 (m, 4H), methyl)-8- 3.29 (s, 2H), 3.68 − 3.66 (m, dimethylamino-2- 2H), 2.58 − 2.55 (m, 2H), oxo-8-phenyl-1,3- 2.15 − 2.13 (m, 1H), 1.98 (s, diazaspiro[4.5]decan- 6H), 1.77 (bs, 2H), 1.64 − 3-yl]-N-methyl- 1.61 (m, 4H), 1.46 − 1.27 (m, acetamide 6H). SC_1355 CIS-8- INT-1019 4- SC_1308 1H NMR (DMSO d6): δ 513.4 Dimethylamino-1- methylpiperidin- 7.36 − 7.32 (m, 4H), 7.26 − [(1-hydroxy- 4-ol 7.23 (m, 1H), 6.02 (s, 1H), cyclobutyl)- 4.37 (s, 1H), 3.96 − 3.95 (m, methyl]-3-[2-(4- 2H), 3.90 − 3.80 (m, 1H), hydroxy-4- 3.50 − 3.40 (m, 1H), 3.30 (m, methyl-piperidin- 1H), 3.10 (s, 2H), 3.00 − 2.93 1-yl)-2-oxo- (m, 1H), 2.68 − 2.65 (m, 2H), ethyl]-8-phenyl- 2.09 − 2.04 (m, 4H), 1.97 (s, 1,3- 6H), 1.90 − 1.86 (m, 2H), diazaspiro[4.5]decan- 1.64 − 1.61 (m, 1H), 1.48 − 2-one 1.40 (m, 5H), 1.37 − 1.30 (m, 4H), 1.22 (m, 2H), 1.11 (s, 3H). SC_1356 CIS-2-[1- INT-1058 2- SC_1308 1H NMR (600 MHz, 461.3 (Cyclobutyl- aminoethanol DMSO) δ 7.72 (t, 1H), methyl)-8- 7.40 − 7.33 (m, 2H), 7.15 dimethylamino-8- (t 2H), 4.81 (tdd, 0.15H), 4.65 (4-fluorophenyl)- (ddq, 0.75H), 3.66 (s, 2H), 2-oxo-1,3- 3.48 (q), 3.25 (q), 3.17 (s, diazaspiro[4.5]decan- 2H), 3.11 (q, 2H), 3.05 (d, 3-yl]-N-(2- 2H), 2.66 − 2.60 (m, 2H), hydroxy-ethyl)-acetamide 2.57 − 2.47 (m, 1H), 2.06 − 1.92 (m, 10H), 1.85 − 1.73 (m, 2H), 1.75 − 1.63 (m, 2H), 1.40 − 1.28 (m, 4H). Not all signals could be intergrated due to overlap with solvent peaks; two rotamers observed in spectrum. SC_1357 TRANS-1- INT-1062 morpholine procedure 1HNMR (DMSO-d6, 400 455.1 (Cyclopropyl- described MHz), δ (ppm) = 7.44 − 7.29 methyl)-8- (m, 5H), 3.96 (s, 2H), 3.56 dimethylamino-3- (bs, 4H), 3.42 − 3.40 (m, 4H), (2-morpholin-4- 3.29 (s, 2H), 2.67 (bs, 2H), yl-2-oxo-ethyl)-8- 2.55 − 2.54 (d, 2H, J = 6.36 phenyl-1,3- Hz), 1.92 (s, 6H), 1.56 − .144 diazaspiro[4.5]decan- (m, 6H), 0.51 − 0.48 (m, 2-one 1H), 0.16 − 0.14 (m, 2H), (−0.26) − (−0.27) (m, 2H). SC_1358 TRANS-8- INT-1060 morpholine SC_1357 1HNMR (DMSO-d6, 400 401.3 Dimethylamino-3- MHz at 100 0C.), δ (ppm) = (2-morpholin-4- 