8-Amino-2-Oxo-1,3-Diaza-Spiro-[4.5]-Decane Derivatives
20230183222 · 2023-06-15
Assignee
Inventors
- Sven Kuehnert (Dueren, DE)
- Rene Michael Koenigs (Erkelenz, DE)
- Achim Kless (Aachen, DE)
- Anita Wegert (Aldenhoven, DE)
- Paul Ratcliffe (Aachen, DE)
- Ruth Jostock (Stolberg, DE)
- Thomas KOCH (Stolberg, DE)
- Klaus Linz (Rheinbach, DE)
- Wolfgang Schroeder (Aachen, DE)
Cpc classification
C07D405/04
CHEMISTRY; METALLURGY
A61P29/00
HUMAN NECESSITIES
C07D235/02
CHEMISTRY; METALLURGY
C07D403/06
CHEMISTRY; METALLURGY
C07D405/06
CHEMISTRY; METALLURGY
C07D401/04
CHEMISTRY; METALLURGY
C07D409/04
CHEMISTRY; METALLURGY
C07D401/06
CHEMISTRY; METALLURGY
International classification
C07D409/06
CHEMISTRY; METALLURGY
C07D235/02
CHEMISTRY; METALLURGY
C07D401/04
CHEMISTRY; METALLURGY
C07D401/06
CHEMISTRY; METALLURGY
C07D403/06
CHEMISTRY; METALLURGY
C07D405/04
CHEMISTRY; METALLURGY
C07D405/06
CHEMISTRY; METALLURGY
Abstract
The invention relates to 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) ##STR00150## wherein R.sup.1 and R.sup.2 independently of one another mean —H; —C.sub.1-C.sub.6-alkyl, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —OH, —OCH.sub.3, —CN and —CO.sub.2CH.sub.3; a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —OH, —OCH.sub.3, —CN and —CO.sub.2CH.sub.3; wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted; or a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —OH, —OCH.sub.3, —CN and —CO.sub.2CH.sub.3; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted; or R.sup.1 and R.sup.2 together with the nitrogen atom to which they are attached form a ring and mean —(CH.sub.2).sub.3-6—; —(CH.sub.2).sub.2—O—(CH.sub.2).sub.2—; or —(CH.sub.2).sub.2—NR.sup.A—(CH.sub.2).sub.2—, wherein R.sup.A means —H or —C.sub.1-C.sub.6-alkyl, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br and —I; R.sup.3 means —C.sub.1-C.sub.6-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or 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—; 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; or a moiety according to general formula (X); ##STR00151## 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, —SR.sup.21, —S(═O)R.sup.21, —S(═O).sub.2R.sup.21, —S(═O).sub.2OR.sup.21, and —S(═O).sub.2NR.sup.21R.sup.22; wherein R.sup.21, R.sup.22 and R.sup.23 independently of one another mean —H; —C.sub.1-C.sub.6-alkyl, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH.sub.2, and —O—C.sub.1-C.sub.6-alkyl; a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted; wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH.sub.2, —C.sub.1-C.sub.6-alkyl and —O—C.sub.1-C.sub.6-alkyl; a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH.sub.2, —C.sub.1-C.sub.6-alkyl and —O—C.sub.1-C.sub.6-alkyl; a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl moiety is optionally connected through —C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH.sub.2, —C.sub.1-C.sub.6-alkyl and —O—C.sub.1-C.sub.6-alkyl; a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl moiety is optionally connected through —C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH.sub.2, —C.sub.1-C.sub.6-alkyl and —O—C.sub.1-C.sub.6-alkyl; or R.sup.21 and R.sup.22 within —C(═O)NR.sup.21R.sup.22, —OC(═O)NR.sup.21R.sup.22, —NR.sup.21R.sup.22, —NR.sup.23—(CH.sub.2).sub.1-6—C(═O)NR.sup.21R.sup.22, —NR.sup.23C(═O)NR.sup.21R.sup.22, or —S(═O).sub.2NR.sup.21R.sup.22 together with the nitrogen atom to which they are attached form a ring and mean —(CH.sub.2).sub.3-6—; —(CH.sub.2).sub.2—O—(CH.sub.2).sub.2—; or —(CH.sub.2).sub.2—NR.sup.B—(CH.sub.2).sub.2—, wherein R.sup.B means —H or —C.sub.1-C.sub.6-alkyl, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br and —I; or a physiologically acceptable salt thereof.
2. The compound according to claim 1, wherein R.sup.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 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 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 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—C.sub.1-C.sub.4-alkyl, —O—(CH.sub.2CH.sub.2—O).sub.1-30—H, —O—(CH.sub.2CH.sub.2—O).sub.1-30—CH.sub.3, —C(═O)OH, —C(═O)OC.sub.1-C.sub.4-alkyl, —C(═O)NH.sub.2, —C(═O)NHC.sub.1-C.sub.4-alkyl, —C(═O)N(C.sub.1-C.sub.4-alkyl).sub.2, —S(═O)C.sub.1-C.sub.4-alkyl and —S(═O).sub.2C.sub.1-C.sub.4-alkyl.
18. The compound according to claim 1, wherein R.sup.5 means a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —C.sub.1-C.sub.4-alkyl, —C.sub.1-C.sub.4-alkyl-OH, —O—C.sub.1-C.sub.4-alkyl, —O—(CH.sub.2CH.sub.2—O).sub.1-30—H, —O—(CH.sub.2CH.sub.2—O).sub.1-30—CH.sub.3, —C(═O)OH, —C(═O)C.sub.1-C.sub.4-alkyl, —C(═O)OC.sub.1-C.sub.4-alkyl, —C(═O)NH.sub.2, —C(═O)NHC.sub.1-C.sub.4-alkyl, —C(═O)N(C.sub.1-C.sub.4-alkyl).sub.2, —NH.sub.2, —NHC.sub.1-C.sub.4-alkyl, N(C.sub.1-C.sub.4-alkyl).sub.2, —NHC(═O)—C.sub.1C.sub.4-alkyl, —NC.sub.1-C.sub.4-alkylC(═O)C.sub.1-C.sub.4-alkyl, —S(═O)C.sub.1-C.sub.4-alkyl and —S(═O).sub.2C.sub.1-C.sub.4-alkyl; wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted.
19. The compound according to claim 1, wherein R.sup.5 means a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —C.sub.1-C.sub.4-alkyl, —C.sub.1-C.sub.4-alkyl-OH, —O—C.sub.1-C.sub.4-alkyl, —O—(CH.sub.2CH.sub.2—O).sub.1-30—H, —O—(CH.sub.2CH.sub.2—O).sub.1-30—CH.sub.3, —C(═O)OH, —C(═O)C.sub.1-C.sub.4-alkyl, —C(═O)OC.sub.1-C.sub.4-alkyl, —C(═O)NH.sub.2, —C(═O)NHC.sub.1-C.sub.4-alkyl, —C(═O)N(C.sub.1-C.sub.4-alkyl).sub.2, —NH.sub.2, —NHC.sub.1-C.sub.4-alkyl, N(C.sub.1-C.sub.4-alkyl).sub.2, —NHC(═O)—C.sub.1C.sub.4-alkyl, —NC.sub.1-C.sub.4-alkylC(═O)C.sub.1-C.sub.4-alkyl, —S(═O)C.sub.1-C.sub.4-alkyl and —S(═O).sub.2C.sub.1-C.sub.4-alkyl; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted.
20. The compound according to claim 1, which has a structure according to any of general formulas (II-A) to (VIII-C): ##STR00152## ##STR00153## ##STR00154## wherein in each case R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.5 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.
21. The compound according to claim 1, wherein R.sup.5 is selected from the group consisting of: ##STR00155## ##STR00156## ##STR00157##
22. The compound according to claim 1, wherein R.sup.1 means —H or —CH.sub.3; R.sup.2 means —C.sub.1-C.sub.6-alkyl, linear or branched, saturated, unsubstituted; R.sup.3 means -phenyl, -thienyl or -pyridinyl, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —CN, —CH.sub.3, —CH.sub.2CH.sub.3, —CH.sub.2F, —CHF.sub.2, —CF.sub.3, —OCF.sub.3, —OH, —OCH.sub.3, —C(═O)NH.sub.2, C(═O)NHCH.sub.3, —C(═O)N(CH.sub.3).sub.2, —NH.sub.2, —NHCH.sub.3, —N(CH.sub.3).sub.2, —NHC(═O)CH.sub.3, —CH.sub.2OH, SOCH.sub.3 and SO.sub.2CH.sub.3; or R.sup.4 means —H; —C.sub.1-C.sub.6-alkyl, linear or branched, saturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, ═O, —S(═O).sub.2—C.sub.1-C.sub.4-alkyl and —O—C.sub.1-C.sub.4-alkyl; 3-6-membered cycloalkyl, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, and —O—C.sub.1-C.sub.4-alkyl, wherein said 3-6-membered cycloalkyl is connected through —C.sub.1-C.sub.6-alkylene; 3-12-membered heterocycloalkyl, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, and —O—C.sub.1-C.sub.4-alkyl; wherein said 3-12-membered heterocycloalkyl is optionally connected through —C.sub.1-C.sub.6-alkylene-, unsubstituted or substituted with ═O; 6-14-membered aryl, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, and —O—C.sub.1-C.sub.4-alkyl; wherein said 6-14-membered aryl is optionally connected through —C.sub.1-C.sub.6-alkylene- or —S(═O).sub.2—; R.sup.5 means —H; —C.sub.1-C.sub.6-alkyl, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, ═O, —OH, —O—C.sub.1-C.sub.4-alkyl, —O—(CH.sub.2CH.sub.2—O).sub.1-30—H, —O—(CH.sub.2CH.sub.2—O).sub.1-30—CH.sub.3, —C(═O)OH, —C(═O)C.sub.1-C.sub.4-alkyl, —C(═O)OC.sub.1-C.sub.4-alkyl, —C(═O)NH.sub.2, —C(═O)NHC.sub.1-C.sub.4-alkyl, —C(═O)N(C.sub.1-C.sub.4-alkyl).sub.2, —S(═O)C.sub.1-C.sub.4-alkyl, —S(═O).sub.2C.sub.1-C.sub.4-alkyl, —NH.sub.2, —NH—C.sub.1-C.sub.4-alkyl, —N(C.sub.1-C.sub.4-alkyl).sub.2, —NHC(═O)—C.sub.1-C.sub.4-alkyl, —NH—S(═O).sub.2C.sub.1-C.sub.4-alkyl; or 3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, ═O, —OH, —C.sub.1-C.sub.4-alkyl, —C.sub.1-C.sub.4-alkyl-OH, —NH.sub.2, —NH—C.sub.1-C.sub.4-alkyl, —N(C.sub.1-C.sub.4-alkyl).sub.2, —NHC(═O)—C.sub.1-C.sub.4-alkyl, —NHS(═O).sub.2—C.sub.1-C.sub.4-alkyl, —O—C.sub.1-C.sub.4-alkyl, —O—(CH.sub.2CH.sub.2—O).sub.1-30—H, —O—(CH.sub.2CH.sub.2—O).sub.1-30—CH.sub.3, —C(═O)OH, —C(═O)OC.sub.1-C.sub.4-alkyl, —C(═O)C.sub.1-C.sub.4-alkyl, —C(═O)NH.sub.2, —C(═O)NHC.sub.1-C.sub.4-alkyl, —C(═O)N(C.sub.1-C.sub.4-alkyl).sub.2, —S(═O)C.sub.1-C.sub.4-alkyl, —S(═O).sub.2C.sub.1-C.sub.4-alkyl, -phenyl, —C(═O)-phenyl, —C(═O)-pyridyl, -pyridyl, -thiazolyl, —N-methyldiazolyl, -pyrimidinyl, and -pyridazinyl; 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 3-12-membered heterocycloalkyl, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, ═O, —OH, —C.sub.1-C.sub.4-alkyl, —NH.sub.2, —NH—C.sub.1-C.sub.4-alkyl, —N(C.sub.1-C.sub.4-alkyl).sub.2, —NHC(═O)—C.sub.1-C.sub.4-alkyl, —NHS(═O).sub.2—C.sub.1-C.sub.4-alkyl, —O—C.sub.1-C.sub.4-alkyl, —O—(CH.sub.2CH.sub.2—O).sub.1-30—H, —O—(CH.sub.2CH.sub.2—O).sub.1-30—CH.sub.3, —C(═O)OH, —C(═O)OC.sub.1-C.sub.4-alkyl, —C(═O)C.sub.1-C.sub.4-alkyl, —C(═O)NH.sub.2, —C(═O)NHC.sub.1-C.sub.4-alkyl, —C(═O)N(C.sub.1-C.sub.4-alkyl).sub.2, —S(═O)C.sub.1-C.sub.4-alkyl, —S(═O).sub.2C.sub.1-C.sub.4-alkyl, -phenyl, —C(═O)-phenyl, —C(═O)-pyridyl, -pyridyl, -thiazolyl, —N-methyldiazolyl, -pyrimidinyl, and -pyridazinyl; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted; and 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.
23. The compound according to claim 1, which has a structure according to general formula (I′) ##STR00158## wherein R.sup.1 to R.sup.5, R.sup.10 to R.sup.20 are defined as in claim 1, or a physiologically acceptable salt thereof.
24. The compound according to claim 1, which has a structure according to general formula (IX) ##STR00159## wherein R.sup.C means —H or —OH; R.sup.3 means -phenyl or -3-fluorophenyl; R.sup.5 means C.sub.1-C.sub.6-alkyl, linear or branched, saturated, unsubstituted or monosubstituted with —OH, —CN, —NH.sub.2, —NHC(═O)C.sub.1-C.sub.4-alkyl, —NHS(═O).sub.2—C.sub.1-C.sub.4-alkyl, or —S(═O).sub.2—C.sub.1-C.sub.4-alkyl; or 3-6-membered heterocycloalkyl, saturated, unsubstituted or substituted with —OH; wherein said 3-6-membered heterocycloalkyl is optionally connected through —CH.sub.2— or —(CH.sub.2).sub.2—; or a physiologically acceptable salt thereof.
25. The compound according to claim 24, wherein the 3-6-membered heterocycloalkyl is selected from the group consisting of oxetanly, tetrahydrofuranyl and tetrahydropyranyl.
26. The compound according to claim 1, which is selected from the group consisting of CIS-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-butyramide; CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-(2-methoxy-ethoxy)-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(2-methoxy-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(2-methylsulfonyl-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-1-(Cyclobutyl-methyl)-8-methylamino-3-(2-methylsulfonyl-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-methylsulfonyl-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-butyronitrile; CIS-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-butyramide; CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl-propionitrile; CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-methyl-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-3-(2-methylsulfonyl-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-3-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propionitrile; CIS-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetonitrile; CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-(tetrahydro-pyran-4-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one; CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-morpholin-4-yl-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-3-(3-Chloro-propyl)-1-(cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-butyric acid methyl ester; CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propionitrile; CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetonitrile; CIS-3-Acetyl-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-8-Dimethylamino-3-(2-methylsulfonyl-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one CIS-1-Acetyl-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-(2-methylsulfonyl-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-8-Dimethylamino-3-(2-methylsulfonyl-ethyl)-1-(oxetan-3-yl-methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-8-Dimethylamino-1-(3-methoxy-propyl)-3-(2-methylsulfonyl-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-8-Dimethylamino-8-phenyl-1-(p-tolylsulfonyl)-1,3-diazaspiro[4.5]decan-2-one; CIS-8-Dimethylamino-3-[(1,1-dioxo-thian-4-yl)-methyl]-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[(4-hydroxy-tetrahydro-pyran-4-yl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-8-phenyl-3-tetrahydro-pyran-4-yl-1,3-diazaspiro[4.5]decan-2-one; CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[(4-hydroxy-1,1-dioxo-thian-4-yl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-tetrahydro-pyran-4-yl-1,3-diazaspiro[4.5]decan-2-one; CIS-1-[[8-Dimethylamino-3-(2-methylsulfonyl-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-methyl]-cyclobutane-1-carbonitrile; CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-[(4-hydroxy-tetrahydro-pyran-4-yl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-[(4-hydroxy-1,1-dioxo-thian-4-yl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-(1,1-dioxo-thian-4-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-8-Dimethylamino-3-(1,1-dioxo-thian-4-yl)-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-3-(1-Acetyl-piperidin-4-yl)-1-(cyclopropyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-3-(1-Benzoyl-piperidin-4-yl)-1-(cyclopropyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-8-phenyl-3-[1-(pyridine-4-carbonyl)-piperidin-4-yl]-1,3-diazaspiro[4.5]decan-2-one; CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[(4-hydroxy-tetrahydro-pyran-4-yl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-(4-hydroxy-tetrahydro-pyran-4-yl)-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-3-[(1-Acetyl-piperidin-4-yl)-methyl]-1-(cyclopropyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-8-phenyl-3-piperidin-4-yl-1,3-diazaspiro[4.5]decan-2-one; CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-(2-hydroxy-2-methyl-propyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-8-phenyl-3-(1-pyrimidin-5-yl-piperidin-4-yl)-1,3-diazaspiro[4.5]decan-2-one; CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-8-phenyl-3-(1-phenyl-piperidin-4-yl)-1,3-diazaspiro[4.5]decan-2-one; CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-8-phenyl-3-(piperidin-4-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one; CIS-3-(1-Benzoyl-piperidin-4-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one CIS-8-Dimethylamino-8-phenyl-3-[1-(pyridine-4-carbonyl)-piperidin-4-yl]-1,3-diazaspiro[4.5]decan-2-one; CIS-3-(1-Acetyl-piperidin-4-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[(4-hydroxy-1,1-dioxo-thian-4-yl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-hydroxy-2-methyl-propyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; and the physiologically acceptable salts thereof.
27. The compound according to claim 1 for use in the treatment of pain.
28. A medicament comprising a compound according to claim 1.
29. A compound according to general formula (IIIa) or (IIIb), ##STR00160## wherein R.sup.1, R.sup.2 and R.sup.3 are defined as in claim 1; and PG is a protecting group; or a physiologically acceptable salt thereof.
30. 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.
31. 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
[0179] “RT” means room temperature (23 7° C.), “M” are indications of concentration in mol/l, “aq.” means aqueous, “sat.” means saturated, “sol.” means solution, “conc.” means concentrated.
[0180] Further abbreviations: [0181] brine saturated aqueous sodium chloride solution [0182] CC column chromatography [0183] cHex cyclohexane [0184] DCM dichloromethane [0185] DIPEA N,N-diisopropylethylamine [0186] DMF N,N-dimethylformamide [0187] Et Ethyl [0188] ether diethyl ether [0189] EE ethyl acetate [0190] EtOAc ethyl acetate [0191] EtOH ethanol [0192] h hour(s) [0193] H.sub.2O water [0194] HATU O-(7-aza-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate [0195] LDA Lithium-di-isoproyl-amid [0196] Me Methyl [0197] m/z mass-to-charge ratio [0198] MeOH methanol [0199] MeCN acetonitrile [0200] min minutes [0201] MS mass spectrometry [0202] NBS N-bromo-succinimide [0203] NEt.sub.3 triethylamine [0204] PE Petrol Ether (60-80° C.) [0205] RM reaction mixture [0206] RT room temperature [0207] T3P 2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide [0208] tBME tert-.butyl methyl ether [0209] THF tetrahydrofuran [0210] v/v volume to volume [0211] w/w weight to weight
[0212] The yields of the compounds prepared were not optimised. All temperatures are uncorrected.
[0213] All starting materials, which are not explicitly described, were either commercially available (the details of suppliers such as for example Acros, Aldrich, Bachem, Butt park, Enamine, Fluka, Lancaster, Maybridge, Merck, Sigma, TCI, Oakwood, etc. can be found in the Symyx® Available Chemicals Database of MDL, San Ramon, US or the SciFinder® Database of the ACS, Washington D.C., US, respectively, for example) or the synthesis thereof has already been described precisely in the specialist literature (experimental guidelines can be found in the Reaxys® Database of Elsevier, Amsterdam, NL or the SciFinder® Database of the ACS, Washington D.C., US, respectively, for example) or can be prepared using the conventional methods known to the person skilled in the art.
[0214] The mixing ratios of solvents or eluents for chromatography are specified in v/v.
[0215] 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.
[0216] Remark Regarding Stereochemistry
[0217] 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:
##STR00014##
[0218] 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:
##STR00015##
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
[0219] ##STR00016##
Step 1: CIS-1-((1-(benzyloxy)cyclobutyl)methyl)-3-(3,4-dimethoxybenzyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
[0220] NaOH (1.42 g, 35.5 mmol) was added to a solution of CIS-3-(3,4-dimethoxybenzyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-794) (3 g, 7.09 mmol) in DMSO (90 mL) under argon atmosphere and the reaction mixture was stirred at 80° C. for 30 min. ((1-(Bromomethyl)cyclobutoxy)methyl)benzene (5.4 g, 21.3 mmol) was added and stirring was continued for 2 days at 80° C. The reaction completion was monitored by TLC. The reaction mixture was diluted with water (500 mL) and extracted with diethyl ether (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 (230-400 mesh silica gel; 65-70% EtOAc in petroleum ether as eluent) to afford 2.5 g (59%) of CIS-1-((1-(benzyloxy)cyclobutyl)methyl)-3-(3,4-dimethoxybenzyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (TLC system: 10% MeOH in DCM; Rf: 0.8).
