U.S. patent application number 15/405919 was filed with the patent office on 2017-07-13 for 3-(carboxymethyl)-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives.
The applicant listed for this patent is Gruenenthal GmbH. Invention is credited to Florian JAKOB, Ruth JOSTOCK, Achim KLESS, Thomas KOCH, Rene Michael KOENIGS, Sven KUEHNERT, Klaus LINZ, Paul RATCLIFFE, Klaus SCHIENE, Wolfgang SCHROEDER, Anita WEGERT.
Application Number | 20170197971 15/405919 |
Document ID | / |
Family ID | 55129635 |
Filed Date | 2017-07-13 |
United States Patent
Application |
20170197971 |
Kind Code |
A1 |
KUEHNERT; Sven ; et
al. |
July 13, 2017 |
3-(Carboxymethyl)-8-Amino-2-Oxo-1,3-Diaza-Spiro-[4.5]-Decane
Derivatives
Abstract
The invention relates to
3-(carboxymethyl)-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane
derivatives, their preparation and their use in medicine,
particularly in the treatment of pain.
Inventors: |
KUEHNERT; Sven; (Dueren,
DE) ; KOENIGS; Rene Michael; (Erkelenz, DE) ;
JAKOB; Florian; (Aachen, DE) ; KLESS; Achim;
(Aachen, DE) ; RATCLIFFE; Paul; (Aachen, DE)
; JOSTOCK; Ruth; (Stolberg, DE) ; KOCH;
Thomas; (Stolberg, DE) ; LINZ; Klaus;
(Rheinbach, DE) ; SCHROEDER; Wolfgang; (Aachen,
DE) ; SCHIENE; Klaus; (Juechen, DE) ; WEGERT;
Anita; (Aldenhoven, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Gruenenthal GmbH |
Aachen |
|
DE |
|
|
Family ID: |
55129635 |
Appl. No.: |
15/405919 |
Filed: |
January 13, 2017 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 409/12 20130101;
C07D 413/06 20130101; A61P 29/00 20180101; C07D 487/04 20130101;
C07D 401/12 20130101; C07D 405/12 20130101; C07D 235/02 20130101;
C07D 401/06 20130101; C07K 5/06026 20130101; C07D 413/12 20130101;
A61P 25/04 20180101; C07D 417/12 20130101; C07D 405/06 20130101;
C07D 403/12 20130101; C07D 403/06 20130101 |
International
Class: |
C07D 487/04 20060101
C07D487/04; C07D 401/12 20060101 C07D401/12; C07D 403/12 20060101
C07D403/12; C07D 403/06 20060101 C07D403/06; C07D 405/06 20060101
C07D405/06; C07D 413/12 20060101 C07D413/12; C07D 401/06 20060101
C07D401/06; C07D 405/12 20060101 C07D405/12; C07D 413/06 20060101
C07D413/06; C07D 417/12 20060101 C07D417/12; C07D 235/02 20060101
C07D235/02; C07D 409/12 20060101 C07D409/12 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 13, 2016 |
EP |
16 151 014.4 |
Claims
1. A compound according to general formula (I) ##STR00181## 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(.dbd.O)--, --C(.dbd.O)O--, or
--S(.dbd.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(.dbd.O)--, --C(.dbd.O)O--, --C(.dbd.O)O--CH.sub.2--, or
--S(.dbd.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(.dbd.O)--, --C(.dbd.O)O--,
--C(.dbd.O)O--CH.sub.2--, or --S(.dbd.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(.dbd.O)--, --C(.dbd.O)O--, --C(.dbd.O)O--CH.sub.2--, or
--S(.dbd.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(.dbd.O)--, --C(.dbd.O)O--, --C(.dbd.O)O--CH.sub.2--, or
--S(.dbd.O).sub.2--; X means --O--, --S-- or --NR.sup.6--; R.sup.5
means --H; --C.sub.1-C.sub.6-alkyl, linear or branched, saturated
or unsaturated, unsubstituted, mono- or polysubstituted; a
3-12-membered cycloalkyl moiety, saturated or unsaturated,
unsubstituted, mono- or polysubstituted; wherein said 3-12-membered
cycloalkyl moiety is optionally connected through
--C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted; a
3-12-membered heterocycloalkyl moiety, saturated or unsaturated,
unsubstituted, mono- or polysubstituted; wherein said 3-12-membered
heterocycloalkyl moiety is optionally connected through
--C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted; a
6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted;
wherein said 6-14-membered aryl moiety is optionally connected
through --C.sub.1-C.sub.6-alkylene-, linear or branched, saturated
or unsaturated, unsubstituted, mono- or polysubstituted; or a
5-14-membered heteroaryl moiety, unsubstituted, mono- or
polysubstituted; wherein said 5-14-membered heteroaryl moiety is
optionally connected through --C.sub.1-C.sub.6-alkylene-, linear or
branched, saturated or unsaturated, unsubstituted, mono- or
polysubstituted; in case X means NR.sup.6, R.sup.6 means --H;
--C.sub.1-C.sub.6-alkyl, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted; a
3-12-membered cycloalkyl moiety, saturated or unsaturated,
unsubstituted, mono- or polysubstituted; wherein said 3-12-membered
cycloalkyl moiety is optionally connected through
--C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted; a
3-12-membered heterocycloalkyl moiety, saturated or unsaturated,
unsubstituted, mono- or polysubstituted; wherein said 3-12-membered
heterocycloalkyl moiety is optionally connected through
--C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted; a
6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted;
wherein said 6-14-membered aryl moiety is optionally connected
through --C.sub.1-C.sub.6-alkylene-, linear or branched, saturated
or unsaturated, unsubstituted, mono- or polysubstituted; or a
5-14-membered heteroaryl moiety, unsubstituted, mono- or
polysubstituted; wherein said 5-14-membered heteroaryl moiety is
optionally connected through --C.sub.1-C.sub.6-alkylene-, linear or
branched, saturated or unsaturated, unsubstituted, mono- or
polysubstituted; or in case X means NR.sup.6, R.sup.5 and R.sup.6
together with the nitrogen atom to which they are attached form a
3-12-membered heterocycloalkyl moiety, saturated or unsaturated,
unsubstituted, mono- or polysubstituted; R.sup.9, R.sup.10,
R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16,
R.sup.17, R.sup.18, R.sup.19, and R.sup.20 independently of one
another mean --H, --F, --Cl, --Br, --I, --OH, or
--C.sub.1-C.sub.6-alkyl, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted; wherein
"mono- or polysubstituted" means that one or more hydrogen atoms
are replaced by a substituent independently of one another selected
from the group consisting of --F, --Cl, --Br, --I, --CN,
--R.sup.21, --C(.dbd.O)R.sup.21, --C(.dbd.O)OR.sup.21,
--C(.dbd.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, .dbd.O, --OR.sup.21,
--OC(.dbd.O)R.sup.21, --OC(.dbd.O)OR.sup.21,
--OC(.dbd.O)NR.sup.21R.sup.22, --NO.sub.2, --NR.sup.21R.sup.22,
--NR.sup.21--(CH.sub.2).sub.1-6--C(.dbd.O)R.sup.22,
--NR.sup.21--(CH.sub.2).sub.1-6--C(.dbd.O)OR.sup.22,
--NR.sup.23--(CH.sub.2).sub.1-6--C(.dbd.O)NR.sup.21R.sup.22,
--NR.sup.21C(.dbd.O)R.sup.22, --NR.sup.21C(.dbd.O)--OR.sup.22,
--NR.sup.23C(.dbd.O)NR.sup.21R.sup.22,
--NR.sup.21S(.dbd.O).sub.2R.sup.22, --SR.sup.21,
--S(.dbd.O)R.sup.21, --S(.dbd.O).sub.2R.sup.21,
--S(.dbd.O).sub.2OR.sup.21, and --S(.dbd.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(.dbd.O)NR.sup.21R.sup.22, --OC(.dbd.O)NR.sup.21R.sup.22,
--NR.sup.21R.sup.22,
--NR.sup.23--(CH.sub.2).sub.1-6--C(.dbd.O)NR.sup.21R.sup.22,
--NR.sup.23C(.dbd.O)NR.sup.21R.sup.22, or
--S(.dbd.O).sub.2NR.sup.21R.sup.22 together with the nitrogen atom
to which they are attached form a ring and mean
--(CH.sub.2).sub.3-6--; --(CH.sub.2).sub.2--O--(CH.sub.2).sub.2--;
or --(CH.sub.2).sub.2--NR.sup.B--(CH.sub.2).sub.2--, wherein
R.sup.B means --H or --C.sub.1-C.sub.6-alkyl, linear or branched,
saturated or unsaturated, unsubstituted or substituted with one,
two, three or four substituents independently of one another
selected from the group consisting of --F, --Cl, --Br and --I; or a
physiologically acceptable salt thereof.
2. The compound according to claim 1, wherein R.sup.9, R.sup.10,
R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16,
R.sup.17, R.sup.18, R.sup.19, and R.sup.20 independently of one
another mean --H, --F, --OH, or --C.sub.1-C.sub.6-alkyl.
3. The compound according to claim 1, wherein R.sup.1 means --H;
and R.sup.2 means --C.sub.1-C.sub.6-alkyl, linear or branched,
saturated or unsaturated, unsubstituted, mono- or
polysubstituted.
4. The compound according to claim 1, wherein R.sup.1 means
--CH.sub.3; and R.sup.2 means --C.sub.1-C.sub.6-alkyl, linear or
branched, saturated or unsaturated, unsubstituted, mono- or
polysubstituted.
5. The compound according to claim 1, wherein R.sup.1 means --H or
--CH.sub.3; and wherein R.sup.2 means --CH.sub.2-cycloalkyl,
--CH.sub.2-cyclobutyl, --CH.sub.2-cyclopentyl, --CH.sub.2-oxetanyl
or --CH.sub.2-tetrahydrofuranyl.
6. The compound according to claim 1, wherein R.sup.1 and R.sup.2
together with the nitrogen atom to which they are attached form a
ring and mean --(CH.sub.2).sub.3-6--.
7. The compound according to claim 1, wherein R.sup.3 means
--C.sub.1-C.sub.6-alkyl, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted.
8. The compound according to claim 1, wherein R.sup.3 means a
6-14-membered aryl moiety, unsubstituted, mono- or
polysubstituted.
9. The compound according to claim 1, wherein R.sup.3 means a
5-14-membered heteroaryl moiety, unsubstituted, mono- or
polysubstituted.
10. The compound according to claim 1, wherein R.sup.4 means
--H.
11. The compound according to claim 1, wherein R.sup.4 means
--C.sub.1-C.sub.6-alkyl, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted.
12. The compound according to claim 1, wherein R.sup.4 means a
3-12-membered cycloalkyl moiety, saturated or unsaturated,
unsubstituted, mono- or polysubstituted; wherein the 3-12-membered
cycloalkyl moiety is connected through --C.sub.1-C.sub.6-alkylene-,
linear or branched, saturated or unsaturated, unsubstituted, mono-
or polysubstituted.
13. The compound according to claim 1, wherein R.sup.4 means a
3-12-membered heterocycloalkyl moiety, saturated or unsaturated,
unsubstituted, mono- or polysubstituted; wherein said 3-12-membered
heterocycloalkyl moiety is connected through
--C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted.
14. The compound according to claim 1, wherein R.sup.4 means a
6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted;
wherein said 6-14-membered aryl moiety is connected through
--C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted.
15. The compound according to claim 1, wherein R.sup.4 means a
5-14-membered heteroaryl moiety, unsubstituted, mono- or
polysubstituted; wherein said 5-14-membered heteroaryl moiety is
connected through --C.sub.1-C.sub.6-alkylene-, linear or branched,
saturated or unsaturated, unsubstituted, mono- or
polysubstituted.
16. The compound according to claim 1, wherein R.sup.5 means
--H.
17. The compound according to claim 1, wherein R.sup.5 means
--C.sub.1-C.sub.6-alkyl, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted.
18. The compound according to claim 1, wherein R.sup.5 means a
3-12-membered cycloalkyl moiety, saturated or unsaturated,
unsubstituted, mono- or polysubstituted, wherein said 3-12-membered
cycloalkyl moiety is optionally connected through
--C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted.
19. The compound according to claim 1, wherein R.sup.5 means a
3-12-membered heterocycloalkyl moiety, saturated or unsaturated,
unsubstituted, mono- or polysubstituted; wherein said 3-12-membered
heterocycloalkyl moiety is optionally connected through
--C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted.
20. The compound according to claim 1, wherein R.sup.5 means a
5-14-membered heteroaryl moiety, unsubstituted, mono- or
polysubstituted; wherein said 5-14-membered heteroaryl moiety is
optionally connected through --C.sub.1-C.sub.6-alkylene-, linear or
branched, saturated or unsaturated, unsubstituted, mono- or
polysubstituted.
21. The compound according to claim 1, wherein X means NR.sup.6 and
R.sup.5 and R.sup.6 together with the nitrogen atom to which they
are attached form a 3-12-membered heterocycloalkyl moiety,
saturated or unsaturated, unsubstituted, mono- or
polysubstituted.
22. The compound according to claim 1, wherein X means NR.sup.6 and
R.sup.6 means --H or --C.sub.1-C.sub.6-alkyl, linear or branched,
saturated or unsaturated, unsubstituted, mono- or
polysubstituted.
23. The compound according to claim 1, which has a structure
according to any of general formulas (II-A) to (VIII-C):
##STR00182## ##STR00183## ##STR00184## wherein in each case
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 and X are
defined as in claim 1, R.sup.C means --H, --OH, --F, --CN or
--C.sub.1-C.sub.4-alkyl; R.sup.D means --H or --F; or a
physiologically acceptable salt thereof.
24. The compound according to claim 1, wherein the substructure
##STR00185## has a meaning selected from the group consisting of:
##STR00186## ##STR00187## ##STR00188## ##STR00189## ##STR00190##
##STR00191## ##STR00192## ##STR00193## ##STR00194##
25. The compound according to claim 1, wherein R.sup.1 means --H or
--CH.sup.3; R.sup.2 means --CH.sub.3, --CH.sub.2CH.sub.3 or
--CH.sub.2--C(H)(CH.sub.3).sub.2; R.sup.3 means -phenyl, -thienyl
or -pyridinyl, in each case unsubstituted or monosubstituted with
--F; R.sup.4 means -- H; --C.sub.1-C.sub.6-alkyl, linear or
branched, saturated, unsubstituted or substituted with one, two,
three or four substituents independently of one another selected
from the group consisting of --F, --Cl, --Br, --I, --CN, --OH,
.dbd.O, --N(CH.sub.3).sub.2 and --O--CH.sub.3; or -cyclopropyl,
-cyclobutyl, -cyclopentyl or -cyclohexyl, unsubstituted or
monosubstituted with --F, --OH, --CN or --CH.sub.3, wherein said
-cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl is connected
through --CH.sub.2-- or --CH.sub.2CH.sub.2--; -oxetanyl
unsubstituted or monosubstituted with --F, --OH, --CN or
--CH.sub.3, wherein said -oxetanyl is connected through
--CH.sub.2-- or --CH.sub.2CH.sub.2--; X means --O-- or
--NR.sup.6--; R.sup.5 means -- H; --C.sub.1-C.sub.6-alkyl, linear
or branched, saturated or unsaturated, unsubstituted or substituted
with one, two, three or four substituents independently of one
another selected from the group consisting of --F, --Cl, --Br, --I,
--CN, --O--CH.sub.3, --O--(CH.sub.2--CH.sub.2--O).sub.1-10--H,
--O--(CH.sub.2CH.sub.2--O).sub.1-10--CH.sub.3, --C(.dbd.O)OH,
--C(.dbd.O)OCH.sub.3, --C(.dbd.O)NH.sub.2, --C(.dbd.O)NHCH.sub.3,
--C(.dbd.O)N(CH.sub.3).sub.2, --OH, --S(.dbd.O)CH.sub.3,
--S(.dbd.O).sub.2CH.sub.3, unsubstituted --C(.dbd.O)-morpholinyl,
--NH--C(.dbd.O)--CH.sub.3, --N(CH.sub.3).sub.2 and
NH--S(.dbd.O).sub.2--CH.sub.3; -cyclopropyl, -cyclobutyl,
-cyclopentyl or -cyclohexyl, unsubstituted or monosubstituted with
--F, --OH, --CN or --CH.sub.3, wherein said -cyclopropyl,
-cyclobutyl, cyclopentyl or cyclohexyl is optionally connected
through --CH.sub.2-- or --CH.sub.2CH.sub.2--; -heterocyclobutyl,
-heterocyclopentyl, or -heterocyclohexyl, in each case
unsubstituted or substituted with one, two, three or four
substituents independently of one another selected from the group
consisting of --F, --Cl, --Br, --I, --CN, --O--CH.sub.3,
--O--(CH.sub.2--CH.sub.2--O).sub.1-10--H,
--O--(CH.sub.2CH.sub.2--O).sub.1-10--CH.sub.3,
--C.sub.1-C.sub.4-alkyl, --C(.dbd.O)OH, --C(.dbd.O)OCH.sub.3,
--C(.dbd.O)NH.sub.2, --C(.dbd.O)NHCH.sub.3,
--C(.dbd.O)N(CH.sub.3).sub.2, .dbd.O, --OH, --SCH.sub.3,
--S(.dbd.O)CH.sub.3, --S(.dbd.O).sub.2CH.sub.3, unsubstituted
--C(.dbd.O)-morpholinyl, --NH--C(.dbd.O)--CH.sub.3,
--N(CH.sub.3).sub.2 and NH--S(.dbd.O).sub.2--CH.sub.3; wherein said
-heterocyclobutyl, -heterocyclopentyl, or -heterocyclohexyl is
optionally connected through --CH.sub.2-- or --CH.sub.2CH.sub.2--;
-oxazolyl, -isoxazolyl, -pyrazolyl, -pyridinyl, -pyridazinyl,
-pyrazinyl, -thiazolyl, -thiadiazolyl, -imidazolyl, -pyrimidinyl,
or 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine, in each case
unsubstituted or substituted with one, two, three or four
substituents independently of one another selected from the group
consisting of --F, --Cl, Br, --I, --CN, --OH, --CH.sub.3,
--O--CH.sub.3, --C(.dbd.O)OH, --C(.dbd.O)OCH.sub.3,
--C(.dbd.O)NH.sub.2, --C(.dbd.O)NHCH.sub.3,
--C(.dbd.O)N(CH.sub.3).sub.2, --S(.dbd.O)CH.sub.3,
--S(.dbd.O).sub.2CH.sub.3 and --S--CH.sub.3, wherein said
-oxazolyl, -isoxazolyl, -pyrazolyl, -pyridinyl, -pyridazinyl,
-pyrazinyl, -thiazolyl, -thiadiazolyl, -imidazolyl, -pyrimidinyl,
or 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine is optionally
connected through --CH.sub.2--; or -phenyl, unsubstituted or
substituted with one, two, three or four substituents independently
of one another selected from the group consisting of --F, --Cl, Br,
--I, --CN, --OH, --CH.sub.3, --O--CH.sub.3, --C(.dbd.O)OH,
--C(.dbd.O)OCH.sub.3, --C(.dbd.O)NH.sub.2, --C(.dbd.O)NHCH.sub.3,
--C(.dbd.O)N(CH.sub.3).sub.2, S(.dbd.O)CH.sub.3, --S(.dbd.O).sub.2
CH.sub.3 and --S--CH.sub.3, wherein said -phenyl is optionally
connected through --CH.sub.2--; in case X means NR.sup.6, R.sup.6
means --H or --CH.sub.3; or in case X means NR.sup.6, R.sup.5 and
R.sup.6 together with the nitrogen atom to which they are attached
form a -pyrrolidinyl, -piperidinyl, -piperazinyl, -morpholinyl,
-thiomorpholinyl, -thiomorpholinyl dioxide or
-(methylsulfonyl)piperazinyl, in each case unsubstituted or
substituted with one, two, three or four substituents independently
of one another selected from the group consisting of .dbd.O, --OH,
--CH.sub.2--OH, --C(.dbd.O)NH.sub.2, and --S(.dbd.O).sub.2CH.sub.3,
wherein said -pyrrolidinyl, -piperidinyl, -piperazinyl,
-morpholinyl, -thiomorpholinyl, -thiomorpholinyl dioxide or
-(methylsulfonyl)piperazinyl is optionally condensed with an
imidazole moiety, unsubstituted; and R.sup.9, R.sup.10, R.sup.11,
R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17,
R.sup.18, R.sup.9, and R.sup.20 mean --H.
26. The compound according to claim 1, which has a structure
according to general formula (I') ##STR00195## wherein R.sup.1 to
R.sup.5, R.sup.9 to R.sup.20, and X are defined as in claim 1, or a
physiologically acceptable salt thereof.
27. The compound according to claim 1, which has a structure
according to general formula (IX) ##STR00196## wherein R.sup.C
means --H or --OH; R.sup.3 means -phenyl or -3-fluorophenyl;
R.sup.5 means --H, --CH.sub.3, --CH.sub.2CH.sub.2OH, or
--CH.sub.2C(.dbd.O)NH.sub.2; R.sup.6 means --H or --CH.sup.3; or
R.sup.5 and R.sup.6 together with the nitrogen atom to which they
are attached form a ring and mean --(CH.sub.2).sub.5--, wherein
said ring is unsubstituted or substituted with one or two
substituents independently of one another selected from the group
consisting of --CH.sub.3, --OH, --S(.dbd.O).sub.2CH.sub.3 and
--C(.dbd.O)NH.sub.2; R.sup.9 and R.sup.10 independently of one
another mean --H or --CH.sub.3; or a physiologically acceptable
salt thereof.
28. The compound according to claim 1, which is selected from the
group consisting of
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-e-
thoxy]-ethoxy]-ethoxy]-ethyl]-acetamide;
CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-
spiro[4.5]decan-3-yl]-acetyl]amino]-pyridine-2-carboxylic acid
methyl ester;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-N-[(1R)-2-hydroxy-1-methyl-ethyl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-[(1S)-2-hydroxy-1-methyl-ethyl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-methyl-N-(methylcarbamoyl-methyl)-acetamide;
CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-
spiro[4.5]decan-3-yl]-acetyl]amino]-nicotinic acid methyl ester;
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-
spiro[4.5]decan-3-yl]-acetyl]-methyl-amino]-2-methyl-propionamide;
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-
spiro[4.5]decan-3-yl]-acetyl]amino]-N,2-dimethyl-propionamide;
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-
spiro[4.5]decan-3-yl]-acetyl]-methyl-amino]-N,2-dimethyl-propionamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-[(dimethyl-carbamoyl)-methyl]-N-methyl-acetamide;
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-
spiro[4.5]decan-3-yl]-acetyl]amino]-2-methyl-propionamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(5-methoxy-pyridin-2-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(6-methoxy-pyridin-2-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(4-methoxy-pyridin-2-yl)-acetamide;
CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-
spiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-pyridine-2-carboxylic
acid amide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-N-[(3-hydroxy-cyclobutyl)-methyl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-[(3-hydroxy-cyclobutyl)-methyl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-[(1-hydroxy-cyclopropyl)-methyl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(3-morpholin-4-yl-3-oxo-propyl)-acetamide;
CIS-N-(1-Cyano-cyclopropyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-ox-
o-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-[(3-hydroxy-cyclopentyl)-methyl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-[[(2R)-2-hydroxy-cyclohexyl]-methyl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethyl]-ace-
tamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-N-[(1-hydroxy-cyclohexyl)-methyl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-
-ethyl]-acetamide;
CIS-N-(6-Cyano-pyridin-2-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-o-
xo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-
spiro[4.5]decan-3-yl]-acetyl]amino]-nicotinic acid methyl ester;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(3-methoxy-pyridin-2-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-etho-
xy]-ethoxy]-ethyl]-acetamide;
CIS-N-(4-Cyano-pyridin-2-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-o-
xo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(5-methoxy-pyrimidin-2-yl)-acetamide;
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-
spiro[4.5]decan-3-yl]-acetyl]amino]-isonicotinic acid methyl ester;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(2-methoxy-pyridin-4-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(6-fluoro-pyridin-3-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(2-methyl-pyrimidin-5-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(5-methyl-pyrimidin-2-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(3-fluoro-pyridin-2-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(3-fluoro-pyridin-4-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(6-methoxy-pyridin-3-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(2-methyl-pyridin-3-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(4-methyl-pyridin-3-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(3-methyl-pyridin-4-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(6-methyl-pyridin-3-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(5-fluoro-pyridin-2-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(5-methyl-pyridin-2-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(4-methyl-pyridin-2-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(3-methyl-pyridin-2-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(3-methoxy-pyridin-4-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(6-methoxy-pyridazin-3-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(5-methylsulfonyl-pyridin-2-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(5-methoxy-pyridin-2-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(6-methylsulfonyl-pyridin-3-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(6-methoxy-pyrazin-2-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(4-methoxy-pyridin-2-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(4-methoxy-pyrimidin-2-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(oxazol-5-yl-methyl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(oxazol-2-yl-methyl)-acetamide;
CIS-1-(Cyclobutyl-methyl)-3-[2-[(3
S,4S)-3,4-dihydroxy-piperidin-1-yl]-2-oxo-ethyl]-8-dimethylamino-8-phenyl-
-1,3-diazaspiro[4.5]decan-2-one; CIS-1-(Cyclobutyl-methyl)-3-[2-[(3
S,4S)-3,4-dihydroxy-pyrrolidin-1-yl]-2-oxo-ethyl]-8-dimethylamino-8-pheny-
l-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-(Cyclobutyl-methyl)-3-[2-[(3
S,4R)-3,4-dihydroxy-pyrrolidin-1-yl]-2-oxo-ethyl]-8-dimethylamino-8-pheny-
l-1,3-diazaspiro[4.5]decan-2-one;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-cyclopropyl-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-N-methyl-acetamide;
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-(3-hydroxy-piperidin-1-yl)-
-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-[(1-hydroxy-cyclobutyl)-methyl]-acetamide;
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-
spiro[4.5]decan-3-yl]-acetyl]amino]-N,N-dimethyl-acetamide;
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-oxo-2-(5,6,7,8-tetrahydro--
[1,2,4]triazolo[1,5-a]pyrazin-7-yl)-ethyl]-8-phenyl-1,3-diazaspiro[4.5]dec-
an-2-one;
CIS-3-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl--
1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N,N-dimethyl-propionamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-[2-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy-
]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethyl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(4-methoxy-pyrimidin-5-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(2-methoxy-pyrimidin-5-yl)-acetamide;
CIS-N-(5-Cyano-pyridin-2-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-o-
xo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-
spiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-pyridine-4-carboxylic
acid amide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyrimidin-4-yl)-acetamide;
CIS-N-(2-Cyano-pyrimidin-5-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-
-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;
CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-
spiro[4.5]decan-3-yl]-acetyl]amino]-pyridine-2-carboxylic acid
amide;
CIS-N-(3-Cyano-pyridin-2-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-o-
xo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-
spiro[4.5]decan-3-yl]-acetyl]amino]-acetamide;
CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-
spiro[4.5]decan-3-yl]-acetyl]amino]-pyridine-3-carboxylic acid
amide;
CIS-N-(4-Cyano-pyrimidin-2-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-
-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-([1,3,4]thiadiazol-2-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-thiazol-2-yl-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(5-methyl-isoxazol-3-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-isoxazol-3-yl-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(1-methyl-1H-pyrazol-3-yl)-acetamide;
CIS-N-(4-Cyano-5-methylsulfanyl-1H-pyrazol-3-yl)-2-[1-(cyclobutyl-methyl)-
-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(5-methoxy-pyrazin-2-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(pyridazin-4-yl-methyl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-[(2-hydroxyphenyl)-methyl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-[(1-methyl-1H-imidazol-4-yl)-methyl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-[(4-methyl-pyridin-3-yl)-methyl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(pyrimidin-2-yl-methyl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(pyridazin-3-yl-methyl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(pyrimidin-4-yl-methyl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(pyrazin-2-yl-methyl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(oxazol-4-yl-methyl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-[(2-methyl-pyridin-3-yl)-methyl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-[(2-methoxy-pyridin-3-yl)-methyl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-[(4-methoxy-pyridin-3-yl)-methyl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-[(6-methyl-pyridin-2-yl)-methyl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-[(6-methoxy-pyridin-2-yl)-methyl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-[(2-methoxyphenyl)-methyl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(o-tolyl-methyl)-acetamide;
CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-
spiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-pyridine-3-carboxylic
acid amide;
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,-
3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-pyridine-4-carboxylic
acid amide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyrimidin-4-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(2-methoxy-pyrimidin-4-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(4-hydroxy-pyrimidin-5-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(2-hydroxy-pyrimidin-5-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(5-hydroxy-pyridin-2-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(1,1-dioxo-thian-4-yl)-acetamide;
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan--
4-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-2-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[-
4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide;
CIS-2-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[-
4.5]decan-3-yl]-N-methyl-acetamide;
CIS-N-(5-Cyano-pyrimidin-4-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-
-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(5-methylsulfanyl-pyridin-2-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(4-methoxy-pyrimidin-2-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(6-methylsulfanyl-pyridin-2-yl)-acetamide;
CIS-2-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[-
4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide;
CIS-2-[[2-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazasp-
iro[4.5]decan-3-yl]-acetyl]amino]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-methyl-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(6-hydroxy-pyridin-2-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-[(2-methoxy-pyrimidin-5-yl)-methyl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-[(4-methoxy-pyrimidin-2-yl)-methyl]-acetamide;
CIS-N-(2-Cyano-pyrimidin-4-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-
-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-[6-(methyl sulfinyl)-pyridin-2-yl]-acetamide;
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazasp-
iro[4.5]decan-3-yl]-acetyl]amino]-2-methyl-propionamide;
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazasp-
iro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-acetamide;
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazasp-
iro[4.5]decan-3-yl]-acetyl]amino]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl]-acetamide;
CIS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-methylamino-2-oxo-8-p-
henyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[-
4.5]decan-3-yl]-N-methyl-N-(methylcarbamoyl-methyl)-acetamide;
CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl]-N-(2-methyl
sulfonyl-ethyl)-acetamide;
CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-5-yl-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(6-methyl sulfonyl-pyridin-2-yl)-acetamide;
CIS-2-[8-Dimethylamino-1-[(dimethyl-carbamoyl)-methyl]-2-oxo-8-phenyl-1,3-
-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide;
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazasp-
iro[4.5]decan-3-yl]-acetyl]-methyl-amino]-2-methyl-propionamide;
CIS-1-(Cyclobutyl-methyl)-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethy-
l]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[-
4.5]decan-3-yl]-N-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-eth-
oxy]-ethoxy]-ethoxy]-ethyl]-acetamide;
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazasp-
iro[4.5]decan-3-yl]-acetyl]amino]-N,N-dimethyl-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(5-hydroxy-pyrimidin-2-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(4-methyl sulfonyl-pyridin-2-yl)-acetamide;
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-
spiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-acetamide;
CIS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-
-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;
CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-3-
-yl)-N-methyl-acetamide;
CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro-
[4.5]decan-3-yl]-N-methyl-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-[4-(methyl sulfinyl)-pyridin-2-yl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(3-hydroxy-pyridin-2-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(2-methyl sulfonyl-ethyl)-acetamide;
CIS-1-(Cyclobutyl-methyl)-3-[2-[(3
S,4R)-3,4-dihydroxy-pyrrolidin-1-yl]-2-oxo-ethyl]-8-dimethylamino-8-pheny-
l-1,3-diazaspiro[4.5]decan-2-one;
CIS-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[-
4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide;
CIS-2-[8-Dimethylamino-1-[(dimethyl-carbamoyl)-methyl]-2-oxo-8-phenyl-1,3-
-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide;
CIS-2-[8-Dimethylamino-1-[(dimethyl-carbamoyl)-methyl]-2-oxo-8-phenyl-1,3-
-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;
CIS-2-[[2-[8-Dimethylamino-1-(2-methyl-propyl)-2-oxo-8-phenyl-1,3-diazasp-
iro[4.5]decan-3-yl]-acetyl]amino]-acetamide;
CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl]-acetamide;
CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;
CIS-2-[[2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazas-
piro[4.5]decan-3-yl]-acetyl]amino]-acetamide;
CIS-2-[8-Dimethylamino-1-(2-methyl-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[-
4.5]decan-3-yl]-N-methyl-acetamide;
CIS-1-(Cyclobutyl-methyl)-3-[2-[(3
S,4R)-3,4-dihydroxy-pyrrolidin-1-yl]-2-oxo-ethyl]-8-methylamino-8-phenyl--
1,3-diazaspiro[4.5]decan-2-one;
CIS-2-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,-
3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;
CIS-2-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,-
3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide;
CIS-2-[[2-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-pheny-
l-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide;
CIS-2-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,-
3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide;
CIS-2-[[2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diaz-
aspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-N-methyl-acetamide;
CIS-2-[[2-(8-Dimethylamino-2-oxo-8-phenyl-1-propyl-1,3-diazaspiro[4.5]dec-
an-3-yl)-acetyl]amino]-acetamide;
CIS-2-[[2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phen-
yl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide;
CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide;
CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl]-N-(1,1-dioxo-thian-4-yl)-acetamide;
CIS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspi-
ro[4.5]decan-3-yl]-N-methyl-acetamide;
CIS-2-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-phenyl-1,3-
-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide;
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,-
3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide;
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazasp-
iro[4.5]decan-3-yl]-acetyl]amino]-N,2-dimethyl-propionamide;
CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro-
[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide;
CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro-
[4.5]decan-3-yl]-N-methyl-N-(methylcarbamoyl-methyl)-acetamide;
CIS-8-Dimethylamino-1-(3-methoxy-propyl)-3-[2-oxo-2-(3-oxo-piperazin-1-yl-
)-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-N-(Carbamoyl-methyl)-2-[8-dimethylamino-1-(3-methoxy-propyl)-2-oxo-8--
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;
CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro-
[4.5]decan-3-yl]-N-[(3-hydroxy-cyclobutyl)-methyl]-acetamide;
CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro-
[4.5]decan-3-yl]-N-[(3-hydroxy-cyclobutyl)-methyl]-acetamide;
CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro-
[4.5]decan-3-yl]-N-[(3-hydroxy-cyclopentyl)-methyl]-acetamide;
CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro-
[4.5]decan-3-yl]-N-pyridazin-4-yl-acetamide;
CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro-
[4.5]decan-3-yl]-N-(6-methoxy-pyridin-2-yl)-acetamide;
CIS-N-(2-Cyanoethyl)-2-[8-dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phen-
yl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;
CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro-
[4.5]decan-3-yl]-N-pyrimidin-5-yl-acetamide;
CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro-
[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyridin-2-yl)-acetamide;
CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl]-N-pyridin-3-yl-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(2-methoxy-ethyl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-e-
thoxy]-ethoxy]-ethoxy]-ethyl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[-
4.5]decan-3-yl]-N-methyl-acetamide;
CIS-(2S)-1-[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-d-
iazaspiro[4.5]decan-3-yl]-acetyl]-pyrrolidine-2-carboxylic acid
amide;
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-
spiro[4.5]decan-3-yl]-acetyl]amino]-N,N-dimethyl-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(oxetan-3-yl)-acetamide;
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-
spiro[4.5]decan-3-yl]-acetyl]amino]-acetamide;
CIS-1-(Cyclobutyl-methyl)-8-dimethyl
amino-3-[2-oxo-2-(3-oxo-piperazin-1-yl)-ethyl]-8-phenyl-1,3-diazaspiro[4.-
5]decan-2-one;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(1,1-dioxo-thian-4-yl)-acetamide;
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-[2-(hydroxymethyl)-morphol-
in-4-yl]-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-
-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;
CIS-N-(Cyano-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phe-
nyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;
CIS-N-(2-Acetylamino-ethyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-ox-
o-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(2-methylsulfonyl-ethyl)-acetamide;
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan--
4-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-[(1,1-dioxo-thian-4-yl)-methyl]-acetamide;
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-(4-methylsulfonyl-piperazi-
n-1-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-N-(2-Cyanoethyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phe-
nyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(2-hydroxy-2-methyl-propyl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(2-morpholin-4-yl-2-oxo-ethyl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-[2-(2-hydroxy-ethoxy)-ethyl]-acetamide;
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-
spiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-[2-(methanesulfonamido)-ethyl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-[(1-hydroxy-cyclopentyl)-methyl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-[(4-hydroxy-cyclohexyl)-methyl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-[2-(2-methoxy-ethoxy)-ethyl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-[2-(dimethylamino)ethyl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-[methyl-(2-methyl-propyl)-amino]-2-oxo-8-p-
henyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-methyl-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(6-methyl-pyridin-2-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-pyridazin-3-yl-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-pyrimidin-5-yl-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-pyridazin-4-yl-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(6-methoxy-pyrimidin-4-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(2-methyl-pyridin-4-yl)-acetamide;
CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl]-N-pyridin-4-yl-acetamide;
CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-acetamide;
CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-ethyl)-acetamide;
CIS-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-
-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-acetamide;
CIS-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-
-diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-ethyl)-acetamide;
CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro-
[4.5]decan-3-yl]-N-(4-methoxy-pyridin-2-yl)-acetamide;
CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro-
[4.5]decan-3-yl]-N-(pyrimidin-4-yl-methyl)-acetamide;
CIS-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-p-
henyl-1-propyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl]-N-pyridin-2-yl-acetamide;
CIS-2-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-phenyl-1,3-
-diazaspiro[4.5]decan-3-yl]-acetamide;
CIS-2-[[2-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-phenyl-
-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide;
CIS-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-
-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;
CIS-3-[2-(1,1-Dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-methylamino-8-phe-
nyl-1-propyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-pyridin-2-yl-acetamide;
CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-morpholin-4-yl-
-2-oxo-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-
-diazaspiro[4.5]decan-3-yl]-acetamide;
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(2-morpholin-4-yl-2-oxo-ethyl-
)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(4-methylsulfanyl-pyridin-2-yl)-acetamide;
CIS-3-[2-(1,1-Dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-methylamino-8-phe-
nyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-2-(8-Methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-acetam-
ide;
CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)--
acetamide;
CIS-3-[2-(1,1-Dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-ethylam-
ino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
TRANS-3-[2-(1,1-Dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-ethylamino-8-ph-
enyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[-
4.5]decan-3-yl]-N-methyl-acetamide;
CIS-2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-acetami-
de;
TRANS-2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-ac-
etamide;
CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3--
yl)-N-(2-hydroxy-ethyl)-N-methyl-acetamide;
CIS-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-1-[-
(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dion-
e;
CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N--
phenyl-acetamide;
CIS-N-(Carbamoyl-methyl)-2-[1-(cyclopropyl-methyl)-8-dimethylamino-2-oxo--
8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;
CIS-2-(8-Dimethylamino-2,4-dioxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)--
N-phenyl-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-acetamide;
CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy-
]-ethyl]-acetamide;
CIS-3-[2-(1,1-Dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-1-[(1-hydroxy-cyclo-
butyl)-methyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione;
CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-[2-
-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethyl]-acetamide;
CIS-N-(Carbamoyl-methyl)-N-methyl-2-(8-methylamino-2-oxo-8-phenyl-1,3-dia-
zaspiro[4.5]decan-3-yl)-acetamide;
CIS-N-(Carbamoyl-methyl)-2-(8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro-
[4.5]decan-3-yl)-N-methyl-acetamide;
CIS-N-(Carbamoyl-methyl)-2-[8-dimethylamino-1-(oxetan-3-yl-methyl)-2-oxo--
8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;
CIS-N-(2-Hydroxy-ethyl)-N-methyl-2-(8-methylamino-2-oxo-8-phenyl-1,3-diaz-
aspiro[4.5]decan-3-yl)-acetamide;
CIS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspi-
ro[4.5]decan-3-yl]-acetamide;
CIS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspi-
ro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-
-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-N-methyl-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-
-diazaspiro[4.5]decan-3-yl]-acetic acid tert-butyl ester;
CIS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspi-
ro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-N-methyl-acetamide;
CIS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspi-
ro[4.5]decan-3-yl]-N-(2-methyl sulfonyl-ethyl)-acetamide;
CIS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fl-
uorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;
CIS-1-[2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-pheny-
l-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]-piperidine-4-carboxylic
acid amide;
CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-[2-(4-meth-
yl
sulfonyl-piperidin-1-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-
-2-one;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2--
oxo-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide;
TRANS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazasp-
iro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide;
TRANS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-
-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;
CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-[2-(4-hydroxy-4-m-
ethyl-piperidin-1-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one-
;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-8-(4-fluorophenyl)-2-oxo-1,-
3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide;
TRANS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-(2-morpholin-4-yl-2-oxo-et-
hyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
TRANS-8-Dimethylamino-3-(2-morpholin-4-yl-2-oxo-ethyl)-8-phenyl-1,3-diaza-
spiro[4.5]decan-2-one;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-8-(4-fluorophenyl)-2-oxo-1,3-
-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-N-methyl-acetamide;
CIS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-8-(4-fl-
uorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;
CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[2-(4-hydroxy-4-methyl-piper-
idin-1-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-[2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-
spiro[4.5]decan-3-yl]-acetyl]-piperidine-4-carboxylic acid amide;
TRANS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazas-
piro[4.5]decan-3-yl]-acetamide;
TRANS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazas-
piro[4.5]decan-3-yl]-N-methyl-acetamide;
TRANS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazin-
an-4-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[2-(4-methyl
sulfonyl-piperidin-1-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-
-one;
CIS-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl-
]-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-on-
e;
TRANS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)--
acetamide;
TRANS-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-ox-
o-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-(dimethylamino)-8-phenyl-1-(2,2,2-trifluoroethyl)-3-(2-(trifluorome-
thyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-(dimethylamino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1-(3-
,3,3-trifluoropropyl)-1,3-diazaspiro[4.5]decan-2-one and the
physiologically acceptable salts thereof.