7.39 − 7.36 (m, 4H), 7.26 − yl-2-oxo-ethyl)-8- 7.23 (m, 1H), 6.35 (m, 1H), phenyl-1,3- 3.91 (s, 2H), 3.59 (t, 4H, J = diazaspiro[4.5]decan- 4.8 Hz), 3.45 (t, 4H, J = 4.8 2-one Hz), 3.27 (s, 2H), 2.18 − 2.15 (m, 2H), 2.0 − 1.99 (m, 8H), 1.78 − 1.73 (m, 2H), 1.48 − 1.43 (m, 2H). SC_1359 CIS-2-[1- INT-1058 2- SC_1308 1H NMR (600 MHz, 475.3 (Cyclobutyl- (methyl- DMSO) δ 7.37 (dd, 2H), methyl)-8- amino)ethanol 7.15 (t, 2H), 4.82 (t, 0.2H), dimethylamino-8- 4.63 (t, 0.2H), 3.98 (s, 1H), (4-fluorophenyl)- 3.91 (s, 1H), 3.51 (q, 1H), 2-oxo-1,3- 3.45 (q, 1H), 3.37 − 3.26 diazaspiro[4.5]decan- (m, 2H), 3.18 (d, 2H), 3.04 3-yl]-N-(2- (dd, 2H), 2.96 (s, 1H), 2.80 hydroxy-ethyl)-N- (s, 2H), 2.64 (d, 2H), 2.56 − methyl-acetamide 2.47 (m, 1H), 2.08 − 2.00 (m, 2H), 2.00 − 1.91 (m, 8H), 1.79 (ddt, 2H), 1.75 − 1.65 (m, 2H), 1.37 (d, 2H), 1.31 (td, 2H). Two rotamers are observed. SC_1360 CIS-N- INT-1058 2- SC_1308 1H NMR (600 MHz, 488.3 (Carbamoyl- methylamino- DMSO) δ 7.46 (s, 0.4H), methyl)-2-[1- acetamide 7.37 (dd, 2H), 7.30 (s, (cyclobutyl- hydrochloride 0.6H), 7.20 − 7.12 (m, 2H), methyl)-8- 6.99 (s, 0.6H), 3.97 (s, 1H), dimethylamino-8- 3.90 (s, 1H), 3.83 (d, 2H), (4-fluorophenyl)- 3.18 (d, 2H), 3.04 (dd, 2H), 2-oxo-1,3- 2.94 (s, 2H), 2.76 (s, 1H), diazaspiro[4.5]decan- 2.67 − 2.60 (m, 2H), 2.57 − 3-yl]-N- 2.47 (m, 1H), 2.07 − 1.92 methyl-acetamide (m, 10H), 1.83 − 1.74 (m, 2H), 1.74 − 1.63 (m, 2H), 1.40 − 1.27 (m, 4H). Two rotamers are observed. SC_1361 CIS-1- INT-991 4- SC_1308 1H NMR (DMSO d6): δ 483.4 (Cyclopropyl- hydro- methyl- 7.36 − 7.33 (m, 4H), 7.25 − methyl)-8- chloride piperidin-4-ol 7.23 (m, 1H), 4.37 (s, 1H), dimethylamino-3- 3.92 − 3.84 (m, 3H), 3.48 − [2-(4-hydroxy-4- 3.46 (m, 1H), 3.25 − 3.21 (m, methyl-piperidin- 3H), 2.99 − 2.92 (m, 3H), 1-yl)-2-oxo- 2.67 − 2.64 (m, 2H), 2.20 − ethyl]-8-phenyl- 2.15 (t, 2H), 1.97 (s, 6H), 1,3- 1.44 − 1.21 (m, 8H), 1.11 (s, diazaspiro[4.5]decan- 3H), 0.93 − 0.92 (m, 1H), 2-one 0.47 − 0.45 (m, 2H), 0.44 − 0.43 (m, 2H). SC_1362 CIS-1-[2-[1- INT-991 piperidine-4- SC_1308 