Step 2: CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
[0221] TFA (12 mL) was added to CIS-1-((1-(benzyloxy)cyclobutyl)methyl)-3-(3,4-dimethoxybenzyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (2.5 g, 4.18 mmol) at 0° C. and the resulting mixture was stirred at 70° C. for 6 h. The reaction completion was monitored by LCMS. The reaction mixture was concentrated under reduced pressure. To the residue sat. aq. NaHCO.sub.3 was added (until pH 10) and the organic product was extracted with DCM (3×150 mL). The combined organic extracts were dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by column chromatography (230-400 mesh silica gel; 5% MeOH in DCM as eluent) to afford 500 mg (33%) of CIS-8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-799) (TLC system: 10% MeOH in DCM; Rf: 0.5). [M+H].sup.+ 358.2
Synthesis of INT-951: CIS-1-[(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-methyl]-cyclobutane-1-carbonitrile
[0222] ##STR00017##
Step 1: 1-((CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutanecarbonitrile
[0223] 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 (3×200 mL). The combined organic extracts were dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford 5 g (crude) of 1-((CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutane-carbonitrile as gummy brown liquid. The material was used for the next step without further purification.
Step 2: 1-((CIS-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl) cyclobutanecarboxamide
[0224] TFA (100 mL) was added to 1-((CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutanecarbonitrile (5 g, 10.28 mmol) at 0° C. and the reaction mixture at mixture was stirred at RT for 2 days. The reaction mixture was concentrated in vacuo. To the residue sat. aq. NaHCO.sub.3 was added (until pH 10) and the organic product was extracted with dichloromethane (3×150 mL). 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
[0225] Thionyl chloride (35 mL) was added to 1-((cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutanecarboxamide (3.5 g, 9.11 mmol) at RT and the resulting mixture was stirred at reflux for 2 h. The reaction mixture was concentrated in vacuo. To the residue sat. aq. NaHCO.sub.3 was added (until pH 10) and the organic product was extracted with dichloromethane (3×150 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
[0226] ##STR00018##
[0227] 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
[0228] ##STR00019##
Step 1: 1-Cyclobutylmethyl-3-(4-methoxy-benzyl)-9,12-dioxa-1,3-diazadispiro[4.2.4.2]tetradecan-2-one
[0229] To a stirred solution of 3-(4-methoxy-benzyl)-9,12-dioxa-1,3-diazadispiro[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-diazadispiro[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
[0230] To a stirred solution of 1-cyclobutylmethyl-3-(4-methoxy-benzyl)-9,12-dioxa-1,3-diazadispiro[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
[0231] 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
[0232] 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
[0233] 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
[0234] ##STR00020##
Step 1: Ethyl 5-cyano-2-oxo-5-(pyridin-2-yl)cyclohexanecarboxylate
[0235] 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
[0236] A solution of ethyl 5-cyano-2-oxo-5-(pyridin-2-yl)cyclohexanecarboxylate (68.0 g, 250.0 mmol) was added to a mixture of conc. aq. HCl and glacial acetic acid (170 mL/510 mL) at 0° C. The reaction mixture was heated to 100° C. for 16 h. All volatiles were evaporated under reduced pressure. The residue was diluted with sat. aq. NaHCO.sub.3 and extracted with ethyl acetate (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
[0237] ##STR00021##
Step 1: 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile
[0238] 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
[0239] 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
[0240] A mixture of 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carboxamide (25.0 g, 95.41 mmol), sodium hypochlorite (5 wt % aq. solution, 700 mL, 477.09 mmol) and KF—Al.sub.2O.sub.3 (125.0 g) in methanol (500 mL) was heated to 80° C. for 16 h. The reaction mixture was filtered through celite and the solid residue was washed with methanol. The combined filtrate was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate (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
[0241] 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
[0242] Sodium cyanoborohydride (13.7 g, 0.213 mol) was added portionwise to a solution of 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-amine (12.5 g, 53.418 mmol) and 35 wt % aq. formaldehyde (45 mL, 0.534 mol) in acetonitrile (130 mL) at 0° C. The reaction mixture was warmed up to room temperature and stirred for 16 h. The reaction mixture was quenched with sat. aq. NH.sub.4Cl and concentrated under reduced pressure. The residue was dissolved in water and extracted with EtOAc (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
[0243] ##STR00022##
Step 1: 8-(Dimethylamino)-1,4-dioxaspiro 4.5] decane-8-carbonitrile
[0244] Dimethylamine hydrochloride (52 g, 0.645 mol) was added to the solution of 1,4-dioxaspiro-[4.5]-decan-8-one (35 g, 0.224 mmol) in MeOH (35 mL) at RT under argon atmosphere. The solution was stirred for 10 min and 40 wt % aq. dimethylamine (280 mL, 2.5 mol) and KCN (32 g, 0.492 mol) were sequentially added. The reaction mixture was stirred for 48 h at RT, then diluted with water (100 mL) and extracted with EtOAc (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
[0245] 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
[0246] 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). The aqueous layer was basified to pH 10 with solid NaOH and extracted with ethyl acetate (2×200 mL). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The solid residue was washed with hexane and dried in vacuo to afford 7 g of 4-dimethylamino-4-phenyl-cyclohexan-1-one (INT-965) (25% over 2 steps) as a brown solid. [M+H].sup.+ 218.1
Synthesis of INT-966: 3-[(4-Methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decane-2,8-dione
[0247] ##STR00023##
Step 1: 9,12-Dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}.2{circumflex over ( )}{5}]tetradecane-1,3-dione
[0248] 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
[0249] Cs.sub.2CO.sub.3 (258.7 g, 796.1 mmol) was added to the solution of 73a (150 g, 663.4 mmol) in MeCN (1.5 L) under argon atmosphere and the reaction mixture was stirred for 30 min. A solution of p-methoxybenzyl bromide (96 mL, 663.4 mmol) was added. The reaction mixture was stirred at RT for 48 h. The reaction completion was monitored by TLC. The reaction mixture was quenched with sat. aq. NH.sub.4Cl (1.0 L) and the organic product was extracted with EtOAc (2×1.5 L). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was washed with diethyl ether and pentane and dried under reduced pressure to afford 151 g (65%) of 2-[(4-Methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4{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
[0250] 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
[0251] 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 (2×2.0 L). The aqueous layer was basified to pH 10 with 50% aq. NaOH and then extracted with DCM (2×2.0 L). 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
[0252] ##STR00024##
Step 1: CIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
[0253] 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
[0254] TFA (0.2 mL) was added to the solution of CIS-1-(cyclobutylmethyl)-8-(dimethylamino)-3-(4-methoxybenzyl)-8-(3-methoxyphenyl)-1,3-diazaspiro[4.5]decan-2-one (300 mg, 0.57 mmol) in DCM (1.5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 3 h. The reaction completion was monitored by TLC. The reaction mixture was quenched with sat. aq. NaHCO.sub.3 and the organic product was extracted with DCM (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-1-(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
[0255] ##STR00025##
Step 1: 8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile
[0256] Dimethylamine hydrochloride (76.4 g, 936.4 mmol) was added to a solution of 3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decane-2,8-dione (INT-966) (90 g, 312.13 mmol) in MeOH (180 mL) at RT under argon atmosphere. The solution was stirred for 15 min and 40 wt % aq. dimethylamine (780 mL) and KCN (48.76 g, 749.11 mmol) were sequentially added. The reaction mixture was stirred for 48 h and the completion of the reaction was monitored by NMR. The reaction mixture was diluted with water (1.0 L) and the organic product was extracted with ethyl acetate (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
[0257] 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 (2×200 mL). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The reaction was carried out in 4 batches (15 g×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]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
[0258] ##STR00026##
[0259] 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 (150 mL) 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
[0260] ##STR00027##
Step 1: 8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decane-2,4-dione
[0261] In a sealed tube 4-dimethylamino-4-phenyl-cyclohexan-1-one (INT-965) (2 g, 9.22 mmol) was suspended in 40 mL EtOH/H.sub.2O (1:1 v/v) at RT under argon atmosphere. (NH.sub.4).sub.2CO.sub.3 (3.62 g, 23.04 mmol) and KCN (0.6 g, 9.22 mmol) were added. The reaction mixture was stirred at 60° C. for 18 h. The reaction mixture was cooled to 0° C. and diluted with ice-water and filtered through a glass filter. The solid residue was dried under reduced pressure to afford 8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decane-2,4-dione (1.8 g, 86%) as an off white crystalline solid (TLC: 80% EtOAc in hexane; Rf: 0.25).
Step 2: 8-(dimethylamino)-8-phenyl-1, 3-diazaspiro [4, 5] decan-2-one
[0262] 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
[0263] 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
[0264] ##STR00028##
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
[0265] 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 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 combined 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
[0266] CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5] decan-1-yl]-acetic acid tert-butyl ester (200 mg, 0.4 mmol) was dissolved in TFA (5 mL) and heated to reflux overnight. After cooling to RT all volatiles are removed in vacuo. The residue was taken up in THF (1 mL) and added dropwise to diethyl ether (20 mL). The resulting precipitate was filtered off and dried under reduced pressure to give CIS-2-(8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-acetic acid; 2,2,2-trifluoro-acetic acid salt (INT-977) (119 mg) as a white solid. [M+H].sup.+ 332.2
Synthesis of INT-978: CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-N,N-dimethyl-acetamide
[0267] ##STR00029##
[0268] CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-acetic acid (INT-977) trifluoroacetic acid salt (119 mg, 0.35 mmol) was dissolved in DCM (5 mL). Triethylamine (0.21 mL, 1.6 mmol), dimethylamine (0.54 mL, 1.1 mmol) and T3P (0.63 mL, 1.1 mmol) were sequentially added. The reaction mixture was stirred at RT overnight, then diluted with 1 M aq. Na.sub.2CO.sub.3 (5 mL). The aqueous layer was extracted with DCM (3×5 mL), the combined organic layers were dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to yield CIS-2-(8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-N,N-dimethyl-acetamide (INT-978) (39 mg) as a white solid. [M+H].sup.+ 359.2
Synthesis of INT-982: CIS-8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
[0269] ##STR00030##
Step 1: CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-1-((1-methylcyclobutyl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
[0270] 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 residue by 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
[0271] 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
[0272] ##STR00031##
Step 1: CIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
[0273] 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.
Step 2: CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
[0274] 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
[0275] ##STR00032##
Step 1: CIS-3-benzyl-1-(cyclobutylmethyl)-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
[0276] 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-(ethyl(methyl)amino)-8-phenyl-1,3-diazaspiro [4.5]decan-2-one
[0277] 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)
[0278] Sodium metal (1.18 g, 51.68 mmol, 10 equiv.) was added to liquid ammonia (˜25 mL) at −78° C. The resulting mixture was stirred for 10 min at −78° C. A solution of CIS-3-benzyl-1-(cyclobutylmethyl)-8-(ethyl(methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (2.3 g, 5.16 mmol) in THF (25 mL) was added at −78° C. The reaction mixture was stirred for 15 min, then quenched with sat. aq. NH.sub.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
[0279] ##STR00033##
[0280] 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
[0281] ##STR00034##
Step 1: CIS-8-(dimethylamino)-1-[2-(1-methoxycyclobutyl)ethyl]-3-[(4-methoxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
[0282] 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)
[0283] 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-1008: CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one
[0284] ##STR00035##
Step 1 and step 2: ethyl-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-amine hydrochloride (INT-1004)
[0285] 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 and the residue was diluted with ether (60 ml), and a freshly prepared PhLi solution was added [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). The reaction mixture was stirred at RT for 1.5 h, quenched with saturated NH.sub.4Cl solution (100 ml) at 0° C. and extracted with ethyl acetate (2×750 ml). The combined organic layer was washed with water (3×350 ml), brine (300 ml), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The resulting residue was dissolved in ethyl methyl ketone (100 ml) and trimethylsilyl chloride (37.5 ml) was added at 0° C. The resulting mixture was stirred at RT for 16 h. The precipitated solid was filtered off and washed with acetone followed by THF to get 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)
[0286] 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. aq. HCl (62.5 ml) at 0° C. and the resulting mixture was stirred at RT for 16 h. The reaction mixture was basified with aq. NaOH (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 the yield is given for 2 combined batches. Yield: 92% (17.0 g, 78.34 mmol).
Step 4: cis and trans mixture of 8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (INT-1006 and INT-1007)
[0287] 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 added and stirring was continued at 60° C. for 18 h. The reaction mixture was cooled down to RT. The precipitated solid 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 of 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)
[0288] 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, 960 ml) was added a solution of L-tartaric acid in MeOH (25 ml) and the resulting mixture stirred at RT for 2 h and then kept in refrigerator for 16 h. The precipitated solid was filtered off and washed with MeOH-DCM (1:5, 50 ml) to get tartrate salt of 8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (7.5 g) as a white solid. To this solid sat. aq. NaHCO.sub.3 was added (pH˜8) and the resulting mixture was extracted with 25% MeOH-DCM (2×800 ml). Combined organic layer was washed with water (300 ml), brine (300 ml), dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was triturated with 20% DCM-hexane and the resulting solid was dried under reduced pressure to afford CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione as white solid. This step was done in 2 batches (12 g & 2.4 g) and the 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)
[0289] To a slurry of LiAlH.sub.4 (793 mg, 20.91 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, 6.97 mmol, 1.0 eq.) in THF (60 ml) at 0° C. and the reaction mixture was heated to 65° C. for 16 h. The reaction 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 pad. The residue 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 to give crude product which 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+1].sup.+=274.2.
Synthesis of INT-1026: CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
[0290] ##STR00036##
Step 1: 2-methyl-N-(1,4-dioxaspiro[4.5]decan-8-ylidene)propane-2-sulfinamide
[0291] 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
[0292] 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
[0293] 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)propane-2-sulfinamide (6.0 g, 17.80 mmol) in DCM (60 mL) at 0° C. The reaction mixture was stirred at RT for 2 h. The reaction mixture was concentrated in vacuo. The residue was washed with diethyl ether to yield 3 g (crude) of 8-phenyl-1,4-dioxaspiro[4.5]decan-8-amine hydrochloride as a brown solid (TLC system: 5% MeOH in DCM; Rf: 0.10).
Step 4: 8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amine
[0294] 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)
[0295] 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
[0296] 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
[0297] 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
[0298] 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)
[0299] LiAlH.sub.4 (1M 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]+=344.2.
Synthesis of INT-1031: CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one
[0300] ##STR00037##
Step 1: CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one
[0301] 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
[0302] 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-1037: 8-(dimethylamino)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile
[0303] ##STR00038##
Step 1: 9,12-dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}.2{circumflex over ( )}{5}]tetradecan-3-one
[0304] 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
[0305] 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)
[0306] 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
[0307] ##STR00039##
[0308] 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-1052: CIS-3-(2-amino-2-methylpropyl)-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
[0309] ##STR00040##
Step 1: CIS-3-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanenitrile
[0310] NaH (60% in mineral oil) (1.76 g, 44.04 mmol) was added to the solution of CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-983) (3.6 g, 11.01 mmol) in DMSO (150 mL) at RT under argon atmosphere. 2-Cyano-2-methylpropyl 4-methylbenzenesulfonate (113 mg, 0.45 mmol) was added to the reaction mixture in one portion. The reaction mixture was heated at 70° C. for 16 h. The reaction mixture was cooled to 0° C. and quenched with water (20 mL). The organic product was extracted with EtOAc (2×200 mL). 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 column chromatography (silica gel 100-200 mesh, 0-10% MeOH in DCM) to get 2.1 g, 46% of CIS-3-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanenitrile as an off-white solid (TLC system: 5% MeOH in DCM; Rf: 0.60).
Step 2: CIS-3-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanamide
[0311] H.sub.2O.sub.2 (30% in water) (8 mL) was added to a solution of CIS-3-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanenitrile (2.0 g, 4.90 mmol) in DMSO (50 mL) at RT under argon atmosphere. A solution of KOH (1.1 g, 19.6 mmol) in water (10 mL) was added dropwise to the reaction mixture. The reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with water (300 mL) and the organic product was extracted with EtOAc (2×100 mL). The combined organic extracts were dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel 100-200 mesh, 0-5% MeOH in DCM) to get 0.44 g (21%) of CIS-3-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanamide as a gummy solid (TLC system: 5% MeOH in DCM; R.sub.f: 0.30) and 1.1 g of CIS-3-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanenitrile was also reisolated (TLC system: 5% MeOH in DCM; Rf: 0.30).
Step 3: CIS-3-(2-amino-2-methylpropyl)-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1052)
[0312] PhI(OCOCF.sub.3).sub.2 (703.5 mg, 1.636 mmol) was added to a solution of CIS-3-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanamide (410 mg, 0.962 mmol) in mixture of acetonitrile (15 mL) and water (15 mL) at RT under argon atmosphere. The reaction mixture was stirred for 18 h at RT. The reaction mixture was diluted with water (15 mL) and the aqueous layer was washed with EtOAc (2×20 mL). The water layer was basified with solid NaHCO.sub.3 and the organic product was extracted with EtOAc (2×30 mL). The organic layer was dried over anhydr. Na.sub.2SO.sub.4 and solvent was concentrated under reduced pressure to afford 350 mg, 91% of CIS-3-(2-amino-2-methylpropyl)-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one as gummy solid (TLC system: 5% MeOH in DCM; Rf: 0.15). Mass: m/z 399.3 (M+H).sup.+.
Synthesis of INT-1054: CIS-8-(dimethylamino)-8-(m-tolyl)-1,3-diazaspiro[4.5]decan-2-one
[0313] ##STR00041##
[0314] To a stirred solution of 4-dimethylamino-4-phenyl-cyclohexanone (50 g, 230.1 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 stirred for 15 min. NaCN (22.5 g, 460.83 mmol) was added to the reaction mixture and stirred for 16 h at RT. The reaction mixture was extracted with DCM (3×750 ml). Organic layer was washed with water (750 ml), brine (750 ml) and dried over Na.sub.2SO.sub.4. The solvent was evaporated under reduced pressure. The residue was triturated with DCM/hexane to get crude 1-amino-4-dimethylamino-4-phenyl-cyclohexanecarbonitrile (50 g, 90%) as off white solid which was used in next step without purification. Yield: 78% (44 g, 181 mmol). Mass: m/z 244.2 (M+H).sup.+.
Synthesis of INT-1055 and INT-1056: CIS- and TRANS-3-(2-amino-2-methylpropyl)-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
[0315] ##STR00042##
Step 1: N-(1-cyano-4-(dimethylamino)-4-phenylcyclohexyl)cyclobutanecarboxamide (CIS-/TRANS mixture)
[0316] To a solution of 1-amino-4-dimethylamino-4-phenyl-cyclohexanecarbonitrile (INT-1054) (5.0 g, 20.57 mmol, 1.0 eq.) in THF (100 mL) were added cyclobutanecarboxylic acid (2.50 g, 24.69 mmol, 1.2 eq), DIPEA (10.5 mL, 61.71 mmol, 3.0 eq) and T3P (18.38 mL, 30.85 mmol, 1.5 eq). The reaction mixture was stirred at RT for 16 h, diluted with water (100 mL) and extracted with EtOAc (2×200 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 cyclobutanecarboxylic acid (1-cyano-4-dimethylamino-4-phenyl-cyclohexyl)-amide as a light yellow sticky material which was used in the next step without further purification. Mass: m/z 326.3 (M+H).sup.+.
Step 2: 1-(aminomethyl)-N.SUP.1.-(cyclobutylmethyl)-N.SUP.4.,N.SUP.4.-dimethyl-4-phenylcyclohexane-1,4-diamine (CIS/TRANS-mixture)
[0317] To suspension of LiAlH.sub.4 (2.81 g, 73.84 mmol, 6.0 eq.) in dry THF (25 mL) was added a solution cyclobutanecarboxylic acid (1-cyano-4-dimethylamino-4-phenyl-cyclohexyl)-amide (4.0 g, 12.3 mmol, 1.0 eq.) in dry THF (35 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 stirred at RT for 2 h. The reaction mixture was filtered through celite and washed with THF (100 mL). Filtrate was concentrated under reduced pressure to get crude 1-aminomethyl-N-cyclobutylmethyl-N′,N′-dimethyl-4-phenyl-cyclohexane-1,4-diamine (3.0 g) as a light yellow sticky material which was used in the next step without further purification. Mass: m/z 316.4 (M+H).sup.+.
