U.S. patent application number 13/709104 was filed with the patent office on 2013-04-25 for novel cyclopropane indolinone derivatives.
This patent application is currently assigned to Hoffmann-La Roche Inc.. The applicant listed for this patent is Hoffmann-La Roche Inc.. Invention is credited to Li Chen, Lichun Feng, Yun He, Mengwei Huang, Hongying Yun.
Application Number | 20130102604 13/709104 |
Document ID | / |
Family ID | 43447167 |
Filed Date | 2013-04-25 |
United States Patent
Application |
20130102604 |
Kind Code |
A1 |
Chen; Li ; et al. |
April 25, 2013 |
NOVEL CYCLOPROPANE INDOLINONE DERIVATIVES
Abstract
The present invention relates to a compound of formula (I)
##STR00001## as well as pharmaceutically acceptable salt thereof,
wherein R.sup.1 to R.sup.4 have the significance given in claim 1.
The compound may be used, for example, for the treatment or
prophylaxis of obesity, hyperglycemia, dyslipidemia, and type 1 or
type 2 diabetes.
Inventors: |
Chen; Li; (Shanghai, CN)
; Feng; Lichun; (Shanghai, CN) ; He; Yun;
(Shanghai, CN) ; Huang; Mengwei; (Shanghai,
CN) ; Yun; Hongying; (Shanghai, CN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Hoffmann-La Roche Inc.; |
Nutley |
NJ |
US |
|
|
Assignee: |
Hoffmann-La Roche Inc.
Nutley
NJ
|
Family ID: |
43447167 |
Appl. No.: |
13/709104 |
Filed: |
December 10, 2012 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
12959408 |
Dec 3, 2010 |
8354443 |
|
|
13709104 |
|
|
|
|
Current U.S.
Class: |
514/235.2 ;
514/253.09; 514/254.09; 514/278; 514/376; 514/397; 514/404;
514/409; 544/230; 544/70; 546/15; 548/216; 548/300.7; 548/357.5;
548/411 |
Current CPC
Class: |
C07D 401/08 20130101;
C07D 401/10 20130101; C07D 403/10 20130101; C07D 209/96 20130101;
C07D 405/06 20130101; C07D 413/06 20130101; C07D 401/06 20130101;
C07D 413/12 20130101; A61P 3/00 20180101; C07D 209/34 20130101;
C07D 403/04 20130101; A61P 3/10 20180101; A61P 43/00 20180101; C07D
413/10 20130101; A61P 3/04 20180101; C07D 491/107 20130101; C07D
403/06 20130101; A61P 3/06 20180101; C07D 401/14 20130101; C07D
403/12 20130101; C07D 401/12 20130101 |
Class at
Publication: |
514/235.2 ;
548/411; 514/409; 546/15; 514/278; 544/230; 514/254.09; 544/70;
514/253.09; 548/357.5; 514/404; 548/300.7; 514/397; 548/216;
514/376 |
International
Class: |
C07D 209/96 20060101
C07D209/96; C07D 401/10 20060101 C07D401/10; C07D 403/10 20060101
C07D403/10; C07D 413/10 20060101 C07D413/10; C07D 401/14 20060101
C07D401/14; C07D 413/12 20060101 C07D413/12; C07D 401/06 20060101
C07D401/06; C07D 405/06 20060101 C07D405/06; C07D 413/06 20060101
C07D413/06; C07D 403/06 20060101 C07D403/06; C07D 403/04 20060101
C07D403/04; C07D 491/107 20060101 C07D491/107; C07D 401/08 20060101
C07D401/08; C07D 403/12 20060101 C07D403/12 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 11, 2009 |
CN |
PCT/CN2009/075500 |
Claims
1. A compound of formula (I) ##STR00189## wherein R.sup.1 and
R.sup.2 are each independently selected from the group consisting
of: hydrogen, alkyl, pyridinyl, phenyl, halophenyl, alkoxyphenyl,
alkylsulfonylphenyl, cyanophenyl and trifluoromethylphenyl; or
R.sup.1 and R.sup.2, together with the carbon atom to which they
are attached, form cycloalkyl or tetrahydropyranyl; R.sup.3 is
selected from the group consisting of: hydrogen, pyridinyl,
piperidinyl, carboxypyridinyl, tetrahydropyranyl, alkylamino,
morpholinyl, morpholinylalkylamino, alkylmorpholinylalkylamino,
alkylsulfonylpiperidinyl, alkylpiperazinyl,
alkylaminoalkylpiperazinyl, pyridinylpiperazinyl,
alkylaminopyrrolidinyl, 1H-imidazolyl, carboxyalkyl-1H-imidazolyl,
carboxy-1H-imidazolyl, cycloalkylsulfonylaminocarbonylpyridinyl and
substituted phenyl, wherein substituted phenyl is phenyl
substituted with one or two substituents independently selected
from the group consisting of: alkyl, halogen, hydroxyalkylamino,
carboxy, alkylsulfonyl, alkylaminocarbonyl,
alkylsulfonylaminocarbonyl, piperidinylcarbonyl,
piperazinylcarbonyl, morpholinylcarbonyl,
pyridinylpiperazinylcarbonyl, alkylpiperazinylcarbonyl,
alkylsulfonylpiperazinylcarbonyl,
alkylpyrrolidinylalkylaminocarbonyl,
alkyl-1H-pyrazolylaminocarbonyl, oxo-oxazolidinyl,
oxo-pyrrolidinyl, oxo-imidazolidinyl,
morpholinylalkylaminocarbonyl, alkylaminoalkylpiperazinylcarbonyl,
cycloalkyl-1H-pyrazolylaminocarbonyl and
cycloalkylsulfonylaminocarbonyl; R.sup.4 is selected from the group
consisting of: hydrogen, halogen, carboxy, cyano, trifluoromethyl
and alkylsulfonyl; and n is 0, 1, 2 or 3; or a pharmaceutically
acceptable salt or ester thereof.
2. A compound according to claim 1, wherein one of R.sup.1 and
R.sup.2 is selected from hydrogen and alkyl and the other is
selected from the group consisting of: pyridinyl, halophenyl,
alkylsulfonylphenyl, cyanophenyl and trifluoromethylphenyl.
3. A compound according to claim 1, wherein one of R.sup.1 and
R.sup.2 is selected from hydrogen and isopropyl and the other is
selected from the group consisting of: pyridinyl, fluorophenyl,
chlorophenyl, cyanophenyl, methylsulfonylphenyl and
trifluoromethylphenyl.
4. A compound according to claim 1 wherein R.sup.3 is selected from
the group consisting of: pyridinyl, carboxypyridinyl,
tetrahydropyranyl, dialkylamino, morpholinyl,
alkylsulfonylpiperidinyl, alkylpiperazinyl,
dialkylaminoalkylpiperazinyl, dialkylaminopyrrolidinyl,
carboxyalkyl-1H-imidazolyl, carboxy-1H-imidazolyl or substituted
phenyl, wherein substituted phenyl is phenyl substituted with one
or two substituents independently selected from alkyl, halogen,
carboxy, alkylsulfonyl, alkylaminocarbonyl,
alkylsulfonylaminocarbonyl, piperidinylcarbonyl,
piperazinylcarbonyl, morpholinylcarbonyl,
pyridinylpiperazinylcarbonyl, alkylpiperazinylcarbonyl,
alkylsulfonylpiperazinylcarbonyl,
alkylpyrrolidinylalkylaminocarbonyl,
alkyl-1H-pyrazolylaminocarbonyl, oxo-oxazolidinyl, oxo-pyrrolidinyl
and oxo-imidazolidinyl.
5. A compound according to claim 1, wherein R.sup.3 is selected
from the group consisting of: carboxypyridinyl,
carboxyalkyl-1H-imidazolyl, carboxyphenyl and phenyl substituted
with carboxy and oxo-oxazolidinyl.
6. A compound according to claim 1, wherein R.sup.4 is selected
from the group consisting of: hydrogen, halogen and carboxy.
7. A compound according to claim 1, wherein R.sup.4 is selected
from the group consisting of: hydrogen, fluoro, chloro and
carboxy.
8. A compound according to claim 1, wherein n is 0 or 1.
9. A compound according to claim 1 selected from the group
consisting of:
(1S,2R)-3-((2-(3-methoxyphenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1-
'-yl)methyl)benzoic acid;
(1R,2S)-3-((2-(3-methoxyphenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1-
'-yl)methyl)benzoic acid;
(1S,2S)-3-((2-(3-methoxyphenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1-
'-yl)methyl)benzoic acid;
(1R,2R)-3-((2-(3-methoxyphenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1-
'-yl)methyl)benzoic acid;
(1S,2S)-3-((2-(4-methoxyphenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1-
'-yl)methyl)benzoic acid;
(1R,2R)-3-((2-(4-methoxyphenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1-
'-yl)methyl)benzoic acid;
(1S,2R)-3-((2-(4-methoxyphenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1-
'-yl)methyl)benzoic acid; and
(1R,2S)-3-((2-(4-methoxyphenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1-
'-yl)methyl)benzoic acid.
10. A compound according to claim 1 selected from the group
consisting of:
(1S,2R)-3-((2'-oxo-2-(pyridin-3-yl)spiro[cyclopropane-1,3'-indoline]--
1'-yl)methyl)benzoic acid;
(1R,2S)-3-((2'-oxo-2-(pyridin-3-yl)spiro[cyclopropane-1,3'-indoline]-1'-y-
l)methyl)benzoic acid;
(1R,2S)-4-((2'-oxo-2-(pyridin-3-yl)spiro[cyclopropane-1,3'-indoline]-1'-y-
l)methyl)benzoic acid; and
(1S,2R)-4-((2'-oxo-2-(pyridin-3-yl)spiro[cyclopropane-1,3'-indoline]-1'-y-
l)methyl)benzoic acid.
11. A compound according to claim 1 selected from the group
consisting of:
(R)-3-((5'-fluoro-2,2-dimethyl-2'-oxospiro[cyclopropane-1,3'-indoline-
]-1'-yl)methyl)benzoic acid;
(S)-3-((5'-fluoro-2,2-dimethyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)benzoic acid;
(R)-3-(5'-fluoro-2,2-dimethyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)-5-(2-oxooxazolidin-3-yl)benzoic acid;
(S)-3-(5'-fluoro-2,2-dimethyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)-5-(2-oxooxazolidin-3-yl)benzoic acid;
(R)-methyl-3-(2,2-dimethyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)-
-5-(2-oxooxazolidin-3-yl)benzoate;
(S)-methyl-3-(2,2-dimethyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)-
-5-(2-oxooxazolidin-3-yl)benzoate;
(R)-3-(2,2-dimethyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)-5-(2-h-
ydroxyethylamino)benzoic acid; and
(S)-3-(2,2-dimethyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)-5-(2-h-
ydroxyethylamino)benzoic acid.
12. A compound according to claim 1 selected from the group
consisting of:
(R)-3-[(2-oxo-2'',3'',5'',6''-tetrahydrodispiro[indole-3,1'-cycloprop-
ane-2',4''-pyran]-1(2H)-yl)methyl]benzoic acid;
(S)-3-[(2-oxo-2'',3'',5'',6''-tetrahydrodispiro[indole-3,1'-cyclopropane--
2',4''-pyran]-1(2H)-yl)methyl]benzoic acid;
(R)-3-(2-oxo-1,3-oxazolidin-3-yl)-5-(2-oxo-2'',3'',5'',6''-tetrahydrodisp-
iro[indole-3,1'-cyclopropane-2',4''-pyran]-1(2H)-yl)benzoic acid;
(S)-3-(2-oxo-1,3-oxazolidin-3-yl)-5-(2-oxo-2'',3'',5'',6''-tetrahydrodisp-
iro[indole-3,1'-cyclopropane-2',4''-pyran]-1(2H)-yl)benzoic acid;
(R)-methyl-3-(2-oxo-1,3-oxazolidin-3-yl)-5-(2-oxo-2'',3'',5'',6''-tetrahy-
drodispiro[indole-3,1'-cyclopropane-2',4''-pyran]-1(2H)-yl)benzoate;
and
(S)-methyl-3-(2-oxo-1,3-oxazolidin-3-yl)-5-(2-oxo-2'',3'',5'',6''-tetrahy-
drodispiro[indole-3,1'-cyclopropane-2',4''-pyran]-1(2H)-yl)benzoate.
13. A compound according to claim 1 selected from the group
consisting of:
(1R,2R)-2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-
-carboxylic acid;
(1S,2S)-2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-car-
boxylic acid;
(1R,2S)-2-(4-cyanophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-carb-
oxylic acid;
(1S,2R)-2-(4-cyanophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-carb-
oxylic acid;
(1R,2R)-2-(4-cyanophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-carb-
oxylic acid;
(1S,2S)-2-(4-cyanophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-carb-
oxylic acid;
(1S,2R)-2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-car-
boxylic acid; and
(1R,2S)-2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-car-
boxylic acid.
14. A pharmaceutical composition comprising a compound according to
claim 1 and a therapeutically inert carrier.
Description
PRIORITY TO RELATED APPLICATION(S)
[0001] This application is a continuation application of U.S. Ser.
No. 12/959,408, filed Dec. 3, 2010, which claims the benefit of
International Patent Application No. PCT/CN2009/075500, filed Dec.
11, 2009, which is hereby incorporated by reference in its
entirety.
FIELD OF THE INVENTION
[0002] The invention relates to compounds which are activators of
AMP-activated protein kinase (AMPK) and which are useful in the
treatment or prophylaxis of diseases that are related to AMPK
regulation, such as obesity, dyslipidemia, hyperglycemia, type 1 or
type 2 diabetes.
BACKGROUND OF THE INVENTION
[0003] Obesity and type 2 diabetes, hypertension, cancer, and
cardiovascular disease, are diseases that feature serious
disturbances in glucose or lipid metabolism that severely affect
the health and quality of life of affected individuals. The
increasing prevalence of these diseases makes finding new drug
targets for treating these syndromes an urgent task.
[0004] AMP-activated protein kinase acts as a cellular energy
sensor and regulator. It is activated by an increase in the
cellular AMP:ATP ratio induced by metabolic stress, hormone and
nutrient signals. Once activated, AMPK switches on catabolic
pathways that generate ATP and switches off ATP-consuming anabolic
pathways by acute regulation of the activity of key enzymes in
metabolism and chronic regulation of the expression of pivotal
transcription factors (Hardie, D G. Nature reviews 8 (2007b),
774-785; Woods, A et al. Molecular and cellular biology 20 (2000),
6704-6711). The growing evidence of AMPK regulatory effects on
glucose and lipid metabolism makes it a potential drug target for
treatment of diabetes and metabolic syndrome (Carling, D. Trends
Biochem Sci 29 (2004), 18-24; Hardie, D G. Annual review of
pharmacology and toxicology 47 (2007a), 185-210; Kahn, B B et al.
Cell metabolism 1 (2005), 15-25; Long, Y C et al. The Journal of
clinical investigation 116 (2006), 1776-1783).
[0005] At the physiological level, this concept has been supported
by two adipokines, leptin and adiponectin, both of which exert
excellent effects on glucose and lipid metabolism (Friedman, J M
and Halaas, J L. Nature 395 (1998), 763-770; Muoio, D M et al.
Diabetes 46 (1997), 1360-1363; Yamauchi, T et al. Nature medicine 7
(2001), 941-946). Recent studies suggest that leptin and
adiponectin exert their antidiabetic effects by activating AMPK.
Leptin stimulates muscle fatty acid oxidation by activating AMPK
directly and through a hypothalamic-adrenergic pathway (Minokoshi,
Y et al. Nature 415 (2002), 339-343). Adiponectin stimulates
glucose uptake and fatty acid oxidation in vitro by activation of
AMPK. Furthermore, it exerts its hypoglycemic effect by decreasing
PEPCK and G6Pase expression, whereas the administration of dominant
negative .alpha.1 adenovirus reverses the effect in vivo (Yamauchi,
T et al. Nature medicine 8 (2002), 1288-1295).
[0006] At the pharmacological level, the concept of AMPK as a
potential target for treating metabolic syndrome has been further
supported by the discovery of two major classes of existing
antidiabetic drugs: thiazolidinediones (rosiglitazone, troglitazone
and pioglitazone) and biguanides (metformin and phenformin)
activate AMPK in cultured cells and in vivo. Rosiglitazone is
traditionally considered to be a PPAR.gamma. agonist and exerts its
antidiabetic effects through differentiation of adipocytes (Semple,
R K et al. The Journal of clinical investigation 116 (2006),
581-589). Recent findings indicate that AMPK may be involved in the
antidiabetic effects of rosiglitazone (Brunmair, B et al. The
Journal of biological chemistry 277 (2002), 25226-25232; Kadowaki,
T et al. The Journal of clinical investigation 116 (2006),
1784-1792). In the case of metformin, an existing antidiabetic
agent without a defined mechanism of action, recent studies
demonstrate that it could activate AMPK in vitro and in vivo by
inhibiting complex I (El-Mir, M Y et al. The Journal of biological
chemistry 275 (2000), 223-228; Owen, M R et al. The Biochemical
journal 348 Pt 3 (2000), 607-614; Zhou, G et al. The Journal of
clinical investigation 108 (2001), 1167-1174), and the hypoglycemic
effect could be blocked completely by knockout of its upstream
kinase LKB1, confirming the key role of AMPK in mediating the
antidiabetic effect of metformin (Shaw, R J et al. Science (New
York) N.Y. 310 (2005), 1642-1646).
[0007] Most recently, Cool and coworkers have identified a small
direct AMPK activator, A-769662, which exerts antidiabetic effects
in vivo (Cool, B et al. Cell metabolism 3 (2006), 403-416). Jia
Li's laboratory has identified a small AMPK activator, PT1, which
activates the inactive forms of AMPK .alpha.2.sub.398 and
.alpha.1.sub.394 with micromolar activity and exerts some cellular
effects (Pang, T et al. The Journal of biological chemistry 283
(2008), 16051-16060).
[0008] It has been found that the compounds of the present
invention are potent AMPK activators. The compounds of the
invention are therefore useful in the treatment or prophylaxis of
diseases that are related to AMPK regulation, such as obesity,
dyslipidemia, hyperglycemia, type 1 or type 2 diabetes and
cancer.
SUMMARY OF THE INVENTION
[0009] The present invention relates in part to a compound of
formula (I)
##STR00002##
wherein [0010] R.sup.1 and R.sup.2 are each independently selected
from the group consisting of: hydrogen, alkyl, pyridinyl, phenyl,
halophenyl, alkoxyphenyl, alkylsulfonylphenyl, cyanophenyl and
trifluoromethylphenyl; [0011] or R.sup.1 and R.sup.2, together with
the carbon atom to which they are attached, form cycloalkyl or
tetrahydropyranyl; [0012] R.sup.3 is selected from the group
consisting of: hydrogen, pyridinyl, piperidinyl, carboxypyridinyl,
tetrahydropyranyl, alkylamino, morpholinyl, morpholinylalkylamino,
alkylmorpholinylalkylamino, alkylsulfonylpiperidinyl,
alkylpiperazinyl, alkylaminoalkylpiperazinyl, pyridinylpiperazinyl,
alkylaminopyrrolidinyl, 1H-imidazolyl, carboxyalkyl-1H-imidazolyl,
carboxy-1H-imidazolyl, cycloalkylsulfonylaminocarbonylpyridinyl and
substituted phenyl, wherein substituted phenyl is phenyl
substituted with one or two substituents independently selected
from the group consisting of: alkyl, halogen, hydroxyalkylamino,
carboxy, alkylsulfonyl, alkylaminocarbonyl,
alkylsulfonylaminocarbonyl, piperidinylcarbonyl,
piperazinylcarbonyl, morpholinylcarbonyl,
pyridinylpiperazinylcarbonyl, alkylpiperazinylcarbonyl,
alkylsulfonylpiperazinylcarbonyl,
alkylpyrrolidinylalkylaminocarbonyl,
alkyl-1H-pyrazolylaminocarbonyl, oxo-oxazolidinyl,
oxo-pyrrolidinyl, oxo-imidazolidinyl,
morpholinylalkylaminocarbonyl, alkylaminoalkylpiperazinylcarbonyl,
cycloalkyl-1H-pyrazolylaminocarbonyl and
cycloalkylsulfonylaminocarbonyl; [0013] R.sup.4 is selected from
the group consisting of: hydrogen, halogen, carboxy, cyano,
trifluoromethyl and alkylsulfonyl; and [0014] n is 0, 1, 2 or 3;
[0015] or a pharmaceutically acceptable salt or ester thereof.
[0016] The invention also relates to a process for the manufacture
of these novel compounds and medicaments containing them. The
compounds of the invention have activation effect on AMP (adenosine
monophosphate)-activated protein kinase, which results in lowered
blood glucose. The invention thus also concerns the use of such
compounds for the treatment or prophylaxis of diseases that are
related to AMPK regulation, such as obesity, dyslipidemia,
hyperglycemia, type 1 or type 2 diabetes.
DETAILED DESCRIPTION OF THE INVENTION
[0017] The present invention relates in part to a compound of
formula (I)
##STR00003##
wherein [0018] R.sup.1 and R.sup.2 are each independently selected
from the group consisting of: hydrogen, alkyl, pyridinyl, phenyl,
halophenyl, alkoxyphenyl, alkylsulfonylphenyl, cyanophenyl and
trifluoromethylphenyl; [0019] or R.sup.1 and R.sup.2, together with
the carbon atom to which they are attached, form cycloalkyl or
tetrahydropyranyl; [0020] R.sup.3 is selected from the group
consisting of: hydrogen, pyridinyl, piperidinyl, carboxypyridinyl,
tetrahydropyranyl, alkylamino, morpholinyl, morpholinylalkylamino,
alkylmorpholinylalkylamino, alkylsulfonylpiperidinyl,
alkylpiperazinyl, alkylaminoalkylpiperazinyl, pyridinylpiperazinyl,
alkylaminopyrrolidinyl, 1H-imidazolyl, carboxyalkyl-1H-imidazolyl,
carboxy-1H-imidazolyl, cycloalkylsulfonylaminocarbonylpyridinyl and
substituted phenyl, wherein substituted phenyl is phenyl
substituted with one or two substituents independently selected
from the group consisting of: alkyl, halogen, hydroxyalkylamino,
carboxy, alkylsulfonyl, alkylaminocarbonyl,
alkylsulfonylaminocarbonyl, piperidinylcarbonyl,
piperazinylcarbonyl, morpholinylcarbonyl,
pyridinylpiperazinylcarbonyl, alkylpiperazinylcarbonyl,
alkylsulfonylpiperazinylcarbonyl,
alkylpyrrolidinylalkylaminocarbonyl,
alkyl-1H-pyrazolylaminocarbonyl, oxo-oxazolidinyl,
oxo-pyrrolidinyl, oxo-imidazolidinyl,
morpholinylalkylaminocarbonyl, alkylaminoalkylpiperazinylcarbonyl,
cycloalkyl-1H-pyrazolylaminocarbonyl and
cycloalkylsulfonylaminocarbonyl; [0021] R.sup.4 is selected from
the group consisting of: hydrogen, halogen, carboxy, cyano,
trifluoromethyl and alkylsulfonyl; and [0022] n is 0, 1, 2 or 3;
[0023] or a pharmaceutically acceptable salt or ester thereof.
[0024] As used herein, the term "alkyl", alone or in combination,
signifies a saturated, linear- or branched chain alkyl group
containing 1 to 8, preferably 1 to 6, more preferably 1 to 4 carbon
atoms, for example methyl, ethyl, propyl, isopropyl, 1-butyl,
2-butyl, tert-butyl and the like. Preferred "alkyl" groups are
methyl, ethyl, isopropyl, tert-butyl.
[0025] The term "alkoxy", alone or in combination, signifies a
group alkyl-O--, wherein the "alkyl" is as defined above; for
example methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, i-butoxy,
2-butoxy, t-butoxy and the like. Preferred alkoxy groups are
methoxy and ethoxy and more preferably methoxy.
[0026] The term "cycloalkyl", alone or in combination, refers to a
saturated carbon ring containing from 3 to 7 carbon atoms,
preferably from 3 to 6 carbon atoms, for example, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
Preferred cycloalkyl groups are cyclopropyl and cyclopentyl,
cyclopropyl being particularly preferred.
[0027] The term "halogen" or "halo", alone or in combination, means
fluorine, chlorine, bromine or iodine. Halogen is preferably
fluorine, chlorine or bromine.
[0028] The term "halophenyl" means phenyl substituted by
halogen.
[0029] The term "carboxy", alone or in combination, refers to the
group --COOH.
[0030] The term "carbonyl", alone or in combination, refers to the
group --C(O)--.
[0031] The term "amino", alone or in combination, refers to primary
(--NH.sub.2--), secondary (--NH--) or tertiary amino (--N--).
[0032] The term "hydroxy", alone or in combination, refers to the
group --OH.
[0033] The term "sulfonyl", alone or in combination, refers to the
group --S(O).sub.2--.
[0034] The compounds according to the present invention may exist
in the form of their pharmaceutically acceptable salts. The term
"pharmaceutically acceptable salt" refers to conventional
acid-addition salts or base-addition salts that retain the
biological effectiveness and properties of the compounds of formula
(I) and are formed from suitable non-toxic organic or inorganic
acids or organic or inorganic bases. Acid-addition salts include
for example those derived from inorganic acids such as hydrochloric
acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic
acid, phosphoric acid and nitric acid, and those derived from
organic acids such as p-toluenesulfonic acid, salicylic acid,
methanesulfonic acid, oxalic acid, succinic acid, citric acid,
malic acid, lactic acid, fumaric acid, and the like. Base-addition
salts include those derived from ammonium, potassium, sodium and,
quaternary ammonium hydroxides, such as for example, tetramethyl
ammonium hydroxide. The chemical modification of a pharmaceutical
compound into a salt is a technique well known to pharmaceutical
chemists in order to obtain improved physical and chemical
stability, hygroscopicity, flowability and solubility of compounds.
It is for example described in Bastin R. J. et al., Organic Process
Research & Development 2000, 4, 427-435; or in Ansel, H. et
al., In: Pharmaceutical Dosage Forms and Drug Delivery Systems, 6th
ed. (1995), pp. 196 and 1456-1457. Preferred are the sodium salts
of the compounds of formula (I).
[0035] "Pharmaceutically acceptable esters" means that compounds of
general formula (I) may be derivatized at functional groups to
provide derivatives which are capable of conversion back to the
parent compounds in vivo. Examples of such compounds include
physiologically acceptable and metabolically labile ester
derivatives, such as methoxymethyl esters, methylthiomethyl esters
and pivaloyloxymethyl esters. Additionally, any physiologically
acceptable equivalents of the compounds of general formula (I),
similar to the metabolically labile esters, which are capable of
producing the parent compounds of general formula (I) in vivo, are
within the scope of this invention. Preferred are the methyl and
ethyl esters of the compounds of formula (I).
[0036] Preferred is a compound according of formula (I) wherein one
of R.sup.1 and R.sup.2 is selected from hydrogen and alkyl and the
other is selected from the group consisting of: pyridinyl,
halophenyl, alkylsulfonylphenyl, cyanophenyl and
trifluoromethylphenyl, or R.sup.1 and R.sup.2, together with the
carbon atom to which they are attached form cycloalkyl or
tetrahydropyranyl
[0037] In an embodiment, the compound of formula (I) is one wherein
one of R.sup.1 and R.sup.2 is selected from hydrogen and alkyl and
the other is selected from the group consisting of: pyridinyl,
halophenyl, alkylsulfonylphenyl, cyanophenyl and
trifluoromethylphenyl.
[0038] Further preferred is a compound of formula (I) wherein one
of R.sup.1 and R.sup.2 is selected from hydrogen and isopropyl and
the other is selected from the group consisting of: pyridinyl,
fluorophenyl, chlorophenyl, cyanophenyl, methylsulfonylphenyl and
trifluoromethylphenyl.
[0039] Preferred is a compound according of formula (I) wherein
R.sup.3 is the group consisting of: pyridinyl, carboxypyridinyl,
tetrahydropyranyl, dialkylamino, morpholinyl,
alkylsulfonylpiperidinyl, alkylpiperazinyl,
dialkylaminoalkylpiperazinyl, dialkylaminopyrrolidinyl,
carboxyalkyl-1H-imidazolyl, carboxy-1H-imidazolyl or substituted
phenyl, wherein substituted phenyl is phenyl substituted with one
or two substituents independently selected from alkyl, halogen,
carboxy, alkylsulfonyl, alkylaminocarbonyl,
alkylsulfonylaminocarbonyl, piperidinylcarbonyl,
piperazinylcarbonyl, morpholinylcarbonyl,
pyridinylpiperazinylcarbonyl, alkylpiperazinylcarbonyl,
alkylsulfonylpiperazinylcarbonyl,
alkylpyrrolidinylalkylaminocarbonyl,
alkyl-1H-pyrazolylaminocarbonyl, oxo-oxazolidinyl, oxo-pyrrolidinyl
and oxo-imidazolidinyl.
[0040] Also preferred is a compound of formula (I) wherein R.sup.3
is selected from the group consisting of: carboxypyridinyl,
carboxyalkyl-1H-imidazolyl, carboxyphenyl and phenyl substituted
with carboxy and oxo-oxazolidinyl.
[0041] A compound of formula (I) wherein R.sup.4 is selected from
the group consisting of: hydrogen, halogen, cyano, trifluoromethyl
and alkylsulfonyl is also preferred.
[0042] A compound of formula (I) wherein R.sup.4 is selected from
the group consisting of: hydrogen, halogen, carboxy, cyano,
trifluoromethyl and alkylsulfonyl is also preferred.
[0043] In particular, preferred is a compound of formula (I)
wherein R.sup.4 is hydrogen or halogen.
[0044] In particular, preferred is a compound of formula (I)
wherein R.sup.4 is selected from the group consisting of: hydrogen,
halogen and carboxy.
[0045] In an embodiment, R.sup.4 is selected from the group
consisting of: hydrogen, fluoro, chloro, and carboxy.
[0046] Furthermore, preferred is a compound of formula (I) wherein
R.sup.4 is selected from the group consisting of: hydrogen, fluoro
and chloro.
[0047] A compound of formula (I) wherein n is 0 or 1 is
preferred.
