U.S. patent application number 17/010089 was filed with the patent office on 2021-02-04 for 3-((hetero-)aryl)-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives.
This patent application is currently assigned to Grunenthal GmbH. The applicant listed for this patent is Grunenthal GmbH. Invention is credited to Ruth JOSTOCK, Achim KLESS, Thomas KOCH, Rene KOENIGS, Ingo KONETZKI, Sven KUEHNERT, Klaus LINZ, Paul RATCLIFFE, Wolfgang SCHROEDER, Anita WEGERT.
Application Number | 20210032256 17/010089 |
Document ID | / |
Family ID | 1000005064813 |
Filed Date | 2021-02-04 |
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United States Patent
Application |
20210032256 |
Kind Code |
A1 |
KUEHNERT; Sven ; et
al. |
February 4, 2021 |
3-((Hetero-)Aryl)-8-Amino-2-Oxo-1,3-Diaza-Spiro-[4.5]-Decane
Derivatives
Abstract
The invention relates to
3-((hetero-)aryl)-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; (Erkelenz, DE) ; KLESS;
Achim; (Aachen, DE) ; WEGERT; Anita;
(Aldenhoven, DE) ; KONETZKI; Ingo; (Aachen,
DE) ; RATCLIFFE; Paul; (Aachen, DE) ; JOSTOCK;
Ruth; (Stolberg, DE) ; KOCH; Thomas;
(Stolberg, DE) ; LINZ; Klaus; (Rheinbach, DE)
; SCHROEDER; Wolfgang; (Aachen, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Grunenthal GmbH |
Aachen |
|
DE |
|
|
Assignee: |
Grunenthal GmbH
Aachen
DE
|
Family ID: |
1000005064813 |
Appl. No.: |
17/010089 |
Filed: |
September 2, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16450331 |
Jun 24, 2019 |
10807988 |
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17010089 |
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16207854 |
Dec 3, 2018 |
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16450331 |
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15923948 |
Mar 16, 2018 |
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16207854 |
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15405485 |
Jan 13, 2017 |
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15923948 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 409/14 20130101;
C07D 235/02 20130101; C07D 403/14 20130101; C07D 401/02 20130101;
C07D 401/04 20130101; C07D 413/14 20130101; C07D 405/02 20130101;
C07D 471/04 20130101; C07D 487/04 20130101; C07D 405/06 20130101;
C07D 409/04 20130101; C07D 405/14 20130101; C07D 413/02 20130101;
C07D 401/14 20130101; C07D 403/04 20130101; C07D 417/04
20130101 |
International
Class: |
C07D 487/04 20060101
C07D487/04; C07D 403/04 20060101 C07D403/04; C07D 235/02 20060101
C07D235/02; C07D 401/04 20060101 C07D401/04; C07D 409/14 20060101
C07D409/14; C07D 405/06 20060101 C07D405/06; C07D 403/14 20060101
C07D403/14; C07D 413/14 20060101 C07D413/14; C07D 417/04 20060101
C07D417/04; C07D 405/14 20060101 C07D405/14; C07D 401/14 20060101
C07D401/14; C07D 471/04 20060101 C07D471/04; C07D 405/02 20060101
C07D405/02; C07D 401/02 20060101 C07D401/02; C07D 413/02 20060101
C07D413/02; C07D 409/04 20060101 C07D409/04 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 13, 2016 |
EP |
16 151 012.8 |
Claims
1. A compound according to general formula (I) ##STR00267## 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--; R.sup.5 means a 6-14-membered aryl moiety,
unsubstituted, mono- or polysubstituted; or a 5-14-membered
heteroaryl moiety, unsubstituted, mono- or polysubstituted;
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,
--C(.dbd.O)NH--(CH.sub.2CH.sub.2--O).sub.1-30--CH.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, .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, --CO.sub.2H, --C(.dbd.O)O--C.sub.1-C.sub.6-alkyl,
--C(.dbd.O)NH.sub.2, --C(.dbd.O)NHC.sub.1-C.sub.6-alkyl,
--C(.dbd.O)N(C.sub.1-C.sub.6-alkyl).sub.2,
--O--C.sub.1-C.sub.6-alkyl and
--S(.dbd.O).sub.2--C.sub.1-C.sub.6-alkyl; a 3-12-membered
cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono-
or poly-substituted; 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, mono- or
polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety
is optionally connected through --C.sub.1-C.sub.6-alkylene-, linear
or branched, saturated or unsaturated, unsubstituted or substituted
with one, two, three or four substituents independently of one
another selected from the group consisting of --F, --Cl, --Br, --I,
--CN, --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--;
--(CH.sub.2).sub.2--S(.dbd.O).sub.2--(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, --C.sub.1-C.sub.6-alkyl,
--C(.dbd.O)--C.sub.1-C.sub.6-alkyl, or
--S(.dbd.O).sub.2--C.sub.1-C.sub.6-alkyl, wherein said
C.sub.1-C.sub.6-alkyl is 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, --CO.sub.2H,
--C(.dbd.O)O--C.sub.1-C.sub.6-alkyl and --C(.dbd.O)NH.sub.2; and
wherein said ring is 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, .dbd.O,
--OH, --NH.sub.2, --C.sub.1-C.sub.6-alkyl and
--O--C.sub.1-C.sub.6-alkyl; or a physiologically acceptable salt
thereof.
2. The compound according to claim 1, wherein R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17, R.sup.18,
R.sup.19, and R.sup.20 independently of one another mean --H, --F,
--OH, or --C.sub.1-C.sub.6-alkyl.
3. The compound according to claim 1, wherein R.sup.1 means --H;
and R.sup.2 means --C.sub.1-C.sub.6-alkyl, linear or branched,
saturated or unsaturated, unsubstituted, mono- or
polysubstituted.
4. The compound according to claim 1, wherein R.sup.1 means
--CH.sub.3; and R.sup.2 means --C.sub.1-C.sub.6-alkyl, linear or
branched, saturated or unsaturated, unsubstituted, mono- or
polysubstituted.
5. The compound according to claim 1, wherein R.sup.1 means --H or
--CH.sub.3; and wherein R.sup.2 means --CH.sub.2-cycloalkyl,
--CH.sub.2-cyclobutyl, --CH.sub.2-cyclopentyl, --CH.sub.2-oxetanyl
or --CH.sub.2-tetrahydrofuranyl.
6. The compound according to claim 1, wherein R.sup.1 and R.sup.2
together with the nitrogen atom to which they are attached form a
ring and mean --(CH.sub.2).sub.3-6--.
7. The compound according 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
-phenyl, unsubstituted, mono- or polysubstituted.
17. The compound according to claim 1, wherein R.sup.5 means a
monocyclic 5-6-membered heteroaryl moiety, unsubstituted, mono- or
polysubstituted.
18. The compound according to claim 1, wherein R.sup.5 means a
bicyclic 9-10-membered heteroaryl moiety, unsubstituted, mono- or
polysubstituted.
19. The compound according to claim 17, wherein R.sup.5 means
-1,2-benzodioxole, -pyrazinyl, -pyridazinyl, -pyridinyl,
-pyrimidinyl, -thienyl, -imidazolyl, -benzimidazolyl, -thiazolyl,
-1,3,4-thiadiazolyl, -benzothiazolyl, -oxazolyl, -benzoxazolyl,
-pyrazolyl, -quinolinyl, -isoquinolinyl, -quinazolinyl, -indolyl,
-indolinyl, -benzo[c][1,2,5]oxadiazolyl, -imidazo[1,2-a]pyrazinyl,
or -1H-pyrrolo[2,3-b]pyridinyl, in each case unsubstituted, mono-
or polysubstituted.
20. The compound according to claim 1, which has a structure
according to any of general formulas (II-A) to (VIII-C):
##STR00268## ##STR00269## ##STR00270## ##STR00271## wherein in each
case R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are defined as
in any of the preceding claims, R.sup.C means --H, --OH, --F, --CN
or --C.sub.1-C.sub.4-alkyl; R.sup.D means --H or --F; or a
physiologically acceptable salt thereof.
21. The compound according to claim 1, wherein R.sup.5 is selected
from the group consisting of: ##STR00272## ##STR00273##
##STR00274## ##STR00275## ##STR00276## ##STR00277## ##STR00278##
##STR00279## ##STR00280## ##STR00281## ##STR00282## ##STR00283##
##STR00284## ##STR00285## ##STR00286## ##STR00287## ##STR00288##
##STR00289## ##STR00290## ##STR00291## ##STR00292## ##STR00293##
##STR00294##
22. The compound according to claim 1, wherein R.sup.1 means --H or
--CH.sub.3; R.sup.2 means --C.sub.1-C.sub.6-alkyl, linear or
branched, saturated, unsubstituted; cyclopropyl connected through
--CH.sub.2--; or tetrahydropyranyl connected through --CH.sub.2--;
R.sup.3 means -phenyl, benzyl, -thienyl or -pyridinyl, in each case
unsubstituted or substituted with one, two, three or four
substituents independently of one another selected from the group
consisting of --F, --Cl, --CN, --CH.sub.2CH.sub.3, --CH.sub.2F,
--CHF.sub.2, --CF.sub.3, --OCF.sub.3, --OH, --OCH.sub.3,
--C(.dbd.O)NH.sub.2, C(.dbd.O)NHCH.sub.3,
--C(.dbd.O)N(CH.sub.3).sub.2, --NH.sub.2, --NHCH.sub.3,
--N(CH.sub.3).sub.2, --NHC(.dbd.O)CH.sub.3, --CH.sub.2OH,
SOCH.sub.3 and SO.sub.2CH.sub.3; or R.sup.4 means --H;
--C.sub.1-C.sub.6-alkyl, linear or branched, saturated,
unsubstituted or substituted with one, two, three or four
substituents independently of one another selected from the group
consisting of --F, --Cl, --Br, --I, --CN, --OH,
--O--C.sub.1-C.sub.4-alkyl, --C(.dbd.O)NH--C.sub.1-C.sub.6-alkyl,
--C(.dbd.O)N(C.sub.1-C.sub.6-alkyl).sub.2 or --C(.dbd.O)NRR'
wherein R and R' together with the nitrogen atom to which they are
attached form a ring and mean --(CH.sub.2).sub.3-5--; 3-6-membered
cycloalkyl, unsubstituted or substituted with one, two, three or
four substituents independently of one another selected from the
group consisting of --F, --Cl, --Br, --I, --CN, --OH, and
--O--C.sub.1-C.sub.4-alkyl, wherein said 3-6-membered cycloalkyl is
connected through --C.sub.1-C.sub.6-alkylene; 3-6-membered
heterocycloalkyl, unsubstituted or substituted with one, two, three
or four substituents independently of one another selected from the
group consisting of --F, --Cl, --Br, --I, --CN, --OH, and
--O--C.sub.1-C.sub.4-alkyl, wherein said 3-6-membered
heterocycloalkyl is connected through --C.sub.1-C.sub.6-alkylene;
-phenyl, unsubstituted or monosubstituted with --OCH.sub.3; wherein
said -phenyl is connected through --C.sub.1-C.sub.6-alkylene-; or
-pyridyl, unsubstituted, mono- or polysubstituted; wherein said
-pyridyl is connected through --C.sub.1-C.sub.6-alkylene-; R.sup.5
means phenyl, -1,2-benzodioxole, -pyrazinyl, -pyridazinyl,
-pyridinyl, -pyrimidinyl, -thienyl, -imidazolyl, -benzimidazolyl,
-thiazolyl, -1,3,4-thiadiazolyl, -benzothiazolyl, -oxazolyl,
-benzoxazolyl, -pyrazolyl, -quinolinyl, -isoquinolinyl,
-quinazolinyl, -indolyl, -indolinyl, -benzo[c][1,2,5]oxadiazolyl,
-imidazo[1,2-a]pyrazinyl, or -1H-pyrrolo[2,3-b]pyridinyl, in each
case unsubstituted or substituted with one, two, three or four
substituents independently of one another selected from the group
consisting of --F; --Cl; --Br; --I; --CN; --C.sub.1-C.sub.4-alkyl;
--C.sub.1-C.sub.4-alkyl-OH; --CF.sub.3;
--C.sub.1-C.sub.4-alkyl-CF.sub.3;
--C.sub.1-C.sub.4-alkyl-C(.dbd.O)NH.sub.2;
--C.sub.1-C.sub.4-alkyl-C(.dbd.O)NHC.sub.1-C.sub.6-alkyl;
--C.sub.1-C.sub.4-alkyl-C(.dbd.O)N(C.sub.1-C.sub.6-alkyl).sub.2;
--C.sub.1-C.sub.4-alkyl-S(.dbd.O).sub.2--C.sub.1-C.sub.4-alkyl;
--C(.dbd.O)--C.sub.1-C.sub.4-alkyl; --C(.dbd.O)OH;
--C(.dbd.O)O--C.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;
--C(.dbd.O)NH(C.sub.1-C.sub.4-alkyl-OH);
--C(.dbd.O)N(C.sub.1-C.sub.4-alkyl)(C.sub.1-C.sub.4-alkyl-OH);
--C(.dbd.O)NH--(CH.sub.2CH.sub.2O).sub.1-30--CH.sub.3; --NH.sub.2;
--NHC.sub.1-C.sub.4-alkyl; --N(C.sub.1-C.sub.4-alkyl).sub.2;
--NHC.sub.1-C.sub.4-alkyl-OH; --NCH.sub.3C.sub.1-C.sub.4-alkyl-OH;
--NH--C.sub.1-C.sub.4-alkyl-C(.dbd.O)NH.sub.2;
--NCH.sub.3--C.sub.1-C.sub.4-alkyl-C(.dbd.O)NH.sub.2;
--NHC(.dbd.O)--C.sub.1-C.sub.4-alkyl;
--NCH.sub.3C(.dbd.O)--C.sub.1-C.sub.4-alkyl; --OH;
--O--C.sub.1-C.sub.4-alkyl; --OCF.sub.3;
--O--C.sub.1-C.sub.4-alkyl-CO.sub.2H;
--O--C.sub.1-C.sub.4-alkyl-C(.dbd.O)O--C.sub.1-C.sub.4-alkyl;
--O--C.sub.1-C.sub.4-alkyl-CONH.sub.2; --S--C.sub.1-C.sub.4-alkyl;
--S(.dbd.O)C.sub.1-C.sub.4-alkyl;
--S(.dbd.O).sub.2C.sub.1-C.sub.4-alkyl; and
--S(.dbd.O).sub.2N(C.sub.1-C.sub.4-alkyl).sub.2; 3-12-membered
cycloalkyl, saturated or unsaturated, unsubstituted, mono- or
polysubstituted; wherein said 3-12-membered cycloalkyl is
optionally connected through --CH.sub.2--, --O--, --NH--,
--NCH.sub.3--, --NH--(CH.sub.2).sub.1-3--,
--NCH.sub.3(CH.sub.2).sub.1-3--, --(C.dbd.O)--, --NHC(.dbd.O)--,
--NCH.sub.3C(.dbd.O)--, --C(.dbd.O)NH--(CH.sub.2).sub.1-3--,
--C(.dbd.O)NCH.sub.3--(CH.sub.2).sub.1-3--; 3-12-membered
heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or
polysubstituted; wherein said 3-12-membered heterocycloalkyl is
optionally connected through --CH.sub.2--, --O--, --NH--,
--NCH.sub.3--, --NH--(CH.sub.2).sub.1-3--,
--NCH.sub.3(CH.sub.2).sub.1-3--, --(C.dbd.O)--, --NHC(.dbd.O)--,
--NCH.sub.3C(.dbd.O)--, --C(.dbd.O)NH--(CH.sub.2).sub.1-3--,
--C(.dbd.O)NCH.sub.3--(CH.sub.2).sub.1-3--; 6-14-membered aryl,
unsubstituted, mono- or polysubstituted; wherein said 6-14-membered
aryl is optionally connected through --CH.sub.2--, --O--, --NH--,
--NCH.sub.3--, --NH--(CH.sub.2).sub.1-3--,
--NCH.sub.3(CH.sub.2).sub.1-3--, --(C.dbd.O)--, --NHC(.dbd.O)--,
--NCH.sub.3C(.dbd.O)--, --C(.dbd.O)NH--(CH.sub.2).sub.1-3--,
--C(.dbd.O)NCH.sub.3--(CH.sub.2).sub.1-3--; or 5-14-membered
heteroaryl, unsubstituted, mono- or polysubstituted; wherein said
5-14-membered heteroaryl is optionally connected through
--CH.sub.2--, --O--, --NH--, --NCH.sub.3--,
--NH--(CH.sub.2).sub.1-3--, --NCH.sub.3(CH.sub.2).sub.1-3--,
--(C.dbd.O)--, --NHC(.dbd.O)--, --NCH.sub.3C(.dbd.O)--,
--C(.dbd.O)NH--(CH.sub.2).sub.1-3--,
--C(.dbd.O)NCH.sub.3--(CH.sub.2).sub.1-3--; and R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17, R.sup.18,
R.sup.19, and R.sup.20 mean --H.
23. The compound according to claim 1, which has a structure
according to general formula (I') ##STR00295## wherein R.sup.1 to
R.sup.5, R.sup.11 to R.sup.20 are defined as in claim 1, or a
physiologically acceptable salt thereof.
24. The compound according to claim 1, which has a structure
according to general formula (IX) or (X) ##STR00296## wherein
R.sup.2 means --H or --CH.sub.3; R.sup.3 means -phenyl or
-3-fluorophenyl; R.sup.C means --H or --OH; R.sup.E means --H,
--CH.sub.3, --F, --CF.sub.3, -cyclopropyl, -aziridinyl, --OH;
--OCF.sub.3; --O--C.sub.1-C.sub.4-alkyl-CO.sub.2H;
--O--C.sub.1-C.sub.4-alkyl-C(.dbd.O)O--C.sub.1-C.sub.4-alkyl; or
--O--C.sub.1-C.sub.4-alkyl-CONH.sub.2; R.sup.F means --CF.sub.3,
-cyclopropyl, --S(.dbd.O).sub.2CH.sub.3, --NH.sub.2;
--NHC.sub.1-C.sub.4-alkyl; --N(C.sub.1-C.sub.4-alkyl).sub.2;
--NHC.sub.1-C.sub.4-alkyl-OH; --NCH.sub.3C.sub.1-C.sub.4-alkyl-OH;
--NH--C.sub.1-C.sub.4-alkyl-C(.dbd.O)NH.sub.2;
--NCH.sub.3--C.sub.1-C.sub.4-alkyl-C(.dbd.O)NH.sub.2;
--NHC(.dbd.O)--C.sub.1-C.sub.4-alkyl;
--NCH.sub.3C(.dbd.O)--C.sub.1-C.sub.4-alkyl; -6-14-membered aryl,
unsubstituted, mono- or polysubstituted; or -5-14-membered
heteroaryl, unsubstituted, mono- or polysubstituted; U means
.dbd.CH-- or .dbd.N--; and V means .dbd.CH-- or .dbd.N--; or a
physiologically acceptable salt thereof.
25. The compound according to claim 1, which has a structure
according to general formula (XI) ##STR00297## wherein R.sup.2
means --H or --CH.sub.3; R.sup.3 means -phenyl or -3-fluorophenyl;
R.sup.H means --CN; --CF.sub.3;
--C.sub.1-C.sub.4-alkyl-C(.dbd.O)NH.sub.2;
--C(.dbd.O)--C.sub.1-C.sub.4-alkyl; --C(.dbd.O)OH;
--C(.dbd.O)O--C.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;
--C(.dbd.O)NH(C.sub.1-C.sub.4-alkyl-OH);
--C(.dbd.O)N(C.sub.1-C.sub.4-alkyl)(C.sub.1-C.sub.4-alkyl-OH);
--C(.dbd.O)NH--(CH.sub.2CH.sub.2O).sub.1-30--CH.sub.3;
-3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted,
mono- or polysubstituted; wherein said 3-12-membered cycloalkyl is
optionally connected through --CH.sub.2--, --NH--, --NCH.sub.3--,
--NH--(CH.sub.2).sub.1-3--, --NCH.sub.3(CH.sub.2).sub.1-3--,
--(C.dbd.O)--, --NHC(.dbd.O)--, --NCH.sub.3C(.dbd.O)--,
--C(.dbd.O)NH--(CH.sub.2).sub.1-3--,
--C(.dbd.O)NCH.sub.3--(CH.sub.2).sub.1-3--; or -3-12-membered
heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or
polysubstituted; 6-14-membered aryl, unsubstituted, mono- or
polysubstituted; wherein said 3-12-membered heterocycloalkyl is
optionally connected through --CH.sub.2--, --NH--, --NCH.sub.3--,
--NH--(CH.sub.2).sub.1-3--, --NCH.sub.3(CH.sub.2).sub.1-3--,
--(C.dbd.O)--, --NHC(.dbd.O)--, --NCH.sub.3C(.dbd.O)--,
--C(.dbd.O)NH--(CH.sub.2).sub.1-3--,
--C(.dbd.O)NCH.sub.3--(CH.sub.2).sub.1-3--; R.sup.G means
--CF.sub.3, --S(.dbd.O).sub.2CH.sub.3; --NH.sub.2;
--NHC.sub.1-C.sub.4-alkyl; --N(C.sub.1-C.sub.4-alkyl).sub.2;
--NHC.sub.1-C.sub.4-alkyl-OH; --NCH.sub.3C.sub.1-C.sub.4-alkyl-OH;
--NH--C.sub.1-C.sub.4-alkyl-C(.dbd.O)NH.sub.2;
--NCH.sub.3--C.sub.1-C.sub.4-alkyl-C(.dbd.O)NH.sub.2;
--NHC(.dbd.O)--C.sub.1-C.sub.4-alkyl;
--NCH.sub.3C(.dbd.O)--C.sub.1-C.sub.4-alkyl; -3-12-membered
cycloalkyl, saturated or unsaturated, unsubstituted, mono- or
polysubstituted; wherein said 3-12-membered cycloalkyl is
optionally connected through --CH.sub.2--, --NH--, --NCH.sub.3--,
--NH--(CH.sub.2).sub.1-3--, --NCH.sub.3(CH.sub.2).sub.1-3--,
--(C.dbd.O)--, --NHC(.dbd.O)--, --NCH.sub.3C(.dbd.O)--,
--C(.dbd.O)NH--(CH.sub.2).sub.1-3--,
--C(.dbd.O)NCH.sub.3--(CH.sub.2).sub.1-3--; or -3-12-membered
heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or
polysubstituted; 6-14-membered aryl, unsubstituted, mono- or
polysubstituted; wherein said 3-12-membered heterocycloalkyl is
optionally connected through --CH.sub.2--, --NH--, --NCH.sub.3--,
--NH--(CH.sub.2).sub.1-3--, --NCH.sub.3(CH.sub.2).sub.1-3--,
--(C.dbd.O)--, --NHC(.dbd.O)--, --NCH.sub.3C(.dbd.O)--,
--C(.dbd.O)NH--(CH.sub.2).sub.1-3--,
--C(.dbd.O)NCH.sub.3--(CH.sub.2).sub.1-3--; or a physiologically
acceptable salt thereof.
26. The compound according to claim 1, which is selected from the
group consisting of
cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
op[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;
cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
op[4.5]decan-3-yl]-pyrazine-2-carbonitrile;
cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
op[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile;
cis-5-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[-
4.5]decan-3-yl]-pyrimidine-2-carbonitrile;
cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
op[4.5]decan-3-yl]-pyrimidine-2-carboxylic acid amide;
cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
op[4.5]decan-3-yl]-2-methylsulfonyl-pyrimidine-4-carbonitrile;
cis-5-[1-(2-Methoxy-ethyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.-
5]decan-3-yl]-pyrimidine-2-carbonitrile;
cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-5-methylsulfonyl-benzonitrile;
cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-benzamide;
cis-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-benzamide;
cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carboxylic acid amide;
cis-5-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[-
4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile;
cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;
cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-pyrimidine-5-carbonitrile;
cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-methoxy-pyrimi-
din-5-yl)-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]-pyrimidine-5-carboxylic acid amide;
cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-methyl-benzamide;
cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-3-
-yl)-pyrimidine-2-carbonitrile;
cis-5-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro-
[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;
cis-5-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspi-
ro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;
cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-benzamide;
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[2-(trifluoromethyl)-
-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-hydroxy-pyrimi-
din-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-5-[8-Dimethylamino-1-(2-methyl-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[-
4.5]decan-3-yl]-pyrimidine-2-carbonitrile;
cis-5-[8-Dimethylamino-1-(2-hydroxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[-
4.5]decan-3-yl]-pyrimidine-2-carbonitrile;
cis-5-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[-
4.5]decan-3-yl]-4-methyl-pyridine-2-carbonitrile;
cis-1-(Cyclobutyl-methyl)-3-(5-methoxy-pyrazin-2-yl)-8-methylamino-8-phen-
yl-1,3-diazaspiro[4.5]decan-2-one;
cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N,N-dimethyl-benzamide;
cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N-ethyl-N-(2-hydroxy-ethyl)-benzamide;
cis-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[-
4.5]decan-3-yl]-5-methylsulfonyl-benzonitrile;
cis-1-(Cyclobutyl-methyl)-8-methylamino-3-[2-methylsulfonyl-4-(trifluorom-
ethyl)-phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-4-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[-
4.5]decan-3-yl]-N,N-dimethyl-3-(trifluoromethyl)-benzenesulfonic
acid amide;
cis-4-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-
-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile;
cis-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-3-[2-(trifluoro-
methyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-5-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;
cis-5-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,-
3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;
cis-2-[3-(2-Cyano-pyrimidin-5-yl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diaz-
aspiro[4.5]decan-1-yl]-N,N-dimethyl-acetamide;
cis-1-(Cyclobutyl-methyl)-8-methylamino-8-phenyl-3-[2-(trifluoromethyl)-p-
yrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-5-[8-Dimethylamino-8-(3-fluorophenyl)-1-(4-methoxy-butyl)-2-oxo-1,3-d-
iazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;
cis-5-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro-
[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile;
cis-5-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-phenyl-1,3-
-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;
cis-N-(Cyclobutyl-methyl)-5-[1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-f-
luorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carboxylic
acid amide;
cis-5-[1-(3-Methoxy-propyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4-
.5]decan-3-yl]-pyrimidine-2-carbonitrile;
cis-5-[8-Dimethylamino-8-(3-fluorophenyl)-1-methyl-2-oxo-1,3-diazaspiro[4-
.5]decan-3-yl]-pyrimidine-2-carbonitrile;
cis-4-Methoxy-5-[1-(3-methoxy-propyl)-8-methylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;
cis-4-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[-
4.5]decan-3-yl]-pyrimidine-2-carbonitrile;
cis-5-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[-
4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile;
cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(6-methylsulfanyl-pyrimidin-4-
-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-2-[3-(2-Cyano-pyrimidin-4-yl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diaz-
aspiro[4.5]decan-1-yl]-N,N-dimethyl-acetamide;
cis-6-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-pyrimidine-4-carbonitrile;
cis-2-(8-Dimethylamino-2-oxo-3,8-diphenyl-1,3-diazaspiro[4.5]decan-1-yl)--
N,N-dimethyl-acetamide;
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3,8-diphenyl-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]-pyrimidine-5-carbonitrile;
cis-8-Dimethylamino-1-(2-methoxy-ethyl)-3,8-diphenyl-1,3-diazaspiro[4.5]d-
ecan-2-one;
cis-5-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[-
4.5]decan-3-yl]-4-methyl-pyridine-2-carbonitrile;
cis-N,N-Dimethyl-2-(8-methylamino-2-oxo-3,8-diphenyl-1,3-diazaspiro[4.5]d-
ecan-1-yl)-acetamide;
cis-5-[1-[(1-Cyano-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-d-
iazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;
cis-5-[1-[(1-Cyano-cyclobutyl)-methyl]-8-(ethyl-methyl-amino)-2-oxo-8-phe-
nyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;
CIS-4-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl]-benzonitrile;
cis-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl]-benzonitrile;
cis-5-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-phenyl-1,3-
-diazaspiro[4.5]decan-3-yl]-pyridine-2-carbonitrile;
cis-2-[3-(2-Cyano-pyrimidin-5-yl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diaz-
aspiro[4.5]decan-1-yl]-N-propyl-acetamide;
cis-5-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile;
cis-4-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[-
4.5]decan-3-yl]-3-methoxy-benzonitrile;
cis-5-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro-
[4.5]decan-3-yl]-6-methoxy-pyridine-2-carbonitrile;
cis-4-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl]-benzamide;
cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl]-pyridine-2-carbonitrile;
cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl]-N-[(1-hydroxy-cyclobutyl)-methyl]-pyridine-2-
-carboxylic acid amide;
cis-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl]-benzonitrile;
cis-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-benzonitrile;
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[2-(trifluoromethyl)-
-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-4-methyl-pyridine-2-carboxylic acid methyl ester;
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(5-methoxy-pyrazin-2-yl)-8-ph-
enyl-1,3-diazaspiro[4.5]decan-2-one;
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(2-methoxy-pyrimidin-5-yl)-8--
phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-benzonitrile;
cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-4-methyl-pyridine-2-carbonitrile;
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(5-fluoro-pyrimidin-2-yl)-8-p-
henyl-1,3-diazaspiro[4.5]decan-2-one;
cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-3-methoxy-benzonitrile;
cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-benzoic acid methyl ester;
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-(2-pyrrolidin-1-yl-p-
yrimidin-4-yl)-1,3-diazaspiro[4.5]decan-2-one;
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-(5-pyridin-2-yl-thio-
phen-2-yl)-1,3-diazaspiro[4.5]decan-2-one;
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-methylsulfonyl-4-(trifluor-
omethyl)-phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[6-(trifluoromethyl)-
-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-1-(Cyclobutyl-methyl)-3-(2,4-dimethoxy-phenyl)-8-dimethylamino-8-phen-
yl-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]-4-methylsulfonyl-benzonitrile;
cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-2-fluoro-benzonitrile;
cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N,N-dimethyl-3-(trifluoromethyl)-benzenesulfonic
acid amide;
cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-benzonitrile;
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(2-methyl-imidazo[1,2-a]pyraz-
in-6-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(4-methylsulfonyl-phenyl)-8-p-
henyl-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]-5-methoxy-benzonitrile;
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3,8-diphenyl-1,3-diazaspiro[4.5-
]decan-2-one;
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-pyrazin-2-yl-1,3-dia-
zaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-morpholin-4-yl-
-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-[2-(4-methyl-pipe-
razin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-3-(2-morpholin-4-yl-p-
yrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-(2-piper-
azin-1-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one
hydrochloride;
cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-3-[2-(4-methyl-pipera-
zin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-8-phenyl-3-(2-piperaz-
in-1-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one
dihydrochloride;
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl)-
-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-1-(Cyclobutyl-methyl)-8-methylamino-3-[4-methyl-6-(trifluoromethyl)-p-
yridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-1-(Cyclopropyl-methyl)-8-dimethylamino-3-(4-methylsulfonyl-phenyl)-8--
phenyl-1,3-diazaspiro[4.5]decan-2-one
cis-1-(Cyclopropyl-methyl)-8-methylamino-3-(4-methylsulfonyl-phenyl)-8-ph-
enyl-1,3-diazaspiro[4.5]decan-2-one;
cis-1-(Cyclopropyl-methyl)-8-dimethylamino-3-(2-fluoro-4-methylsulfonyl-p-
henyl)-8-phenyl-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]-benzamide; formic acid;
cis-2-[8-Dimethylamino-1-[2-(1-methoxy-cyclobutyl)-ethyl]-2-oxo-8-phenyl--
1,3-diazaspiro[4.5]decan-3-yl]-benzamide;
cis-8-Dimethylamino-1-[2-(1-methoxy-cyclobutyl)-ethyl]-3-(2-methyl-pyrimi-
din-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-5-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-
-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;
cis-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-
-diazaspiro[4.5]decan-3-yl]-benzonitrile;
cis-4-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-
-diazaspiro[4.5]decan-3-yl]-3-methoxy-benzonitrile;
cis-4-[8-Ethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3--
diazaspiro[4.5]decan-3-yl]-3-methoxy-benzonitrile;
cis-2-[8-Ethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3--
diazaspiro[4.5]decan-3-yl]-benzonitrile;
cis-5-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-
-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile;
cis-2-[8-Dimethylamino-1-(oxetan-3-yl-methyl)-2-oxo-8-phenyl-1,3-diazaspi-
ro[4.5]decan-3-yl]-benzamide;
cis-4-Methoxy-5-(8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3--
yl)-pyrimidine-2-carbonitrile;
cis-2-(8-Methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzam-
ide;
cis-8-Dimethylamino-3-[2-(3-oxo-piperazin-1-yl)-pyrimidin-5-yl]-8-phe-
nyl-1,3-diazaspiro[4.5]decan-2-one;
cis-3-(2-Cyclopropyl-pyrimidin-5-yl)-8-dimethylamino-8-phenyl-1,3-diazasp-
iro[4.5]decan-2-one
cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-pheny-
l-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-(2-methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4-
.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-(2-piperazin-1-yl-pyrimidin-5-yl)-1,3-diaz-
aspiro[4.5]decan-2-one;
trans-2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benza-
mide;
cis-2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-be-
nzamide;
cis-2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-
-benzonitrile;
cis-2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzoni-
trile;
cis-3-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-
-yl)-pyrimidin-2-yl]-benzonitrile;
cis-8-Dimethylamino-3-[2-(4-methylsulfonyl-piperazin-1-yl)-pyrimidin-5-yl-
]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-3-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-p-
yrimidin-2-yl]-benzamide
cis-8-[(Cyclopropyl-methyl)-methyl-amino]-8-phenyl-3-[2-(trifluoromethyl)-
-pyrimidin-5-yl]-1,3-diazaspirop[4.5]decan-2-one;
cis-8-Dimethylamino-3-[2-(4-methyl-piperazine-1-carbonyl)-pyrimidin-5-yl]-
-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
trans-4-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3-met-
hoxy-benzonitrile;
cis-4-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3-metho-
xy-benzonitrile;
cis-3-[2-(4-Acetyl-piperazin-1-yl)-pyrimidin-5-yl]-8-dimethylamino-8-phen-
yl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-(2-pyridin-4-yl-pyrimidin-5-yl)-1,3-diazas-
piro[4.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-(2-pyridin-3-yl-pyrimidin-5-yl)-1,3-diazas-
piro[4.5]decan-2-one;
cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-(2-
-hydroxy-ethyl)-pyrimidine-2-carboxylic acid amide;
cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyri-
midine-2-carboxylic acid amide;
cis-8-Dimethylamino-3-[2-morpholin-4-yl-4-(trifluoromethyl)-pyrimidin-5-y-
l]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-4-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-p-
yrimidin-2-yl]-benzonitrile;
cis-5-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-4-metho-
xy-pyrimidine-2-carbonitrile;
trans-5-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-4-met-
hoxy-pyrimidine-2-carbonitrile;
cis-8-Dimethylamino-3-[2-(morpholine-4-carbonyl)-pyrimidin-5-yl]-8-phenyl-
-1,3-diazaspiro[4.5]decan-2-one;
cis-2-[4-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl-
)-pyrimidin-2-yl]-piperazin-1-yl]-acetic acid methyl ester;
cis-8-Dimethylamino-3-[2-(methylsulfonyl-methyl)-phenyl]-8-phenyl-1,3-dia-
zaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-(4-methyl-2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-
-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-pyrimidin-5-yl]--
8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-(4-fluoro-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5-
]decan-2-one;
cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-(2-
-hydroxy-ethyl)-N-methyl-pyrimidine-2-carboxylic acid amide;
cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2-mo-
rpholin-4-yl-isonicotinonitrile;
cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benz-
amide;
cis-8-Dimethylamino-3-(2-fluoro-4-methylsulfonyl-phenyl)-8-phenyl-1-
,3-diazaspiro[4.5]decan-2-one;
cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3-fl-
uoro-benzonitrile;
cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3,5--
difluoro-benzonitrile;
cis-8-Dimethylamino-3-(2-methoxy-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[-
4.5]decan-2-one;
cis-3-[2-(Benzylamino)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diaza-
spiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[2-(4-fluorophenyl)-pyrimidin-5-yl]-8-phenyl-1,3-di-
azaspiro[4.5]decan-2-one;
trans-8-Benzyl-8-dimethylamino-3-(2-morpholin-4-yl-pyrimidin-5-yl)-1,3-di-
azaspiro[4.5]decan-2-one;
cis-8-Benzyl-8-dimethylamino-3-(2-morpholin-4-yl-pyrimidin-5-yl)-1,3-diaz-
aspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-(2-pyridin-2-yl-pyrimidin-5-yl)-1,3-diazas-
piro[4.5]decan-2-one;
cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3,5--
difluoro-benzamide;
cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3-fl-
uoro-benzamide;
cis-8-Benzyl-8-dimethylamino-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-d-
iazaspiro[4.5]decan-2-one;
trans-8-Benzyl-8-dimethylamino-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-
-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-thiophen-2-yl-3-[2-(trifluoromethyl)-pyrimidin-5-yl-
]-1,3-diazaspiro[4.5]decan-2-one;
trans-8-Dimethylamino-8-thiophen-2-yl-3-[2-(trifluoromethyl)-pyrimidin-5--
yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-2-[2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-p-
henoxy]-acetic acid;
cis-8-Dimethylamino-8-phenyl-3-(2-piperidin-1-yl-pyrimidin-5-yl)-1,3-diaz-
aspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-(2-pyrrolidin-1-yl-pyrimidin-5-yl)-1,3-dia-
zaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-(2-pyrimidin-5-yl-pyrimidin-5-yl)-1,3-diaz-
aspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-[2-(piperazine-1-carbonyl)-pyrimidin-5-yl]-
-1,3-diazaspiro[4.5]decan-2-one;
trans-8-Benzyl-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3--
yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2-mo-
rpholin-4-yl-pyridine-4-carboxylic acid amide;
cis-8-Dimethylamino-3-[2-(3,5-dimethyl-isoxazol-4-yl)-pyrimidin-5-yl]-8-p-
henyl-1,3-diazaspiro[4.5]decan-2-one;
cis-3-[2-(Benzothiazol-6-yl)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-
-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[2-fluoro-4-(trifluoromethyl)-phenyl]-8-phenyl-1,3--
diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-(6-morpholin-4-yl-pyridin-3-yl)-8-phenyl-1,3-diazas-
piro[4.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-(2-phenyl-thiazol-4-yl)-1,3-diazaspiro[4.5-
]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-[2-(tetrahydro-pyran-4-ylamino)-pyrimidin--
5-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[2-(4-hydroxy-piperidin-1-yl)-pyrimidin-5-yl]-8-phe-
nyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-(4-phenyl-thiazol-2-yl)-1,3-diazaspiro[4.5-
]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-[2-(1H-pyrrolo[2,3-b]pyridin-1-yl)-pyrimid-
in-5-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-[2-(3,4,5-trifluoro-phenyl)-pyrimidin-5-yl-
]-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-o-tolyl-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-m-tolyl-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-p-tolyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-[4-(trifluoromethyl)-phenyl]-1,3-diazaspir-
o[4.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-[3-(trifluoromethyloxy)-phenyl]-1,3-diazas-
piro[4.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-[4-(trifluoromethyloxy)-phenyl]-1,3-diazas-
piro[4.5]decan-2-one;
cis-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benz-
oic acid methyl ester;
cis-3-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benz-
oic acid methyl ester;
cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benz-
oic acid methyl ester;
cis-3-(1,3-Benzodioxol-5-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]-
decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-quinolin-5-yl-1,3-diazaspiro[4.5]decan-2-o-
ne;
cis-3-(2,3-Dihydro-1H-indol-6-yl)-8-dimethylamino-8-phenyl-1,3-diazasp-
iro[4.5]decan-2-one;
cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-4-me-
thyl-pyridine-2-carboxylic acid methyl ester;
cis-8-Dimethylamino-3-(6-methoxy-4-methyl-pyridin-3-yl)-8-phenyl-1,3-diaz-
aspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[2-methyl-5-(trifluoromethyl)-2H-pyrazol-3-yl]-8-ph-
enyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-(3-methoxy-pyridin-2-yl)-8-phenyl-1,3-diazaspiro[4.-
5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-[5-(trifluoromethyl)-pyridin-2-yl]-1,3-dia-
zaspiro[4.5]decan-2-one;
cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-nico-
tinonitrile;
cis-8-Dimethylamino-3-(3-methyl-pyridin-2-yl)-8-phenyl-1,3-diazaspiro[4.5-
]decan-2-one;
cis-8-Dimethylamino-3-(6-methoxy-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.-
5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-[3-(trifluoromethyl)phenyl]-1,3-diazaspiro-
[4.5]decan-2-one;
cis-3-(1,3-Benzodioxol-4-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]-
decan-2-one;
cis-8-Dimethylamino-3-[2-(2-oxo-1,3-dihydro-indol-4-yl)-pyrimidin-5-yl]-8-
-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[2-(3,5-dimethyl-1H-pyrazol-1-yl)-pyrimidin-5-yl]-8-
-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[2-(3-hydroxy-piperidin-1-yl)-pyrimidin-5-yl]-8-phe-
nyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[2-(3-hydroxy-piperidin-1-yl)-pyrimidin-5-yl]-8-phe-
nyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-pyrimidin-5-
-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-2-[4-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl-
)-pyrimidin-2-yl]-piperazin-1-yl]-acetic acid;
cis-8-Dimethylamino-3-[2-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrimid-
in-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Benzyl-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl-
]-1,3-diazaspiro[4.5]decan-2-one;
trans-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-thi-
ophen-2-yl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-thiop-
hen-2-yl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-4-(trifluorometh-
yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-(1-methyl-1H-benzoimidazol-2-yl)-3-[2-(trifluoromet-
hyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-(1-methyl-1H-benzoimidazol-2-yl)-3-[4-methyl-6-(tri-
fluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[2-(2-hydroxy-ethylamino)-pyrimidin-5-yl]-8-phenyl--
1,3-diazaspiro[4.5]decan-2-one;
cis-3-[2-(Benzyl-methyl-amino)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1-
,3-diazaspiro[4.5]decan-2-one;
cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-[2-
-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethyl]-pyrimidine-2-carboxylic
acid amide;
cis-8-Dimethylamino-3-[2-(1H-indazol-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-d-
iazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[2-[(2-hydroxy-ethyl)-methyl-amino]-pyrimidin-5-yl]-
-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-3-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benz-
amide;
cis-8-Dimethylamino-3-[3-fluoro-5-(trifluoromethyl)-pyridin-2-yl]-8-
-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-(5-methyl-pyrazin-2-yl)-8-phenyl-1,3-diazaspiro[4.5-
]decan-2-one;
cis-8-Dimethylamino-3-(5-fluoro-pyrimidin-4-yl)-8-phenyl-1,3-diazaspiro[4-
.5]decan-2-one;
cis-8-Dimethylamino-3-(5-fluoro-pyrimidin-2-yl)-8-phenyl-1,3-diazaspiro[4-
.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-pyrazin-2-yl-1,3-diazaspiro[4.5]decan-2-on-
e;
cis-3-([2,1,3]Benzoxadiazol-5-yl)-8-dimethylamino-8-phenyl-1,3-diazaspi-
ro[4.5]decan-2-one;
cis-2-[2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-p-
henoxy]-acetamide;
cis-8-Dimethylamino-8-phenyl-3-(5-pyridin-4-yl-thiophen-2-yl)-1,3-diazasp-
iro[4.5]decan-2-one;
cis-2-[2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-p-
henoxy]-acetic acid methyl ester;
cis-8-Dimethylamino-3-(2-morpholin-4-yl-pyrimidin-4-yl)-8-phenyl-1,3-diaz-
aspiro[4.5]decan-2-one;
cis-3-[2-(3,4-Difluoro-phenyl)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1-
,3-diazaspiro[4.5]decan-2-one;
cis-2-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-p-
yrimidin-2-yl]-benzonitrile;
cis-3-(2-Amino-pyrimidin-5-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.-
5]decan-2-one;
cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-p-
yrimidin-2-yl]-cyclopropanecarboxylic acid amide;
cis-2[4-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-
-pyrimidin-2-yl]-piperazin-1-yl]-acetamide;
cis-8-Dimethylamino-8-phenyl-3-(6-piperazin-1-yl-pyridin-3-yl)-1,3-diazas-
piro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-8-phenyl-
-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-4-methyl-pyrimid-
in-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-d-
iazaspiro[4.5]decan-2-one;
cis-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro-
[4.5]decan-3-yl]-pyrimidine-5-carbonitrile;
cis-8-Dimethylamino-3-[2-(4-methyl-piperazin-1-yl)-pyrimidin-5-yl]-8-phen-
yl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-[2-(trif-
luoromethyl)-pyrimidin-5-yl]-1,3-diazaspirop[4.5]decan-2-one;
cis-2-[1-(3-Methoxy-propyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspirop[-
4.5]decan-3-yl]-pyrimidine-5-carbonitrile;
cis-8-Dimethylamino-8-phenyl-3-[6-(trifluoromethyl)-pyridin-3-yl]-1,3-dia-
zaspiro[4.5]decan-2-one;
cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyri-
dine-2-carbonitrile;
cis-8-Dimethylamino-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diaz-
aspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-(2-methyl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4-
.5]decan-2-one;
cis-8-Dimethylamino-1-[(2-methoxyphenyl)-methyl]-3-(2-methyl-pyrimidin-5--
yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-8-phenyl-3-[2-(triflu-
oromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-methyl-pyrimid-
in-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-8-phenyl-3-pyrimidin--
5-yl-1,3-diazaspiro[4.5]decan-2-one;
cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-4-me-
thyl-pyridine-2-carbonitrile;
cis-8-Dimethylamino-3-(2-methyl-pyrimidin-5-yl)-8-phenyl-1-(pyridin-2-yl--
methyl)-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-pyrimidin-5-yl-1,3-diazaspiro[4.5]decan-2--
one;
cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-pyri-
midin-5-yl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Amino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-[2-(trifluoromet-
hyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-(3-fluorophenyl)-8-phenyl-1,3-diazaspiro[4.5]decan--
2-one;
cis-8-Dimethylamino-3-(3-methylsulfonyl-phenyl)-8-phenyl-1,3-diazas-
piro[4.5]decan-2-one;
cis-8-Dimethylamino-3-(4-methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4-
.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-pyridazin-3-yl-1,3-diazaspiro[4.5]decan-2--
one;
cis-3-Methoxy-4-(8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]deca-
n-3-yl)-benzonitrile;
cis-8-Dimethylamino-3-(2-fluorophenyl)-8-phenyl-1,3-diazaspiro[4.5]decan--
2-one;
cis-8-Dimethylamino-8-phenyl-3-(2-phenyl-pyrimidin-5-yl)-1,3-diazas-
piro[4.5]decan-2-one;
cis-8-Methylamino-1-(oxetan-3-yl-methyl)-8-phenyl-3-[2-(trifluoromethyl)--
pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-1-(Cyclopropyl-methyl)-8-methylamino-8-phenyl-3-[2-(trifluoromethyl)--
pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benz-
onitrile;
cis-8-Dimethylamino-3-(4-fluorophenyl)-8-phenyl-1,3-diazaspiro[4-
.5]decan-2-one;
cis-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benz-
onitrile;
cis-8-Ethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-[2-
-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-3-(2-methyl-pyrimidin-
-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[2-(morpholin-4-yl-methyl)-pyrimidin-5-yl]-8-phenyl-
-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[2-(methyl-tetrahydro-pyran-4-yl-amino)-pyrimidin-5-
-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-5-[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]-pyrimidine-2-carboxylic acid amide;
cis-1-(Cyclopropyl-methyl)-3-(2-fluoro-4-methylsulfonyl-phenyl)-8-methyla-
mino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-2-[[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)--
pyrimidin-2-yl]-methyl-amino]-acetamide;
cis-2-[[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)--
pyrimidin-2-yl]amino]-acetamide;
cis-1-(Cyclopropyl-methyl)-8-methylamino-3-[4-methyl-6-(trifluoromethyl)--
pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl-
)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-p-
yrimidin-2-yl]-thiophene-2-carboxylic acid amide;
cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-p-
yrimidin-2-yl]-benzamide;
cis-8-Dimethylamino-8-phenyl-3-(5-phenyl-thiophen-2-yl)-1,3-diazaspiro[4.-
5]decan-2-one;
cis-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[2-(methylsulfonyl-methyl)-p-
henyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-1-(Cyclopropyl-methyl)-8-methylamino-3-[2-(methylsulfonyl-methyl)-phe-
nyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-(3-fluorophenyl)-3-[2-(methylsulfonyl-methyl)-pheny-
l]-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-(4-fluorophenyl)-3-[2-(methylsulfonyl-methyl)-pheny-
l]-1,3-diazaspiro[4.5]decan-2-one;
cis-8-[Methyl-(tetrahydro-furan-3-yl-methyl)-amino]-8-phenyl-3-[2-(triflu-
oromethyl)-pyrimidin-5-yl]-1,3-diazaspirop[4.5]decan-2-one
(enantiomer 1);
cis-8-[Methyl-(tetrahydro-furan-3-yl-methyl)-amino]-8-phenyl-3-[2-(triflu-
oromethyl)-pyrimidin-5-yl]-1,3-diazaspirop[4.5]decan-2-one
(enantiomer 2);
cis-8-Dimethylamino-8-(3-fluorophenyl)-3-(4-methyl-2-morpholin-4-yl-pyrim-
idin-5-yl)-1,3-diazaspiro[4.5]decan-2-one;
cis-3-[6-(4-Acetyl-piperazin-1-yl)-4-methyl-pyridin-3-yl]-8-dimethylamino-
-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-3-[2-(4-Acetyl-piperazin-1-yl)-4-methyl-pyrimidin-5-yl]-8-dimethylami-
no-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-(4-methyl-6-pyridin-4-yl-pyridin-3-yl)-8-phenyl-1,3-
-diazaspiro[4.5]decan-2-one;
cis-3-[2-(4-Acetyl-piperazin-1-yl)-4-(trifluoromethyl)-pyrimidin-5-yl]-8--
dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[2-(3-oxo-piperazin-1-yl)-4-(trifluoromethyl)-pyrim-
idin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-isoquinolin-4-yl-8-phenyl-1,3-diazaspiro[4.5]decan--
2-one;
cis-8-Dimethylamino-3-isoquinolin-5-yl-8-phenyl-1,3-diazaspiro[4.5]-
decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1,3-diazas-
piro[4.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-(2-pyridin-4-yl-thiazol-4-yl)-1,3-diazaspi-
ro[4.5]decan-2-one;
cis-8-[Methyl-(tetrahydro-furan-3-yl-methyl)-amino]-3-(2-morpholin-4-yl-p-
yrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (enantiomer
1);
cis-8-[Methyl-(tetrahydro-furan-3-yl-methyl)-amino]-3-(2-morpholin-4-yl-p-
yrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (enantiomer
2);
cis-3-[2-(Azetidin-1-yl)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-dia-
zaspiro[4.5]decan-2-one;
cis-3-[2-(3,3-Difluoro-azetidin-1-yl)-pyrimidin-5-yl]-8-dimethylamino-8-p-
henyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[6-morpholin-4-yl-5-(trifluoromethyl)-pyridin-3-yl]-
-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Methylamino-3-[6-morpholin-4-yl-5-(trifluoromethyl)-pyridin-3-yl]-8-
-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-[5-(trifluoromethyloxy)-pyridin-2-yl]-1,3--
diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-(5-methylsulfonyl-pyridin-2-yl)-8-phenyl-1,3-diazas-
piro[4.5]decan-2-one;
cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-nico-
tinonitrile;
cis-3-[2-(4-Cyclopropyl-1H-[1,2,3]triazol-1-yl)-pyrimidin-5-yl]-8-dimethy-
lamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[4-methyl-2-(3-oxo-piperazin-1-yl)-pyrimidin-5-yl]--
8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyri-
dine-2-carboxylic acid amide;
cis-3-[4-(Azetidin-1-yl)-2-methyl-pyrimidin-5-yl]-8-dimethylamino-8-pheny-
l-1,3-diazaspiro[4.5]decan-2-one;
cis-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benz-
amide;
cis-8-Dimethylamino-3-[2-(methylsulfonyl-methyl)-phenyl]-8-thiophen-
-2-yl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-(3-fluorophenyl)-3-[2-methyl-5-(trifluoromethyl)-2H-
-pyrazol-3-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-(4-methyl-2-morpholin-4-yl-pyrimidin-5-yl)-8-thioph-
en-2-yl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-(6-methylsulfonyl-pyridin-3-yl)-8-phenyl-1,3-diazas-
piro[4.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1,3-diazas-
piro[4.5]decan-2-one;
cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-p-
yrimidin-2-yl]-acetamide;
cis-3-[2-(4-Methyl-piperazin-1-yl)-pyrimidin-5-yl]-8-[methyl-(tetrahydro--
furan-3-yl-methyl)-amino]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
(enantiomer 1);
cis-3-[2-(4-Methyl-piperazin-1-yl)-pyrimidin-5-yl]-8-[methyl-(tetrahydro--
furan-3-yl-methyl)-amino]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
(enantiomer 2);
cis-8-Dimethylamino-3-(4,6-dimethyl-2-morpholin-4-yl-pyrimidin-5-yl)-8-ph-
enyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-thiophen-2-yl-1-
,3-diazaspiro[4.5]decan-2-one;
cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyri-
dine-3-carboxylic acid amide;
cis-8-Dimethylamino-3-[2-methyl-5-(trifluoromethyl)-2H-pyrazol-3-yl]-8-th-
iophen-2-yl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[2-[(2-hydroxy-ethyl)-methyl-amino]-pyrimidin-5-yl]-
-8-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[2-(2-oxo-1,3-dihydro-indol-4-yl)-pyrimidin-5-yl]-8-
-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[4-methyl-6-(3-oxo-piperazin-1-yl)-pyridin-3-yl]-8--
phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-(4-methyl-6-pyridin-2-yl-pyridin-3-yl)-8-phenyl-1,3-
-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-(4-methylsulfonyl-pyridin-3-yl)-8-phenyl-1,3-diazas-
piro[4.5]decan-2-one;
cis-3-(Benzothiazol-7-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]dec-
an-2-one;
cis-8-Dimethylamino-8-(4-fluorophenyl)-3-(4-methyl-2-morpholin-4-
-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one;
cis-2-[8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-2-ox-
o-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N,N-dimethyl-acetamide;
cis-8-Dimethylamino-3-[2-(2-methyl-1-oxo-2,3-dihydro-isoindol-4-yl)-pyrim-
idin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-2-[[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)--
2-methyl-pyrimidin-4-yl]amino]-acetamide;
cis-2-[3-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-p-
yridin-4-yl]-acetamide;
cis-8-Dimethylamino-3-[4-(methylsulfonyl-methyl)-pyridin-3-yl]-8-phenyl-1-
,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[6-(4-methyl-3-oxo-piperazin-1-yl)-pyridin-3-yl]-8--
phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-(2,4-dimethyl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspi-
ro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[2-(1-oxo-2,3-dihydro-isoindol-4-yl)-pyrimidin-5-yl-
]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; 2,2,2-trifluoro-acetic
acid;
cis-8-Dimethylamino-3-[6-[(2-hydroxy-ethyl)-methyl-amino]-5-(trifluoromet-
hyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-[2-[4-(trifluoromethyl)-1H-[1,2,3]triazol--
1-yl]-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[2-(4-isopropyl-1H-[1,2,3]triazol-1-yl)-pyrimidin-5-
-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[6-(1,1-dioxo-[1,4]thiazinan-4-yl)-pyridin-3-yl]-8--
phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2-mo-
rpholin-4-yl-nicotinonitrile;
cis-8-Dimethylamino-3-(1-methylsulfonyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8--
phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-(1H-indol-4-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-
-one;
cis-8-Dimethylamino-3-(2-hydroxy-benzooxazol-7-yl)-8-phenyl-1,3-diaz-
aspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[2-fluoro-4-(trifluoromethyloxy)-phenyl]-8-phenyl-1-
,3-diazaspiro[4.5]decan-2-one;
cis-4-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-p-
yrimidin-2-yl]-benzamide; 2,2,2-trifluoro-acetic acid;
cis-8-Dimethylamino-3-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-8-phenyl-1-
,3-diazaspiro[4.5]decan-2-one;
cis-3-(1-Acetyl-1H-indol-4-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.-
5]decan-2-one;
cis-8-Dimethylamino-3-(1H-indol-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-
-one;
cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-
-5-methyl-nicotinonitrile;
cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-5-fl-
uoro-nicotinonitrile;
cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1-(2-ox-
o-2-pyrrolidin-1-yl-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-5-me-
thyl-pyridine-3-carboxylic acid amide;
cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-5-fl-
uoro-pyridine-3-carboxylic acid amide;
cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-m-tol-
yl-1,3-diazaspiro[4.5]decan-2-one;
cis-3-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-ison-
icotinonitrile;
cis-8-Dimethylamino-3-[3-fluoro-5-(2-oxo-1,3-dihydro-indol-4-yl)-pyridin--
2-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-[3-(t-
rifluoromethyloxy)-phenyl]-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-[3-(t-
rifluoromethyl)phenyl]-1,3-diazaspirop[4.5]decan-2-one;
cis-8-Dimethylamino-8-(3-methoxyphenyl)-3-[4-methyl-6-(trifluoromethyl)-p-
yridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-8-(5-Chloro-thiophen-2-yl)-8-dimethylamino-3-[4-methyl-6-(trifluorome-
thyl)-pyridin-3-yl]-1,3-diazaspirop[4.5]decan-2-one;
cis-8-Dimethylamino-8-(3-fluorophenyl)-3-[4-methyl-6-(trifluoromethyl)-py-
ridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-(2-methylamino-pyrimidin-5-yl)-8-phenyl-1,3-diazasp-
iro[4.5]decan-2-one;
cis-8-(5-Chloro-thiophen-2-yl)-8-dimethylamino-3-(4-methyl-2-morpholin-4--
yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one;
cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-p-
yrimidin-2-yl]-N-methyl-cyclopropanecarboxylic acid amide;
cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-p-
yrimidin-2-yl]-N,2,5-trimethyl-2H-pyrazole-3-carboxylic acid amide;
cis-3-[4,6-Bis(trifluoromethyl)-pyridin-3-yl]-8-dimethylamino-8-phenyl-1,-
3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[2-[(2-hydroxy-ethyl)-methyl-amino]-quinazolin-6-yl-
]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-(2-morpholin-4-yl-quinazolin-6-yl)-8-phenyl-1,3-dia-
zaspiro[4.5]decan-2-one;
cis-8-[Methyl-(oxetan-3-yl-methyl)-amino]-8-phenyl-3-[2-(trifluoromethyl)-
-pyrimidin-5-yl]-1,3-diazaspirop[4.5]decan-2-one;
cis-3-(1-Acetyl-1H-indol-3-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.-
5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-quinazolin-6-yl-1,3-diazaspiro[4.5]decan-2-
-one;
cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-
-2-(2-oxo-1,3-dihydro-indol-4-yl)-isonicotinonitrile;
cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-p-
yrimidin-2-yl]-N-methyl-tetrahydro-pyran-4-carboxylic acid amide;
cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-p-
yrimidin-2-yl]-N,2,2-trimethyl-propionamide;
cis-8-Dimethylamino-3-[2-(1-methyl-2-oxo-1,3-dihydro-indol-4-yl)-pyrimidi-
n-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-(2-morpholin-4-yl-1H-benzoimidazol-5-yl)-8-phenyl-1-
,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-(3-fluoro-5-methyl-phenyl)-3-[4-methyl-6-(trifluoro-
methyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[6-(2-oxo-1,3-dihydro-indol-4-yl)-pyridin-3-yl]-8-p-
henyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-(3-hydroxyphenyl)-3-[4-methyl-6-(trifluoromethyl)-p-
yridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-3-[6-(Azetidin-1-yl)-5-(trifluoromethyl)-pyridin-3-yl]-8-dimethylamin-
o-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-3-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspi-
ro[4.5]decan-3-yl]-isonicotinonitrile;
cis-3-[3,5-Bis(trifluoromethyl)-pyridin-2-yl]-8-dimethylamino-8-phenyl-1,-
3-diazaspiro[4.5]decan-2-one
cis-8-Dimethylamino-3-(5-fluoro-6-morpholin-4-yl-pyridin-3-yl)-8-phenyl-1-
,3-diazaspiro[4.5]decan-2-one;
cis-8-(3-Chlorophenyl)-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl)-py-
ridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[5-(2-oxo-1,3-dihydro-indol-4-yl)-pyridin-2-yl]-8-p-
henyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-[5-(trifluoromethyl)-[1,3,4]thiadiazol-2-y-
l]-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-(2-oxo-1,3-dihydro-indol-4-yl)-8-phenyl-1,3-diazasp-
iro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[2-[(2-hydroxy-ethyl)-methyl-amino]-1H-benzoimidazo-
l-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-(5-methyl-6-morpholin-4-yl-pyridin-3-yl)-8-phenyl-1-
,3-diazaspiro[4.5]decan-2-one;
cis-1-(Cyclopropyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-(5-methyl-
sulfonyl-pyridin-2-yl)-1,3-diazaspiro[4.5]decan-2-one;
cis-1-(Cyclopropyl-methyl)-8-(3-fluorophenyl)-8-methylamino-3-(5-methylsu-
lfonyl-pyridin-2-yl)-1,3-diazaspiro[4.5]decan-2-one;
cis-1-(Cyclobutyl-methyl)-8-(3-fluorophenyl)-8-methylamino-3-[2-(trifluor-
omethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-1-(Cyclopropyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[2-(trifl-
uoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-1-(Cyclopropyl-methyl)-8-(3-fluorophenyl)-8-methylamino-3-[2-(trifluo-
romethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-(3-fluorophenyl)-3-[2-(trifluoromethyl)-pyrimidin-5-
-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-1-(Cyclopropyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[2-methyl-
-5-(trifluoromethyl)-2H-pyrazol-3-yl]-1,3-diazaspiro[4.5]decan-2-one
cis-1-(Cyclopropyl-methyl)-8-(3-fluorophenyl)-8-methylamino-3-[2-methyl-5-
-(trifluoromethyl)-2H-pyrazol-3-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Methylamino-3-(4-methyl-2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1-
,3-diazaspiro[4.5]decan-2-one;
cis-3-[5-(Azetidin-1-yl)-3-methyl-pyridin-2-yl]-8-dimethylamino-8-(3-fluo-
rophenyl)-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-(3-fluorophenyl)-3-(5-methylsulfonyl-pyridin-2-yl)--
1,3-diazaspiro[4.5]decan-2-one;
cis-3-(6-(azetidin-1-yl)-4-fluoropyridin-3-yl)-8-(dimethylamino)-8-phenyl-
-1,3-diazaspiro[4.5]decan-2-one;
cis-3-(6-(azetidin-1-yl)pyridin-3-yl)-8-(dimethylamino)-8-(3-fluorophenyl-
)-1,3-diazaspiro[4.5]decan-2-one;
cis-3-(1-(cyclopropanecarbonyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-8-(d-
imethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one;
cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-(2-hydroxyethyl)-3-(trifluo-
romethyl)-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one;
cis-3-(1-(cyclopropylmethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-8-(dime-
thylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one;
cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-(methylsulfonyl)-3-(trifluo-
romethyl)-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one;
cis-1-(cyclopropylmethyl)-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-(meth-
ylsulfonyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan--
2-one;
cis-2-(5-(8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro-
[4.5]decan-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-N,N-dimethylacetamid-
e;
cis-2-(5-(1-(cyclopropylmethyl)-8-(dimethylamino)-8-(3-fluorophenyl)-2--
oxo-1,3-diazaspiro[4.5]decan-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-N,-
N-dimethylacetamide;
cis-8-(dimethylamino)-3-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-phenyl-
-1,3-diazaspiro[4.5]decan-2-one;
cis-8-(dimethylamino)-3-(3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-phenyl-
-1,3-diazaspiro[4.5]decan-2-one;
cis-8-(dimethylamino)-8-phenyl-3-(1H-pyrrolo[2,3-c]pyridin-4-yl)-1,3-diaz-
aspiro[4.5]decan-2-one;
cis-8-(dimethylamino)-8-phenyl-3-(2-(pyridazin-4-yl)pyrimidin-5-yl)-1,3-d-
iazaspiro[4.5]decan-2-one;
cis-8-(dimethylamino)-3-(2-(2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-5-yl)-
-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-methyl-3-(thiophen-2-yl)-1H-
-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one;
cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-methyl-3-morpholino-1H-pyra-
zol-5-yl)-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;
cis-3-(4-methyl-6-(trifluoromethyl)pyridin-3-yl)-8-(methylamino)-8-phenyl-
-1,3-diazaspiro[4.5]decan-2-one;
cis-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-8-(methylamino)-8-ph-
enyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(4-(methylsulfonyl)pyridin-3-y-
l)-1,3-diazaspiro[4.5]decan-2-one;
cis-8-(dimethylamino)-3-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-8-(-
3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one;
cis-3-(1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-8-(dimethylamin-
o)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one;
cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-(oxetan-3-ylmethyl)-3-(trif-
luoromethyl)-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one;
cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-(2-(methylsulfonyl)ethyl)-3-
-(trifluoromethyl)-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one;
cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(4-methyl-2-(methylamino)pyrim-
idin-5-yl)-1,3-diazaspiro[4.5]decan-2-one;
cis-3-(2-cyclopropoxy-4-methylpyrimidin-5-yl)-8-(dimethylamino)-8-(3-fluo-
rophenyl)-1,3-diazaspiro[4.5]decan-2-one;
cis-N-(5-(8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]d-
ecan-3-yl)-4-methylpyrimidin-2-yl)-N-methylcyclopropanecarboxamide;
cis-N-(5-(8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]d-
ecan-3-yl)-4-methylpyrimidin-2-yl)-N-methylpivalamide;
cis-3-(4-(azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-5-yl)-8-(dimethylam-
ino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one;
cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(4-(oxetan-3-ylmethoxy)-2-(tri-
fluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one;
cis-3-(2-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)-8-(dimethyl-
amino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one;
cis-3-(2-cyclopropyl-4-(2-hydroxyethyl)(methyl)amino)pyrimidin-5-yl)-8-(d-
imethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one and
the physiologically acceptable salts thereof.