Step 3: N-((1-((cyclobutylmethyl)amino)-4-(dimethylamino)-4-phenylcyclohexyl)methyl)-2-methyl-2-(methylthio)propanamide (CIS/TRANS-mixture)
[0318] To a solution of crude 1-aminomethyl-N-cyclobutylmethyl-N′,N′-dimethyl-4-phenyl-cyclohexane-1,4-diamine (3.0 g, 9.23 mmol, 1.0 eq.) in THF (50 mL) were added 2-methyl-2-methylsulfanyl-propionic acid (1.23 g, 9.23 mmol, 1.0 eq), DIPEA (4.81 mL, 27.69 mmol, 3.0 eq) and T3P (8.3 mL, 13.84 mmol, 1.5 eq, 50% solution in EtOAc) at 0° C. and the resulting mixture was stirred at RT for 16 h. The reaction mixture was diluted with DCM (300 mL), washed with water (100 mL) and brine (100 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to get crude N-[1-(cyclobutylmethyl-amino)-4-dimethylamino-4-phenyl-cyclohexylmethyl]-2-methyl-2-methylsulfanyl-propionamide as a light yellow sticky material which was used in the next step without further purification. Mass: m/z 432.1 (M+H).sup.+.
Step 4: N.SUP.1.-(cyclobutylmethyl)-N.SUP.4.,N.SUP.4.-dimethyl-1-(((2-methyl-2-(methylthio)propyl)amino)methyl)-4-phenylcyclohexane-1,4-diamine (CIS/TRANS-mixture)
[0319] To a solution of crude N-[1-(cyclobutylmethyl-amino)-4-dimethylamino-4-phenyl-cyclohexylmethyl]-2-methyl-2-methylsulfanyl-propionamide (2.5 g, 5.8 mmol, 1.0 eq.) in THF (60 mL) was added BH.sub.3×Me.sub.2S (2.75 ml, 29.0 mmol, 5.0 eq.). The reaction mixture was stirred at RT for 16 h, then quenched with MeOH (10 mL) and 2N HCl (10 mL) at 0° C. and stirred at RT for 30 min. The resulting mixture was concentrated under reduced pressure, diluted with water (50 mL), basified with sat. aq. NaHCO.sub.3 and extracted with DCM (2×250 mL). Combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to get crude N-cyclobutylmethyl-N′,N′-dimethyl-1-[(2-methyl-2-methylsulfanyl-propylamino)-methyl]-4-phenyl-cyclohexane-1,4-diamine as a light yellow sticky material which was used in the next step without further purification. Mass: m/z 418.4 (M+H).sup.+.
Step 5: CIS- and TRANS-3-(2-amino-2-methylpropyl)-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1055 and INT-1056)
[0320] To a solution of crude N-cyclobutylmethyl-N′,N′-dimethyl-1-[(2-methyl-2-methylsulfanyl-propylamino)-methyl]-4-phenyl-cyclohexane-1,4-diamine (2.0 g, 4.79 mmol, 1.0 eq.) in toluene (30 ml) was added KOH (1.61 g, 28.77 mmol, 6.0 eq) in water (60 mL) at 0° C. followed by addition of COCl.sub.2 (5.84 L 16.76 mmol, 3.5 eq., 20% in toluene). The reaction mixture was stirred at RT for 16 h, then basified with sat. aq. NaHCO.sub.3 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-1-cyclobutylmethyl-8-dimethylamino-3-(2-methyl-2-methylsulfanyl-propyl)-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (INT-1055) as peak 2 (45 mg) and TRANS-1-cyclobutylmethyl-8-dimethylamino-3-(2-methyl-2-methylsulfanyl-propyl)-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (INT-1056) as peak 1 (300 mg). Mass: m/z 444.1 (M+H).sup.+ (trans), m/z 444.0 (M+H).sup.+ (cis).
Synthesis of INT-1059: TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
[0321] ##STR00043##
Step 1: TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione
[0322] 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)
[0323] 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
[0324] ##STR00044##
Step 1: 1-amino-4-dimethylamino-4-phenyl-cyclohexanecarbonitrile
[0325] 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
[0326] 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
[0327] 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)
[0328] 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-dimethylamino-8-phenyl-1-(2,2,2-trifluoro-ethyl)-1,3-diaza-spiro[4.5]decan-2-one (INT-1069) as minor isomer (non-polar spot on TLC) (120 mg, 92.93% by HPLC) as off-white solids. CIS-isomer: LC-MS: m/z [M+1].sup.+=356.2 (MW calc.=355.40). HPLC: 98.53%, Column: Xbridge C-18 (100×4.6), 5μ, 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).
Synthesis of INT-1071: CIS-8-(dimethylamino)-8-phenyl-1-(2,2,2-trifluoroethyl)-1,3-diazaspiro[4.5]decan-2-one
[0329] ##STR00045##
Step 1: tert-butyl CIS-2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate
[0330] To a solution of CIS-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (INT-976) (10.0 g, 36.63 mmol, 1.0 eq.) in dry THF (1.5 L) was added potassium tert-butoxide (7.14 mg, 36.63 mmol, 1.1 eq.) at RT. The reaction mixture was stirred for 30 min followed by addition of tert-butyl bromo acetate (4.51 g, 40.293 mmol, 1.1 eq.). The reaction mixture was stirred at RT for 4 h, poured into ice-water and extracted with EtOAc (2×700 mL). The organic layer was washed with water (400 mL), brine (400 mL) and dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (neutral alumina; 1% MeOH/Hexane) to yield CIS-(8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic acid tert-butyl ester (7 g, 18.06 mmol, 49%) as a white solid. LC-MS: m/z [M+1].sup.+=387.9 (MW calc.=387.52).
Step 2: mixture of CIS-(1-cyclopropylmethyl-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic acid cyclopropylmethyl ester and CIS-(1-cyclopropylmethyl-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic acid tert-butyl ester
[0331] To a solution of CIS-(8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic acid tert-butyl ester (2.0 g, 5.16 mmol, 1.0 eq.) in dry DMF (40 mL) was added 60 wt % NaH (413 mg, 10.33 mmol, 2 eq.) at RT. The reaction mixture was stirred for 30 min followed by addition of bromomethylcyclopropane (1.74 g, 12.91 mmol, 2.5 eq.). The reaction mixture was stirred at RT for 20 h, poured slowly into ice-water and extracted with EtOAc (2×400 mL). The organic layer was washed with water (2×200 mL), brine (200 mL) and dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to get crude product which was purified by column chromatography (neutral alumina; 30% EA/Hexane) to yield a mixture of CIS-(1-cyclopropylmethyl-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic acid cyclopropylmethyl ester and CIS-(1-cyclopropylmethyl-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic acid tert-butyl ester (3:2) (1.1 g, 2.505 mmol, 48%) as a light brown sticky liquid. LC-MS: m/z [M+1].sup.+=440.0, 442.0 (MW calc.=439.59, 441.61).
Step 3: CIS-2-(1-cyclopropylmethyl-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetamide
[0332] To a mixture of CIS-(1-cyclopropylmethyl-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic acid cyclopropylmethyl ester and CIS-(1-cyclopropylmethyl-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic acid tert-butyl ester (2.0 g, 4.55 mmol, 1.0 eq.) in dry MeOH (5 mL) was added 7M NH.sub.3 in MeOH (15 mL) and the reaction mixture was stirred in a sealed tube at 95° C. for 48 h. Solvent was evaporated under reduced pressure to get crude product which was purified by column chromatography (neutral alumina; 2% MeOH/DCM) to yield CIS-2-(1-cyclopropylmethyl-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetamide (1.2 g, 3.15 mmol, 68%) as an off-white solid. LC-MS (Method 1): m/z [M+H].sup.+=385.2 (MW calc.=384.52).
Step 4: CIS-(1-cyclopropylmethyl-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl) acetonitrile (INT-1071)
[0333] To a solution of CIS-2-(1-cyclopropylmethyl-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetamide (1.7 g, 4.42 mmol, 1.0 eq.) in dry DMF (40 mL) was added cyanuric chloride (2.4 g, 13.28 mmol, 3 eq.) at RT. The reaction mixture was stirred at RT for 1.5 h, basified (pH˜9) with sat. aq. NaHCO.sub.3 and extracted with EtOAc (2×400 mL). The combined organic layer was washed with water (2×300 mL), brine (300 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to get crude product which was purified by column chromatography (neutral alumina; 80% DCM/Hexane) to yield CIS-(1-cyclopropylmethyl-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl) acetonitrile (1.1 g, 3.00 mmol, 68%) as an off-white solid. LC-MS: m/z [M+1].sup.+=367.3 (MW calc.=366.50).
[0334] 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 Inter- in analogy m/z mediate Chemical Name Chemical Structure to method [M + H].sup.+ INT- 794 CIS-3-(3,4-dimethoxybenzyl)-8-(dimethylamino)-8- phenyl-1,3-diazaspiro[4.5]decan-2-one
Synthesis of Exemplary Compounds
Synthesis of SC_4001: CIS-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-butyramide
[0335] ##STR00099##
[0336] CIS-4-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-butyronitrile (SC_4012) (201 mg, 0.5 mmol) was dissolved in DMSO (7 mL) and K.sub.2CO.sub.3 (136 mg, 1 mmol) and hydrogen peroxide (30% in water, 0.7 mL) were added. The resulting mixture was stirred at RT for 18 h, then quenched with 2N aq. NaOH (5 mL) and extracted with ethyl acetate (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-4-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-butyramide SC_4001 (58 mg) as a white solid. [M+H].sup.+ 427.3
Synthesis of SC_4003: CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
[0337] ##STR00100##
[0338] In an oven dried flask, sodium hydroxide powder (28 mg, 0.7 mmol) was added to DMSO (0.25 mL) at RT. The mixture was stirred for 5 min, then CIS-1-(cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-987) (60 mg, 0.18 mmol) was added and the reaction mixture was stirred for 10 min at RT. 1-[2-(2-Bromo-ethoxy)ethoxy]-2-methoxy-ethane (120 mg, 0.53 mmol) was added and the resulting mixture was stirred for 30 min at RT and for 2 h at 60° C. Water was added and the aqueous layer was extracted with DCM (3×10 mL). The combined organic layers were dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by flash chromatography to yield CIS-1-(cyclobutyl-methyl)-8-dimethylamino-3-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_4003) (38 mg) as a white solid. [M+H].sup.+ 488.3
Synthesis of SC_4010: CIS-1-(Cyclobutyl-methyl)-8-methylamino-3-(2-methylsulfonyl-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
[0339] ##STR00101##
[0340] N-Iodosuccinimide (30 mg, 0.14 mmol) was added to a suspension of CIS-1-(cyclobutyl-methyl)-8-dimethylamino-3-(2-methylsulfonyl-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_4009) (40 mg, 0.09 mmol) in a mixture of acetonitrile and THF (1:1 v/v, 20 mL) at RT and the resultant 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 under reduced pressure. 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. The residue was purified by flash chromatography and prep. HPLC to give 16 mg of CIS-1-(cyclobutyl-methyl)-8-methylamino-3-(2-methylsulfonyl-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_4010). [M+H].sup.+ 434.2
Synthesis of SC_4012: CIS-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-butyronitrile
[0341] ##STR00102##
[0342] Potassium cyanide (131 mg, 2 mmol) and sodium iodide (202 mg, 1.4 mmol) were added to a solution of CIS-3-(3-chloro-propyl)-1-(cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_4027) (57 mg, 1.4 mmol) in DMSO (5 mL) at RT and the resulting mixture was stirred at 90° C. for 18 h. The reaction mixture was quenched with water (5 mL) and extracted with ethyl acetate (5×25 mL). The combined organic layers were dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by flash chromatography to yield CIS-4-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-butyronitrile (SC_4012) (38 mg) as a white solid. [M+H].sup.+ 409.3
Synthesis of SC_4013: CIS-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-butyramide
[0343] ##STR00103##
[0344] CIS-4-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-butyric acid methyl ester (SC_4028) (59 mg, 0.13 mmol) was treated with 2M methylamine in methanol (1.5 mL) and heated for 100 min at 100° C. in a closed vessel. Volatiles were removed under a stream of nitrogen, the residue was taken up in 2M methylamine in methanol (1.5 mL) and heated for 50 min at 120° C. in a closed vessel. All volatiles were removed under a stream of nitrogen to afford the crude product, which was purified by column chromatography to yield 49 mg of CIS-4-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-butyramide (SC_4013) as a white solid. [M+H].sup.+ 441.3
Synthesis of SC_4025: CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-(tetrahydro-pyran-4-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one
[0345] ##STR00104##
[0346] KOtBu (1M in THF) (0.5 mL, 0.504 mmol) was added to a suspension of CIS-8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-799) (0.15 g, 0.42 mmol) in THF (4 mL) at 0° C. The reaction mixture was stirred for 10 min and a solution of 4-(bromomethyl)tetrahydro-2H-pyran (90 mg, 0.504 mmol) in THF (2 mL) was added. The reaction mixture was stirred at 70° C. for 16 h, then quenched with sat. aq. NH.sub.4Cl (5 mL) and extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with water, brine, dried over anhydr. Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by preparative TLC to afford 0.044 g of CIS-8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-(tetrahydro-pyran-4-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one (SC_4025) as an off-white solid (TLC system: 10% MeOH in DCM R.sub.f: 0.52.). [M+H].sup.+ 456.3
Synthesis of SC_4027: CIS-3-(3-Chloro-propyl)-1-(cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
[0347] ##STR00105##
[0348] Sodium hydride (60% suspension in mineral oil, 23 mg, 0.6 mmol) was added to a solution of CIS-1-(cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-987) (100 mg, 0.3 mmol) in THF (3 mL) at 0° C. and the resulting mixture was stirred for 30 min at 50° C. A solution of 1-bromo-3-chloro-propane (0.14 mL, 1.5 mmol) in THF (0.7 mL) was added at 50° C. and stirring was continued at 80° C. for 18 h. The reaction mixture was quenched with cold water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by flash chromatography to yield CIS-3-(3-chloro-propyl)-1-(cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_4027) (50 mg) as a white powder. [M+H].sup.+ 418.3
Synthesis of SC_4028: CIS-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-butyric acid methyl ester
[0349] ##STR00106##
[0350] CIS-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-butyronitrile SC_4012 (345 mg, 0.85 mmol) was dissolved in 5 mL conc. HCl and stirred for 6 h at 100° C. Volatiles were removed under reduced pressure to afford the crude product as hydrochloride salt. This salt was dissolved in MeOH/toluene and concentrated under reduced pressure. The latter dissolution/evaporation cycle was repeated, yielding 380 mg of CIS-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro [4.5]decan-3-yl]-butyric acid methyl ester SC_4028. [M+H].sup.+ 442.
Synthesis of SC_4031: CIS-3-acetyl-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
[0351] ##STR00107##
[0352] To the mixture of CIS-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (INT-976) (3.5 g, 12.83 mmol, 1.0 eq.) and K.sub.2CO.sub.3 (3.54 g, 25.66 mmol, 2.0 eq.) in THF (200 ml) at 0° C. was added acetyl chloride (1.4 ml, 19.23 mmol, 1.5 eq.). The reaction mixture was stirred at RT for 3 h, diluted with DCM (300 ml) and filtered through Celite. The filtrate was washed with sat. aq. NaHCO.sub.3 (100 ml), water (100 ml) and brine (100 ml). The organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel neutralized with ammonia, 5% MeOH/DCM) to yield CIS-3-acetyl-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (SC-4031) as an off white solid. Note: This reaction was done in two parallel batches of 3.5 g scale and yield given for two combined batches. Yield: 63% (5.1 g, 16.19 mmol). .sup.1HNMR (DMSO-d6, 400 MHz), δ (ppm)=8.05 (bs, 1H), 7.36-7.25 (m, 5H), 3.44 (s, 2H), 2.31 (s, 5H, CH3+CH2), 1.92 (s, 6H), 1.83-1.76 (m, 4H), 1.39 (bs, 2H). Mass: m/z 316.1 [M+H].sup.+
Synthesis of SC_4032: CIS-8-(dimethylamino)-3-(2-(methylsulfonyl)ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
[0353] ##STR00108##
[0354] KOtBu (1M in THF) (1.1 mL, 0.11 mmol) was added to the suspension of CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976) (0.3 g, 0.11 mmol) in THF (10 mL) at 0° C. The reaction mixture was stirred for 10 min and 1-bromo-2-(methylsulfonyl)ethane (0.16 g, 0.09 mmol) was added. The reaction mixture was stirred at 0° C. for 4 h, then quenched with sat. aq. NH.sub.4C.sub.1 (15 mL) and the organic product was extracted with DCM (3×20 mL). The combined organic extracts were washed with brine, dried over anhydr. Na.sub.2SO.sub.4 and concentrated under reduced pressure. Purification of the residue by reverse phase preparative HPLC afforded 180 mg (43%) of CIS-8-(dimethylamino)-3-(2-(methylsulfonyl)ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_4032) as an off white solid (TLC system: 10% MeOH in DCM R.sub.f: 0.3.). .sup.1H NMR (DMSO-d6): δ 7.37-7.23 (m, 5H), 6.90 (br s, 1H), 3.43 (t, 2H), 3.26 (t, 2H), 3.10 (s, 2H), 2.95 (s, 3H), 2.32 (br m, 2H), 1.93 (s, 6H), 1.79-1.76 (m, 4H), 1.38-1.36 (m, 2H). Mass: m/z 380.2 [M+H].sup.+
Synthesis of SC_4033: CIS-1-acetyl-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
[0355] ##STR00109##
Step 1: CIS-1-acetyl-8-(dimethylamino)-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
[0356] To a solution of CIS-8-dimethylamino-3-(4-methoxy-benzyl)-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (INT-975) (19.5 g, 49.6 mmol, 1.0 eq.) in THF (180 ml) was added 2.5M solution of n-BuLi in hexane (39.7 ml, 99.23 mmol, 2.0 eq.) at 0° C. and the resulting mixture was stirred for 1 h. A solution of acetyl chloride (7.7 g, 99.23 mmol, 2.0 eq.) in THF (20 ml) was added dropwise at 0° C. The cooling bath was removed, the reaction mixture was stirred at RT for 16 h, then cooled down to 0° C. again, quenched with water and extracted with ethyl acetate (2×200 ml). The combined organic extracts were washed with brine (250 ml), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; 30% EtOAc/Hexane) to yield CIS-1-acetyl-8-dimethylamino-3-(4-methoxy-benzyl)-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (6.1 g, 14.02 mmol, 28%) as a light yellow sticky solid. Mass: m/z 436.3 [M+H].sup.+
Step 2: CIS-1-acetyl-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_4033)
[0357] To a solution of CIS-1-acetyl-8-dimethylamino-3-(4-methoxy-benzyl)-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (5.0 g, 11.5 mmol, 1.0 eq.) in acetonitrile (60 ml) was added a solution cerium(IV) ammonium nitrate (18.98 g, 34.5 mmol, 3.0 eq.) in water (60 ml) at 0° C. and the reaction mixture was stirred at RT for 2 h. The reaction mixture was quenched with aq. NaHCO.sub.3 solution (50 ml) and extracted with ethyl acetate (2×100 ml). The combined organic layer was washed with brine (2×100 ml), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel neutralized with TEA; 2/3 v/v EtOAc/Hexane) to yield CIS-1-acetyl-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (SC 4033) as an off white solid. Yield: 61% (4.9 g, 15.55 mmol). .sup.1HNMR (DMSO-d6, 400 MHz), δ (ppm)=7.57 (s, 1H), 7.33-7.23 (m, 5H), 3.21 (s, 2H), 3.03 (t, 2H, J=12.78 Hz), 2.60 (d, 2H, J=13.32 Hz), 2.32 (s, 3H), 1.89 (s, 6H), 1.37-1.32 (m, 4H). Mass: m/z 316.2 [M+H].sup.+
Synthesis of SC_4034: CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-3-(2-(methylsulfonyl)ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
[0358] ##STR00110##
[0359] To a solution of CIS-8-dimethylamino-3-(2-methanesulfonyl-ethyl)-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (SC_4032) (150 mg, 0.395 mmol, 1.0 eq.) in dry DMF (5 ml) was added 60% NaH (47 mg, 1.18 mmol, 3.0 eq.) at RT and the reaction mixture was stirred for 20 min. Bromomethylcyclopropane (160 mg, 1.18 mmol, 3.0 eq.) was added and the reaction mixture was stirred for 16 h. The reaction mixture was quenched with ice-water (20 ml) and extracted with EtOAc (2×20 ml). The combined organic layers were washed with water (20 ml) and brine (20 ml), dried over anhydr. Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; 3% MeOH/DCM) to yield CIS-1-cyclopropylmethyl-8-dimethylamino-3-(2-methanesulfonyl-ethyl)-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (80 mg, 0.18 mmol, 47%) (SC_4034) as a white solid. .sup.1HNMR (CDCl3, 400 MHz), δ (ppm)=7.36-7.24 (m, 5H, merged with CDCl3), 3.65 (t, 2H, J=6.46 Hz), 3.27 (t, 2H, J=6.46 Hz), 3.23 (s, 2H), 3.04 (d, 2H, J=6.7 Hz), 2.94 (s, 3H), 2.65-2.62 (m, 2H), 2.30-2.23 (m, 2H), 2.02 (s, 6H), 1.46-1.40 (m, 4H), 1.02-0.98 (m, 1H), 0.53-0.49 (m, 2H), 0.33-0.29 (2H). Mass: m/z 434.0 (M+H).sup.+ (MW calc.=433.61).