[0048] Particularly preferred is a compound of formula (I) selected
from the group consisting of: [0049]
(1R,2S)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)benzoic acid; [0050]
(1S,2R)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)benzoic acid; [0051]
(1R,2R)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)benzoic acid; [0052]
(1S,2S)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)benzoic acid; [0053]
(1S,2R)-3-((2-(3-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)benzoic acid; [0054]
(1R,2S)-3-((2-(3-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)benzoic acid; [0055]
(1R,2R)-((2-(4-(methylsulfonyl)phenyl)-2'-oxospiro[cyclopropane-1,3'-indo-
line]-1'-yl)methyl)benzoic acid; [0056]
(1S,2S)-((2-(4-(methylsulfonyl)phenyl)-2'-oxospiro[cyclopropane-1,3'-indo-
line]-1'-yl)methyl)benzoic acid; [0057]
(1S,2R)-3-((2-(4-cyanophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)methyl)benzoic acid; [0058]
(1R,2S)-3-((2-(4-cyanophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)methyl)benzoic acid; [0059]
(1S,2R)-2-chloro-5-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-ind-
oline]-1'-yl)methyl)benzoic acid; [0060]
(1R,2S)-2-chloro-5-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-ind-
oline]-1'-yl)methyl)benzoic acid; [0061]
(1S,2R)-3-((2-(4-(methylsulfonyl)phenyl)-2'-oxospiro[cyclopropane-1,3'-in-
doline]-1'-yl)methyl)benzoic acid; [0062]
(1R,2S)-3-((2-(4-(methylsulfonyl)phenyl)-2'-oxospiro[cyclopropane-1,3'-in-
doline]-1'-yl)methyl)benzoic acid; [0063]
(1S,2R)-3-((2-(2-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)benzoic acid; [0064]
(1R,2S)-3-((2-(2-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)benzoic acid; [0065]
(1S,2S)-3-((2-(2-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)benzoic acid; [0066]
(1R,2R)-3-((2-(2-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)benzoic acid; [0067]
(1S,2R)-3-((2-(3-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)benzoic acid; [0068]
(1R,2S)-3-((2-(3-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)benzoic acid; [0069]
(1S,2S)-3-((2-(3-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)benzoic acid; [0070]
(1R,2R)-3-((2-(3-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)benzoic acid; [0071]
(1S,2S)-3-((2'-oxo-2-(2-(trifluoromethyl)phenyl)-spiro[cyclopropane-1,3'--
indoline]-1'-yl)methyl)benzoic acid; [0072]
(1R,2R)-3-((2'-oxo-2-(2-(trifluoromethyl)phenyl)-spiro[cyclopropane-1,3'--
indoline]-1'-yl)methyl)benzoic acid; [0073]
(1S,2R)-((5'-chloro-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indo-
line]-1'-yl)methyl)benzoic acid; [0074]
(1R,2S)-((5'-chloro-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indo-
line]-1'-yl)methyl)benzoic acid; [0075]
(1R,2R)-3-((5'-chloro-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-in-
doline]-1'-yl)methyl)benzoic acid; [0076]
(1S,2S)-3-((5'-chloro-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-in-
doline]-1'-yl)methyl)benzoic acid; [0077]
(1R,2R)-3-((5'-bromo-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-ind-
oline]-1'-yl)methyl)benzoic acid; [0078]
(1S,2S)-3-((5'-bromo-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-ind-
oline]-1'-yl)methyl)benzoic acid; [0079]
(1S,2R)-3-((5'-bromo-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-ind-
oline]-1'-yl)methyl)benzoic acid; [0080]
(1R,2S)-3-((5'-bromo-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-ind-
oline]-1'-yl)methyl)benzoic acid; [0081]
(1S,2S)-3-((2-(4-cyanophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)methyl)benzoic acid; [0082]
(1R,2R)-3-((2-(4-cyanophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)methyl)benzoic acid; [0083]
(1S,2R)-3-((2-(3-methoxyphenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1-
'-yl)methyl)benzoic acid; [0084]
(1R,2S)-3-((2-(3-methoxyphenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1-
'-yl)methyl)benzoic acid; [0085]
(1S,2S)-3-((2-(3-methoxyphenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1-
'-yl)methyl)benzoic acid; [0086]
(1R,2R)-3-((2-(3-methoxyphenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1-
'-yl)methyl)benzoic acid; [0087]
(1S,2S)-3-((2-(4-methoxyphenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1-
'-yl)methyl)benzoic acid; [0088]
(1R,2R)-3-((2-(4-methoxyphenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1-
'-yl)methyl)benzoic acid; [0089]
(1S,2R)-3-((2-(4-methoxyphenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1-
'-yl)methyl)benzoic acid; [0090]
(1R,2S)-3-((2-(4-methoxyphenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1-
'-yl)methyl)benzoic acid; [0091]
(1S,2R)-3-((2-(4-chlorophenyl)-5'-fluoro-2'-oxospiro[cyclopropane-1,3'-in-
doline]-1'-yl)methyl)benzoic acid; [0092]
(1R,2S)-3-((2-(4-chlorophenyl)-5'-fluoro-2'-oxospiro[cyclopropane-1,3'-in-
doline]-1'-yl)methyl)benzoic acid; [0093]
(1S,2S)-3-((2-(4-chlorophenyl)-5'-fluoro-2'-oxospiro[cyclopropane-1,3'-in-
doline]-1'-yl)methyl)benzoic acid; [0094]
(1R,2R)-3-((2-(4-chlorophenyl)-5'-fluoro-2'-oxospiro[cyclopropane-1,3'-in-
doline]-1'-yl)methyl)benzoic acid; [0095]
(1S,2R)-3-((-2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1-
'-yl)methyl)benzoic acid; [0096]
(1R,2S)-3-((-2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1-
'-yl)methyl)benzoic acid; [0097]
(1S,2R)-3-((2'-oxo-2-(pyridin-3-yl)spiro[cyclopropane-1,3'-indoline]-1'-y-
l)methyl)benzoic acid; [0098]
(1R,2S)-3-((2'-oxo-2-(pyridin-3-yl)spiro[cyclopropane-1,3'-indoline]-1'-y-
l)methyl)benzoic acid; [0099]
(1S,2S)-3-((-2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1-
'-yl)methyl)benzoic acid; [0100]
(1R,2R)-3-((-2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1-
'-yl)methyl)benzoic acid; [0101]
(1S,2S)-3-((2-(4-chlorophenyl)-2-isopropyl-2'-oxospiro[cyclopropane-1,3'--
indoline]-1'-yl)methyl)benzoic acid; [0102]
(1R,2R)-3-((2-(4-chlorophenyl)-2-isopropyl-2'-oxospiro[cyclopropane-1,3'--
indoline]-1'-yl)methyl)benzoic acid; [0103]
(1S,2S)-3-((2-(4-cyanophenyl)-2-methyl-2'-oxospiro[cyclopropane-1,3'-indo-
line]-1'-yl)methyl)benzoic acid; [0104]
(1R,2R)-3-((2-(4-cyanophenyl)-2-methyl-2'-oxospiro[cyclopropane-1,3'-indo-
line]-1'-yl)methyl)benzoic acid; [0105]
(1S,2R)-3-((2-(4-cyanophenyl)-2-methyl-2'-oxospiro[cyclopropane-1,3'-indo-
line]-1'-yl)methyl)benzoic acid; [0106]
(1R,2S)-3-((2-(4-cyanophenyl)-2-methyl-2'-oxospiro[cyclopropane-1,3'-indo-
line]-1'-yl)methyl)benzoic acid; [0107]
(+)-3-((2-(4-chlorophenyl)-2-isopropyl-2'-oxospiro[(trans)-cyclopropane-1-
,3'-indoline]-1'-yl)methyl)benzoic acid; [0108]
(-)-3-((2-(4-chlorophenyl)-2-isopropyl-2'-oxospiro[(trans)-cyclopropane-1-
,3'-indoline]-1'-yl)methyl)benzoic acid; [0109]
(1S,2S)-3-((2-(4-chlorophenyl)-2-isopropyl-2'-oxospiro[cyclopropane-1,3'--
indoline]-1'-yl)methyl)benzoic acid; [0110]
(1R,2R)-3-((2-(4-chlorophenyl)-2-isopropyl-2'-oxospiro[cyclopropane-1,3'--
indoline]-1'-yl)methyl)benzoic acid; [0111]
(+)-3-((2-(4-chlorophenyl)-5'-fluoro-2-isopropyl-2'-oxospiro[(trans)-cycl-
opropane-1,3'-indoline]-1'-yl)methyl)benzoic acid; [0112]
(-)-3-((2-(4-chlorophenyl)-5'-fluoro-2-isopropyl-2'-oxospiro[(trans)-cycl-
opropane-1,3'-indoline]-1'-yl)methyl)benzoic acid; [0113]
(1S,2S)-3-((2-(4-chlorophenyl)-5'-fluoro-2-isopropyl-2'-oxospiro[cyclopro-
pane-1,3'-indoline]-1'-yl)methyl)benzoic acid; [0114]
(1R,2R)-3-((2-(4-chlorophenyl)-5'-fluoro-2-isopropyl-2'-oxospiro[cyclopro-
pane-1,3'-indoline]-1'-yl)methyl)benzoic acid; [0115]
(1S,2S)-3-((5'-fluoro-2-(4-fluorophenyl)-2-isopropyl-2'-oxospiro[cyclopro-
pane-1,3'-indoline]-1'-yl)methyl)benzoic acid; [0116]
(1R,2R)-3-((5'-fluoro-2-(4-fluorophenyl)-2-isopropyl-2'-oxospiro[cyclopro-
pane-1,3'-indoline]-1'-yl)methyl)benzoic acid; [0117]
(1S,2S)-3-((2-(3-fluorophenyl)-2-isopropyl-2'-oxospiro[cyclopropane-1,3'--
indoline]-1'-yl)methyl)benzoic acid; [0118]
(1R,2R)-3-((2-(3-fluorophenyl)-2-isopropyl-2'-oxospiro[cyclopropane-1,3'--
indoline]-1'-yl)methyl)benzoic acid; [0119]
(1S,2S)-3-((2-(3-chlorophenyl)-2-isopropyl-2'-oxospiro[cyclopropane-1,3'--
indoline]-1'-yl)methyl)benzoic acid; [0120]
(1R,2R)-3-((2-(3-chlorophenyl)-2-isopropyl-2'-oxospiro[cyclopropane-1,3'--
indoline]-1'-yl)methyl)benzoic acid; [0121]
(1S,2S)-3-((2-(4-fluorophenyl)-2-isopropyl-2'-oxospiro[cyclopropane-1,3'--
indoline]-1'-yl)methyl)benzoic acid; [0122]
(1R,2R)-3-((2-(4-fluorophenyl)-2-isopropyl-2'-oxospiro[cyclopropane-1,3'--
indoline]-1'-yl)methyl)benzoic acid; [0123]
(+)-3-((2-(4-chlorophenyl)-2-isopropyl-2'-oxospiro[(trans)-cyclopropane-1-
,3'-indoline]-1'-yl)methyl)benzoic acid; [0124]
(-)-3-((2-(4-chlorophenyl)-2-isopropyl-2'-oxospiro[(trans)-cyclopropane-1-
,3'-indoline]-1'-yl)methyl)benzoic acid; [0125]
(1R,2S)-3-((2-(4-chlorophenyl)-2-methyl-2'-oxospiro[cyclopropane-1,3'-ind-
oline]-1'-yl)methyl)benzoic acid; [0126]
(1S,2R)-3-((2-(4-chlorophenyl)-2-methyl-2'-oxospiro[cyclopropane-1,3'-ind-
oline]-1'-yl)methyl)benzoic acid; [0127]
(+)-3-((2-(4-chlorophenyl)-2-methyl-2'-oxospiro[(trans)-cyclopropane-1,3'-
-indoline]-1'-yl)methyl)benzoic acid; [0128]
(-)-3-((2-(4-chlorophenyl)-2-methyl-2'-oxospiro[(trans)-cyclopropane-1,3'-
-indoline]-1'-yl)methyl)benzoic acid; [0129]
(1R,2R)-3-((2-(4-chlorophenyl)-2-methyl-2'-oxospiro[cyclopropane-1,3'-ind-
oline]-1'-yl)methyl)benzoic acid; [0130]
(1S,2S)-3-((2-(4-chlorophenyl)-2-methyl-2'-oxospiro[cyclopropane-1,3'-ind-
oline]-1'-yl)methyl)benzoic acid; [0131]
(+)-3-((2-(4-chlorophenyl)-2-methyl-2'-oxospiro[(cis)-cyclopropane-1,3'-i-
ndoline]-1'-yl)methyl)benzoic acid; [0132]
(-)-3-((2-(4-chlorophenyl)-2-methyl-2'-oxospiro[(cis)-cyclopropane-1,3'-i-
ndoline]-1'-yl)methyl)benzoic acid; [0133]
(1R,2S)-3-((2-(4-cyanophenyl)-5'-fluoro-2-methyl-2'-oxospiro[cyclopropane-
-1,3'-indoline]-1'-yl)methyl)benzoic acid; [0134]
(1S,2R)-3-((2-(4-cyanophenyl)-5'-fluoro-2-methyl-2'-oxospiro[cyclopropane-
-1,3'-indoline]-1'-yl)methyl)benzoic acid; [0135]
(-)-3-((2-(4-cyanophenyl)-5'-fluoro-2-methyl-2'-oxospiro[(trans)-cyclopro-
pane-1,3'-indoline]-1'-yl)methyl)benzoic acid; [0136]
(+)-3-((2-(4-cyanophenyl)-5'-fluoro-2-methyl-2'-oxospiro[(trans)-cyclopro-
pane-1,3'-indoline]-1'-yl)methyl)benzoic acid; [0137]
(1S,2S)-3-((2-(4-cyanophenyl)-2-isopropyl-2'-oxospiro[cyclopropane-1,3'-i-
ndoline]-1'-yl)methyl)benzoic acid; [0138]
(1R,2R)-3-((2-(4-cyanophenyl)-2-isopropyl-2'-oxospiro[cyclopropane-1,3'-i-
ndoline]-1'-yl)methyl)benzoic acid; [0139]
(-)-3-((2-(4-cyanophenyl)-2-isopropyl-2'-oxospiro[(trans)-cyclopropane-1,-
3'-indoline]-1'-yl)methyl)benzoic acid; [0140]
(+)-3-((2-(4-cyanophenyl)-2-isopropyl-2'-oxospiro[(trans)-cyclopropane-1,-
3'-indoline]-1'-yl)methyl)benzoic acid; [0141]
(1R,2R)-3-((2-(4-cyanophenyl)-5'-fluoro-2-methyl-2'-oxospiro[cyclopropane-
-1,3'-indoline]-1'-yl)methyl)benzoic acid; [0142]
(1S,2S)-3-((2-(4-cyanophenyl)-5'-fluoro-2-methyl-2'-oxospiro[cyclopropane-
-1,3'-indoline]-1'-yl)methyl)benzoic acid; [0143]
(-)-3-((2-(4-cyanophenyl)-5'-fluoro-2-methyl-2'-oxospiro[(cis)-cyclopropa-
ne-1,3'-indoline]-1'-yl)methyl)benzoic acid; [0144]
(+)-3-((2-(4-cyanophenyl)-5'-fluoro-2-methyl-2'-oxospiro[(cis)-cyclopropa-
ne-1,3'-indoline]-1'-yl)methyl)benzoic acid; [0145]
(1R,2S)-3-((2-(4-chlorophenyl)-5'-fluoro-2-methyl-2'-oxospiro[cyclopropan-
e-1,3'-indoline]-1'-yl)methyl)benzoic acid; [0146]
(1S,2R)-3-((2-(4-chlorophenyl)-5'-fluoro-2-methyl-2'-oxospiro[cyclopropan-
e-1,3'-indoline]-1'-yl)methyl)benzoic acid; [0147]
(-)-3-((2-(4-chlorophenyl)-5'-fluoro-2-methyl-2'-oxospiro[(trans)-cyclopr-
opane-1,3'-indoline]-1'-yl)methyl)benzoic acid; [0148]
(+)-3-((2-(4-chlorophenyl)-5'-fluoro-2-methyl-2'-oxospiro[(trans)-cyclopr-
opane-1,3'-indoline]-1'-yl)methyl)benzoic acid; [0149]
(1S,2R)-2-(4-chlorophenyl)-1'-(3-(piperidine-1-carbonyl)benzyl)spiro[cycl-
opropane-1,3'-indolin]-2'-one; [0150]
(1R,2S)-2-(4-chlorophenyl)-1'-(3-(piperidine-1-carbonyl)benzyl)spiro[cycl-
opropane-1,3'-indolin]-2'-one; [0151]
(1R,2S)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)-N-isopropylbenzamide; [0152]
(1S,2R)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)-N-isopropylbenzamide; [0153]
(1S,2R)-2-(4-chlorophenyl)-1'-(3-(piperazine-1-carbonyl)benzyl)spiro[cycl-
opropane-1,3'-indolin]-2'-one; [0154]
(1R,2S)-2-(4-chlorophenyl)-1'-(3-(piperazine-1-carbonyl)benzyl)spiro[cycl-
opropane-1,3'-indolin]-2'-one; [0155]
(1R,2S)-2-(4-chlorophenyl)-1'-(3-(morpholine-4-carbonyl)benzyl)spiro[cycl-
opropane-1,3'-indolin]-2'-one; [0156]
(1S,2R)-2-(4-chlorophenyl)-1'-(3-(morpholine-4-carbonyl)benzyl)spiro[cycl-
opropane-1,3'-indolin]-2'-one; [0157]
(1R,2S)-2-(4-chlorophenyl)-1'-(3-(4-(pyridin-4-yl)piperazine-1-carbonyl)b-
enzyl)spiro[cyclopropane-1,3'-indolin]-2'-one; [0158]
(1S,2R)-2-(4-chlorophenyl)-1'-(3-(4-(pyridin-4-yl)piperazine-1-carbonyl)b-
enzyl)spiro[cyclopropane-1,3'-indolin]-2'-one; [0159]
(1S,2R)-2-(4-chlorophenyl)-1'-(3-(4-isopropylpiperazine-1-carbonyl)benzyl-
)spiro[cyclopropane-1,3'-indolin]-2'-one; [0160]
(1R,2S)-2-(4-chlorophenyl)-1'-(3-(4-isopropylpiperazine-1-carbonyl)benzyl-
)spiro[cyclopropane-1,3'-indolin]-2'-one; [0161]
3-(((1S,2R)-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)-N-(2-((S)-1-methylpyrrolidin-2-yl)ethyl)benzamide
[0162]
3-(((1R,2S)-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)-N-(2-((S)-1-methylpyrrolidin-2-yl)ethyl)benzamide;
[0163]
(1R,2S)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)-N-(3-methyl-1H-pyrazol-5-yl)benzamide; [0164]
(1S,2R)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)-N-(3-methyl-1H-pyrazol-5-yl)benzamide; [0165]
(1S,2R)-6-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)picolinic acid; [0166]
(1R,2S)-6-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)picolinic acid; [0167]
(1S,2R)-6-((2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)picolinic acid; [0168]
(1R,2S)-6-((2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)picolinic acid; [0169]
(1S,2R)-2-(4-chlorophenyl)-1'-((tetrahydro-2H-pyran-4-yl)methyl)spiro[cyc-
lopropane-1,3'-indolin]-2'-one; [0170]
(1R,2S)-2-(4-chlorophenyl)-1'-((tetrahydro-2H-pyran-4-yl)methyl)spiro[cyc-
lopropane-1,3'-indolin]-2'-one; [0171]
(1S,2R)-2-(4-chlorophenyl)-1'-(2-(diethylamino)ethyl)spiro[cyclopropane-1-
,3'-indolin]-2'-one; [0172]
(1R,2S)-2-(4-chlorophenyl)-1'-(2-(diethylamino)ethyl)spiro[cyclopropane-1-
,3'-indolin]-2'-one; [0173]
(1S,2R)-2-(4-chlorophenyl)-1'-(2-morpholinoethyl)spiro[cyclopropane-1,3'--
indolin]-2'-one; [0174] (1R,2S)-2-(4-chlorophenyl)-1'-(2-morp
holino ethyl)spiro[cyclopropane-1,3'-indolin]-2'-one; [0175]
(1S,2R)-2-(4-chlorophenyl)-1'-((1-(methylsulfonyl)piperidin-4-yl)methyl)s-
piro[cyclopropane-1,3'-indolin]-2'-one; [0176]
(1R,2S)-2-(4-chlorophenyl)-1'-((1-(methylsulfonyl)piperidin-4-yl)methyl)s-
piro[cyclopropane-1,3'-indolin]-2'-one; [0177]
(1S,2R)-2-(4-chlorophenyl)-1'-(2-(4-isopropylpiperazin-1-yl)ethyl)spiro[c-
yclopropane-1,3'-indolin]-2'-one; [0178]
(1R,2S)-2-(4-chlorophenyl)-1'-(2-(4-isopropylpiperazin-1-yl)ethyl)spiro[c-
yclopropane-1,3'-indolin]-2'-one; [0179]
(1S,2R)-2-(4-chlorophenyl)-1
'-(2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)ethyl)spiro[cyclopropane-1,-
3'-indolin]-2'-one; [0180]
(1R,2S)-2-(4-chlorophenyl)-1'-(2-(4-(2-(dimethylamino)ethyl)piperazin-1-y-
l)ethyl)spiro[cyclopropane-1,3'-indolin]-2'-one; [0181]
(1S,2R)-2-(4-chlorophenyl)-1'-(2-((5)-3-(dimethylamino)pyrrolidin-1-yl)et-
hyl)spiro[cyclopropane-1,3'-indolin]-2'-one; [0182]
(1R,2S)-2-(4-chlorophenyl)-1'-(2-((5)-3-(dimethylamino)pyrrolidin-1-yl)et-
hyl)spiro[cyclopropane-1,3'-indolin]-2'-one; [0183]
(1S,2R)-2-(4-chlorophenyl)-1'-(2-((R)-3-(dimethylamino)pyrrolidin-1-yl)et-
hyl)spiro[cyclopropane-1,3'-indolin]-2'-one; [0184]
(1R,2S)-2-(4-chlorophenyl)-1'-(2-((R)-3-(dimethylamino)pyrrolidin-1-yl)et-
hyl)spiro[cyclopropane-1,3'-indolin]-2'-one; [0185]
(1R,2S)-2-(4-chlorophenyl)-1'-(pyridin-4-ylmethyl)spiro[cyclopropane-1,3'-
-indolin]-2'-one; [0186]
(1S,2R)-2-(4-chlorophenyl)-1'-(pyridin-4-ylmethyl)spiro[cyclopropane-1,3'-
-indolin]-2'-one; [0187]
(1S,2R)-2-(4-chlorophenyl)-1'-(pyridin-3-ylmethyl)spiro[cyclopropane-1,3'-
-indolin]-2'-one; [0188]
(2R,1S)-2-(4-chlorophenyl)-1'-(pyridin-3-ylmethyl)spiro[cyclopropane-1,3'-
-indolin]-2'-one; [0189]
(1S,2R)-2-(4-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]--
1'-yl)-1H-imidazol-1-yl)acetic acid; [0190]
(1R,2S)-2-(4-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]--
1'-yl)-1H-imidazol-1-yl)acetic acid; [0191]
(1S,2R)-1-(2-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]--
1'-yl)ethyl)-1H-imidazole-4-carboxylic acid; [0192]
(1R,2S)-1-(2-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]--
1'-yl)ethyl)-1H-imidazole-4-carboxylic acid; [0193]
(1S,2S)-1-(2-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]--
1'-yl)ethyl)-1H-imidazole-4-carboxylic acid; [0194]
(1R,2R)-1-(2-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]--
1'-yl)ethyl)-1H-imidazole-4-carboxylic acid; [0195]
(1S,2R)-3-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)benzoic acid; [0196]
(1R,2S)-3-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)benzoic acid; [0197]
(1S,2S)-3-(-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)benzoic acid; [0198]
(1R,2R)-3-(-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)benzoic acid; [0199]
(1S,2S)-2-(4-chlorophenyl)-1'-(3-(morpholine-4-carbonyl)phenyl)spiro[cycl-
opropane-1,3'-indolin]-2'-one; [0200]
(1R,2R)-2-(4-chlorophenyl)-1'-(3-(morpholine-4-carbonyl)phenyl)spiro[cycl-
opropane-1,3'-indolin]-2'-one; [0201]
(1S,2S)-2-(4-chlorophenyl)-1'-(3-(4-methylpiperazine-1-carbonyl)phenyl)sp-
iro[cyclopropane-1,3'-indolin]-2'-one; [0202]
(1R,2R)-2-(4-chlorophenyl)-1'-(3-(4-methylpiperazine-1-carbonyl)phenyl)sp-
iro[cyclopropane-1,3'-indolin]-2'-one; [0203]
(1S,2S)-2-(4-chlorophenyl)-1'-(3-(4-(methylsulfonyl)piperazine-1-carbonyl-
)phenyl)spiro[cyclopropane-1,3'-indolin]-2'-one; [0204]
(1R,2R)-2-(4-chlorophenyl)-1'-(3-(4-(methylsulfonyl)piperazine-1-carbonyl-
)phenyl)spiro[cyclopropane-1,3'-indolin]-2'-one; [0205]
(1R,2S)-2-(4-chlorophenyl)-1'-(3-(morpholine-4-carbonyl)phenyl)spiro[cycl-
opropane-1,3'-indolin]-2'-one; [0206]
(1S,2R)-2-(4-chlorophenyl)-1'-(3-(morpholine-4-carbonyl)phenyl)spiro[cycl-
opropane-1,3'-indolin]-2'-one; [0207]
(1S,2R)-2-(4-chlorophenyl)-1'-(3-(4-methylpiperazine-1-carbonyl)phenyl)sp-
iro[cyclopropane-1,3'-indolin]-2'-one; [0208]
(1R,2S)-2-(4-chlorophenyl)-1'-(3-(4-methylpiperazine-1-carbonyl)phenyl)sp-
iro[cyclopropane-1,3'-indolin]-2'-one; [0209]
(1R,2S)-2-(4-chlorophenyl)-1'-(3-(4-(methylsulfonyl)piperazine-1-carbonyl-
)phenyl)spiro[cyclopropane-1,3'-indolin]-2'-one; [0210]
(1S,2R)-2-(4-chlorophenyl)-1'-(3-(4-(methylsulfonyl)piperazine-1-carbonyl-
)phenyl)spiro[cyclopropane-1,3'-indolin]-2'-one; [0211]
(1R,2R)-3-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)-N-(methylsulfonyl)benzamide; [0212]
(1S,2S)-3-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)-N-(methylsulfonyl)benzamide; [0213]
(1S,2S)-3-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)-5-(2-oxooxazolidin-3-yl)benzoic acid; [0214]
(1R,2R)-3-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)-5-(2-oxooxazolidin-3-yl)benzoic acid; [0215]
(1S,2S)-3-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)-5-(methylsulfonyl)benzoic acid; [0216]
(1R,2R)-3-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)-5-(methylsulfonyl)benzoic acid; [0217]
(1S,2S)-3-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)-5-(2-oxopyrrolidin-1-yl)benzoic acid; [0218]
(1R,2R)-3-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)-5-(2-oxopyrrolidin-1-yl)benzoic acid; [0219]
(1R,2R)-3-(2-(4-chlorophenyl)-5'-fluoro-2-isopropyl-2'-oxospiro[cycloprop-
ane-1,3'-indoline]-1'-yl)-5-(2-oxooxazolidin-3-yl)benzoic acid;
[0220]
(1S,2S)-3-(2-(4-chlorophenyl)-5'-fluoro-2-isopropyl-2'-oxospiro[cycloprop-
ane-1,3'-indoline]-1'-yl)-5-(2-oxooxazolidin-3-yl)benzoic acid;
[0221]
(1R,2S)-3-(2-(4-chlorophenyl)-5'-fluoro-2-isopropyl-2'-oxospiro[cycloprop-
ane-1,3'-indoline]-1'-yl)-5-(2-oxooxazolidin-3-yl)benzoic acid;
[0222]
(1S,2R)-3-(2-(4-chlorophenyl)-5'-fluoro-2-isopropyl-2'-oxospiro[cycloprop-
ane-1,3'-indoline]-1'-yl)-5-(2-oxooxazolidin-3-yl)benzoic acid;
[0223]
(1R,2R)-3-(2-(4-chlorophenyl)-2-isopropyl-2'-oxospiro[cyclopropane-1,3'-i-
ndoline]-1'-yl)-5-(2-oxooxazolidin-3-yl)benzoic acid; [0224]
(1S,2S)-3-(2-(4-chlorophenyl)-2-isopropyl-2'-oxospiro[cyclopropane-1,3'-i-
ndoline]-1'-yl)-5-(2-oxooxazolidin-3-yl)benzoic acid; [0225]
(1S,2S)-3-(2-(4-cyanophenyl)-2-isopropyl-2'-oxospiro[cyclopropane-1,3'-in-
doline]-1'-yl)-5-(2-oxooxazolidin-3-yl)benzoic acid; [0226]
(1R,2R)-3-(2-(4-cyanophenyl)-2-isopropyl-2'-oxospiro[cyclopropane-1,3'-in-
doline]-1'-yl)-5-(2-oxooxazolidin-3-yl)benzoic acid; [0227]
(1S,2S)-3-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)-5-(2-oxoimidazolidin-1-yl)benzoic acid; [0228]
(1R,2R)-3-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)-5-(2-oxoimidazolidin-1-yl)benzoic acid; [0229]
(R)-3-((5'-fluoro-2,2-dimethyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)benzoic acid; [0230]
(S)-3-((5'-fluoro-2,2-dimethyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)benzoic acid; [0231]
(R)-3-(5'-fluoro-2,2-dimethyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)-5-(2-oxooxazolidin-3-yl)benzoic acid; [0232]
(S)-3-(5'-fluoro-2,2-dimethyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)-5-(2-oxooxazolidin-3-yl)benzoic acid; [0233]
(R)-3-[(2-oxo-2'',3'',5'',6''-tetrahydrodispiro[indole-3,1'-cyclopropane--
2',4''-pyran]-1(2H)-yl)methyl]benzoic acid; [0234]
(S)-3-[(2-oxo-2'',3'',5'',6''-tetrahydrodispiro[indole-3,1'-cyclopropane--
2',4''-pyran]-1(2H)-yl)methyl]benzoic acid; [0235]
(R)-3-(2-oxo-1,3-oxazolidin-3-yl)-5-(2-oxo-2'',3'',5'',6''-tetrahydrodisp-
iro[indole-3,1'-cyclopropane-2',4''-pyran]-1(2H)-yl)benzoic acid;
[0236]
(S)-3-(2-oxo-1,3-oxazolidin-3-yl)-5-(2-oxo-2'',3'',5'',6''-tetrahydrodisp-
iro[indole-3,1'-cyclopropane-2',4''-pyran]-1(2H)-yl)benzoic acid;
[0237]
(1S,2S)-2-chloro-5-((2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-ind-
oline]-1'-yl)methyl)benzoic acid; [0238]
(1R,2R)-2-chloro-5-((2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-ind-
oline]-1'-yl)methyl)benzoic acid; [0239]
(1R,2S)-4-((2'-oxo-2-(pyridin-3-yl)spiro[cyclopropane-1,3'-indoline]-1'-y-
l)methyl)benzoic acid; [0240]
(1S,2R)-4-((2'-oxo-2-(pyridin-3-yl)spiro[cyclopropane-1,3'-indoline]-1'-y-
l)methyl)benzoic acid; [0241]
(1S,2R)-4-((2-(4-cyanophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)methyl)benzoic acid; [0242]
(1R,2S)-4-((2-(4-cyanophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)methyl)benzoic acid; [0243]
(1R,2S)-4-((2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)benzoic acid; [0244]
(1R,2S)-4-((2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)benzoic acid; [0245]
(1S,2R)-2-chloro-5-((2-(4-chlorophenyl)-5'-fluoro-2'-oxospiro[cyclopropan-
e-1,3'-indoline]-1'-yl)methyl)benzoic acid; [0246]
(1R,2S)-2-chloro-5-((2-(4-chlorophenyl)-5'-fluoro-2'-oxospiro[cyclopropan-
e-1,3'-indoline]-1'-yl)methyl)benzoic acid; [0247]
(1R,2S)-3-((2-(3-chloro-4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-ind-
oline]-1'-yl)methyl)benzoic acid; [0248]
(1S,2R)-3-((2-(3-chloro-4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-ind-
oline]-1'-yl)methyl)benzoic acid; [0249]
(1R,2S)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)-N-methylbenzamide; [0250]
(1S,2R)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)-N-methylbenzamide; [0251]
(1S,2R)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)-N,N-dimethylbenzamide; [0252]
(1R,2S)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)-N,N-dimethylbenzamide; [0253]
(1R,2S)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)-N-(3-morpholinopropyl)benzamide; [0254]
(1S,2R)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)-N-(3-morpholinopropyl)benzamide; [0255]
(1R,2S)-2-(4-chlorophenyl)-1'-(3-(4-(2-(dimethylamino)ethyl)piperazine-1--
carbonyl)benzyl)spiro[cyclopropane-1,3'-indolin]-2'-one; [0256]
(1S,2R)-2-(4-chlorophenyl)-1'-(3-(4-(2-(dimethylamino)ethyl)piperazine-1--
carbonyl)benzyl)spiro[cyclopropane-1,3'-indolin]-2'-one; [0257]
(1R,2S)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)-N-(2-morpholino ethyl)benzamide; [0258]
(1S,2R)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)-N-(2-morpholino ethyl)benzamide; [0259]
(1R,2S)-2-(4-chlorophenyl)-1'-(3-(4-(methylsulfonyl)piperazine-1-carbonyl-
)benzyl)spiro[cyclopropane-1,3'-indolin]-2'-one; [0260]
(1S,2R)-2-(4-chlorophenyl)-1'-(3-(4-(methylsulfonyl)piperazine-1-carbonyl-
)benzyl)spiro[cyclopropane-1,3'-indolin]-2'-one; [0261]
(1S,2R)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)-N-(3-cyclopropyl-1H-pyrazol-5-yl)benzamide; [0262]
(1R,2S)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)-N-(3-cyclopropyl-1H-pyrazol-5-yl)benzamide; [0263]
(1R,2S)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)benzamide; [0264]
(1R,2S)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)benzamide; [0265]
(1R,2S)-6-((2-(4-cyanophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)methyl)-N-(cyclopropylsulfonyl)picolinamide; [0266]
(1S,2R)-6-((2-(4-cyanophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)methyl)-N-(cyclopropylsulfonyl)picolinamide; [0267]
(1S,2R)-4-((2-(4-cyanophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)methyl)-N-(cyclopropylsulfonyl)benzamide; [0268]
(1R,2S)-4-((2-(4-cyanophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)methyl)-N-(cyclopropylsulfonyl)benzamide; [0269]
(1R,2S)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)-N-(methylsulfonyl)benzamide; [0270]
(1S,2R)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)-N-(methylsulfonyl)benzamide; [0271]
(1R,2S)-3-((2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)-N-(methylsulfonyl)benzamide; [0272]
(1S,2R)-3-((2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)-N-(methylsulfonyl)benzamide; [0273]
(1S,2R)--N-(cyclopropylsulfonyl)-3-((2-(4-fluorophenyl)-2'-oxospiro[cyclo-
propane-1,3'-indoline]-1'-yl)methyl)benzamide; [0274]
(1R,2S)--N-(cyclopropylsulfonyl)-3-((2-(4-fluorophenyl)-2'-oxospiro[cyclo-
propane-1,3'-indoline]-1'-yl)methyl)benzamide; [0275]
(1S,2R)--N-(cyclopropylsulfonyl)-4-((2-(4-fluorophenyl)-2'-oxospiro[cyclo-
propane-1,3'-indoline]-1'-yl)methyl)benzamide; [0276]
(1R,2S)--N-(cyclopropylsulfonyl)-4-((2-(4-fluorophenyl)-2'-oxospiro[cyclo-
propane-1,3'-indoline]-1'-yl)methyl)benzamide; [0277]
(1S,2R)-2-(4-chlorophenyl)-1'-(piperidin-4-ylmethyl)spiro[cyclopropane-1,-
3'-indolin]-2'-one; [0278]
(1R,2S)-2-(4-chlorophenyl)-1'-(piperidin-4-ylmethyl)spiro[cyclopropane-1,-
3'-indolin]-2'-one; [0279]
(1S,2R)-2-(4-chlorophenyl)-1'-(2-(piperidin-1-yl)ethyl)spiro[cyclopropane-
-1,3'-indolin]-2'-one; [0280]
(1R,2S)-2-(4-chlorophenyl)-1'-(2-(piperidin-1-yl)ethyl)spiro[cyclopropane-
-1,3'-indolin]-2'-one; [0281]
(1S,2R)-2-(4-chlorophenyl)-1'-(2-(3-morpholinopropylamino)ethyl)spiro[cyc-
lopropane-1,3'-indolin]-2'-one; [0282]
(1R,2S)-2-(4-chlorophenyl)-1'-(2-(3-morpholinopropylamino)ethyl)spiro[cyc-
lopropane-1,3'-indolin]-2'-one; [0283]
(1S,2R)-2-(4-chlorophenyl)-1'-(2-(3-morpholinopropylamino)ethyl)spiro[cyc-
lopropane-1,3'-indolin]-2'-one; [0284]
(1R,2S)-2-(4-chlorophenyl)-1'-(2-(3-morpholinopropylamino)ethyl)spiro[cyc-
lopropane-1,3'-indolin]-2'-one; [0285]
(1S,2R)-2-(4-chlorophenyl)-1'-(2-(2-morpholinoethylamino)ethyl)spiro[cycl-
opropane-1,3'-indolin]-2'-one; [0286]
(1R,2S)-2-(4-chlorophenyl)-1'-(2-(2-morpholinoethylamino)ethyl)spiro[cycl-
opropane-1,3'-indolin]-2'-one; [0287]
(1S,2R)-2-(4-chlorophenyl)-1'-(2-(4-(pyridin-4-yl)piperazin-1-yl)ethyl)sp-
iro[cyclopropane-1,3'-indolin]-2'-one; [0288]
(1R,2S)-2-(4-chlorophenyl)-1'-(2-(4-(pyridin-4-yl)piperazin-1-yl)ethyl)sp-
iro[cyclopropane-1,3'-indolin]-2'-one; [0289]
(1S,2R)-2-(4-chlorophenyl)-1'-(2-(2-(2,6-dimethylmorpholino)ethylamino)et-
hyl)spiro[cyclopropane-1,3'-indolin]-2'-one; [0290]
(1R,2S)-2-(4-chlorophenyl)-1'-(2-(2-(2,6-dimethylmorpholino)ethylamino)et-
hyl)spiro[cyclopropane-1,3'-indolin]-2'-one; [0291]
(1S,2R)-2-(4-chlorophenyl)-1'-(1H-imidazol-4-yl)spiro[cyclopropane-1,3'-i-
ndolin]-2'-one; [0292]
(1R,2S)-2-(4-chlorophenyl)-1'-(1H-imidazol-4-yl)spiro[cyclopropane-1,3'-i-
ndolin]-2'-one; [0293]
(1S,2R)-3-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)-N-(methylsulfonyl)benzamide; [0294]
(1R,2S)-3-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)-N-(methylsulfonyl)benzamide; [0295]
(1S,2S)-3-(2-(4-chlorophenyl)-2-methyl-2'-oxospiro[cyclopropane-1,3'-indo-
line]-1'-yl)-5-(2-oxooxazolidin-3-yl)benzoic acid; [0296]
(1R,2R)-3-(2-(4-chlorophenyl)-2-methyl-2'-oxospiro[cyclopropane-1,3'-indo-
line]-1'-yl)-5-(2-oxooxazolidin-3-yl)benzoic acid; [0297]
(1S,2S)-3-(2-(4-chlorophenyl)-2-isopropyl-2'-oxospiro[cyclopropane-1,3'-i-
ndoline]-1'-yl)-5-(2-oxooxazolidin-3-yl)benzoic acid; [0298]
(1R,2R)-3-(2-(4-chlorophenyl)-2-isopropyl-2'-oxospiro[cyclopropane-1,3'-i-
ndoline]-1'-yl)-5-(2-oxooxazolidin-3-yl)benzoic acid; [0299]
(1S,2S)-3-(2-(4-chlorophenyl)-2-isopropyl-2'-oxospiro[cyclopropane-1,3'-i-
ndoline]-1'-yl)-5-(2-oxooxazolidin-3-yl)benzoic acid; [0300]
(1R,2R)-3-(2-(4-chlorophenyl)-2-isopropyl-2'-oxospiro[cyclopropane-1,3'-i-
ndoline]-1'-yl)-5-(2-oxooxazolidin-3-yl)benzoic acid; [0301]
(R)-methyl-3-(2,2-dimethyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)-
-5-(2-oxooxazolidin-3-yl)benzoate; [0302]
(S)-methyl-3-(2,2-dimethyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)-
-5-(2-oxooxazolidin-3-yl)benzoate; [0303]
(R)-3-(5'-fluoro-2,2-dimethyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)-5-(2-hydroxyethylamino)benzoic acid; [0304]
(S)-3-(5'-fluoro-2,2-dimethyl-2'-oxospiro[cyclopropane-1,3
'-indoline]-1'-yl)-5-(2-hydroxyethylamino)benzoic acid; [0305]
(R)-methyl-3-(2-oxo-1,3-oxazolidin-3-yl)-5-(2-oxo-2'',3'',5'',6''-tetrahy-
drodispiro[indole-3,1'-cyclopropane-2',4''-pyran]-1(2H)-yl)benzoate;
[0306]
(S)-methyl-3-(2-oxo-1,3-oxazolidin-3-yl)-5-(2-oxo-2'',3'',5'',6''--
tetrahydrodispiro[indole-3,1'-cyclopropane-2',4''-pyran]-1(2H)-yl)benzoate-
; [0307]
(1S,2R)-1'-(3-fluorobenzyl)-2-(4-fluorophenyl)-2'-oxospiro[cyclop-
ropane-1,3'-indoline]-5'-carboxylic acid; [0308]
(1R,2S)-1'-(3-fluorobenzyl)-2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1-
,3'-indoline]-5'-carboxylic acid; [0309]
(1R,2R)-1'-(2-fluorobenzyl)-2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1-
,3'-indoline]-5'-carboxylic acid; [0310]
(1S,2S)-1'-(2-fluorobenzyl)-2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1-
,3'-indoline]-5'-carboxylic acid; [0311]
(1R,2R)-2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-car-
boxylic acid; [0312]
(1S,2S)-2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-car-
boxylic acid; [0313]
(1R,2S)-2-(4-cyanophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-carb-
oxylic acid; [0314]
(1S,2R)-2-(4-cyanophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-carb-
oxylic acid; [0315]
(1R,2R)-2-(4-cyanophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-carb-
oxylic acid; [0316]
(1S,2S)-2-(4-cyanophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-carb-
oxylic acid; [0317]
(1S,2R)-2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-car-
boxylic acid; and [0318]
(1R,2S)-2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-car-
boxylic acid.
[0319] Also particularly preferred is a compound of formula (I)
selected from the group consisting of: [0320]
(2S,1R)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)benzoic acid; [0321]
(1S,2R)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)benzoic acid; [0322]
(1S,2R)-3-((2-(3-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)benzoic acid; [0323]
(1R,2S)-3-((2-(3-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)benzoic acid; [0324]
(1S,2R)-3-((2-(4-cyanophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)methyl)benzoic acid; [0325]
(1R,2S)-3-((2-(4-cyanophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)methyl)benzoic acid; [0326]
(1S,2R)-3-((2-(4-(methylsulfonyl)phenyl)-2'-oxospiro[cyclopropane-1,3'-in-
doline]-1'-yl)methyl)benzoic acid; [0327]
(1R,2S)-3-((2-(4-(methylsulfonyl)phenyl)-2'-oxospiro[cyclopropane-1,3'-in-
doline]-1'-yl)methyl)benzoic acid; [0328]
(1S,2R)-3-((2-(2-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)benzoic acid; [0329]
(1R,2S)-3-((2-(2-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)benzoic acid; [0330]
(1S,2S)-3-((2-(2-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)benzoic acid; [0331]
(1R,2R)-3-((2-(2-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)benzoic acid; [0332]
(1S,2R)-3-((2-(3-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)benzoic acid; [0333]
(1R,2S)-3-((2-(3-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)benzoic acid; [0334]
(1S,2S)-3-((2'-oxo-2-(2-(trifluoromethyl)phenyl)-spiro[cyclopropane-1,3'--
indoline]-1'-yl)methyl)benzoic acid; [0335]
(1R,2R)-3-((2'-oxo-2-(2-(trifluoromethyl)phenyl)-spiro[cyclopropane-1,3'--
indoline]-1'-yl)methyl)benzoic acid; [0336]
(1S,2R)-((5'-chloro-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indo-
line]-1'-yl)methyl)benzoic acid; [0337]
(1R,2S)-((5'-chloro-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indo-
line]-1'-yl)methyl)benzoic acid; [0338]
(1S,2S)-3-((2-(4-chlorophenyl)-5'-fluoro-2'-oxospiro[cyclopropane-1,3'-in-
doline]-1'-yl)methyl)benzoic acid; [0339]
(1R,2R)-3-((2-(4-chlorophenyl)-5'-fluoro-2'-oxospiro[cyclopropane-1,3'-in-
doline]-1'-yl)methyl)benzoic acid; [0340]
(1S,2R)-3-((2'-oxo-2-(pyridin-3-yl)spiro[cyclopropane-1,3'-indoline]-1'-y-
l)methyl)benzoic acid; [0341]
(1R,2S)-3-((2'-oxo-2-(pyridin-3-yl)spiro[cyclopropane-1,3'-indoline]-1'-y-
l)methyl)benzoic acid; [0342]
(+)-3-((2-(4-chlorophenyl)-2-isopropyl-2'-oxospiro[(trans)-cyclopropane-1-
,3'-indoline]-1'-yl)methyl)benzoic acid; [0343]
(-)-3-((2-(4-chlorophenyl)-2-isopropyl-2'-oxospiro[(trans)-cyclopropane-1-
,3'-indoline]-1'-yl)methyl)benzoic acid; [0344]
(1S,2S)-3-((2-(4-chlorophenyl)-2-isopropyl-2'-oxospiro[cyclopropane-1,3'--
indoline]-1'-yl)methyl)benzoic acid; [0345]
(1R,2R)-3-((2-(4-chlorophenyl)-2-isopropyl-2'-oxospiro[cyclopropane-1,3'--
indoline]-1'-yl)methyl)benzoic acid; [0346]
(1S,2R)-6-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)picolinic acid; [0347]
(1R,2S)-6-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)picolinic acid; [0348]
(1S,2R)-6-((2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)picolinic acid; [0349]
(1R,2S)-6-((2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)picolinic acid; [0350]
(1S,2R)-2-(4-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]--
1'-yl)-1H-imidazol-1-yl)acetic acid; [0351]
(1R,2S)-2-(4-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]--
1'-yl)-1H-imidazol-1-yl)acetic acid; [0352]
(1S,2R)-3-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)benzoic acid; [0353]
(1R,2S)-3-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)benzoic acid; [0354]
(1S,2S)-3-(-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)benzoic acid; [0355]
(1R,2R)-3-(-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)benzoic acid; [0356]
(1S,2S)-3-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)-5-(2-oxooxazolidin-3-yl)benzoic acid; [0357]
(1R,2R)-3-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)-5-(2-oxooxazolidin-3-yl)benzoic acid; [0358]
(1S,2S)-2-chloro-5-((2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-ind-
oline]-1'-yl)methyl)benzoic acid; [0359]
(1R,2R)-2-chloro-5-((2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-ind-
oline]-1'-yl)methyl)benzoic acid; [0360]
(1R,2S)-4-((2'-oxo-2-(pyridin-3-yl)spiro[cyclopropane-1,3'-indoline]-1'-y-
l)methyl)benzoic acid; [0361]
(1S,2R)-4-((2'-oxo-2-(pyridin-3-yl)spiro[cyclopropane-1,3'-indoline]-1'-y-
l)methyl)benzoic acid; [0362]
(1S,2R)-4-((2-(4-cyanophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)methyl)benzoic acid; [0363]
(1R,2S)-4-((2-(4-cyanophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)methyl)benzoic acid; [0364]
(1R,2S)-4-((2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)benzoic acid; [0365]
(1R,2S)-4-((2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)benzoic acid; [0366]
(1S,2R)-2-chloro-5-((2-(4-chlorophenyl)-5'-fluoro-2'-oxospiro[cyclopropan-
e-1,3'-indoline]-1'-yl)methyl)benzoic acid; [0367]
(1R,2S)-2-chloro-5-((2-(4-chlorophenyl)-5'-fluoro-2'-oxospiro[cyclopropan-
e-1,3'-indoline]-1'-yl)methyl)benzoic acid; [0368]
(1R,2S)-3-((2-(3-chloro-4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-ind-
oline]-1'-yl)methyl)benzoic acid; [0369]
(1S,2R)-3-((2-(3-chloro-4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-ind-
oline]-1'-yl)methyl)benzoic acid; [0370]
(1R,2S)-6-((2-(4-cyanophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)methyl)-N-(cyclopropylsulfonyl)picolinamide; [0371]
(1S,2R)-6-((2-(4-cyanophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)methyl)-N-(cyclopropylsulfonyl)picolinamide; [0372]
(1S,2R)-4-((2-(4-cyanophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)methyl)-N-(cyclopropylsulfonyl)benzamide; [0373]
(1R,2S)-4-((2-(4-cyanophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)methyl)-N-(cyclopropylsulfonyl)benzamide; [0374]
(1R,2S)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)-N-(methylsulfonyl)benzamide; [0375]
(1S,2R)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)-N-(methylsulfonyl)benzamide; [0376]
(1R,2S)-3-((2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)-N-(methylsulfonyl)benzamide; [0377]
(1S,2R)-3-((2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)-N-(methylsulfonyl)benzamide; [0378]
(1S,2R)--N-(cyclopropylsulfonyl)-3-((2-(4-fluorophenyl)-2'-oxospiro[cyclo-
propane-1,3'-indoline]-1'-yl)methyl)benzamide; [0379]
(1R,2S)--N-(cyclopropylsulfonyl)-3-((2-(4-fluorophenyl)-2'-oxospiro[cyclo-
propane-1,3'-indoline]-1'-yl)methyl)benzamide; [0380]
(1S,2R)--N-(cyclopropylsulfonyl)-4-((2-(4-fluorophenyl)-2'-oxospiro[cyclo-
propane-1,3'-indoline]-1'-yl)methyl)benzamide; [0381]
(1R,2S)--N-(cyclopropylsulfonyl)-4-((2-(4-fluorophenyl)-2'-oxospiro[cyclo-
propane-1,3'-indoline]-1'-yl)methyl)benzamide; [0382]
(1S,2R)-1'-(3-fluorobenzyl)-2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1-
,3'-indoline]-5'-carboxylic acid; [0383]
(1R,2S)-1'-(3-fluorobenzyl)-2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1-
,3'-indoline]-5'-carboxylic acid; [0384]
(1R,2R)-1'-(2-fluorobenzyl)-2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1-
,3'-indoline]-5'-carboxylic acid; [0385]
(1S,2S)-1'-(2-fluorobenzyl)-2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1-
,3'-indoline]-5'-carboxylic acid; [0386]
(1R,2R)-2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-car-
boxylic acid; [0387]
(1S,2S)-2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-car-
boxylic acid; [0388]
(1R,2S)-2-(4-cyanophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-carb-
oxylic acid; [0389]
(1S,2R)-2-(4-cyanophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-carb-
oxylic acid; and [0390] (1R,2R) and
(1S,2S)-2-(4-cyanophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-carb-
oxylic acid.