1H NMR (DMSO): δ 7.34 − 496.4 (Cyclopropyl- hydro- carboxamide 7.32 (m, 4H), 7.25 − 7.24 (m, methyl)-8- chloride 2H), 6.77 (s, 1H), 4.21 − 4.29 dimethylamino-2- (m, 1H), 3.94 − 3.86 (m, 2H), oxo-8-phenyl-1,3- 3.78 (m, 1H), 3.22 (s, 2H), diazaspiro[4.5]decan- 2.96 − 2.93 (m, 3H), 2.67 − 3-yl]-acetyl]- 2.57 (m, 2H), 2.50 (t, 1H), piperidine-4- 2.30 (m, 1H), 2.20 − 2.15 (m, carboxylic acid 2H), 1.97 (s, 6H), 1.69 − 1.67 amide (m, 2H), 1.42 − 1.31 (m, 6H), 0.92 (m, 1H), 0.47 − 0.43 (m, 2H), 0.27 − 0.24 (m, 2H). SC_1363 TRANS-2-[1- INT-1061 t-butyl- procedure 1HNMR at 100oC. (DMSO- 385.2 (Cyclopropyl- bromoacetate described d6, 400 MHz), δ (ppm) = methyl)-8- (step 1), 7 N 7.40 − 7.29 (m, 5H), 6.76 (bs, dimethylamino-2- ammonia in 2H), 3.68 (s, 2H), 3.33 (s, oxo-8-phenyl-1,3- methanol 2H), 2.61 − 2.60 (m, 4H), diazaspiro[4.5]decan- (step 2) 2.00 (s, 6H), 1.61 − .153 (m, 3-y]- 6H), 0.58 − 0.56 (m, 1H), acetamide 0.22 − 0.20 (m, 2H), (−0.16) − (−0.18) (m, 2H). SC_1364 TRANS-2-[1- INT-1062 methylamine SC_1357 1HNMR at 100oC. (DMSO- 399.2 (Cyclopropyl- d6, 400 MHz), δ (ppm) = methyl)-8- 7.43 − 7.27 (m, 6H), 3.68 (s, dimethylamino-2- 2H), 3.32 (s, 2H), 2.64 − 2.58 oxo-8-phenyl-1,3- (m, 7H), 1.99 (s, 6H), 1.66 − diazaspiro[4.5]decan- .152 (m, 6H), 0.58 − 0.56 (m, 3-yl]-N- 1H), 0.23 − 0.19 (m, 2H), methyl-acetamide (−0.15) − (−0.17) (m, 2H). SC_1365 TRANS-1- INT-1062 1,4-thiazinane SC_1357 1HNMR at 100oC. (DMSO- 503.3 (Cyclopropyl- 1,1-dioxide d6, 400 MHz), δ (ppm) = methyl)-8- 7.40 − 7.28 (m, 5H), 4.06 (s, dimethylamino-3- 2H), 3.90 − 3.88 (m, 4H), [2-(1,1-dioxo- 3.34 (s, 2H), 3.14 (bs, 4H), [1,4]thiazinan-4- 2.66 − 2.60 (m, 4H), 1.99 (s, yl)-2-oxo-ethyl]- 6H), 1.63 − .152 (m, 6H), 8-phenyl-1,3- 0.58-0.56 (m, 1H), 0.23 − diazaspiro[4.5]decan- 0.20 (m, 2H), (−0.16) − 2-one (−0.17) (m, 2H). SC_1366 CIS-1- INT-991 4- SC_1308 1H NMR (DMSO d6): δ 531.4 (Cyclopropyl- hydro- (methyl 7.36 − 7.32 (m, 4H), 7.26 − methyl)-8- chloride sulfonyl)piper- 7.23 (m, 1H), 4.40 (m, 1H), dimethylamino-3- idine 4.04 − 