Synthesis of SC_4037: CIS-8-(dimethylamino)-8-phenyl-1-tosyl-1,3-diazaspiro[4.5]decan-2-one
[0360] ##STR00111##
Step 1: CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-8-phenyl-1-tosyl-1,3-diazaspiro[4.5]decan-2-one
[0361] CIS-8-(dimethylamino)-3-[(4-methoxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-975) (500 mg, 1.271 mmol) was dissolved in THF (8 mL) under nitrogen atmosphere and the solution was cooled down to −78° C. [Bis(trimethylsilyl)amino]lithium (1M in THF, 1.5 equiv., 1.906 mmol, 1.9 mL) was added dropwise and the reaction mixture was stirred at −78° C. for 30 min, then at 0° C. for 30 min. The reaction mixture was cooled down to −78° C. again and the solution of p-toluenesulfonyl chloride (1.5 equiv., 1.906 mmol) in THF (5 mL) was added. The reaction mixture was stirred further 2.5 h at −78° C. and then the temperature was allowed to increase to RT overnight. The reaction mixture was quenched by the addition of sat. aq. NaHCO.sub.3 (20 mL). The aqueous phase was extracted with EtOAc (3×40 mL). The combined organic extracts were washed with brine (30 mL), dried over MgSO.sub.4 and concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (elution with gradient DCM/EtOH 100/0 to 97/3) yielded 281 mg (40%) of CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-8-phenyl-1-tosyl-1,3-diazaspiro[4.5]decan-2-one. .sup.1H NMR (600 MHz, DMSO) δ 7.90-7.84 (m, 2H), 7.47-7.40 (m, 2H), 7.42-7.27 (m, 4H), 7.27-7.22 (m, 1H), 7.15-7.06 (m, 2H), 6.92-6.83 (m, 2H), 4.16 (s, 2H), 3.72 (s, 3H), 3.24 (s, 2H), 2.99 (ddd, 2H), 2.70-2.62 (m, 2H), 2.42 (s, 3H), 2.01 (s, 6H), 1.56-1.49 (m, 2H), 1.31 (td, 2H). Mass: m/z 548.3 (M+H).sup.+.
Step 2: CIS-8-(dimethylamino)-8-phenyl-1-tosyl-1,3-diazaspiro[4.5]decan-2-one (SC_4037)
[0362] In analogy to the method described for INT-982 (step 2) CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-8-phenyl-1-tosyl-1,3-diazaspiro[4.5]decan-2-one was reacted with trifluoroacetic acid to be converted into CIS-8-(dimethylamino)-8-phenyl-1-tosyl-1,3-diazaspiro[4.5]decan-2-one (SC_4037). .sup.1HNMR (DMSO-d.sub.6, 400 MHz), δ (ppm)=7.82 (d, 2H, J=8.0 Hz), 7.48 (s, 1H), 7.40 (d, 2H, J=7.88 Hz), 7.35-7.24 (m, 5H), 3.27 (s, 2H), 2.97 (t, 2H, J=11.88 Hz), 2.66 (d, 2H, J=12.76 Hz), 2.39 (s, 3H), 2.0 (s, 6H), 1.60 (d, 2H, J=11.04 Hz), 1.38 (t, 2H, J=13.56 Hz). Mass: m/z 427.9 (M+H).sup.+.
Synthesis of SC_4038: CIS-8-(dimethylamino)-3-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl)-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
[0363] ##STR00112##
Step 1: CIS-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-3-((tetrahydro-2H-thiopyran-4-yl)methyl)-1,3-diazaspiro[4.5]decan-2-one
[0364] NaH (60% in mineral oil) (84.03 mg, 2.101 mmol) was added to an ice cold solution of CIS-8-(methylamino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one (INT-799) (500 mg, 1.401 mmol) in DMF (5 mL) under argon atmosphere and the resulting mixture was stirred for 2 min. The reaction mixture was allowed to warm up to RT and a solution of (tetrahydro-2H-thiopyran-4-yl)methyl 4-methylbenzenesulfonate (481.5 mg, 1.681 mmol) in DMF (4.8 mL) was added. The reaction mixture was stirred at RT for 16 h. The reaction progress was monitored by LCMS. The reaction mixture was diluted with water (50 mL) and the organic product was extracted with EtOAc (3×40 mL). The combined organic extracts were dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to give 550 mg of crude product. The crude product was purified by prep-HPLC (column LUNA-PHENYL HEXYL-C18 (150*30 mm) 5 μm, detection at 215 nm, eluent 10 mM ammonium bicarbonate in water/Acetonitrile gradient 45/55 to 2/98, flow rate: 25 ml/min) to afford 235 mg (35%) of CIS-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-3-((tetrahydro-2H-thiopyran-4-yl)methyl)-1,3-diazaspiro[4.5]decan-2-one as an off white solid (TLC system: 5% MeOH in DCM Rf: 0.63.). Mass: m/z 472.3 (M+H).sup.+.
Step 2: CIS-8-(dimethylamino)-3-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl)-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_4038)
[0365] A solution of oxone (599.53 mg, 0.975 mmol) in water (6 mL) was added to a solution of CIS-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-3-((tetrahydro-2H-thiopyran-4-yl)methyl)-1,3-diazaspiro[4.5]decan-2-one (230 mg, 0.488 mmol) in MeOH (8 mL) at RT under argon atmosphere. The reaction mixture was stirred for 16 h. The reaction progress was monitored by LCMS. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give 330 mg of crude product, which was purified by prep. HPLC (column LUNA-PHENYL HEXYL-C18 (150*30 mm) 5 μm, detection at 215 nm, eluent 10 mM ammonium bicarbonate in water/Acetonitrile gradient 45/55 to 2/98, flow rate: 25 ml/min) to get 128 mg (52%) of CIS-8-(dimethylamino)-3-(4-(bromomethyl)-1-Ξ6-thiane-1,1-dione)-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_4038) as an off white solid (TLC system: 10% MeOH in DCM Rf: 0.53). .sup.1H NMR (DMSO-d6): δ 7.37-7.25 (m, 5H), 6.01 (s, 1H), 3.26 (s, 2H), 3.09-2.99 (m, 8H), 2.69-2.65 (m, 2H), 2.09-1.82 (m, 15H), 1.66-1.51 (m, 3H), 1.41-1.33 (m, 5H). Mass: m/z 504.2 (M+H).sup.+.
Synthesis of SC_4044: CIS-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-3-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
[0366] ##STR00113##
[0367] NaH (0.14 g, 3.501 mmol, 60% dispersion in mineral oil) was added to a solution of CIS-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-799) (0.25 g, 0.700 mmol) in THF (40 mL) at 0° C. under argon atmosphere. The solution of 1,6-dioxaspiro[2.5]octane (0.479 g, 4.200 mmol) in THF (2 mL) was added dropwise and the reaction mixture was stirred at 85° C. for 16 h. The reaction mixture was cooled to 0° C. and quenched with water (50 mL). The organic product was extracted with ethyl acetate (2×50 mL). Combined organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 230-400 mesh size, 0-60% EtOAc in pet ether as eluent) followed by reverse phase prep HPLC to get 0.180 g of CIS-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-3-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one formiate. The product formiate salt was taken in water (20 mL), basified with solid NaHCO.sub.3 and extracted with ethyl acetate (2×20 mL). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford 0.130 g (39%) of CIS-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-3-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_4044) as an off white solid. (TLC system: 5% MeOH in DCM; Rf: 0.3). .sup.1H NMR (DMSO-d6): δ 7.37-7.34 (m, 4H), 7.27-7.26 (m, 1H), 6.04 (s, 1H), 4.51 (s, 1H), 3.61-3.56 (m, 4H), 3.43 (s, 2H), 3.09-3.05 (m, 4H), 2.70-2.67 (m, 2H), 2.07-1.82 (m, 12H), 1.63-1.61 (m, 1H), 1.51-1.30 (m, 9H). Mass: m/z 472.3 (M+H).sup.+.
Synthesis of SC_4049: CIS-(5s,8s)-3-(1-benzoylpiperidin-4-yl)-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
[0368] ##STR00114##
[0369] Triethylamine (0.51 mL, 3.65 mmol) was added to a stirred solution of CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-3-(piperidin-4-yl)-1,3-diazaspiro[4.5]decan-2-one hydrochloride (0.3 g, 0.73 mmol) in DCM (10 mL) at 0° C. under argon atmosphere. After 10 min, acetyl chloride (86 mg, 1.09 mmol) was added dropwise at 0° C. and the reaction mixture was stirred at RT for 16 h. The reaction mixture was quenched with sat. aq. NaHCO.sub.3. The organic product was extracted with DCM (2×50 mL), the combined organic layer was dried over anhydr. Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by reverse phase prep. HPLC to afford 0.133 g (40%) of CIS-3-(1-acetylpiperidin-4-yl)-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_4049) as a white solid. (TLC system: 10% MeOH in DCM; Rf: 0.55). .sup.1H NMR (DMSO-d6): δ 7.36-7.33 (m, 2H), 7.28-7.25 (m, 3H), 4.70-4.67 (m, 1H), 3.98-3.81 (m, 2H), 3.12-3.04 (m, 5H), 2.65-2.57 (m, 3H), 2.26 (t, 2H), 2.06-2.04 (m, 9H), 1.79-1.70 (m, 2H), 1.50-1.39 (m, 6H), 1.02 (m, 1H), 0.53-0.50 (m, 2H), 0.34-0.31 (m, 2H). Mass: m/z 453.3 (M+H).sup.+.
Synthesis of SC_4052: CIS-1-(cyclobutylmethyl)-8-(dimethylamino)-3-(2-(1-hydroxycyclohexyl)ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
[0370] ##STR00115##
Step 1: CIS-3-(2-(1-(benzyloxy)cyclohexyl)ethyl)-1-(cyclobutylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro [4.5]decan-2-one
[0371] In analogy to the method described for SC_4034 CIS-1-(cyclobutylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-787) was reacted with 2-(4-(benzyloxy)tetrahydro-2H-pyran-4-yl)ethyl 4-methylbenzenesulfonate to be converted into CIS-3-(2-(1-(benzyloxy)cyclohexyl)ethyl)-1-(cyclobutylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one. Mass: m/z 558.4 (M+H).sup.+.
Step 2: CIS-1-(cyclobutylmethyl)-8-(dimethylamino)-3-(2-(1-hydroxycyclohexyl)ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_4052)
[0372] Trifluoroacetic acid (20 mL) was added to CIS-3-(2-(1-(benzyloxy)cyclohexyl)ethyl)-1-(cyclobutylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (0.4 g, 0.71 mmol) at RT. The reaction mixture was stirred at RT for 16 h and then concentrated under reduced pressure. To the residue sat. aq. NaHCO.sub.3 was added and the organic product was extracted with dichloromethane (3×150 mL). The combined organic extract was 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; 4-8% MeOH in DCM as eluent) and further by reverse phase prep HPLC to afford 0.112 g (40%) of CIS-1-(cyclobutylmethyl)-8-(dimethylamino)-3-(2-(1-hydroxycyclohexyl)ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_4052) as a white solid. (TLC system: 10% MeOH in DCM; Rf: 0.45). .sup.1H NMR (DMSO-d6): δ 7.37-7.32 (m, 4H), 7.27-7.23 (m, 1H), 4.25 (s, 1H), 3.62-3.49 (m, 4H), 3.17-3.13 (m, 2H), 3.09 (s, 2H), 3.01 (d, 2H), 2.66-2.63 (m, 2H), 2.05-2.02 (m, 1H), 1.97-1.91 (m, 9H), 1.80-1.65 (m, 4H), 1.53-1.43 (m, 5H), 1.38-1.35 (m, 6H). Mass: m/z 470.4 (M+H).sup.+.
Synthesis of SC_4054: CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-3-(piperidin-4-yl)-1,3-diazaspiro[4.5]decan-2-one
[0373] ##STR00116##
Step 1: CIS-tert-butyl 4-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)piperidine-1-carboxylate
[0374] In analogy to the method described for SC_4044 CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-983) was reacted with tert-butyl 4-(tosyloxy)piperidine-1-carboxylate to be converted into CIS-tert-butyl 4-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)piperidine-1-carboxylate. Mass: m/z 511.4 (M+H).sup.+.
Step 2: CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-3-(piperidin-4-yl)-1,3-diazaspiro[4.5]decan-2-one (SC_4054)
[0375] 4N HCl in dioxane (20 mL) was added to a solution of CIS-tert-butyl 4-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)piperidine-1-carboxylate (1.9 g, 3.7 mmol) in DCM (30 mL) at 0° C. under argon atmosphere. The reaction was stirred at 0° C. for 2 h and then concentrated under reduced pressure to get CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-3-(piperidin-4-yl)-1,3-diazaspiro[4.5]decan-2-one hydrochloride as gummy, which was triturated with diethyl ether to get CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-3-(piperidin-4-yl)-1,3-diazaspiro[4.5]decan-2-one hydrochloride (SC_4054) as an off-white solid. (TLC system: 10% MeOH in DCM; Rf: 0.15). .sup.1H NMR (DMSO-d6): δ 7.37-7.32 (m, 4H), 7.28-7.23 (m, 1H), 3.58-3.50 (m, 2H), 3.10 (s, 2H), 2.94-2.89 (m, 4H), 2.66-2.62 (m, 2H), 2.46-2.41 (m, 2H), 2.13 (t, 2H), 1.97 (s, 6H), 1.49-1.41 (m, 6H), 1.32-1.29 (m, 2H), 0.93-0.88 (m, 1H), 0.46-0.42 (m, 2H), 0.25-0.24 (m, 2H). Mass: m/z 411.3 (M+H).sup.+.
Synthesis of SC_4055: CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-3-(2-hydroxy-2-methylpropyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
[0376] ##STR00117##
Step 1: tert-butyl 2-(CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate
[0377] In analogy to the method described for SC_4027 CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-983) was reacted with tert-butyl bromoacetate to be converted into tert-butyl 2-(CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate. Mass: m/z 442.3 (M+H).sup.+.
Step 2: methyl CIS-2-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate
[0378] 4M HCl in dioxane (8 mL) was added to tert-butyl CIS-2-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate (800 mg, 1.81 mmol) in DCM (6 mL) at 0° C. The reaction mixture was stirred at RT for 16 h and then concentrated under reduced pressure. The residue was suspended in DCM and the resulting mixture was concentrated under reduced pressure again. The residue was washed with diethyl ether (5 mL) to give CIS-2-(8-(dimethylamino)-3-oxo-8-phenyl-2-azaspiro[4,5]decan-2-yl)acetic acid hydrochloride which was dissolved in methanol (10 mL) and refluxed for 2 h. The reaction mixture was cooled down to RT and concentrated under reduced pressure. The residue was partitioned between EtOAc and sat. aq. NaHCO.sub.3. The organic layer was separated and washed with water, brine, dried over anhydr. Na.sub.2SO.sub.4 and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel 100-200 mesh, 0-3% MeOH in DCM) yielded 500 mg (56%) of methyl CIS-2-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate as a solid. (TLC system: 10% MeOH in DCM Rf: 0.20). Mass: m/z 400.3 (M+H).sup.+.
Step 3: CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-3-(2-hydroxy-2-methylpropyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC 4055)
[0379] Methylmagnesium bromide (3M in Et.sub.2O, 2.1 mL, 6.25 mmol) was added to a solution of methyl CIS-2-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate (500 mg, 1.25 mmol) in THF (10 mL) at 0° C. The reaction mixture was warmed to RT and stirred for 2 h. The reaction mixture was quenched with sat. aq. NH.sub.4Cl and the organic product was extracted with DCM (3×25 mL). The combined organic extracts were washed with water, brine, dried over anhydr. Na.sub.2SO.sub.4 and concentrated under reduced pressure. Purification of the resulting residue by column chromatography (silica gel 100-200 mesh, 0-3% MeOH in DCM) followed by preparative HPLC yielded 80 mg (16%) of CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-3-(2-hydroxy-2-methylpropyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_4055) as a solid. (TLC system: 10% MeOH in DCM R.sub.f: 0.20). .sup.1H NMR (DMSO d6): δ 7.36-7.33 (m, 4H), 7.26-7.24 (m, 1H), 4.39 (s, 1H), 3.30 (m, 2H), 2.95-2.91 (m, 4H), 2.69-2.66 (m, 2H), 2.18-2.13 (m, 2H), 1.97 (s, 6H), 1.37-1.31 (m, 4H), 1.03 (s, 6H), 0.92-0.91 (m, 1H), 0.46-0.43 (m, 2H), 0.26-0.23 (m, 2H). Mass: m/z 400.3 (M+H).sup.+.
Synthesis of SC_4056: CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-3-(1-(pyrimidin-5-yl)piperidin-4-yl)-1,3-diazaspiro[4.5]decan-2-one
[0380] ##STR00118##
[0381] CsCO.sub.3 (1.27 g, 3.90 mmol) was added to a solution of CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-3-(piperidin-4-yl)-1,3-diazaspiro[4.5]decan-2-one hydrochloride (SC_4054) (0.4 g, 0.97 mmol), XanthPhos (85 mg, 0.146 mmol), Pd.sub.2(dba).sub.3 (89 mg, 0.097 mmol) and 5-bromopyrimidine (0.31 g, 1.95 mmol) in 1,4-dioxane (20 mL). The mixture was purged with argon for 5 min and then stirred for 16 h at 120° C. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was diluted with DCM (20 mL), filtered through a pad of celite and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel 230-400 mesh size, 5-10% methanol in DCM as eluent) to afford 0.4 g of the desired product, which was further purified by reverse phase prep HPLC to afford 172 mg (36%) of CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-3-(1-(pyrimidin-5-yl)piperidin-4-yl)-1,3-diazaspiro[4.5]decan-2-one (SC_4056) as off-white solid. (TLC system: 10% MeOH in DCM; Rf: 0.35). .sup.1H NMR (CDCl3): δ 8.64 (s, 1H), 8.34 (s, 2H), 7.36-7.33 (m, 2H), 7.29-7.27 (m, 2H), 7.24 (m, 1H), 4.00-3.96 (m, 1H), 3.78-3.76 (m, 2H), 3.09-3.06 (m, 4H), 2.96-2.90 (m, 2H), 2.66-2.63 (m, 2H), 2.30-2.24 (m, 2H), 2.04 (s, 6H), 1.83-1.81 (m, 2H), 1.73-1.61 (m, 2H), 1.45-1.40 (m, 4H), 1.04-1.01 (m, 1H), 0.54-0.50 (m, 2H), 0.35-0.32 (m, 2H). Mass: m/z 489.3 (M+H).sup.+.
Synthesis of SC_4057: CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-3-(1-(pyrimidin-5-yl)piperidin-4-yl)-1,3-diazaspiro[4.5]decan-2-one
[0382] ##STR00119##
[0383] Triethylamine (0.23 mL, 1.70 mmol) was added to a solution of CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-3-(piperidin-4-yl)-1,3-diazaspiro[4.5]decan-2-one hydrochloride (SC_4054) (0.35 g, 0.85 mmol) and phenylboronic acid (0.21 g, 1.70 mmol) in acetonitrile (15 mL). Copper(II) acetate (155 mg, 0.85 mmol) was added and the reaction mixture was stirred at 100° C. for 24 h. The reaction mixture was cooled to RT, filtered through a pad of celite and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (3% MeOH/DCM) to give 100 mg of CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-3-(1-phenylpiperidin-4-yl)-1,3-diazaspiro[4.5]decan-2-one, which was further purified by reverse phase prep HPLC to afford 38 mg (9%) of CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-3-(1-phenylpiperidin-4-yl)-1,3-diazaspiro[4.5]decan-2-one (SC_4057) as an off-white solid. (TLC system: 10% MeOH in DCM; Rf: 0.65). .sup.1H NMR (DMSO-d6): δ 7.36-7.33 (m, 2H), 7.29-7.27 (m, 2H), 7.24-7.21 (m, 3H), 6.91 (d, 2H), 6.81 (t, 1H), 3.95-3.91 (m, 1H), 3.72-3.69 (m, 2H), 3.11-3.06 (m, 4H), 2.84-2.79 (m, 2H), 2.65-2.62 (m, 2H), 2.26 (t, 2H), 2.04 (s, 6H), 1.79-1.70 (m, 4H), 1.45-1.40 (m, 4H), 1.05-1.01 (m, 1H), 0.53-0.51 (m, 2H), 0.34-0.32 (m, 2H). Mass: m/z 487.4 (M+H).sup.+.