29. The compound according to claim 1 for use in the treatment of
pain.
30. A medicament comprising a compound according to claim 1.
Description
[0001] The invention relates to
3-(carboxymethyl)-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane
derivatives, their preparation and use in medicine, particularly in
various neurological disorders, including but not limited to pain,
neurodegenerative disorders, neuroinflammatory disorders,
neuropsychiatric disorders, substance abuse/dependence.
[0002] Opioid receptors are a group of Gi/o protein-coupled
receptors which are widely distributed in the human body. The
opioid receptors are currently subdivided into four major classes,
i.e. the three classical opioid receptors mu-opioid (MOP) receptor,
kappa-opioid (KOP) receptor, and delta-opioid (DOP) receptor as
well as the opioid receptor-like (ORL-1) receptor, which was more
recently discovered based on its high homology with said classical
opioid receptors. After identification of the endogenous ligand of
the ORL-1 receptor, known as nociceptin/orphanin FQ, a highly basic
17 amino acid peptide isolated from tissue extracts in 1995, the
ORL-1 receptor was renamed "nociceptin opioid peptide receptor" and
abbreviated as "NOP-receptor".
[0003] The classical opioid receptors (MOP, KOP and DOP) as well as
the NOP receptor are widely distributed/expressed in the human
body, including in the brain, the spinal cord, on peripheral
sensory neurons and the intestinal tract, wherein the distribution
pattern differs between the different receptor classes.
[0004] Nociceptin acts at the molecular and cellular level in very
much the same way as opioids. However, its pharmacological effects
sometimes differ from, and even oppose those of opioids.
NOP-receptor activation translates into a complex pharmacology of
pain modulation, which, depending on route of administration, pain
model and species involved, leads to either pronociceptive or
antinociceptive activity. Furthermore, the NOP receptor system is
upregulated under conditions of chronic pain. Systemic
administration of selective NOP receptor agonists was found to
exert a potent and efficacious analgesia in non-human primate
models of acute and inflammatory pain in the absence of side
effects. The activation of NOP receptors has been demonstrated to
be devoid of reinforcing effects but to inhibit opioid-mediated
reward in rodents and non-human primates (Review: Schroeder et al,
Br J Pharmacol 2014; 171 (16): 3777-3800, and references
therein).
[0005] Besides the involvement of the NOP receptor in nociception,
results from preclinical experiments suggest that NOP receptor
agonists might be useful inter alia in the treatment of
neuropsychiatric disorders (Witkin et al, Pharmacology &
Therapeutics, 141 (2014) 283-299; Jenck et al., Proc. Natl. Acad.
Sci. USA 94, 1997, 14854-14858). Remarkably, the DOP receptor is
also implicated to modulate not only pain but also neuropsychiatric
disorders (Mabrouk et al, 2014; Pradhan et al., 2011).
[0006] Strong opioids acting at the MOP receptor site are widely
used to treat moderate to severe acute and chronic pain. However,
the therapeutic window of strong opioids is limited by severe side
effects such as nausea and vomiting, constipation, dizziness,
somnolence, respiratory depression, physical dependence and abuse.
Furthermore, it is known that MOP receptor agonists show only
reduced effectiveness under conditions of chronic and neuropathic
pain.
[0007] It is known that some of the above mentioned side-effects of
strong opioids are mediated by activation of classic
opioid-receptors within the central nervous system. Furthermore,
peripheral opioid receptors, when activated, can inhibit
transmission of nociceptive signals shown in both, clinical and
animal studies (Gupta et al., 2001; Kalso et al., 2002; Stein et
al., 2003; Zollner et al., 2008).
[0008] Thus, to avoid CNS-mediated adverse effects after systemic
administration, one approach has been to provide peripherally
restricted opioid receptor ligands that do not easily cross the
blood-brain barrier and therefore distribute poorly to the central
nervous system (see for instance WO 2015/192039). Such peripherally
acting compounds might combine effective analgesia with limited
side-effects.
[0009] Another approach has been to provide compounds which
interact with both the NOP receptor and the MOP receptor. Such
compounds have for instance been described in WO 2004/043967, WO
2012/013343 and WO 2009/118168.
[0010] A further approach has been to provide multi-opioid receptor
analgesics that modulate more than one of the opioid receptor
subtypes to provide additive or synergistic analgesia and/or
reduced side effects like abuse liability or tolerance.
[0011] On the one hand, it would be desirable to provide analgesics
that selectively act on the NOP receptor system but less pronounced
on the classic opioid receptor system, especially MOP receptor
system, whereas it would be desirable to distinguish between
central nervous activity and peripheral nervous activity. On the
other hand, it would be desirable to provide analgesics that act on
the NOP receptor system and also to a balanced degree on the MOP
receptor system, whereas it would be desirable to distinguish
between central nervous activity and peripheral nervous
activity.
[0012] There is a need for medicaments which are effective in the
treatment of pain and which have advantages compared to the
compounds of the prior art. Where possible, such medicaments should
contain such a small dose of active ingredient that satisfactory
pain therapy can be ensured without the occurrence of intolerable
treatment-emergent adverse events.
[0013] It is an object of the invention to provide
pharmacologically active compounds, preferably analgesics that have
advantages compared to the prior art.
[0014] This object has been achieved by the subject-matter of the
patent claims.
[0015] A first aspect of the invention relates to
3-(carboxymethyl)-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane
derivatives according to general formula (I)
##STR00001##
wherein R.sup.1 and R.sup.2 independently of one another mean
--H;
[0016] --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;
preferably with the proviso that R.sup.1 and R.sup.2 do not
simultaneously mean --H; 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;
[0017] --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(.dbd.O)--, --C(.dbd.O)O--, or --S(.dbd.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(.dbd.O)--, --C(.dbd.O)O--, --C(.dbd.O)O--CH.sub.2--, or
--S(.dbd.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(.dbd.O)--, --C(.dbd.O)O--,
--C(.dbd.O)O--CH.sub.2--, or --S(.dbd.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(.dbd.O)--, --C(.dbd.O)O--, --C(.dbd.O)O--CH.sub.2--, or
--S(.dbd.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(.dbd.O)--, --C(.dbd.O)O--, --C(.dbd.O)O--CH.sub.2--, or
--S(.dbd.O).sub.2--; X means --O--, --S-- or --NR.sup.6--; R.sup.5
means
--H;
[0018] --C.sub.1-C.sub.6-alkyl, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted; a
3-12-membered cycloalkyl moiety, saturated or unsaturated,
unsubstituted, mono- or polysubstituted; wherein said 3-12-membered
cycloalkyl moiety is optionally connected through
--C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted; a
3-12-membered heterocycloalkyl moiety, saturated or unsaturated,
unsubstituted, mono- or polysubstituted; wherein said 3-12-membered
heterocycloalkyl moiety is optionally connected through
--C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted; a
6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted;
wherein said 6-14-membered aryl moiety is optionally connected
through --C.sub.1-C.sub.6-alkylene-, linear or branched, saturated
or unsaturated, unsubstituted, mono- or polysubstituted; or a
5-14-membered heteroaryl moiety, unsubstituted, mono- or
polysubstituted; wherein said 5-14-membered heteroaryl moiety is
optionally connected through --C.sub.1-C.sub.6-alkylene-, linear or
branched, saturated or unsaturated, unsubstituted, mono- or
polysubstituted; in case X means NR.sup.6, R.sup.6 means
H;
[0019] --C.sub.1-C.sub.6-alkyl, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted; a
3-12-membered cycloalkyl moiety, saturated or unsaturated,
unsubstituted, mono- or polysubstituted; wherein said 3-12-membered
cycloalkyl moiety is optionally connected through
--C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted; a
3-12-membered heterocycloalkyl moiety, saturated or unsaturated,
unsubstituted, mono- or polysubstituted; wherein said 3-12-membered
heterocycloalkyl moiety is optionally connected through
--C.sub.1-C.sub.6-alkylene-, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted; a
6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted;
wherein said 6-14-membered aryl moiety is optionally connected
through --C.sub.1-C.sub.6-alkylene-, linear or branched, saturated
or unsaturated, unsubstituted, mono- or polysubstituted; or a
5-14-membered heteroaryl moiety, unsubstituted, mono- or
polysubstituted; wherein said 5-14-membered heteroaryl moiety is
optionally connected through --C.sub.1-C.sub.6-alkylene-, linear or
branched, saturated or unsaturated, unsubstituted, mono- or
polysubstituted; or in case X means NR.sup.6, R.sup.5 and R.sup.6
together with the nitrogen atom to which they are attached form a
3-12-membered heterocycloalkyl moiety, saturated or unsaturated,
unsubstituted, mono- or polysubstituted; R.sup.9, R.sup.10,
R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.5, 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(.dbd.O)R.sup.21, --C(.dbd.O)OR.sup.21,
--C(.dbd.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, .dbd.O, --OR.sup.21,
--OC(.dbd.O)R.sup.21, OC(.dbd.O)OR.sup.21,
--OC(.dbd.O)NR.sup.21R.sup.22, --NO.sub.2, --NR.sup.21R.sup.22,
--NR.sup.21--(CH.sub.2).sub.1-6--C(.dbd.O)R.sup.22,
--NR.sup.21--(CH.sub.2).sub.1-6--C(.dbd.O)OR.sup.22, --NR.sup.23
(CH.sub.2).sub.1-6--C(.dbd.O)NR.sup.21R.sup.22,
--NR.sup.21C(.dbd.O)R.sup.22, --NR.sup.21C(.dbd.O)--OR.sup.22,
--NR.sup.23C(.dbd.O)NR.sup.21R.sup.22,
--NR.sup.21S(.dbd.O).sub.2R.sup.22, --SR.sup.21,
--S(.dbd.O)R.sup.21, --S(.dbd.O).sub.2R.sup.21,
--S(.dbd.O).sub.2OR.sup.21, and --S(.dbd.O).sub.2NR.sup.21R.sup.22;
wherein R.sup.21, R.sup.22 and R.sup.23 independently of one
another mean
--H;
[0020] --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(.dbd.O)NR.sup.21R.sup.22, --OC(.dbd.O)NR.sup.21R.sup.22,
--NR.sup.21R.sup.22,
--NR.sup.23--(CH.sub.2).sub.1-6--C(.dbd.O)NR.sup.21R.sup.22,
--NR.sup.23C(.dbd.O)NR.sup.21R.sup.22, or
--S(.dbd.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.
[0021] Preferably, aryl includes but is not limited to phenyl and
naphthyl. Preferably, heteroaryl includes but is not limited to
-1,2-benzodioxole, -pyrazinyl, -pyridazinyl, -pyridinyl,
-pyrimidinyl, -thienyl, -imidazolyl, -benzimidazolyl, -thiazolyl,
-1,3,4-thiadiazolyl, -benzothiazolyl, -oxazolyl, -benzoxazolyl,
-pyrazolyl, -quinolinyl, -isoquinolinyl, -quinazolinyl, -indolyl,
-indolinyl, -benzo[c][1,2,5]oxadiazolyl, -imidazo[1,2-a]pyrazinyl,
or -1H-pyrrolo[2,3-b]pyridinyl. Preferably, cycloalkyl includes but
is not limited to -cyclopropyl, -cyclobutyl, -cyclopentyl and
-cyclohexyl. Preferably, heterocycloalkyl includes but is not
limited to -aziridinyl, -azetidinyl, -pyrrolidinyl, -piperidinyl,
-piperazinyl, -morpholinyl, -sulfamorpholinyl, -oxiridinyl,
-oxetanyl, tetrahydropyranyl, and -pyranyl.
[0022] When a moiety is connected through an asymmetric group such
as --C(.dbd.O)O-- or --C(.dbd.O)O--CH.sub.2--, said asymmetric
group may be arranged in either direction. For example, when
R.sup.4 is connected to the core structure through --C(.dbd.O)O--,
the arrangement may be either R.sup.4--C(.dbd.O)O-core or
core-C(.dbd.O)O--R.sup.4.
[0023] In preferred embodiments of the compound according to the
invention, R.sup.9, R.sup.10, R.sup.11, R.sup.2, 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; preferably --H.
[0024] In a preferred embodiment of the compound according to the
invention, 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. Preferably,
R.sup.1 means --H and R.sup.2 means --CH.sub.3.
[0025] In another preferred embodiment of the compound according to
the invention, 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. Preferably,
R.sup.1 means --CH.sub.3 and R.sup.2 means --CH.sub.3.
[0026] In still another preferred embodiment of the compound
according to the invention, 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--. Preferably, 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--.
[0027] In yet another preferred embodiment, [0028] R.sup.1 means
--H or --CH.sub.3; and [0029] R.sup.2 means a 3-12-membered
cycloalkyl moiety, saturated or unsaturated, unsubstituted; wherein
said 3-12-membered cycloalkyl moiety is connected through
--CH.sub.2--, unsubstituted; preferably --CH.sub.2-cycloalkyl,
--CH.sub.2-cyclobutyl or --CH.sub.2-cyclopentyl; or R.sup.2 means a
3-12-membered heterocycloalkyl moiety, saturated or unsaturated,
unsubstituted; wherein said 3-12-membered heterocycloalkyl moiety
is connected through --CH.sub.2--, unsubstituted; preferably
--CH.sub.2-oxetanyl or --CH.sub.2-tetrahydrofuranyl.
[0030] In a preferred embodiment of the compound according to the
invention, R.sup.3 means --C.sub.1-C.sub.6-alkyl, linear or
branched, saturated or unsaturated, unsubstituted, mono- or
polysubstituted. Preferably, R.sup.3 means --C.sub.1-C.sub.6-alkyl,
linear or branched, saturated or unsaturated, unsubstituted or
monosubstituted with --OCH.sub.3.
[0031] In another preferred embodiment of the compound according to
the invention, R.sup.3 means a 6-14-membered aryl moiety,
unsubstituted, mono- or polysubstituted, optionally connected
through --C.sub.1-C.sub.6-alkylene-, linear or branched, saturated
or unsaturated, unsubstituted. In a preferred embodiment, R.sup.3
means -phenyl unsubstituted, mono- or polysubstituted. More
preferably, R.sup.3 means -phenyl unsubstituted, mono- or
disubstituted with --F, --Cl, --CH.sub.3, --CF.sub.3, --OH,
--OCH.sub.3, --OCF.sub.3 or --OCH.sub.2OCH.sub.3, preferably --F.
In another preferred embodiment, R.sup.3 means -benzyl
unsubstituted, mono- or polysubstituted. More preferably, R.sup.3
means -benzyl unsubstituted, mono- or disubstituted with --F, --Cl,
--CH.sub.3, --CF.sub.3, --OH, --OCH.sub.3, --OCF.sub.3 or
--OCH.sub.2OCH.sub.3, preferably --F.
[0032] In still another preferred embodiment of the compound
according to the invention, R.sup.3 means a 5-14-membered
heteroaryl moiety, unsubstituted, mono- or polysubstituted.
Preferably, R.sup.3 means -thienyl or -pyridinyl, in each case
unsubstituted, mono- or polysubstituted. More preferably, R.sup.3
means -thienyl, -pyridinyl, -imidazolyl or benzimidazolyl, in each
case unsubstituted or monosubstituted with --F, --Cl or
--CH.sub.3.
[0033] In a preferred embodiment of the compound according to the
invention, R.sup.4 means --H.
[0034] In another preferred embodiment of the compound according to
the invention, R.sup.4 means --C.sub.1-C.sub.6-alkyl, linear or
branched, saturated or unsaturated, unsubstituted, mono- or
polysubstituted. Preferably, R.sup.4 means --C.sub.1-C.sub.6-alkyl,
linear or branched, saturated or unsaturated, unsubstituted or
monosubstituted with a substituent selected from the group
consisting of --F, --Cl, --Br, --I, --CN, --CF.sub.3, --OH,
--O--C.sub.1-C.sub.4-alkyl, --OCF.sub.3,
--O--(CH.sub.2CH.sub.2--O).sub.1-30--H,
--O--(CH.sub.2CH.sub.2--O).sub.1-30--CH.sub.3,
--OC(.dbd.O)C.sub.1-C.sub.4-alkyl,
--C(.dbd.O)C.sub.1-C.sub.4-alkyl, --C(.dbd.O)OH,
--C(.dbd.O)OC.sub.1-C.sub.4-alkyl, --C(.dbd.O)NH.sub.2,
--C(.dbd.O)NHC.sub.1-C.sub.4-alkyl,
--C(.dbd.O)NHC.sub.1-C.sub.4-alkylene-CN,
--C(.dbd.O)NHC.sub.1-C.sub.4-alkylene-O--C.sub.1-C.sub.4-alkyl,
--C(.dbd.O)N(C.sub.1-C.sub.4-alkyl).sub.2;
--S(.dbd.O)C.sub.1-C.sub.4-alkyl, and
--S(.dbd.O).sub.2C.sub.1-C.sub.4-alkyl; or with
--C(.dbd.O)NR.sup.21R.sup.22 wherein R.sup.21 and R.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; or with
--C(.dbd.O)NH-3-12-membered cycloalkyl, saturated or unsaturated,
unsubstituted or monosubstituted with --F, --Cl, --Br, --I, --CN,
or --OH; or with --C(.dbd.O)NH-3-12-membered heterocycloalkyl,
saturated or unsaturated, unsubstituted or monosubstituted with
--F, --Cl, --Br, --I, --CN, or --OH. More preferably, R.sup.4 means
--C.sub.1-C.sub.6-alkyl, linear or branched, saturated or
unsaturated, unsubstituted or monosubstituted with
--O--C.sub.1-C.sub.4-alkyl or
--C(.dbd.O)N(C.sub.1-C.sub.4-alkyl).sub.2.
[0035] In still another preferred embodiment of the compound
according to the invention, 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.
Preferably, R.sup.4 means a 3-12-membered cycloalkyl moiety,
saturated or unsaturated, unsubstituted, mono- or polysubstituted;
wherein said 3-12-membered cycloalkyl moiety is connected through
--CH.sub.2-- or --CH.sub.2CH.sub.2--. More preferably, R.sup.4
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, --O--C.sub.1-C.sub.4-alkyl, --C(.dbd.O)OH,
--C(.dbd.O)OC.sub.1-C.sub.4-alkyl, --C(.dbd.O)NH.sub.2,
--C(.dbd.O)NHC.sub.1-C.sub.4-alkyl,
--C(.dbd.O)N(C.sub.1-C.sub.4-alkyl).sub.2,
--S(.dbd.O)C.sub.1-C.sub.4-alkyl and
--S(.dbd.O).sub.2C.sub.1-C.sub.4-alkyl; wherein said 3-12-membered
cycloalkyl moiety is connected through --CH.sub.2-- or
--CH.sub.2CH.sub.2--.
[0036] In a preferred embodiment of the compound according to the
invention, 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.
Preferably, 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 --CH.sub.2-- or --CH.sub.2CH.sub.2--. More preferably,
R.sup.4 means -oxetanyl, -tetrahydrofuranyl or -tetrahydropyranyl,
in each case unsubstituted or substituted with one, two, three or
four substituents independently of one another selected from the
group consisting of --F, --Cl, --Br, --I, --CN, --OH,
--C.sub.1-C.sub.4-alkyl, --O--C.sub.1-C.sub.4-alkyl, --C(.dbd.O)OH,
--C(.dbd.O)OC.sub.1-C.sub.4-alkyl, --C(.dbd.O)NH.sub.2,
--C(.dbd.O)NHC.sub.1-C.sub.4-alkyl,
--C(.dbd.O)N(C.sub.1-C.sub.4-alkyl).sub.2,
--S(.dbd.O)C.sub.1-C.sub.4-alkyl and
--S(.dbd.O).sub.2C.sub.1-C.sub.4-alkyl; wherein said -oxetanyl,
-tetrahydrofuranyl or -tetrahydropyranyl is connected through
--CH.sub.2-- or --CH.sub.2CH.sub.2--.
[0037] In yet another preferred embodiment of the compound
according to the invention, 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. Preferably,
R.sup.4 means -phenyl, unsubstituted, mono- or polysubstituted;
wherein said -phenyl is connected through --CH.sub.2-- or
--CH.sub.2CH.sub.2--. More preferably, R.sup.4 means -phenyl,
unsubstituted or substituted with one, two, three or four
substituents independently of one another selected from the group
consisting of --F, --Cl, --Br, --I, --CN, --OH,
--C.sub.1-C.sub.4-alkyl, --O--C.sub.1-C.sub.4-alkyl, --C(.dbd.O)OH,
--C(.dbd.O)OC.sub.1-C.sub.4-alkyl, --C(.dbd.O)NH.sub.2,
--C(.dbd.O)NHC.sub.1-C.sub.4-alkyl,
--C(.dbd.O)N(C.sub.1-C.sub.4-alkyl).sub.2,
--S(.dbd.O)C.sub.1-C.sub.4-alkyl and
--S(.dbd.O).sub.2C.sub.1-C.sub.4-alkyl; wherein said -phenyl is
connected through --CH.sub.2-- or --CH.sub.2CH.sub.2--.
[0038] In a further preferred embodiment of the compound according
to the invention, 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. Preferably, R.sup.4 means a 5-14-membered
heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein
said -phenyl is connected through --CH.sub.2-- or
--CH.sub.2CH.sub.2--. More preferably, R.sup.4 means -pyridinyl,
-pyrimidinyl, -pyrazinyl, or -pyrazolinyl, in each case
unsubstituted or substituted with one, two, three or four
substituents independently of one another selected from the group
consisting of --F, --Cl, --Br, --I, --CN, --OH,
--C.sub.1-C.sub.4-alkyl, --O--C.sub.1-C.sub.4-alkyl, --C(.dbd.O)OH,
--C(.dbd.O)OC.sub.1-C.sub.4-alkyl, --C(.dbd.O)NH.sub.2,
--C(.dbd.O)NHC.sub.1-C.sub.4-alkyl,
--C(.dbd.O)N(C.sub.1-C.sub.4-alkyl).sub.2,
--S(.dbd.O)C.sub.1-C.sub.4-alkyl and
--S(.dbd.O).sub.2C.sub.1-C.sub.4-alkyl; wherein said -pyridinyl,
-pyrimidinyl, -pyrazinyl, or -pyrazolinyl is connected through
--CH.sub.2-- or --CH.sub.2CH.sub.2--.
[0039] In a preferred embodiment of the compound according to the
invention, R.sup.5 means --H.
[0040] In another preferred embodiment of the compound according to
the invention, R.sup.5 means --C.sub.1-C.sub.6-alkyl, linear or
branched, saturated or unsaturated, unsubstituted, mono- or
polysubstituted. Preferably, R.sup.5 means --C.sub.1-C.sub.6-alkyl,
linear or branched, saturated, unsubstituted, mono- or
polysubstituted. More preferably, R.sup.5 means
--C.sub.1-C.sub.6-alkyl, linear or branched, saturated,
unsubstituted or monosubstituted with a substituent selected from
the group consisting of --F, --Cl, --Br, --I, --CN, --OH,
--O--C.sub.1-C.sub.4-alkyl, --C(.dbd.O)OH,
--C(.dbd.O)OC.sub.1-C.sub.4-alkyl, --C(.dbd.O)NH.sub.2,
--C(.dbd.O)NHC.sub.1-C.sub.4-alkyl,
--C(.dbd.O)N(C.sub.1-C.sub.4-alkyl).sub.2,
--S(.dbd.O)C.sub.1-C.sub.4-alkyl,
--S(.dbd.O).sub.2C.sub.1-C.sub.4-alkyl,
--C(.dbd.O)--C.sub.3-12heterocycloalkyl,
--NH--C(.dbd.O)--C.sub.1-C.sub.4-alkyl,
--N(C.sub.1-C.sub.4-alkyl).sub.2 and
NH--S(.dbd.O).sub.2--C.sub.1-C.sub.4-alkyl.
[0041] In still another preferred embodiment of the compound
according to the invention, R.sup.5 means a 3-12-membered
cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono-
or polysubstituted, wherein said 3-12-membered cycloalkyl moiety is
optionally connected through --C.sub.1-C.sub.6-alkylene-, linear or
branched, saturated or unsaturated, unsubstituted, mono- or
polysubstituted. Preferably, R.sup.5 means a 3-6-membered
cycloalkyl moiety, saturated, 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, unsubstituted; more preferably -cyclopropyl,
-cyclobutyl, -cyclopentyl or -cyclohexyl, unsubstituted or
monosubstituted with --F, --OH, --CN or --C.sub.1-C.sub.4-alkyl,
wherein said -cyclopropyl, -cyclobutyl -cyclopentyl or -cyclohexyl
is optionally connected through --CH.sub.2-- or
--CH.sub.2CH.sub.2--.
[0042] In a preferred embodiment of the compound according to the
invention, R.sup.5 means a 3-12-membered heterocycloalkyl moiety,
saturated or unsaturated, unsubstituted, mono- or polysubstituted;
wherein said 3-12-membered heterocycloalkyl moiety is optionally
connected through --C.sub.1-C.sub.6-alkylene-, linear or branched,
saturated or unsaturated, unsubstituted, mono- or polysubstituted.
Preferably, R.sup.5 means a 4-6-membered heterocycloalkyl moiety,
saturated or unsaturated, unsubstituted, mono- or polysubstituted.
More preferably, R.sup.5 means -heterocyclobutyl or
-tetrahydro-2H-thiopyranyl dioxide, unsubstituted.
[0043] In yet another preferred embodiment of the compound
according to the invention, R.sup.5 means a 5-14-membered
heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein
said 5-14-membered heteroaryl moiety is optionally connected
through --C.sub.1-C.sub.6-alkylene-, linear or branched, saturated
or unsaturated, unsubstituted, mono- or polysubstituted.
Preferably, R.sup.5 means a 5-6-membered heteroaryl moiety,
unsubstituted, mono- or polysubstituted, wherein said 5-6-membered
heteroaryl moiety is optionally connected through --CH.sub.2--.
More preferably, R.sup.5 means a 5-6-membered heteroaryl moiety,
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, --O--C.sub.1-C.sub.4-alkyl, --C(.dbd.O)OH,
--C(.dbd.O)OC.sub.1-C.sub.4-alkyl, --C(.dbd.O)NH.sub.2,
--C(.dbd.O)NHC.sub.1-C.sub.4-alkyl,
--C(.dbd.O)N(C.sub.1-C.sub.4-alkyl).sub.2,
--S(.dbd.O)C.sub.1-C.sub.4-alkyl,
--S(.dbd.O).sub.2C.sub.1-C.sub.4-alkyl and
--S--C.sub.1-C.sub.4-alkyl, wherein said 5-6-membered heteroaryl
moiety is optionally connected through --CH.sub.2--. Still more
preferably, R.sup.5 means -oxazolyl, -isoxazolyl, -pyrazolyl,
-pyridinyl, -pyridazinyl, -pyrazinyl, -thiazolyl, -thiadiazolyl,
-imidazolyl or -pyrimidinyl, in each case unsubstituted or
substituted with one, two, three or four substituents independently
of one another selected from the group consisting of --F, --Cl, Br,
--I, --CN, --OH, --C.sub.1-C.sub.4-alkyl,
--O--C.sub.1-C.sub.4-alkyl, --C(.dbd.O)OH,
--C(.dbd.O)OC.sub.1-C.sub.4-alkyl, --C(.dbd.O)NH.sub.2,
--C(.dbd.O)NHC.sub.1-C.sub.4-alkyl,
--C(.dbd.O)N(C.sub.1-C.sub.4-alkyl).sub.2,
S(.dbd.O)C.sub.1-C.sub.4-alkyl,
--S(.dbd.O).sub.2C.sub.1-C.sub.4-alkyl and
--S--C.sub.1-C.sub.4-alkyl, wherein said -oxazolyl, -isoxazolyl,
-pyrazolyl, -pyridinyl, -pyridazinyl, -pyrazinyl, -thiazolyl,
-thiadiazolyl, -imidazolyl or -pyrimidinyl is optionally connected
through --CH.sub.2--.
[0044] In a further preferred embodiment of the compound according
to the invention, R.sup.5 means 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. Preferably,
R.sup.5 means -phenyl, unsubstituted or substituted with one, two,
three or four substituents independently of one another selected
from the group consisting of --F, --Cl, Br, --I, --CN, --OH,
--C.sub.1-C.sub.4-alkyl, --O--C.sub.1-C.sub.4-alkyl, --C(.dbd.O)OH,
--C(.dbd.O)OC.sub.1-C.sub.4-alkyl, --C(.dbd.O)NH.sub.2,
--C(.dbd.O)NHC.sub.1-C.sub.4-alkyl,
--C(.dbd.O)N(C.sub.1-C.sub.4-alkyl).sub.2,
S(.dbd.O)C.sub.1-C.sub.4-alkyl,
--S(.dbd.O).sub.2C.sub.1-C.sub.4-alkyl and
--S--C.sub.1-C.sub.4-alkyl, wherein said -phenyl is optionally
connected through --CH.sub.2--.
[0045] In a preferred embodiment of the compound according to the
invention, X means NR.sup.6 and R.sup.5 and R.sup.6 together with
the nitrogen atom to which they are attached form a 3-12-membered
heterocycloalkyl moiety, saturated or unsaturated, unsubstituted,
mono- or polysubstituted. Preferably, X means NR.sup.6 and R.sup.5
and R.sup.6 together with the nitrogen atom to which they are
attached form a 5-6-membered heterocycloalkyl moiety, saturated or
unsaturated, unsubstituted, mono- or polysubstituted. More
preferably, X means NR.sup.6 and R.sup.5 and R.sup.6 together with
the nitrogen atom to which they are attached form -pyrrolidinyl,
-piperidinyl, -piperazinyl, -morpholinyl, -thiomorpholinyl,
-thiomorpholinyl dioxide or -(methylsulfonyl)piperazinyl, in each
case unsubstituted or substituted with one, two, three or four
substituents independently of one another selected from the group
consisting of .dbd.O, --OH, --CH.sub.2--OH and --C(.dbd.O)NH.sub.2,
wherein said -pyrrolidinyl, -piperidinyl, piperazinyl,
-morpholinyl, -thiomorpholinyl, -thiomorpholinyl dioxide or
-(methylsulfonyl)piperazinyl is optionally condensed with an
imidazole moiety, unsubstituted.
[0046] In a preferred embodiment of the compound according to the
invention R.sup.5 means
-- H;
[0047] --C.sub.1-C.sub.6-alkyl, linear or branched, saturated or
unsaturated, unsubstituted or substituted with one, two, three or
four substituents independently of one another selected from the
group consisting of --F, --Cl, --Br, --I, --CN, --O--CH.sub.3,
--O--(CH.sub.2--CH.sub.2--O).sub.1-10--H,
--O--(CH.sub.2CH.sub.2--O).sub.1-10--CH.sub.3, --C(.dbd.O)OH,
--C(.dbd.O)OCH.sub.3, --C(.dbd.O)NH.sub.2, --C(.dbd.O)NHCH.sub.3,
--C(.dbd.O)N(CH.sub.3).sub.2, --OH, --S(.dbd.O)CH.sub.3,
--S(.dbd.O).sub.2CH.sub.3, unsubstituted --C(.dbd.O)-morpholinyl,
--NH--C(.dbd.O)--CH.sub.3, --N(CH.sub.3).sub.2 and
NH--S(.dbd.O).sub.2--CH.sub.3; -cyclopropyl, -cyclobutyl,
-cyclopentyl or -cyclohexyl, unsubstituted or monosubstituted with
--F, --OH, --CN or --CH.sub.3, wherein said -cyclopropyl,
-cyclobutyl, cyclopentyl or cyclohexyl is optionally connected
through --CH.sub.2-- or --CH.sub.2CH.sub.2--; -heterocyclobutyl,
-heterocyclopentyl, or -heterocyclohexyl, in each case
unsubstituted or substituted with one, two, three or four
substituents independently of one another selected from the group
consisting of --F, --Cl, --Br, --I, --CN, --O--CH.sub.3,
--O--(CH.sub.2--CH.sub.2--O).sub.1-10--H,
--O--(CH.sub.2CH.sub.2--O).sub.1-10--CH.sub.3,
--C.sub.1-C.sub.4-alkyl, --C(.dbd.O)OH, --C(.dbd.O)OCH.sub.3,
--C(.dbd.O)NH.sub.2, --C(.dbd.O)NHCH.sub.3,
--C(.dbd.O)N(CH.sub.3).sub.2, .dbd.O, --OH, --SCH.sub.3,
--S(.dbd.O)CH.sub.3, --S(.dbd.O).sub.2CH.sub.3, unsubstituted
--C(.dbd.O)-morpholinyl, --NH--C(.dbd.O)--CH.sub.3,
--N(CH.sub.3).sub.2 and NH--S(.dbd.O).sub.2--CH.sub.3; wherein said
-heterocyclobutyl, heterocyclopentyl, or -heterocyclohexyl is
optionally connected through --CH.sub.2-- or --CH.sub.2CH.sub.2--;
-oxazolyl, -isoxazolyl, -pyrazolyl, -pyridinyl, -pyridazinyl,
-pyrazinyl, -thiazolyl, -thiadiazolyl, -imidazolyl, -pyrimidinyl,
or 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine, in each case
unsubstituted or substituted with one, two, three or four
substituents independently of one another selected from the group
consisting of --F, --Cl, Br, --I, --CN, --OH, --CH.sub.3,
--O--CH.sub.3, --C(.dbd.O)OH, --C(.dbd.O)OCH.sub.3,
--C(.dbd.O)NH.sub.2, --C(.dbd.O)NHCH.sub.3,
--C(.dbd.O)N(CH.sub.3).sub.2, S(.dbd.O)CH.sub.3,
--S(.dbd.O).sub.2CH.sub.3 and --S--CH.sub.3, wherein said
-oxazolyl, -isoxazolyl, -pyrazolyl, -pyridinyl, -pyridazinyl,
-pyrazinyl, -thiazolyl, -thiadiazolyl, -imidazolyl, -pyrimidinyl,
or 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine is optionally
connected through --CH.sub.2--; or -phenyl, unsubstituted or
substituted with one, two, three or four substituents independently
of one another selected from the group consisting of --F, --Cl, Br,
--I, --CN, --OH, --CH.sub.3, --O--CH.sub.3, --C(.dbd.O)OH,
--C(.dbd.O)OCH.sub.3, --C(.dbd.O)NH.sub.2, --C(.dbd.O)NHCH.sub.3,
--C(.dbd.O)N(CH.sub.3).sub.2, --S(.dbd.O)CH.sub.3,
--S(.dbd.O).sub.2 CH.sub.3 and --S--CH.sub.3, wherein said -phenyl
is optionally connected through --CH.sub.2--; in case X means
NR.sup.6, R.sup.6 means --H or --CH.sub.3; or in case X means
NR.sup.6, R.sup.5 and R.sup.6 together with the nitrogen atom to
which they are attached form a -pyrrolidinyl, -piperidinyl,
-piperazinyl, -morpholinyl, -thiomorpholinyl, -thiomorpholinyl
dioxide or -(methylsulfonyl)piperazinyl, in each case unsubstituted
or substituted with one, two, three or four substituents
independently of one another selected from the group consisting of
.dbd.O, --OH, --CH.sub.2--OH, --C(.dbd.O)NH.sub.2, and
--S(.dbd.O).sub.2CH.sub.3, wherein said -pyrrolidinyl,
-piperidinyl, -piperazinyl, -morpholinyl, -thiomorpholinyl,
-thiomorpholinyl dioxide or -(methylsulfonyl)piperazinyl is
optionally condensed with an imidazole moiety, unsubstituted;
[0048] In a preferred embodiment of the compound according to the
invention, X means NR.sup.6 and R.sup.6 means --H or
--C.sub.1-C.sub.6-alkyl, linear or branched, saturated or
unsaturated, unsubstituted, mono- or polysubstituted. Preferably,
R.sup.6 means --H or --CH.sub.3.
[0049] In preferred embodiments, the compound according to the
invention has a structure according to any of general formulas
(II-A) to (VIII-C):
##STR00002## ##STR00003## ##STR00004## ##STR00005##
wherein in each case R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6 and X are defined as above, 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.
[0050] Preferably, the substructure of the compounds according to
general formula (I) represented by R.sup.5, X, R.sup.9 and
R.sup.10, i.e.
##STR00006##
or the corresponding substructure of any of above general formulas
(II-A) to (VIII-C) has preferably a meaning selected from the group
consisting of:
##STR00007## ##STR00008## ##STR00009## ##STR00010## ##STR00011##
##STR00012## ##STR00013## ##STR00014## ##STR00015## ##STR00016##
##STR00017## ##STR00018## ##STR00019## ##STR00020##
##STR00021##
[0051] In a particularly preferred embodiment of the compound
according to the invention
R.sup.1 means --H or --CH.sub.3; R.sup.2 means --CH.sub.3,
--CH.sub.2CH.sub.3 or --CH.sub.2--C(H)(CH.sub.3).sub.2; R.sup.3
means -phenyl, -thienyl or -pyridinyl, in each case unsubstituted
or monosubstituted with --F; R.sup.4 means
--H;
[0052] --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, .dbd.O,
--N(CH.sub.3).sub.2 and --O--CH.sub.3; or -cyclopropyl,
-cyclobutyl, -cyclopentyl or -cyclohexyl, unsubstituted or
monosubstituted with --F, --OH, --CN or --CH.sub.3, wherein said
-cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl is connected
through --CH.sub.2-- or --CH.sub.2CH.sub.2--; -oxetanyl
unsubstituted or monosubstituted with --F, --OH, --CN or
--CH.sub.3, wherein said -oxetanyl is connected through
--CH.sub.2-- or --CH.sub.2CH.sub.2--; X means --O-- or
--NR.sup.6--; R.sup.5 means
H;
[0053] --C.sub.1-C.sub.6-alkyl, linear or branched, saturated or
unsaturated, unsubstituted or substituted with one, two, three or
four substituents independently of one another selected from the
group consisting of --F, --Cl, --Br, --I, --CN, --O--CH.sub.3,
--O--(CH.sub.2--CH.sub.2--O).sub.1-10--H,
--O--(CH.sub.2CH.sub.2--O).sub.1-10--CH.sub.3, --C(.dbd.O)OH,
--C(.dbd.O)OCH.sub.3, --C(.dbd.O)NH.sub.2, --C(.dbd.O)NHCH.sub.3,
--C(.dbd.O)N(CH.sub.3).sub.2, --OH, --S(.dbd.O)CH.sub.3,
--S(.dbd.O).sub.2CH.sub.3, unsubstituted --C(.dbd.O)-morpholinyl,
--NH--C(.dbd.O)--CH.sub.3, --N(CH.sub.3).sub.2 and
NH--S(.dbd.O).sub.2--CH.sub.3; -cyclopropyl, -cyclobutyl,
-cyclopentyl or -cyclohexyl, unsubstituted or monosubstituted with
--F, --OH, --CN or --CH.sub.3, wherein said -cyclopropyl,
-cyclobutyl, cyclopentyl or cyclohexyl is optionally connected
through --CH.sub.2-- or --CH.sub.2CH.sub.2--; -heterocyclobutyl,
-heterocyclopentyl, or -heterocyclohexyl, in each case
unsubstituted or substituted with one, two, three or four
substituents independently of one another selected from the group
consisting of --F, --Cl, --Br, --I, --CN, --O--CH.sub.3,
--O--(CH.sub.2--CH.sub.2--O).sub.1-10--H,
--O--(CH.sub.2CH.sub.2--O).sub.1-10--CH.sub.3,
--C.sub.1-C.sub.4-alkyl, --C(.dbd.O)OH, --C(.dbd.O)OCH.sub.3,
--C(.dbd.O)NH.sub.2, --C(.dbd.O)NHCH.sub.3,
--C(.dbd.O)N(CH.sub.3).sub.2, .dbd.O, --OH, --SCH.sub.3,
--S(.dbd.O)CH.sub.3, --S(.dbd.O).sub.2CH.sub.3, unsubstituted
--C(.dbd.O)-morpholinyl, --NH--C(.dbd.O)--CH.sub.3,
--N(CH.sub.3).sub.2 and NH--S(.dbd.O).sub.2--CH.sub.3; wherein said
-heterocyclobutyl, heterocyclopentyl, or -heterocyclohexyl is
optionally connected through --CH.sub.2-- or --CH.sub.2CH.sub.2--;
-oxazolyl, -isoxazolyl, -pyrazolyl, -pyridinyl, -pyridazinyl,
-pyrazinyl, -thiazolyl, -thiadiazolyl, -imidazolyl, -pyrimidinyl,
or 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine, in each case
unsubstituted or substituted with one, two, three or four
substituents independently of one another selected from the group
consisting of --F, --Cl, Br, --I, --CN, --OH, --CH.sub.3,
--O--CH.sub.3, --C(.dbd.O)OH, --C(.dbd.O)OCH.sub.3,
--C(.dbd.O)NH.sub.2, --C(.dbd.O)NHCH.sub.3,
--C(.dbd.O)N(CH.sub.3).sub.2, S(.dbd.O)CH.sub.3,
--S(.dbd.O).sub.2CH.sub.3 and --S--CH.sub.3, wherein said
-oxazolyl, -isoxazolyl, -pyrazolyl, -pyridinyl, -pyridazinyl,
-pyrazinyl, -thiazolyl, -thiadiazolyl, -imidazolyl, -pyrimidinyl,
or 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine is optionally
connected through --CH.sub.2--; or -phenyl, unsubstituted or
substituted with one, two, three or four substituents independently
of one another selected from the group consisting of --F, --Cl, Br,
--I, --CN, --OH, --CH.sub.3, --O--CH.sub.3, --C(.dbd.O)OH,
--C(.dbd.O)OCH.sub.3, --C(.dbd.O)NH.sub.2, --C(.dbd.O)NHCH.sub.3,
--C(.dbd.O)N(CH.sub.3).sub.2, --S(.dbd.O)CH.sub.3,
--S(.dbd.O).sub.2 CH.sub.3 and --S--CH.sub.3, wherein said -phenyl
is optionally connected through --CH.sub.2--; in case X means
NR.sup.6, R.sup.6 means --H or --CH.sub.3; or in case X means
NR.sup.6, R.sup.5 and R.sup.6 together with the nitrogen atom to
which they are attached form a -pyrrolidinyl, -piperidinyl,
-piperazinyl, -morpholinyl, -thiomorpholinyl, -thiomorpholinyl
dioxide or -(methylsulfonyl)piperazinyl, in each case unsubstituted
or substituted with one, two, three or four substituents
independently of one another selected from the group consisting of
.dbd.O, --OH, --CH.sub.2--OH, --C(.dbd.O)NH.sub.2, and
--S(.dbd.O).sub.2CH.sub.3, wherein said -pyrrolidinyl,
-piperidinyl, -piperazinyl, -morpholinyl, -thiomorpholinyl,
-thiomorpholinyl dioxide or -(methylsulfonyl)piperazinyl is
optionally condensed with an imidazole moiety, unsubstituted; and
R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,
R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19, and R.sup.20 mean
--H.