27. The compound according to claim 1 adapted for use in the
treatment of pain.
28. A medicament comprising a compound according to claim 1.
29. A method of treating pain, said method comprising administering
to a patient in need thereof an effective amount therefor of at
leas one compound according to claim 1.
30. A method of treating a disorder selected from the group
consisting of neurodegenerative disorders, neuroinflammatory
disorders, neuropsychiatric disorders, and substance
abuse/dependence, said method comprising administering to a patient
in need thereof an effective amount therefor of at least one
compound according to claim 1.
Description
[0001] This application is a continuation of U.S. patent
application Ser. No. 16/450,331, filed Jun. 24, 2019, pending,
which is a continuation of U.S. patent application Ser. No.
16/207,854, filed Dec. 3, 2018, abandoned, which is a continuation
of U.S. patent application Ser. No. 15/923,948, filed Mar. 16,
2018, abandoned; which is a continuation of U.S. patent application
Ser. No. 15/405,485, filed Jan. 13, 2017, abandoned; which claims
foreign priority benefit under 35 U.S.C. .sctn. 119 of European
Patent Application No. 16 151 012.8, filed Jan. 13, 2016, the
disclosures of which are incorporated herein by reference.
[0002] The invention relates to
3-((hetero-)aryl)-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.
[0003] 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".
[0004] 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.
[0005] 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).
[0006] 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).
[0007] 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.
[0008] 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).
[0009] 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.
[0010] 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.
[0011] 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.
[0012] 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.
[0013] 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.
[0014] It is an object of the invention to provide
pharmacologically active compounds, preferably analgesics that have
advantages compared to the prior art.
[0015] This object has been achieved by the subject-matter of the
patent claims.
[0016] A first aspect of the invention relates to
3-((hetero-)aryl)-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;
[0017] --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;
[0018] --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--; R.sup.5 means a 6-14-membered aryl moiety,
unsubstituted, mono- or polysubstituted; or a 5-14-membered
heteroaryl moiety, unsubstituted, mono- or polysubstituted;
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,
--C(.dbd.O)NH--(CH.sub.2CH.sub.2--O).sub.1-30--CH.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, .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;
[0019] --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,
--CO.sub.2H, --C(.dbd.O)O--C.sub.1-C.sub.6-alkyl,
--C(.dbd.O)NH.sub.2, --C(.dbd.O)NHC.sub.1-C.sub.6-alkyl,
--C(.dbd.O)N(C.sub.1-C.sub.6-alkyl).sub.2,
--O--C.sub.1-C.sub.6-alkyl and
--S(.dbd.O).sub.2--C.sub.1-C.sub.6-alkyl; a 3-12-membered
cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono-
or polysubstituted; wherein said 3-12-membered cycloalkyl moiety is
optionally connected through --C.sub.1-C.sub.6-alkylene-, linear or
branched, saturated or unsaturated, unsubstituted or substituted
with one, two, three or four substituents independently of one
another selected from the group consisting of --F, --Cl, --Br, --I,
--CN, --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, mono- or
polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety
is optionally connected through --C.sub.1-C.sub.6-alkylene-, linear
or branched, saturated or unsaturated, unsubstituted or substituted
with one, two, three or four substituents independently of one
another selected from the group consisting of --F, --Cl, --Br, --I,
--CN, --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--;
--(CH.sub.2).sub.2--S(.dbd.O).sub.2--(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, --C.sub.1-C.sub.6-alkyl,
--C(.dbd.O)--C.sub.1-C.sub.6-alkyl, or
--S(.dbd.O).sub.2--C.sub.1-C.sub.6-alkyl, wherein said
--C.sub.1-C.sub.6-alkyl is 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, --CO.sub.2H,
--C(.dbd.O)O--C.sub.1-C.sub.6-alkyl and --C(.dbd.O)NH.sub.2; and
wherein said ring is 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 a physiologically acceptable salt thereof.
[0020] "(Hetero-)aryl" means "heteroaryl or aryl". 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.
[0021] 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.
[0022] In preferred embodiments of the compound according to the
invention, 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;
preferably --H.
[0023] 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.
[0024] 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.
[0025] 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--.
[0026] In yet another preferred embodiment, [0027] R.sup.1 means
--H or --CH.sub.3; and [0028] 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.
[0029] 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.
[0030] 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,
--CH.sub.3, --CF.sub.3, --OH, --OCH.sub.3, --OCF.sub.3 or
--OCH.sub.2OCH.sub.3, preferably --F.
[0031] 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.
[0032] In a preferred embodiment of the compound according to the
invention, R.sup.4 means --H.
[0033] 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,
--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,
--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.
[0034] 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--.
[0035] 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--.
[0036] 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--.
[0037] 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--.
[0038] In a preferred embodiment of the compound according to the
invention, R.sup.5 means -phenyl, 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; --CF.sub.3;
-3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted,
mono- or polysubstituted; preferably -cyclopropyl, saturated,
unsubstituted; -3-12-membered heterocycloalkyl, saturated or
unsaturated, unsubstituted, mono- or polysubstituted; preferably
-pyrrolidinyl, -piperidinyl, -morpholinyl, -piperazinyl,
-thiomorpholinyl, or -thiomorpholinyl dioxide, in each case
saturated, unsubstituted or monosubstituted with
--C.sub.1-C.sub.4-alkyl; -6-14-membered aryl, unsubstituted, mono-
or poly-substituted; preferably -phenyl, unsubstituted;
--O--C.sub.1-C.sub.4-alkyl; --S--C.sub.1-C.sub.4-alkyl;
--C(.dbd.O)OH; --C(.dbd.O)O--C.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;
--C(.dbd.O)N(C.sub.1-C.sub.4-alkyl)(C.sub.1-C.sub.4-alkyl-OH);
--C(.dbd.O)NH--(CH.sub.2).sub.1-3-3-12-membered cycloalkyl,
saturated or unsaturated, unsubstituted or monosubstituted with
--OH; preferably --C(.dbd.O)NH--(CH.sub.2).sub.1-3-cyclobutyl,
saturated or unsaturated, unsubstituted or monosubstituted with
--OH; --C(.dbd.O)-3-12-membered heterocycloalkyl, saturated or
unsaturated, unsubstituted, mono- or polysubstituted; preferably
--C(.dbd.O)-morpholinyl, saturated, unsubstituted;
--S(.dbd.O)C.sub.1-C.sub.4-alkyl;
--S(.dbd.O).sub.2C.sub.1-C.sub.4-alkyl; and
--S(.dbd.O).sub.2N(C.sub.1-C.sub.4-alkyl).sub.2.
[0039] In another preferred embodiment of the compound according to
the invention, R.sup.5 means -1,2-benzodioxole, -pyrazinyl,
-pyridazinyl, -pyridinyl, -pyrimidinyl, -thienyl, -imidazolyl,
-benzimidazolyl, -thiazolyl, -1,3,4-thiadiazolyl, -benzothiazolyl,
-oxazolyl, -benzoxazolyl, -pyrazolyl, -quinolinyl, -isoquinolinyl,
-quinazolinyl, -indolyl, -indolinyl, -benzo[c][1,2,5]oxadiazolyl,
-imidazo[1,2-a]pyrazinyl, or -1H-pyrrolo[2,3-b]pyridinyl, in each
case unsubstituted, mono- or polysubstituted; preferably
-pyrazinyl, -pyridazinyl, -pyridinyl, -pyrimidinyl, or -thienyl, in
each case unsubstituted, mono- or polysubstituted. Preferably,
R.sup.5 means -pyrazinyl, -pyridazinyl, -pyridinyl, -pyrimidinyl,
or -thienyl, 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; --CF.sub.3; -3-12-membered
cycloalkyl, saturated or unsaturated, unsubstituted, mono- or
polysubstituted; preferably -cyclopropyl, saturated, unsubstituted;
-3-12-membered heterocycloalkyl, saturated or unsaturated,
unsubstituted, mono- or polysubstituted; preferably -pyrrolidinyl,
-piperidinyl, -morpholinyl, -piperazinyl, -thiomorpholinyl, or
-thiomorpholinyl dioxide, in each case saturated, unsubstituted or
monosubstituted with --C.sub.1-C.sub.4-alkyl; -6-14-membered aryl,
unsubstituted, mono- or poly-substituted; preferably -phenyl,
unsubstituted; --O--C.sub.1-C.sub.4-alkyl;
--S--C.sub.1-C.sub.4-alkyl; --C(.dbd.O)OH;
--C(.dbd.O)O--C.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;
--C(.dbd.O)N(C.sub.1-C.sub.4-alkyl)(C.sub.1-C.sub.4-alkyl-OH);
--C(.dbd.O)NH--(CH.sub.2).sub.1-3-3-12-membered cycloalkyl,
saturated or unsaturated, unsubstituted or monosubstituted with
--OH; preferably --C(.dbd.O)NH--(CH.sub.2).sub.1-3-cyclobutyl,
saturated or unsaturated, unsubstituted or monosubstituted with
--OH; --C(.dbd.O)-3-12-membered heterocycloalkyl, saturated or
unsaturated, unsubstituted, mono- or polysubstituted; preferably
--C(.dbd.O)-morpholinyl, saturated, unsubstituted;
--S(.dbd.O)C.sub.1-C.sub.4-alkyl;
--S(.dbd.O).sub.2C.sub.1-C.sub.4-alkyl; and
--S(.dbd.O).sub.2N(C.sub.1-C.sub.4-alkyl).sub.2.
[0040] In still another preferred embodiment of the compound
according to the invention, R.sup.5 means a bicyclic 9-10-membered
heteroaryl moiety, unsubstituted, mono- or polysubstituted.
Preferably, R.sup.5 means imidazo[1,2-a]pyrazine, unsubstituted or
monosubstituted with --C.sub.1-C.sub.4-alkyl.
[0041] Preferably, R.sup.5 means -phenyl, -1,2-benzodioxole,
-pyrazinyl, -pyridazinyl, -pyridinyl, -pyrimidinyl, -thienyl,
-imidazolyl, -benzimidazolyl, -thiazolyl, -1,3,4-thiadiazolyl,
-benzothiazolyl, -oxazolyl, -benzoxazolyl, -pyrazolyl, -quinolinyl,
-isoquinolinyl, -quinazolinyl, -indolyl, -indolinyl,
-benzo[c][1,2,5]oxadiazolyl, -imidazo[1,2-a]pyrazinyl, or
-1H-pyrrolo[2,3-b]pyridinyl, in each case unsubstituted or
substituted with one, two, three or four substituents independently
of one another selected from the group consisting of
--F; --Cl; --Br; --I;
[0042] --CN; --C.sub.1-C.sub.4-alkyl; --CF.sub.3;
--C.sub.1-C.sub.4-alkyl-C(.dbd.O)NH.sub.2;
--C.sub.1-C.sub.4-alkyl-S(.dbd.O).sub.2--C.sub.1-C.sub.4-alkyl;
--C(.dbd.O)--C.sub.1-C.sub.4-alkyl; --C(.dbd.O)OH;
--C(.dbd.O)O--C.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;
--C(.dbd.O)NH(C.sub.1-C.sub.4-alkyl-OH);
--C(.dbd.O)N(C.sub.1-C.sub.4-alkyl)(C.sub.1-C.sub.4-alkyl-OH);
--C(.dbd.O)NH--(CH.sub.2CH.sub.2O).sub.1-30--CH.sub.3; --NH.sub.2;
--NHC.sub.1-C.sub.4-alkyl; --N(C.sub.1-C.sub.4-alkyl).sub.2;
--NHC.sub.1-C.sub.4-alkyl-OH; --NCH.sub.3C.sub.1-C.sub.4-alkyl-OH;
--NH--C.sub.1-C.sub.4-alkyl-C(.dbd.O)NH.sub.2;
--NCH.sub.3--C.sub.1-C.sub.4-alkyl-C(.dbd.O)NH.sub.2;
--NHC(.dbd.O)--C.sub.1-C.sub.4-alkyl;
--NCH.sub.3C(.dbd.O)--C.sub.1-C.sub.4-alkyl; --OH;
--O--C.sub.1-C.sub.4-alkyl; --OCF.sub.3;
--O--C.sub.1-C.sub.4-alkyl-CO.sub.2H;
--O--C.sub.1-C.sub.4-alkyl-C(.dbd.O)O--C.sub.1-C.sub.4-alkyl;
--O--C.sub.1-C.sub.4-alkyl-CONH.sub.2; --S--C.sub.1-C.sub.4-alkyl;
--S(.dbd.O)C.sub.1-C.sub.4-alkyl;
--S(.dbd.O).sub.2C.sub.1-C.sub.4-alkyl; and
--S(.dbd.O).sub.2N(C.sub.1-C.sub.4-alkyl).sub.2; -3-12-membered
cycloalkyl, saturated or unsaturated, unsubstituted, mono- or
polysubstituted; wherein said 3-12-membered cycloalkyl is
optionally connected through --CH.sub.2--, --NH--, --NCH.sub.3--,
--NH--(CH.sub.2).sub.1-3--, --NCH.sub.3(CH.sub.2).sub.1-3--,
--(C.dbd.O)--, --NHC(.dbd.O)--, --NCH.sub.3C(.dbd.O)--,
--C(.dbd.O)NH--(CH.sub.2).sub.1-3--,
--C(.dbd.O)NCH.sub.3--(CH.sub.2).sub.1-3--; -3-12-membered
heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or
polysubstituted; wherein said 3-12-membered heterocycloalkyl is
optionally connected through --CH.sub.2--, --NH--, --NCH.sub.3--,
--NH--(CH.sub.2).sub.1-3--, --NCH.sub.3(CH.sub.2).sub.1-3--,
--(C.dbd.O)--, --NHC(.dbd.O)--, --NCH.sub.3C(.dbd.O)--,
--C(.dbd.O)NH--(CH.sub.2).sub.1-3--,
--C(.dbd.O)NCH.sub.3--(CH.sub.2).sub.1-3--; -6-14-membered aryl,
unsubstituted, mono- or polysubstituted; wherein said 6-14-membered
aryl is optionally connected through --CH.sub.2--, --NH--,
--NCH.sub.3--, --NH--(CH.sub.2).sub.1-3--,
--NCH.sub.3(CH.sub.2).sub.1-3--, --(C.dbd.O)--, --NHC(.dbd.O)--,
--NCH.sub.3C(.dbd.O)--, --C(.dbd.O)NH--(CH.sub.2).sub.1-3--,
--C(.dbd.O)NCH.sub.3--(CH.sub.2).sub.1-3--; or -5-14-membered
heteroaryl, unsubstituted, mono- or polysubstituted; wherein said
5-14-membered heteroaryl is optionally connected through
--CH.sub.2--, --NH--, --NCH.sub.3--, --NH--(CH.sub.2).sub.1-3--,
--NCH.sub.3(CH.sub.2).sub.1-3--, --(C.dbd.O)--, --NHC(.dbd.O)--,
--NCH.sub.3C(.dbd.O)--, --C(.dbd.O)NH--(CH.sub.2).sub.1-3--,
--C(.dbd.O)NCH.sub.3--(CH.sub.2).sub.1-3--.
[0043] 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, and
R.sup.5 are defined as above, R.sup.C means --H, --OH, --F, --CN or
--C.sub.1-C.sub.4-alkyl; preferably --H or --OH; R.sup.D means --H
or --F; or a physiologically acceptable salt thereof.
[0044] Preferably, in the compounds according to general formula
(I) or any of the compounds according to general formulas (II-A) to
(VIII-C), R.sup.5 is selected from the group consisting of:
##STR00006## ##STR00007## ##STR00008## ##STR00009## ##STR00010##
##STR00011## ##STR00012## ##STR00013## ##STR00014## ##STR00015##
##STR00016## ##STR00017## ##STR00018## ##STR00019## ##STR00020##
##STR00021## ##STR00022## ##STR00023## ##STR00024## ##STR00025##
##STR00026## ##STR00027## ##STR00028## ##STR00029## ##STR00030##
##STR00031##
[0045] 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
--C.sub.1-C.sub.6-alkyl, linear or branched, saturated,
unsubstituted; cyclopropyl connected through --CH.sub.2--; or
tetrahydropyranyl connected through --CH.sub.2--; R.sup.3 means
-phenyl, benzyl, -thienyl or -pyridinyl, in each case unsubstituted
or substituted with one, two, three or four substituents
independently of one another selected from the group consisting of
--F, --Cl, --CN, --CH.sub.3, --CH.sub.2CH.sub.3, --CH.sub.2F,
--CHF.sub.2, --CF.sub.3, --OCF.sub.3, --OH, --OCH.sub.3,
--C(.dbd.O)NH.sub.2, C(.dbd.O)NHCH.sub.3,
--C(.dbd.O)N(CH.sub.3).sub.2, --NH.sub.2, --NHCH.sub.3,
--N(CH.sub.3).sub.2, --NHC(.dbd.O)CH.sub.3, --CH.sub.2OH,
SOCH.sub.3 and SO.sub.2CH.sub.3; or R.sup.4 means
--H;
[0046] --C.sub.1-C.sub.6-alkyl, linear or branched, saturated,
unsubstituted or substituted with one, two, three or four
substituents independently of one another selected from the group
consisting of --F, --Cl, --Br, --I, --CN, --OH,
--O--C.sub.1-C.sub.4-alkyl, --C(.dbd.O)NH--C.sub.1-C.sub.6-alkyl,
--C(.dbd.O)N(C.sub.1-C.sub.6-alkyl).sub.2 or --C(.dbd.O)NRR'
wherein R and R' together with the nitrogen atom to which they are
attached form a ring and mean --(CH.sub.2).sub.3-5--; 3-6-membered
cycloalkyl, unsubstituted or substituted with one, two, three or
four substituents independently of one another selected from the
group consisting of --F, --Cl, --Br, --I, --CN, --OH, and
--O--C.sub.1-C.sub.4-alkyl, wherein said 3-6-membered cycloalkyl is
connected through --C.sub.1-C.sub.6-alkylene; 3-6-membered
heterocycloalkyl, unsubstituted or substituted with one, two, three
or four substituents independently of one another selected from the
group consisting of --F, --Cl, --Br, --I, --CN, --OH, and
--O--C.sub.1-C.sub.4-alkyl, wherein said 3-6-membered
heterocycloalkyl is connected through --C.sub.1-C.sub.6-alkylene;
-phenyl, unsubstituted or monosubstituted with --OCH.sub.3; wherein
said -phenyl is connected through --C.sub.1-C.sub.6-alkylene-; or
-pyridyl, unsubstituted, mono- or polysubstituted; wherein said
-pyridyl is connected through --C.sub.1-C.sub.6-alkylene-; R.sup.5
means -phenyl, -1,2-benzodioxole, -pyrazinyl, -pyridazinyl,
-pyridinyl, -pyrimidinyl, -thienyl, -imidazolyl, -benzimidazolyl,
-thiazolyl, -1,3,4-thiadiazolyl, -benzothiazolyl, -oxazolyl,
-benzoxazolyl, -pyrazolyl, -quinolinyl, -isoquinolinyl,
-quinazolinyl, -indolyl, -indolinyl, -benzo[c][1,2,5]oxadiazolyl,
-imidazo[1,2-a]pyrazinyl, or -1H-pyrrolo[2,3-b]pyridinyl, in each
case unsubstituted or substituted with one, two, three or four
substituents independently of one another selected from the group
consisting of [0047] --F; --Cl; --Br; --I; [0048] --CN;
--C.sub.1-C.sub.4-alkyl; --CF.sub.3;
--C.sub.1-C.sub.4-alkyl-CF.sub.3;
--C.sub.1-C.sub.4-alkyl-C(.dbd.O)NH.sub.2;
--C.sub.1-C.sub.4-alkyl-C(.dbd.O)NHC.sub.1-C.sub.6-alkyl;
--C.sub.1-C.sub.4-alkyl-C(.dbd.O)N(C.sub.1-C.sub.6-alkyl).sub.2;
--C.sub.1-C.sub.4-alkyl-S(.dbd.O).sub.2--C.sub.1-C.sub.4-alkyl;
[0049] --C(.dbd.O)--C.sub.1-C.sub.4-alkyl; --C(.dbd.O)OH;
--C(.dbd.O)O--C.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;
--C(.dbd.O)NH(C.sub.1-C.sub.4-alkyl-OH);
--C(.dbd.O)N(C.sub.1-C.sub.4-alkyl)(C.sub.1-C.sub.4-alkyl-OH);
--C(.dbd.O)NH--(CH.sub.2CH.sub.2O).sub.1-30--CH.sub.3; [0050]
--NH.sub.2; --NHC.sub.1-C.sub.4-alkyl;
--N(C.sub.1-C.sub.4-alkyl).sub.2; --NHC.sub.1-C.sub.4-alkyl-OH;
--NCH.sub.3C.sub.1-C.sub.4-alkyl-OH;
--NH--C.sub.1-C.sub.4-alkyl-C(.dbd.O)NH.sub.2;
--NCH.sub.3--C.sub.1-C.sub.4-alkyl-C(.dbd.O)NH.sub.2;
--NHC(.dbd.O)--C.sub.1-C.sub.4-alkyl;
--NCH.sub.3C(.dbd.O)--C.sub.1-C.sub.4-alkyl; [0051] --OH;
--O--C.sub.1-C.sub.4-alkyl; --OCF.sub.3;
--O--C.sub.1-C.sub.4-alkyl-CO.sub.2H;
--O--C.sub.1-C.sub.4-alkyl-C(.dbd.O)O--C.sub.1-C.sub.4-alkyl;
--O--C.sub.1-C.sub.4-alkyl-CONH.sub.2; [0052]
--S--C.sub.1-C.sub.4-alkyl; --S(.dbd.O)C.sub.1-C.sub.4-alkyl;
--S(.dbd.O).sub.2C.sub.1-C.sub.4-alkyl; and
--S(.dbd.O).sub.2N(C.sub.1-C.sub.4-alkyl).sub.2; [0053]
3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted,
mono- or polysubstituted; wherein said 3-12-membered cycloalkyl is
optionally connected through --CH.sub.2--, --O--, --NH--,
--NCH.sub.3--, --NH--(CH.sub.2).sub.1-3--,
--NCH.sub.3(CH.sub.2).sub.1-3--, --(C.dbd.O)--, --NHC(.dbd.O)--,
--NCH.sub.3C(.dbd.O)--, --C(.dbd.O)NH--(CH.sub.2).sub.1-3--,
--C(.dbd.O)NCH.sub.3--(CH.sub.2).sub.1-3--; [0054] 3-12-membered
heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or
polysubstituted; wherein said 3-12-membered heterocycloalkyl is
optionally connected through --CH.sub.2--, --O--, --NH--,
--NCH.sub.3--, --NH--(CH.sub.2).sub.1-3--,
--NCH.sub.3(CH.sub.2).sub.1-3--, --(C.dbd.O)--, --NHC(.dbd.O)--,
--NCH.sub.3C(.dbd.O)--, --C(.dbd.O)NH--(CH.sub.2).sub.1-3--,
--C(.dbd.O)NCH.sub.3--(CH.sub.2).sub.1-3--; [0055] 6-14-membered
aryl, unsubstituted, mono- or polysubstituted; wherein said
6-14-membered aryl is optionally connected through --CH.sub.2--,
--O--, --NH--, --NCH.sub.3--, --NH--(CH.sub.2).sub.1-3--,
--NCH.sub.3(CH.sub.2).sub.1-3--, --(C.dbd.O)--, --NHC(.dbd.O)--,
--NCH.sub.3C(.dbd.O)--, --C(.dbd.O)NH--(CH.sub.2).sub.1-3--,
--C(.dbd.O)NCH.sub.3--(CH.sub.2).sub.1-3--; or [0056] 5-14-membered
heteroaryl, unsubstituted, mono- or polysubstituted; wherein said
5-14-membered heteroaryl is optionally connected through
--CH.sub.2--, --O--, --NH--, --NCH.sub.3--,
--NH--(CH.sub.2).sub.1-3--, --NCH.sub.3(CH.sub.2).sub.1-3--,
--(C.dbd.O)--, --NHC(.dbd.O)--, --NCH.sub.3C(.dbd.O)--,
--C(.dbd.O)NH--(CH.sub.2).sub.1-3--,
--C(.dbd.O)NCH.sub.3--(CH.sub.2).sub.1-3--; and [0057] 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.
[0058] 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
--C.sub.1-C.sub.6-alkyl, linear or branched, saturated,
unsubstituted; preferably, R.sup.2 means --CH.sub.3 or
--CH.sub.2CH.sub.3; more preferably, R.sup.1 and R.sup.2 both mean
--CH.sub.3; and/or R.sup.3 means -phenyl, -thienyl or -pyridinyl,
in each case unsubstituted or substituted with one, two, three or
four substituents independently of one another selected from the
group consisting of --F, --Cl, --CN, --CH.sub.3,
--CH.sub.2CH.sub.3, --CH.sub.2F, --CHF.sub.2, --CF.sub.3,
--OCF.sub.3, --OH, --OCH.sub.3, --C(.dbd.O)NH.sub.2,
C(.dbd.O)NHCH.sub.3, --C(.dbd.O)N(CH.sub.3).sub.2, --NH.sub.2,
--NHCH.sub.3, --N(CH.sub.3).sub.2, --NHC(.dbd.O)CH.sub.3,
--CH.sub.2OH, SOCH.sub.3 and SO.sub.2CH.sub.3; preferably, R.sup.3
means -phenyl, -thienyl or -pyridinyl, in each case unsubstituted
or substituted with --F; more preferably, R.sup.3 means phenyl,
unsubstituted; and/or R.sup.4 means
--H;
[0059] --C.sub.1-C.sub.6-alkyl, linear or branched, saturated,
unsubstituted or substituted with one, two, three or four
substituents independently of one another selected from the group
consisting of --F, --Cl, --Br, --I, --CN, --OH, and
--O--C.sub.1-C.sub.4-alkyl; or 3-6-membered cycloalkyl,
unsubstituted or substituted with one, two, three or four
substituents independently of one another selected from the group
consisting of --F, --Cl, --Br, --I, --CN, --OH, and
--O--C.sub.1-C.sub.4-alkyl, wherein said 3-6-membered cycloalkyl is
connected through --C.sub.1-C.sub.6-alkylene; preferably, R.sup.4
means 3-6-membered cycloalkyl, unsubstituted or substituted with
one, two, three or four substituents independently of one another
selected from the group consisting of --F, --Cl, --Br, --I, --CN,
--OH, and --O--C.sub.1-C.sub.4-alkyl, wherein said 3-6-membered
cycloalkyl is connected through --CH.sub.2-- or
--CH.sub.2CH.sub.2--; more preferably, R.sup.4 means -cyclobutyl,
unsubstituted or monosubstituted with --OH, wherein said
-cyclobutyl is connected through --CH.sub.2--; and/or R.sup.5 means
-phenyl, -pyrazinyl, -pyridazinyl, -pyridinyl, -pyrimidinyl,
-thienyl, or imidazo[1,2-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; --C.sub.1-C.sub.4-alkyl; --CF.sub.3;
-3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted,
mono- or polysubstituted; preferably cyclopropyl, saturated,
unsubstituted; -3-12-membered heterocycloalkyl, saturated or
unsaturated, unsubstituted, mono- or polysubstituted; preferably
-pyrrolidinyl, -morpholinyl, -piperazinyl, -thiomorpholinyl, or
-thiomorpholinyl dioxide, in each case saturated, unsubstituted or
monosubstituted with --C.sub.1-C.sub.4-alkyl; -6-14-membered aryl,
unsubstituted, mono- or polysubstituted; preferably -phenyl,
unsubstituted; --O--C.sub.1-C.sub.4-alkyl;
--S--C.sub.1-C.sub.4-alkyl; --C(.dbd.O)OH;
--C(.dbd.O)O--C.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;
--C(.dbd.O)N(C.sub.1-C.sub.4-alkyl)(C.sub.1-C.sub.4-alkyl-OH);
(.dbd.O)NH--(CH.sub.2).sub.1-3-3-12-membered cycloalkyl, saturated
or unsaturated, unsubstituted or monosubstituted with --OH;
preferably --C(.dbd.O)NH--(CH.sub.2).sub.1-3-cyclobutyl, saturated
or unsaturated, unsubstituted or monosubstituted with --OH;
--C(.dbd.O)--3-12-membered heterocycloalkyl, saturated or
unsaturated, unsubstituted, mono- or polysubstituted; preferably
--C(.dbd.O)-morpholinyl, saturated, unsubstituted;
--S(.dbd.O)C.sub.1-C.sub.4-alkyl;
--S(.dbd.O).sub.2C.sub.1-C.sub.4-alkyl; and
--S(.dbd.O).sub.2N(C.sub.1-C.sub.4-alkyl).sub.2; and/or 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.
[0060] Preferably, the compound according to the invention is
selected from the group consisting of
TABLE-US-00001 SC_3001
cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3002
cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-pyrazine-2-carbonitrile SC_3003
cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile
SC_3004
cis-5-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3005
cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carboxylic acid amide
SC_3006
cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-2-methylsulfonyl-pyrimidine-4-carbonitrile
SC_3007
cis-5-[1-(2-Methoxy-ethyl)-8-methylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3008
cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-5-methylsulfonyl-benzonitrile SC_3009
cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-benzamide SC_3010
cis-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-benzamide SC_3011
cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-p-
henyl-1,3- diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carboxylic acid
amide SC_3012
cis-5-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile
SC_3013
cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-p-
henyl-1,3- diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile
SC_3014
cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carbonitrile SC_3015
cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-meth-
oxy-pyrimidin- 5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
SC_3016
cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carboxylic acid amide
SC_3017
cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-N-methyl-benzamide SC_3018
cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1-propyl-1,3-diazaspiro[4.5]-
decan-3-yl)- pyrimidine-2-carbonitrile SC_3019
cis-5-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3020
cis-5-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-pheny1-1,3-
diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3021
cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-benzamide SC_3022
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[2-(trifluoro-
methyl)- pyrimidin-5-yl]-1,3-diazaspiro[4.51decan-2-one SC_3023
cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-hydroxy-
-pyrimidin- 5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3024
cis-5-[8-Dimethylamino-1-(2-methyl-propy1)-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3025
cis-5-[8-Dimethylamino-1-(2-hydroxy-ethyl)-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3026
cis-5-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-4-methyl-pyridine-2-carbonitrile SC_3027
cis-1-(Cyclobutyl-methyl)-3-(5-methoxy-pyrazin-2-yl)-8-methylamino-
-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one SC_3028
cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-N,N-dimethyl-benzamide SC_3029
cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-N-ethyl-N-(2-hydroxy-ethyl)-benzamide
SC_3030
cis-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-5-methylsulfonyl-benzonitrile SC_3031
cis-1-(Cyclobutyl-methyl)-8-methylamino-3-[2-methylsulfony1-4-
(trifluoromethyl)-phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
SC_3032
cis-4-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-N,N-dimethyl-3-(trifluoromethyl)-benzenesulfon-
ic acid amide SC_3033
cis-4-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-
-1,3- diazaspiro[4.5]decan-3-yl]-benzonitrile SC_3034
cis-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-3-[2-
(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one
SC_3035
cis-5-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-
-1,3- diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3036
cis-5-[8-Dimethylamino-1-](1-methyl-cyclobutyl)-methyl]-2-oxo-8-ph-
enyl-1,3- diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile
SC_3037
cis-2-[3-(2-Cyano-pyrimidin-5-yl)-8-dimethylamino-2-oxo-8-phenyl-1-
,3- diazaspiro[4.5]decan-1-yl]-N,N-dimethyl-acetamide SC_3038
cis-1-(Cyclobutyl-methyl)-8-methylamino-8-phenyl-3-[2-(trifluorome-
thyl)- pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3039
cis-5-[8-Dimethy1amino-8-(3-fluorophenyl)-1-(4-methoxy-butyl)-2-ox-
o-1,3- diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3040
cis-5-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile
SC_3041
cis-5-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-phe-
nyl-1,3- diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile
SC_3042
cis-N-(Cyclobutyl-methyl)-5-[1-(cyclobutyl-methyl)-8-dimethylamino-
-8-(3-
fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carboxyli-
c acid amide SC_3043
cis-5-[1-(3-Methoxy-propyl)-8-methylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3044
cis-5-[8-Dimethylamino-8-(3-fluorophenyl)-1-methyl-2-oxo-1,3-
diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3045
cis-4-Methoxy-5-[1-(3-methoxy-propyl)-8-methylamino-2-oxo-8-phenyl-
-1,3- diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3046
cis-4-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3047
cis-5-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile
SC_3048
cis-4-[1-(Cyclobuty1-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3049
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(6-methylsulfanyl-pyri-
midin-4-yl)- 8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3050
cis-2-[3-(2-Cyano-pyrimidin-4-yl)-8-dimethylamino-2-oxo-8-phenyl-1-
,3- diazaspiro[4.5]decan-1-yl]-N,N-dimethyl-acetamide SC_3051
cis-6-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-pyrimidine-4-carbonitrile SC_3052
cis-2-(8-Dimethylamino-2-oxo-3,8-diphenyl-1,3-diazaspiro[4.5]decan-
-1-yl)-N,N- dimethyl-acetamide SC_3053
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3,8-diphenyl-1,3-
diazaspiro[4.5]decan-2-one SC_3054
cis-2-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carbonitrile SC_3055
cis-8-Dimethylamino-1-(2-methoxy-ethyl)-3,8-diphenyl-1,3-diazaspir-
o[4.5]decan- 2-one SC_3056
cis-5-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-4-methyl-pyridine-2-carbonitrile SC_3057
cis-N,N-Dimethyl-2-(8-methylamino-2-oxo-3,8-diphenyl-1,3-diazaspir-
o[4.5]decan- 1-yl)-acetamide SC_3058
cis-5-[1-[(1-Cyano-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-pheny-
l-1,3- diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3059
cis-5-[1-[(1-Cyano-cyclobutyl)-methyl]-8-(ethyl-methyl-amino)-2-ox-
o-8-phenyl-
1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3060
cis-4-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-p-
henyl-1,3- diazaspiro[4.5]decan-3-yl]-benzonitrile SC_3061
cis-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-p-
henyl-1,3- diazaspiro[4.5]decan-3-yl]-benzonitrile SC_3063
cis-5-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-phe-
nyl-1,3- diazaspiro[4.5]decan-3-yl]-pyridine-2-carbonitrile SC_3064
cis-2-[3-(2-Cyano-pyrimidin-5-yl)-8-dimethylamino-2-oxo-8-phenyl-1-
,3- diazaspiro[4.5]decan-1-yl]-N-propyl-acetamide SC_3065
cis-5-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-
-1,3-
diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile
SC_3066
cis-4-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-3-methoxy-benzonitrile SC_3067
cis-5-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-6-methoxy-pyridine-2-carbonitrile
SC_3068
cis-4-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-p-
henyl-1,3- diazaspiro[4.5]decan-3-yl]-benzamide SC_3069
cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-p-
henyl-1,3- diazaspiro[4.5]decan-3-yl]-pyridine-2-carbonitrile
SC_3070
cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-p-
henyl-1,3-
diazaspiro[4.5]decan-3-yl]-N-[(1-hydroxy-cyclobutyl)-methyl]-pyridine-2-
carboxylic acid amide SC_3071
cis-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-p-
henyl-1,3- diazaspiro[4.5]decan-3-yl]-benzonitrile SC_3072
cis-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-benzonitrile SC_3073
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[2-(trifluoro-
methyl)- pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3074
cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-4-methyl-pyridine-2-carboxylic acid
methyl ester SC_3075
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(5-methoxy-pyrazin-2-y-
l)-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one SC_3076
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(2-methoxy-pyrimidin-5-
-yl)-8- phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3077
cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-benzonitrile SC_3078
cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-4-methyl-pyridine-2-carbonitrile SC_3079
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(5-fluoro-pyrimidin-2--
yl)-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one SC_3080
cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-3-methoxy-benzonitrile SC_3081
cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-benzoic acid methyl ester SC_3082
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-(2-pyrrolidin-
-1-yl- pyrimidin-4-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3083
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-(5-pyridin-2--
yl-thiophen- 2-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3084
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-methylsulfonyl-4-
(trifluoromethyl)-phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
SC_3085
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[6-(trifluoro-
methyl)- pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3086
cis-1-(Cyclobutyl-methyl)-3-(2,4-dimethoxy-phenyl)-8-dimethylamino-
-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one SC_3087
cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-4-methylsulfonyl-benzonitrile SC_3088
cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-2-fluoro-benzonitrile SC_3089
cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-N,N-dimethyl-3-(trifluoromethyl)-benzenesulfon-
ic acid amide SC_3090
cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-benzonitrile SC_3091
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(2-methyl-imidazo[1,2--
alpyrazin-6- yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3092
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(4-methylsulfonyl-phen-
yl)-8- phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3093
cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-5-methoxy-benzonitrile SC_3094
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3,8-diphenyl-1,3-
diazaspiro[4.5]decan-2-one SC_3096
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-pheny1-3-pyrazin-2-yl--
1,3- diazaspiro[4.5]decan-2-one SC_3097
cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-morphol-
in-4-yl- pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
SC_3098
cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-[2-(4-meth-
yl-piperazin-
1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
SC_3099
cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-3-(2-morpholin-
-4-yl- pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
SC_3100
cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-(-
2-piperazin- 1-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one
hydrochloride SC_3101
cis-1-[(1-Hydroxy-cyclobutyl1)-methyl]-8-methylamino-3-[2-(4-methy-
l-piperazin-
1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
SC_3102
cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-8-phenyl-3-(2--
piperazin-1- yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one
dihydrochloride SC_3103
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[4-methyl-6-(trifluoro-
methyl)- pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
SC_3104
cis-1-(Cyclobutyl-methyl)-8-methylamino-3-[4-methyl-6-(trifluorome-
thyl)-pyridin- 3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
SC_3105
cis-1-(Cyclopropyl-methyl)-8-dimethylamino-3-(4-methylsulfonyl-phe-
nyl)-8- phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3106
cis-1-(Cyclopropyl-methyl)-8-methylamino-3-(4-methylsulfonyl-pheny-
l)-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one SC_3107
cis-1-(Cyclopropyl-methyl)-8-dimethylamino-3-(2-fluoro-4-methylsul-
fonyl- phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3108
cis-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-p-
henyl-1,3- diazaspiro[4.5]decan-3-yl]-benzamide; formic acid
SC_3109
cis-2-[8-Dimethylamino-1-[2-(1-methoxy-cyclobutyl)-ethyl]-2-oxo-8--
phenyl-1,3- diazaspiro[4.5]decan-3-yl]-benzamide SC_3110
cis-8-Dimethylamino-1-[2-(1-methoxy-cyclobutyl)-ethyl]-3-(2-methyl-
-pyrimidin- 5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3111
cis-5-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phe-
ny1-1,3- diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile
SC_3112
cis-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phe-
ny1-1,3- diazaspiro[4.5]decan-3-yl]-benzonitrile SC_3113
cis-4-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phe-
ny1-1,3- diazaspiro[4.5]decan-3-yl]-3-methoxy-benzonitrile SC_3114
cis-4-[8-Ethy1amino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phen-
yl-1,3- diazaspiro[4.5]decan-3-yl]-3-methoxy-benzonitrile SC_3115
cis-2-[8-Ethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phen-
yl-1,3- diazaspiro[4.5]decan-3-yl]-benzonitrile SC_3116
cis-5-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phe-
ny1-1,3-
diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile
SC_3117
cis-2-[8-Dimethylamino-1-(oxetan-3-yl-methyl)-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-benzamide SC_3118
cis-4-Methoxy-5-(8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]d-
ecan-3-yl)- pyrimidine-2-carbonitrile SC_3119
cis-2-(8-Methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-
-benzamide SC_3120
cis-8-Dimethylamino-3-[2-(3-oxo-piperazin-1-yl)-pyrimidin-5-yl]-8--
phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3121
cis-3-(2-Cyclopropyl-pyrimidin-5-yl)-8-dimethylamino-8-pheny1-1,3-
diazaspiro[4.5]decan-2-one SC_3122
cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]--
8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3123
cis-8-Dimethylamino-3-(2-methylsulfonyl-phenyl)-8-phenyl-1,3-
diazaspiro[4.5]decan-2-one SC_3124
cis-8-Dimethylamino-8-phenyl-3-(2-piperazin-1-yl-pyrimidin-5-yl)-1-
,3- diazaspiro[4.5]decan-2-one SC_3125
trans-2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl-
)-benzamide SC_3126
cis--2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-
-benzamide SC_3127
cis-2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)--
benzamide SC_3128
cis-2-(8-Ethylamino-2-oxo-8-pheny1-1,3-diazaspiro[4.5]decan-3-yl)--
benzamide SC_3129
cis-3-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan--
3-yl)- pyrimidin-2-yl]-benzonitrile SC_3130
cis-8-Dimethylamino-3-[2-(4-methylsulfonyl-piperazin-1-yl)-pyrimid-
in-5-yl]-8- phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3131
cis-3-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan--
3-yl)- pyrimidin-2-yl]-benzamide SC_3132
cis-8-[(Cyclopropyl-methyl)-methy1-amino]-8-phenyl-3-[2-(trifluoro-
methyl)- pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3133
cis-8-Dimethylamino-3-[2-(4-methyl-piperazine-1-carbonyl)-pyrimidi-
n-5-yl]-8- phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3134
trans-4-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl-
)-3-methoxy- benzonitrile SC_3135
cis-4-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)--
3-methoxy- benzonitrile SC_3136
cis-3-[2-(4-Acetyl-piperazin-l-yl)-pyrimidin-5-yl]-8-dimethylamino-
-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3137
cis-8-Dimethylamino-8-phenyl-3-(2-pyridin-4-yl-pyrimidin-5-yl)-1,3-
- diazaspiro[4.5]decan-2-one SC_3138
cis-8-Dimethylamino-8-phenyl-3-(2-pyridin-3-yl-pyrimidin-5-yl)-1,3-
- diazaspiro[4.5]decan-2-one SC_3139
cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-y-
l)-N-(2- hydroxy-ethyl)-pyrimidine-2-carboxylic acid amide SC_3140
cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-y-
l) pyrimidine-2-carboxylic acid amide SC_3141
cis-8-Dimethylamino-3-[2-morpholin-4-yl-4-(trifluoromethyl)-pyrimi-
din-5-yl]-8- phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3142
cis-4-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan--
3-yl)- pyrimidin-2-yl]-benzonitrile SC_3143
cis-5-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]--
4-methoxy- pyrimidine-2-carbonitrile SC_3144
trans-5-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl-
]-4-methoxy- pyrimidine-2-carbonitrile SC_3145
cis-8-Dimethylamino-3-[2-(morpholine-4-carbonyl)-pyrimidin-5-yl]-8-
-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3146
cis-2-[4-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]dec-
an-3-yl)- pyrimidin-2-yl]-piperazin-1-yl]-acetic acid methyl ester
SC_3147
cis-8-Dimethylamino-3-[2-(methylsulfonyl-methyl)-phenyl]-8-phenyl--
1,3- diazaspiro[4.5]decan-2-one SC_3148
cis-8-Dimethylamino-3-(4-methyl-2-morpholin-4-yl-pyrimidin-5-yl)-8-
-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3149
cis-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-pyrimidin-
-5-yl]-8- phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3150
cis-8-Dimethylamino-3-(4-fluoro-pyridin-3-yl)-8-phenyl-1,3-diazasp-
iro[4.5]decan- 2-one SC_3151
cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-y-
l)-N-(2- hydroxy-ethyl)-N-methyl-pyrimidine-2-carboxylic acid amide
SC_3152
cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-y-
l)-2- morpholin-4-yl-isonicotinonitrile SC_3153
cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-y-
l]-benzamide SC_3154
cis-8-Dimethylamino-3-(2-fluoro-4-methylsulfonyl-phenyl)-8-phenyl--
1,3- diazaspiro[4.5]decan-2-one SC_3155
cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-y-
l)-3-fluoro- benzonitrile SC_3156
cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-y-
l)-3,5- difluoro-benzonitrile SC_3157
cis-8-Dimethylamino-3-(2-methoxy-pyrimidin-5-yl)-8-phenyl-1,3-
diazaspiro[4.5]decan-2-one SC_3158
cis-3-[2-(Benzylamino)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,-
3- diazaspiro[4.5]decan-2-one SC_3159
cis-8-Dimethylamino-3-[2-(4-fluorophenyl)-pyrimidin-5-yl]-8-phenyl-
-1,3- diazaspiro[4.5]decan-2-one SC_3160
trans-8-Benzyl-8-dimethylamino-3-(2-morpholin-4-yl-pyrimidin-5-yl)-
-1,3- diazaspiro[4.5]decan-2-one SC_3161
cis-8-Benzyl-8-dimethylamino-3-(2-morpholin-4-yl-pyrimidin-5-yl)-1-
,3- diazaspiro[4.5]decan-2-one SC_3162
cis-8-Dimethylamino-8-phenyl-3-(2-pyridin-2-yl-pyrimidin-5-yl)-1,3-
- diazaspiro[4.5]decan-2-one SC_3163
cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-y-
l)-3,5- difluoro-benzamide SC_3164
cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-y-
l)-3-fluoro- benzamide SC_3165
cis-8-Benzyl-8-dimethylamino-3-[2-(trifluoromethyl)-pyrimidin-5-yl-
]-1,3- diazaspiro[4.5]decan-2-one SC_3166
trans-8-Benzyl-8-dimethylamino-3-[2-(trifluoromethyl)-pyrimidin-5--
yl]-1,3- diazaspiro[4.5]decan-2-one SC_3167
cis-8-Dimethylamino-8-thiophen-2-yl-3-[2-(trifluoromethyl)-pyrimid-
in-5-yl]-1,3- diazaspiro[4.5]decan-2-one SC_3168
trans-8-Dimethylamino-8-thiophen-2-yl-3-[2-(trifluoromethyl)-pyrim-
idin-5-yl]- 1,3-diazaspiro[4.5]decan-2-one SC_3169
cis-2-[2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan--
3-yl) phenoxy]-acetic acid SC_3170
cis-8-Dimethylamino-8-phenyl-3-(2-piperidin-1-yl-pyrimidin-5-yl)-1-
,3- diazaspiro[4.5]decan-2-one SC_3171
cis-8-Dimethylamino-8-phenyl-3-(2-pyrrolidin-1-yl-pyrimidin-5-yl)--
1,3- diazaspiro[4.5]decan-2-one SC_3172
cis-8-Dimethylamino-8-phenyl-3-(2-pyrimidin-5-yl-pyrimidin-5-yl)-1-
,3- diazaspiro[4.5]decan-2-one SC_3173
cis-8-Dimethylamino-8-phenyl-3-[2-(piperazine-1-carbonyl)-pyrimidi-
n-5-yl]-1,3- diazaspiro[4.5]decan-2-one SC_3174
trans-8-Benzyl-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyr-
idin-3-yl]- 1,3-diazaspiro[4.5]decan-2-one SC_3175
cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-y-
l)-2- morpholin-4-yl-pyridine-4-carboxylic acid amide SC_3176
cis-8-Dimethylamino-3-[2-(3,5-dimethyl-isoxazol-4-yl)-pyrimidin-5--
yl]-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one SC_3177
cis-3-[2-(Benzothiazol-6-yl)-pyrimidin-5-yl]-8-dimethylamino-8-phe-
nyl-1,3- diazaspiro[4.5]decan-2-one SC_3178
cis-8-Dimethylamino-3-[2-fluoro-4-(trifluoromethyl)-phenyl]-8-phen-
yl-1,3- diazaspiro[4.5]decan-2-one SC_3179
cis-8-Dimethylamino-3-(6-morpholin-4-yl-pyridin-3-yl)-8-phenyl-1,3-
- diazaspiro[4.5]decan-2-one SC_3180
cis-8-Dimethylamino-8-phenyl-3-(2-phenyl-thiazol-4-yl)-1,3-diazasp-
iro[4.5[decan- 2-one SC_3181
cis-8-Dimethylamino-8-phenyl-3-[2-(tetrahydro-pyran-4-ylamino)-pyr-
imidin-5-yl]- 1,3-diazaspiro[4.5]decan-2-one SC_3182
cis-8-Dimethylamino-3-[2-(4-hydroxy-piperidin-1-yl)-pyrimidin-5-yl-
]-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one SC_3183
cis-8-Dimethylamino-8-phenyl-3-(4-phenyl-thiazol-2-yl)-1,3-diazasp-
iro[4.5]decan- 2-one SC_3184
cis-8-Dimethylamino-8-phenyl-3-[2-(1H-pyrrolo[2,3-b]pyridin-1-yl)--
pyrimidin-5- yl]-1,3-diazaspiro[4.5]decan-2-one SC_3185
cis-8-Dimethylamino-8-phenyl-3-[2-(3,4,5-trifluoro-phenyl)-pyrimid-
in-5-yl]-1,3- diazaspiro[4.5]decan-2-one SC_3186
cis-8-Dimethylamino-3-o-tolyl-8-phenyl-1,3-diazaspiro[4.5]decan-2--
one SC_3187
cis-8-Dimethylamino-3-m-tolyl-8-phenyl-1,3-diazaspiro[4.5]decan-2--
one SC_3188
cis-8-Dimethylamino-8-phenyl-3-p-tolyl-1,3-diazaspiro[4.5]decan-2--
one SC_3189
cis-8-Dimethylamino-8-phenyl-3-[4-(trifluoromethyl)-phenyl]-1,3-
diazaspiro[4.5]decan-2-one SC_3190
cis-8-Dimethylamino-8-phenyl-3-[3-(trifluoromethyloxy)-phenyl]-1,3-
- diazaspiro[4.5]decan-2-one SC_3191
cis-8-Dimethylamino-8-phenyl-3-[4-(trifluoromethyloxy)-phenyl]-1,3-
- diazaspiro[4.5]decan-2-one SC_3192
cis-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-y-
l)-benzoic acid methyl ester SC_3193
cis-3-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-y-
l)-benzoic acid methyl ester SC_3194
cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-y-
l)-benzoic acid methyl ester SC_3195
cis-3-(1,3-Benzodioxol-5-yl)-8-dimethylamino-8-phenyl-1,3-diazaspi-
ro[4.5]decan- 2-one SC_3196
cis-8-Dimethylamino-8-phenyl-3-quinolin-5-yl-1,3-diazaspiro[4.5]de-
can-2-one SC_3197
cis-3-(2,3-Dihydro-1H-indol-6-yl)-8-dimethylamino-8-phenyl-1,3-
diazaspiro[4.5]decan-2-one SC_3198
cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-y-
l)-4-methyl- pyridine-2-carboxylic acid methyl ester SC_3199
cis-8-Dimethylamino-3-(6-methoxy-4-methyl-pyridin-3-yl)-8-phenyl-1-
,3- diazaspiro[4.5]decan-2-one SC_3200
cis-8-Dimethylamino-3-[2-methyl-5-(trifluoromethyl)-2H-pyrazol-3-y-
l]-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one SC_3201
cis-8-Dimethylamino-3-(3-methoxy-pyridin-2-yl)-8-phenyl-1,3-
diazaspiro[4.5]decan-2-one SC_3202
cis-8-Dimethylamino-8-phenyl-3-[5-(trifluoromethyl)-pyridin-2-yl]--
1,3- diazaspiro[4.5]decan-2-one SC_3203
cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-y-
l)- nicotinonitrile SC_3204
cis-8-Dimethylamino-3-(3-methyl-pyridin-2-yl)-8-phenyl-1,3-
diazaspiro[4.5]decan-2-one SC_3205
cis-8-Dimethylamino-3-(6-methoxy-pyridin-3-yl)-8-phenyl-1,3-
diazaspiro[4.5]decan-2-one SC_3206
cis-8-Dimethylamino-8-phenyl-3-[3-(trifluoromethyl)phenyl]-1,3-
diazaspiro[4.5]decan-2-one SC_3207
cis-3-(1,3-Benzodioxol-4-yl)-8-dimethylamino-8-phenyl-1,3-diazaspi-
ro[4.5]decan- 2-one SC_3208
cis-8-Dimethylamino-3-[2-(2-oxo-1,3-dihydro-indol-4-yl)-pyrimidin--
5-yl]-8- phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3209
cis-8-Dimethylamino-3-[2-(3,5-dimethyl-1H-pyrazol-1-yl)-pyrimidin--
5-yl]-8- phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3210
cis-8-Dimethylamino-3-[2-(3-hydroxy-piperidin-1-yl)-pyrimidin-5-yl-
]-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one SC_3211
cis-8-Dimethylamino-3-[2-(3-hydroxy-piperidin-1-yl)-pyrimidin-5-yl-
]-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one SC_3212
cis-8-Dimethylamino-3-[2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-pyri-
midin-5-yl]-8- phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3213
cis-2-[4-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]dec-
an-3-yl)- pyrimidin-2-yl]-piperazin-1-yl]-acetic acid SC_3214
cis-8-Dimethylamino-3-[2-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)--
pyrimidin-5- yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3215
cis-8-Benzyl-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyrid-
in-3-yl]-1,3- diazaspiro[4.5]decan-2-one SC_3216
trans-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl-
]-8-thiophen- 2-yl-1,3-diazaspiro[4.5]decan-2-one SC_3217
cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]--
8-thiophen-2- y1-1,3-diazaspiro[4.5]decan-2-one SC_3218
cis-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-4-(triflu-
oromethyl)- pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
SC_3219
cis-8-Dimethylamino-8-(1-methyl-1H-benzoimidazol-2-yl)-3-[2-(trifl-
uoromethyl)- pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3220
cis-8-Dimethylamino-8-(1-methyl-1H-benzoimidazol-2-yl)-3-[4-methyl-
-6- (trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one
SC_3221
cis-8-Dimethylamino-3-[2-(2-hydroxy-ethylamino)-pyrimidin-5-yl]-8--
phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3222
cis-3-[2-(Benzyl-methyl-amino)-pyrimidin-5-yl]-8-dimethylamino-8-p-
henyl-1,3- diazaspiro[4.5]decan-2-one SC_3223
cis-5-(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]-pyrimidine-2-carboxylic
acid amide SC_3224
cis-8-Dimethylamino-3-[2-(1H-indazol-1-yl)-pyrimidin-5-yl]-8-pheny-
l-1,3 diazaspiro[4.5]decan-2-one SC_3225
cis-8-Dimethylamino-3-[2-[(2-hydroxy-ethyl)-methyl-amino]-pyrimidi-
n-5-yl]-8- phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3226
cis-3-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-y-
l)-benzamide SC_3227
cis-8-Dimethylamino-3-[3-fluoro-5-(trifluoromethyl)-pyridin-2-yl]--
8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3228
cis-8-Dimethylamino-3-(5-methyl-pyrazin-2-yl)-8-phenyl-1,3-
diazaspiro[4.5]decan-2-one SC_3229
cis-8-Dimethylamino-3-(5-fluoro-pyrimidin-4-yl)-8-phenyl-1,3-
diazaspiro[4.5]decan-2-one SC_3230
cis-8-Dimethylamino-3-(5-fluoro-pyrimidin-2-yl)-8-pheny1-1,3-
diazaspiro[4.5]decan-2-one SC_3231
cis-8-Dimethylamino-8-phenyl-3-pyrazin-2-yl-1,3-diazaspiro[4.5]dec-
an-2-one SC_3232
cis-3-([2,1,3]Benzoxadiazol-5-yl)-8-dimethylamino-8-phenyl-1,3-
diazaspiro[4.5]decan-2-one SC_3233
cis-2-[2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan--
3-yl)- phenoxy]-acetamide SC_3234
cis-8-Dimethylamino-8-phenyl-3-(5-pyridin-4-yl-thiophen-2-yl)-1,3-
diazaspiro[4.5]decan-2-one SC_3235
cis-2-[2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan--
3-yl)- phenoxy]-acetic acid methyl ester SC_3236
cis-8-Dimethylamino-3-(2-morpholin-4-yl-pyrimidin-4-yl)-8-phenyl-1-
,3- diazaspiro[4.5]decan-2-one SC_3237
cis-3-[2-(3,4-Difluoro-phenyl)-pyrimidin-5-yl]-8-dimethylamino-8-p-
henyl-1,3- diazaspiro[4.5]decan-2-one SC_3238
cis-2-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan--
3-yl)- pyrimidin-2-yl]-benzonitrile SC_3239
cis-3-(2-Amino-pyrimidin-5-yl)-8-dimethylamino-8-phenyl-1,3-
diazaspiro[4.5]decan-2-one SC_3240
cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan--
3-yl)- pyrimidin-2-yl]-cyclopropanecarboxylic acid amide SC_3241
cis-2-[4-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]dec-
an-3-yl)- pyrimidin-2-yl]-piperazin-1-yl]-acetamide SC_3242
cis-8-Dimethylamino-8-phenyl-3-(6-piperazin-1-yl-pyridin-3-yl)-1,3-
- diazaspiro[4.5]decan-2-one SC_3243
cis-8-Dimethylamino-3-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-8-
-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3244
cis-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-4-methyl--
pyrimidin-5- yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3245
cis-8-Dimethylamino-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl-
]-1,3- diazaspiro[4.5]decan-2-one SC_3246
cis-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carbonitrile SC_3247
cis-8-Dimethylamino-3-[2-(4-methyl-piperazin-1-yl)-pyrimidin-5-yl]-
-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3248
cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-[-
2- (trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one
SC_3249
cis-2-[1-(3-Methoxy-propyl)-8-methylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carbonitrile SC_3250
cis-8-Dimethylamino-8-phenyl-3-[6-(trifluoromethyl)-pyridin-3-yl]--
1,3- diazaspiro[4.5]decan-2-one SC_3251
cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-y-
l)-pyridine- 2-carbonitrile SC_3252
cis-8-Dimethylamino-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1-
,3- diazaspiro[4.5]decan-2-one SC_3253
cis-8-Dimethylamino-3-(2-methyl-pyrimidin-5-yl)-8-phenyl-1,3-
diazaspiro[4.5]decan-2-one SC_3254
cis-8-Dimethylamino-1-[(2-methoxyphenyl)-methyl]-3-(2-methyl-pyrim-
idin-5-yl)- 8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3255
cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-8-phenyl-3-[2-
(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one
SC_3256
cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-methyl--
pyrimidin-5- yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3257
cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-8-phenyl-3-pyr-
imidin-5-yl 1,3-diazaspiro[4.5]decan-2-one SC_3258
cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-y-
l)-4-methyl- pyridine-2-carbonitrile SC_3259
cis-8-Dimethylamino-3-(2-methyl-pyrimidin-5-yl)-8-phenyl-1-(pyridi-
n-2-yl- methyl)-1,3-diazaspiro[4.5]decan-2-one SC_3260
cis-8-Dimethylamino-8-phenyl-3-pyrimidin-5-yl-1,3-diazaspiro[4.5]d-
ecan-2- one SC_3261
cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-p-
yrimidin-5- yl-1,3-diazaspiro[4.5]decan-2-one SC_3262
cis-8-Amino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-[2-(trifl-
uoromethyl)- pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3263
cis-8-Dimethylamino-3-(3-fluorophenyl)-8-phenyl-1,3-diazaspiro[4.5-
]decan-2-one SC_3264
cis-8-Dimethylamino-3-(3-methylsulfonyl-phenyl)-8-phenyl-1,3-
diazaspiro[4.5]decan-2-one SC_3265
cis-8-Dimethylamino-3-(4-methylsulfonyl-phenyl)-8-phenyl-1,3-
diazaspiro[4.5]decan-2-one SC_3266
cis-8-Dimethylamino-8-phenyl-3-pyridazin-3-yl-1,3-diazaspiro[4.5]d-
ecan-2-one SC_3267
cis-3-Methoxy-4-(8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]d-
ecan-3-yl)- benzonitrile SC_3268
cis-8-Dimethylamino-3-(2-fluorophenyl)-8-phenyl-1,3-diazaspiro[4.5-
]decan-2-one SC_3269
cis-8-Dimethylamino-8-phenyl-3-(2-phenyl-pyrimidin-5-yl)-1,3-
diazaspiro[4.5]decan-2-one SC_3270
cis-8-Methylamino-1-(oxetan-3-yl-methyl)-8-phenyl-3-[2-(trifluorom-
ethyl)- pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3271
cis-1-(Cyclopropyl-methyl)-8-methylamino-8-phenyl-3-[2-(trifluorom-
ethyl)- pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3272
cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-y-
l)- benzonitrile SC_3273
cis-8-Dimethylamino-3-(4-fluorophenyl)-8-phenyl-1,3-diazaspiro[4.5-
]decan-2-one SC_3274
cis-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-y-
l)- benzonitrile SC_3275
cis-8-Ethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-[2-
(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one
SC_3276
cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-3-(2-methyl-py-
rimidin-5- yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3277
cis-8-Dimethylamino-3-[2-(morpholin-4-yl-methyl)-pyrimidin-5-yl]-8-
-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3278
cis-8-Dimethylamino-3-[2-(methyl-tetrahydro-pyran-4-yl-amino)-pyri-
midin-5-yl]- 8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3279
cis-5-[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)-ethoxyl-ethoxy]--
ethyl]- pyrimidine-2-carboxylic acid amide SC_3280
cis-1-(Cyclopropyl-methyl)-3-(2-fluoro-4-methylsulfonyl-phenyl)-8--
methylamino- 8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3281
cis-2-[[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-
-3-yl)- pyrimidin-2-yl]-methyl-aminol-acetamide SC_3282
cis-2-[[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-
-3-yl)- pyrimidin-2-yl]amino]-acetamide SC_3283
cis-1-(Cyclopropyl-methyl)-8-methylamino-3-[4-methyl-6-(trifluorom-
ethyl)- pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
SC_3284
cis-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[4-methyl-6-(trifluor-
omethyl)- pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
SC_3285
cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan--
3-yl)- pyrimidin-2-yl]-thiophene-2-carboxylic acid amide SC_3286
cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan--
3-yl)- pyrimidin-2-yl]-benzamide SC_3287
cis-8-Dimethylamino-8-phenyl-3-(5-phenyl-thiophen-2-yl)-1,3-
diazaspiro[4.5]decan-2-one SC_3288
cis-1-(Cyclopropyl-methyl)-8-methylamino-3-[2-(methylsulfonyl-meth-
yl)- phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3289
cis-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[2-(methylsulfonyl-me-
thyl)-phenyl]- 8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3290
cis-8-Dimethylamino-8-(3-fluorophenyl)-3-[2-(methylsulfonyl-methyl-
)-phenyl]- 1,3-diazaspiro[4.5]decan-2-one SC_3291
cis-8-Dimethylamino-8-(4-fluorophenyl)-3-[2-(methylsulfonyl-methyl-
)-phenyl]- 1,3-diazaspiro[4.5]decan-2-one SC_3292
cis-8-[Methyl-(tetrahydro-furan-3-yl-methyl)-amino]-8-phenyl-3-[2-
(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one
(enantiomer 1) SC_3293
cis-8-[Methyl-(tetrahydro-furan-3-yl-methyl)-amino]-8-phenyl-3-[2-
(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one
(enantiomer 2) SC_3294
cis-8-Dimethylamino-8-(3-fluorophenyl)-3-(4-methyl-2-morpholin-4-y-
l-pyrimidin- 5-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3295
cis-3-[6-(4-Acetyl-piperazin-1-yl)-4-methyl-pyridin-3-yl]-8-dimeth-
ylamino-8- phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3296
cis-3-[2-(4-Acetyl-piperazin-1-yl)-4-methyl-pyrimidin-5-yl]-8-dime-
thylamino-8- phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3297
cis-8-Dimethylamino-3-(4-methyl-6-pyridin-4-yl-pyridin-3-yl)-8-phe-
nyl-1,3- diazaspiro[4.5]decan-2-one SC_3298
cis-3-[2-(4-Acetyl-piperazin-1-yl)-4-(trifluoromethyl)-pyrimidin-5-
-yl]-8- dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
SC_3299
cis-8-Dimethylamino-3-[2-(3-oxo-piperazin-1-yl)-4-(trifluoromethyl-
)-pyrimidin-5- yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3300
cis-8-Dimethylamino-3-isoquinolin-4-yl-8-phenyl-1,3-diazaspiro[4.5-
]decan-2-one SC_3301
cis-8-Dimethylamino-3-isoquinolin-5-yl-8-phenyl-1,3-diazaspiro[4.5-
]decan-2-one SC_3302
cis-8-Dimethylamino-8-phenyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1,3-
- diazaspiro[4.5]decan-2-one SC_3303
cis-8-Dimethylamino-8-phenyl-3-(2-pyridin-4-yl-thiazol-4-yl)-1,3-
diazaspiro[4.5]decan-2-one SC_3304
cis-8-[Methyl-(tetrahydro-furan-3-yl-methyl)-amino]-3-(2-morpholin-
-4-yl- pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
(enantiomer 1) SC_3305
cis-8-[Methyl-(tetrahydro-furan-3-yl-methyl)-amino]-3-(2-morpholin-
-4-yl- pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
(enantiomer 2) SC_3306
cis-3-[2-(Azetidin-1-yl)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl--
1,3- diazaspiro[4.5]decan-2-one SC_3307
cis-3-[2-(3,3-Difluoro-azetidin-1-yl)-pyrimidin-5-yl]-8-dimethylam-
ino-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one SC_3308
cis-8-Dimethylamino-3-[6-morpholin-4-yl-5-(trifluoromethyl)-pyridi-
n-3-yl]-8- phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3309
cis-8-Methylamino-3-[6-morpholin-4-yl-5-(trifluoromethyl)-pyridin--
3-yl]-8- phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3310
cis-8-Dimethylamino-8-phenyl-3-[5-(trifluoromethyloxy)-pyridin-2-y-
l]-1,3- diazaspiro[4.5]decan-2-one SC_3311
cis-8-Dimethylamino-3-(5-methylsulfonyl-pyridin-2-yl)-8-phenyl-1,3-
- diazaspiro[4.5]decan-2-one SC_3312
cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-y-
l)- nicotinonitrile SC_3313
cis-3-[2-(4-Cyclopropyl-1H-[1,2,3]triazol-1-yl)-pyrimidin-5-yl]-8--
dimethylamino- 8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3314
cis-8-Dimethylamino-3-[4-methyl-2-(3-oxo-piperazin-1-yl)-pyrimidin-
-5-yl]-8- phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3315
cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-y-
l)-pyridine- 2-carboxylic acid amide SC_3316
cis-3-[4-(Azetidin-1-yl)-2-methyl-pyrimidin-5-yl]-8-dimethylamino--
8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3317
cis-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-y-
l)-benzamide SC_3318
cis-8-Dimethylamino-3-[2-(methylsulfonyl-methyl)-phenyl]-8-thiophe-
n-2-yl-1,3- diazaspiro[4.5]decan-2-one SC_3319
cis-8-Dimethylamino-8-(3-fluorophenyl)-3-[2-methyl-5-(trifluoromet-
hyl)-2H- pyrazol-3-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3320
cis-8-Dimethylamino-3-(4-methyl-2-morpholin-4-yl-pyrimidin-5-yl)-8-
-thiophen-2- yl-1,3-diazaspiro[4.5]decan-2-one SC_3321
cis-8-Dimethylamino-3-(6-methylsulfonyl-pyridin-3-yl)-8-phenyl-1,3-
- diazaspiro[4.5]decan-2-one SC_3322
cis-8-Dimethylamino-8-phenyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1,3-
- diazaspiro[4.5]decan-2-one SC_3323
cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan--
3-yl)- pyrimidin-2-yl]-acetamide SC_3324