Synthesis of SC_4064: CIS-3-((1-aminocyclopropyl)methyl)-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
[0384] ##STR00120##
[0385] To a solution titanium isopropoxide (0.89 mL, 3.0 mmol, 2 eq.) in dry THF (15 mL) was added EtMgBr (3 M in Et.sub.2O) (2 mL, 6.0 mmol, 4 eq.) at −78° C. and the resulting mixture was stirred for 1.5 h at −78° C. A solution of CIS-(1-cyclopropylmethyl-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetonitrile (INT-1071) (550 mg, 1.50 mmol, 1.0 eq.) in THF (5 mL) was added dropwise at −78° C. The reaction mixture was stirred at same temperature for 10 min, then warmed to RT and stirred for 1.5 h. The reaction mixture was cooled again to −78° C., BF.sub.3.Math.Et.sub.2O (0.37 mL, 3.0 mmol, 2 eq.) was added and the resulting mixture was stirred at −78° C. for 10 min and at RT for 1.5 h. The reaction mixture was basified (pH˜ 9-10) with 10 wt % aq. NaOH, stirred for 30 min and extracted with EtOAc (2×250 mL). The combined organic layer was washed with water (2×150 mL), brine (200 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to get crude product which was purified by column chromatography (neutral alumina; 2.5% MeOH/DCM) to yield CIS-3-(1-amino-cyclopropylmethyl)-1-cyclopropylmethyl-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (SC_4064) as off white solid. This step was done in two batches of 550 mg scale and yield is given for combined batches. Yield: 16% (200 g, 0.25 mmol). LC-MS: m/z [M+H].sup.+=397.1 (MW calc.=396.57). .sup.1HNMR (DMSO-d.sub.6, 400 MHz), δ (ppm)=7.35-7.25 (5H), 3.24 (s, 2H), 3.00 (s, 2H), 2.92 (d, 2H, J=6.48 Hz), 2.68-2.65 (m, 2H), 2.19-2.07 (m, 2H), 1.97 (s, 6H), 1.75 (bs, 2H), 1.43-1.36 (m, 4H), 0.93 (bs, 1H), 0.46-0.36 (m, 6H), 0.25-0.23 (m, 2H).
Synthesis of SC_4071: CIS-1-(cyclobutylmethyl)-8-(dimethylamino)-3-(2-(3-hydroxyoxetan-3-yl)ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
[0386] ##STR00121##
Step 1: 2-(3-(benzyloxy)oxetan-3-yl)acetaldehyde
[0387] To a stirred solution of 3-alkyl-3-(benzyloxy)oxetane (10.0 g, 49.01 mmol, prepared from 3-alkyl-3-hydroxyoxetane and benzyl bromide) in acetone (300 mL) and water (200 mL) was added potassium osmate(VI) dihydrate (0.61 g, 1.66 mmol). The reaction mixture was cooled to 0° C. and sodium periodate (41.93 g, 916.07 mmol) was added portionwise over a period of 15 min. The reaction mixture was allowed to stir for 1 h at 0° C. The reaction mixture was filtered and the filter cake was washed with acetone (300 mL). The combined filtrate was concentrated under reduced pressure and the aqueous layer was extracted with dichloromethane (2×300 mL). The combined organic layer was washed with water (2×200 mL), brine (300 mL), dried was over anhydr. Na.sub.2SO.sub.4 and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel 230-400 mesh size 30-40% EtOAc in Pet. ether as eluent) to afford 2-(3-(benzyloxy)oxetan-3-yl)acetaldehyde (4.5 g, 43%) as a liquid. (TLC system: 40% EtOAc in Pet. ether; Rf: 0.4).
Step 2: 2-(3-(benzyloxy)oxetan-3-yl)ethanol
[0388] To a cold stirred solution of 2-(3-(benzyloxy)oxetan-3-yl)ethanol (4.50 g, 21.84 mmol) in methanol (50 mL) was added portionwise NaBH.sub.4 (1.24 g, 32.76 mmol). The reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was quenched with water (30 mL), concentrated under reduced pressure and the residue was taken in DCM (150 mL). The organic layer was washed with water (100 mL) and brine (100 mL), dried over anhydr. Na.sub.2SO.sub.4 and concentrated under reduced pressure to get 5.0 g of crude 2-(3-(benzyloxy)oxetan-3-yl)ethanol which was used in the next step without further purification.
Step 3: 2-(3-(benzyloxy)oxetan-3-yl)ethyl 4-methylbenzenesulfonate
[0389] To a stirred solution of 2-(3-(benzyloxy)oxetan-3-yl)ethanol (5.0 g, 24.03 mmol) in DCM (15 mL) were added triethylamine (13.4 mL, 96.15 mmol) and DMAP (0.29 g, 2.40 mmol). The reaction mixture was cooled to 0° C. and tosyl chloride (9.13 g, 48.07 mmol) was added to the reaction mixture portionwise. The reaction mixture was stirred at RT for 16 h, then diluted with sat. aq. NaHCO.sub.3 and the organic product was extracted with DCM (200 mL). The organic layer was dried over anhydr. Na.sub.2SO.sub.4 and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (230-400 mesh silica gel; 20-40% EtOAc in Pet. ether as eluent) to afford 2-(3-(benzyloxy)oxetan-3-yl)ethyl 4-methylbenzenesulfonate (4.0 g, 50% over 2 steps) as an off-white solid.
Step 4: CIS-3-(2-(3-(benzyloxy)oxetan-3-yl)ethyl)-1-(cyclobutylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
[0390] NaH (0.29 g, 7.33 mmol, 60% dispersion in mineral oil) was added to a solution of CIS-1-(cyclobutylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-987) (0.50 g, 1.46 mmol) in DMF (15 mL) at RT under argon atmosphere and the resulting mixture was stirred for 10 min. 2-(3-(Benzyloxy)oxetan-3-yl)ethyl 4-methylbenzenesulfonate (1.58 g, 4.39 mmol) was added and the reaction mixture was stirred at 120° C. for 16 h. The reaction progress was monitored by LCMS. The reaction mixture was cooled to 0° C. and quenched with sat. aq. NaHCO.sub.3 (50 mL). The organic product was extracted with DCM (2×100 mL), the combined organic phase was dried over anhydr. Na.sub.2SO.sub.4 and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography (silica gel 230-400 mesh size 2-5% methanol in DCM as eluent) to afford 0.40 g (51%) of CIS-3-(2-(3-(benzyloxy)oxetan-3-yl)ethyl)-1-(cyclobutylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one as a brown oil. (TLC system: 10% MeOH in DCM; Rf: 0.6).
Step 5: CIS-1-(cyclobutylmethyl)-8-(dimethylamino)-3-(2-(3-hydroxyoxetan-3-yl)ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_4071)
[0391] CIS-3-(2-(3-(benzyloxy)oxetan-3-yl)ethyl)-1-(cyclobutylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (0.38 g, 0.71 mmol) in THF (4 mL) was added to sodium metal (0.32 g, 14.31 mmol) in liquid ammonia (5 mL) at −78° C. The reaction mixture was stirred for 20 min at −78° C., then quenched with saturated NH.sub.4Cl solution and the organic product was extracted with EtOAc (2×20 mL). The combined organic layer was dried over anhydr. Na.sub.2SO.sub.4 and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography (silica gel 230-400 mesh 2-5% methanol in DCM as eluent) to afford 0.155 g (49%) of CIS-1-(cyclobutylmethyl)-8-(dimethylamino)-3-(2-(3-hydroxyoxetan-3-yl)ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_4071) as an off-white solid. (TLC system: 5% MeOH in DCM; Rf: 0.4). .sup.1H NMR (DMSO-d6): δ 7.36-7.32 (m, 4H), 7.26-7.23 (m, 1H), 5.62 (s, 1H), 4.38-4.31 (m, 4H), 3.14-3.10 (m, 4H), 3.01 (d, 2H), 2.64-2.63 (m, 2H), 2.49 (m, 1H), 2.02-1.96 (m, 10H), 1.87-1.77 (m, 6H), 1.39 (t, 2H), 1.28 (d, 2H). Mass: m/z 442.3 (M+H).sup.+.
Synthesis of SC_4072: CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-3-(2-methyl-2-(2-oxopyrrolidin-1-yl)propyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
[0392] ##STR00122##
Step 1: CIS-4-chloro-N-(1-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2-methylpropan-2-yl)butanamide
[0393] In analogy to the method described for SC_4049 CIS-3-(2-amino-2-methylpropyl)-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1052) was reacted with 4-chlorobutanoyl chloride to be converted into CIS-4-chloro-N-(1-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2-methylpropan-2-yl)butanamide. Mass: m/z 503.3 (M+H).sup.+.
Step 2: CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-3-(2-methyl-2-(2-oxopyrrolidin-1-yl)propyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_4072)
[0394] NaH (60% in mineral oil) (95.62 mg, 2.390 mmol) was added to a solution of CIS-4-chloro-N-(1-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2-methylpropan-2-yl)butanamide (0.3 g, 0.598 mmol) in THF (30 mL) at 0° C. under argon atmosphere. The reaction mixture was stirred at 70° C. for 4 h, then cooled to 0° C. and quenched with water (15 mL). The organic product was extracted with EtOAc (2×30 mL). 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 column chromatography (silica gel 230-400 mesh, 0-10% MeOH in DCM) and reverse phase HPLC to yield 80 mg (28%) of CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-3-(2-methyl-2-(2-oxopyrrolidin-1-yl)propyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_4072) as a white solid (TLC system: 5% MeOH in DCM; Rf: 0.30). .sup.1H NMR (DMSO-d6): δ 7.37-7.32 (m, 4H), 7.27-7.24 (m, 1H), 3.34-3.27 (m, 4H), 3.16-3.13 (m, 4H), 2.93 (d, 2H), 2.67-2.64 (m, 2H), 2.16-2.05 (m, 4H), 1.97 (s, 6H), 1.40-1.36 (m, 4H), 1.29 (s, 6H), 0.93-0.92 (m, 1H), 0.46-0.44 (m, 2H), 0.26-0.24 (m, 2H). Mass: m/z 503.3 (M+H).sup.+.
Synthesis of SC_4080: CIS-8-(dimethylamino)-8-phenyl-3-(1-phenylpiperidin-4-yl)-1,3-diazaspiro[4.5]decan-2-one
[0395] ##STR00123##
[0396] KOtBu (94.26 mg, 0.840 mmol) was added to a solution of CIS-8-(dimethylamino)-8-phenyl-3-(piperidin-4-yl)-1,3-diazaspiro[4.5]decan-2-one (INT-1050) (0.25 g, 0.70 mmol), bromobenzene (109.9 mg, 0.70 mmol), BINAP (65.38 mg, 0.105 mmol) and Pd.sub.2(dba).sub.3 (96.15 mg, 0.105 mmol) in toluene (40 mL). The mixture was purged with argon for 5 min and stirred for 16 h at 90° C. The reaction mixture was cooled to RT and diluted with DCM (20 mL), filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by flash chromatography (silica gel 230-400 mesh, 5-10% methanol in DCM as eluent) followed by reverse phase prep. HPLC to afford 57 mg (18%) of CIS-8-(dimethylamino)-8-phenyl-3-(1-phenylpiperidin-4-yl)-1,3-diazaspiro[4.5]decan-2-one (SC_4080) as an off-white solid. (TLC system: 10% MeOH in DCM; R.sub.f: 0.40). Reverse prep HPLC condition: mobile phase: 10 mM ammonium bicarbonate in H.sub.2O/acetonitrile; column: INERTSIL-ODS(250*19 mm) 5 μm; gradient (% B): 0/65, 8/80, 8.1/98, 12/98, 12.1/65, 15/65; flow rate: 18 ml/min; diluent: ACN+THF+MeOH+H.sub.2O. .sup.1H NMR (DMSO-d6): δ 7.36-7.30 (m, 4H), 7.23 (t, 1H), 7.18-7.14 (m, 2H), 6.90 (d, 2H), 6.72 (t, 2H), 3.72-3.69 (m, 2H), 3.65-3.60 (m, 1H), 3.01 (s, 2H), 2.70-2.65 (m, 2H), 2.28 (br s, 2H), 1.93 (s, 6H), 1.78 (br m, 4H), 1.68-1.60 (m, 2H), 1.57-1.55 (m, 2H), 1.34-1.31 (m, 2H). Mass: m/z 433.3 (M+H).sup.+.
Synthesis of SC_4084: CIS-1-(1-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2-methylpropan-2-yl)pyrrolidine-2,5-dione
[0397] ##STR00124##
Step 1: CIS-4-(1-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2-methylpropan-2-ylamino)-4-oxobutanoic acid
[0398] Succinic anhydride (233.3 mg, 2.330 mmol) was added to a stirred solution of CIS-3-(2-amino-2-methylpropyl)-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (0.58 g, 1.457 mmol) in DCM (15 mL) at RT under argon atmosphere. The reaction mixture was stirred at RT for 4 h and then concentrated under reduced pressure to yield 440 mg of crude CIS-4-(1-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2-methylpropan-2-ylamino)-4-oxobutanoic acid as an off-white solid (TLC system: 5% MeOH in DCM; Rf: 0.35).
Step 2: CIS-1-(1-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2-methylpropan-2-yl)pyrrolidine-2,5-dione (SC_4084)
[0399] Acetyl chloride (2.2 mL) was added to a solution of CIS-4-(1-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2-methylpropan-2-ylamino)-4-oxobutanoic acid (0.44 g, 0.883 mmol) in EtOAc (30 mL) at 0° C. under argon atmosphere. The reaction mixture was stirred at 80° C. for 16 h. The reaction mixture was cool to RT, concentrated under reduced pressure, quenched with sat. aq. NaHCO.sub.3 and the organic product was extracted with EtOAc (2×30 mL). The combined organic extracts were dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel 230-400 mesh, 0-8% MeOH in DCM) followed by reverse phase prep HPLC to get 50 mg (9%) of CIS-1-(1-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2-methylpropan-2-yl)pyrrolidine-2,5-dione (SC_4084) as a white solid (TLC system: 5% MeOH in DCM; Rf: 0.30). Reverse prep HPLC condition: mobile phase: 10 mM ammonium bicarbonate in H.sub.2O/acetonitrile; column: INERTSIL-ODS(250*19 mm) 5 μm; gradient (% B): 0/80, 9/90, 9.1/80, 12/80; flow rate: 18 ml/min; diluent: ACN+THF+H.sub.2O. .sup.1H NMR (DMSO-d6): δ 7.35-7.34 (m, 4H), 7.27-7.24 (m, 1H), 3.34 (s, 2H), 3.19 (s, 2H), 2.87 (d, 2H), 2.66-2.64 (m, 2H), 2.43 (s, 4H), 2.13-2.08 (m, 2H), 1.97 (s, 6H), 1.51 (s, 6H), 1.37-1.32 (m, 4H), 0.89-0.87 (m, 1H), 0.45-0.42 (m, 2H), 0.27-0.24 (m, 2H). Mass: m/z 481.3 (M+H).sup.+.
Synthesis of SC_4096: CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-3-(1-(pyridazin-4-yl)piperidin-4-yl)-1,3-diazaspiro[4.5]decan-2-one
[0400] ##STR00125##
Step 1: CIS-3-(1-(6-chloropyridazin-4-yl)piperidin-4-yl)-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
[0401] DIPEA (0.566 g, 4.3 mmol) was added to a solution of CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-3-(piperidin-4-yl)-1,3-diazaspiro[4.5]decan-2-one (SC_4054) (0.6 g, 1.4 mmol) and 3,5-dichloropyridazine (310 mg, 2.10 mmol) in N-methyl-2-pyrrolidone (30 mL). The reaction mixture was purged with argon for 10 min and stirred for 16 h at 80° C. The reaction mixture was quenched with water and extracted with EtOAc (3×20 mL). The combined organic layer was concentrated under reduced pressure and the crude product was purified by flash chromatography (silica gel 230-400 mesh size, 5-10% methanol in dichloromethane as eluent) to afford 250 mg of CIS-3-(1-(6-chloropyridazin-4-yl)piperidin-4-yl)-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one) as a light brown solid. (TLC system: 10% MeOH in DCM; Rf: 0.35).
Step 2: CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-3-(1-(pyridazin-4-yl)piperidin-4-yl)-1,3-diazaspiro[4.5]decan-2-one (SC_4096)
[0402] 10% Pd—C (125 mg) was added to a solution of CIS-3-(1-(6-chloropyridazin-4-yl)piperidin-4-yl)-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one) (0.25 g, 0.47 mmol) and triethylamine (96 mg, 0.95 mmol) in ethanol. The resultant mixture was hydrogenated under balloon pressure for 4 h. The reaction mixture was diluted with EtOH (10 mL); filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel 230-400 mesh, 5-10% methanol in DCM as eluent) and further purified by reverse phase prep HPLC to afford 85 mg (17%) of CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-3-(1-(pyridazin-4-yl)piperidin-4-yl)-1,3-diazaspiro[4.5]decan-2-one (SC_4096) as an off-white solid. (TLC system: 10% MeOH in DCM; Rf: 0.35). Reverse prep HPLC condition: column X-BRIDGE C.sub.18 (4.6×150 mm) 3.5 μm; mobile phase: 10 mM ammonium acetate in water (A)/acetonitrile (B); gradient time(min)/% B: 0/5, 1.2/5, 3/55, 5/70, 7/95, 10/95, 12/100, 14/5, 16/5; flow rate: 1 ml/min; diluent: (acetonitrile/water). .sup.1H NMR (DMSO): δ 8.92 (m, 1H), 8.55-8.54 (m, 1H), 7.34-7.30 (m, 4H), 7.24-7.21 (m, 1H), 6.91-6.89 (m, 1H), 4.09-4.07 (d, 2H), 3.84 (m, 1H), 3.09 (s, 2H), 2.95-2.90 (m, 4H), 2.62-2.59 (d, 2H), 2.12-2.09 (t, 2H), 1.96 (s, 6H), 1.60-1.56 (m, 4H), 1.42-1.39 (m, 2H), 1.31-1.28 (m, 2H), 0.91 (m, 1H), 0.46-0.43 (m, 2H), 0.26-0.23 (m, 2H). Mass: m/z 489.4 (M+H).sup.+.
Synthesis of SC_4091: CIS-1-(cyclobutylmethyl)-8-(dimethylamino)-3-(2-methyl-2-(methylsulfonyl)propyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
[0403] ##STR00126##
[0404] To a solution of 1-cyclobutylmethyl-8-dimethylamino-3-(2-methyl-2-methylsulfanyl-propyl)-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (45 mg, 0.1 mmol, 1.0 eq) in THF/H.sub.2O (6 ml, 5:1) was added oxone (119 mg, 0.19 mmol, 1.9 eq.) at 0° C. The reaction mixture was stirred at RT for 16 h, then quenched with sat. aq. NaHSO.sub.3, diluted with EtOAc (50 mL) and washed with sat. aq. NaHCO.sub.3 (25 ml). Organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (neutral alumina; 1.5% MeOH in DCM) to yield 1-cyclobutylmethyl-8-dimethylamino-3-(2-methanesulfonyl-2-methyl-propyl)-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (SC_4091) (100 mg, 0.17 mmol, 94%) as an off-white solid. .sup.1HNMR at 100° C. (DMSO-d6, 400 MHz), δ (ppm)=7.33-7.24 (m, 5H), 3.41 (s, 2H), 3.29 (s, 2H), 3.10 (d, 2H, J=7.04 Hz), 2.87 (s, 3H), 2.63-2.56 (m, 3H), 2.12-2.01 (m, 10H), 1.83-1.81 (m, 4H), 1.47-1.27 (m, 10H). Mass: m/z 576.0 (M+H).sup.+.
Synthesis of SC_4098: TRANS-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-3-(2-(methylsulfonyl)ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
[0405] ##STR00127##
Step 1: TRANS-8-(dimethylamino)-3-(2-(methylthio)ethyl)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione
[0406] In analogy to the method described for SC_4034 TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione (step 1 of INT-1059) was reacted with 1-bromo-2-methylsulfanyl-ethane to be converted into TRANS-8-(dimethylamino)-3-(2-(methylthio)ethyl)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione. Mass: m/z 362.2 (M+H).sup.+.
Step 2: TRANS-8-(dimethylamino)-3-(2-(methylthio)ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
[0407] To a slurry of LiAlH4 (315 mg, 8.31 mmol, 6.0 eq.) in THF (10 mL) was added a solution of TRANS-8-dimethylamino-3-(2-methylsulfanyl-ethyl)-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (500 mg, 1.38 mmol, 1.0 eq.) in THF (10 mL) at 0° C. under argon atmosphere and the reaction mixture was stirred at reflux for 16 h. The reaction mixture was cooled to 0° C. and quenched with sat. aq. Na.sub.2SO.sub.4 (10 mL). The resulting suspension was stirred at RT for 30 min. The reaction mixture was filtered through celite and filter cake was washed with 10% MeOH in DCM (30 mL). The combined filtrate was dried over anhydr. Na.sub.2SO.sub.4 and concentrated under reduced pressure and residue was dissolved in HCOOH (15 mL) and NaBH.sub.4 (314 mg, 8.31 mmol, 6.0 eq.) was added portionwise at 0° C. The reaction mixture was stirred at RT for 3 h, then basified with sat. aq. NaHCO.sub.3 up to pH˜8 and extracted with EtOAc (2×50 mL). Combined organic layer was washed with brine (30 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to get crude TRANS-8-dimethylamino-3-(2-methylsulfanyl-ethyl)-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (400 mg, 1.29 mmol, 83%) as a brown solid which was used in the next step without further purification. LC-MS: m/z [M+1].sup.+=348.4 (MW calc. 347.52).