3.88 (m, 3H), 3.31 (m, [2-(4- 1H), 3.02 (s, 2H), 2.94 (t, methylsulfonyl- 1H), 2.94 − 2.92 (m, 5H), piperidin-l-yl)-2- 2.67 − 2.50 (m, 3H), 2.20 − oxo-ethyl]-8- 2.15 (m, 2H), 2.08 − 1.97 (m, phenyl-1,3- 8H), 1.56 (m, 1H), 1.42 − diazaspiro[4.5]decan- 1.31 (m, 5H), 0.92 (m, 1H), 2-one 0.47 − 0.43 (m, 2H), 0.27 − 0.24 (m, 2H). SC_1368 CIS-8- INT-1019 1,4-thiazinane SC_1308 1H NMR (600 MHz, 533.3 Dimethylamino-3- 1,1-dioxide DMSO) δ 7.35 (d, 4H), [2-(1,1-dioxo- 7.29 − 7.22 (m, 1H), 4.09 (s, [1,4]thiazinan-4- 2H), 3.83 (dt, 4H), 3.25 − yl)-2-oxo-ethyl]- 3.19 (m, 2H), 3.15 − 3.05 1-[(1-hydroxy- (m, 4H), 2.72 − 2.65 (m, cyclobutyl)- 2H), 2.12 − 2.04 (m, 6H), methyl]-8-phenyl- 1.99 (s, 6H), 1.88 (dt, 2H), 1,3- 1.68 − 1.59 (m, 1H), 1.50 diazaspiro[4.5]decan- (d, 2H), 1.43 − 1.29 (m, 2-one 3H). SC_1369 TRANS-2-(8- INT-1060 t-butyl- SC_1363 1HNMR (DMSO-d6, 400 331.2 Dimethylamino-2- bromoacetate MHz at 100 0C.), δ (ppm) = oxo-8-phenyl-1,3- (step 1), 7 N 7.37 − 7.24 (m, 5H), 6.74 (bs, diazaspiro[4.5]decan- ammonia in 2H), 6.38 (s, 1H), 3.62 (s, 3-yl)-acetamide methanol 2H), 3.27 (s, 2H), 2.19 − 2.14 (step 2) (m, 2H), 2.01 − 1.96 (m, 8H), 1.78 − 1.73 (m, 2H), 1.48 − 1.43 (m, 2H). SC_1370 TRANS-8- INT-1060 1,4-thiazinane SC_1357 1HNMR (DMSO-d6, 400 449.2 Dimethylamino-3- 1,1-dioxide MHz at 100 0C.), δ (ppm) = [2-(1,1-dioxo- 7.37 − 7.24 (m, 5H), 6.41 (s, [1,4]thiazinan-4- 1H), 4.0 (s, 2H), 3.89 (bs, yl)-2-oxo-ethyl]- 4H), 3.28 (s, 2H), 3.14 (bs, 8-phenyl-1,3- 4H), 2.15 (m, 2H), 1.99 (m, diazaspiro[4.5]decan- 8H), 1.78 − 1.73 (m, 2H), 2-one 1.48 − 1.43 (m, 2H). SC_1371 CIS-8- INT-1068 t-butyl- SC_1363 413.2 (dimethylamino)- bromoacetate 8-phenyl-1-(2,2,2- (step 1), 7 N trifluoroethyl)-3- ammonia in (2- methanol (trifluoro- (step 2) methyl)pyrimidin- 5-yl)-1,3- diazaspiro[4.5]decan- 2-one SC_1372 CIS-8- INT-1070 t-butyl- SC_1363 (dimethylamino)- bromoacetate 8-phenyl-3-(2- (step 1), 7 N (trifluoro- ammonia in methyl)pyrimidin- methanol 5-yl)-1-(3,3,3- (step 2) trifluoropropyl)- 1,3- diazaspiro[4.5]decan- 2-one