[0054] In a particularly preferred embodiment of the compound
according to the invention R.sup.1 means --H or --CH.sub.3;
and/or
R.sup.2 means --CH.sub.3, --CH.sub.2CH.sub.3 or
--CH.sub.2--C(H)(CH.sub.3).sub.2; and/or R.sup.3 means -phenyl,
-thienyl or -pyridinyl, in each case unsubstituted; preferably,
R.sup.3 means phenyl unsubstituted; and/or R.sup.4 means
--H;
[0055] --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, .dbd.O,
--N(CH.sub.3).sub.2 and --O--CH.sub.3; or -cyclopropyl,
-cyclobutyl, -cyclopentyl or -cyclohexyl, unsubstituted or
monosubstituted with --F, --OH, --CN or --CH.sub.3, wherein said
-cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl is connected
through --CH.sub.2-- or --CH.sub.2CH.sub.2--; preferably, R.sup.4
means -cyclobutyl, unsubstituted or monosubstituted with --OH,
wherein said -cyclobutyl is connected through --CH.sub.2--; and/or
X means --O-- or --NR.sup.6--; and/or R.sup.5 means
--H;
[0056] --C.sub.1-C.sub.6-alkyl, linear or branched, saturated or
unsaturated, unsubstituted or substituted with one, two, three or
four substituents independently of one another selected from the
group consisting of --F, --Cl, --Br, --I, --CN, --O--CH.sub.3,
--O--(CH.sub.2--CH.sub.2--O).sub.1-10--H,
--O--(CH.sub.2CH.sub.2--O).sub.1-10--CH.sub.3, --C(.dbd.O)OH,
--C(.dbd.O)OCH.sub.3, --C(.dbd.O)NH.sub.2, --C(.dbd.O)NHCH.sub.3,
--C(.dbd.O)N(CH.sub.3).sub.2, --OH, --S(.dbd.O)CH.sub.3,
--S(.dbd.O).sub.2CH.sub.3, unsubstituted --C(.dbd.O)-morpholinyl,
--NH--C(.dbd.O)--CH.sub.3, --N(CH.sub.3).sub.2 and
NH--S(.dbd.O).sub.2--CH.sub.3; preferably, R.sup.5 means
--C.sub.1-C.sub.6-alkyl, linear or branched, saturated or
unsaturated, unsubstituted or monosubstituted with --OH;
-cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl,
unsubstituted or monosubstituted with --F, --OH, --CN or
--CH.sub.3, wherein said -cyclopropyl, -cyclobutyl, cyclopentyl or
cyclohexyl is optionally connected through --CH.sub.2-- or
--CH.sub.2CH.sub.2--; -heterocyclobutyl, -tetrahydro-2H-thiopyranyl
dioxide, --CH.sub.2-heterocyclobutyl or
--CH.sub.2-tetrahydro-2H-thiopyranyl dioxide, in each case
unsubstituted; -oxazolyl, -isoxazolyl, -pyrazolyl, -pyridinyl,
-pyridazinyl, -pyrazinyl, -thiazolyl, -thiadiazolyl, -imidazolyl or
-pyrimidinyl, in each case unsubstituted or substituted with one,
two, three or four substituents independently of one another
selected from the group consisting of --F, --Cl, Br, --I, --CN,
--OH, --CH.sub.3, --O--CH.sub.3, --C(.dbd.O)OH,
--C(.dbd.O)OCH.sub.3, --C(.dbd.O)NH.sub.2, --C(.dbd.O)NHCH.sub.3,
--C(.dbd.O)N(CH.sub.3).sub.2, --S(.dbd.O)CH.sub.3,
--S(.dbd.O).sub.2CH.sub.3 and --S--CH.sub.3, wherein said
-oxazolyl, -isoxazolyl, -pyrazolyl, -pyridinyl, -pyridazinyl,
-pyrazinyl, -thiazolyl, -thiadiazolyl, -imidazolyl or -pyrimidinyl
is optionally connected through --CH.sub.2--; preferably, R.sup.5
means -pyridinyl unsubstituted; or -phenyl, unsubstituted or
substituted with one, two, three or four substituents independently
of one another selected from the group consisting of --F, --Cl, Br,
--I, --CN, --OH, --CH.sub.3, --O--CH.sub.3, --C(.dbd.O)OH,
--C(.dbd.O)OCH.sub.3, --C(.dbd.O)NH.sub.2, --C(.dbd.O)NHCH.sub.3,
--C(.dbd.O)N(CH.sub.3).sub.2, --S(.dbd.O)CH.sub.3,
--S(.dbd.O).sub.2 CH.sub.3 and --S--CH.sub.3, wherein said -phenyl
is optionally connected through --CH.sub.2--; and/or in case X
means NR.sup.6, R.sup.6 means --H or --CH.sub.3; or in case X means
NR.sup.6, R.sup.5 and R.sup.6 together with the nitrogen atom to
which they are attached form a -pyrrolidinyl, -piperidinyl,
-piperazinyl, -morpholinyl, -thiomorpholinyl, -thiomorpholinyl
dioxide or -(methylsulfonyl)piperazinyl, in each case unsubstituted
or substituted with one, two, three or four substituents
independently of one another selected from the group consisting of
.dbd.O, --OH, --CH.sub.2--OH and --C(.dbd.O)NH.sub.2, wherein said
-pyrrolidinyl, -piperidinyl, -piperazinyl, -morpholinyl,
-thiomorpholinyl, -thiomorpholinyl dioxide or
-(methylsulfonyl)piperazinyl is optionally condensed with an
imidazole moiety, unsubstituted; and/or R.sup.9, R.sup.10,
R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16,
R.sup.17, R.sup.18, R.sup.19, and R.sup.20 mean --H.
[0057] Preferably, the compound according to the invention is
selected from the group consisting of
TABLE-US-00001 SC_1001
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-d-
iazaspiro[4.5]decan-3-yl]-
N-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-et-
hoxy]-ethyl]- acetamide SC_1002
CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,-
3-diazaspiro[4.5]decan-3- yl]-acetyl]amino]-pyridine-2-carboxylic
acid methyl ester SC_1003
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-
N-[(1R)-2-hydroxy-1-methyl-ethyl]-acetamide SC_1004
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-
N-[(1S)-2-hydroxy-1-methyl-ethyl]-acetamide SC_1005
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-
N-methyl-N-(methylcarbamoyl-methyl)-acetamide SC_1006
CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,-
3-diazaspiro[4.5]decan-3- yl]-acetyl]amino]-nicotinic acid methyl
ester SC_1007
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,-
3-diazaspiro[4.5]decan-3-
yl]-acetyl]-methyl-amino]-2-methyl-propionamide SC_1008
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,-
3-diazaspiro[4.5]decan-3-
yl]-acetyl]amino]-N,2-dimethyl-propionamide SC_1009
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,-
3-diazaspiro[4.5]decan-3-
yl]-acetyl]-methyl-amino]-N,2-dimethyl-propionamide SC_1010
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-
N-[(dimethyl-carbamoyl)-methyl]-N-methyl-acetamide SC_1011
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,-
3-diazaspiro[4.5]decan-3- yl]-acetyl]amino]-2-methyl-propionamide
SC_1012
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(5-methoxy-pyridin-2-yl)-acetamide
SC_1013
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(6-methoxy-pyridin-2-yl)-acetamide
SC_1014
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(4-methoxy-pyridin-2-yl)-acetamide
SC_1015
CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,-
3-diazaspiro[4.5]decan-3-
yl]-acetyl]amino]-N-methyl-pyridine-2-carboxylic acid amide SC_1016
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-
N-[(3-hydroxy-cyclobutyl)-methyl]-acetamide SC_1017
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-
N-[(3-hydroxy-cyclobutyl)-methyl]-acetamide SC_1018
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-
N-[(1-hydroxy-cyclopropyl)-methyl]-acetamide SC_1019
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-
N-(3-morpholin-4-yl-3-oxo-propyl)-acetamide SC_1020
CIS-N-(1-Cyano-cyclopropyl)-2-[1-(cyclobutyl-methyl)-8-dimethylami-
no-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetamide SC_1021
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-
N-[(3-hydroxy-cyclopentyl)-methyl]-acetamide SC_1022
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-
N-[[(2R)-2-hydroxy-cyclohexyl]-methyl]-acetamide SC_1023
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-
N-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethyl]-acetamide
SC_1024
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-
N-[(1-hydroxy-cyclohexyl)-methyl]-acetamide SC_1025
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-
N-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethyl]-acetamide
SC_1026
CIS-N-(6-Cyano-pyridin-2-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylam-
ino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetamide
SC_1027
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,-
3-diazaspiro[4.5]decan-3- yl]-acetyl]amino]-nicotinic acid methyl
ester SC_1028
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(3-methoxy-pyridin-2-yl)-acetamide
SC_1029
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-
N-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethyl-
]-acetamide SC_1030
CIS-N-(4-Cyano-pyridin-2-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylam-
ino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetamide
SC_1031
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(5-methoxy-pyrimidin-2-yl)-acetamide
SC_1032
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,-
3-diazaspiro[4.5]decan-3- yl]-acetyl]amino]-isonicotinic acid
methyl ester SC_1033
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(2-methoxy-pyridin-4-yl)-acetamide
SC_1034
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(6-fluoro-pyridin-3-yl)-acetamide
SC_1035
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(2-methyl-pyrimidin-5-yl)-acetamide
SC_1036
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(5-methyl-pyrimidin-2-yl)-acetamide
SC_1037
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(3-fluoro-pyridin-2-yl)-acetamide
SC_1038
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(3-fluoro-pyridin-4-yl)-acetamide
SC_1039
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(6-methoxy-pyridin-3-yl)-acetamide
SC_1040
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(2-methyl-pyridin-3-yl)-acetamide
SC_1041
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(4-methyl-pyridin-3-yl)-acetamide
SC_1042
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(3-methyl-pyridin-4-yl)-acetamide
SC_1043
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(6-methyl-pyridin-3-yl)-acetamide
SC_1044
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(5-fluoro-pyridin-2-yl)-acetamide
SC_1045
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(5-methyl-pyridin-2-yl)-acetamide
SC_1046
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(4-methyl-pyridin-2-yl)-acetamide
SC_1047
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(3-methyl-pyridin-2-yl)-acetamide
SC_1048
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(3-methoxy-pyridin-4-yl)-acetamide
SC_1049
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(6-methoxy-pyridazin-3-yl)-acetamide
SC_1050
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-
N-(5-methylsulfonyl-pyridin-2-yl)-acetamide SC_1051
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(5-methoxy-pyridin-2-yl)-acetamide
SC_1052
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-
N-(6-methylsulfonyl-pyridin-3-yl)-acetamide SC_1053
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(6-methoxy-pyrazin-2-yl)-acetamide
SC_1054
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(4-methoxy-pyridin-2-yl)-acetamide
SC_1055
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(4-methoxy-pyrimidin-2-yl)-acetamide
SC_1056
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(oxazol-5-yl-methyl)-acetamide SC_1057
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(oxazol-2-yl-methyl)-acetamide SC_1058
CIS-1-(Cyclobutyl-methyl)-3-[2-[(3S,4S)-3,4-dihydroxy-piperidin-1--
yl]-2-oxo-ethyl]-8-
dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1059
CIS-1-(Cyclobutyl-methyl)-3-[2-[(3S,4S)-3,4-dihydroxy-pyrrolidin-1-
-yl]-2-oxo-ethyl]-8-
dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1060
CIS-1-(Cyclobutyl-methyl)-3-[2-[(3S,4R)-3,4-dihydroxy-pyrrolidin-1-
-yl]-2-oxo-ethyl]-8-
dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1061
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-cyclopropyl-acetamide SC_1062
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(2-hydroxy-ethyl)-N-methyl-acetamide
SC_1063
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-(3-hydroxy-piperidi-
n-1-yl)-2-oxo-ethyl]-8- phenyl-1,3-diazaspiro[4.5]decan-2-one
SC_1064
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-
N-[(1-hydroxy-cyclobutyl)-methyl]-acetamide SC_1065
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,-
3-diazaspiro[4.5]decan-3- yl]-acetyl]amino]-N,N-dimethyl-acetamide
SC_1066
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-oxo-2-(5,6,7,8-tetr-
ahydro-[1,2,4]triazolo[1,5-
a]pyrazin-7-yl)-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
SC_1067
CIS-3-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,-
3-diazaspiro[4.5]decan-3-
yl]-acetyl]amino]-N,N-dimethyl-propionamide SC_1068
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-
N-[2-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-
-ethoxy]-ethoxy]- ethyl]-acetamide SC_1069
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(4-methoxy-pyrimidin-5-yl)-acetamide
SC_1070
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(2-methoxy-pyrimidin-5-yl)-acetamide
SC_1072
CIS-N-(5-Cyano-pyridin-2-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylam-
ino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetamide
SC_1073
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,-
3-diazaspiro[4.5]decan-3-
yl]-acetyl]amino]-N-methyl-pyridine-4-carboxylic acid amide SC_1074
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(5-methoxy-pyrimidin-4-yl)-acetamide
SC_1075
CIS-N-(2-Cyano-pyrimidin-5-yl)-2-[1-(cyclobutyl-methyl)-8-dimethyl-
amino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetamide
SC_1076
CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,-
3-diazaspiro[4.5]decan-3- yl]-acetyl]amino]-pyridine-2-carboxylic
acid amide SC_1077
CIS-N-(3-Cyano-pyridin-2-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylam-
ino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetamide
SC_1078
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,-
3-diazaspiro[4.5]decan-3- yl]-acetyl]amino]-acetamide SC_1079
CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,-
3-diazaspiro[4.5]decan-3- yl]-acetyl]amino]-pyridine-3-carboxylic
acid amide SC_1080
CIS-N-(4-Cyano-pyrimidin-2-yl)-2-[1-(cyclobutyl-methyl)-8-dimethyl-
amino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetamide
SC_1081
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-([1,3,4]thiadiazol-2-yl)-acetamide
SC_1082
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-thiazol-2-yl-acetamide
SC_1083
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(5-methyl-isoxazol-3-yl)-acetamide
SC_1084
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-isoxazol-3-yl-acetamide SC_1085
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(1-methyl-1H-pyrazol-3-yl)-acetamide
SC_1086
CIS-N-(4-Cyano-5-methylsulfanyl-1H-pyrazol-3-yl)-2-[1-(cyclobutyl--
methyl)-8-dimethylamino-
2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide SC_1087
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(5-methoxy-pyrazin-2-yl)-acetamide
SC_1088
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(pyridazin-4-yl-methyl)-acetamide
SC_1089
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-[(2-hydroxyphenyl)-methyl]-acetamide
SC_1090
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-
N-[(1-methyl-1H-imidazol-4-yl)-methyl]-acetamide SC_1091
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-
N-[(4-methyl-pyridin-3-yl)-methyl]-acetamide SC_1092
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(pyrimidin-2-yl-methyl)-acetamide
SC_1093
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(pyridazin-3-yl-methyl)-acetamide
SC_1094
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(pyrimidin-4-yl-methyl)-acetamide
SC_1095
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(pyrazin-2-yl-methyl)-acetamide SC_1096
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(oxazol-4-yl-methyl)-acetamide SC_1097
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-
N-[(2-methyl-pyridin-3-yl)-methyl]-acetamide SC_1098
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-
N-[(2-methoxy-pyridin-3-yl)-methyl]-acetamide SC_1099
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-
N-[(4-methoxy-pyridin-3-yl)-methyl]-acetamide SC_1100
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-
N-[(6-methyl-pyridin-2-yl)-methyl]-acetamide SC_1101
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-
N-[(6-methoxy-pyridin-2-yl)-methyl]-acetamide SC_1102
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-[(2-methoxyphenyl)-methyl]-acetamide
SC_1103
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(o-tolyl-methyl)-acetamide SC_1104
CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,-
3-diazaspiro[4.5]decan-3-
yl]-acetyl]amino]-N-methyl-pyridine-3-carboxylic acid amide SC_1105
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,-
3-diazaspiro[4.5]decan-3- yl]-acetyl]amino]-pyridine-4-carboxylic
acid amide SC_1106
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(6-methoxy-pyrimidin-4-yl)-acetamide
SC_1107
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(2-methoxy-pyrimidin-4-yl)-acetamide
SC_1109
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(4-hydroxy-pyrimidin-5-yl)-acetamide
SC_1110
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(2-hydroxy-pyrimidin-5-yl)-acetamide
SC_1111
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(5-hydroxy-pyridin-2-yl)-acetamide
SC_1112
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(1,1-dioxo-thian-4-yl)-acetamide
SC_1113
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-(1,1-dioxo-[1,4]thi-
azinan-4-yl)-2-oxo-ethyl]- 8-phenyl-1,3-diazaspiro[4.5]decan-2-one
SC_1114
CIS-2-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diaz-
aspiro[4.5]decan-3-yl]-N- pyrimidin-4-yl-acetamide SC_1115
CIS-2-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diaz-
aspiro[4.5]decan-3-yl]-N- methyl-acetamide SC_1117
CIS-N-(5-Cyano-pyrimidin-4-yl)-2-[1-(cyclobutyl-methyl)-8-dimethyl-
amino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetamide
SC_1118
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-
N-(5-methylsulfanyl-pyridin-2-yl)-acetamide SC_1119
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(4-methoxy-pyrimidin-2-yl)-acetamide
SC_1120
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-
N-(6-methylsulfanyl-pyridin-2-yl)-acetamide SC_1121
CIS-2-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diaz-
aspiro[4.5]decan-3-yl]-N- (2-hydroxy-ethyl)-acetamide SC_1122
CIS-2-[[2-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3--
diazaspiro[4.5]decan-3- yl]-acetyl]amino]-acetamide SC_1123
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-methyl-acetamide SC_1124
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(2-hydroxy-ethyl)-acetamide SC_1125
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(6-hydroxy-pyridin-2-yl)-acetamide
SC_1126
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-
N-[(2-methoxy-pyrimidin-5-yl)-methyl]-acetamide SC_1127
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-
N-[(4-methoxy-pyrimidin-2-yl)-methyl]-acetamide SC_1128
CIS-N-(2-Cyano-pyrimidin-4-yl)-2-[1-(cyclobutyl-methyl)-8-dimethyl-
amino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetamide
SC_1129
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-
N-[6-(methylsulfinyl)-pyridin-2-yl]-acetamide SC_1130
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3--
diazaspiro[4.5]decan-3- yl]-acetyl]amino]-2-methyl-propionamide
SC_1131
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3--
diazaspiro[4.5]decan-3- yl]-acetyl]amino]-N-methyl-acetamide
SC_1132
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3--
diazaspiro[4.5]decan-3- yl]-acetyl]amino]-acetamide SC_1133
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-
N-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl]-acetamide SC_1134
CIS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-methylamino-2--
oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide
SC_1135
CIS-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diaz-
aspiro[4.5]decan-3-yl]-N-
methyl-N-(methylcarbamoyl-methyl)-acetamide SC_1136
CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-p-
henyl-1,3-
diazaspiro[4.5]decan-3-yl]-N-(2-methylsulfonyl-ethyl)-acetamide
SC_1137
CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-p-
henyl-1,3- diazaspiro[4.5]decan-3-yl]-N-pyrimidin-5-yl-acetamide
SC_1138
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-
N-(6-methylsulfonyl-pyridin-2-yl)-acetamide SC_1139
CIS-2-[8-Dimethylamino-1-[(dimethyl-carbamoyl)-methyl]-2-oxo-8-phe-
nyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide
SC_1140
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3--
diazaspiro[4.5]decan-3-
yl]-acetyl]-methyl-amino]-2-methyl-propionamide SC_1141
CIS-1-(Cyclobutyl-methyl)-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-o-
xo-ethyl]-8-methylamino-8- phenyl-1,3-diazaspiro[4.5]decan-2-one
SC_1142
CIS-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diaz-
aspiro[4.5]decan-3-yl]-N-
[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-etho-
xy]-ethyl]-acetamide SC_1143
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3--
diazaspiro[4.5]decan-3- yl]-acetyl]amino]-N,N-dimethyl-acetamide
SC_1144
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(5-hydroxy-pyrimidin-2-yl)-acetamide
SC_1145
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-
N-(4-methylsulfonyl-pyridin-2-yl)-acetamide SC_1146
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,-
3-diazaspiro[4.5]decan-3- yl]-acetyl]amino]-N-methyl-acetamide
SC_1147
CIS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino--
2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide
SC_1148
CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1-propyl-1,3-diazaspiro[4.5]-
decan-3-yl)-N-methyl- acetamide SC_1149
CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-dia-
zaspiro[4.5]decan-3-yl]- N-methyl-acetamide SC_1150
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-
N-[4-(methylsulfinyl)-pyridin-2-yl]-acetamide SC_1151
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(3-hydroxy-pyridin-2-yl)-acetamide
SC_1152
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(2-methylsulfonyl-ethyl)-acetamide
SC_1154
CIS-1-(Cyclobutyl-methyl)-3-[2-[(3S,4R)-3,4-dihydroxy-pyrrolidin-1-
-yl]-2-oxo-ethyl]-8-
dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1155
CIS-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diaz-
aspiro[4.5]decan-3-yl]-N- (2-hydroxy-ethyl)-acetamide SC_1156
CIS-2-[8-Dimethylamino-1-[(dimethyl-carbamoyl)-methyl]-2-oxo-8-phe-
nyl-1,3- diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide
SC_1157
CIS-2-[8-Dimethylamino-1-[(dimethyl-carbamoyl)-methyl]-2-oxo-8-phe-
nyl-1,3- diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1158
CIS-2-[[2-[8-Dimethylamino-1-(2-methyl-propyl)-2-oxo-8-phenyl-1,3--
diazaspiro[4.5]decan-3- yl]-acetyl]amino]-acetamide SC_1159
CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-p-
henyl-1,3- diazaspiro[4.5]decan-3-yl]-acetamide SC_1160
CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-p-
henyl-1,3- diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1161
CIS-2-[[2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-
-diazaspiro[4.5]decan-3- yl]-acetyl]amino]-acetamide SC_1162
CIS-2-[8-Dimethylamino-1-(2-methyl-propyl)-2-oxo-8-phenyl-1,3-diaz-
aspiro[4.5]decan-3-yl]-N- methyl-acetamide SC_1163
CIS-1-(Cyclobutyl-methyl)-3-[2-[(3S,4R)-3,4-dihydroxy-pyrrolidin-1-
-yl]-2-oxo-ethyl]-8-
methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1164
CIS-2-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-ph-
enyl-1,3- diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1165
CIS-2-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-ph-
enyl-1,3- diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide
SC_1166
CIS-2-[[2-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo--
8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide
SC_1167
CIS-2-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-ph-
enyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide
SC_1168
CIS-2-[[2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan- 3-yl]-acetyl]amino]-acetamide SC_1169
CIS-2-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-
-1,3-diazaspiro[4.5]decan- 3-yl]-N-methyl-acetamide SC_1171
CIS-2-[[2-(8-Dimethylamino-2-oxo-8-phenyl-1-propyl-1,3-diazaspiro[-
4.5]decan-3-yl)- acetyl]amino]-acetamide SC_1172
CIS-2-[[2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-
-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide
SC_1173
CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-p-
henyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide
SC_1174
CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-p-
henyl-1,3-
diazaspiro[4.5]decan-3-yl]-N-(1,1-dioxo-thian-4-yl)-acetamide
SC_1175
CIS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-d-
iazaspiro[4.5]decan-3- yl]-N-methyl-acetamide SC_1176
CIS-2-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-phe-
nyl-1,3- diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1177
CIS-2-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-
-1,3-diazaspiro[4.5]decan- 3-yl]-N-(2-hydroxy-ethyl)-acetamide
SC_1178
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-ph-
enyl-1,3- diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide
SC_1179
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3--
diazaspiro[4.5]decan-3- yl]-acetyl]amino]-N,2-dimethyl-propionamide
SC_1180
CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-dia-
zaspiro[4.5]decan-3-yl]- N-(2-hydroxy-ethyl)-acetamide SC_1181
CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-dia-
zaspiro[4.5]decan-3-yl]-
N-methyl-N-(methylcarbamoyl-methyl)-acetamide SC_1182
CIS-8-Dimethylamino-1-(3-methoxy-propyl)-3-[2-oxo-2-(3-oxo-piperaz-
in-1-yl)-ethyl]-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one SC_1183
CIS-N-(Carbamoyl-methyl)-2-[8-dimethylamino-1-(3-methoxy-propyl)-2-
-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide
SC_1184
CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-dia-
zaspiro[4.5]decan-3-yl]-
N-[(3-hydroxy-cyclobutyl)-methyl]-acetamide SC_1185
CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-dia-
zaspiro[4.5]decan-3-yl]-
N-[(3-hydroxy-cyclobutyl)-methyl]-acetamide SC_1186
CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-dia-
zaspiro[4.5]decan-3-yl]-
N-[(3-hydroxy-cyclopentyl)-methyl]-acetamide SC_1187
CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-dia-
zaspiro[4.5]decan-3-yl]- N-pyridazin-4-yl-acetamide SC_1188
CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-dia-
zaspiro[4.5]decan-3-yl]- N-(6-methoxy-pyridin-2-yl)-acetamide
SC_1189
CIS-N-(2-Cyanoethyl)-2-[8-dimethylamino-1-(3-methoxy-propyl)-2-oxo-
-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetamide SC_1190
CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-dia-
zaspiro[4.5]decan-3-yl]- N-pyrimidin-5-yl-acetamide SC_1191
CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-dia-
zaspiro[4.5]decan-3-yl]- N-pyrimidin-4-yl-acetamide SC_1192
CIS-2-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-
-1,3-diazaspiro[4.5]decan-
3-yl]-N-(6-methoxy-pyridin-2-yl)-acetamide SC_1193
CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-p-
henyl-1,3- diazaspiro[4.5]decan-3-yl]-N-pyridin-3-yl-acetamide
SC_1195
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- acetamide SC_1196
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-pyrimidin-4-yl-acetamide SC_1197
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(2-methoxy-ethyl)-acetamide SC_1198
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(2-hydroxy-ethyl)-acetamide SC_1199
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-
N-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-et-
hoxy]-ethyl]- acetamide SC_1201
CIS-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diaz-
aspiro[4.5]decan-3-yl]-N- methyl-acetamide SC_1203
CIS-(2S)-1-[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-pheny-
l-1,3- diazaspiro[4.5]decan-3-yl]-acetyl]-pyrrolidine-2-carboxylic
acid amide SC_1204
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,-
3-diazaspiro[4.5]decan-3- yl]-acetyl]amino]-N,N-dimethyl-acetamide
SC_1205
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(oxetan-3-yl)-acetamide SC_1206
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,-
3-diazaspiro[4.5]decan-3- yl]-acetyl]amino]-acetamide SC_1207
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-oxo-2-(3-oxo-pipera-
zin-1-yl)-ethyl]-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one SC_1208
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(1,1-dioxo-thian-4-yl)-acetamide
SC_1209
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-[2-(hydroxymethyl)--
morpholin-4-yl]-2-oxo-
ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1210
CIS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino--
2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide
SC_1211
CIS-N-(Cyano-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-ox-
o-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetamide SC_1212
CIS-N-(2-Acetylamino-ethyl)-2-[1-(cyclobutyl-methyl)-8-dimethylami-
no-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetamide SC_1213
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(2-methylsulfonyl-ethyl)-acetamide
SC_1214
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-(1,1-dioxo-[1,4]thi-
azinan-4-yl)-2-oxo-ethyl]- 8-phenyl-1,3-diazaspiro[4.5]decan-2-one
SC_1215
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-
N-[(1,1-dioxo-thian-4-yl)-methyl]-acetamide SC_1216
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-(4-methylsulfonyl-p-
iperazin-1-yl)-2-oxo-
ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1217
CIS-N-(2-Cyanoethyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-ox-
o-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetamide SC_1218
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(2-hydroxy-2-methyl-propyl)-acetamide
SC_1219
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-
N-(2-morpholin-4-yl-2-oxo-ethyl)-acetamide SC_1220
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-[2-(2-hydroxy-ethoxy)-ethyl]-acetamide
SC_1222
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,-
3-diazaspiro[4.5]decan-3- yl]-acetyl]amino]-N-methyl-acetamide
SC_1223
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-
N-[2-(methanesulfonamido)-ethyl]-acetamide SC_1224
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-
N-[(1-hydroxy-cyclopentyl)-methyl]-acetamide SC_1225
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-
N-[(4-hydroxy-cyclohexyl)-methyl]-acetamide SC_1226
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-[2-(2-methoxy-ethoxy)-ethyl]-acetamide
SC_1227
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-[2-(dimethylamino)ethyl]-acetamide
SC_1228
CIS-2-[1-(Cyclobutyl-methyl)-8-[methyl-(2-methyl-propyl)-amino]-2--
oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide
SC_1229
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-methyl-acetamide SC_1230
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-pyrimidin-4-yl-acetamide SC_1231
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(6-methyl-pyridin-2-yl)-acetamide
SC_1232
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-pyridazin-3-yl-acetamide SC_1233
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-pyrimidin-5-yl-acetamide SC_1234
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-pyridazin-4-yl-acetamide SC_1235
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(6-methoxy-pyrimidin-4-yl)-acetamide
SC_1236
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-(2-methyl-pyridin-4-yl)-acetamide
SC_1300
CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-p-
henyl-1,3- diazaspiro[4.5]decan-3-yl]-N-pyridin-4-yl-acetamide
SC_1301
CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-p-
henyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-acetamide
SC_1302
CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-p-
henyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-ethyl)-acetamide
SC_1303
CIS-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phe-
nyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-acetamide
SC_1304
CIS-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phe-
nyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-ethyl)-acetamide
SC_1305
CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-dia-
zaspiro[4.5]decan-3-yl]- N-(4-methoxy-pyridin-2-yl)-acetamide
SC_1306
CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-dia-
zaspiro[4.5]decan-3-yl]- N-(pyrimidin-4-yl-methyl)-acetamide
SC_1308
CIS-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-eth-
yl]-8-phenyl-1-propyl-1,3- diazaspiro[4.5]decan-2-one SC_1309
CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-p-
henyl-1,3- diazaspiro[4.5]decan-3-yl]-N-pyridin-2-yl-acetamide
SC_1310
CIS-2-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-phe-
nyl-1,3- diazaspiro[4.5]decan-3-yl]-acetamide SC_1311
CIS-2-[[2-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-
-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide
SC_1312
CIS-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phe-
nyl-1,3- diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1313
CIS-3-[2-(1,1-Dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-methylamin-
o-8-phenyl-1-propyl-1,3- diazaspiro[4.5]decan-2-one SC_1317
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- N-pyridin-2-yl-acetamide SC_1318
CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-morphol-
in-4-yl-2-oxo-ethyl)-8- phenyl-1,3-diazaspiro[4.5]decan-2-one
SC_1319
CIS-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phe-
nyl-1,3- diazaspiro[4.5]decan-3-yl]-acetamide SC_1320
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(2-morpholin-4-yl-2-ox-
o-ethyl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_1321
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-
N-(4-methylsulfanyl-pyridin-2-yl)-acetamide SC_1322
CIS-3-[2-(1,1-Dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-methylamin-
o-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_1323
CIS-2-(8-Methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-
-acetamide SC_1324
CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-y-
l)-acetamide
SC_1325
CIS-3-[2-(1,1-Dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-ethylamino-
-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_1326
TRANS-3-[2-(1,1-Dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-ethylami-
no-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_1327
CIS-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diaz-
aspiro[4.5]decan-3-yl]-N- methyl-acetamide SC_1328
CIS-2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)--
acetamide SC_1329
TRANS-2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl-
)-acetamide SC_1330
CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-y-
l)-N-(2-hydroxy-ethyl)-N- methyl-acetamide SC_1331
CIS-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-eth-
yl]-1-[(1-hydroxy-
cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione
SC_1332
CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-y-
l)-N-phenyl-acetamide SC_1333
CIS-N-(Carbamoyl-methyl)-2-[1-(cyclopropyl-methyl)-8-dimethylamino-
-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide
SC_1334
CIS-2-(8-Dimethylamino-2,4-dioxo-8-phenyl-1,3-diazaspiro[4.5]decan-
-3-yl)-N-phenyl-acetamide SC_1335
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]- acetamide SC_1336
CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-p-
henyl-1,3-
diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]--
ethyl]-acetamide SC_1337
CIS-3-[2-(1,1-Dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-1-[(1-hydrox-
y-cyclobutyl)-methyl]-8-
methylamino-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione SC_1338
CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-y-
l)-N-[2-[2-[2-(2-methoxy- ethoxy)-ethoxy]-ethoxy]-ethyl]-acetamide
SC_1339
CIS-N-(Carbamoyl-methyl)-N-methyl-2-(8-methylamino-2-oxo-8-phenyl--
1,3- diazaspiro[4.5]decan-3-yl)-acetamide SC_1340
CIS-N-(Carbamoyl-methyl)-2-(8-dimethylamino-2-oxo-8-phenyl-1,3-dia-
zaspiro[4.5]decan-3-yl)- N-methyl-acetamide SC_1341
CIS-N-(Carbamoyl-methyl)-2-[8-dimethylamino-1-(oxetan-3-yl-methyl)-
-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide
SC_1342
CIS-N-(2-Hydroxy-ethyl)-N-methyl-2-(8-methylamino-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan- 3-yl)-acetamide SC_1343
CIS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-d-
iazaspiro[4.5]decan-3- yl]-acetamide SC_1344
CIS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-d-
iazaspiro[4.5]decan-3- yl]-N-(2-hydroxy-ethyl)-acetamide SC_1345
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2--
oxo-1,3-
diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-N-methyl-acetamide
SC_1346
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2--
oxo-1,3- diazaspiro[4.5]decan-3-yl]-acetic acid tert-butyl ester
SC_1347
CIS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-d-
iazaspiro[4.5]decan-3- yl]-N-(2-hydroxy-ethyl)-N-methyl-acetamide
SC_1348
CIS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-d-
iazaspiro[4.5]decan-3- yl]-N-(2-methylsulfonyl-ethyl)-acetamide
SC_1349
CIS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino--
8-(3-fluorophenyl)-2-
oxo-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1350
CIS-1-[2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo--
8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-acetyl]-piperidine-4-carboxylic acid
amide SC_1351
CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-[2-(4-meth-
ylsulfonyl-piperidin-1-
yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1352
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2--
oxo-1,3- diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide
SC_1353
TRANS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3--
diazaspiro[4.5]decan-3- yl]-N-(2-hydroxy-ethyl)-acetamide SC_1354
TRANS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamin-
o-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide
SC_1355
CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-[2-(4-hydr-
oxy-4-methyl-piperidin-1-
yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1356
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-8-(4-fluorophenyl)-2--
oxo-1,3- diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide
SC_1357
TRANS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-(2-morpholin-4-yl-2-
-oxo-ethyl)-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one SC_1358
TRANS-8-Dimethylamino-3-(2-morpholin-4-yl-2-oxo-ethyl)-8-phenyl-1,-
3-diazaspiro[4.5]decan- 2-one SC_1359
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-8-(4-fluorophenyl)-2--
oxo-1,3-
diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-N-methyl-acetamide
SC_1360
CIS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino--
8-(4-fluorophenyl)-2-
oxo-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1361
CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[2-(4-hydroxy-4-methy-
l-piperidin-1-yl)-2-oxo-
ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1362
CIS-1-[2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,-
3-diazaspiro[4.5]decan-3- yl]-acetyl]-piperidine-4-carboxylic acid
amide SC_1363
TRANS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
-diazaspiro[4.5]decan- 3-yl]-acetamide SC_1364
TRANS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
-diazaspiro[4.5]decan- 3-yl]-N-methyl-acetamide SC_1365
TRANS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[2-(1,1-dioxo-[1,4]-
thiazinan-4-yl)-2-oxo-
ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1366
CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[2-(4-methylsulfonyl--
piperidin-1-yl)-2-oxo-
ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1368
CIS-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-eth-
yl]-1-[(1-hydroxy-
cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1369
TRANS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-
-yl)-acetamide SC_1370
TRANS-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-e-
thyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_1371
CIS-8-(dimethylamino)-8-phenyl-1-(2,2,2-trifluoroethyl)-3-(2-(trif-
luoromethyl)pyrimidin-5-yl)- 1,3-diazaspiro[4.5]decan-2-one SC_1372
CIS-8-(dimethylamino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-y-
l)-1-(3,3,3-trifluoropropyl)- 1,3-diazaspiro[4.5]decan-2-one
and the physiologically acceptable salts thereof.
[0058] According to the invention, unless expressly stated
otherwise, "--C.sub.1-C.sub.4-alkyl", "--C.sub.1-C.sub.6-alkyl" and
any other alkyl residues can be linear or branched, saturated or
unsaturated. Linear saturated alkyl includes methyl, ethyl,
n-propyl, n-butyl, n-pentyl and n-hexyl. Examples of branched
saturated alkyl include but are not limited to iso-propyl,
sec-butyl, and tert-butyl. Examples of linear unsaturated alkyl
include but are not limited to vinyl, propenyl, allyl, and
propargyl.
[0059] According to the invention, unless expressly stated
otherwise, "--C.sub.1-C.sub.4-alkyl", "--C.sub.1-C.sub.6-alkyl" and
any other alkyl residues can be unsubstituted, mono- or
polysubstituted. Examples of substituted alkyl include but are not
limited to --CH.sub.2CH.sub.2OH, --CH.sub.2CH.sub.2OCH.sub.3,
--CH.sub.2CH.sub.2CH.sub.2OCH.sub.3,
--CH.sub.2CH.sub.2S(.dbd.O).sub.2CH.sub.3,
--CH.sub.2C(.dbd.O)NH.sub.2, --C(CH.sub.3).sub.2C(.dbd.O)NH.sub.2,
--CH.sub.2C(CH.sub.3).sub.2C(.dbd.O)NH.sub.2, and
--CH.sub.2CH.sub.2C(.dbd.O)N(CH.sub.3).sub.2.
[0060] According to the invention, unless expressly stated
otherwise, "--C.sub.1-C.sub.6-alkylene-",
"--C.sub.1-C.sub.4-alkylene" and any other alkylene residue can be
unsubstituted, mono- or polysubstituted. Examples of saturated
alkylene include but are not limited to --CH.sub.2--,
--CH(CH.sub.3)--, --C(CH.sub.3).sub.2--, --CH.sub.2CH.sub.2--,
--CH(CH.sub.3)CH.sub.2--, --CH.sub.2CH(CH.sub.3)--,
--CH(CH.sub.3)--CH(CH.sub.3)--, --C(CH.sub.3).sub.2CH.sub.2--,
--CH.sub.2C(CH.sub.3).sub.2--, --CH(CH.sub.3)C(CH.sub.3).sub.2--,
--C(CH.sub.3).sub.2CH(CH.sub.3)--,
C(CH.sub.3).sub.2C(CH.sub.3).sub.2--, --CH.sub.2CH.sub.2CH.sub.2--,
and --C(CH.sub.3).sub.2CH.sub.2CH.sub.2--. Examples of unsaturated
alkylene include but are not limited to --CH.dbd.CH--,
--C.ident.C--, --C(CH.sub.3).dbd.CH--, --CH.dbd.C(CH.sub.3)--,
--C(CH.sub.3).dbd.C(CH.sub.3)--, --CH.sub.2CH.dbd.CH--,
--CH.dbd.CHCH.sub.2--, --CH.dbd.CH--CH.dbd.CH--, and
--CH.dbd.CH--C.ident.C--.