Step 3: TRANS-8-dimethylamino-1-(1-hydroxy-cyclobutylmethyl)-3-(2-methylsulfanyl-ethyl)-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one
[0408] To a solution of TRANS-8-dimethylamino-3-(2-methylsulfanyl-ethyl)-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (450 mg, 1.29 mmol, 1.0 eq.) in DMSO (10 mL) was added NaOH (363 mg, 9.07 mmol, 7.0 eq.) at RT. The reaction mixture was heated to 60° C. for 30 min, then cooled to RT and 1-oxa-spiro[2.3]hexane (435 mg, 5.18 mmol, 4.0 eq.) was added. The reaction mixture was stirred at 60° C. for 48 h, then quenched with ice water (25 mL), extracted with EtOAc (2×50 mL). Combined organic layer was washed with brine (25 ml), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to get the crude product which was purified by column chromatography (neutral alumina; 4% MeOH/DCM) to yield TRANS-8-dimethylamino-1-(1-hydroxy-cyclobutylmethyl)-3-(2-methylsulfanyl-ethyl)-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (120 mg, 0.27 mmol, 21%) as a brown liquid. LC-MS: m/z [M+1].sup.+=432.0 (MW calc. 431.64.
Step 4: TRANS-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-3-(2-(methylsulfonyl)ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_4098)
[0409] In analogy to the method described for step 2 of SC_4038 TRANS-8-dimethylamino-1-(1-hydroxy-cyclobutylmethyl)-3-(2-methylsulfanyl-ethyl)-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one was reacted with oxone to be converted into TRANS-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-3-(2-(methylsulfonyl)ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_4098). Mass: m/z 464.3 (M+H).sup.+. .sup.1HNMR (DMSO-d.sub.6, 400 MHz), δ (ppm)=7.39-7.28 (m, 5H), 5.35 (s, 1H), 3.59-3.56 (m, 2H), 3.42-3.34 (m, 4H), 2.97-2.95 (m, 3H), 2.66 (s, 2H), 2.67 (bs, 2H), 2.59-2.56 (m, 2H), 2.00 (s, 6H), 1.77-0.163 (m, 6H), 1.50-1.27 (m, 5H), 1.05-0.98 (m, 1H).
Synthesis of SC_5063: CIS-2,2-dimethyl-3-(8-(methylamino)-2-oxo-8-phenyl-1,3-diazaspiro [4.5]decan-3-yl)propanenitrile
[0410] ##STR00128##
Step 1: CIS-3-(8-(dimethylamino)-1-(methoxymethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanenitrile
[0411] To a solution of CIS-3-(8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-2,2-dimethyl-propionitrile (SC_5062) (1.8 g, 5.08 mmol, 1.0 eq.) in THF (20 ml) was added NaH (95%, 366 mg, 15.25 mmol, 3.0 eq.) at 0° C. and the reaction mixture was stirred for 20 min at RT. A solution of methoxymethyl chloride (0.57 ml, 7.62 mmol, 1.5 eq.) in THF (5 ml) was added at 0° C. and the resulting mixture was stirred at RT for 16 h. The reaction mixture was diluted with water (20 ml) and extracted with EtOAc (2×50 ml). The combined organic layers were washed with water (50 ml) and brine (50 ml), dried over anhydr. Na.sub.2SO.sub.4 and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (neutral alumina; 0.2% MeOH/DCM) to yield CIS-3-(8-(dimethylamino)-1-(methoxymethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanenitrile (700 mg, 1.75 mmol, 34%) as an off-white sticky solid. LC-MS: m/z [M+H].sup.+=399.3 (MW calc.=398.54).
Step 2: CIS-3-(1-(methoxymethyl)-8-(methylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanenitrile
[0412] To a solution of CIS-3-(8-(dimethylamino)-1-(methoxymethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanenitrile (700 mg, 1.75 mmol, 1.0 eq.) in acetonitrile (20 ml) and THF (10 ml) was added N-iodosuccinimide (590 mg, 2.63 mmol, 1.5 eq.) at 0° C. and the mixture was stirred at RT for 3 h. The reaction mixture was diluted with water (20 ml) and 1N aq. NaOH (5 ml) and extracted with DCM (2×30 ml). The combined organic layers were washed with brine (40 ml), dried over anhydr. Na.sub.2SO.sub.4 and concentrated under reduced pressure to give CIS-3-(1-(methoxymethyl)-8-(methylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanenitrile (350 mg, 0.911 mmol, 52%) which was used directly for next step without further purification. LC-MS: m/z [M+H]+=385.2 (MW calc.=384.52).
Step 3: CIS-2,2-dimethyl-3-(8-(methylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)propanenitrile (SC_5063)
[0413] To a solution of CIS-3-(1-(methoxymethyl)-8-(methylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2,2-dimethylpropanenitrile (400 mg, 1.04 mmol, 1.0 eq.) in MeOH (10 ml) was added 2M aq. HCl (30 ml) at 0° C. and the mixture was stirred at RT for 16 h. The reaction mixture was basified with 2M aq. NaOH and extracted with DCM (2×25 ml). The combined organic layers were washed with brine (30 ml), dried over anhydr. Na.sub.2SO.sub.4 and concentrated under reduced pressure to give CIS-2,2-dimethyl-3-(8-(methylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)propanenitrile (SC_5063) (300 mg, 0.882 mmol, 84%) which was 95.72% pure according to HPLC. LC-MS: m/z [M+H].sup.+=341.27 (MW calc.=340.46). .sup.1HNMR (DMSO-d6, 400 MHz), δ (ppm)=7.42-7.19 (m, 5H), 6.78 (bs, 1H), 3.36 (s, 2H), 3.18 (s, 2H), 1.96-1.85 (m, 7H), 1.66 (bs, 2H), 1.46-1.43 (m, 2H), 1.25 (s, 6H).
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_4002 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-[2-[2-[2- INT-987 19-bromo-2,5,8,11,14,17- SC_4003 620.4 [2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]- hexaoxanonadecane ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_4004 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-[2-[2-[2- INT-987 22-bromo-2,5,8,11,14,17,20- SC_4003 664.4 [2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]- heptaoxadocosane ethoxy]-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_4005 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-[2-[2-[2- INT-987 16-bromo-2,5,8,11,14- SC_4003 576.4 (2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethyl]-8- pentaoxahexadecane phenyl-1,3-diazaspiro[4.5]decan-2-one SC_4006 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-(2- INT-987 1-bromo-2-(2- SC_4003 444.3 methoxy-ethoxy)-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan- methoxyethoxy)ethane 2-one SC_4007 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(2-methoxy- INT-987 1-bromo-2-methoxyethane SC_4003 400.3 ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_4008 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-[2-[2-(2- INT-987 13-bromo-2,5,8,11- SC_4003 532.4 methoxy-ethoxy)-ethoxy]-ethoxy]-ethyl]-8-phenyl-1,3- tetraoxatridecane diazaspiro[4.5]decan-2-one SC_4009 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(2- INT-987 1-bromo-2- SC_4025 448.3 methylsulfonyl-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2- (methylsulfonyl)ethane one SC_4011 CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]- INT-799 1-bromo-2- SC_4025 464.3 3-(2-methylsulfonyl-ethyl)-8-phenyl-1,3- (methylsulfonyl)ethane diazaspiro[4.5]decan-2-one SC_4014 CIS-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- INT-799 3-bromo-2,2- SC_4025 423.3 phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2,2-dimethyl- dimethylpropanenitrile propionitrile SC_4017 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-[2-[2-[2- INT-987 25-bromo- SC_4003 708.5 [2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]- 2,5,8,11,14,17,20,23- ethoxy]-ethoxy]-ethoxy]-ethyl]-8-phenyl-1,3- octaoxapentacosane diazaspiro[4.5]decan-2-one SC_4018 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-methyl-8- INT-987 Methyliodide SC_4025 356.3 phenyl-1,3-diazaspiro[4.5]decan-2-one SC_4021 CIS-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-3- SC_4011 — SC_4010 450.2 (2-methylsulfonyl-ethyl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_4022 CIS-3-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino- SC_4029 — SC_4010 397.3 2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propionitrile SC_4024 CIS-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino- SC_4030 — SC_4010 383.2 2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetonitrile SC_4026 CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]- INT-799 4-(2-bromoethyl)morpholine SC_4025 471.3 3-(2-morpholin-4-yl-ethyl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_4029 CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)- INT-799 3-bromopropanenitrile SC_4025 411.3 methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]- propionitrile SC_4030 CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)- INT-799 2-bromoacetonitrile SC_4025 397.3 methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]- acetonitrile
TABLE-US-00004 Ex- Reactant in analogy m/z ample Chemical name I Reactant II to method .sup.1H NMR data (M + H).sup.+ SC_ CIS-8-Dimethylamino-3- SC_4032 toluene-4-sulfonic SC_4034 .sup.1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 450.1 4035 (2-methylsulfonyl-ethyl)-1- acid 7.34-7.25 (m, 5H), 4.59 (t, 2H, 6.64 Hz) (oxetan-3-yl-methyl)- oxetan-3-ylmethyl 4.35 (bs, 2H), 3.48 (bs, 2H), 3.21 (s, 2H), 8-phenyl-1,3-diazaspiro[4.5] ester 3.13 (bs, 1H), 2.95 (s, 3H), 2.67-2.65 (m, decan-2-one 2H), 1.97 (s, 8H), 1.41-1.30 (m, 4H). SC_ CIS-8-Dimethylamino-1- SC_4032 1-bromo-3-methoxy- SC_4034 .sup.1HNMR (CDCl3, 400 MHz), δ (ppm) = 452.3 4036 (3-methoxy-propyl)-3-(2- propane 7.35-7.25 (m, 5H, merged with CDCl3), methylsulfonyl-ethyl)-8-phenyl- 3.64 (t, 2H, J = 6.32 Hz), 3.44 (t, 2H, J = 1,3-diazaspiro[4.5]decan-2-one 6.08 Hz), 3.34 (s, 3H), 3.28-3.19 m, 6H), 2.95 (s, 3H), 2.64-2.61 (m, 2H), 2.22-2.16 (m, 2H), 2.01 (s, 6H), 1.89-1.86 (m, 2H), 1.29-1.27 (m, 4H). SC_ CIS-1-(Cyc1obutyl-methyl)-8- INT-987 1,6-dioxaspiro SC_4027 .sup.1H NMR (DMSO-d6): δ 7.37-7.31 (m, 4H), 456.3 4039 dimethylamino-3-[(4-hydroxy- [2.5]octane 7.26-7.23 (m, 1H), 4.52 (s, 1H), 3.60-3.56 tetrahydro-pyran-4-yl)-methyl]- (m, 4H), 3.28 (s, 2H), 3.03-3.01 (m, 4H), 8-phenyl-1,3-diazaspiro[4.5] 2.68-2.65 (m, 2H), 2.49-2.46 (m, 1H), 2.06- decan-2-one 1.92 (m, 10H), 1.82-1.65 (m, 4H), 1.49-1.44 (m, 2H), 1.34-1.31 (m, 6H). SC_ CIS-1-(Cyclopropyl-methyl)-8- INT-983 tetrahydro-2H-pyran- SC_4027 .sup.1H NMR (DMSO-d6): δ 7.34-7.25 (m, 5H), 412.3 4040 dimethylamino-8-phenyl-3- 4-yl 4- 3.86-3.84 (m, 2H), 3.76-3.70 (m, 1H), 3.35 tetrahydro-pyran-4-yl-1,3- methylbenzene- (m, 2H), 3.13 (s, 2H), 2.91 (d, 2H), 2.66- diazaspiro[4.5]decan-2-one sulfonate 2.62 (m, 2H), 2.14 (t, 2H), 1.97 (s, 6H), 1.66-1.58 (m, 2H), 1.46-1.23 (m, 6H), 0.91 (m, 1H), 0.44 (m, 2H), 0.24 (m, 2H). SC_ CIS-1-(Cyclobutyl-methyl)-8- INT-987 1-oxa-6- SC_4027 .sup.1H NMR (DMSO-d6): δ 7.37-7.23 (m, 5H), 504.3 4041 dimethylamino-3-[(4-hydroxy- thiaspiro[2.5]octane (for step 1), 5.02 (s, 1H), 3.27 (s, 2H), 3.17-3.03 (m, 1,1-dioxo-thian-4-yl)-methyl]-8- (step 1) SC_4038 6H), 2.97-2.94 (m, 2H), 2.68-2.65 (m, 2H), phenyl-1,3-diazaspiro[4.5]decan- (for step 2) 2.54-2.46 (m, 1H), 2.07-1.92 (m, 10H), 2-one 1.87-1.84 (m, 4H), 1.80-1.66 (m, 4H), 1.34-1.31 (m, 4H). SC_ CIS-8-Dimethylamino-1-[(1- INT-799 tetrahydro-2H-pyran- SC_4027 .sup.1H NMR (DMSO-d6): δ 7.37-7.23 (m, 5H), 442.3 4042 hydroxy-cyclobutyl)-methyl]-8- 4-yl 4- 6.05 (s, 1H), 3.87-3.84 (m, 2H), 3.74-3.73 phenyl-3-tetrahydro-pyran-4-yl- methylbenzene- (m, 1H), 3.36-3.35 (m, 2H), 3.24 (s, 2H), 1,3-diazaspiro[4.5]decan-2-one sulfonate 3.07 (s, 2H), 2.66-2.63 (m, 2H), 2.06-1.83 (m, 12H), 1.65-1.58 (m, 3H), 1.48-1.32 (m, 7H). SC_ CIS-1-[[8-Dimethylamino-3-(2- SC_4032 toluene-4-sulfonic SC_4034 .sup.1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 473.2 4043 methylsulfonyl-ethyl)-2-oxo-8- acid 1-cyano- 7.33-7.32 (m, 2H), 7.25 (s, 3H), 3.69-3.66 (t, phenyl-1,3-diazaspiro[4.5]decan- cyclobutylmethyl 2H, J = 5), 3.41 (s, 2H), 3.30-3.25 (m, 1-yl]-methyl]-cyclobutane-1- ester 4H), 2.95 (s, 3H), 2.67-2.64 (d, 2H, J = 13.4), carbonitrile 2.45 (bs, 4H), 2.19-2.08 (m, 4H), 2.02 (s, 6H), 1.46-1.39 (m, 2H). SC_ CIS-8-Dimethylamino-1-[(1- INT-799 1-oxa-6- SC_4044 .sup.1H NMR (DMSO-d6): δ 7.37-7.25 (m, 5H), 520.3 4045 hydroxy-cyclobutyl)-methyl]-3- thiaspiro[2.5]octane (for step 1), 5.93 (s, 1H), 5.01 (s, 1H), 3.41 (s, 2H), 3.16- [(4-hydroxy-1,1-dioxo-thian-4- (step 1) step 2 of 3.09 (m, 6H), 2.98-2.95 (m, 2H), 2.70-2.66 yl)-methyl]-8-phenyl-1,3- SC_4038 (m, 2H), 2.06-2.03 (m, 4H), 1.97 (s, 6H), diazaspiro[4.5]decan-2-one (for step 2) 1.89-1.87 (m, 6H), 1.64-1.61 (m, 1H), 1.45- 1.31 (m, 5H). SC_ CIS-1-(Cyclopropyl-methyl)-8- INT-983 tetrahydro-2H- SC_4044 .sup.1H NMR (DMSO-d6): δ 7.37-7.26 (m, 5H), 460.3 4046 dimethylamino-3-(1,1-dioxo- thiopyran-4-yl 4- (for step 1), 4.08-4.02 (m, 1H), 3.17-3.03 (m, 8H), 2.67- thian-4-yl)-8-phenyl-1,3- methylbenzene- step 2 of 2.63 (m, 2H), 2.32-2.04 (m,12H), 1.46-1.39 diazaspiro[4.5]decan-2-one sulfonate SC_4038 (m, 4H), 1.02-0.99 (m, 1H), 0.54-0.50 (m, (step 1) (for step 2) 2H), 0.34-0.30 (m, 2H). SC_ CIS-8-Dimethylamino-3-(1,1- INT-799 tetrahydro-2H- SC_4044 .sup.1H NMR (DMSO-d6): δ 7.37-7.32 (m, 4H), 490.3 4047 dioxo-thian-4-yl)-1-[(1-hydroxy- thiopyran-4-yl 4- (for step 1), 7.27-7.23 (m, 1H), 5.94 (s, 1H), 3.97-3.91 cyclobutyl)-methyl]-8-phenyl- methylbenzene- step 2 of (m, 1H), 3.33-3.31 (m, 2H), 3.27 (s, 2H), 1,3-diazaspiro[4.5]decan-2-one sulfonate SC_4038 3.07 (s, 2H), 3.02-2.99 (m, 2H), 2.64-2.61 (step 1) (for step 2) (m, 2H), 2.12-2.02 (m, 6H), 1.97 (s, 6H), 1.88-1.85 (m, 4H), 1.66-1.61 (m, 1H), 1.50- 1.29 (m, 5H). SC_ CIS-3-(1-Benzoyl-piperidin-4- SC_4054 benzoyl chloride SC_4048 .sup.1H NMR (CDCl3): δ 7.40-7.34 (m, 7H), 515.4 4049 yl)-1-(cyclopropyl-methyl)-8- 7.30-7.27 (m, 3H), 4.79 (m, 1H), 4.06-4.00 dimethylamino-8-phenyl-1,3- (m, 1H), 3.78 (br m, 1H), 3.90-3.05 (m, 5H), diazaspiro[4.5]decan-2-one 2.80-2.77 (br m, 1H), 2.65 (d, 2H), 2.27 (t, 2H), 2.05 (s, 6H), 1.82-1.62 (m, 3H), 1.46- 1.41 (m, 5H), 1.04-0.99 (m, 1H), 0.53-0.50 (m, 2H), 0.33-0.30 (m, 2H). SC_ CIS-1-(Cyclopropyl-methyl)-8- SC_4054 isonicotinoyl chloride SC_4048 .sup.1H NMR (CDCl3): δ 8.67-8.66 (m, 2H), 516.3 4050 dimethylamino-8-phenyl-3-[1- hydrochloride 7.36-7.35 (m, 2H), 7.30-7.27 (m, 3H), 7.25- (pyridine-4-carbonyl)-piperidin- 7.24 (m, 2H), 4.80-4.77 (m, 1H), 4.06-4.01 4-yl]-1,3-diazaspiro[4.5]decan- (m, 1H), 3.65-3.62 (m, 1H), 3.14-3.05 (m, 2-one 5H), 2.82 (t, 1H), 2.67-2.65 (m, 2H), 2.28 (m, 2H), 2.05 (s, 6H), 1.86-1.84 (m, 1H), 1.71-1.62 (m, 2H), 1.46-1.39 (m, 5H), 1.03- 0.99 (m, 1H), 0.53-0.50 (m, 2H), 0.34-0.33 (m, 2H). SC_ CIS-1-(Cyclopropyl-methyl)-8- INT-983 1,6-dioxaspiro SC_4044 .sup.1H NMR (DMSO-d6): δ 7.37-7.33 (m, 4H), 442.3 4051 dimethylamino-34(4-hydroxy- [2.5]octane 7.27-7.23 (m, 1H), 4.54 (s, 1H), 3.60-3.53 tetrahydro-pyran-4-yl)-methyl]- (m, 4H), 3.32 (m, 2H), 3.03 (s, 2H), 2.91 (d, 8-phenyl-1,3- 2H), 2.67 (d, 2H), 2.15 (t, 2H), 1.97 (s, 6H), diazaspiro[4.5]decan-2-one 1.49-1.44 (m, 2H), 1.40-1.31 (m, 6H), 0.95- 0.90 (m, 1H), 0.46-0.43 (m, 2H), 0.30-0.21 (m, 2H). SC_ CIS-3-[(1-Acetyl- SC_4058 acetyl chloride SC_4048 .sup.1H NMR (DMSO d6): δ 7.35-7.34 (m, 4H), 467.3 4053 piperidin-4-yl)- 7.25 (m, 1H), 4.31-4.28 (m, 1H), 3.77-3.74 methyl]-1-(cyclopropyl-methyl)- (m, 1H), 3.15 (s, 2H), 2.97-2.90 (m, 5H), 8-dimethylamino-8-phenyl-1,3- 2.68-2.64 (m, 2H), 2.19-2.13 (m, 2H), 1.97- diazaspiro[4.5]decan-2-one 1.95 (m, 9H), 1.76 (m, 1H), 1.59-1.52 (m, 2H), 1.43-1.31 (m, 4H), 1.03-0.87 (m, 3H), 0.45-0.44 (m, 2H), 0.25-0.24 (m, 2H). SC_ CIS-1-(Cyclopropyl-methyl)-8- INT-983 tert-butyl 4- SC_4034 .sup.1H NMR (DMSO d6): δ 7.37-7.34 (m, 4H), 425.3 4058 dimethylamino-8-phenyl-3- ((tosyloxy)methyl) (for step 1), 7.27-7.23 (m, 1H), 3.13 (s, 2H), 2.91-2.87 (piperidin-4-yl-methyl)-1,3- piperidine-1- step 2 of (m, 6H), 2.67-2.64 (m, 2H), 2.39-2.33 (m, diazaspiro[4.5]decan-2-one carboxylate SC_4054 2H), 2.18-2.12 (m, 2H), 1.97 (s, 6H), 1.58- (step 1) (for step 2) 1.54 (m, 1H), 1.47-1.30 (m, 6H), 0.98-0.88 (m, 3H), 0.46-0.42 (m, 2H), 0.26-0.22 (m, 2H). SC_ CIS-3-(1-Benzoyl-piperidin-4- INT-976 tert-butyl 4- SC_4054 .sup.1H NMR (DMSO d6): δ 7.42-7.23 (m, 10H), 461.3 4059 yl)-8-dimethylamino-8-phenyl- (tosyloxy)piperidine- (for 6.67 (br s, 1H), 4.51 (m, 1H), 3.75 (m, 1H), 1,3-diazaspiro[4.5]decan-2-one 1-carboxylate (step 1), steps 1,2), 3.54 (m, 1H), 3.05 (s, 3H), 2.75 (m, 1H), benzoyl chloride SC_4048 2.34 (m, 2H), 1.93 (s, 6H), 1.77 (m, 4H), (step 3) (for step 3) 1.55-1.35 (m, 6H). SC_ CIS-8-Dimethylamino-8-phenyl- INT-976 isonicotinoyl SC_4054 .sup.1H NMR (DMSO d6): δ 8.64-8.62 (m, 2H), 462.3 4060 3-[1-(pyridine-4-carbonyl)- chloride (for steps 7.37-7.32 (m, 6H), 7.26-7.23 (m, 1H), 6.67 piperidin-4-yl]-1,3- hydrochloride 1, 2), (br s, 1H), 4.50 (d, 1H), 3.80-3.73 (m, 1H), diazaspiro[4.5]decan-2-one SC_4048 3.40-3.37 (m, 1H), 3.11-3.05 (m, 3H), 2.78 (for step 3) (t, 1H), 2.36-2.33 (m, 2H), 1.93 (s, 6H), 1.80-1.65 (m, 4H), 1.61-1.52 (m, 3H), 1.49- 1.35 (m, 3H). SC_ CIS-3-(1-Acetyl-piperidin-4-yl)- INT-976 acetyl chloride SC_4054 .sup.1H NMR (DMSO-d6): δ 7.36-7.23 (m, 5H), 399.3 4061 8-dimethylamino-8-phenyl-1,3- (for steps 6.68 (br, s, 1H), 4.40 (d, 1H), 3.80 (d, 1H), diazaspiro[4.5]decan-2-one 1, 2), 3.69 (m, 1H), 3.05-2.99 (m, 3H), 2.32 (m, SC_4048 3H), 1.95-1.92 (m, 9H), 1.78-1.76 (m, 4H), (for step 3) 1.50-1.46 (m, 3H), 1.33-1.30 (m, 3H). SC_ CIS-1-(Cyclopropyl-methyl)-8- INT-983 1-oxa-6- SC_4044 .sup.1H NMR (DMSO-d6): δ 7.37-7.33 (m, 4H), 490.3 4062 dimethylamino-3-[(4-hydroxy- thiaspiro[2.5]octane (for step 1), 7.27-7.24 (m, 1H), 5.04 (s, 1H), 3.30 (m, 1,1-dioxo-thian-4-yl)-methyl]-8- (step 1) step 2 of 2H), 3.15-3.07 (m, 4H), 2.97-2.92 (m, 4H), phenyl-1,3-diazaspiro[4.5]decan- SC_4038 2.69-2.66 (m, 2H), 2.18-2.13 (m, 2H), 1.97 2-one (for step 2) (s, 6H), 1.87-1.84 (m, 4H), 1.38-1.31 (m, 4H), 0.94-0.91 (m. 1H), 0.47-0.43 (m, 2H), 0.26-0.24 (m, 2H). SC_ CIS-8-Dimethylamino-1-[(1- INT-799 tert-butyl SC_4055 .sup.1H NMR (DMSO-d6): δ 7.37-7.33 (m, 4H), 430.3 4063 hydroxy-cyclobutyl)-methyl]-3- bromoacetate 7.26-7.23 (m, 1H), 6.11 (s, 1H), 4.41 (s, (2-hydroxy-2-methyl-propyl)-8- (step 1), 1H), 3.42 (s, 2H), 3.09 (s, 2H), 2.98 (s, 2H), phenyl-1,3-diazaspiro[4.5]decan- methylmagnesium 2.70-2.67 (m, 2H), 2.07-2.02 (m, 4H), 1.97 2-one bromide (step 3) (s, 6H), 1.91-1.83 (m, 3H), 1.63-1.61 (m, 1H), 1.45-1.42 (m, 2H), 1.36-1.32 (m, 3H), 1.04 (s, 6H). SC_ CIS-8-Dimethylamino-1,3-bis(2- INT-976 1-bromo-2- SC_4003 1H NMR (600 MHz, DMSO) δ 7.40-7.32 380.2 4066 methylsulfonyl-ethyl)-8-phenyl- methylsulfonyl- (m, 4H), 7.30-7.23 (m, 1H), 3.52 (t, 2H), 1,3-diazaspiro [4.5]decan-2-one ethane 3.46-3.31 (m, 1H), 3.27 (s, 2H), 3.05 (s, 3H), 2.97 (s, 3H), 2.72-2.63 (m, 2H), 2.11-2.01 (m, 2H), 1.99 (s, 6H), 1.45-1.36 (m, 4H). SC_ CIS-N-[1-[[1-Cyclopropyl- SC_4064 acetyl chloride SC_4048 [0375] 1HNMR (DMSO-d6, 400 MHz), δ 439.1 4067 methyl)-8-dimethylamino-2-oxo- (ppm) = 7.98 (s, 1H), 7.36-7.25 (m, 5H), 8-phenyl-1,3-diazaspiro[4.5] 3.25 (s, 2H), 3.12 (s, 2H), 2.89 (d, 2H, J = decan-3-yl]-methyl]- 6.48 Hz), 2.67-2.64 (m, 2H), 2.16-2.07 (m, cyclopropyl]-acetamide 2H), 1.97 (s, 6H), 1.67 (s, 3H), 1.44-1.36 (m, 4H), 0.91 (bs, 1H), 0.62-0.42 (m, 6H), 0.25-0.23 (m, 2H). SC_ CIS-1-(Cyclopropyl-methyl)-8- SC_4058 5-bromo-2- SC_4056 1H NMR (DMSO d6): δ 8.52 (s, 1H), 8.45 503.4 4068 dimethylamino-8-phenyl-3-[(1- (trifluoromethyl) (s, 2H), 7.37-7.33 (m, 4H), 7.27-7.23 (m, pyrimidin-5-yl-piperidin-4-yl)- pyrimidine 1H), 3.83-3.80 (m, 2H), 3.17 (s, 2H), 2.96- methyl]-1,3-diazaspiro[4.5] 2.75 (m, 4H), 2.73-2.65 (m, 4H), 2.16 (m, decan-2-one 2H), 1.98 (s, 6H), 1.65 (m, 1H), 1.65-1.63 (m, 2H), 1.40-1.32 (m, 4H), 1.20-1.17 (m, 2H), 0.94 (m, 1H), 0.46-0.44 (m, 2H), 0.26- 0.24 (m, 2H). SC_ CIS-8-Dimethylamino-8-phenyl- INT-1051 5-bromopyrimidine SC_4056 1H NMR (DMSO d6): δ 8.52 (s, 1H) ,8.45 449.3 4069 3-[(1-pyrimidin-5-yl-piperidin-4- (s, 2H), 7.37-7.33 (m, 4H), 7.26-7.23 (m, yl)-methyl]-1,3- 1H), 6.72 (broad s, 1H), 3.82-3.79 (m, 2H), diazaspiro[4.5]decan-2-one 3.18 (s, 2H), 2.90-2.89(m, 2H), 2.72-2.69 (m, 2H), 2.30 (m, 2H), 1.92 (s, 6H), 1.79- 1.69 (m, 5H), 1.64-1.61 (m, 2H), 1.35 (m, 2H), 1.20-1.12 (m, 2H). SC_ CIS-8-Dimethylamino-8- INT-1050 5-bromopyrimidine SC_4056 1H NMR (DMSO d6): δ 8.52 (s, 1H), 8.46 435.3 4070 phenyl-3-(1-pyrimidin-5- (s, 2H), 7.36-7.30 (m, 4H), 7.24-7.22 (m, yl-piperidin-4- 1H), 6.71 (br s, 1H), 3.90-3.88 (m, 2H), yl)-1,3-diazaspiro[4.5]decan- 3.71-3.67 (m, 1H), 3.00 (s, 2H), 2.84-2.79 2-one (m, 2H), 2.28 (br s, 2H), 1.92 (s, 6H), 1.78 (br m, 4H), 1.66-1.55 (m, 4H), 1.34-1.33 (m, 2H). SC_ CIS-1-(Cyclopropyl-methyl)-8- INT-1052 4-chlorobutanoyl SC_4048 1H NMR (DMSO d6): δ 7.37-7.32 (m, 4H), 467.3 4072 dimethylamino-3-[2-methyl-2-(2- chloride (step 1), 7.27-7.24 (m, 1H), 3.40-3.36 (m, 4H), 3.16 oxo-pyrrolidin-1-yl)-propyl]-8- (step 1) procedure (s, 2H), 2.92 (d, 2H), 2.69-2.66 (m, 2H), phenyl-1,3-diazaspiro[4.5]decan- described 2.19-2.07 (m, 4H), 1.97 (s, 6H), 1.79-1.75 2-one (step 2) (m, 2H), 1.37-1.29 (m, 4H), 1.26 (s, 6H), 0.93-0.92 (m, 1H), 0.47-0.42 (m, 2H), 0.27- 0.24 (m, 2H). SC_ CIS-1-(Cyclopropyl-methyl)-8- INT-1052 3-chloropropane-1- SC_4072 1H NMR (DMSO d6): δ 7.37-7.32 (m, 4H), 503.3 4073 dimethylamino-3-[2-(1,1-dioxo- sulfonyl chloride 7.27-7.24 (m, 1H), 3.34-3.27 (m, 4H), 3.16- [1,2]thiazolidin-2-yl)-2-methyl- (step 1) 3.13 (m, 4H), 2.93 (d, 2H), 2.67-2.64 (m, propyl]-8-phenyl-1,3- 2H), 2.16-2.05 (m, 4H), 1.97 (s, 6H), 1.40- diazaspiro[4.5]decan-2-one 1.36 (m, 4H), 1.29 (s, 6H), 0.93-0.92 (m, 1H), 0.46-0.44 (m, 2H), 0.26-0.24 (m, 2H). SC_ CIS-8-Dimethylamino-1-[(1- INT-799 2-(4- SC_4052 1H NMR (DMSO d6): δ 7.37-7.34 (m, 4H), 486.4 4074 hydroxy-cyclobutyl)-methyl]-3- (benzyloxy) 7.27-7.24 (m, 1H), 6.17 (s, 1H), 4.28 (br s, [2-(4-hydroxy-tetrahydro-pyran- tetrahydro- 1H), 3.61-3.51 (m, 4H), 3.25 (s, 2H), 3.22- 4-yl)-ethyl]-8-phenyl-1,3- 2H-pyran-4-yl) 3.18 (m, 2H), 3.07 (s, 2H), 2.68-2.65 (m, diazaspiro[4.5]decan-2-one ethyl 4- 2H), 2.06-2.03 (m, 4H), 1.97 (s, 6H), 1.91- methylbenzene- 1.83 (m, 2H), 1.64-1.61 (m, 1H), 1.57-1.50 sulfonate (m, 2H), 1.47-1.29 (m, 9H). SC_ CIS-1-(Cyclobutyl-methyl)-8- INT-987 4-allyl-4- SC_4071 1H NMR (DMSO d6): δ 7.37-7.23 (m, 5H), 518.3 4075 dimethylamino-3-[2-(4-hydroxy- (benzyloxy) 4.76 (s, 1H), 3.16-3.10 (m, 6H), 3.01 (d, 1,1-dioxo-thian-4-yl)-ethyl]-8- tetrahydro- 2H), 2.91-2.88 (m, 2H), 2.67-2.63 (m, 2H), phenyl-1,3-diazaspiro[4.5]decan- 2H-thiopyran 2.02-1.82 (m, 14H), 1.80-1.65 (m, 5H), 1.58 2-one (m, 2H), 1.42-1.35 (m, 2H), 1.28-1.26 (m, 2H). SC_ CIS-3-[(1-Acetyl-piperidin-4-yl)- INT-1051 acetyl chloride SC_4048 1H NMR (DMSO d6): δ 7.37-7.23 (m, 5H), 413.3 4076 methyl]-8-dimethylamino-8- 6.72 (b s, 1H), 4.30-4.27 (m, 1H), 3.76-3.73 phenyl-1,3-diazaspiro[4.5]decan- (m, 1H), 3.03 (s, 2H), 2.96-2.91 (m, 1H), 2-one 2.86-2.81 (m, 2H), 2.44 (m, 1H), 2.32 (m, 2H), 1.95-1.92 (m, 9H), 1.79-1.68 (m, 5H), 1.58-1.50 (m, 2H), 1.36-1.34 (m, 2H), 1.05- 1.01 (m, 1H), 0.98-0.92 (m, 1H). SC_ CIS-8-Dimethylamino-3-(2- SC_4032 2-chloro-l-pyrrolidin- SC_4003 1H NMR (600 MHz, DMSO) δ 7.38-7.30 491.3 4077 methylsulfonyl-ethyl)-1-(2-oxo- 1-yl-ethanone (m, 4H), 7.29-7.22 (m, 1H), 3.79 (s, 2H), 2-pyrrolidin-1-yl-ethyl)-8- 3.53-3.48 (m, 5H), 3.35-3.27 (m, 5H), phenyl-1,3-diazaspiro[4.5] 2.96 (s, 3H), 2.67-2.59 (m, 2H), 1.98- decan-2-one 1.87 (m, 10H), 1.77 (p, 2H), 1.44-1.34 (m, 4H) SC_ TRANS-8-Dimethylamino-3-(2- INT-1059 1-bromo-2- SC_4003 1HNMR (DMSO-d6 ,400 MHz at 100 0 C.), 380.2 4078 methylsulfonyl-ethyl)-8-phenyl- methylsulfonyl- δ (ppm) = 7.35-7.24 (m, 5H), 6.43 (s, 1H), 1,3-diazaspiro[4.5]decan- ethane 3.50 (t, 2H, J = 6.46 Hz), 3.31-3.22 (m, 4H), 2-one 2.95 (3H, merged with DMSO-water), 2.17 (bs, 2H), 1.99 (bs, 8H), 1.72 (bs, 2H), 1.45- 1.39 (m, 2H). SC_ CIS-8-Dimethylamino-1-[(1- INT-799 4-allyl-4- SC_4071 1H NMR (DMSO-d6): δ 7.37-7.33 (m, 4H), 534.3 4079 hydroxy-cyclobutyl)-methyl]-3- (benzyloxy) 7.27-7.24 (m, 1H), 6.13 (br s, 1H), 3.26 (s, [2-(4-hydroxy-1,1-dioxo-thian-4- tetrahydro- 2H), 3.20-3.11 (m, 4H), 3.07 (s, 2H), 2.92- yl)-ethyl]-8-phenyl-1,3- 2H-thiopyran 2.89 (m, 2H), 2.68-2.65 (m, 2H), 2.05-2.01 diazaspiro[4.5]decan-2-one (m, 4H), 1.97 (s, 6H), 1.89-1.85 (m, 8H), 1.64-1.60 (m, 3H), 1.43-1.32 (m, 4H). SC_ CIS-N-[2-[1-(Cyclopropyl- INT-1052 acetyl chloride SC_4048 1H NMR (CDCl3, 400 MHz), δ (ppm) = 441.3 4081 methyl)-8-dimethylamino-2-oxo- 7.53 (s, 1H), 7.36-7.28 (m, 5H), 3.28 (s, 8-phenyl-1,3- 2H), 3.08-3.04 (m, 4H), 2.66-2.63 (m, 2H), diazaspiro[4.5]decan-3-yl]-1,1- 2.31-2.25 (m, 2H), 2.03 (s, 6H), 1.87 (s, dimethyl-ethyl]-acetamide 3H), 1.51-1.41 (m, 4H), 1.35 (s, 6H), 1.02 (bs, 1H), 0.53-0.51 (m, 2H), 0.33-0.32 (m, 2H). SC_ CIS-N-[2-[1-(Cyclopropyl- INT-1052 methanesulfonyl SC_4048 1HNMR (CDCl3, 400 MHz), δ (ppm) = 477.2 4082 methyl)-8-dimethylamino-2-oxo- chloride 7.34-7.25 (m, 5H), 6.16 (s, 1H), 3.31 (s, 8-phenyl-1,3- 2H), 3.10-3.05 (m, 4H), 2.97 (s, 3H), 2.67- diazaspiro[4.5]decan-3-yl]-1,1- 2.63 (m, 2H), 2.32-2.25 (m, 2H), 2.03 (s, dimethyl-ethyl]-methanesulfonic 6H), 1.51-1.43 (m, 4H), 1.37 (s, 6H), 1.01- acid amide 0.99 (m, 1H), 0.52-0.50 (m, 2H), 0.32 (m, 2H). SC_ CIS-8-Dimethylamino-1-[(1- INT-799 3-(benzyloxy)-3- SC_4071 1H NMR (DMSO-d6): δ 7.36-7.33 (m, 4H), 458.3 4083 hydroxy-cyclobutyl)-methyl]-3- vinyloxetane 7.26-7.25 (m, 1H), 6.12 (s, 1H), 5.65 (s, [2-(3-hydroxy-oxetan-3-yl)- 1H), 4.39 (d, 2H), 4.33 (d, 2H), 3.29 (s, 2H), ethyl]-8-phenyl-1,3- 3.17-3.14 (m, 2H), 3.08 (s, 2H), 2.68-2.65 diazaspiro[4.5]decan-2-one 1.91-1.86 (m, 4H), 1.69-1.59 (m, 1H), 1.43- (m, 2H), 2.07-2.02 (m, 4H), 1.97 (s, 6H), 1.40 (m, 4H), 1.38-1.31 (m, 1H). SC_ CIS-N-[2-[8-Dimethylamino-1- INT-1053 acetyl chloride SC_4048 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 471.3 4085 [(1-hydroxy-cyclobutyl)-methyl]- 7.48 (s, 1H), 7.32 (m, 5H), 5.95 (s, 1H), 2-oxo-8-phenyl-1,3- 3.29-3.26 (m, 4H), 3.06 (s, 2H), 2.65-2.62 diazaspiro[4.5]decan-3-yl[-1,1- (m, 2H), 2.05-1.99 (m, 4H), 1.93 (s, 6H), dimethyl-ethyl]-acetamide 1.85-1.82 (m, 2H), 1.67 (s, 3H), 1.60-1.59 (m, 1H), 1.43-1.26 (m, 5H), 1.13 (m, 6H). SC_ CIS-N-[2-[8-Dimethylamino-1- INT-1053 methanesulfonyl SC_4048 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 507.1 [(1-hydroxy-cyclobutyl)-methyl]- chloride 7.35-7.25 (m, 5H), 6.90 (s, 1H), 5.95 (s, 4086 2-oxo-8-phenyl-1,3- 1H), 3.44 (s, 2H), 3.14 (s, 2H), 3.10 (s, 2H), diazaspiro[4.5]decan-3-yl]-1,1- 2.92 (s, 3H), 2.68-2.66 (m, 3H), 2.08-2.03 dimethyl-ethyl]-methanesulfonic (m, 4H), 1.97 (s, 6H), 1.88-1.85 (m, 2H), acid amide 1.47-1.31 (m, 7H), 1.21 (s, 6H). SC_ CIS-1-(Cyclopropyl-methyl)-8- SC_4054 3-bromopyridine SC_4056 1H NMR (DMSO d6): δ 8.26 (d, 1H), 7.93 488.4 4087 dimethylamino-8-phenyl-3-(1- (m, 1H), 7.35-7.27 (m, 4H), 7.25-7.23 (m, pyridin-3-yl-piperidin-4-yl)-1,3- 2H), 7.17-7.15 (m, 1H), 3.80 (d, 2H), 3.77- diazaspiro[4.5]decan-2-one 3.68 (m, 1H), 3.29-3.27 (m, 1H), 3.13 (s, 2H), 2.91 (d, 2H), 2.77 (t, 2H), 2.64-2.62 (m, 1H), 2.14 (t, 2H), 1.97 (s, 6H), 1.72-1.68 (m, 2H), 1.61-1.59 (m, 2H), 1.44 (t, 2H), 1.32 (d, 2H), 0.94-0.90 (m, 1H), 0.47-0.44 (m, 2H), 0.28-0.25 (m, 2H). SC_ CIS-1-(Cyclopropyl-methyl)-8- INT-1063 1-bromo-2- SC_4032 1H NMR (600 MHz, DMSO) δ 7.44-7.36 452.2 4088 dimethylamino-8-(3- methylsulfonyl- (m, 1H), 7.18 (d, 1H), 7.15 (dt, 1H), 7.10 fluorophenyl)-3-(2- ethane (td, 1H), 3.51 (t, 2H), 3.32 (t, 2H), 3.23 (s, methylsulfonyl-ethyl)-1,3- 2H), 2.96 (s, 3H), 2.93 (d, 2H), 2.68-2.60 diazaspiro[4.5]decan-2-one (m, 2H), 2.18-2.10 (m, 2H), 2.00 (s, 6H), 1.45-1.33 (m, 4H), 0.93 (tdd, 1H), 0.50-0.41 (m, 2H), 0.31-.022 (m, 2H). SC_ CIS-1-(Cyclopropyl-methyl)-8- SC_4054 4-bromopyridine SC_4056 1H NMR (DMSO d6): δ 8.09-8.08 (d, 2H), 488.4 4089 dimethylamino-8-phenyl-3-(1- 7.33-7.30 (m, 4H), 7.24-7.23 (m, 1H), 6.77- pyridin-4-yl-piperidin-4-yl)-1,3- 76 (d, 2H), 3.98-3.96 (d, 2H), 3.80 (m, 1H), diazaspiro[4.5]decan-2-one 3.09 (s, 2H), 2.91-2.84 (m, 4H), 2.62-2.59 (m, 2H), 2.15-2.10 (m, 2H), 1.94 (m, 6H), 1.59-1.56 (m, 4H), 1.42-1.37 (m, 2H), 1.33- 1.29 (m, 2H), 0.91-0.90 (m, 1H), 0.46-0.43 (m, 2H), 0.26 (m, 2H). SC_ CIS-8-Dimethylamino-1- INT-1053 4-chlorobutanoyl SC_4072 1H NMR (DMSO-d6): δ 7.37-7.32 (m, 4H), 497.4 4090 [(1-hydroxy-cyclobutyl)- chloride (step 1) 7.27-7.25 (m, 1H), 6.03 (s, 1H), 3.43 (s, methyl]-3- 2H), 3.39 (t, 2H), 3.27 (s, 2H), 2.09 (s, 2H), [2-methyl-2-(2-oxo-pyrrolidin-1- 2.69-2.66 (m, 2H), 2.12 (t, 2H), 2.07-2.03 yl)-propyl]-8-phenyl-1,3- (m, 4H), 1.96 (s, 6H), 1.90-1.86 (m, 2H), diazaspiro[4.5]decan-2-one 1.84-1.76 (m, 2H), 1.63-1.61 (m, 1H), 1.45- 1.43 (m, 2H), 1.41 (m, 3H), 1.35-1.31 (m, 6H). SC_ TRANS-1-(Cyclobutyl-methyl)- INT-1056 — SC_4091 1HNMR (DMSO-d6, 400 MHz), δ (ppm) 476.3 4092 8-dimethylamino-3-(2-methyl-2- 7.44-7.29 (m, 5H), 3.38 (s, 2H), 3.34 (s, methylsulfonyl-propyl)-8-phenyl- 2H), 2.94 (s, 3H), 2.87 (s, 3H), 2.64 (d, 2H, 1,3-diazaspiro[4.5]decan-2-one J = 12.24 Hz), 2.60 (d, 2H, J = 7.24 Hz), 2.10-2.06 (m, 1H), 1.90 (s, 6H), 1.73-1.49 (m, 6H), 1.42-1.33 (m, 6H), 1.27 (s, 6H). SC_ CIS-8-Dimethylamino-3-[2-(1,1- INT-799 3-chloropropane-1- SC_4072 1H NMR (DMSO-d6): δ 7.37-7.32 (m, 4H), 533.3 4093 dioxo-[1,2]thiazolidin-2-yl)-2- sulfonyl chloride 7.27-7.23 (m, 1H), 6.01 (s, 1H), 3.42 (s, methyl-propyl]-1-[(1-hydroxy- (step 1) 2H), 3.36-3.31 (m, 2H), 3.18-3.13 (m, 4H), cyclobutyl)-methyl]-8-phenyl- 3.10 (s, 2H), 2.68-2.64 (m, 2H), 2.10-2.03 1,3-diazaspiro[4.5]decan-2-one (m, 6H), 1.96 (s, 6H), 1.90-1.84 (m, 2H), 1.70-1.60 (m,1H), 1.47-1.44 (m, 2H), 1.41- 1.35 (m, 3H), 1.32 (s, 6H). SC_ CIS-1-(Cyclopropyl-methyl)-8- INT-1063 1,6-dioxaspiro SC_4044 1H NMR (DMSO-d6): δ 7.34-7.29 (m, 1H), 460.3 4094 dimethylamino-8-(3- [2.5]octane 7.06-7.04 (m, 1H), 6.99-6.95 (m, 2H), 4.43 fluorophenyl)-3-[(4-hydroxy- (s, 1H), 3.82-3.78 (m, 2H), 3.74-3.71 (m, tetrahydro-pyran-4-yl)-methyl]- 2H), 3.28 (s, 2H), 3.14 (s, 2H), 3.06 (d, 2H), 1,3-diazaspiro[4.5]decan-2-one 2.59 (d, 2H).2.26 (t, 2H),2.05 (s, 6H).1.58-1.49 (m, 4H),1,47-1.42 (m, 4H),1.02 (m, 1H), 0.54-0.51 (m, 2H), 0.33-031 (m, 2H) SC_ CIS-8-Dimethylamino-1-[(1- INT-1072 5-bromopyrimidine SC_4056 519.3 4095 hydroxy-cyclobutyl)-methyl]- 8-phenyl-3-(1-pyrimidin-5-yl- piperidin-4-yl)-1,3- diazaspiro[4.5]decan-2-one SC_ CIS-2-[8-Dimethylamino-3-(2- SC_4032 2-chloro-N,N- SC_4003 1H NMR (600 MHz, DMSO) δ 7.35 (d, 4H), 465.3 4097 methylsulfonyl-ethyl)-2-oxo-8- dimethyl-acetamide 7.29-7.22 (m, 1H), 3.86 (s, 2H), 3.51 (t, 2H), phenyl-1,3-diazaspiro[4.5]decan- 3.32 (t, 2H), 3.29 (s, 2H), 3.03 (s, 3H), 1-yl]-N,N-dimethyl-acetamide 2.97 (s, 3H), 2.84 (s, 3H), 2.64 (d, 2H), 2.02-1.86 (m, 8H), 1.44-1.35 (m, 4H). SC_ CIS-1-(Cyclopropyl-methyl)-8- INT-1073 5-bromopyrimidine SC_4056 507.3 4099 dimethylamino-8-(3- fluorophenyl)-3-(1-pyrimidin-5- yl-piperidin-4-yl)-1,3- diazaspiro[4.5]decan-2-one SC_ CIS-1-(cyclopropylmethyl)-8-(3- SC_4088 SC_4010 438.2 4100 fluorophenyl)-8-(methylamino)- 3-(2-(methylsulfonyl)ethyl)-1,3- diazaspiro[4.5]decan-2-one SC_ CIS-1-(cyclopropylmethyl)-8- INT-983 1-oxaspiro[2.3] SC_4044 4101 (dimethylamino)-3- hexane ((1-hydroxycyclobutyl)methyl)-8- phenyl-1,3-diazaspiro [4.5]decan-2-one SC_ CIS-8-(dimethylamino)-8- INT-1074 1-oxa-6-thiaspiro SC_4044 4102 (3-fluorophenyl)- [2.5]octane (for step 1), 3-((4-hydroxy- (step 1) step 2 of 1,1-dioxidotetrahydro- SC_4038 2H-thiopyran-4-yl)methyl)-1-((1- (for step 2) hydroxycyclobutyl)methyl)- 1,3-diazaspiro[4.5]decan-2-one SC_ CIS-8-(dimethylamino)-8-(3- INT-1074 1,6- SC_4044 4103 fluorophenyl)- 1-((1- dioxaspiro[2.5] hydroxycyclobutyl)methyl)-3- octane ((4-hydroxytetrahydro-2H-pyran- 4-yl)methyl)-1,3-diazaspiro[4.5] decan-2-one SC_ CIS-1-(cyclopropylmethyl)-8- INT-1063 1-oxa-6- SC_4044 4104 (dimethylamino)-8- thiaspiro[2.5]octane (for step 1), (3-fluorophenyl)-3- (step 1) step 2 of ((4-hydroxy-1,1- SC_4038 dioxidotetrahydro-2H- (for step 2) thiopyran-4-yl)methyl)-1,3- diazaspiro[4.5]decan-2-one SC_ CIS-1-(cyclopropylmethyl)-8- INT-983 3-(bromomethyl) SC_4032 4105 (dimethylamino)-3-(oxetan-3- oxetane ylmethyl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_ CIS-8-(dimethylamino)-8- INT-976 (R)-1-(thiophen-3- SC_4032 398.2 4106 phenyl-3-((S)-1-(thiophen-3- yl)propan-2-yl yl)propan-2-yl)-1,3- methanesulfonate diazaspiro[4.5]decan-2-one SC_ CIS-8-(dimethylamino)-8- INT-976 (1-(trifluoromethyl) SC_4032 4107 phenyl-1,3-bis((1- cyclopropyl) (trifluoromethyl)cyclopropyl) methyl 4-methyl- methyl)-1,3-diazaspiro[4.5] benzenesulfonate decan-2-one SC_ CIS-8-(dimethylamino)-1,3- INT-976 (1-fluorocyclopropyl) SC_4032 4108 bis((1- methyl 4-methyl- fluorocyclopropyl)methyl)-8- benzenesulfonate phenyl-1,3-diazaspiro[4.5]decan- 2-one SC_ CIS-1-(cyclopropylmethyl)-8- INT-983 (3-(bromomethyl) SC_4032 4109 (dimethylamino)-3-((3- oxetan-3-yl) (hydroxymethyl)oxetan-3- methanol yl)methyl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_ CIS-3-((3-aminooxetan-3- INT-983 tert-butyl (3- SC_4034 4110 yl)methyl)-1- (bromomethyl) (for step 1), (cyclopropylmethyl)-8- oxetan- step 2 of (dimethylamino)-8-phenyl-1,3- 3-yl)carbamate SC_4054 diazaspiro[4.5]decan-2-one (for step 2) SC_ CIS-3-(8-(dimethylamino)-1-((1- INT-983 (1-cyanocyclobutyl) SC_4032 4111 f1uorocyclopropyl)methyl)-2- methyl 1,4-methyl- oxo-8-phenyl-1,3- benzenesulfonate diazaspiro[4.5]decan-3-yl)- 2,2-dimethylpropanenitrile SC_ CIS-3-(8-(dimethylamino)-1-((1- INT-976 2-cyano-2- SC_4032 4112 fluorocyclopropyl)methyl)-2- methylpropyl (step 1), oxo-8-phenyl-l,3- 4- methyl- SC_4034 diazaspiro[4.5]decan-3-yl)-2,2- benzenesulfonate (step 2) dimethylpropanenitrile (step 1), (1-fluorocyclopropyl) methyl 4-methyl benzenesulfonate (step 2) SC_ CIS-3-[8-(Ethyl-methyl-amino)- INT-797 3-bromo-2,2- step 1 of .sup.1HNMR (DMSO-d6, 400 MHz, at 100 0 C.), 369.2 5061 2-oxo-8-phenyl-1,3- dimethyl- INT-897 δ (ppm) = 7.34-7.21 (m, 5H), 6.70 (bs, 1H), diazaspiro[4.5]decan-3-yl]-2,2- propionitrile 3.28 (s, 2H), 3.19 (s, 2H), 2.32-2.24 (m, dimethyl-propionitrile 4H), 2.06 (s, 3H), 1.87-1.82 (m, 4H), 1.45- 1.37 (bs, 2H), 1.27 (s, 6H), 0.93 (t, 3H, 6.8 Hz). SC_ CIS-3-(8-Dimethylamino-2-oxo- INT-976 3-bromo-2,2- step 1 of .sup.1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 355.2 5062 8-phenyl-1,3- dimethyl- INT-897 7.35-7.24 (m, 5H), 7.03 (bs, 1H), 3.25 (s, diazaspiro[4.5]decan-3-yl)-2,2- propionitrile 2H), 3.15 (s, 2H), 2.32 (bs, 2H), 1.92 (s, dimethyl-propionitrile 6H), 1.82 (bs, 4H), 1.38 (bs, 2H), 1.24 (s, 6H). SC_ CIS-3-]8-(Ethyl-methyl-amino)- SC_5061 methyl iodide step 1 of .sup.1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 383.2 5065 1-methyl-2-oxo-8-phenyl-1,3- INT-953 7.34-722 (m, 5H), 3.38 (s, 2H), 3.21 (s, 2H), diazaspiro[4.5]decan-3-yl]-2,2- 2.71-2.64 (m, 5H), 2.19-2.16 (m, 4H), 1.96 dimethyl-propionitrile (s, 3H), 1.37-1.30 (m, 4H), 1.25 (s, 6H), 0.98 (t, 3H, J = 6 .48 Hz). SC_ CIS-3-(8-Ethylamino-2-oxo-8- INT-1008 3-bromo-2,2- step 1 of .sup.1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 355.1 5068 phenyl-1,3-diazaspiro[4.5]decan- dimethyl- INT-897 7.42 (d, 12H, J = 7.32 Hz), 7.30 (t, 2H, J = 3-yl)-2,2-dimethyl-propionitrile propionitrile 7.20 Hz), 7.17 (t, 1H, J = 7.12 Hz), 6.78 (s, 1H), 3.35 (s, 2H), 3.17 (s, 2H), 2.05 (m, 7H), 1.67-1.43 (m, 4H), 1.25 (s, 6H), 0.91 (t, 3H, J = 6.78 Hz). SC_ TRANS-3-[1-(Cyclopropyl- INT 1059 3-bromo-2,2- step 1 of .sup.1HNMR at 20° C. (DMSO-d6, 400 MHz), δ 409.2 5080 methyl)-8-dimethylamino- dimethyl- INT-897 (ppm) = 7 .44-7.28 (m, 5H), 3.46 (s, 2H), 2-oxo-8-phenyl-1,3- propionitrile (step 1), (for step 1), 3.23 (s, 2H), 2.72-2.66 (m, 2H), 2.57-2.55 diazaspiro[4.5]decan-3-yl]-2,2- cyclopropylmethyl- step 1 of (m, 2H), 1.91 (s, 6H), 1.55-1.45 (m, 6H), dimethyl-propionitrile bromide (step 2) INT-953 1.27 (s, 6H), 0.51 (bs, 1H), 0.19-0.14 (m, (for step 2) 2H), (−0.22)-(−0.26) (m, 2H).
[0414] Chemical Structure of all Examples
##STR00129## ##STR00130## ##STR00131## ##STR00132## ##STR00133## ##STR00134## ##STR00135## ##STR00136## ##STR00137## ##STR00138## ##STR00139## ##STR00140## ##STR00141## ##STR00142## ##STR00143## ##STR00144## ##STR00145## ##STR00146## ##STR00147## ##STR00148## ##STR00149##
[0415] Pharmacological Investigations
[0416] 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)
[0417] Human Mu-Opioid Peptide (hMOP) Receptor Binding Assay
[0418] 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-alkyl-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).
[0419] Human Kappa-Opioid Peptide (hKOP) Receptor Binding Assay
[0420] 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 Ki values are calculated by using the Cheng-Prusoff equation, (Cheng and Prusoff, 1973).
[0421] Human Delta-Opioid Peptide (hDOP) Receptor Binding Assay
[0422] 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 Ki values are calculated by using the Cheng-Prusoff equation, (Cheng and Prusoff, 1973).
[0423] Human Nociceptin/Orphanin FQ Peptide (hNOP) Receptor Binding Assay
[0424] 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).
[0425] 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. Turkcu. Finland). Half-maximal inhibitory concentration (IC50) values reflecting 5000 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 hMOP Ki [nM] or % hNOP Ki μinhibition at Example [nM] 1M SC_4001 2.3 80.5 SC_4002 28 755 SC_4003 7.7 39.5 SC_4004 44 305 SC_4005 19 64.5 SC_4006 3.6 16 SC_4007 2.6 58 SC_4008 7.3 69.8 SC_4009 1.1 37.4 SC_4010 9.5 87 SC_4011 13 210 SC_4012 1.6 99.7 SC_4013 5.8 40.5 SC_4014 2.1 84 SC_4017 45 375 SC_4018 1.3 19.7 SC_4021 83 636.7 SC_4022 140 555 SC_4024 155 285 SC_4025 26 206 SC_4026 57 643 SC_4031 119 1430 SC_4032 345 8530 SC_4033 — 15%@1 μM SC_4034 11 245 SC_4035 69 1580 SC_4036 8 210 SC_4037 815 185 SC_4038 69 1290 SC_4039 3 165 SC_4040 19 270 SC_4041 4 125 SC_4042 11 290 SC_4043 4 124 SC_4044 19 1065 SC_4045 17 415 SC_4046 15 655 SC_4047 8 265 SC_4048 46 805 SC_4049 11 220 SC_4050 19 255 SC_4051 21 770 SC_4052 3 175 SC_4053 34 1350 SC_4054 26 1305 SC_4055 54 1865 SC_4056 10 1755 SC_4057 3 1050 SC_4058 15 540 SC_4059 710 9%@1 μM SC_4060 1170 5%@1 μM SC_4061 710 9%@1 μM SC_4062 27 1810 SC_4063 15 2910 SC_4064 5 495 SC_4066 40 3045 SC_4067 12 615 SC_4068 13 985 SC_4069 140 6900 SC_4070 140 8% SC_4071 1 63 SC_4072 10 255 SC_4073 6 300 SC_4074 12 460 SC_4075 1 39 SC_4076 235 17% SC_4077 75 3230 SC_4078 125 74 SC_4079 6 415 SC_4080 145 4145 SC_4081 10 765 SC_4082 10 270 SC_4083 10 235 SC_4084 118 2465 SC_4085 3 495 SC_4086 6 570 SC_4087 12 535 SC_4088 6 935 SC_4089 64 275 SC_4090 6 520 SC_4091 0.4 76 SC_4092 16 17 SC_4093 17 1000 SC_4094 23 1980 SC_4095 8 630 SC_4096 36 330 SC_4097 114 4355 SC_4098 395 96 SC_5061 705 6%@1 μM SC_5062 84 2925 SC_5063 690 4%@1 μM SC_5065 0%@1 μM 13%@1 μM (DOP 40%) SC_5068 0%@1 μM 8%@1 μM (KOP 40%) SC_5075 10 305 SC_5080 24 230
[0426] Protocol for [.sup.35S]GTPγS Functional NOP/MOP/KOP/DOP Assays
[0427] Cell membrane preparations of CHO-K1 cells transfected with the human MOP receptor (Art.-No. RBHOMM) or the human DOP receptor (Art.-No. RBHODM), and HEK293 cells transfected with the human NOP receptor (Art.-No. RBHORLM) or the human KOP receptor (Art.-No. 6110558) are available from PerkinElmer (Waltham, 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.).
[0428] The [.sup.35S]GTPγS assays are carried out essentially as described by Gillen et al (2000). They are run as homogeneous scintillation proximity (SPA) assays in microtiter luminescence plates, where each well contains 1.5 mg of WGA-coated SPA-beads. To test the agonistic activity of test compounds on recombinant hNOP, hMOP, hDOP, and hKOP receptor expressing cell membranes from CHO-K1 or HEK293 cells, 10 or 5 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 MgCl2, 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.).
[0429] The unstimulated basal binding activity (UBS.sub.obs [cpm]) is determined from 12 unstimulated incubates and is set as 100% basal binding. For determination of the potency and the efficacy, the arithmetic mean of the observed total [.sup.35S]GTPγS binding (TB.sub.obs [cpm]) of all incubates (duplicates) stimulated by the receptor-specific agonists (i.e. N/OFQ, SNC80, DAMGO, or U69,593) are transformed in percent total binding (TB.sub.obs [%]) relative to the basal binding activity (i.e. 100% binding). The potency (EC.sub.50) of the respective agonist and its maximal achievable total [.sup.35S]GTPγS binding (TB.sub.calc [%]) above its calculated basal binding (UBS.sub.calc [%]) are determined from its transformed data (TB.sub.obs [%]) by means of nonlinear regression analysis with XLfit for each individual concentration series. Then the difference between the calculated unstimulated [.sup.35S]GTPγS binding (UBS.sub.calc [%]) and the maximal achievable total [.sup.35S]GTPγS binding (TB.sub.calc [%]) by each tested agonist is determined (i.e. B1.sub.calc [%]). This difference (B1.sub.calc [%]) as a measure of the maximal achievable enhancement of [.sup.35S]GTPγS binding by a given agonist is used to calculate the relative efficacy of test compounds versus the maximal achievable enhancement by a receptor-specific full agonist, e.g. N/OFQ (B1.sub.calc-N/OFQ [%]) which is set as 100% relative efficacy for the hNOP receptor. Likewise, the percentage efficacies of test compounds at the hDOP, hMOP, or hKOP receptor are determined versus the calculated maximal enhancement of [.sup.35S]GTPγS binding by the full agonists SNC80 (B1.sub.calc-SNC80 [%]), DAMGO (B1.sub.calc-DAMGO [%]) and U69,593 (B1.sub.calc-U69,593 [%]) which are set as 100% relative efficacy at each receptor, respectively.
[0430] The foregoing description and examples have been set forth merely to illustrate the invention and are not intended to be limiting. Since modifications of the described embodiments incorporating the spirit and substance of the invention may occur to persons skilled in the art, the invention should be construed broadly to include all variations within the scope of the appended claims and equivalents thereof.