[0477] Chemical Structure of All Examples

##STR00145## ##STR00146## ##STR00147## ##STR00148## ##STR00149## ##STR00150## ##STR00151## ##STR00152## ##STR00153## ##STR00154## ##STR00155## ##STR00156## ##STR00157## ##STR00158## ##STR00159## ##STR00160## ##STR00161## ##STR00162## ##STR00163## ##STR00164## ##STR00165## ##STR00166## ##STR00167## ##STR00168## ##STR00169## ##STR00170## ##STR00171## ##STR00172## ##STR00173## ##STR00174## ##STR00175## ##STR00176## ##STR00177##

[0478] Pharmacological Investigations

[0479] 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)

[0480] Human Mu-Opioid Peptide (hMOP) Receptor Binding Assay

[0481] 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 μl/well) included 1 nM of [N-allyl-2,3-.sup.3H]naloxone as ligand (PerkinElmer Life Sciences, Inc. Boston, Mass., USA), and either test compound in dilution series or 25 μM unlabelled naloxone for determination of unspecific binding. The test compound was diluted with 25% DMSO in H.sub.2O to yield a final 0.5% DMSO concentration, which also served as a respective vehicle control. The assay was started by adding wheat germ agglutinin coated SPA beads (GE Healthcare UK Ltd., Buckinghamshire, UK) which had been preloaded with hMOP receptor membranes (PerkinElmer Life Sciences, Inc. Boston, Mass., USA). After incubation for 90 minutes at RT and centrifugation for 20 minutes at 500 rpm the signal rate was measured by means of a 1450 Microbeta Trilux 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).

[0482] Human Kappa-Opioid Peptide (hKOP) Receptor Binding Assay

[0483] 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 μl per well includes 2 nM of [.sup.3H]U69,593 as ligand, and either test compound in dilution series or 100 μM 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 μl final assay volume per well) which has been preloaded for 15 minutes at room temperature with hKOP receptor membranes (14.8 μg/250 μl 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, values are calculated by using the Cheng-Prusoff equation, (Cheng and Prusoff, 1973).

[0484] Human Delta-Opioid Peptide (hDOP) Receptor Binding Assay

[0485] 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 μl/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 μM 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 μl final assay volume per well) which has been preloaded for 15 minutes at room temperature with hDOP receptor membranes (15.2 μg/250 μl 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).