[0061] According to the invention, unless expressly stated
otherwise, "--C.sub.1-C.sub.6-alkylene-",
"--C.sub.1-C.sub.4-alkylene" and any other alkylene residue can be
unsubstituted, mono- or polysubstituted. Examples of substituted
--C.sub.1-C.sub.6-alkylene- include but are not limited to --CHF--,
--CF.sub.2--, --CHOH-- and --C(.dbd.O)--.
[0062] According to the invention, moieties may be connected
through --C.sub.1-C.sub.6-alkylene-, i.e. the moieties may not be
directly bound to the core structure of compound according to
general formula (I), but may be connected to the core structure of
compound according to general formula (I) or its periphery through
a --C.sub.1-C.sub.6-alkylene-linker.
[0063] According to the invention, "3-12-membered cycloalkyl
moiety" means a non-aromatic, monocyclic, bicyclic or tricyclic
moiety comprising 3 to 12 ring carbon atoms but no heteroatoms in
the ring. Examples of preferred saturated 3-12-membered cycloalkyl
moieties according to the invention include but are not limited to
cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane,
cyclooctane, hydrindane, and decaline. Examples of preferred
unsaturated 3-12-membered cycloalkyl moiety moieties according to
the invention include but are not limited to cyclopropene,
cyclobutene, cyclopentene, cyclopentadiene, cyclohexene,
1,3-cyclohexadiene, and 1,4-cyclohexadiene. The 3-12-membered
cycloalkyl moiety, which is bonded to the compound according to the
invention, in its periphery may optionally be condensed with a
3-12-membered heterocycloalkyl moiety, saturated or unsaturated,
unsubstituted, mono- or polysubstituted; and/or with a
6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted;
and/or with a 5-14-membered heteroaryl moiety, unsubstituted, mono-
or polysubstituted. Under these circumstances, the ring atoms of
the condensed moieties are not included in the 3 to 12 ring atoms
of the 3-12-membered cycloalkyl moiety. Examples of 3-12-membered
cycloalkyl moieties condensed with 3-12-membered heterocycloalkyl
moieties include but are not limited to octahydro-1H-indol,
decahydroquinoline, decahydroisoquinoline,
octahydro-2H-benzo[b][1,4]oxazin, and decahydroquinoxalin, which in
each case are connected through the 3-12-membered cycloalkyl
moiety. Examples of 3-12-membered cycloalkyl moieties condensed
with 6-14-membered aryl moieties include but are not limited to
2,3-dihydro-1H-indene and tetraline, which in each case are
connected through the 3-12-membered cycloalkyl moiety. Examples of
3-12-membered cycloalkyl moieties condensed with 5-14-membered
heteroaryl moieties include but are not limited to
5,6,7,8-tetrahydroquinoline and 5,6,7,8-tetrahydroquinazoline,
which in each case are connected through the 3-12-membered
cycloalkyl moiety.
[0064] According to the invention, the 3-12-membered cycloalkyl
moiety may optionally be connected through
--C.sub.1-C.sub.6-alkylene-, i.e. the 3-12-membered cycloalkyl
moiety may not be directly bound to the compound according to
general formula (I) but may be connected thereto through a
--C.sub.1-C.sub.6-alkylene-linker. Examples include but are not
limited to --CH.sub.2-cyclopropyl, --CH.sub.2-cyclobutyl,
--CH.sub.2-cyclopentyl, --CH.sub.2-cyclohexyl,
--CH.sub.2CH.sub.2-cyclopropyl, --CH.sub.2CH.sub.2-cyclobutyl,
--CH.sub.2CH.sub.2-cyclopentyl, and
--CH.sub.2CH.sub.2-cyclohexyl.
[0065] According to the invention, unless expressly stated
otherwise, the 3-12-membered cycloalkyl moiety can be
unsubstituted, mono- or polysubstituted. Examples of substituted
3-12-membered cycloalkyl moieties include but are not limited to
--CH.sub.2-1-hydroxy-cyclobutyl.
[0066] According to the invention, "3-12-membered heterocycloalkyl
moiety" means a non-aromatic, monocyclic, bicyclic or tricyclic
moiety comprising 3 to 12 ring atoms, wherein each cycle comprises
independently of one another 1, 2, 3, 4 or more heteroatoms
independently of one another selected from the group consisting of
nitrogen, oxygen and sulfur, whereas sulfur may be oxidized
(S(.dbd.O) or S(.dbd.O).sub.2), whereas the remaining ring atoms
are carbon atoms, and whereas bicyclic or tricyclic systems may
share common heteroatom(s). Examples of preferred saturated
3-12-membered heterocycloalkyl moieties according to the invention
include but are not limited to aziridin, azetidine, pyrrolidine,
imidazolidine, pyrazolidine, piperidine, piperazine, triazolidine,
tetrazolidine, oxiran, oxetane, tetrahydrofurane, tetrahydropyrane,
thiirane, thietane, tetrahydrothiophene, diazepane, oxazolidine,
isoxazolidine, thiazolidine, isothiazolidine, thiadiazolidine,
morpholine, thiomorpholine. Examples of preferred unsaturated
3-12-membered heterocycloalkyl moiety moieties according to the
invention include but are not limited to oxazoline, pyrazoline,
imidazoline, isoxazoline, thiazoline, isothiazoline, and
dihydropyran. The 3-12-membered heterocycloalkyl moiety, which is
bonded to the compound according to the invention, in its periphery
may optionally be condensed with a 3-12-membered cycloalkyl moiety,
saturated or unsaturated, unsubstituted, mono- or polysubstituted;
and/or with a 6-14-membered aryl moiety, unsubstituted, mono- or
polysubstituted; and/or with a 5-14-membered heteroaryl moiety,
unsubstituted, mono- or polysubstituted. Under these circumstances,
the ring atoms of the condensed moieties are not included in the 3
to 12 ring atoms of the 3-12-membered heterocycloalkyl moieties.
Examples of 3-12-membered heterocycloalkyl moieties condensed with
3-12-membered cycloalkyl moieties include but are not limited to
octahydro-1H-indol, decahydroquinoline, decahydroisoquinoline,
octahydro-2H-benzo[b][1,4]-oxazin, and decahydroquinoxalin, which
in each case are connected through the 3-12-membered
heterocycloalkyl moiety. An examples of a 3-12-membered
heterocycloalkyl moiety condensed with a 6-14-membered aryl moiety
includes but is not limited to 1,2,3,4-tetrahydroquinoline, which
is connected through the 3-12-membered heterocycloalkyl moiety. An
example of a 3-12-membered heterocycloalkyl moiety condensed with a
5-14-membered heteroaryl moieties includes but is not limited to
5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine, which is
connected through the 3-12-membered heterocycloalkyl moiety.
[0067] According to the invention, the 3-12-membered
heterocycloalkyl moiety may optionally be connected through
--C.sub.1-C.sub.6-alkylene-, i.e. the 3-12-membered
heterocycloalkyl moiety may not be directly bound to the compound
according to general formula (I) but may be connected thereto
through a --C.sub.1-C.sub.6-alkylene-linker. Said linker may be
connected to a carbon ring atom or to a hetero ring atom of the
3-12-membered heterocycloalkyl moiety. Examples include but are not
limited to --CH.sub.2-oxetane, --CH.sub.2-pyrrolidine,
--CH.sub.2-piperidine, --CH.sub.2-morpholine,
--CH.sub.2CH.sub.2-oxetane, --CH.sub.2CH.sub.2-pyrrolidine,
--CH.sub.2CH.sub.2-piperidine, and
--CH.sub.2CH.sub.2-morpholine.
[0068] According to the invention, unless expressly stated
otherwise, the 3-12-membered heterocycloalkyl moiety can be
unsubstituted, mono- or polysubstituted. Examples of substituted
3-12-membered heterocycloalkyl moieties include but are not limited
to 2-carboxamido-N-pyrrolidinyl-, 3,4-dihydroxy-N-pyrrolidinyl,
3-hydroxy-N-pyrimidinyl, 3,4-dihydroxy-N-pyrimidinyl,
3-oxo-N-piperazinyl, -tetrahydro-2H-thiopyranyl dioxide and
thiomorpholinyl dioxide.
[0069] According to the invention, "6-14-membered aryl moiety"
means an aromatic, monocyclic, bicyclic or tricyclic moiety
comprising 6 to 14 ring carbon atoms but no heteroatoms in the
ring. Examples of preferred 6-14-membered aryl moieties according
to the invention include but are not limited to benzene,
naphthalene, anthracen, and phenanthren. The 6-14-membered aryl
moiety, which is bonded to the compound according to the invention,
in its periphery may optionally be condensed with a 3-12-membered
cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono-
or polysubstituted; and/or with a 3-12-membered heterocycloalkyl
moiety, saturated or unsaturated, unsubstituted, mono- or
polysubstituted; and/or with a 5-14-membered heteroaryl moiety,
unsubstituted, mono- or polysubstituted. Under these circumstances,
the ring atoms of the condensed moieties are not included in the 6
to 14 ring carbon atoms of the 6-14-membered heterocycloalkyl
moieties. Examples of 6-14-membered aryl moieties condensed with
3-12-membered cycloalkyl moieties include but are not limited to
2,3-dihydro-1H-indene and tetraline, which in each case are
connected through the 6-14-membered aryl moiety. An example of a
6-14-membered aryl moiety condensed with a 3-12-membered
heterocycloalkyl moiety includes but is not limited to
1,2,3,4-tetrahydroquinoline, which is connected through the
6-14-membered aryl moiety. Examples of 6-14-membered aryl moieties
condensed with 5-14-membered heteroaryl moieties include but are
not limited to quinoline, isoquinoline, phenazine and phenoxacine,
which in each case are connected through the 6-14-membered aryl
moiety.
[0070] According to the invention, the 6-14-membered aryl moiety
may optionally be connected through --C.sub.1-C.sub.6-alkylene-,
i.e. the 6-14-membered aryl moiety may not be directly bound to the
compound according to general formula (I) but may be connected
thereto through a --C.sub.1-C.sub.6-alkylene-linker. Said linker
may be connected to a carbon ring atom or to a hetero ring atom of
the 6-14-membered aryl moiety. Examples include but are not limited
to --CH.sub.2--C.sub.6H.sub.5, --CH.sub.2CH.sub.2--C.sub.6H.sub.5
and --CH.dbd.CH--C.sub.6H.sub.5.
[0071] According to the invention, unless expressly stated
otherwise, the 6-14-membered aryl moiety can be unsubstituted,
mono- or polysubstituted. Examples of substituted 6-14-membered
aryl moieties include but are not limited to 2-fluorophenyl,
3-fluorophenyl, 2-methoxyphenyl and 3-methoxyphenyl.
[0072] According to the invention, "5-14-membered heteroaryl
moiety" means an aromatic, monocyclic, bicyclic or tricyclic moiety
comprising 6 to 14 ring atoms, wherein each cycle comprises
independently of one another 1, 2, 3, 4 or more heteroatoms
independently of one another selected from the group consisting of
nitrogen, oxygen and sulfur, whereas the remaining ring atoms are
carbon atoms, and whereas bicyclic or tricyclic systems may share
common heteroatom(s). Examples of preferred 5-14-membered
heteroaryl moieties according to the invention include but are not
limited to pyrrole, pyrazole, imidazole, triazole, tetrazole,
furane, thiophene, oxazole, isoxazole, thiazole, isothiazole,
pyridine, pyridazine, pyrimidine, pyrazine, indolicine,
9H-chinolicine, 1,8-naphthyridine, purine, imidazo[1,2-a]pyrazine,
and pteridine. The 5-14-membered heteroaryl moiety, which is bonded
to the compound according to the invention, in its periphery may
optionally be condensed with a 3-12-membered cycloalkyl moiety,
saturated or unsaturated, unsubstituted, mono- or polysubstituted;
and/or with a 3-12-membered heterocycloalkyl moiety, saturated or
unsaturated, unsubstituted, mono- or polysubstituted; and/or with a
6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted.
Under these circumstances, the ring atoms of the condensed moieties
are not included in the 6 to 14 ring carbon atoms of the
6-14-membered heterocycloalkyl moieties. Examples of 5-14-membered
heteroaryl moieties condensed with 3-12-membered cycloalkyl
moieties include but are not limited to 5,6,7,8-tetrahydroquinoline
and 5,6,7,8-tetrahydroquinazoline, which in each case are connected
through the 5-14-membered heteroaryl moiety. An examples of a
5-14-membered heteroaryl moiety condensed with a 3-12-membered
heterocycloalkyl moiety includes but is not limited to
5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine, which is
connected through the 5-14-membered heteroaryl moiety. Examples of
5-14-membered heteroaryl moieties condensed with 6-14-membered aryl
moieties include but are not limited to quinoline, isoquinoline,
phenazine and phenoxacine, which in each case are connected through
the 5-14-membered heteroaryl moiety.
[0073] According to the invention, the 5-14-membered heteroaryl
moiety may optionally be connected through
--C.sub.1-C.sub.6-alkylene-, i.e. the 5-14-membered heteroaryl
moiety may not be directly bound to the compound according to
general formula (I) but may be connected thereto through a
--C.sub.1-C.sub.6-alkylene-linker. Said linker may be connected to
a carbon ring atom or to a hetero ring atom of the 5-14-membered
heteroaryl moiety. Examples include but are not limited to
--CH.sub.2-oxazole, --CH.sub.2-isoxazole, --CH.sub.2-imidazole,
--CH.sub.2-pyridine, --CH.sub.2-pyrimidine, --CH.sub.2-pyridazine,
--CH.sub.2CH.sub.2-oxazole, --CH.sub.2CH.sub.2-isoxazole,
--CH.sub.2CH.sub.2-imidazole, --CH.sub.2CH.sub.2-pyridine,
--CH.sub.2CH.sub.2-pyrimidine, and
--CH.sub.2CH.sub.2-pyridazine.
[0074] According to the invention, unless expressly stated
otherwise, the 5-14-membered heteroaryl moiety can be
unsubstituted, mono- or polysubstituted. Examples of 5-14-membered
heteroaryl moieties include but are not limited to
2-methoxy-4-pyridinyl, 2-methoxy-5-pyridinyl,
3-methoxy-4-pyridinyl, 3-methoxy-6-pyridinyl,
4-methoxy-2-pyridinyl, 2-methylsulfonyl-5-pyridinyl,
3-methylsulfonyl-6-pyridinyl, 3-methoxy-6-pyridazinyl,
2-nitrilo-5-pyrimidinyl, 4-hydroxy-2-pyrimidinyl,
4-methoxy-pyrimidinyl, and 2-methoxy-6-pyrazinyl.
[0075] Preferably, the compounds according to the invention have a
structure according to general formula (I')
##STR00022##
wherein R.sup.1 to R.sup.5, R.sup.9 to R.sup.20, and X are defined
as above, or a physiologically acceptable salt thereof.
[0076] In one preferred embodiment, the excess of the cis-isomer so
designated is at least 50% de, more preferably at least 75% de, yet
more preferably at least 90% de, most preferably at least 95% de
and in particular at least 99% de.
[0077] Preferably, the compounds according to the invention have a
structure according to general formula (IX)
##STR00023##
wherein R.sup.C means --H or --OH; R.sup.3 means -phenyl or
-3-fluorophenyl; R.sup.5 means --H, --CH.sub.3,
--CH.sub.2CH.sub.2OH, or --CH.sub.2C(.dbd.O)NH.sub.2; R.sup.6 means
--H or --CH.sub.3; or R.sup.5 and R.sup.6 together with the
nitrogen atom to which they are attached form a ring and mean
--(CH.sub.2).sub.5--, wherein said ring is unsubstituted or
substituted with one or two substituents independently of one
another selected from the group consisting of --CH.sub.3, --OH,
--S(.dbd.O).sub.2CH.sub.3 and --C(.dbd.O)NH.sub.2; R.sup.9 and
R.sup.10 independently of one another mean --H or --CH.sub.3; or a
physiologically acceptable salt thereof.
[0078] In a preferred embodiment, the compounds according to the
invention are in the form of the free bases.
[0079] In another preferred embodiment, the compounds according to
the invention are in the form of the physiologically acceptable
salts.
[0080] For the purposes of the description, a "salt" is to be
understood as being any form of the compound in which it assumes an
ionic form or is charged and is coupled with a counter-ion (a
cation or anion) or is in solution. The term is also to be
understood as meaning complexes of the compound with other
molecules and ions, in particular complexes which are associated
via ionic interactions. Preferred salts are physiologically
acceptable, in particular physiologically acceptable salts with
anions or acids or also a salt formed with a physiologically
acceptable acid.
[0081] Physiologically acceptable salts with anions or acids are
salts of the particular compound in question with inorganic or
organic acids which are physiologically acceptable, in particular
when used in humans and/or mammals. Examples of physiologically
acceptable salts of particular acids include but are not limited to
salts of hydrochloric acid, sulfuric acid, and acetic acid.
[0082] The invention also includes isotopic isomers of a compound
according to the invention, wherein at least one atom of the
compound is replaced by an isotope of the respective atom which is
different from the naturally predominantly occurring isotope, as
well as any mixtures of isotopic isomers of such a compound.
Preferred isotopes are .sup.2H (deuterium), .sup.3H (tritium),
.sup.13C and .sup.14C.
[0083] Certain compounds according to the invention are useful for
modulating a pharmacodynamic response from one or more opioid
receptors (mu, delta, kappa, NOP/ORL-1) either centrally or
peripherally, or both. The pharmacodynamic response may be
attributed to the compound either stimulating (agonizing) or
inhibiting (antagonizing) the one or more receptors. Certain
compounds according to the invention may antagonize one opioid
receptor, while also agonizing one or more other receptors.
Compounds according to the invention having agonist activity may be
either full agonists or partial agonists.
[0084] As used herein, compounds that bind to receptors and mimic
the regulatory effects of endogenous ligands are defined as
"agonists". Compounds that bind to a receptor but produce no
regulatory effect, but rather block the binding of ligands to the
receptor, are defined as "antagonists".
[0085] In certain embodiments, the compounds according to the
invention are agonists at the mu opioid (MOP) and/or kappa opioid
(KOP) and/or delta opioid (DOP) and/or nociceptin opioid
(NOP/ORL-1) receptors.
[0086] The compounds according to the invention potently bind to
the MOP and/or KOP and/or DOP and/or NOP receptors.
[0087] The compounds according to the invention can be modulators
at the MOP and/or KOP and/or DOP and/or NOP receptors, and
therefore the compounds according to the invention can be
used/administered to treat, ameliorate, or prevent pain.
[0088] In some embodiments, the compounds according to the
invention are agonists of one or more opioid receptors. In some
embodiments, the compounds according to the invention are agonists
of the MOP and/or KOP and/or DOP and/or NOP receptors.
[0089] In some embodiments, the compounds according to the
invention are antagonists of one or more opioid receptors. In some
embodiments, the compounds according to the invention are
antagonists of the MOP and/or KOP and/or DOP and/or NOP
receptors.
[0090] In some embodiments, the compounds according to the
invention have both, (i) agonist activity at the NOP receptor; and
(ii) agonist activity at one or more of the MOP, KOP, and DOP
receptors.
[0091] In some embodiments, the compounds according to the
invention have both, (i) agonist activity at the NOP receptor; and
(ii) antagonist activity at one or more of the MOP, KOP, and DOP
receptors.
[0092] In some embodiments, the compounds according to the
invention have both, (i) antagonist activity at the NOP receptor;
and (ii) agonist activity at one or more of the MOP, KOP, and DOP
receptors.
[0093] In some embodiments, the compounds according to the
invention have both, (i) antagonist activity at the NOP receptor;
and (ii) antagonist activity at one or more of the MOP, KOP, and
DOP receptors.
[0094] In some embodiments, preferably with respect to receptors of
the peripheral nervous system, the compounds according to the
invention have selective agonist activity at the NOP receptor. In
some embodiments, preferably with respect to receptors of the
peripheral nervous system, the compounds according to the invention
[0095] have agonist activity at the NOP receptor, but no
significant activity at the MOP receptor; [0096] have agonist
activity at the NOP receptor, but no significant activity at the
KOP receptor; [0097] have agonist activity at the NOP receptor, but
no significant activity at the DOP receptor; [0098] have agonist
activity at the NOP receptor, but no significant activity at the
MOP receptor as well as no significant activity at the KOP
receptor; [0099] have agonist activity at the NOP receptor, but no
significant activity at the MOP receptor as well as no significant
activity at the DOP receptor; or [0100] have agonist activity at
the NOP receptor, but no significant activity at the MOP receptor
as well as no significant activity at the KOP receptor as well as
no significant activity at the DOP receptor.
[0101] In some embodiments, preferably with respect to receptors of
the peripheral nervous system, the compounds according to the
invention have balanced agonist activity at the NOP receptor as
well as at the MOP receptor. In some embodiments, preferably with
respect to receptors of the peripheral nervous system, the
compounds according to the invention [0102] have agonist activity
at the NOP receptor as well as agonist activity at the MOP
receptor; [0103] have agonist activity at the NOP receptor as well
as agonist activity at the MOP receptor as well as agonist activity
at the KOP receptor; [0104] have agonist activity at the NOP
receptor as well as agonist activity at the MOP receptor as well as
agonist activity at the DOP receptor; [0105] can be regarded as
opioid pan agonists, i.e. have agonist activity at the NOP receptor
as well as agonist activity at the MOP receptor as well as agonist
activity at the KOP receptor as well as agonist activity at the DOP
receptor; [0106] have agonist activity at the NOP receptor as well
as agonist activity at the MOP receptor, but no significant
activity at the KOP receptor; [0107] have agonist activity at the
NOP receptor as well as agonist activity at the MOP receptor, but
no significant activity at the DOP receptor; or [0108] have agonist
activity at the NOP receptor as well as agonist activity at the MOP
receptor, but no significant activity at the KOP receptor as well
as no significant activity at the DOP receptor.
[0109] In some embodiments, preferably with respect to receptors of
the peripheral nervous system, the compounds according to the
invention have balanced agonist activity at the NOP receptor as
well as at the KOP receptor. In some embodiments, preferably with
respect to receptors of the peripheral nervous system, the
compounds according to the invention [0110] have agonist activity
at the NOP receptor as well as agonist activity at the KOP
receptor; [0111] have agonist activity at the NOP receptor as well
as agonist activity at the KOP receptor as well as agonist activity
at the MOP receptor; [0112] have agonist activity at the NOP
receptor as well as agonist activity at the KOP receptor as well as
agonist activity at the DOP receptor; [0113] have agonist activity
at the NOP receptor as well as agonist activity at the KOP
receptor, but no significant activity at the MOP receptor; [0114]
have agonist activity at the NOP receptor as well as agonist
activity at the KOP receptor, but no significant activity at the
DOP receptor; or [0115] have agonist activity at the NOP receptor
as well as agonist activity at the KOP receptor, but no significant
activity at the MOP receptor as well as no significant activity at
the DOP receptor.
[0116] In some embodiments, preferably with respect to receptors of
the peripheral nervous system, the compounds according to the
invention have balanced agonist activity at the NOP receptor as
well as at the DOP receptor. In some embodiments, preferably with
respect to receptors of the peripheral nervous system, the
compounds according to the invention [0117] have agonist activity
at the NOP receptor as well as agonist activity at the DOP
receptor; [0118] have agonist activity at the NOP receptor as well
as agonist activity at the DOP receptor, but no significant
activity at the MOP receptor; [0119] have agonist activity at the
NOP receptor as well as agonist activity at the DOP receptor, but
no significant activity at the KOP receptor; or [0120] have agonist
activity at the NOP receptor as well as agonist activity at the DOP
receptor, but no significant activity at the MOP receptor as well
as no significant activity at the KOP receptor.
[0121] In some embodiments, preferably with respect to receptors of
the peripheral nervous system, the compounds according to the
invention have selective agonist activity at the KOP receptor. In
some embodiments, preferably with respect to receptors of the
peripheral nervous system, the compounds according to the invention
[0122] have agonist activity at the KOP receptor, but no
significant activity at the MOP receptor; [0123] have agonist
activity at the KOP receptor, but no significant activity at the
NOP receptor; [0124] have agonist activity at the KOP receptor, but
no significant activity at the DOP receptor; [0125] have agonist
activity at the KOP receptor, but no significant activity at the
MOP receptor as well as no significant activity at the NOP
receptor; [0126] have agonist activity at the KOP receptor, but no
significant activity at the MOP receptor as well as no significant
activity at the DOP receptor; or [0127] have agonist activity at
the KOP receptor, but no significant activity at the MOP receptor
as well as no significant activity at the NOP receptor as well as
no significant activity at the DOP receptor.
[0128] In some embodiments, preferably with respect to receptors of
the peripheral nervous system, the compounds according to the
invention have agonist activity at the MOP receptor, agonist
activity at the KOP receptor, and antagonist activity at the DOP
receptor. In some embodiments, preferably with respect to receptors
of the peripheral nervous system, the compounds according to the
invention [0129] have agonist activity at the MOP receptor as well
as agonist activity at the KOP receptor as well as antagonist
activity at the DOP receptor; [0130] have agonist activity at the
MOP receptor as well as agonist activity at the KOP receptor as
well as antagonist activity at the DOP receptor as well as agonist
activity at the NOP receptor; [0131] have agonist activity at the
MOP receptor as well as agonist activity at the KOP receptor as
well as antagonist activity at the DOP receptor as well as
antagonist activity at the NOP receptor; or [0132] have agonist
activity at the MOP receptor as well as agonist activity at the KOP
receptor as well as antagonist activity at the DOP receptor, no
significant activity at the NOP receptor.
[0133] In some embodiments, preferably with respect to receptors of
the central nervous system, the compounds according to the
invention have selective agonist activity at the NOP receptor. In
some embodiments, preferably with respect to receptors of the
central nervous system, the compounds according to the invention
[0134] have agonist activity at the NOP receptor, but no
significant activity at the MOP receptor; [0135] have agonist
activity at the NOP receptor, but no significant activity at the
KOP receptor; [0136] have agonist activity at the NOP receptor, but
no significant activity at the DOP receptor; [0137] have agonist
activity at the NOP receptor, but no significant activity at the
MOP receptor as well as no significant activity at the KOP
receptor; [0138] have agonist activity at the NOP receptor, but no
significant activity at the MOP receptor as well as no significant
activity at the DOP receptor; or [0139] have agonist activity at
the NOP receptor, but no significant activity at the MOP receptor
as well as no significant activity at the KOP receptor as well as
no significant activity at the DOP receptor.
[0140] In some embodiments, preferably with respect to receptors of
the central nervous system, the compounds according to the
invention have selective antagonist activity at the NOP receptor.
In some embodiments, preferably with respect to receptors of the
central nervous system, the compounds according to the invention
[0141] have antagonist activity at the NOP receptor, but no
significant activity at the MOP receptor; [0142] have antagonist
activity at the NOP receptor, but no significant activity at the
KOP receptor; [0143] have antagonist activity at the NOP receptor,
but no significant activity at the DOP receptor; [0144] have
antagonist activity at the NOP receptor, but no significant
activity at the MOP receptor as well as no significant activity at
the KOP receptor; [0145] have antagonist activity at the NOP
receptor, but no significant activity at the MOP receptor as well
as no significant activity at the DOP receptor; or [0146] have
antagonist activity at the NOP receptor, but no significant
activity at the MOP receptor as well as no significant activity at
the KOP receptor as well as no significant activity at the DOP
receptor.
[0147] In some embodiments, preferably with respect to receptors of
the central nervous system, the compounds according to the
invention have antagonist activity at the NOP receptor as well as
agonist activity at the DOP receptor. In some embodiments,
preferably with respect to receptors of the central nervous system,
the compounds according to the invention [0148] have antagonist
activity at the NOP receptor as well as agonist activity at the DOP
receptor; [0149] have antagonist activity at the NOP receptor as
well as agonist activity at the DOP receptor, but no significant
activity at the MOP receptor; [0150] have antagonist activity at
the NOP receptor as well as agonist activity at the DOP receptor,
but no significant activity at the KOP receptor; or [0151] have
antagonist activity at the NOP receptor as well as agonist activity
at the DOP receptor, but no significant activity at the MOP
receptor as well as no significant activity at the KOP
receptor.
[0152] For the purpose of the specification, "no significant
activity" means that the activity (agonist/antagonist) of the given
compound at this receptor is lower by a factor of 1000 or more
compared to its activity (agonist/antagonist) at one or more of the
other opioid receptors.
[0153] A further aspect of the invention relates to the compounds
according to the invention as medicaments.
[0154] A further aspect of the invention relates to the compounds
according to the invention for use in the treatment of pain. A
further aspect of the invention relates to a method of treating
pain comprising the administration of a pain alleviating amount of
a compound according to the invention to a subject in need thereof,
preferably to a human. The pain is preferably acute or chronic. The
pain is preferably nociceptive or neuropathic.
[0155] A further aspect of the invention relates to the compounds
according to the invention for use in the treatment of
neurodegenerative disorders, neuroinflammatory disorders,
neuropsychiatric disorders, and substance abuse/dependence. A
further aspect of the invention relates to a method of treating any
one of the aforementioned disorders, diseases or conditions
comprising the administration of a therapeutically effective amount
of a compound according to the invention to a subject in need
thereof, preferably to a human.
[0156] Another aspect of the invention relates to a pharmaceutical
composition which contains a physiologically acceptable carrier and
at least one compound according to the invention.
[0157] Preferably, the composition according to the invention is
solid, liquid or pasty; and/or contains the compound according to
the invention in an amount of from 0.001 to 99 wt. %, preferably
from 1.0 to 70 wt. %, based on the total weight of the
composition.
[0158] The pharmaceutical composition according to the invention
can optionally contain suitable additives and/or auxiliary
substances and/or optionally further active ingredients.
[0159] Examples of suitable physiologically acceptable carriers,
additives and/or auxiliary substances are fillers, solvents,
diluents, colorings and/or binders. These substances are known to
the person skilled in the art (see H. P. Fiedler, Lexikon der
Hilfsstoffe fur Pharmazie, Kosmetik and angrenzende Gebiete, Editio
Cantor Aulendoff).
[0160] The pharmaceutical composition according to the invention
contains the compound according to the invention in an amount of
preferably from 0.001 to 99 wt. %, more preferably from 0.1 to 90
wt. %, yet more preferably from 0.5 to 80 wt. %, most preferably
from 1.0 to 70 wt. % and in particular from 2.5 to 60 wt. %, based
on the total weight of the pharmaceutical composition.
[0161] The pharmaceutical composition according to the invention is
preferably for systemic, topical or local administration,
preferably for oral administration.
[0162] Another aspect of the invention relates to a pharmaceutical
dosage form which contains the pharmaceutical composition according
to the invention.
[0163] In one preferred embodiment, the pharmaceutical dosage form
according to the invention is produced for administration twice
daily, for administration once daily or for administration less
frequently than once daily. Administration is preferably systemic,
in particular oral.
[0164] The pharmaceutical dosage form according to the invention
can be administered, for example, as a liquid dosage form in the
form of injection solutions, drops or juices, or as a semi-solid
dosage form in the form of granules, tablets, pellets, patches,
capsules, plasters/spray-on plasters or aerosols. The choice of
auxiliary substances etc. and the amounts thereof to be used depend
on whether the form of administration is to be administered orally,
perorally, parenterally, intravenously, intraperitoneally,
intradermally, intramuscularly, intranasally, buccally, rectally or
locally, for example to the skin, the mucosa or into the eyes.
[0165] Pharmaceutical dosage forms in the form of tablets, dragees,
capsules, granules, drops, juices and syrups are suitable for oral
administration, and solutions, suspensions, readily reconstitutable
dry preparations and also sprays are suitable for parenteral,
topical and inhalatory administration. Compounds according to the
invention in a depot, in dissolved form or in a plaster, optionally
with the addition of agents promoting penetration through the skin,
are suitable percutaneous administration preparations.
[0166] The amount of the compounds according to the invention to be
administered to the patient varies in dependence on the weight of
the patient, on the type of administration, on the indication and
on the severity of the disease. Usually, from 0.00005 mg/kg to 50
mg/kg, preferably from 0.001 mg/kg to 10 mg/kg, of at least one
compound according to the invention is administered.
[0167] Another aspect of the invention relates to a process for the
preparation of the compounds according to the invention. Suitable
processes for the synthesis of the compounds according to the
invention are known in principle to the person skilled in the
art.
[0168] Preferred synthesis routes are described below:
[0169] The compounds according to the invention can be obtained via
different synthesis routes. Depending on the synthesis route,
different intermediates are prepared and subsequently further
reacted.
[0170] In a preferred embodiment, the synthesis of the compounds
according to the invention proceeds via a synthesis route which
comprises the preparation of an intermediate according to general
formula (IIIa):
##STR00024##
wherein R.sup.1, R.sup.2 and R.sup.3 are defined as above.
[0171] In another preferred embodiment, the synthesis of the
compounds according to the invention proceeds via a synthesis route
which comprises the preparation of an intermediate according to
general formula (IIIb):
##STR00025##
wherein R.sup.1, R.sup.2 and R.sup.3 are defined as above and PG is
a protecting group.
[0172] Preferably the protecting group is -p-methoxybenzyl.
Therefore, in another preferred embodiment, the synthesis of the
compounds according to the invention proceeds via a synthesis route
which comprises the preparation of an intermediate according to
general formula (IIIc):
##STR00026##
wherein R.sup.1, R.sup.2 and R.sup.3 are defined as above.
[0173] As already indicated, in general formula (IIIc), the
-p-methoxybenzyl moiety represents a protecting group which can be
cleaved in the course of the synthesis route.
[0174] In yet another preferred embodiment, the synthesis of the
compounds according to the invention proceeds via a synthesis route
which comprises the preparation of [0175] an intermediate according
to general formula (IIIa) and according to general formula (IIIb);
or [0176] an intermediate according to general formula (IIIa) and
according to general formula (IIIc); or [0177] an intermediate
according to general formula (IIIb) and according to general
formula (IIIc); or [0178] an intermediate according to general
formula (IIIa), according to general formula (IIIb) and according
to general formula (IIIc).
[0179] The following examples further illustrate the invention but
are not to be construed as limiting its scope.
EXAMPLES
[0180] "RT" means room temperature (23.+-.7.degree. C.), "M" are
indications of concentration in mol/l, "aq." means aqueous,
"anhydr." means anhydrous, "sat." means saturated, "sol." means
solution, "conc." means concentrated.
[0181] Further abbreviations:
brine saturated aqueous sodium chloride solution CC column
chromatography cHex cyclohexane DCM dichloromethane
DIPEA N,N-diisopropylethylamine
DMF N,N-dimethylformamide
[0182] EDCl 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Et ethyl
ether diethyl ether EE ethyl acetate EtOAc ethyl acetate EtOH
ethanol h hour(s) H.sub.2O water HATU
O-(7-aza-benzotriazol-1-yl)-N,N,N',N'-tetramethyluroniumhexafluorophospha-
te LDA Lithium-di-isoproyl-amid Me methyl m/z mass-to-charge ratio
MeOH methanol MeCN acetonitrile min minutes MS mass spectrometry
NBS N-bromo-succinimide NEt.sub.3 triethylamine Pd.sub.2(dba).sub.3
tris(dibenzylideneacetone)dipalladium(0) PE petroleum ether
(60-80.degree. C.) RM reaction mixture RT room temperature T3P
2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide
tBME tert-butyl methyl ether THF tetrahydrofuran TFA
trifluoroacetic acid v/v volume to volume w/w weight to weight
XantPhos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
[0183] The yields of the compounds prepared were not optimised. All
temperatures are uncorrected.
[0184] 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.RTM. Available Chemicals Database of MDL, San Ramon,
US or the SciFinder.RTM. 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.RTM. Database of Elsevier,
Amsterdam, NL or the SciFinder.RTM. Database of the ACS, Washington
D.C., US, repspectively, for example) or can be prepared using the
conventional methods known to the person skilled in the art.
[0185] The mixing ratios of solvents or eluents for chromatography
are specified in v/v.
[0186] All the intermediate products and exemplary compounds were
analytically characterised by mass spectrometry (MS, m/z for
[M+H]+). In addition .sup.1H-NMR and .sup.13C spectroscopy was
carried out for all the exemplary compounds and selected
intermediate products.
[0187] Remark Regarding Stereochemistry
[0188] 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:
##STR00027##
[0189] 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:
##STR00028##
[0190] Synthesis of Intermediates
Synthesis of INT-799:
CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazas-
piro[4.5]decan-2-one
##STR00029##
[0191] Step 1:
CIS-1-((1-(benzyloxy)cyclobutyl)methyl)-3-(3,4-dimethoxybenzyl)-8-(dimeth-
ylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
[0192] 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.degree. 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.degree. C. The reaction completion was monitored by TLC. The
reaction mixture was diluted with water (500 mL) and extracted with
diethyl ether (4.times.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-(dimeth-
ylamino)-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
[0193] TFA (12 mL) was added to
CIS-1-((1-(benzyloxy)cyclobutyl)methyl)-3-(3,4-dimethoxybenzyl)-8-(dimeth-
ylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (2.5 g, 4.18 mmol)
at 0.degree. C. and the resulting mixture was stirred at 70.degree.
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.times.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-diazas-
piro[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)-met-
hyl]-cyclobutane-1-carbonitrile
##STR00030##
[0194] Step 1:
1-((CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-8-phenyl-1,3-diazaspi-
ro[4.5]decan-1-yl)methyl)cyclobutanecarbonitrile
[0195] 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.degree. C. portionwise over 10 min.
1-(Bromomethyl)cyclobutanecarbonitrile (4.4 g, 25.44 mmol) was
added dropwise over 10 minutes at 0.degree. 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.times.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-diazaspi-
ro[4.5]decan-1-yl)methyl)cyclobutanecarbonitrile 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
[0196] TFA (100 mL) was added to
1-((CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-8-phenyl-1,3-diazaspi-
ro[4.5]decan-1-yl)methyl)cyclobutanecarbonitrile (5 g, 10.28 mmol)
at 0.degree. 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.times.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)me-
thyl) 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
[0197] Thionyl chloride (35 mL) was added to
1-((cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)me-
thyl)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.times.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)-met-
hyl]-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)-m-
ethyl]-1,3-diazaspiro[4.5]decan-2-one
##STR00031##
[0199] 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.degree. 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.times.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)-m-
ethyl]-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
##STR00032##
[0200] Step 1:
1-Cyclobutylmethyl-3-(4-methoxy-benzyl)-9,12-dioxa-1,3-diaza-dispiro[4.2.-
4.2]tetradecan-2-one
[0201] To a stirred solution of
3-(4-methoxy-benzyl)-9,12-dioxa-1,3-diaza-dispiro[4.2.4.2]tetradecan-2-on-
e (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.times.200 ml). The combined organic phase was dried
over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The
resulting residue was purified column chromatography (neutral
aluminum oxide, EtOAc-petroleum ether (2:8)) to give
1-cyclobutylmethyl-3-(4-methoxy-benzyl)-9,12-dioxa-1,3-diaza-dispiro[4.2.-
4.2]tetradecan-2-one (2.4 g, 50%, white solid). TLC system:
EtOAc-pet ether (6:4); R.sub.f=0.48.
Step 2:
1-Cyclobutylmethyl-3-(4-methoxy-benzyl)-1,3-diaza-spiro[4.5]decane-
-2,8-dione
[0202] To a stirred solution of
1-cyclobutylmethyl-3-(4-methoxy-benzyl)-9,12-dioxa-1,3-diaza-dispiro[4.2.-
4.2]tetradecan-2-one (1 g, 2.5 mmol) in MeOH (7 ml) was added 10%
aq. HCl (8 ml) at 0.degree. 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.times.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-di-
one (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
[0203] 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.degree. C. (ice bath). A solution of
1-cyclobutylmethyl-3-(4-methoxy-benzyl)-1,3-diaza-spiro[4.5]decane-2,8-di-
one (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.degree. 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.times.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-methoxyben-
zyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
[0204] 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 (.about.0.degree. C.) and a solution of
phenylmagnesium bromide (26 ml, .about.2M in THF) was added slowly
at 0.degree. C.-5.degree. 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.times.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-phe-
nyl-1,3-diazaspiro[4.5]decan-2-one
[0205] 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.degree. C.-5.degree. C. The
reaction mixture was warmed to RT and stirred for 20 h, then
quenched with methanolic NH.sub.3 (10 ml, .about.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
##STR00033##
[0206] Step 1: Ethyl
5-cyano-2-oxo-5-(pyridin-2-yl)cyclohexanecarboxylate
[0207] 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.degree. C. and
stirred for 16 h at RT. The reaction mixture was quenched with sat.
aq. NH.sub.4Cl and extracted with EtOAc (2.times.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
[0208] 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.degree. C. The reaction mixture was
heated to 100.degree. 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.times.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
##STR00034##
[0209] Step 1:
8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile
[0210] 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.degree. 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.times.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
[0211] 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.degree. 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
[0212] 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.degree. 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.times.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
[0213] 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.degree.