cis-3-[2-(4-Methyl-piperazin-1-yl)-pyrimidin-5-yl]-8-[methyl-(tetr-
ahydro-furan-3-
yl-methyl)-amino]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
(enantiomer 1) SC_3325
cis-3-[2-(4-Methyl-piperazin-1-yl)-pyrimidin-5-yl]-8-[methyl-(tetr-
ahydro-furan-3-
yl-methyl)-amino]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
(enantiomer 2) SC_3326
cis-8-Dimethylamino-3-(4,6-dimethyl-2-morpholin-4-yl-pyrimidin-5-y-
l)-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one SC_3327
cis-8-Dimethylamino-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-thiophen-
-2-yl-1,3- diazaspiro[4.5]decan-2-one SC_3328
cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-y-
l)-pyridine- 3-carboxylic acid amide SC_3329
cis-8-Dimethylamino-3-[2-methyl-5-(trifluoromethyl)-2H-pyrazol-3-y-
l]-8- thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one SC_3330
cis-8-Dimethylamino-3-[2-[(2-hydroxy-ethyl)-methyl-amino]-pyrimidi-
n-5-yl]-8- thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one SC_3331
cis-8-Dimethylamino-3-[2-(2-oxo-1,3-dihydro-indol-4-yl)-pyrimidin--
5-yl]-8- thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one SC_3332
cis-8-Dimethylamino-3-[4-methyl-6-(3-oxo-piperazin-1-yl)-pyridin-3-
-yl]-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one SC_3333
cis-8-Dimethylamino-3-(4-methyl-6-pyridin-2-yl-pyridin-3-yl)-8-phe-
nyl-1,3- diazaspiro[4.5]decan-2-one SC_3334
cis-8-Dimethylamino-3-(4-methylsulfonyl-pyridin-3-yl)-8-phenyl-1,3-
- diazaspiro[4.5]decan-2-one SC_3335
cis-3-(Benzothiazol-7-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[-
4.5]decan-2- one SC_3336
cis-8-Dimethylamino-8-(4-fluorophenyl)-3-(4-methyl-2-morpholin-4-y-
l-pyrimidin- 5-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3337
cis-2-[8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-y-
l]-2-oxo-8-
phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N,N-dimethyl-acetamide
SC_3338
cis-8-Dimethylamino-3-[2-(2-methyl-1-oxo-2,3-dihydro-isoindol-4-yl-
)-pyrimidin- 5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3339
cis-2-[[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-
-3-yl)-2- methyl-pyrimidin-4-yl]amino]-acetamide SC_3340
cis-2-[3-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan--
3-yl)-pyridin- 4-yl]-acetamide SC_3341
cis-8-Dimethylamino-3-[4-(methylsulfonyl-methyl)-pyridin-3-yl]-8-p-
henyl-1,3- diazaspiro[4.5]decan-2-one SC_3342
cis-8-Dimethylamino-3-[6-(4-methyl-3-oxo-piperazin-1-yl)-pyridin-3-
-yl]-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one SC_3343
cis-8-Dimethylamino-3-(2,4-dimethyl-pyrimidin-5-yl)-8-phenyl-1,3-
diazaspiro[4.5]decan-2-one SC_3344
cis-8-Dimethylamino-3-[2-(1-oxo-2,3-dihydro-isoindol-4-yl)-pyrimid-
in-5-yl]-8- phenyl-1,3-diazaspiro[4.5]decan-2-one;
2,2,2-trifluoro-acetic acid SC_3345
cis-8-Dimethylamino-3-[6-[(2-hydroxy-ethyl)-methyl-amino]-5-(trifl-
uoromethyl)- pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
SC_3346
cis-8-Dimethylamino-8-phenyl-3-[2-[4-(trifluoromethyl)-1H-[1,2,3]t-
riazol-1-yl]- pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one
SC_3347
cis-8-Dimethylamino-3-[2-(4-isopropyl-1H-[1,2,3]triazol-1-yl)-pyri-
midin-5-yl]-8- phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3348
cis-8-Dimethylamino-3-[6-(1,1-dioxo-[1,4]thiazinan-4-yl)-pyridin-3-
-yl]-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one SC_3349
cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-y-
l)-2- morpholin-4-yl-nicotinonitrile SC_3350
cis-8-Dimethylamino-3-(1-methylsulfonyl-1H-pyrrolo[2,3-b]pyridin-5-
-yl)-8- phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3351
cis-8-Dimethylamino-3-(1H-indol-4-yl)-8-phenyl-1,3-diazaspiro[4.5]-
decan-2-one SC_3352
cis-8-Dimethylamino-3-(2-hydroxy-benzooxazol-7-yl)-8-phenyl-1,3
diazaspiro[4.5]decan-2-one SC_3353
cis-8-Dimethylamino-3-[2-fluoro-4-(trifluoromethyloxy)-phenyl]-8-p-
henyl-1,3- diazaspiro[4.5]decan-2-one SC_3354
cis-4-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan--
3-yl)- pyrimidin-2-yl]-benzamide; 2,2,2-trifluoro-acetic acid
SC_3355
cis-8-Dimethylamino-3-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-8-p-
henyl-1,3- diazaspiro[4.5]decan-2-one SC_3356
cis-3-(1-Acetyl-1H-indol-4-yl)-8-dimethylamino-8-phenyl-1,3-
diazaspiro[4.5]decan-2-one SC_3357
cis-8-Dimethylamino-3-(1H-indol-3-yl)-8-phenyl-1,3-diazaspiro[4.5]-
decan-2-one SC_3358
cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-y-
l)-5-methyl nicotinonitrile SC_3359
cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-y-
l)-5-fluoro nicotinonitrile SC_3360
cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]--
1-(2-oxo-2-
pyrrolidin-1-yl-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
SC_3361
cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-y-
l)-5-methyl pyridine-3-carboxylic acid amide SC_3362
cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-y-
l)-5-fluoro- pyridine-3-carboxylic acid amide SC_3363
cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]--
8-m-tolyl-1,3- diazaspiro[4.5]decan-2-one SC_3364
cis-3-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-y-
l)- isonicotinonitrile SC_3365
cis-8-Dimethylamino-3-[3-fluoro-5-(2-oxo-1,3-dihydro-indol-4-yl)-p-
yridin-2-yl]-8- phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3366
cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]--
8-[3 - (trifluoromethyloxy)-phenyl]-1,3-diazaspiro[4.5]decan-2-one
SC_3367
cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]--
8-[3- (trifluoromethyl)phenyl]-1,3-diazaspiro[4.5]decan-2-one
SC_3368
cis-8-Dimethylamino-8-(3-methoxyphenyl)-3-[4-methyl-6-(trifluorome-
thyl)- pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3369
cis-8-(5-Chloro-thiophen-2-yl)-8-dimethylamino-3-[4-methyl-6-(trif-
luoromethyl)- pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3370
cis-8-Dimethylamino-8-(3-fluorophenyl)-3-[4-methyl-6-(trifluoromet-
hyl)-pyridin- 3-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3371
cis-8-Dimethylamino-3-(2-methylamino-pyrimidin-5-yl)-8-phenyl-1,3-
diazaspiro[4.5]decan-2-one SC_3372
cis-8-(5-Chloro-thiophen-2-yl)-8-dimethylamino-3-(4-methyl-2-morph-
olin-4-yl- pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3373
cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan--
3-yl)- pyrimidin-2-yl]-N-methyl-cyclopropanecarboxylic acid amide
SC_3374
cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan--
3-yl)- pyrimidin-2-yl]-N,2,5-trimethyl-2H-pyrazole-3-carboxylic
acid amide SC_3375
cis-3-[4,6-Bis(trifluoromethyl)-pyridin-3-yl]-8-dimethylamino-8-ph-
enyl-1,3- diazaspiro[4.5]decan-2-one SC_3376
cis-8-Dimethylamino-3-[2-[(2-hydroxy-ethyl)-methyl-amino]-quinazol-
in-6-yl]-8- phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3377
cis-8-Dimethylamino-3-(2-morpholin-4-yl-quinazolin-6-yl)-8-phenyl--
1,3- diazaspiro[4.5]decan-2-one SC_3378
cis-8-[Methyl-(oxetan-3-yl-methyl)-amino]-8-phenyl-3-[2-(trifluoro-
methyl)- pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3379
cis-3-(1-Acetyl-1H-indol-3-yl)-8-dimethylamino-8-phenyl-1,3-
diazaspiro[4.5]decan-2-one SC_3380
cis-8-Dimethylamino-8-phenyl-3-quinazolin-6-yl-1,3-diazaspiro[4.5]-
decan-2-one SC_3381
cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-y-
l)-2-(2-oxo- 1,3-dihydro-indol-4-yl)-isonicotinonitrile SC_3382
cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan--
3-yl)- pyrimidin-2-yl]-N-methyl-tetrahydro-pyran-4-carboxylic acid
amide SC_3383
cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan--
3-yl)- pyrimidin-2-yl]-N,2,2-trimethyl-propionamide SC_3384
cis-8-Dimethylamino-3-[2-(1-methyl-2-oxo-1,3-dihydro-indol-4-yl)-p-
yrimidin-5- yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3385
cis-8-Dimethylamino-3-(2-morpholin-4-yl-1H-benzoimidazol-5-yl)-8-p-
henyl-1,3- diazaspiro[4.5]decan-2-one SC_3386
cis-8-Dimethylamino-8-(3-fluoro-5-methyl-phenyl)-3-[4-methyl-6-
(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one
SC_3387
cis-8-Dimethylamino-3-[6-(2-oxo-1,3-dihydro-indol-4-yl)-pyridin-3--
yl]-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one SC_3388
cis-8-Dimethylamino-8-(3-hydroxyphenyl)-3-[4-methyl-6-(trifluorome-
thyl)- pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3389
cis-3-[6-(Azetidin-1-yl)-5-(trifluoromethyl)-pyridin-3-yl]-8-dimet-
hylamino-8- phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3390
cis-3-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
diazaspiro[4.5]decan-3-yl]-isonicotinonitrile SC_3391
cis-3-[3,5-Bis(trifluoromethyl)-pyridin-2-yl]-8-dimethylamino-8-ph-
enyl-1,3- diazaspiro[4.5]decan-2-one SC_3392
cis-8-Dimethylamino-3-(5-fluoro-6-morpholin-4-yl-pyridin-3-yl)-8-p-
henyl-1,3- diazaspiro[4.5]decan-2-one SC_3393
cis-8-(3-Chlorophenyl)-8-dimethylamino-3-[4-methyl-6-(trifluoromet-
hyl)-pyridin- 3-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3394
cis-8-Dimethylamino-3-[5-(2-oxo-1,3-dihydro-indol-4-yl)-pyridin-2--
yl]-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one SC_3395
cis-8-Dimethylamino-8-phenyl-3-[5-(trifluoromethyl)-[1,3,4]thiadia-
zol-2-yl]-1,3- diazaspiro[4.5]decan-2-one SC_3396
cis-8-Dimethylamino-3-(2-oxo-1,3-dihydro-indol-4-yl)-8-phenyl-1,3-
diazaspiro[4.5]decan-2-one SC_3397
cis-8-Dimethylamino-3-[2-[(2-hydroxy-ethyl)-methyl-amino]-1H-benzo-
imidazol- 5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3398
cis-8-Dimethylamino-3-(5-methyl-6-morpholin-4-yl-pyridin-3-yl)-8-p-
henyl-1,3- diazaspiro[4.5]decan-2-one SC_3399
cis-1-(Cyclopropyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-(5-
- methylsulfonyl-pyridin-2-yl)-1,3-diazaspiro[4.5]decan-2-one
SC_3400
cis-1-(Cyclopropyl-methyl)-8-(3-fluorophenyl)-8-methylamino-3-(5-
methylsulfonyl-pyridin-2-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3401
cis-1-(Cyclobutyl-methyl)-8-(3-fluorophenyl)-8-methylamino-3-[2-
(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one
SC_3402
cis-1-(Cyclopropyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[2-
- (trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one
SC_3403
cis-1-(Cyclopropyl-methyl)-8-(3-fluorophenyl)-8-methylamino-3-[2-
(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one
SC_3404
cis-8-Dimethylamino-8-(3-fluorophenyl)-3-[2-(trifluoromethyl)-pyri-
midin-5-yl]- 1,3-diazaspiro[4.5]decan-2-one SC_3405
cis-1-(Cyclopropyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[2-
-methyl-5-
(trifluoromethyl)-2H-pyrazol-3-yl]-1,3-diazaspiro[4.5]decan-2-one
SC_3406
cis-1-(Cyclopropyl-methyl)-8-(3-fluorophenyl)-8-methylamino-3-[2-m-
ethyl-5-
(trifluoromethyl)-2H-pyrazol-3-yl]1-1,3-diazaspiro[4.5]decan-2-one
SC_3407
cis-8-Methylamino-3-(4-methyl-2-morpholin-4-yl-pyrimidin-5-yl)-8-p-
henyl-1,3- diazaspiro[4.5]decan-2-one SC_3408
cis-3-[5-(Azetidin-1-yl)-3-methyl-pyridin-2-yl]-8-dimethylamino-8--
(3- fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one SC_3409
cis-8-Dimethylamino-8-(3-fluorophenyl)-3-(5-methylsulfonyl-pyridin-
-2-yl)-1,3- diazaspiro[4.5]decan-2-one SC_3410
cis-3-(6-(azetidin-1-yl)-4-fluoropyridin-3-yl)-8-(dimethylamino)-8-
-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3411
cis-3-(6-(azetidin-1-yl)pyridin-3-yl)-8-(dimethylamino)-8-(3-fluor-
ophenyl)-1,3- diazaspiro[4.5]decan-2-one SC_3412
cis-3-(1-(cyclopropanecarbonyl)-3-(trifluoromethyl)-1H-pyrazol-5-y-
l)-8-
(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one
SC_3413
cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-(2-hydroxyethyl)-3-
(trifluoromethyl)-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one
SC_3414
cis-3-(1-(cyclopropylmethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)--
8-
(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one
SC_3415
cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-(methylsulfonyl)-3-
(trifluoromethyl)-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one
SC_3416
cis-1-(cyclopropylmethyl)-8-(dimethylamino)-8-(3-fluorophenyl)-3-(-
1-
(methylsulfonyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]-
decan- 2-one SC_3417
cis-2-(5-(8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspir-
o[4.5]decan-
3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-N,N-dimethylacetamide
SC_3418
cis-2-(5-(1-(cyclopropylmethyl)-8-(dimethylamino)-8-(3-fluoropheny-
l)-2-oxo-1,3-
diazaspiro[4.5]decan-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-N,N-
dimethylacetamide SC_3419
cis-8-(dimethylamino)-3-(1-methyl1-1H-pyrrolo[2,3-b]pyridin-5-yl)--
8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3420
cis-8-(dimethylamino)-3-(3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-
-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3421
cis-8-(dimethylamino)-8-phenyl-3-(1H-pyrrolo[2,3-c]pyridin-4-yl)-1-
,3- diazaspiro[4.5]decan-2-one SC_3422
cis-8-(dimethylamino)-8-phenyl-3-(2-(pyridazin-4-yl)pyrimidin-5-yl-
)-1,3- diazaspiro[4.5]decan-2-one SC_3423
cis-8-(dimethylamino)-3-(2-(2-oxo-1,2-dihydropyridin-4-yl)pyrimidi-
n-5-yl)-8- phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3424
cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-methyl-3-(thiophen-2-
-yl)-1H- pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3425
cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-methyl-3-morpholino--
1H-pyrazol- 5-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3426
cis-8-(dimethylamino)-8-phenyl-1-(2,2,2-trifluoroethyl)-3-(2-
(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one
SC_3427
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
SC_3428
cis-3-(4-methyl-6-(trifluoromethyl)pyridin-3-yl)-8-(methylamino)-8-
-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3429
cis-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-8-(methylamin-
o)-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one SC_3430
cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(4-(methylsulfonyl)pyri-
din-3-yl)-1,3- diazaspiro[4.5]decan-2-one SC_3431
cis-8-(dimethylamino)-3-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5--
yl)-8-(3 - fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one SC_3432
cis-3-(1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-8-(dimet-
hylamino)-8-(3- fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one
SC_3433
cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-(oxetan-3-ylmethyl)--
3-
(trifluoromethyl)-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one
SC_3434
cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-(2-(methylsulfonyl)e-
thyl)-3-
(trifluoromethyl)-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one
SC_3435
cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(4-methyl-2-(methylamin-
o)pyrimidin- 5-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3436
cis-3-(2-cyclopropoxy-4-methylpyrimidin-5-yl)-8-(dimethylamino)-8--
(3- fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one SC_3437
cis-N-(5-(8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspir-
o[4.5]decan-3-
yl)-4-methylpyrimidin-2-yl)-N-methylcyclopropanecarboxamide SC_3438
cis-N-(5-(8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspir-
o[4.5]decan-3- yl)-4-methylpyrimidin-2-yl)-N-methylpivalamide
SC_3439
cis-3-(4-(azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-5-yl)-8-(dim-
ethylamino)-8- (3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one
SC_3440
cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(4-(oxetan-3-ylmethoxy)-
-2- (trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one
SC_3441
cis-3-(2-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)-8-(d-
imethylamino)- 8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one
SC_3442
cis-3-(2-cyclopropyl-4-((2-hydroxyethyl)(methyl)amino)pyrimidin-5--
yl)-8-
(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one
and the physiologically acceptable salts thereof.
[0061] 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.
[0062] 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.
[0063] 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(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--.
[0064] 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)--.
[0065] 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.
[0066] 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 decahydro-quinoxalin, 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.
[0067] 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.
[0068] 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.
[0069] 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, tetra-hydrothiophene, diazepane, oxazolidine,
isoxazolidine, thiazolidine, isothiazolidine, thiadiazoli-dine,
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 decahydro-quinoxalin, 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.
[0070] 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.
[0071] 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.
[0072] 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.
[0073] 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.
[0074] 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.
[0075] 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.
[0076] 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.
[0077] 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.
[0078] Preferably, the compound according to the invention has a
structure according to general formula (I')
##STR00032## [0079] wherein R.sup.1 to R.sup.5, R.sup.11 to
R.sup.20 are defined as above, or a physiologically acceptable salt
thereof.
[0080] 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.
[0081] In a preferred embodiment, the compound according to the
invention has a structure according to general formula (IX) or
(X)
##STR00033##
wherein R.sup.2 means --H or --CH.sub.3; R.sup.3 means -phenyl or
-3-fluorophenyl; R.sup.C means --H or --OH; R.sup.E means --H,
--CH.sub.3, --F, --CF.sub.3, -cyclopropyl, -aziridinyl, --OH;
--OCF.sub.3; --O--C.sub.1-C.sub.4-alkyl-CO.sub.2H;
--O--C.sub.1-C.sub.4-alkyl-C(.dbd.O)O--C.sub.1-C.sub.4-alkyl; or
--O--C.sub.1-C.sub.4-alkyl-CONH.sub.2; R.sup.F means --CF.sub.3,
-cyclopropyl, --S(.dbd.O).sub.2CH.sub.3, --NH.sub.2;
--NHC.sub.1-C.sub.4-alkyl; --N(C.sub.1-C.sub.4-alkyl).sub.2;
--NHC.sub.1-C.sub.4-alkyl-OH; --NCH.sub.3C.sub.1-C.sub.4-alkyl-OH;
--NH--C.sub.1-C.sub.4-alkyl-C(.dbd.O)NH.sub.2;
--NCH.sub.3--C.sub.1-C.sub.4-alkyl-C(.dbd.O)NH.sub.2;
--NHC(.dbd.O)--C.sub.1-C.sub.4-alkyl;
--NCH.sub.3C(.dbd.O)--C.sub.1-C.sub.4-alkyl; -6-14-membered aryl,
unsubstituted, mono- or polysubstituted; or -5-14-membered
heteroaryl, unsubstituted, mono- or polysubstituted; U means
.dbd.CH-- or .dbd.N--; and V means .dbd.CH-- or .dbd.N--; or a
physiologically acceptable salt thereof.
[0082] In a preferred embodiment, the compound according to the
invention has a structure according to general formula (XI)
##STR00034##
wherein R.sup.2 means --H or --CH.sub.3; R.sup.3 means -phenyl or
-3-fluorophenyl; R.sup.H means --CN; --C.sub.1-C.sub.4-alkyl;
--CF.sub.3; --C.sub.1-C.sub.4-alkyl-C(.dbd.O)NH.sub.2;
--C.sub.1-C.sub.4-alkyl-S(.dbd.O).sub.2--C.sub.1-C.sub.4-alkyl;
--C(.dbd.O)--C.sub.1-C.sub.4-alkyl; --C(.dbd.O)OH;
--C(.dbd.O)O--C.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;
--C(.dbd.O)NH(C.sub.1-C.sub.4-alkyl-OH);
--C(.dbd.O)N(C.sub.1-C.sub.4-alkyl)(C.sub.1-C.sub.4-alkyl-OH);
--C(.dbd.O)NH--(CH.sub.2CH.sub.2O).sub.1-30--CH.sub.3;
-3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted,
mono- or polysubstituted; wherein said 3-12-membered cycloalkyl is
optionally connected through --CH.sub.2--, --NH--, --NCH.sub.3--,
--NH--(CH.sub.2).sub.1-3--, --NCH.sub.3(CH.sub.2).sub.1-3--,
--(C.dbd.O)--, --NHC(.dbd.O)--, --NCH.sub.3C(.dbd.O)--,
--C(.dbd.O)NH--(CH.sub.2).sub.1-3--,
--C(.dbd.O)NCH.sub.3--(CH.sub.2).sub.1-3--; or -3-12-membered
heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or
polysubstituted; 6-14-membered aryl, unsubstituted, mono- or
polysubstituted; wherein said 3-12-membered heterocycloalkyl is
optionally connected through --CH.sub.2--, --NH--, --NCH.sub.3--,
--NH--(CH.sub.2).sub.1-3--, --NCH.sub.3(CH.sub.2).sub.1-3--,
--(C.dbd.O)--, --NHC(.dbd.O)--, --NCH.sub.3C(.dbd.O)--,
--C(.dbd.O)NH--(CH.sub.2).sub.1-3--,
--C(.dbd.O)NCH.sub.3--(CH.sub.2).sub.1-3--; R.sup.G means
--CF.sub.3, --S(.dbd.O).sub.2CH.sub.3; --NH.sub.2;
--NHC.sub.1-C.sub.4-alkyl; --N(C.sub.1-C.sub.4-alkyl).sub.2;
--NHC.sub.1-C.sub.4-alkyl-OH; --NCH.sub.3C.sub.1-C.sub.4-alkyl-OH;
--NH--C.sub.1-C.sub.4-alkyl-C(.dbd.O)NH.sub.2;
--NCH.sub.3--C.sub.1-C.sub.4-alkyl-C(.dbd.O)NH.sub.2;
--NHC(.dbd.O)--C.sub.1-C.sub.4-alkyl;
--NCH.sub.3C(.dbd.O)--C.sub.1-C.sub.4-alkyl; -3-12-membered
cycloalkyl, saturated or unsaturated, unsubstituted, mono- or
polysubstituted; wherein said 3-12-membered cycloalkyl is
optionally connected through --CH.sub.2--, --NH--, --NCH.sub.3--,
--NH--(CH.sub.2).sub.1-3--, --NCH.sub.3(CH.sub.2).sub.1-3--,
--(C.dbd.O)--, --NHC(.dbd.O)--, --NCH.sub.3C(.dbd.O)--,
--C(.dbd.O)NH--(CH.sub.2).sub.1-3--,
--C(.dbd.O)NCH.sub.3--(CH.sub.2).sub.1-3--; or -3-12-membered
heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or
polysubstituted; 6-14-membered aryl, unsubstituted, mono- or
polysubstituted; wherein said 3-12-membered heterocycloalkyl is
optionally connected through --CH.sub.2--, --NH--, --NCH.sub.3--,
--NH--(CH.sub.2).sub.1-3--, --NCH.sub.3(CH.sub.2).sub.1-3--,
--(C.dbd.O)--, --NHC(.dbd.O)--, --NCH.sub.3C(.dbd.O)--,
--C(.dbd.O)NH--(CH.sub.2).sub.1-3--,
--C(.dbd.O)NCH.sub.3--(CH.sub.2).sub.1-3--; or a physiologically
acceptable salt thereof.
[0083] In a preferred embodiment, the compounds according to the
invention are in the form of the free bases.
[0084] In another preferred embodiment, the compounds according to
the invention are in the form of the physiologically acceptable
salts.
[0085] 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.
[0086] 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.
[0087] 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.
[0088] 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.
[0089] 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".
[0090] 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.
[0091] The compounds according to the invention potently bind to
the MOP and/or KOP and/or DOP and/or NOP receptors.
[0092] 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.
[0093] 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.
[0094] 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.
[0095] 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.
[0096] 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.
[0097] 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.
[0098] 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.
[0099] 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
[0100] have agonist activity at the NOP receptor, but no
significant activity at the MOP receptor; [0101] have agonist
activity at the NOP receptor, but no significant activity at the
KOP receptor; [0102] have agonist activity at the NOP receptor, but
no significant activity at the DOP receptor; [0103] 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; [0104] 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 [0105] 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.
[0106] 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 [0107] have agonist activity
at the NOP receptor as well as agonist activity at the MOP
receptor; [0108] 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; [0109] 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; [0110] 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; [0111] have agonist activity at the NOP receptor as well
as agonist activity at the MOP receptor, but no significant
activity at the KOP receptor; [0112] 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 [0113] 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.
[0114] 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 [0115] have agonist activity
at the NOP receptor as well as agonist activity at the KOP
receptor; [0116] 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; [0117] 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; [0118] have agonist activity
at the NOP receptor as well as agonist activity at the KOP
receptor, but no significant activity at the MOP receptor; [0119]
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 [0120] 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.
[0121] 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 [0122] have agonist activity
at the NOP receptor as well as agonist activity at the DOP
receptor; [0123] have agonist activity at the NOP receptor as well
as agonist activity at the DOP receptor, but no significant
activity at the MOP receptor; [0124] 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 [0125] 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.
[0126] 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
[0127] have agonist activity at the KOP receptor, but no
significant activity at the MOP receptor; [0128] have agonist
activity at the KOP receptor, but no significant activity at the
NOP receptor; [0129] have agonist activity at the KOP receptor, but
no significant activity at the DOP receptor; [0130] 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; [0131] 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 [0132] 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.
[0133] 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 [0134] 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; [0135] 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; [0136] 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 [0137] 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.
[0138] 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
[0139] have agonist activity at the NOP receptor, but no
significant activity at the MOP receptor; [0140] have agonist
activity at the NOP receptor, but no significant activity at the
KOP receptor; [0141] have agonist activity at the NOP receptor, but
no significant activity at the DOP receptor; [0142] 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; [0143] 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 [0144] 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.
[0145] 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
[0146] have antagonist activity at the NOP receptor, but no
significant activity at the MOP receptor; [0147] have antagonist
activity at the NOP receptor, but no significant activity at the
KOP receptor; [0148] have antagonist activity at the NOP receptor,
but no significant activity at the DOP receptor; [0149] 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; [0150] 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 [0151] 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.
[0152] 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 [0153] have antagonist
activity at the NOP receptor as well as agonist activity at the DOP
receptor; [0154] have antagonist activity at the NOP receptor as
well as agonist activity at the DOP receptor, but no significant
activity at the MOP receptor; [0155] 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 [0156] 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.
[0157] 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.
[0158] A further aspect of the invention relates to the compounds
according to the invention as medicaments.
[0159] 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.
[0160] 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.
[0161] 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.
[0162] 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.
[0163] The pharmaceutical composition according to the invention
can optionally contain suitable additives and/or auxiliary
substances and/or optionally further active ingredients.
[0164] 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).
[0165] 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.
[0166] The pharmaceutical composition according to the invention is
preferably for systemic, topical or local administration,
preferably for oral administration.
[0167] Another aspect of the invention relates to a pharmaceutical
dosage form which contains the pharmaceutical composition according
to the invention.
[0168] 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.
[0169] 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.
[0170] 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.
[0171] 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.
[0172] 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.
[0173] Preferred synthesis routes are described below:
[0174] 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.
[0175] 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):
##STR00035##
wherein R.sup.1, R.sup.2 and R.sup.3 are defined as above.
[0176] 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):
##STR00036##
wherein R.sup.1, R.sup.2 and R.sup.3 are defined as above and PG is
a protecting group.
[0177] 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):
##STR00037##
wherein R.sup.1, R.sup.2 and R.sup.3 are defined as above.
[0178] 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.
[0179] In yet another preferred embodiment, the synthesis of the
compounds according to the invention proceeds via a synthesis route
which comprises the preparation of [0180] an intermediate according
to general formula (IIIa) and according to general formula (IIIb);
or [0181] an intermediate according to general formula (IIIa) and
according to general formula (IIIc); or [0182] an intermediate
according to general formula (IIIb) and according to general
formula (IIIc); or [0183] an intermediate according to general
formula (IIIa), according to general formula (IIIb) and according
to general formula (IIIc).
[0184] The following examples further illustrate the invention but
are not to be construed as limiting its scope.
EXAMPLES
[0185] "RT" means room temperature (23.+-.7.degree. C.), "M" are
indications of concentration in mol/l, "aq." means aqueous, "sat."
means saturated, "sol." means solution, "conc." means
concentrated.
[0186] Further abbreviations:
brine saturated aqueous sodium chloride solution CC column
chromatography cHex cyclohexane dba dibenzylideneacetone DCM
dichloromethane
DIPEA N,N-diisopropylethylamine
DMF N,N-dimethylformamide
[0187] 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'-tetramethyluroniumhexafluorophosphat-
e LDA lithium diisoproylamide Me methyl m/z mass-to-charge ratio
MeOH methanol MeCN acetonitrile min minutes MS mass
spectrometry
NBS N-bromosuccinimide
NIS N-iodosuccinimide
[0188] NEt.sub.3 triethylamine PE petroleum ether (60-80.degree.
C.) RM reaction mixture RT room temperature TFA trifluoroacetic
acid T3P
2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide
tBME tert-butyl methyl ether THF tetrahydrofurane v/v volume to
volume w/w weight to weight Xantphos
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
[0189] The yields of the compounds prepared were not optimised. All
temperatures are uncorrected.
[0190] 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.
[0191] The mixing ratios of solvents or eluents for chromatography
are specified in v/v.
[0192] All the intermediate products and exemplary compounds were
analytically characterised by mass spectrometry (MS, m/z for
[M+H].sup.+). In addition .sup.1H-NMR and .sup.13C spectroscopy was
carried out for all the exemplary compounds and selected
intermediate products.
[0193] Remark Regarding Stereochemistry
[0194] 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:
##STR00038##
[0195] 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:
##STR00039##
Synthesis of Intermediates
Synthesis of INT-600:
5-(cis-8-(Dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyr-
imidine-2-carbonitrile
##STR00040##
[0197] Cs.sub.2CO.sub.3 (1.1 g, 3.66 mmol) was added to the
solution of
CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
(INT-976) (0.5 g, 1.83 mmol), Xanthphos (0.158 g, 0.274 mmol),
Pd.sub.2(dba).sub.3 (0.083 g, 0.091 mmol) and
5-bromopyrimidine-2-carbonitrile (0.52 g, 2.74 mmol) in 1,4-dioxane
(20 mL) under argon atmosphere. The reaction mixture was stirred
for 16 h at 90.degree. C., then cooled to RT and concentrated under
reduced pressure. The residue was suspended in EtOAc (20 mL) and
filtered through a plug of celite. The filtrate was concentrated
under reduced pressure and the resulting residue was purified by
flash chromatography on silica gel to afford
5-(cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyr-
imidine-2-carbonitrile (INT-600) (0.4 g) as a white solid.
Synthesis of INT-799:
CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazas-
piro[4.5]decan-2-one
##STR00041##
[0198] 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
[0199] 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
[0200] 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
##STR00042##
[0201] Step 1:
1-((CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-8-phenyl-1,3-diazaspi-
ro[4.5]decan-1-yl)methyl)cyclobutanecarbonitrile
[0202] 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)cyclobutane-carbonitrile as gummy brown
liquid. The material was used for the next step without further
purification.
Step 2:
1-((CIS-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan--
1-yl)methyl) cyclobutanecarboxamide
[0203] 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
[0204] 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
##STR00043##
[0206] 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
##STR00044##
[0207] Step 1:
1-Cyclobutylmethyl-3-(4-methoxy-benzyl)-9,12-dioxa-1,3-diazadispiro[4.2.4-
.2]tetradecan-2-one
[0208] To a stirred solution of
3-(4-methoxy-benzyl)-9,12-dioxa-1,3-diazadispiro[4.2.4.2]tetradecan-2-one
(4 g, 12.04 mmol) in anhydrous DMF (60 ml) was added NaH (1.38 g,
60% dispersion in oil, 36.14 mmol) at RT. The reaction mixture was
stirred for 10 min, bromomethylcyclobutane (3 ml, 26.5 mmol) was
added dropwise and stirring was continued for 50 h. TLC analysis
showed complete consumption of the starting material. The reaction
mixture was quenched with sat. aq. NH.sub.4Cl (50 ml) and extracted
with EtOAc (3.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-diazadispiro[4.2.4-
.2]tetradecan-2-one (2.4 g, 50%, white solid). TLC system:
EtOAc--pet ether (6:4); R.sub.f=0.48.
Step 2:
1-Cyclobutylmethyl-3-(4-methoxy-benzyl)-1,3-diaza-spiro[4.5]decane-
-2,8-dione
[0209] To a stirred solution of
1-cyclobutylmethyl-3-(4-methoxy-benzyl)-9,12-dioxa-1,3-diazadispiro[4.2.4-
.2]tetradecan-2-one (1 g, 2.5 mmol) in MeOH (7 ml) was added 10%
aq. HCl (8 ml) at 0.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
[0210] 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
[0211] 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
[0212] 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
##STR00045##
[0213] Step 1: Ethyl
5-cyano-2-oxo-5-(pyridin-2-yl)cyclohexanecarboxylate
[0214] 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
[0215] 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
##STR00046##
[0216] Step 1:
8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile
[0217] 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
[0218] 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
[0219] 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
[0220] 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
[0221] 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
##STR00047##
[0222] Step 1: 8-(Dimethylamino)-1,4-dioxaspiro 4.5]
decane-8-carbonitrile
[0223] 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
[0224] 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
[0225] 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
##STR00048##
[0226] Step 1: 9,12-Dioxa-2,4-diazadispiro[4.2.4 {8}.2
{5}]tetradecane-1,3-dione
[0227] 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
[0228] 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
[0229] 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
[0230] 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
##STR00049##
[0231] Step 1:
CIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazasp-
iro[4.5]decan-2-one
[0232] 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
[0233] 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
##STR00050##
[0234] Step 1:
8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-c-
arbonitrile
[0235] 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
[0236] 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
##STR00051##
[0238] 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
##STR00052##
[0239] Step 1:
8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decane-2,4-dione
[0240] 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
[0241] 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
[0242] 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
##STR00053##
[0243] 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
[0244] 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 under 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
[0245]
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
##STR00054##
[0247]
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
##STR00055##
[0248] Step 1:
CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-1-((1-methylcyclobutyl)methyl)--
8-phenyl-1,3-diazaspiro[4.5]decan-2-one
[0249] 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
[0250] 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
##STR00056##
[0251] Step 1:
CIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazasp-
iro[4.5]decan-2-one
[0252] 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
[0253] 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
##STR00057##
[0254] Step 1:
CIS-3-benzyl-1-(cyclobutylmethyl)-8-(methylamino)-8-phenyl-1,3-diazaspiro-
[4.5]decan-2-one
[0255] 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
[0256] 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; Rf: 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)
[0257] 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.4C.sub.1, 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].sup.+ 356.3
Synthesis of INT-987:
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]dec-
an-2-one
##STR00058##
[0259] 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
##STR00059##
[0260] 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
[0261] 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)
[0262] 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-989:
CIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[-
4.5]decan-2-one
##STR00060##
[0264]
CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
(INT-976) (1250 mg, 4.6 mmol), 5-bromo-2-chloro-pyrimidine (1.5
equiv., 6.7 mmol, 1327 mg), Cs.sub.2CO.sub.3 (2 equiv., 9.15 mmol,
2980 mg), XantPhos (0.15 equiv., 0.69 mmol, 397 mg) and
Pd.sub.2(dba).sub.3 (0.05 equiv., 0.23 mmol, 209 mg) were dissolved
in dry 1,4-dioxane (120 equiv., 549 mmol, 47 mL) under nitrogen
atmosphere and stirred at 90.degree. C. overnight. The reaction
mixture was cooled down, diluted with water (50 mL), extracted with
DCM (3.times.70 mL), the combined organic phases were dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure. The
residue (2.8 g) was suspended in 10 mL DCM and stirred for 10 min.
The resulting precipitate was filtered off and washed with small
amount of DCM to give 1213 mg of
CIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[-
4.5]decan-2-one (INT-989) as a white solid. The mother liquor was
concentrated under reduced pressure (1428 mg), suspended in 3 mL
DCM, 3 mL pentane were slowly added and the mixture was stirred for
30 min. The precipitate was filtered off, washed with small amounts
of pentane and DCM to give second portion of INT-989 (215 mg) as a
light yellow solid. .sup.1H NMR (600 MHz, DMSO) .delta. 8.94 (s,
2H), 7.88 (s, 1H), 7.41-7.33 (m, 4H), 7.27 (tt, 1H), 3.65 (s, 2H),
2.49-2.32 (m, 2H), 1.98-1.88 (m, 2H), 1.96 (s, 6H), 1.87-1.73 (m,
2H), 1.53-1.47 (m, 2H). Mass: m/z 386.2 (M+H).sup.+.
Synthesis of INT-991: lithium
CIS-5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyr-
imidine-2-carboxylate
##STR00061##
[0266] Methyl
CIS-5-[8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]pyr-
imidine-2-carboxylate (INT-990) (950 mg, 2.32 mmol) was suspended
in a mixture of MeOH (140 equiv., 325 mmol, 13 mL) and THF (70
equiv., 162 mmol, 13 mL). Lithium hydroxide 2M aq. sol. (1.3 mL)
was added. The reaction mixture was stirred 5 days at RT.
Additional 1.3 mL of lithium hydroxide 2M aq. sol. were added and
the reaction mixture was stirred for 2 h at RT. The solvents were
removed under reduced pressure. The residue was suspended in EtOAc
(10 mL) and stirred overnight. The precipitate was filtered off
(1.07 g) and washed with DCM (3 mL), pentane and dried under
reduced pressure. The resulting solid (960 mg) containing INT-990
and residual lithium salts was used directly in the next steps.
Mass: m/z 394.2 (M-Li).sup.-.
Synthesis of INT-1008:
CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one
##STR00062##
[0267] Step 1 and step 2:
ethyl-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-amine hydrochloride
(INT-1004)
[0268] A mixture of 1,4-dioxa-spiro[4.5]decan-8-one (25.0 g, 160.25
mmol, 1.0 eq.) and 2M solution of EtNH.sub.2 in THF (200 ml, 2.5
eq. 400.64 mmol) in EtOH (30 ml) was stirred at RT for 48 h. The
reaction mixture was concentrated under argon atmosphere and the
residue was diluted with ether (60 ml), and a freshly prepared PhLi
solution was added [prepared by addition of 2.5M n-BuLi in THF
(70.5 ml, 1.1 eq. 176.27 mmol) to a solution of bromobenzene
(27.675 g, 1.1 eq. 176.275 mmol) in ether (100 ml) at -30.degree.
C. and stirred at RT for 1 h). The reaction mixture was stirred at
RT for 1.5 h, quenched with saturated NH.sub.4Cl solution (100 ml)
at 0.degree. C. and extracted with ethyl acetate (2.times.750 ml).
The combined organic layer was washed with water (3.times.350 ml),
brine (300 ml), dried over Na.sub.2SO.sub.4 and concentrated under
reduced pressure. The resulting residue was dissolved in ethyl
methyl ketone (100 ml) and trimethylsilyl chloride (37.5 ml) was
added at 0.degree. C. The resulting mixture was stirred at RT for
16 h. The precipitated solid was filtered off and washed with
acetone followed by THF to get
ethyl-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-amine hydrochloride
as an off white solid. This reaction was done in 2 batches of 25 g
scale and the yield is given for 2 combined batches. Yield: 18%
(17.1 g, 57.575 mmol). LCMS: m/z 262.2 (M+H).sup.+.
Step 3: 4-ethylamino-4-phenyl-cyclohexanone (INT-1005)
[0269] To a solution of
ethyl-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-amine hydrochloride
(10.1 g, 34.0 mmol, 1 eq.) in water (37.5 ml) was added conc. aq.
HCl (62.5 ml) at 0.degree. C. and the resulting mixture was stirred
at RT for 16 h. The reaction mixture was basified with aq. NaOH (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 the yield is given for 2
combined batches. Yield: 92% (17.0 g, 78.34 mmol).
Step 4: cis and trans Mixture of
8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione
(INT-1006 and INT-1007)
[0270] To a solution of 4-ethylamino-4-phenyl-cyclohexanone (17 g,
78.341 mmol, 1.0 eq.) in EtOH (250 ml) and water (200 ml) was added
(NH.sub.4).sub.2CO.sub.3 (18.8 g, 195.85 mmol, 2.5 eq.) and the
reaction mixture was stirred at RT for 15 min KCN (5.09 g, 78.341
mmol, 1.0 eq.) was added and stirring was continued at 60.degree.
C. for 18 h. The reaction mixture was cooled down to RT. The
precipitated solid was filtered off, washed with water (250 ml),
EtOH (300 ml), hexane (200 ml) and dried under reduced pressure to
yield cis and trans mixture of
8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (13.0 g,
45.29 mmol, 58%) as a white solid. Yield: 58% (13 g, 45.296 mmol).
LC-MS: m/z [M+1].sup.+=288.2.
Step 5:
CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione
(INT-1006)
[0271] To a solution of cis and trans mixture of
8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (12 g)
in MeOH-DCM (1:1, 960 ml) was added a solution of L-tartaric acid
in MeOH (25 ml) and the resulting mixture stirred at RT for 2 h and
then kept in refrigerator for 16 h. The precipitated solid was
filtered off and washed with MeOH-DCM (1:5, 50 ml) to get tartrate
salt of 8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione
(7.5 g) as a white solid. To this solid sat. aq. NaHCO.sub.3 was
added (pH-8) and the resulting mixture was extracted with 25%
MeOH-DCM (2.times.800 ml). Combined organic layer was washed with
water (300 ml), brine (300 ml), dried over anhydrous
Na.sub.2SO.sub.4 and concentrated under reduced pressure. The
residue was triturated with 20% DCM-hexane and the resulting solid
was dried under reduced pressure to afford
CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione as
white solid. This step was done in 2 batches (12 g & 2.4 g) and
the yield is given for 2 combined batches. Yield: 31.2% (5.0 g,
17.421 mmol). LC-MS: m/z [M+1].sup.+=288.0.
Step 6: CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one
(INT-1008)
[0272] To a slurry of LiAlH.sub.4 (793 mg, 20.91 mmol, 3.0 eq.) in
THF (15 ml) was added a suspension of
CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (2.0
g, 6.97 mmol, 1.0 eq.) in THF (60 ml) at 0.degree. C. and the
reaction mixture was heated to 65.degree. C. for 16 h. The reaction
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 pad. The residue was washed with 15% MeOH-DCM (500
ml). The combined filtrate was dried over anhydrous
Na.sub.2SO.sub.4 and concentrated under reduced pressure to give
crude product which was triturated with 15% DCM-Hexane to afford
CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one
(INT-1008) (1.6 g, 5.86 mmol, 84%) as a white solid. Yield: 84%
(1.6 g, 5.86 mmol). LC-MS: m/z [M+1].sup.+=274.2.
Synthesis of INT-1026:
CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro-
[4.5]decan-2-one
##STR00063##
[0273] Step 1:
2-methyl-N-(1,4-dioxaspiro[4.5]decan-8-ylidene)propane-2-sulfinamide
[0274] 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
[0275] 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
[0276] 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
[0277] 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)
[0278] 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
[0279] 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 14.51 decane-2,4-dione
[0280]
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
[0281] 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)
[0282] 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
##STR00064##
[0283] Step 1:
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methox-
yphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one
[0284] 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
[0285] 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-1037:
8-(dimethylamino)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile
##STR00065##
[0286] Step 1: 9,12-dioxa-2,4-diazadispiro[4.2.4 {8}.2
{5}]tetradecan-3-one
[0287] 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
[0288] 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)
[0289] 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
##STR00066##
[0291] 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
##STR00067##
[0292] Step 1:
TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione
[0293] 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)
[0294] 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
##STR00068##
[0295] Step 1:
1-amino-4-dimethylamino-4-phenyl-cyclohexanecarbonitrile
[0296] 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
[0297] 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
[0298] 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)-cyclohexane-
-1,4-diamine (4.2 g, crude) as a light yellow sticky material which
was directly used in the next step without further purification.
LC-MS: m/z [M+1].sup.+=330.0 (MW calc. 329.40).
Step 4: CIS- and
TRANS-8-dimethylamino-8-phenyl-1-(2,2,2-trifluoro-ethyl)-1,3-diaza-spiro[-
4.5]decan-2-one (INT-1068 and INT-1069)
[0299] To a solution of
1-aminomethyl-N,N'-dimethyl-4-phenyl-N-(2,2,2-trifluoro-ethyl)-cyclohexan-
e-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).
[0300] For further intermediates the synthesis in analogy to
previously described methods is given in the following table. The
syntheses of the building blocks and intermediates have either been
described previously within this application or can be performed in
analogy to the herein described methods or by methods known to the
person, skilled in the art. Such a person will also know which
building blocks and intermediates need to be chosen for synthesis
of each exemplary compound.
TABLE-US-00002 in analogy m/z Intermediate Chemical Name Chemical
Structure to method [M + H].sup.+ INT-601
CIS-5-(-8-(dimethylamino)-8-(3-fluorophenyl)-2-
oxo-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2- carbonitrile
##STR00069## INT-600 395.1 INT-794 CIS-3-(3,4-dimethoxybenzyl)-8-
(dimethylamino)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one
##STR00070## 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
##STR00071## INT-974 390.3 INT-797
CIS-8-(Ethyl-methyl-amino)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one
##STR00072## INT-976 288.2 INT-949
CIS-8-Dimethylamino-1-ethyl-8-phenyl-1,3-
diazaspiro[4.5]decan-2-one ##STR00073## 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
##STR00074## INT-952 432.3 INT-954
4-Dimethylamino-4-(5-methyl-thiophen-2-yl)- cyclohexan-1-one
##STR00075## INT-965 238.1 INT-955
4-Dimethylamino-4-thiophen-2-yl-cyclohexan-1- one ##STR00076##
INT-965 224.1 INT-956 1-(1-Methyl-1H-pyrazol-3-yl)-4-oxo-
cyclohexane-1-carbonitrile ##STR00077## INT-958 204.1 INT-957
4-Oxo-1-pyrazin-2-yl-cyclohexane-1-carbonitrile ##STR00078##
INT-958 202.1 INT-959 4-Dimethylamino-4-(1-methyl-1H-pyrazol-3-yl)-
cyclohexan-1-one ##STR00079## INT-961 222.2 INT-960
4-Dimethylamino-4-pyrazin-2-yl-cyclohexan-1- one ##STR00080##
INT-961 220.1 INT-962 4-Dimethylamino-4-(3-methoxyphenyl)-
cyclohexan-1-one ##STR00081## INT-965 248.2 INT-963
CIS-3-Benzyl-8-dimethylamino-8-phenyl-1,3-
diazaspiro[4.5]decan-2-one ##STR00082## INT-975 364.2 INT-964
4-(Ethyl-methyl-amino)-4-phenyl-cyclohexan-1- one ##STR00083##
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 ##STR00084## 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 ##STR00085##
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 ##STR00086## INT-971 478.3
INT-970 CIS-8-Dimethylamino-8-(4-methoxyphenyl)-3-
[(4-methoxyphenyl)-methyl]-1,3- diazaspiro[4.5]decan-2-one
##STR00087## SC_2017 424.3 INT-972
CIS-8-Dimethylamino-8-(3-methoxyphenyl)-3-
[(4-methoxyphenyl)-methyl]-1,3- diazaspiro[4.5]decan-2-one
##STR00088## SC_2017 424.3 INT-973
CIS-8-Dimethylamino-8-(4-fluorophenyl)-3-[(4-
methoxyphenyl)-methyl]-1,3- diazaspiro[4.5]decan-2-one ##STR00089##
INT-974 412.2 INT-979 CIS-8-Dimethylamino-1-(3-methoxy-propyl)-8-
phenyl-1,3-diazaspiro[4.5]decan-2-one ##STR00090## INT-984 346.2
INT-980 CIS-8-Dimethylamino-1-(2-methoxy-ethyl)-8-
phenyl-1,3-diazaspiro[4.5]decan-2-one ##STR00091## INT-984 332.2
INT-981 CIS-8-Dimethylamino-8-phenyl-1-propyl-1,3-
diazaspiro[4.5]decan-2-one ##STR00092## INT-984 316.2 INT-983
CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-8-
phenyl-1,3-diazaspiro[4.5]decan-2-one ##STR00093## INT-984 328.2
INT-985 CIS-1-(Cyclobutyl-methyl)-8-(methyl-propyl-
amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one ##STR00094## INT-986
370.3 INT-990 methyl CIS-5-(8-(dimethylamino)-2-oxo-8-
phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine- 2-carboxylate
##STR00095## INT-989 410.2 INT-992
CIS-3-(2-chloro-4-methylpyrimidin-5-yl)-8-
(dimethylamino)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one
##STR00096## INT-989 400.2 INT-993
4-benzyl-4-(dimethylamino)cyclohexanone ##STR00097## INT-965 232.3
INT-994 CIS-8-benzyl-8-(dimethylamino)-1,3-
diazaspiro[4.5]decan-2-one ##STR00098## INT-976 288.2 INT-995
TRANS-8-benzyl-8-(dimethylamino)-1,3- diazaspiro[4.5]decan-2-one
##STR00099## INT-976 288.2 INT-997
CIS-8-(dimethylamino)-8-(thiophen-2-yl)-1,3-
diazaspiro[4.5]decan-2-one ##STR00100## INT-976 280.1 INT-998
TRANS-8-(dimethylamino)-8-(thiophen-2-yl)-
1,3-diazaspiro[4.5]decan-2-one ##STR00101## INT-976 280.1 INT-999
4-(dimethylamino)-4-(1-methyl-1H-
benzo[d]imidazol-2-yl)cyclohexanone ##STR00102## INT-965 272.2
INT-1000 CIS-8-(dimethylamino)-8-(1-methyl-1H-
benzo[d]imidazol-2-yl)-1,3-diazaspiro[4.5]decan- 2-one ##STR00103##
INT-976 328.2 INT-1001 TRANS-8-(dimethylamino)-8-(1-methyl-1H-
benzo[d]imidazol-2-yl)-1,3-diazaspiro[4.5]decan- 2-one ##STR00104##
INT-976 328.2 INT-1002 CIS-3-(2-chloropyrimidin-4-yl)-8-
(dimethylamino)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one
##STR00105## INT-989 386.9 INT-1009
TRANS-8-ethylamino-8-phenyl-1,3-diaza- spiro[4.5]decan-2-one
##STR00106## INT-1008 274.2 INT-1024
CIS-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-
diazaspiro[4.5]decan-2-one ##STR00107## INT-977 (step 2) 292.2
INT-1025 CIS-8-(dimethylamino)-8-(4-fluorophenyl)-1,3-
diazaspiro[4.5]decan-2-one ##STR00108## INT-974, INT-977 (step 2)
292.2 INT-1027 CIS-3-(2-chloropyrimidin-5-yl)-8-
(dimethylamino)-8-(thiophen-2-yl)-1,3- diazaspiro[4.5]decan-2-one
##STR00109## INT-989 392.1 INT-1039 CIS-8-(dimethylamino)-8-(3-
(trifluoromethoxy)phenyl)-1,3- diazaspiro[4.5]decan-2-one
##STR00110## INT-1038 358.2 INT-1040 (CIS)-8-(dimethylamino)-8-(3-
(trifluoromethyl)phenyl)-1,3- diazaspiro[4.5]decan-2-one
##STR00111## INT-1038 342.2 INT-1041
(CIS)-8-(dimethylamino)-8-(3-methoxyphenyl)-
1,3-diazaspiro[4.5]decan-2-one ##STR00112## INT-1038 304.2 INT-1042
(CIS)-8-(5-chlorothiophen-2-yl)-8-
(dimethylamino)-1,3-diazaspiro[4.5]decan-2-one ##STR00113##
INT-1038 314.1 INT-1043 (CIS)-8-(dimethylamino)-8-(3-fluoro-5-
methylphenyl)-1,3-diazaspiro[4.5]decan-2-one ##STR00114## INT-1038
306.2 INT-1044 (CIS)-8-(3-chlorophenyl)-8-(dimethylamino)-1,3-
diazaspiro[4.5]decan-2-one ##STR00115## INT-1038 308.2 INT-1045
(CIS)-3-(5-chloro-3-fluoropyridin-2-yl)-8-
(dimethylamino)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one
##STR00116## INT-989 403.2 INT-1047
(CIS)-8-(methyl(oxetan-3-ylmethyl)amino)-8-
phenyl-1,3-diazaspiro[4.5]decan-2-one ##STR00117## INT-1026 330.5
INT-1048 (CIS)-3-(6-chloropyridin-3-yl)-8-
(dimethylamino)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one
##STR00118## INT-989 385.2 INT-1049
(CIS)-3-(5-chloropyridin-2-yl)-8- (dimethylamino)-8-phenyl-1,3-
diazaspiro[4.5]decan-2-one ##STR00119## INT-989 385.2 INT-1061
TRANS-1-(cyclopropyl-methyl)-8- dimethylamino-8-phenyl-1,3-
diazaspiro[4.5]decan-2-one ##STR00120## INT-984 328.2 INT-1063
CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-
(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one ##STR00121##
INT-1031 346.2 INT-1066 TRANS-1-(cyclobutylmethyl)-8-
(dimethylamino)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one
##STR00122## INT-987 342.3 INT-1070
CIS-8-(dimethylamino)-8-phenyl-1-(3,3,3-
trifluoropropyl)-1,3-diazaspiro[4.5]decan-2-one ##STR00123##
INT-1068 360.2 INT-1074
CIS-8-(dimethylamino)-8-(3-fluorophenyl)-1-((1-
hydroxycyclobutyl)methyl)-1,3- diazaspiro[4.5]decan-2-one
##STR00124## INT-1031 376.2 INT-1076
CIS-3-(2-chloro-4-methylpyrimidin-5-yl)-8-
(dimethylamino)-8-(3-fluorophenyl)-1,3- diazaspiro[4.5]decan-2-one
##STR00125## INT-989 418.2 INT-1077
CIS-3-(4-chloro-2-(trifluoromethyl)pyrimidin-5-
yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-
diazaspiro[4.5]decan-2-one ##STR00126## INT-989 472.2 INT-1078
CIS-3-(4-chloro-2-cyclopropylpyrimidin-5-yl)-8-
(dimethylamino)-8-(3-fluorophenyl)-1,3- diazaspiro[4.5]decan-2-one
##STR00127## INT-989 444.2
Synthesis of Exemplary Compounds
Synthesis of SC_3013:
cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile
##STR00128##
[0302] NaH (60% in mineral oil, 0.076 g, 3.19 mmol, 3 equiv.) was
added to a solution of
5-(cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyr-
imidine-2-carbonitrile INT_600 (0.4 g, 1.06 mmol) in DMF (5 mL) at
0.degree. C. The mixture was stirred for 30 min at RT and then
cooled to 0.degree. C.
(1-(Tert-butyldimethylsilyloxy)cyclobutyl)methyl
4-methylbenzenesulfonate (1.18 g, 3.19 mmol, 3 equiv.) was added
dropwise over a period of 5 min and the reaction mixture was
allowed to warm up to RT and further heated to 70.degree. C. for 16
h. The reaction mixture was diluted with water (10 mL) and
extracted with EtOAc (3.times.20 mL). The combined organic layers
were dried over anhydrous Na.sub.2SO.sub.4 and the solvent was
removed in vacuo. The residue was purified by silica gel flash
chromatography to afford
CIS-5-[8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile (0.25
g).
Synthesis of SC_3014:
cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-pyrimidine-5-carbonitrile
##STR00129##
[0304]
cis-1-(Cyclobutylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[-
4.5]decan-2-one INT-987 (500 mg, 1.464 mmol),
2-chloropyrimidine-5-carbonitrile (409 mg, 2.928 mmol) and
Cs.sub.2CO.sub.3 (954 mg, 2.928 mmol) in 1,4-dioxane (6 ml) were
stirred under an nitrogen atmosphere for 18 h at 105.degree. C. The
reaction mixture was cooled to RT, 2N aqueous NaOH solution (3 ml)
was added and stirring was continued for 10 min. The mixture was
extracted first with EtOAc and then with a blend of DCM (30 ml) and
methanol (5 ml). The organic layers were combined and concentrated
under reduced pressure. The residue was purified by flash
chromatography on silica gel (elution with a DCM/EtOAc gradient)
provided
cis-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-pyrimidine-5-carbonitrile SC_3014 (57 mg).
Synthesis of SC_3016:
cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-pyrimidine-5-carboxylic acid amide
##STR00130##
[0306]
cis-2-[1-(Cyclobutylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]pyrimidine-5-carbonitrile SC_3014 (40 mg,
0.09 mmol) was dissolved in DMSO (1.2 mL) and K.sub.2CO.sub.3 (25
mg, 0.18 mmol) and hydrogen peroxide (30%, 0.13 mL 1.260 mmol) were
added. The reaction mixture was stirred at RT for 20 h, then
diluted with 2N NaOH (10 mL) and extracted with DCM (3.times.20
mL). The combined organic layers were dried over Na.sub.2SO.sub.4,
concentrated in vacuo. 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]-pyrimidine-5-carboxylic acid amide SC_3016 (40
mg) as a white solid.
Synthesis of SC_3022:
cis-1-(Cyclobutylmethyl)-8-(dimethylamino)-8-phenyl-3-[2-(trifluoromethyl-
)pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one
##STR00131##
[0308]
cis-1-(Cyclobutylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[-
4.5]decan-2-one INT-987 (240 mg, 0.7 mmol), Pd-XPhos Generation 2
(138 mg, 0.17 mmol), Cs.sub.2CO.sub.3 (457 mg, 1.4 mmol) and
5-bromo-2-(trifluoromethyl)pyrimidine (319 mg, 1.4 mmol) were
suspended in anhydrous 1,4-dioxane (3 mL) under nitrogen atmosphere
and the resulting mixture was stirred at 100.degree. C. overnight.
The reaction mixture was cooled to RT and water (3 mL) was added.
The aqueous layer was extracted with DCM (3.times.10 mL), the
combined organic layers were dried over Na.sub.2SO.sub.4 and
concentrated in vacuo. The residue was purified by flash
chromatography on silica gel to yield the title compound. Final
purification using a strong cation exchange resin gave
cis-1-(cyclobutylmethyl)-8-(dimethylamino)-8-phenyl-3-[2-(trifluoromethyl-
)pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3022 (145 mg) as
a white solid.
Synthesis of SC_3028:
cis-4-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N,N-dimethyl-benzamide
##STR00132##
[0309] Step 1: Lithium
4-(cis-1-(cyclobutylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspi-
ro[4.5]decan-3-yl)benzoate
[0310] Methyl
4-(cis-1-(cyclobutylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspi-
ro [4.5]decan-3-yl)benzoate SC_3081 (400 mg) was dissolved in
methanol (5 mL) and DCM (5 mL). Lithium hydroxide solution (2 M in
water, 1 mL) was added and the resulting mixture was stirred
overnight at RT. All volatiles were removed in vacuo to yield
lithium
4-(cis-1-(cyclobutylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspi-
ro[4.5]decan-3-yl)benzoate (403 mg).