[0486] Human Nociceptin/Orphanin FQ Peptide (hNOP) Receptor Binding Assay

[0487] 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 μl/well) included 0.5 nM of [leucyl-.sup.3H]nociceptin as ligand (PerkinElmer Life Sciences, Inc. Boston, Mass., USA), and either test compound in dilution series or 1 μM 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, Mass., USA). After incubation for 60 minutes at RT and centrifugation for 20 minutes at 500 rpm the signal rate was measured by means of a 1450 Microbeta Trilux 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-00005 hNOP hMOP Example Ki [nM] Ki [nM] SC_1001 33 206 SC_1002 2.1 160 SC_1003 3.7 102 SC_1004 3.6 84 SC_1005 6.3 115.5 SC_1006 2.2 150 SC_1007 29.5 190 SC_1008 5.4 117.5 SC_1009 17 390 SC_1010 9.8 175 SC_1011 9.1 112.5 SC_1012 1.8 47.5 SC_1013 1 220 SC_1014 2.6 175 SC_1015 1.3 140 SC_1016 3.1 76.5 SC_1017 2.6 130 SC_1018 2.8 106.5 SC_1019 4.6 170 SC_1020 2 86 SC_1021 1.6 94 SC_1022 2.1 20.5 SC_1023 13 270 SC_1024 3.7 26.5 SC_1025 22 125 SC_1026 2 67.3 SC_1027 7.6 55 SC_1028 4.8 104 SC_1029 52.3 303.3 SC_1030 3.1 74.5 SC_1031 3.6 43 SC_1032 4.9 69.5 SC_1033 3.9 75.5 SC_1034 2.1 47 SC_1035 1.3 21.5 SC_1036 2.7 39 SC_1037 1.8 45 SC_1038 1.6 41.5 SC_1039 1.3 34.5 SC_1040 1.1 15 SC_1041 1.7 20.5 SC_1042 1.8 57 SC_1043 1.1 21.5 SC_1044 1.7 43 SC_1045 1.6 44.5 SC_1046 2.3 54 SC_1047 2.5 49 SC_1048 1 43.5 SC_1049 2.9 48.5 SC_1050 0.8 40 SC_1051 1.6 36.5 SC_1052 1.6 24.5 SC_1053 2.7 53 SC_1054 2.6 74.5 SC_1055 2.5 29 SC_1056 3.3 10 SC_1057 1.9 11 SC_1058 2.9 78 SC_1059 7.4 45 SC_1060 5.1 40.5 SC_1061 2.2 12.6 SC_1062 2.6 47.5 SC_1063 1.6 22 SC_1064 4.2 33 SC_1065 4.8 26.5 SC_1066 1.9 23 SC_1067 7.5 31.5 SC_1068 68.5 360 SC_1069 1.4 16.5 SC_1070 1 13.5 SC_1071 3.6 38.5 SC_1072 2.8 62 SC_1073 3.5 25 SC_1074 5.9 37 SC_1075 1.5 19.5 SC_1076 0.8 72 SC_1077 1.8 20.5 SC_1078 1.3 23.3 SC_1079 1.7 26.2 SC_1080 6.4 19.5 SC_1081 1.9 64 SC_1082 1 81.5 SC_1083 1.5 44 SC_1084 1.1 59 SC_1085 3.8 71 SC_1086 0.8 16.5 SC_1087 2.4 28.2 SC_1088 2 19.5 SC_1089 1.4 16.5 SC_1090 3 27.5 SC_1091 1.3 15.5 SC_1092 1.8 26.5 SC_1093 4.2 43 SC_1094 2.8 10.4 SC_1095 1.8 12.5 SC_1096 1.6 12 SC_1097 1.6 15 SC_1098 1.5 10 SC_1099 1.5 4.5 SC_1100 1 2.3 SC_1101 3.4 6 SC_1102 2 4.4 SC_1103 0.4 7.2 SC_1104 1.2 23 SC_1105 4 50.5 SC_1106 11 122 SC_1107 1.8 45 SC_1109 2.8 16 SC_1110 9.8 31.5 SC_1111 1.6 30 SC_1112 1.3 30.5 SC_1113 0.8 30 SC_1114 109.5 850 SC_1115 140 145 SC_1117 4.1 37.5 SC_1118 2.4 114.3 SC_1119 6.5 73.5 SC_1120 2.9 125 SC_1121 115 630 SC_1122 124.5 480 SC_1123 2.6 24.8 SC_1124 1.8 33.8 SC_1125 2.2 23 SC_1126 3.5 29.5 SC_1127 2.6 2.7 SC_1128 1.9 72 SC_1129 1.7 37.3 SC_1130 68.5 160 SC_1131 34.5 215 SC_1132 23.5 410 SC_1133 6.4 25.5 SC_1134 26 140 SC_1135 73 370 SC_1136 14 57.5 SC_1137 5.8 99 SC_1138 0.9 23.5 SC_1139 215 515 SC_1140 51.5 150 SC_1141 4.8 165 SC_1142 265 1200 SC_1143 17 200 SC_1144 9.8 73.5 SC_1145 3.4 60.5 SC_1146 2.2 21.2 SC_1147 2.6 34.2 SC_1148 40 18.8 SC_1149 62 102.5 SC_1150 4.9 55.5 SC_1151 1.6 13.5 SC_1152 0.9 13.7 SC_1153 1.6 37 SC_1154 4.5 29 SC_1155 14.1 114.5 SC_1156 155 1215 SC_1157 170 1120 SC_1158 12.5 144.5 SC_1159 22.5 81.5 SC_1160 20 84.5 SC_1161 60 86 SC_1162 15.3 47.5 SC_1163 30.5 119 SC_1164 8.2 16.5 SC_1165 