[0391] The compounds of the present invention can be prepared by
any conventional means. Suitable processes for synthesizing these
compounds are provided in the schemes below. In the following
schemes, R.sup.5 is hydrogen, halogen, oxo-oxazolidinyl,
oxo-imidazolidinyl. R.sup.6 and R.sup.7 are independently selected
from hydrogen, alkyl, cycloalkyl, alkylsulfonyl,
cycloalkylsulfonyl, aminoalkyl and aminocycloalkyl. R.sup.1,
R.sup.2, R.sup.3, R.sup.4 and n are as defined above unless
otherwise indicated.
##STR00004## ##STR00005##
[0392] The compounds of formula Ia and Ib can be prepared according
to Scheme 1. Intermediate III is prepared as by the condensation
reaction between II and different aldehydes or ketones.
Cyclopropanation of III affords the intermediate IV. Alkylation
between IV and bromide V affords the ester VI. Ester VII can be
obtained by introducing R.sup.5 to the intermediate VI under copper
salts catalysts. Hydrolysis of the methyl ester VII gives the
corresponding acid Ia. Amide Ib can be prepared by the coupling
reaction between the acid Ia and amine VIII.
[0393] The condensation reaction between II and different aldehydes
is carried out in refluxing toluene or refluxing alcohol overnight
when using base such as piperidine or pyrrolidine as catalyst.
[0394] Cyclopropanation of III is carried out in organic solvents
such as DMSO at 50.degree. C. for several hours by treating
trimethylsulfoxoniumiodide with sodium hydride to generate
sulfurylide in situation.
[0395] In the third step outlined in Scheme 1, when n=1, alkylation
of IV and the bromide V affords the methyl ester VI by using bases
such as NaH, K.sub.2CO.sub.3 or Cs.sub.2CO.sub.3 in organic
solvents such as THF, DMF at room temperature for several hours;
when n=0, coupling of IV with arylbromide V can be carried out in
the presence of a copper source such as copper(I) iodide (CuI), in
combination with a ligand such as 2,2'-bipyridine, proline,
N,N'-dimethyl glycine or ethylene glycol, in the presence of a
suitable base such as triethylamine, sodium carbonate, potassium
carbonate, cesium carbonate, sodium methoxide, sodium
tert-butoxide, potassium tert-butoxide, sodium hydride or
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The reaction can be
carried out in a suitable solvent like acetonitrile,
dichloromethane, tetrahydrofuran, toluene, benzene, 1,4-dioxane,
N,N-dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidinone
at a temperature between 100.degree. C. and 180.degree. C. for 15
to 60 minutes under microwave irradiation. Alternatively, the
reactions can be carried out at a heated temperature such as
80.degree. C. for a longer reaction time without microwave
irradiation. (Ley, S. V. et al., Angew. Chem. Int. Ed. 42 (2003)
5400).
[0396] In the fourth step, introduction of R.sup.5 to the methyl
ester VI can be carried out in the presence of a copper source such
as copper(I) iodide (CuI), in combination with a ligand such as
2,2'-bipyridine, proline, N,N'-dimethyl glycine or ethylene glycol,
in the presence of a suitable base such as triethylamine, sodium
carbonate, potassium carbonate, cesium carbonate, sodium methoxide,
sodium tert-butoxide, potassium tert-butoxide, sodium hydride or
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The reaction can be
carried out in a suitable solvent like acetonitrile,
dichloromethane, tetrahydrofuran, toluene, benzene, 1,4-dioxane,
N,N-dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidinone
at a temperature between 100.degree. C. and 180.degree. C. for 15
to 60 minutes under microwave irradiation. Alternatively, the
reactions can be carried out at a heated temperature such as
80.degree. C. for a longer reaction time without microwave
irradiation. (Ley, S. V. et al., Angew. Chem. Int. Ed. 42 (2003)
5400).
[0397] Hydrolysis of the methyl esters VII can be carried out in
the presence of an aqueous inorganic base such as lithium
hydroxide, sodium hydroxide, or potassium hydroxide in a solvent
such as methanol, 1,4-dioxane or tetrahydrofuran at room
temperature for several hours to give the stereoisomers of Ia.
[0398] Conversion of the acids Ia to the corresponding amides Ib
with suitable amines VIII can be easily accomplished using well
known methods. The reaction is typically carried out in the
presence of a coupling reagent such as dicyclohexyl carbodiimide
(DCC), benzotriazol-1-yl-oxy-tris-pyrrolidinophosphonium
hexafluorophosphate (PyBop),
o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU),
o-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HBTU) or
1-ethyl-3-(3'-dimethylamino)carbodiimide hydrochloride salt (EDCI),
in the presence or absence of hydroxybenzotriazole (HOBt) or
N,N-dimethylaminopyridine (DMAP), in the presence of a base such as
triethylamine or N,N-diisopropyl ethylamine. The reaction can be
carried out in a solvent such as dichloromethane or
N,N-dimethylformamide at room temperature for several hours
(Montalbetti, C. A. G. N. et al., Tetrahedron 61 (2005) 10827).
##STR00006## ##STR00007##
[0399] The compounds of formula Ic and Id can be prepared according
to Scheme 2. The diazo compound X can be obtained by treating the
isatin IX with p-toluenesulfonyl hydrazide under basic conditions.
Cyclopropanation of alkene XI with diazo compound X by Rh catalyst
affords the intermediate XII. Alkylation or arylation of XII with
the bromide V afforded the methyl ester XIII. Introduction of
R.sup.5 to XIII by using copper salts as catalyst gave intermediate
XIV.
[0400] Hydrolysis of the methyl ester gives the corresponding acids
Ic. The hydrolysis can be carried out in the presence of an aqueous
inorganic base such as lithium hydroxide, sodium hydroxide, or
potassium hydroxide in a solvent such as methanol, 1,4-dioxane or
tetrahydrofuran at room temperature for several hours.
[0401] Conversion of the acids Ic to the corresponding amides Id
with suitable amines VIII can be easily accomplished using methods
well known to someone skilled in the art. The reaction is typically
carried out in the presence of a coupling reagent such as
dicyclohexyl carbodiimide (DCC),
benzotriazol-1-yl-oxy-tris-pyrrolidinophosphonium
hexafluorophosphate (PyBop),
o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU),
o-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HBTU) or
1-ethyl-3-(3'-dimethylamino)carbodiimide hydrochloride salt (EDCI),
in the presence or absence of hydroxybenzotriazole (HOBt) or
N,N-dimethylaminopyridine (DMAP), in the presence of a base such as
triethylamine or N,N-diisopropyl ethylamine. The reaction can be
carried out in a solvent such as dichloromethane or
N,N-dimethylformamide at room temperature for several hours
(Montalbetti, C. A. G. N. et al., Tetrahedron 61 (2005) 10827).
##STR00008##
[0402] The compounds of formula Ie can be prepared according to
Scheme 3. Alkylation of IV with the alkyl halide XV by using a base
such as NaH, K.sub.2CO.sub.3 or Cs.sub.2CO.sub.3 in organic solvent
such as THF or DMF at room temperature for several hours affords
the formula of Ie.
##STR00009##
[0403] The compounds of formula If can be prepared according to
Scheme 4. Alkylation of IV with the bromide XVI by using a base
such as NaH, K.sub.2CO.sub.3 or Cs.sub.2CO.sub.3 in organic solvent
such as THF or DMF at room temperature for several hours affords
the bromide XVII. If can be obtained by treating XVII with amine
VIII under basic condition such as NaH, K.sub.2CO.sub.3 or
Cs.sub.2CO.sub.3 in organic solvent such as THF or DMF at room
temperature.
##STR00010##
[0404] The compounds of formula Ig can be prepared according to
Scheme 5.
[0405] The alkylation between IV and the XVIII affords the
intermediate XIX, which can be treated with TFA to give aldehyde
XX. Amines Ig can be prepared by reductive amination between XX and
different amines VIII.
[0406] In the first step outlined in Scheme 5, alkylation between
IV and the iodide XVIII can be carried out by using bases such as
NaH, K.sub.2CO.sub.3 or Cs.sub.2CO.sub.3 in organic solvents such
as THF, DMF at room temperature for several hours.
[0407] In the second step outlined in Scheme 5, deprotection of XIX
with TFA can be carried out in solvent such as DCM or THF at room
temperature for several hours.
[0408] Reductive amination of XX with different amines VIII can be
carried out in organic solvents such as DCM, THF by using reducing
reagents such as NaBH.sub.4 or NaHB(OAc).sub.3 at room temperature
to afford formula Ig.
##STR00011##
[0409] The compounds of formula Ih and Ii can be prepared according
to Scheme 6. Ih and Ii can be obtained by alkylation of IV with XXI
by using bases such as NaH, K.sub.2CO.sub.3 or Cs.sub.2CO.sub.3 in
organic solvents such as THF or DMF at room temperature for several
hours.
##STR00012##
[0410] The compounds of formula Ij and Ik can be prepared according
to Scheme 7. The coupling between IV and idoimidazole XXII followed
by deprotection in the presence of TFA affords Ij. Subsequent
alkylation with XXIII affords formula XXIV. Finally, hydrolysis of
the methyl esters XXIV provides the corresponding acids Ik.
[0411] In the first step outlined in Scheme 7, the coupling
reaction can be carried out in the presence of a copper source such
as copper(I) iodide (CuI), in combination with a ligand such as
2,2'-bipyridine, proline, N,N'-dimethyl glycine or ethylene glycol,
in the presence of a suitable base such as triethylamine, sodium
carbonate, potassium carbonate, cesium carbonate, sodium methoxide,
sodium tert-butoxide, potassium tert-butoxide, sodium hydride or
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The reaction can be
carried out in a suitable solvent like acetonitrile,
dichloromethane, tetrahydrofuran, toluene, benzene, 1,4-dioxane,
N,N-dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidinone
at a temperature between 100.degree. C. and 180.degree. C. for 15
to 60 minutes under microwave irradiation. Alternatively, the
reactions can be carried out without the use of a microwave at a
raised temperature such as 80.degree. C. for a longer reaction time
(Ley, S. V. et al., Angew. Chem. Int. Ed. 42 (2003) 5400).
Deprotection can be carried out in organic solvent such as DCM or
THF with TFA at room temperature to afford stereoisomers Ij.
[0412] The alkylation of Ij with bromide XXIII is carried out by
using bases such as NaH, K.sub.2CO.sub.3 or Cs.sub.2CO.sub.3 in
organic solvents such as THF or DMF at room temperature for several
hours.
[0413] Finally, hydrolysis of the methyl ester gives the compounds
Ik. The hydrolysis can be carried out in the presence of an aqueous
inorganic base such as lithium hydroxide, sodium hydroxide, or
potassium hydroxide in a solvent such as methanol, 1,4-dioxane or
tetrahydrofuran at room temperature for several hours.
##STR00013##
[0414] The compounds of formula IL can be prepared according to
Scheme 8. The alkylation between IV and ethylene dibromide XXV
affords the bromides XXVI. Nucleophilic substitution reaction
between the ester XXVII and the bromide XXVI gives the methyl
esters XXVIII. Hydrolysis of the methyl esters furnishes the
corresponding acids IL.
[0415] In the first step outlined in Scheme 8, the condensation
between IV and ethylene dibromide can be carried out in organic
solvents (THF or DMF) by using bases such as NaH, K.sub.2CO.sub.3
or Cs.sub.2CO.sub.3 at room temperature for several hours.
[0416] In the second step outlined in Scheme 8, the substitution
reaction between the imidazole XXVII and XXVI can be carried out in
organic solvents such as THF or DMF by using bases such as NaH,
K.sub.2CO.sub.3 or Cs.sub.2CO.sub.3 at room temperature for several
hours.
[0417] Finally, hydrolysis of the methyl ester XXVII can afford the
compounds IL. The reaction can be carried out in the presence of an
aqueous inorganic bases such as lithium hydroxide, sodium
hydroxide, or potassium hydroxide in a solvent such as methanol,
1,4-dioxane or tetrahydrofuran at room temperature for several
hours.
[0418] The invention also relates to a process for the preparation
of a compound of formula (I) comprising one of the following
steps:
a) the reaction of a compound of formula (A)
##STR00014##
in the presence of R.sup.6R.sup.7NH and a coupling agent; b) the
reaction of a compound of formula (B)
##STR00015##
in the presence of Y--CH.sub.2--R and a base; c) the reaction of a
compound of formula (C)
##STR00016##
in the presence of R.sup.6R.sup.7NH and a base; d) the reaction of
a compound of formula (D)
##STR00017##
in the presence of R.sup.6R.sup.7NH and a reducing agent; e) the
reaction of a compound of formula (E)
##STR00018##
in the presence of a compound of formula (E1)
##STR00019##
and in the presence of a base; f) the reaction of a compound of
formula (F)
##STR00020##
in the presence of a base; g) the reaction of a compound of formula
(G)
##STR00021##
in the presence of a base; wherein R.sup.1, R.sup.2, R.sup.3,
R.sup.4 and n are defined as in any one of claims 1 to 8; wherein
R.sup.5 is hydrogen, halogen, oxo-oxazolidinyl or
oxo-imidazolidinyl; wherein R.sup.6 and R.sup.7 are independently
selected from hydrogen, alkyl, cycloalkyl, alkylsulfonyl,
cycloalkylsulfonyl, aminoalkyl and aminocycloalkyl; wherein X is
carbon or nitrogen; wherein Y is Br, I, or OTs; wherein Q is Br or
I; and wherein R is alkyl.
[0419] In step (a), the coupling reagent is for example
dicyclohexyl carbodiimide (DCC),
benzotriazol-1-yl-oxy-tris-pyrrolidinophosphonium
hexafluorophosphate (PyBop),
o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU),
o-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethylur onium
hexafluorophosphate (HBTU) or
1-ethyl-3-(3'-dimethylamino)carbodiimide hydrochloride salt (EDCI).
Step (a) can be carried out in the presence or absence of
hydroxybenzotriazole (HOBt) or N,N-dimethylaminopyridine (DMAP), in
the presence of a base such as triethylamine or N,N-diisopropyl
ethylamine. The reaction of step (a) can be carried out in a
solvent such as dichloromethane or N,N-dimethylformamide. The
reaction can be carried out at room temperature for several
hours.
[0420] In step (b), the base can be for example NaH,
K.sub.2CO.sub.3 or Cs.sub.2CO.sub.3. Step (b) can be carried out in
an organic solvent such as THF or DMF. This reaction can proceed at
room temperature for several hours.
[0421] In step (c), the base can be for example NaH,
K.sub.2CO.sub.3 or Cs.sub.2CO.sub.3. Step (c) can be done in an
organic solvent such as THF or DMF. The reaction can proceed at
room temperature.
[0422] The reaction of step (d) can be carried out in an organic
solvent such as DCM or THF. The reducing agent of step (d) can be
for example NaBH.sub.4 or NaHB(OAc).sub.3. The reaction can proceed
at room temperature.
[0423] In step (e), the base can be for example NaH,
K.sub.2CO.sub.3 or Cs.sub.2CO.sub.3. The solvent can be an organic
solvent such as THF or DMF. The reaction can be carried out at room
temperature for several hours.
[0424] In step (f), the base can be an inorganic base such as
lithium hydroxide, sodium hydroxide or potassium hydroxide. The
solvent of step (f) can be for example methanol, 1,4-dioxane or
tetrahydrofuran. The reaction can proceed at room temperature for
several hours.
[0425] In step (g), the base can be an inorganic base such as
lithium hydroxide, sodium hydroxide or potassium hydroxide. The
solvent of step (g) can be for example methanol, 1,4-dioxane or
tetrahydrofuran. The reaction can proceed at room temperature for
several hours.
[0426] The invention also relates to a compound of formula (I) for
use as therapeutically active substance.
[0427] The invention also relates to a pharmaceutical composition
comprising a compound of formula (I) and a therapeutically inert
carrier.
[0428] The use of a compound of formula (I) for the preparation of
medicaments useful in the treatment or prophylaxis diseases that
are related to AMPK regulation is an object of the invention.
[0429] The invention relates in particular to the use of a compound
of formula (I) for the preparation of a medicament for the
treatment or prophylaxis of obesity, hyperglycemia, dyslipidemia,
type 1 or type 2 diabetes, in particular type 2 diabetes.
[0430] Said medicaments, e.g. in the form of pharmaceutical
preparations, can be administered orally, e.g. in the form of
tablets, coated tablets, dragees, hard and soft gelatin capsules,
solutions, emulsions or suspensions. The administration can,
however, also be effected rectally, e.g. in the form of
suppositories, or parenterally, e.g. in the form of injection
solutions with an effective amount of a compound as defined
above.
[0431] The above-mentioned pharmaceutical composition can be
obtained by processing the compounds according to this invention
with pharmaceutically inert inorganic or organic carriers. Lactose,
corn starch or derivatives thereof, talc, stearic acids or its
salts can be used, for example, as such carriers for tablets,
coated tablets, dragees and hard gelatin capsules. Suitable
carriers for soft gelatin capsules are, for example, vegetable
oils, waxes, fats, semi-solid and liquid polyols and the like.
Depending on the nature of the active substance no carriers are,
however, usually required in the case of soft gelatin capsules.
Suitable carriers for the production of solutions and syrups are,
for example, water, polyols, glycerol, vegetable oil and the like.
Suitable carriers for suppositories are, for example, natural or
hardened oils, waxes, fats, semi-liquid or liquid polyols and the
like.
[0432] The pharmaceutical composition can, moreover, contain
preservatives, solubilizers, stabilizers, wetting agents,
emulsifiers, sweeteners, colorants, flavorants, salts for varying
the osmotic pressure, buffers, masking agents or antioxidants. They
can also contain still other therapeutically valuable
substances.
[0433] The dosage depends on various factors such as manner of
administration, species, age and/or individual state of health. The
doses to be administered daily are about 5-400 mg/kg, preferably
about 10-100 mg/kg, and can be taken singly or distributed over
several administrations.
[0434] A compound of formula (I) when manufactured according to the
above process is also an object of the invention.
[0435] Furthermore, the invention also relates to a method for the
treatment or prophylaxis of diseases that are related to AMPK
regulation, which method comprises administering an effective
amount of a compound of formula (I).
[0436] The invention further relates to a method for the treatment
or prophylaxis of obesity, hyperglycemia, dyslipidemia, type 1 or
type 2 diabetes, in particular type 2 diabetes, which method
comprises administering an effective amount of a compound of
formula (I).
[0437] Furthermore, the invention also relates to a compound of
formula (I) for the preparation of medicaments useful in the
treatment of cancer that are related to AMPK regulation and
provides a method for the treatment of cancer that are related to
AMPK regulation.
[0438] The invention will be illustrated by the following examples
which have no limiting character. Unless explicitly otherwise
stated, all reactions, reaction conditions, abbreviations and
symbols have the meanings well known to a person of ordinary skill
in organic chemistry.
EXAMPLES
Material and Instrumentation
[0439] Intermediates and final compounds were purified by flash
chromatography using one of the following instruments: i) Biotage
SP1 system and the Quad 12/25 Cartridge module. ii) ISCO
combi-flash chromatography instrument. Silica gel Brand and pore
size: i) KP-SIL 60 .ANG., particle size: 40-60 .mu.M; ii) CAS
registry NO: Silica Gel: 63231-67-4, particle size: 47-60 micron
silica gel; iii) ZCX from Qingdao Haiyang Chemical Co., Ltd, pore:
200-300 or 300-400.
[0440] Intermediates and final compounds were purified by
preparative HPLC on reversed phase column using X Bridge.TM. Perp
C.sub.18 (5 .mu.m, OBD.TM. 30.times.100 mm) column or SunFire.TM.
Perp C.sub.18 (5 m, OBD.TM. 30.times.100 mm) column.
[0441] LC/MS spectra were obtained using a MicroMass Plateform LC
(Waters.TM. alliance 2795-ZQ2000). Standard LC/MS conditions were
as follows (running time 6 min):
Acidic condition: A: 0.1% formic acid in H.sub.2O; B: 0.1% formic
acid in acetonitrile; Basic condition: A: 0.01% NH.sub.3.H.sub.2O
in H.sub.2O; B: acetonitrile; Neutral condition: A: H.sub.2O; B:
acetonitrile.
[0442] Mass spectra (MS): generally only ions which indicate the
parent mass are reported, and unless otherwise stated the mass ion
quoted is the positive mass ion-(M+H).sup.+.
[0443] The microwave assisted reactions were carried out in a
Biotage Initiator Sixty.
[0444] NMR Spectra were obtained using Bruke Avance 400 MHz.
[0445] All reactions involving air-sensitive reagents were
performed under an argon atmosphere. Reagents were used as received
from commercial suppliers without further purification unless
otherwise noted.
Example 1
(1R,2S) and
(1S,2R)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)benzoic acid
##STR00022##
[0446] Synthesis of
(Z)-3-(4-chloro-benzylidene)-1,3-dihydro-indol-2-one
[0447] Oxindole (0.13 g, 1 mmol), 4-chlorobenzaldehyde (0.17 g, 1.2
mmol) were mixed in alcohol; then pyrrolidine (0.17 ml, 2 mmol) was
added. The mixture was refluxed for 3 hours. The formed
precipitates was collected by filtration and washed with alcohol
twice to give the title compound as yellow powder (0.24 g, 92%).
LC/MS m/e calcd. for C.sub.15H.sub.10ClNO 255, observed
(M+H).sup.+: 256.1.
Synthesis of (1R,2S) and
(1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
##STR00023##
[0449] A solution of dimethylsulfoxoniummethylide was prepared as
under argon from a 60% NaH mineral oil dispersion (88 mg, 2.2
mmol), trimethylsulfoxoniumiodide (484 mg, 2.2 mmol), and DMSO (10
mL). After 20 min, a solution of
(Z)-3-(4-chloro-benzylidene)-1,3-dihydro-indol-2-one (510 mg, 2
mmol) in THF (5 mL) was added dropwise over 20 min. After stirring
for 1 hour at room temperature and another 1 hour at 50.degree. C.,
the solution was poured into ice-cold water (20 mL) and extracted
with ether (3.times.20 mL). The combined ethereal extracts were
washed with brine, dried and evaporated to an oil, which was
purified by flash column chromatography (gradient elution, 15-25%
ethyl acetate in petroleum ether to give the title compound as
white solid (333 mg, 62%). LC/MS m/e calcd. for
C.sub.16H.sub.12ClNO 269, observed (M+H).sup.+: 270.5. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 1.95 (dd, J=8.97, 4.67 Hz, 1H)
2.21 (dd, J=7.83, 4.80 Hz, 1H) 3.04 (t, J=8.46 Hz, 1H) 6.08 (d,
J=7.58 Hz, 1H) 6.59-6.71 (m, 1H) 6.87 (d, J=7.58 Hz, 1H) 7.01-7.10
(m, 1H) 7.27-7.33 (m, 2H) 7.33-7.40 (m, 2H) 10.59 (s, 1H).
Synthesis of racemic (1R,2S) and
(1S,2R)-methyl-3-(((2-(4-chlorophenyl)-2'-oxospiro[cyclo-propane-1,3'-ind-
oline]-1'-yl)methyl)benzoate
##STR00024##
[0451] (1R,2S) and
(1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
(2.1 mmol), methyl-(3-bromomethyl)-benzoate (725 mg, 3.15 mmol) and
Cs.sub.2CO.sub.3 (1.369 g, 4.2 mmol) were mixed in anhydrous DMF
and stirred at room temperature for 14 h. HPLC monitored the
reaction finished. The solvent was removed under reduced pressure.
The residue was purified by flash column chromatography (gradient
elution, 15-25% ethyl acetate in petroleum ether) to give the title
compound as white powder (586 mg, 67%). LC/MS m/e calcd. for
C.sub.25H.sub.20ClNO.sub.3: 417, observed (M+H).sup.+: 418.1
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 2.12 (dd, J=9.09,
4.80 Hz, 1H) 2.38 (dd, J=8.08, 5.05 Hz, 1H) 3.22 (t, J=8.59 Hz, 1H)
3.85 (s, 3H) 5.11 (s, 2H) 6.16 (d, J=7.33 Hz, 1H) 6.72 (t, J=7.58
Hz, 1H) 6.94 (d, J=7.83 Hz, 1H) 7.07 (t, J=7.71 Hz, 1H) 7.30-7.41
(m, 4H) 7.52 (t, J=7.71 Hz, 1H) 7.59-7.66 (m, 1H) 7.88 (d, J=7.58
Hz, 1H) 7.92 (s, 1H).
Synthesis of (1R,2S) and
(1S,2R)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)benzoic acid
##STR00025##
[0453] (1R,2S) and
(1S,2R)-methyl-3-(((2-(4-chlorophenyl)-2'-oxospiro[cyclo-propane-1,3'-ind-
oline]-1'-yl)methyl)benzoate (48 mg) was dissolved in 1 mL of
methanol; then 0.1 mL of water was added followed by lithium
hydroxide (10 mg). The mixture was stirred for 14 hours at room
temperature. The solvent was removed under reduced pressure. The
residue was dissolved in 2 mL of DMF and purified by preparative
HPLC to give the title compound as white powder (10 mg). LC/MS m/e
calcd. for C.sub.24H.sub.18ClNO.sub.3:403, observed (M+H).sup.+:
404.1 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 2.12 (dd,
J=9.09, 4.80 Hz, 1H) 2.40 (dd, J=7.96, 4.93 Hz, 1H) 3.19-3.24 (m,
1H) 5.10 (s, 2H) 6.17 (d, J=7.33 Hz, 1H) 6.72 (t, J=7.58 Hz, 1H)
6.95 (d, J=7.83 Hz, 1H) 7.08 (t, J=7.83 Hz, 1H) 7.30-7.41 (m, 4H)
7.50 (t, J=7.71 Hz, 1H) 7.60 (d, J=7.58 Hz, 1H) 7.82-7.89 (m, 2H)
13.04 (s, 1H).
Example 2
(1R,2R) and
(1S,2S)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)benzoic acid
##STR00026##
[0455] The title compound was prepared in analogy to Example 1
starting from methyl-(3-bromomethyl)-benzoate (commercially
available), (1R,2S) and
(1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.24H.sub.18ClNO.sub.3: 403.1, observed (M+H).sup.+: 404.2.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 2.26 (dd, J=8.97,
4.67 Hz, 1H) 2.34 (dd, J=8.34, 4.80 Hz, 1H) 3.34 (t, J=8.72 Hz, 1H)
4.84-5.01 (m, 2H) 6.95 (d, J=7.58 Hz, 1H) 7.04 (t, J=7.45 Hz, 1H)
7.14-7.23 (m, 2H) 7.29-7.37 (m, 4H) 7.41-7.52 (m, 2H) 7.76 (s, 1H)
7.83 (d, J=7.58 Hz, 1H) 13.05 (br. s., 1H).
Example 3
(1S,2R) and
(1R,2S)-3-((2-(3-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)benzoic acid
##STR00027##
[0457] The title compound was prepared in analogy to Example 1
starting from methyl-(3-bromomethyl)-benzoate (commercially
available), (1R,2S) and
(1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.24H.sub.18ClNO.sub.3: 403.1, observed (M+H).sup.+: 404.1.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 2.10 (dd, J=9.22,
4.93 Hz, 1H) 2.45 (dd, J=7.96, 4.93 Hz, 1H) 3.19-3.25 (m, 1H) 5.10
(s, 2H) 6.17 (d, J=7.33 Hz, 1H) 6.71 (t, J=7.58 Hz, 1H) 6.95 (d,
J=7.83 Hz, 1H) 7.08 (t, J=7.71 Hz, 1H) 7.27 (s, 1H) 7.30-7.37 (m,
2H) 7.42 (s, 1H) 7.50 (t, J=7.58 Hz, 1H) 7.60 (d, J=7.83 Hz, 1H)
7.80-7.99 (m, 2H).
Example 4
(1R,2R) and
(1S,2S)-((2-(4-(methylsulfonyl)phenyl)-2'-oxospiro[cyclopropane-1,3'-indo-
line]-1'-yl)methyl)benzoic acid
##STR00028##
[0459] The title compound was prepared in analogy to Example 1
starting from methyl-(3-bromomethyl)-benzoate (commercially
available), (1R,2R) and
(1S,2S)-2-(4-(methylsulfonyl)phenyl)spiro[cyclopropane-1,3'-indolin]--
2'-one prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.25H.sub.21NO.sub.5S: 447, observed (M+H).sup.+: 448.2.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 2.34 (dd, J=8.84,
4.80 Hz, 1H) 2.42 (dd, J=8.34, 4.80 Hz, 1H) 3.47 (t, J=8.72 Hz, 1H)
4.86-5.02 (m, 2H) 6.97 (d, J=7.83 Hz, 1H) 7.06 (t, J=7.58 Hz, 1H)
7.17-7.27 (m, 2H) 7.43-7.52 (m, 2H) 7.60 (d, J=8.34 Hz, 2H) 7.75
(s, 1H) 7.80-7.88 (m, 3H).
Example 5
(1S,2R) and
(1R,2S)-3-((2-(4-cyanophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)methyl)benzoic acid
##STR00029##
[0461] The title compound was prepared in analogy to Example 1
starting from methyl-(3-bromomethyl)-benzoate (commercially
available), (1S,2R) and
(1R,2S)-2-(4-cyanophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.25H.sub.18N.sub.2O.sub.3: 394, observed (M+H).sup.+: 395.1.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 2.16 (dd, J=8.84,
5.05 Hz, 1H) 2.45-2.50 (m, 1H) 3.26-3.33 (m, 1H) 5.10 (s, 1H) 6.18
(d, J=7.58 Hz, 1H) 6.71 (t, J=7.58 Hz, 1H) 6.95 (d, J=7.83 Hz, 1H)
7.08 (t, J=7.83 Hz, 1H) 7.47-7.57 (m, 3H) 7.60 (d, J=7.83 Hz, 1H)
7.79 (d, J=8.08 Hz, 2H) 7.83-7.89 (m, 2H) 13.04 (br. s., 1H).
Example 6
(1S,2R) and
(1R,2S)-2-chloro-5-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-ind-
oline]-1'-yl)methyl)benzoic acid
##STR00030##
[0463] The title compound was prepared in analogy to Example 1
starting from 5-Bromomethyl-2-chloro-benzoic acid methyl ester
(commercially available), (1S,2R) and
(1R,2S)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.24H.sub.17Cl.sub.2NO.sub.3: 437, observed (M+H).sup.+: 438.3.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 2.07-2.15 (m, 1H)
2.39 (dd, J=7.83, 5.05 Hz, 1H) 3.20 (t, J=8.72 Hz, 1H) 5.06 (s, 2H)
6.16 (d, J=7.58 Hz, 1H) 6.73 (t, J=7.58 Hz, 1H) 6.97 (d, J=7.83 Hz,
1H) 7.09 (t, J=7.83 Hz, 1H) 7.28-7.40 (m, 4H) 7.43-7.57 (m, 2H)
7.73 (s, 1H).
Example 7
(1S,2R) and
(1R,2S)-3-((2-(4-(methylsulfonyl)phenyl)-2'-oxospiro[cyclopropane-1,3'-in-
doline]-1'-yl)methyl)benzoic acid
##STR00031##
[0465] The title compound was prepared in analogy to Example 1
starting from methyl-(3-bromomethyl)-benzoate (commercially
available), (1R,2S) and
(1S,2R)-2-(4-(methylsulfonyl)phenyl)spiro[cyclopropane-1,3'-indolin]--
2'-one prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.25H.sub.21NO.sub.5S: 447, observed (M+H).sup.+: 448.2.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 2.18 (dd, J=9.09,
5.05 Hz, 1H) 2.51-2.55 (m, 1H) 3.20 (s, 3H) 3.32 (t, J=8.59 Hz, 1H)
5.06-5.17 (m, 2H) 6.22 (d, J=7.33 Hz, 1H) 6.71 (t, J=7.45 Hz, 1H)
6.95 (d, J=7.58 Hz, 1H) 7.08 (t, J=7.83 Hz, 1H) 7.51 (t, J=7.83 Hz,
1H) 7.62 (d, J=8.59 Hz, 3H) 7.84-7.90 (m, 4H) 13.06 (br.s.,
1H).
Example 8
(1S,2R) and
(1R,2S)-3-((2-(2-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)benzoic acid
##STR00032##
[0467] The title compound was prepared in analogy to Example 1
starting from methyl-(3-bromomethyl)-benzoate (commercially
available), (1R,2S) and
(1S,2R)-2-(2-fluorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.24H.sub.18FNO.sub.3: 387, observed (M+H).sup.+: 388.2.
.sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 2.22-2.34 (m, 2H)
3.21 (t, J=8.59 Hz, 1H) 5.06-5.28 (m, 2H) 6.02 (d, J=7.58 Hz, 1H)
6.62-6.71 (m, 1H) 6.88 (d, J=7.83 Hz, 1H) 6.91-6.99 (m, 1H)
7.01-7.16 (m, 1H) 7.25 (t, J=7.07 Hz, 1H) 7.29-7.37 (m, 1H) 7.46
(t, J=7.71 Hz, 1H) 7.50-7.57 (m, 2H) 7.96 (d, J=7.83 Hz, 1H) 8.05
(s, 1H).
Example 9
(1S,2S) and
(1R,2R)-3-((2-(2-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)benzoic acid
##STR00033##
[0469] The title compound was prepared in analogy to Example 1
starting from methyl-(3-bromomethyl)-benzoate (commercially
available), (1R,2R) and
(1S,2S)-2-(2-fluorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.24H.sub.18FNO.sub.3: 387, observed (M+H).sup.+: 388.1.
.sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 2.29 (dd, J=8.97,
4.67 Hz, 1H) 2.35 (dd, J=8.34, 4.80 Hz, 1H) 3.22 (t, J=8.72 Hz, 1H)
4.89-5.12 (m, 2H) 6.92 (d, J=7.83 Hz, 1H) 6.99-7.25 (m, 5H)
7.23-7.34 (m, 1H) 7.38-7.51 (m, 3H) 7.88-8.02 (m, 2H).
Example 10
(1S,2R) and
(1R,2S)-3-((2-(3-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)benzoic acid
##STR00034##
[0471] The title compound was prepared in analogy to Example 1
starting from methyl-(3-bromomethyl)-benzoate (commercially
available), (1R,2S) and
(1S,2R)-2-(3-fluorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.24H.sub.18FNO.sub.3: 387, observed (M+H).sup.+: 388.1.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 2.07-2.15 (m, 1H)
2.45 (dd, J=8.08, 5.05 Hz, 1H) 3.24 (t, J=8.46 Hz, 1H) 5.10 (s, 2H)
6.20 (d, J=7.58 Hz, 1H) 6.95 (d, J=7.83 Hz, 1H) 7.04-7.18 (m, 3H)
7.22 (d, J=10.11 Hz, 1H) 7.31-7.40 (m, 1H) 7.50 (t, J=7.71 Hz, 1H)
7.60 (d, J=7.83 Hz, 1H) 7.81-7.91 (m, 2H) 13.05 (s, 1H).
Example 11
(1S,2S) and
(1R,2R)-3-((2-(3-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)benzoic acid
##STR00035##
[0473] The title compound was prepared in analogy to Example 1
starting from methyl-(3-bromomethyl)-benzoate (commercially
available), (1R,2R) and
(1S,2S)-2-(3-fluorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.24H.sub.18FNO.sub.3: 387, observed (M+H).sup.+: 388.2.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 2.27 (dd, J=8.84,
4.80 Hz, 1H) 2.38 (dd, J=8.34, 4.80 Hz, 1H) 3.36-3.41 (m, 1H)
4.88-4.99 (m, 2H) 6.96 (d, J=7.83 Hz, 1H) 7.04 (t, J=7.83 Hz, 2H)
7.12-7.24 (m, 4H) 7.27 7.34 (m, 1H) 7.41-7.48 (m, 2H) 7.78 (s, 1H)
7.82 (d, J=6.57 Hz, 1H).
Example 12
(1S,2S) and
(1R,2R)-3-((2'-oxo-2-(2-(trifluoromethyl)phenyl)-spiro[cyclopropane-1,3'--
indoline]-1'-yl)methyl)benzoic acid
##STR00036##
[0475] The title compound was prepared in analogy to Example 1
starting from methyl-(2-(trifluoromethyl)phenyl)-benzoate
(commercially available), (1R,2R) and
(1S,2S)-2-(3-fluorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.25H.sub.18F.sub.3NO.sub.3: 437, observed (M+H).sup.+: 438.1.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 2.16 (dd, J=9.09,
5.05 Hz, 1H) 2.57 (dd, J=7.58, 5.56 Hz, 1H) 3.27 (t, J=8.21 Hz, 1H)
4.91-5.26 (m, 2H) 6.07 (d, J=7.33 Hz, 1H) 6.63 (t, J=7.20 Hz, 1H)
6.93 (d, J=7.83 Hz, 1H) 7.05 (t, J=7.33 Hz, 1H) 7.44-7.55 (m, 2H)
7.60 (t, J=7.96 Hz, 2H) 7.76 (t, J=7.58 Hz, 1H) 7.87 (t, J=8.84 Hz,
2H) 7.96 (s, 1H) 12.99 (br. s., 1H).
Example 13
(1S,2R) and
(1R,2S)-((5'-chloro-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indo-
line]-1'-yl)methyl)benzoic acid
##STR00037##
[0477] The title compound was prepared in analogy to Example 1
starting from methyl-(3-bromomethyl)-benzoate (commercially
available), (1R,2S) and
(1S,2R)-5'-chloro-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]--
2'-one prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.24H.sub.17Cl.sub.2NO.sub.3: 437, observed (M+H).sup.+: 438.2.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 2.16 (dd, J=9.09,
5.05 Hz, 1H) 2.56 (dd, J=8.08, 5.05 Hz, 1H) 3.26 (t, J=8.59 Hz, 1H)
5.10 (s, 2H) 6.19 (d, J=2.02 Hz, 1H) 6.96 (d, J=8.34 Hz, 1H) 7.14
(dd, J=8.34, 2.02 Hz, 1H) 7.39 (q, J=8.42 Hz, 4H) 7.50 (t, J=7.58
Hz, 1H) 7.54-7.61 (m, 1H) 7.81-7.89 (m, 2H) 13.07 (s, 1H).
Example 14
(1R,2R) and
(1S,2S)-3-((5'-chloro-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-in-
doline]-1'-yl)methyl)benzoic acid
##STR00038##
[0479] The title compound was prepared in analogy to Example 1
starting from methyl-(3-bromomethyl)-benzoate (commercially
available), (1R,2R) and
(1S,2S)-5'-chloro-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]--
2'-one prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.24H.sub.17Cl.sub.2NO.sub.3: 437, observed (M+H).sup.+: 438.1.
.sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 2.32 (dd, J=9.09,
5.05 Hz, 1H) 2.44 (dd, J=8.59, 5.05 Hz, 1H) 3.37 (t, J=8.97 Hz, 1H)
4.82-5.10 (m, 4H) 6.87 (d, J=8.08 Hz, 1H) 7.19 (d, J=2.02 Hz, 1H)
7.21 (s, 1H) 7.31 (s, 4H) 7.39-7.49 (m, 2H) 7.85 (s, 1H) 7.93 (d,
J=7.07 Hz, 1H).
Example 15
(1R,2R) and
(1S,2S)-3-((5'-bromo-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-ind-
oline]-1'-yl)methyl)benzoic acid
##STR00039##
[0481] The title compound was prepared in analogy to Example 1
starting from methyl-(3-bromomethyl)-benzoate (commercially
available), (1R,2R) and
(1S,2S)-5'-bromo-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2-
'-one prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.24H.sub.17BrClNO.sub.3: 481, observed (M+H).sup.+: 482.1.
.sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 2.25-2.37 (m, 2H)
3.34-3.40 (m, 1H) 5.05-5.21 (m, 2H) 6.19 (d, J=1.77 Hz, 1H) 6.83
(d, J=8.34 Hz, 1H) 7.20-7.30 (m, 3H) 7.32-7.40 (m, 2H) 7.50 (t,
J=7.71 Hz, 1H) 7.60 (d, J=7.83 Hz, 1H) 7.90-8.01 (m, 2H).
Example 16
(1S,2R) and
(1R,2S)-3-((5'-bromo-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-ind-
oline]-1'-yl)methyl)benzoic acid
##STR00040##
[0483] The title compound was prepared in analogy to Example 1
starting from methyl-(3-bromomethyl)-benzoate (commercially
available) and racemic (1S,2R) and
(1R,2S)-5'-bromo-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-on-
e prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.24H.sub.17BrClNO.sub.3: 481, observed (M+H).sup.+: 482.1.
.sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 2.33 (dd, J=8.97,
4.93 Hz, 1H) 2.44 (dd, J=8.84, 5.05 Hz, 1H) 3.38 (t, J=8.84 Hz, 1H)
4.85 (s, 1H) 5.05 (d, J=16.17 Hz, 1H) 6.81-6.86 (m, 1H) 7.31 (s,
4H) 7.33-7.38 (m, 2H) 7.41-7.49 (m, 2H) 7.85 (s, 1H) 7.94 (d,
J=7.07 Hz, 1H).
Example 17
(1S,2S) and
(1R,2R)-3-((2-(4-cyanophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)methyl)benzoic acid
##STR00041##
[0485] The title compound was prepared in analogy to Example 1
starting from methyl-(3-bromomethyl)-benzoate (commercially
available), (1S,2S) and
(1R,2R)-2-(4-cyanophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.25H.sub.18N.sub.2O.sub.3: 394, observed (M+H).sup.+: 394.2.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta.ppm 2.23 (dd, J=8.84, 5.05
Hz, 1H) 2.52 (dd, J=8.59, 5.31 Hz, 1H) 3.23 (t, J=8.72 Hz, 1H) 4.95
(d, J=61.89 Hz, 2H) 6.82 (d, J=7.83 Hz, 1H) 7.00-7.05 (m, 1H) 7.10
(0=7.45 Hz, 1H) 7.19-7.26 (m, 1H) 7.43 (s, 2H) 7.49 (d, J=8.08 Hz,
2H) 7.65 (d, J=8.08 Hz, 2H) 7.96 (s, 1H) 8.02 (d, J=7.33 Hz,
1H).
Example 18
(1S,2R) and
(1R,2S)-3-((2-(3-methoxyphenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1-
'-yl)methyl)benzoic acid
##STR00042##
[0487] The title compound was prepared in analogy to Example 1
starting from methyl-(3-bromomethyl)-benzoate (commercially
available), (1R,2S) and
(1S,2R)-2-(3-methoxyphenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.25H.sub.21NO.sub.4: 399, observed (M+H).sup.+: 400.1. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 2.09 (q, J=4.46 Hz, 1H) 2.41
(dd, J=8.08, 4.80 Hz, 1H) 3.20 (t, J=8.84 Hz, 1H) 3.72 (s, 3H) 5.10
(s, 2H) 6.22 (d, J=7.33 Hz, 1H) 6.70 (t, J=7.58 Hz, 1H) 6.81-6.89
(m, 3H) 6.94 (d, J=7.83 Hz, 1H) 7.06 (t, J=7.71 Hz, 1H) 7.22 (t,
J=8.08 Hz, 1H) 7.50 (t, J=7.58 Hz, 1H) 7.60 (d, J=7.58 Hz, 1H) 7.85
(d, J=7.83 Hz, 1H) 7.89 (s, 1H) 13.04 (br. s., 1H).
Example 19
(1S,2S) and
(1R,2R)-3-((2-(3-methoxyphenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1-
'-yl)methyl)benzoic acid
##STR00043##
[0489] The title compound was prepared in analogy to Example 1
starting from methyl-(3-bromomethyl)-benzoate (commercially
available), (1R,2R) and
(1S,2S)-2-(3-methoxyphenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.25H.sub.21NO.sub.4: 399, observed (M+H).sup.+: 400.2. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 2.24 (dd, J=9.09, 4.55 Hz,
1H) 2.34 (dd, J=8.59, 4.55 Hz, 1H) 3.31 (t, J=8.72 Hz, 1H) 3.72 (s,
3H) 4.88-5.02 (m, 2H) 6.76-6.82 (m, 1H) 6.85-6.90 (m, 2H) 6.95 (d,
J=7.58 Hz, 1H) 7.04 (t, J=7.45 Hz, 1H) 7.19 (t, J=7.96 Hz, 3H)
7.39-7.49 (m, 2H) 7.77-7.88 (m, 2H) 13.02 (br.s., 1H).
Example 20
(1S,2S) and
(1R,2R)-3-((2-(4-methoxyphenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1-
'-yl)methyl)benzoic acid
##STR00044##
[0491] The title compound was prepared in analogy to Example 1
starting from methyl-(3-bromomethyl)-benzoate (commercially
available), (1R,2R) and
(1S,2S)-2-(4-methoxyphenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.25H.sub.21NO.sub.4: 399, observed (M+H).sup.+: 400.1. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 2.23 (dd, J=8.84, 4.55 Hz,
1H) 2.30 (dd, J=8.46, 4.67 Hz, 1H) 3.26 (t, J=8.72 Hz, 1H) 3.73 (s,
3H) 4.85-5.02 (m, 2H) 6.84 (d, J=8.59 Hz, 1H) 6.93 (d, J=7.58 Hz,
1H) 7.03 (t, J=7.58 Hz, 1H) 7.14-7.27 (m, 4H) 7.42-7.52 (m, 2H)
7.77 (s, 1H) 7.82 (d, J=7.07 Hz, 1H) 13.02 (br. s., 1H).
Example 21
(1S,2R) and
(1R,2S)-3-((2-(4-methoxyphenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1-
'-yl)methyl)benzoic acid
##STR00045##
[0493] The title compound was prepared in analogy to Example 1
starting from methyl-(3-bromomethyl)-benzoate (commercially
available), (1R,2S) and
(1S,2R)-2-(4-methoxyphenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.25H.sub.21NO.sub.4: 399, observed (M+H).sup.+: 400.1. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 2.05-2.14 (m, 1H) 2.33 (dd,
J=7.96, 4.67 Hz, 1H) 3.17 (t, J=8.46 Hz, 1H) 3.73 (s, 3H) 5.10 (d,
J=2.27 Hz, 2H) 6.15 (d, J=7.33 Hz, 1H) 6.69 (t, J=7.20 Hz, 1H) 6.87
(d, J=8.59 Hz, 1H) 6.93 (d, J=7.58 Hz, 1H) 7.05 (t, J=7.33 Hz, 1H)
7.22 (d, J=8.59 Hz, 2H) 7.50 (t, J=7.58 Hz, 1H) 7.60 (d, J=7.83 Hz,
1H) 7.84-7.90 (m, 2H) 13.05 (br. s., 1H).
Example 22
(1S,2R) and
(1R,2S)-3-((2-(4-chlorophenyl)-5'-fluoro-2'-oxospiro[cyclopropane-1,3'-in-
doline]-1'-yl)methyl)benzoic acid
##STR00046##
[0495] The title compound was prepared in analogy to Example 1
starting from methyl-(3-bromomethyl)-benzoate (commercially
available), (1S,2R) and
(1R,2S)-2-(4-chlorophenyl)-5'-fluorospiro[cyclopropane-1,3'-indolin]--
2'-one prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.24H.sub.17ClFNO.sub.3: 421, observed (M+H).sup.+: 422.1.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 2.17 (dd, J=9.09,
4.80 Hz, 1H) 2.45-2.50 (m, 1H) 3.26 (t, J=8.59 Hz, 1H) 5.03-5.17
(m, 2H) 5.98-6.05 (m, 1H) 6.88-6.97 (m, 2H) 7.38 (q, J=8.59 Hz, 4H)
7.47-7.54 (m, 1H) 7.55-7.63 (m, 1H) 7.81-7.91 (m, 2H) 13.05 (s,
1H).
Example 23
(1S,2S) and
(1R,2R)-3-((2-(4-chlorophenyl)-5'-fluoro-2'-oxospiro[cyclopropane-1,3'-in-
doline]-1'-yl)methyl)benzoic acid
##STR00047##
[0497] The title compound was prepared in analogy to Example 1
starting from methyl-(3-bromomethyl)-benzoate (commercially
available), (1S,2S) and
(1R,2R)-2-(4-chlorophenyl)-5'-fluorospiro[cyclopropane-1,3'-indolin]--
2'-one prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.24H.sub.17ClFNO.sub.3: 421, observed (M+H).sup.+: 422.1.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 2.28-2.42 (m, 2H)
3.41 (t, J=8.84 Hz, 1H) 4.82-5.02 (m, 2H) 6.86-6.96 (m, 1H)
6.98-7.07 (m, 1H) 7.19 (dd, J=8.59, 2.53 Hz, 1H) 7.34 (s, 4H)
7.41-7.53 (m, 2H) 7.74 (s, 1H) 7.83 (d, J=6.82 Hz, 1H) 13.04 (br.
s., 1H).
Example 24
(1S,2R) and
(1R,2S)-3-O-2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)benzoic acid
##STR00048##
[0499] The title compound was prepared in analogy to Example 1
starting from methyl-(3-bromomethyl)-benzoate (commercially
available) and racemic
(1S,2R)-2-(4-fluorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.24H.sub.18FNO.sub.3: 421, observed (M+H).sup.+: 422.1.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 2.12 (dd, J=9.09,
4.80 Hz, 1H) 2.38 (dd, J=7.83, 5.05 Hz, 1H) 3.21 (t, J=8.59 Hz, 1H)
5.10 (s, 2H) 6.12 (d, J=7.58 Hz, 1H) 6.70 (t, J=7.58 Hz, 1H) 6.94
(d, J=7.83 Hz, 1H) 7.07 (t, J=7.71 Hz, 1H) 7.14 (t, J=8.72 Hz, 2H)
7.35 (dd, J=8.34, 5.56 Hz, 2H) 7.50 (t, J=7.58 Hz, 1H) 7.60 (d,
J=7.58 Hz, 1H) 7.81-7.90 (m, 2H) 13.03 (br. s., 1H).
Example 25
(1S,2R) and
(1R,2S)-3-((2'-oxo-2-(pyridin-3-yl)spiro[cyclopropane-1,3'-indoline]-1'-y-
l)methyl)benzoic acid
##STR00049##
[0501] The title compound was prepared in analogy to Example 1
starting from methyl-(3-bromomethyl)-benzoate (commercially
available), (1S,2R) and
(1R,2S)-2-(pyridin-3-yl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as were in Scheme 1. LC/MS m/e calcd. for
C.sub.23H.sub.18N.sub.2O.sub.3: 370, observed (M+H).sup.+: 371.1.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 2.18 (dd, J=8.59,
5.05 Hz, 1H) 3.27 (t, J=8.59 Hz, 2H) 5.11 (s, 2H) 6.14 (d, J=7.33
Hz, 1H) 6.71 (t, J=7.45 Hz, 1H) 6.97 (d, J=7.58 Hz, 1H) 7.05-7.15
(m, 1H) 7.46-7.57 (m, 2H) 7.61 (d, J=7.33 Hz, 1H) 7.90 (br. s., 1H)
7.86 (d, J=7.33 Hz, 2H) 8.57 (br. s., 1H) 8.66 (br.s., 1H).
Example 26
(1S,2S) and
(1R,2R)-3-((-2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1-
'-yl)methyl)benzoic acid
##STR00050##
[0503] The title compound was prepared in analogy to Example 1
starting from methyl-(3-bromomethyl)-benzoate (commercially
available), (1S,2S) and
(1R,2R)-2-(4-fluorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.24H.sub.18FNO.sub.3: 421, observed (M+H).sup.+: 422.1.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 2.26 (dd, J=8.97,
4.67 Hz, 1H) 2.33 (dd, J=8.34, 4.80 Hz, 1H) 3.14-3.29 (m, 1H)
4.83-5.02 (m, 2H) 6.95 (d, J=7.58 Hz, 1H) 7.04 (t, J=7.33 Hz, 1H)
7.10 (t, J=8.72 Hz, 2H) 7.15-7.23 (m, 2H) 7.35 (dd, J=8.21, 5.68
Hz, 2H) 7.40-7.53 (m, 2H) 7.76 (s, 1H) 7.82 (d, J=7.33 Hz, 1H).
Example 27
(1S,2S) and
(1R,2R)-3-((2-(4-chlorophenyl)-2-isopropyl-2'-oxospiro[cyclopropane-1,3'--
indoline]-1'-yl)methyl)benzoic acid
##STR00051##
[0504] Synthesis of 1-(4-iodo-phenyl)-2-methyl-propan-1-one
[0505] A 2.0 M solution of Isopropylmagnesium chloride (10 ml, 20
mmol) was added dropwise (30 min), under nitrogen, to a stirred
solution of freshly distilled 4-iodobenzoyl chloride (5.32 g, 20
mmol) and Fe(acac).sub.3 (0.35 g, 1 mmol) in 150 ml of dry THF at
room temperature. After addition, the stirring was continued for 10
min at the same temperature. The reaction was quenched by pouring
the mixture into dilute hydrochloric acid and extracted with
several portions of ether. The combined ether extracts were washed
with aq. NaHCO.sub.3, water, and dried over Na.sub.2SO.sub.4.
Removal of the organic solvents under vacuum gave the product as
colorless oil. And the crude product was used for the next step
without further purification.
Synthesis of 1-iodo-4-(2-methyl-1-methylene-propyl)-benzene
[0506] To a solution of 7.07 g (20 mmol) of
methyltriphenylphosphonium bromide in 50 mL of dry THF at 0.degree.
C. were added t-BuLi of (14.7 ml, 1.5 M in hexane) and the solution
turned brown. After 1 hour of stirring at 0.degree. C., the crude
1-(4-Iodo-phenyl)-2-methyl-propan-1-one from the last step in 20 mL
of THF were added dropwise and the solution was stirred for 14
hours at room temperature. After cooling to ca.20.degree. C., 52 mL
of water were added and the solution was extracted with
dichloromethane (3.times.50 mL). The organic layer was dried over
MgSO.sub.4 and the solvent was removed to give the crude title
compound as white solid. The product was used for the next step
without further purification.
Synthesis of 3-diazo-5-fluoroindolin-2-one
[0507] 5-Fluoroisatin (64.3 mmol) was suspended in MeOH (300 mL).
The suspension was heated to reflux where upon a deep-red solution
was obtained. To this hot solution was added tosylhydrazine (64.8
mmol) in one portion. A yellow product started precipitating from
the hot mixture. The reaction was allowed to cool to room
temperature and the pale tosylhydrazone was filtered off. The
product was used for the next step without further
purification.
[0508] The tosylhydrazone (38.1 mmol) was treated with a solution
of NaOH (76.1 mmol) in water 375 mL. The reaction mixture was
stirred for 15 hours in a water bath at 50.degree. C. and then
allowed to cool to room temperature. The reaction mixture was
neutralized by addition of dry ice whereupon diazo compound was
precipitated. (5.94 g, 88%).
Synthesis of (1S,2S) and
(1R,2R)-5'-fluoro-2-(4-iodophenyl)-2-isopropylspiro[cyclopropane-1,3'-ind-
olin]-2'-one
##STR00052##
[0510] The 3-diazo-5-fluoroindolin-2-one (0.177 g, 1 mmol) and
Rh(OAc).sub.2 dimer (2.2 mg) were placed into a Schlenk tube under
Argon atmosphere, then dissolved in dry benzene (3 mL). The mixture
was heated to 80.degree. C. for 10 minutes. The
1-iodo-4-(3-methylbut-1-en-2-yl)benzene (0.544 g) was dissolved in
dry THF (2 mL) and added into the mixture in one portion. The
mixture was concentrated in vacuo, the residue was purified by
flash column chromatography (Petroleum ether: AcOEt=5:1) to give
the title compound as white powder (0.446 g, 53%). LC/MS m/e calcd.
for C.sub.19H.sub.17FINO: 421, observed (M+H).sup.+: 422.1.
Synthesis of (1S,2S) and
(1R,2R)-methyl-3-((-5'-fluoro-2-(4-iodophenyl)-2-isopropyl-2'-oxospiro[cy-
clopropane-1,3'-indoline]-1'-yl)methyl)benzoate
##STR00053##
[0512] (1S,2S) and
(1R,2R)-5'-fluoro-2-(4-iodophenyl)-2-isopropylspiro[cyclopropane-1,3'-ind-
olin]-2'-one (0.88 g, 2.1 mmol), methyl-(3-bromomethyl)-benzoate
(725 mg, 3.15 mmol) and Cs.sub.2CO.sub.3 (1.37 g, 4.2 mmol) were
mixed in anhydrous DMF and stirred at room temperature for 14
hours. The solvent was removed under reduced pressure. The residue
was purified by flash column chromatography (gradient elution,
15-25% ethyl acetate in petroleum ether) to give the title product
as white solid (1.10 g, 92%). LC/MS m/e calcd. for
C.sub.28H.sub.25FINO: 569, observed (M+H).sup.+: 570.1
Synthesis of (1S,2S) and
(1R,2R)-methyl-3-((2-(4-cyanophenyl)-5'-fluoro-2-isopropyl-2'-oxospiro[cy-
clopropane-1,3'-indoline]-1'-yl)methyl)benzoate
##STR00054##
[0514] A solution of (1S,2S) and
(1R,2R)-methyl-3-((-5'-fluoro-2-(4-iodophenyl)-2-isopropyl-2'-oxospiro[cy-
clopropane-1,3'-indoline]-1'-yl)methyl)benzoate (1.35 g, 2.4 mmol),
NaCN (240 mg, 4.9 mmol), CuI (50 mg, 0.3 mmol) and
Pd(PPh.sub.3).sub.4 (140 mg, 0.12 mmol) in tetrahydrofuran (9.0 mL)
was stirred at 65.degree. C. for 2 hours. The mixture was cooled to
room temperature and extracted with ethyl acetate and washed with
brine, dried over anhydrous sodium sulfate, concentrated in vacuo.
Purification by flash column chromatography eluting with
Hexane/ethyl acetate (8:1 to 4:1) to afford light yellow oil (500
mg, yield 45.5%) LC/MS m/e calcd. for
C.sub.29H.sub.25FN.sub.2O.sub.3: 469, observed (M+H).sup.+:
469.2
Synthesis of (1S,2S) and
(1R,2R)-3-((2-(4-cyanophenyl)-5'-fluoro-2-isopropyl-2'-oxospiro[cycloprop-
ane-1,3'-indoline]-1'-yl)methyl)benzoic acid
##STR00055##
[0516] To a solution of (1S,2S) and
(1R,2R)-methyl-3-((2-(4-cyanophenyl)-5'-fluoro-2-isopropyl-2'-oxospiro[cy-
clopropane-1,3'-indoline]-1'-yl)methyl)benzoate (500 mg, 1.1 mmol)
in tetrahydrofuran (10 mL) was added 30% sodium hydroxide in water
(3 mL) at room temperature and the mixture was stirred at that
temperature for 16 hours. The mixture was neutralized with 2 N
aqueous hydrochloric acid solution, diluted with ethyl acetate (50
mL), washed with water, dried over anhydrous sodium sulfate and
then concentrated in vacuo. Purification by waters automated flash
system (column: Xterra 30 mm.times.100 mm, sample manager 2767,
pump 2525, detector: ZQ mass and UV 2487, solvent system:
acetonitrile and 0.1% trifluoro-acetic acid in water) afforded the
title compound (270 mg, 59.5%) as a white solid: LC/MS m/e calcd.
for C.sub.28H.sub.23FN.sub.2O.sub.3: 454, observed (M+H).sup.+:
455.2 .sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 7.97 (s, 1H),
7.94 (d, J=7.83 Hz, 1H), 7.85 (dd, J=7.96, 1.64 Hz, 1H), 7.67 (dd,
J=7.96, 1.39 Hz, 1H), 7.61 (d, J=7.58 Hz, 1H), 7.48 (q, J=7.83 Hz,
2H), 6.74-6.86 (m, 3H), 5.28 (d, J=15.92 Hz, 1H), 5.17 (dd, J=8.72,
2.40 Hz, 1H), 4.97 (d, J=16.17 Hz, 1H), 3.04 (dt, J=13.64, 6.82 Hz,
1H), 2.23-2.28 (m, 1H), 2.20-2.23 (m, 1H), 0.92 (d, J=7.07 Hz, 3H),
0.81 (d, J=6.82 Hz, 3H).
Example 28
(1S,2S) and
(1R,2R)-3-((2-(4-cyanophenyl)-2-methyl-2'-oxospiro[cyclopropane-1,3'-indo-
line]-1'-yl)methyl)benzoic acid
##STR00056##
[0518] The title compound was prepared in analogy to Example 27
starting from methyl-(3-bromomethyl)-benzoate (commercially
available), (1S,2S) and
(1R,2R)-4-(2-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-2-yl)benz-
onitrile prepared as in Scheme 2. LC/MS m/e calcd. for
C.sub.26H.sub.20FN.sub.2O.sub.3: 408, observed (M+H).sup.+: 409.1
.sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 7.96 (d, J=7.58 Hz,
1H) 7.87 (s, 1H) 7.67 (d, J=8.08 Hz, 2H) 7.53-7.57 (m, 1H) 7.48 (t,
J=7.71 Hz, 3H) 7.32 (d, J=7.58 Hz, 1H) 7.26 (t, J=7.71 Hz, 1H) 7.11
(t, J=7.58 Hz, 1H) 6.97 (d, J=7.83 Hz, 1H) 5.12 (d, J=15.92 Hz, 1H)
4.75 (d, J=15.92 Hz, 1H) 2.49 (d, J=5.05 Hz, 1H) 2.10 (d, J=5.05
Hz, 1H) 1.72 (s, 3H).
Example 29
(1S,2R) and
(1R,2S)-3-((2-(4-cyanophenyl)-2-methyl-2'-oxospiro[cyclopropane-1,3'-indo-
line]-1'-yl)methyl)benzoic acid
##STR00057##
[0520] The title compound was prepared in analogy to Example 27
starting from methyl-(3-bromomethyl)-benzoate (commercially
available) and racemic (1S,2R) and
(1R,2S)-4-(2-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-2-yl)benzonit-
rile prepared as in Scheme 2. LC/MS m/e calcd. for
C.sub.26H.sub.20FN.sub.2O.sub.3: 408, observed (M+H).sup.+: 409.1
.sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 7.91-7.97 (m, 2H)
7.57 (br. s., 4H) 7.47 (t, J=7.33 Hz, 2H) 7.04 (t, J=7.83 Hz, 1H)
6.86 (d, J=8.08 Hz, 1H) 6.61 (t, J=7.71 Hz, 1H) 5.61 (d, J=7.58 Hz,
1H) 5.18-5.26 (m, 1H) 5.01-5.10 (m, 1H) 2.37 (d, J=5.05 Hz, 1H)
2.19 (d, J=5.05 Hz, 1H) 1.88 (s, 3H).
Example 30 and Example 31
(-)-3-((2-(4-chlorophenyl)-2-isopropyl-2'-oxospiro[(trans)-cyclopropane-1,-
3'-indoline]-1'-yl)methyl)benzoic acid and
(+)-3-((2-(4-chlorophenyl)-2-isopropyl-2'-oxospiro[(trans)-cyclopropane-1-
,3'-indoline]-1'-yl)methyl)benzoic acid
##STR00058##
[0522] The tile compounds were obtained by separation of the
stereoisomers of (1S,2S) and
(1R,2R)-3-((2-(4-chlorophenyl)-2-isopropyl-2'-oxospiro[cyclopropane-1,3'--
indoline]-1'-yl)methyl)benzoic acid (Example 32) by chiral
preparative HPLC (Chiralpak AD) eluting with a mixture of
n-heptane/5% isopropanol.
(+)-3-((2-(4-chlorophenyl)-2-isopropyl-2'-oxospiro[(trans)-cyclopropane-1,-
3'-indoline]-1'-yl)methyl)benzoic acid
[0523] LC/MS m/e calcd. for C.sub.27H.sub.24ClNO.sub.3: 445,
observed (M+H).sup.+: 446.7. .sup.1H NMR (400 MHz, MeOD) .delta.ppm
8.01 (s, 1H) 7.96 (d, J=7.58 Hz, 1H) 7.64 (d, J=7.83 Hz, 1H)
7.46-7.52 (m, 3H) 7.05-7.12 (m, 1H) 7.10 (d, J=8.08 Hz, 1H) 6.89
(d, J=7.83 Hz, 1H) 6.64 (t, J=7.58 Hz, 1H) 6.53 (d, J=8.34 Hz, 1H)
5.50-5.53 (m, 2H) 5.31 (d, J=15.92 Hz, 1H) 5.00 (d, J=16.17 Hz, 1H)
3.01 (dt, J=13.83, 6.85 Hz, 1H) 2.20 (d, J=4.80 Hz, 1H) 2.15 (d,
J=4.80 Hz, 1H) 0.94 (d, J=7.07 Hz, 3H) 0.82 (d, J=6.82 Hz, 3H).
[.alpha.].sub.D.sup.25=+114 (c=5 mg/mL, CH.sub.2Cl.sub.2).
(-)-3-((2-(4-chlorophenyl)-2-isopropyl-2'-oxospiro[[(trans)-cyclopropane-1-
,3'-indoline]-1'-yl)methyl)benzoic acid
[0524] LC/MS m/e calcd. for C.sub.27H.sub.24ClNO.sub.3: 445,
observed (M+H).sup.+: 446.5. .sup.1H NMR (400 MHz, MeOD) .delta.ppm
8.01 (s, 1H) 7.96 (d, J=7.58 Hz, 1H) 7.64 (d, J=7.83 Hz, 1H)
7.46-7.52 (m, 3H) 7.05-7.12 (m, 1H) 7.10 (d, J=8.08 Hz, 1H) 6.89
(d, J=7.83 Hz, 1H) 6.64 (t, J=7.58 Hz, 1H) 6.53 (d, J=8.34 Hz, 1H)
5.50-5.53 (m, 2H) 5.31 (d, J=15.92 Hz, 1H) 5.00 (d, J=16.17 Hz, 1H)
3.01 (dt, J=13.83, 6.85 Hz, 1H) 2.20 (d, J=4.80 Hz, 1H) 2.15 (d,
J=4.80 Hz, 1H) 0.94 (d, J=7.07 Hz, 3H) 0.82 (d, J=6.82 Hz, 3H).
[.alpha.].sub.D.sup.25=-126.00 (c=5.2 mg/mL, CH.sub.2Cl.sub.2).
Example 32
(1S,2S) and
(1R,2R)-3-((2-(4-chlorophenyl)-2-isopropyl-2'-oxospiro[cyclopropane-1,3'--
indoline]-1'-yl)methyl)benzoic acid
##STR00059##
[0526] The title compound was prepared in analogy to Example 27
starting from methyl-(3-bromomethyl)-benzoate (commercially
available), (1R,2R) and
(1S,2S)-2-(4-chlorophenyl)-2-isopropylspiro[cyclopropane-1,3'-indolin-
]-2'-one prepared as in Scheme 2. LC/MS m/e calcd. for
C.sub.27H.sub.24ClNO.sub.3: 445, observed (M+H).sup.+: 446.5.
.sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 8.01 (s, 1H) 7.96
(d, J=7.58 Hz, 1H) 7.64 (d, J=7.83 Hz, 1H) 7.46-7.52 (m, 3H)
7.05-7.12 (m, 1H) 7.10 (d, J=8.08 Hz, 1H) 6.89 (d, J=7.83 Hz, 1H)
6.64 (t, J=7.58 Hz, 1H) 6.53 (d, J=8.34 Hz, 1H) 5.50-5.53 (m, 2H)
5.31 (d, J=15.92 Hz, 1H) 5.00 (d, J=16.17 Hz, 1H) 3.01 (dt,
J=13.83, 6.85 Hz, 1H) 2.20 (d, J=4.80 Hz, 1H) 2.15 (d, J=4.80 Hz,
1H) 0.94 (d, J=7.07 Hz, 3H) 0.82 (d, J=6.82 Hz, 3H).
Example 33 and Example 34
(+)-3-((2-(4-chlorophenyl)-5'-fluoro-2-isopropyl-2'-oxospiro[(trans)-cyclo-
propane-1,3'-indoline]-1'-yl)methyl)benzoic acid and
(-)-3-((2-(4-chlorophenyl)-5'-fluoro-2-isopropyl-2'-oxospiro[(trans)-cycl-
opropane-1,3'-indoline]-1'-yl)methyl)benzoic acid
##STR00060##
[0528] The tile compounds were obtained by separation of the
stereoisomers of (1S,2S) and
(1R,2R)-3-((2-(4-chlorophenyl)-5'-fluoro-2-isopropyl-2'-oxospiro[cyclopro-
pane-1,3'-indoline]-1'-yl)methyl)benzoic acid (Example 35) by
chiral preparative HPLC (Chiralpak AD) eluting with a mixture of
n-heptane/5% isopropanol.
(+)-3-((2-(4-chlorophenyl)-5'-fluoro-2-isopropyl-2'-oxospiro[[(trans)-cycl-
opropane-1,3'-indoline]-1'-yl)methyl)benzoic acid
[0529] LC/MS m/e calcd. for C.sub.27H.sub.23ClFNO.sub.3: 463,
observed (M+H).sup.+: 464.2. .sup.1H NMR (400 MHz, MeOD) .delta.ppm
8.01 (s, 1H) 7.98 (d, J=7.83 Hz, 1H) 7.64 (d, J=7.58 Hz, 1H)
7.47-7.54 (m, 1H) 7.51 (t, J=7.07 Hz, 2H) 7.18 (dd, J=8.34, 1.52
Hz, 1H) 6.85 (d, J=4.55 Hz, 1H) 6.79-6.88 (m, 1H) 6.59 (d, J=8.08
Hz, 1H) 5.31 (d, J=16.17 Hz, 1H) 5.25 (dd, J=8.97, 2.15 Hz, 1H)
5.00 (d, J=16.17 Hz, 1H) 3.02 (dt, J=13.64, 6.82 Hz, 1H) 2.25 (d,
J=4.80 Hz, 1H) 2.18-2.23 (m, 1H) 0.95 (d, J=6.82 Hz, 3H) 0.85 (d,
J=6.57 Hz, 3H). White powder MS (ESI) (M+H).sup.+ 463.5;
[.alpha.].sub.D.sup.25=109.52 (c=5 mg/mL, CH.sub.2Cl.sub.2).
(-)-3-((2-(4-chlorophenyl)-5'-fluoro-2-isopropyl-2'-oxospiro[[(trans)-cycl-
opropane-1,3'-indoline]-1'-yl)methyl)benzoic acid
[0530] LC/MS m/e calcd. for C.sub.27H.sub.23ClFNO.sub.3: 463,
observed (M+H).sup.+: 464.1. .sup.1H NMR (400 MHz, MeOD) .delta.ppm
8.01 (s, 1H) 7.98 (d, J=7.83 Hz, 1H) 7.64 (d, J=7.58 Hz, 1H)
7.47-7.54 (m, 1H) 7.51 (t, J=7.07 Hz, 2H) 7.18 (dd, J=8.34, 1.52
Hz, 1H) 6.85 (d, J=4.55 Hz, 1H) 6.79-6.88 (m, 1H) 6.59 (d, J=8.08
Hz, 1H) 5.31 (d, J=16.17 Hz, 1H) 5.25 (dd, J=8.97, 2.15 Hz, 1H)
5.00 (d, J=16.17 Hz, 1H) 3.02 (dt, J=13.64, 6.82 Hz, 1H) 2.25 (d,
J=4.80 Hz, 1H) 2.18-2.23 (m, 1H) 0.95 (d, J=6.82 Hz, 3H) 0.85 (d,
J=6.57 Hz, 3H). White powder MS (ESI) (M+H).sup.+ 463.8;
[.alpha.]D25=-133.26 (c=5 mg/mL, CH.sub.2Cl.sub.2).
Example 35
(1S,2S) and
(1R,2R)-3-((2-(4-chlorophenyl)-5'-fluoro-2-isopropyl-2'-oxospiro[cyclopro-
pane-1,3'-indoline]-1'-yl)methyl)benzoic acid
##STR00061##
[0532] The title compound was prepared in analogy to Example 27
starting from methyl-(3-bromomethyl)-benzoate (commercially
available), (1R,2R) and
(1S,2S)-2-(4-chlorophenyl)-5'-fluoro-2-isopropylspiro[cyclopropane-1,-
3'-indolin]-2'-one prepared as in Scheme 2. LC/MS m/e calcd. for
C.sub.27H.sub.23ClFNO.sub.3: 463, observed (M+H).sup.+: 464.2.
.sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 8.01 (s, 1H) 7.98
(d, J=7.83 Hz, 1H) 7.64 (d, J=7.58 Hz, 1H) 7.47-7.54 (m, 1H) 7.51
(t, J=7.07 Hz, 2H) 7.18 (dd, J=8.34, 1.52 Hz, 1H) 6.85 (d, J=4.55
Hz, 1H) 6.79-6.88 (m, 1H) 6.59 (d, J=8.08 Hz, 1H) 5.31 (d, J=16.17
Hz, 1H) 5.25 (dd, J=8.97, 2.15 Hz, 1H) 5.00 (d, J=16.17 Hz, 1H)
3.02 (dt, J=13.64, 6.82 Hz, 1H) 2.25 (d, J=4.80 Hz, 1H) 2.18-2.23
(m, 1H) 0.95 (d, J=6.82 Hz, 3H) 0.85 (d, J=6.57 Hz, 3H).
Example 36
(1S,2S) and
(1R,2R)-3-((5'-fluoro-2-(4-fluorophenyl)-2-isopropyl-2'-oxospiro[cyclopro-
pane-1,3'-indoline]-1'-yl)methyl)benzoic acid
##STR00062##
[0534] The title compound was prepared in analogy to Example 27
starting from methyl-(3-bromomethyl)-benzoate (commercially
available), (1S,2S) and (1R,2R)-2-(4-fluoro
phenyl)-5'-fluoro-2-isopropylspiro[cyclopropane-1,3'-indolin]-2'-one
racemic prepared as in Scheme 2. LC/MS m/e calcd. for
C.sub.27H.sub.23F.sub.2NO.sub.3: 447, observed (M+H).sup.+: 448.1.
.sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 7.99 (s, 1H) 7.95
(d, J=7.83 Hz, 1H) 7.61 (d, J=7.83 Hz, 1H) 7.49 (d, J=7.58 Hz, 1H)
7.46-7.54 (m, 1H) 7.22 (td, J=8.65, 2.65 Hz, 1H) 6.77-6.92 (m, 3H)
6.60 (ddd, J=8.27, 5.62, 2.27 Hz, 1H) 5.29 (d, J=15.92 Hz, 1H) 5.20
(dd, J=8.84, 2.27 Hz, 1H) 4.98 (d, J=15.92 Hz, 1H) 2.99 (dt,
J=13.64, 6.82 Hz, 1H) 2.23 (d, J=4.80 Hz, 1H) 2.16-2.21 (m, 1H)
0.93 (d, J=6.82 Hz, 3H) 0.83 (d, J=6.82 Hz, 3H).
Example 37
(1S,2S) and
(1R,2R)-3-((2-(3-fluorophenyl)-2-isopropyl-2'-oxospiro[cyclopropane-1,3'--
indoline]-1'-yl)methyl)benzoic acid
##STR00063##
[0536] The title compound was prepared in analogy to Example 27
starting from methyl-(3-bromomethyl)-benzoate (commercially
available), (1R,2R) and
(1S,2S)-2-(3-fluorophenyl)-2-isopropylspiro[cyclopropane-1,3'-indolin-
]-2'-one prepared as in Scheme 2. LC/MS m/e calcd. for
C.sub.27H.sub.24FNO.sub.3: 429, observed (M+H).sup.+: 430.1.
.sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 8.02 (s, 1H) 7.95
(d, J=7.33 Hz, 1H) 7.61 (d, J=7.58 Hz, 1H) 7.48 (t, J=7.58 Hz, 1H)
7.31 (d, J=7.83 Hz, 1H) 7.06 (dd, J=10.86, 7.58 Hz, 2H) 7.11 (d,
J=6.32 Hz, 1H) 6.89 (t, J=8.08 Hz, 1H) 6.56-6.68 (m, 1H) 6.38 (d,
J=7.58 Hz, 1H) 5.50 (t, J=8.21 Hz, 1H) 5.28 (dd, J=15.92, 10.36 Hz,
1H) 5.01 (d, J=16.42 Hz, 2H) 5.07 (s, 1H) 3.01 (d, J=6.82 Hz, 1H)
2.19 (d, J=5.56 Hz, 1H) 2.12-2.26 (m, 1H) 0.95 (dd, J=6.82, 3.28
Hz, 3H) 0.85 (dd, J=6.82, 3.79 Hz, 3H).
Example 38
(1S,2S) and
(1R,2R)-3-((2-(3-chlorophenyl)-2-isopropyl-2'-oxospiro[cyclopropane-1,3'--
indoline]-1'-yl)methyl)benzoic acid
##STR00064##
[0538] The title compound was prepared in analogy to Example 27
starting from methyl-(3-bromomethyl)-benzoate (commercially
available) (1R,2R) and
(1S,2S)-2-(3-chlorophenyl)-2-isopropylspiro[cyclopropane-1,3'-indolin]-2'-
-one prepared as in Scheme 2. LC/MS m/e calcd. for
C.sub.27H.sub.24ClNO.sub.3: 445, observed (M+H).sup.+: 446.1.
.sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 8.02 (d, J=9.85 Hz,
1H) 7.96 (d, J=7.58 Hz, 1H) 7.62 (d, J=7.58 Hz, 1H) 7.40-7.52 (m,
3H) 7.32 (d, J=7.58 Hz, 1H) 7.03-7.12 (m, J=7.01, 7.01, 7.01, 7.01
Hz, 2H) 6.89 (dd, J=11.75, 7.96 Hz, 1H) 6.62 (dt, J=10.61, 7.71 Hz,
1H) 6.46-6.51 (m, 1H) 5.48 (dd, J=16.67, 7.58 Hz, 1H) 5.27 (t,
J=16.42 Hz, 1H) 4.95-5.08 (m, 1H) 3.01 (dt, J=13.64, 6.82 Hz, 1H)
2.19 (d, J=4.55 Hz, 1H) 2.15 (t, J=5.18 Hz, 1H) 0.94 (d, J=6.82 Hz,
3H) 0.83 (dd, J=6.69, 2.91 Hz, 3H).
Example 39
(1S,2S) and
(1R,2R)-3-((2-(4-fluorophenyl)-2-isopropyl-2'-oxospiro[cyclopropane-1,3'--
indoline]-1'-yl)methyl)benzoic acid
##STR00065##
[0540] The title compound was prepared in analogy to Example 27
starting from methyl-(3-bromomethyl)-benzoate (commercially
available), (1R,2R) and
(1S,2S)-2-(4-fluorophenyl)-2-isopropylspiro[cyclopropane-1,3'-indolin-
]-2'-one prepared as in Scheme 2. LC/MS m/e calcd. for
C.sub.27H.sub.24FNO.sub.3: 429, observed (M+H).sup.+: 430.1.
.sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 8.02 (s, 1H) 7.96
(d, J=7.83 Hz, 1H) 7.62 (d, J=7.83 Hz, 1H) 7.49 (q, J=7.49 Hz, 2H)
7.19 (td, J=8.72, 2.53 Hz, 1H) 7.07 (t, J=7.71 Hz, 1H) 6.89 (d,
J=7.83 Hz, 1H) 6.83 (td, J=8.72, 2.78 Hz, 1H) 6.63 (t, J=7.58 Hz,
1H) 6.57 (ddd, J=8.21, 5.68, 2.02 Hz, 1H) 5.49 (d, J=7.58 Hz, 1H)
5.30 (d, J=16.17 Hz, 1H) 5.01 (d, J=16.17 Hz, 1H) 3.00 (dt,
J=13.64, 6.82 Hz, 1H) 2.20 (d, J=4.55 Hz, 1H) 2.15 (d, J=4.55 Hz,
1H) 0.94 (d, J=7.07 Hz, 3H) 0.83 (d, J=6.82 Hz, 3H).
Example 40 and Example 41
(-)-3-((2-(4-chlorophenyl)-2-isopropyl-2'-oxospiro[(trans)-cyclopropane-1,-
3'-indoline]-1'-yl)methyl)benzoic acid and
(+)-3-((2-(4-chlorophenyl)-2-isopropyl-2'-oxospiro[(trans)-cyclopropane-1-
,3'-indoline]-1'-yl)methyl)benzoic acid
##STR00066##
[0542] The tile compounds were obtained by separation of the
stereoisomers of (1S,2S) and
(1R,2R)-3-((2-(4-chlorophenyl)-2-isopropyl-2'-oxospiro[cyclopropane-1,3'--
indoline]-1'-yl)methyl)benzoic acid (Example 27) by chiral
preparative HPLC (Chiralpak AD) eluting with a mixture of
n-heptane/5% isopropanol.
(+)-3-((2-(4-chlorophenyl)-2-isopropyl-2'-oxospiro[[(trans)-cyclopropane-1-
,3'-indoline]-1'-yl)methyl)benzoic acid
[0543] LC/MS m/e calcd. for C.sub.28H.sub.23FN.sub.2O.sub.3: 454,
observed (M+H).sup.+: 455.6. .sup.1H NMR (400 MHz, MeOD) .delta.ppm
7.97 (s, 1H) 7.94 (d, J=7.83 Hz, 1H) 7.85 (dd, J=7.96, 1.64 Hz, 1H)
7.67 (dd, J=7.96, 1.39 Hz, 1H) 7.61 (d, J=7.58 Hz, 1H) 7.48 (q,
J=7.83 Hz, 2H) 6.74-6.86 (m, 3H) 5.28 (d, J=15.92 Hz, 1H) 5.17 (dd,
J=8.72, 2.40 Hz, 1H) 4.97 (d, J=16.17 Hz, 1H) 3.04 (dt, J=13.64,
6.82 Hz, 1H) 2.23-2.28 (m, 1H) 2.20-2.23 (m, 1H) 0.92 (d, J=7.07
Hz, 3H) 0.81 (d, J=6.82 Hz, 3H). White powder. MS (ESI)
(M+H).sup.+; [.alpha.].sub.D.sup.25=166.88 (c=5 mg/mL,
CH.sub.2Cl.sub.2).