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.times.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
[0214] 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.degree. 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.times.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
##STR00035##
[0215] Step 1: 8-(Dimethylamino)-1,4-dioxaspiro 4.5]
decane-8-carbonitrile
[0216] 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.times.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
[0217] 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.degree. C. under argon atmosphere. The reaction
mixture was stirred for 4 h at -10.degree. C. to 0.degree. C. and
then at RT for 18 h. The reaction completion was monitored by TLC.
The reaction mixture was cooled to 0.degree. C., diluted with sat.
aq. NH.sub.4Cl (1 L) and extracted with EtOAc (2.times.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
[0218] 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.degree. 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.times.150 mL). The
aqueous layer was basified to pH 10 with solid NaOH and extracted
with ethyl acetate (2.times.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
##STR00036##
[0219] Step 1: 9,12-Dioxa-2,4-diazadispiro[4.2.4 {8}.2
{5}]tetradecane-1,3-dione
[0220] 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.degree. C. for 16 h. The reaction
completion was monitored by TLC. The reaction mixture was cooled to
0.degree. 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
{8}.2 {5}]tetradecane-1,3-dione. The filtrate was extracted with
DCM (2.times.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 {8}.2 {5}]tetradecane-1,3-dione
(TLC system: 10% Methanol in DCM; Rf: 0.4).
Step 2:
2-[(4-Methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4
{8}.2 {5}] tetradecane-1,3-dione
[0221] 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.times.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
{8}.2 {5}]tetradecane-1,3-dione as an off white solid (TLC system:
10% MeOH in DCM; Rf: 0.6).
Step 3:
2-[(4-Methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4
{8}.2 {5}] tetradecan-3-one
[0222] 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.degree. 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
{8}.2 {5}]tetradecane-1,3-dione (150 g, 433.05 mmol) was added at
0.degree. 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.degree. C., quenched with sat. aq. NaHCO.sub.3 (500 mL)
and filtered through celite pad. The filtrate was extracted with
EtOAc (2.times.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 {8}
.2 {5}]tetradecan-3-one as an off-white solid. (TLC system: 10%
MeOH in DCM, Rf: 0.5).
Step 4:
3-[(4-Methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decane-2,8-dione
[0223] A solution of
2-[(4-methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4
{8}.2 {5}] tetradecan-3-one (120 g, 361.03 mmol) in 6N aq. HCl (2.4
L) was stirred at 0.degree. 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.times.2.0 L). The aqueous layer was basified
to pH 10 with 50% aq. NaOH and then extracted with DCM (2.times.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-metho-
xyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one
##STR00037##
[0224] Step 1:
CIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazasp-
iro[4.5]decan-2-one
[0225] 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-(meth-
oxymethoxy)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
[0226] TFA (0.2 mL) was added to the solution of
CIS-1-(cyclobutylmethyl)-8-(dimethylamino)-3-(4-methoxybenzyl)-8-(3-metho-
xyphenyl)-1,3-diazaspiro[4.5]decan-2-one (300 mg, 0.57 mmol) in DCM
(1.5 mL) at 0.degree. C. The reaction mixture was stirred at
0.degree. 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.times.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-metho-
xyphenyl)-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-d-
iazaspiro[4.5]decan-2-one
##STR00038##
[0227] Step 1:
8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-c-
arbonitrile
[0228] 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.times.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]d-
ecane-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
[0229] 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-c-
arbonitrile (15 g, 43.83 mmol) in THF (300 mL) at 0.degree. 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.degree. C., quenched with sat. aq.
NH.sub.4Cl (200 mL) and the organic product was extracted with
EtOAc (2.times.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.times.2 and 5
g.times.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-d-
iazaspiro[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
##STR00039##
[0231] 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.times.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.times.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
##STR00040##
[0232] Step 1:
8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decane-2,4-dione
[0233] 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.degree. C. for 18 h. The
reaction mixture was cooled to 0.degree. 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
[0234] 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.degree. C.
under argon atmosphere. The reaction mixture was stirred for 4 h at
60.degree. C. The reaction completion was monitored by TLC. The
reaction mixture was cooled to 0.degree. 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
[0235] 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)-acet-
ic acid; 2,2,2-trifluoro-acetic acid salt
##STR00041##
[0236] Step 1:
CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5] decan-1-yl]-acetic acid tert-butyl ester
[0237] 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.degree. C. and treated with LDA solution (2M in
THF/heptane/ether, 25.4 mL, 50.8 mmol). The resulting mixture was
was allowed to warm up to RT over 30 min. The solution was then
cooled to 0.degree. 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.times.). 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-phen-
yl-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-y-
l)-acetic acid trifluoroacetic acid salt
[0238]
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
##STR00042##
[0240]
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.times.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-diazasp-
iro[4.5]decan-2-one
##STR00043##
[0241] Step 1:
CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-1-((1-methylcyclobutyl)methyl)--
8-phenyl-1,3-diazaspiro[4.5]decan-2-one
[0242] 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.degree. C. The reaction mixture was heated to 60.degree. C.
for 16 h. After cooling down to RT, water (100 mL) was added and
the mixture was extracted with DCM (3.times.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
[0243] To the solution of
CIS-8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-8-phenyl-1,3-diazasp-
iro [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-diazasp-
iro[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
##STR00044##
[0244] Step 1:
CIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazasp-
iro[4.5]decan-2-one
[0245] 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-diazasp-
iro [4.5]decan-2-one.
Step 2:
CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diaz-
aspiro[4.5]decan-2-one
[0246] In analogy to the method described for INT-982 step 2
CIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazasp-
iro[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
##STR00045##
[0247] Step 1:
CIS-3-benzyl-1-(cyclobutylmethyl)-8-(methylamino)-8-phenyl-1,3-diazaspiro-
[4.5]decan-2-one
[0248] 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.times.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.times.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
[0249] 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.times.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-dia-
zaspiro [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-diaz-
aspiro[4.5]decan-2-one (INT-986)
[0250] Sodium metal (1.18 g, 51.68 mmol, 10 equiv.) was added to
liquid ammonia (.about.25 mL) at -78.degree. C. The resulting
mixture was stirred for 10 min at -78.degree. C. A solution of
CIS-3-benzyl-1-(cyclobutylmethyl)-8-(ethyl(methyl)amino)-8-phenyl-1,3-dia-
zaspiro[4.5]decan-2-one (2.3 g, 5.16 mmol) in THF (25 mL) was added
at -78.degree. 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.times.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]+ 356.3
Synthesis of INT-987:
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]dec-
an-2-one
##STR00046##
[0252] In analogy to the method as described for INT-982 step 2
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[(4-methoxyphenyl)-m-
ethyl]-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]dec-
an-2-one (INT-987).
Synthesis of INT-988:
CIS-8-(dimethylamino)-1-(2-(1-methoxycyclobutyl)ethyl)-8-phenyl-1,3-diaza-
spiro[4.5]decan-2-one
##STR00047##
[0253] Step 1:
CIS-8-(dimethylamino)-1-[2-(1-methoxycyclobutyl)ethyl]-3-[(4-methoxypheny-
l)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
[0254] 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.degree. C. The reaction mixture was quenched with
water and extracted with DCM (3.times.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)me-
thyl]-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)
[0255] In analogy to the method described for INT-982 step 2
CIS-8-(dimethylamino)-1-[2-(1-methoxycyclobutyl)ethyl]-3-[(4-methoxypheny-
l)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-diaza-
spiro[4.5] decan-2-one (INT-988). Mass: m/z 386.3 (M+H).sup.+.
Synthesis of INT-992:
CIS-2-[8-Dimethylamino-1-(2-methyl-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[-
4.5]decan-3-yl]-acetic acid
##STR00048##
[0257]
CIS-8-Dimethylamino-1-(2-methyl-propyl)-8-phenyl-1,3-diazaspiro[4.5-
]decan-2-one (INT-241) (0.9 g, 2.73 mmol) was added to a solution
of NaH (60 wt % in mineral oil, 1.64 g, 41.03 mmol) in DMF (20 mL)
at RT. The reaction mixture was stirred at RT for 15 min, then
cooled to 0.degree. C. and ethyl 2-bromoacetate (4.56 g, 27.35
mmol) was added dropwise. The resulting mixture was stirred at RT
for 2 days. The reaction completion was monitored by TLC. The
reaction mixture was quenched with water and concentrated under
reduced pressure. The residue was diluted with small amount of
water and acidified by acetic acid. The resulting mixture was
concentrated under reduced pressure again. The crude product was
purified by silica gel flash chromatography using 230-400 mesh (25
vol % MeOH in DCM) to afford 1.1 g of
CIS-2-[8-dimethylamino-1-(2-methyl-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[-
4.5]decan-3-yl]-acetic acid (INT-992) as a solid. [M+H].sup.+
388.3
Synthesis of INT-994:
CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl]-acetic acid
##STR00049##
[0258] Step 1: ethyl
2-(cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3
yl)acetate
[0259] KOtBu (1M in THF) (54.90 mL, 54.95 mmol) was added to a
solution of
CIS-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
(INT-976) (10 g, 36.63 mmol) in THF (950 mL) under argon atmosphere
at 0.degree. C. and the reaction mixture was stirred for 15 min. A
solution of ethyl bromoacetate (5.06 mL, 43.96 mmol) in THF (50 mL)
was added. The reaction mixture was warmed up to RT and stirred for
48 h. The reaction completion was monitored by TLC. Solvent was
evaporated under reduced pressure and the crude product was
purified by column chromatography to yield the desired product in 2
fractions: fraction 1: 2.2 g ethyl
2-(cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)ace-
tate (68% pure according to LCMS) as an off-white solid and
Fraction 2: 3.2 g of ethyl
2-(cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)ace-
tate (32% pure according to LCMS) as well as 1.1 g of unreacted
starting material. Fraction 1 was used further without additional
purification.
Step 2:
2-(cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-
-yl)acetic acid
[0260] A mixture of
ethyl-2-(CIS-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3--
yl)acetate (68% pure, 2.2 g, 6.128 mmol) and powdered NaOH (981 mg,
24.513 mmol) in toluene (40 mL) was stirred at 80.degree. C. for 3
h under argon atmosphere. Ester hydrolysis was monitored by LCMS.
Toluene was evaporated under reduced pressure and the resulting
crude product (2.4 g) was further purified by reverse phase prep.
HPLC to yield 0.93 g of
2-(CIS-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)ace-
tic acid.
Step 3:
2-(cis-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-p-
henyl-1,3-diazaspiro[4.5]decan-3-yl)acetic acid
[0261] To a solution of
2-(CIS-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)ace-
tic acid (1.5 g, 4.532 mmol) in toluene (45 mL) was added in one
portion powdered NaOH (725.08 mg, 18.127 mmol) under argon
atmosphere at RT. The reaction mixture was stirred at 80.degree. C.
for 4 h. Toluene was evaporated under reduced pressure to get the
residue which was dissolved in DMSO (45 mL) under argon atmosphere.
The solution was stirred at 55.degree. C. for 1 h. To the reaction
mixture was added dropwise a solution of 1-oxaspiro[2.3]hexane
(1.144 g, 13.596 mmol) in DMSO (12 mL) via syring pump (flow rate
10 mL/h). The reaction mixture was stirred at 55.degree. C. for 65
h. The reaction progress was monitored by LCMS. DMSO was evaporated
in vacuo. The residue was dissolved in water (50 mL), cooled to
0.degree. C. and pH was adjusted to 3-4 with acetic acid. The
resulting mixture was concentrated under reduced pressure and the
crude product was purified by column chromatography (elution with
8-10% MeOH in DCM) to yield 750 mg (78%) of
2-(cis-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl)acetic acid (INT-994) as an off-white
solid. [M+H].sup.+ 416.2
Synthesis of INT-998:
CIS-2-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,-
3-diazaspiro[4.5]decan-3-yl]-acetic acid; 2,2,2-trifluoro-acetic
acid salt
##STR00050##
[0262] Step 1: CIS-tert-butyl
2-[8-(dimethylamino)-1-[(1-methylcyclobutyl)methyl]-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]acetate
[0263]
CIS-8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-8-phenyl-1,3-d-
iazaspiro[4.5]decan-2-one (INT-982) (2.8 g, 7.9 mmol) was dissolved
in THF (110 mL) and the solution was cooled to 0.degree. C. Lithium
diisopropylamide solution in THF/heptane/ethylbenzene (2M, 16 mL)
was added dropwise. The reaction mixture was stirred for 30 min and
t-butyl-bromoacetate was added dropwise at the same temperature.
The reaction mixture was concentrated in vacuo, water was added and
the resulting mixture was extracted with DCM (3.times.250 mL). The
combined organic layers were dried over Na.sub.2SO.sub.4,
concentrated in vacuo and the residue was purified by flash
chromatography to yield CIS-tert-butyl
2-[8-(dimethylamino)-1-[(1-methylcyclobutyl)methyl]-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]acetate (1670 mg) as a white solid.
Step 2:
CIS-2-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-ph-
enyl-1,3-diazaspiro[4.5]decan-3-yl]-acetic acid;
2,2,2-trifluoro-acetic acid salt
[0264] CIS-tert-butyl
2-[8-(dimethylamino)-1-[(1-methylcyclobutyl)methyl]-2-oxo-8-phenyl-1,3-di-
aza-spiro[4.5]decan-3-yl]acetat (2250 mg, 4.8 mmol) was treated
with TFA (18 mL) at RT. After stirring for 10 min, all volatiles
were removed in vacuo. The residue was triturated with diethyl
ether (30 mL) using ultrasonic bath, the solid rest was dried under
reduced pressure to yield
CIS-2-[8-dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,-
3-diazaspiro [4.5]decan-3-yl]-acetic acid; 2,2,2-trifluoro-acetic
acid salt (INT-998) (2.2 g) as a brown solid. [M+H].sup.+ 413.3
Synthesis of INT-1008:
CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one
##STR00051##
[0265] Step 1 and step 2:
ethyl-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-amine hydrochloride
(INT-1004)
[0266] A mixture of 1,4-dioxa-spiro[4.5]decan-8-one (25.0 g, 160.25
mmol, 1.0 eq.) and 2M solution of EtNH.sub.2 in THF (200 ml, 2.5
eq. 400.64 mmol) in EtOH (30 mL) was stirred at RT for 48 h. The
reaction mixture was concentrated under argon atmosphere. The
residue was diluted with ether (60 mL) and added to the freshly
prepared PhLi solution [prepared by addition of 2.5M n-BuLi in THF
(70.5 mL, 1.1 eq. 176.27 mmol) to a solution of bromobenzene
(27.675 g, 1.1 eq. 176.275 mmol) in ether (100 mL) at -30.degree.
C. and stirred at RT for 1 h] at RT. The reaction mixture was
stirred at RT for 1.5 h, then cooled down to 0.degree. C. and
quenched with sat. aq. NH.sub.4Cl (100 mL). The resulting mixture
was extracted with EtOAc (2.times.750 mL), combined organic
extracts were washed with water (3.times.350 mL), brine (300 mL),
dried over Na.sub.2SO.sub.4 and concentrated under reduced
pressure. The crude product was dissolved in ethylmethyl ketone
(100 mL) and TMSCl (37.5 mL) was added at 0.degree. C. The reaction
mixture was stirred at RT for 16 h, the precipitate formed was
filtered off and washed with acetone and THF to give
ethyl-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-amine hydrochloride
as an off-white solid. This reaction was done in 2 batches of 25 g
scale and the yield is given for 2 combined batches. Yield: 18%
(17.1 g, 57.575 mmol). LCMS: m/z 262.2 (M+H).sup.+.
Step 3: 4-ethylamino-4-phenyl-cyclohexanone (INT-1005)
[0267] To a solution of
ethyl-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-amine hydrochloride
(10.1 g, 34.0 mmol, 1 eq.) in water (37.5 mL) was added conc. HCl
(62.5 mL) at 0.degree. C. and the reaction mixture was stirred at
RT for 16 h. The reaction mixture was basified with 1N aq. NaOH to
pH .about.14 at 0.degree. C. and extracted with DCM (2.times.750
mL). Organic layer was washed with water (400 mL), brine (400 mL),
dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure
to yield 4-ethylamino-4-phenyl-cyclohexanone which was used in the
next step without further purification. This reaction was carried
out in another batch of 15.1 g scale and yield is given for 2
combined batches. Yield: 92% (17.0 g, 78.34 mmol).
Step 4: mixture of CIS- and
TRANS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione
(INT-1006 and INT-1007)
[0268] To a solution of 4-ethylamino-4-phenyl-cyclohexanone (17 g,
78.341 mmol, 1.0 eq.) in EtOH (250 mL) and water (200 mL) was added
(NH.sub.4).sub.2CO.sub.3 (18.8 g, 195.85 mmol, 2.5 eq.) and the
reaction mixture was stirred at RT for 15 min. KCN (5.09 g, 78.341
mmol, 1.0 eq.) was and the resulting mixture was stirred at
60.degree. C. for 18 h. The reaction mixture was cooled to RT, the
precipitate was filtered off, washed with water (250 mL), EtOH (300
mL), hexane (200 mL) and dried under reduced pressure to yield CIS-
and TRANS-mixture
8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (13.0 g,
45.29 mmol, 58%) as a white solid. Yield: 58% (13 g, 45.296 mmol).
LC-MS: m/z [M+1].sup.+=288.2.
Step 5:
CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione
(INT-1006)
[0269] To a solution of cis and trans mixture of
8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (12 g)
in MeOH/DCM (1:1 v/v, 960 mL) was added a solution of L-tartaric
acid in MeOH (25 mL). The resulting mixture was stirred at RT for 2
h and then kept in refrigerator for 16 h. The solid material was
filtered off and washed with MeOH/DCM (1:5, 50 ml) to get
8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione tartrate
(7.5 g) as a white solid. The solid was suspended in sat. aq.
NaHCO.sub.3 (pH-8) and the resulting mixture was extracted with 25%
MeOH-DCM (2.times.800 ml). Combined organic extracts were washed
with water (300 ml), brine (300 ml) and dried over anhydrous
Na.sub.2SO.sub.4. The solvent was evaporated under reduced pressure
and the residue was triturated with 20% DCM-hexane to afford
CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione as a
white solid. This step was done in 2 batches (12 g & 2.4 g) and
yield is given for 2 combined batches. Yield: 31.2% (5.0 g, 17.421
mmol). LC-MS: m/z [M+1].sup.+=288.0.
Step 6: CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one
(INT-1008)
[0270] To a slurry of LiAlH.sub.4 (793 mg, 20.905 mmol, 3.0 eq.) in
THF (15 mL) was added a suspension of
cis-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (2.0
g, 6.968 mmol, 1.0 eq.) in THF (60 mL) at 0.degree. C. and the
reaction mixture was stirred at 65.degree. C. for 16 h. The
resulting mixture was cooled to 0.degree. C., quenched with sat.
aq. Na.sub.2SO.sub.4 (20 ml), stirred at RT for 1 h and filtered
through celite. The celite layer was washed with 15% MeOH-DCM (500
ml). The combined filtrate was dried over anhydrous
Na.sub.2SO.sub.4 and concentrated under reduced pressure. The
resulting crude product was triturated with 15% DCM-Hexane to
afford CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one
(INT-1008) (1.6 g, 5.86 mmol, 84%) as a white solid. Yield: 84%
(1.6 g, 5.86 mmol). LC-MS: m/z [M+H].sup.+=274.2.
Synthesis of INT-1019:
CIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl)acetic acid hydrochloride
##STR00052##
[0271] Step 1: tert-butyl
CIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl)acetate
[0272] The solution of
CIS-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-1,3-diazas-
piro[4.5]decan-2-one (INT-799) (1.8 g, 5.042 mmol) in THF (40 mL)
was cooled down to 0.degree. C. and KOtBu (1 M in THF, 5.55 mL,
5.546 mmol) was added. The resulting mixture was stirred for 10 min
followed by the dropwise addition of tert-butyl bromoacetate (1.081
g, 5.546 mmol). The ice bath was removed and the reaction mixture
was stirred for 2 h, then quenched with sat. aq. NH.sub.4Cl (40 mL)
and extracted with EtOAc (2.times.80 mL). The combined organic
extracts were dried over anhydr. Na.sub.2SO.sub.4 and concentrated
under reduced pressure. Crude product was purified by column
chromatography (silica gel 100-200 mesh, 0-4% MeOH in DCM as
eluent) to afford 1.7 g of tert-butyl
CIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl)acetate as an off white solid.
Step 2:
CIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-p-
henyl-1,3-diazaspiro[4.5]decan-3-yl)acetic acid hydrochloride
[0273] 4N HCl in dioxane (30 mL) was added to the solution of
tert-butyl
CIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl)acetate (1.7 g, 3.609 mmol) in 1,4
dioxane (10 mL). The resulting mixture was stirred at RT for 16 h
and then concentrated under reduced pressure to afford 1.5 g of
CIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl)acetic acid hydrochloride (INT-1019)
as a hygroscopic solid. TLC R.sub.f (10% MeOH in DCM)=0.2. LC-MS:
m/z [M+H].sup.+=416.3.
Synthesis of INT-1020: sodium
CIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2,4-dioxo-8-phen-
yl-1,3-diazaspiro[4.5]decan-3-yl)acetate
##STR00053##
[0274] Step 1: tert-butyl
CIS-2-(8-(dimethylamino)-2,4-dioxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl-
)acetate
[0275] To the suspension of tert-butyl
CIS-2-(8-(dimethylamino)-2,4-dioxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl-
)acetate (INT-1018) (0.5 g, 1.74 mmol) in DMF (11 mL) was added
portionwise sodium hydride (60% in mineral oil, 70 mg, 1.74 mmol, 1
equiv.). The reaction mixture was stirred until the evolution of
hydrogen was over and a clear solution was formed (ca. 40 min).
Tert-butyl bromoacetate (257 .mu.L, 1.74 mmol, 1 equiv.) was added,
the reaction mixture was stirred at RT overnight, quenched with ca.
40 mL water and stirred for 2 h. The precipitate was filtered off,
washed with water, hexane and dried under reduced pressure to give
tert-butyl
CIS-2-(8-(dimethylamino)-2,4-dioxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl-
)acetate (653 mg, 93%) which was used further without additional
purification. LC-MS: m/z [M+H].sup.+=402.2.
Step 2: sodium
CIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2,4-dioxo-8-phen-
yl-1,3-diazaspiro[4.5]decan-3-yl)acetate (INT-1020)
[0276] Sodium hydroxide (135 mg, 3.37 mmol, 4 equiv.) was suspended
in dimethyl sulfoxide (1.8 mL, 25.26 mmol, 30 equiv.) and the
mixture was stirred at RT for 10 min. Tert-butyl
CIS-2-(8-(dimethylamino)-2,4-dioxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl-
)acetate (338 mg, 0.84 mmol, 1 equiv.) was added, the reaction
mixture was stirred 5 min at RT and then heated up to 50.degree. C.
[1-[Tert-butyl(dimethyl)silyl]oxycyclobutyl]methyl
4-methylbenzenesulfonate (936 mg, 2.53 mmol, 3 equiv.) was added
and the reaction mixture was stirred at 60.degree. C. for 3 days.
The resulting mixture was cooled down to RT, diluted with water (5
mL), extracted with EtOAc (1.times.10 mL) and the aqueous phase was
concentrated under reduced pressure to give crude sodium
CIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2,4-dioxo-8-phen-
yl-1,3-diazaspiro[4.5]decan-3-yl)acetate (INT-1020) (473 mg) which
was used in the next step without further purification. LC-MS: m/z
[M+H].sup.+=452.2.
Synthesis of INT-1026:
CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro-
[4.5]decan-2-one
##STR00054##
[0277] Step 1:
2-methyl-N-(1,4-dioxaspiro[4.5]decan-8-ylidene)propane-2-sulfinamide
[0278] 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.degree. 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.times.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-sulfi-
namide
[0279] 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.degree. C. under argon
atmosphere. The reaction mixture was stirred for 2 h at -10.degree.
C. to 0.degree. C. The reaction completion was monitored by TLC.
The reaction mixture was quenched with sat. aq. NH.sub.4Cl (50 mL)
at 0.degree. C. and the organic product was extracted with EtOAc
(3.times.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
[0280] 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.degree. 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
[0281] 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.degree. C. The reaction mixture was stirred at RT for 16 h. The
reaction mixture was concentrated in vacuo at 30.degree. C. and to
the residue sat. aq. NaHCO.sub.3 was added. The organic product was
extracted with DCM (3.times.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-amin-
e 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)
[0282] 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-amin-
e (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.degree. 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.times.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]dec-
an-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-phenylcyclohexanon-
e
[0283] 5% sulfuric acid in water (25 mL) was added to
N-methyl-8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]dec-
an-8-amine (2.50 g, 7.55 mmol) at 0.degree. 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.times.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-diazasp-
iro[4.5]decane-2,4-dione
[0284]
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.degree. C. for 16 h. The reaction mixture
was diluted with ice-water and the organic product was extracted
with DCM (2.times.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-dia-
zaspiro[4.5]decane-2,4-dione
[0285] 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-diazaspir-
o[4.5]decane-2,4-dione) and 60 mg of isomer 2
(TRANS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazasp-
iro[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 .mu.m, gradient (T/B %): 0/35, 8/55, 8.1/98, 10/98,
10.1/35, 13/35, flow rate: 25 ml/min, diluent: mobile
phase+THF.
Step 9:
CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-dia-
zaspiro[4.5]decan-2-one (INT-1026)
[0286] 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.degree. C. under argon
atmosphere. The reaction mixture was stirred at 65.degree. C. for
16 h. The mixture was cooled to 0.degree. C., quenched with sat.
aq. Na.sub.2SO.sub.4 (1000 mL) and filtered through celite pad. The
filtrate was dried over anhydrous Na.sub.2SO.sub.4 and concentrated
in vacuo. The residue was purified by column chromatography (silica
gel 230-400 mesh; 5-6% MeOH in DCM) to yield 0.3 g (78%) of
CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro-
[4.5]decan-2-one (INT-1026) as an off white solid. (TLC system: 10%
MeOH in DCM, Rf: 0.2). LC-MS: m/z [M+1].sup.+=344.2.
Synthesis of INT-1031:
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-1,3-diazaspi-
ro[4.5]decan-2-one
##STR00055##
[0287] Step 1:
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methox-
yphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one
[0288] In analogy to the method described for INT-952
CIS-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-d-
iazaspiro[4.5]decan-2-one (INT-974) was converted into
CIS-1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methox-
yphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one.
Step 2:
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-1,3-d-
iazaspiro[4.5]decan-2-one
[0289] In analogy to the method described for INT-982 step 2
1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphe-
nyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one was converted into
1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-1,3-diazaspiro[4-
.5]decan-2-one (INT-1031).
Synthesis of INT-1032:
CIS-2-[1-(cyclobutylmethyl)-8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,-
3-diazaspiro[4.5]decan-3-yl]acetic acid trifluoroacetate
##STR00056##
[0291] In analogy to the method described for INT-998 step 2
2-[1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-dia-
zaspiro[4.5]decan-3-yl]-acetic acid tert-butyl ester (SC_1346) was
converted into
2-[1-(cyclobutylmethyl)-8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-di-
azaspiro[4.5]decan-3-yl]acetic acid trifluoroacetate
(INT-10322).
Synthesis of INT-1034:
CIS-(8-methylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic
acid
##STR00057##
[0292] Step 1:
CIS-[8-dimethylamino-2-oxo-8-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1-
,3-diaza-spiro[4.5]dec-3-yl]-acetic acid tert-butyl ester
[0293] In analogy to the method described for INT-988 Step 1
CIS-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one
(INT-967) was converted into
CIS-[8-dimethylamino-2-oxo-8-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1-
,3-diaza-spiro[4.5]dec-3-yl]-acetic acid tert-butyl ester
(INT-1033). LC-MS: m/z [M+H].sup.+=388.3
Step 2:
CIS-[8-dimethylamino-2-oxo-8-phenyl-1-(2-trimethylsilanyl-ethoxyme-
thyl)-1,3-diaza-spiro[4.5]dec-3-yl]-acetic acid tert-butyl
ester
[0294] To a suspension of
CIS-(8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic
acid tert-butyl ester (INT-1033) (8.1 g, 20.90 mmol, 1.0 eq.) in
DMF (300 mL) was added NaH (603 mg, 25.11 mmol, 1.2 eq.) at RT and
the reaction mixture was stirred for 40 min.
Trimethylsilylethoxymethyl chloride (SEMCl) was added (4.06 ml,
23.02 mmol, 1.1 eq). The resulting mixture was stirred at RT for 16
h, then diluted with ice-water (100 mL) and extracted with ethyl
acetate (2.times.500 mL). The combined organic layer was washed
with water (150 mL), brine (200 mL), dried over Na.sub.2SO.sub.4
and concentrated under reduced pressure. The resulting crude
product was purified by column chromatography (silica gel, 30%
ethyl acetate/hexane) to yield
CIS-[8-dimethylamino-2-oxo-8-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1-
,3-diaza-spiro[4.5]dec-3-yl]-acetic acid tert-butyl ester (4.0 g,
7.736 mmol, 37%) as a light yellow dense sticky liquid. LC-MS: m/z
[M+H].sup.+=518.3
Step 3:
CIS-[8-methylamino-2-oxo-8-phenyl-1-(2-trimethylsilanyl-ethoxymeth-
yl)-1,3-diaza-spiro[4.5]dec-3-yl]-acetic acid tert-butyl ester
[0295] In analogy to the method described for INT-986 Step 1
CIS-[8-dimethylamino-2-oxo-8-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1-
,3-diaza-spiro[4.5]dec-3-yl]-acetic acid tert-butyl ester was
converted into
CIS-[8-methylamino-2-oxo-8-phenyl-1-(2-trimethylsilanyl-ethoxymethyl-
)-1,3-diaza-spiro[4.5]dec-3-yl]-acetic acid tert-butyl ester.
LC-MS: m/z [M+H].sup.+=504.2
Step 4:
CIS-(8-methylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-ac-
etic acid (INT-1034)
[0296] To a solution of
CIS-[8-methylamino-2-oxo-8-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-
-diaza-spiro[4.5]dec-3-yl]-acetic acid tert-butyl ester (1.6 g,
3.180 mmol, 1.0 eq.) in MeOH (48 mL) was added 2N aq. HCl (48 mL)
and the mixture was stirred at RT for 16 h. The reaction mixture
concentrated under reduced pressure, diluted with MeOH (40 mL),
basified with 1M aq. LiOH (pH-12) and stirred at RT for 16 h. The
reaction mixture was concentrated under reduced pressure and
acidified to pH-6 with aq. NaHSO.sub.4. The reaction mixture was
extracted with 20% MeOH/DCM (5.times.200 ml). The combined organic
layer was dried over anhydr. Na.sub.2SO.sub.4 and concentrated
under reduced pressure to yield
CIS-(8-methylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic
acid (INT-1034) (850 mg, 0.681 mmol, 84%) as an off white solid.
The product was used in the next step without further purification.
LC-MS: m/z [M+H].sup.+=318.2
Synthesis of INT-1035:
CIS-(8-dimethylamino-1-oxetan-3-ylmethyl-2-oxo-8-phenyl-1,3-diaza-spiro[4-
.5]dec-3-yl)-acetic acid
##STR00058##
[0297] Step 1:
CIS-(8-dimethylamino-1-oxetan-3-ylmethyl-2-oxo-8-phenyl-1,3-diaza-spiro[4-
.5]dec-3-yl)-acetic acid oxetan-3-ylmethyl ester
[0298] In analogy to the method described for INT-986 Step 1
CIS-(8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic
acid tert-butyl ester (INT-1033) was converted into
CIS-(8-dimethylamino-1-oxetan-3-ylmethyl-2-oxo-8-phenyl-1,3-diaza-spiro[4-
.5]dec-3-yl)-acetic acid oxetan-3-ylmethyl ester.
Step 2:
CIS-(8-dimethylamino-1-oxetan-3-ylmethyl-2-oxo-8-phenyl-1,3-diaza--
spiro[4.5]dec-3-yl)-acetic acid (INT-1035)
Synthesis of INT-1037:
8-(dimethylamino)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile
##STR00059##
[0299] Step 1: 9,12-dioxa-2,4-diazadispiro[4.2.4 {8}.2
{5}]tetradecan-3-one
[0300] Lithiumaluminiumhydride (2.2 equiv., 292 mmol) was suspended
in THF (400 mL) and the suspension was cooled to 0.degree. 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.degree. C. The reaction mixture was stirred 1.5 h at 0.degree.
C., then overnight at RT and then 2 h at 40.degree. C. The reaction
mixture was cooled down to 0.degree. 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.degree. C., the precipitate was filtered off and dried under
reduced pressure to yield 9,12-dioxa-2,4-diazadispiro[4.2.4 {8}.2
{5}]tetradecan-3-one (11.4 g, 41%). Mass: m/z 213.2
(M+H).sup.+.
Step 2: 1,3-diazaspiro[4.5]decane-2,8-dione
[0301] In analogy to the method described for INT-1003 step 3
9,12-dioxa-2,4-diazadispiro[4.2.4 {8}.2 {5}]tetradecan-3-one was
treated with conc. aq. HCl to be converted into
1,3-diazaspiro[4.5]decane-2,8-dione. Mass: m/z 169.1
(M+H).sup.+.
Step 3:
8-(dimethylamino)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile
(INT-1037)
[0302] 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
##STR00060##
[0304] 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.times.). The combined organic phases were
dried over anhydr. Na.sub.2SO.sub.4 and concentrated under reduced
pressure. The residue was purified by flash chromatography on
silica gel (DCM/MeOH, 100/0 to 65/35) to yield
CIS-8-(dimethylamino)-8-(m-tolyl)-1,3-diazaspiro[4.5]decan-2-one
(INT-1038) (81 mg, 31%). Mass: m/z 288.2 (M+H).sup.+.
Synthesis of INT-1059:
TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
##STR00061##
[0305] Step 1:
TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione
[0306] 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.degree. 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 (.about.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 .about.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, .about.9-10%).
Step 2:
TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
(INT-1059)
[0307] 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
##STR00062##
[0308] Step 1:
1-amino-4-dimethylamino-4-phenyl-cyclohexanecarbonitrile
[0309] 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.times.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-trifluoroace-
tamide
[0310] 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.degree. 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.times.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)cycl-
ohexane-1,4-diamine
[0311] 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.degree. C. The reaction mixture was stirred at RT for 16 h, then
quenched with sat. aq. Na.sub.2SO.sub.4 at 0.degree. 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)-cyclohexa-
ne-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)
[0312] To a solution of
1-aminomethyl-N',N'-dimethyl-4-phenyl-N-(2,2,2-trifluoro-ethyl)-cyclohexa-
ne-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.degree. C. followed by addition of COCl.sub.2 (15.6 ml, 44.66
mmol, 3.5 eq., 20% in toluene) at 0.degree. C. and stirred at RT
for 16 h. Reaction mixture was basified with sat NaHCO.sub.3
solution and extracted with DCM (2.times.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.times.4.6), 5.mu., 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), .delta. (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).
[0313] To a solution of
CIS-(8-dimethylamino-1-oxetan-3-ylmethyl-2-oxo-8-phenyl-1,3-diaza-spiro[4-
.5]dec-3-yl)-acetic acid oxetan-3-ylmethyl ester (300 mg, 0.636
mmol, 1.0 eq.) in THF/H.sub.2O (8 mL, 1.5:1) was added LiOH (160
mg, 3.821 mmol, 6.0 eq.). The reaction mixture was stirred at RT
for 16 h, concentrated under reduced pressure, neutralized with aq.
NaHSO.sub.4 to pH-6 and extracted with 5% MeOH/DCM (3.times.200
mL). the combined organic extract was dried over Na.sub.2SO.sub.4
and concentrated under reduced pressure. The residue was triturated
with 15% DCM-Hexane to yield
CIS-(8-dimethylamino-1-oxetan-3-ylmethyl-2-oxo-8-phenyl-1,3-diaza-spiro[4-
.5]dec-3-yl)-acetic acid (INT-1035) (210 mg, 0.523 mmol, 82%) as an
off-white solid.