Step 2
cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-dia-
zaspiro [4.5]decan-3-yl]-N,N-dimethyl-benzamide (SC_3028)
[0311] Lithium
4-(cis-1-(cyclobutylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspi-
ro [4.5]decan-3-yl)benzoate (80 mg, 0.17 mmol) was suspended in DCM
(1 mL) and triethylamine (0.23 mL, 1.7 mmol) and dimethylamine (2M
solution in THF, 0.17 mL) and T3P (0.20 mL, 0.34 mmol) were
sequentially added. The resulting mixture was stirred for 18 h at
RT. Water (10 mL) was added and the mixture was extracted with DCM
(3.times.20 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-4-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-N,N-dimethyl-benzamide SC_3028 (28 mg) as white
solid.
Synthesis of SC_3045:
cis-4-Methoxy-5-[1-(3-methoxypropyl)-8-(methylamino)-2-oxo-8-phenyl-1,3-d-
iazaspiro[4.5]decan-3-yl]pyrimidine-2-carbonitrile
##STR00133##
[0313] N-iodosuccinimide (150 mg, 0.67 mmol) was added to a
suspension of
cis-5-[8-(dimethylamino)-1-(3-methoxypropyl)-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile SC_3040 (214
mg, 0.44 mmol) in acetonitrile/THF (2/1 v/v, 10 mL) at RT and the
resulting mixture was stirred for 16 h at RT. The reaction mixture
was basified with 2N NaOH solution to pH-10 and the organic product
was extracted with DCM (10 mL.times.3). The combined organic
extracts were dried over anhydrous Na.sub.2SO.sub.4, the solvent
was removed in vacuo and the residue was purified by preparative
flash chromatography to give
cis-4-methoxy-5-[1-(3-methoxypropyl)-8-(methylamino)-2-oxo-8-phenyl-1,3-d-
iazaspiro[4.5]decan-3-yl]pyrimidine-2-carbonitrile SC_3045 (81 mg)
as a solid.
Synthesis of SC_3064:
cis-2-[3-(2-cyano-pyrimidin-5-yl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diaz-
aspiro[4.5]decan-1-yl]-N-propyl-acetamide
##STR00134##
[0315] Sodium hydroxide (51 mg, 1.3 mmol) was added to anhydrous
DMSO (4.5 mL) and stirred for 10 minutes at room temperature.
cis-5-[8-(Dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]pyr-
imidine-2-carbonitrile INT_600 (80 mg, 0.21 mmol) was added and the
resulting mixture was stirred at room temperature for 5 min and
then heated to 50.degree. C. 2-Bromo-N-propyl-acetamide (153 mg,
0.85 mmol) was added and stirring was continued at 50.degree. C.
for one hour. The reaction mixture was quenched with water (25 mL)
and extracted with ethyl acetate (2.times.10 mL). The combined
organic layers were washed with water (5 mL) and brine (5 mL),
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-[3-(2-cyano-pyrimidin-5-yl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diaz-
aspiro[4.5]decan-1-yl]-N-propyl-acetamide SC_3064 (22 mg) as a
solid.
Synthesis of SC_3065:
5-(cis-1-(Cyclobutylmethyl)-8-(ethyl(methyl)amino)-2-oxo-8-phenyl-1,3-dia-
zaspiro[4.5]decan-3-yl)-4-methoxypyrimidine-2-carbonitrile
##STR00135##
[0317] Cs.sub.2CO.sub.3 (274 mg, 0.84 mmol) was added to the
solution of
cis-1-(cyclobutylmethyl)-8-(ethyl(methyl)amino)-8-phenyl-1,3-diazaspiro[4-
.5]decan-2-one INT_986 (150 mg, 0.42 mmol), Xanthphos (36 mg, 0.063
mmol), Pd.sub.2(dba).sub.3 (19 mg, 0.0211 mmol) and
5-bromo-4-methoxypyrimidine-2-carbonitrile (135 mg, 0.633 mmol) in
1,4-dioxane (10 mL) under argon atmosphere. The mixture was flushed
again with argon for 5 min and the reaction mixture was stirred at
90.degree. C. for 5 h. The reaction mixture was cooled to room
temperature. The residue was diluted with water (20 mL) and the
organic product was extracted with ethyl acetate (3.times.10 mL).
The combined organic extracts were dried over anhydrous
Na.sub.2SO.sub.4 and the solvent was concentrated under reduced
pressure. The residue was purified by preparative TLC
(EtOAc/petroleum ether 1/9) to afford a white solid (0.15 g), which
was further washed with n-pentane to give 0.1 g of
5-(cis-1-(cyclobutylmethyl)-8-(ethyl(methyl)amino)-2-oxo-8-phenyl-1,3-dia-
zaspiro[4.5]decan-3-yl)-4-methoxypyrimidine-2-carbonitrile
SC_3065.
Synthesis of SC_3008:
cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspir-
o[4.5]decan-3-yl]-5-methylsulfonyl-benzonitrile
##STR00136##
[0319]
cis-2-[1-(Cyclobutylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-di-
azaspiro[4.5]decan-3-yl]-5-methylsulfanyl-benzonitrile (320 mg,
0.66 mmol, prepared from 2-iodo-5-(methylthio)benzonitrile and
INT-987 analogously to SC_3022) was dissolved in a mixture of
methanol (9 mL) and water (8 mL). Oxone.RTM. (807 mg, 1.3 mmol) was
added at RT and the resulting mixture was stirred at RT for 18 h.
Water (10 mL) was added and the mixture was extracted with DCM
(3.times.20 mL). The combined organic layers were dried over
Na.sub.2SO.sub.4, concentrated in vacuo. The residue was purified
by flash chromatography on silica gel to yield
cis-2-[1-(cyclobutylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspi-
ro[4.5]decan-3-yl]-5-methylsulfonyl-benzonitrile SC_3008 (66 mg) as
a white solid.
Synthesis of SC_3023:
cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-hydroxy-pyrimi-
din-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
##STR00137##
[0321] Boron tribromide (1M in DCM, 0.38 mL, 0.387 mmol) was added
to the solution of
cis-8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-methoxy-pyrimi-
din-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3015 (180 mg,
0.387 mmol) in DCM (2 mL) at 0.degree. C. The reaction mixture was
stirred for 30 min at 0.degree. C. and then for 16 h at room
temperature, quenched with methanol (2 mL), the solvents were
removed under reduced pressure and the residue was purified by
normal phase preparative HPLC to yield
cis-8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-hydroxy-pyrimi-
din-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3023 (60 mg,
34%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d6, .delta. in
ppm): .delta. 8.43 (s, 2H), 7.35-7.25 (m, 5H), 5.50 (s, 1H), 3.67
(s, 2H), 3.19 (s, 2H), 2.69-2.65 (m, 2H), 2.19-2.10 (m, 4H),
1.98-1.85 (m, 8H), 1.68-1.61 (m, 1H), 1.51-1.39 (m, 5H).
Synthesis of SC_3025:
cis-5-[8-Dimethylamino-1-(2-hydroxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[-
4.5]decan-3-yl]-pyrimidine-2-carbonitrile
##STR00138##
[0322] Step 1:
5-(cis-1-(2-(tert-Butyldimethylsilyloxy)ethyl)-8-(dimethylamino)-2-oxo-8--
phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carbonitrile
[0323] NaH (60% in mineral oil, 63.8 mg, 1.59 mmol) was added at
0.degree. C. to the solution of
5-(cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyr-
imidine-2-carbonitrile INT-600 (0.2 g, 0.53 mmol) in DMF (8 mL) for
10 min at 0.degree. C. The reaction mixture was stirred at RT for
30 min, (3-bromopropoxy)(tert-butyl)dimethylsilane (252 mg, 1.06
mmol) was added dropwise over 5 min at 0.degree. C. and the mixture
was stirred for further 16 h at RT. The reaction mixture was
diluted with water (15 mL) and extracted with diethyl ether
(3.times.25 mL). The combined organic extracts were dried over
anhydrous Na.sub.2SO.sub.4, the solvents were removed under reduced
pressure and the residue was purified by flash chromatography on
silica gel to afford
5-(cis-1-(2-(tert-butyldimethylsilyloxy)ethyl)-8-(dimethylamino)-2-oxo-8--
phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carbonitrile (100
mg, 34%) as a white solid.
Step 2:
cis-5-[8-Dimethylamino-1-(2-hydroxy-ethyl)-2-oxo-8-phenyl-1,3-diaz-
aspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile (SC_3025)
[0324] 1M TBAF solution in THF (0.36 mL, 0.36 mmol) was added to
5-(cis-1-(2-(tert-butyldimethylsilyloxy)ethyl)-8-(dimethylamino)-2-oxo-8--
phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carbonitrile (0.1
g, 0.18 mmol) in THF (5 mL) at 0.degree. C. The reaction mixture
was stirred at RT for 30 min, diluted with water (10 mL) and
extracted with diethyl ether (3.times.25 mL). The combined organic
extracts were washed with sat. aq. NaHCO.sub.3, water and brine and
dried over anhydrous Na.sub.2SO.sub.4. The solvents were evaporated
under reduced pressure and the residue was purified by preparative
TLC (ethyl acetate/n-hexane=45:55) and then washed with n-pentane
(5 mL) to give of
cis-5-[8-dimethylamino-1-(2-hydroxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[-
4.5]decan-3-yl]-pyrimidine-2-carbonitrile (70 mg, 80%) as a white
solid. .sup.1H NMR (400 MHz, DMSO-d6, .delta. in ppm): .delta. 9.18
(s, 2H), 7.38-7.26 (m, 5H), 4.84 (t, 1H), 3.82 (s, 2H), 3.55-3.51
(m, 2H), 3.26-3.20 (m, 2H), 2.73-2.70 (m, 2H), 2.17-2.11 (m, 2H),
2.00 (s, 6H), 1.57-1.43 (m, 4H).
Synthesis of SC_3097:
CIS-8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-morpholin-4-yl-
-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
##STR00139##
[0326] starting from here until the end of the section all
procedures were added
Step 1: 4-(5-bromopyrimidin-2-yl)morpholine
[0327] K.sub.2CO.sub.3 (14.2 g, 103 mmol) was added to the solution
of morpholine (9.0 g, 103 mmol) in acetonitrile (900 mL) and the
resulting suspension was stirred at RT for 1 h.
5-Bromo-2-chloropyrimidine (20 g, 103 mmol) was added portionwise.
The reaction mixture was stirred for 16 h at 80.degree. C., then
cooled down to RT and diluted with EtOAc (100 mL) and water (50
mL). The organic product was extracted with EtOAc (2.times.100 mL).
The combined organic layer was washed with brine (100 mL), dried
over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced
pressure. The resulting residue was purified by column
chromatography on silica gel (100-200 mesh) (20% EtOAc in petroleum
ether) to afford 18.0 g (71%) of
4-(5-bromopyrimidin-2-yl)morpholine as an off white solid (TLC
system: 30% EtOAc in pet ether, Rf: 0.6).
Step 2:
CIS-8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-morphol-
in-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
(SC_3097)
[0328] K.sub.2CO.sub.3 (0.53 g, 3.85 mmol, 2.5 equiv.) was added to
the suspension of
CIS-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-1,3-diazas-
piro[4.5]decan-2-one (INT-799) (0.55 g, 1.54 mmol, 1 equiv.) and
4-(5-bromopyrimidin-2-yl)morpholine (0.37 g, 1.54 mmol, 1 equiv.)
in dioxane (20 mL) and the resulting suspension was purged with
nitrogen for 5 min. Copper(I) iodide (0.29 g, 1.54 mmol, 1 equiv.)
and trans-1,2-diaminocyclohexane (0.35 g, 3.085 mmol, 2 equiv.)
were sequentially added, the reaction vessel was sealed and the
reaction mixture was stirred at 130.degree. C. for 4 h. The
reaction mixture was cooled down to RT and diluted with EtOAc (20
mL) and aq. ammonia (10 mL). The organic product was extracted with
EtOAc (2.times.50 mL). The combined organic layer was washed with
brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4 and
concentrated under reduced pressure. Purification of the resulting
residue by column chromatography on silica gel (100-200 mesh)
(60-70% EtOAc in petroleum ether) afforded 0.35 g (48%) of
CIS-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-3-(2-morph-
olin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
(SC_3097) as an off white solid (TLC system: EtOAc, R.sub.f: 0.7).
.sup.1H NMR (DMSO-d6): .delta. 8.60 (s, 2H), 7.36-7.35 (m, 4H),
7.27-7.24 (m, 1H), 5.50 (s, 1H), 3.72 (s, 2H), 3.62-3.61 (m, 8H),
3.21 (s, 2H), 2.70-2.66 (m, 2H), 2.19-2.11 (m, 4H), 1.98 (s, 6H),
1.93-1.85 (m, 2H), 1.66-1.64 (m, 1H), 1.53-1.42 (m, 5H). Mass: m/z
521.3 (M+H).sup.+.
Synthesis of SC_3099:
CIS-1-[(1-hydroxy-cyclobutyl)-methyl]-8-methylamino-3-(2-morpholin-4-yl-p-
yrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
##STR00140##
[0330] N-Iodosuccinimide (162 mg, 0.72 mmol) was added to the
solution
CIS-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-3-(2-morpholinopyri-
midin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC-3097) (250
mg, 0.48 mmol) in acetonitrile (8.0 mL) and THF (8.0 mL) at
0.degree. C. and the resulting mixture was stirred for 16 h at RT.
The reaction mixture was concentrated under reduced pressure. The
residue was dissolved in EtOAc (2.times.30 mL), the organic layer
was washed with 2N aq. NaOH solution, dried over anhydrous
Na.sub.2SO.sub.4 and concentrated under reduced pressure. The
residue was purified by reverse phase prep. HPLC to yield 0.12 g
(49%) of
CIS-1-((1-hydroxycyclobutyl)methyl)-8-(methylamino)-3-(2-morpholinopyrimi-
din-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_3099) as an
off white solid (TLC system 5% MeOH in DCM Rf: 0.5). Preparative
reverse phase HPLC conditions: column: Luna-Phenyl-Hexyl-C18
(150*19 mm) 5 .mu.m; mobile phase: 10 mM ammonium
bicarbonate/acetonitrile, gradient (T/% B): 0/50, 7/85, 7.1/98,
9/98, 9.1/50, 12/50; flow Rate: 25 ml/min; diluent: mobile
phase+THF. .sup.1H NMR (DMSO-d6): .delta. 8.63 (s, 2H), 7.49-7.47
(m, 2H), 7.34-7.30 (t, 2H), 7.21-7.17 (m, 1H), 5.60 (s, 1H), 3.76
(s, 2H), 3.64-3.62 (m, 8H), 3.35 (m, 2H), 2.26-2.20 (m, 3H),
2.12-2.08 (m, 2H), 1.90-1.88 (m, 7H), 1.79-1.73 (m, 2H), 1.65-1.63
(m, 1H), 1.52-1.44 (m, 3H). Mass: m/z 507.3 (M+H).sup.+.
Synthesis of SC_3100:
CIS-8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-(2-piper-
azin-1-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one
hydrochloride
##STR00141##
[0331] Step 1: tert-butyl
4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate
[0332] In analogy to the method described for SC_3097 step 1
tert-butyl piperazine-1-carboxylate was reacted with
5-bromo-2-chloropyrimidine to be converted into tert-butyl
4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate.
Step 2: tert-butyl
4-(5-((cis)-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phe-
nyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate
[0333] K.sub.2CO.sub.3 (0.38 g, 2.8 mmol, 2.5 equiv.) was added to
the suspension of
CIS-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-1,3-diazas-
piro[4.5]decan-2-one (0.4 g, 1.12 mmol, 1 equiv.) (INT-799) and
tert-butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate (0.38
g, 1.12 mmol, 1 equiv.) in dioxane (25 mL) and the resulting
mixture was purged with nitrogen for 5 min Copper(I) iodide (0.21
g, 1.12 mmol, 1 equiv.) and trans-1,2-diaminocyclohexane (0.25 g,
2.24 mmol, 2 equiv.) were sequentially added, the reaction vessel
was sealed and the reaction mixture was stirred for 10 h at
130.degree. C. The reaction mixture was cooled down to RT and
diluted with EtOAc (20 mL) and aq. ammonia (10 mL). The organic
product was extracted with e EtOAc (2.times.50 mL). The combined
organic layer was washed with brine (50 mL), dried over anhydrous
Na.sub.2SO.sub.4 and concentrated under reduced pressure.
Purification of the residue by column chromatography on silica gel
(100-200 mesh) (60-70% EtOAc in petroleum ether) afforded 0.5 g
(72%) of tert-butyl
4-(5-((cis)-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phe-
nyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate
as an off white solid (TLC system: 1:1 EtOAc/pet ether, Rf:
0.3).
Step 3:
CIS-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-3-(-
2-(piperazin-1-yl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one
hydrochloride (SC_3100)
[0334] 4N HCl in dioxane (2 mL) was added to tert-butyl
4-(5-(cis-8-(dimethylamino)-1-(1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-
-1,3-diazaspiro[4.5]decan-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate
(0.15 g, 0.24 mmol). The resulting mixture was stirred at 0.degree.
C. for 6 h and then concentrated under reduced pressure to give a
pale yellow solid which was triturated with n-pentane and
lyophilized with water for 16 h to yield 0.14 g of
CIS-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-3-(2-(pipe-
razin-1-yl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one
hydrochloride (SC_3100) as a pale yellow solid. .sup.1H NMR
(DMSO-d6): .delta. 10.42 (br s, 1H), 9.34 (br s, 2H), 8.63 (s, 2H),
7.70-7.68 (m, 2H), 7.54-7.50 (m, 3H), 3.88-3.86 (m, 4H), 3.77 (m,
4H), 3.16-3.11 (m, 6H), 2.52-2.49 (m, 6H), 2.47 (m, 2H), 2.10-2.07
(m, 2H), 2.00-1.95 (t, 2H), 1.87-1.81 (m, 3H), 1.70-1.68 (m, 2H),
1.58 (m, 1H). Mass: m/z 520.3 (M+H).sup.+.
Synthesis of SC_3103:
CIS-1-(cyclobutyl-methyl)-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl)-
-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
##STR00142##
[0336] Cs.sub.2CO.sub.3 (2 g, 6.451 mmol) was added to an argon
purged solution of
CIS-1-(cyclobutylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]de-
can-2-one (INT-987) (1.1 g, 3.225 mmol, 1 equiv.), Xantphos (279
mg, 0.483 mmol, 0.15 equiv.), Pd.sub.2(dba).sub.3 (295 mg, 0.322
mmol, 0.1 equiv.) and 5-bromo-4-methyl-2-(trifluoromethyl)pyridine
(774 mg, 3.225 mmol, 1 equiv.) in 1,4-dioxane (55 mL). The mixture
was purged again with argon for 15 min. The reaction mixture was
stirred at 90.degree. C. for 18 h, then cooled down to RT, filtered
through Celite and washed with EtOAc (80 mL). The filtrate was
concentrated under reduced pressure. The resulting residue was
purified by flash chromatography (neutral alumina, 0-3% methanol in
DCM) to afford 0.6 g (37%) of
CIS-1-(cyclobutylmethyl)-8-(dimethylamino)-3-(4-methyl-6-(trifluoromethyl-
)pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_3103) as
an off white solid. (TLC system: 5% MeOH in DCM; Rf: 0.5). .sup.1H
NMR (DMSO-d6): .delta. 8.56 (s, 1H), 7.80 (s, 1H), 7.34-7.24 (m,
5H), 3.71 (s, 2H), 3.17 (d, 2H), 2.70-2.56 (m, 3H), 2.31 (s, 3H),
2.17-2.11 (m, 2H), 2.03-2.00 (m, 8H), 1.82-1.73 (m, 4H), 1.54-1.41
(m, 4H). Mass: m/z 501.3 (M+H).sup.+.
Synthesis of SC_3105:
CIS-1-(cyclopropyl-methyl)-8-dimethylamino-3-(4-methylsulfonyl-phenyl)-8--
phenyl-1,3-diazaspiro[4.5]decan-2-one
##STR00143##
[0338] NaH (60% in mineral oil) (36.80 mg, 0.92 mmol) was added
portionwise to the solution of
CIS-8-(dimethylamino)-3-(4-(methylsulfonyl)phenyl)-8-phenyl-1,3-diazaspir-
o[4.5]decan-2-one (200 mg, 0.46 mmol, prepared from INT-976 and
1-bromo-4-(methylsulfonyl)benzene by analogy with SC_3103) in DMF
(30 mL) at 0.degree. C. under argon atmosphere and the resulting
mixture was stirred for 10 min. (Bromomethyl)cyclopropane (122 mg,
0.92 mmol) was added dropwise at 0.degree. C., ice bath was removed
and the reaction mixture was further stirred for 4 h at room
temperature. The reaction progress was monitored by TLC. The
reaction mixture was diluted with water (30 mL) and the
precipitated solid was filtered. Purification by column
chromatography (silica gel 100-200 mesh, 50-60% ethyl acetate in
hexane as eluent) to get 80 mg (35%) of
CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-3-(4-(methylsulfonyl)phenyl)--
8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_3105) as off white
solid (TLC system: 10% MeOH in DCM; Rf: 0.70). 1H NMR (CDCl3):
.delta. 7.85-7.83 (d, 2H), 7.73-7.71 (d, 2H), 7.39-7.36 (m, 2H),
7.32-7.27 (m, 3H), 3.64 (s, 2H), 3.20 (d, 2H), 3.00 (s, 3H),
2.75-2.71 (m, 2H), 2.43-2.36 (m, 2H), 2.07 (s, 6H), 1.57 (m, 2H),
1.50 (m, 2H), 1.11-1.06 (m, 1H), 0.59-0.54 (m, 2H), 0.41-0.37 (m,
2H). Mass: m/z 482.2 (M+H).sup.+.
Synthesis of SC_3109:
CIS-2-[8-Dimethylamino-1-[2-(1-methoxy-cyclobutyl)-ethyl]-2-oxo-8-phenyl--
1,3-diazaspiro[4.5]decan-3-yl]-benzamide
##STR00144##
[0339] Step 1:
CIS-2-(8-(dimethylamino)-1-(2-(1-methoxycyclobutyl)ethyl)-2-oxo-8-phenyl--
1,3-diazaspiro[4.5]decan-3-yl)benzonitrile
[0340] In analogy to the method described for SC_3103
CIS-8-(dimethylamino)-1-(2-(1-methoxycyclobutyl)ethyl)-8-phenyl-1,3-diaza-
spiro[4.5]decan-2-one was reacted with 2-bromobenzonitrile to be
converted into
CIS-2-(8-(dimethylamino)-1-(2-(1-methoxycyclobutyl)ethyl)-2-oxo-8-ph-
enyl-1,3-diazaspiro[4.5]decan-3-yl)benzonitrile
Step 2:
CIS-2-[8-Dimethylamino-1-[2-(1-methoxy-cyclobutyl)-ethyl]-2-oxo-8--
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide SC_3109
[0341]
CIS-2-[8-(dimethylamino)-1-[2-(1-methoxycyclobutyl)ethyl]-2-oxo-8-p-
henyl-1,3-diazaspiro[4.5]decan-3-yl]benzonitrile (57.0 mg, 1.0
equiv.) was dissolved in DMSO (1.6 mL), hydrogen peroxide (0.167
mL, 14.0 equiv., 30 mass % in water solution) and K.sub.2CO.sub.3
(32.4 mg, 2.0 equiv.) were added and the reaction mixture was
stirred at RT for 18 h. The reaction mixture was then quenched with
10 mL water, extracted with DCM (3.times.10 mL), the combined
organic extracts were dried over Na.sub.2SO.sub.4 and concentrated
under reduced pressure (24 mg crude product). The aqueous phase was
concentrated to dryness (91 mg), suspended in DCM, the precipitate
was filtered off and the organic solution was concentrated under
reduced pressure to give additional 56 mg of the crude product. The
combined crude product was purified by column chromatography on
silica gel (DCM/EtOH 95/5) to give 37 mg (62%) of
CIS-2-[8-dimethylamino-1-[2-(1-methoxy-cyclobutyl)-ethyl]-2-oxo-8-phenyl--
1,3-diazaspiro[4.5]decan-3-yl]-benzamide (SC_3109) as a white
solid. .sup.1H NMR (600 MHz, DMSO) .delta. 7.52-7.48 (s, 1H),
7.47-7.31 (m, 7H), 7.29-7.23 (m, 1H), 7.25-7.22 (s, 1H), 7.24-7.18
(m, 1H), 3.68-3.65 (s, 3H), 3.13-3.10 (s, 2H), 3.09-3.02 (m, 2H),
2.71-2.65 (m, 2H), 2.21-2.12 (m, 2H), 2.09-1.99 (m, 2H), 2.02-1.98
(s, 6H), 1.97-1.86 (m, 4H), 1.77-1.67 (m, 1H), 1.64-1.52 (m, 3H),
1.44-1.36 (td, 2H). Mass: m/z 505.32 (M+H).sup.+.
Synthesis of SC_3112:
CIS-2-(1-((1-hydroxycyclobutyl)methyl)-8-(methylamino)-2-oxo-8-phenyl-1,3-
-diazaspiro[4.5]decan-3-yl)benzonitrile
##STR00145##
[0342] Step 1:
CIS-2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)ben-
zonitrile
[0343] In analogy to the method described for SC_3103
1-bromo-2-cyanobenzene was reacted with
CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
(INT-976) to be converted into
CIS-2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)ben-
zonitrile
Step 2:
CIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-p-
henyl-1,3-diazaspiro[4.5]decan-3-yl)benzonitrile
[0344] To a solution of
CIS-2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)ben-
zonitrile (500 mg, 1.336 mmol, 1.0 equiv.) in DMSO (16 ml) was
added sodium hydroxide (213 mg, 5.334 mmol, 4.0 equiv.) and the
mixture was stirred at 60.degree. C. for 30 min A solution of
1-oxa-spiro[2.3]hexane (237 mg, 6.68 mmol, 5.0 equiv.) in DMSO (4
ml) was added at RT and the reaction mixture was stirred at
55.degree. C. for 16 h. The reaction mixture was diluted with water
(100 ml) and extracted with EtOAc (100 ml). The organic layer was
washed with water (50 ml) and brine (50 ml), dried over anhydrous
Na.sub.2SO.sub.4 and concentrated under reduced pressure. The
residue was purified by column chromatography on silica gel
(EtOAc/Hexane, 7/3) to yield
CIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1-
,3-diazaspiro[4.5]decan-3-yl)benzonitrile (200 mg, 0.436 mmol, 32%)
as an off white solid. Mass: m/z 459.4 (M+H).sup.+
Step 3:
CIS-2-(1-((1-hydroxycyclobutyl)methyl)-8-(methylamino)-2-oxo-8-phe-
nyl-1,3-diazaspiro[4.5]decan-3-yl)benzonitrile (SC_3112)
[0345] In analogy to the method described for SC_3099
CIS-2-(8-(dimethylamino)-1-(1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,-
3-diazaspiro[4.5]decan-3-yl)benzonitrile was reacted with
N-iodosuccinimide to be converted into
CIS-2-(1-(1-hydroxycyclobutyl)methyl)-8-(methylamino)-2-oxo-8-phenyl-1,3--
diazaspiro[4.5]decan-3-yl)benzonitrile (SC_3112). Yield: 29%.
.sup.1H NMR (DMSO-d6, 400 MHz), .delta. (ppm)=7.75 (dd, 1H, J=7.76
Hz, 1.16 Hz), 7.70-7.65 (m, 1H), 7.50 (d, 1H, J=8.16 Hz), 7.44-7.42
(m, 2H), 7.35-7.25 (m, 3H), 7.17-7.15 (m, 1H), 5.49 (s, 1H), 3.85
(s, 2H), 3.32 (s, 2H), 2.29-2.23 (m, 2H), 2.12-2.23 (m, 2H), 1.87
(bs, 6H), 1.73-1.46 (m, 6H). Mass: m/z 445.26 (M+H).sup.+.
Synthesis of SC_3120:
CIS-8-(dimethylamino)-3-(2-(3-oxopiperazin-1-yl)pyrimidin-5-yl)-8-phenyl--
1,3-diazaspiro[4.5]decan-2-one
##STR00146##
[0347]
CIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diaza-
spiro[4.5]decan-2-one (INT-989) (100 mg, 0.259 mmol) was placed
into a reaction vial for microwave reactor (5 mL), the vial was
flushed with nitrogen, anhydrous n-butanol (50 equiv., 13.0 mmol,
1.2 mL), diisopropylethylamine (5 equiv., 1.30 mmol, 0.224 mL) and
piperazine-2-one (1.2 equiv., 0.311 mmol, 31 mg) were added, the
vial was sealed and the reaction mixture was stirred for 2.5 h at
140.degree. C. (conventional heating). The reaction mixture was
cooled down, transferred into a 1-neck flask and concentrated under
reduced pressure. The resulting residue (128 mg) was purified by
flash chromatography on aluminium oxide (neutral) (DCM/MeOH
gradient 100/0 to 97/3) to yield 65 mg (56%)
CIS-8-(dimethylamino)-3-(2-(3-oxopiperazin-1-yl)pyrimidin-5-yl)--
8-phenyl-1,3-diazaspiro-[4.5]decan-2-one (SC_3120). .sup.1H NMR
(600 MHz, DMSO) .delta. 8.60 (s, 2H), 8.01 (s, 1H), 7.46 (s, 1H),
7.43-7.30 (m, 4H), 7.27 (td, 1H), 4.09 (s, 2H), 3.91-3.75 (m, 2H),
3.62-3.40 (m, 2H), 3.30-3.09 (m, 2H), 2.61-2.51 (m, 2H), 2.44-2.25
(m, 2H), 1.97 (s, 6H), 1.93-1.80 (m, 2H), 1.55-1.41 (m, 2H). Mass:
m/z 437.27 (M+H).sup.+.
Synthesis of SC_3129:
CIS-3-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-
pyrimidin-2-yl)benzonitrile
##STR00147##
[0349]
CIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diaza-
spiro[4.5]decan-2-one (INT-989) (1 equiv., 0.47 mmol, 180 mg),
Pd(PPh.sub.3).sub.4 (0.1 equiv., 0,047 mmol, 54 mg) and
(3-cyanophenyl)boronic acid (1.5 equiv., 0.70 mmol, 103 mg) were
dissolved in degassed dry tetrahydrofurane (9.5 mL) and sodium
carbonate 1M aq. sol. (1.9 equiv., 0.89 mmol, 0.89 mL) was added.
The resulting clear reaction mixture was stirred overnight at
70.degree. C. Additional portion of Pd(PPh.sub.3).sub.4 (0.1
equiv., 0.047 mmol, 54 mg) was added and the reaction was stirred
further 12 h at 70.degree. C. The reaction mixture was diluted with
EtOAc (50 mL), stirred for 10 min, the precipitate was filtered off
and the filtrate was concentrated under reduced pressure. The
resulting residue (285 mg) was purified by flash chromatography on
silica gel (gradient DCM/MeOH, 100/0 to 80/20) to yield 130 mg
(62%) of
CIS-3-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-
pyrimidin-2-yl)benzonitrile (SC_3129). .sup.1H NMR (600 MHz, DMSO)
.delta. 9.13 (s, 2H), 8.60 (dp, 2H), 7.93 (dt, 1H), 7.88 (s, 1H),
7.72 (dd, 1H), 7.42-7.35 (m, 5H), 7.28 (d, 1H), 3.73 (s, 2H),
2.01-1.91 (m, 2H), 1.98 (s, 10H), 1.57-1.48 (m, 2H). Mass: m/z
453.24 (M+H).sup.+.
Synthesis of SC_3130:
CIS-8-(dimethylamino)-3-(2-(4-(methylsulfonyl)piperazin-1-yl)pyrimidin-5--
yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
##STR00148##
[0351]
CIS-8-(dimethylamino)-8-phenyl-3-(2-(piperazin-1-yl)pyrimidin-5-yl)-
-1,3-diazaspiro[4.5]decan-2-one (SC_3124) (100 mg, 0.23 mmol) was
dissolved in DCM (150 equiv., 34 mmol, 2.2 mL) under nitrogen
atmosphere. To the resulting solution 4-dimethylaminopyridine (0.05
equiv., 0.012 mmol, 1.4 mg) and diisopropylethylamine (3 equiv.,
0.67 mmol, 0.119 mL) were added and the mixture was cooled to
0.degree. C. Methansulfonylchloride (2 equiv., 0.46 mmol, 0.036 mL)
was added, ice bath was removed and the reaction mixture was
stirred for 2 h at RT. The reaction mixture was quenched with water
(5 mL), diluted with DCM (10 mL), the resulting brown suspension
was filtered through a glass filter, the filtrate transferred to a
separating funnel, the organic phase separated and the aqueous
phase extracted with DCM (2.times.10 mL). The combined organic
phases were dried over MgSO.sub.4 and concentrated under reduced
pressure. The resulting residue (81 mg) was purified by flash
chromatography on aluminium oxide (gradient DCM/EtOH 97/3 to 96/4)
to yield 51 mg (43%) of
CIS-8-(dimethylamino)-3-(2-(4-(methylsulfonyl)piperazin-1-yl)pyrimidin-5--
yl)-8-phenyl-1,3-diazaspiro-[4.5]decan-2-one (SC_3130). .sup.1H NMR
(600 MHz, DMSO) .delta. 8.59 (s, 2H), 7.46 (s, 1H), 7.39 (d, 1H),
7.37 (s, 3H), 7.28 (d, 1H), 3.79-3.74 (m, 4H), 3.54 (s, 2H),
3.18-3.13 (m, 4H), 2.87 (s, 3H), 2.43-2.32 (m, 2H), 1.97 (s, 6H),
1.92-1.87 (m, 2H), 1.51-1.41 (m, 2H). Mass: m/z 514.26
(M+H).sup.+.
Synthesis of SC_3132:
CIS-8-((cyclopropylmethyl)(methyl)amino)-8-phenyl-3-(2-(trifluoromethyl)p-
yrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one
##STR00149##
[0352] Step 1:
CIS-8-(methylamino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-di-
azaspiro[4.5]decan-2-one
[0353] In analogy to the method described for SC_3099
CIS-8-(dimethylamino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3--
diazaspiro[4.5]decan-2-one (SC_3245) was reacted with
N-iodosuccinimide to be converted into
CIS-8-(methylamino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-di-
azaspiro[4.5]decan-2-one.
Step 2:
CIS-1-(4-methoxybenzyl)-8-(methylamino)-8-phenyl-3-(2-(trifluorome-
thyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one
[0354] NaH (60% in mineral oil) (296.3 mg, 7.407 mmol, 1.5 equiv.)
was added portionwise to the solution
CIS-8-(methylamino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-di-
azaspiro[4.5]decan-2-one (2 g, 4.938 mmol, 1 equiv.) in DMF (20 mL)
at 0.degree. C. under argon atmosphere and the resulting mixture
was stirred for 10 min 1-(Bromomethyl)-4-methoxybenzene (1.092 g,
5.432 mmol, 1.1 equiv.) was added dropwise. The reaction mixture
was allowed to warm up to RT and stirred for 16 h. The reaction
progress was monitored by LCMS. The reaction mixture was diluted
with water (150 mL) and the organic product was extracted with
EtOAc (3.times.60 mL). The combined organic extracts were dried
over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced
pressure. The resulting residue was purified by flash
chromatography (silica gel 230-400 mesh; 0-4% MeOH/DCM) to afford 2
g (77%) of
CIS-1-(4-methoxybenzyl)-8-(methylamino)-8-phenyl-3-(2-(trifluoro-
methyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one as an off
white solid (TLC system 5% MeOH in DCM Rf: 0.55).
Step 3:
CIS-8-((cyclopropylmethyl)(methyl)amino)-1-(4-methoxybenzyl)-8-phe-
nyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one
[0355] (Bromomethyl)cyclopropane (0.461 mL, 4.762 mmol, 5 equiv.)
was added dropwise to a mixture of
CIS-1-(4-methoxybenzyl)-8-(methylamino)-8-phenyl-3-(2-(trifluoromethyl)py-
rimidin-5-yl)-1,3-diazaspiro-[4.5]decan-2-one (500 mg, 0.952 mmol,
1 equiv.) and K.sub.2CO.sub.3 (657 mg, 4.762 mmol, 5 equiv.) in
acetonitrile (20 mL) at RT under argon atmosphere. The reaction
vessel was sealed and the mixture was stirred at 95.degree. C. for
24 h. Reaction progress was monitored by LCMS. The reaction mixture
was diluted with water (50 mL) and the organic product was
extracted with EtOAc (2.times.50 mL). The combined organic extracts
were dried over anhydrous Na.sub.2SO.sub.4 and concentrated under
reduced pressure. The resulting residue was purified by flash
chromatography (silica gel 230-400 mesh; 0-40% EtOAc/petroleum
ether) to afford 220 mg (39%) of
CIS-8-((cyclopropylmethyl)(methyl)amino)-1-(4-methoxybenzyl)-8-phenyl-3-(-
2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one
as an off white solid (TLC 50% EtOAc in petroleum ether, Rf: 0.65)
and 230 mg of the unreacted starting material.
Step 4:
CIS-8-((cyclopropylmethyl)(methyl)amino)-8-phenyl-3-(2-(trifluorom-
ethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one (SC_3132)
[0356] TFA (4.2 mL) was added drop wise to a solution of
CIS-8-((cyclopropylmethyl)(methyl)amino)-1-(4-methoxybenzyl)-8-phenyl-3-(-
2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one
(210 mg, 0.363 mmol) in DCM (0.05 mL) at 0.degree. C. under argon
atmosphere. The reaction mixture was allowed to warm up to RT and
stirred for 16 h. The reaction progress was monitored by LCMS. The
excess of TFA was evaporated under reduced pressure and the
residual amount of TFA was removed as an azeotropic mixture with
DCM (2.times.5 mL). The crude product was purified by preparative
HPLC to yield 105 mg (63%) of
CIS-8-((cyclopropylmethyl)(methyl)amino)-8-phenyl-3-(2-(trifluoromethyl)p-
yrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one (SC_3132) as an off
white solid (TLC system 50% EtOAc in pe ether, Rf: 0.35). .sup.1H
NMR (DMSO-d6): .delta. 9.17 (s, 2H), 8.10 (br s, 1H), 7.35-7.33 (m,
4H), 7.25-7.22 (m, 1H), 3.72 (s, 2H), 2.43 (m, 2H), 2.13 (s, 3H),
1.97-1.82 (m, 6H), 1.49 (m, 2H), 0.75-0.71 (m, 1H), 0.41-0.39 (m,
2H), 0.06--0.01 (m, 2H). Mass: m/z=460.2 (M+H).
Synthesis of SC_3133:
CIS-8-Dimethylamino-3-[2-(4-methyl-piperazine-1-carbonyl)-pyrimidin-5-yl]-
-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
##STR00150##
[0358] 1-Methylpiperazine (2 equiv., 0.5 mmol, 55 .mu.L) and
[5-[8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]pyrimi-
dine-2-carbonyl]oxylithium (INT-990) (100 mg, 0.25 mmol) were
suspended in DCM (1.6 mL), triethylamine (10 equiv., 2.5 mmol, 336
.mu.L) and propylphosphonic anhydride (>50 wt. % solution in
ethyl acetate) (2 equiv., 0.5 mmol, 297 .mu.L) were sequentially
added and the reaction mixture was stirred at RT for 2 h. The
resulting mixture was quenched with 2M aq. NaOH (2 mL), organic
phase was separated and aqueous phase was extracted with
dichloromethane (3.times.10 mL). The combined organic extracts were
dried over Na.sub.2SO.sub.4 and concentrated under reduced
pressure. The residue (88 mg) was dissolved in 3 mL DCM and 6 mL
pentane were slowly added. The resulting mixture was stirred for 30
min. The precipitate was filtered off and dried under reduced
pressure to give 69 mg (58%) of
CIS-8-dimethylamino-3-[2-(4-methyl-piperazine-1-carbonyl)-pyrimidin-5-yl]-
-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_3133). .sup.1H NMR
(600 MHz, DMSO) .delta. 9.03 (s, 2H), 7.87 (s, 1H), 7.42-7.34 (m,
5H), 7.28 (d, 1H), 3.69 (s, 2H), 3.62 (dd, 2H), 3.17-3.12 (m, 2H),
2.57-2.51 (m, 2H), 2.36 (t, 2H), 2.25-2.21 (m, 2H), 2.21 (s, 3H),
1.98-1.89 (m, 2H), 1.96 (s, 6H), 1.56-1.46 (m, 2H). Mass: m/z
478.29 (M+H).sup.+.
Synthesis of SC_3146:
CIS-5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyr-
imidine-2-carboxamide
##STR00151##
[0360] Methyl
CIS-5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyr-
imidine-2-carboxylate (INT-990) (100 mg, 0.244 mmol) was dissolved
in 7N NH.sub.3 in methanol (25 equiv. NH.sub.3, 0.9 mL) in a
microwave reactor vial. The reaction vessel was sealed, the
reaction mixture was stirred for 5 days at RT and then concentrated
under reduced pressure. The residue was purified by flash
chromatography on neutral aluminum oxide (DCM/EtOH, gradient 90/10
to 74/26) to yield 38 mg (39%) of
CIS-5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyr-
imidine-2-carboxamide (SC_3140). .sup.1H NMR (600 MHz, DMSO)
.delta. 9.07 (s, 2H), 8.02 (d, 1H), 7.93 (s, 1H), 7.59-7.55 (m,
1H), 7.38 (d, 4H), 7.28 (ddd, 1H), 3.72 (s, 2H), 2.49-2.37 (m, 2H),
1.99-1.92 (m, 8H), 1.88-1.75 (m, 2H), 1.56-1.45 (m, 2H). Mass: m/z
395.22 (M+H).sup.+.
Synthesis of SC_3146: methyl
CIS-2-(4-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3--
yl)pyrimidin-2-yl)piperazin-1-yl)acetate
##STR00152##
[0362]
CIS-8-(dimethylamino)-8-phenyl-3-(2-(piperazin-1-yl)pyrimidin-5-yl)-
-1,3-diazaspiro[4.5]decan-2-one (SC_3124) (200 mg, 0.46 mmol) was
dissolved in dry acetonitrile (5 mL) under nitrogen atmosphere,
K.sub.2CO.sub.3 (1.2 equiv., 0.55 mmol, 76 mg) and
methyl-2-chloroacetate (1.5 equiv., 0.69 mmol, 0.06 mL) were
sequentially added and the reaction mixture was stirred at reflux
for 5 h. A new portion of methyl-2-chloroacetate (1.5 equiv., 0.69
mmol, 0.06 mL) was added and the reaction mixture was stirred at
reflux overnight. The reaction mixture was concentrated under
reduced pressure. The residue was suspended in DCM, the precipitate
was filtered off and washed with DCM. The combined filtrate was
concentrated under reduced pressure to give 106 mg of crude
product. Flash chromatography on silica gel (eluent DCM/EtOH
gradient 98/2 to 96/4) yielded 168 mg (72%) of methyl
CIS-2-(4-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3--
yl)pyrimidin-2-yl)piperazin-1-yl)acetate (SC_3146). .sup.1H NMR
(600 MHz, DMSO) .delta. 8.54 (s, 2H), 7.42 (s, 1H), 7.37 (m, 4H),
7.27 (m, 1H), 3.63 (t, 7H), 3.52 (s, 2H), 3.27 (s, 2H), 2.54 (t,
4H), 2.45-2.30 (m, 2H), 1.96 (s, 6H), 1.93-1.83 (m, 4H), 1.52-1.42
(m, 2H). Mass: m/z 508.4 (M+H).sup.+.
Synthesis of SC_3162:
CIS-8-(dimethylamino)-8-phenyl-3-(2-(pyridin-2-yl)pyrimidin-5-yl)-1,3-dia-
zaspiro[4.5]decan-2-one
##STR00153##
[0364]
CIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diaza-
spiro[4.5]decan-2-one (INT-989) (200 mg, 0.52 mmol),
tributyl(2-pyridyl)stannane (1.5 equiv., 0.78 mmol, 286 mg) and
Pd(PPh.sub.3).sub.4 (0.1 equiv., 0.052 mmol, 60 mg) were dissolved
in degassed anhydrous DMF (150 equiv., 77.7 mmol, 6 mL) under
nitrogen atmosphere. Cesium fluoride (2.2 equiv., 1.14 mmol, 173
mg) was added and the reaction mixture was stirred at 90.degree. C.
overnight. The resulting suspension was cooled down to RT, diluted
with water (10 mL), extracted with ethylacetate (30 mL), then DCM
(30 mL), the DCM phase was dried over MgSO.sub.4 and concentrated
under reduced pressure to give 320 mg of crude product. Flash
chromatography on silica gel (eluent DCM/0.1N NH.sub.3 in MeOH,
gradient 95/5 to 70/30) yielded 72 mg (33%) of
CIS-8-(dimethylamino)-8-phenyl-3-(2-(pyridin-2-yl)pyrimidin-5-yl)-1,3-dia-
zaspiro[4.5]decan-2-one (SC_3162). .sup.1H NMR (600 MHz, DMSO)
.delta. 9.13 (s, 2H), 8.71-8.67 (m, 1H), 8.30 (d, 1H), 7.92 (td,
1H), 7.86 (s, 1H), 7.46 (dd, 1H), 7.43-7.35 (m, 5H), 7.31-7.25 (m,
1H), 3.73 (s, 2H), 2.48-2.33 (m, 2H), 2.00-1.78 (m, 10H), 1.57-1.47
(m, 2H). Mass: m/z 429.2 (M+H).sup.+.
Synthesis of SC_3169:
CIS-2-(2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-
phenoxy)acetic acid
##STR00154##
[0365] Step 1:
CIS-2-(2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-
phenoxy)acetonitrile
[0366] In analogy to the method described for SC_3103
CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
(INT-976) was reacted with 2-(2-bromophenoxy)acetonitrile to be
converted into
CIS-2-(2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-
phenoxy)acetonitrile.
Step 2:
CIS-2-(2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]deca-
n-3-yl)phenoxy)acetic acid (SC_3169)
[0367]
CIS-2-(2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-
-3-yl)phenoxy)acetonitrile (134 mg, 0.331 mmol) was dissolved in
conc. aq. HCl (1.4 mL, 50 equiv.). The reaction mixture was heated
to 100.degree. C. for 2 h and cooled down to RT. The precipitate
was filtered off, washed with water (2.times.) and dried under
reduced pressure to give 31 mg (22%) of
CIS-2-(2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-
phenoxy)acetic acid (SC_3169). .sup.1H NMR (600 MHz, DMSO) .delta.
7.75-7.71 (m, 1H), 7.59-7.48 (m, 4H), 7.27 (dd, 1H), 7.15 (ddd,
1H), 6.97-6.90 (m, 2H), 4.65 (s, 2H), 3.43 (s, 2H), 2.70 (d, 2H),
2.56 (s, 6H), 2.31 (t, 2H), 1.93-1.86 (m, 2H), 1.33-1.22 (m, 2H).
Mass: m/z 424.2 (M+H).sup.+.
Synthesis of SC_3173:
CIS-8-(dimethylamino)-8-phenyl-3-(2-(piperazine-1-carbonyl)pyrimidin-5-yl-
)-1,3-diazaspiro[4.5]decan-2-one
##STR00155##
[0368] Step 1: CIS-tert-butyl
4-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyri-
midine-2-carbonyl)piperazine-1-carboxylate
[0369] In analogy to the method described for SC_3133 lithium
CIS-5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyr-
imidine-2-carboxylate (INT-990) was reacted with
1-(tert-butoxycarbonyl)piperazine to be converted into
CIS-tert-butyl
4-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyri-
midine-2-carbonyl)piperazine-1-carboxylate.
Step 2:
CIS-8-(dimethylamino)-8-phenyl-3-(2-(piperazine-1-carbonyl)pyrimid-
in-5-yl)-1,3-diazaspiro[4.5]decan-2-one (SC_3173)
[0370] CIS-tert-butyl
4-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyri-
midine-2-carbonyl)piperazine-1-carboxylate (230 mg, 0.41 mmol) was
dissolved in TFA (2.2 mL, 28.6 mmol, 70 equiv.). The reaction
mixture was stirred at RT for 2.5 h and then concentrated under
reduced pressure. The residue was dissolved in DCM and aq. sat
Na.sub.2CO.sub.3 was added (until pH 10). The organic phase was
separated and the aq. phase was extracted with DCM (2.times.). The
combined organic extracts were dried over MgSO.sub.4 and
concentrated under reduced pressure. Recrystallization of the
residue from DCM/pentane gave 105 mg (56%) of
CIS-8-(dimethylamino)-8-phenyl-3-(2-(piperazine-1-carbonyl)pyrimidin-5-yl-
)-1,3-diazaspiro[4.5]decan-2-one (SC_3173). .sup.1H NMR (600 MHz,
DMSO) .delta. 9.04 (s, 2H), 7.89 (s, 1H), 7.42-7.32 (m, 4H),
7.31-7.26 (m, 1H), 3.69 (s, 2H), 3.65 (t, 2H), 3.21 (t, 2H), 2.90
(t, 2H), 2.79-2.74 (m, 2H), 2.43 (s, 2H), 1.98 (s, 9H), 1.89-1.75
(m, 1H), 1.53-1.47 (m, 2H). Mass: m/z 464.3 (M+H).sup.+.
Synthesis of SC_3182:
CIS-8-(dimethylamino)-3-(2-(4-hydroxypiperidin-1-yl)pyrimidin-5-yl)-8-phe-
nyl-1,3-diazaspiro[4.5]decan-2-one
##STR00156##
[0372] Et.sub.3N (0.39 g, 3.89 mmol) was added to the solution of
CIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[-
4.5]decan-2-one (INT-989) (0.5 g, 1.29 mmol) and piperidin-4-ol
(0.32 g, 3.24 mmol) in DMF (10 mL) at RT. The reaction mixture was
stirred at 130.degree. C. for 16 h, cooled down to RT and
concentrated under reduced pressure. The residue was diluted with
10% aq. NaOH and the organic product was extracted with 1/9 v/v
MeOH/DCM. The combined organic layer was dried over anhydrous
Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was
purified by preparative TLC using 10% MeOH/DCM as eluent to afford
130 mg of
CIS-8-(dimethylamino)-3-(2-(4-hydroxypiperidin-1-yl)pyrimidin-5-yl)-8-phe-
nyl-1,3-diazaspiro[4.5]decan-2-one (SC_3182) as an off-white solid
(TLC system: 10% MeOH in DCM; Rf: 0.1). .sup.1H NMR (DMSO-d6):
.delta. 8.50 (s, 2H), 7.39-7.26 (m, 6H), 4.68 (d, 1H), 4.19-4.16
(m, 2H), 3.69-3.67 (m, 1H), 3.51 (s, 2H), 3.14 (t, 2H), 2.33 (m,
2H), 1.94-1.71 (m, 12H), 1.45 (m, 2H), 1.30-1.23 (m, 2H). Mass: m/z
451.2 (M+H).sup.+.
Synthesis of SC_3186:
CIS-8-(dimethylamino)-3-(3-methylpyridin-2-yl)-8-phenyl-1,3-diazaspiro[4.-
5]decan-2-one
##STR00157##
[0374] Compound was synthesized within a parallel array. An
argon-flushed dry reaction vessel equipped with a septum was loaded
with the solutions of INT-976 (0.1 M, 1 mL) and
1-bromo-2-methylbenzene (0.15 M, 1 mL) in dioxane. To the resulting
mixture Cs.sub.2CO.sub.3 (200 .mu.mol), XantPhos (10 .mu.mol) and
Pd.sub.2(dba).sub.3 (5 .mu.mol) were added. The reaction vessel was
flushed with argon once again, sealed and the reaction mixture was
shaken at 100.degree. C. overnight. The resulting mixture was
cooled down to RT and the solvent was removed under reduced
pressure. The residue was taken up in 3 mL dichloromethane and 3 mL
water, the organic phase was separated, the aqueous phase was
extracted with dichloromethane (2.times.3 mL). Combined organic
phases were concentrated under reduced pressure. The residue was
purified by HPLC to give
CIS-8-(dimethylamino)-3-(3-methylpyridin-2-yl)-8-phenyl-1,3-diazaspi-
ro[4.5]decan-2-one (SC_3186). Mass: m/z 363.2 (M+H).sup.+.
Synthesis of SC_3208:
CIS-4-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-
pyrimidin-2-yl)indolin-2-one
##STR00158##
[0376]
CIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diaza-
spiro[4.5]decan-2-one (INT-989) (150 mg, 0.38 mmol),
Pd(t-Bu.sub.3P).sub.2 (0.1 equiv., 0.02 mmol, 10 mg) and
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (2
equiv., 0.78 mmol, 201 mg) were dissolved in degassed anhydrous THF
(80 equiv., 31 mmol, 2.5 mL) and 1M aq. Na.sub.2CO.sub.3 (5.5
equiv., 2.14 mmol, 2.14 mL) was added. The resulting mixture was
stirred at 60.degree. C. for 8 h and then at RT overnight. The
reaction mixture was diluted with water until precipitation
occurred. The precipitate was filtered off, suspended in 30 mL DCM,
filtered off again, washed with pentane (5 mL) and dried under
reduced pressure to give 143 mg (76%) of
CIS-4-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-
pyrimidin-2-yl)indolin-2-one (SC_3208). .sup.1H NMR (600 MHz, DMSO)
.delta. 10.45 (s, 1H), 9.10 (s, 2H), 7.87 (d, 1H), 7.84-7.80 (m,
1H), 7.39 (d, 5H), 7.29 (dt, 2H), 6.91 (d, 1H), 3.82 (s, 2H), 3.72
(s, 2H), 2.41 (d, 2H), 2.03-1.74 (m, 9H), 1.60-1.44 (m, 3H). Mass:
m/z 484.26 (M+H).sup.+.
Synthesis of SC_3221:
CIS-8-(dimethylamino)-3-(2-((2-hydroxyethyl)amino)pyrimidin-5-yl)-8-pheny-
l-1,3-diazaspiro[4.5]decan-2-one
##STR00159##
[0377] Step 1:
CIS-8-(dimethylamino)-3-(2-((2-methoxyethyl)amino)pyrimidin-5-yl)-8-pheny-
l-1,3-diazaspiro[4.5]decan-2-one
[0378] In analogy to the method described for SC_3103
2-methoxyethanamine was reacted with
CIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[-
4.5]decan-2-one (INT-989) to be converted into
CIS-8-(dimethylamino)-3-(2-(2-methoxyethyl)amino)pyrimidin-5-yl)-8-phenyl-
-1,3-diazaspiro[4.5]decan-2-one.
Step 2:
CIS-8-(dimethylamino)-3-(2-((2-hydroxyethyl)amino)pyrimidin-5-yl)--
8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_3221)
[0379] BBr.sub.3 (1M in DCM) (2.2 mL, 2.22 mmol) was added to the
solution of
CIS-8-(dimethylamino)-3-(2-(2-methoxyethyl)amino)pyrimidin-5-yl)-8-phe-
nyl-1,3-diazaspiro[4.5]decan-2-one (0.55 g, 1.06 mmol) in DCM (20
mL) at -78.degree. C. over 15 min. The reaction mixture was stirred
at RT for 4 h, then quenched with water and concentrated under
reduced pressure. The residue was purified by preparative reverse
phase HPLC to afford 82 mg (19%) of
CIS-8-(dimethylamino)-3-(2-(2-hydroxyethyl)amino)pyrimidin-5-yl)-
-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_3221) (TLC system: 10%
MeOH in DCM (Ammonia atmosphere); Rf: 0.3). .sup.1H NMR (DMSO-d6):
.delta. 8.41 (s, 2H), 7.39-7.24 (m, 6H), 6.70 (t, 1H), 4.64 (br, s,
1H), 3.50-3.45 (m, 4H), 3.28-3.25 (m, 2H), 2.37 (br m, 2H),
1.94-1.86 (m, 10H), 1.45 (m, 2H). Mass: m/z 411.2 (M+H).sup.+
Synthesis of SC_3224:
CIS-3-(2-(1H-indazol-1-yl)pyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3--
diazaspiro[4.5]decan-2-one
##STR00160##
[0381] K.sub.2CO.sub.3 (0.53 g, 3.89 mmol) was added to the
solution of
CIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[-
4.5]decan-2-one (500 mg, 1.29 mmol) and 1H-indazole (306 mg, 2.59
mmol) in DMF (10 mL). The reaction mixture was stirred at
140.degree. C. for 48 h, cooled down to RT and concentrated under
reduced pressure. The residue was diluted with DCM (50 mL),
filtered through Celite and the filtrate was concentrated under
reduced pressure. The residue was purified by flash chromatography
using neutral alumina (0-10% MeOH/DCM) followed by reverse phase
HPLC to afford 77 mg (13%) of
CIS-3-(2-(1H-indazol-1-yl)pyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3--
diazaspiro[4.5]decan-2-one (SC_3224) as off-white solid (TLC
system: 10% MeOH in DCM; Rf: 0.6). .sup.1H NMR (DMSO-d6): .delta.
9.10 (s, 2H), 8.57-8.55 (d, 1H), 8.41 (s, 1H), 7.89-7.87 (d, 1H),
7.82 (br s, 1H), 7.57-7.53 (t, 1H), 7.39-7.28 (m, 6H), 3.72 (s,
2H), 2.45 (m, 2H), 1.98-1.93 (m, 10H), 1.52 (m, 2H). Mass: m/z
468.2 (M+H).sup.+.
Synthesis of SC_3235: CIS-methyl
2-(2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)phen-
oxy)acetate
##STR00161##
[0383]
CIS-2-(2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-
-3-yl)phenoxy)acetic acid (120 mg, 0.28 mmol) was dissolved in
methanol (1.4 mL, 125 equiv.) and thionyl chloride (4 equiv., 1.13
mmol, 83 .mu.L) was added dropwise. The reaction mixture was
stirred at RT overnight, diluted with aq. sat. NaHCO.sub.3 and
extracted with DCM (3.times.). The combined organic phases were
dried over MgSO.sub.4 and concentrated under reduced pressure. The
residue (112 mg) was purified by flash chromatography on silica get
(gradient DCM/MeOH 97/3 to 88/12) to give 92 mg (74%) of CIS-methyl
2-(2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)phen-
oxy)acetate (SC_3235). .sup.1H NMR (600 MHz, DMSO) .delta.
7.40-7.33 (m, 4H), 7.29 (dd, 1H), 7.28-7.24 (m, 1H), 7.13 (td, 1H),
6.99-6.91 (m, 2H), 4.76 (s, 2H), 3.67 (s, 3H), 3.55 (s, 2H),
2.45-2.26 (m, 2H), 2.07 (s, 2H), 1.98 (s, 6H), 1.94-1.75 (m, 4H),
1.52-1.45 (m, 2H). Mass: m/z 438.2 (M+H).sup.+.
Synthesis of SC_3238:
CIS-2-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-
pyrimidin-2-yl)benzonitrile
##STR00162##
[0385]
CIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diaza-
spiro[4.5]decan-2-one (INT-989) (240 mg, 0.56 mmol),
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex
with dichloromethane (0.05 equiv., 0.028 mmol, 23 mg) and
(2-cyanophenyl)boronic acid (1.125 equiv., 0.63 mmol, 92 mg) were
dissolved in degassed 1,2-dimethoxyethane (100 equiv., 56 mmol, 5.8
mL) and Cs.sub.2CO.sub.3 (3.3 equiv., 1.84 mmol, 600 mg) in water
(175 equiv., 98 mmol, 1.8 mL) was added. The resulting clear
reaction mixture was stirred 3 days at 60.degree. C. The reaction
mixture was diluted with water (15 mL) and extracted with EtOAc
(2.times.15 mL). Combined organic phases were dried over MgSO.sub.4
and concentrated under reduced pressure. The residue (355 mg) was
purified by flash chromatography on silica get (gradient DCM/MeOH
95/5 to 70/30) to give 60 mg of product, which was further purified
by HPLC to give 15.4 mg (6%) of
CIS-2-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-
pyrimidin-2-yl)benzonitrile (SC_3238). .sup.1H NMR (600 MHz, DMSO)
.delta. 9.17 (s, 2H), 8.27 (dd, 1H), 7.94 (dd, 1H), 7.81 (td, 1H),
7.65 (td, 1H), 7.42-7.35 (m, 5H), 7.28 (ddt, 1H), 3.75 (s, 2H),
2.49-2.34 (m, 1H), 2.00-1.76 (m, 11H), 1.55-1.51 (m, 2H). Mass: m/z
453.24 (M+H).sup.+.
Synthesis of SC_3239:
CIS-3-(2-aminopyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4-
.5]decan-2-one
##STR00163##
[0387] Microwave reactor vial was loaded with
CIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[-
4.5]decan-2-one (INT-989) (250 mg, 0.65 mmol), flushed with
nitrogen, 7N solution of NH.sub.3 in methanol (108 equiv., 70 mmol,
10 mL) and dioxane (37 equiv., 24 mmol, 2 mL) were added, the vial
was sealed and the reaction mixture was stirred at 115.degree. C.
for 12 h in the microwave reactor. The reaction mixture was then
cooled down to 4.degree. C. overnight. The precipitate formed was
filtered off, washed with DCM (small amount), water (2.times.),
ether (2.times.) and dried under reduced pressure to give 180 mg
(76%) of
CIS-3-(2-aminopyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4-
.5]decan-2-one (SC_3239) as an off-white solid. .sup.1H NMR (600
MHz, DMSO) .delta. 8.39 (s, 2H), 7.40-7.32 (m, 5H), 7.26 (tt, 1H),
6.25 (s, 2H), 3.51 (s, 2H), 2.37 (s, 2H), 2.07 (s, 2H), 1.96 (s,
6H), 1.94-1.68 (m, 4H), 1.47 (d, 2H). Mass: m/z 367.23
(M+H).sup.+.
Synthesis of SC_3240:
CIS-N-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-
pyrimidin-2-yl)cyclopropanecarboxamide
##STR00164##
[0389]
CIS-3-(2-aminopyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazas-
piro[4.5]decan-2-one (SC_3239) (50 mg, 0.14 mmol) and
4-dimethylaminopyridine (1.3 equiv., 0.18 mmol, 22 mg) were
dissolved in dry pyridine (200 equiv., 27 mmol, 2.2 mL) under
nitrogen atmosphere. Cyclopropancarbonyl chloride (1.3 equiv., 0.18
mmol, 16 .mu.L) was added in one portion and the reaction mixture
was stirred at RT for 3 h. Additional portion of
cyclopropancarbonyl chloride (3 equiv., 0.42 mmol, 37 .mu.L) was
added and the reaction mixture was stirred at 90.degree. C. for 1
h. The reaction mixture was diluted with water (5 mL) and aq. sat.
NaHCO.sub.3 (5 mL), extracted with DCM (3.times.10 mL), organic
phases were washed with brine, dried over Na.sub.2SO.sub.4 and the
solvent was removed under reduced pressure. The residue was
suspended thoroughly in 3 mL DCM, the precipitate was filtered off,
washed with ether and dried under reduced pressure to give 47 mg
(79%) of
CIS-N-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-
pyrimidin-2-yl)cyclopropanecarboxamide (SC_3240) as a white solid.
.sup.1H NMR (600 MHz, DMSO) .delta. 10.66 (s, 1H), 8.81 (s, 2H),
7.67 (s, 1H), 7.41-7.33 (m, 4H), 7.31-7.21 (m, 1H), 3.62 (s, 2H),
2.45-2.32 (m, 2H), 2.01 (td, 1H), 1.96 (s, 6H), 1.93-1.78 (m, 3H),
1.52-1.47 (m, 2H), 0.82-0.72 (m, 4H). Mass: m/z 435.3
(M+H).sup.+.
Synthesis of SC_3242:
CIS-8-(dimethylamino)-8-phenyl-3-(6-(piperazin-1-yl)pyridin-3-yl)-1,3-dia-
zaspiro[4.5]decan-2-one
##STR00165##
[0390] Step 1: 4-(5-bromopyrimidin-2-yl)piperazine
[0391] In analogy to the method described for SC_3097 step 1
5-bromo-2-chloro-pyridine was reacted with piperazine to be
converted into 4-(5-bromopyrimidin-2-yl)piperazine.