(-)-3-((2-(4-chlorophenyl)-2-isopropyl-2'-oxospiro[[(trans)-cyclopropane-1-
,3'-indoline]-1'-yl)methyl)benzoic acid
[0544] LC/MS m/e calcd. for C.sub.28H.sub.23FN.sub.2O.sub.3: 454,
observed (M+H).sup.+: 455.5. .sup.1H NMR (400 MHz, MeOD) .delta.ppm
7.97 (s, 1H) 7.94 (d, J=7.83 Hz, 1H) 7.85 (dd, J=7.96, 1.64 Hz, 1H)
7.67 (dd, J=7.96, 1.39 Hz, 1H) 7.61 (d, J=7.58 Hz, 1H) 7.48 (q,
J=7.83 Hz, 2H) 6.74-6.86 (m, 3H) 5.28 (d, J=15.92 Hz, 1H) 5.17 (dd,
J=8.72, 2.40 Hz, 1H) 4.97 (d, J=16.17 Hz, 1H) 3.04 (dt, J=13.64,
6.82 Hz, 1H) 2.23-2.28 (m, 1H) 2.20-2.23 (m, 1H) 0.92 (d, J=7.07
Hz, 3H) 0.81 (d, J=6.82 Hz, 3H). [.alpha.].sub.D.sup.25=-151.37
(c=5 mg/mL, CH.sub.2Cl.sub.2).
Example 42
(1R,2S) and
(1S,2R)-3-((2-(4-chlorophenyl)-2-methyl-2'-oxospiro[cyclopropane-1,3'-ind-
oline]-1'-yl)methyl)benzoic acid
##STR00067##
[0546] The title compound was prepared in analogy to Example 27
starting from methyl-(3-bromomethyl)-benzoate (commercially
available), (1R,2S) and
(1S,2R)-2-(4-chlorophenyl)-2-methylspiro[cyclopropane-1,3'-indolin]-2-
'-one prepared as in Scheme 2. LC/MS m/e calcd. for
C.sub.25H.sub.20ClNO.sub.3: 417, observed (M+H).sup.+: 418.1
.sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm: 1.86 (s, 3H) 2.15
(d, J=5.05 Hz, 1H) 2.31 (d, J=5.05 Hz, 1H) 5.07 (d, 1H) 5.22 (d,
1H) 5.67 (d, J=7.58 Hz, 1H) 6.62 (t, J=7.58 Hz, 1H) 6.85 (d, J=7.83
Hz, 1H) 7.04 (t, J=7.83 Hz, 1H) 7.29 (s, 2H) 7.48 (t, J=7.96 Hz,
1H) 7.60 (d, J=7.83 Hz, 1H) 7.93-7.98 (m, 2H).
Example 43 and Example 44
(+)-3-((2-(4-chlorophenyl)-2-methyl-2'-oxospiro[(trans)-cyclopropane-1,3'--
indoline]-1'-yl)methyl)benzoic acid and
(-)-3-((2-(4-chlorophenyl)-2-methyl-2'-oxospiro[(trans)-cyclopropane-1,3'-
-indoline]-1'-yl)methyl)benzoic acid
##STR00068##
[0548] The tile compounds were obtained by separation of the
stereoisomers of (1R,2S) and
(1S,2R)-3-((2-(4-chlorophenyl)-2-methyl-2'-oxospiro[cyclopropane-1,3'-ind-
oline]-1'-yl)methyl)benzoic acid (Example 42) by chiral preparative
HPLC (Chiralpak AD) eluting with a mixture of n-heptane/5%
isopropanol.
(+)-3-((2-(4-chlorophenyl)-2-methyl-2'-oxospiro[[(trans)-cyclopropane-1,3'-
-indoline]-1'-yl)methyl)benzoic acid
[0549] LC/MS m/e calcd. for C.sub.25H.sub.20ClNO.sub.3: 417,
observed (M+H).sup.+: 418.6. .sup.1H NMR (400 MHz, MeOD) .delta.ppm
1.86 (s, 3H) 2.15 (d, J=4.80 Hz, 1H) 2.31 (d, J=5.05 Hz, 1H) 5.07
(d, 1H) 5.23 (d, 1H) 5.67 (d, J=7.33 Hz, 1H) 6.62 (t, J=7.58 Hz,
1H) 6.85 (d, J=7.83 Hz, 1H) 7.04 (t, J=7.71 Hz, 1H) 7.30 (br. s.,
3H) 7.48 (t, J=7.83 Hz, 1H) 7.60 (d, J=7.58 Hz, 1H) 7.90-8.01 (m,
2H). [.alpha.].sub.D.sup.25=168.00 (c=4 mg/mL, MeOH).
(-)-3-((2-(4-chlorophenyl)-2-methyl-2'-oxospiro[[(trans)-cyclopropane-1,3'-
-indoline]-1'-yl)methyl)benzoic acid
[0550] LC/MS m/e calcd. for C.sub.25H.sub.20ClNO.sub.3: 417,
observed (M+H).sup.+: 418.5. .sup.1H NMR (400 MHz, MeOD) .delta.ppm
1.83 (s, 3H) 2.12 (d, J=4.80 Hz, 1H) 2.28 (d, J=4.80 Hz, 1H) 5.04
(d, 1H) 5.19 (d, 1H) 5.64 (d, J=7.58 Hz, 1H) 6.59 (t, J=7.71 Hz,
1H) 6.82 (d, J=7.83 Hz, 1H) 7.01 (t, J=7.71 Hz, 1H) 7.27 (br. s.,
2H) 7.45 (t, J=7.96 Hz, 1H) 7.57 (d, J=7.58 Hz, 1H) 7.89-7.96 (m,
2H). [.alpha.].sub.D.sup.25=-158.42 (c=4 mg/mL, MeOH).
Example 45
(1R,2R) and
(1S,2S)-3-((2-(4-chlorophenyl)-2-methyl-2'-oxospiro[cyclopropane-1,3'-ind-
oline]-1'-yl)methyl)benzoic acid
##STR00069##
[0552] The title compound was prepared in analogy to Example 27
starting from methyl-(3-bromomethyl)-benzoate (commercially
available), (1R,2R) and
(1S,2S)-2-(4-chlorophenyl)-2-methylspiro[cyclopropane-1,3'-indolin]-2-
'-one prepared as in Scheme 2. LC/MS m/e calcd. for
C.sub.25H.sub.20ClNO.sub.3: 417, observed (M+H).sup.+: 418.1
.sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 1.69 (s, 3H) 2.05
(d, J=4.80 Hz, 1H) 2.45 (d, J=4.80 Hz, 1H) 4.75 (d, J=15.92 Hz, 1H)
5.12 (d, J=16.17 Hz, 1H) 6.94 (d, J=7.83 Hz, 1H) 7.09 (t, J=7.58
Hz, 1H) 7.24 (d, J=7.58 Hz, 2H) 7.21 (s, 1H) 7.27-7.31 (m, 3H) 7.46
(t, J=7.58 Hz, 1H) 7.51-7.56 (m, 1H) 7.89 (s, 1H) 7.95 (d, J=7.58
Hz, 1H).
Example 46 and Example 47
(+)-3-((2-(4-chlorophenyl)-2-methyl-2'-oxospiro[(cis)-cyclopropane-1,3'-in-
doline]-1'-yl)methyl)benzoic acid and
(-)-3-((2-(4-chlorophenyl)-2-methyl-2'-oxospiro[(cis)-cyclopropane-1,3'-i-
ndoline]-1'-yl)methyl)benzoic acid
##STR00070##
[0554] The tile compounds were obtained by separation of the
stereoisomers of (1R,2R) and
(1S,2S)-3-((2-(4-chlorophenyl)-2-methyl-2'-oxospiro[cyclopropane-1,3'-ind-
oline]-1'-yl)methyl)benzoic acid (Example 45) by chiral preparative
HPLC (Chiralpak AD) eluting with a mixture of n-heptane/5%
isopropanol.
(+)-3-((2-(4-chlorophenyl)-2-methyl-2'-oxospiro[[(cis)-cyclopropane-1,3'-i-
ndoline]-1'-yl)methyl)benzoic acid
[0555] LC/MS m/e calcd. for C.sub.25H.sub.20ClNO.sub.3: 417,
observed (M+H).sup.+: 418.5. .sup.1H NMR (400 MHz, MeOD) .delta.ppm
1.70 (s, 3H) 2.06 (d, J=5.05 Hz, 1H) 2.46 (d, J=5.05 Hz, 1H) 4.77
(d, J=15.92 Hz, 1H) 5.13 (d, J=16.17 Hz, 1H) 6.96 (d, J=7.83 Hz,
1H) 7.10 (t, J=7.58 Hz, 1H) 7.25 (t, J=7.58 Hz, 3H) 7.28-7.33 (m,
3H) 7.48 (t, J=7.58 Hz, 1H) 7.56 (d, 1H) 7.90 (s, 1H) 7.96 (d,
J=7.58 Hz, 1H). [.alpha.].sub.D.sup.25=257.43 (c=4 mg/mL,
MeOH).
(-)-3-((2-(4-chlorophenyl)-2-methyl-2'-oxospiro[[(cis)-cyclopropane-1,3'-i-
ndoline]-1'-yl)methyl)benzoic acid
[0556] LC/MS m/e calcd. for C.sub.25H.sub.20ClNO.sub.3: 417,
observed (M+H).sup.+: 418.4. .sup.1H NMR (400 MHz, MeOD) .delta.ppm
1.70 (s, 3H) 2.06 (d, J=5.05 Hz, 1H) 2.46 (d, J=5.05 Hz, 1H) 4.77
(d, J=16.17 Hz, 1H) 5.13 (d, J=15.92 Hz, 1H) 6.95 (d, J=7.83 Hz,
1H) 7.10 (t, J=7.58 Hz, 1H) 7.24 (t, J=7.45 Hz, 3H) 7.28-7.32 (m,
3H) 7.48 (t, J=7.71 Hz, 1H) 7.55 (d, 1H) 7.90 (s, 1H) 7.96 (d,
J=7.58 Hz, 1H). [.alpha.].sub.D.sup.25=-260.784 (c=4 mg/mL,
MeOH).
Example 48
(1R,2S) and
(1S,2R)-3-((2-(4-cyanophenyl)-5'-fluoro-2-methyl-2'-oxospiro[cyclopropane-
-1,3'-indoline]-1'-yl)methyl)benzoic acid
##STR00071##
[0558] The title compound was prepared in analogy to Example 27
starting from methyl-(3-bromomethyl)-benzoate (commercially
available), (1R,2S) and
(1S,2R)-4-(5'-fluoro-2-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-
-2-yl)benzonitrile prepared as in Scheme 2. LC/MS m/e calcd. for
C.sub.26H.sub.19FN.sub.2O.sub.3: 426, observed (M+H).sup.+: 427.1
.sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 1.87 (s, 3H) 2.21
(d, J=5.31 Hz, 1H) 2.40 (d, J=5.31 Hz, 1H) 5.04 (d, 1H) 5.21 (d,
1H) 5.36 (dd, J=8.84, 2.27 Hz, 1H) 6.73-6.87 (m, 1H) 6.80 (d,
J=4.55 Hz, 1H) 7.48 (t, J=7.71 Hz, 1H) 7.59 (s, 2H) 7.69 (br. s.,
2H) 7.94 (d, J=7.58 Hz, 1H) 7.91 (s, 1H).
Example 49 and Example 50
(+)-3-((2-(4-cyanophenyl)-5'-fluoro-2-methyl-2'-oxospiro[(trans)-cycloprop-
ane-1,3'-indoline]-1'-yl)methyl)benzoic acid and
(-)-3-((2-(4-cyanophenyl)-5'-fluoro-2-methyl-2'-oxospiro[(trans)-cyclopro-
pane-1,3'-indoline]-1'-yl)methyl)benzoic acid
##STR00072##
[0560] The tile compounds were obtained by separation of the
stereoisomers of (1R,2S) and
(1S,2R)-3-((2-(4-cyanophenyl)-5'-fluoro-2-methyl-2'-oxospiro[cyclopropane-
-1,3'-indoline]-1'-yl)methyl)benzoic acid (Example 48) by chiral
preparative HPLC (Chiralpak AD) eluting with a mixture of
n-heptane/5% isopropanol.
(+)-3-((2-(4-cyanophenyl)-5'-fluoro-2-methyl-2'-oxospiro[[(trans)-cyclopro-
pane-1,3'-indoline]-1'-yl)methyl)benzoic acid
[0561] LC/MS m/e calcd. for C.sub.26H.sub.19FN.sub.2O.sub.3: 426,
observed (M+H).sup.+: 427.5. .sup.1H NMR (400 MHz, MeOD) .delta.ppm
1.87 (s, 3H) 2.21 (d, J=5.31 Hz, 1H) 2.41 (d, J=5.31 Hz, 1H) 5.04
(d, 1H) 5.21 (d, 1H) 5.36 (dd, J=8.84, 2.27 Hz, 1H) 6.73-6.87 (m,
1H) 6.80 (d, J=4.80 Hz, 1H) 7.48 (t, J=7.71 Hz, 2H) 7.60 (d, J=7.83
Hz, 2H) 7.69 (br. s., 2H) 7.94 (d, J=7.58 Hz, 1H) 7.92 (s, 1H).
[.alpha.].sub.D.sup.25=203.431 (c=4 mg/mL, MeOH).
(-)-3-((2-(4-cyanophenyl)-5'-fluoro-2-methyl-2'-oxospiro[[(trans)-cyclopro-
pane-1,3'-indoline]-1'-yl)methyl)benzoic acid
[0562] LC/MS m/e calcd. for C.sub.26H.sub.19FN.sub.2O.sub.3: 426,
observed (M+H).sup.+: 427.6. .sup.1H NMR (400 MHz, MeOD) .delta.ppm
1.88 (s, 3H) 2.22 (d, J=5.31 Hz, 1H) 2.41 (d, J=5.31 Hz, 1H) 5.05
(d, 1H) 5.21 (d, 1H) 5.36 (dd, J=8.84, 2.27 Hz, 1H) 6.80 (d, J=4.55
Hz, 1H) 6.74-6.85 (m, 1H) 7.48 (t, J=7.71 Hz, 1H) 7.60 (d, J=7.58
Hz, 2H) 7.71 (br. s., 2H) 7.95 (d, J=7.58 Hz, 1H) 7.92 (s, 1H).
White powder MS (ESI) (M+H).sup.+ 427.6;
[.alpha.].sub.D.sup.25=-209.00 (c=4 mg/mL, MeOH).
Example 51
(1S,2S) and
(1R,2R)-3-((2-(4-cyanophenyl)-2-isopropyl-2'-oxospiro[cyclopropane-1,3'-i-
ndoline]-1'-yl)methyl)benzoic acid
##STR00073##
[0564] The title compound was prepared in analogy to Example 27
starting from methyl-(3-bromomethyl)-benzoate (commercially
available), (1R,2R) and
(1S,2S)-4-(2-isopropyl-2'-oxospiro[cyclopropane-1,3'-indoline]-2-yl)b-
enzonitrile prepared as in Scheme 2. LC/MS m/e calcd. for
C.sub.28H.sub.24N.sub.2O.sub.3: 436, observed (M+H).sup.+: 437.1
.sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 0.81 (d, J=6.82 Hz,
3H) 0.92 (d, J=6.82 Hz, 3H) 2.18 (d, 1H) 2.22 (d, 1H) 2.98-3.09 (m,
1H) 4.98 (d, J=16.17 Hz, 1H) 5.30 (d, J=15.92 Hz, 1H) 5.43 (d,
J=7.58 Hz, 1H) 6.61 (t, J=7.58 Hz, 1H) 6.71 (dd, J=8.08, 1.52 Hz,
1H) 6.88 (d, J=7.83 Hz, 1H) 7.06 (t, J=7.71 Hz, 1H) 7.48 (t, J=7.71
Hz, 1H) 7.44 (dd, J=8.08, 1.77 Hz, 1H) 7.68 (dd, J=7.83, 1.52 Hz,
1H) 7.63 (d, J=7.83 Hz, 1H) 7.83 (dd, J=7.96, 1.64 Hz, 1H) 7.94 (d,
J=7.83 Hz, 1H) 7.99 (s, 1H).
Example 52 and Example 53
(+)-3-((2-(4-cyanophenyl)-2-isopropyl-2'-oxospiro[(trans)-cyclopropane-1,3-
'-indoline]-1'-yl)methyl)benzoic acid and
(-)-3-((2-(4-cyanophenyl)-2-isopropyl-2'-oxospiro[(trans)-cyclopropane-1,-
3'-indoline]-1'-yl)methyl)benzoic acid
##STR00074##
[0566] The title compounds were obtained by separation of the
stereoisomers of (1S,2S) and
(1R,2R)-3-((2-(4-cyanophenyl)-5'-fluoro-2-methyl-2'-oxospiro[cyclopropane-
-1,3'-indoline]-1'-yl)methyl)benzoic acid (Example 51) by chiral
preparative HPLC (Chiralpak AD) eluting with a mixture of
n-heptane/5% isopropanol.
(+)-3-((2-(4-cyanophenyl)-2-isopropyl-2'-oxospiro[[(trans)-cyclopropane-1,-
3'-indoline]-1'-yl)methyl)benzoic acid
[0567] LC/MS m/e calcd. for C.sub.28H.sub.24N.sub.2O.sub.3: 436,
observed (M+H).sup.+: 437.7. .sup.1H NMR (400 MHz, MeOD) .delta.ppm
0.80 (d, J=6.82 Hz, 3H) 0.92 (d, J=6.82 Hz, 3H) 2.17 (d, 1H) 2.22
(d, 1H) 2.97-3.10 (m, J=6.88, 6.88, 6.88, 6.88 Hz, 1H) 4.98 (d,
J=16.17 Hz, 1H) 5.30 (d, J=15.92 Hz, 1H) 5.43 (d, J=7.58 Hz, 1H)
6.61 (t, J=7.58 Hz, 1H) 6.71 (dd, J=8.08, 1.52 Hz, 1H) 6.88 (d,
J=7.83 Hz, 1H) 7.06 (t, J=7.71 Hz, 1H) 7.48 (t, J=7.71 Hz, 1H) 7.44
(dd, J=8.08, 1.77 Hz, 1H) 7.67 (dd, J=7.96, 1.64 Hz, 1H) 7.63 (d,
J=7.83 Hz, 1H) 7.83 (dd, J=7.96, 1.64 Hz, 1H) 7.94 (d, J=7.83 Hz,
1H) 7.99 (s, 1H). [.alpha.].sub.D.sup.25=180.88 (c=4 mg/mL,
MeOH).
(-)-3-((2-(4-cyanophenyl)-2-isopropyl-2'-oxospiro[[(trans)-cyclopropane-1,-
3'-indoline]-1'-yl)methyl)benzoic acid
[0568] LC/MS m/e calcd. for C.sub.28H.sub.24N.sub.2O.sub.3: 436,
observed (M+H).sup.+: 437.5. .sup.1H NMR (400 MHz, MeOD) .delta.ppm
0.81 (d, J=6.82 Hz, 3H) 0.93 (d, J=6.82 Hz, 3H) 2.18 (dd, 1H)
2.21-2.25 (m, 1H) 3.03 (d, J=6.82 Hz, 1H) 4.98 (d, J=15.92 Hz, 1H)
5.30 (d, J=16.17 Hz, 1H) 5.44 (d, J=7.58 Hz, 1H) 6.62 (t, J=7.58
Hz, 1H) 6.72 (dd, J=8.08, 1.52 Hz, 1H) 6.89 (d, J=7.83 Hz, 1H) 7.07
(t, J=7.71 Hz, 1H) 7.48 (t, J=7.71 Hz, 1H) 7.45 (dd, J=8.08, 1.52
Hz, 1H) 7.68 (d, J=7.83 Hz, 1H) 7.65 (dd, J=18.57, 7.71 Hz, 1H)
7.84 (dd, J=7.96, 1.64 Hz, 1H) 7.95 (d, J=7.83 Hz, 1H) 7.99 (s,
1H). [.alpha.].sub.D.sup.25=-182.52 (c=4 mg/mL, MeOH).
Example 54
(1R,2R) and
(1S,2S)-3-((2-(4-cyanophenyl)-5'-fluoro-2-methyl-2'-oxospiro[cyclopropane-
-1,3'-indoline]-1'-yl)methyl)benzoic acid
##STR00075##
[0570] The title compound was prepared in analogy to Example 27
starting from methyl-(3-bromomethyl)-benzoate (commercially
available), (1R,2R) and
(1S,2S)-4-(5'-fluoro-2-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-
-2-yl)benzonitrile prepared as in Scheme 2. LC/MS m/e calcd. for
C.sub.26H.sub.19FN.sub.2O.sub.3: 426, observed (M+H).sup.+: 427.1
.sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 1.71 (s, 3H) 2.14
(d, J=5.05 Hz, 1H) 2.50 (d, J=5.31 Hz, 1H) 4.73 (d, J=15.92 Hz, 1H)
5.10 (d, J=15.92 Hz, 1H) 6.92 (d, J=4.29 Hz, 1H) 6.98 (dd, J=9.09,
2.53 Hz, 1H) 7.16 (dd, J=8.84, 2.53 Hz, 1H) 7.47 (t, J=7.71 Hz, 2H)
7.46 (br. s., 1H) 7.51-7.56 (m, 1H) 7.67 (d, J=8.59 Hz, 2H) 7.85
(s, 1H) 7.95 (d, J=7.83 Hz, 1H).
Example 55 and Example 56
(+)-3-((2-(4-cyanophenyl)-5'-fluoro-2-methyl-2'-oxospiro[(cis)-cyclopropan-
e-1,3'-indoline]-1'-yl)methyl)benzoic acid and
(-)-3-((2-(4-cyanophenyl)-5'-fluoro-2-methyl-2'-oxospiro[(cis)-cyclopropa-
ne-1,3'-indoline]-1'-yl)methyl)benzoic acid
##STR00076##
[0572] The title compounds were obtained by separation of the
stereoisomers of (1R,2R) and
(1S,2S)-3-((2-(4-cyanophenyl)-5'-fluoro-2-methyl-2'-oxospiro[cyclopropane-
-1,3'-indoline]-1'-yl)methyl)benzoic acid (Example 54) by chiral
preparative HPLC (Chiralpak AD) eluting with a mixture of
n-heptane/5% isopropanol.
(+)-3-((2-(4-cyanophenyl)-5'-fluoro-2-methyl-2'-oxospiro[[(cis)-cyclopropa-
ne-1,3'-indoline]-1'-yl)methyl)benzoic acid
[0573] LC/MS m/e calcd. for C.sub.26H.sub.19FN.sub.2O.sub.3: 426,
observed (M+H).sup.+: 426.8. .sup.1H NMR (400 MHz, MeOD) .delta.ppm
1.71 (s, 3H) 2.14 (d, J=5.05 Hz, 1H) 2.50 (d, J=5.05 Hz, 1H) 4.73
(d, J=15.92 Hz, 1H) 5.10 (d, J=15.66 Hz, 1H) 6.93 (d, J=4.29 Hz,
1H) 6.98 (dd, J=9.09, 2.53 Hz, 1H) 7.16 (dd, J=8.72, 2.40 Hz, 1H)
7.47 (t, J=7.71 Hz, 3H) 7.53 (br. s., 1H) 7.67 (d, J=8.59 Hz, 2H)
7.85 (s, 1H) 7.95 (d, J=7.58 Hz, 1H). [.alpha.].sub.D.sup.25=313.53
(c=4 mg/mL, MeOH).
(-)-3-((2-(4-cyanophenyl)-5'-fluoro-2-methyl-2'-oxospiro[[(cis)-cyclopropa-
ne-1,3'-indoline]-1'-yl)methyl)benzoic acid
[0574] LC/MS m/e calcd. for C.sub.26H.sub.19FN.sub.2O.sub.3: 426,
observed (M+H).sup.+: 426.5. .sup.1H NMR (400 MHz, MeOD) .delta.ppm
1.71 (s, 3H) 2.14 (d, J=5.31 Hz, 1H) 2.50 (d, J=5.05 Hz, 1H) 4.73
(d, J=15.92 Hz, 1H) 5.10 (d, J=15.92 Hz, 1H) 6.92 (d, J=4.55 Hz,
1H) 6.98 (dd, J=9.09, 2.53 Hz, 1H) 7.16 (dd, J=8.72, 2.40 Hz, 1H)
7.47 (t, J=7.58 Hz, 3H) 7.52-7.59 (m, 1H) 7.67 (d, J=8.59 Hz, 2H)
7.84 (s, 1H) 7.95 (d, J=7.83 Hz, 1H [.alpha.].sub.D.sup.25=-286.00
(c=4 mg/mL 00, MeOH).
Example 57
(1R,2S) and
(1R,2S)-3-((2-(4-chlorophenyl)-5'-fluoro-2-methyl-2'-oxospiro[cyclopropan-
e-1,3'-indoline]-1'-yl)methyl)benzoic acid
##STR00077##
[0576] The title compound was prepared in analogy to Example 27
starting from methyl-(3-bromomethyl)-benzoate (commercially
available), (1R,2S) and
(1S,2R)-2-(4-chlorophenyl)-5'-fluoro-2-methylspiro[cyclopropane-1,3'--
indolin]-2'-one prepared as in Scheme 2. LC/MS m/e calcd. for
C.sub.25H.sub.19ClFNO.sub.3: 435, observed (M+H).sup.+: 436.5.
.sup.1H NMR (400 MHz, MeOD) .delta.ppm 1.88 (s, 3H) 2.20 (d, J=5.05
Hz, 1H) 2.37 (d, J=5.05 Hz, 1H) 5.02-5.10 (m, 1H) 5.18-5.25 (m, 1H)
5.41 (dd, J=8.84, 2.27 Hz, 1H) 6.72-6.86 (m, 1H) 6.80 (d, J=5.05
Hz, 1H) 7.30 (br. s., 2H) 7.50 (t, J=7.71 Hz, 1H) 7.61 (d, J=7.58
Hz, 1H) 7.96 (d, J=8.08 Hz, 1H) 7.94 (br. s., 1H).
Example 58 and Example 59
(+)-3-((2-(4-chlorophenyl)-5'-fluoro-2-methyl-2'-oxospiro[(trans)-cyclopro-
pane-1,3'-indoline]-1'-yl)methyl)benzoic acid and
(-)-3-((2-(4-chlorophenyl)-5'-fluoro-2-methyl-2'-oxospiro[(trans)-cyclopr-
opane-1,3'-indoline]-1'-yl)methyl)benzoic acid
##STR00078##
[0578] The title compounds were obtained by separation of the
stereoisomers of (1R,2S) and
(1R,2S)-3-((2-(4-chlorophenyl)-5'-fluoro-2-methyl-2'-oxospiro[cyclopropan-
e-1,3'-indoline]-1'-yl)methyl)benzoic acid (Example 57) by chiral
preparative HPLC (Chiralpak AD) eluting with a mixture of
n-heptane/5% isopropanol.
(+)-3-((2-(4-chlorophenyl)-5'-fluoro-2-methyl-2'-oxospiro[[(trans)-cyclopr-
opane-1,3'-indoline]-1'-yl)methyl)benzoic acid
[0579] LC/MS m/e calcd. for C.sub.25H.sub.19ClFNO.sub.3: 435,
observed (M+H).sup.+: 436.5. .sup.1H NMR (400 MHz, MeOD) .delta.ppm
1.87 (s, 3H) 2.19 (d, J=5.05 Hz, 1H) 2.36 (d, J=5.05 Hz, 1H)
5.01-5.10 (m, 1H) 5.17-5.26 (m, 1H) 5.41 (dd, J=8.97, 2.15 Hz, 1H)
6.67-6.86 (m, 3H) 7.34 (br. s., 2H) 7.49 (t, J=7.58 Hz, 2H) 7.60
(d, J=7.83 Hz, 1H) 7.89-7.99 (m, 2H). [.alpha.].sub.D.sup.25=191.09
(c=4 mg/mL, MeOH).
(-)-3-((2-(4-chlorophenyl)-5'-fluoro-2-methyl-2'-oxospiro[[(trans)-cyclopr-
opane-1,3'-indoline]-1'-yl)methyl)benzoic acid
[0580] LC/MS m/e calcd. for C.sub.25H.sub.19ClFNO.sub.3: 435,
observed (M+H).sup.+: 436.7. .sup.1H NMR (400 MHz, MeOD) .delta.ppm
1.88 (s, 3H) 2.20 (d, J=5.05 Hz, 1H) 2.37 (d, J=5.05 Hz, 1H) 5.06
(d, 1H) 5.22 (d, 1H) 5.41 (dd, J=8.84, 2.27 Hz, 1H) 6.75-6.85 (m,
1H) 6.81 (d, J=4.80 Hz, 1H) 7.32 (br. s., 2H) 7.50 (t, J=7.71 Hz,
2H) 7.61 (d, J=7.83 Hz, 1H) 7.93-7.99 (m, 2H).
[.alpha.].sub.D.sup.25=-186.14 (c=4 mg/mL, MeOH).
Example 60
(1S,2R) and
(1R,2S)-2-(4-chlorophenyl)-1'-(3-(piperidine-1-carbonyl)benzyl)spiro[cycl-
opropane-1,3'-indolin]-2'-one
##STR00079##
[0582]
3-(((1S,2R)-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoli-
ne]-1'-yl)methyl)benzoic acid and
3-(((1R,2S)-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)benzoic acid (prepared according to Scheme 1) (60 mg,
0.15 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (EDC.HCl) (44 mg, 0.225 mmol 1.5 mmol), anhydrous
1-Hydroxybenzotriazole (HOBt) (31 mg, 0.225 mmol) and piperidine
(15 mg, 0.18 mmol) were dissolved in DMF. The mixture was stirred
at room temperature for 14 hours. (1R,2S) and
(1S,2R)-2-(4-chlorophenyl)-1'-(3-(piperidine-1-carbonyl)benzyl)spiro[cycl-
opropane-1,3'-indolin]-2'-one were purified by preparative HPLC as
a white solid (42 mg, 60%). LC/MS m/e calcd. for
C.sub.29H.sub.27ClN.sub.2O.sub.2: 470, observed (M+H).sup.+: 471.2
.sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 1.41 (br. s., 2H)
1.67 (br. s., 4H) 2.19-2.30 (m, 2H) 3.28 (br.s., 2H) 3.30 (s, 1H)
3.69 (br. s., 2H) 5.14 (s, 2H) 6.11 (d, J=7.33 Hz, 1H) 6.74 (t,
J=7.20 Hz, 1H) 6.91 (d, J=7.83 Hz, 1H) 7.03-7.15 (m, 1H) 7.20-7.28
(m, 2H) 7.28-7.38 (m, 4H) 7.43-7.57 (m, 2H).
Example 61
(1R,2S) and
(1S,2R)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)-N-isopropylbenzamide
##STR00080##
[0584] The title compound was prepared in analogy to Example 60
starting from isopropyl amine, (3-bromomethyl)-benzoate
(commercially available), (1R,2S) and
(1S,2R)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)benzoic acid prepared as in Scheme 1. LC/MS m/e calcd.
for C.sub.27H.sub.25ClN.sub.2O.sub.2: 444, observed (M+H).sup.+:
445.2 .sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 1.23 (d,
J=6.82 Hz, 6H) 2.21 (d, J=8.59 Hz, 2H) 3.21-3.28 (m, 1H) 4.07-4.25
(m, 1H) 5.10 (s, 2H) 6.05 (d, J=7.58 Hz, 1H) 6.69 (t, J=7.58 Hz,
1H) 6.88 (d, J=7.83 Hz, 1H) 7.05 (t, J=7.83 Hz, 1H) 7.16-7.25 (m,
2H) 7.25-7.34 (m, 2H) 7.37-7.52 (m, 2H) 7.69 (d, J=7.58 Hz, 1H)
7.78 (s, 1H).
Example 62
(1S,2R) and
(1R,2S)-2-(4-chlorophenyl)-1'-(3-(piperazine-1-carbonyl)benzyl)spiro[cycl-
opropane-1,3'-indolin]-2'-one
##STR00081##
[0586] The title compound was prepared in analogy to Example 60
starting from piperazine, (3-bromomethyl)-benzoate (commercially
available), (1R,2S) and
(1S,2R)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)benzoic acid prepared as in Scheme 1. LC/MS m/e calcd.
for C.sub.28H.sub.26ClN.sub.3O.sub.2: 471, observed (M+H).sup.+:
472.2 .sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 2.17-2.30 (m,
2H) 3.51 (br. s., 8H) 3.21-3.35 (m, 1H) 5.04-5.23 (m, 2H) 6.10 (d,
J=7.58 Hz, 1H) 6.74 (t, J=7.45 Hz, 1H) 6.95 (d, J=7.83 Hz, 1H)
7.05-7.16 (m, 1H) 7.23 (d, J=8.34 Hz, 2H) 7.29-7.38 (m, 2H)
7.40-7.49 (m, 2H) 7.49-7.58 (m, 2H).
Example 63
(1R,2S) and
(1S,2R)-2-(4-chlorophenyl)-1'-(3-(morpholine-4-carbonyl)benzyl)spiro[cycl-
opropane-1,3'-indolin]-2'-one
##STR00082##
[0588] The title compound was prepared in analogy to Example 60
starting from morpholine, (3-bromomethyl)-benzoate (commercially
available) and (1R,2S) and
(1S,2R)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)benzoic acid prepared as in Scheme 1. LC/MS m/e calcd.
for C.sub.28H.sub.25ClN.sub.2O.sub.3: 472, observed (M+H).sup.+:
473.2 .sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 2.15-2.27 (m,
2H) 3.18-3.36 (m, 1H) 3.47 (br. s., 4H) 3.70 (br. s., 4H) 5.11 (s,
2H) 6.08 (d, J=7.58 Hz, 1H) 6.71 (t, J=7.58 Hz, 1H) 6.88 (d, J=8.08
Hz, 1H) 7.01-7.12 (m, 1H) 7.17-7.26 (m, 2H) 7.25-7.40 (m, 4H)
7.43-7.56 (m, 2H).
Example 64
(1R,2S) and
(1S,2R)-2-(4-chlorophenyl)-1'-(3-(4-(pyridin-4-yl)piperazine-1-carbonyl)b-
enzyl)spiro[cyclopropane-1,3'-indolin]-2'-one
##STR00083##
[0590] The title compound was prepared in analogy to Example 60
starting from 1-(pyridin-4-yl)piperazine, (3-bromomethyl)-benzoate
(commercially available), (1R,2S) and
(1S,2R)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)benzoic acid prepared as in Scheme 1. LC/MS m/e calcd.
for C.sub.33H.sub.29ClN.sub.4O.sub.2: 548, observed (M+H).sup.+:
549.1 .sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 2.20-2.29 (m,
2H) 3.26-3.31 (m, 1H) 3.58 (br. s., 4H) 3.88 (br. s., 4H) 5.08-5.25
(m, 2H) 6.14 (d, J=7.58 Hz, 1H) 6.77 (t, J=7.58 Hz, 1H) 6.92 (d,
J=7.83 Hz, 1H) 7.12 (t, J=7.20 Hz, 3H) 7.21-7.32 (m, 4H) 7.41 (s,
1H) 7.45 (d, J=7.33 Hz, 1H) 7.50-7.61 (m, 2H) 8.19 (d, J=7.58 Hz,
2H).
Example 65
(1S,2R) and
(1R,2S)-2-(4-chlorophenyl)-1'-(3-(4-isopropylpiperazine-1-carbonyl)benzyl-
)spiro[cyclopropane-1,3'-indolin]-2'-one
##STR00084##
[0592] The title compound was prepared in analogy to Example 60
starting from 1-isopropylpiperazine, (3-bromomethyl)-benzoate
(commercially available), (1R,2S) and
(1S,2R)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)benzoic acid prepared as in Scheme 1. LC/MS m/e calcd.
for C.sub.31H.sub.32ClN.sub.3O.sub.2: 513, observed (M+H).sup.+:
514.2 .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.ppm 1.37 (d, J=6.32
Hz, 6H) 2.04 (dd, J=7.71, 4.67 Hz, 1H) 2.28 (dd, J=9.22, 4.67 Hz,
1H) 2.86 (br. s., 2H) 3.35 (t, J=8.46 Hz, 1H) 3.61 (br. s., 6H)
4.96 (d, J=15.92 Hz, 1H) 5.18 (d, J=16.17 Hz, 1H) 6.02 (d, J=7.33
Hz, 1H) 6.71-6.82 (m, 2H) 7.06-7.19 (m, 3H) 7.31 (s, 1H) 7.33-7.39
(m, 1H) 7.39-7.51 (m, 3H).
Example 66
3-(((1S,2R)-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)methyl)-N-(2-((S)-1-methylpyrrolidin-2-yl)ethyl)benzamide and
3-(((1R,2S)-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)-N-(2-((S)-1-methylpyrrolidin-2-yl)ethyl)benzamide
##STR00085##
[0594] The title compound was prepared in analogy to Example 60
starting from (2S)-2-(3-aminopropyl)-N-methylpyrrolidine,
(3-bromomethyl)-benzoate (commercially available), (1R,2S) and
(1S,2R)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)benzoic acid prepared as in Scheme 1. LC/MS m/e calcd.
for C.sub.31H.sub.32ClN.sub.3O.sub.2: 513, observed (M+H).sup.+:
514.2 1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 1.76-1.94 (m, 2H)
2.00-2.20 (m, 2H) 2.24 (d, J=8.59 Hz, 2H) 2.26-2.37 (m, 1H)
2.42-2.58 (m, 1H) 2.94 (s, 3H) 3.10-3.22 (m, 1H) 3.25-3.31 (m, 1H)
3.35-3.43 (m, 1H) 3.52 (t, J=6.69 Hz, 2H) 3.63-3.75 (m, 1H) 5.13
(s, 2H) 6.09 (d, J=7.58 Hz, 1H) 6.73 (t, J=7.58 Hz, 1H) 6.91 (d,
J=7.83 Hz, 1H) 7.09 (t, J=7.71 Hz, 1H) 7.21-7.28 (m, 2H) 7.28-7.37
(m, 2H) 7.45-7.52 (m, 1H) 7.52-7.60 (m, 1H) 7.76 (d, J=7.58 Hz, 1H)
7.85 (s, 1H).
Example 67
(1R,2S) and
(1S,2R)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)-N-(3-methyl-1H-pyrazol-5-yl)benzamide
##STR00086##
[0596] The title compound was prepared in analogy to Example 60
starting from 3-methyl-1H-pyrazol-5-amine, (3-bromomethyl)-benzoate
(commercially available), racemic (1R,2S) and
(1S,2R)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)benzoic acid prepared as in Scheme 1. LC/MS m/e calcd.
for C.sub.28H.sub.23ClN.sub.4O.sub.2: 482, observed (M+H).sup.+:
483.2 .sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 2.23 (d,
J=8.59 Hz, 2H) 2.55 (s, 3H) 3.26-3.32 (m, 1H) 5.08-5.23 (m, 2H)
5.85 (d, J=1.01 Hz, 1H) 6.08 (d, J=7.07 Hz, 1H) 6.73 (t, J=7.58 Hz,
1H) 6.94 (d, J=7.83 Hz, 1H) 7.07-7.14 (m, 1H) 7.19 (d, J=8.08 Hz,
2H) 7.30 (d, J=8.59 Hz, 2H) 7.48 (t, J=7.71 Hz, 1H) 7.58 (d, J=8.34
Hz, 1H) 7.80 (d, J=7.83 Hz, 1H) 7.85 (s, 1H).
Example 68
(1S,2R) and
(1R,2S)-6-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)picolinic acid
##STR00087##
[0598] The title compound was prepared in analogy to Example 1
starting from 6-bromomethyl-pyridine-2-carboxylic acid methyl ester
(commercially available), (1R,2S) and
(1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.23H.sub.17ClN.sub.2O.sub.3: 404, observed (M+H).sup.+: 405.2
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 2.12 (dd, J=9.09,
4.80 Hz, 1H) 2.39 (dd, J=8.08, 4.80 Hz, 1H) 3.22 (t, J=8.59 Hz, 1H)
5.14 (s, 2H) 6.15 (d, J=7.33 Hz, 1H) 6.73 (t, J=7.45 Hz, 1H) 6.88
(d, J=7.58 Hz, 1H) 7.00-7.10 (m, 1H) 7.26 (d, J=1.01 Hz, 1H) 7.38
(s, 4H) 7.84-7.98 (m, 2H).