[0314] 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-241
CIS-8-(dimethylamino)-1-isobutyl-8-
phenyl-1,3-diazaspiro[4.5]decan-2-one ##STR00063## INT-982 330.3
INT-794 CIS-3-(3,4-dimethoxybenzyl)-8-
(dimethylamino)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one
##STR00064## INT-975 424.3 INT-796 CIS-8-Dimethylamino-3-[(4-
methoxyphenyl)-methyl]-8-(3- methoxy-propyl)-1,3-
diazaspiro[4.5]decan-2-one ##STR00065## INT-974 390.3 INT-797
CIS-8-(Ethyl-methyl-amino)-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one
##STR00066## INT-976 288.2 INT-949 CIS-8-Dimethylamino-1-ethyl-8-
phenyl-1,3-diazaspiro[4.5]decan-2-one ##STR00067## INT-984 302.2
INT-950 CIS-1-(Cyclobutyl-methyl)-8-
dimethylamino-8-phenyl-3-[phenyl-
methyl]-1,3-diazaspiro[4.5]decan-2- one ##STR00068## INT-952 432.3
INT-954 4-Dimethylamino-4-(5-methyl-
thiophen-2-yl)-cyclohexan-1-one ##STR00069## INT-965 238.1 INT-955
4-Dimethylamino-4-thiophen-2-yl- cyclohexan-1-one ##STR00070##
INT-965 224.1 INT-956 1-(1-Methyl-1H-pyrazol-3-yl)-4-oxo-
cyclohexane-1-carbonitrile ##STR00071## INT-958 204.1 INT-957
4-Oxo-1-pyrazin-2-yl-cyclohexane-1- carbonitrile ##STR00072##
INT-958 202.1 INT-959 4-Dimethylamino-4-(1-methyl-1H-
pyrazol-3-yl)-cyclohexan-1-one ##STR00073## INT-961 222.2 INT-960
4-Dimethylamino-4-pyrazin-2-yl- cyclohexan-1-one ##STR00074##
INT-961 220.1 INT-962 4-Dimethylamino-4-(3-
methoxyphenyl)-cyclohexan-1-one ##STR00075## INT-965 248.2 INT-963
CIS-3-Benzyl-8-dimethylamino-8-
phenyl-1,3-diazaspiro[4.5]decan-2-one ##STR00076## INT-975 364.2
INT-964 4-(Ethyl-methyl-amino)-4-phenyl- cyclohexan-1-one
##STR00077## INT-965 232.2 INT-967 CIS-8-Dimethylamino-8-[4-
(methoxymethyloxy)-phenyl]-3-[(4- methoxyphenyl)-methyl]-1,3-
diazaspiro[4.5]decan-2-one ##STR00078## INT-974 454.3 INT-968
CIS-8-Dimethylamino-8-[3- (methoxymethyloxy)-phenyl]-3-[(4-
methoxyphenyl)-methyl]-1,3- diazaspiro[4.5]decan-2-one ##STR00079##
INT-974 454.3 INT-969 CIS-1-(Cyclobutyl-methyl)-8-
dimethylamino-8-(4-hydroxyphenyl)-
3-[(4-methoxyphenyl)-methyl]-1,3- diazaspiro[4.5]decan-2-one
##STR00080## INT-971 478.3 INT-970 CIS-8-Dimethylamino-8-(4-
methoxyphenyl)-3-[(4- methoxyphenyl)-methyl]-1,3-
diazaspiro[4.5]decan-2-one ##STR00081## SC_2017 424.3 INT-972
CIS-8-Dimethylamino-8-(3- methoxyphenyl)-3-[(4-
methoxyphenyl)-methyl]-1,3- diazaspiro[4.5]decan-2-one ##STR00082##
SC_2017 424.3 INT-973 CIS-8-Dimethylamino-8-(4-
fluorophenyl)-3-[(4-methoxyphenyl)-
methyl]-1,3-diazaspiro[4.5]decan-2- one ##STR00083## INT-974 412.2
INT-979 CIS-8-Dimethylamino-1-(3-methoxy- propyl)-8-phenyl-1,3-
diazaspiro[4.5]decan-2-one ##STR00084## INT-984 346.2 INT-980
CIS-8-Dimethylamino-1-(2-methoxy- ethyl)-8-phenyl-1,3-
diazaspiro[4.5]decan-2-one ##STR00085## INT-984 332.2 INT-981
CIS-8-Dimethylamino-8-phenyl-1-
propyl-1,3-diazaspiro[4.5]decan-2-one ##STR00086## INT-984 316.2
INT-983 CIS-1-(Cyclopropyl-methyl)-8- dimethylamino-8-phenyl-1,3-
diazaspiro[4.5]decan-2-one ##STR00087## INT-984 328.2 INT-985
CIS-1-(Cyclobutyl-methyl)-8-(methyl- propyl-amino)-8-phenyl-1,3-
diazaspiro[4.5]decan-2-one ##STR00088## INT-986 370.3 INT-989
CIS-2-[1-[(1-Cyano-cyclobutyl)- methyl]-8-dimethylamino-2-oxo-8-
phenyl-1,3-diazaspiro[4.5]decan-3-yl]- acetic acid ##STR00089##
INT-992 425.2 INT-990 CIS-2-[8-Dimethylamino-1-(3-
methoxy-propyl)-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-acetic acid ##STR00090## INT-992 404.2
INT-991 CIS-2-[1-(Cyclopropyl-methyl)-8-
dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetic
acid ##STR00091## INT-992 386.2 INT-993
CIS-2-[1-(Cyclobutyl-methyl)-8- dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-acetic acid ##STR00092## INT-992 400.3
INT-995 CIS-2-(8-Dimethylamino-2-oxo-8- phenyl-1-propyl-1,3-
diazaspiro[4.5]decan-3-yl)-acetic acid ##STR00093## INT-992 374.2
INT-996 CIS-2-[8-Dimethylamino-1-[(dimethyl-
carbamoyl)-methyl]-2-oxo-8-phenyl-
1,3-diazaspiro[4.5]decan-3-yl]-acetic acid; 2,2,2-trifluoro-acetic
acid salt ##STR00094## INT-998 417.2 INT-997
CIS-2-[8-Dimethylamino-1-(2- methoxy-ethyl)-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-acetic acid; 2,2,2-trifluoro-acetic acid
##STR00095## INT-998 390.2 INT-999 CIS-2-[1-(Cyclobutyl-methyl)-8-
dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetic
acid; 2,2,2-trifluoro-acetic acid salt ##STR00096## INT-998 400.3
INT-1000 4-benzyl-4- (dimethylamino)cyclohexanone ##STR00097##
INT-965 232.3 INT-1001 CIS-8-benzyl-8-(dimethylamino)-1,3-
diazaspiro[4.5]decan-2-one ##STR00098## INT-976 288.2 INT-1002
TRANS-8-benzyl-8-(dimethylamino)- 1,3-diazaspiro[4.5]decan-2-one
##STR00099## INT-976 288.2 INT-1009
CIS-8-(dimethylamino)-8-(thiophen-2-
yl)-1,3-diazaspiro[4.5]decan-2-one ##STR00100## INT-976 280.1
INT-1010 TRANS-8-(dimethylamino)-8- (thiophen-2-yl)-1,3-
diazaspiro[4.5]decan-2-one ##STR00101## INT-976 280.1 INT-1011
4-(dimethylamino)-4-(1-methyl-1H-
benzo[d]imidazol-2-yl)cyclohexanone ##STR00102## INT-965 272.2
INT-1012 CIS-8-(dimethylamino)-8-(1-methyl-
1H-benzo[d]imidazol-2-yl)-1,3- diazaspiro[4.5]decan-2-one
##STR00103## INT-976 328.2 INT-1013 TRANS-8-(dimethylamino)-8-(1-
methyl-1H-benzo[d]imidazol-2-yl)-1,3- diazaspiro[4.5]decan-2-one
##STR00104## INT-976 328.2 INT-1014
CIS-2-(8-(dimethylamino)-2-oxo-8-
phenyl-1,3-diazaspiro[4.5]decan-3- yl)acetic acid trifluoroacetate
salt ##STR00105## steps 1 and 2 of INT-994 332.2 INT-1015
CIS-2-(8-(ethylamino)-2-oxo-8- phenyl-1,3-diazaspiro[4.5]decan-3-
yl)acetic acid trifluoroacetate salt ##STR00106## steps 1 and 2 of
INT-994 332.2 INT-1016 TRANS-8-(ethylamino)-8-phenyl-1,3-
diazaspiro[4.5]decan-2-one ##STR00107## INT-1008 274.2 INT-1017
TRANS-2-(8-(ethylamino)-2-oxo-8- phenyl-1,3-diazaspiro[4.5]decan-3-
yl)acetic acid trifluoroacetate salt ##STR00108## steps 1 and 2 of
INT-994 332.2 INT-1018 CIS-8-(dimethylamino)-8-phenyl-1,3-
diazaspiro[4.5]decane-2,4-dione ##STR00109## INT-976 288.2 INT-1024
CIS-8-(dimethylamino)-8-(3- fluorophenyl)-1,3-
diazaspiro[4.5]decan-2-one ##STR00110## INT-977 (step 2) 292.2
INT-1025 CIS-8-(dimethylamino)-8-(4- fluorophenyl)-1,3-
diazaspiro[4.5]decan-2-one ##STR00111## INT-974, INT-977 (step 2)
292.2 INT-1039 CIS-8-(dimethylamino)-8-(3-
(trifluoromethoxy)phenyl)-1,3- diazaspiro[4.5]decan-2-one
##STR00112## INT-1038 358.2 INT-1040 (CIS)-8-(dimethylamino)-8-(3-
(trifluoromethyl)phenyl)-1,3- diazaspiro[4.5]decan-2-one
##STR00113## INT-1038 342.2 INT-1041 (CIS)-8-(dimethylamino)-8-(3-
methoxyphenyl)-1,3- diazaspiro[4.5]decan-2-one ##STR00114##
INT-1038 304.2 INT-1042 (CIS)-8-(5-chlorothiophen-2-yl)-8-
(dimethylamino)-1,3- diazaspiro[4.5]decan-2-one ##STR00115##
INT-1038 314.1 INT-1043 (CIS)-8-(dimethylamino)-8-(3-fluoro-
5-methylphenyl)-1,3- diazaspiro[4.5]decan-2-one ##STR00116##
INT-1038 306.2 INT-1044 (CIS)-8-(3-chlorophenyl)-8-
(dimethylamino)-1,3- diazaspiro[4.5]decan-2-one ##STR00117##
INT-1038 308.2 INT-1047 (CIS)-8-(methyl(oxetan-3-
ylmethyl)amino)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one
##STR00118## INT-1026 330.5 INT-1057 CIS-1-(cyclobutylmethyl)-8-
(dimethylamino)-8-(4-fluorophenyl)- 1,3-diazaspiro[4.5]decan-2-one
##STR00119## INT-1031 360.3 INT-1058 CIS-2-(1-(cyclobutylmethyl)-8-
(dimethylamino)-8-(4-fluorophenyl)-2-
oxo-1,3-diazaspiro[4.5]decan-3- yl)acetic acid trifluoroacetate
##STR00120## INT-998 418.3 INT-1060
TRANS-2-(8-(dimethylamino)-2-oxo-
8-phenyl-1,3-diazaspiro[4.5]decan-3- yl)acetic acid
trifluoroacetate salt ##STR00121## steps 1 and 2 of INT-994 332.2
INT-1061 TRANS-1-(cyclopropyl-methyl)-8-
dimethylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2-one ##STR00122##
INT-984 328.2 INT-1062 TRANS-2-[1-(cyclopropyl-methyl)-8-
dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetic
acid trifluoroacetate salt ##STR00123## INT-998 386.2 INT-1063
CIS-1-(cyclopropylmethyl)-8- (dimethylamino)-8-(3-fluorophenyl)-
1,3-diazaspiro[4.5]decan-2-one ##STR00124## INT-1031 346.2 INT-1066
TRANS-1-(cyclobutylmethyl)-8- (dimethylamino)-8-phenyl-1,3-
diazaspiro[4.5]decan-2-one ##STR00125## INT-987 342.3 INT-1067
TRANS-2-[1-(cyclobutyl-methyl)-8- dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-acetic acid; 2,2,2-trifluoro-acetic acid
salt ##STR00126## INT-998 400.3 INT-1070
CIS-8-(dimethylamino)-8-phenyl-1- (3,3,3-trifluoropropyl)-1,3-
diazaspiro[4.5]decan-2-one ##STR00127## INT-1068 360.2 INT-1074
CIS-8-(dimethylamino)-8-(3- fluorophenyl)-1-((1-
hydroxycyclobutyl)methyl)-1,3- diazaspiro[4.5]decan-2-one
##STR00128## INT-1031 376.2
[0315] Synthesis of Exemplary Compounds
Synthesis of SC_1051:
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(5-methoxy-pyridin-2-yl)-acetamide
##STR00129##
[0317] Into a dry reaction vessel were added successively 1 mL of a
solution of
CIS-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-acetic acid (INT-993) (0.1 M in DCM), 2 mL of a
solution of 5-methoxy-pyridin-2-amine (0.2 M in DCM), 0.07 ml of
triethylamine and 0.118 mL of a solution of T3P (1.7 M, 50% in
EtOAc). The reaction mixture was stirred at RT overnight, then
quenched with 3 mL aq. Na.sub.2CO.sub.3 (1 M) and stirred at RT for
1 h. The organic layer was separated and the aq. layer was
extracted with DCM (2.times.). The combined organic layers were
concentrated under reduced pressure and the resulting crude product
was purified by HPLC to obtain
CIS-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(5-methoxy-pyridin-2-yl)-acetamide (SC_1051).
[M+H].sup.+ 506.3
Synthesis of SC_1073:
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-
spiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-pyridine-4-carboxylic
acid amide
##STR00130##
[0319] To a mixture of
CIS-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-acetic acid trifluoroacetate (INT-999) (100 mg,
0.19 mmol) and 2-amino-N-methylisonicotinamide (118 mg, 0.78 mmol)
in DCM (6 ml) were added HATU (148 mg, 0.39 mmol) and DIPEA (0.13
ml, 0.78 mmol) at RT and the reaction mixture was stirred at same
temperature for 16 h. The reaction mixture was washed with 1M aq.
Na.sub.2CO.sub.3 (1 mL) and 2M aq. NaOH (1 mL). The combined
aqueous layers were extracted with DCM (3.times.5 mL). The combined
organic layers were washed with water (3 mL) and brine (3 ml),
dried over magnesium sulfate, filtered and concentrated in vacuum.
Column chromatography (silica gel, cHex/tBuOMe/1N methanolic
ammonia 1:1:0.05) of the crude product provided
CIS-2-[[2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-
spiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-pyridine-4-carboxylic
acid amide (SC_1073) (27 mg). [M+H].sup.+ 533.3
Synthesis of SC_1076:
CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-
spiro[4.5]decan-3-yl]-acetyl]amino]-pyridine-2-carboxylic acid
amide
##STR00131##
[0321]
CIS-N-(6-Cyano-pyridin-2-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylami-
no-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide
(SC_1026) (30 mg, 0.06 mmol) was dissolved in DMSO (0.2 mL) and
potassium carbonate (17 mg, 0.12 mmol) and hydrogen peroxide (30%
in water, 0.12 mmol) were added at 0.degree. C. The resulting
mixture was stirred for 18 h, then water was added and the reaction
mixture was extracted with DCM (3.times.5 mL). The combined organic
layers were dried over Na.sub.2SO.sub.4, concentrated in vacuo and
the resulting crude product was purified by flash chromatography to
yield
CIS-6-[[2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-
spiro[4.5]decan-3-yl]-acetyl]amino]-pyridine-2-carboxylic acid
amide SC_1076 (14 mg) as a white solid. [M+H].sup.+ 519.3
Synthesis of SC_1110:
CIS-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(2-hydroxy-pyrimidin-5-yl)-acetamide
##STR00132##
[0323] A solution of
CIS-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o [4.5]decan-3-yl]-N-(2-methoxy-pyrimidin-5-yl)-acetamide (SC_1070)
(80 mg, 0.16 mmol) in DCM (12 mL) was cooled to 0.degree. C. and
treated with a boron tribromide solution (1M in DCM, 1.26 mL, 1.26
mmol). After stirring at RT for 16 h the reaction mixture was
quenched with MeOH, diluted with water and extracted with DCM
(3.times.). The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The
resulting crude product was purified by column chromatography
(reversed phase silica gel C18, water/MeCN 100:0->20:80) to
yield
CIS-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(2-hydroxy-pyrimidin-5-yl)-acetamide (SC_1110)
(17 mg). [M+H].sup.+ 493.3
Synthesis of SC_1128:
CIS-N-(2-Cyano-pyrimidin-4-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-
-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide
##STR00133##
[0325]
CIS-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-dia-
zaspiro[4.5]decan-3-yl]-acetamide (SC_1195) (50 mg, 0.1255 mmol),
4-bromopyrimidine-2-carbonitrile (0.1882 mmol), 4,5-XantPhos
(0.0188 mmol), Cs.sub.2CO.sub.3 (0.2509 mmol) and
Pd.sub.2(dba).sub.3 (0.0063 mmol) were dissolved in 1,4-dioxane (6
mL). The reaction mixture was degassed by three consecutive
vacuum/nitrogen-refill cycles and then stirred at 90.degree. C. for
18 h. Water (2 mL) was added and the resulting mixture was
extracted with ethyl acetate (3.times.6 mL). The combined organic
layers were dried over Na.sub.2SO.sub.4, concentrated in vacuo and
purified by flash chromatography to yield
CIS-N-(2-cyano-pyrimidin-4-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-
-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide (SC_1128)
(43 mg) as a white solid. [M+H].sup.+ 502.3
Synthesis of SC_1129:
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-[6-(methylsulfinyl)-pyridin-2-yl]-acetamide
##STR00134##
[0327]
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-dia-
zaspiro[4.5]decan-3-yl]-N-(6-methylsulfanyl-pyridin-2-yl)-acetamide
SC_1120 (30.0 mg) was dissolved in
1,1,1,3,3,3-hexafluoropropan-2-ol (0.303 mL) and hydrogen peroxide
(30% in water, 12 L) was added. The resulting mixture was stirred
at 60.degree. C. for 1 h. Then sat. aq. Na.sub.2S.sub.2O.sub.3 (2
mL) was added and the aqueous layer was extracted with DCM
(3.times.5 mL). The combined organic layers were dried over
Na.sub.2SO.sub.4, concentrated in vacuo and purified by flash
chromatography to yield
CIS-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-[6-(methylsulfinyl)-pyridin-2-yl]-acetamide
(SC_1129) (8 mg) as a white solid. [M+H].sup.+ 538.3
Synthesis of SC_1136:
CIS-2-[8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl]-N-(2-methylsulfonyl-ethyl)-acetamide
##STR00135##
[0329] 50% Propylphosphonic anhydride (T3P) solution in EtOAc
(0.766 mL, 1.204 mmol) was added to a solution of crude
CIS-2-[8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl]-acetic acid (INT-994) (250 mg, 0.602
mmol), 2-(methylsulfonyl)ethanamine hydrochloride (115.4 mg, 0.723
mmol) and diisopropylethylamine (0.410 mL, 2.408 mmol) in DCM (15
mL) at 0.degree. C. The reaction mixture was warmed to RT and
stirred for 4 h. The reaction mixture was quenched with water and
the organic product was extracted with DCM (3.times.20 mL). The
combined organic layer was washed with sat. aq. NaHCO.sub.3 (10
mL), brine (10 mL) and dried over anhydr. Na.sub.2SO.sub.4 and
concentrated under reduced pressure The crude product was purified
by preparative HPLC to give 56 mg (25%) of
CIS-2-[8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl]-N-(2-methylsulfonyl-ethyl)-acetamide
(SC_1136) as an off-white solid. (TLC system: 10% MeOH in DCM Rf:
0.62). [M+H].sup.+ 521.3
Synthesis of SC_1138:
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(6-methylsulfonyl-pyridin-2-yl)-acetamide
##STR00136##
[0331]
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-dia-
zaspiro[4.5]decan-3-yl]-N-(6-methylsulfanyl-pyridin-2-yl)-acetamide
(SC_1120) (22 mg) was dissolved in a water/methanol (500 L/500 L)
and oxone (39 mg) was added. The resulting mixture was stirred at
RT for 18 h. Then 2N aq. NaOH (2 mL) was added and the aqueous
layer was extracted with DCM (3.times.5 mL). The combined organic
layers were dried over Na.sub.2SO.sub.4, concentrated in vacuo and
the residue was purified by flash chromatography to yield
CIS-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-(6-methylsulfonyl-pyridin-2-yl)-acetamide
(SC_1138) (14 mg) as a white solid. [M+H].sup.+ 554.3
Synthesis of SC_1149:
CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro-
[4.5]decan-3-yl]-N-methyl-acetamide
##STR00137##
[0333]
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4-
.5]decan-2-one (INT-987) (0.2 g, 0.57 mmol) was added to a solution
of NaH (60% in mineral oil) (0.15 g, 3.47 mmol) in DMF (5 mL) at RT
and the reaction mixture was stirred at RT for 1 h. The reaction
mixture was cooled to 0.degree. C. and 2-bromo-N-methylacetamide
(0.52 g, 3.47 mmol) in DMF (2 mL) was added dropwise. the resulting
mixture was stirred for 30 min at 0.degree. C. and then at RT for
16 h. The reaction completion was monitored by TLC. The reaction
mixture was quenched with sat. aq. NH.sub.4Cl and the organic
product was extracted with EtOAc (2.times.10 mL). The combined
organic extracts were dried over anhydrous Na.sub.2SO.sub.4 and
concentrated under reduced pressure. Purified of the crude product
by preparative TLC using 5% MeOH in DCM as a mobile phase gave 45 g
(18%) of
CIS-2-[8-dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,
3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide (SC_1149) as an
off-white solid. (TLC system: 10% MeOH in DCM; Rf: 0.3).
[M+H].sup.+ 417.3
Synthesis of SC_1303:
CIS-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-
-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-acetamide
##STR00138##
[0335] N-Iodosuccinimide (71.8 mg, 0.31 9 mmol) was added to a
solution of
CIS-2-[8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-acetamide (SC_1301)
(100 mg, 0.213 mmol) in a mixture of acetonitrile and THF (1:1 v/v,
5 mL) at 0.degree. C. and the resulting mixture was stirred at RT
for 16 h. The reaction mixture was basified with 2N NaOH solution
to pH-10 and the organic product was extracted with ethyl acetate
(10 mL.times.3). The combined organic extracts were dried over
anhydr. Na.sub.2SO.sub.4 and concentrated under reduced pressure.
The resulting crude product was purified by preparative reverse
phase HPLC to give 50 mg of the desired product as a formiate. The
isolated product was diluted with water (5 mL) and basified with
sat. aq. NaHCO.sub.3. The product was extracted with EtOAc (10
mL.times.2), combined organic layer was dried over anhydr.
Na.sub.2SO.sub.4 and concentrated in vacuo to yield 42 mg (43%) of
CIS-2-[1-[(1-hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-
-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-acetamide (SC_1303) as
an off-white solid (TLC system: 5% MeOH in DCM; R.sub.f: 0.42.).
[M+H].sup.+ 457.3
Synthesis of SC_1308:
CIS-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-p-
henyl-1-propyl-1,3-diazaspiro[4.5]decan-2-one
##STR00139##
[0337] 50 wt % solution of T3P (2.32 g, 3.65 mmol) in EtOAc was
added to a suspension of
CIS-2-(8-dimethylamino-2-oxo-8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-3-
-yl)-acetic acid hydrochlorid (INT-995) (600 mg, 1.46 mmol),
thiomorpholin-1,1-dioxide (237 mg, 1.76 mmol) and
diisopropylethylamine (1.27 mL, 7.30 mmol) in THF (10 mL) at
0.degree. C. The reaction mixture was warmed to RT and stirred for
16 h. The reaction mixture was quenched with water, the organic
product was extracted with EtOAc (3.times.25 mL). The combined
organic extracts were washed with water, brine, dried over
anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure
to give the crude compound. Purification by flash silica column
chromatography using 4-5% methanol in DCM as eluent yielded 250 mg
(34%) of
CIS-8-dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]--
8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-2-one (SC_1308) as a
solid (TLC system: 10% MeOH in DCM R.sub.f: 0.30). [M+H].sup.+
491.3
Synthesis of SC_1324:
CIS-2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)ace-
tamide
##STR00140##
[0339] The suspension of TFA salt of
CIS-(8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic
acid (500 mg, 1.12 mmol, 1.0 eq.) in THF (40 ml) was cooled to
0.degree. C. and DIPEA (0.78 ml, 4.48 mmol, 4.0 eq.),
1-hydroxy-1H-benzotriazole ammonium salt (287 mg, 1.68 mmol, 1.5
eq.) and EDCl (321 mg, 1.68 mmol, 1.5 eq.) were sequentially added.
The resulting mixture was stirred at RT for 16 h and then
concentrated under reduced pressure. Crude product was purified by
column chromatography (neutral alumina; 0.5% NH.sub.3 in 20%
MeOH/DCM) to yield
CIS-2-(8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-aceta-
mide (SC_1324) (250 mg, 0.75 mmol, 67%) as an off-white solid.
[M+H].sup.+ 331.2
Synthesis of SC_1332:
CIS-2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N--
phenylacetamide
##STR00141##
[0341] KOtBu (1M in THF) (1.4 mL, 1.37 mmol) was added to the
solution of
CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (250
mg, 0.915 mmol) in THF (15 mL) under argon atmosphere at 0.degree.
C. and the reaction mixture was stirred for 30 min.
2-Bromo-N-phenylacetamide (312 mg, 1.46 mmol) was added, the ice
bath was removed and the reaction mixture was stirred for 4 h. Sat.
aq. NH.sub.4Cl (10 mL) was added and the resulting mixture was
extracted with EtOAc (2.times.50 mL). The combined organic extracts
were dried over anhydr. Na.sub.2SO.sub.4 and concentrated under
reduced pressure. The crude product was purified by reverse phase
preparative HPLC to give 60 mg (16%) of
CIS-2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N--
phenylacetamide (SC_1332) as a white solid. .sup.1H NMR
(CDCl.sub.3): .delta. 8.32 (br s, 1H), 7.50-7.48 (d, 2H), 7.39-7.36
(m, 2H), 7.33-7.26 (m, 5H), 7.12-7.08 (t, 1H), 5.90 (br s, 1H),
3.90 (s, 2H), 3.25 (s, 2H), 2.12 (m, 4H), 1.99 (s, 6H), 1.94-1.91
(m, 2H), 1.58-1.53 (m, 2H). [M+H].sup.+ 407.2
Synthesis of SC-1346:
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-
-diazaspiro[4.5]decan-3-yl]-acetic acid tert-butyl ester
##STR00142##
[0343] KOtBu (187 mg, 1.67 mmol) was added to a solution of
CIS-1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-1,3-diazaspi-
ro[4.5]decan-2-one (INT-1031) (400 mg, 1.1 mmol) in dry THF (9 mL)
at 0.degree. C. The mixture was stirred for 15 min at this
temperature and t-butyl-bromoacetate (0.246 mL, 1.67 mmol) was
added subsequently. After stirring for 1 h at 0.degree. C., the
reaction was quenched with water, diluted with EtOAc and stirred
for 5 min at RT. The layers were separated and the aqueous layer
was extracted two times with ethyl acetate. The combined organic
extracts were dried over anhydrous Na.sub.2SO.sub.4 and
concentrated under reduced pressure. The crude product was purified
by flash chromatography (silica, 0.5 M NH.sub.3 in MeOH/DCM
gradient) to yield 395 mg (75%) of
CIS-2-[1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-
-diazaspiro[4.5]decan-3-yl]-acetic acid tert-butyl ester (SC_1346)
as a white solid. .sup.1H NMR (600 MHz, DMSO) .delta. 7.43-7.36 (m,
1H), 7.17 (d, 1H), 7.13 (dt, 1H), 7.09 (td, 1H), 3.75 (d, 2H), 3.21
(s, 2H), 3.05 (d, 2H), 2.67-2.61 (m, 2H), 2.08-2.00 (m, 2H), 1.99
(d, 7H), 1.98-1.93 (m, 2H), 1.83-1.75 (m, 2H), 1.75-1.65 (m, 2H),
1.39 (d, 8H), 1.38-1.29 (m, 5H). [M+H].sup.+ 474.3
SC-1357:
TRANS-1-(cyclopropylmethyl)-8-(dimethylamino)-3-(2-morpholino-2-o-
xoethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
##STR00143##
[0345] To a solution of
TRANS-2-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diaza-
spiro[4.5]decan-3-yl)acetic acid trifluoroacetate (300 mg, 0.6
mmol, 1.0 eq.) in DCM (10 mL) were added DIPEA (0.62 mL, 3.6 mmol,
6.0 eq.) and HATU (296 mg, 0.78 mmol, 1.3 eq.) followed by
morpholine (102 mg, 1.08 mmol, 1.8 eq.) at 0.degree. C. The
reaction mixture was stirred at RT for 16 h, then quenched with
water (25 mL) and extracted with DCM (50 mL.times.2). Combined
organic layer was washed with brine (25 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The resulting crude product was purified by prep HPLC to get
TRANS-1-cyclopropylmethyl-8-dimethylamino-3-(2-morpholin-4-yl-2-oxo-ethyl-
)-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (SC-1357) (55 mg, 0.12
mmol, 20%) as a white solid. .sup.1HNMR (DMSO-d.sub.6, 400 MHz),
.delta. (ppm)=7.44-7.29 (m, 5H), 3.96 (s, 2H), 3.56 (bs, 4H),
3.42-3.40 (m, 4H), 3.29 (s, 2H), 2.67 (bs, 2H), 2.55-2.54 (d, 2H,
J=6.36 Hz), 1.92 (s, 6H), 1.56-1.44 (m, 6H), 0.51-0.48 (m, 1H),
0.16-0.14 (m, 2H), (-0.26)-(-0.27) (m, 2H). [M+H].sup.+ 455.1
Synthesis of INT-1363:
TRANS-2-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diaza-
spiro[4.5]decan-3-yl)acetamide
##STR00144##
[0346] Step 1: tert-butyl
TRANS-2-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diaza-
spiro[4.5]decan-3-yl)acetate
[0347] In analogy to the method described for INT-1019 step 1
TRANS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5-
]decan-2-one (INT-1061) was converted into tert-butyl
TRANS-2-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diaza-
spiro[4.5]decan-3-yl)acetate. LC-MS: m/z [M+H].sup.+=442.3
Step 2:
TRANS-2-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,-
3-diazaspiro[4.5]decan-3-yl)acetamide (INT-1363)
[0348] A mixture of
TRANS-(1-cyclopropylmethyl-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro-
[4.5]dec-3-yl)-acetic acid tert-butyl ester (250 mg, 0.56 mmol, 1.0
eq.) and 7M NH.sub.3 in MeOH (5 mL) was heated in sealed tube at
90.degree. C. for 16 h, then cooled down to RT and concentrated
under reduced pressure. The residue was purified by column
chromatography (silica gel basified with aq. NH.sub.3; 10% MeOH in
DCM) to yield
2-(1-cyclopropylmethyl-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5-
]dec-3-yl)-acetamide (77 mg, 0.2 mmol, 35%) as a white solid.
LC-MS: m/z [M+1].sup.+=385.2 (MW calc. 384.52); .sup.1H NMR at
100.degree. C. (DMSO-d6, 400 MHz), .delta. (ppm)=7.40-7.29 (m, 5H),
6.76 (bs, 2H), 3.68 (s, 2H), 3.33 (s, 2H), 2.61-2.60 (m, 4H), 2.00
(s, 6H), 1.61-1.53 (m, 6H), 0.58-0.56 (m, 1H), 0.22-0.20 (m, 2H),
(-0.16)-(-0.18) (m, 2H).
[0349] 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 Reactant Reactant in analogy m/z Example Chemical
Name I II to method [M + H].sup.+ SC_1001
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 2,5,8,11,14,17,20- SC_1308 721.5
diazaspiro[4.5]declan-3-yl]-N-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-
heptaoxadocosan-22-amine
ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethyl]-acetamide SC_1002
CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,-
3- INT 993 methyl 6-aminopicolinate SC_1308 534.3
diazaspiro[4.5]declan-3-yl]-acetyl]amino]-pyridine-2-carboxylic
acid methyl ester SC_1003
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 (R)-2-aminopropan-1-ol SC_1308 457.3
diazaspiro[4.5]declan-3-yl]-N-[(1R)-2-hydroxy-1-methyl-ethyl]-
acetamide SC_1004
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 (S)-2-aminopropan-1-ol SC_1308 457.3
diazaspiro[4.5]declan-3-yl]-N-[(1S)-2-hydroxy-1-methyl-ethyl]-
acetamide SC_1005
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 N-methyl-2- SC_1308 484.3
diazaspiro[4.5]declan-3-yl]-N-methyl-N-(methylcarbamoyl-methyl-
(methylamino)acetamide acetamide SC_1006
CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,-
3- INT 993 methyl 6-aminonicotinate SC_1308 534.3
diazaspiro[4.5]declan-3-yl]-acetyl]amino]-nicotinic acid methyl
ester SC_1007
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,-
3- INT 993 2-methyl-2- SC_1308 498.3
diazaspiro[4.5]declan-3-yl]-acetyl]-methyl-amino]-2-methyl-
(methylamino)propanamide propionamide SC_1008
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,-
3- INT 993 2-amino-N,2-dimethylpropanamide SC_1308 498.3
diazaspiro[4.5]declan-3-yl]-acetyl]amino-N,2-dimethyl-propionamide
SC_1009
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,-
3- INT 993 N,2-dimethyl-2-(methylamino)- SC_1308 512.4
diazaspiro[4.5]declan-3-yl]-acetyl]methyl-amino]-N,2-dimethyl-
propanamide propionamide SC_1010
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 N,N-dimethyl-2- SC_1308 498.3
diazaspiro[4.5]declan-3-yl]-N-[(dimethyl-carbomoyl)-methyl]-N-methyl-
(methylamino)acetamide acetamide SC_1011
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,-
3- INT 993 2-amino-2-methylpropanamide SC_1308 484.3
diazaspiro[4.5]declan-3-yl]-acetyl]amino]-2-methyl-propionamide
SC_1012
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 5-methoxypyridin-2-amine SC_1308 506.3
diazaspiro[4.5]declan-3-yl]-N-(5-methoxy-pyridin-2-yl)-acetamide
SC_1013
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 6-methoxypyridin-2-amine SC_1308 506.3
diazaspiro[4.5]declan-3-yl]-N-(6-methoxy-pyridin-2-yl)-acetamide
SC_1014
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 4-methoxypyridin-2-amine SC_1308 506.3
diazaspiro[4.5]declan-3-yl]-N-(4-methoxy-pyridin-2-yl)-acetamide
SC_1015
CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,-
3- INT 999 6-amino-N-methylpicolinamide SC_1073 533.3
diazaspiro[4.5]declan-3-yl]-acetyl]amino]-N-methyl-pyridine-2-
carboxylic acid amide SC_1016
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 cis-3-(aminomethyl)cyclobutanol SC_1308 483.3
diazaspiro[4.5]declan-3-yl]-N-[(3-hydroxy-cyclobutyl)-methyl]-
acetamide SC_1017
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 trans-3-(aminomethyl) SC_1308 483.3
diazaspiro[4.5]declan-3-yl]-N-[(3-hydroxy-cyclobutyl)-methyl]-
cyclobutanol acetamide SC_1018
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 1-(aminomethyl)cyclopropanol SC_1308 469.3
diazaspiro[4.5]declan-3-yl]-N-[(1-hydroxy-cyclobutyl)-methyl]-
acetamide SC_1019
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 3-amino-1-morpholinopropan-1- SC_1308 540.3
diazaspiro[4.5]declan-3-yl]-N-(3-morpholin-4-yl-3-oxo-propyl)- one
acetamide SC_1020
CIS-N-(1-cyano-cyclopropyl)-2-[1-(cyclobutyl-methyl)-8- INT 993
1-aminocyclopropanecarbonitrile SC_1308 464.3
dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-
acetamide SC_1021
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 3-(aminomethyl)cyclopentanol SC_1308 497.3
diazaspiro[4.5]declan-3-yl]-N-[3-hydroxy-cyclopentyl)-methyl]-
acetamide SC_1022
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 (1R)-2-(aminomethyl) SC_1308 511.4
diazaspiro[4.5]declan-3-yl]-N-[[(2R)-2-hydroxy-cyclohexyl]-methyl]-
cyclohexanol acetamide SC_1023
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 2,5,8,11-tetraoxatridecan-13-amine SC_1308 589.4
diazaspiro[4.5]declan-3-yl]-N-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-
ethoxy]-ethyl]-acetamide SC_1024
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 1-(aminomethyl)cyclohexanol SC_1308 511.4
diazaspiro[4.5]declan-3-yl]-N-[[2R-2-hydroxy-cyclohexyl]-methyl]-
acetamide SC_1025
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 2,5,8,11,14-pentaoxahexadecan- SC_1308 633.4
diazaspiro[4.5]declan-3-yl]-N-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-
16-amine ethoxy]-ethoxy]-ethyl]-acetamide SC_1026
CIS-N-(6-Cyano-pyridin-2-yl)-2-[1-(cyclobutyl-methyl)-8- INT 993
6-aminopicolinonitrile SC_1308 501.3
dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-
acetamide SC_1027
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,-
3- INT 993 methyl 2-aminonicotinate SC_1308 534.3
diazaspiro[4.5]declan-3-yl]-acetyl]amino]-nicotinic acid methyl
ester SC_1028
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 3-methoxypyridin-2-amine SC_1308 506.3
diazaspiro[4.5]decan-3-yl]-N-(3-methoxy-pyridin-2-yl)-acetamide
SC_1029
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 2,5,8,11,14,17-hexaoxanonadecan- SC_1308 677.4
diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-
19-amine ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethyl]-acetamide SC_1030
CIS-N-(4-Cyano-pyridin-2-yl)-2-[1-(cyclobutyl-methyl)-8- INT 993
2-aminoisonicotinonitrile SC_1308 501.3
dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-
acetamide SC_1031
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 5-methoxypyrimidin-2-amine SC_1308 507.3
diazaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyrimidin-2-yl)-acetamide
SC_1032
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,-
3- INT 993 methyl 2-aminoisonicotinate SC_1308 534.3
diazaspiro[4.5]decan-3-yl]-acetyl]amino]-isonicotinic acid methyl
ester SC_1033
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 2-methoxypyridin-4-amine SC_1051 506.3
diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-pyridin-4-yl)-acetamide
SC_1034
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 6-fluoropyridin-3-amine SC_1051 494.3
diazaspiro[4.5]decan-3-yl]-N-(6-fluoro-pyridin-3-yl)-acetamide
SC_1035
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 2-methylpyrimidin-5-amine SC_1051 491.3
diazaspiro[4.5]decan-3-yl]-N-(2-methyl-pyrimidin-5-yl)-acetamide
SC_1036
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 5-methylpyrimidin-2-amine SC_1051 491.3
diazaspiro[4.5]decan-3-yl]-N-(5-methyl-pyrimidin-2-yl)-acetamide
SC_1037
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 3-fluoropyridin-2-amine SC_1051 494.3
diazaspiro[4.5]decan-3-yl]-N-(3-fluoro-pyridin-2-yl)-acetamide
SC_1038
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 3-fluoropyridin-4-amine SC_1051 494.3
diazaspiro[4.5]decan-3-yl]-N-(3-fluoro-pyridin-4-yl)-acetamide
SC_1039
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 6-methoxypyridin-3-amine SC_1051 506.3
diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyridin-3-yl)-acetamide
SC_1040
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 2-methylpyridin-3-amine SC_1051 490.3
diazaspiro[4.5]decan-3-yl]-N-(2-methyl-pyridin-3-yl)-acetamide
SC_1041
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 4-methylpyridin-3-amine SC_1051 490.3
diazaspiro[4.5]decan-3-yl]-N-(4-methyl-pyridin-3-yl)-acetamide
SC_1042
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 3-methylpyridin-4-amine SC_1051 490.3
diazaspiro[4.5]decan-3-yl]-N-(3-methyl-pyridin-4-yl)-acetamide
SC_1043
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 6-methylpyridin-3-amine SC_1051 490.3
diazaspiro[4.5]decan-3-yl]-N-(6-methyl-pyridin-3-yl)-acetamide
SC_1044
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 5-fluoropyridin-2-amine SC_1051 494.3
diazaspiro[4.5]decan-3-yl]-N-(5-fluoro-pyridin-2-yl)-acetamide
SC_1045
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 5-methylpyridin-2-amine SC_1051 490.3
diazaspiro[4.5]decan-3-yl]-N-(5-methyl-pyridin-2-yl)-acetamide
SC_1046
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 4-methylpyridin-2-amine SC_1051 490.3
diazaspiro[4.5]decan-3-yl]-N-(4-methyl-pyridin-2-yl)-acetamide
SC_1047
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 3-methylpyridin-2-amine SC_1051 490.3
diazaspiro[4.5]decan-3-yl]-N-(3-methyl-pyridin-2-yl)-acetamide
SC_1048
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 3-methoxypyridin-4-amine SC_1051 506.3
diazaspiro[4.5]decan-3-yl]-N-(3-methoxy-pyridin-4-yl)-acetamide
SC_1049
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 6-methoxypyridazin-3-amine SC_1051 507.3
diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyridazin-3-yl)-acetamide
SC_1050
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 5-(methylsulfonyl)pyridin-2-amine SC_1051 554.3
diazaspiro[4.5]decan-3-yl]-N-(5-methylsulfonyl-pyridin-2-yl)-acetamide
SC_1052
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 6-(methylsulfonyl)pyridin-3-amine SC_1051 554.3
diazaspiro[4.5]decan-3-yl]-N-(6-methylsulfonyl-pyridin-3-yl)-acetamide
SC_1053
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 6-methoxypyrazin-2-amine SC_1051 507.3
diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyrazin-2-yl)-acetamide
SC_1054
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 4-methoxypyridin-2-amine SC_1051 506.3
diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyridin-2-yl)-acetamide
SC_1055
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 4-methoxypyrimidin-2-amine SC_1051 507.3
diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyrimidin-2-yl)-acetamide
SC_1056
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 oxazol-5-ylmethanamine SC_1051 480.3
diazaspiro[4.5]decan-3-yl]-N-(oxazol-5-yl-methyl)-acetamide SC_1057
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 oxazol-2-ylmethanamine SC_1051 480.3
diazaspiro[4.5]decan-3-yl]-N-(oxazol-2-yl-methyl)-acetamide SC_1058
CIS-1-(Cyclobutyl-methyl)-3-[2-[(3S,4S)-3,4-dihydroxy-piperidin-1--
yl]- INT 993 (3S,4S)-piperidine-3,4-diol SC_1051 499.3
2-oxo-ethyl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
SC_1059
CIS-1-(Cyclobutyl-methyl)-3-[2-[(3S,4S)-3,4-dihydroxy-pyrrolidin-1-
- INT 993 (3S,4S)-pyrrolidine-3,4-diol SC_1051 485.3
yl]-2-oxo-ethyl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-
one SC_1060
CIS-1-(Cyclobutyl-methyl)-3-[2-[(3S,4R)-3,4-dihydroxy-pyrrolidin-1-
- INT 993 (3S,4R)-pyrrolidine-3,4-diol SC_1051 485.3
yl]-2-oxo-ethyl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-
one SC_1061
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 cyclopropanamine SC_1051 439.3
diazaspiro[4.5]decan-3-yl]-N-cyclopropyl-acetamide SC_1062
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 2-(methylamino)ethanol SC_1051 457.3
diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-N-methyl-acetamide
SC_1063
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-(3-hydroxy-piperidi-
n- INT 993 piperidin-3-ol SC_1051 483.3