Step 2:
CIS-8-(dimethylamino)-8-phenyl-3-(6-(piperazin-1-yl)pyridin-3-yl)--
1,3-diazaspiro [4.5]decan-2-one (SC_3242)
[0392]
CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
(INT-976) (80 mg, 0.29 mmol), 4-(5-bromopyrimidin-2-yl)piperazine
(2 equiv., 0.56 mmol, 142 mg) and potassium phosphate (4 equiv.,
1.17 mmol, 248 mg) were suspended in N,N'-dimethylethylenediamine
(18 equiv., 5.27 mmol, 0.6 mL) under nitrogen atmosphere. The
reaction mixture was stirred at 80.degree. C. for 2 h, diluted with
water (10 mL) and extracted with DCM (3.times.15 mL). The combined
organic phases contained a precipitate which was filtered off,
washed with isopropanol and dried under reduced pressure to give 79
mg (62%) of
CIS-8-(dimethyl-amino)-8-phenyl-3-(6-(piperazin-1-yl)pyridin-3-yl)-1,3-di-
azaspiro[4.5]decan-2-one (SC_3242). .sup.1H NMR (600 MHz, DMSO)
.delta. 8.15 (d, 1H), 7.85 (dd, 1H), 7.41-7.33 (m, 4H), 7.32-7.23
(m, 2H), 6.74 (d, 1H), 3.51 (s, 2H), 3.30-3.25 (m, 4H), 2.78-2.73
(m, 4H), 2.43-2.31 (m, 2H), 1.96 (s, 6H), 1.93-1.79 (m, 4H),
1.50-1.42 (m, 2H). Mass: m/z 435.3 (M+H).sup.+.
Synthesis of SC_3275:
CIS-8-(ethylamino)-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-3-(2-(trifluo-
romethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one
##STR00166##
[0394]
CIS-8-amino-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-3-(2-(trifluor-
omethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one (70 mg, 0.15
mmol) was dissolved in anhydrous DCM (3.8 mL) under nitrogen
atmosphere. Acetic acid (0.1 equiv., 0.015 mmol, 0.8 .mu.L) and
acetaldehyde (1.1 equiv., 0.16 mmol, 9 .mu.L) were sequentially
added and the resulting mixture was stirred at RT for 1 h. Sodium
triacetoxyborohydride (2 equiv., 0.29 mmol, 62 mg) was added and
the reaction mixture was stirred at RT overnight and then at
50.degree. C. for 5 h. Additional amounts of acetaldehyde (1.1
equiv., 0.16 mmol, 9 .mu.L) and sodium triacetoxyborohydride (2
equiv., 0.29 mmol, 62 mg) were added and the reaction mixture was
stirred further 24 h at 50.degree. C. The resulting mixture was
cooled down to RT, quenched with aq. sat. NaHCO.sub.3 until pH
>7, diluted with water and extracted with DCM (3.times.). The
combined organic layers were dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure. The residue (70 mg) was
purified by flash chromatography on silica gel (DCM/EtOH gradient
99/1 to 95/5) to yield 43 mg (58%) of
CIS-8-(ethylamino)-1-(1-hydroxycyclobutyl)methyl)-8-phenyl-3-(2-(trifluor-
omethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one (SC_3275).
.sup.1H NMR (600 MHz, DMSO) .delta. 9.26 (s, 2H), 7.55-7.49 (m,
2H), 7.33 (t, 2H), 7.21 (d, 1H), 3.92 (s, 2H), 2.38 (td, 2H),
2.17-2.06 (m, 3H), 2.00-1.87 (m, 4H), 1.81 (td, 2H), 1.72-1.64 (m,
1H), 1.60-1.50 (m, 1H), 1.49-1.43 (m, 2H), 0.99 (t, 3H). Mass: m/z
504.3 (M+H).sup.+
Synthesis of SC_3292 and SC_3293: Enantiomer 1 and Enantiomer 2 of
CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-3-(2-(trifluor-
omethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one
##STR00167##
[0396] Cs.sub.2CO.sub.3 (0.85 g, 2.61 mmol) was added to an argon
purged solution of
CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro-
[4.5]decan-2-one (INT-1026) (0.3 g, 0.87 mmol), Xanthphos (45 mg,
0.087 mmol), Pd.sub.2(dba).sub.3 (80 mg, 0.087 mmol) and
5-bromo-2-(trifluoromethyl)pyrimidine (0.29 g, 1.30 mmol) in
1,4-dioxane (15 mL). The mixture was purged with argon for 5 min
and stirred at 90.degree. C. for 16 h. The reaction mixture was
cooled to RT, diluted with EtOAc (20 mL), filtered through Celite
and the filtrate was concentrated under reduced pressure. The crude
product was purified by flash chromatography (silica gel 230-400
mesh; 3% MeOH in DCM) to get the compound which was further
purified by reverse phase preparative HPLC to afford 0.1 g (23%) of
CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-3-(2-(trifluor-
omethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one (TLC system:
10% MeOH in DCM; Rf: 0.4) as a mixture of enantiomers. Reverse
phase preparative HPLC conditions: mobile phase: 10 mM ammonium
bicarbonate in H.sub.2O/acetonitrile; column: X-BRIDGE-C18
(150*19), 5 .mu.m; mobile phase gradient (min/% B): 0/30, 8/82,
8.1/100, 10/100, 10.1/30, 12/30; flow rate: 19 ml/min; diluent:
mobile phase+THF. Enantiomeric mixture of
CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-3-(2-(trifluor-
omethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one (100 mg) was
separated by chiral SFC to afford 35 mg of enantiomer 1 (SC-3292)
and 40 mg of enantiomer 2 (SC-3293) as off-white solids.
Preparative SFC conditions: column: Chiralpak IA (250.times.30) mm,
5 .mu.m; % CO.sub.2: 50.0%; % co-solvent: 50.0% (100% Methanol);
total flow: 70.0 g/min; back pressure: 100.0 bar; UV: 256 nm; stack
time: 13.5 min; load/inj.: 9.5 mg; no. of injections: 11. SC-3292:
.sup.1H NMR (DMSO-d6): .delta. 9.15 (s, 2H), 8.23 (broad s, 1H),
7.37-7.25 (m, 5H), 3.68-3.58 (m, 5H), 3.37-3.36 (m, 1H), 2.32 (m,
3H), 2.13-1.89 (m, 10H), 1.47 (m, 3H). SC-3293: .sup.1H NMR
(DMSO-d6): .delta. 9.15 (s, 2H), 8.23 (broad s, 1H), 7.37-7.36 (m,
4H), 7.26-7.24 (m, 1H), 3.68-3.56 (m, 5H), 3.37-3.36 (m, 1H),
2.31-2.28 (m, 3H), 2.13-1.86 (m, 10H), 1.48 (m, 3H). Mass: m/z
490.3 (M+H).sup.+.
Synthesis of SC_3313:
CIS-3-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)pyrimidin-5-yl)-8-(dimethyl-
amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
##STR00168##
[0397] Step 1:
5-bromo-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)pyrimidine
[0398] 2-Azido-5-bromo-pyrimidine (400 mg, 1.94 mmol) and
ethynylcyclopropane (1.3 equiv., 2.522 mmol, 0.21 mL) were
dissolved in tert-butanol (5 mL). The solutions of sodium ascorbate
(0.1 equiv., 0.194 mmol, 38 mg) in water (2.5 mL) and copper(II)
sulfate pentahydrate (0.1 equiv., 0.194 mmol, 48 mg) in water (2.5
mL) were sequentially added. The reaction mixture was stirred under
ambient conditions for 18 h, then diluted with 20 mL 1M aq.
NH.sub.4OH and extracted with EtOAc (3.times.30 mL). The combined
organic extracts were washed with brine, dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure. Crude
product (510 mg) was purified by flash chromatography on silica gel
(DCM/EtOH 99/1) to yield 143 mg of
5-bromo-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)pyrimidine as a
white solid. Mass: m/z 266.0 (M+H).sup.+.
Step 2:
CIS-3-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)pyrimidin-5-yl)-8-(d-
imethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_3313)
[0399] In analogy to the method described for SC_3103
CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
(INT-976) was reacted with
5-bromo-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)pyrimidine to be
converted into
CIS-3-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)pyrimidin-5-yl)-8-(dim-
ethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_3313).
.sup.1H NMR (600 MHz, DMSO) .delta. 9.09 (d, 2H), 8.50 (d, 1H),
7.91 (s, 1H), 7.42-7.34 (m, 2H), 7.38 (s, 3H), 7.31-7.25 (m, 1H),
3.72 (s, 2H), 2.48-2.31 (m, 2H), 2.10-2.01 (m, 1H), 1.99-1.77 (m,
10H), 1.58-1.46 (m, 2H), 1.00-0.91 (m, 2H), 0.84 (tt, 2H). Mass:
m/z 459.3 (M+H).sup.+.
Synthesis of SC_3319:
CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-3-(2-(trifluor-
omethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one
##STR00169##
[0401] Cs.sub.2CO.sub.3 (145 mg, 0.45 mmol, 2 equiv.),
CIS-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one
(INT-1024) (65 mg, 0.223 mmol, 1 equiv.), Xanthphos (19 mg, 0.033
mmol, 0.15 equiv.), Pd.sub.2(dba).sub.3 (10 mg, 0.011 mmol, 0.05
equiv.) and 5-bromo-1-methyl-3-(trifluoromethyl)pyrazole (102 mg,
0.446 mmol, 2 equiv.) were loaded into a microwave reactor vial
(2-5 mL), the vial was sealed and flushed with nitrogen (3.times.).
1,4-Dioxane (1.5 mL) was added via syringe and the reaction mixture
was stirred at 110.degree. C. in the microwave reactor for 10 h.
The resulting mixture was cooled down to RT, solution of Xanthphos
(19 mg, 0.033 mmol, 0.15 equiv.) and Pd.sub.2(dba).sub.3 (10 mg,
0.011 mmol, 0.05 equiv.) in 1,4 dioxane (1 mL) was added, and the
reaction mixture was stirred at 130.degree. C. in the microwave
reactor for further 10 h. The resulting suspension was cooled to
RT, quenched with water and extracted with DCM (3.times.). The
combined organic layer was dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure. The resulting residue was
purified by flash chromatography (gradient 0% to 16% MeOH in DCM)
to yield 41 mg (42%) of
CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-3-(2-(trifluor-
omethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one (SC_3319).
.sup.1H NMR (600 MHz, DMSO) .delta. 7.71 (s, 1H), 7.41 (q, 1H),
7.21-7.12 (m, 2H), 7.09 (td, 1H), 6.63 (s, 1H), 3.75 (s, 2H), 3.55
(s, 2H), 2.42-2.27 (m, 2H), 1.99-1.89 (m, 8H), 1.88-1.73 (m, 2H),
1.56-1.49 (m, 2H). Mass: m/z 440.2 (M+H).sup.+.
Synthesis of SC_3340:
CIS-2-(3-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-
pyridin-4-yl)acetamide
##STR00170##
[0402] Step 1:
CIS-2-(3-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-
pyridin-4-yl)acetonitrile
[0403] In analogy to the method described for SC_3097 step 2
CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
(INT-976) was reacted with (3-bromo-pyridin-4-yl)-acetonitrile to
be converted into
CIS-2-(3-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-
pyridin-4-yl)acetonitrile.
Step 2:
CIS-2-(3-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]deca-
n-3-yl)pyridin-4-yl)acetamide (SC_3340)
[0404] To a solution of
CIS-2-(3-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-
pyridin-4-yl)acetonitrile (600 mg, 1.54 mmol, 1.0 equiv.) in EtOH
(50 ml) was added NaOH (247 mg, 6.16 mmol, 4.0 equiv.). The
reaction mixture was stirred at reflux for 16 h and then
concentrated under reduced pressure. The resulting residue was
purified by column chromatography (neutral alumina; 4% MeOH in DCM)
and finally by preparative HPLC (column Gemini NX-C18
(50.times.4.6), 3 .mu.m, diluent: DMSO, mobile phase: gradient
0.05% HCOOH in water/ACN flow rate: 1 ml/min) to yield
CIS-2-(3-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-
pyridin-4-yl)acetamide (SC_3340) (40 mg, 0,098 mmol, 4% yield after
two steps) as an off white solid. .sup.1HNMR (DMSO, 400 MHz)
.delta. 8.40 (s, 1H), 8.32 (d, 1H, J=4.92 Hz), 7.49 (s, 1H),
7.36-7.24 (m, 7H), 6.99 (s, 1H), 3.49-3.46 (m, 4H), 2.32 (bs, 2H),
1.94-1.77 (m, 10H), 1.52 (bs, 2H). Mass: m/z 408.2 (M+H).sup.+.
Synthesis of SC_3352:
CIS-8-(dimethylamino)-3-(2-hydroxybenzo[d]oxazol-7-yl)-8-phenyl-1,3-diaza-
spiro[4.5]decan-2-one
##STR00171##
[0405] Step 1:
CIS-7-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3--
((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one
[0406] In analogy to the method described for SC_3103
CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
(INT-976) was reacted with
7-bromo-3-(2-trimethylsilanyl-ethoxymethyl)-3H-benzooxazol-2-one
(prepared from 7-bromobenzo[d]oxazol-2(3H)-one and
trimethylsilylethoxymethylchloride following a standart procedure)
to be converted into
CIS-7-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3--
((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one. Mass:
m/z 537.2 (M+H).sup.+.
Step 2:
CIS-8-(dimethylamino)-3-(2-hydroxybenzo[d]oxazol-7-yl)-8-phenyl-1,-
3-diazaspiro[4.5]decan-2-one (SC_3352)
[0407] To a solution of
CIS-7-[8-dimethylamino-2-oxo-8-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-
-1,3-diaza-spiro[4.5]dec-3-yl]-3H-benzooxazol-2-one (350 mg, 0.65
mmol, 1.0 eq) in 1,4-dioxane (2 mL) was added 4M HCl in dioxane (6
mL) dropwise at 0.degree. C. The reaction mixture was stirred at RT
for 48 h and then concentrated under reduced pressure. The residue
was taken in DCM (200 mL) and washed with sat. aq. NaHCO.sub.3 (100
mL). Organic layer was dried over Na.sub.2SO.sub.4 and concentrated
under reduced pressure to get the crude product which was purified
by column chromatography (neutral alumina; 2% MeOH/DCM) to yield
CIS-7-(8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-3H-be-
nzooxazol-2-one (SC_3352) (85 mg, 0.21 mmol, 32%) as an off white
solid. .sup.1HNMR (DMSO-d6, 400 MHz at 100.degree. C.), .delta.
(ppm)=11.19 (bs, 1H), 7.37-7.23 (m, 6H), 7.14 (s, 1H), 7.04 (t, 1H,
J=8.06), 6.76 (d, 1H, J=7.68 Hz), 3.69 (s, 2H), 2.38-2.26 (m, 2H),
2.08-1.76 (m, 10H), 1.56-1.51 (m, 2H). Mass: m/z 407.1
(M+H).sup.+.
Synthesis of SC_3354:
CIS-4-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-
pyrimidin-2-yl)benzamide trifluoroacetate salt
##STR00172##
[0409]
3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspir-
o[4.5]decan-2-one (INT 989) (200 mg, 0.52 mmol, 1 equiv.),
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (129 mg,
0.52 mmol, 1 equiv.), Pd.sub.2(dba).sub.3 (95 mg, 0.10 mmol, 0.2
equiv.), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl
(X-Phos) (99 mg, 0.21 mmol, 0.4 equiv.) were loaded into microwave
reactor vessel and flushed with nitrogen (2.times.). Anhydrous
1,4-dioxane (9 mL) and sodium carbonate (213 mg, 2.07 mmol, 4
equiv.) were sequentially added. The reaction mixture was stirred 8
h at 120.degree. C. in the microwave reactor and then concentrated
under reduced pressure. The residue was suspended in EtOAc/water
(1/1, v/v) and filtered through a glass filter. The solid residue
was dissolved in MeOH/DCM/TFA, filtered through Celite pad and the
filtrate was concentrated under reduced pressure to give 75 mg
(25%) of
CIS-4-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-
pyrimidin-2-yl)benzamide trifluoroacetate salt (SC_3354). .sup.1H
NMR (600 MHz, DMSO) .delta. 9.05 (s, 2H), 8.42 (s, 1H), 8.34 (d,
2H), 8.03 (s, 1H), 7.98 (d, 2H), 7.74-7.65 (m, 2H), 7.58 (t, 2H),
7.56-7.52 (m, 1H), 7.40 (s, 1H), 3.58 (s, 2H), 2.70 (d, 2H), 2.60
(s, 6H), 2.25 (t, 2H), 1.91 (d, 2H), 1.39 (t, 2H). Mass: m/z 471.3
(M+H).sup.+.
Synthesis of SC_3357:
CIS-8-(dimethylamino)-3-(1H-indol-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-
-2-one
##STR00173##
[0410] Step 1:
CIS-8-(dimethylamino)-8-phenyl-3-(1-tosyl-1H-indol-3-yl)-1,3-diazaspiro[4-
.5]decan-2-one
[0411] In analogy to the method described for SC_3103
CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
(INT-976) was reacted with 3-bromo-1-(toluene-4-sulfonyl)-1H-indole
to be converted into
CIS-8-(dimethylamino)-8-phenyl-3-(1-tosyl-1H-indol-3-yl)-1,3-diazasp-
iro[4.5]decan-2-one. Mass: m/z 543.1 (M+H).sup.+.
Step 2:
CIS-8-(dimethylamino)-3-(1H-indol-3-yl)-8-phenyl-1,3-diazaspiro[4.-
5]decan-2-one (SC_3357)
[0412] To a solution of
8-dimethylamino-8-phenyl-3-[1-(toluene-4-sulfonyl)-1H-indol-3-yl]-1,3-dia-
za-spiro[4.5]decan-2-one (275 mg, 0.51 mmol, 1.0 eq.) in EtOH (24
mL) was added 10N aq. NaOH (1.2 mL) at RT. The reaction mixture was
heated to reflux for 1.5 h, then concentrated, diluted with water
(50 mL) and extracted with EtOAc (150 mL). Organic layer was dried
over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The
residue was purified by column chromatography (neutral alumina; 2%
MeOH/DCM) to afford
CIS-8-dimethylamino-3-(1H-indol-3-yl)-8-phenyl-1,3-diaza-spiro[4.5-
]decan-2-one (SC_3357) (130 mg, 0.33 mmol, 65%) as light brown
solid. .sup.1H NMR (DMSO-d6, 400 MHz at 100.degree. C.), .delta.
(ppm)=10.55 (bs, 1H), 7.62-7.60 (d, 1H, J=7.96 Hz), 7.37-7.23 (m,
7H), 7.04 (t, 1H, J=7.48 Hz), 6.92 (t, 1H, J=7.44 Hz), 6.71 (bs,
1H), 3.61 (s, 2H), 2.38-2.33 (m, 2H), 2.04-1.82 (m, 10H), 1.59-1.54
(m, 2H). Mass: m/z 389.3 (M+H).sup.+.
Synthesis of SC_3379:
CIS-3-(1-acetyl-1H-indol-3-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[-
4.5]decan-2-one
##STR00174##
[0414] To a solution of
8-dimethylamino-3-(1H-indol-3-yl)-8-phenyl-1,3-diaza-spiro[4.5]decan-2-on-
e (SC_3357) (150 mg, 0.38 mmol, 1.0 eq.) in DCM (6 mL) were added
NaOH (39 mg, 0.96 mmol, 2.5 eq.) and Bu.sub.4NHSO.sub.4 (129 mg,
0.38 mmol, 1.0 eq.) at 0.degree. C. and the reaction mixture was
stirred for 30 min followed by addition of acetyl chloride (54
.mu.l, 0.76 mmol, 2.0 eq.). The reaction mixture was stirred at RT
for 16 h, then diluted with DCM (150 ml) and washed with water (50
mL) and brine (50 mL). Organic layer was dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure. The
residue was purified by column chromatography (neutral alumina; 1%
MeOH/DCM) followed by prep HPLC to afford
3-(1-acetyl-1H-indol-3-yl)-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]d-
ecan-2-one (SC_3379) as off white solid. Note: Two batches of same
reactions were done and yield was calculated accordingly. Yield:
13% (45 mg, 0.1 mmol). 1HNMR (DMSO-d6, 400 MHz at 100.degree. C.),
.delta. (ppm)=8.34-8.32 (d, 1H, J=7.88 Hz), 7.90 (d, 1H, J=7.36
Hz), 7.67 (s, 1H), 7.37-7.10 (m, 8H), 3.71 (s, 2H), 2.57 (s, 3H),
2.38-2.32 (m, 2H), 2.04-1.88 (m, 10H), 1.61-1.59 (m, 2H). Mass: m/z
431.2 (M+H).sup.+.
Synthesis of SC_3388:
CIS-8-(dimethylamino)-8-(3-hydroxyphenyl)-3-(4-methyl-6-(trifluoromethyl)-
pyridin-3-yl)-1,3-diazaspiro[4.5]decan-2-one
##STR00175##
[0416]
CIS-8-(dimethylamino)-8-(3-methoxyphenyl)-3-[4-methyl-6-(trifluorom-
ethyl)-3-pyridyl]-1,3-diazaspiro[4.5]decan-2-one (SC_3368) (42 mg,
0.091 mmol) was dissolved in DCM (2 mL) and the solution was cooled
to 0.degree. C. Boron tribromide (1M sol. in DCM, 4 equiv., 0.36
mmol, 0.36 mL) was added in one portion. The reaction mixture was
allowed to stir at RT overnight, then quenched with methanol and
diluted with water. The resulting mixture was extracted with DCM
(2.times.), the combined organic phases weres dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure. The
residue was purified by flash chromatography on silica gel (eluent
gradient DCM/EtOH) to yield 16 mg (39%) of
CIS-8-(dimethylamino)-8-(3-hydroxyphenyl)-3-(4-methyl-6-(trifluoromethyl)-
pyridin-3-yl)-1,3-diazaspiro[4.5]decan-2-one (SC_3388). .sup.1H NMR
(600 MHz, DMSO) .delta. 8.57 (s, 1H), 7.80 (s, 1H), 7.52 (s, 1H),
7.14 (t, 1H), 6.77 (d, 1H), 6.74 (s, 1H), 6.66 (dd, 1H), 3.61 (s,
2H), 2.32 (s, 3H), 2.31-2.19 (m, 2H), 2.01-1.89 (m, 8H), 1.88-1.70
(m, 2H), 1.54 (t, 2H). Mass: m/z 449.2 (M+H).sup.+.
Synthesis of SC_3396:
CIS-4-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)ind-
olin-2-one
##STR00176##
[0417] Step 1:
CIS-4-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-1--
(4-methoxybenzyl)indoline-2,3-dione
[0418] In analogy to the method described for SC_3242
CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
(INT-976) was reacted with
4-bromo-1-(4-methoxy-benzyl)-1H-indole-2,3-dione to be converted
into
CIS-4-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-1--
(4-methoxybenzyl)indoline-2,3-dione. Mass: m/z 539.2
(M+H).sup.+.
Step 2:
CIS-4-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-
-yl)-1-(4-methoxybenzyl)indolin-2-one
[0419] To a solution of
CIS-4-(8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-1-(4--
methoxy-benzyl)-1H-indole-2,3-dione (600 mg, 1.11 mmol, 1.0 eq) in
EtOH (9 mL) was added hydrazine hydrate (9 mL) at RT. The reaction
mixture was stirred at reflux for 16 h, then concentrated, diluted
with water (50 mL) and extracted with EtOAc (200 mL). Organic layer
was dried over Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure. The resulting residue was purified by column
chromatography (neutral alumina, 0.5% MeOH/DCM) to afford
8-dimethylamino-3-[1-(4-methoxy-benzyl)-2-oxo-2,3-dihydro-1H-indol-4-yl]--
8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (275 mg, 0.52 mmol, 47%)
as a brown solid. Mass: m/z 525.2 (M+H).sup.+.
Step 3:
CIS-4-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-
-yl)indolin-2-one (SC_3396)
[0420] A solution of
CIS-8-dimethylamino-3-[1-(4-methoxy-benzyl)-2-oxo-2,3-dihydro-1H-indol-4--
yl]-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (275 mg, 0.52 mmol,
1.0 eq.) in TFA (4 mL) was stirred at 90.degree. C. in a sealed
tube for 16 h. The reaction mixture was cooled to RT, concentrated
under reduced pressure, diluted with water (50 mL), basified with
sat. aq. NaHCO.sub.3 and extracted with EtOAc (200 mL). The organic
phase was washed with brine (50 mL), dried over Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure. The resulting
residue was purified by column chromatography (neutral alumina, 5%
MeOH in DCM) to afford
CIS-8-dimethylamino-3-(2-oxo-2,3-dihydro-1H-indol-4-yl)-8-phenyl-1,3-diaz-
a-spiro[4.5]decan-2-one (SC_3396) (60 mg, 0.14 mmol, 28%) as an
off-white solid. .sup.1H NMR (DMSO-d6, 400 MHz, 100.degree. C.):
.delta. (ppm)=9.98 (bs, 1H), 7.36-7.22 (m, 5H), 7.09 (t, 1H, J=7.94
Hz), 6.95-6.88 (m, 2H), 6.59 (d, 1H, J=7.52 Hz), 3.57 (s, 2H), 3.49
(s, 2H), 2.36-2.31 (m, 2H), 2.03 (s, 6H), 1.97-1.85 (m, 4H),
1.55-1.51 (m, 2H). Mass: m/z 405.3 (M+H).sup.+.
[0421] The following compounds were prepared in analogy and by
combining previously described methods:
TABLE-US-00003 in analogy m/z Example Chemical Name Reactant I
Reactant II to method [M + H].sup.+ SC_3001
cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- INT-987
5-bromopyrimidine-2- SC-3022 445.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2- carbonitrile
carbonitrile SC_3002
cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- INT-987
5-bromopyrazine-2- SC-3022 445.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrazine-2-carbonitrile
carbonitrile SC_3003
cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- INT-987
5-bromo-4-
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-
methoxypyrimidine-2- SC-3022 475.3 2-carbonitrile carbonitrile
SC_3004 cis-5-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-
INT-980 5-bromopyrimidine-2- SC-3022 435.2
1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile
carbonitrile SC_3005
cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- SC_3001 --
SC_3016 463.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carboxylic acid
amide SC_3006 cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-
INT-987 5-bromo-2-(methylthio)- SC-3022 523.2
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2-methylsulfonyl-
pyrimidine-4-carbonitrile (step 1); pyrimidine-4-carbonitrile
SC_3008 (step 2) SC_3007
cis-5-[1-(2-Methoxy-ethyl)-8-methylamino-2-oxo-8-phenyl- SC_3004 --
SC_3045 421.2
1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3008
cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- INT-987
2-iodo-5- SC-3022 521.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-5-methylsulfonyl-
(methylthio)benzonitrile (step 1); benzonitrile (step 1) SC_3008
(step 2) SC_3009
cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- SC_3090 --
SC_3016 461.3 phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide
SC_3010 cis-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-
SC_3072 -- SC_3016 461.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide SC_3011
cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2- SC_3013
-- SC_3016 479.3
oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-
carboxylic acid amide SC_3012
cis-5-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl- SC_3003
-- SC_3045 461.3
1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2- carbonitrile
SC_3013 cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-
INT-600 -- SC_3013 461.3
oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-
carbonitrile SC_3014
cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- INT-987
2-chloropyrimidine-5- SC_3014 445.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-5- carbonitrile
carbonitrile SC_3015
cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2- INT-976
5-bromo-2- SC_3013 466.3
methoxy-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-
methoxypyrimidine one (step 1); 1-(tert-butyldimethyl-
silyloxy)cyclobutyl)methyl 4-methylbenzene-sulfonate (step 2)
SC_3016 cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-
SC_3014 -- SC_3016 463.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carboxylic acid
amide SC_3017 cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-
SC_3081 methanamine SC_3028 475.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-benzamide SC_3018
cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1-propyl-1,3- INT-600
1-bromopropane SC_3013 419.2
diazaspiro[4.5]decan-3-yl)-pyrimidine-2-carbonitrile SC_3019
cis-5-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8- INT-600
1-bromo-3-methoxypropane SC-3013 449.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2- carbonitrile
SC_3020 cis-5-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-
INT-600 (bromomethyl)cyclopropane SC-3013 431.2
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2- carbonitrile
SC_3021 cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-
SC_3081 ammonia SC-3028 461.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide SC_3022
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-342- INT-987
5-bromo-2- SC_3022 488.3
(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-
(trifluoromethyl)pyrimidine one SC_3023
cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2- SC_3015
-- SC_3023 452.3
hydroxy-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2- one
SC_3024 cis-5-[8-Dimethylamino-1-(2-methyl-propyl)-2-oxo-8-phenyl-
INT-600 1-bromo-2-methylpropane SC_3013 433.3
1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3025
cis-5-[8-Dimethylamino-1-(2-hydroxy-ethyl)-2-oxo-8-phenyl- INT-600
(3-bromopropoxy)(tert- SC-3025 421.2
1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile
butyl)dimethylsilane SC_3026
cis-5-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl- SC_3078
-- SC_3045 444.3
1,3-diazaspiro[4.5]decan-3-yl]-4-methyl-pyridine-2- carbonitrile
SC_3027 cis-1-(Cyclobutyl-methyl)-3-(5-methoxy-pyrazin-2-yl)-8-
SC_3075 -- SC_3045 436.3
methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3028
cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- SC_3081 --
SC_3028 489.3 phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N,N-dimethyl-
benzamide SC_3029
cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- SC_3081 --
SC_3028 533.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-ethyl-N-(2-hydroxy-
ethyl)-benzamide SC_3030
cis-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl- SC_3008
-- SC_3045 507.2
1,3-diazaspiro[4.5]decan-3-yl]-5-methylsulfonyl-benzonitrile
SC_3031 cis-1-(Cyclobutyl-methyl)-8-methylamino-3-[2- SC_3084 --
SC_3031 550.2
methylsulfonyl-4-(trifluoromethyl)-phenyl]-8-phenyl-1,3-
diazaspiro[4.5]decan-2-one SC_3032
cis-4-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl- SC_3089
-- SC_3032 579.3 1,3-diazaspiro[4.5]decan-3-yl]-N,N-dimethyl-3-
(trifluoromethyl)-benzenesulfonic acid amide SC_3033
cis-4-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-
INT-797 4-bromobenzonitrile SC_3013 457.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile (step 1);
(bromomethyl)cyclobutane (step 2) SC_3034
cis-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-3-
INT-797 5-bromo-2- SC-3013 502.3
[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-
(trifluoromethyl)pyrimidine 2-one (step 1);
(bromomethyl)cyclobutane (step 2) SC_3035
cis-5-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-
INT-797 5-bromopyrimidine-2- SC_3013 459.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2- carbonitrile
(step 1); carbonitrile (bromomethyl)cyclobutane (step 2) SC_3036
cis-5-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2- INT-982
5-bromopyrimidine-2- SC_3022 459.3
oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-
carbonitrile carbonitrile SC_3037
cis-2-[3-(2-Cyano-pyrimidin-5-yl)-8-dimethylamino-2-oxo-8- INT-978
5-bromopyrimidine-2- SC_3065 462.3
phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N,N-dimethyl- carbonitrile
acetamide SC_3038
cis-1-(Cyclobutyl-methyl)-8-methylamino-8-phenyl-342- SC_3022 --
SC_3038 474.2
(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2- one
SC_3039 cis-5-[8-Dimethylamino-8-(3-fluorophenyl)-1-(4-methoxy-
INT-601 1-bromo-4-methoxybutane SC_3064 481.3
butyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-
carbonitrile SC_3040
cis-5-[8-Dimethylamino-143-methoxy-propyl)-2-oxo-8- INT-979
5-bromo-4- SC_3022 479.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-
methoxypyrimidine-2- 2-carbonitrile carbonitrile SC_3041
cis-5-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2- INT_600
(1-cyanocyclobutyl)methyl SC_3013 470.3
oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-
4-methylbenzenesulfonate carbonitrile SC_3042
cis-N-(Cyclobutyl-methyl)-5-[1-(cyc lobutyl-methyl)-8- INT-601
(bromomethyl)cyclobutane SC_3064 549.3
dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-
diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carboxylic acid amide
SC_3043 cis-5-[1-(3-Methoxy-propyl)-8-methylamino-2-oxo-8-phenyl-
SC_3019 -- SC_3043 435.2
1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3044
cis-5-[8-Dimethylamino-8-(3-fluorophenyl)-1-methyl-2-oxo- INT_600
iodomethane SC_3013 409.2
1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3045
cis-4-Methoxy-5-[1-(3-methoxy-propyl)-8-methylamino-2- SC_3040 --
SC_3045 465.3
oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-
carbonitrile SC_3046
cis-4-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl- INT-980
4-bromopyrimidine-2- SC_3022 435.2
1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile
carbonitrile SC_3047
cis-5-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl- INT-980
5-bromo-4- SC_3022 465.3
1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-
methoxypyrimidine-2- carbonitrile carbonitrile SC_3048
cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- INT-987
4-bromopyrimidine-2- SC_3022 445.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2- carbonitrile
carbonitrile SC_3049
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(6- INT-987
4-bromo-6-(methylthio)- SC_3022 466.3
methylsulfanyl-pyrimidin-4-yl)-8-phenyl-1,3- pyrimidine
diazaspiro[4.5]decan-2-one SC_3050
cis-2-[3-(2-Cyano-pyrimidin-4-yl)-8-dimethylamino-2-oxo-8- SC_3022
4-bromopyrimidine-2- SC_3022 462.3
phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N,N-dimethyl- carbonitrile
acetamide SC_3051
cis-6-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- INT-987
6-bromopyrimidine-4- SC_3022 445.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-4- carbonitrile
carbonitrile SC_3052 cis-2-(8-Dimethylamino-2-oxo-3,8-diphenyl-1,3-
INT-987 bromobenzene SC_3022 435.3
diazaspiro[4.5]decan-1-yl)-N,N-dimethyl-acetamide SC_3053
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3,8-diphenyl-1,3- INT-987
bromobenzene SC_3022 418.3 diazaspiro[4.5]decan-2-one SC_3054
cis-248-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl- INT-980
5-chloropyrimidine-2- SC_3022 435.2
1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carbonitrile
carbonitrile SC_3055
cis-8-Dimethylamino-1-(2-methoxy-ethyl)-3,8-diphenyl-1,3- INT-980
bromobenzene SC_3022 408.3 diazaspiro[4.5]decan-2-one SC_3056
cis-5-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl- INT-980
5-bromo-4- SC_3022 448.3
1,3-diazaspiro[4.5]decan-3-yl]-4-methyl-pyridine-2-
methylpicolinonitrile carbonitrile SC_3057
cis-N,N-Dimethyl-2-(8-methylamino-2-oxo-3,8-diphenyl-1,3- SC_3052
-- SC_3045 421.3 diazaspiro[4.5]decan-1-yl)-acetamide SC_3058
cis-5-[1-[(1-Cyano-cyclobutyl)-methyl]-8-methylamino-2-oxo- SC_3041
-- SC_3058 456.2
8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2- carbonitrile
SC_3059 cis-5-[1-[(1-Cyano-cyclobutyl)-methyl]-8-(ethyl-methyl-
INT-797 5-bromopyrimidine-2- SC_3013 484.3
amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]- carbo-nitrile
(step 1); pyrimidine-2-carbonitrile 1-(bromo- methyl)cyclobutane-
carbonitrile (step 2) SC_3060
CIS-4-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]- INT-987
4-bromobenzonitrile SC_3013 459.3
2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile (step
1); (1-(tert- butyldimethylsilyloxy) cyclobutyl)methyl 4-
methylbenzene-sulfonate (2 step) SC_3061
cis-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2- INT-987
3-bromobenzonitrile (step SC_3013 459.3
oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile 1);
(1-(tert- butyldimethylsilyloxy)cyclo butyl)methyl 4-
methylbenzene-sulfonate (step 2) SC_3063
cis-5-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2- INT-987
5-bromopicolinonitrile (step SC_3013 469.3
oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyridine-2- 1);
1-(bromomethyl)cyclo- carbonitrile butanecarbonitrile (step 2)
SC_3064 cis-2-[3-(2-Cyano-pyrimidin-5-yl)-8-dimethylamino-2-oxo-8-
INT-600 2-bromo-N-propylacetamide SC_3064 476.3
phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N-propyl-acetamide SC_3065
cis-5-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-
INT-986 5-bromo-4- SC_3065 489.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-
methoxypyrimidine-2- 2-carbonitrile carbonitrile SC_3066
cis-4-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl- SC_3080
-- SC_3066 459.3
1,3-diazaspiro[4.5]decan-3-yl]-3-methoxy-benzonitrile SC_3067
cis-5-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8- INT-979
5-bromo-6- SC_3022 478.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-6-methoxy-pyridine-2-
methoxypicolinonitrile carbonitrile SC_3068
cis-4-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2- SC_3060
-- SC_3016 477.3
oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide SC_3069
cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2- INT-976
5-bromopicolinonitrile (step SC_3013 460.3
oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyridine-2- 1);
1-(tert-butyldimethyl- carbonitrile silyloxy)cyclobutyl)methyl
4-methylbenzene-sulfonate (step 2) SC_3070
cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2- INT-976
5-bromopicolinonitrile (step SC_3013 562.3
oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(1-hydroxy- 1);
1-(tert-butyldimethyl- cyclobutyl)-methyl]-pyridine-2-carboxylic
acid amide silyloxy)cyclobutyl)methyl 4-methylbenzene-sulfonate
(step 2) SC_3071
cis-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2- INT-976
2-bromobenzonitrile (step SC_3013 459.3
oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile 1);
1-(tert-butyldimethyl- silyloxy)cyclobutyl)methyl
4-methylbenzene-sulfonate (step 2) SC_3072
cis-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- INT-987
3-iodobenzonitrile SC_3022 443.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile SC_3073
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[2- INT-987
5-bromo-2- SC_3022 488.3
(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-
(trifluoromethyl)pyrimidine one SC_3074
cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- INT-987
methyl 5-bromo-4-methyl- SC_3022 491.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methyl-pyridine-2-
picolinate carboxylic acid methyl ester SC_3075
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(5-methoxy- INT-987
2-bromo-5-methoxypyrazine SC_3022 450.3
pyrazin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3076
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(2-methoxy- INT-987
5-bromo-2- SC_3022 450.3
pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
methoxypyrimidine SC_3077
cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- INT-987
4-iodobenzonitrile SC_3022 443.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile SC_3078
cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- INT-987
5-bromo-4- SC_3022 458.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methyl-pyridine-2-
methylpicolinonitrile carbonitrile SC_3079
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(5-fluoro- INT-987
2-bromo-5-fluoropyrimidine SC_3022 438.3
pyrimidin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3080
cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- INT-987
4-bromo-3- SC_3022 473.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-3-methoxy-benzonitrile
methoxybenzonitrile SC_3081
cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- INT-987
methyl 4-iodobenzoate SC_3022 476.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzoic acid methyl ester
SC_3082 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-(2-
INT-987 4-iodo-2-(pyrrolidin-1- SC_3022 489.3
pyrrolidin-1-yl-pyrimidin-4-yl)-1,3-diazaspiro[4.5]decan-2-one
yl)pyrimidine SC_3083
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-(5- INT-987
2-(5-bromothiophen-2- SC_3022 501.3
pyridin-2-yl-thiophen-2-yl)-1,3-diazaspiro[4.5]decan-2-one
yl)pyridine SC_3084 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3[2-
INT-987 1-bromo-2- SC_3022 564.2
methylsulfonyl-4-(trifluoromethyl)-phenyl]-8-phenyl-1,3-
(methylsulfonyl)-4- diazaspiro[4.5]decan-2-one
(trifluoromethyl)benzene SC_3085
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-346- INT-987
5-bromo-2- SC_3022 487.3
(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one
(trifluoromethyl)pyridine SC_3086
cis-1-(Cyclobutyl-methyl)-3-(2,4-dimethoxy-phenyl)-8- INT-987
1-bromo-2,4- SC_3022 478.3
dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
dimethoxybenzene SC_3087
cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- INT 987
2-iodo-4-(methylthio)- SC_3022/ 521.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methylsulfonyl-
benzonitrile (SC_3022) SC_3008 benzonitrile SC_3088
cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- INT-987
5-bromo-2- SC_3022 461.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2-fluoro-benzonitrile
fluorobenzonitrile SC_3089
cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- INT-987
4-bromo-N,N-dimethyl-3- SC_3022 593.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N,N-dimethyl-3-
(trifluoromethyl) (trifluoromethyl)-benzenesulfonic acid amide
benzenesulfonamide SC_3090
cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- INT-987
2-bromobenzonitrile SC_3022 443.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile SC_3091
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(2-methyl- INT-987
6-bromo-2- SC_3022 473.3 imidazo[1,2-alpyrazin-6-yl)-8-phenyl-1,3-
methylimidazo[1,2- diazaspiro[4.5]decan-2-one a]pyrazine SC_3092
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(4- INT-987 (4-
SC_3022/ 496.3
methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-
iodophenyl)(methyl)sulfane SC_3008 one SC_3093
cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- INT-987
2-bromo-5- SC_3022 473.3
phenyl-1,3-diazaspiro[4.5]decan-3-yl]-5-methoxy-benzonitrile
methoxybenzonitrile SC_3094
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3,8-diphenyl-1,3- INT-987
bromobenzene SC_3022 418.3 diazaspiro[4.5]decan-2-one SC_3096
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3- INT-987
2-bromopyrazine SC_3022 420.3
pyrazin-2-yl-1,3-diazaspiro[4.5]decan-2-one
TABLE-US-00004 in analogy to m/z Example Chemical name Reactant I
Reactant II method .sup.1H NMR data (M + H).sup.+ SC_3098
cis-8-Dimethylamino-1-[(1- INT-799 5-bromo-2-(4- SC_3097 1H NMR
(DMSO-d6): .delta. 8.56 (s, 2H), 534.4
hydroxy-cyclobutyl)-methyl]-3-[2- methylpiperazin-1- 7.36-7.35 (m,
4H), 7.27-7.24 (m, 1H), 5.52 (s, (4-methyl-piperazin-1-yl)-
yl)pyrimidine 1H), 3.71 (s, 2H), 3.64 (m, 4H), 3.21 (s, 2H),
pyrimidin-5-yl]-8-phenyl-1,3- 2.69-2.67 (m, 2H), 2.32 (m, 4H),
diazaspiro[4.5]decan-2-one 2.19-2.11 (m, 7H), 1.98 (s, 6H),
1.92-1.86 (m, 2H), 1.66-1.64 (m, 1H), 1.52-1.42 (m, 5H). SC_3101
cis-1-[(1-Hydroxy-cyclobutyl)- SC_3098 SC_3099 1H NMR (DMSO-d6):
.delta. 8.58 (s, 2H), 520.4 methyl]-8-methylamino-3-[2-(4- 7.48 (d,
2H), 7.32 (t, 2H), 7.19 (t, 1H), 5.61 (s,
methyl-piperazin-1-yl)-pyrimidin- 1H), 3.75 (s, 2H), 3.66-3.64 (m,
4H), 3.30 (s, 5-yl]-8-phenyl-1,3- 2H), 2.35-2.32 (m, 4H), 2.25-2.19
(m, 5H), diazaspiro[4.5]decan-2-one 2.12-2.07 (m, 2H), 1.90-1.88
(m, 7H), 1.79-1.73 (m, 2H), 1.65-1.63 (m, 1H), 1.50-1.44 (m, 3H)
SC_3102 cis-1-[(1-Hydroxy-cyclobutyl)- SC_3100 SC_3099 1H NMR
(DMSO-d6): .delta. 9.51 (br s, 2H), 506.3
methyl]-8-methylamino-8-phenyl- 9.15 (br s, 2H), 8.65 (s, 2H),
7.69-7.68 (m, 3-(2-piperazin-1-yl-pyrimidin-5- 2H), 7.50-7.41 (m,
3H), 3.88-3.86 (m, 4H), yl)-1,3-diazaspiro[4.5]decan-2-one 3.79 (m,
2H), 3.65 (m, 2H), 3.16-3.13 (m, dihydrochloride 4H), 2.64-2.62 (m,
2H), 2.38-2.33 (m, 2H), 2.16-2.04 (m, 7H), 1.90-1.84 (m, 2H),
1.76-1.70 (m, 3H), 1.60-1.58 (m, 1H). SC_3104
cis-1-(Cyclobutyl-methyl)-8- SC_3103 SC_3099 1H NMR (DMSO-d6):
.delta. 8.59 (s, 1H), 487.3 methylamino-3-[4-methyl-6- 7.81 (s,
1H), 7.44 (d, 2H), 7.30 (t, 2H), 7.17 (t,
(trifluoromethyl)-pyridin-3-yl]-8- 1H), 3.76 (s, 2H), 3.21 (d, 2H),
2.61-2.57 (m, phenyl-1,3-diazaspiro[4.5]decan-2- 1H), 2.32 (s, 3H),
2.29-2.17 (m, 3H), one 2.03-1.97 (m, 2H), 1.91-1.88 (m, 5H),
1.84-1.67 (m, 6H), 1.51-1.48 (m, 2H). SC_3106
cis-1-(Cyclopropyl-methyl)-8- SC_3105 SC_3099 1H NMR (DMSO-d6):
.delta. 7.90-7.88 (d, 2H), 468.2 methylamino-3-(4-methylsulfonyl-
7.82-7.80 (d, 2H), 7.50-7.48 (d, 2H), phenyl)-8-phenyl-1,3-
7.35-7.32 (m, 2H), 7.22-7.19 (m, 1H), 3.80 (s,
diazaspiro[4.5]decan-2-one 2H), 3.14-3.10 (m, 5H), 2.29-2.23 (m,
3H), 1.91-1.79 (m, 7H), 1.42-1.39 (m, 2H), 1.05-1.04 (m, 1H),
0.50-0.47 (m, 2H), 0.34-0.32 (m, 2H). SC_3107
cis-1-(Cyclopropyl-methyl)-8- INT-983 1-bromo-2-fluoro-4- SC3103
(step 1H NMR (DMSO-d6): .delta. 7.85 (t, 1H), 500.2
dimethylamino-3-(2-fluoro-4- (methylsulfonyl)benzene 1), SC_3105
7.79-7.76 (m, 1H), 7.72-7.69 (m, 1H),
methylsulfonyl-phenyl)-8-phenyl- (step 1), (step 2) 7.37-7.33 (m,
4H), 7.27-7.24 (m, 1H), 3.81 (s, 2H),
1,3-diazaspiro[4.5]decan-2-one (Bromomethyl)cyclopropane 3.24 (s,
3H), 3.07 (d, 2H), 2.71-2.68 (m, 2H), (step 2) 2.28-2.22 (m, 2H),
1.99 (s, 6H), 1.53-1.42 (m, 4H), 1.00-0.99 (m, 1H), 0.53-0.49 (m,
2H), 0.34-0.30 (m, 2H). SC_3108 cis-2-[8-Dimethylamino-1-[(1-
SC_3071 SC_3016 1H NMR (600 MHz, DMSO) .delta. 477.3
hydroxy-cyclobutyl)-methyl]-2- 7.59-7.55 (s, 1H), 7.47-7.39 (m,
2H), 7.39-7.31 (m, oxo-8-phenyl-1,3- 5H), 7.30-7.21 (m, 3H),
3.77-3.73 (s, diazaspiro[4.5]decan-3-yl]- 2H), 3.21-3.17 (s, 1H),
2.72-2.66 (d, 2H), benzamide; formic acid 2.17-2.09 (m, 5H),
2.02-1.99 (s, 6H), 1.95-1.86 (m, 2H), 1.71-1.60 (m, 3H), 1.49-1.37
(m, 3H) SC_3109 cis-2-[-Dimethylamino-1-[2-(1- INT988
2-bromobenzonitrile SC_3097 (step 1H NMR (600 MHz, DMSO) .delta.
505.3 methoxy-cyclobutyl)-ethyl]-2-oxo- 1), SC_3109 7.52-7.48 (s,
1H), 7.47-7.31 (m, 7H), 7.29-7.23 (m,
8-phenyl-1,3-diazaspiro[4.5]decan- (step 2) 1H), 7.25-7.22 (s, 1H),
7.24-7.18 (m, 3-yl]-benzamide 1H), 3.68-3.65 (s, 3H), 3.13-3.10 (s,
2H), 3.09-3.02 (m, 2H), 2.71-2.65 (m, 2H), 2.21-2.12 (m, 2H),
2.09-1.99 (m, 2H), 2.02-1.98 (s, 6H), 1.97-1.86 (m, 4H), 1.77-1.67
(m, 1H), 1.64-1.52 (m, 3H), 1.44-1.36 (td, 2H). SC_3110
cis-8-Dimethylamino-1-[2-(1- INT-988 5-bromo2-methyl- SC_3103 1H
NMR (600 MHz, DMSO) .delta. 478.3 methoxy-cyclobutyl)-ethyl]-3-(2-
pyrimidine 8.94-8.90 (s, 2H), 7.41-7.34 (d, 4H),
methyl-pyrimidin-5-yl)-8-phenyl- 7.32-7.24 (ddd, 1H), 3.76-3.72 (s,
2H), 1,3-diazaspiro[4.5]decan-2-one 3.15-3.08 (m, 5H), 2.72-2.65
(m, 2H), 2.57-2.52 (s, 3H), 2.25-2.16 (m, 2H), 2.11-2.02 (m, 2H),
2.03-1.99 (s, 6H), 1.99-1.86 (m, 4H), 1.78-1.68 (tq, 1H), 1.65-1.51
(m, 3H), 1.50-1.44 (d, 2H). SC_3111
cis-5-[1-[(1-Hydroxy-cyclobutyl)- INT-799 5-bromo-2- SC_3103 (step
1H NMR (600 MHz, DMSO) .delta. 447.3 methyl]-8-methylamino-2-oxo-8-
cyanopyrimidine 1), SC_3099 9.24-9.20 (s, 2H), 7.53-7.48 (m, 2H),
7.37-7.31 (t, phenyl-1,3-diazaspiro[4.5]decan-3- (step 2) 2H),
7.25-7.19 (t, 1H), 3.93-3.89 (s, 2H), yl]-pyrimidine-2-carbonitrile
3.42-3.36 (m, 2H), 2.35-2.26 (td, 2H), 2.18-2.10 (tt, 2H),
2.09-2.04 (s, 1H), 1.97-1.88 (m, 2H), 1.93-1.90 (s, 6H), 1.86-1.77
(td, 2H), 1.72-1.62 (s, 1H), 1.59-1.54 (d, 1H), 1.48-1.43 (d, 2H).
SC_3113 cis-4-[1-[(1-Hydroxy-cyclobutyl)- INT-976
1-bromo-4-cyano-2- SC_3112 1HNMR (DMSO-d6, 400 MHz), .delta. (ppm)
= 7.54 (s, 475.3 methyl]-8-methylamino-2-oxo-8- methoxybenzene 1H),
7.50 (d, 1H, J = 8.16 Hz), phenyl-1,3-diazaspiro[4.5]decan-3- (step
1) 7.46-7.39 (m, 3H), 7.30 (t, 2H, J = 7.48 Hz),
yl]-3-methoxy-benzonitrile 7.18 (t, 1H, J = 7.16 Hz), 5.59 (s, 1H),
3.85 (s, 3H), 3.73 (s, 2H), 3.30 (s, 2H, merged with DMSO-water),
2.32-2.08 (m, 4H), 1.91-1.87 (m, 7H), 1.68-1.47 (m, 6H). SC_3114
cis-4-[8-Ethylamino-1-[(1-hydroxy- INT- 4-Bromo-3-methoxy- SC_3112
(step 1HNMR (DMSO-d6, 400 MHz), .delta. (ppm) = 7.54 (s, 489.1
cyclobutyl)-methyl]-2-oxo-8- 1008 benzonitrile (step 1) 1, step 2)
1H), 7.51-7.45 (m, 3H), 7.40 (d, 1H,
phenyl-1,3-diazaspiro[4.5]decan-3- J = 8.24 Hz), 7.29 (t, 2H, J =
7.58 Hz), yl]-3-methoxy-benzonitrile 7.17 (t, 1H, J = 7.12 (Hz),
5.60 (s, 1H), 3.85 (s, 3H), 3.73 (s, 2H), 3.21 (s, 2H, merged with
DMSO-H2O), 2.32-2.27 (m, 2H), 2.08 (bs, 5H), 1.96-1.87 (m, 4H),
1.68-1.46 (m, 6H), 0.97 (t, 3H, J = 4.0 Hz). SC_3115
cis-2-[8-Ethylamino-1-[(1-hydroxy- INT- 2-bromo-benzonitrile
SC_3112 (step 1HNMR (DMSO-d6, 400 MHz), .delta. (ppm) = 7.82 (d,
1H, 458.9 cyclobutyl)-methyl]-2-oxo-8- 1008 (step 1) 1, step 2) J =
7.56 Hz), 7.71 (t, 1H, J = 6.98 Hz),
phenyl-1,3-diazaspiro[4.5]decan-3- 7.53-7.47 (m, 3H), 7.37-7.27 (m,
yl]-benzonitrile 3H), 7.19-7.17 (m, 1H), 5.55 (s, 1H), 3.87 (s,
2H), 3.38 (s, 2H), 2.36-2.32 (m, 2H), 2.10 (bs, 4H), 1.94-1.86 (m.
4H), 1.75-1.48 (6H), 0.98 (bs, 3H). SC_3116
cis-5-[1-[(1-Hydroxy-cyclobutyl)- INT-799 5-bromo-4-methoxy-
SC_3103 (step 1HNMR (DMSO-d6, 400 MHz, at 100.degree. C.), 477.2
methyl]-8-methylamino-2-oxo-8- pyrimidine-2- 1), SC_3099 .delta.
(ppm) = 8.79 (s, 1H), 7.46 (d, 2H, J = 7.84 Hz),
phenyl-1,3-diazaspiro[4.5]decan-3- carbonitrile (step 1) (step 2)
7.32 (t, 2H, J = 7.12 Hz), 7.19 (t, 1H, J = 7.28 Hz),
yl]-4-methoxy-pyrimidine-2- 5.09 (bs, 1H), 4.05 (s, 3H),
carbonitrile 3.85 (s, 2H), 3.38 (s, 2H), 2.31-2.15 (m, 4H), 1.98
(m, 7H), 1.74-1.51 (m, 6H). SC_3117
cis-2-[8-Dimethylamino-1-(oxetan- SC_3274 toluene-4-sulfonic
SC_3105 (step 1HNMR (DMSO-d6, 400 MHz), .delta. (ppm) = 7.52 (s,
463.4 3-yl-methyl)-2-oxo-8-phenyl-1,3- acid oxetan-3- 1), SC_3016
1H), 7.43-7.33 (m, 6H), diazaspiro[4.5]decan-3-yl]- ylmethyl ester
(step (step 2) 7.30-7.17 (m, 4H), 4.63 (t, 2H, J = 6.9 Hz), 4.39
(t, 2H, benzamide 1) J = 6.08 Hz), 3.64 (s, 2H), 3.38 (d, 2H, J =
7.32 Hz), 3.21-3.15 (m, 1H), 2.70-2.66 (m, 2H), 2.08-1.98 (m, 8H),
1.54-1.35 (m, 4H). SC_3118 cis-4-Methoxy-5-(8-methylamino- INT-976
5-bromo-4-methoxy- SC_3103 (step 1HNMR (DMSO-d6, 400 MHz), .delta.
(ppm) = 8.80 (s, 393.0 2-oxo-8-phenyl-1,3- pyrimidine-2- 1),
SC_3099 1H), 7.86 (bs, 1H), 7.43 (d, 2H, J = 7.84 Hz),
diazaspiro[4.5]decan-3-yl)- carbonitrile (step 1) (step 2) 7.32 (t,
2H, J = 7.32 Hz), pyrimidine-2-carbonitrile 7.21-7.18 (m, 1H), 4.02
(s, 3H), 3.83 (s, 2H), 2.07-2.00 (m, 3H), 1.90-1.74 (m, 7H), 1.48
(d, 2H, J = 13.8 Hz). SC_3119 cis-2-(8-Methylamino-2-oxo-8- INT-976
2-bromo-benzonitrile SC_3103 (step 1HNMR (DMSO-d6, 400 MHz) .delta.
7.51 (bs, 379.4 phenyl-1,3-diazaspiro[4.5]decan-3- (step 1) 1),
SC_3099 1H), 7.43-7.37 (m, 4H), 7.33-2.29 (m, 3H, J = 8.28 Hz),
yl)-benzamide (step 2), 7.22-7.16 (m, 3H), 6.93 (bs, 1H), SC_3016
(step 3.64 (s, 2H), 2.03-1.97 (m, 2H), 1.86 (bs, 3) 5H), 1.73-1.58
(m, 4H). SC_3121 cis-3-(2-Cyclopropyl-pyrimidin-5- INT-976
5-bromo-2- SC_3103 1H NMR (600 MHz, DMSO) .delta. 8.80 (s, 2H),
392.3 yl)-8-dimethylamino-8-phenyl-1,3- cyclopropyl- 7.67 (s, 1H),
7.41-7.32 (m, 4H), diazaspiro[4.5]decan-2-one pyrimidine 7.31-7.22
(ddt, 1H), 3.60 (s, 2H), 2.42-2.36 (m, 2H), 2.18-2.08 (m, 1H),
1.98-1.85 (m, 4H), 1.96 (s, 6H), 1.47 (s, 2H), 0.98-0.91 (m, 2H),
0.93-0.86 (m, 2H). SC_3122 cis-8-Dimethylamino-3-[4-methyl- INT-976
5-bromo-4-methyl-2- SC_3103 1H NMR (600 MHz, DMSO) .delta. 8.57 (s,
1H), 433.2 6-(trifluoromethyl)-pyridin-3-yl]-8-
(trifluoromethyl)pyridine 7.79 (s, 1H), 7.52 (s, 1H), 7.40-7.32 (m,
phenyl-1,3-diazaspiro[4.5]decan-2- 4H), 7.30-7.22 (tt, 1H), 3.61
(s, 2H), one 2.39-2.30 (m, 5H), 1.96 (s, 6H), 2.00-1.91 (m, 2H),
1.84 (s, 2H), 1.57-1.53 (s, 2H). SC_3123 cis-8-Dimethylamino-3-(2-
INT-976 1-bromo-2- SC_3103 1H NMR (600 MHz, DMSO) .delta. 428.2
methylsulfonyl-phenyl)-8-phenyl- methylsulfonyl- 7.98-7.92 (dd,
1H), 7.81-7.74 (td, 1H), 1,3-diazaspiro[4.5]decan-2-one benzene
7.61-7.54 (td, 1H), 7.52-7.46 (m, 2H), 7.41-7.31 (m, 2H), 7.35 (s,
2H), 7.29-7.22 (tt, 1H), 3.49 (s, 2H), 3.25 (s, 3H), 2.37 (s, 2H),
1.99-1.96 (m, 1H), 1.98-1.94 (s, 6H), 1.95-1.91 (d, 1H), 1.83-1.79
(m, 2H), 1.58-1.55 (s, 2H). SC_3124 cis-8-Dimethylamino-8-phenyl-3-
INT-989 Piperazine-2-one SC_3120 1H NMR (600 MHz, DMSO) .delta.
8.52 (s, 2H), 436.3 (2-piperazin-1-yl-pyrimidin-5-yl)- 7.41-7.31
(m, 5H), 3.59-3.54 (m, 4H), 1,3-diazaspiro[4.5]decan-2-one 3.52 (s,
2H), 2.76-2.70 (m, 4H), 2.55 (s, 3H), 2.49-2.33 (m, 2H), 1.96 (s,
6H), 1.93-1.83 (m, 4H), 1.51-1.43 (s, 2H). SC_3125
trans-2-(8-Ethylamino-2-oxo-8- SC_3127 SC_3016 1HNMR (DMSO-d6, 400
MHz), .delta. (ppm) = 7.56-7.20 (m, 393.1
phenyl-1,3-diazaspiro[4.5]decan-3- 12H), 3.60 (s, 2H),
yl)-benzamide 2.08-1.92 (m, 6H), 1.69 (bs, 2H), 1.56 (bs, 2H), 0.93
(t, 3H). SC_3126 cis--2-(8-Ethylamino-2-oxo-8- SC_3128 SC_3016
.sup.1HNMR (DMSO-d.sub.6, 400 MHz), .delta. (ppm) = 7.51-2.38 (m,
393.4 phenyl-1,3-diazaspiro[4.5]decan-3- 5H), 7.32-7.30 (m, 3H),
yl)-benzamide 7.22-7.18 (m, 3H), 6.93 (s, 1H), 3.63 (s, 2H),
2.07-1.98 (m, 4H), 1.86-1.72 (m, 4H), 1.60-1.57 (m, 2H), 0.93 (t,
3H). SC_3127 cis-2-(8-Ethylamino-2-oxo-8- INT- 2-bromo-benzonitrile
SC_3103 1HNMR (DMSO-d6, 400 MHz), .delta. (ppm) = 7.77 (d, 375.1
phenyl-1,3-diazaspiro[4.5]decan-3- 1009 1H, J = 6.8 Hz), 7.69-7.65
(m, 1H), yl)-benzonitrile 7.51 (d, 1H, J = 8.4 Hz), 7.44 (d, 2H, J
= 7.6 Hz), 7.39 (s, 1H), 7.34-7.28 (m, 3H), 7.17 (t, 1H, 7.2 Hz),
3.77 (s, 2H), 2.10-2.04 (m, 4H), 1.91-1.88 (m, 2H), 1.80-1.74 (m,
3H), 1.61-1.58 (m, 2H), 0.94 (t, 3H, J = 6.8 Hz). SC_3128
cis-2-(8-Ethylamino-2-oxo-8- INT- 2-bromo-benzonitrile SC_3103
.sup.1HNMR (DMSO-d.sub.6, 400 MHz), .delta. (ppm) = 7.89 (bs, 375.1
phenyl-1,3-diazaspiro[4.5]decan-3- 1008 1H), 7.79 (d, 1H, J = 7.6),
7.69 (t, yl)-benzonitrile 1H, J = 7.6 Hz), 7.54-7.50 (m, 3H),
7.36-7.30 (m, 3H), 7.18 (t, 1H, J = 7.2 Hz), 3.73 (s, 2H),
2.08-1.92 (m, 7H), 1.71 (bs, 2H), 1.59 (bs, 2H,), 0.93 (t, 3H, J =
6.4 Hz). SC_3131 cis-3-[5-(8-Dimethylamino-2-oxo- SC_3129 SC_3016
1H NMR (600 MHz, DMSO) .delta. 9.11 (s, 2H), 471.3
8-phenyl-1,3-diazaspiro[4.5]decan- 8.79 (t, 1H), 8.43 (dt, 1H),
8.09 (s, 1H), 3-yl)-pyrimidin-2-yl]-benzamide 7.94 (dt, 1H), 7.84
(s, 1H), 7.56 (t,
1H), 7.41-7.35 (m, 4H), 7.28 (ddd, 1H), 3.72 (s, 2H), 2.00-1.84 (m,
2H), 1.98 (s, 6H), 1.53 (s, 2H). SC_3134
trans-4-(8-Ethylamino-2-oxo-8- INT- 4-Bromo-3-methoxy- SC_3103
1HNMR (DMSO-d6, 400 MHz), .delta. (ppm) = 7.71 (bs, 405.3
phenyl-1,3-diazaspiro[4.5]decan-3- 1009 benzonitrile 1H), 7.56-7.49
(m, 4H), 7.37 (d, yl)-3-methoxy-benzonitrile 1H, J = 6.6 Hz), 7.31
(t, 2H, J = 7.10 Hz), 7.19-7.17 (m, 1H), 3.87 (s, 3H), 3.62 (s,
2H), 2.06-1.90 (m, 7H), 1.69-1.53 (m, 4H), 0.92 (t, 3H, J = 6.70
Hz). SC_3135 cis-4-(8-Ethylamino-2-oxo-8- INT- 4-Bromo-3-methoxy-
SC_3103 1HNMR (DMSO-d6, 400 MHz), .delta. (ppm) = 7.52-7.50 (m,
405.2 phenyl-1,3-diazaspiro[4.5]decan-3- 1008 benzonitrile 2H),
7.44-7.43 (m, 2H), yl)-3-methoxy-benzonitrile 736 (d, 1H, J = 8.04
Hz), 7.30-7.19 (m, 4H), 3.83 (s, 3H), 3.63 (s, 2H), 2.05-1.72 (m,
8H), 1.53-1.50 (m, 2H), 0.92 (t, 3H). SC_3136
cis-3-[2-(4-Acetyl-piperazin-1-yl)- SC_3124 acetyl chloride SC_3130
478.3 pyrimidin-5-yl]-8-dimethylamino-
8-phenyl-1,3-diazaspiro[4.5]decan- 2-one SC_3137
cis-8-Dimethylamino-8-phenyl-3- INT-989 pyridine-4-boronic SC_3129
1H NMR (600 MHz, DMSO) .delta. 9.16 (s, 2H), 429.2
(2-pyridin-4-yl-pyrimidin-5-yl)-1,3- acid 8.70 (d, 1H), 8.18 (s,
1H), 7.91 (s, 1H), diazaspiro[4.5]decan-2-one 7.42-7.35 (m, 4H),
7.28 (tt, 1H), 3.73 (s, 2H), 2.49-2.37 (m, 2H), 1.98 (s, 6H),
2.01-1.87 (m, 2H), 1.58-1.47 (m, 2H). SC_3138
cis-8-Dimethylamino-8-phenyl-3- INT-989 pyridine-3-boronic SC_3129
1H NMR (600 MHz, DMSO) .delta. 9.43 (dd, 429.2
(2-pyridin-3-yl-pyrimidin-5-yl)-1,3- acid 1H), 9.13 (s, 2H), 8.65
(dd, 1H), diazaspiro[4.5]decan-2-one 8.58 (dt, 1H), 7.52 (ddd, 1H),
7.42-7.36 (m, 4H), 7.28 (ddd, 1H), 3.72 (s, 2H), 1.98 (s, 6H),
2.02-1.89 (m, 4H), 1.57-1.46 (m, 4H). SC_3139
cis-5-(8-Dimethylamino-2-oxo-8- INT-991 2-aminoethanol SC_3133 1H
NMR (600 MHz, DMSO) .delta. 9.08 (s, 2H), 439.3
phenyl-1,3-diazaspiro[4.5]decan-3- 8.59 (t, 1H), 7.94 (s, 1H),
7.43-7.30 (m, yl)-N-(2-hydroxy-ethyl)- 5H), 7.30-7.21 (m, 1H), 3.72
(s, 2H), pyrimidine-2-carboxylic acid amide 3.51 (q, 2H), 2.49-2.37
(m, 2H), 2.00-1.90 (m, 10H), 1.89-1.74 (m, 2H), 1.57-1.48 (m, 2H),
1.38-1.32 (m, 1H). SC_3141 cis-8-Dimethylamino-3-[2- INT-976
4-[5-bromo-4- SC_3103 1H NMR (600 MHz, DMSO) .delta. 8.59 (d, 1H),
505.3 morpholin-4-yl-4-(trifluoromethyl)-
(trifluoromethyl)pyrimidin- 7.39-7.35 (m, 5H), 7.27 (d, 1H), 3.73
(t, pyrimidin-5-yl]-8-phenyl-1,3- 2- 4H), 3.67 (q, 4H), 3.28-3.22
(m, 1H), diazaspiro[4.5]decan-2-one yl]morpholine 2.41-2.28 (m,
2H), 1.98 (s, 6H), 1.94-1.80 (m, 3H), 1.53-1.42 (m, 2H). SC_3142
cis-4-[5-(8-Dimethylamino-2-oxo- INT-989 4- SC_3129 1H NMR (600
MHz, DMSO) .delta. 9.15 (s, 2H), 453.2
8-phenyl-1,3-diazaspiro[4.5]decan- cyanophenylboronic 8.49-8.43 (m,
2H), 7.99-7.92 (m, 2H), 3-yl)-pyrimidin-2-yl]-benzonitrile acid
7.89 (s, 1H), 7.38 (m, 4H), 7.28 (td, 1H), 3.73 (s, 2H), 2.48-2.35
(m, 1H), 2.03-1.90 (m, 10H), 1.55-1.48 (m, 2H). SC_3143
cis-5-(8-Ethylamino-2-oxo-8- INT- 5-Bromo-4-methoxy- SC_3103
(DMSO-d6, 400 MHz), .delta. (ppm) = 8.79 (s, 407.2
phenyl-1,3-diazaspiro[4.5]decan-3- 1008 pyrimidine-2- 1H), 7.60 (s,
1H), 7.41 (d, 2H, J = 7.72 Hz), yl)-4-methoxy-pyrimidine-2-
carbonitrile 7.28 (t, 2H, J = 7.54 Hz), 7.16 (t, 1H, J = 7.32 Hz),
carbonitrile 3.97 (s, 3H), 3.72 (s, 2H), 2.02 (bs, 4H), 1.90-1.69
(m, 5H), 1.51-1.48 (m, 2H), 0.89 (t, 3H, J = 6.56 Hz). SC_3144
trans-5-(8-Ethylamino-2-oxo-8- INT- 5-Bromo-4-methoxy- SC_3103
1HNMR (DMSO-d6, 400 MHz), .delta. (ppm) = 407.3
phenyl-1,3-diazaspiro[4.5]decan-3- 1009 pyrimidine-2- 8.87 (s, 1H),
8.10 (bs, 1H), 7.50 (d, 2H, J = 7.52 Hz),
yl)-4-methoxy-pyrimidine-2- carbonitrile 7.31 (t, 2H, J = 7.20 Hz),
7.18 (t, carbonitrile 1H, J = 6.88 Hz), 4.04 (s, 3H), 3.74 (s, 2H),
2.07-1.95 (m, 6H), 1.70-1.54 (m, 4H), 0.93 (t, 3H, J = 6.62 Hz).