Example 69
(1S,2R) and
(1R,2S)-6-((2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)picolinic acid
##STR00088##
[0600] The title compound was prepared in analogy to Example 1
starting from 6-bromomethyl-pyridine-2-carboxylic acid methyl ester
(commercially available) and (1R,2S) and
(1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.23H.sub.17FN.sub.2O.sub.3: 388, observed (M+H).sup.+: 389.1
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 2.06-2.18 (m, 1H)
2.32-2.39 (m, 1H) 3.13-3.31 (m, 1H) 5.12 (s, 2H) 6.13 (d, 1H) 6.68
(t, 1H) 6.88 (d, 1H) 6.98-7.08 (m, 1H) 7.10-7.18 (m, 2H) 7.23 (d,
1H) 7.33-7.47 (m, 2H) 7.79-7.93 (m, 2H).
Example 70
(1S,2R) and
(1R,2S)-2-(4-chlorophenyl)-1'-((tetrahydro-2H-pyran-4-yl)methyl)spiro[cyc-
lopropane-1,3'-indolin]-2'-one
##STR00089##
[0602] Racemic
(1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
and
(1R,2S)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
(270 mg, 1.0 mmol, 1.0 equiv.) were added to a stirred solution of
sodium hydride (60%, 60 mg, 1.5 mmol) in 5 mL of DMF under argon
atmosphere at 0.degree. C. After stirring for 1 hour,
4-bromomethyl-tetrahydropyran (215 mg, 1.2 mmol) was added. The
reaction mixture was stirred for 14 hours at room temperature. The
crude product was purified by HPLC to give the title compound as a
white solid (258 mg, 70%). LC/MS m/e calcd. for
C.sub.22H.sub.22ClNO.sub.2: 367, observed (M+H).sup.+: 368.2
.sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 1.39-1.55 (m, 2H)
1.65 (dd, J=13.14, 1.77 Hz, 2H) 2.11-2.25 (m, 3H) 3.22 (t, J=8.46
Hz, 1H) 3.37-3.47 (m, 2H) 3.79 (d, J=7.33 Hz, 2H) 3.94-4.04 (m, 2H)
6.09 (d, J=7.58 Hz, 1H) 6.76 (t, J=7.58 Hz, 1H) 7.11 (d, J=7.83 Hz,
1H) 7.17-7.25 (m, 3H) 7.33 (d, J=8.34 Hz, 2H). MS calcd. For
C.sub.22H.sub.22ClNO.sub.2 367, obsd. (ESI.sup.+)
[(M+H).sup.+]368.
Example 71
(1S,2R) and
(1R,2S)-2-(4-chlorophenyl)-1'-(2-(diethylamino)ethyl)spiro[cyclopropane-1-
,3'-indolin]-2'-one
##STR00090##
[0604] The title compound was prepared in analogy to Example 70
starting from 2-Chloro-N,N-diethylethaneamine hydrochloride
(commercially available), (1S,2R) and
(1R,2S)-2-(4-chlorophenyl)Spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.22H.sub.25ClN.sub.2O: 368, observed (M+H).sup.+: 369.1
.sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 1.41 (t, J=7.20 Hz,
6H) 2.21-2.31 (m, 2H) 3.32 (t, J=8.59 Hz, 1H) 3.39-3.55 (m, 4H)
3.60 (t, J=6.44 Hz, 2H) 4.23-4.42 (m, 2H) 6.16 (d, J=7.58 Hz, 1H)
6.85 (t, J=7.45 Hz, 1H) 7.19 (d, J=7.83 Hz, 1H) 7.24-7.32 (m, 3H)
7.33-7.40 (m, 2H).
Example 72
(1S,2R) and
(1R,2S)-2-(4-chlorophenyl)-1'-(2-morpholinoethyl)spiro[cyclopropane-1,3'--
indolin]-2'-one
##STR00091##
[0606] The title compound was prepared in analogy to Example 70
starting from 4-(2-chloroethyl)morpholine hydrochloride
(commercially available), (1S,2R) and
(1R,2S)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.22H.sub.23ClN.sub.2O.sub.2: 382, observed (M+H).sup.+: 383.1
.sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 2.21-2.29 (m, 2H)
3.30 (t, J=8.72 Hz, 1H) 3.54-3.69 (m, 2H) 3.97 (br. s., 8H)
4.21-4.32 (m, 1H) 4.36-4.48 (m, 1H) 6.15 (d, J=7.33 Hz, 1H) 6.83
(t, J=7.20 Hz, 1H) 7.14-7.21 (m, 1H) 7.22-7.30 (m, 3H) 7.31-7.39
(m, 2H).
Example 73
(1S,2R) and
(1R,2S)-2-(4-chlorophenyl)-1'4(1-(methylsulfonyl)piperidin-4-yl)methyl)sp-
iro[cyclopropane-1,3'-indolin]-2'-one
##STR00092##
[0608] The title compound was prepared in analogy to Example 70
starting from 4-chloromethyl-1-methanesulfonyl-piperidine
(commercially available), (1R,2S) and
(1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.23H.sub.25ClN.sub.2O.sub.3S: 444, observed (M+H).sup.+: 445.1
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 1.23-1.41 (m, 2H)
1.66-1.78 (m, 2H) 1.84-1.98 (m, 1H) 2.02 (dd, J=9.09, 4.80 Hz, 1H)
2.30 (dd, J=7.71, 4.67 Hz, 1H) 2.67 (t, J=11.75 Hz, 2H) 2.83 (s,
3H) 3.11 (t, J=8.46 Hz, 1H) 3.56 (d, J=12.13 Hz, 2H) 3.71 (d,
J=7.33 Hz, 2H) 6.12 (d, J=7.33 Hz, 1H) 6.66-6.80 (m, 1H) 7.10-7.20
(m, 2H) 7.25-7.34 (m, 2H) 7.34-7.43 (m, 2H).
Example 74
(1S,2R) and
(1R,2S)-2-(4-chlorophenyl)-1'-(2-(4-isopropylpiperazin-1-yl)ethyl)spiro[c-
yclopropane-1,3'-indolin]-2'-one
##STR00093##
[0609] (1R,2S) and
(1S,2R)-2-(4-chlorophenyl)-1'-(2,2-dimethoxyethyl)spiro[cyclopropane-1,3'-
-indolin]-2'-one
##STR00094##
[0611] To a solution of (1R,2S) and
(1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
(135 mg, 1 mmol) in DMF (1 mL) was added KHMDS (0.5 M in THF, 1.1
mL) was dropwise at room temperature. The mixture was stirred for
half an hour before adding bromoacetaldehyde dimethyl acetal (95
mg, 0.55 mmol). The mixture was warmed to 50.degree. C. and stirred
at that temperature for 2 hours. The mixture was poured into water,
extracted with ethyl acetate (3.times.15 mL), dried and
concentrated under reduced pressure. Purification by flash column
chromatography on silica gel, eluting with hexanes-EtOAc (6:1 and
then 4:1) gave the desire product as colorless oil (268 mg, 75%).
LC/MS m/e calcd. for C.sub.20H.sub.20ClNO.sub.3: 3570, observed
(M+H).sup.+: 358.7.
(1R,2S) and
(1S,2R)-2-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)acetaldehyde
##STR00095##
[0613] A suspension of (1R,2S) and
(1S,2R)-2-(4-chlorophenyl)-1'-(2,2-dimethoxyethyl)spiro[cyclopropane-1,3'-
-indolin]-2'-one (1 g) in water (1 mL) was cooled to 0.degree. C.
and treated with a mixture of DCM and TFA(1:1, 6 mL) for 2 hours.
The reaction mixture was poured into saturated aq. NaHCO.sub.3
solution and extracted with DCM (3.times.6 mL). The combined
organic layers were washed with brine and dried over
Na.sub.2SO.sub.4. The solvent was evaporated under reduced
pressure. The crude product was used for next step directly without
any further purification. LC/MS m/e calcd. for
C.sub.18H.sub.14ClNO.sub.2: 311, observed (M+H).sup.+: 312.3.
(1S,2R) and
(1R,2S)-2-(4-chlorophenyl)-1'-(2-(4-isopropylpiperazin-1-yl)ethyl)spiro[c-
yclopropane-1,3'-indolin]-2'-one
##STR00096##
[0615] A mixture of (1R,2S) and
(1S,2R)-2-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)acetaldehyde (0.1 mmol), (1-Isopropyl)piperazine (0.15 mmol) and
acetic acid (catalytic amount) in DCM (2 ml) was stirred for 20
minutes at room temperature. The mixture was cooled to 0.degree. C.
and NaBH(OAc).sub.3 (2 mmol) was added carefully. The mixture was
warmed to room temperature and stirred for 14 hours at room
temperature. The mixture was concentrated under reduced pressure
and dissolved in DMF. Purification by preparative HPLC gave the
title product as colorless oil (35 mg). LC/MS m/e calcd. for
C.sub.25H.sub.30ClN.sub.3O: 423, observed (M+H).sup.+: 424.1
.sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 1.37 (d, J=6.57 Hz,
6H) 2.18 (dd, J=8.46, 5.94 Hz, 2H) 2.46-2.64 (m, 1H) 2.85 (d,
J=3.54 Hz, 2H) 3.22 (s, 2H) 3.50 (d, J=6.57 Hz, 2H) 3.90-4.27 (m,
2H) 6.09 (d, J=7.58 Hz, 1H) 6.76 (s, 1H) 7.10 (d, J=7.83 Hz, 1H)
7.16-7.25 (m, 3H) 7.33 (d, J=8.59 Hz, 2H).
Example 75
(1S,2R) and
(1R,2S)-2-(4-chlorophenyl)-1'-(2-(4-(2-(dimethylamino)ethyl)piperazin-1-y-
l)ethyl)spiro[cyclopropane-1,3'-indolin]-2'-one
##STR00097##
[0617] The title compound was prepared in analogy to Example 74
starting from 1-(2-Dimethylamino-ethyl)-piperazine,
bromoacetaldehyde dimethyl acetal (commercially available), (1R,2S)
and
(1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.26H.sub.33ClN.sub.4O: 452, observed (M+H).sup.+: 453.1
.sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 2.15-2.33 (m, 3H)
2.86 (t, J=5.81 Hz, 3H) 2.96 (s, 6H) 3.27 (t, J=8.59 Hz, 3H)
3.45-3.76 (m, 3H) 4.32 (d, J=48.76 Hz, 3H) 6.12 (d, J=7.58 Hz, 1H)
6.81 (t, J=7.20 Hz, 1H) 7.11-7.19 (m, 1H) 7.20-7.28 (m, 3H)
7.30-7.41 (m, 2H).
Example 76
(1S,2R)-2-(4-chlorophenyl)-1'-(2-((S)-3-(dimethylamino)pyrrolidin-1-yl)eth-
yl)spiro[cyclopropane-1,3'-indolin]-2'-one and
(1R,2S)-2-(4-chlorophenyl)-1'-(2-((S)-3-(dimethylamino)pyrrolidin-1-yl)et-
hyl)spiro[cyclopropane-1,3'-indolin]-2'-one
##STR00098##
[0619] The title compound was prepared in analogy to Example 74
starting from (3S)-(-)-3-(dimethylamino)pyrrolidine,
bromoacetaldehyde dimethyl acetal (commercially available), (1R,2S)
and
(1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.24H.sub.28ClN.sub.3O: 409, observed (M+H).sup.+: 410.2
.sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 1.32 (s, 2H)
2.09-2.40 (m, 5H) 2.50-2.76 (m, 1H) 2.96 (d, J=6.82 Hz, 6H)
3.15-3.32 (m, 3H) 3.43-3.55 (m, 1H) 3.66 (br. s., 3H) 3.75-3.93 (m,
1H) 4.00-4.42 (m, 5H) 6.09 (d, J=7.58 Hz, 1H) 6.79 (t, J=7.58 Hz,
1H) 7.13 (d, J=7.58 Hz, 1H) 7.18-7.26 (m, 3H) 7.28-7.40 (m,
2H).
Example 77
(1S,2R)-2-(4-chlorophenyl)-1'-(2-((R)-3-(dimethylamino)pyrrolidin-1-yl)eth-
yl)spiro[cyclopropane-1,3'-indolin]-2'-one and
(1R,2S)-2-(4-chlorophenyl)-1'-(2-((R)-3-(dimethylamino)pyrrolidin-1-yl)et-
hyl)spiro[cyclopropane-1,3'-indolin]-2'-one
##STR00099##
[0621] The title compound was prepared in analogy to Example 74
starting from (3R)-(+)-3-(dimethylamino)pyrrolidine,
bromoacetaldehyde dimethyl acetal (commercially available), (1R,2S)
and
(1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.29H.sub.27ClN.sub.2O.sub.2: 470, observed (M+H).sup.+: 471.2
1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 1.32 (s, 1H) 2.04-2.39
(m, 4H) 2.47-2.69 (m, 1H) 2.95 (d, J=6.82 Hz, 6H) 3.23 (s, 3H) 3.58
(br. s., 4H) 3.72-3.93 (m, 1H) 3.98-4.50 (m, 4H) 6.09 (d, J=7.33
Hz, 1H) 6.79 (t, J=7.58 Hz, 1H) 7.13 (d, J=7.83 Hz, 1H) 7.17-7.25
(m, 3H) 7.28-7.39 (m, 2H).
Example 78
(1R,2S) and
(1S,2R)-2-(4-chlorophenyl)-1'-(pyridin-4-ylmethyl)spiro[cyclopropane-1,3'-
-indolin]-2'-one
##STR00100##
[0623] (1R,2S) and
(1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
(135 mg, 0.5 mmol), 4-bromomethyl-pyridine (98 mg, 0.6 mmol) and
Cs.sub.2CO.sub.3 (245 mg, 0.75 mmol) were dissolved in DMF (2 mL).
The mixture was stirred at room temperature for 14 hours. The
mixture was poured into water, extracted with ethyl acetate, dried
and concentrated under reduced pressure. The residue was dissolved
in 2 mL of DMF. Purification by preparative HPLC gave the title
compound as little yellow solid (140 mg, 76%). LC/MS m/e calcd. for
C.sub.22H.sub.17ClN.sub.2O: 360, observed (M+H).sup.+: 361.2
.sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 2.22-2.37 (m, 2H)
3.32-3.40 (m, 1H) 5.39 (s, 2H) 6.15 (d, J=7.58 Hz, 1H) 6.74-6.85
(m, 1H) 6.92 (d, J=7.83 Hz, 1H) 7.10-7.19 (m, 1H) 7.24-7.42 (m, 4H)
7.93 (d, J=6.32 Hz, 2H) 8.80 (d, J=6.06 Hz, 2H). MS calcd. for
C.sub.22H.sub.17ClN.sub.2O 360, obsd. (ESI.sup.+)
[(M+H).sup.+]361.1.
Example 79
(1S,2R) and
(2R,1S)-2-(4-chlorophenyl)-1'-(pyridin-3-ylmethyl)spiro[cyclopropane-1,3'-
-indolin]-2'-one
##STR00101##
[0625] The title compound was prepared in analogy to Example 78
starting from 3-bromomethyl-pyridine (commercially available),
(1R,2S) and
(1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.29H.sub.27ClN.sub.2O.sub.2: 470, observed (M+H).sup.+: 471.2
.sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 2.25 (dd, J=8.59,
1.77 Hz, 2H) 3.31 (br. s., 1H) 5.28 (d, J=3.03 Hz, 2H) 6.12 (d,
J=7.58 Hz, 1H) 6.71-6.85 (m, 1H) 7.03 (d, J=8.08 Hz, 1H) 7.12-7.19
(m, 1H) 7.21-7.29 (m, 2H) 7.30-7.39 (m, 2H) 7.86-7.99 (m, 1H) 8.40
(d, J=8.59 Hz, 1H) 8.74 (d, J=5.31 Hz, 1H) 8.84 (s, 1H).
Example 80
(1S,2R) and
(1R,2S)-2-(4-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]--
1'-yl)-1H-imidazol-1-yl)acetic acid
##STR00102##
[0626] (1S,2R) and
(1R,2S)-2-(4-chlorophenyl)-1'-(1-trityl-1H-imidazol-4-yl)spiro[cyclopropa-
ne-1,3'-indolin]-2'-one
##STR00103##
[0628] 4-Iodo-1-trityl-1H-imidazole (210 mg, 0.48 mmol) was added
to a suspension of racemic
(1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
(107 mg, 0.4 mmol) in acetonitrile (2 mL) under a nitrogen
atmosphere. A steady stream of nitrogen was bubbled through the
suspension as it was heated to 40.degree. C. over 15 minutes.
Potassium carbonate (110 mg, 0.8 mmol), copper (I) iodide (12 mg,
15 mol %), and N,N-dimethylethylenediamine (0.12 mmol, 30 mol %)
were added and the reaction mixture was heated to 80.degree. C. and
kept for 21 hours under nitrogen atmosphere. The mixture was cooled
to room temperature, filtered and concentrated to give the title
product. The residue was purified by flash column chromatography
(gradient elution, 5-10% ethyl acetate in petroleum ether) to give
racemic
trans-2-(4-chlorophenyl)-1'-(1H-imidazol-4-trityl)spiro[cyclopropane-1,3'-
-indolin]-2'-one (157 mg, 68%). LC/MS m/e calcd. for
C.sub.38H.sub.28ClN.sub.3O: 577, observed (M+H).sup.+: 578.2 MS
calcd. for C.sub.38H.sub.28ClN.sub.3O 578, obsd. (ESI.sup.+)
[(M+H).sup.+]579.3.
(1S,2R) and
(1R,2S)-2-(4-chlorophenyl)-1'-(1H-imidazol-4-yl)spiro[cyclopropane-1,3'-i-
ndolin]-2'-one
##STR00104##
[0630] To a solution of racemic (1S,2R) and
(1R,2S)-2-(4-chlorophenyl)-1'-(1-trityl-1H-imidazol-4-yl)spiro[cyclopropa-
ne-1,3'-indolin]-2'-one (115 mg, 0.2 mmol) in DCM (2 mL) and water
(0.5 mL) was added TFA (0.1 mL) dropwise at 0.degree. C. The
mixture was stirred for 14 hours at room temperature. The mixture
was poured into the sat. aqueous NaHCO.sub.3 solution, extracted
with DCM (3.times.10 mL), dried and concentrated to give the title
product. The residue was dissolved in 2 mL of DMF. Purification by
preparative HPLC gave the title compound as white powder (60 mg,
89%). LC/MS m/e calcd. for C.sub.19H.sub.14ClN.sub.3O: 335,
observed (M+H).sup.+: 336.1 .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta.ppm 2.13 (dd, J=9.09, 5.05 Hz, 1H) 2.42 (dd, J=8.08, 4.80
Hz, 1H) 3.23 (t, J=8.72 Hz, 1H) 6.20 (d, J=7.58 Hz, 1H) 6.81 (t,
J=7.20 Hz, 1H) 7.16 (t, J=7.83 Hz, 1H) 7.30-7.45 (m, 5H) 7.66 (s,
1H) 8.27 (s, 1H). MS calcd. for C.sub.19H.sub.14ClN.sub.3O 335,
obsd. (ESI.sup.+) [(M+H).sup.+]336.3.
Synthesis of (1S,2R) and
(1R,2S)-2-(4-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]--
1'-yl)-1H-imidazol-1-yl)acetic acid
##STR00105##
[0632] To a mixture of racemic (1S,2R) and
(1S,2R)-2-(4-chlorophenyl)-1'-(1H-imidazol-4-yl)spiro[cyclopropane-1,3'-i-
ndolin]-2'-one (0.4 mmol, 134 mg), methyl-bromoacetate (61.2 mg,
0.4 mmol) and 5 mg of TEBA (0.008 mmol) in 2 mL of DCM was added
50% KOH (0.5 mL). The reaction mixture was stirred at room
temperature for 14 hours. Then the mixture was concentrated under
reduced pressure and acidified to pH.about.4. The residue was
dissolved in 2 mL of DMF. Purification by preparative HPLC gave the
title compound as a white powder (113 mg, 68%). LC/MS m/e calcd.
for C.sub.21H.sub.16ClN.sub.3O.sub.3: 393, observed (M+H).sup.+:
394.2 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 2.05-2.16 (m,
1H) 2.39 (dd, J=7.96, 4.93 Hz, 1H) 3.20 (t, J=8.72 Hz, 1H) 4.97 (s,
2H) 6.18 (d, J=7.07 Hz, 1H) 6.79 (t, J=7.20 Hz, 1H) 7.06-7.22 (m,
1H) 7.38 (s, 4H) 7.54 (d, J=1.01 Hz, 1H) 7.69 (d, J=7.83 Hz, 1H)
7.74 (d, J=1.26 Hz, 1H). MS calcd. for
C.sub.21H.sub.16ClN.sub.3O.sub.3 393, obsd. (ESI.sup.+)
[(M+H).sup.+]394.3.
Example 81
(1S,2R) and
(1R,2S)-1-(2-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]--
1'-yl)ethyl)-1H-imidazole-4-carboxylic acid
##STR00106##
[0633] Synthesis of (1S,2R) and
(1R,2S)-1'-(2-bromoethyl)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indol-
in]-2'-one
##STR00107##
[0635] To a solution of (1R,2S) and
(1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
(173 mg, 0.64 m mol) in DMF (2 mL) was added KHMDS (0.5 M, 1.4 mL)
dropwise at room temperature. The mixture was stirred for half an
hour before adding ethylene dibromide (300 mg, 1.6 mmol). The
mixture was warmed to 50.degree. C. and stirred at that temperature
for 14 hours. The mixture was poured into water, extracted with
ethyl acetate (3.times.15 mL), dried and concentrated under reduced
pressure. The residue was purified by flash column chromatography
(gradient elution, 5-10% ethyl acetate in petroleum ether) to give
the title compound as white solid (98 mg, 41%). LC/MS m/e calcd.
for C.sub.18H.sub.15BrClNO: 375, observed (M+H).sup.+: 376.
Synthesis of (1S,2R) and
(1R,2S)-methyl-1-(2-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-ind-
oline]-1'-yl)ethyl)-1H-imidazole-4-carboxylate
##STR00108##
[0637] To a solution of methyl-imidazole-4-carboxylate (100 mg, 0.2
mmol) in 1 mL of anhydrous DMF was added NaH (60% disp.) (8.8 mg,
0.22 mmol) at room temperature. The reaction mixture was stirred
for 1 hour at that temperature. To the mixture was added a solution
of racemic (1R,2S) and
(1S,2R)-1'-(2-bromoethyl)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indol-
in]-2'-one (75.2 mg, 0.2 mmol) in 1 mL of DMF. The reaction was
stirred at room temperature for 14 hours and then concentrated
under reduced pressure. The residue was dissolved in EtOAc and
washed with saturated aqueous NaHCO.sub.3. The layers were
separated and the aqueous layer was extracted with EtOAc. The
organic layers were combined and washed with brine, dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to
give the title compound as white solid (30 mg, 35%). LC/MS m/e
calcd. for C.sub.23H.sub.20ClN.sub.3O.sub.3: 421, observed
(M+H).sup.+: 422.3.
Synthesis of (1S,2R) and
(1R,2S)-1-(2-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]--
1'-yl)ethyl)-1H-imidazole-4-carboxylic acid
##STR00109##
[0639] To a solution of
methyl-1-(2-((1S,2R)-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-ind-
oline]-1'-yl)ethyl)-1H-imidazole-4-carboxylate and
methyl-1-(2-((1R,2S)-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-ind-
oline]-1'-yl)ethyl)-1H-imidazole-4-carboxylate (0.07 mmol) in
methanol (2 mL) and water (1 mL) was added LiOH.H.sub.2O (18 mg,
0.4 mmol) in one portion. The mixture was stirred at room
temperature for 3 hours until the starting material was consumed.
The mixture was concentrated under reduced pressure and acidified
to pH.about.3. The residue was dissolved in 2 mL of DMF.
Purification by preparative HPLC gave the title compound as a white
powder (26 mg, 88%). LC/MS m/e calcd. for
C.sub.22H.sub.18ClN.sub.3O.sub.3: 407, observed (M+H).sup.+: 408.8
.sup.1H NMR (400 MHz, MeOD) .delta.ppm 2.10 (dd, J=28.17, 8.46 Hz,
2H) 3.10 (s, 1H) 4.31 (s, 2H) 4.86 (s, 2H) 6.05 (d, J=7.33 Hz, 1H)
6.75 (s, 1H) 6.90-7.45 (m, 6H) 7.86 (s, 1H) 8.27 (s, 1H).
Example 82
(1S,2S) and
(1R,2R)-1-(2-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]--
1'-yl)ethyl)-1H-imidazole-4-carboxylic acid
##STR00110##
[0641] The title compound was prepared in analogy to Example 81
starting from methyl-imidazole-4-carboxylate, ethylene dibromide
(commercially available), (1R,2S) and
(1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.22H.sub.18ClN.sub.3O.sub.3: 407, observed (M+H).sup.+: 408.8
.sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 2.25 (dd, J=8.59,
1.77 Hz, 2H) 3.31 (br. s., 1H) 5.28 (d, J=3.03 Hz, 2H) 6.12 (d,
J=7.58 Hz, 1H) 6.71-6.85 (m, 1H) 7.03 (d, J=8.08 Hz, 1H) 7.12-7.19
(m, 1H) 7.21-7.29 (m, 2H) 7.30-7.39 (m, 2H) 7.86-7.99 (m, 1H) 8.40
(d, J=8.59 Hz, 1H) 8.74 (d, J=5.31 Hz, 1H) 8.84 (s, 1H).
Example 83
(1S,2R) and
(1R,2S)-3-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)benzoic acid
##STR00111##
[0642] Synthesis of (1S,2R) and
(1R,2S)-methyl-3-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoli-
ne]-1'-yl)benzoate
##STR00112##
[0644] A Schlenk tube was charged with CuI (9.6 mg, 0.05 mmol, 5.0
mol %), racemic (1R,2S) and
(1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
(270 mg, 1.0 mmol), and K.sub.2CO.sub.3 (276 mg, 2.0 mmol),
evacuated, and backfilled with argon. N,N'-Dimethylethylenediamine
(11 .mu.L, 0.10 mmol, 10 mol %), ethyl 3-iodobenzoate (278.8 mg,
1.01 mmol), and acetonitrile (1.5 mL) were added under argon. The
Schlenk tube was sealed with a Teflon valve and the reaction
mixture was stirred at 80.degree. C. for 23 hours. HPLC monitored
the reaction finished. The solvent was removed under reduced
pressure. The residue was purified by flash column chromatography
column (gradient elution, 5-10% ethyl acetate in petroleum ether)
to give the title compound as a yellow powder (290 mg, 72%). LC/MS
m/e calcd. for C.sub.24H.sub.18ClNO.sub.3: 403, observed
(M+H).sup.+: 404.1.
Synthesis of (1S,2R) and
(1R,2S)-3-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)benzoic acid
##STR00113##
[0646] To a solution of
methyl-3-((1S,2R)-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoli-
ne]-1'-yl)benzoate and
methyl-3-((1R,2S)-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoli-
ne]-1'-yl)benzoate (50 mg) in 1 mL of methanol was added 0.1 mL of
water, followed by lithium hydroxide (10 mg), The mixture was
stirred for 14 hours at room temperature. HPLC monitored the
reaction finished. The solvent was removed under reduced pressure.
The residue was dissolved in 2 mL of DMF. Purification by
preparative HPLC gave the title compound as a white powder. (11 mg)
LC/MS m/e calcd. for C.sub.23H.sub.16ClNO.sub.3 389, observed
(M+H).sup.+: 390.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm
2.14 (dd, J=9.09, 5.05 Hz, 1H) 2.41 (dd, J=8.08, 5.05 Hz, 1H) 3.25
(t, J=8.59 Hz, 1H) 6.19 (d, J=7.33 Hz, 1H) 6.77-6.86 (m, 2H) 7.12
(t, J=7.71 Hz, 1H) 7.36-7.46 (m, 4H) 7.72 (t, J=7.83 Hz, 1H)
7.76-7.85 (m, 1H) 8.01-8.09 (m, 2H).
Example 84
(1S,2S) and
(1R,2R)-3-(-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)benzoic acid
##STR00114##
[0648] The title compound was prepared in analogy to Example 81
starting from methyl-ethyl-3-iodobenzoate (commercially available),
(1R,2R) and
(1S,2S)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1 LC/MS m/e calcd. for
C.sub.23H.sub.16ClNO.sub.3 389, observed (M+H).sup.+: 390.1.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 2.31-2.42 (m, 2H)
3.42 (t, J=8.72 Hz, 1H) 6.88 (d, J=7.58 Hz, 1H) 7.15 (t, J=7.20 Hz,
1H) 7.22-7.28 (m, 1H) 7.28-7.36 (m, 3H) 7.36-7.41 (m, 2H) 7.60-7.70
(m, 2H) 7.86 (s, 1H) 7.93-8.00 (m, 1H) 13.24 (br. s, 1H).
Example 85
(1S,2S) and
(1R,2R)-2-(4-chlorophenyl)-1'-(3-(morpholine-4-carbonyl)phenyl)spiro[cycl-
opropane-1,3'-indolin]-2'-one
##STR00115##
[0650] A mixture of (1S,2S) and
(1R,2R)-3-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)benzoic acid (117 mg, 0.3 mmol),
0-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate (TBTU)(145 mg, 0.45 mmol),
N,N-Diisopropylethylamine (DIPEA) (154 .mu.L, 0.9 mmol) and
morpholine (79 .mu.L, 0.9 mmol) in DMF (2 mL) was stirred at room
temperature for 14 hours. Purification by preparative HPLC gave
desired product as a white solid (83 mg, 60%). LC/MS m/e calcd. for
C.sub.27H.sub.23ClN.sub.2O.sub.3:458, observed (M+H).sup.+: 459.2
.sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 2.23-2.31 (m, 2H)
3.28-3.32 (m, 1H) 3.77 (br. s., 8H) 6.16 (d, J=7.58 Hz, 1H) 6.81
(t, J=7.58 Hz, 1H) 6.93 (d, J=7.83 Hz, 1H) 7.11-7.19 (m, 1H)
7.26-7.33 (m, 2H) 7.33-7.38 (m, 2H) 7.56 (d, J=7.58 Hz, 1H)
7.60-7.67 (m, 2H) 7.68-7.76 (m, 1H).
Example 86
(1S,2S) and
(1R,2R)-2-(4-chlorophenyl)-1'43-(4-methylpiperazine-1-carbonyl)phenyl)spi-
ro[cyclopropane-1,3'-indolin]-2'-one
##STR00116##
[0652] The title compound was prepared in analogy to Example 85
starting from 1-methylpiperazine, methyl-3-iodobenzoate
(commercially available), (1R,2R) and
(1S,2S)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.28H.sub.26ClN.sub.3O.sub.2: 471, observed (M+H).sup.+: 472.2
.sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 2.22-2.35 (m, 2H)
2.98 (s, 3H) 3.35-3.39 (m, 1H) 6.17 (d, J=7.58 Hz, 1H) 6.83 (t,
J=7.58 Hz, 1H) 6.96 (d, J=8.08 Hz, 1H) 7.13-7.21 (m, 1H) 7.27-7.33
(m, 2H) 7.34-7.40 (m, 2H) 7.60-7.65 (m, 1H) 7.68-7.80 (m, 3H).
Example 87
(1S,2S) and
(1R,2R)-2-(4-chlorophenyl)-1'-(3-(4-(methylsulfonyl)piperazine-1-carbonyl-
)phenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
##STR00117##
[0654] The title compound was prepared in analogy to Example 85
starting from 1-methanesulfonyl-piperazine, methyl-3-iodobenzoate
(commercially available), (1R,2R) and
(1S,2S)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.28H.sub.26ClN.sub.3O.sub.4S: 535, observed (M+H).sup.+: 536.2
.sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 2.22-2.36 (m, 2H)
2.90 (s, 3H) 3.35-3.39 (m, 1H) 3.58-4.01 (m, 8H) 6.16 (d, J=7.58
Hz, 1H) 6.82 (t, J=7.58 Hz, 1H) 6.95 (d, J=7.58 Hz, 1H) 7.16 (t,
J=7.83 Hz, 1H) 7.27-7.40 (m, 4H) 7.58 (d, J=7.33 Hz, 1H) 7.62-7.79
(m, 3H).
Example 88
(1R,2S) and
(1S,2R)-2-(4-chlorophenyl)-1'-(3-(morpholine-4-carbonyl)phenyl)spiro[cycl-
opropane-1,3'-indolin]-2'-one
##STR00118##
[0656] The title compound was prepared in analogy to Example 85
starting from morpholine, methyl-3-iodobenzoate (commercially
available), (1R,2S) and
(1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.27H.sub.23ClN.sub.2O.sub.3: 458, observed (M+H).sup.+: 459.1
.sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 2.34 (dd, J=8.97,
4.93 Hz, 1H) 2.44 (dd, J=8.59, 5.05 Hz, 1H) 3.35-3.39 (m, 1H) 3.67
(br. s., 8H) 6.96 (d, J=7.83 Hz, 1H) 7.17-7.26 (m, 2H) 7.26-7.36
(m, 5H) 7.41 (s, 1H) 7.46-7.52 (m, 2H) 7.64 (t, J=7.83 Hz, 1H).
Example 89
(1S,2R) and
(1R,2S)-2-(4-chlorophenyl)-1'43-(4-methylpiperazine-1-carbonyl)phenyl)spi-
ro[cyclopropane-1,3'-indolin]-2'-one
##STR00119##
[0658] The title compound was prepared in analogy to Example 85
starting from 1-methylpiperazine, methyl-3-iodobenzoate
(commercially available), (1R,2S) and
(1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.28H.sub.26ClN.sub.3O.sub.2: 471, observed (M+H).sup.+: 472.2
.sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 2.34 (dd, J=9.09,
5.05 Hz, 1H) 2.43 (dd, J=8.59, 5.05 Hz, 1H) 2.93 (s, 3H) 3.17 (br.
s., 4H) 3.40 (t, J=8.84 Hz, 1H) 3.62 (br. s., 4H) 6.97 (d, J=7.83
Hz, 1H) 7.16-7.25 (m, 2H) 7.26-7.38 (m, 5H) 7.49 (s, 1H) 7.55 (t,
J=7.71 Hz, 2H) 7.67 (t, J=7.83 Hz, 1H).
Example 90
(1R,2S) and
(1S,2R)-2-(4-chlorophenyl)-1'-(3-(4-(methylsulfonyl)piperazine-1-carbonyl-
)phenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
##STR00120##
[0660] The title compound was prepared in analogy to Example 85
starting from 1-Methanesulfonyl-piperazine, methyl-3-iodobenzoate
(commercially available), (1S,2R) and
(1R,2S)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.28H.sub.26ClN.sub.3O.sub.4S: 535, observed (M+H).sup.+: 536.2
.sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 2.32 (dd, J=8.97,
4.93 Hz, 1H) 2.43 (dd, J=8.72, 4.93 Hz, 1H) 2.86 (s, 3H) 3.20 (br.
s., 4H) 3.38 (t, J=8.84 Hz, 1H) 3.71 (br. s., 4H) 6.96 (d, J=7.83
Hz, 1H) 7.14-7.24 (m, 2H) 7.24-7.36 (m, 5H) 7.46 (s, 1H) 7.47-7.53
(m, 2H) 7.64 (t, J=7.83 Hz, 1H).
Example 91
(1R,2R) and
(1S,2S)-3-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)-N-(methylsulfonyl)benzamide
##STR00121##
[0662] The title compound was prepared in analogy to Example 85
starting from methanesulfonamide, methyl-3-iodobenzoate
(commercially available), (1R,2R) and
(1S,2S)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.24H.sub.19ClN.sub.2O.sub.4S: 466, observed (M+H).sup.+: 467.2
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 2.31-2.41 (m, 2H)
3.37 (s, 3H) 3.43 (t, J=8.72 Hz, 1H) 6.90 (d, J=7.83 Hz, 1H) 7.16
(t, J=7.33 Hz, 1H) 7.25 (dd, J=7.83, 1.01 Hz, 1H) 7.27-7.35 (m, 3H)
7.35-7.43 (m, 2H) 7.62-7.70 (m, 2H) 7.94-7.99 (m, 2H) 12.24 (br.
s., 1H).
Example 92
(1S,2S) and
(1R,2R)-3-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)-5-(2-oxooxazolidin-3-yl)benzoic acid
##STR00122##
[0663] Synthesis of 3-bromo-5-iodo-benzoic acid methylester
[0664] To a suspension of 3-bromo-5-iodo-benzoic acid (6.5 g, 20
mmol) in 25 mL of methanol was added SOCl.sub.2 (1.14 mL, 40 mmol)
dropwise at 0.degree. C. The mixture was then warmed to room
temperature and stirred at room temperature for 2 days. The
precipitates formed were collected by filtration to afford the
desired product as white solid 5.12 g (75%). LC/MS m/e calcd. for
C.sub.8H.sub.6BrIO.sub.2: 341, observed (M+H).sup.+: 342.2.
Synthesis of (1S,2S) and
(1R,2R)-methyl-3-bromo-5-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3-
'-indoline]-1'-yl)benzoate
##STR00123##
[0666] A Schlenk tube charged with CuI (214 mg, 1.124 mmol, 20 mmol
%), (1S,2S) and
(1R,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
(1.50 g, 5.62 mmol) and K.sub.2CO.sub.3 (2.30 g, 16.86 mmol) was
evacuated and backfilled with argon. N,N'-dimethylethylenediamine
(242 .mu.L, 2.25 mmol, 40 mol %), 3-Bromo-5-iodo-benzoic acid
methyl ester (2.30 g, 6.75 mmol, 1.2 equiv.) and acetonitrile (5
mL) were added under argon. The Schlenk tube was sealed with a
Teflon valve and the reaction mixture was stirred at 90.degree. C.
for 3 hours. HPLC monitor the reaction finished. The solvent was
removed under reduced pressure. The residue was purified by flash
column chromatography (gradient elution, 5-15% ethyl acetate in
petroleum ether) to give the title compound as white powder (1.3 g,
48%). LC/MS m/e calcd. for C.sub.24H.sub.17BrClNO.sub.3: 482,
observed (M+H).sup.+: 483.
Synthesis of racemic methyl-(1R,2R) and
(1S,2S)-3-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)-5-(2-oxooxazolidin-3-yl)benzoate
##STR00124##
[0668] A mixture of (1S,2S) and
(1R,2R)-3-bromo-5-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indol-
ine]-1'-yl)benzoate (120 mg, 0.25 mmol), oxazolidin-2-one (27 mg,
0.3 mmol), CuI (10 mg, 20 mmol %), Dimethylamino-acetic acid (11
mg, 40 mmol %) and K.sub.2CO.sub.3 (68 mg, 0.5 mmol) in DMSO (5.0
mL) was stirred at 150.degree. C. under microwave irradiation for
1.5 hours. The precipitate was filtered off and the filtrate was
concentrated to give the crude desired product (43 mg, 35%) which
was used for the next step without further purification.
Synthesis of (1S,2S) and
(1R,2R)-3-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)-5-(2-oxooxazolidin-3-yl)benzoic acid
##STR00125##
[0670] To a solution of (1S,2S) and
(1R,2R)-3-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)-5-(2-oxooxazolidin-3-yl)benzoate (43 mg, 0.088 mmol) in MeOH (2
mL) and H.sub.2O (0.2 mL) was added lithium hydroxide (18 mg, 0.44
mmol). The reaction mixture was stirred at room temperature until
TLC indicated no further reaction. The methanol was removed under
reduced pressure. After quenching with concentrated HCl (3.0 N),
the mixture was extracted with ethyl acetate for three times. The
organic layers were dried over anhydrous Na.sub.2SO.sub.4 and
concentrated to give the crude product. Purification by preparative
HPLC gave desired product as white solid (29 mg, 70%). LC/MS m/e
calcd. for C.sub.26H.sub.19ClN.sub.2O.sub.5: 474, observed
(M+H).sup.+: 475.1 .sup.1H NMR (400 MHz, MeOD-d4) .delta.ppm
2.22-2.33 (m, 2H) 3.35-3.39 (m, 1H) 4.22 (t, J=8.08 Hz, 2H) 4.56
(t, J=7.96 Hz, 2H) 6.15 (d, J=7.07 Hz, 1H) 6.81 (t, J=7.20 Hz, 1H)
6.96 (d, J=7.83 Hz, 1H) 7.15 (t, J=7.33 Hz, 1H) 7.33 (q, J=8.51 Hz,
4H) 7.91 (s, 1H) 8.11 (t, J=2.02 Hz, 1H) 8.26 (s, 1H).