5.7 63.5 SC_1166 17 72.5 SC_1167 18 92 SC_1168 37 125 SC_1169 36.5 370 SC_1171 43 130 SC_1172 27.5 106 SC_1173 38.5 120 SC_1174 12.9 195 SC_1175 28.5 9.6 SC_1176 9 56 SC_1177 39 660 SC_1178 16 390 SC_1179 87.5 180 SC_1180 80 230 SC_1181 125 435 SC_1182 47.5 320 SC_1183 130 185 SC_1184 110 153.3 SC_1185 47 165 SC_1186 95.5 355 SC_1187 43 127.5 SC_1188 9.1 175 SC_1189 70.5 75.5 SC_1190 11.2 123.5 SC_1191 29 150 SC_1192 17 680 SC_1193 9.9 41 SC_1195 4.4 6.2 SC_1196 2.1 64.8 SC_1197 5.4 60 SC_1198 4.9 47 SC_1199 35 230 SC_1201 13.3 123.7 SC_1203 5.2 47.5 SC_1204 2.5 77.2 SC_1205 2.2 37 SC_1206 1.2 61.5 SC_1207 2.9 38 SC_1208 1.8 90 SC_1209 3.2 46 SC_1210 4.4 83.5 SC_1211 2.4 18.7 SC_1212 4.8 37.7 SC_1213 1.8 31.7 SC_1214 1 56.7 SC_1215 3.9 25 SC_1216 1.2 49 SC_1217 2.2 25.7 SC_1218 5.2 59 SC_1219 4.2 73.7 SC_1220 4 51 SC_1221 17 180 SC_1222 2.6 63 SC_1223 2.5 43.5 SC_1224 1.6 15 SC_1225 1.8 49.5 SC_1226 2.6 12.5 SC_1227 4.6 63 SC_1228 665 1740 SC_1229 2.8 22.5 SC_1230 1.5 36.5 SC_1231 2 51.5 SC_1232 1.4 32.5 SC_1233 0.5 26.5 SC_1234 1.8 53.5 SC_1236 3.3 83 SC_1300 13 130 SC_1301 23 44 SC_1302 27 66.5 SC_1303 145 215 SC_1304 280 400 SC_1305 19 105.5 SC_1306 59 45 SC_1308 22 97 SC_1309 12.5 100 SC_1310 8.1 17 SC_1311 11.5 44 SC_1312 295 520 SC_1313 305 1015 SC_1317 1.4 53.5 SC_1318 89 960 SC_1319 4 71 SC_1320 4 51 SC_1321 17 180 SC_1322 6%@1 μM 9%@1 μM SC_1323 12%@1 μM 7%@1 μM SC_1324 330 6025 SC_1325 0%@1 μM 5%@1 μM SC_1326 0%@1 μM 625 SC_1327 11 120 SC_1328 2%@1 μM 6%@1 μM SC_1329 0%@1 μM 4%@1 μM SC_1330 465 18%@1 μM SC_1331 10 38 SC_1332 52 1950 SC_1333 36 300 SC_1334 195 1605 SC_1335 2 24 SC_1336 — — SC_1337 23 — SC_1338 475 14%@1 μM SC_1339 1110 9%@1 μM SC_1340 230 14%@1 μM SC_1341 170 2905 SC_1342 1140 10%@1 μM SC_1343 12 95 SC_1344 13 145 SC_1345 1 185 SC_1346 2 400 SC_1347 31 615 SC_1348 8 97 SC_1349 1 165 SC_1350 8 510 SC_1351 1 235 SC_1352 1 135 SC_1353 66 80.5 SC_1354 465 210 SC_1355 7 325 SC_1356 11 86 SC_1357 100 15.5 SC_1358 73 51.5 SC_1359 10 260 SC_1360 15 180 SC_1361 13 255 SC_1362 6 240 SC_1363 185 225 SC_1364 230 73.5 SC_1365 160 4.4 SC_1366 1 205 SC_1368 7 360 SC_1369 465 1805 SC_1370 100 11

[0488] Protocol for [.sup.35S]G-TPγS Functional NOP/MOP/KOP/DOP Assays

[0489] Cell membrane preparations of CHO-K1 cells transfected with the human MOP receptor (Art.-No. RBHOMM) or the human DOP receptor (Art.-No. RBHODM), and HEK293 cells transfected with the human NOP receptor (Art.-No. RBHORLM) or the human KOP receptor (Art.-No. 6110558) are available from PerkinElmer (Waltham, Mass.). Membranes from CHO-K1 cells transfected with the human nociceptin/orphanin FQ peptide (hNOP) receptor (Art.-No. 93-0264C2, DiscoveRx Corporation, Freemont, Calif.) are also used. [.sup.35S]GTPγS (Art.-No. NEG030H; Lot-No. #0112, #0913, #1113 calibrated to 46.25 TBq/mmol) is available from PerkinElmer (Waltham, Mass.).

[0490] 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 μg 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 MgCl.sub.2, 1 mM EDTA, 1 mM dithiothreitol, 1.28 mM NaN.sub.3, and 10 μM 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, Mass.).

[0491] 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.

[0492] 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.