1-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1064
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 1-(aminomethyl)cyclobutanol SC_1051 483.3
diazaspiro[4.5]declan-3-yl]-N-[(1-hydroxy-cyclobutyl)-methyl]-
acetamide SC_1065
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,-
3- INT 993 2-amino-N,N-dimethylacetamide SC_1051 484.3
diazaspiro[4.5]declan-3-yl]-acetyl]amino]-N,N-dimethyl-acetamide
SC_1066
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-oxo-2-(5,6,7,8- INT
993 5,6,7,8-tetrahydro- SC_1051 506.3
tetrahydro-[1,2,4[1,5-a]pyrazin-7-yl)-ethyl]-8-phenyl-1,3-
[1,2,4]triazolo[1,5-a]pyrazine diazaspiro[4.5]decan-2-one SC_1067
CIS-3-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,-
3- INT 993 3-amino-N,N- SC_1051 498.3
diazaspiro[4.5]declan-3-yl]-acetyl]amino]-N,N-dimethyl-propionamide
dimethylpropanamide SC_1068
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 2,5,8,11,14,17,20,23-octaoxa- SC_1308 765.5
diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-
pentacosan-25-amine
ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethyl]-acetamide
SC_1069
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 4-methoxypyrimidin-5-amine SC_1308 507.3
diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyrimidin-5-yl)-acetamide
SC_1070
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 2-methoxypyrimidin-5-amine SC_1308 507.3
diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-pyrimidin-5-yl)-acetamide
SC_1072 CIS-N-(5-Cyano-pyridin-2-yl)-2-[1-(cyclobutyl-methyl)-8-
INT 993 6-aminonicotinonitrile SC_1308 501.3
dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-
acetamide SC_1074
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 5-methoxypyrimidin-4-amine SC_1308 507.3
diazaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyrimidin-4-yl)-acetamide
SC_1075 CIS-N-(2-Cyano-pyrimidin-5-yl)-2-[1-(cyclobutyl-methyl)-8-
INT 993 5-aminopyrimidine-2-carbonitrile SC_1308 502.3
dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-
acetamide SC_1077
CIS-N-(3-Cyano-pyridin-2-yl)-2-[1-(cyclobutyl-methyl)-8- INT 993
2-aminonicotinonitrile SC_1308 501.3
dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-
acetamide SC_1078
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,-
3- INT 993 2-aminoacetamide SC_1308 456.3
diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide SC_1079
CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,-
3- SC_1072 -- SC_1076 519.3
diazaspiro[4.5]decan-3-yl]-acetyl]amino]-pyridine-3-carboxylic acid
amide SC_1080
CIS-N-(4-Cyano-pyrimidin-2-yl)-2-[1-(cyclobutyl-methyl)-8- INT 993
2-aminopyrimidine-4-carbonitrile SC_1308 502.3
dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-
acetamide SC_1081
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 1,3,4-thiadiazol-2-amine SC_1051 483.2
diazaspiro[4.5]decan-3-yl]-N-([1,3,4]thiadiazol-2-yl)-acetamide
SC_1082
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 thiazol-2-amine SC_1051 482.3
diazaspiro[4.5]decan-3-yl]-N-thiazol-2-yl-acetamide SC_1083
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 5-methylisoxazol-3-amine SC_1051 480.3
diazaspiro[4.5]decan-3-yl]-N-(5-methyl-isoxazol-3-yl)-acetamide
SC_1084
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 isoxazol-3-amine SC_1051 466.3
diazaspiro[4.5]decan-3-yl]-N-isoxazol-3-yl-acetamide SC_1085
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 1-methyl-1H-pyrazol-3-amine SC_1051 479.3
diazaspiro[4.5]decan-3-yl]-N-(1-methyl-1H-pyrazol-3-yl)-acetamide
SC_1086
CIS-N-(4-Cyano-5-methylsulfanyl-1H-pyrazol-3-yl)-2-[1-(cyclobutyl-
INT 993 3-amino-5-(methylthio)-1H- SC_1051 536.3
methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-
pyrazole-4-carbonitrile yl]-acetamide SC_1087
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 5-methoxypyrazin-2-amine SC_1051 507.3
diazaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyrazin-2-yl)-acetamide
SC_1088
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 pyridazin-4-ylmethanamine SC_1051 491.3
diazaspiro[4.5]decan-3-yl]-N-(pyridazin-4-yl-methyl)-acetamide
SC_1089
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 2-(aminomethyl)phenol SC_1051 505.3
diazaspiro[4.5]decan-3-yl]-N-[2-hydroxyphenyl)methyl]-acetamide
SC_1090
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 (1-methyl-1H-imidazol-4- SC_1051 493.3
diazaspiro[4.5]decan-3-yl]-N-[(1-methyl-1H-imidazol-4-yl)-methyl]-
yl)methanamine acetamide SC_1091
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 (4-methylpyridin-3-yl) SC_1051 504.3
diazaspiro[4.5]decan-3-yl]-N-[(4-methyl-pyridin-3-yl)-methyl]-
methanamine acetamide SC_1092
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 pyrimidin-2-ylmethanamine SC_1051 491.3
diazaspiro[4.5]decan-3-yl]-N-(pyrimidin-2-yl-methyl)-acetamide
SC_1093
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 pyridazin-3-ylmethanamine SC_1051 491.3
diazaspiro[4.5]decan-3-yl]-N-(pyridazin-3-yl-methyl)-acetamide
SC_1094
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 pyrimidin-4-ylmethanamine SC_1051 491.3
diazaspiro[4.5]decan-3-yl]-N-(pyrimidin-4-yl-methyl)-acetamide
SC_1095
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 pyrazin-2-ylmethanamine SC_1051 491.3
diazaspiro[4.5]decan-3-yl]-N-(pyrazin-2-yl-methyl)-acetamide
SC_1096
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 oxazol-4-ylmethanamine SC_1051 480.3
diazaspiro[4.5]decan-3-yl]-N-(oxazol-4-yl-methyl)-acetamide SC_1097
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 (2-methylpyridin-3-yl) SC_1051 504.3
diazaspiro[4.5]decan-3-yl]-N-[(4-methyl-pyridin-3-yl)-methyl]-
methanamine acetamide SC_1098
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 (2-methoxypyridin-3- SC_1051 520.3
diazaspiro[4.5]decan-3-yl]-N-[(2-methoxy-pyridin-3-yl)-methyl]-
yl)methanamine acetamide SC_1099
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 (4-methoxypyridin-3- SC_1051 520.3
diazaspiro[4.5]decan-3-yl]-N-[(4-methoxy-pyridin-3-yl)-methyl]-
yl)methanamine acetamide SC_1100
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 (6-methylpyridin-2-yl) SC_1051 504.3
diazaspiro[4.5]decan-3-yl]-N-[(6-methyl-pyridin-2-yl)-methyl]-
methanamine acetamide SC_1101
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 (6-methoxypyridin-2- SC_1051 520.3
diazaspiro[4.5]decan-3-yl]-N-[(6-methoxy-pyridin-2-yl)-methyl]-
yl)methanamine acetamide SC_1102
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 (2-methoxyphenyl)methanamine SC_1051 519.3
diazaspiro[4.5]decan-3-yl]-N-[(2-methoxyphenyl)-methyl]-acetamide
SC_1103
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 o-tolylmethanamine SC_1051 503.3
diazaspiro[4.5]decan-3-yl]-N-(o-tolyl-methyl)-acetamide SC_1104
CIS-6-[[2-[-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
- INT 999 6-amino-N-methylnicotinamide SC_1073 533.3
diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-pyridine-3-
carboxylic acid amide SC_1105
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,-
3- SC 1030 -- SC_1076 519.3
diazaspiro[4.5]decan-3-yl]-acetyl]amino]-pyridine-4-carboxylic acid
amide SC_1106
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 6-methoxypyrimidin-4-amine SC_1308 507.3
diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyrimidin-4-yl)-acetamide
SC_1107
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 2-methoxypyrimidin-4-amine SC_1308 507.3
diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-pyrimidin-4-yl)-acetamide
SC_1109
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- SC
1069 SC_1110 493.3
diazaspiro[4.5]decan-3-yl]-N-(4-hydroxy-pyrimidin-5-yl)-acetamide
SC_1111
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 6-aminopyridin-3-ol SC_1308 492.3
diazaspiro[4.5]decan-3-yl]-N-(5-hydroxy-pyridin-2-yl)-acetamide
SC_1112
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 4-aminotetrahydro-2H-thiopyran SC_1308 531.3
diazaspiro[4.5]decan-3-yl]-N-(1,1-dioxo-thian-4-yl)-acetamide
1,1-dioxide SC_1113
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-(1,1-dioxo- INT 993
thiomorpholine 1,1-dioxide SC_1308 517.3
[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-
one SC_1114
CIS-2-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3- INT
997 pyrimidin-4-amine SC_1308 467.3
diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide SC_1115
CIS-2-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3- INT
997 methylamine SC_1308 403.3
diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1117
CIS-N-(5-Cyano-pyrimidin-4-yl)-2-[1-(cyclobutyl-methyl)-8- INT 993
4-aminopyrimidine-5-carbonitrile SC_1308 502.3
dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-
acetamide SC_1118
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 5-(methylthio)pyridin-2-amine SC_1308 522.3
diazaspiro[4.5]decan-3-yl]-N-(5-methylsulfanyl-pyridin-2-yl)-acetamide
SC_1119
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 4-methoxypyrimidin-2-amine SC_1308 507.3
diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyrimidin-2-yl)-acetamide
SC_1120
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 6-(methylthio)pyridin-2-amine SC_1308 522.3
diazaspiro[4.5]decan-3-yl]-N-(6-methylsulfanyl-pyridin-2-yl)-acetamide
SC_1121
CIS-2-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3- INT
997 2-aminoethanol SC_1308 433.3
diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide SC_1122
CIS-2-[[2[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-
INT 997 2-aminoacetamide SC_1308 446.3
diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide SC_1123
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 methylamine SC_1308 413.3
diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1124
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 2-aminoethanol SC_1308 443.3
diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide SC_1125
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 6-aminopyridin-2-ol SC_1308 492.3
diazaspiro[4.5]decan-3-yl]-N-(6-hydroxy-pyridin-2-yl)-acetamide
SC_1126
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 (2-methoxypyrimidin-5- SC_1308 521.3
diazaspiro[4.5]decan-3-yl]-N-[(2-methoxy-pyrimidin-5-yl)-methyl]-
yl)methanamine acetamide SC_1127
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 (4-methoxypyrimidin-2- SC_1308 521.3
diazaspiro[4.5]decan-3-yl]-N-[(4-methoxy-pyrimidin-2-yl)-methyl]-
yl)methanamine acetamide SC_1130
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-
SC 1011 2-amino-2-methylpropanamide SC_1303 470.3
diazaspiro[4.5]decan-3-yl]-acetyl]amino]-2-methyl-propionamide
SC_1131
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-
SC 1222 -- SC_1303 456.3
diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-acetamide SC_1132
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-
SC 1078 -- SC_1303 442.3
diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide SC_1133
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 2-(2-(2-methoxyethoxy)ethoxy)- SC_1308 545.4
diazaspiro[4.5]decan-3-yl]-N-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl]-
ethanamine acetamide SC_1134
CIS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-methylamino-2-
SC 1146 2-(methylamino)acetamide SC_1303 456.3
oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide
SC_1135
CIS-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3- SC
1005 N-methyl-2- SC_1303 470.3
diazaspiro[4.5]decan-3-yl]-N-methyl-N-(methylcarbamoyl-methyl)-
(methylamino)acetamide acetamide SC_1137
CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-
INT 994 pyrimidin-5-amine SC_1136 493.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-5-yl-acetamide
SC_1139
CIS-2-[8-Dimethylamino-1-[(dimethyl-carbamoyl)-methyl]-2-oxo-8- INT
996 2-aminoethanol SC_1308 460.3
phenyl-1,3-diazaspiro[4.5-yl]-N-(2-hydroxy-ethyl)-acetamide SC_1140
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-
SC 1007 -- SC_1303 484.3
diazaspiro[4.5]decan-3-yl]-acetyl]-methyl-amino]-2-methyl-
propionamide SC_1141
CIS-1-(Cyclobutyl-methyl)-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-o-
xo- SC 1214 -- SC_1303 503.3
ethyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
SC_1142
CIS-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3- SC
1199 -- SC_1303 707.5
diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-
ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethyl]-acetamide SC_1143
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-
SC 1065 -- SC_1303 470.3
diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N,N-dimethyl-acetamide
SC_1144
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- SC
1070 -- SC_1110 493.3
diazaspiro[4.5]decan-3-yl]-N-(5-hydroxy-pyrimidin-2-yl)-acetamide
SC_1145
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
SC_1321 -- SC_1138 554.3
diazaspiro[4.5]decan-3-yl]-N-(4-methylsulfonyl-pyridin-2-yl)-acetamide
SC_1146
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,-
3- INT 993 2-amino-N-methylacetamide SC_1308 470.3
diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-acetamide SC_1147
CIS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-
INT 993 2-(methylamino)acetamide SC_1308 470.3
2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide
SC_1148 CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1-propyl-1,3- INT 995
methylamine SC_1136 387.3
diazaspiro[4.5]decan-3-yl)-N-methyl-acetamide
SC_1150
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
SC_1321 -- SC_1129 538.3
diazaspiro[4.5]decan-3-yl]-N-[4-(methylsulfinyl)-pyridin-2-yl]-
acetamide SC_1151
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 2-aminopyridin-3-ol SC_1308 492.3
diazaspiro[4.5]decan-3-yl]-N-(3-hydroxy-pyridin-2-yl)-acetamide
SC_1152
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 2-(methylsulfonyl)ethanamine SC_1308 505.3
diazaspiro[4.5]decan-3-yl]-N-(2-methylsulfonyl-ethyp-acetamide
SC_1154
CIS-1-(Cyclobutyl-methyl)-3-[2-[(3S,4R)-3,4-dihydroxy-pyrrolidin-1-
- INT 993 (3S,4R)-pyrrolidine-3,4-diol SC_1308 485.3
yl]-2-oxo-ethyl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-
one SC_1155
CIS-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3- SC
1198 -- SC_1303 429.3
diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide SC_1156
CIS-2-[8-Dimethylamino-1-[(dimethyl-carbamoyl)-methyl]-2-oxo-8- INT
996 pyrimidin-4-amine SC_1308 494.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide
SC_1157
CIS-2-[8-Dimethylamino-1-[(dimethyl-carbamoyl)-methyl]-2-oxo-8- INT
996 methylamine SC_1308 430.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1158
CIS-2-[[2-[8-Dimethylamino-1-(2-methyl-propyl)-2-oxo-8-phenyl-1,3-
INT 992 2-aminoacetamide SC_1136 444.3
diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide SC_1159
CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-
INT 994 NH.sub.4Cl SC_1136 415.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide SC_1160
CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-
INT 994 methylamine SC_1136 429.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1161
CIS-2-[[2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-
- INT 987 N-(2-amino-2-oxoethyl)-2- SC_1149 460.3
diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide bromoacetamide
SC_1162
CIS-2-[8-Dimethylamino-1-(2-methyl-propyl)-2-oxo-8-phenyl-1,3- INT
984 2-bromo-N-methylacetamide SC_1149 401.3
diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1163
CIS-1-(Cyclobutyl-methyl)-3-[2-[(3S,4R)-3,4-dihydroxy-pyrrolidin-1-
- SC 1154 -- SC_1303 471.3
yl]-2-oxo-ethyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-
one SC_1164
CIS-2-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-
INT 998 methylamine SC_1308 427.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1165
CIS-2-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-
INT 998 pyrimidin-4-amine SC_1308 491.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide
SC_1166
CIS-2-[[2-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo--
8- INT 998 2-aminoacetamide SC_1308 470.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide
SC_1167
CIS-2-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-
INT 998 2-aminoethanol SC_1308 457.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide
SC_1168
CIS-2-[[2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-
INT 983 N-(2-amino-2-oxoethyl)-2- SC_1149 442.3
1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide
bromoacetamide SC_1169
CIS-2-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-
- INT 986 2-bromo-N-methylacetamide SC_1149 427.3
1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1171
CIS-2-[[2-(8-Dimethylamino-2-oxo-8-phenyl-1-propyl-1,3- INT 995
2-aminoacetamide SC_1308 430.3
diazaspiro[4.5]decan-3-yl)-acetyl]amino]-acetamide SC_1172
CIS-2-[[2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-
- INT 994 2-aminoacetamide SC_1308 472.3
8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide
SC_1173
CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-
INT 994 2-aminoethanol SC_1308 459.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide
SC_1174
CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-
INT 994 4-aminotetrahydro-2H-thiopyran SC_1308 547.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(1,1-dioxo-thian-4-yl)-
1,1-dioxide acetamide SC_1175
CIS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 983 2-bromo-N-methylacetamide SC_1149 399.3
diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1176
CIS-2-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8- INT
951 2-bromo-N-methylacetamide SC_1149 438.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1177
CIS-2-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-
- INT 998 2-aminoethanol SC_1308 457.3
1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide
SC_1178
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-
INT 998 2-aminoacetamide SC_1308 470.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide
SC_1179
CIS-2-[[2-[1-(Cyclobulyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-
SC 1008 -- SC_1303 484.3
diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N,2-dimethyl-propionamide
SC_1180
ClS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3- INT
990 2-aminoethanol SC_1308 447.3
diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamidc SC_1181
CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3- INT
990 N-methyl-2- SC_1308 488.3
diazaspiro[4.5]decan-3-yl]-N-melhyl-N-(methylcarbamoyl-methyl)-
(methylamino)acetamide acetamide SC_1182
CIS-8-Dimethylamino-1-(3-methoxy-propyl)-3-[2-oxo-2-(3-oxo- INT 990
piperazin-2-one SC_1308 486.3
piperazin-1-yl)-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
SC_1183
CIS-N-(Carbamoyl-methyl)-2-[8-dimethylamino-1-(3-methoxy-propyl)-
INT 990 2-(methylamino)acetamide SC_1308 474.3
2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide
SC_1184
CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3- INT
990 cis-3-(aminomethyl)cyclobutanol SC_1073 487.3
diazaspiro[4.5]decan-3-yl]-N-[(3-hydroxy-cyclobutyl)-methyl]-acetamide
SC_1185
CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3- INT
990 trans-3-(aminomethyl)cyclobutanol SC_1073 487.3
diazaspiro[4.5]decan-3-yl]-N-[(3-hydroxy-cyclobutyl)-methyl]-acetamide
SC_1186
CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3- INT
990 3-(aminomethyl)cyclopentanol SC_1073 501.3
diazaspiro[4.5]decan-3-yl]-N-[(3-hydroxy-cyclopentyl)-methyl]-
acetamide SC_1187
CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3- INT
990 pyridazin-4-amine SC_1308 481.3
diazaspiro[4.5]decan-3-yl]-N-pyridazin-4-yl-acetamide SC_1188
CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3- INT
990 6-methoxypyridin-2-amine SC_1308 510.3
diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyridin-2-yl)-acetamide
SC_1189
CIS-N-(2-Cyanoethyl)-2-[8-dimethylamino-1-(3-methoxy-propyl)-2- INT
990 3-aminopropanenitrile SC_1308 456.3
oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide SC_1190
CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3- INT
990 pyrimidin-5-amine SC_1308 481.3
diazaspiro[4.5]decan-3-yl]-N-pyrimidin-5-yl-acetamide SC_1191
CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3- INT
990 pyrimidin-4-amine SC_1308 481.3
diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide SC_1192
CIS-2-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-
- INT 999 6-methoxypyridin-2-amine SC_1073 520.3
1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyridin-2-yl)-acetamide
SC_1193
CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-
INT 995 pyridin-3-amine SC_1308 492.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridin-3-yl-acetamide
SC_1195
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 999 NH.sub.4Cl SC_1073 399.3
diazaspiro[4.5]decan-3-yl]-acetamide SC_1196
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 999 pyrimidin-4-amine SC_1073 477.3
diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide SC_1197
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 999 2-methoxyethanamine SC_1073 457.3
diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-ethyl)-acetamide SC_1198
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 999 2-aminoethanol SC_1073 443.3
diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide SC_1199
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 2,5,8,11,14,17,20- SC_1308 721.5
diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-
heptaoxadocosan-22-amine
ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethyl]-acetamide SC_1201
CIS-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3- SC
1229 -- SC_1303 399.3 diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide
SC_1203
CIS-(2S)-1-[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- INT
993 (S)-pyrrolidine-2-carboxamide SC_1308 496.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]-pyrrolidine-2-carboxylic
acid amide SC_1204
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,-
3- INT 993 2-amino-N,N-dimethylacetamide SC_1308 484.3
diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N,N-dimethyl-acetamide
SC_1205
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 oxetan-3-amine SC_1308 455.3
diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-acetamide SC_1206
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,-
3- INT 993 2-aminoacetamide SC_1308 456.3
diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide SC_1207
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-oxo-2-(3-oxo- INT
999 piperazin-2-one SC_1073 482.3
piperazin-1-yl-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
SC_1208
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 999 4-aminotetrahydro-2H-thiopyran SC_1073 531.3
diazaspiro[4.5]decan-3-yl]-N-(1,1-dioxo-thian-4-yl)-acetamide
1,1-dioxide SC_1209
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-[2-(hydroxymethyl)-
INT 999 morpholin-2-ylmethanol SC_1073 499.3
morpholin-4-yl]-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
SC_1210
CIS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-
INT 993 2-(methylamino)acetamide SC_1308 470.3
2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide
SC_1211
CIS-N-(Cyano-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-
INT 993 2-aminoacetonitrile SC_1308 438.3
oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide SC_1212
CIS-N-(2-Acetylamino-ethyl)-2-[1-(cyclobutyl-methyl)-8- INT 993
N-(2-aminoethyl)acetamide SC_1308 484.3
dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-
acetamide SC_1213
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 999 2-(methylsulfonyl)ethan-amine SC_1073 505.3
diazaspiro[4.5]decan-3-yl]-N-(2-methylsulfonyl-ethyp-acetamide
SC_1214 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-(1,1-dioxo-
INT 999 thiomorpholine 1,1-dioxide SC_1073 517.3
[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-
one SC_1215
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 999 4-(aminomethyl)tetra-hydro-2H- SC_1073 545.3
diazaspiro[4.5]decan-3-yl]-N-[(1,1-dioxo-thian-4-yl)-methyl]-acetamide
thiopyran 1,1-dioxide SC_1216
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-(4-methylsulfonyl-
INT 999 1-(methylsulfonyl-piperazine SC_1073 546.3
piperazin-1-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
SC_1217
CIS-N-(2-Cyanoethyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-
INT 993 3-aminopropanenitrile SC_1308 452.3
oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide SC_1218
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 1-amino-2-methylpropan-2-ol SC_1308 471.3
diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-2-methyl-propyl)-acetamide
SC_1219
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 2-amino-1-morpholinoethanone SC_1308 526.3
diazaspiro[4.5]decan-3-yl]-N-(2-morpholin-4-yl-2-oxo-ethyl)-acetamide
SC_1220
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 2-(2-aminoethoxy)ethanol SC_1308 487.3
diazaspiro[4.5]decan-3-yl]-N-[2-(2-hydroxy-ethoxy)-ethyl]-acetamide
SC_1222
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,-
3- INT 993 2-amino-N-methylacetamide SC_1308 470.3
diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-acetamide SC_1223
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 N-(2-aminoethyl)-
diazaspiro[4.5]decan-3-yl]-N-[2-(methanesulfonamido)-ethyl]-acetamide
methanesulfonamide SC_1308 520.3 SC_1224
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 1-(aminomethyl)-cyclopentanol SC_1308 497.3
diazaspiro[4.5]decan-3-yl]-N-[(1-hydroxy-cyclopentyl)-methyl]-
acetamide SC_1225
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 4-(aminomethyl)cyclohexanol SC_1308 511.4
diazaspiro[4.5]decan-3-yl]-N-[(4-hydroxy-cyclohexyl)-methyl]-
acetamide SC_1226
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 2-(2-methoxyethoxy)-ethanamine SC_1308 501.3
diazaspiro[4.5]decan-3-yl]-N-[2-(2-methoxy-ethoxy)-ethyl]-acetamide
SC_1227
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 N.sup.1,N.sup.1-dimethylethane-1,2-diamine SC_1308 470.3
diazaspiro[4.5]decan-3-yl]-N-[2-(dimethylamino)ethyl]-acetamide
SC_1228
CIS-2-[1-(Cyclobutyl-methyl)-8-[methyl-(2-methyl-propyl)-amino]-2-
INT 953 2-bromo-N-methylacetamide SC_1149 455.3
oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide
SC_1229
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 999 methylamine SC_1073 413.3
diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1230
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 pyrimidin-4-amine SC_1051 477.3
diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide SC_1231
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 6-methylpyridin-2-amine SC_1051 490.3
diazaspiro[4.5]decan-3-yl]-N-(6-methyl-pyridin-2-yl)-acetamide
SC_1232
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 pyridazin-3-amine SC_1051 477.3
diazaspiro[4.5]decan-3-yl]-N-pyridazin-3-yl-acetamide SC_1233
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 pyrimidin-5-amine SC_1051 477.3
diazaspiro[4.5]decan-3-yl]-N-pyrimidin-5-yl-acetamide SC_1234
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 pyridazin-4-amine SC_1051 477.3
diazaspiro[4.5]decan-3-yl]-N-pyridazin-4-yl-acetamide SC_1235
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 6-methoxypyrimidin-4-amine SC_1051 507.3
diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyrimidin-4-yl)-acetamide
SC_1236
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 2-methylpyridin-4-amine SC_1051 490.3
diazaspiro[4.5]decan-3-yl]-N-(2-methyl-pyridin-4-yl)-acetamide
SC_1300
CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-
INT 994 pyridin-4-amine SC_1308 492.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridin-4-yl-acetamide
SC_1301
CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-
INT 994 oxetan-3-amine SC_1308 471.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-acetamide
SC_1302
CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-
INT 994 2-methoxyethanamine SC_1308 473.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-ethyl)-acetamide
SC_1304
CIS-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8- SC
1301 -- SC_1303 459.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-ethyl)-acetamide
SC_1305
CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3- SC
1302 -- SC_1308 510.3
diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyridin-2-yl)-acetamide
SC_1306
CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3- INT
990 pyrimidin-4-ylmethanamine SC_1073 495.3
diazaspiro[4.5]decan-3-yl]-N-(pyrimidin-4-yl-methyl)-acetamide
SC_1309
CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-
SC 1159 -- SC_1128 492.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridin-2-yl-acetamide
SC_1310
CIS-2-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8- INT
989 NH.sub.4Cl SC_1308 424.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide SC_1311
CIS-2-[[2-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-
- INT 989 2-aminoacetamide SC_1308 481.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide
SC_1312
CIS-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8- SC
1160 -- SC_1303 415.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1313
CIS-3-[2-(1,1-Dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-methylamin-
o- SC 1308 -- SC_1303 477.2
8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-2-one SC_1317
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 pyridin-2-amine SC_1051 476.3
diazaspiro[4.5]decan-3-yl]-N-pyridin-2-yl-acetamide SC_1318
CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyp-methyl]-3-(2- INT 994
morpholine SC_1136 485.3
morpholin-4-yl-2-oxo-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
SC_1319
CIS-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8- SC
1159 -- SC_1303 401.2
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide SC_1320
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(2-morpholin-4-yl-2-
INT 993 morpholine SC_1308 469.3
oxo-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1321
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
INT 993 4-(methylthio)pyridin-2-amine SC_1073 522.3
diazaspiro[4.5]decan-3-yl]-N-(4-methylsulfanyl-pyridin-2-yl)-acetamide
in analogy m/z Example Chemical name Reactant I Reactant II to
method .sup.1H NMR data (M + H).sup.+ SC_1322
CIS-3-[2-(1,1-Dioxo-[1,4]thiazinan-4- INT-1014 thiomorpholin-
SC_1308 .sup.1HNMR data (DMSO-d6, 400 MHz), .delta. (ppm) = 7.40
(d, 2H, J = 7.2 435.3 yl)-2-oxo-ethyl]-8-methylamino-8- 1,1-dioxide
(for step 1), Hz), 7.31 (t, 2H, J = 7.44 Hz), 7.18 (t, 1H, J = 6.78
Hz), 6.61 (bs, phenyl-1,3-diazaspiro[4.5]decan-2- SC_1303 1H), 3.98
(s, 2H), 3.82 (bs, 4H), 3.21 (bs, 4H), 3.09 (s, 2H), 1.95 one (for
step 2) (t, 2H, J = 11.74 Hz), 1.85 (bs, 5H), 1.65 (bs, 2H), 1.48
(bs, 2H). SC_1323 CIS-2-(8-Methylamino-2-oxo-8- SC_1324 SC_1303
.sup.1HNMR (DMSO-d6, 400 MHz), .delta. (ppm) = 7.41 (d, 2H, J =
7.60 317.2 phenyl-1,3-diazaspiro[4.5]decan-3- Hz), 7.30 (t, 2H, J =
7.60 Hz), 7.23 (s, 1H), 7.18 (t, 1H, J = 7.08 yl)-acetamide Hz),
6.95 (s, 1H), 6.58 (s, 1H), 3.58 (s, 2H), 3.21 (s, 2H), 1.96- 1.80
(m, 7H), 1.69-1.66 (m, 2H), 1.47 (d, 2H, J = 11.76 Hz). SC_1324
CIS-2-(8-Dimethylamino-2-oxo-8- INT-1014 procedure -- 331.2
phenyl-1,3-diazaspiro[4.5]decan-3- described yl)-acetamide SC_1325
CIS-3-[2-(1,1-Dioxo-[1,4]thiazinan-4- INT-1015 thiomorpholin-
SC_1308 .sup.1HNMR (DMSO-d6, 400 MHz), .delta. (ppm) = 7.42 (d, 2H,
J = 7.2 449.4 yl)-2-oxo-ethyl]-8-ethylamino-8- 1,1-dioxide (for
step 1), Hz), 7.29 (t, 2H, J = 7.2 Hz), 7.17 (t, 1H), 6.61 (s, 1H),
5.75 (s, phenyl-1,3-diazaspiro[4.5]decan-2- SC_1303 1H), 3.98 (s,
2H), 3.82 (s, 4H), 3.21 (s, 4H), 3.09 (s, 2H), 2.07- one (for step
2) 1.93 (m, 4H), 1.87-1.83 (m, 2H), 1.69-1.66 (m, 2H), 1.48-1.45
(m, 2H), 0.92 (t, 3H, J = 6.8 Hz). SC_1326 TRANS-3-[2-(1,1-Dioxo-
INT-1017 thiomorpholin- SC_1308 .sup.1HNMR (DMSO-d6, 400 MHz),
.delta. (ppm) = 7.50 (d, 2H, J = 7.4 449.2
[1,4]thiazinan-4-yl-2-oxo-ethyl]-8- 1,1-dioxide (for step 1), Hz),
7.30 (t, 2H, J = 7.2 Hz), 7.18-7.15 (m, 2H), 4.00 (s, 2H),
ethylamino-8-phenyl-1,3- SC_1303 (for 3.84 (bs, 4H), 3.24 (s, 2H),
3.19 (s, 2H), 3.11 (s, 2H), 2.07- diazaspiro[4.5]decan-2-one step
2) 1.44(m, 11H), 0.91 (t, 3H, J = 6.6 Hz). SC_1327
CIS-2[1-(Cyclobutyl-methyl)-8- INT-998 methylamine SC_1308 .sup.1H
NMR (DMSO-d6): .delta. 7.71-7.70 (m, 1H), 7.43 (d, 2H), 7.30 (t,
399.3 methylamino-2-oxo-8-phenyl-1,3- (step 1) (for step 1), 2H),
7.18 (t, 1H), 3.64 (s, 2H), 3.21 (s, 2H), 3.08 (d, 2H), 2.57-
diazaspiro[4.5]decan-3-yl]-N-methyl- SC_1303 2.54 (m, 4H), 2.25 (m,
1H), 2.11-2.06 (m, 2H), 1.97-1.82 (m, acetamide (for step 2) 7H),
1.80-1.67 (m, 4H), 1.59 (m, 2H), 1.36-1.35 (m, 2H). SC_1328
CIS-2-(8-Ethylamino-2-oxo-8-phenyl- INT-1015 SC_1324 .sup.1HNMR
(DMSO-d6, 400 MHz), .delta. (ppm) = 7.43 (d, 2H, J = 7.6 331.1
1,3-diazaspiro[4.5]decan-3-yl)- Hz), 7.29 (t, 2H, J = 7.2 Hz), 7.22
(s, 1H), 7.17 (t, 1H, J = 6.8 acetamide Hz), 6.95 (s, 1H), 6.58 (s,
1H), 3.58 (s, 2H), 3.20 (s, 2H), 2.07-2.05 (m, 2H), 1.93 (t, 2H, J
= 11.2), 1.85-1.82 (m, 2H), 1.69-1.67 (m, 2H,), 1.48-1.45 (m, 2H),
0.92 (t, 3H, J = 6.8 Hz). SC_1329 TRANS-2-(8-Ethylamino-2-oxo-8-
INT-1017 SC_1324 .sup.1HNMR (DMSO-d6, 400 MHz), .delta. (ppm) =
7.49 (d, 2H, J = 7.56 331.2 phenyl-1,3-diazaspiro[4.5]decan-3- Hz),
7.29 (t, 2H, J = 7.66 Hz), 7.24 (s, 1H), 7.16 (t, 1H), 7.24
yl)-acetamide Hz), 7.11 (bs, 1H), 6.98 (bs, 1H), 3.59 (s, 2H), 3.17
(s, 2H), 2.09- 1.95 (m, 4H). SC_1330
CIS-2-(8-Dimethylamino-2-oxo-8- INT-1014 2- SC_1308 .sup.1HNMR
(DMSO-d6, 400 MHz at 100.degree. C.), .delta. (ppm) = 7.34-7.23
389.2 phenyl-1,3-diazaspiro[4.5]decan-3- (methylamino)- (m, 5H),
6.41 (s, 1H), 4.4 (bs, 1H), 3.89 (s, 2H), 3.53-3.52 (m,
yl)-N-(2-hydroxy-ethyl)-N-methyl- ethanol 2H), 3.34 (t, 2H, J =
5.56 Hz), 3.13 (s, 2H), 2.89 (s, 2H), 2.31- acetamide 2.27 (m, 2H),
2.01 (s, 6H), 1.89-1.78 (m, 4H), 1.46-1.41 (m, 2H). SC_1331
CIS-8-Dimethylamino-3-[2-(1,1- INT-1020 1,4-thiazinane SC_1308
.sup.1H NMR (600 MHz, DMSO) .delta. 7.35 (qd, 4H), 7.26 (tt, 1H),
4.40 547.3 dioxo-[1,4]thiazinan-4-yl)-2-oxo- 1,1-dioxide (s, 2H),
3.89 (dt, 4H), 3.26 (t, 2H), 3.11 (d, 2H), 2.64-2.58 (m,
ethyl]-1-[(1-hydroxy-cyclobutyl)- 2H), 2.45 (td, 2H), 2.14 (tt,
2H), 2.03 (td, 2H), 1.98 (s, 6H), 1.97- methyl]-8-phenyl-1,3- 1.88
(m, 2H), 1.70-1.63 (m, 1H), 1.58-1.47 (m, 3H).
diazaspiro[4.5]decane-2,4-dione SC_1332
CIS-2-(8-Dimethylamino-2-oxo-8- INT-976 procedure .sup.1H NMR
(CDCl3): .delta. 8.32 (br s, 1H), 7.50-7.48 (d, 2H), 7.39- 407.2
phenyl-1,3-diazaspiro[4.5]decan-3- described 7.36 (m, 2H),
7.33-7.26 (m, 5H), 7.12-7.08 (t, 1H), 5.90 (br s,
yl)-N-phenyl-acetamide 1H), 3.90 (s, 2H), 3.25 (s, 2H), 2.12 (m,
4H), 1.99 (s, 6H), 1.94- 1.91 (m, 2H),1.58-1.53 (m, 2H). SC_1333
CIS-N-(Carbamoyl-methyl)-2-[1- INT-991 2-methylamino- SC_1308
.sup.1HNMR (DMSO-d6, 400 MHz at 100.degree. C.), .delta. (ppm) =
7.34-7.23 388.3 (cyclopropyl-methyl)-8- acetamide.cndot.HCl (m,
5H), 6.85 (bs, 2H), 3.94 (s, 2H), 3.88 (s, 2H), 3.26 (s, 2H),
dimethylamino-2-oxo-8-phenyl-1,3- 3.00-2.99 (m, 2H), 2.95 (s, 3H),
2.61 (d, 2H, J = 13.2 Hz), 2.22 (t,
diazaspiro[4.5]decan-3-yl]-N-methyl- 2H, J = 12 Hz), 2.06 (s, 6H),
1.47-1.38 (m, 4H), 0.98 (m, 1H), acetamide 0.48 (d, 2H, J = 7.6
Hz), 0.28 (d, 2H, 4.8 Hz). SC_1334
CIS-2-(8-Dimethylamino-2,4-dioxo-8- INT-1018 2-Bromo-N- SC_1332
.sup.1HNMR (DMSO-d6): .delta. 10.19 (s, 1H), 8.80 (br s,1H ), 7.52-
421.2 phenyl-1,3-diazaspiro[4.5]decan-3- phenylacet- 7.520 (d, 2H),
7.42-7.34 (m, 4H), 7.31-7.27 (m, 3H), 7.06-7.02
yl)-N-phenyl-acetamide amide (t, 1H), 4.11 (s, 2H), 2.49-2.45 (m,
2H), 2.03-1.93 (m, 8H), 1.71- 1.68 (m, 2H), 1.60-1.54 (m, 2H).
SC_1335 CIS-2-[1-(Cyclobutyl-methyl)-8- INT-998 NH.sub.4Cl SC_1308
.sup.1H NMR (DMSO-d6): .delta. 7.36-7.22 (m, 6H), 6.93 (br s, 1H),
3.61 399.3 dimethylamino-2-oxo-8-phenyl-1,3- (s, 2H), 3.18 (s, 2H),
3.04 (d, 2H), 2.66-2.63 (m, 2H), 2.54-2.52
diazaspiro[4.5]decan-3-yl]-acetamide (m, 1H), 2.07-1.93 (m, 10H),
1.81-1.67 (m, 4H), 1.39-1.29 (m, 4H). SC_1336
CIS-2-[8-Dimethylamino-1-[(1- INT-1019 2,5,8,11- SC_1308 .sup.1H
NMR (DMSO-d6): .delta. 7.37-7.33 (m, 2H), 7.28-7.26 (m, 3H), 605.3
hydroxy-cyclobutyl)-methyl]-2-oxo-8- tetraoxatridecan- 6.67 (t,
1H), 6.31 (br, s, 1H), 3.83 (s, 2H), 3.65-3.59 (m, 10H),
phenyl-1,3-diazaspiro[4.5]decan-3- 13-amine 3.55-3.52 (m, 4H),
3.46-3.42 (m, 2H), 3.37 (s, 5H), 3.29 (s, 2H),
yl]-N-[2-[2-[2-(2-methoxy-ethoxy)- 2.68-2.65 (m, 2H), 2.20-2.06 (m,
12H), 1.78-1.71 (m, 1H), 1.59- ethoxy]-ethoxy]-ethyl]-acetamide
1.56 (m, 2H), 1.48-1.37 (m, 3H). SC_1337
CIS-3-[2-(1,1-Dioxo-[1,4]thiazinan-4- SC_1331 SC_1303 .sup.1H NMR
(600 MHz, DMSO) .delta. 7.46 (d, 2H), 7.33 (t, 2H), 7.21 (t, 533.3
yl)-2-oxo-ethyl]-1-[(1-hydroxy- 1H), 4.42 (s, 2H), 3.90 (dt, 4H),
3.49 (s, 2H), 3.28 (t, 2H), 3.12 cyclobutyl)-methyl]-8-methylamino-
(t, 2H), 2.47 (dd, 2H), 2.35-2.25 (m, 2H), 2.15-2.08 (m, 2H),
8-phenyl-1,3-diazaspiro[4.5]decane- 1.98-1.89 (m, 6H), 1.84 (d,
2H), 1.71-1.63 (m, 1H), 1.58- 2,4-dione 1.48 (m, 3H). SC_1338
CIS-2-(8-Dimethylamino-2-oxo-8- INT-976 2-bromo-N- SC_1332 .sup.1H
NMR (DMSO-d6): .delta. 7.78 (t, 1H), 7.37-7.23 (m, 5H), 6.89 (br
521.3 phenyl-1,3-diazaspiro[4.5]decan-3- (2,5,8,11- s, 1H), 3.60
(s, 2H), 3.49-3.47 (m, 10H), 3.43-3.37 (m, 4H),
yl)-N-[2-[2-[2-(2-methoxy-ethoxy)- tetraoxatridecan- 3.22-3.17 (m,
5H), 3.08 (s, 2H), 2.30 (br m, 2H), 1.92-1.74 (m,
ethoxy]-ethoxy]-ethyl]-acetamide 13- 10H), 1.38 (br m, 2H).
yl)acetamide SC_1339 CIS-N-(Carbamoyl-methyl)-N- INT-1034
2-methylamino- SC_1308 .sup.1HNMR (DMSO-d6, 400 MHz at 100.degree.