Example 93
(1S,2S) and
(1R,2R)-3-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)-5-(methylsulfonyl)benzoic acid
##STR00126##
[0672] The title compound was prepared in analogy to Example 92
starting from methanesulfinic acid sodium salt,
3-bromo-5-iodo-benzoic acid (commercially available), (1R,2R) and
(1S,2S)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.24H.sub.18ClNO.sub.5S: 467, observed (M+H).sup.+: 468.1
.sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 2.27-2.36 (m, 2H)
3.28 (s, 3H) 3.38 (t, J=8.59 Hz, 1H) 6.18 (d, J=7.58 Hz, 1H) 6.85
(t, J=7.20 Hz, 1H) 7.00 (d, J=7.83 Hz, 1H) 7.14-7.23 (m, 1H)
7.28-7.40 (m, 4H) 8.38 (t, J=1.89 Hz, 1H) 8.49 (s, 1H) 8.62 (s,
1H).
Example 94
(1S,2S) and
(1R,2R)-3-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)-5-(2-oxopyrrolidin-1-yl)benzoic acid
##STR00127##
[0674] The title compound was prepared in analogy to Example 92
starting from 2-pyrrolidone, 3-bromo-5-iodo-benzoic acid
(commercially available), (1R,2R) and
(1S,2S)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.27H.sub.21ClN.sub.2O.sub.4: 472, observed (M+H).sup.+: 4731.2
.sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 2.18-2.35 (m, 4H)
2.67 (t, J=8.08 Hz, 2H) 3.35-3.39 (m, 1H) 4.05 (t, J=7.07 Hz, 2H)
6.16 (d, J=7.07 Hz, 1H) 6.82 (t, J=7.45 Hz, 1H) 6.97 (d, J=7.33 Hz,
1H) 7.12-7.20 (m, 1H) 7.34 (q, J=8.67 Hz, 4H) 7.95 (s, 1H) 8.20 (t,
J=1.89 Hz, 1H) 8.33 (s, 1H).
Example 95
(1R,2R) and
(1S,2S)-3-(2-(4-chlorophenyl)-5'-fluoro-2-isopropyl-2'-oxospiro[cycloprop-
ane-1,3'-indoline]-1'-yl)-5-(2-oxooxazolidin-3-yl)benzoic acid
##STR00128##
[0675] Synthesis of (1S,2S) and
(1R,2R)-methyl-3-bromo-5-(2-(4-chlorophenyl)-5'-fluoro-2-isopropyl-2'-oxo-
spiro[cyclopropane-1,3'-indoline]-1'-yl)benzoate
##STR00129##
[0677] (1R,2R) and
(1S,2S)-2-(4-chlorophenyl)-5'-fluoro-2-isopropylspiro[cyclopropane-1,3'-i-
ndolin]-2'-one prepared according to Scheme 2 (0.33 g, 1 mmol), and
the 3-bromo-5-iodo-benzoic acid methyl ester (0.409 g, 1.2 mmol),
CuI (20 mg), K.sub.2CO.sub.3 (0.276 g, 2 mmol) were placed in a
Schlenk tube under argon atmosphere and dissolved in dry
acetonitrile. The N,N'-dimethyl-1,2-ethanediamine (21 .mu.L) was
added into the mixture. The mixture was stirred at 80.degree. C.
for 14 hours. The solvent was removed in vacuo and the residue was
purified by flash column chromatography to give the title compound
as white powder (0.444 g, 82%). LC/MS m/e calcd. for
C.sub.27H.sub.22BrClFNO.sub.3: 541, observed (M+H).sup.+: 542.
Synthesis of (1R,2R) and
(1S,2S)-methyl-3-(2-(4-chlorophenyl)-5'-fluoro-2-isopropyl-2'-oxospiro[cy-
clopropane-1,3'-indoline]-1'-yl)-5-(2-oxooxazolidin-3-yl)benzoate
##STR00130##
[0679]
3-bromo-5-((1S,2S)-2-(4-chlorophenyl)-5'-fluoro-2-isopropyl-2'-oxos-
piro[cyclopropane-1,3'-indoline]-1'-yl)benzoate,
3-bromo-5-((1R,2R)-2-(4-chlorophenyl)-5'-fluoro-2-isopropyl-2'-oxospiro[c-
yclopropane-1,3'-indoline]-1'-yl)benzoate (0.545 g, 1 mmol),
2-oxazolidone (0.105 g, 1.2 mmol), CuI (20 mg), and K.sub.2CO.sub.3
(0.276 g, 2 mmol) were placed in a Schlenk tube under Argon
atmosphere and dissolved in dry acetonitrile. The
N,N'-dimethyl-1,2-ethanediamine (21 .mu.L, 20% equiv) was added
into the mixture. The mixture was stirred at 80.degree. C. for 14
hours. The solvent was removed in vacuo and the residue was
purified by flash column chromatography to give the title compound
as white powder (0.40 g, 73%). LC/MS m/e calcd. for
C.sub.30H.sub.26ClFN.sub.2O.sub.5: 548, observed (M+H).sup.+:
549.5
Synthesis of (1R,2R) and
(1S,2S)-3-(2-(4-chlorophenyl)-5'-fluoro-2-isopropyl-2'-oxospiro[cycloprop-
ane-1,3'-indoline]-1'-yl)-5-(2-oxooxazolidin-3-yl)benzoic acid
##STR00131##
[0681] To a solution of (1R,2R) and
(1S,2S)-3-bromo-5-(2-(4-chlorophenyl)-5'-fluoro-2-isopropyl-2'-oxospiro[c-
yclopropane-1,3'-indoline]-1'-yl)benzoate (27.4 mg) in methanol (2
mL) and water (1 mL) was added LiOH.H.sub.2O (18 mg, 0.4 mmol) in
one portion. The mixture was stirred at room temperature for 3
hours until the starting material was consumed. The mixture was
concentrated under reduced pressure and acidified to pH.about.3.
The precipitates was collected by filtration and dissolved in 2 mL
of DMF. Purification by preparative HPLC gave the title compound as
white solid (15 mg). LC/MS m/e calcd. for
C.sub.29H.sub.24ClFN.sub.2O.sub.5 534, observed (M+H).sup.+: 545.7.
.sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 0.89 (dd, J=20.34,
6.69 Hz, 6H) 2.21-2.28 (m, 2H) 2.89-3.01 (m, 1H) 4.22 (t, J=8.08
Hz, 2H) 4.55 (t, J=8.08 Hz, 2H) 5.28 (dd, J=8.84, 2.27 Hz, 1H) 6.65
(dd, J=8.34, 1.77 Hz, 1H) 6.80-6.89 (m, 2H) 7.19 (dd, J=8.34, 2.02
Hz, 1H) 7.45-7.54 (m, 2H) 7.86 (s, 1H) 8.09 (s, 1H) 8.22 (s,
1H).
Example 96
(1R,2S) and
(1S,2R)-3-(2-(4-chlorophenyl)-5'-fluoro-2-isopropyl-2'-oxospiro[cycloprop-
ane-1,3'-indoline]-1'-yl)-5-(2-oxooxazolidin-3-yl)benzoic acid
##STR00132##
[0683] The title compound was prepared in analogy to Example 95
starting from 2-oxazolidone (commercially available),
bromo-5-iodo-benzoic acid methyl ester prepared in Example 92,
(1S,2R) and
(1R,2S)-2-(4-chlorophenyl)-5'-fluoro-2-isopropylspiro[cyclopropane-1,3'-i-
ndolin]-2'-one prepared as in Scheme 2. LC/MS m/e calcd. for
C.sub.29H.sub.24ClFN.sub.2O.sub.5: 534, observed (M+H).sup.+: 535.1
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 0.55-0.61 (m, 3H)
0.87 (s, 3H) 2.11-2.18 (m, 1H) 2.28-2.39 (m, 2H) 4.07-4.19 (m, 2H)
4.42-4.52 (m, 2H) 6.84-6.98 (m, 1H) 7.07-7.15 (m, 1H) 7.23 (d,
J=8.34 Hz, 1H) 7.32-7.42 (m, 1H) 7.52 (d, J=9.35 Hz, 1H) 7.64 (br.
s., 1H) 7.79 (br. s., 1H) 8.11 (br. s., 1H).
Example 97
(1R,2R) and
(1S,2S)-3-(2-(4-chlorophenyl)-2-isopropyl-2'-oxospiro[cyclopropane-1,3'-i-
ndoline]-1'-yl)-5-(2-oxooxazolidin-3-yl)benzoic acid
##STR00133##
[0685] The title compound was prepared in analogy to Example 95
starting from 2-oxazolidone (commercially available),
bromo-5-iodo-benzoic acid methyl ester prepared as in Example 92,
(1R,2R) and
(1S,2S)-2-(4-chlorophenyl)-2-isopropylspiro[cyclopropane-1,3'-indolin]-2'-
-one prepared as in Scheme 2. LC/MS m/e calcd. for
C.sub.29H.sub.25ClN.sub.2O.sub.5: 516, observed (M+H).sup.+: 516.1
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 0.77 (d, 3H) 0.85
(d, 3H) 2.10-2.16 (m, 1H) 2.18-2.25 (m, 1H) 2.81-2.97 (m, 1H) 4.17
(t, 2H) 4.50 (t, 2H) 5.49 (d, 1H) 6.64 (d, 1H) 6.71 (t, 1H) 6.86
(d, 1H) 7.10 (t, 1H) 7.22 (d, 1H) 7.45-7.62 (m, 2H) 7.77 (s, 1H)
7.98 (s, 1H) 8.20 (s, 1H).
Example 98
(1S,2S) and
(1R,2R)-3-(2-(4-cyanophenyl)-2-isopropyl-2'-oxospiro[cyclopropane-1,3'-in-
doline]-1'-yl)-5-(2-oxooxazolidin-3-yl)benzoic acid
##STR00134##
[0687] The title compound was prepared in analogy to Example 95
starting from 2-oxazolidone (commercially available),
bromo-5-iodo-benzoic acid methyl ester prepared as in example 92,
(1R,2R) and
(1S,2S)-4-(2-isopropyl-2'-oxospiro[cyclopropane-1,3'-indoline]-2-yl)benzo-
nitrile prepared as in Scheme 2. LC/MS m/e calcd. for
C.sub.30H.sub.25lN.sub.3O.sub.5: 507, observed (M+H).sup.+: 508.2
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 0.78 (d, 3H) 0.86
(d, 3H) 2.14-2.21 (m, 1H) 2.23-2.33 (m, 1H) 2.85-3.02 (m, 1H)
4.10-4.24 (m, 2H) 4.50 (t, 2H) 5.43 (d, 1H) 6.68 (t, 1H) 6.79-6.89
(m, 2H) 7.11 (t, 1H) 7.61 (d, 2H) 7.70 (d, 2H) 7.80 (s, 1H)
7.94-8.02 (m, 2H) 8.22 (s, 1H) 13.45 (s, 1H).
Example 99
(1S,2S) and
(1R,2R)-3-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)-5-(2-oxoimidazolidin-1-yl)benzoic acid
##STR00135##
[0689] The title compound was prepared in analogy to Example 92
starting from ethyleneurea (commercially available),
bromo-5-iodo-benzoic acid methyl ester prepared as in Example 92,
(1R,2R) and
(1S,2S)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.26H.sub.20ClN.sub.3O.sub.4: 473, observed (M+H).sup.+: 474.2
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 2.14 (dd, J=9.22,
4.93 Hz, 1H) 2.41 (dd, J=7.96, 4.67 Hz, 1H) 3.22-3.28 (m, 1H)
3.43-3.49 (m, 1H) 3.92-3.98 (m, 1H) 6.19 (d, J=7.58 Hz, 1H) 6.80
(t, J=7.71 Hz, 1H) 6.85 (d, J=7.83 Hz, 1H) 7.12 (t, J=8.34 Hz, 1H)
7.22 (s, 1H) 7.42 (q, J=8.59 Hz, 3H) 7.64 (s, 1H) 7.99 (t, J=2.02
Hz, 1H) 8.13 (s, 1H).
Example 100
(R) and
(S)-3-((5'-fluoro-2,2-dimethyl-2'-oxospiro[cyclopropane-1,3'-indol-
ine]-1'-yl)methyl)benzoic acid
##STR00136##
[0690] Synthesis of 5-fluoro-3-(propan-2-ylidene)indolin-2-one
[0691] A mixture of 5-fluoro-1,3-dihydro-indol-2-one (2.84 g, 20
mmol), acetone (2.2 mL, 30 mmol) and piperidine (0.8 mL, 8 mmol) in
methanol (100 mL) was heated to reflux for 16 hours. Then the
reaction mixture was allowed to cool to room temperature. The solid
was collected by filtration, washed with methanol (20 mL) and dried
in vacuo to afford
5-fluoro-3-isopropylidene-1,3-dihydro-indol-2-one (2.6 g, 68%) as
powder.
Synthesis of (R) and
(S)-5'-fluoro-2,2-dimethylspiro[cyclopropane-1,3'-indolin]-2'-one
[0692] A solution of NaH (60%) (0.6 g, 15 mmol) and
trimethylsulfoxonium iodide (3.3 g, 15 mmol) in dimethyl sulfoxide
(30 mL) was stirred for 30 minutes at 25.degree. C. Then a solution
of 5-fluoro-3-isopropylidene-1,3-dihydro-indol-2-one (2.6 g, 13.6
mmol) in dry tetrahydrofuran (30 mL) was added dropwise over 20
minutes. After being stirred for 1 hour at 25.degree. C. and 1 hour
at 50.degree. C., the reaction solution was poured into ice-cold
water and extracted with ether (3.times.100 mL), washed with water,
dried over anhydrous sodium sulfate, filtered and concentrated in
vacuo. The residue was recrystallized from ether to afford the
title compound as white solid (2.39 g, 85%).
Synthesis of methyl-(R) and
(S)-3-((5'-fluoro-2,2-dimethyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)benzoate
[0693] 3-Bromomethyl-benzoic acid methyl ester (610 mg, 2.68 mmol)
was added to a suspension of cesium carbonate (1.2 g, 3.66 mmol)
and (R) and
(S)-5'-fluoro-2,2-dimethylspiro[cyclopropane-1,3'-indolin]-2'-one
(500 mg, 2.44 mmol) in DMF (10 mL). The reaction mixture was
stirred for 1 hour at 25.degree. C. Then extracted with ethyl
acetate (3.times.25 mL), washed with brine, dried over anhydrous
sodium sulfate, filtered and concentrated in vacuo to afford the
title compound as white powder (850 mg, 98%).
Synthesis of
3-((5'-fluoro-2,2-dimethyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)-
methyl)benzoic acid
[0694] A mixture of (R) and
(S)-3-((5'-fluoro-2,2-dimethyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)benzoate (850 mg, 2.4 mmol) in tetrahydrofuran (10 mL)
and 30% sodium hydroxide in water (5 mL) was stirred at 25.degree.
C. for 16 hours. The mixture was neutralized with a 2 N aqueous
hydrochloric acid solution, diluted with ethyl acetate (50 mL),
washed with water, dried over anhydrous sodium sulfate and then
concentrated in vacuo. Purification by waters automated flash
system (column: Xterra 30 mm.times.100 mm, sample manager 2767,
pump 2525, detector: ZQ mass and UV 2487, solvent system:
acetonitrile and 0.1% trifluoro-acetic acid in water) afforded the
title compound as white solid (410 mg, 50%): LC/MS m/e calcd. for
C.sub.20H.sub.18FNO.sub.3 (M+H).sup.+: 340.37, observed: 340.2;
LC/MS m/e calcd. for C.sub.20H.sub.18FNO.sub.3: 339, observed
(M+H).sup.+: 340.1 .sup.1H NMR (400 MHz, DMSO-d6) .delta.ppm 1.37
(s, 3H) 1.48 (s, 3H) 1.76 (d, J=4.29 Hz, 1H) 1.88 (d, J=4.29 Hz,
1H) 5.04 (dd, 2H) 6.91-7.08 (m, 2H) 7.17 (dd, J=9.35, 2.53 Hz, 1H)
7.44-7.57 (m, 2H) 7.80-7.93 (m, 2H) 12.99 (s, 1H).
Example 101
(R) and
(S)-3-(5'-fluoro-2,2-dimethyl-2'-oxospiro[cyclopropane-1,3'-indoli-
ne]-1'-yl)-5-(2-oxooxazolidin-3-yl)benzoic acid
##STR00137##
[0695] Synthesis of
methyl-3-bromo-5-(2-oxooxazolidin-3-yl)benzoate
[0696] A suspension of 3-bromo-5-iodo-benzoic acid methyl ester
(682 mg, 2 mmol), oxazolidin-2-one (191 mg, 2.2 mmol), CuI (76 mg,
0.4 mmol), potassium carbonate (545 mg, 4 mmol) and
N,N'-dimethyl-ethane-1,2-diamine (86 uL, 0.8 mmol) in acetonitrile
(15 mL) was stirred for 16 hours at 90.degree. C. The precipitate
was filtered off and washed with ethyl acetate. The filtrate was
concentrated in vacuo to afford
3-bromo-5-(2-oxo-oxazolidin-3-yl)-benzoic acid methyl ester (480
mg, 80%) which was used for next step without further
purification.
Synthesis of (R) and
(S)-methyl-3-(5'-fluoro-2,2-dimethyl-2'-oxospiro[cyclopropane-1,3'-indoli-
ne]-1'-yl)-5-(2-oxooxazolidin-3-yl)benzoate
##STR00138##
[0698] A suspension of (R) and
(S)-5'-fluoro-2,2-dimethylspiro[cyclopropane-1,3'-indolin]-2'-one
(2 mmol) (prepared as in Example 100),
methyl-3-bromo-5-(2-oxooxazolidin-3-yl)benzoate (682 mg, 2 mmol),
CuI (76 mg, 0.4 mmol), potassium carbonate (545 mg, 4 mmol) and
N,N'-dimethyl-ethane-1,2-diamine(86 uL, 0.8 mmol) in acetonitrile
(15 mL) was stirred for 16 hours at 90.degree. C. The precipitate
was filtered off and washed with ethyl acetate. The filtrate was
concentrated in vacuo to afford the title compound as white powder
(480 mg, 80%) which was used for the next step without further
purification.
Synthesis of (R) and
(S)-3-(5'-fluoro-2,2-dimethyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)-5-(2-oxooxazolidin-3-yl)benzoic acid
##STR00139##
[0700] A mixture of (R) and
(S)-methyl-3-(5'-fluoro-2,2-dimethyl-2'-oxospiro[cyclopropane-1,3'-indoli-
ne]-1'-yl)-5-(2-oxooxazolidin-3-yl)benzoate (850 mg, 2.4 mmol) in
tetrahydrofuran (10 mL) and 30% sodium hydroxide in water (5 mL)
was stirred at 25.degree. C. for 16 hours. The mixture was
neutralized with a 2N aqueous hydrochloric acid solution, diluted
with ethyl acetate (50 mL), washed with water, dried over anhydrous
sodium sulfate and then concentrated in vacuo. Purification by
waters automated flash system (column: Xterra 30 mm.times.100 mm,
sample manager 2767, pump 2525, detector: ZQ mass and UV 2487,
solvent system: acetonitrile and 0.1% trifluoro-acetic acid in
water) afforded the title compound (410 mg, 50%) as a white solid:
LC/MS m/e calcd. for C.sub.20H.sub.18FNO.sub.3: 340, observed
(M+H).sup.+: 340.; .sup.1H NMR (400 MHz, MeOD) .delta.ppm 1.50 (s,
3H) 1.57 (s, 3H) 1.86 (d, J=4.29 Hz, 1H) 1.93 (d, J=4.55 Hz, 1H)
4.22 (t, J=7.96 Hz, 2H) 4.56 (t, J=7.96 Hz, 2H) 6.86-6.94 (m, 1H)
6.94-7.02 (m, 1H) 7.06 (d, J=8.59 Hz, 1H) 7.84 (s, 1H) 8.03 (br.
s., 1H) 8.25 (br. s., 1H).
Example 102
(R) and
(S)-3-[(2-oxo-2'',3'',5'',6''-tetrahydrodispiro[indole-3,1'-cyclop-
ropane-2',4''-pyran]-1(2H)-yl)methyl]benzoic acid
##STR00140##
[0702] The title compound was prepared in analogy to Example 100
starting from methyl-(3-bromomethyl)-benzoate,
4-methylene-tetrahydro-pyran and isatin (commercially available)
according to Scheme 2. LC/MS m/e calcd. for
C.sub.22H.sub.21NO.sub.4: 363, observed (M+H).sup.+: 364.2 .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 1.66-1.76 (m, 1H) 1.76-1.81
(m, 1H) 1.88-2.04 (m, 3H) 2.09-2.16 (m, 1H) 3.21-3.29 (m, 1H)
3.42-3.46 (m, 1H) 3.54-3.66 (m, 2H) 4.99 (d, 1H) 5.12 (d, 1H)
6.95-7.04 (m, 2H) 7.19 (t, 2H) 7.48 (t, J=7.58 Hz, 1H) 7.57 (d, 1H)
7.84 (d, J=7.83 Hz, 1H) 7.87 (s, 1H) 12.98 (d, J=2.27 Hz, 1H).
Example 103
(R) and
(S)-3-(2-oxo-1,3-oxazolidin-3-yl)-5-(2-oxo-2'',3'',5'',6''-tetrahy-
drodispiro[indole-3,1'-cyclopropane-2',4''-pyran]-1(2H)-yl)benzoic
acid
##STR00141##
[0704] The title compound was prepared in analogy to Example 101
starting from methyl-3-bromo-5-(2-oxooxazolidin-3-yl)benzoate
prepared as in Example 101, 4-methylene-tetrahydro-pyran, isatin
(commercially available) according to Scheme 2. LC/MS m/e calcd.
for C.sub.24H.sub.22N.sub.2O.sub.6: 434, observed (M+H).sup.+:
434.2 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 1.72-1.80 (m,
1H) 1.83 (d, J=4.29 Hz, 1H) 1.91-2.01 (m, 3H) 2.06-2.16 (m, 1H)
3.36-3.44 (m, 1H) 3.50-3.56 (m, 1H) 3.58-3.65 (m, 2H) 4.13-4.21 (m,
2H) 4.48 (t, J=7.96 Hz, 2H) 6.90 (d, J=8.08 Hz, 1H) 7.07 (t, 1H)
7.23 (t, 1H) 7.29 (d, J=7.58 Hz, 1H) 7.71 (s, 1H) 7.92 (s, 1H) 8.19
(s, 1H) 13.40 (s, 1H).
Example 104
(1S,2S) and
(1R,2R)-2-chloro-5-((2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-ind-
oline]-1'-yl)methyl)benzoic acid
##STR00142##
[0706] The title compound was prepared in analogy to Example 1
starting from methyl-2-chloro-(3-bromomethyl)-benzoate
(commercially available), (1S,2S) and
(1R,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.24H.sub.17ClFNO.sub.3: 421, observed (M+H).sup.+: 422.2 1H
NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 2.22-2.29 (m, 1H) 2.32 (dd,
J=8.34, 4.80 Hz, 1H) 3.29-3.32 (m, 1H) 4.81-4.98 (m, 2H) 6.96-7.00
(m, 1H) 7.02-7.14 (m, 3H) 7.17-7.23 (m, 2H) 7.32 (dd, J=8.46, 5.68
Hz, 2H) 7.37 (dd, J=8.34, 2.27 Hz, 1H) 7.50 (d, J=8.34 Hz, 1H) 7.56
(d, J=2.02 Hz, 1H) 13.46 (br.s., 1H).
Example 105
(1R,2S) and
(1S,2R)-4-((2'-oxo-2-(pyridin-3-yl)spiro[cyclopropane-1,3'-indoline]-1'-y-
l)methyl)benzoic acid
##STR00143##
[0708] The title compound was prepared in analogy to Example 1
starting from 4-bromomethyl-benzoic acid methyl ester (commercially
available), (1R,2S) and
(1S,2R)-2-(pyridin-3-yl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.23H.sub.18ClN.sub.2O.sub.3: 370, observed (M+H).sup.+: 371.2
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 2.14-2.23 (m, 1H)
3.30 (t, 1H) 5.10 (s, 2H) 6.14 (d, 1H) 6.70 (t, 1H) 6.93 (d, 1H)
7.10 (t, 1H) 7.45 (d, 2H) 7.57-7.65 (m, 1H) 7.93 (d, 2H) 8.06 (d,
1H) 8.61 (d, 1H) 8.71 (s, 1H).
Example 106
(1S,2R) and
(1R,2S)-4-((2-(4-cyanophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)methyl)benzoic acid
##STR00144##
[0710] The title compound was prepared in analogy to Example 1
starting from 4-bromomethyl-benzoic acid methyl ester (commercially
available), (1R,2S) and
(1S,2R)-4-(2'-oxospiro[cyclopropane-1,3'-indoline]-2-yl)benzonitrile
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.25H.sub.18ClN.sub.2O.sub.3: 394, observed (M+H).sup.+: 395.2
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 2.11-2.20 (m, 1H)
2.43-2.50 (m, 1H) 5.10 (s, 2H) 6.16 (d, 1H) 6.70 (t, 1H) 6.92 (d,
1H) 7.08 (t, 1H) 7.43 (d, 2H) 7.55 (d, 2H) 7.80 (d, 2H) 7.93 (d,
2H).
Example 107
(1R,2S) and
(1R,2S)-4-((2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)benzoic acid
##STR00145##
[0712] The title compound was prepared in analogy to Example 1
starting from 4-bromomethyl-benzoic acid methyl ester (commercially
available), (1R,2S) and
(1S,2R)-2-(4-fluorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.24H.sub.18FlNO.sub.3: 387, observed (M+H).sup.+: 388.1
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 2.05-2.14 (m, 1H)
2.30-2.40 (m, 1H) 3.21 (t, 2H) 5.09 (s, 2H) 6.10 (d, 1H) 6.70 (t,
1H) 6.92 (d, 1H) 7.07 (t, 1H) 7.11-7.20 (m, 2H) 7.31-7.38 (m, 2H)
7.44 (d, 2H) 7.93 (d, 2H).
Example 108
(1S,2R) and
(1R,2S)-2-chloro-5-((2-(4-chlorophenyl)-5'-fluoro-2'-oxospiro[cyclopropan-
e-1,3'-indoline]-1'-yl)methyl)benzoic acid
##STR00146##
[0714] The title compound was prepared in analogy to Example 1
starting from methyl-2-chloro-(3-bromomethyl)-benzoate
(commercially available), (1R,2S) and
(1S,2R)-2-(4-chlorophenyl)-5'-fluorospiro[cyclopropane-1,3'-indolin]-2'-o-
ne prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.24H.sub.16Cl.sub.2FNO.sub.3: 455, observed (M+H).sup.+: 456.2
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 2.15 (dd, J=9.09,
4.80 Hz, 1H) 2.46-2.50 (m, 1H) 3.25 (t, J=8.59 Hz, 1H) 5.05 (s, 2H)
6.00 (dd, J=8.97, 1.89 Hz, 1H) 6.91-6.98 (m, 2H) 7.33-7.42 (m, 4H)
7.44-7.49 (m, 1H) 7.52-7.57 (m, 1H) 7.73 (d, J=2.02 Hz, 1H) 13.47
(br. s., 1H).
Example 109
(1R,2S) and
(1S,2R)-3-((2-(3-chloro-4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-ind-
oline]-1'-yl)methyl)benzoic acid
##STR00147##
[0716] The title compound was prepared in analogy to Example 1
starting from 3-bromomethyl-benzoic acid methyl ester (commercially
available), (1R,2S) and
(1S,2R)-2-(3-chloro-4-fluorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-on-
e prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.24H.sub.17ClFNO.sub.3: 421, observed (M+H).sup.+: 422.2
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 2.04-2.15 (m, 1H)
2.40-2.49 (m, 1H) 3.21 (t, 1H) 5.09 (s, 2H) 6.18 (d, 1H) 6.75 (t,
1H) 6.96 (d, 1H) 7.06-7.14 (m, 1H) 7.29-7.39 (m, 2H) 7.46-7.53 (m,
1H) 7.56-7.65 (m, 2H) 7.82-7.93 (m, 2H) 13.03 (s, 1H).
Example 110
(1R,2S) and
(1S,2R)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)-N-methylbenzamide
##STR00148##
[0718] The title compound was prepared in analogy to Example 60
starting from 3-bromomethyl-benzoic acid methyl ester (commercially
available), (1R,2S) and
(1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.25H.sub.21ClN.sub.2O.sub.2: 416, observed (M+H).sup.+: 417.1
.sup.1H NMR (400 MHz, MeOH-d.sub.4) .delta.ppm 2.24 (d, J=8.84 Hz,
2H) 2.93 (s, 3H) 3.27-3.39 (m, 1H) 5.13 (s, 2H) 6.09 (d, J=7.58 Hz,
1H) 6.73 (t, J=7.71 Hz, 1H) 6.91 (d, J=7.83 Hz, 1H) 7.03-7.13 (m,
1H) 7.21-7.28 (m, 2H) 7.29-7.38 (m, 2H) 7.41-7.50 (m, 1H) 7.50-7.56
(m, 1H) 7.72 (d, J=7.58 Hz, 1H) 7.82 (s, 1H). MS calcd. For
C.sub.25H.sub.21N.sub.2O.sub.2 381, obsd. (ESI.sup.+)
[(M+H).sup.+]382.
Example 111
(1S,2R) and
(1R,2S)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)-N,N-dimethylbenzamide
##STR00149##
[0720] The title compound was prepared in analogy to Example 60
starting from 3-bromomethyl-benzoic acid methyl ester,
dimethylamine, methylamine (commercially available), (1R,2S) and
(1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.29H.sub.27ClN.sub.2O.sub.2: 470, observed (M+H).sup.+: 471.2
.sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 2.15-2.24 (m, 2H)
2.90 (s, 3H) 3.06 (s, 3H) 3.21-3.35 (m, 1H) 5.09 (s, 2H) 6.05 (d,
J=7.58 Hz, 1H) 6.69 (t, J=7.58 Hz, 1H) 6.89 (d, J=8.08 Hz, 1H)
7.01-7.10 (m, 1H) 7.19 (d, J=8.59 Hz, 2H) 7.25-7.38 (m, 4H)
7.40-7.49 (m, 2H).
Example 112
(1R,2S) and
(1S,2R)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)-N-(3-morpholinopropyl)benzamide
##STR00150##
[0722] The title compound was prepared in analogy to Example 60
starting from form 3 3-morpholinopropan-1-amine,
3-bromomethyl-benzoic acid methyl ester (commercially available),
(1R,2S) and
(1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.31H.sub.32ClN.sub.3O.sub.3: 529, observed (M+H).sup.+: 530.2
.sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 2.02-2.15 (m, 2H)
2.24 (d, J=8.59 Hz, 2H) 3.15 (br. s., 2H) 3.23 (d, J=8.08 Hz, 2H)
3.25-3.31 (m, 1H) 3.47-3.57 (m, 4H) 3.79 (t, J=12.38 Hz, 2H) 4.06
(br. s., 2H) 5.14 (s, 2H) 6.09 (d, J=7.33 Hz, 1H) 6.73 (t, J=7.58
Hz, 1H) 6.91 (d, J=8.08 Hz, 1H) 7.09 (t, J=7.71 Hz, 1H) 7.20-7.28
(m, 2H) 7.28-7.37 (m, 2H) 7.49 (t, J=7.71 Hz, 1H) 7.53-7.61 (m, 1H)
7.78 (d, J=8.08 Hz, 1H) 7.87 (s, 1H).
Example 113
(1R,2S) and
(1S,2R)-2-(4-chlorophenyl)-1'-(3-(4-(2-(dimethylamino)ethyl)piperazine-1--
carbonyl)benzyl)spiro[cyclopropane-1,3'-indolin]-2'-one
##STR00151##
[0724] The title compound was prepared in analogy to Example 60
starting from N,N-dimethyl-2-(piperazin-1-yl)ethanamine,
3-bromomethyl-benzoic acid methyl ester (commercially available),
(1R,2S) and
(1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.32H.sub.35ClN.sub.4O.sub.2: 542, observed (M+H).sup.+: 543.1
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta.ppm 2.04 (dd, J=7.96, 4.67
Hz, 1H) 2.28 (dd, J=8.97, 4.67 Hz, 1H) 2.93 (s, 6H) 3.18 (br. s.,
4H) 3.34 (t, J=8.59 Hz, 1H) 3.62 (br. s., 4H) 3.87 (br. s., 4H)
4.95 (d, J=15.92 Hz, 1H) 5.16 (d, J=15.92 Hz, 1H) 6.02 (d, J=7.58
Hz, 2H) 6.70-6.84 (m, 2H) 7.06-7.19 (m, 3H) 7.31 (s, 1H) 7.35 (d,
J=5.31 Hz, 1H) 7.43 (d, J=6.06 Hz, 3H).
Example 114
(1R,2S) and
(1S,2R)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)-N-(2-morpholinoethyl)benzamide
##STR00152##
[0726] The title compound was prepared in analogy to Example 60
starting from 2-morpholinoethanamine, 3-bromomethyl-benzoic acid
methyl ester (commercially available), (1R,2S) and
(1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.30H.sub.30ClN.sub.3O.sub.3: 515, observed (M+H).sup.+: 516.2
.sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 2.24 (d, J=8.59 Hz,
2H) 3.20 (br. s., 2H) 3.29 (s, 1H) 3.42 (t, J=5.81 Hz, 2H) 3.69
(br. s., 4H) 3.80 (t, J=5.81 Hz, 2H) 4.08 (br. s., 2H) 5.14 (d,
J=1.52 Hz, 2H) 6.09 (d, J=7.33 Hz, 1H) 6.73 (t, J=7.58 Hz, 1H) 6.91
(d, J=8.08 Hz, 1H) 7.04-7.13 (m, 1H) 7.22-7.28 (m, 2H) 7.29-7.36
(m, 2H) 7.50 (t, J=7.71 Hz, 1H) 7.55-7.62 (m, 1H) 7.80 (d, J=7.58
Hz, 1H) 7.90 (s, 1H).
Example 115
(1R,2S) and
(1S,2R)-2-(4-chlorophenyl)-1'-(3-(4-(methylsulfonyl)piperazine-1-carbonyl-
)benzyl)spiro[cyclopropane-1,3'-indolin]-2'-one
##STR00153##
[0728] The title compound was prepared in analogy to Example 60
starting from 1-(methylsulfonyl)piperazine, 3-bromomethyl-benzoic
acid methyl ester (commercially available), (1R,2S) and
(1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.29H.sub.28ClN.sub.3O.sub.4S: 549, observed (M+H).sup.+: 550.2
.sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 8.19-8.05 (m, 2H)
7.49 (s, 3H) 7.25 (br. s., 4H) 7.09-7.05 (m, 1H) 6.88 (br. s., 2H)
6.50 (br. s., 2H) 5.29-5.12 (m, 2H) 4.23 (d, J=7.58 Hz, 1H)
3.64-3.56 (m, 1H) 3.41 (d, J=7.58 Hz, 1H) 3.29-3.19 (m, 1H) 3.11
(d, J=8.08 Hz, 2H) 3.07-2.99 (m, 2H) 2.98-2.91 (m, 2H) 2.88-2.75
(m, 2H).
Example 116
(1S,2R) and
(1R,2S)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)-N-(3-cyclopropyl-1H-pyrazol-5-yl)benzamide
##STR00154##
[0730] The title compound was prepared in analogy to Example 60
starting from 3-cyclopropyl-1H-pyrazol-5-amine,
3-bromomethyl-benzoic acid methyl ester (commercially available),
(1R,2S) and
(1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.30H.sub.25ClN.sub.4O.sub.2: 508, observed (M+H).sup.+: 509.2
.sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 0.66-0.77 (m, 2H)
1.02 (dd, J=8.34, 1.77 Hz, 2H) 2.24 (d, J=8.59 Hz, 2H) 2.47-2.57
(m, 1H) 3.26-3.32 (m, 1H) 5.07-5.25 (m, 2H) 5.65 (s, 1H) 6.09 (d,
J=7.58 Hz, 1H) 6.73 (t, J=7.58 Hz, 1H) 6.96 (d, J=7.83 Hz, 1H)
7.07-7.14 (m, 1H) 7.20 (d, J=8.34 Hz, 2H) 7.31 (d, J=8.34 Hz, 2H)
7.49 (t, J=7.83 Hz, 1H) 7.55-7.63 (m, 1H) 7.80 (d, J=7.83 Hz, 1H)
7.83 (s, 1H).
Example 117
(1S,2R) and
(1R,2S)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)benzamide
##STR00155##
[0732] The title compound was prepared in analogy to Example 60
starting from 5-cyclopropyl-1H-pyrazol-3-amine,
3-bromomethyl-benzoic acid methyl ester, (commercially available),
(1R,2S) and
(1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.30H.sub.25ClN.sub.4O.sub.2: 508, observed (M+H).sup.+: 509.2
.sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 0.54-0.77 (m, 2H)
0.79-0.95 (m, 2H) 1.62-1.77 (m, 1H) 2.05 (s, 1H) 2.18-2.30 (m, 2H)
3.23-3.31 (m, 1H) 5.07-5.26 (m, 2H) 6.09 (d, J=6.82 Hz, 1H) 6.72
(t, J=7.58 Hz, 1H) 6.95 (d, J=7.83 Hz, 1H) 7.05-7.14 (m, 1H)
7.14-7.20 (m, 2H) 7.30 (d, J=8.34 Hz, 2H) 7.51 (t, J=7.71 Hz, 1H)
7.62 (d, J=7.83 Hz, 1H) 7.89 (d, J=7.83 Hz, 1H) 7.94 (s, 1H).
Example 118
(1R,2S) and
(1S,2R)-6-((2-(4-cyanophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)methyl)-N-(cyclopropylsulfonyl)picolinamide
##STR00156##
[0734] The title compound was prepared in analogy to Example 60
starting from methyl-6-(bromomethyl)picolinate,
cyclopropanesulfonamide and (1R,2S) and
(1S,2R)-4-(2'-oxospiro[cyclopropane-1,3'-indoline]-2-yl)benzonitrile
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.27H.sub.22N.sub.4O.sub.4S: 498, observed (M+H).sup.+: 499.2
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 1.02-1.15 (m, 2H)
1.14-1.24 (m, 2H) 2.08-2.20 (m, 1H) 2.43-2.48 (m, 1H) 2.99-3.15 (m,
1H) 3.27-3.34 (m, 1H) 5.19 (s, 2H) 6.14 (d, 1H) 6.72 (t, 1H) 6.99
(d, 1H) 7.09 (t, 1H) 7.47 (d, 1H) 7.59 (d, 2H) 7.79 (d, 2H)
7.92-8.06 (m, 2H).
Example 119
(1S,2R) and
(1R,2S)-4-((2-(4-cyanophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)methyl)-N-(cyclopropylsulfonyl)benzamide
##STR00157##
[0736] The title compound was prepared in analogy to Example 60
starting from 4-bromomethyl-benzoic acid methyl ester,
cyclopropanesulfonamide (commercially available), (1R,2S) and
(1S,2R)-4-(2'-oxospiro[cyclopropane-1,3'-indoline]-2-yl)benzonitrile
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.28H.sub.23ClN.sub.3O.sub.4S: 497, observed (M+H).sup.+:
498.2, .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 0.69-0.79 (m,
2H) 0.83-0.92 (m, 2H) 2.11-2.18 (m, 1H) 2.44-2.49 (m, 1H) 2.91-3.00
(m, 1H) 3.12-3.20 (m, 1H) 3.27-3.32 (m, 1H) 5.04 (s, 2H) 6.15 (d,
1H) 6.68 (t, 1H) 6.91 (d, 1H) 7.02-7.09 (m, 2H) 7.28-7.37 (m, 2H)
7.50-7.59 (m, 2H) 7.77-7.82 (m, 2H) 7.87-7.94 (m, 2H).
Example 120
(1R,2S) and
(1S,2R)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)-N-(methylsulfonyl)benzamide
##STR00158##
[0738] The title compound was prepared in analogy to Example 60
starting from 3-bromomethyl-benzoic acid methyl ester,
methylsulfonamide (commercially available), (1R,2S) and
1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.25H.sub.21ClN.sub.2O.sub.4S: 480, observed (M+H).sup.+: 481.2
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 2.08-2.18 (m, 1H)
2.35-2.42 (m, 1H) 2.92 (s, 3H) 3.13-3.25 (m, 2H) 4.95-5.13 (m, 2H)
6.15 (d, 1H) 6.70 (t, 1H) 6.87 (d, 1H) 7.02-7.10 (m, 2H) 7.30-7.44
(m, 6H) 7.81-7.89 (m, 2H).
Example 121
(1R,2S) and
(1S,2R)-3-((2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-
-yl)methyl)-N-(methylsulfonyl)benzamide
##STR00159##
[0740] The title compound was prepared in analogy to Example 60
starting from 3-bromomethyl-benzoic acid methyl ester,
methylsulfonamide (commercially available), (1R,2S) and
(1S,2R)-2-(4-fluorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.25H.sub.21FN.sub.2O.sub.4S: 470, observed (M+H).sup.+: 471.2
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 2.10-2.18 (m, 1H)
2.33-2.42 (m, 1H) 3.18-3.27 (m, 1H) 3.38 (s, 3H) 5.10 (s, 2H) 6.12
(d, 1H) 6.71 (t, 1H) 6.89-6.97 (m, 1H) 7.03-7.09 (m, 1H) 7.11-7.18
(m, 2H) 7.31-7.41 (m, 2H) 7.48-7.55 (m, 1H) 7.56-7.63 (m, 1H)
7.82-7.93 (m, 2H).