SC_3145 cis-8-Dimethylamino-3-[2- INT-991 morpholine SC_3133 1H NMR
(600 MHz, DMSO) .delta. 9.04 (s, 2H), 478.3
(morpholine-4-carbonyl)- 7.88 (s, 1H), 7.42-7.30 (m, 5H),
pyrimidin-5-yl]-8-phenyl-1,3- 7.30-7.22 (m, 1H), 3.75-3.58 (m, 6H),
3.51 (t, diazaspiro[4.5]decan-2-one 2H), 3.20 (t, 2H), 2.50-2.33
(m, 2H), 1.99-1.90 (m, 8H), 1.89-1.74 (m, 2H), 1.54-1.44 (m, 2H).
SC_3147 cis-8-Dimethylamino-3-[2- INT-976 1-bromo-2- SC_3103 1H NMR
(600 MHz, DMSO) .delta. 7.47 (d, 1H), 442.2
(methylsulfonyl-methyl)-phenyl]-8- (methylsulfonylmethyl)benzene
7.42-7.31 (m, 6H), 7.30-7.22 (m, 3H),
phenyl-1,3-diazaspiro[4.5]decan-2- 4.50 (s, 2H), 3.56 (s, 2H), 2.88
(s, 3H), one 2.42-2.28 (m, 2H), 2.07 (s, 2H), 1.98-1.90 (m, 8H),
1.89-1.69 (m, 2H), 1.61-1.48 (d, 2H). SC_3148
cis-8-Dimethylamino-3-(4-methyl- INT-992 morpholine SC_3120 1H NMR
(600 MHz, DMSO) .delta. 8.14 (s, 1H), 451.3
2-morpholin-4-yl-pyrimidin-5-yl)- 7.40-7.32 (m, 4H), 7.26 (td, 1H),
7.21 (s, 8-phenyl-1,3-diazaspiro[4.5]decan- 1H), 3.69-3.60 (m, 8H),
3.38 (s, 2H), 2-one 2.41-2.27 (m, 2H), 2.20 (s, 3H), 1.97 (s, 6H),
1.95-1.76 (m, 4H), 1.54-1.45 (s, 2H). SC_3149
cis-8-Dimethylamino-3-[2-(1,1- INT-989 thiomorpholine-1,1- SC_3120
1H NMR (600 MHz, DMSO) .delta. 8.63 (s, 2H), 485.2
dioxo-[1,4]thiazinan-4-yl)- dioxide hydrochloride 7.50 (br s, 1H),
7.41-7.33 (m, 4H), 7.27 (td, pyrimidin-5-yl]-8-phenyl-1,3- 1H),
4.17-4.12 (m, 4H), 3.55 (s, 2H), diazaspiro[4.5]decan-2-one
3.12-3.06 (m, 4H), 2.47-2.27 (m, 2H), 2.04-1.74 (m, 10H), 1.51-1.42
(m, 2H). SC_3150 cis-8-Dimethylamino-3-(4-fluoro- INT-976
3-bromo-4-fluoro- SC_3103 1H NMR (600 MHz, DMSO) .delta. 8.70 (d,
1H), 369.2 pyridin-3-yl)-8-phenyl-1,3- pyridine 8.36 (dd, 1H), 7.54
(s, 1H), 7.36 (td, 5H), diazaspiro[4.5]decan-2-one 7.26 (s, 1H),
3.61 (s, 2H), 2.44-2.28 (m, 2H), 2.01-1.74 (m, 10H), 1.92 (d, 2H),
1.56-1.45 (m, 2H). SC_3151 cis-5-(8-Dimethylamino-2-oxo-8- INT-991
2- SC_3133 1H NMR (600 MHz, DMSO) .delta. 9.03 (d, 2H), 453.2
phenyl-1,3-diazaspiro[4.5]decan-3- (methylamino)ethanol 7.86 (s,
1H), 7.40-7.23 (m, 5H), 3.69 (s, yl)-N-(2-hydroxy-ethyl)-N-methyl-
2H), 3.61 (q, 1H), 3.50 (t, 1H), 3.45 (d, 1H),
pyrimidine-2-carboxylic acid amide 3.17 (t, 1H), 3.01 and 2.83
(both s, together 3H, amide rotamers), 2.49-2.36 (m, 2H), 2.00-1.89
(m, 8H), 1.89-1.73 (m, 2H), 1.55-1.47 (m, 2H). SC_3152
cis-5-(8-Dimethylamino-2-oxo-8- INT-976 5-bromo-2- SC_3103 1H NMR
(600 MHz, DMSO) .delta. 8.24 (s, 1H), 461.3
phenyl-1,3-diazaspiro[4.5]decan-3- morpholino-pyridine- 7.67-7.30
(m, 5H), 7.29 (s, 1H), yl)-2-morpholin-4-yl- 4-carbonitrile
3.70-3.65 (m, 4H), 3.51-3.44 (m, 4H), 2.37-2.22 (m,
isonicotinonitrile 2H), 2.10-1.87 (m, 10H), 1.53-1.31 (m, 2H).
SC_3153 cis-4-(8-Dimethylamino-2-oxo-8- SC_3272 SC_3016 1H NMR (600
MHz, DMSO) .delta. 7.79 (d, 2H), 393.2
phenyl-1,3-diazaspiro[4.5]decan-3- 7.62 (d, 2H), 7.41-7.34 (m, 4H),
7.27 (td, yl)-benzamide 1H), 7.13-7.09 (m, 1H), 3.62 (s, 2H),
2.46-2.35 (m, 2H), 1.97 (s, 6H), 1.93-1.76 (m, 4H), 1.51-1.45 (m,
2H). SC_3154 cis-8-Dimethylamino-3-(2-fluoro- INT-976
1-bromo-2-fluoro-4- SC_3103 1H NMR (600 MHz, DMSO) .delta. 446.2
4-methylsulfonyl-phenyl)-8- methylsulfonyl- 7.89-7.83 (m, 1H), 7.76
(dd, 1H), 7.70 (dd, 1H), phenyl-1,3-diazaspiro[4.5]decan-2- benzene
7.40-7.32 (m, 5H), 7.29-7.23 (m, 1H), 3.69 (s, one 2H), 3.23 (s,
3H), 2.43-2.30 (m, 2H), 1.96 (s, 6H), 1.94-1.88 (m, 2H), 1.53-1.47
(m, 2H). SC_3155 cis-4-(8-Dimethylamino-2-oxo-8- INT-976
4-bromo-3-fluoro- SC_3103 1H NMR (600 MHz, DMSO) .delta. 393.2
phenyl-1,3-diazaspiro[4.5]decan-3- benzonitrile 7.85-7.79 (m, 2H),
7.73 (s, 1H), 7.62 (dd, 1H), yl)-3-fluoro-benzonitrile 7.40-7.31
(m, 4H), 7.26 (tt, 1H), 3.69 (s, 2H), 2.40-2.31 (m, 2H), 1.95 (s,
6H), 1.94-1.87 (m, 2H), 1.87-1.75 (m, 2H), 1.52-1.46 (m, 2H).
SC_3156 cis-4-(8-Dimethylamino-2-oxo-8- INT-976
4-bromo-3,5-difluoro- SC_3103 1H NMR (600 MHz, DMSO) .delta. 7.85
(d, 2H), 411.2 phenyl-1,3-diazaspiro[4.5]decan-3- benzonitrile 7.61
(s, 1H), 7.39-7.31 (m, 4H), 7.25 (tt, yl)-3,5-difluoro-benzonitrile
1H), 3.53 (s, 2H), 2.42-2.33 (m, 2H), 1.98-1.89 (m, 8H), 1.82-1.78
(m, 2H), 1.54-1.47 (m, 2H). SC_3157 cis-8-Dimethylamino-3-(2-
INT-989 methanol instead of SC_3120 1H NMR (600 MHz, DMSO) .delta.
8.76 (s, 2H), 382.2 methoxy-pyrimidin-5-yl)-8-phenyl- n-butanol as
a solvent 7.41-7.33 (m, 5H), 7.27 (ddt, 1H), 3.86 (s,
1,3-diazaspiro[4.5]decan-2-one 3H), 3.60 (s, 2H), 2.47-2.30 (m,
2H), 2.01-1.74 (m, 10H), 1.52-1.45 (m, 2H). SC_3158
cis-3-[2-(Benzylamino)-pyrimidin- INT-989 benzylamine SC_3120 1H
NMR (600 MHz, DMSO) .delta. 8.43 (s, 2H), 457.3
5-yl]-8-dimethylamino-8-phenyl- 7.50-7.45 (m, 1H), 7.46-7.33 (m,
5H), 1,3-diazaspiro[4.5]decan-2-one 7.31-7.23 (m, 4H), 7.19 (tq,
1H), 4.46 (d, 2H), 4.02 (s, 1H), 3.50 (s, 2H), 2.41-2.31 (m, 2H),
1.97 (s, 6H), 1.88 (s, 2H), 1.49-1.41 (m, 2H). SC_3159
cis-8-Dimethylamino-3-[2-(4- INT-989 (4- SC_3129 1H NMR (600 MHz,
DMSO) .delta. 9.07 (s, 2H), 446.2 fluorophenyl)-pyrimidin-5-yl]-8-
fluorophenyl)boronic 8.37-8.30 (m, 2H), 7.83 (s, 1H),
phenyl-1,3-diazaspiro[4.5]decan-2- acid 7.44-7.35 (m, 4H),
7.34-7.25 (m, 3H), 3.69 (s, one 2H), 2.47-2.30 (m, 2H), 2.08-1.80
(m, 10H), 1.55-1.46 (m, 2H). SC_3160
trans-8-Benzyl-8-dimethylamino-3- INT-995 4-(5-bromopyrimidin-
SC_3103 1H NMR (600 MHz, DMSO) .delta. 8.57 (s, 2H), 451.3
(2-morpholin-4-yl-pyrimidin-5-yl)- 2-yl)morpholine 7.60 (s, 1H),
7.27 (t, 2H), 7.22-7.15 (m, 1,3-diazaspiro[4.5]decan-2-one 3H),
3.68-3.62 (m, 4H), 3.64-3.57 (m, 4H), 3.49 (s, 2H), 2.66 (s, 2H),
2.22 (s, 6H), 1.80-1.70 (m, 4H), 1.51-1.43 (m, 4H). SC_3161
cis-8-Benzyl-8-dimethylamino-3- INT-994 4-(5-bromopyrimidin-
SC_3103 1H NMR (600 MHz, DMSO) .delta. 8.45 (s, 2H), 451.3
(2-morpholin-4-yl-pyrimidin-5-yl)- 2-yl)morpholine 7.27 (t, 2H),
7.22-7.15 (m, 3H), 7.11 (s, 1,3-diazaspiro[4.5]decan-2-one 1H),
3.68-3.56 (m, 8H), 2.64 (s, 2H), 2.26 (s, 6H), 1.87-1.77 (m, 4H),
1.42 (d, 2H), 1.15 (dt, 2H). SC_3163
cis-4-(8-Dimethylamino-2-oxo-8- SC_3156 SC_3016 1H NMR (600 MHz,
DMSO) .delta. 8.08 (s, 1H), 429.2
phenyl-1,3-diazaspiro[4.5]decan-3- 7.65-7.58 (m, 2H), 7.48 (br s,
1H), yl)-3,5-difluoro-benzamide 7.39-7.31 (m, 4H), 7.28-7.22 (m,
1H), 3.49 (s, 2H), 2.40-2.32 (m, 2H), 1.96 (s, 6H), 1.95-1.90 (m,
2H), 1.87-1.77 (m, 2H), 1.54-1.49 (m, 2H). SC_3164
cis-4-(8-Dimethylamino-2-oxo-8- SC_3155 SC_3016 1H NMR (600 MHz,
DMSO) .delta. 7.95 (s, 1H), 411.2
phenyl-1,3-diazaspiro[4.5]decan-3- 7.72-7.64 (m, 2H), 7.61 (t, 1H),
yl)-3-fluoro-benzamide 7.54-7.50 (m, 1H), 7.40-7.32 (m, 5H), 7.26
(tt, 1H), 3.62 (s, 2H), 2.41-2.31 (m, 2H), 1.96 (s, 6H), 1.93-1.88
(m, 2H), 1.86-1.75 (m, 2H), 1.53-1.45 (m, 2H). SC_3165
cis-8-Benzyl-8-dimethylamino-3- INT-994 5-bromo-2- SC_3103 1H NMR
(600 MHz, DMSO) .delta. 9.07 (s, 2H), 434.2
[2-(trifluoromethyl)-pyrimidin-5- (trifluoromethyl)pyrimidine 7.77
(s, 1H), 7.29 (t, 2H), 7.24-7.17 (m,
yl]-1,3-diazaspiro[4.5]decan-2-one 3H), 3.55 (s, 2H), 2.66 (s, 2H),
2.26 (s, 6H), 1.86 (dt, 4H), 1.44 (d, 2H), 1.25-1.17 (m, 2H).
SC_3166 trans-8-Benzyl-8-dimethylamino-3- INT-995 5-bromo-2-
SC_3103 1H NMR (600 MHz, DMSO) .delta. 9.16 (s, 2H), 434.2
[2-(trifluoromethyl)-pyrimidin-5- (trifluoromethyl)pyrimidine 8.28
(s, 1H), 7.27 (t, 2H), 7.22-7.16 (m,
yl]-1,3-diazaspiro[4.5]decan-2-one 3H), 3.67 (s, 2H), 2.66 (s, 2H),
2.24 (s, 6H), 1.84-1.72 (m, 4H), 1.49 (q, 4H). SC_3167
cis-8-Dimethylamino-8-thiophen-2- INT-997 5-bromo-2- SC_3103 1H NMR
(600 MHz, DMSO) .delta. 9.19 (d, 2H), 426.1
yl-3-[2-(trifluoromethyl)- (trifluoromethyl)pyrimidine 7.97 (s,
1H), 7.43 (t, 1H), 7.07 (dd, 1H), pyrimidin-5-yl]-1,3- 6.97 (d,
1H), 3.78 (s, 2H), 2.40-2.27 (m, 2H), diazaspiro[4.5]decan-2-one
2.04 (s, 6H), 1.96 (t, 2H), 1.90-1.79 (m,
2H), 1.60-1.52 (m, 2H). SC_3168 trans-8-Dimethylamino-8-thiophen-
INT-998 5-bromo-2- SC_3103 1H NMR (600 MHz, DMSO) .delta. 9.20 (s,
2H), 426.1 2-yl-3-[2-(trifluoromethyl)- (trifluoromethyl)pyrimidine
8.00 (s, 1H), 7.45 (dd, 1H), 7.09 (dd, 1H), pyrimidin-5-yl]-1,3-
7.02-6.97 (m, 1H), 3.81 (s, 2H), 2.12 (d,
diazaspiro[4.5]decan-2-one 4H), 2.03 (s, 6H), 1.85 (t, 2H),
1.62-1.54 (m, 2H). SC_3170 cis-8-Dimethylamino-8-phenyl-3- INT-989
piperidine SC_3120 1H NMR (DMSO-d6): .delta. 8.49 (s, 2H), 435.3
(2-piperidin-1-yl-pyrimidin-5-yl)- 7.39-7.24 (m, 6H), 3.65-3.63 (m,
4H), 3.50 (s, 1,3-diazaspiro[4.5]decan-2-one 2H), 2.36-2.32 (m,
2H), 1.95-1.86 (m, 10H), 1.61-1.56 (m, 2H), 1.50-1.44 (m, 6H).
SC_3171 cis-8-Dimethylamino-8-phenyl-3- INT-989 pyrrolidine SC_3120
1H NMR (CDCl3): .delta. 8.43 (s, 2H), 421.3
(2-pyrrolidin-1-yl-pyrimidin-5-yl)- 7.41-7.38 (m, 2H), 7.32-7.30
(m, 3H), 5.05 (br s, 1H), 1,3-diazaspiro[4.5]decan-2-one 3.53 (t,
4H), 3.45 (s, 2H), 2.30-2.06 (m, 10H), 1.99-1.96 (m, 6H), 1.62-1.58
(m, 2H). SC_3172 cis-8-Dimethylamino-8-phenyl-3- INT-989
pyrimidin-5- SC_3129 1H NMR (600 MHz, DMF) .delta. 9.56 (s, 2H),
430.2 (2-pyrimidin-5-yl-pyrimidin-5-yl)- ylboronic acid 9.27 (s,
1H), 9.17 (s, 2H), 8.35 (s, 1H), 1,3-diazaspiro[4.5]decan-2-one
7.89 (d, 2H), 7.63 (dq, 3H), 3.73 (s, 2H), 3.04 (d, 2H), 2.81 (s,
6H), 2.57 (td, 2H), 2.06 (d, 2H), 1.58 (td, 2H). SC_3174
trans-8-Benzyl-8-dimethylamino-3- INT-995 5-bromo-4-methyl-2-
SC_3103 1H NMR (600 MHz, DMSO) .delta. 8.57 (s, 1H), 447.2
[4-methyl-6-(trifluoromethyl)- (trifluoromethyl)pyridine 7.80 (s,
1H), 7.67 (s, 1H), 7.27 (t, 2H), pyridin-3-yl]-1,3- 7.23-7.15 (m,
3H), 3.58 (d, 2H), 2.67 (s, 2H), diazaspiro[4.5]decan-2-one 2.31
(s, 3H), 2.22 (d, 6H), 1.82-1.72 (m, 4H), 1.56 (dd, 2H), 1.48 (td,
2H). SC_3175 cis-5-(8-Dimethylamino-2-oxo-8- SC_3152 SC_3016 480.6
phenyl-1,3-diazaspiro[4.5]decan-3- yl)-2-morpholin-4-yl-pyridine-4-
carboxylic acid amide SC_3176 cis-8-Dimethylamino-3-[2-(3,5-
INT-989 (3,5- SC_3129 1H NMR (600 MHz, DMSO) .delta. 9.05 (s, 2H),
447.2 dimethyl-isoxazol-4-yl)-pyrimidin- dimethylisoxazol-4- 7.80
(s, 1H), 7.43-7.34 (m, 4H), 7.28 (tt, 5-yl]-8-phenyl-1,3-
yl)boronic acid 1H), 3.68 (s, 2H), 2.69 (s, 3H), 2.47 (s, 3H),
diazaspiro[4.5]decan-2-one 2.43-2.35 (m, 2H), 2.01-1.79 (m, 10H),
1.50 (s, 2H). SC_3177 cis-3-[2-(Benzothiazol-6-yl)- INT-989
1,3-benzothiazol-6- SC_3129 1H NMR (600 MHz, DMSO) .delta. 9.46 (s,
1H), 485.2 pyrimidin-5-yl]-8-dimethylamino- ylboronic acid 9.12 (s,
2H), 9.07 (s, 1H), 8.49 (d, 1H), 8-phenyl-1,3-diazaspiro[4.5]decan-
8.16 (d, 1H), 7.84 (s, 1H), 7.39 (d, 4H), 7.29 (d, 2-one 1H), 3.73
(s, 2H), 2.42 (d, 2H), 1.97 (d, 10H), 1.54 (d, 2H). SC_3178
cis-8-Dimethylamino-3-[2-fluoro- INT-976 1-bromo-2-fluoro-4-
SC_3103 1H NMR (600 MHz, DMSO) .delta. 7.80 (t, 1H), 436.2
4-(trifluoromethyl)-phenyl]-8- (trifluoromethyl)benzene 7.65 (dd,
1H), 7.53 (dd, 1H), 7.40-7.32 (m,
phenyl-1,3-diazaspiro[4.5]decan-2- 4H), 7.29-7.23 (m, 1H), 3.66 (s,
2H), one 2.36 (s, 2H), 1.97-1.88 (m, 8H), 1.85-1.75 (m, 2H),
1.53-1.46 (m, 2H). SC_3179 cis-8-Dimethylamino-3-(6- INT-976
4-(5-bromo-2- as SC_3097 1H NMR (600 MHz, DMSO) .delta. 8.20 (d,
1H), 436.3 morpholin-4-yl-pyridin-3-yl)-8- pyridyl)morpholine step
2 7.89 (dd, 1H), 7.37 (p, 5H), 7.27 (d, 1H),
phenyl-1,3-diazaspiro[4.5]decan-2- 6.79 (d, 1H), 3.71-3.66 (m, 4H),
3.53 (s, one 2H), 2.43-2.32 (m, 2H), 1.96 (s, 7H), 1.91-1.85 (m,
5H), 1.49-1.42 (m, 2H). SC_3180 cis-8-Dimethylamino-8-phenyl-3-
INT-976 4-bromo-2- SC_3103 1H NMR (DMSO-d6): .delta. 7.89-7.87 (m,
2H), 433.2 (2-phenyl-thiazol-4-yl)-1,3- phenylthiazole 7.55 (br s,
1H), 7.43-7.35 (m, 8H), diazaspiro[4.5]decan-2-one 7.29-7.26 (m,
1H), 3.82 (s, 2H), 2.45 (br m, 2H), 1.96-1.79 (m, 10H), 1.53-1.50
(m, 2H). SC_3181 cis-8-Dimethylamino-8-phenyl-3- INT-989
tetrahydro-2H-pyran- SC_3103 1H NMR (DMSO-d6): .delta. 8.42 (s,
2H), 451.3 [2-(tetrahydro-pyran-4-ylamino)- 4-amine 7.39-7.35 (m,
5H), 7.27-7.24 (m, 1H), 6.83 (d, pyrimidin-5-yl]-1,3- 1H),
3.84-3.79 (m, 3H), 3.50 (s, 2H), diazaspiro[4.5]decan-2-one
3.38-3.35 (m, 2H), 2.36-2.32 (m, 2H), 1.94-1.77 (m, 12H), 1.50-1.40
(m, 4H). SC_3183 cis-8-Dimethylamino-8-phenyl-3- INT-976 2-bromo-4-
SC_3103 1H NMR (DMSO-d6): .delta. 8.09 (br s, 1H), 433.2
(4-phenyl-thiazol-2-yl)-1,3- phenylthiazole 7.87 (d, 2H), 7.51 (s,
1H), 7.37-7.24 (m, 8H), diazaspiro[4.5]decan-2-one 3.87 (s, 2H),
2.43 (m, 2H), 1.96-1.84 (m, 10H), 1.54 (m, 2H). SC_3184
cis-8-Dimethylamino-8-phenyl-3- INT-976 1H-pyrrolo[2,3- SC_3103 1H
NMR (DMSO-d6): .delta. 9.07 (s, 2H), 468.2
[2-(1H-pyrrolo[2,3-b]pyridin-1-yl)- b]pyridine 8.35-8.33 (m, 1H),
8.10-8.04 (m, 2H), 7.83 (br s, pyrimidin-5-yl]-1,3- 1H), 7.41-7.37
(m, 4H), 7.29-7.21 (m, 2H), diazaspiro[4.5]decan-2-one 6.72-6.71
(d, 1H), 3.71 (s, 2H), 2.49 (m, 2H), 1.97 (m, 10H), 1.52 (m, 2H).
SC_3185 cis-8-Dimethylamino-8-phenyl-3- INT-989 (3,4,5- SC_3129 1H
NMR (600 MHz, DMSO) .delta. 9.11 (s, 2H), 481.2
[2-(3,4,5-trifluoro-phenyl)- trifluorophenyl)boronic 8.12-8.03 (m,
2H), 7.89 (s, 1H), pyrimidin-5-yl]-1,3- acid 7.42-7.34 (m, 4H),
7.28 (dq, 1H), 3.71 (s, 2H), diazaspiro[4.5]decan-2-one 2.48-2.35
(m, 2H), 1.99-1.79 (m, 10H), 1.58-1.47 (m, 2H). SC_3187
cis-8-Dimethylamino-3-m-tolyl-8- INT-976 1-bromo-3- SC_3186 363.2
phenyl-1,3-diazaspiro[4.5]decan-2- methylbenzene one SC_3188
cis-8-Dimethylamino-8-phenyl-3-p- INT-976 1-bromo-4- SC_3186 363.2
tolyl-1,3-diazaspiro[4.5]decan-2- methylbenzene one SC_3189
cis-8-Dimethylamino-8-phenyl-3- INT-976 1-bromo-4- SC_3186 417.2
[4-(trifluoromethyl)-phenyl]-1,3- trifluoromethylbenzene
diazaspiro[4.5]decan-2-one SC_3190 cis-8-Dimethylamino-8-phenyl-3-
INT-976 1-bromo-3- SC_3186 433.2 [3-(trifluoromethyloxy)-phenyl]-
(trifluoromethoxy)benzene 1,3-diazaspiro[4.5]decan-2-one SC_3191
cis-8-Dimethylamino-8-phenyl-3- INT-976 1-bromo-4- SC_3186 433.2
[4-(trifluoromethyloxy)-phenyl]- (trifluoromethoxy)benzene
1,3-diazaspiro[4.5]decan-2-one SC_3192
cis-2-(8-Dimethylamino-2-oxo-8- INT-976 methyl 2- SC_3186 407.2
phenyl-1,3-diazaspiro[4.5]decan-3- bromobenzoate yl)-benzoic acid
methyl ester SC_3193 cis-3-(8-Dimethylamino-2-oxo-8- INT-976 methyl
3- SC_3186 407.2 phenyl-1,3-diazaspiro[4.5]decan-3- bromobenzoate
yl)-benzoic acid methyl ester SC_3194
cis-4-(8-Dimethylamino-2-oxo-8- INT-976 methyl 4- SC_3186 407.2
phenyl-1,3-diazaspiro[4.5]decan-3- bromobenzoate yl)-benzoic acid
methyl ester SC_3195 cis-3-(1,3-Benzodioxol-5-yl)-8- INT-976 5-
SC_3186 393.2 dimethylamino-8-phenyl-1,3- bromobenzo[d][1,3]dioxole
diazaspiro[4.5]decan-2-one SC_3196 cis-8-Dimethylamino-8-phenyl-3-
INT-976 5-bromoquinoline SC_3186 400.2 quinolin-5-yl-1,3-
diazaspiro[4.5]decan-2-one SC_3197
cis-3-(2,3-Dihydro-1H-indol-6-yl)- INT-976 6-bromoindoline SC_3186
390.2 8-dimethylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2-one
SC_3198 cis-5-(8-Dimethylamino-2-oxo-8- INT-976 methyl 5-bromo-4-
SC_3186 422.2 phenyl-1,3-diazaspiro[4.5]decan-3- methylpicolinate
yl)-4-methyl-pyridine-2-carboxylic acid methyl ester SC_3199
cis-8-Dimethyl amino-3-(6- INT-976 5-bromo-2-methoxy- SC_3186 394.2
methoxy-4-methyl-pyridin-3-yl)-8- 4-methylpyridine
phenyl-1,3-diazaspiro[4.5]decan-2- one SC_3200
cis-8-Dimethylamino-3-[2-methyl- INT-976 5-bromo-1-methyl-3-
SC_3186 421.2 5-(trifluoromethyl)-2H-pyrazol-3-
(trifluoromethyl)-1H- yl]-8-phenyl-1,3- pyrazole
diazaspiro[4.5]decan-2-one SC_3201 cis-8-Dimethylamino-3-(3-
INT-976 2-bromo-3- SC_3186 380.2 methoxy-pyridin-2-yl)-8-phenyl-
methoxypyridine 1,3-diazaspiro[4.5]decan-2-one SC_3202
cis-8-Dimethylamino-8-phenyl-3- INT-976 2-bromo-5- SC_3186 418.2
[5-(trifluoromethyl)-pyridin-2-yl]- trifluoromethylpyridine
1,3-diazaspiro[4.5]decan-2-one SC_3203
cis-5-(8-Dimethylamino-2-oxo-8- INT-976 3-bromo-5- SC_3186 375.2
phenyl-1,3-diazaspiro[4.5]decan-3- cyanopyridine
yl)-nicotinonitrile SC_3204 cis-8-Dimethylamino-3-(3-methyl-
INT-976 2-bromo-3- SC_3186 364.2 pyridin-2-yl)-8-phenyl-1,3-
methylpyridine diazaspiro[4.5]decan-2-one SC_3205
cis-8-Dimethylamino-3-(6- INT-976 5-bromo-2- SC_3186 380.2
methoxy-pyridin-3-yl)-8-phenyl- methoxypyridine
1,3-diazaspiro[4.5]decan-2-one SC_3206
cis-8-Dimethylamino-8-phenyl-3- INT-976 1-bromo-3- SC_3186 417.2
[3-(trifluoromethyl)phenyl]-1,3- trifluoromethylbenzene
diazaspiro[4.5]decan-2-one SC_3207 cis-3-(1,3-Benzodioxol-4-yl)-8-
INT-976 4- SC_3186 393.2 dimethylamino-8-phenyl-1,3-
bromobenzo[d][1,3]dioxole diazaspiro[4.5]decan-2-one SC_3209
cis-8-Dimethylamino-3-[2-(3,5- INT-976 3,5-dimethyl-1H- SC_3103 1H
NMR (DMSO-d6): .delta. 9.00 (s, 2H), 446.2
dimethyl-1H-pyrazol-1-yl)- pyrazole 7.81 (br s, 1H), 7.38-7.27 (m,
5H), 6.07 (s, 1H), pyrimidin-5-yl]-8-phenyl-1,3- 3.69 (s, 2H), 2.45
(m, 5H), 2.17 (s, 3H), diazaspiro[4.5]decan-2-one 1.96-1.91 (m,
10H), 1.51 (br m, 2H). SC_3210 cis-8-Dimethylamino-3-[2-(3- INT-989
rac-piperidin-3-ol SC_3182 1H NMR (DMSO-d6): 8.48 (s, 2H), 451.2
hydroxy-piperidin-1-yl)-pyrimidin- 7.39-7.35 (m, 5H), 7.27-7.24 (m,
1H), 4.82 (d, 5-yl]-8-phenyl-1,3- 1H), 4.39-4.36 (m, 1H), 4.24-4.21
(m, 1H), diazaspiro[4.5]decan-2-one 3.51 (s, 2H), 3.41-3.36 (m,
1H), 2.92-2.87 (m, 1H), 2.77-2.72 (m, 1H), 2.42-2.32 (m, 2H),
2.00-1.66 (m, 12H), 1.46-1.39 (m, 2H), 1.34 (t, 2H). SC_3211
cis-8-Dimethylamino-3-[2-(3- INT-989 rac-piperidin-3-ol SC_3182 1H
NMR (DMSO-d6): 8.48 (s, 2H), 7.35 (m, 451.3
hydroxy-piperidin-1-yl)-pyrimidin- 5H), 7.25 (m, 1H), 4.82 (d, 1H),
5-yl]-8-phenyl-1,3- 4.39-4.37 (m, 1H), 4.24-4.21 (m, 1H), 3.51 (s,
2H), diazaspiro[4.5]decan-2-one 3.40-3.39 (m, 1H), 2.90-2.87 (m,
1H), 2.77-2.72 (m, 1H), 2.37 (m, 2H), 2.00-1.66 (m, 12H), 1.45 (m,
2H), 1.34 (t, 2H). SC_3212 cis-8-Dimethylamino-3-[2-[4-(2- INT-989
2-piperazin-1- SC_3120 1H NMR (600 MHz, DMSO) .delta. 8.53 (s, 2H),
480.3 hydroxy-ethyl)-piperazin-1-yl]- ylethanol 7.37 (p, 5H), 7.27
(d, 1H), 3.62 (t, 4H), pyrimidin-5-yl]-8-phenyl-1,3- 3.53 (q, 4H),
2.49-2.27 (m, 7H), 1.96 (s, 6H), diazaspiro[4.5]decan-2-one
1.94-1.73 (m, 4H), 1.51-1.40 (m, 2H). SC_3213
cis-2-[4-[5-(8-Dimethylamino-2- SC_3146 INT-991 1H NMR (600 MHz,
DMSO) .delta. 8.53 (s, 2H), 494.3 oxo-8-phenyl-1,3- 7.57 (s, 1H),
7.42 (d, 4H), 7.33 (d, 1H), diazaspiro[4.5]decan-3-yl)- 3.68 (t,
4H), 3.19 (s, 2H), 2.62 (t, 4H), 2.37 (d,
pyrimidin-2-yl]-piperazin-1-yl]- 2H), 2.20-1.96 (m, 8H), 1.88 (t,
2H), acetic acid 1.43 (t, 2H). SC_3214 cis-8-Dimethylamino-3-[2-(1-
INT-989 1-methyl-4-(4,4,5,5- SC_3208 1H NMR (600 MHz, DMSO + 2 vol
% TFA) 484.3 methyl-1H-pyrrolo[2,3-b]pyridin-4- tetramethyl-1,3,2-
.delta. 9.85 (s, 1H), 9.13 (s, 2H), 8.41 (d, 2H),
yl)-pyrimidin-5-yl]-8-phenyl-1,3- dioxaborolan-2-yl)- 7.99 (s, 1H),
7.72 (s, 2H), 7.66-7.46 (m, diazaspiro[4.5]decan-2-one 2,3- 4H),
7.30 (s, 1H), 3.88 (s, 2H), 3.60 (s, 6H), dihydropyrrolo[2,3-
2.77-2.71 (m, 2H), 2.30-2.26 (m, 2H), b]pyridine 1.94-1.89 (m, 2H),
1.75 (s, 3H), 1.41-1.35 (m, 2H). SC_3215
cis-8-Benzyl-8-dimethylamino-3- INT-994 5-bromo-4-methyl-2- SC_3103
1H NMR (600 MHz, DMSO) .delta. 8.52 (s, 1H), 447.2
[4-methyl-6-(trifluoromethyl)- (trifluoromethyl)pyridine 7.76 (s,
1H), 7.23 (dd, 2H), 7.19-7.11 (m, pyridin-3-yl]-1,3- 4H), 2.62 (s,
2H), 2.27 (s, 6H), 2.25 (s, 3H), diazaspiro[4.5]decan-2-one 1.86
(td, 2H), 1.80 (dt, 2H), 1.57-1.49 (m, 2H), 1.09 (td, 2H). SC_3216
trans-8-Dimethylamino-3-[4- INT-998 5-bromo-4-methyl-2- SC_3103 1H
NMR (600 MHz, DMSO) .delta. 8.61 (s, 1H), 439.2
methyl-6-(trifluoromethyl)-pyridin- (trifluoromethyl)pyridine 7.83
(s, 1H), 7.53-7.49 (m, 1H), 7.45 (dd, 3-yl]-8-thiophen-2-yl-1,3-
1H), 7.09 (dd, 1H), 6.99 (dd, 1H), 3.70 (s,
diazaspiro[4.5]decan-2-one 2H), 2.35 (s, 3H), 2.19-2.05 (m, 4H),
2.02 (s, 6H), 1.93-1.85 (m, 2H), 1.64 (dt, 2H). SC_3217
cis-8-Dimethylamino-3-[4-methyl- INT-997 5-bromo-4-methyl-2-
SC_3103 1H NMR (600 MHz, DMSO) .delta. 8.58 (s, 1H), 439.2
6-(trifluoromethyl)-pyridin-3-yl]-8- (trifluoromethyl)pyridine 7.80
(s, 1H), 7.45 (s, 1H), 7.42 (dd, 1H), thiophen-2-yl-1,3- 7.05 (dd,
1H), 6.95 (dd, 1H), 3.67 (s, 2H), diazaspiro[4.5]decan-2-one 2.33
(s, 3H), 2.32-2.25 (m, 2H), 2.04 (s, 6H), 2.00-1.92 (m, 2H),
1.89-1.76 (m, 2H), 1.62 (dt, 2H). SC_3218
cis-8-Dimethylamino-3-[2-(1,1- INT-976 4-[5-bromo-4- SC_3103 1H NMR
(600 MHz, DMSO) .delta. 8.65 (s, 1H), 553.2
dioxo-[1,4]thiazinan-4-yl)-4- (trifluoromethyl)pyrimidin- 7.42 (s,
1H), 7.41-7.31 (m, 5H), 7.25 (tt,
(trifluoromethyl)-pyrimidin-5-yl]- 2-yl]-1,4- 1H), 4.23 (t, 4H),
3.22 (t, 4H), 8-phenyl-1,3-diazaspiro[4.5]decan- thiazinane 1,1-
2.40-2.26 (m, 2H), 1.97-1.88 (m, 8H), 2-one dioxide (prepared as
1.87-1.75 (m, 2H), 1.54-1.42 (m, 2H). SC_3097 step 1) SC_3219
cis-8-Dimethylamino-8-(1-methyl- INT- 5-bromo-2- SC_3103 1H NMR
(600 MHz, DMSO) .delta. 9.14 (s, 2H), 474.2
1H-benzoimidazol-2-yl)-3-[2- 1000 (trifluoromethyl)pyrimidine 8.65
(s, 1H), 7.63 (d, 1H), 7.51 (d, 1H),
(trifluoromethyl)-pyrimidin-5-yl]- 7.25 (ddd, 1H), 7.19 (ddd, 1H),
4.02 (s, 3H), 1,3-diazaspiro[4.5]decan-2-one 3.61 (s, 2H), 2.26 (d,
2H), 2.18 (s, 6H), 2.16-2.09 (m, 2H), 1.87 (s, 2H), 1.78 (d, 2H).
SC_3220 cis-8-Dimethylamino-8-(1-methyl- INT- 5-bromo-4-methyl-2-
SC_3103 1H NMR (600 MHz, DMSO) .delta. 8.56 (s, 1H), 487.3
1H-benzoimidazol-2-yl)-3-[4- 1000 (trifluoromethyl)pyridine 8.10
(s, 1H), 7.80 (s, 1H), 7.60 (d, 1H),
methyl-6-(trifluoromethyl)-pyridin- 7.50 (d, 1H), 7.23 (ddd, 1H),
7.17 (td, 1H), 3-yl]-1,3-diazaspiro[4.5]decan-2- 4.02 (s, 3H), 3.50
(s, 2H), 2.34-2.25 (m, 5H), one 2.19-2.09 (m, 8H), 1.90-1.74 (m,
4H). SC_3222 cis-3-[2-(Benzyl-methyl-amino)- INT-976
N-benzyl-5-bromo-N- SC_3103 1H NMR (DMSO-d6): .delta. 8.52 (s, 2H),
471.2 pyrimidin-5-yl]-8-dimethylamino- methylpyrimidin-2- 7.39-7.33
(m, 5H), 7.30-7.17 (m, 6H), 4.81 (s,
8-phenyl-1,3-diazaspiro[4.5]decan- amine 2H), 3.52 (s, 2H), 3.03
(s, 3H), 2.45-2.32 (m, 2-one 2H), 1.95-1.86 (m, 10H), 1.47-1.43 (m,
2H). SC_3223 cis-5-(8-Dimethylamino-2-oxo-8- INT-976 ethyl 5-
SC_3103 (step 1H NMR (DMSO-d6): .delta. 9.04 (s, 2H), 585.3
phenyl-1,3-diazaspiro[4.5]decan-3- bromopyrimidine-2- 1), INT-991
8.24-8.23 (m, 1H), 7.42-7.39 (m, 2H),
yl)-N-[2-[2-[2-(2-methoxy-ethoxy)- carboxylate (step 1), (step 2),
7.32-7.31 (m, 3H), 5.70 (s, 1H), 3.70-3.60 (m, 16H),
ethoxy]-ethoxy]-ethyl]-pyrimidine- 2,5,8,11- SC_3133 (step
3.54-3.52 (m, 2H), 3.35 (s, 3H), 2-carboxylic acid amide
tetraoxatridecan-13- 3) 2.21-2.00 (m, 12H), 1.66-1.64 (m, 2H).
amine (step 3) SC_3225 cis-8-Dimethylamino-3-[2-[(2- INT-989 2-
SC_3182 1H NMR (DMSO-d6): .delta. 8.46 (s, 2H), 425.2
hydroxy-ethyl)-methyl-amino]- (methylamino)ethanol 7.39-7.33 (m,
5H), 7.27-7.24 (m, 1H), 4.62 (t, pyrimidin-5-yl]-8-phenyl-1,3- 1H),
3.61-3.50 (m, 6H), 3.08 (s, 3H), diazaspiro[4.5]decan-2-one
2.36-2.33 (m, 2H), 1.95-1.86 (m, 10H), 1.47-1.45 (m, 2H). SC_3226
cis-3-(8-Dimethylamino-2-oxo-8- INT-976 5-bromo-4-methyl-2- SC_3103
(step 487.3 phenyl-1,3-diazaspiro[4.5]decan-3-
(trifluoromethyl)pyridine 1), SC_3016 yl)-benzamide (step 2)
SC_3227 cis-8-Dimethylamino-3-[3-fluoro- INT-976
2-bromo-3-fluoro-5- SC_3186 417.1
5-(trifluoromethyl)-pyridin-2-yl]-8- (trifluoromethyl)pyridine
phenyl-1,3-diazaspiro[4.5]decan-2- one SC_3228
cis-8-Dimethylamino-3-(5-methyl- INT-976 2-bromo-5- SC_3186 459.1
pyrazin-2-yl)-8-phenyl-1,3- methylpyrazine
diazaspiro[4.5]decan-2-one SC_3229 cis-8-Dimethylamino-3-(5-fluoro-
INT-976 4-bromo-5- SC_3186 433.2 pyrimidin-4-yl)-8-phenyl-1,3-
fluoropyrimidine diazaspiro[4.5]decan-2-one SC_3230
cis-8-Dimethylamino-3-(5-fluoro- INT-976 2-bromo-5- SC_3186 458.1
pyrimidin-2-yl)-8-phenyl-1,3- fluoropyrimidine
diazaspiro[4.5]decan-2-one SC_3231 cis-8-Dimethylamino-8-phenyl-3-
INT-976 2-bromopyrazine SC_3186 471.1 pyrazin-2-yl-1,3-
diazaspiro[4.5]decan-2-one SC_3232
cis-3-([2,1,3]Benzoxadiazol-5-yl)- INT-976 5- SC_3186 444.1
8-dimethylamino-8-phenyl-1,3- bromobenzo[c][1,2,5]-
diazaspiro[4.5]decan-2-one oxadiazole SC_3233
cis-2-[2-(8-Dimethylamino-2-oxo- SC_3169 ammonium chloride SC_3133
1H NMR (600 MHz, DMSO) .delta. 7.73 (s, 1H), 423.2
8-phenyl-1,3-diazaspiro[4.5]decan- 7.40-7.32 (m, 4H), 7.31 (s, 1H),
7.26 (dd, 3-yl)-phenoxy]-acetamide 1H), 7.18 (td, 1H), 6.98-6.91
(m, 2H), 4.50 (s, 2H), 3.52 (s, 2H), 2.42-2.29 (m, 2H), 2.01-1.71
(m, 10H), 1.55-1.48 (m, 2H). SC_3234
cis-8-Dimethylamino-8-phenyl-3- INT-976 4-(5-bromothiophen- SC_3103
1H NMR (DMSO-d6): .delta. 8.45-8.43 (d, 2H), 433.2
(5-pyridin-4-yl-thiophen-2-yl)-1,3- 2-yl)pyridine 7.87 (br s, 1H),
7.54-7.53 (d, 1H), diazaspiro[4.5]decan-2-one 7.49-7.48 (m, 2H),
7.38-7.27 (m, 5H), 6.35-6.34 (d, 2H), 3.64 (s, 2H), 2.42 (m, 2H),
1.96-1.90 (m, 10H), 1.51-1.49 (m, 2H). SC_3236
cis-8-Dimethylamino-3-(2- INT- morpholine SC_3120 1H NMR (600 MHz,
DMSO) .delta. 8.07 (d, 1H), 437.3 morpholin-4-yl-pyrimidin-4-yl)-8-
1002 7.93 (s, 1H), 7.37 (dt, 5H), 7.27 (t, 1H),
phenyl-1,3-diazaspiro[4.5]decan-2- 3.65 (s, 2H), 3.58 (s, 8H),
2.40-2.27 (m, 2H), one 1.94 (s, 6H), 1.92-1.80 (m, 4H), 1.43 (d,
2H). SC_3237 cis-3-[2-(3,4-Difluoro-phenyl)- INT-989 (3,4- SC_3129
1H NMR (600 MHz, DMSO) .delta. 9.08 (s, 2H), 463.2
pyrimidin-5-yl]-8-dimethylamino- difluorophenyl)boronic 8.22-8.12
(m, 2H), 7.54 (dt, 1H), 8-phenyl-1,3-diazaspiro[4.5]decan- acid
7.41-7.37 (m, 4H), 7.29 (s, 1H), 3.70 (s, 2H), 2-one 2.06-1.75 (m,
12H), 1.50 (d, 2H). SC_3241 cis-2-[4-[5-(8-Dimethylamino-2- SC_3213
ammonium chloride SC_3133 1H NMR (600 MHz, DMSO) .delta. 8.53 (s,
2H), 493.3 oxo-8-phenyl-1,3- 7.38 (d, 5H), 7.27 (s, 1H), 7.23 (s,
1H), diazaspiro[4.5]decan-3-yl)- 7.11 (s, 1H), 3.67 (t, 4H),
3.54-3.50 (m, 2H), pyrimidin-2-yl]-piperazin-1-yl]- 2.89 (s, 2H),
2.47 (t, 4H), 2.39-2.35 (m, acetamide 2H), 1.96 (s, 7H), 1.93-1.82
(m, 3H), 1.48-1.44 (m, 2H). SC_3243 cis-8-Dimethylamino-3-[6-(4-
INT-976 1-(5-bromo-2- SC_3242 (step 1H NMR (600 MHz, DMSO) .delta.
8.16 (d, 1H), 449.3 methyl-piperazin-1-yl)-pyridin-3-
pyridyl)-4-methyl- 2) 7.86 (dd, 1H), 7.41-7.33 (m, 4H), 7.32 (s,
yl]-8-phenyl-1,3- piperazine 1H), 7.27 (t, 1H), 6.78 (d, 1H), 3.51
(s, 2H), diazaspiro[4.5]decan-2-one 2.55-2.45 (m, 4H), 2.42-2.27
(m, 6H), 2.21 (s, 3H), 1.96 (s, 6H), 1.93-1.73 (m, 4H), 1.46 (t,
2H). SC_3244 cis-8-Dimethylamino-3-[2-(1,1- INT-976
4-(5-bromo-4-methyl- SC_3103 1H NMR (600 MHz, DMSO) .delta. 8.20
(s, 1H), 499.3 dioxo-[1,4]thiazinan-4-yl)-4- pyrimidin-2-yl)-1,4-
7.36 (h, 4H), 7.30-7.17 (m, 2H), methyl-pyrimidin-5-yl]-8-phenyl-
thiazinane 1,1- 4.23-4.17 (m, 4H), 3.13 (t, 4H), 2.44-2.28 (m,
1,3-diazaspiro[4.5]decan-2-one dioxide 2H), 2.24 (s, 3H), 1.97 (s,
6H), 1.91 (d, 4H), 1.55-1.44 (m, 2H). SC_3245
cis-8-Dimethylamino-8-phenyl-3- INT-976 5-bromo-2- SC_3103 1H NMR
(600 MHz, DMSO) .delta. 9.17 (s, 2H), 419.2
[2-(trifluoromethyl)-pyrimidin-5- (trifluoromethyl)- 8.03 (s, 1H),
7.38 (s, 4H), 7.28 (tt, 1H), yl]-1,3-diazaspiro[4.5]decan-2-one
pyrimidine 3.73 (s, 2H), 2.49-2.35 (m, 2H), 1.97 (s, 6H), 1.97-1.92
(m, 2H), 1.90-1.73 (m, 2H), 1.55-1.49 (m, 2H). SC_3246
cis-2-[8-Dimethylamino-1-(3- INT-979 2-chloropyrimidine- SC_3103 1H
NMR (600 MHz, DMSO) .delta. 9.02 (s, 2H), 449.3
methoxy-propyl)-2-oxo-8-phenyl- 5-carbonitrile 7.40-7.31 (m, 5H),
3.86 (s, 2H), 3.26 (s, 1,3-diazaspiro[4.5]decan-3-yl]- 3H),
3.29-3.19 (m, 2H), 2.73-2.67 (m, pyrimidine-5-carbonitrile 2H),
2.16 (td, 2H), 2.00 (s, 7H), 1.83 (dt, 2H), 1.50-1.40 (m, 5H).
SC_3247 cis-8-Dimethylamino-3-[2-(4- INT-989 1-Methylpiperazin
SC_3120 1H NMR (600 MHz, DMSO) .delta. 8.54 (s, 2H), 450.3
methyl-piperazin-1-yl)-pyrimidin- 7.48-7.33 (m, 5H), 7.31-7.21 (m,
1H), 5-yl]-8-phenyl-1,3- 3.63 (dd, 4H), 2.45-2.29 (m, 6H), 2.20 (s,
diazaspiro[4.5]decan-2-one 3H), 1.96 (s, 6H), 1.94-1.78 (m, 4H),
1.51-1.42 (m, 2H). SC_3248 cis-8-Dimethylamino-1-[(1- SC_3245
[1-[tert- INT-988 (step 1H NMR (600 MHz, DMSO) .delta. 9.24 (s,
2H), 504.3 hydroxy-cyclobutyl)-methyl]-8- butyl(dimethyl)silyl]- 1)
7.38 (d, 4H), 7.27 (p, 1H), 3.89 (s, 2H),
phenyl-3-[2-(trifluoromethyl)- oxycyclobutyl]methyl 2.73-2.67 (m,
2H), 2.26 (ddd, 2H), 2.19 (tt, 2H), pyrimidin-5-yl]-1,3- 4- 2.08
(s, 1H), 2.00 (s, 6H), 1.92 (qd, 2H), diazaspiro[4.5]decan-2-one
methylbenzenesulfonate 1.73-1.64 (m, 1H), 1.60-1.50 (m, 3H),
1.50-1.45 (m, 2H). SC_3249 cis-2-[1-(3-Methoxy-propyl)-8- SC_3246
SC_3099 1H NMR (600 MHz, DMSO) .delta. 9.05 (s, 2H), 435.3
methylamino-2-oxo-8-phenyl-1,3- 7.49-7.44 (m, 2H), 7.34 (t, 2H),
7.21 (t, diazaspiro[4.5]decan-3-yl]- 1H), 3.90 (s, 2H), 3.26 (s,
3H), 2.23 (td, 2H), pyrimidine-5-carbonitrile 2.07 (s, 1H), 1.91
(d, 5H), 1.86-1.78 (m, 2H), 1.73 (tt, 2H), 1.42 (d, 2H). SC_3250
cis-8-Dimethylamino-8-phenyl-3- INT-976 5-bromo-2- SC_3103 1H NMR
(600 MHz, DMSO) .delta. 8.88 (d, 1H), 419.3
[6-(trifluoromethyl)-pyridin-3-yl]- (trifluoromethyl)pyridine 8.24
(dd, 1H), 7.86 (s, 1H), 7.78 (d, 1H),
1,3-diazaspiro[4.5]decan-2-one 7.41-7.34 (m, 4H), 7.27 (t, 1H),
3.69 (s, 2H), 2.42 (s, 2H), 1.97 (s, 6H), 1.96-1.74 (m, 4H),
1.53-1.47 (m, 2H). SC_3251 cis-5-(8-Dimethylamino-2-oxo-8- INT-976
5-bromopyridine-2- SC_3103 1H NMR (600 MHz, DMSO) .delta. 8.92 (d,
1H), 376.2 phenyl-1,3-diazaspiro[4.5]decan-3- carbonitrile 8.15
(dd, 1H), 7.95 (br s, 1H), 7.90 (d, 1H),
yl)-pyridine-2-carbonitrile 7.41-7.34 (m, 4H), 7.27 (t, 1H), 3.69
(s, 2H), 2.44-2.40 (m, 2H), 1.97 (s, 6H), 1.96-1.89 (m, 3H),
1.90-1.70 (m, 1H), 1.53-1.46 (m, 2H). SC_3252
cis-8-Dimethylamino-3-(2- INT-989 morpholine SC_3120 1H NMR (600
MHz, DMSO) .delta. 8.57 (s, 2H), 437.3
morpholin-4-yl-pyrimidin-5-yl)-8- 7.46-7.42 (m, 1H), 7.40-7.34 (m,
4H), phenyl-1,3-diazaspiro[4.5]decan-2- 7.27 (td, 1H), 3.64 (dd,
4H), 3.59 (dd, 4H), one 3.54 (s, 2H), 2.46-2.29 (m, 2H), 1.96 (s,
7H), 1.93-1.73 (m, 3H), 1.50-1.44 (m, 2H). SC_3253 ci
s-8-Dimethylamino-3-(2-methyl- INT-976 5-bromo-2-methyl- SC_3103 1H
NMR (600 MHz, DMSO) .delta. 8.86 (s, 2H), 366.3
pyrimidin-5-yl)-8-phenyl-1,3- pyrimidine 7.69 (s, 1H), 7.41-7.33
(m, 5H), diazaspiro[4.5]decan-2-one 7.31-7.19 (m, 1H), 3.62 (s,
2H), 2.53 (s, 3H), 2.48-2.31 (m, 2H), 1.97 (s, 6H), 1.95-1.77 (m,
4H), 1.52-1.46 (m, 2H). SC_3254 cis-8-Dimethylamino-1-[(2- SC_3253
2-methoxybenzyl SC_3105 1H NMR (DMSO-d6): .delta. 8.90 (s, 2H),
486.2 methoxyphenyl)-methyl]-3-(2- bromide 7.39-7.34 (m, 3H),
7.28-7.22 (m, 4H), methyl-pyrimidin-5-yl)-8-phenyl- 6.95-6.87 (m,
2H), 4.58 (s, 2H), 3.89 (s, 3H), 3.63 (s,
1,3-diazaspiro[4.5]decan-2-one 2H), 2.68-2.64 (m, 5H), 2.35-2.28
(m, 2H), 2.01 (s, 6H), 1.49-1.43 (m, 4H). SC_3255
cis-1-[(1-Hydroxy-cyclobutyl)- SC_3248 SC_3099 1H NMR (600 MHz,
DMSO) .delta. 9.26 (s, 2H), 490.3 methyl]-8-methylamino-8-phenyl-
7.51 (d, 2H), 7.34 (t, 2H), 7.22 (t, 1H),
3-[2-(trifluoromethyl)-pyrimidin-5- 3.92 (s, 2H), 3.41 (s, 1H),
2.31 (td, 2H), 2.15 (td, yl]-1,3-diazaspiro[4.5]decan-2-one 2H),
2.07 (d, 1H), 1.93 (d, 7H), 1.83 (dt, 2H), 1.67 (t, 1H), 1.56 (q,
1H), 1.47 (d, 2H). SC_3256 cis-8-Dimethylamino-1-[(1- SC_3253
[1-[tert- INT-988 (step 1H NMR (600 MHz, DMSO) .delta. 8.92 (s,
2H), 450.3 hydroxy-cyclobutyl)-methyl]-3-(2- butyl(dimethyl)silyl]-
1) 7.37 (d, 4H), 7.27 (td, 1H), 3.79 (s, 2H),
methyl-pyrimidin-5-yl)-8-phenyl- oxycyclobutyl]methyl 3.27 (s, 1H),
2.72-2.65 (m, 2H), 2.54 (s, 3H), 1,3-diazaspiro[4.5]decan-2-one 4-
2.25-2.19 (m, 2H), 2.16 (tt, 2H), 2.07 (s, methylbenzenesulfonate
2H), 2.00 (s, 6H), 1.95-1.86 (m, 2H), 1.67 (qd, 1H), 1.55 (td, 2H),
1.51-1.42 (m, 3H). SC_3257 cis-1-[(1-Hydroxy-cyclobutyl)- SC_3260
SC_3099 1H NMR (600 MHz, DMSO) .delta. 9.07 (s, 2H), 422.3
methyl]-8-methylamino-8-phenyl- 8.81 (s, 1H), 7.53-7.48 (m, 2H),
7.33 (t, 3-pyrimidin-5-yl-1,3- 2H), 7.24-7.18 (m, 1H), 3.86 (s,
2H), diazaspiro[4.5]decan-2-one 2.29 (td, 2H), 2.14 (tt, 2H), 2.07
(s, 1H), 1.96-1.87 (m, 8H), 1.82 (td, 2H), 1.71-1.62 (m, 1H), 1.54
(dp, 1H), 1.49-1.43 (m, 2H). SC_3258
cis-5-(8-Dimethylamino-2-oxo-8- INT-976 5-bromo-4-methyl- SC_3103
1H NMR (600 MHz, DMSO) .delta. 8.57 (s, 1H), 390.2
phenyl-1,3-diazaspiro[4.5]decan-3- pyridine-2- 7.92 (s, 1H),
7.61-7.57 (m, 1H), yl)-4-methyl-pyridine-2- carbonitrile 7.42-7.32
(m, 4H), 7.25 (tt, 1H), 3.63 (s, 2H), carbonitrile 2.38 (d, 2H),
2.28 (s, 3H), 2.00-1.90 (m, 9H), 1.90-1.72 (m, 1H), 1.59-1.49 (m,
2H). SC_3259 cis-8-Dimethylamino-3-(2-methyl- SC_3253 2- SC_3105 1H
NMR (DMSO-d6): .delta. 8.94 (s, 2H), 457.2
pyrimidin-5-yl)-8-phenyl-1- (bromomethyl)pyridine 8.52-8.51 (m,
1H), 7.77-7.74 (m, 1H), (pyridin-2-yl-methyl)-1,3- 7.45-7.42 (d,
1H), 7.38-7.22 (m, 6H), 4.47 (s, 2H), diazaspiro[4.5]decan-2-one
3.84 (s, 2H), 2.66-2.63 (m, 2H), 2.54 (s, 3H), 2.06-2.03 (m, 2H),
1.92 (s, 6H), 1.57-1.42 (m, 4H). SC_3260 INT-976 5-bromopyrimidine
SC_3103 1H NMR (600 MHz, DMSO) .delta. 8.98 (s, 2H), 352.2 8.76 (s,
1H), 7.78 (s, 1H), 7.41-7.34 (m, 4H), 7.31-7.24 (m, 1H), 3.65 (s,
2H), 2.49-2.34 (m, 2H), 1.97 (s, 6H), 1.95-1.76 (m, 4H), 1.50 (t,
2H). SC_3261 cis-8-Dimethylamino-1-[(1- SC_3260 [1-[tert- INT-988
(step 1H NMR (600 MHz, DMSO) .delta. 9.04 (s, 2H), 436.3
hydroxy-cyclobutyl)-methyl]-8- butyl(dimethyl)silyl]- 1) 8.80 (s,
1H), 7.37 (d, 4H), 7.27 (p, 1H), phenyl-3-pyrimidin-5-yl-1,3-
oxycyclobutyl]methyl 3.83 (s, 2H), 3.28 (s, 1H), 2.72-2.65 (m, 2H),
diazaspiro[4.5]decan-2-one 4- 2.23 (td, 1H), 2.17 (tt, 1H), 2.07
(s, 2H), methylbenzenesulfonate 2.00 (s, 6H), 1.91 (dt, 2H),
1.72-1.63 (m, 1H), 1.60-1.45 (m, 5H). SC_3262
cis-8-Amino-1-[(1-hydroxy- SC_3255 SC_3099 1H NMR (600 MHz, DMSO)
.delta. 9.29 (s, 2H), 476.2 cyclobutyl)-methyl]-8-phenyl-3-[2-
7.68-7.63 (m, 2H), 7.33 (t, 2H), (trifluoromethyl)-pyrimidin-5-yl]-
7.26-7.18 (m, 1H), 3.97 (s, 2H), 3.45 (s, 2H), 2.43 (td,
1,3-diazaspiro[4.5]decan-2-one 2H), 2.14 (tt, 2H), 1.99 (td, 2H),
1.96-1.90 (m, 2H), 1.71-1.54 (m, 4H), 1.52-1.47 (m, 2H). SC_3263
cis-8-Dimethylamino-3-(3- INT-976 1-bromo-3-fluoro- SC_3103 1H NMR
(600 MHz, DMSO) .delta. 368.2 fluorophenyl)-8-phenyl-1,3- benzene
7.58-7.50 (m, 2H), 7.41-7.33 (m, 4H), diazaspiro[4.5]decan-2-one
7.33-7.23 (m, 3H), 6.77-6.71 (m, 1H), 3.58 (s, 2H), 2.48-2.31 (m,
2H), 1.97 (s, 6H), 1.92-1.80 (m, 4H), 1.47 (t, 2H). SC_3264
cis-8-Dimethylamino-3-(3- INT-976 1-bromo-3- SC_3103 1H NMR (600
MHz, DMSO) .delta. 8.13 (t, 1H), 428.2
methylsulfonyl-phenyl)-8-phenyl- methylsulfonylbenzene 7.88 (d,
1H), 7.65 (s, 1H), 7.53 (t, 1H), 1,3-diazaspiro[4.5]decan-2-one
7.47 (dt, 1H), 7.41-7.35 (m, 4H), 7.28 (qd, 1H), 3.66 (s, 2H), 3.16
(s, 3H), 2.49-2.36 (m, 2H), 1.97 (s, 6H), 1.96-1.74 (m, 4H),
1.53-1.47 (m, 2H). SC_3265 cis-8-Dimethylamino-3-(4- INT-976
1-bromo-4- SC_3103 1H NMR (600 MHz, DMSO) .delta. 428.2
methylsulfonyl-phenyl)-8-phenyl- methylsulfonylbenzene 7.83-7.70
(m, 5H), 7.41-7.34 (m, 4H), 7.27 (tt, J = 7.1,
1,3-diazaspiro[4.5]decan-2-one 1.9 Hz, 1H), 3.65 (s, 2H), 3.12 (s,
3H), 2.49-2.31 (m, 2H), 1.97 (s, 6H), 1.95-1.75 (m, 4H), 1.49 (t, J
= 8.6 Hz, 2H). SC_3266 cis-8-Dimethylamino-8-phenyl-3- INT-976
3-bromopyridazine SC_3103 1H NMR (600 MHz, DMSO) .delta. 8.82 (dd,
J = 4.6, 352.2 pyridazin-3-yl-1,3- 1.4 Hz, 1H), 8.45 (dd, J = 9.2,
1.4 Hz, diazaspiro[4.5]decan-2-one 1H), 7.95 (br s, 1H), 7.55 (dd,
J = 9.2, 4.5 Hz, 1H), 7.42-7.34 (m, 4H), 7.28 (t, J = 6.8 Hz, 1H),
3.83 (s, 2H), 2.47-2.29 (m, 1H), 1.97 (s, 10H), 1.54-1.48 (m, 2H).