C.), .delta. (ppm) = 7.43 (d, 388.3
methyl-2-(8-methylamino-2-oxo-8- acetamide.cndot.HCl 2H, J = 7.52
Hz), 7.31 (t, 2H, J = 7.44 Hz), 7.18 (t, 1H, J = 7.20
phenyl-1,3-diazaspiro[4.5]decan-3- Hz), 6.8 (bs, 2H), 3.88 (s, 4H),
3.25 (s, 2H), 2.95 (3H, merged yl)-acetamide with DMSO water),
1.97-1.85 (m, 7H), 1.77-1.50 (m, 4H). SC_1340
CIS-N-(Carbamoyl-methyl)-2-(8- INT-1014 2-methylamino- SC_1308
.sup.1HNMR (DMSO-d6, 400 MHz at 100 0C), .delta. (ppm) = 7.33-7.23
402.1 dimethylamino-2-oxo-8-phenyl-1,3- acetamide.cndot.HCl (m,
5H), 6.84 (bs, 2H), 6.45 (s, 1H), 3.87 (s, 4H), 3.13 (s, 2H),
diazaspiro[4.5]decan-3-yl)-N-methyl- 2.95 (3H, merged with DMSO
water), 2.32-2.27 (m, 2H), 2.01 acetamide (s, 6H), 1.88-1.77 (m,
4H), 1.46-1.41 (m, 2H). SC_1341 CIS-N-(Carbamoyl-methyl)-2-[8-
INT-1035 2-methylamino- SC_1308 .sup.1HNMR (DMSO-d6, 400 MHz at
100.degree. C.), .delta. (ppm) = 7.33-7.24 472.3
dimethylamino-1-(oxetan-3-yl- acetamide.cndot.HCl (m, 5H), 6.8 (bs,
2H), 4.63 (t, 2H, J = 5.6 Hz), 4.39 (s, 2H), 3.93-
methyl)-2-oxo-8-phenyl-1,3- 3.87 (m, 4H), 3.36 (d, 2H, J = 6.8 Hz),
3.24 (m, 3H), 2.95 (s, 3H), diazaspiro[4.5]decan-3-yl]-N-methyl-
2.66-2.60 (m, 2H), 2.06-2.03 (m, 8H), 1.44-1.37 (m, 4H). acetamide
SC_1342 CIS-N-(2-Hydroxy-ethyl)-N-methyl- INT-1034 2- SC_1308
.sup.1HNMR (DMSO-d6, 400 MHz at 100.degree. C.), .delta. (ppm) =
7.41 (d, 375.0 2-(8-methylamino-2-oxo-8-phenyl- (methylamino)- 2H,
J = 7.48 Hz), 7.31 (t, 2H, J = 7.60 Hz), 7.18 (t, 1H), J = 7.18
1,3-diazaspiro[4.5]decan-3-yl)- ethanol Hz), 6.24 (s, 1H),
4.58-4.36 (m, 1H), 3.92 (bs, 2H), 3.52 (bs, acetamide 2H), 3.34 (t,
2H, J = 5.72 Hz), 3.24 (s, 2H), 2.96-2.84 (m, 3H), 1.97-1.84 (m,
7H), 1.74-1.49 (m, 4H). SC_1343 CIS-2[1-(Cyclopropyl-methyl)-8-
INT-991 ammonium SC_1308 .sup.1H NMR (DMSO d6): .delta. 7.34-7.25
(m, 6H), 6.96 (s, 1H), 3.63 (s, 385.3
dimethylamino-2-oxo-8-phenyl-1,3- chloride 2H), 3.22 (m, 2H), 2.93
(d, 2H), 2.67-2.64 (m, 2H), 2.16 (t, 2H),
diazaspiro[4.5]decan-3-yl]-acetamide 1.97 (s, 6H), 1.43-1.31 (m,
4H), 0.93 (m, 1H), 0.46-0.45 (m, 2H), 0.26 (m, 2H). SC_1344
CIS-2-[-(Cyclopropyl-methyl)-8- INT-991 2-aminoethanol SC_1308
.sup.1H NMR (DMSO d6): .delta. 7.77-7.75 (m, 1H), 7.36-7.33 (m,
4H),
429.3 dimethylamino-2-oxo-8-phenyl-1,3- 7.26-7.23 (m, 1H),
4.65-4.63 (m, 1H), 3.67 (s, 2H), 3.39-3.35 (m,
diazaspiro[4.5]decan-3-yl]-N-(2- 2H), 3.21 (s, 2H), 3.12-3.09 (m,
2H), 2.94-2.93 (m, 2H), 2.67- hydroxy-ethyl)-acetamide 2.64 (m,
2H), 2.19-2.14 (t, 2H), 1.97 (s, 6H), 1.42-1.31 (m, 4H), 0.93-0.92
(s, 1H), 0.48-0.44 (m, 2H), 0.27-0.25 (m, 2H). SC_1345
CIS-2-[1-(Cyclobutyl-methyl)-8- INT-1032 2- SC_1308 .sup.1H NMR
(600 MHz, DMSO) .delta. 7.39 (td, 1H), 7.16 (dd, 1H), 7.13 475.3
dimethylamino-8-(3-fluorophenyl)-2- (methylamino)- (dt, 2H), 7.08
(td, 1H), 3.99 (s, 1H), 3.91 (s, 1H), 3.52 (q, 1H),
oxo-1,3-diazaspiro[4.5]decan-3-yl]-N- ethanol 3.45 (d, 1H),
3.40-3.36 (m, 0H), 3.34-3.28 (m, 2H), 3.19 (d,
(2-hydroxy-ethyl)-N-methyl- 2H), 3.05 (dd, 2H), 2.96 (s, 2H), 2.80
(s, 2H), 2.66-2.60 (m, acetamide 3H), 2.07-1.93 (m, 3H), 1.99 (s,
7H), 1.85-1.74 (m, 2H), 1.75- 1.65 (m, 3H), 1.40-1.28 (m, 5H).
SC_1346 CIS-2-[1-(Cyclobutyl-methyl)-8- INT-1031 tert-butyl-bromo
procedure .sup.1H NMR (600 MHz, DMSO) .delta. 7.43-7.36 (m, 1H),
7.17 (d, 1H), 474.3 dimethylamino-8-(3-fluorophenyl)-2- acetate
described 7.13 (dt, 1H), 7.09 (td, 1H), 3.75 (d, 2H), 3.21 (s, 2H),
3.05 (d, oxo-1,3-diazaspiro[4.5]decan-3-yl]- 2H), 2.67-2.61 (m,
2H), 2.08-2.00 (m, 2H), 1.99 (d, 7H), 1.98- acetic acid tert-butyl
ester 1.93 (m, 2H), 1.83-1.75 (m, 2H), 1.75-1.65 (m, 2H), 1.39 (d,
8H), 1.38-1.29 (m, 5H). SC_1347 CIS-2-[1-(Cyclopropyl-methyl)-8-
INT-991 2- SC_1308 .sup.1H NMR (DMSO): .delta. 7.36-7.32 (m, 4H),
7.26-7.23 (m, 1H), 4.83- 444.3 dimethylamino-2-oxo-8-phenyl-1,3-
(methylamino)- 4.63 (m, 1H), 3.99-3.91 (m, 2H), 3.50-3.44 (m, 2H),
3.32-3.28 diazaspiro[4.5]decan-3-yl]-N-(2- ethanol (m, 2H),
3.22-3.20 (m, 2H), 2.95-2.92 (m, 3H), 2.79 (s, 2H),
hydroxy-ethyl)-N-methyl-acetamide 2.67-2.65 (m, 2H), 2.20-2.15 (m,
2H), 1.97(s, 6H), 1.42-1.30 (m, 4H), 0.93-0.90 (s, 1H), 0.47-0.43
(m, 2H), 0.27-0.25 (m, 2H). SC_1348
CIS-2-[1-(Cyclopropyl-methyl)-8- INT-991 2- SC_1308 .sup.1H NMR
(DMSO): .delta. 8.05-8.02 (m, 1H), 7.37-7.32 (m, 4H), 7.26- 491.3
dimethylamino-2-oxo-8-phenyl-1,3- (methylsulfonyl) 7.22 (m, 1H),
3.67 (s , 2H), 3.49-3.44 (m, 2H), 3.25-3.21 (m,
diazaspiro[4.5]decan-3-yl]-N-(2- ethanamine 4H), 2.98-2.93 (m, 5H),
2.67-2.64 (m, 2H), 2.19-2.13 (m, 2H),
methylsulfonyl-ethyl)-acetamide 1.97 (s, 6H), 1.45-1.31 (m, 4H),
0.95-0.91 (s, 1H), 0.48-0.44 (m, 2H), 0.28-0.24 (m, 2H). SC_1349
CIS-N-(Carbamoyl-methyl)-2-[1- INT-1032 2-methylamino- SC_1308 1H
NMR (600 MHz, DMSO) .delta. 7.39 (td, 1H), 7.31 (s, 1H), 7.19-
488.3 (cyclobutyl-methyl)-8-dimethylamino- acetamide 7.05 (m, 3H),
6.99 (s, 1H), 4.00-3.78 (m, 4H), 3.18 (d, 2H),
8-(3-fluorophenyl)-2-oxo-1,3- hydrochloride 3.07-3.02 (m, 2H), 2.94
(s, 2H), 2.76 (s, 1H), 2.66-2.59 (m,
diazaspiro[4.5]decan-3-yl]-N-methyl- 2H), 2.06-1.93 (m, 9H),
1.84-1.73 (m, 2H), 1.70 (dt, 2H), acetamide 1.43-1.28 (m, 4H)
(mixture of amide rotamers) SC_1350
CIS-1-[2-[8-Dimethylamino-1-[(1- INT-1019 piperidine-4- SC_1308
1HNMR (DMSO d6): .delta. 7.37-7.25 (m, 6H), 6.77 (s, 1H), 6.02 (s,
526.4 hydroxy-cyclobutyl)-methyl]-2-oxo-8- carboxamide 1H),
4.26-4.23 (m, 1H), 4.02-3.91 (m, 2H), 3.79-3.75 (m, 1H),
phenyl-1,3-diazaspiro[4.5]decan-3- 3.31 (m, 2H), 3.10 (s, 2H),
3.00-2.93 (t, 1H), 2.68-2.65 (m, 2H),
yl]-acetyl]-piperidine-4-carboxylic 2.60-2.58 (m, 2H), 2.32-2.27
(m, 2H), 2.06-2.03 (m, 4H), 1.91- acid amide 1.83 (m, 8H),
1.67-1.61 (m, 2H), 1.49-1.40 (m, 2H), 1.36-1.30 (m, 4H). SC_1351
CIS-8-Dimethylamino-1-[(1-hydroxy- INT-1019 4- SC_1308 1H NMR (DMSO
d6): .delta. 7.37-7.23 (m, 5H), 6.00 (s, 1H), 4.45- 561.3
cyclobutyl)-methyl]-3-[2-(4- (methylsulfonyl) 4.41 (m, 1H),
4.08-3.91 (m, 3H), 3.17 (s, 3H), 3.10-2.99 (m, 2H),
methylsulfonyl-piperidin-1-yl)-2-oxo- piperidine 2.92 (s, 3H),
2.73-2.65 (m, 3H), 2.06-1.83 (m, 15H), 1.64-1.46
ethyl]-8-phenyl-1,3- (m, 4H), 1.40-1.30 (m, 4H).
diazaspiro[4.5]decan-2-one SC_1352 CIS-2-[1-(Cyclobutyl-methyl)-8-
INT-1032 2-aminoethanol SC_1308 1HNMR (600 MHz, DMSO) .delta. 7.73
(t, 1H), 7.39 (td, 1H), 7.19- 461.3
dimethylamino-8-(3-fluorophenyl)-2- 7.05 (m, 3H), 4.66 (t, 1H),
3.67 (s, 2H), 3.43-3.35 (m, 2H),
oxo-1,3-diazaspiro[4.5]decan-3-yl]-N- 3.18 (s, 2H), 3.11 (q, 2H),
3.05 (d, 2H), 2.65-2.58 (m, 2H), 2.55- (2-hydroxy-ethyl)-acetamide
2.45 (m, 1H), 2.07-1.93 (m, 10H), 1.84-1.73 (m, 2H), 1.74- 1.64 (m,
2H), 1.41-1.29 (m, 4H). SC_1353 TRANS-2-[1-(Cyclobutyl-methyl)-8-
INT-1067 2-aminoethanol SC_1357 1HNMR at 100.degree. C. (DMSO-d6,
400 MHz), .delta. (ppm) = 7.44-7.38 443.1
dimethylamino-2-oxo-8-phenyl-1,3- (m, 5H), 7.29 (t, 1H, J = 6.48
Hz), 4.29 (bs, 1H), 3.69 (s, 2H), diazaspiro[4.5]decan-3-yl]-N-(2-
3.48-3.44 (m, 2H), 3.28 (s, 2H), 3.21-3.17 (m, 2H), 2.69-2.67(m,
hydroxy-ethyl)-acetamide 2H), 2.58-2.55 (d, 2H, J = 11.6 Hz),
2.19-2.12 (m, 1H), 1.98 (s, 6H), 1.82-1.74 (m, 2H), 1.71-1.60 (m,
4H), 1.58-1.46 (m, 6H). SC_1354 TRANS-N-(Carbamoyl-methyl)-2-[1-
INT-1067 2-methylamino- SC_1357 1HNMR at 100.degree. C. (DMSO-d6,
400 MHz), .delta. (ppm) = 7.40-7.28 470.4
(cyclobutyl-methyl)-8-dimethylamino- acetamide (m, 5H), 6.87 (bs,
2H), 3.94-3.90 (m, 4H), 3.29 (s, 2H), 3.68- 2-oxo-8-phenyl-1,3-
hydrochloride 3.66 (m, 2H), 2.58-2.55 (m, 2H), 2.15-2.13 (m, 1H),
1.98 (s, 6H), diazaspiro[4.5]decan-3-yl]-N-methyl- 1.77 (bs, 2H),
1.64-1.61 (m, 4H), 1.46-1.27 (m, 6H). acetamide SC_1355
CIS-8-Dimethylamino-1-[(1-hydroxy- INT-1019 4- SC_1308 1H NMR (DMSO
d6): .delta. 7.36-7.32 (m, 4H), 7.26-7.23 (m, 1H), 513.4
cyclobutyp-methyl]-3-[2-(4-hydroxy- methylpiperidin- 6.02 (s, 1H),
4.37 (s, 1H), 3.96-3.95 (m, 2H), 3.90-3.80 (m, 1H),
4-methyl-piperidin-1-yl)-2-oxo-ethyl]- 4-ol 3.50-3.40 (m, 1H), 3.30
(m, 1H), 3.10 (s, 2H), 3.00-2.93 (m, 1H),
8-phenyl-1,3-diazaspiro[4.5]decan-2- 2.68-2.65 (m, 2H), 2.09-2.04
(m, 4H), 1.97 (s, 6H), 1.90-1.86 (m, one 2H), 1.64-1.61 (m, 1H),
1.48-1.40 (m, 5H), 1.37-1.30 (m, 4H), 1.22 (m, 2H), 1.11 (s, 3H).
SC_1356 CIS-2-[-(Cyclobutyl-methyl)-8- INT-1058 2-aminoethanol
SC_1308 1H NMR (600 MHz, DMSO) .delta. 7.72 (t, 1H), 7.40-7.33 (m,
2H), 461.3 dimethylamino-8-(4-fluorophenyl)-2- 7.15 (t, 2H), 4.81
(tdd, 0.15H), 4.65 (ddq, 0.75H), 3.66 (s, 2H),
oxo-1,3-diazaspiro[4.5]decan-4-yl]-N- 3.48 (q), 3.25 (q), 3.17 (s,
2H), 3.11 (q, 2H), 3.05 (d, 2H), 2.66- (2-hydroxy-ethyl)-acetamide
2.60 (m, 2H), 2.57-2.47 (m, 1H), 2.06-1.92 (m, 10H, 1.85- 1.73 (m,
2H), 1.75-1.63 (m, 2H), 1.40-1.28 (m, 4H). Not all signals could be
intergrated due to overlap with solvent peaks; two rotamers
observed in spectrum. SC_1357 TRANS-1-(Cyclopropyl-methyl)-8-
INT-1062 morpholine procedure 1HNMR (DMSO-d6, 400 MHz), .delta.
(ppm) = 7.44-7.29 (m, 5H), 455.1 dimethylamino-3-(2-morpholin-4-yl-
described 3.96 (s, 2H), 3.56 (bs, 4H), 3.42-3.40 (m, 4H), 3.29 (s,
2H), 2.67 2-oxo-ethyl)-8-phenyl-1,3- (bs, 2H), 2.55-2.54 (d, 2H, J
= 6.36 Hz), 1.92 (s, 6H), 1.56-.144 diazaspiro[4.5]decan-2-one (m,
6H), 0.51-0.48 (m, 1H), 0.16-0.14 (m, 2H), (-0.26)-(-0.27) (m, 2H).
SC_1358 TRANS-8-Dimethylamino-3-(2- INT-1060 morpholine SC_1357
1HNMR (DMSO-d6, 400 MHz at 100.degree. C.), .delta. (ppm) =
7.39-7.36 401.3 morpholin-4-yl-2-oxo-ethyl)-8- (m, 4H), 7.26-7.23
(m, 1H), 6.35 (m, 1H), 3.91 (s, 2H), 3.59 (t,
phenyl-1,3-diazaspiro[4.5]decan-2- 4H, J = 4.8 Hz), 3.45 (t, 4H, J
= 4.8 Hz), 3.27 (s, 2H), 2.18-2.15 one (m, 2H), 2.0-1.99 (m, 8H),
1.78-1.73 (m, 2H), 1.48-1.43 (m, 2H). SC_1359
CIS-2-[-(Cyclobutyl-methyl)-8- INT-1058 2- SC_1308 1HNMR (600 MHz,
DMSO) .delta. 7.37 (dd, 2H), 7.15 (t, 2H), 4.82 475.3
dimethylamino-8-(4-fluorophenyl)-2- (methylamino) (t, 0.2H), 4.63
(t, 0.2H), 3.98 (s, 1H), 3.91 (s, 1H), 3.51 (q, 1H),
oxo-1,3-diazaspiro[4.5]decan-3-yl]-N- ethanol 3.45 (q, 1H),
3.37-3.26 (m, 2H), 3.18 (d, 2H), 3.04 (dd, 2H),
(2-hydroxy-ethyl)-N-methyl- 2.96 (s, 1H), 2.80 (s, 2H), 2.64 (d,
2H), 2.56-2.47 (m, 1H), 2.08- acetamide 2.00 (m, 2H), 2.00-1.91 (m,
8H), 1.79 (ddt, 2H),1.75-1.65 (m, 2H), 1.37 (d, 2H), 1.31 (td, 2H).
Two rotamers are observed. SC_1360 CIS-N-(Carbamoyl-methyl)-2-[1-
INT-1058 2-methylamino- SC_1308 1HNMR (600 MHz, DMSO) .delta. 7.46
(s, 0.4H), 7.37 (dd, 2H), 488.3
(cyclobutyl-methyl)-8-dimethylamino- acetamide 7.30 (s, 0.6H),
7.20-7.12 (m, 2H), 6.99 (s, 0.6H), 3.97 (s, 1H),
8-(4-fluorophenyl)-2-oxo-1,3- hydrochloride 3.90 (s, 1H), 3.83 (d,
2H), 3.18 (d, 2H), 3.04 (dd, 2H), 2.94 (s,
diazaspiro[4.5]decan-3-yl]-N-methyl- 2H), 2.76 (s, 1H), 2.67-2.60
(m, 2H), 2.57-2.47 (m, 1H), 2.07- acetamide 1.92 (m, 10H),
1.83-1.74 (m, 2H), 1.74-1.63 (m, 2H), 1.40 1.27 (m, 4H). Two
rotamers are observed. SC_1361 CIS-1-(Cyclopropyl-methyl)-8-
INT-991 4- SC_1308 1HNMR (DMSO d6): .delta. 7.36-7.33 (m, 4H),
7.25-7.23 (m, 1H), 483.4 dimethylamino-3-[2-(4-hydroxy-4- hydro-
methylpiperidin- 4.37 (s, 1H), 3.92-3.84 (m, 3H), 3.48-3.46 (m,
1H), 3.25-3.21 (m, methyl-piperidin-1-yl)-2-oxo-ethyl]-8- chloride
4-ol 3H), 2.99-2.92 (m, 3H), 2.67-2.64 (m, 2H), 2.20-2.15 (t, 2H),
phenyl-1,3-diazaspiro[4.5]decan-2- 1.97 (s, 6H), 1.44-1.21 (m, 8H),
1.11 (s, 3H), 0.93-0.92 (m, 1H), one 0.47-0.45 (m, 2H), 0.44-0.43
(m, 2H). SC_1362 CIS-1-[2-[1-(Cyclopropyl-methyl)-8- INT-991
piperidine-4- SC_1308 1HNMR (DMSO): .delta. 7.34-7.32 (m, 4H),
7.25-7.24 (m, 2H), 6.77 496.4 dimethylamino-2-oxo-8-phenyl-1,3-
hydro- carboxamide (s, 1H), 4.21-4.29 (m, 1H), 3.94-3.86 (m, 2H),
3.78 (m, 1H), 3.22 diazaspiro[4.5]decan-3-yl]-acetyl]- chloride (s,
2H), 2.96-2.93 (m, 3H), 2.67-2.57 (m, 2H), 2.50 (t, 1H), 2.30
piperidine-4-carboxylic acid amide (m, 1H), 2.20-2.15 (m, 2H), 1.97
(s, 6H), 1.69-1.67 (m, 2H), 1.42-1.31 (m, 6H), 0.92 (m, 1H),
0.47-0.43 (m, 2H), 0.27-0.24 (m, 2H). SC_1363
TRANS-2-[1-(Cyclopropyl-methyl)-8- INT-1061 t-butyl- procedure
1HNMR at 100.degree. C. (DMSO-d6, 400 MHz), .delta. (ppm) =
7.40-7.29 385.2 dimethylamino-2-oxo-8-phenyl-1,3- bromoacetate
described (m, 5H), 6.76 (bs, 2H), 3.68 (s, 2H), 3.33 (s, 2H),
2.61-2.60 (m, diazaspiro[4.5]decan-3-yl]-acetamide (step 1), 7N
4H), 2.00 (s, 6H), 1.61-.153 (m, 6H), 0.58-0.56 (m, 1H), 0.22-
ammonia in 0.20 (m, 2H), (-0.16)-(-0.18) (m, 2H). methanol (step 2)
SC_1364 TRANS-2-[1-(Cyclopropyl-methyl)-8- INT-1062 methylamine
SC_1357 1HNMR at 100.degree. C. (DMSO-d6, 400 MHz), .delta. (ppm) =
7.43-7.27 399.2 dimethylamino-2-oxo-8-phenyl-1,3- (m, 6H), 3.68 (s,
2H), 3.32 (s, 2H), 2.64-2.58 (m, 7H), 1.99 (s,
diazaspiro[4.5]decan-3-yl]-N-methyl- 6H), 1.66-.152 (m, 6H),
0.58-0.56 (m, 1H), 0.23-0.19 (m, 2H), acetamide (-0.15)-(-0.17) (m,
2H). SC_1365 TRANS-1-(Cyclopropyl-methyl)-8- INT-1062
1,4-thiazinane SC_1357 1HNMR at 100.degree. C. (DMSO-d6, 400 MHz),
.delta. (ppm) = 7.40-7.28 503.3 dimethylamino-3-[2-(1,1-dioxo-
1,1-dioxide (m, 5H), 4.06 (s, 2H), 3.90-3.88 (m, 4H), 3.34 (s, 2H),
3.14 (bs, [1,4]thiazinan-4-yl)-2-oxo-ethyl]-8- 4H), 2.66-2.60 (m,
4H), 1.99 (s, 6H), 1.63-.152 (m, 6H), 0.58-
phenyl-1,3-diazaspiro[4.5]decan-2- 0.56 (m, 1H), 0.23-0.20 (m, 2H),
(-0.16)-(-0.17) (m, 2H). one SC_1366 CIS-1-(Cyclopropyl-methyl)-8-
INT-991 4- SC_1308 1HNMR (DMSO d6): .delta. 7.36-7.32 (m, 4H),
7.26-7.23 (m, 1H), 531.4 dimethylamino-3-[2-(4- hydro-
(methylsulfonyl) 4.40 (m, 1H), 4.04-3.88 (m, 3H), 3.31 (m, 1H),
3.02 (s, 2H), 2.94 methylsulfonyl-piperidin-1-yl)-2-oxo- chloride
piperidine (t, 1H), 2.94-2.92 (m, 5H), 2.67-2.50 (m, 3H), 2.20-2.15
(m, 2H), ethyl]-8-phenyl-1,3- 2.08-1.97 (m, 8H), 1.56 (m, 1H),
1.42-1.31 (m, 5H), 0.92 (m, diazaspiro[4.5]decan-2-one 1H),
0.47-0.43 (m, 2H), 0.27-0.24 (m, 2H). SC_1368
CIS-8-Dimethylamino-3-[2-(1,1- INT-1019 1,4-thiazinane SC_1308
1HNMR (600 MHz, DMSO) .delta. 7.35 (d, 4H), 7.29-7.22 (m, 533.3
dioxo-[1,4]thiazinan-4-yl)-2-oxo- 1,1-dioxide 1H), 4.09 (s, 2H),
3.83 (dt, 4H), 3.25-3.19 (m, 2H), 3.15-3.05
ethyl]-1-[(1-hydroxy-cyclobutyl)- (m, 4H), 2.72-2.65 (m, 2H),
2.12-2.04 (m, 6H), 1.99 (s, 6H), methyl]-8-phenyl-1,3- 1.88 (dt,
2H), 1.68-1.59 (m, 1H), 1.50 (d, 2H), 1.43-1.29 (m,
diazaspiro[4.5]decan-2-one 3H). SC_1369
TRANS-2-(8-Dimethylamino-2-oxo- INT-1060 t-butyl- SC_1363 1HNMR
(DMSO-d6, 400 MHz at 100.degree. C.), .delta. (ppm) = 7.37-7.24
331.2 8-phenyl-1,3-diazaspiro[4.5]decan-3- bromoacetate (m, 5H),
6.74 (bs, 2H), 6.38 (s, 1H), 3.62 (s, 2H), 3.27 (s, 2H),
yl)-acetamide (step 1), 7N 2.19-2.14 (m, 2H), 2.01-1.96 (m, 8H),
1.78-1.73 (m, 2H), 1.48- ammonia in 1.43 (m, 2H). methanol (step 2)
SC_1370 TRANS-8-Dimethylamino-3-[2-(1,1- INT-1060 1,4-thiazinane
SC_1357 1HNMR (DMSO-d6, 400 MHz at 100.degree. C.), .delta. (ppm) =
7.37-7.24 449.2 dioxo-[1,4]thiazinan-4-yl)-2-oxo- 1,1-dioxide (m,
5H), 6.41 (s, 1H), 4.0 (s, 2H), 3.89 (bs, 4H), 3.28 (s, 2H),
ethyl]-8-phenyl-1,3- 3.14 (bs, 4H), 2.15 (m, 2H), 1.99 (m, 8H),
1.78-1.73 (m, 2H), diazaspiro[4.5]decan-2-one 1.48-1.43 (m, 2H).
SC_1371 CIS-8-(dimethylamino)-8-phenyl-1- INT-1068 t-butyl- SC_1363
413.2 (2,2,2-trifluoroethyl)-3-(2- bromoacetate
(trifluoromethyl)pyrimidin-5-yl)-1,3- (step 1), 7N
diazaspiro[4.5]decan-2-one ammonia in methanol (step 2)
SC_1372 CIS-8-(dimethylamino)-8-phenyl-3- INT-1070 t-butyl- SC_1363
(2-(trifluoromethyl)pyrimidin-5-yl)-1- bromoacetate
(3,3,3-trifluoropropyl)-1,3- (step 1), 7N
diazaspiro[4.5]decan-2-one ammonia in methanol (step 2)
[0350] Chemical Structure of all Examples
##STR00145## ##STR00146## ##STR00147## ##STR00148## ##STR00149##
##STR00150## ##STR00151## ##STR00152## ##STR00153## ##STR00154##
##STR00155## ##STR00156## ##STR00157## ##STR00158## ##STR00159##
##STR00160## ##STR00161## ##STR00162##
##STR00163## ##STR00164## ##STR00165## ##STR00166## ##STR00167##
##STR00168## ##STR00169## ##STR00170## ##STR00171## ##STR00172##
##STR00173## ##STR00174## ##STR00175## ##STR00176## ##STR00177##
##STR00178## ##STR00179## ##STR00180##
[0351] Pharmacological Investigations
[0352] 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)
[0353] Human Mu-Opioidpeptide (hMOP) Receptor Binding Assay
[0354] 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 .mu.l/well) included 1 nM of [N-allyl-2,3-.sup.3H]naloxone as
ligand (PerkinElmer Life Sciences, Inc. Boston, Mass., USA), and
either test compound in dilution series or 25 .mu.M unlabelled
naloxone for determination of unspecific binding. The test compound
was diluted with 25% DMSO in H.sub.2O to yield a final 0.5% DMSO
concentration, which also served as a respective vehicle control.
The assay was started by adding wheat germ agglutinin coated SPA
beads (GE Healthcare UK Ltd., Buckinghamshire, UK) which had been
preloaded with hMOP receptor membranes (PerkinElmer Life Sciences,
Inc. Boston, Mass., USA). After incubation for 90 minutes at RT and
centrifugation for 20 minutes at 500 rpm the signal rate was
measured by means of a 1450 Microbeta Trilux .beta.-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).
[0355] Human Kappa-Opioidpeptide (hKOP) Receptor Binding Assay
[0356] 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 .mu.l per well includes 2 nM of
[.sup.3H]U69,593 as ligand, and either test compound in dilution
series or 100 .mu.M unlabelled naloxone for determination of
unspecific binding. The test compound is diluted with 25% DMSO in
H.sub.2O to yield a final 0.5% DMSO concentration which serves as
respective vehicle control, as well. The assays are started by the
addition of wheat germ agglutinin coated SPA beads (1 mg SPA
beads/250 .mu.l final assay volume per well) which has been
preloaded for 15 minutes at room temperature with hKOP receptor
membranes (14.8 .mu.g/250 .mu.l final assay volume per well). After
short mixing on a mini-shaker, the microtiter plates are covered
with a lid and the assay plates are incubated for 90 minutes at
room temperature. After this incubation, the microtiter plates are
sealed with a topseal and centrifuged for 20 minutes at 500 rpm.
The signal rate is measured after a short delay of 5 minutes by
means of a 1450 Microbeta Trilux .beta.-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).
[0357] Human Delta-Opioidpeptide (hDOP) Receptor Binding Assay
[0358] 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 .mu.l/well) includes 1 nM of
[Tyrosyl-3,5-.sup.3H]2-D-Ala-deltorphin II as ligand, and either
test compound in dilution series or 10 .mu.M unlabelled naloxone
for determination of unspecific binding. The test compound is
diluted with 25% DMSO in H.sub.2O to yield a final 0.5% DMSO
concentration which serves as respective vehicle control, as well.
The assays are started by the addition of wheat germ agglutinin
coated SPA beads (1 mg SPA beads/250 .mu.l final assay volume per
well) which has been preloaded for 15 minutes at room temperature
with hDOP receptor membranes (15.2 .mu.g/250 .mu.l final assay
volume per well). After short mixing on a mini-shaker, the
microtiter plates are covered with a lid and the assay plates are
incubated for 120 minutes at room temperature and centrifuged for
20 minutes at 500 rpm. The signal rate is measured by means of a
1450 Microbeta Trilux 1-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).
[0359] Human Nociceptin/Orphanin FQ Peptide (hNOP) Receptor Binding
Assay
[0360] The hNOP receptor binding assay was performed as homogeneous
SPA-assay (scintillation proximity assay) using the assay buffer 50
mM TRIS-HCl, 10 mM MgCl.sub.2, 1 mM EDTA (pH 7.4). The final assay
volume (250 l/well) included 0.5 nM of [leucyl-.sup.3H]nociceptin
as ligand (PerkinElmer Life Sciences, Inc. Boston, Mass., USA), and
either test compound in dilution series or 1 M unlabelled
nociceptin for determination of unspecific binding. The test
compound was diluted with 25% DMSO in H.sub.2O to yield a final
0.5% DMSO concentration, which also served as a respective vehicle
control. The assay was started by adding wheat germ agglutinin
coated SPA beads (GE Healthcare UK Ltd., Buckinghamshire, UK) which
had been preloaded with hMOP receptor membranes (PerkinElmer Life
Sciences, Inc. Boston, Mass., USA). After incubation for 60 minutes
at RT and centrifugation for 20 minutes at 500 rpm the signal rate
was measured by means of a 1450 Microbeta Trilux 1-counter
(PerkinElmer Life Sciences/Wallac, Turku, Finland). Half-maximal
inhibitory concentration (IC50) values reflecting 50% displacement
of [.sup.3H]nociceptin-specific receptor binding were calculated by
nonlinear regression analysis and Ki values were calculated by
using the Cheng-Prusoff equation, (Cheng and Prusoff, 1973).
TABLE-US-00004 Example hNOP Ki [nM] hMOP Ki [nM] SC_1001 33 206
SC_1002 2.1 160 SC_1003 3.7 102 SC_1004 3.6 84 SC_1005 6.3 115.5
SC_1006 2.2 150 SC_1007 29.5 190 SC_1008 5.4 117.5 SC_1009 17 390
SC_1010 9.8 175 SC_1011 9.1 112.5 SC_1012 1.8 47.5 SC_1013 1 220
SC_1014 2.6 175 SC_1015 1.3 140 SC_1016 3.1 76.5 SC_1017 2.6 130
SC_1018 2.8 106.5 SC_1019 4.6 170 SC_1020 2 86 SC_1021 1.6 94
SC_1022 2.1 20.5 SC_1023 13 270 SC_1024 3.7 26.5 SC_1025 22 125
SC_1026 2 67.3 SC_1027 7.6 55 SC_1028 4.8 104 SC_1029 52.3 303.3
SC_1030 3.1 74.5 SC_1031 3.6 43 SC_1032 4.9 69.5 SC_1033 3.9 75.5
SC_1034 2.1 47 SC_1035 1.3 21.5 SC_1036 2.7 39 SC_1037 1.8 45
SC_1038 1.6 41.5 SC_1039 1.3 34.5 SC_1040 1.1 15 SC_1041 1.7 20.5
SC_1042 1.8 57 SC_1043 1.1 21.5 SC_1044 1.7 43 SC_1045 1.6 44.5
SC_1046 2.3 54 SC_1047 2.5 49 SC_1048 1 43.5 SC_1049 2.9 48.5
SC_1050 0.8 40 SC_1051 1.6 36.5 SC_1052 1.6 24.5 SC_1053 2.7 53
SC_1054 2.6 74.5 SC_1055 2.5 29 SC_1056 3.3 10 SC_1057 1.9 11
SC_1058 2.9 78 SC_1059 7.4 45 SC_1060 5.1 40.5 SC_1061 2.2 12.6
SC_1062 2.6 47.5 SC_1063 1.6 22 SC_1064 4.2 33 SC_1065 4.8 26.5
SC_1066 1.9 23 SC_1067 7.5 31.5 SC_1068 68.5 360 SC_1069 1.4 16.5
SC_1070 1 13.5 SC_1071 3.6 38.5 SC_1072 2.8 62 SC_1073 3.5 25
SC_1074 5.9 37 SC_1075 1.5 19.5 SC_1076 0.8 72 SC_1077 1.8 20.5
SC_1078 1.3 23.3 SC_1079 1.7 26.2 SC_1080 6.4 19.5 SC_1081 1.9 64
SC_1082 1 81.5 SC_1083 1.5 44 SC_1084 1.1 59 SC_1085 3.8 71 SC_1086
0.8 16.5 SC_1087 2.4 28.2 SC_1088 2 19.5 SC_1089 1.4 16.5 SC_1090 3
27.5 SC_1091 1.3 15.5 SC_1092 1.8 26.5 SC_1093 4.2 43 SC_1094 2.8
10.4 SC_1095 1.8 12.5 SC_1096 1.6 12 SC_1097 1.6 15 SC_1098 1.5 10
SC_1099 1.5 4.5 SC_1100 1 2.3 SC_1101 3.4 6 SC_1102 2 4.4 SC_1103
0.4 7.2 SC_1104 1.2 23 SC_1105 4 50.5 SC_1106 11 122 SC_1107 1.8 45
SC_1109 2.8 16 SC_1110 9.8 31.5 SC_1111 1.6 30 SC_1112 1.3 30.5
SC_1113 0.8 30 SC_1114 109.5 850 SC_1115 140 145 SC_1117 4.1 37.5
SC_1118 2.4 114.3 SC_1119 6.5 73.5 SC_1120 2.9 125 SC_1121 115 630
SC_1122 124.5 480 SC_1123 2.6 24.8 SC_1124 1.8 33.8 SC_1125 2.2 23
SC_1126 3.5 29.5 SC_1127 2.6 2.7 SC_1128 1.9 72 SC_1129 1.7 37.3
SC_1130 68.5 160 SC_1131 34.5 215 SC_1132 23.5 410 SC_1133 6.4 25.5
SC_1134 26 140 SC_1135 73 370 SC_1136 14 57.5 SC_1137 5.8 99
SC_1138 0.9 23.5 SC_1139 215 515 SC_1140 51.5 150 SC_1141 4.8 165
SC_1142 265 1200 SC_1143 17 200 SC_1144 9.8 73.5 SC_1145 3.4 60.5
SC_1146 2.2 21.2 SC_1147 2.6 34.2 SC_1148 40 18.8 SC_1149 62 102.5
SC_1150 4.9 55.5 SC_1151 1.6 13.5 SC_1152 0.9 13.7 SC_1153 1.6 37
SC_1154 4.5 29 SC_1155 14.1 114.5 SC_1156 155 1215 SC_1157 170 1120
SC_1158 12.5 144.5 SC_1159 225 81.5 SC_1160 20 84.5 SC_1161 60 86
SC_1162 15.3 47.5 SC_1163 30.5 119 SC_1164 8.2 16.5 SC_1165 5.7
63.5 SC_1166 17 72.5 SC_1167 18 92 SC_1168 37 125 SC_1169 36.5 370
SC_1171 43 130 SC_1172 27.5 106 SC_1173 38.5 120 SC_1174 12.9 195
SC_1175 28.5 9.6 SC_1176 9 56 SC_1177 39 660 SC_1178 16 390 SC_1179
87.5 180 SC_1180 80 230 SC_1181 125 435 SC_1182 47.5 320 SC_1183
130 185 SC_1184 110 153.3 SC_1185 47 165 SC_1186 95.5 355 SC_1187
43 127.5 SC_1188 9.1 175 SC_1189 70.5 75.5 SC_1190 11.2 123.5
SC_1191 29 150 SC_1192 17 680 SC_1193 9.9 41 SC_1195 4.4 6.2
SC_1196 2.1 64.8 SC_1197 5.4 60 SC_1198 4.9 47 SC_1199 35 230
SC_1201 13.3 123.7 SC_1203 5.2 47.5 SC_1204 2.5 77.2 SC_1205 2.2 37
SC_1206 1.2 61.5 SC_1207 2.9 38 SC_1208 1.8 90 SC_1209 3.2 46
SC_1210 4.4 83.5 SC_1211 2.4 18.7 SC_1212 4.8 37.7 SC_1213 1.8 31.7
SC_1214 1 56.7 SC_1215 3.9 25 SC_1216 1.2 49 SC_1217 2.2 25.7
SC_1218 5.2 59 SC_1219 4.2 73.7 SC_1220 4 51 SC_1221 17 180 SC_1222
2.6 63 SC_1223 2.5 43.5 SC_1224 1.6 15 SC_1225 1.8 49.5 SC_1226 2.6
12.5 SC_1227 4.6 63 SC_1228 665 1740 SC_1229 2.8 22.5 SC_1230 1.5
36.5 SC_1231 2 51.5 SC_1232 1.4 32.5 SC_1233 0.5 26.5 SC_1234 1.8
53.5 SC_1236 3.3 83 SC_1300 13 130 SC_1301 23 44 SC_1302 27 66.5
SC_1303 145 215 SC_1304 280 400 SC_1305 19 105.5 SC_1306 59 45
SC_1308 22 97 SC_1309 12.5 100 SC_1310 8.1 17 SC_1311 11.5 44
SC_1312 295 520 SC_1313 305 1015 SC_1317 1.4 53.5 SC_1318 89 960
SC_1319 4 71 SC_1320 4 51
SC_1321 17 180 SC_1322 6%@1 .mu.M 9%@1 .mu.M SC_1323 12%@1 .mu.M
7%@1 .mu.M SC_1324 330 6025 SC_1325 0%@1 .mu.M 5%@1 .mu.M SC_1326
0%@1 .mu.M 625 SC_1327 11 120 SC_1328 2%@1 .mu.M 6%@1 .mu.M SC_1329
0%@1 .mu.M 4%@1 .mu.M SC_1330 465 18%@1 .mu.M SC_1331 10 38 SC_1332
52 1950 SC_1333 36 300 SC_1334 195 1605 SC_1335 2 24 SC_1336 -- --
SC_1337 23 -- SC_1338 475 14%@1 .mu.M SC_1339 1110 9%@1 .mu.M
SC_1340 230 14%@1 .mu.M SC_1341 170 2905 SC_1342 1140 10%@1 .mu.M
SC_1343 12 95 SC_1344 13 145 SC_1345 1 185 SC_1346 2 400 SC_1347 31
615 SC_1348 8 97 SC_1349 1 165 SC_1350 8 510 SC_1351 1 235 SC_1352
1 135 SC_1353 66 80.5 SC_1354 465 210 SC_1355 7 325 SC_1356 11 86
SC_1357 100 15.5 SC_1358 73 51.5 SC_1359 10 260 SC_1360 15 180
SC_1361 13 255 SC_1362 6 240 SC_1363 185 225 SC_1364 230 73.5
SC_1365 160 4.4 SC_1366 1 205 SC_1368 7 360 SC_1369 465 1805
SC_1370 100 11
[0361] Protocol for [.sup.35S]GTP.gamma.S Functional
NOP/MOP/KOP/DOP Assays
[0362] 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]GTP.gamma.S (Art.-No.
NEG030H; Lot-No. #0112, #0913, #1113 calibrated to 46.25 TBq/mmol)
is available from PerkinElmer (Waltham, Mass.).
[0363] The [.sup.35S]GTP.gamma.S 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 .mu.g membrane protein per assay are
incubated with 0.4 nM [.sup.35S]GTP.gamma.S 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 .mu.M GDP for 45 min at
room temperature. The microtiter plates are then centrifuged for 10
min at 830 to sediment the SPA beads. The microtiter plates are
sealed and the bound radioactivity [cpm] is determined after a
delay of 15 min by means of a 1450 Microbeta Trilux (PerkinElmer,
Waltham, Mass.).
[0364] 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]GTP.gamma.S
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]GTP.gamma.S 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]GTP.gamma.S binding (UBS.sub.calc [%]) and
the maximal achievable total [.sup.35S]GTP.gamma.S binding
(TB.sub.calc [%]) by each tested agonist is determined (i.e.
Bl.sub.calc [%]). This difference (Bl.sub.calc [%]) as a measure of
the maximal achievable enhancement of [.sup.35S]GTP.gamma.S 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 (Bl.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]GTP.gamma.S binding by the full agonists
SNC80 (Bl.sub.calc-SNC80 [%]), DAMGO (Bl.sub.calc-DAMGO [%]) and
U69,593 (Bl.sub.calc-U69,593 [%]) which are set as 100% relative
efficacy at each receptor, respectively.
[0365] 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.
* * * * *