Example 122
(1S,2R) and
(1R,2S)--N-(cyclopropylsulfonyl)-3-((2-(4-fluorophenyl)-2'-oxospiro[cyclo-
propane-1,3'-indoline]-1'-yl)methyl)benzamide
##STR00160##
[0742] The title compound was prepared in analogy to Example 60
starting from 3-bromomethyl-benzoic acid methyl ester,
cyclopropanesulfonamide (commercially available), (1R,2S) and
(1S,2R)-2-(4-fluorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.27H.sub.23FN.sub.2O.sub.4S: 490, observed (M+H).sup.+: 491.2
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 0.84-0.94 (m, 2H)
0.94-1.04 (m, 2H) 2.08-2.18 (m, 1H) 2.32-2.40 (m, 1H) 2.98-3.09 (m,
1H) 3.21 (t, 1H) 5.06 (s, 2H) 6.09 (d, 1H) 6.68 (t, 1H) 6.89 (d,
1H) 7.00-7.18 (m, 4H) 7.33-7.50 (m, 4H) 7.80-7.92 (m, 2H).
Example 123
(1S,2R) and
(1R,2S)--N-(cyclopropylsulfonyl)-4-((2-(4-fluorophenyl)-2'-oxospiro[cyclo-
propane-1,3'-indoline]-1'-yl)methyl)benzamide
##STR00161##
[0744] The title compound was prepared in analogy to Example 60
starting from 4-bromomethyl-benzoic acid methyl ester,
cyclopropanesulfonamide (commercially available), (1R,2S) and
(1S,2R)-2-(4-fluorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.27H.sub.23FN.sub.2O.sub.4S: 490, observed (M+H).sup.+: 491.2
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 0.70-0.81 (m, 2H)
0.84-0.91 (m, 2H) 2.06-2.17 (m, 1H) 2.31-2.40 (m, 1H) 2.91-3.02 (m,
1H) 3.14-3.24 (m, 2H) 5.04 (s, 2H) 6.09 (d, 1H) 6.68 (t, 1H) 6.89
(d, 1H) 7.05 (t, 2H) 7.11-7.19 (m, 3H) 7.89 (d, 2H).
Example 124
(1S,2R) and
(1R,2S)-2-(4-chlorophenyl)-1'-(piperidin-4-ylmethyl)spiro[cyclopropane-1,-
3'-indolin]-2'-one
##STR00162##
[0746] The title compound was prepared in analogy to Example 70
starting from 4-(chloromethyl)piperidine (commercially available),
(1R,2S) and
(1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.22H.sub.23ClN.sub.2O: 366, observed (M+H).sup.+: 367.2
.sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 1.51-1.67 (m, 2H)
1.96 (br. s., 2H) 2.12-2.21 (m, 2H) 2.21-2.35 (m, 1H) 2.93-3.07 (m,
2H) 3.22 (t, J=8.59 Hz, 1H) 3.38-3.50 (m, 2H) 3.84 (d, J=7.33 Hz,
2H) 6.09 (d, J=7.58 Hz, 1H) 6.77 (t, J=7.58 Hz, 1H) 7.11 (d, J=7.83
Hz, 1H) 7.16-7.26 (m, 3H) 7.29-7.35 (m, 2H).
Example 125
(1S,2R) and
(1R,2S)-2-(4-chlorophenyl)-1'-(2-(piperidin-1-yl)ethyl)spiro[cyclopropane-
-1,3'-indolin]-2'-one
##STR00163##
[0748] The title compound was prepared in analogy to Example 70
starting from with 1-(2-chloroethyl)piperidine (commercially
available), (1R,2S) and
(1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.23H.sub.25ClN.sub.2O: 380, observed (M+H).sup.+: 371.2
.sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 1.62 (br. s., 1H)
1.89 (br. s., 3H) 2.05 (br. s., 2H) 2.21-2.30 (m, 2H) 3.09 (br. s.,
2H) 3.30 (t, J=8.59 Hz, 1H) 3.48-3.62 (m, 2H) 3.76 (br. s., 1H)
3.93 (br. s., 1H) 4.22-4.32 (m, 1H) 4.34-4.46 (m, 1H) 6.15 (d,
J=7.58 Hz, 1H) 6.84 (t, J=7.58 Hz, 1H) 7.15-7.21 (m, 1H) 7.23-7.31
(m, 3H) 7.33-7.40 (m, 2H).
Example 126
(1S,2R) and
(1R,2S)-2-(4-chlorophenyl)-1'42-(3-morpholinopropylamino)ethyl)spiro[cycl-
opropane-1,3'-indolin]-2'-one
##STR00164##
[0750] The title compound was prepared in analogy to Example 70
starting from 1-(3-chloropropyl)piperidine (commercially
available), (1R,2S) and
(1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.24H.sub.27ClN.sub.2O: 394, observed (M+H).sup.+: 395.2
.sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 1.46-1.62 (m, 1H)
1.69-1.91 (m, 3H) 1.98 (d, J=14.91 Hz, 2H) 2.15-2.27 (m, 4H) 2.97
(t, J=12.76 Hz, 2H) 3.17-3.29 (m, 3H) 3.57 (d, J=12.13 Hz, 2H)
3.92-4.07 (m, 2H) 6.11 (d, J=7.58 Hz, 1H) 6.79 (t, J=7.58 Hz, 1H)
7.12 (d, J=7.83 Hz, 1H) 7.18-7.26 (m, 3H) 7.28-7.37 (m, 2H).
Example 127
(1S,2R) and
(1R,2S)-2-(4-chlorophenyl)-1'-(2-(3-morpholinopropylamino)ethyl)spiro[cyc-
lopropane-1,3'-indolin]-2'-one
##STR00165##
[0752] The title compound was prepared in analogy to Example 81
starting from dibromo ethylene, 3-morpholinopropan-1-amine
(commercially available), (1R,2S) and
(1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.25H.sub.30ClN.sub.3O.sub.2: 439, observed (M+H).sup.+: 440.1
.sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 2.07-2.32 (m, 6H)
3.26 (s, 8H) 3.47 (t, J=5.94 Hz, 3H) 4.24 (d, J=28.55 Hz, 3H) 6.12
(d, J=7.07 Hz, 1H) 6.81 (t, J=7.07 Hz, 1H) 7.14 (d, J=7.58 Hz, 1H)
7.19-7.29 (m, 3H) 7.30-7.39 (m, 2H).
Example 128
(1S,2R) and
(1R,2S)-2-(4-chlorophenyl)-1'42-(2-morpholinoethylamino)ethyl)spiro[cyclo-
propane-1,3'-indolin]-2'-one
##STR00166##
[0754] The title compound was prepared in analogy to Example 81
starting from dibromo ethylene, 2-morpholinoethanamine
(commercially available), (1R,2S) and
(1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.24H.sub.28ClN.sub.3O.sub.2: 425, observed (M+H).sup.+: 426.2
.sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 2.09-2.34 (m, 3H)
3.02 (br. s., 4H) 3.17 (t, J=6.19 Hz, 2H) 3.27 (t, J=8.72 Hz, 1H)
3.44-3.61 (m, 4H) 3.87 (t, J=4.67 Hz, 4H) 4.12-4.45 (m, 2H) 6.11
(d, J=7.83 Hz, 1H) 6.80 (t, J=7.58 Hz, 1H) 7.10-7.18 (m, 1H)
7.20-7.27 (m, 3H) 7.29-7.40 (m, 2H).
Example 129
(1S,2R) and
(1R,2S)-2-(4-chlorophenyl)-1'-(2-(4-(pyridin-4-yl)piperazin-1-yl)ethyl)sp-
iro[cyclopropane-1,3'-indolin]-2'-one
##STR00167##
[0756] The title compound was prepared in analogy to Example 81
starting from dibromo ethylene, 1-(pyridin-4-yl)piperazine
(commercially available), (1R,2S) and
(1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.27H.sub.27ClN.sub.4O: 458, observed (M+H).sup.+: 459.2
.sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 1.32 (s, 2H)
2.02-2.40 (m, 3H) 3.26 (s, 1H) 3.47 (d, J=9.09 Hz, 8H) 4.02 (br.
s., 4H) 4.25 (s, 2H) 6.11 (d, J=7.33 Hz, 1H) 6.80 (s, 1H) 7.12-7.18
(m, 1H) 7.19-7.27 (m, 3H) 7.32 (t, J=8.97 Hz, 4H) 8.27 (d, J=7.83
Hz, 2H).
Example 130
(1S,2R) and
(1R,2S)-2-(4-chlorophenyl)-1'-(2-(2-(2,6-dimethylmorpholino)
ethylamino)ethyl)spiro[cyclopropane-1,3'-indolin]-2'-one
##STR00168##
[0758] The title compound was prepared in analogy to Example 81
starting from 2-(2,6-dimethylmorpholino)ethanamine, dibromo
ethylene (commercially available), (1R,2S) and
(1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.26H.sub.32ClN.sub.3O.sub.2: 453, observed (M+H).sup.+: 454.1
.sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 1.22 (dd, J=6.32,
2.27 Hz, 2H) 1.26-1.37 (m, 6H) 2.15-2.32 (m, 3H) 2.43-2.67 (m, 1H)
2.88 (br. s., 3H) 3.26 (d, J=8.59 Hz, 2H) 3.40-3.62 (m, 4H)
3.70-3.96 (m, 1H) 4.13 (br. s., 4H) 6.05-6.21 (m, 1H) 6.81 (t,
J=7.58 Hz, 1H) 7.06-7.18 (m, 1H) 7.24 (d, J=8.34 Hz, 3H) 7.29-7.38
(m, 2H).
Example 131
(1S,2R) and
(1R,2S)-2-(4-chlorophenyl)-1'-(1H-imidazol-4-yl)spiro[cyclopropane-1,3'-i-
ndolin]-2'-one
##STR00169##
[0759] Synthesis of (1S,2R) and
(1R,2S)-2-(4-chlorophenyl)-1'-(1-trityl-1H-imidazol-4-yl)spiro[cyclopropa-
ne-1,3'-indolin]-2'-one
##STR00170##
[0761] 4-iodo-1-trityl-1H-imidazole (210 mg, 0.48 mmol) was added
to a suspension of (1R,2S) and
(1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
(107 mg, 0.4 mmol) in acetonitrile (2 mL) under a nitrogen
atmosphere. A steady stream of nitrogen was bubbled through the
suspension as it was heated to 40.degree. C. over 15 minutes.
Potassium carbonate (110 mg, 0.8 mmol), copper (I) iodide (12 mg,
15 mol %), and N,N-dimethylethylenediamine (0.12 mmol, 30 mol %)
were added and the reaction mixture was heated to 80.degree. C. for
21 hours under nitrogen atmosphere. The mixture was cooled to room
temperature, filtrated, and concentrated to give the title product.
The residue was purified by flash column chromatography (gradient
elution, 5-10% ethyl acetate in petroleum ether) to give racemic
trans-2-(4-chlorophenyl)-1'-(1H-imidazol-4-trityl)spiro[cyclopropane-1,3'-
-indolin]-2'-one (157 mg, 68%). LC/MS m/e calcd. for
C.sub.38H.sub.28ClN.sub.3O: 577, observed (M+H).sup.+: 578.3.
Synthesis of (1S,2R) and
(1R,2S)-2-(4-chlorophenyl)-1'-(1H-imidazol-4-yl)spiro[cyclopropane-1,3'-i-
ndolin]-2'-one
##STR00171##
[0763] (1S,2R) and
(1R,2S)-2-(4-chlorophenyl)-1'-(1-trityl-1H-imidazol-4-yl)spiro[cyclopropa-
ne-1,3'-indolin]-2'-one (115 mg, 0.2 mmol) was dissolved in DCM (2
mL) and water (0.5 mL). TFA (0.1 mL) was added dropwise at
0.degree. C. The mixture was stirred for 14 hours at room
temperature. The mixture was poured into the sat. NaHCO.sub.3,
extracted with DCM (3.times.10 mL), dried and concentrated to give
the title product. The residue was dissolved in 2 mL of DMF.
Purification by preparative HPLC to give the title compound as
white powder (60 mg, 89%). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta.ppm 2.13 (dd, J=9.09, 5.05 Hz, 1H) 2.42 (dd, J=8.08, 4.80
Hz, 1H) 3.23 (t, J=8.72 Hz, 1H) 6.20 (d, J=7.58 Hz, 1H) 6.81 (t,
J=7.20 Hz, 1H) 7.16 (t, J=7.83 Hz, 1H) 7.30-7.45 (m, 5H) 7.66 (s,
1H) 8.27 (s, 1H). LC/MS m/e calcd. for C.sub.19H.sub.14ClN.sub.3O
335, observed (M+H).sup.+: 336.3.
Example 132
(1S,2R) and
(1R,2S)-3-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'--
yl)-N-(methylsulfonyl)benzamide
##STR00172##
[0765] The title compound was prepared in analogy to Example 85
starting from methylsulfonamide, methyl-3-iodobenzoate
(commercially available), (1R,2S) and
(1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 1. LC/MS m/e calcd. for
C.sub.24H.sub.19ClN.sub.2O.sub.4S: 466, observed (M+H).sup.+: 467.2
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 2.15 (dd, J=9.09,
4.80 Hz, 1H) 2.44 (dd, J=8.08, 4.80 Hz, 1H) 3.25 (t, J=8.59 Hz, 1H)
3.41 (s, 3H) 6.21 (d, J=7.58 Hz, 1H) 6.79-6.88 (m, 2H) 7.10-7.17
(m, 1H) 7.37-7.45 (m, 4H) 7.75 (t, J=7.83 Hz, 1H) 7.80-7.85 (m, 1H)
8.04 (d, J=7.83 Hz, 1H) 8.11-8.16 (m, 1H) 12.29 (br. s., 1H).
Example 133
(1S,2S) and
(1R,2R)-3-(2-(4-chlorophenyl)-2-methyl-2'-oxospiro[cyclopropane-1,3'-indo-
line]-1'-yl)-5-(2-oxooxazolidin-3-yl)benzoic acid
##STR00173##
[0767] The title compound was prepared in analogy to Example 95
starting from oxazolidin-2-one (commercially available),
3-bromo-5-iodobenzoic acid methylester prepared in Example 92,
(1R,2R) and
(1S,2S)-2-(4-chlorophenyl)-2-methylspiro[cyclopropane-1,3'-indolin]-2'-on-
e prepared as in Scheme 2. LC/MS m/e calcd. for
C.sub.27H.sub.21ClN.sub.2O.sub.5: 488, observed (M+H).sup.+: 489.1
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 1.66 (s, 3H) 2.18
(d, J=4.80 Hz, 1H) 2.38 (d, J=5.05 Hz, 1H) 4.12 (t, J=8.08 Hz, 2H)
4.47 (t, J=7.96 Hz, 2H) 6.95 (d, J=8.08 Hz, 1H) 7.15 (t, J=7.45 Hz,
1H) 7.25-7.34 (m, 5H) 7.45 (d, J=7.33 Hz, 1H) 7.59-7.62 (m, 1H)
7.85 (t, J=2.02 Hz, 1H) 8.12 (s, 1H).
Example 134
(1S,2S) and
(1R,2R)-3-(2-(4-chlorophenyl)-2-isopropyl-2'-oxospiro[cyclopropane-1,3'-i-
ndoline]-1'-yl)-5-(2-oxooxazolidin-3-yl)benzoic acid
##STR00174##
[0769] The title compound was prepared in analogy to Example 95
starting from oxazolidin-2-one, 3-bromo-5-iodobenzoic methylester
(prepared as in Example 92), (1R,2R) and
(1S,2S)-2-(4-chlorophenyl)-2-isopropylspiro[cyclopropane-1,3'-indolin]-2'-
-one prepared as in Scheme 2. LC/MS m/e calcd. for
C.sub.29H.sub.25ClN.sub.2O.sub.5: 516, observed (M+H).sup.+: 517.2
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 0.77 (d, 3H) 0.89
(d, 3H) 2.16 (d, 1H) 2.28 (d, 1H) 2.95-3.02 (m, 1H) 4.17-4.25 (m,
2H) 4.40-4.58 (m, 2H) 5.43 (d, 1H) 6.65-6.76 (m, 1H) 6.78-6.91 (m,
2H) 7.11 (t, 1H) 7.61 (d, 1H) 7.69 (d, 1H) 7.79 (s, 1H) 7.92-8.03
(m, 2H) 8.21 (s, 1H) 13.44 (s, 1H).
Example 135
(1S,2S) and
(1R,2R)-3-(2-(4-chlorophenyl)-2-isopropyl-2'-oxospiro[cyclopropane-1,3'-i-
ndoline]-1'-yl)-5-(2-oxooxazolidin-3-yl)benzoic acid
##STR00175##
[0771] The title compound was prepared in analogy to Example 95
starting from oxazolidin-2-one (commercially available),
3-bromo-5-iodobenzoic methylester (prepared as in Example 92),
(1S,2S) and
(1R,2R)-2-(4-chlorophenyl)-2-isopropylspiro[cyclopropane-1,3'-indolin]-2'-
-one prepared as in Scheme 2. LC/MS m/e calcd. for
C.sub.29H.sub.25ClN.sub.2O.sub.5: 516, observed (M+H).sup.+: 517.2
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 0.77 (d, 3H) 0.89
(d, 3H) 2.16 (d, 1H) 2.28 (d, 1H) 2.85-3.02 (m, 1H) 4.07-4.25 (m,
2H) 4.41-4.59 (m, 2H) 5.43 (d, 1H) 6.62-6.75 (m, 1H) 6.78-6.91 (m,
2H) 7.11 (t, 1H) 7.61 (d, 1H) 7.69 (d, 1H) 7.79 (s, 1H) 7.92-8.03
(m, 2H) 8.21 (s, 1H) 13.44 (s, 1H).
Example 136
(R) and
(5)-methyl-3-(2,2-dimethyl-2'-oxospiro[cyclopropane-1,3'-indoline]-
-1'-yl)-5-(2-oxooxazolidin-3-yl)benzoate
##STR00176##
[0773] A suspension of (R) and
(5)-5'-fluoro-2,2-dimethylspiro[cyclopropane-1,3'-indolin]-2'-one
(2 mmol) (prepared as in Example 100), methyl
3-bromo-5-(2-oxooxazolidin-3-yl)benzoate (682 mg, 2 mmol) (prepared
as in Example 100), CuI (76 mg, 0.4 mmol), potassium carbonate (545
mg, 4 mmol) and N,N'-dimethyl-ethane-1,2-diamine (86 uL, 0.8 mmol)
in acetonitrile (15 mL) was stirred for 16 hours at 90.degree. C.
The precipitate was filtered off and washed with ethyl acetate. The
filtrate was concentrated in vacuo to afford the title compound as
white powder (480 mg, 80%). LC/MS m/e calcd. for
C.sub.23H.sub.21FN.sub.2O.sub.5: 424, observed (M+H).sup.+: 425.2
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 1.42 (s, 3H) 1.48
(s, 3H) 1.79 (d, J=4.29 Hz, 1H) 1.95 (d, J=4.55 Hz, 1H) 3.90 (s,
3H) 4.17 (t, 2H) 4.48 (t, J=7.96 Hz, 2H) 6.87 (dd, J=8.72, 4.42 Hz,
1H) 7.04 (t, J=9.09 Hz, 1H) 7.27 (dd, J=8.84, 2.53 Hz, 1H) 7.73 (s,
1H) 7.91 (s, 1H) 8.24 (s, 1H).
Example 137
(R) and
(S)-3-(5'-fluoro-2,2-dimethyl-2'-oxospiro[cyclopropane-1,3'-indoli-
ne]-1'-yl)-5-(2-hydroxyethylamino)benzoic acid
##STR00177##
[0775] The title compound was prepared in analogy to Example 95
starting from 2-aminoethanol (commercially available),
methyl-3-bromo-5-iodobenzoate prepared as in Example 92, (R) and
(S)-5'-fluoro-2,2-dimethylspiro[cyclopropane-1,3'-indolin]-2'-one
prepared as in Scheme 2. LC/MS m/e calcd. for
C.sub.21H.sub.21FN.sub.2O.sub.4: 384, observed (M+H).sup.+: 385.1
.sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.ppm 1.48 (s, 3H) 1.56
(s, 3H) 1.83 (d, J=4.55 Hz, 1H) 1.90 (d, J=4.55 Hz, 1H) 3.30-3.37
(m, 2H) 3.76 (t, J=5.68 Hz, 2H) 6.84 (dd, J=8.59, 4.55 Hz, 1H)
6.91-6.99 (m, 2H) 7.03 (dd, J=8.84, 2.27 Hz, 1H) 7.33 (s, 1H) 7.47
(s, 1H).
Example 138
(R) and
(S)-methyl-3-(2-oxo-1,3-oxazolidin-3-yl)-5-(2-oxo-2'',3'',5'',6''--
tetrahydrodispiro[indole-3,1'-cyclopropane-2',4''-pyran]-1(2H)-yl)benzoate
##STR00178##
[0777] The title compound was prepared in analogy to Example 101
starting from methyl-3-bromo-5-(2-oxooxazolidin-3-yl)benzoate
prepared as in Example 101, 4-methylenetetrahydro-2H-pyran, isatin
(commercially available) according to Scheme 2. LC/MS m/e calcd.
for C.sub.25H.sub.24ClN.sub.2O.sub.6: 448, observed (M+H).sup.+:
449.2 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 1.72-1.81 (m,
1H) 1.83 (d, J=4.55 Hz, 1H) 1.92-1.99 (m, 3H) 2.07-2.15 (m, 1H)
3.38-3.47 (m, 1H) 3.51-3.57 (m, 1H) 3.57-3.66 (m, 2H) 3.90 (s, 3H)
4.16 (t, J=7.83 Hz, 2H) 4.49 (t, J=7.83 Hz, 2H) 6.90 (d, J=7.83 Hz,
1H) 7.08 (t, J=7.58 Hz, 1H) 7.23 (t, J=7.71 Hz, 1H) 7.29 (d, J=7.58
Hz, 1H) 7.74 (s, 1H) 7.93 (s, 1H) 8.24 (s, 1H).
Example 139
(1S,2R) and
(1R,2S)-1'-(3-fluorobenzyl)-2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1-
,3'-indoline]-5'-carboxylic acid
##STR00179##
[0778] Synthesis of
(Z)-methyl-3-(4-fluorobenzylidene)-2-oxoindoline-5-carboxylate
[0779] To a solution of methyl-2-oxindole-5-carboxylate (4.764 g)
in EtOH (100 mL) was added 4-fluoro-benzaldehyde (4.72 mL) in one
portion, followed by piperidine (790 uL). The mixture was refluxed
for 3 hours and the yellow precipitate was collected by filtration.
The yellow product was used for the next step without further
purification.
Synthesis of (1S,2R) and
(1R,2S)-methyl-2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-
-5'-carboxylate
##STR00180##
[0781] A solution of dimethylsulfoxoniummethylide was prepared
under argon from a 60% NaH mineral oil dispersion (88 mg, 2.2
mmol), trimethylsulfoxoniumiodide (2.2 mmol) and DMSO (10 mL).
After 20 min, a solution of
(Z)-methyl-3-(4-fluorobenzylidene)-2-oxoindoline-5-carboxylate (594
mg, 2 mmol) in THF (5 mL) was added dropwise over 20 minutes. After
being stirred for 1 hour at room temperature and another 1 hour at
50.degree. C., the solution was poured into ice-cold water (20 mL)
and extracted with ether (3.times.20 mL). The combined ethereal
extracts were washed with brine, dried, and evaporated to an oil,
which was separated by flash column chromatography (gradient
elution, 15-25% ethyl acetate in petroleum ether) to give the tile
product as white solid (317 mg, 51% yield). LC/MS m/e calcd. for
C.sub.18H.sub.14FNO.sub.3: 311, observed (M+H).sup.+: 312.6.
Synthesis of (1R,2S) and
(1S,2R)-2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-car-
boxylic acid
##STR00181##
[0783] To a solution of (1S,2R) and
(1R,2S)-methyl-2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-
-5'-carboxylate (80 mg) in methanol (1 mL); water (0.1 mL) was
added lithium hydroxide (10 mg) at room temperature. The mixture
was stirred for 14 hours at room temperature. HPLC monitored the
reaction finished. The solvent was removed under reduced pressure.
The residue was dissolved in 2 mL of DMF. Purification by
preparative HPLC gave the title compound as white solid (30 mg).
LC/MS m/e calcd. for C.sub.17H.sub.12FNO.sub.3 297, observed
(M-H).sup.+: 296. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm
1.99 (dd, J=9.09, 4.80 Hz, 1H) 2.35 (dd, J=8.08, 4.80 Hz, 1H), 3.11
(t, J=8.46 Hz, 1H) 6.65 (d, J=1.52 Hz, 1H) 6.94 (d, J=8.08 Hz, 1H)
7.14 (t, J=8.84 Hz, 2H) 7.34 (dd, J=8.34, 5.56 Hz, 2H) 7.72 (dd,
J=8.08, 1.52 Hz, 1H) 10.97 (s, 1H) 12.36 (br. s., 1H).
Synthesis of (1R,2S) and
(1S,2R)-methyl-1'-(3-fluorobenzyl)-2-(4-fluorophenyl)-2'-oxospiro[cyclopr-
opane-1,3'-indoline]-5'-carboxylate
##STR00182##
[0785] (1S,2R) and
(1R,2S)-methyl-2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-
-5'-carboxylate (500 mg, 1.61 mmol), 1-bromomethyl-2-fluoro-benzene
(456 mg, 2.14 mmol) and Cs.sub.2CO.sub.3 (785 mg, 4.2 mmol) were
mixed in anhydrous DMF and stirred at room temperature for 8 hours.
HPLC monitored the reaction finished. The solvent was removed under
reduced pressure. The residue was purified by flash column
chromatography (gradient elution, 15-25% ethyl acetate in petroleum
ether) to give title compound as white solid (405 mg, 60%). LC/MS
m/e calcd. for C.sub.25H.sub.19F.sub.2NO.sub.3 420, observed
(M+H).sup.+: 420.5.
Synthesis of (1R,2S) and
(1S,2R)-1'-(3-fluorobenzyl)-2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1-
,3'-indoline]-5'-carboxylic acid
##STR00183##
[0787] To a solution of (1R,2S) and
(1S,2R)-methyl-1'-(3-fluorobenzyl)-2-(4-fluorophenyl)-2'-oxospiro[cyclopr-
opane-1,3'-indoline]-5'-carboxylate (50 mg) in methanol (5 mL), THF
(5 mL) and water (1 mL) was added lithium hydroxide (50 mg) at room
temperature. The mixture was heated to 60.degree. C. and stirred at
60.degree. C. for 3 hours. HPLC monitored the reaction finished.
The solvent was removed under reduced pressure. Purification by
preparative HPLC gave the title compound as white powder (10 mg).
LC/MS m/e calcd. for C.sub.24H.sub.17F.sub.2lNO.sub.3: 405,
observed (M+H).sup.+: 406.2 .sup.1H NMR (400 MHz, MeOD) .delta.ppm
7.83 (dd, J=8.34, 1.52 Hz, 1H) 7.24-7.38 (m, 5H) 7.15 (d, J=2.02
Hz, 1H) 7.18 (d, J=7.83 Hz, 2H) 7.06 (t, J=8.72 Hz, 2H) 6.99 (d,
J=8.08 Hz, 1H) 6.75 (d, J=1.52 Hz, 1H) 5.17 (s, 2H) 2.24-2.35 (m,
2H); MS calcd. C.sub.24H.sub.17F.sub.2NO.sub.3 406, obsd.
(ESI.sup.+) [(M+H).sup.+]406.4.
Example 140
(1R,2R) and
(1S,2S)-1'-(2-fluorobenzyl)-2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1-
,3'-indoline]-5'-carboxylic acid
##STR00184##
[0789] The title compound was prepared in analogy to Example 139
starting from methyl-2-oxoindoline-5-carboxylate,
1-(bromomethyl)-3-fluorobenzene, 4-fluorobenzaldehyde (commercially
available). LC/MS m/e calcd. for C.sub.24H.sub.17F.sub.2lNO.sub.3:
405, observed (M+H).sup.+: 406.2 .sup.1H NMR (400 MHz, MeOD)
.delta.ppm 7.96 (dd, J=8.34, 1.52 Hz, 1H) 7.80 (d, J=1.52 Hz, 1H)
7.32 (dd, J=8.46, 5.43 Hz, 3H) 7.08-7.15 (m, 3H) 7.02 (t, J=8.97
Hz, 3H) 5.01 (d, J=16.93 Hz, 2H) 4.93-5.09 (m, 1H) 2.45 (dd,
J=8.59, 5.05 Hz, 1H) 2.36 (dd, J=9.09, 4.80 Hz, 1H).
Example 141
(1R,2R) and
(1S,2S)-2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-car-
boxylic acid
##STR00185##
[0791] The title compound was prepared in analogy to Example 139
starting from methyl-2-oxoindoline-5-carboxylate,
4-fluorobenzaldehyde (commercially available) LC/MS m/e calcd. for
C.sub.17H.sub.12FNO.sub.3: 297, observed (M+H).sup.+: 298.2 .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 2.19-2.31 (m, 2H) 3.31 (s,
1H) 6.95 (d, J=8.08 Hz, 1H) 7.08 (t, J=8.84 Hz, 2H) 7.33 (dd,
J=8.59, 5.56 Hz, 2H) 7.69 (d, J=1.52 Hz, 1H) 7.83 (dd, J=8.21, 1.64
Hz, 1H) 10.72 (s, 1H).
Example 142
(1R,2S) and
(1S,2R)-2-(4-cyanophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-carb-
oxylic acid
##STR00186##
[0793] The title compound was prepared in analogy to Example 139
starting from methyl-2-oxoindoline-5-carboxylate,
4-formylbenzonitrile (commercially available). LC/MS m/e calcd. for
C.sub.18H.sub.12N.sub.2O.sub.3: 304, observed (M+H).sup.+: 305.2
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 2.02 (dd, J=8.84,
5.05 Hz, 1H) 2.49 (s, 1H) 3.19 (t, J=8.59 Hz, 1H) 6.67 (d, J=1.26
Hz, 1H) 6.94 (d, J=8.08 Hz, 1H) 7.55 (d, =8.08 Hz, 2H) 7.72 (dd,
J=8.21, 0.64 Hz, 1H) 7.79 (d, J=8.34 Hz, 2H) 11.01 (br. s., 1H)
12.40 (br. s., 1H).
Example 143
(1R,2R) and
(1S,2S)-2-(4-cyanophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-carb-
oxylic acid
##STR00187##
[0795] The title compound was prepared in analogy to Example 139
starting from methyl-2-oxoindoline-5-carboxylate,
4-formylbenzonitrile) LC/MS m/e calcd. for
C.sub.18H.sub.12N.sub.2O.sub.3: 304, observed (M+H).sup.+: 305.2
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 2.29-2.37 (m, 2H)
3.45 (t, J=8.72 Hz, 1H) 6.96 (d, J=8.08 Hz, 1H) 7.52 (d, J=8.34 Hz,
2H) 7.73 (dd, J=4.93, 3.41 Hz, 3H) 7.85 (dd, J=8.21, 1.64 Hz, 1H)
10.77 (br. s., 1H).
Example 144
(1S,2R) and
(1R,2S)-2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-car-
boxylic acid
##STR00188##
[0797] To a solution (1R,2S) and
(1S,2R)-methyl-2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-
-5'-carboxylate (80 mg) (prepared as in Example 139) in methanol (1
mL) and water (0.1 mL) was added lithium hydroxide (10 mg) at room
temperature. The mixture was stirred for 14 hours at room
temperature. HPLC monitored the reaction finished. The solvent was
removed under reduced pressure. Purification by preparative HPLC
gave the title compound as white solid (30 mg). LC/MS m/e calcd.
for C.sub.17H.sub.12FNO.sub.3: 297, observed (M+H).sup.+: 298.2
LC/MS m/e calcd for C.sub.17H.sub.12FNO.sub.3 297.08, observed
(M-H).sup.+: 296.1; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm
1.99 (dd, J=9.09, 4.80 Hz, 1H) 2.35 (dd, J=8.08, 4.80 Hz, 1H), 3.11
(t, J=8.46 Hz, 1H) 6.65 (d, J=1.52 Hz, 1H) 6.94 (d, J=8.08 Hz, 1H)
7.14 (t, J=8.84 Hz, 2H) 7.34 (dd, J=8.34, 5.56 Hz, 2H) 7.72 (dd,
J=8.08, 1.52 Hz, 1H) 10.97 (s, 1H) 12.36 (br. s., 1H).
Example 145
Evaluation of AMPK Modulator by Analysis of AMPK and ACC
Phosphorylation
[0798] This method evaluates endogenous expression and
phosphorylation of AMP-activated protein kinase (AMPK) and acetyl
CoA carboxylase (ACC) in L6 cell line using Western blot analysis.
It is used to determine the potency and efficacy of small molecular
AMPK modulators.
[0799] L6 cells (ATCC) are cultured and maintained at DMEM (high
glucose, Gibco, BRL) with 10% fetal bovine serum (FBS, Hyclone). In
an assay, cells are plated at 3.times.10.sup.6 per plate in 10 ml
on a 10 cm dish and they reach subconfluent of 70-80% within 24
hrs. The cells are serum starved overnight prior to be treated with
an AMPK modulator. The compound concentration typically ranges from
0 to 100 .mu.M and treat the cells for 1-4 hrs. Once the incubation
is completed, the medium is aspirated and the cell layer is gently
rinsed with 2 ml of ice-cold PBS. 500 .mu.l of lysis buffer
containing 150 mM NaCl, 5 mM EDTA, 2 mM EGTA, 25 mM NaF, 2 mM
Na.sub.3VO.sub.4, 1 mg/ml of Pefabloc, 1% Triton X-100, and a Roche
Complete Protease Inhibitor Tablet is added and incubated on ice
for 10 min. The cell lysate is harvested and subsequently
centrifugated at 12,000 rpm for 10 min at 4.degree. C. The
supernatant is saved and its protein concentration is determined
using Quick Start Bradford protein quantification kit (B10-Rad). 40
.mu.g is loaded for 7.5% SDS-PAGE analysis and subsequently blotted
to PVDF membrane following a standard procedure. The membrane is
treated with a blocking buffer (5% nonfat milk) for 1 h at room
temperature in agitation. The levels of phospho-AMPK and
phospho-ACC are determined using phospho-AMPK.alpha.(Thr172)(40 H9)
rabbit mAb (Cell Signaling) and phospho-acetyl CoA
carboxylase(Ser79) antibody (Cell Signaling) as primary antibodies
by incubating the blot at 4.degree. C. overnight. The blots are
stripped and re-probed using acetyl CoA carboxylase (C83B10) rabbit
mAb (Cell signaling), AMPK.alpha.(23A3) rabbit mAb (Cell
Signaling), and .beta.-actin antibody (Cell Signaling) to determine
the whole protein level of ACC, AMPK and .beta.-actin,
respectively. Each protein band in a blot is visualized via ECL
Plus Western blotting detection kit (Amersham) and quantified by
the scan analysis. The EC.sub.50 value, defined as an activator
concentration that produces half of the maximal protein
phosphorylation level, and Emax, defined as the maximal
phosphorylation at the infinite activator concentration, are
determined semi-quantitatively and recorded.
[0800] All the compounds of formula (I) are active in the foregoing
AMPK and ACC phosphorylation assay.
Example 146
Scintillation Proximity Assay
Preparation of Enzymes
[0801] Recombinant human AMPK .alpha.1.beta.1.gamma.1,
.alpha.2.beta.1.gamma.1 or AMPK .alpha. subunit truncations
.alpha.1(1-335), .alpha.1(1-394) and .alpha.2(1-394) were
constructed, expressed and purified as described previously (Pang,
T., Zhang, Z. S., Gu, M., Qiu, B. Y., Yu, L. F., Cao, P. R., Shao,
W., Su, M. B., Li, J. Y., Nan, F. J., and Li, J. (2008) or
purchased from Invitrogen (San Diego, Calif., U.S.A.). Rat liver
AMPK heterotrimer enzyme was obtained from Upstate (Billerica,
Mass., U.S.A.).
Scintillation Proximity Assay
[0802] Before the Scintillation Proximity Assay (SPA) assay, 200 nM
recombinant AMPK proteins (.alpha.1.beta.1.gamma.1,
.alpha.2.beta.1.gamma.1, .alpha.1(1-335), .alpha.1(1-394) or
.alpha.2(1-394)) were fully phosphorylated as described previously
(Pang et al., 2008). SPA reactions were performed in 96-well plates
at a final volume of 50 .mu.l containing 20 mM Tris-HCl pH 7.5, 5
mM MgCl.sub.2, 1 mM DTT, 2 .mu.M biotin-SAMS, 2 .mu.M ATP, 0.2
.mu.Ci/well [.gamma.-.sup.33P]ATP, and various amount of activator.
Reactions were initiated by the addition of 50 nM recombinant AMPK
proteins to the reaction solutions and incubated at 30.degree. C.
for 2 hr. After that, reactions were terminated by the addition of
40 .mu.l stop solution containing 80 .mu.g streptavidin-coated SPA
beads per well, 50 mM EDTA, 0.1% Triton X-100 in PBS, pH 7.5 and
incubated for 1 hr. Finally, a 160 .mu.l suspension solution
containing 2.4 M CsCl, 50 mM EDTA, and 0.1% Triton X-100 in PBS (pH
7.5) was added to the reaction solution to suspend SPA beads
completely. SPA signals were determined with a Wallac MicroBeta
plate counter (PerkinElmer) 30 min later for calculation of the
amount of product formed. The amount of products formed in 2 hr was
plotted against activator concentrations to determine the effective
concentration of the activator (EC.sub.50) required for 50% of
maximal enzyme activity.
[0803] Compounds as described above have EC.sub.50 values between
0.5 uM and 50 uM. Preferred compounds have EC.sub.50 values between
0.5 uM and 10 uM. Particularly preferred compounds have EC.sub.50
values between 0.5 uM and 1 uM. These results have been obtained by
using the foregoing Scintillation Proximity Assay (uM means
microMolar).
[0804] The EC.sub.50 values obtained for particular compounds of
formula (I) are listed in the table below.
TABLE-US-00001 Examples EC.sub.50 (uM) Example 1 2.57 Example 2
0.96 Example 3 2.98 Example 4 2.2 Example 5 5.3 Example 6 7.1
Example 7 10.85 Example 8 2.77 Example 9 1.19 Example 10 2.02
Example 11 2.04 Example 12 2.36 Example 13 3.23 Example 14 2.03
Example 15 2.48 Example 16 2.72 Example 17 1.63 Example 18 1.66
Example 19 1.42 Example 20 0.90 Example 21 2.03 Example 22 11.16
Example 23 1.66 Example 24 5.75 Example 26 1.79 Example 60 3.5
Example 61 8.67 Example 62 6.57 Example 63 1.54 Example 64 1.6
Example 65 1.71 Example 66 1.07 Example 67 2.29 Example 68 2.8
Example 70 1.54 Example 71 3.2 Example 72 4.1 Example 73 1.65
Example 74 8.8 Example 75 5.91 Example 76 1.09 Example 77 2.17
Example 78 4.2 Example 79 2.6 Example 80 1.25 Example 81 2.22
Example 82 4.03 Example 83 2.59 Example 84 2.98 Example 85 0.95
Example 86 1.73 Example 87 6.73 Example 88 2.56 Example 89 1.40
Example 90 1.47 Example 91 1.55 Example 92 0.87 Example 93 0.91
Example 94 1.50 Example 110 1.37 Example 111 1.29 Example 112 1.27
Example 113 1.84 Example 114 6.48 Example 115 5.14 Example 116 4.33
Example 117 0.99 Example 124 5.4 Example 125 1.75 Example 126 1.7
Example 127 4.5 Example 128 2.04 Example 129 1.68 Example 130 1.10
Example 131 3.27 Example 132 1.55
Example A
[0805] A compound of formula (I) can be used in a manner known per
se as the active ingredient for the production of tablets of the
following composition:
TABLE-US-00002 Per tablet Active ingredient 200 mg Microcrystalline
cellulose 155 mg Corn starch 25 mg Talc 25 mg
Hydroxypropylmethylcellulose 20 mg 425 mg
Example B
[0806] A compound of formula (I) can be used in a manner known per
se as the active ingredient for the production of capsules of the
following composition:
TABLE-US-00003 Per capsule Active ingredient 100.0 mg Corn starch
20.0 mg Lactose 95.0 mg Talc 4.5 mg Magnesium stearate 0.5 mg 220.0
mg
* * * * *