SC_3267 cis-3-Methoxy-4-(8-methylamino- INT-976 4-bromo-3-methoxy-
SC_3103 (for 1HNMR (DMSO-d6, 400 MHz), .delta. (ppm) = 7.50-7.50
(m, 391.2 2-oxo-8-phenyl-1,3- benzonitrile (step 1) step 1), 2H),
7.42-7.31 (m, 5H), diazaspiro[4.5]decan-3-yl)- SC_3099 (for 7.18
(bs, 2H), 3.83 (s, 3H), 3.64 (s, 2H), benzonitrile step 2)
2.05-21.99 (m, 2H), 1.85 (bs, 5H), 1.70 (bs, 2H), 1.53-1.50 (m,
2H). SC_3268 cis-8-Dimethylamino-3-(2- INT-976 1-bromo-2- SC_3103
1H NMR (600 MHz, DMSO) .delta. 7.46 (td, J = 8.0, 368.2
fluorophenyl)-8-phenyl-1,3- luorobenzene 1.6 Hz, 1H), 7.40-7.32 (m,
5H), diazaspiro[4.5]decan-2-one 7.26 (td, J = 6.7, 3.3 Hz, 1H),
7.24-7.12 (m, 3H), 3.53 (s, 2H), 2.37-2.33 (m, 2H), 1.96 (s, 6H),
1.95-1.74 (m, 4H), 1.49 (t, J = 9.3 Hz, 2H). SC_3269
cis-8-Dimethylamino-8-phenyl-3- INT-976 5-bromo-2-phenyl- SC_3103
1H NMR (600 MHz, DMSO) .delta. 9.07 (s, 2H), 428.3
(2-phenyl-pyrimidin-5-yl)-1,3- pyrimidine 8.34-8.28 (m, 2H), 7.82
(s, 1H), diazaspiro[4.5]decan-2-one 7.52-7.42 (m, 4H), 7.39 (s,
1H), 7.38 (s, 3H), 7.28 (t, J = 4.8 Hz, 1H), 3.70 (s, 2H),
2.43-2.39 (m, 2H), 2.06-1.72 (m, 10H), 1.52 (d, J = 10.8 Hz, 2H).
SC_3270 cis-8-Methylamino-1-(oxetan-3-yl- SC_3245 oxetan-3-ylmethyl
4- SC_3099 (for 1H NMR (DMSO-d6): .delta. 9.24 (s, 2H), 476.2
methyl)-8-phenyl-3-[2- methylbenzenesulfonate step1), 7.49 (d, 2H),
7.34 (t, 2H), 7.21 (t, 1H), (trifluoromethyl)-pyrimidin-5-yl]-
(step 2) SC_3105 (for 4.66-4.62 (m, 2H), 4.44 (t, 2H), 3.87 (s,
2H), 3.55 (d, 1,3-diazaspiro[4.5]decan-2-one step 2) 2H), 3.28-3.23
(m, 1H), 2.36 (m, 1H), 2.20-2.14 (m, 2H), 1.95-1.91 (m, 5H),
1.84-1.77 (m, 2H), 1.43-1.40 (m, 2H). SC_3271
cis-1-(Cyclopropyl-methyl)-8- SC_3245 (bromomethyl)- SC_3099 (for
1H NMR (DMSO-d6): .delta. 9.26 (s, 2H), 460.1
methylamino-8-phenyl-3-[2- cyclopropane step1), 7.50 (d, 2H), 7.35
(t, 2H), 7.22 (t, 1H), 3.89 (s, (trifluoromethyl)-pyrimidin-5-yl]-
SC_3105 (for 2H), 3.13 (d, 2H), 2.29-2.23 (m, 3H),
1,3-diazaspiro[4.5]decan-2-one step 2) 1.92-1.82 (m, 7H), 1.47-1.44
(m, 2H), 1.08-1.05 (m, 1H), 0.52-0.48 (m, 2H), 0.36-0.36-0.32 (m,
2H). SC_3272 cis-4-(8-Dimethylamino-2-oxo-8- INT-976
4-bromobenzonitrile SC_3103 1H NMR (600 MHz, DMSO) .delta. 375.2
phenyl-1,3-diazaspiro[4.5]decan-3- 7.82-7.71 (m, 3H), 7.72-7.67 (m,
2H), yl)-benzonitrile 7.41-7.33 (m, 4H), 7.30-7.23 (m, 1H), 3.63
(s, 2H), 2.45-2.39 (m, 2H), 1.97 (s, 6H), 1.95-1.72 (m, 4H),
1.51-1.44 (m, 2H). SC_3273 cis-8-Dimethylamino-3-(4- INT-976
1-bromo-4-fluoro- SC_3103 368.2 fluorophenyl)-8-phenyl-1,3- benzene
diazaspiro[4.5]decan-2-one SC_3274 cis-2-(8-Dimethylamino-2-oxo-8-
INT-976 2-bromobenzonitrile SC_3103 1H NMR (600 MHz, DMSO) .delta.
7.77 (dd, J = 7.5, 375.2 phenyl-1,3-diazaspiro[4.5]decan-3- 1.6 Hz,
1H), 7.66 (ddd, J = 8.3, 7.5, 1.6 Hz, yl)-benzonitrile 1H), 7.60
(s, 1H), 7.48 (dd, J = 8.3, 1.1 Hz, 1H), 7.39-7.34 (m, 4H), 7.32
(td, J = 7.5, 1.1 Hz, 1H), 7.26 (tt, J = 7.5, 1.6 Hz, 1H), 3.68 (s,
2H), 2.46-2.30 (m, 2H), 2.01-1.75 (m, 10H), 1.59-1.50 (m, 2H).
SC_3276 cis-1-[(1-Hydroxy-cyclobutyl)- SC_3256 SC_3099 1H NMR (600
MHz, DMSO) .delta. 8.94 (s, 2H), 436.3 methyl]-8-methylamino-3-(2-
7.53-7.47 (m, 2H), 7.39-7.30 (m, 2H),
methyl-pyrimidin-5-yl)-8-phenyl- 7.24-7.17 (m, 1H), 3.83 (s, 2H),
1,3-diazaspiro[4.5]decan-2-one 3.54-3.36 (m, 2H), 2.56 (s, 3H),
2.28 (td, 2H), 2.18-2.09 (m, 2H), 1.97-1.86 (m, 7H), 1.81 (td, 2H),
1.71-1.61 (m, 1H), 1.59-1.47 (m, 1H), 1.49-1.42 (m, 2H). SC_3277
cis-8-Dimethyl amino-3-[2- INT-976 4-[(5- SC_3103 1H NMR (600 MHz,
DMSO) .delta. 8.93 (s, 2H), (morpholin-4-yl-methyl)-
bromopyrimidin-2- 7.87-7.65 (m, 1H), 7.42-7.34 (m, 4H),
pyrimidin-5-yl]-8-phenyl-1,3- yl)methyl]morpholine 7.28 (dq, 1H),
3.66-3.62 (m, 2H), 3.61 (s, diazaspiro[4.5]decan-2-one 2H), 3.54
(t, 4H), 2.43 (t, 4H), 1.98 (s, 6H), 1.96-1.74 (m, 4H), 1.52-1.46
(m, 2H). SC_3278 cis-8-Dimethylamino-3-[2-(methyl- INT-989
N-methyltetrahydro- SC_3120 1H NMR (DMSO-d6): .delta. 8.50 (s, 2H),
465.2 tetrahydro-pyran-4-yl-amino)- 2H-pyran-4-amine 7.39-7.35 (m,
5H), 7.27-7.24 (m, 1H), pyrimidin-5-yl]-8-phenyl-1,3- 4.74-4.67 (m,
1H), 3.94-3.90 (m, 2H), 3.50 (s, 2H), diazaspiro[4.5]decan-2-one
3.39 (t, 2H), 2.93 (s, 3H), 2.35 (m, 2H), 1.99-1.71 (m, 12H),
1.50-1.44 (m, 4H). SC_3279 cis-5-[8-Dimethylamino-1-[(1- INT-990
(1-(tert- SC_3105 (step 1H NMR (DMSO-d6): .delta. 9.12 (s, 2H),
669.4 hydroxy-cyclobutyl)-methyl]-2-
butyldimethylsilyloxy)cyclobutyl)methyl 1), SC_3133 8.63 (t, 1H),
7.36-7.33 (m, 4H), 7.26-7.23 (m, oxo-8-phenyl-1,3- 4- (step 2) 1H),
5.25 (s, 1H), 3.85 (s, 2H), 3.52-3.34 (m,
diazaspiro[4.5]decan-3-yl]-N-[2-[2- methylbenzenesulfonate 16H),
3.35 (m, 2H), 3.19 (s, 3H), [2-(2-methoxy-ethoxy)-ethoxy]- (step
1), 2,5,8,11- 2.69-2.66 (m, 2H), 2.25-2.13 (m, 4H), 1.97 (s, 6H),
ethoxy]-ethyl]-pyrimidine-2- tetraoxatridecan-13- 1.92-1.87 (m,
2H), 1.57-1.44 (m, 6H). carboxylic acid amide amine (step 2)
SC_3280 cis-1-(Cyclopropyl-methyl)-3-(2- INT-976
1-bromo-2-fluoro-4- SC_3103 (for 1H NMR (DMSO-d6): .delta. 7.86 (t,
1H), 486.2 fluoro-4-methylsulfonyl-phenyl)-8-
(methylsulfonyl)benzene step 1), 7.81-7.77 (m, 1H), 7.73-7.70 (m,
1H), 7.45 (d, methylamino-8-phenyl-1,3- (step 1), SC_3105 (step
2H), 7.31 (t, 2H), 7.19 (t, 1H), 3.85 (s, 2H),
diazaspiro[4.5]decan-2-one (Bromomethyl)cyclopropane 2), SC_3099
3.24 (s, 3H), 3.09 (d, 2H), 2.29-2.22 (m, 3H), (step 2) (step 3)
1.93-1.90 (m, 5H), 1.74-1.68 (m, 2H), 1.49-1.46 (m, 2H), 1.04 (m,
1H), 0.51-0.46 (m, 2H), 0.34-0.30 (m, 2H). SC_3281
cis-2-[[5-(8-Dimethylamino-2-oxo- INT-989 2- SC_3120 1H NMR
(DMSO-d6): .delta. 8.48 (s, 2H), 438.2
8-phenyl-1,3-diazaspiro[4.5]decan- (methylamino)acetamide 7.39-7.35
(m, 5H), 7.27-7.25 (m, 2H), 6.89 (s, 3-yl)-pyrimidin-2-yl]-methyl-
hydrochloride 1H), 4.08 (s, 2H), 3.51 (s, 2H), 3.07 (s, 3H),
amino]-acetamide 2.36-2.33 (m, 2H), 1.94-1.86 (m, 10H), 1.45 (m,
2H). SC_3282 cis-2-[[5-(8-Dimethylamino-2-oxo- INT-976 tert-butyl
(5- SC_3103 (for 1H NMR (DMSO-d6): .delta. 8.45 (s, 2H), 424.2
8-phenyl-1,3-diazaspiro[4.5]decan- bromopyrimidin-2- step 1),
7.39-7.33 (m, 5H), 7.27-7.22 (m, 2H), 6.92 (s,
3-yl)-pyrimidin-2-yl]amino]- yl)(cyanomethyl)carbamate SC_3100 step
3 1H), 6.86 (t, 1H), 3.74 (d, 2H), 3.51 (s, 2H), acetamide (step 1)
(for step 2) 2.46-2.28 (m, 2H), 1.95-1.86 (m, 10H), 1.45 (m, 2H).
SC_3283 cis-1-(Cyclopropyl-methyl)-8- SC_3284 SC_3099 1H NMR
(DMSO-d6): .delta. 8.61 (s, 1H), 473.3 methylamino-3-[4-methyl-6-
7.82 (s, 1H), 7.46-7.44 (m, 2H), 7.30 (t, 2H),
(trifluoromethyl)-pyridin-3-yl]-8- 7.18 (t, 1H), 3.80 (s, 2H), 3.08
(d, 2H), phenyl-1,3-diazaspiro[4.5]decan-2- 2.33-2.25 (m, 6H),
1.92-1.89 (m, 5H), 1.72 (t, 2H), one 1.56-1.53 (m, 2H), 1.04 (m,
1H), 0.51-0.46 (m, 2H), 0.33-0.30 (m, 2H). SC_3284
cis-1-(Cyclopropyl-methyl)-8- INT-984 5-bromo-4-methyl-2- SC_3103
1H NMR (DMSO-d6): .delta. 8.59 (s, 1H), 487.3
dimethylamino-3-[4-methyl-6- (trifluoromethyl)pyridine 7.82 (s,
1H), 7.35-7.34 (m, 4H), 7.27-7.23 (m,
(trifluoromethyl)-pyridin-3-yl]-8- 1H), 3.75 (s, 2H), 3.06 (d, 2H),
2.71-2.68 (m, phenyl-1,3-diazaspiro[4.5]decan-2- 2H), 2.33-2.24 (m,
5H), 2.00 (m, 6H), one 1.59-1.56 (m, 2H), 1.46 (t, 2H), 1.02-0.99
(m, 1H), 0.53-0.48 (m, 2H), 0.33-0.30 (m, 2H). SC_3285
cis-N-[5-(8-Dimethylamino-2-oxo- SC_3239 thiophene-2-carbonyl
SC_3240 1H NMR (600 MHz, DMSO) .delta. 8.90 (s, 2H), 477.2
8-phenyl-1,3-diazaspiro[4.5]decan- chloride 8.08-8.04 (m, 1H), 7.84
(dd, 1H), 7.71 (s, 3-yl)-pyrimidin-2-yl]-thiophene-2- 1H), 7.38 (d,
5H), 7.27 (td, 1H), 7.19 (dd, carboxylic acid amide 1H), 3.66 (s,
2H), 2.48-2.34 (m, 2H), 1.99-1.75 (m, 10H), 1.54-1.48 (m, 2H).
SC_3286 cis-N-[5-(8-Dimethylamino-2-oxo- SC_3239 benzoyl chloride
SC_3240 1H NMR (600 MHz, DMSO) .delta. 10.84 (s, 471.3
8-phenyl-1,3-diazaspiro[4.5]decan- 1H), 8.91 (s, 2H), 7.98-7.93 (m,
2H), 3-yl)-pyrimidin-2-yl]-benzamide 7.62-7.55 (m, 1H), 7.50 (t,
2H), 7.39 (d, 4H), 7.28 (dt, 1H), 3.67 (s, 2H), 2.48-2.32 (m,
2H), 2.05-1.76 (m, 10H), 1.55-1.49 (m, 2H). SC_3287
cis-8-Dimethylamino-8-phenyl-3- INT-976 2-bromo-5- SC_3103 1H NMR
(DMSO-d6): .delta. 7.80-7.70 (br s, 432.2
(5-phenyl-thiophen-2-yl)-1,3- phenylthiophene 1H), 7.52 (d, 2H),
7.38-7.28 (m, 7H), diazaspiro[4.5]decan-2-one 7.20-7.17 (m, 2H),
6.27 (d, 1H), 3.61 (s, 2H), 2.49 (m, 2H), 1.95-1.91 (m, 10H), 1.48
(m, 2H). SC_3288 cis-1-(Cyclopropyl-methyl)-8- INT-984 1-bromo-2-
SC_3103 1H NMR (CDCl3): .delta. 7.49 (d, 1H), 496.3
dimethylamino-3-[2- (methylsulfonylmethyl)benzene 7.41-7.22 (m,
8H), 4.45 (s, 2H), 3.64 (s, 2H), 3.15 (d,
(methylsulfonyl-methyl)-phenyl]-8- 2H), 2.79 (s, 3H), 2.71-2.67 (m,
2H), 2.37 (t, phenyl-1,3-diazaspiro[4.5]decan-2- 2H), 2.06 (s, 6H),
1.67-1.64 (m, 2H), one 1.55-1.44 (m, 2H), 1.10-1.06 (m, 1H),
0.57-0.52 (m, 2H), 0.39-0.35 (m, 2H). SC_3289
cis-1-(Cyclopropyl-methyl)-8- SC_3288 SC_3099 1H NMR (DMSO-d6):
.delta. 7.49-7.37 (m, 5H), 482.3 methylamino-3-[2-(methylsulfonyl-
7.32-7.30 (m, 3H), 7.19-7.15 (m, 1H), methyl)-phenyl]-8-phenyl-1,3-
4.49 (s, 2H), 3.71 (s, 2H), 3.05 (d, 2H), 2.87 (s,
diazaspiro[4.5]decan-2-one 3H), 2.26-2.20 (m, 3H), 1.91-1.87 (m,
5H), 1.71-1.56 (m, 4H), 1.03-1.01 (m, 1H), 0.49-0.45 (m, 2H),
0.31-0.28 (m, 2H). SC_3290 cis-8-Dimethylamino-8-(3- INT-
1-bromo-2- SC_3103 1H NMR (600 MHz, DMSO) .delta. 7.46 (dd, 460.3
fluorophenyl)-3-[2- 1024 (methylsulfonylmethyl)benzene 1H), 7.39
(td, 2H), 7.33 (dd, 1H), (methylsulfonyl-methyl)-phenyl]- 7.31-7.21
(m, 1H), 7.18 (d, 1H), 7.15 (dd, 1H),
1,3-diazaspiro[4.5]decan-2-one 7.08 (td, 1H), 4.50 (s, 2H), 3.56
(s, 2H), 2.88 (s, 3H), 2.42-2.24 (m, 2H), 1.99-1.89 (m, 8H),
1.88-1.75 (m, 2H), 1.60-1.48 (m, 2H). SC_3291
cis-8-Dimethylamino-8-(4- INT- 1-bromo-2- SC_3103 1H NMR (600 MHz,
DMSO) .delta. 7.46 (dd, 460.3 fluorophenyl)-3-[2- 1025
(methylsulfonylmethyl)benzene 1H), 7.43-7.34 (m, 3H), 7.33 (dd,
1H), (methylsulfonyl-methyl)-phenyl]- 7.28 (td, 2H), 7.16 (t, 2H),
4.49 (s, 2H), 3.55 (s, 1,3-diazaspiro[4.5]decan-2-one 2H), 2.88 (s,
3H), 2.35-2.32 (m, 2H), 1.95 (s, 6H), 1.94-1.88 (m, 2H), 1.88-1.65
(m, 2H), 1.59-1.47 (m, 2H). SC_3294 cis-8-Dimethylamino-8-(3- INT-
4-(5-bromo-4-methyl- SC_3103 1H NMR (600 MHz, DMSO) .delta. 8.13
(s, 1H), 469.3 fluorophenyl)-3-(4-methyl-2- 1024 pyrimidin-2- 7.40
(td, 1H), 7.22-7.11 (m, 4H), 7.08 (td,
morpholin-4-yl-pyrimidin-5-yl)- yl)morpholine 1H), 3.69-3.60 (m,
8H), 2.34-2.31 (m, 1,3-diazaspiro[4.5]decan-2-one 2H), 2.20 (s,
3H), 1.96 (s, 6H), 1.96-1.70 (m, 4H), 1.56-1.43 (m, 2H). SC_3295
cis-3-[6-(4-Acetyl-piperazin-1-yl)- INT-976 1-[4-(5-bromo-4-
SC_3103 1HNMR (DMSO-d6, 400 MHz at 100.degree. C.), .delta. 491.3
4-methyl-pyridin-3-yl]-8- methyl-pyridin-2-yl)- (ppm) = 7.88 (s,
1H), 7.35-7.22 (m, 5H), dimethylamino-8-phenyl-1,3-
piperazin-1-yl]- 6.73 (s, 1H), 6.64 (s, 1H), 3.53-3.50 (m, 8H),
diazaspiro[4.5]decan-2-one ethanone 3.38 (s, 2H), 2.33-2.30 (m,
2H), 2.14 (s, 3H), 2.03-1.88 (m, 13H), 1.56-1.51 (m, 2H). SC_3296
cis-3-[2-(4-Acetyl-piperazin-1-yl)- INT-976 1-[4-(5-bromo-4-
SC_3103 1H-NMR (DMSO-d6, 400 MHz at 100.degree. C.), 492.3
4-methyl-pyrimidin-5-yl]-8- methyl-pyrimidin-2- .delta. (ppm) =
8.11 (s, 1H), 7.35-7.24 (m, 5H), dimethylamino-8-phenyl-1,3-
yl)-piperazin-1-yl]- 6.88 (s, 1H), 3.73 (bs, 4H), 3.52 (bs, 4H),
diazaspiro[4.5]decan-2-one ethanone 3.38 (s, 2H), 2.33 (bs, 2H),
2.22 (s, 3H), 2.03-1.87 (m, 13H), 1.56-1.53 (m, 2H). SC_3297
cis-8-Dimethylamino-3-(4-methyl- INT-976 5-bromo-2-chloro-4-
SC_3103 (for 1H-NMR (DMSO-d6, 400 MHz at 100.degree. C.), 442.3
6-pyridin-4-yl-pyridin-3-yl)-8- methyl-pyridine (step step 1),
.delta. (ppm) = 8.65 (d, 2H, J = 5.92 Hz), 8.50 (s,
phenyl-1,3-diazaspiro[4.5]decan-2- 1), 4-pyridinylboronic SC_3129
(for 1H), 7.96 (d, 2H, J = 5.96 Hz), 7.91 (s, 1H), one acid (step
2) step 2) 7.36-7.23 (m, 5H), 7.07 (s, 1H), 3.57 (s, 2H), 2.38-2.33
(m, 5H), 2.04 (s, 6H), 2.00-1.88 (m, 4H), 1.61-1.57 (m, 2H).
SC_3298 cis-3-[2-(4-Acetyl-piperazin-1-yl)- INT-976
1-[4-(5-bromo-4- SC_3103 1H-NMR (DMSO-d6, 400 MHz at 100.degree.
C.), 546.3 4-(trifluoromethyl)-pyrimidin-5- trifluoromethyl-
.delta. (ppm) = 8.52 (s, 1H), 7.35-7.22 (m, 5H),
yl]-8-dimethylamino-8-phenyl-1,3- pyrimidin-2-yl)- 7.07 (s, 1H),
3.79-3.78 (t, 4H, 5.08 Hz), diazaspiro[4.5]decan-2-one
piperazin-1-yl]- 3.57 (t, 4H, 5.26 Hz), 3.39 (s, 2H), 2.36-2.32 (m,
ethanone 2H), 2.04-1.85 (m, 13H), 1.54-1.50 (m, 2H). SC_3299
cis-8-Dimethylamino-3-[2-(3-oxo- INT-976 4-(5-bromo-4- SC_3103
1HNMR (DMSO-d6, 400 MHz), .delta. (ppm) = 8.55 (s, 518.2
piperazin-1-yl)-4-(trifluoromethyl)- trifluoromethyl- 1H), 7.77
(bs, 1H), 7.35-7.23 (m, pyrimidin-5-yl]-8-phenyl-1,3-
pyrimidin-2-yl)- 5H), 7.09 (s, 1H), 4.20 (s, 2H), 3.92 (t, 2H, J =
5.04 Hz), diazaspiro[4.5]decan-2-one piperazin-2-one 3.39 (s, 2H),
3.33 (bs, 2H), 2.36-2.33 (m, 2H), 2.03-1.85 (m, 10H), 1.54-1.39 (m,
2H). SC_3300 cis-8-Dimethylamino-3- INT-976 4-bromo-isoquinoline
SC_3103 1HNMR (DMSO-d6, 400 MHz at 100.degree. C.), .delta. 401.2
isoquinolin-4-yl-8-phenyl-1,3- (ppm) = 9.16 (s, 1H), 8.41 (s, 1H),
8.13 (d, diazaspiro[4.5]decan-2-one 1H, J = 8.12 Hz), 7.91 (d, 1H,
J = 8.64 Hz), 7.71 (t, 1H, J = 7.58 Hz), 7.67 (t, 1H, J = 7.46 Hz),
7.36-7.23 (m, 5H), 7.14 (s, 1H), 3.67 (s, 2H), 2.41-2.36 (m, 2H),
2.10-1.89 (m, 10H), 1.68-1.64 (m, 2H). SC_3301
cis-8-Dimethylamino-3- INT-976 5-bromo-isoquinoline SC_3103 1HNMR
(DMSO-d6, 400 MHz at 100.degree. C.), .delta. 401.2
isoquinolin-5-yl-8-phenyl-1,3- (ppm) = 9.29 (s, 1H), 8.48 (d, 1H, J
= 5.92 Hz) diazaspiro[4.5]decan-2-one 7.98-7.96 (m, 1H), 7.70-7.64
(m, 3H), 7.36-7.23 (m, 5H), 7.13 (s, 1H), 3.65 (s, 2H), 2.41-2.36
(m, 2H), 2.10-1.90 (m, 10H), 1.68-1.63 (m, 2H). SC_3302
cis-8-Dimethylamino-8-phenyl-3- INT-976 4-bromo-1H- SC_3103 1H NMR
(600 MHz, DMSO) .delta. 11.42 (s, 390.2
(1H-pyrrolo[2,3-b]pyridin-4-yl)- pyrrolo[2,3- 1H), 7.99 (d, 1H),
7.66 (br s, 1H), 1,3-diazaspiro[4.5]decan-2-one b]pyridine
7.43-7.33 (m, 5H), 7.27 (t, 1H), 7.22 (t, 1H), 6.65-6.60 (m, 1H),
3.91 (s, 2H), 2.45-2.27 (m, 2H), 1.98-1.82 (m, 10H), 1.56-1.49 (m,
2H). SC_3303 cis-8-Dimethylamino-8-phenyl-3- INT-976
4-bromo-2-(pyridin- SC_3103 1H NMR (DMSO-d6): .delta. 8.62 (d, 2H),
434.1 (2-pyridin-4-yl-thiazol-4-yl)-1,3- 4-yl)thiazole 7.82 (d,
2H), 7.61 (broad s, 1H), 7.54 (s, 1H), diazaspiro[4.5]decan-2-one
7.40-7.37 (m, 4H), 7.29-7.27 (m, 1H), 3.84 (s, 2H), 2.49 (m, 2H),
1.96-1.79 (m, 10H), 1.51 (m, 2H). SC_3304
cis-8-[Methyl-(tetrahydro-furan-3- INT- 4-(5-bromopyrimidin- step 2
of 1H NMR (DMSO-d6): .delta. 8.56 (s, 2H), 507.3
yl-methyl)-amino]-3-(2-morpholin- 1026 2-yl)morpholine SC_3097 (for
7.65 (broad s, 1H), 7.36-7.23 (m, 5H),
4-yl-pyrimidin-5-yl)-8-phenyl-1,3- synthesis), 3.66-3.55 (m, 10H),
3.49 (s, 2H), 3.38 (m, 1H), diazaspiro[4.5]decan-2-one SC_3292 and
2.32-2.26 (m, 3H), 2.11-1.94 (m, 6H), (enantiomer 1) SC_3293 (for
1.86-1.82 (m, 3H), 1.50-1.41 (m, 3H). separation of enantiomers)
SC_3305 cis-8-[Methyl-(tetrahydro-furan-3- INT-
4-(5-bromopyrimidin- step 2 of 1H NMR (DMSO-d6): .delta. 8.56 (s,
2H), 507.2 yl-methyl)-amino]-3-(2-morpholin- 1026 2-yl)morpholine
SC_3097 (for 7.66 (broad s, 1H), 7.35-7.24 (m, 5H),
4-yl-pyrimidin-5-yl)-8-phenyl-1,3- synthesis), 3.63-3.49 (m, 12H),
3.31 (m, 1H), 2.27 (m, 3H), diazaspiro[4.5]decan-2-one SC_3292 and
2.11-1.84 (m, 10H), 1.42 (m, 3H). (enantiomer 2) SC_3293 (for
separation of enantiomers) SC_3306
cis-3-[2-(Azetidin-1-yl)-pyrimidin- INT-976 2-azetidin-1-yl-5- step
2 of 1HNMR (DMSO-d6, 400 MHz at 100.degree. C.), .delta. 407.2
5-yl]-8-dimethylamino-8-phenyl- bromo-pyrimidine SC_3242 (ppm) =
8.48 (s, 2H), 7.36-7.26 (m, 5H), 1,3-diazaspiro[4.5]decan-2-one
7.07 (s, 1H), 3.99 (t, 4H, J = 7.18 Hz), 3.50 (s, 2H), 2.35-2.26
(m, 4H), 2.03 (s, 6H), 1.95-1.91 (m, 2H), 1.52-1.50 (m, 2H).
SC_3307 cis-3-[2-(3,3-Difluoro-azetidin-1- INT-976 5-bromo-2-(3,3-
step 2 of 1HNMR (DMSO-d6, 400 MHz at 100.degree. C.), .delta. 443.2
yl)-pyrimidin-5-yl]-8- difluoro-azetidin-1- SC_3242 (ppm) = 8.62
(s, 2H), 7.37-7.25 (m, 5H), dimethylamino-8-phenyl-1,3-
yl)-pyrimidine 7.20 (s, 1H), 4.38 (t, 4H, J = 12.40 Hz),
diazaspiro[4.5]decan-2-one 3.55 (s, 2H), 2.36-233 (m, 2H), 2.03 (s,
6H) 1.97-1.89 (m, 4H), 1.53-1.51 (m, 2H). SC_3308
cis-8-Dimethylamino-3-[6- INT-976 4-(5-bromo-3- SC_3103 1HNMR
(DMSO-d6, 400 MHz at 100.degree. C.), .delta. 504.3
morpholin-4-yl-5-(trifluoromethyl)- trifluoromethyl- (ppm) = 8.63
(s, 1H), 8.38 (s, 1H), pyridin-3-yl]-8-phenyl-1,3- pyridin-2-yl)-
7.37-7.25 (m, 6H), 3.71 (bs, 4H), 3.65 (s, 2H),
diazaspiro[4.5]decan-2-one morpholine 3.03 (bs, 4H), 2.37-2.32 (m,
2H), 2.03 (s, 6H), 1.98-1.88 (m, 4H), 1.55-1.52 (m, 2H). SC_3309
cis-8-Methylamino-3-[6- SC_3308 SC_3099 1HNMR (DMSO-d6, 400 MHz at
100.degree. C.), .delta. 490.4 morpholin-4-yl-5-(trifluoromethyl)-
(ppm) = 8.68 (s, 1H), 8.42 (s, 1H), 7.48 (d,
pyridin-3-yl]-8-phenyl-1,3- 2H, J = 8.12 Hz), 7.33 (t, 2H, J = 7.62
Hz), diazaspiro[4.5]decan-2-one 7.20 (t, 1H, J = 7.38 Hz), 7.14 (s,
1H), 3.75-3.71 (m, 6H), 3.03 (t, 4H, J = 8.88 Hz), 2.08-2.02 (m,
2H), 1.95-1.79 (m, 8H), 1.58-1.55 (m, 2H). SC_3310
cis-8-Dimethylamino-8-phenyl-3- INT-976 2-bromo-5- SC_3103 1H NMR
(600 MHz, DMSO) .delta. 435.2 [5-(trifluoromethyloxy)-pyridin-2-
(trifluoromethoxy)- 8.32-8.26 (m, 2H), 7.86-7.82 (m, 1H), 7.79 (dd,
1H), yl]-1,3-diazaspiro[4.5]decan-2-one pyridine 7.41-7.33 (m, 4H),
7.27 (t, 1H), 3.71 (s, 2H), 2.46-2.33 (m, 2H), 1.96 (s, 6H),
1.94-1.72 (m, 4H), 1.47 (t, 2H). SC_3311 cis-8-Dimethylamino-3-(5-
INT-976 2-bromo-5- SC_3103 1H NMR (600 MHz, DMSO) .delta. 8.66 (dd,
429.2 methylsulfonyl-pyridin-2-yl)-8- methylsulfonylpyridine 1H),
8.39 (dd, 1H), 8.14 (dd, 1H), 8.06 (s,
phenyl-1,3-diazaspiro[4.5]decan-2- 1H), 7.42-7.33 (m, 4H), 7.28 (t,
1H), one 3.77 (s, 2H), 3.21 (s, 3H), 2.46-2.32 (m, 2H), 2.03-1.68
(m, 10H), 1.52-1.46 (m, 2H). SC_3312
cis-6-(8-Dimethylamino-2-oxo-8- INT-976 6-bromopyridine-3- SC_3103
1H NMR (600 MHz, DMSO) .delta. 8.66 (d, 1H), 376.2
phenyl-1,3-diazaspiro[4.5]decan-3- carbonitrile 8.34 (d, 1H), 8.08
(dd, 1H), 7.41-7.33 (m, yl)-nicotinonitrile 4H), 7.28 (t, 1H), 3.74
(s, 2H), 2.46-2.30 (m, 2H), 1.96 (s, 6H), 1.94-1.73 (m, 4H),
1.51-1.44 (m, 2H). SC_3314 cis-8-Dimethylamino-3-[4-methyl- INT-976
4-(5-bromo-4-methyl- SC_3103 1HNMR (DMSO-d6, 400 MHz at 100.degree.
C.), .delta. 464.2 2-(3-oxo-piperazin-1-yl)-pyrimidin-
pyrimidin-2-yl)- (ppm) = 8.14 (s, 1H), 7.65 (bs, 1H),
5-yl]-8-phenyl-1,3- piperazin-2-one 7.34-7.23 (m, 5H), 6.89 (s,
1H), 4.16 (s, 2H), diazaspiro[4.5]decan-2-one 3.88 (bs, 2H), 3.39
(s, 2H), 3.29 (bs, 2H), 2.33 (bs, 2H), 2.24 (s, 3H), 2.03-1.87 (m,
10H), 1.53 (bs, 2H). SC_3315 cis-5-(8-Dimethylamino-2-oxo-8-
SC_3312 SC_3016 1H NMR (600 MHz, DMSO) .delta. 8.80 (d, 1H), 394.2
phenyl-1,3-diazaspiro[4.5]decan-3- 8.10 (dd, 1H), 7.95-7.89 (m,
2H), 7.79 (s, yl)-pyridine-2-carboxylic acid 1H), 7.42-7.35 (m,
5H), 7.28 (s, 1H), amide 3.67 (s, 2H), 2.48-2.28 (m, 2H), 1.95 (d,
10H), 1.53-1.46 (m, 2H). SC_3316 cis-3-[4-(Azetidin-1-yl)-2-methyl-
INT-976 4-azetidin-1-yl-5- step 2 of 1HNMR (DMSO-d6, 400 MHz at
100.degree. C.), .delta. 421.2 pyrimidin-5-yl]-8-dimethylamino-
bromo-2-methyl- SC_3242 (ppm) = 7.85 (s, 1H), 7.34-7.23 (m, 5H),
8-phenyl-1,3-diazaspiro[4.5]decan- pyrimidine 6.93 (s, 1H), 4.11
(t, 4H, J = 7.40 Hz), 2-one 3.33 (s, 2H), 2.33-2.30 (m, 7H), 2.02
(s, 6H), 1.96-1.87 (m, 4H), 1.53-1.48 (m, 2H). SC_3317
cis-2-(8-Dimethylamino-2-oxo-8- INT-976 2-bromobenzonitrile SC_3103
(step 1H NMR (600 MHz, DMSO) .delta. 7.50 (s, 1H), 393.2
phenyl-1,3-diazaspiro[4.5]decan-3- 1), SC_3016 7.42 (dd, 1H),
7.42-7.32 (m, 5H), 7.31 (d, yl)-benzamide (step 2) 1H), 7.26 (t,
1H), 7.23-7.13 (m, 3H), 3.53 (s, 2H), 2.41-2.27 (m, 2H), 1.96 (s,
6H), 1.90 (t, 2H), 1.86-1.68 (m, 2H),
1.52-1.48 (m, 2H). SC_3318 cis-8-Dimethylamino-3-[2- INT-997
1-bromo-2- SC_3103 1H NMR (600 MHz, DMSO) .delta. 7.47 (dd, 448.2
(methylsulfonyl-methyl)-phenyl]-8- (methylsulfonylmethyl)- 1H),
7.43-7.36 (m, 2H), 7.34 (dd, 1H), thiophen-2-yl-1,3- benzene 7.29
(ddd, 1H), 7.19 (s, 1H), 7.05 (ddd, 1H), diazaspiro[4.5]decan-2-one
6.94 (d, 1H), 4.50 (s, 2H), 3.61 (s, 2H), 2.89 (s, 3H), 2.35-2.21
(m, 2H), 2.04 (s, 6H), 1.98-1.90 (m, 2H), 1.86-1.70 (m, 2H),
1.66-1.59 (m, 2H). SC_3320 cis-8-Dimethylamino-3-(4-methyl- INT-997
4-(5-bromo-4-methyl- SC_3319 1H NMR (600 MHz, DMSO) .delta. 8.15
(d, 1H), 457.2 2-morpholin-4-yl-pyrimidin-5-yl)- pyrimidin-2- 7.41
(dt, 1H), 7.13 (s, 1H), 7.05 (ddd, 1H), 8-thiophen-2-yl-1,3-
yl)morpholine 6.94 (dd, 1H), 3.71-3.60 (m, 8H), 3.44 (s,
diazaspiro[4.5]decan-2-one 2H), 2.32-2.24 (m, 2H), 2.21 (s, 3H),
2.04 (s, 6H), 1.98-1.88 (m, 2H), 1.87-1.75 (m, 2H), 1.62-1.54 (m,
2H). SC_3321 cis-8-Dimethylamino-3-(6- INT-976 5-bromo-2- SC_3103
1H NMR (600 MHz, DMSO) .delta. 8.89 (d, J = 2.6 Hz, 429.2
methylsulfonyl-pyridin-3-yl)-8- methylsulfonylpyridine 1H), 8.28
(dd, J = 8.9, 2.6 Hz, 1H), phenyl-1,3-diazaspiro[4.5]decan-2- 7.93
(d, 1H), 7.42-7.34 (m, 4H), one 7.31-7.25 (m, 1H), 3.71 (s, 2H),
3.18 (s, 3H), 2.48-2.33 (m, 2H), 2.04-1.76 (m, 10H), 1.54-1.48 (m,
2H). SC_3322 cis-8-Dimethylamino-8-phenyl-3- INT-976 tert-butyl 5-
SC_3103 (for 1H NMR (600 MHz, DMSO) .delta. 11.45 (s, 390.2
(1H-pyrrolo[2,3-b]pyridin-5-yl)- bromopyrrolo[2,3- step 1), 1H),
8.38 (s, 1H), 8.00 (d, 1H), 1,3-diazaspiro[4.5]decan-2-one
b]pyridine-1- SC_3173 (for 7.85-7.81 (m, 1H), 7.70-7.66 (m, 2H),
carboxylate (step 1) step 2) 7.57-7.53 (m, 3H), 7.41 (t, 1H), 6.35
(dd, 1H), 3.54 (s, 2H), 2.75-2.41 (m, 8H, overlapps with solvent
residual peak), 2.30-2.26 (m, 2H), 1.89 (d, 2H), 1.41-1.37 (m, 2H).
SC_3323 cis-N-[5-(8-Dimethylamino-2-oxo- SC_3239 acetyl chloride
SC_3240 1H NMR (600 MHz, DMSO) .delta. 10.36 (s, 409.2
8-phenyl-1,3-diazaspiro[4.5]decan- 1H), 8.82 (s, 2H), 8.40 (s,
rotamer), 7.67 (s, 3-yl)-pyrimidin-2-yl]-acetamide 1H), 7.44-7.31
(m, 4H), 7.27 (td, 1H), (enantiomer 1) 3.62 (s, 2H), 2.46-2.30 (m,
2H), 2.11 (s, 3H), 2.08 (s, rotamer), 1.96 (s, 6H), 1.97 (s,
rotamer), 1.95-1.75 (m, 4H), 1.52-1.47 (m, 2H). SC_3324
cis-3-[2-(4-Methyl-piperazin-1-yl)- INT- 5-bromo-2-(4- step 2 of 1H
NMR (DMSO-d6): .delta. 8.52 (s, 2H), 518.3
pyrimidin-5-yl]-8-[methyl- 1026 methylpiperazin-1- SC_3097 (for
7.64 (broad s, 1H), 7.36-7.23 (m, 5H),
(tetrahydro-furan-3-yl-methyl)- yl)pyrimidine synthesis), 3.66-3.55
(m, 7H), 3.48 (s, 2H), 3.37-3.36 (m, 1H), amino]-8-phenyl-1,3-
SC_3292 and 2.33-2.13 (m, 11H), 2.01-1.82 (m, 9H),
diazaspiro[4.5]decan-2-one SC_3293 (for 1.50-1.41 (m, 3H).
(enantiomer 2) separation of enantiomers) SC_3325
cis-3-[2-(4-Methyl-piperazin-1-yl)- INT- 5-bromo-2-(4- step 2 of 1H
NMR (DMSO-d6): .delta. 8.52 (s, 2H), 518.3
pyrimidin-5-yl]-8-[methyl- 1026 methylpiperazin-1- SC_3097 (for
7.64 (broad s, 1H), 7.36-7.24 (m, 5H),
(tetrahydro-furan-3-yl-methyl)- yl)pyrimidine synthesis), 3.66-3.55
(m, 7H), 3.48 (s, 2H), 3.36 (m, 1H), amino]-8-phenyl-1,3- SC_3292
and 2.34-2.13 (m, 10H), 2.01-1.83 (m, 10H),
diazaspiro[4.5]decan-2-one SC_3293 (for 1.50-1.41 (m, 3H).
separation of enantiomers) SC_3326 cis-8-Dimethylamino-3-(4,6-
INT-976 4-(5-bromo-4,6- SC_3103 -- 465.3 dimethyl-2-morpholin-4-yl-
dimethyl-pyrimidin- pyrimidin-5-yl)-8-phenyl-1,3- 2-yl)morpholine
diazaspiro[4.5]decan-2-one SC_3327 cis-8-Dimethylamino-3-(2- INT-
morpholine SC_3120 1H NMR (600 MHz, DMSO) .delta. 8.58 (s, 2H),
443.2 morpholin-4-yl-pyrimidin-5-yl)-8- 1027 7.43 (dd, 1H),
7.40-7.32 (m, 1H), 7.07 (dd, thiophen-2-yl-1,3- 1H), 6.96 (dd, 1H),
3.67-3.61 (m, 4H), diazaspiro[4.5]decan-2-one 3.62-3.57 (m, 6H),
2.31-2.27 (m, 2H), 2.04 (s, 6H), 1.91 (t, 2H), 1.86-1.82 (m, 2H),
1.56-1.50 (m, 2H). SC_3328 cis-6-(8-Dimethylamino-2-oxo-8- SC_3312
SC_3016 1H NMR (600 MHz, DMSO) .delta. 8.71 (d, J = 2.3 Hz, 394.2
phenyl-1,3-diazaspiro[4.5]decan-3- 1H), 8.24 (d, J = 8.9 Hz, 1H),
yl)-pyridine-3-carboxylic acid 8.12 (dd, J = 9.0, 2.4 Hz, 1H), 7.95
(s, 1H), amide 7.86 (s, 1H), 7.36 (dq, J = 13.7, 6.6, 5.6 Hz, 5H),
7.27 (t, J = 7.2 Hz, 1H), 3.74 (s, 2H), 2.41-2.37 (m, 2H), 1.96 (s,
6H), 1.94-1.87 (m, 2H), 1.86-1.80 (m, 2H), 1.51-1.44 (m, 2H).
SC_3329 cis-8-Dimethylamino-3-[2-methyl- INT-997
5-bromo-1-methyl-3- SC_3319 1H NMR (600 MHz, DMSO) .delta. 428.2
5-(trifluoromethyl)-2H-pyrazol-3- (trifluoromethyl)pyrazole
7.66-7.63 (m, 1H), 7.42 (dd, 1H), 7.06 (dd, 1H),
yl]-8-thiophen-2-yl-1,3- 6.95 (dd, 1H), 6.64 (s, 1H), 3.75 (s, 3H),
3.60 (s, diazaspiro[4.5]decan-2-one 2H), 2.30-2.26 (m, 2H), 2.04
(s, 6H), 1.98-1.90 (m, 2H), 1.83-1.79 (m, 2H), 1.64-1.57 (m, 2H).
SC_3330 cis-8-Dimethylamino-3-[2-[(2- INT- 2- SC_3120 1H NMR (600
MHz, DMSO) .delta. 8.48 (s, 2H), 431.2
hydroxy-ethyl)-methyl-amino]- 1027 (methylamino)ethanol 7.43 (d,
1H), 7.30 (s, 1H), 7.07 (dd, 1H), pyrimidin-5-yl]-8-thiophen-2-yl-
6.96 (d, 1H), 3.61 (dd, 2H), 3.58-3.51 (m,
1,3-diazaspiro[4.5]decan-2-one 4H), 3.09 (s, 3H), 2.34-2.22 (m,
2H), 2.04 (s, 6H), 1.96-1.76 (m, 4H), 1.56-1.50 (m, 2H). SC_3331
cis-8-Dimethylamino-3-[2-(2-oxo- INT- 4-(4,4,5,5- SC_3208 1H NMR
(600 MHz, DMSO) .delta. 10.46 (s, 489.2
1,3-dihydro-indol-4-yl)-pyrimidin- 1027 tetramethyl-1,3,2- 1H),
9.12 (s, 2H), 7.87 (d, 1H), 5-yl]-8-thiophen-2-yl-1,3-
dioxaborolan-2- 7.47-7.42 (m, 1H), 7.31 (t, 1H), 7.08 (dd, 1H),
diazaspiro[4.5]decan-2-one yl)indolin-2-one 6.98 (dd, 1H), 6.92 (d,
1H), 3.83 (s, 2H), 3.77 (s, 2H), 2.35-2.30 (m, 2H), 2.05 (s, 6H),
1.96 (t, 2H), 1.88 (s, 2H), 1.60-1.54 (m, 2H). SC_3332
cis-8-Dimethylamino-3-[4-methyl- INT-976 4-(5-bromo-4-methyl- step
2 of 1H-NMR (DMSO-d6, 400 MHz at 100.degree. C.), .delta. 463.2
6-(3-oxo-piperazin-1-yl)-pyridin-3- pyridin-2-yl)- SC_3097 (ppm) =
7.89 (s, 1H), 7.62 (bs, 1H), yl]-8-phenyl-1,3- piperazin-2-one
7.35-7.22 (m, 5H), 6.73 (s, 1H), 6.62 (s, 1H),
diazaspiro[4.5]decan-2-one 3.96 (s, 2H), 3.68 (t, 2H, J = 5.2 Hz),
3.39 (s, 2H), 3.30 (bs, 2H), 2.35-2.30 (m, 2H), 2.15 (s, 3H),
2.03-1.86 (m, 10H), 1.56-1.51 (m, 2H). SC_3333
cis-8-Dimethylamino-3-(4-methyl- INT-976 5-bromo-2-chloro-4-
SC_3103 (for 1H-NMR (DMSO-d6, 400 MHz at 100.degree. C.), 442.3
6-pyridin-2-yl-pyridin-3-yl)-8- methyl-pyridine (step step 1),
.delta. (ppm) = 8.64 (d, 1H, J = 4.0 Hz), 8.45 (s,
phenyl-1,3-diazaspiro[4.5]decan-2- 1), 2- SC_3162 (for 1H), 8.31
(d, 1H, J = 8.68 Hz), 8.22 (s, 1H), one tributylstannanyl- step 2)
7.88 (t, 1H, J = 7.04 Hz), 7.39-7.35 (m, 5H), pyridine (step 2)
7.26-7.23 (m, 1H), 7.03 (s, 1H), 3.57 (s, 2H), 2.39-2.33 (m, 5H),
2.04 (s, 6H), 2.01-1.88 (m, 4H), 1.61-1.57 (m, 2H). SC_3334
cis-8-Dimethylamino-3-(4- INT-976 3-bromo-4- SC_3103 (for 1HNMR at
100.degree. C. (DMSO-d6, 400 MHz), .delta. 429.3
methylsulfonyl-pyridin-3-yl)-8- methylsulfanyl- step 1), (ppm) =
8.77-8.72 (m, 2H), 7.85-7.84 (m, phenyl-1,3-diazaspiro[4.5]decan-2-
pyridine (step 1) SC_3008 (for 1H), 7.35-7.23 (m, 6H), 3.60 (s,
2H), one step 2) 3.31 (s, 3H), 2.36 (bs, 2H), 2.03-1.82 (m, 10H),
1.60-1.58 (m, 2H). SC_3335 cis-3-(Benzothiazol-7-yl)-8- INT-976
7-bromo- SC_3103 407.1 dimethylamino-8-phenyl-1,3- benzothiazole
diazaspiro[4.5]decan-2-one SC_3336 cis-8-Dimethylamino-8-(4- INT-
4-(5-bromo-4-methyl- SC_3319 1H NMR (600 MHz, DMSO) .delta. 8.13
(s, 1H), 469.3 fluorophenyl)-3-(4-methyl-2- 1025 pyrimidin-2-
7.41-7.35 (m, 2H), 7.22-7.13 (m, 3H),
morpholin-4-yl-pyrimidin-5-yl)- yl)morpholine 3.69-3.60 (m, 8H),
2.35-2.31 (m, 2H), 1,3-diazaspiro[4.5]decan-2-one 2.20 (s, 3H),
1.94 (s, 6H), 1.93-1.74 (m, 4H), 1.53-1.43 (m, 2H). SC_3337
cis-2-[8-Dimethylamino-3[4- SC_3122 2-chloro-N,N- INT-988 (step 1H
NMR (600 MHz, DMSO) .delta. 8.59 (s, 1H), 518.3
methyl-6-(trifluoromethyl)-pyridin- dimethyl-acetamide 1) 7.82 (s,
1H), 7.37-7.32 (m, 4H), 7.25 (ddd, 3-yl]-2-oxo-8-phenyl-1,3- 1H),
4.00 (s, 2H), 3.80 (s, 2H), 3.07 (s, 3H),
diazaspiro[4.5]decan-1-yl]-N,N- 2.87 (s, 3H), 2.71-2.64 (m, 2H),
2.55 (s, dimethyl-acetamide 3H), 2.34 (s, 3H), 2.03 (td, 2H), 1.98
(s, 6H), 1.67-1.58 (m, 2H), 1.49-1.40 (m, 2H). SC_3338
cis-8-Dimethylamino-3-[2-(2- INT-989 2-methyl-4-(4,4,5,5- SC_3208
1H NMR (600 MHz, DMSO) .delta. 9.57 (s, 1H), 497.3
methyl-1-oxo-2,3-dihydro-isoindol- tetramethyl-1,3,2- 9.08 (s, 2H),
8.52 (d, 1H), 8.43 (s, 1H), 4-yl)-pyrimidin-5-yl]-8-phenyl-1,3-
dioxaborolan-2- 7.77 (d, 1H), 7.72 (d, 2H), 7.63 (t, 1H), 7.59 (t,
diazaspiro[4.5]decan-2-one yl)isoindolin-1-one 2H), 7.55 (t, 1H),
4.86 (s, 2H), 3.59 (s, 2H), 3.13 (s, 3H), 2.72 (d, 2H), 2.61 (s,
6H), 2.25 (td, 2H), 1.91 (d, 2H), 1.43-1.35 (m, 2H). SC_3339
cis-2-[[5-(8-Dimethylamino-2-oxo- INT-976 (5-bromo-2-methyl- step 2
of .sup.1HNMR at 100.degree. C. (DMSO-d6, 400 MHz), .delta. 438.4
8-phenyl-1,3-diazaspiro[4.5]decan- pyrimidin-4- SC_3242 (for (ppm)
= 7.93 (s, 1H), 7.36-7.22 (m, 5H), 3-yl)-2-methyl-pyrimidin-4-
ylamino)-acetonitrile step 1), 7.12 (s, 1H), 6.91 (bs, 2H), 6.58
(bs, 1H), yl]amino]-acetamide (step 1) SC_3016 (for 3.94 (d, 2H),
3.46 (s, 2H), 2.35-2.32 (m, 5H), step 2) 2.03-1.97 (m, 8H),
1.91-1.84 (m, 2H), 1.61-1.56 (m, 2H). SC_3341
cis-8-Dimethylamino-3-[4- INT-976 3-bromo-4- step 2 of 1HNMR at
100.degree. C. (DMSO-d6, 400 MHz), .delta. 443.4
(methylsulfonyl-methyl)-pyridin-3- methanesulfonylmethyl- SC_3097
(ppm) = 8.53 (s, 1H), 8.43 (d, 1H, J = 4.88 Hz), yl]-8-phenyl-1,3-
pyridine 7.48 (d, 1H, J = 4.88 Hz), 7.36-7.23 (m,
diazaspiro[4.5]decan-2-one 5H), 7.15 (s, 1H), 4.55 (s, 2H), 3.64
(s, 2H), 2.95 (s, 3H), 2.38-2.33 (m, 2H), 2.04 (s, 6H), 1.99-1.83
(m, 4H), 1.62-1.57 (m, 2H). SC_3342 cis-8-Dimethylamino-3-[6-(4-
INT-976 4-(5-bromo-2- SC_3242 (step 1H NMR (600 MHz, CDCl3) .delta.
8.09 (d, 1H), 463.3 methyl-3-oxo-piperazin-1-yl)-
pyridyl)-1-methyl- 2) 8.00 (dd, 1H), 7.45-7.39 (m, 2H),
pyridin-3-yl]-8-phenyl-1,3- piperazin-2-one 7.37-7.28 (m, 3H), 6.61
(d, 1H), 5.71 (s, 1H), diazaspiro[4.5]decan-2-one 4.04 (s, 2H),
3.87-3.82 (m, 2H), 3.51 (s, 2H), 3.45 (t, 2H), 3.03 (s, 3H),
2.32-2.02 (m, 10H), 2.02-1.94 (m, 2H), 1.64-1.53 (m, 2H). SC_3343
cis-8-Dimethylamino-3-(2,4- INT-976 5-bromo-2,4- SC_3103 1H NMR
(600 MHz, DMSO) .delta. 8.46 (s, 1H), 380.3
dimethyl-pyrimidin-5-yl)-8-phenyl- dimethyl-pyrimidine 7.45-7.33
(m, 5H), 7.28-7.24 (m, 1H), 1,3-diazaspiro[4.5]decan-2-one 3.51 (s,
2H), 2.54 (s, 3H), 2.41-2.28 (m, 5H), 2.03-1.77 (m, 10H), 1.56-1.49
(m, 2H). SC_3344 cis-8-Dimethylamino-3-[2-(1-oxo- INT-989
4-(4,4,5,5- SC_3208 1H NMR (600 MHz, DMSO) .delta. 9.06 (s, 2H),
483.3 2,3-dihydro-isoindol-4-yl)- tetramethyl-1,3,2- 8.67 (s, 1H),
8.52 (d, 1H), 8.39 (s, 1H), pyrimidin-5-yl]-8-phenyl-1,3-
dioxaborolan-2- 7.75 (dd, 3H), 7.66-7.51 (m, 4H), 4.75 (s, 2H),
diazaspiro[4.5]decan-2-one; 2,2,2- yl)isoindolin-1-one 3.58 (s,
2H), 3.18 (s, 2H), 2.75 (d, 2H), trifluoro-acetic acid 2.60 (s,
6H), 2.27 (t, 2H), 1.91 (d, 2H), 1.39 (t, 2H). SC_3345
cis-8-Dimethylamino-3-[6-[(2- INT-976 2-[[5-bromo-3- SC_3103 1H NMR
(600 MHz, DMSO) .delta. 492.3 hydroxy-ethyl)-methyl-amino]-5-
(trifluoromethyl)-2- 8.55-8.51 (m, 1H), 8.35 (d, 1H), 7.62 (s, 1H),
7.37 (td, (trifluoromethyl)-pyridin-3-yl]-8- pyridyl]-methyl- 4H),
7.27 (td, 1H), 3.63 (s, 2H), 3.50 (td,
phenyl-1,3-diazaspiro[4.5]decan-2- amino]ethanol 2H), 3.20 (t, 2H),
2.78 (s, 3H), one 2.43-2.36 (m, 2H), 1.96 (s, 6H), 1.95-1.75 (m,
4H), 1.48 (t, 2H). SC_3346 cis-8-Dimethylamino-8-phenyl-3- INT-976
3,3,3-trifluoroprop-1- SC_3313 1H NMR (600 MHz, DMSO) .delta. 9.56
(d, 1H), 487.3 [2-[4-(trifluoromethyl)-1H- yne, 2-azido-5- 9.16 (s,
2H), 7.99 (s, 1H), 7.42-7.35 (m,
[1,2,3]triazol-1-yl]-pyrimidin-5-yl]- bromo-pyrimidine 4H),
7.31-7.25 (m, 1H), 3.75 (s, 2H), 1,3-diazaspiro[4.5]decan-2-one
2.49-2.34 (m, 2H), 2.05-1.75 (m, 10H),
1.60-1.47 (m, 2H). SC_3347 cis-8-Dimethylamino-3-[2-(4- INT-976
3-methylbut-1-yne, 2- SC_3313 1H NMR (600 MHz, DMSO) .delta. 9.10
(s, 2H), 461.3 isopropyl-1H-[1,2,3]triazol-1-yl)- azido-5-bromo-
8.50 (d, 1H), 7.91 (s, 1H), 7.42-7.35 (m,
pyrimidin-5-yl]-8-phenyl-1,3- pyrimidine 5H), 7.28 (td, 1H), 3.73
(s, 2H), 3.08 (hept, diazaspiro[4.5]decan-2-one 1H), 2.44 (s, 2H),
2.01-1.76 (m, 10H), 1.59-1.48 (m, 2H), 1.30 (d, 6H). SC_3348
cis-8-Dimethylamino-3-[6-(1,1- INT-976 1,4-thiazinane 1,1- SC_3242
1H NMR (600 MHz, DMSO) .delta. 8.23 (d, 1H), 484.2
dioxo-[1,4]thiazinan-4-yl)-pyridin- dioxide, 5-bromo-2- 7.93 (dd,
1H), 7.41-7.33 (m, 5H), 7.27 (t, 3-yl]-8-phenyl-1,3-
chloro-pyridine (step 1H), 6.98 (d, 1H), 3.97 (t, 4H), 3.53 (s,
2H), diazaspiro[4.5]decan-2-one 1) 3.04 (t, 4H), 2.43-2.28 (m, 2H),
1.96 (s, 6H), 1.92-1.72 (m, 4H), 1.51-1.40 (m, 2H). SC_3349
cis-5-(8-Dimethylamino-2-oxo-8- INT-976 5-bromo-2- SC_3242 1H NMR
(600 MHz, DMSO-d6) .delta. 8.66 (d, J = 2.9 Hz, 461.3
phenyl-1,3-diazaspiro[4.5]decan-3- chloropyridine-3- 1H), 8.25 (d,
J = 2.8 Hz, 1H), yl)-2-morpholin-4-yl-nicotinonitrile carbonitrile,
7.60 (s, 1H), 7.41-7.33 (m, 4H), 7.30-7.24 (m, morpholine 1H),
3.74-3.69 (m, 4H), 3.60 (s, 2H), 2.48-2.29 (m, 2H), 1.96 (s, 6H),
1.94-1.68 (m, 4H), 1.52-1.41 (m, 2H). SC_3350
cis-8-Dimethylamino-3-(1- INT-976 5-bromo-1- SC_3103 1H NMR (600
MHz, DMSO) .delta. 8.64 (d, 1H), 468.2
methylsulfonyl-1H-pyrrolo[2,3- methylsulfonyl- 8.28 (d, 1H), 7.65
(dd, 1H), 7.57 (s, 1H), b]pyridin-5-yl)-8-phenyl-1,3- pyrrolo[2,3-
7.38 (dd, 4H), 7.28 (dt, 1H), 6.72 (dd, 1H),
diazaspiro[4.5]decan-2-one b]pyridine 3.68 (s, 2H), 3.65 (s, 3H),
2.48-2.29 (m, 2H), 1.98 (s, 10H), 1.53-1.44 (m, 2H). SC_3351
cis-8-Dimethylamino-3-(1H-indol- INT-976 4-bromo-1-(toluene-
SC_3357 1H-NMR (DMSO-d6, 400 MHz at 100.degree. C.), 389.3
4-yl)-8-phenyl-1,3- 4-sulfonyl)-1H-indole .delta. (ppm) = 10.77
(bs, 1H), 7.37 (bs, 4H), diazaspiro[4.5]decan-2-one (step 1)
7.24-7.18 (m, 3H), 7.02-6.94 (m, 2H), 6.81 (bs, 1H), 6.41 (s, 1H),
3.66 (s, 2H), 2.36-2.33 (m, 2H), 2.05-1.96 (m, 10H), 1.60-156 (m,
2H). SC_3353 cis-8-Dimethylamino-3-[2-fluoro- INT-976
1-bromo-2-fluoro-4- SC_3103 1H NMR (600 MHz, DMSO) .delta. 7.62 (t,
1H), 452.2 4-(trifluoromethyloxy)-phenyl]-8- (trifluoromethoxy)-
7.50-7.46 (m, 1H), 7.40 (dd, 1H),
phenyl-1,3-diazaspiro[4.5]decan-2- benzene 7.38-7.31 (m, 4H), 7.25
(t, 1H), 7.21 (d, 1H), one 3.57 (s, 2H), 2.38 (d, 2H), 1.97-1.88
(m, 8H), 1.84-1.79 (m, 2H), 1.53-1.46 (m, 2H). SC_3355
cis-8-Dimethylamino-3-(1-methyl- INT-976 4-bromo-1-methyl- SC_3103
1H NMR (600 MHz, DMSO) .delta. 8.04 (d, 1H), 404.3
1H-pyrrolo[2,3-b]pyridin-4-yl)-8- pyrrolo[2,3- 7.70 (s, 1H), 7.47
(d, 1H), 7.41-7.33 (m, phenyl-1,3-diazaspiro[4.5]decan-2-
b]pyridine 4H), 7.31-7.24 (m, 2H), 6.65 (d, 1H), one 3.91 (s, 2H),
3.74 (s, 3H), 2.44-2.25 (m, 2H), 2.08-1.74 (m, 10H), 1.52 (t, 2H).
SC_3356 cis-3-(1-Acetyl-1H-indol-4-yl)-8- SC_3351 acetyl chloride
SC_3379 1H-NMR (DMSO-d6, 400 MHz at 100.degree. C.), 431.2
dimethylamino-8-phenyl-1,3- .delta. (ppm) = 8.12 (d, 1H, J = 8.28
Hz), 7.68 (d, diazaspiro[4.5]decan-2-one 1H, J = 3.64 Hz),
7.36-7.22 (m, 6H), 7.16 (d, 1H, J = 7.80 Hz), 7.01 (s, 1H), 6.69
(d, 1H, J = 3.8 Hz), 3.66 (s, 2H), 2.62 (s, 3H), 2.38-2.33 (m, 2H),
2.05-1.92 (m, 10H), 1.61-1.56 (m, 2H). SC_3358
cis-6-(8-Dimethylamino-2-oxo-8- INT-976 6-chloro-5-methyl- SC_3103
1H NMR (600 MHz, DMSO) .delta. 8.64 (s, 1H), 390.2
phenyl-1,3-diazaspiro[4.5]decan-3- pyridine-3- 8.12 (s, 1H), 7.76
(s, 1H), 7.39-7.34 (m, yl)-5-methyl-nicotinonitrile carbonitrile
4H), 7.27 (s, 1H), 3.71 (s, 2H), 2.43-2.15 (m, 5H), 2.11-1.70 (m,
10H), 1.52 (s, 2H). SC_3359 cis-6-(8-Dimethylamino-2-oxo-8- INT-976
6-chloro-5-fluoro- SC_3103 1H NMR (600 MHz, DMSO) .delta. 8.64 (d,
1H), 394.2 phenyl-1,3-diazaspiro[4.5]decan-3- pyridine-3- 8.30 (dd,
1H), 7.95 (s, 1H), 7.40-7.31 (m, yl)-5-fluoro-nicotinonitrile
carbonitrile 4H), 7.29-7.23 (m, 1H), 3.72 (s, 2H), 2.36-2.33 (m,
2H), 1.96 (s, 6H), 1.94-1.79 (m, 4H), 1.52 (t, 2H). SC_3361
cis-6-(8-Dimethylamino-2-oxo-8- SC_3358 SC_3016 1H NMR (600 MHz,
DMSO) .delta. 8.64 (d, 1H), 408.2
phenyl-1,3-diazaspiro[4.5]decan-3- 8.06-8.02 (m, 2H), 7.54 (s, 1H),
7.44 (s, yl)-5-methyl-pyridine-3-carboxylic 1H), 7.38-7.30 (m, 4H),
7.27-7.21 (m, acid amide 1H), 3.67 (s, 2H), 2.37-2.26 (m, 5H),
2.05-1.75 (m, 10H), 1.51 (t, 2H). SC_3362
cis-6-(8-Dimethylamino-2-oxo-8- SC_3359 SC_3016 1H NMR (600 MHz,
DMSO) .delta. 412.2 phenyl-1,3-diazaspiro[4.5]decan-3- 8.65-8.61
(m, 1H), 8.13 (s, 1H), 8.04 (dd, 1H), 7.76 (s,
yl)-5-fluoro-pyridine-3-carboxylic 1H), 7.59 (s, 1H), 7.39-7.30 (m,
4H), acid amide 7.28-7.21 (m, 1H), 3.70 (s, 2H), 2.41-2.23 (m, 2H),
1.96-1.76 (m, 10H), 1.50 (t, 2H). SC_3363
cis-8-Dimethylamino-3-[4-methyl- INT- 5-bromo-4-methyl-2- SC_3319
1H NMR (600 MHz, DMSO) .delta. 8.56 (s, 1H), 447.2
6-(trifluoromethyl)-pyridin-3-yl]-8- 1038 (trifluoromethyl)pyridine
7.80 (s, 1H), 7.52 (s, 1H), 7.24 (t, 1H),
m-tolyl-1,3-diazaspiro[4.5]decan-2- 7.17-7.11 (m, 2H), 7.06 (d,
1H), 3.60 (s, 2H), one 2.39-2.25 (m, 8H), 2.01-1.78 (m, 10H),
1.58-1.48 (m, 2H). SC_3364 cis-3-(8-Dimethylamino-2-oxo-8- INT-976
3-bromopyridine-4- SC_3242 1H NMR (600 MHz, DMSO) .delta. 8.79 (s,
1H), 376.2 phenyl-1,3-diazaspiro[4.5]decan-3- carbonitrile 8.50 (d,
1H), 7.84-7.80 (m, 1H), 7.37 (td, yl)-isonicotinonitrile 4H), 7.26
(td, 1H), 3.79 (s, 2H), 2.43-2.36 (m, 2H), 1.97 (s, 7H), 1.96-1.91
(m, 2H), 1.88-1.81 (m, 2H), 1.61-1.45 (m, 2H). SC_3365
cis-8-Dimethylamino-3-[3-fluoro- INT- 4-(4,4,5,5- SC_3354 1H NMR
(600 MHz, DMSO) .delta. 10.51 (s, 500.2
5-(2-oxo-1,3-dihydro-indol-4-yl)- 1045 tetramethyl-1,3,2- 1H), 8.39
(d, 1H), 7.96 (dd, 1H), pyridin-2-yl]-8-phenyl-1,3- dioxaborolan-2-
7.41-7.32 (m, 4H), 7.28 (dt, 2H), 7.08 (d, 1H), 6.88 (d,
diazaspiro[4.5]decan-2-one yl)indolin-2-one (step 1H), 3.71 (s,
2H), 3.67 (s, 2H), 2) 2.44-2.22 (m, 2H), 1.98-1.87 (m, 11H),
1.58-1.46 (m, 2H). SC_3366 cis-8-Dimethylamino-3-[4-methyl- INT-
5-bromo-4-methyl-2- SC_3319 1H NMR (600 MHz, DMSO) .delta. 8.55 (s,
1H), 517.2 6-(trifluoromethyl)-pyridin-3-yl]-8- 1039
(trifluoromethyl)pyridine 7.79 (s, 1H), 7.51 (t, 2H), 7.38 (dd,
1H), [3-(trifluoromethyloxy)-phenyl]- 7.26 (d, 2H), 3.62 (s, 2H),
2.40-2.34 (m, 2H), 1,3-diazaspiro[4.5]decan-2-one 2.31 (s, 3H),
2.01-1.77 (m, 10H), 1.58-1.49 (m, 2H). SC_3367
cis-8-Dimethylamino-3-[4-methyl- INT- 5-bromo-4-methyl-2- SC_3319
1H NMR (600 MHz, DMSO) .delta. 8.55 (s, 1H), 501.2
6-(trifluoromethyl)-pyridin-3-yl]-8- 1040 (trifluoromethyl)pyridine
7.79 (s, 1H), 7.69-7.56 (m, 5H), 7.52 (s,
[3-(trifluoromethyl)phenyl]-1,3- 1H), 3.61 (s, 2H), 2.44-2.36 (m,
2H), diazaspiro[4.5]decan-2-one 2.31 (s, 3H), 2.02-1.80 (m, 10H),
1.60-1.47 (m, 2H). SC_3368 cis-8-Dimethylamino-8-(3- INT-
5-bromo-4-methyl-2- SC_3319 1H NMR (600 MHz, DMSO) .delta. 8.56 (s,
1H), 463.2 methoxyphenyl)-3-[4-methyl-6- 1041
(trifluoromethyl)pyridine 7.80 (s, 1H), 7.51 (s, 1H), 7.31-7.25 (m,
(trifluoromethyl)-pyridin-3-yl]-1,3- 1H), 6.92 (dt, 1H), 6.87-6.82
(m, 2H), diazaspiro[4.5]decan-2-one 3.75 (s, 3H), 3.61 (s, 2H),
2.35-2.30 (m, 5H), 1.98 (s, 7H), 1.96-1.90 (m, 2H), 1.88-1.80 (m,
2H), 1.60-1.49 (m, 2H). SC_3369 cis-8-(5-Chloro-thiophen-2-yl)-8-
INT- 5-bromo-4-methyl-2- SC_3319 1H NMR (600 MHz, DMSO) .delta.
8.56 (s, 1H), 473.1 dimethylamino-3-[4-methyl-6- 1042
(trifluoromethyl)pyridine 7.79 (s, 1H), 7.39 (s, 1H), 7.04-7.00 (m,
(trifluoromethyl)-pyridin-3-yl]-1,3- 1H), 6.80 (d, 1H), 3.64 (s,
2H), 2.31 (s, 3H), diazaspiro[4.5]decan-2-one 2.22-2.15 (m, 2H),
2.04 (s, 6H), 1.95-1.87 (m, 2H), 1.83-1.77 (m, 2H), 1.63-1.57 (m,
2H). SC_3370 cis-8-Dimethylamino-8-(3- INT- 5-bromo-4-methyl-2-
SC_3319 1H NMR (600 MHz, DMSO) .delta. 8.56 (s, 1H), 451.2
fluorophenyl)-3-[4-methyl-6- 1024 (trifluoromethyl)pyridine 7.80
(s, 1H), 7.51 (s, 1H), 7.41 (td, 1H),
(trifluoromethyl)-pyridin-3-yl]-1,3- 7.21-7.12 (m, 2H), 7.12-7.06
(m, 1H), 3.61 (s, diazaspiro[4.5]decan-2-one 2H), 2.38-2.30 (m,
5H), 1.97 (s, 6H), 1.96-1.90 (m, 2H), 1.90-1.73 (m, 2H), 1.61-1.45
(m, 2H). SC_3371 cis-8-Dimethylamino-3-(2- INT-989 methylamine
SC_3239 1H NMR (600 MHz, DMSO + TFA) .delta. 381.2
methylamino-pyrimidin-5-yl)-8- 8.69 (s, 2H), 8.29 (s, 1H), 7.68 (d,
2H), 7.52 (dt, phenyl-1,3-diazaspiro[4.5]decan-2- 3H), 2.90 (s,
3H), 2.68 (d, 2H), 2.59 (s, 6H), one 2.24 (t, 2H), 1.86 (d, 2H),
1.39-1.31 (m, 2H) SC_3372 cis-8-(5-Chloro-thiophen-2-yl)-8- INT-
4-(5-bromo-4-methyl- SC_3242 1H NMR (600 MHz, DMSO) .delta. 8.15
(d, 1H), 491.2 dimethylamino-3-(4-methyl-2- 1042 pyrimidin-2- 7.15
(s, 1H), 7.05 (d, 1H), 6.82 (d, 1H),
morpholin-4-yl-pyrimidin-5-yl)- yl)morpholine 3.70-3.61 (m, 8H),
3.44 (s, 2H), 2.31-2.12 (m, 1,3-diazaspiro[4.5]decan-2-one 5H),
2.06 (s, 6H), 1.93-1.85 (m, 2H), 1.82-1.69 (m, 2H), 1.64-1.49 (m,
2H). SC_3373 cis-N-[5-(8-Dimethylamino-2-oxo- SC_3371
Cyclopropancarbonyl SC_3240 1H NMR (600 MHz, DMSO) .delta. 8.97 (s,
2H), 449.3 8-phenyl-1,3-diazaspiro[4.5]decan- chlorid 7.83-7.73 (m,
1H), 7.41-7.34 (m, 4H), 3-yl)-pyrimidin-2-yl]-N-methyl- 7.30-7.24
(m, 1H), 3.66 (s, 2H), 3.27 (s, cyclopropanecarboxylic acid amide
3H), 2.47-2.29 (m, 2H), 1.99-1.87 (m, 10H), 1.49 (t, 2H), 0.88-0.80
(m, 2H), 0.70 (dt, 2H). SC_3374 cis-N-[5-(8-Dimethylamino-2-oxo-
SC_3371 2,5-dimethylpyrazole- SC_3240 1H NMR (600 MHz, DMSO)
.delta. 8.83 (s, 2H), 503.3 8-phenyl-1,3-diazaspiro[4.5]decan-
3-carbonyl chloride 7.77 (s, 1H), 7.41-7.32 (m, 4H), 7.27 (td,
3-yl)-pyrimidin-2-yl]-N,2,5- 1H), 5.48 (s, 1H), 3.80 (s, 3H), 3.61
(s, 2H), trimethyl-2H-pyrazole-3-carboxylic 3.40 (s, 3H), 2.46-2.31
(m, 2H), 1.96 (s, acid amide 3H), 1.96 (s, 6H), 1.94-1.74 (m, 5H),
1.52-1.42 (m, 2H). SC_3375 cis-3-[4,6-Bis(trifluoromethyl)- INT-976
5-bromo-2,4- SC_3103 1H NMR (600 MHz, DMSO) .delta. 8.98 (s, 1H),
487.2 pyridin-3-yl]-8-dimethylamino-8- bis(trifluoromethyl)pyridine
8.20 (s, 1H), 7.79 (s, 1H), 7.40-7.32 (m,
phenyl-1,3-diazaspiro[4.5]decan-2- 4H), 7.26 (td, 1H), 3.62 (s,
2H), one 2.44-2.24 (m, 2H), 1.98-1.91 (m, 8H), 1.86 (s, 2H), 1.53
(t, 2H). SC_3376 cis-8-Dimethylamino-3-[2-[(2- INT-976 2-[(6-bromo-
SC_3242 1HNMR at 100.degree. C. (DMSO-d6, 400 MHz), .delta. 475.1
hydroxy-ethyl)-methyl-amino]- quinazolin-2-yl)- (ppm) = 8.99 (s,
1H), 8.28 (d, 1H, J = 9.24 Hz), quinazolin-6-yl]-8-phenyl-1,3-
methyl-amino]- 7.63 (s, 1H), 7.43-7.26 (m, 6H),
diazaspiro[4.5]decan-2-one ethanol 7.13 (s, 1H), 4.31 (bs, 1H),
3.78-3.76 (m, 2H), 3.66 (bs, 4H), 3.24 (s, 3H), 2.43-2.38 (m, 2H),
2.05-1.90 (m, 10H), 1.56-1.54 (m, 2H). SC_3377
cis-8-Dimethylamino-3-(2- INT-976 6-bromo-2- SC_3242 1HNMR at
100.degree. C. (DMSO-d6, 400 MHz), .delta. 487.2
morpholin-4-yl-quinazolin-6-yl)-8- morpholin-4-yl- (ppm) = 9.05 (s,
1H), 8.34 (d, 1H), 7.68 (s, phenyl-1,3-diazaspiro[4.5]decan-2-
quinazoline 1H), 7.48 (d, 1H, J = 9.4 Hz), 7.38-7.27 (m, one 5H),
7.18 (s, 1H), 3.81-3.67 (m, 10H), 2.40-2.38 (m, 2H), 2.05-1.90 (m,
10H), 1.57-1.54 (m, 2H). SC_3378 cis-8-[Methyl-(oxetan-3-yl- INT-
2-trifluoromethyl-5- SC_3103 1H NMR (DMSO-d6): .delta. 9.21-9.15
(s, 2H), 476.2 methyl)-amino]-8-phenyl-3-[2- 1047 bromopyrimidine
8.19-8.18 (broad s, 1H), 7.41-7.34 (m, 4H),
(trifluoromethyl)-pyrimidin-5-yl]- 7.27-7.25 (m, 1H), 4.58-4.56 (m,
2H), 1,3-diazaspiro[4.5]decan-2-one 4.18 (s, 1H), 3.69 (s, 2H),
3.05-2.99 (m, 1H), 2.41-2.36 (m, 4H), 1.91 (m, 7H), 1.47 (s, 2H).
SC_3380 cis-8-Dimethylamino-8-phenyl-3- INT-976 6-bromo-quinazoline
SC_3103 1HNMR at 100.degree. C. (DMSO-d6, 400 MHz), .delta. 402.2
quinazolin-6-yl-1,3- (ppm) = 9.35 (s, 1H), 9.10 (s, 1H), 8.65 (d,
1H, diazaspiro[4.5]decan-2-one J = 9.04) 7.91-7.89 (m, 2H),
7.39-7.27 (m,
5H), 3.75 (s, 2H), 2.42-2.32 (m, 2H), 2.05 (s, 6H), 2.00-1.92 (m,
4H), 1.56 (bs, 2H). SC_3381 cis-5-(8-Dimethylamino-2-oxo-8- INT-976
5-bromo-2-chloro- SC_3103 (for 1H NMR (600 MHz, DMSO) .delta. 8.88
(s, 1H), 507.3 phenyl-1,3-diazaspiro[4.5]decan-3- pyridine-4- step
1), 8.24 (s, 1H), 7.85 (s, 1H), 7.52-7.46 (m,
yl)-2-(2-oxo-1,3-dihydro-indol-4- carbonitrile SC_3129 (for 1H),
7.41-7.29 (m, 6H), 7.27 (td, 1H), yl)-isonicotinonitrile (step 1),
4-(4,4,5,5- step 2) 6.92 (d, 1H), 3.84 (s, 2H), 3.78 (s, 2H),
tetramethyl-1,3,2- 2.48-2.30 (m, 2H), 1.99-1.93 (m, 8H),
dioxaborolan-2- 1.92-1.74 (m, 2H), 1.58-1.54 (m, 2H).
yl)indolin-2-one (step 2) SC_3382 cis-N-[5-(8-Dimethylamino-2-oxo-
SC_3371 tetrahydropyran-4- SC_3240 1H NMR (600 MHz, DMSO) .delta.
8.97 (s, 2H), 493.3 8-phenyl-1,3-diazaspiro[4.5]decan- carbonyl
chloride 7.80 (s, 1H), 7.42-7.34 (m, 4H),
3-yl)-pyrimidin-2-yl]-N-methyl- 7.31-7.25 (m, 1H), 3.79 (ddd, 2H),
3.67 (s, 2H), tetrahydro-pyran-4-carboxylic acid 3.25 (s, 2H), 3.17
(td, 2H), 3.04-2.96 (m, amide 1H), 2.49-2.34 (m, 2H), 1.97 (s, 6H),
1.95-1.74 (m, 4H), 1.68-1.53 (m, 4H), 1.54-1.48 (m, 2H). SC_3383
cis-N-[5-(8-Dimethylamino-2-oxo- SC_3371 pivaloyl chloride SC_3240
1H NMR (600 MHz, DMSO) .delta. 8.98 (s, 2H), 465.3
8-phenyl-1,3-diazaspiro[4.5]decan- 7.42-7.34 (m, 4H), 7.30-7.26 (m,
1H), 3-yl)-pyrimidin-2-yl]-N,2,2- 3.69 (s, 2H), 3.14 (s, 3H),
2.46-2.41 (m, trimethyl-propionamide 2H), 1.99-1.87 (m, 10H),
1.54-1.45 (m, 2H), 0.97 (s, 9H). SC_3384
cis-8-Dimethylamino-3-[2-(1- INT-989 1-methyl-4-(4,4,5,5- SC_3208
1H NMR (600 MHz, CDCl3) .delta. 9.05 (s, 2H), 497.3
methyl-2-oxo-1,3-dihydro-indol-4- tetramethyl-1,3,2- 8.08 (d, 1H),
7.47-7.39 (m, 3H), yl)-pyrimidin-5-yl]-8-phenyl-1,3-
dioxaborolan-2- 7.38-7.31 (m, 3H), 6.91 (d, 1H), 5.46 (s, 1H),
diazaspiro[4.5]decan-2-one yl)indolin-2-one 4.04 (s, 2H), 3.64 (s,
2H), 3.27 (s, 3H), 2.35-2.14 (m, 4H), 2.10 (s, 6H), 2.08-2.01 (m,
3H), 1.73-1.64 (m, 2H), 1.28 (s, 0H). SC_3385
cis-8-Dimethylamino-3-(2- INT-976 6-bromo-1-(tert- SC_3242 (for
1HNMR at 100.degree. C. (DMSO-d6, 400 MHz), .delta. 475.2
morpholin-4-yl-1H-benzoimidazol- butylsilanyl- step 1), step 2
(ppm) = 10.94 (bs, 1H), 7.50 (bs, 1H), 5-yl)-8-phenyl-1,3-
methoxymethyl)-2- of SC_3352 7.39-7.27 (m, 5H), 7.06 (m, 2 H), 6.84
(bs, 1H), diazaspiro[4.5]decan-2-one morpholin-4-yl-1H- (for step
2) 3.72 (t, 4H, 4.56 Hz), 3.55 (s, 2H), 3.45 (t, benzoimidazole
(step 4H, 4.56 Hz), 2.372.24 (m, 2H), 1) 1.95-1.81 (m, 10H),
1.52-1.50 (m, 2H) SC_3386 cis-8-Dimethylamino-8-(3-fluoro- INT-
5-bromo-4-methyl-2- SC_3319 1H NMR (600 MHz, DMSO) .delta. 8.57 (s,
1H), 465.2 5-methyl-phenyl)-3-[4-methyl-6- 1043
(trifluoromethyl)pyridine 7.80 (s, 1H), 7.51 (s, 1H), 6.99 (s, 1H),
(trifluoromethyl)-pyridin-3-yl]-1,3- 6.96-6.89 (m, 2H), 3.61 (s,
2H), 2.34 (s, 3H), diazaspiro[4.5]decan-2-one 2.32 (s, 3H), 2.07
(s, 1H), 1.97 (s, 6H), 1.96-1.89 (m, 2H), 1.88-1.78 (m, 2H), 1.54
(d, 2H). SC_3387 cis-8-Dimethylamino-3-[6-(2-oxo- INT- 4-(4,4,5,5-
SC_3129 1H NMR (600 MHz, DMSO) .delta. 8.83 (d, 1H), 482.3
1,3-dihydro-indol-4-yl)-pyridin-3- 1048 tetramethyl-1,3,2- 8.11
(dd, 1H), 7.77 (d, 1H), 7.64 (s, 1H), yl]-8-phenyl-1,3-
dioxaborolan-2- 7.43-7.34 (m, 5H), 7.31-7.24 (m, 2H),
diazaspiro[4.5]decan-2-one yl)indolin-2-one 6.84 (d, 1H), 3.73 (s,
2H), 3.68 (s, 2H), 2.45-2.31 (m, 2H), 1.99-1.79 (m, 10H), 1.51 (t,
2H). SC_3389 cis-3-[6-(Azetidin-1-yl)-5- INT-976
5-bromo-2-chloro-3- SC_3103 (for 1H NMR (600 MHz, DMSO) .delta.
8.40 (d, 1H), 453.2 (trifluoromethyl)-pyridin-3-yl]-8-
(trifluoromethyl)pyridine step 1), 8.21 (d, 1H), 7.47 (s, 1H),
7.41-7.33 (m, dimethylamino-8-phenyl-1,3- (step 1), azetidine
SC_3120 (for 4H), 7.30-7.24 (m, 1H), 4.03 (t, 4H),
diazaspiro[4.5]decan-2-one (step 2) step 2, 160.degree. C.) 3.58
(s, 2H), 2.47-2.29 (m, 2H), 2.25 (p, 2H), 1.96 (s, 6H), 1.89 (s,
4H), 1.47 (t, 2H). SC_3390 cis-3-[1-(Cyclopropyl-methyl)-8- SC_3364
bromomethylcyclopropane INT-952 1H NMR (600 MHz, DMSO) .delta. 8.82
(s, 1H), 430.3 dimethylamino-2-oxo-8-phenyl- 8.51 (dd, 1H), 7.81
(d, 1H), 7.40-7.33 (m, 1,3-diazaspiro[4.5]decan-3-yl]- 4H),
7.29-7.23 (m, 1H), 3.93 (s, 2H), isonicotinonitrile 3.10 (d, 2H),
2.76-2.70 (m, 2H), 2.29 (ddd, 2H), 2.02 (s, 6H), 1.58 (d, 2H),
1.52-1.44 (m, 2H), 1.01 (ddt, 1H), 0.55-0.49 (m, 2H), 0.37-0.31 (m,
2H). SC_3391 cis-3-[3,5-Bis(trifluoromethyl)- INT-976 2-chloro-3,5-
SC_3103 1H NMR (600 MHz, DMSO) .delta. 9.04 (d, 1H), 487.2
pyridin-2-yl]-8-dimethylamino-8- bis(trifluoromethyl)pyridine 8.58
(d, 1H), 7.96 (s, 1H), 7.41-7.32 (m,
phenyl-1,3-diazaspiro[4.5]decan-2- 4H), 7.29-7.23 (m, 1H), 3.75 (s,
2H), one 2.41-2.25 (m, 2H), 1.98-1.89 (m, 10H), 1.52 (t, 2H).
SC_3392 cis-8-Dimethylamino-3-(5-fluoro- INT-976
4-(5-bromo-3-fluoro- SC_3103 1H NMR (600 MHz, CDCl3) .delta. 8.13
(dd, 454.3 6-morpholin-4-yl-pyridin-3-yl)-8- 2-pyridyl)morpholine
1H), 7.76 (d, 1H), 7.42 (t, 2H), 7.33 (dd,
phenyl-1,3-diazaspiro[4.5]decan-2- 3H), 5.84 (s, 1H), 3.84 (t, 4H),
3.52 (s, 2H), one 3.37 (t, 4H), 2.29-2.12 (m, 4H), 2.08 (s, 6H),
2.01-1.94 (m, 2H), 1.60 (t, 2H). SC_3393 cis-8-(3-Chlorophenyl)-8-
INT- 5-bromo-4-methyl-2- SC_3319 1H NMR (600 MHz, DMSO) .delta.
8.57 (s, 1H), 467.2 dimethylamino-3-[4-methyl-6- 1044
(trifluoromethyl)pyridine 7.80 (s, 1H), 7.55-7.49 (m, 1H),
(trifluoromethyl)-pyridin-3-yl]-1,3- 7.43-7.37 (m, 1H), 7.38-7.29
(m, 3H), 3.61 (s, diazaspiro[4.5]decan-2-one 2H), 2.40-2.24 (m,
5H), 1.99-1.90 (m, 8H), 1.90-1.76 (m, 2H), 1.60-1.47 (m, 2H).
SC_3394 cis-8-Dimethylamino-3-[5-(2-oxo- INT- 4-(4,4,5,5- SC_3354
1H NMR (600 MHz, DMSO) .delta. 8.41 (d, 1H), 482.3
1,3-dihydro-indol-4-yl)-pyridin-2- 1049 tetramethyl-1,3,2- 8.26 (d,
1H), 7.92 (dd, 1H), 7.75 (s, 1H), yl]-8-phenyl-1,3- dioxaborolan-2-
7.41-7.32 (m, 5H), 7.30-7.23 (m, 2H), diazaspiro[4.5]decan-2-one
yl)indolin-2-one 7.01 (d, 1H), 6.83 (d, 1H), 3.75 (s, 2H), 3.61 (s,
2H), 2.46-2.30 (m, 2H), 1.96 (s, 6H), 1.94-1.88 (m, 2H), 1.86-1.82
(m, 2H), 1.48 (t, 2H). SC_3395 cis-8-Dimethylamino-8-phenyl-3-
INT-976 2-bromo-5- SC_3103 1H NMR (600 MHz, DMSO) .delta. 8.69 (s,
1H), 426.2 [5-(trifluoromethyl)- (trifluoromethyl)- 7.42-7.34 (m,
4H), 7.28 (t, 1H), 3.89 (s, [1,3,4]thiadiazol-2-yl]-1,3-
1,3,4-thiadiazole 2H), 2.45-2.31 (m, 2H), 2.07-1.88 (m,
diazaspiro[4.5]decan-2-one 8H), 1.88-1.84 (m, 2H), 1.60-1.53 (m,
2H). SC_3397 cis-8-Dimethylamino-3-[2-[(2- INT-976
2-{[6-bromo-1-(2- SC_3242 (for 1HNMR (DMSO-d6, 400 MHz at
100.degree. C.), .delta. 463.3 hydroxy-ethyl)-methyl-amino]-1H-
trimethylsilanyl- step 1), step 2 (ppm) = 10.62 (bs, 1H), 7.48-7.24
(m, 6H), benzoimidazol-5-yl]-8-phenyl-1,3- ethoxymethyl)-1H- of
SC_3352 7.01-6.91 (m, 2H,), 6.76 (s, 1H), 4.58 (bs,
diazaspiro[4.5]decan-2-one benzoimidazol-2-yl]- (for step 2) 1H),
3.66 (t, 2H, J = 5.62 Hz), 3.54-3.50 (m, methyl-amino}- 4H), 3.09
(s, 3H), 2.37-2.32 (m, 2H), 2.04 (s, ethanol (step 1) 6H),
1.96-1.91 (m, 4H), 1.52-1.40 (m, 2H). SC_3398
cis-8-Dimethylamino-3-(5-methyl- INT-976 4-(5-bromo-3-methyl-
SC_3103 1H NMR (600 MHz, DMSO) .delta. 8.23 (s, 1H), 450.3
6-morpholin-4-yl-pyridin-3-yl)-8- 2-pyridyl)morpholine 7.83 (s,
1H), 7.46-7.33 (m, 5H), phenyl-1,3-diazaspiro[4.5]decan-2-
7.30-7.24 (m, 1H), 3.71 (t, 4H), 3.55 (s, 2H), one 2.93 (t, 4H),
2.41-2.37 (m, 2H), 1.96 (s, 6H), 1.91-1.82 (m, 4H), 1.49-1.44 (m,
2H). SC_3399 cis-1-(Cyclopropyl-methyl)-8- SC_3409
bromomethylcyclopropane SC_3105 1HNMR (DMSO-d6, 400 MHz), .delta.
(ppm) = 8.68-8.68 (d, 501.4 dimethylamino-8-(3-fluorophenyl)- 1H, J
= 2.32 Hz), 8.42-8.40 (d, 3-(5-methylsulfonyl-pyridin-2-yl)- 1H, J
= 9.04 Hz), 8.18-8.15 (m, 1H), 1,3-diazaspiro[4.5]decan-2-one
7.44-7.38 (m, 1H), 7.20-7.08 (m, 3H), 3.90 (s, 2H), 3.22 (s, 3H),
3.11-3.10 (d, 2H, J = 6.68 Hz), 2.71-2.68 (d, 2H, J = 13.6 Hz),
2.27-2.21 (m, 2H), 2.00 (s, 6H), 1.53-1.44 (m, 4H), 1.02-0.99 (m,
1H), 0.54-0.50 (m, 2H), 0.36-0.35 (m, 2H). SC_3400
cis-1-(Cyclopropyl-methyl)-8-(3- SC_3399 SC_3099 1HNMR (DMSO-d6,
400 MHz), .delta. (ppm) = 8.72-8.71 (d, 487.2
fluorophenyl)-8-methylamino-3-(5- 1H, J = 2.28 Hz), 8.42-8.40 (d,
methylsulfonyl-pyridin-2-yl)-1,3- 1H, J = 9.04 Hz), 8.18-8.15 (m,
1H), diazaspiro[4.5]decan-2-one 7.40-7.31 (m, 3H), 7.05-7.01 (m,
1H), 3.93 (s, 2H), 3.23 (s, 3H), 3.14-3.13 (d, 2H, J = 6.76 Hz),
2.42 (bs, 1H), 2.28-2.23 (m, 2H), 1.96-1.88 (m, 5H), 1.79-1.73 (m,
2H), 1.44-1.41 (d, 2H, J = 12.2 Hz), 1.06-1.02 (m, 1H), 0.52-0.47
(m, 2H), 0.36-0.33 (m, 2H). SC_3401 cis-1-(Cyclobutyl-methyl)-8-(3-
SC_3404 bromomethylcyclobutane SC_3105 (for 1HNMR at 100.degree. C.
(DMSO-d6, 400 MHz), .delta. 492.1 fluorophenyl)-8-methylamino-3-[2-
(step 1) step 1), (ppm) = 9.23 (s, 2H), 7.38-7.26 (m, 3H),
(trifluoromethyl)-pyrimidin-5-yl]- SC_3099 (for 7.00 (t, 1H, J =
8.1 Hz), 3.86 (s, 2H), 1,3-diazaspiro[4.5]decan-2-one step 2)
3.30-3.28 (d, 2H, J = 7.24 Hz), 2.68-2.65 (m, 1H), 2.27-2.16 (m,
3H), 2.06-1.78 (m, 13H), 1.46-1.43 (m, 2H). SC_3402
cis-1-(Cyclopropyl-methyl)-8- SC_3404 bromomethylcyclopropane
SC_3105 1HNMR (DMSO-d6, 400 MHz), .delta. (ppm) = 9.21 (s, 492.0
dimethylamino-8-(3-fluorophenyl)- 2H), 7.45-7.39 (m, 1H),
3-[2-(trifluoromethyl)-pyrimidin-5- 7.22-7.18 (m, 2H), 7.14-7.09
(m, 1H), 3.84 (s, 2H), yl]-1,3-diazaspiro[4.5]decan-2-one 3.09 (d,
2H, J = 6.4 Hz), 2.70 (d, 2H, J = 9.6 Hz), 2.32-2.21 (m, 2H), 2.01
(s, 6H), 1.59-1.46 (m, 4H), 1.01-1.00 (m, 1H), 0.54-0.49 (m, 2H),
0.35-0.33 (m, 2H). SC_3403 cis-1-(Cyclopropyl-methyl)-8-(3- SC_3402
SC_3099 1HNMR (DMSO-d6, 400 MHz), .delta. (ppm) = 9.25 (s, 478.4
fluorophenyl)-8-methylamino-3-[2- 2H), 7.41-7.30 (m, 3H), 7.04 (t,
1H, (trifluoromethyl)-pyrimidin-5-yl]- J = 6.8 Hz),
1,3-diazaspiro[4.5]decan-2-one 3.89 (s, 2H), 3.12 (d, 2H, J = 6.8
Hz), 2.41 (bs, 1H), 2.27-2.22 (m, 2H), 1.93-1.78 (m, 7H), 1.46-1.43
(m, 2H), 1.08-1.03 (m, 1H), 0.51-0.47 (m, 2H), 0.33-0.29 (m, 2H).
SC_3404 cis-8-Dimethylamino-8-(3- INT- 2-trifluoromethyl-5- SC_3242
1HNMR at 100.degree. C. (DMSO-d6, 400 MHz), .delta. 437.9
fluorophenyl)-3-[2- 1024 bromopyrimidine (ppm) = 9.15 (s, 2H), 7.75
(s, 1H), (trifluoromethyl)-pyrimidin-5-yl]- 7.44-7.38 (m, 1H),
7.21-7.04 (m, 3H), 3.73 (s, 2H), 1,3-diazaspiro[4.5]decan-2-one
2.38-2.37 (m, 2H), 2.05 (s, 6H), 2.01-1.85 (m, 4H), 1.57-1.53 (m,
2H). SC_3405 cis-1-(Cyclopropyl-methyl)-8- SC_3319
bromomethylcyclopropane SC_3105 1HNMR at 100.degree. C. (DMSO-d6,
400 MHz), .delta. 494.3 dimethylamino-8-(3-fluorophenyl)- (ppm) =
7.39-7.36 (m, 1H), 7.19-7.05 (m, 3-[2-methyl-5-(trifluoromethyl)-
3H), 6.56 (s, 1H), 3.78-3.67 (m, 5H), 2H-pyrazol-3-yl]-1,3-
3.10-3.08 (d, 2H, J = 6.12 Hz), 2.64-2.60 (d, 2H, J = 13.32 Hz),
diazaspiro[4.5]decan-2-one 2.37-2.26 (m, 2H), 2.09 (s, 6H),
1.61-1.49 (m, 4H), 1.10-1.02 (m, 1H), 0.54-0.52 (m, 2H), 0.36-0.33
(m, 2H). SC_3406 cis-1-(Cyclopropyl-methyl)-8-(3- SC_3405 SC_3099
1HNMR at 100.degree. C. (DMSO-d6, 400 MHz), .delta. 480.0
fluorophenyl)-8-methylamino-3-[2- (ppm) = 7.39-7.24 (m, 3H),
6.99-6.96 (m, methyl-5-(trifluoromethyl)-2H- 1H), 6.58 (s, 1H),
3.78-3.71 (m, 5H), pyrazol-3-yl]-1,3- 3.11-3.10 (d, 2H, J = 5.40
Hz), 2.30-2.23 (m, 2H), diazaspiro[4.5]decan-2-one 1.99-1.92 (m,
5H), 1.79-1.72 (m, 2H), 1.58-1.56 (m, 2H), 1.10-1.00 (m, 1H),
0.54-0.52 (m, 2H), 0.36-0.33 (m, 2H). SC_3407
cis-8-Methylamino-3-(4-methyl-2- SC_3148 SC_3099 437.3
morpholin-4-yl-pyrimidin-5-yl)-8-
phenyl-1,3-diazaspiro[4.5]decan-2- one SC_3408
cis-3-[5-(Azetidin-1-yl)-3-methyl- INT- 5-(azetidin-1-yl)-2-
SC_3103 1H NMR (600 MHz, DMSO) .delta. 438.3
pyridin-2-yl]-8-dimethylamino-8- 1024 chloro-3-methyl- 7.44-7.36
(m, 2H), 7.20-7.05 (m, 4H), 6.69 (d, 1H), (3-fluorophenyl)-1,3-
pyridine 3.82 (t, 4H), 3.51 (s, 2H), 2.36-2.26 (m,
diazaspiro[4.5]decan-2-one 4H), 2.15 (s, 3H), 1.96 (s, 6H),
1.94-1.76 (m, 4H), 1.49 (t, 2H). SC_3409 cis-8-Dimethylamino-8-(3-
INT- 2-bromo-5- SC_3103 1H NMR (600 MHz, DMSO) .delta. 8.67 (dd,
447.2 fluorophenyl)-3-(5-methylsulfonyl- 1024 methylsulfonyl- 1H),
8.39 (dd,
1H), 8.14 (dd, 1H), 8.04 (s, pyridin-2-yl)-1,3- pyridine 1H), 7.42
(td, 1H), 7.19 (d, 1H), 7.15 (dt, diazaspiro[4.5]decan-2-one 1H),
7.11 (td, 1H), 3.78 (s, 2H), 3.21 (s, 3H), 2.41-2.37 (m, 2H), 1.97
(s, 6H), 1.94-1.75 (m, 4H), 1.54-1.45 (m, 2H). SC_3410
cis-3-(6-(azetidin-1-yl)-4- INT-976 2-(azetidin-1-yl)-5- SC_3103
fluoropyridin-3-yl)-8- bromo-4- (dimethylamino)-8-phenyl-1,3-
fluoropyridine diazaspiro[4.5]decan-2-one SC_3411
cis-3-(6-(azetidin-1-yl)pyridin-3- INT- 2-(azetidin-1-yl)-5-
SC_3103 yl)-8-(dimethylamino)-8-(3- 1024 bromopyridine
fluorophenyl)-1,3- diazaspiro[4.5]decan-2-one SC_3412
cis-3-(1-(cyclopropanecarbonyl)-3- INT- (5-bromo-3- SC_3103
(trifluoromethyl)-1H-pyrazol-5-yl)- 1024 (trifluoromethyl)-1H-
8-(dimethylamino)-8-(3- pyrazol-1- fluorophenyl)-1,3-
yl)(cyclopropyl)methanone diazaspiro[4.5]decan-2-one SC_3413
cis-8-(dimethylamino)-8-(3- INT- 2-(5-bromo-3- SC_3242
fluorophenyl)-3-(1-(2- 1024 (trifluoromethyl)-1H-
hydroxyethyl)-3-(trifluoromethyl)- pyrazol-1-yl)ethanol
1H-pyrazol-5-yl)-1,3- diazaspiro[4.5]decan-2-one SC_3414
cis-3-(1-(cyclopropylmethyl)-3- INT- 5-bromo-1- SC_3242 480.2
(trifluoromethyl)-1H-pyrazol-5-yl)- 1024 (cyclopropylmethyl)-
8-(dimethylamino)-8-(3- 3-(trifluoromethyl)- fluorophenyl)-1,3-
1H-pyrazole diazaspiro[4.5]decan-2-one SC_3415
cis-8-(dimethylamino)-8-(3- INT- 5-bromo-1- SC_3242
fluorophenyl)-3-(1- 1024 (methylsulfonyl)-3- (methylsulfonyl)-3-
(trifluoromethyl)-1H- (trifluoromethyl)-1H-pyrazol-5-yl)- pyrazole
1,3-diazaspiro[4.5]decan-2-one SC_3416 cis-1-(cyclopropylmethyl)-8-
SC_3415 bromomethylcyclopropane SC_3105 (dimethylamino)-8-(3-
fluorophenyl)-3-(1- (methylsulfonyl)-3-
(trifluoromethyl)-1H-pyrazol-5-yl)- 1,3-diazaspiro[4.5]decan-2-one
SC_3417 cis-2-(5-(8-(dimethylamino)-8-(3- INT- 2-(5-bromo-3-
SC_3242 fluorophenyl)-2-oxo-1,3- 1024 (trifluoromethyl)-1H-
diazaspiro[4.5]decan-3-yl)-3- pyrazol-1-yl)-N,N-
(trifluoromethyl)-1H-pyrazol-1-yl)- dimethylacetamide
N,N-dimethylacetamide SC_3418 cis-2-(5-(1-(cyclopropylmethyl)-8-
SC_3417 bromomethylcyclopropane SC_3105 (dimethylamino)-8-(3-
fluorophenyl)-2-oxo-1,3- diazaspiro[4.5]decan-3-yl)-3-
(trifluoromethyl)-1H-pyrazol-1-yl)- N,N-dimethylacetamide SC_3419
cis-8-(dimethylamino)-3-(1-methyl- INT-976 5-bromo-1-methyl-
SC_3103 404.3 1H-pyrrolo[2,3-b]pyridin-5-yl)-8- 1H-pyrrolo[2,3-
phenyl-1,3-diazaspiro[4.5]decan-2- b]pyridine one SC_3420
cis-8-(dimethylamino)-3-(3-fluoro- INT-976 5-bromo-3-fluoro-1-
SC_3352 408.2 1H-pyrrolo[2,3-b]pyridin-5-yl)-8- ((2-
phenyl-1,3-diazaspiro[4.5]decan-2- (trimethylsilyl)ethoxy)methyl)-
one 1H- pyrrolo[2,3- b]pyridine (step 1) SC_3421
cis-8-(dimethylamino)-8-phenyl-3- INT-976 4-bromo-1-((2- SC_3352
390.2 (1H-pyrrolo[2,3-c]pyridin-4-yl)-
(trimethylsilyl)ethoxy)methyl)- 1,3-diazaspiro[4.5]decan-2-one 1H-
pyrrolo[2,3- c]pyridine SC_3422 cis-8-(dimethylamino)-8-phenyl-3-
INT-989 4-(4,4,5,5- SC_3354 430.2
(2-(pyridazin-4-yl)pyrimidin-5-yl)- tetramethyl-1,3,2-
1,3-diazaspiro[4.5]decan-2-one dioxaborolan-2- yl)pyridazine
SC_3423 cis-8-(dimethylamino)-3-(2-(2-oxo- INT-989 (2-oxo-1,2-
SC_3354 445.2 1,2-dihydropyridin-4-yl)pyrimidin- dihydropyridin-4-
5-yl)-8-phenyl-1,3- yl)boronic acid diazaspiro[4.5]decan-2-one
SC_3424 cis-8-(dimethylamino)-8-(3- INT- 3,5-dibromo-1- SC_3103
(for fluorophenyl)-3-(1-methyl-3- 1024 methyl-1H-pyrazole step 1),
(thiophen-2-yl)-1H-pyrazol-5-yl)- (step 1), thiophen-2- SC_3354
(for 1,3-diazaspiro[4.5]decan-2-one ylboronic acid (step step 2) 2)
SC_3425 cis-8-(dimethylamino)-8-(3- INT- 3,5-dibromo-1- SC_3103
(for fluorophenyl)-3-(1-methyl-3- 1024 methyl-1H-pyrazole step 1),
morpholino-1H-pyrazol-5-yl)-1,3- (step 1), morpholine SC_3103 (for
diazaspiro[4.5]decan-2-one (step 2) step 2) SC_3426
cis-8-(dimethylamino)-8-phenyl-1- INT- 2-trifluoromethyl-5- SC_3103
502.2 (2,2,2-trifluoroethyl)-3-(2- 1068 bromopyrimidine
(trifluoromethyl)pyrimidin-5-yl)- 1,3-diazaspiro[4.5]decan-2-one
SC_3427 cis-8-(dimethylamino)-8-phenyl-3- INT- 2-trifluoromethyl-5-
SC_3103 (2-(trifluoromethyl)pyrimidin-5- 1070 bromopyrimidine
yl)-1-(3,3,3-trifluoropropyl)-1,3- diazaspiro[4.5]decan-2-one
SC_3428 cis-3-(4-methyl-6- SC_3122 SC_3099
(trifluoromethyl)pyridin-3-yl)-8- (methylamino)-8-phenyl-1,3-
diazaspiro[4.5]decan-2-one SC_3429 cis-3-(1-methyl-3- SC_3200
SC_3099 (trifluoromethyl)-1H-pyrazol-5-yl)-
8-(methylamino)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3430
cis-8-(dimethylamino)-8-(3- INT- 3-bromo-4- SC_3103
fluorophenyl)-3-(4- 1024 (methylsulfonyl)pyridine
(methylsulfonyl)pyridin-3-yl)-1,3- diazaspiro[4.5]decan-2-one
SC_3431 cis-8-(dimethylamino)-3-(1-ethyl- INT- 5-bromo-1-ethyl-3-
SC_3242 3-(trifluoromethyl)-1H-pyrazole-5- 1024
(trifluoromethyl)-1H- yl)-8-(3-fluorophenyl)-1,3- pyrazole
diazaspiro[4.5]decan-2-one SC_3432 cis-3-(1-cyclopropyl-3- INT-
5-bromo-1- SC_3242 (trifluoromethyl)-1H-pyrazol-5-yl)- 1024
cyclopropyl-3- 8-(dimethylamino)-8-(3- (trifluoromethyl)-1H-
fluorophenyl)-1,3- pyrazole diazaspiro[4.5]decan-2-one SC_3433
cis-8-(dimethylamino)-8-(3- INT- 5-bromo-1-(oxetan-3- SC_3242
fluorophenyl)-3-(1-(oxetan-3- 1024 ylmethyl)-3-
ylmethyl)-3-(trifluoromethyl)-1H- (trifluoromethyl)-1H-
pyrazol-5-yl)-1,3- pyrazole diazaspiro[4.5]decan-2-one SC_3434
cis-8-(dimethylamino)-8-(3- INT- 5-bromo-1-(2- SC_3242
fluorophenyl)-3-(1-(2- 1024 (methylsulfonyl)ethyl)-
(methylsulfonyl)ethyl)-3- 3-(trifluoromethyl)-
(trifluoromethyl)-1H-pyrazol-5-yl)- 1H-pyrazole
1,3-diazaspiro[4.5]decan-2-one SC_3435 cis-8-(dimethylamino)-8-(3-
INT- methylamine SC_3239 fluorophenyl)-3-(4-methyl-2- 1076
(methylamino)pyrimidin-5-yl)-1,3- diazaspiro[4.5]decan-2-one
SC_3436 cis-3-(2-cyclopropoxy-4- INT- cyclopropanol SC_3224 440.3
methylpyrimidin-5-yl)-8- 1076 (dimethylamino)-8-(3-
fluorophenyl)-1,3- diazaspiro[4.5]decan-2-one SC_3437
cis-N-(5-(8-(dimethylamino)-8-(3- INT- N-(5-bromo-4- SC_3103 481.3
fluorophenyl)-2-oxo-1,3- 1024 methylpyrimidin-2-
diazaspiro[4.5]decan-3-yl)-4- yl)-N- methylpyrimidin-2-yl)-N-
methylcyclopropanecarboxamide methylcyclopropanecarboxamide SC_3438
cis-N-(5-(8-(dimethylamino)-8-(3- INT- N-(5-bromo-4- SC_3103 497.3
fluorophenyl)-2-oxo-1,3- 1024 methylpyrimidin-2-
diazaspiro[4.5]decan-3-yl)-4- yl)-N- methylpyrimidin-2-yl)-N-
methylpivalamide methylpivalamide SC_3439
cis-3-(4-(azetidin-1-yl)-2- INT- azetidine SC_3120 493.2
(trifluoromethyl)pyrimidin-5-yl)-8- 1077 (dimethylamino)-8-(3-
fluorophenyl)-1,3- diazaspiro[4.5]decan-2-one SC_3440
cis-8-(dimethylamino)-8-(3- INT- oxetan-3-ylmethanol SC_3224 524.2
fluorophenyl)-3-(4-(oxetan-3- 1077 ylmethoxy)-2-
(trifluoromethyl)pyrimidin-5-yl)- 1,3-diazaspiro[4.5]decan-2-one
SC_3441 cis-3-(2-cyclopropyl-4-(2,2,2- INT- 2,2,2-trifluoroethanol
SC_3224 508.2 trifluoroethoxy)pyrimidin-5-yl)-8- 1078
(dimethylamino)-8-(3- fluorophenyl)-1,3- diazaspiro[4.5]decan-2-one
SC_3442 cis-3-(2-cyclopropyl-4-((2- INT- 2- SC_3120 483.3
hydroxyethyl)(methyl)amino)pyrimidin- 1078 (methylamino)ethanol
5-yl)-8-(dimethylamino)-8-(3- fluorophenyl)-1,3-
diazaspiro[4.5]decan-2-one
Chemical Structures of all Examples
##STR00177## ##STR00178## ##STR00179## ##STR00180## ##STR00181##
##STR00182## ##STR00183## ##STR00184## ##STR00185## ##STR00186##
##STR00187## ##STR00188## ##STR00189## ##STR00190## ##STR00191##
##STR00192## ##STR00193## ##STR00194## ##STR00195## ##STR00196##
##STR00197## ##STR00198## ##STR00199## ##STR00200## ##STR00201##
##STR00202## ##STR00203## ##STR00204## ##STR00205## ##STR00206##
##STR00207## ##STR00208## ##STR00209## ##STR00210## ##STR00211##
##STR00212## ##STR00213## ##STR00214## ##STR00215## ##STR00216##
##STR00217## ##STR00218## ##STR00219## ##STR00220## ##STR00221##
##STR00222## ##STR00223## ##STR00224## ##STR00225## ##STR00226##
##STR00227## ##STR00228## ##STR00229## ##STR00230## ##STR00231##
##STR00232## ##STR00233## ##STR00234## ##STR00235## ##STR00236##
##STR00237## ##STR00238## ##STR00239## ##STR00240## ##STR00241##
##STR00242## ##STR00243## ##STR00244## ##STR00245## ##STR00246##
##STR00247## ##STR00248## ##STR00249##
##STR00250## ##STR00251## ##STR00252## ##STR00253## ##STR00254##
##STR00255## ##STR00256## ##STR00257## ##STR00258## ##STR00259##
##STR00260## ##STR00261## ##STR00262## ##STR00263## ##STR00264##
##STR00265## ##STR00266##
[0423] Pharmacological Investigations
[0424] 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)
[0425] Human Mu-Opioid Peptide (hMOP) Receptor Binding Assay
[0426] 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).
[0427] Human Kappa-Opioid Peptide (hKOP) Receptor Binding Assay
[0428] 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 K.sub.i values are calculated by
using the Cheng-Prusoff equation, (Cheng and Prusoff, 1973).
[0429] Human Delta-Opioid Peptide (hDOP) Receptor Binding Assay
[0430] 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 .beta.-counter (PerkinElmer Life
Sciences/Wallac, Turku, Finland). Half-maximal inhibitory
concentration (IC50) values reflecting 50% displacement of
[Tyrosyl-3,5-.sup.3H]2-D-Ala-deltorphin II-specific receptor
binding are calculated by nonlinear regression analysis and K.sub.i
values are calculated by using the Cheng-Prusoff equation, (Cheng
and Prusoff, 1973).
[0431] Human Nociceptin/Orphanin FQ Peptide (hNOP) Receptor Binding
Assay
[0432] 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 .mu.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 .mu.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 .beta.-counter (PerkinElmer Life
Sciences/Wallac. Turku. Finland). Half-maximal inhibitory
concentration (IC50) values reflecting 50% displacement of
[.sup.3H]nociceptin-specific receptor binding were calculated by
nonlinear regression analysis and Ki values were calculated by
using the Cheng-Prusoff equation. (Cheng and Prusoff. 1973).
TABLE-US-00005 hNOP Ki hMOP Ki [nM] or % [nM] or % inhibition
inhibition Example at 1 .mu.M at 1 .mu.M SC_3001 0.3 120 SC_3002
1.3 250 SC_3003 0.4 350 SC_3004 19.5 515 SC_3005 0.7 12 SC_3006 1.1
46 SC_3007 85.8 705 SC_3008 0.6 23 SC_3009 1.1 41 SC_3010 2.7 18
SC_3011 4.4 4.4 SC_3012 2.2 120 SC_3013 1.4 39 SC_3014 0.8 29.5
SC_3015 2.6 32.5 SC_3016 4.2 45 SC_3017 2 30 SC_3018 5.2 101.5
SC_3019 10.2 135 SC_3020 10.8 290 SC_3021 1.8 14.5 SC_3022 0.4 37.2
SC_3023 7.7 36 SC_3024 1 145 SC_3025 236.7 1530 SC_3026 4.6 300
SC_3027 5 136 SC_3028 0.6 10.4 SC_3029 1.8 7.3 SC_3030 2.2 59
SC_3031 4.1 45.5 SC_3032 11 245 SC_3033 107 38%@10 .mu.M SC_3034
12.2 730 SC_3035 6.6 1055 SC_3036 1.4 220 SC_3037 33.5 775 SC_3038
1 76 SC_3039 13 380 SC_3040 4 335 SC_3041 0.9 79.5 SC_3042 4.1
136.5 SC_3043 70 655 SC_3044 230 10920 SC_3045 55.5 520 SC_3046
13.9 63 SC_3047 10.1 2105 SC_3048 1 38.5 SC_3049 25 940 SC_3050 85
28 SC_3051 3.6 170 SC_3052 160 355 SC_3053 73.5 1200 SC_3054 16.5
29.5 SC_3055 94.5 215 SC_3056 9.8 49.5 SC_3057 955 245 SC_3058 5
7.8 SC_3059 11.4 320 SC_3060 3 65 SC_3061 4.7 54.5 SC_3063 0.7 38
SC_3064 119 365 SC_3065 6.2 1990 SC_3066 2.2 96 SC_3067 41.5 99.5
SC_3068 5.9 50.5 SC_3069 2.6 49 SC_3070 2.8 12.5 SC_3071 8.2 170
SC_3072 5.9 235 SC_3073 1 110 SC_3074 1.6 55 SC_3075 8.1 260
SC_3076 0.6 35.3 SC_3077 3.2 325 SC_3078 0.6 77.5 SC_3079 1.6 38.5
SC_3080 1.6 90.5 SC_3081 8 1320 SC_3082 39 1110 SC_3083 12 117.3
SC_3084 1.8 22 SC_3085 1.6 107 SC_3086 1.1 43.5 SC_3087 2.8 99
SC_3088 3.1 770 SC_3089 3.3 235 SC_3090 1.3 67 SC_3091 2.3 24
SC_3092 2.2 330 SC_3093 1.1 47 SC_3094 5.4 45.5 SC_3096 14 250
SC_3097 17 18 SC_3098 2 6 SC_3099 13 19 SC_3100 1 1 SC_3101 1 3
SC_3102 2 1 SC_3103 7 1 SC_3104 -- -- SC_3105 2 97 SC_3106 8 165
SC_3107 2 115 SC_3108 5 26 SC_3109 8 19 SC_3110 6 20 SC_3111 8 37
SC_3112 36 120 SC_3113 24 26 SC_3114 245 460 SC_3115 265 915
SC_3116 6 170 SC_3117 92 1380 SC_3118 80 5% SC_3119 22% 10% SC_3120
26 4950 SC_3121 44 30% SC_3122 21 32% SC_3123 82 2260 SC_3124 5
1090 SC_3125 3%@10 .mu.M 52%@10 .mu.M SC_3126 0% 0% SC_3127 0% 3945
SC_3128 0% 1% SC_3129 6 2180 SC_3130 13 4530 SC_3131 4 3090 SC_3132
540 6% SC_3133 19 6515 SC_3134 3%@10 .mu.M 40%@10 .mu.M SC_3135 1%
1% SC_3136 16 5840 SC_3137 5 4235 SC_3138 28 7% SC_3139 59 1690
SC_3140 119 2355 SC_3141 34 7855 SC_3142 9 3750 SC_3143 0% 4%
SC_3144 0% 3590 SC_3145 46 1635 SC_3146 18 7675 SC_3147 27 3325
SC_3148 14 4575 SC_3149 18 6900 SC_3150 105 16% SC_3151 115 3490
SC_3152 24 4775 SC_3153 77 2220 SC_3154 17 3575 SC_3155 34 3495
SC_3156 45 6375 SC_3157 35 5690 SC_3158 19 2540 SC_3159 13 19%
SC_3160 4% 5730 SC_3161 2% 13% SC_3162 5 1325 SC_3163 28 2095
SC_3164 30 880 SC_3165 4% 17% SC_3166 3% 1640 SC_3167 18 3745
SC_3168 11 5 SC_3169 635 3445 SC_3170 7 3610 SC_3171 15 2010
SC_3172 130 7% SC_3173 10 2525 SC_3174 3% 1265 SC_3175 -- --
SC_3176 13 3740 SC_3177 8 4630 SC_3178 6 6700 SC_3179 15 3950
SC_3180 125 2250 SC_3181 22 5490 SC_3182 11 2990 SC_3183 165 1415
SC_3184 19 7645 SC_3185 335 15% SC_3186 33 2210 SC_3187 87 2240
SC_3188 25 1060 SC_3189 57 3470 SC_3190 42 28% SC_3191 27 20%
SC_3192 140 4270 SC_3193 100 2480 SC_3194 28 5120 SC_3195 15 1240
SC_3196 22 1595 SC_3197 44 1680 SC_3198 22 5885 SC_3199 19 4020
SC_3200 7 13% SC_3201 115 3885 SC_3202 25 3210 SC_3203 68 1225
SC_3204 110 14% SC_3205 20 2465 SC_3206 27 2445 SC_3207 39 1505
SC_3208 2 3285 SC_3209 -- -- SC_3210 -- -- SC_3211 -- -- SC_3212 9
2005 SC_3213 52 18% SC_3214 7 19% SC_3215 0% 14% SC_3216 11 14
SC_3217 23 2155 SC_3218 83 15% SC_3219 0% 1% SC_3220 10%@10 .mu.M
24%@10 .mu.M SC_3221 33 1935 SC_3222 6 1910 SC_3223 155 6150
SC_3224 10 1695 SC_3225 13 2520 SC_3226 -- -- SC_3227 16 3785
SC_3228 67 3135 SC_3229 105 3625 SC_3230 145 2485 SC_3231 120 2420
SC_3232 15 3475 SC_3233 38 1390 SC_3234 4 1350 SC_3235 30 1095
SC_3236 285 18% SC_3237 20 17% SC_3238 4 25% SC_3239 35 2410
SC_3240 28 17% SC_3241 8 4610 SC_3242 5 675 SC_3243 6 695 SC_3244
27 4265 SC_3245 67 --
SC_3246 11 1025 SC_3247 16 1220 SC_3248 4 41 SC_3249 740 855
SC_3250 52 -- SC_3251 185 4550 SC_3252 30 -- SC_3253 205 -- SC_3254
22 240 SC_3255 23 150 SC_3256 12 61 SC_3257 150 240 SC_3258 58 7125
SC_3259 45 180 SC_3260 570 nd SC_3261 10 63 SC_3262 540 3060
SC_3263 66 800 SC_3264 145 130 SC_3265 38 2405 SC_3266 245 1055
SC_3267 460 -- SC_3268 41 1625 SC_3269 13 5580 SC_3270 305 31
SC_3271 34 245 SC_3272 115 4175 SC_3273 -- -- SC_3274 63 1880
SC_3275 155 124 SC_3276 24 130 SC_3277 37 13% SC_3278 12 7035
SC_3279 17 78 SC_3280 6 300 SC_3281 19 2580 SC_3282 37 3510 SC_3283
12 1030 SC_3284 5 305 SC_3285 15 20% SC_3286 18 5895 SC_3287 119
18% SC_3288 15 115 SC_3289 84 430 SC_3290 16 6605 SC_3291 350 15%
SC_3292 4% 0% SC_3293 3% 0% SC_3294 9 12% SC_3295 28 2975 SC_3296
10 4530 SC_3297 8 4270 SC_3298 20 17% SC_3299 23 5705 SC_3300 22
565 SC_3301 33 2320 SC_3302 31 1025 SC_3303 450 21% SC_3304 9% 4%
SC_3305 10% 0% SC_3306 9 4555 SC_3307 13 5345 SC_3308 2 2575
SC_3309 17 6910 SC_3310 7 23% SC_3311 14 27% SC_3312 23 1830
SC_3313 10 2400 SC_3314 9 4090 SC_3315 14 5325 SC_3316 255 5430
SC_3317 56 6045 SC_3318 35 1235 SC_3319 4 15% SC_3320 11 1955
SC_3321 13 5715 SC_3322 12 1150 SC_3323 27 5530 SC_3324 12% 5%
SC_3325 53%@10 .mu.M 20%@10 .mu.M SC_3326 -- -- SC_3327 17 3360
SC_3328 31 3295 SC_3329 13 4285 SC_3330 14 1505 SC_3331 2 5265
SC_3332 19 2055 SC_3333 5 1580 SC_3334 17 4005 SC_3335 30 2305
SC_3336 240 13% SC_3337 10 1970 SC_3338 36 7% SC_3339 10 6830
SC_3340 150 5750 SC_3341 15 3460 SC_3342 21 3845 SC_3343 27 16%
SC_3344 1 13% SC_3345 4 1800 SC_3346 12 2580 SC_3347 15 4845
SC_3348 25 4090 SC_3349 8 3980 SC_3350 7 1485 SC_3351 20 2205
SC_3352 37 2160 SC_3353 53 15% SC_3354 2 23% SC_3355 52 4785
SC_3356 9 4805 SC_3357 13 555 SC_3358 51 7020 SC_3359 66 3520
SC_3360 7 2870 SC_3361 27 5095 SC_3362 28 29% SC_3363 33 8% SC_3364
32 4685 SC_3365 2 1655 SC_3366 1285 14% SC_3367 1220 8% SC_3368 195
11% SC_3369 51 3105 SC_3370 4 14% SC_3371 350 9% SC_3372 125 3535
SC_3373 19 18% SC_3374 55 10% SC_3375 13 12% SC_3376 37 1720
SC_3377 22 980 SC_3379 11 635 SC_3380 102 5415 SC_3381 3 1235
SC_3382 29 13% SC_3383 10 17% SC_3384 6 11% SC_3385 33 925 SC_3386
14 0% SC_3387 2 1245 SC_3388 29 185 SC_3389 2 1970 SC_3390 18 465
SC_3391 53 10% SC_3392 7 4490 SC_3393 88 13% SC_3394 6 735 SC_3395
14 4990 SC_3396 44 1730 SC_3397 48 560 SC_3398 9 5640 SC_3399 5 45%
SC_3400 8 635 SC_3401 1 455 SC_3402 7 3630 SC_3403 9 1440 SC_3404
10 5% SC_3405 12 925 SC_3406 24 805 SC_3407 77 13% SC_3408 7 18%
SC_3409 11 25%
[0433] Protocol for [.sup.35S]G-TP.gamma.S Functional
NOP/MOP/KOP/DOP Assays
[0434] Cell membrane preparations of CHO-K.sub.1 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.).
[0435] 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.).
[0436] 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.
B1.sub.calc [%]). This difference (B1.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 (B1.sub.calc-N/OFQ [%])
which is set as 100% relative efficacy for the hNOP receptor.
Likewise, the percentage efficacies of test compounds at the hDOP,
hMOP, or hKOP receptor are determined versus the calculated maximal
enhancement of [.sup.35S]GTP.gamma.S binding by the full agonists
SNC80 (B1.sub.calc-SNC80 [%]), DAMGO (B1.sub.calc-DAMGO [%]) and
U69,593 (B1.sub.calc-U69,593 [%]) which are set as 100% relative
efficacy at each receptor, respectively.
[0437] 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.
* * * * *