U.S. patent application number 14/339981 was filed with the patent office on 2015-02-19 for chemical compounds 251.
This patent application is currently assigned to AstraZeneca AB. The applicant listed for this patent is AstraZeneca AB. Invention is credited to Leslie DAKIN, James Edward DOWLING, Michelle Laurae LAMB, Jon READ, Qibin SU, XiaoLan ZHENG.
Application Number | 20150051185 14/339981 |
Document ID | / |
Family ID | 41050276 |
Filed Date | 2015-02-19 |
United States Patent
Application |
20150051185 |
Kind Code |
A1 |
DAKIN; Leslie ; et
al. |
February 19, 2015 |
Chemical Compounds 251
Abstract
The invention relates to chemical compounds of formula I,
##STR00001## and salts thereof. In some embodiments, the invention
relates to inhibitors or modulators of PIM-1 and/or PIM-2, and/or
PIM-3 protein kinase activity or enzyme function. In still further
embodiments, the invention relates to pharmaceutical compositions
comprising compounds disclosed herein, and their use in the
prevention and treatment of PIM kinase related conditions and
diseases, preferably cancer.
Inventors: |
DAKIN; Leslie; (Waltham,
MA) ; DOWLING; James Edward; (Waltham, MA) ;
LAMB; Michelle Laurae; (Waltham, MA) ; READ; Jon;
(Macclesfield, GB) ; SU; Qibin; (Waltham, MA)
; ZHENG; XiaoLan; (Waltham, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AstraZeneca AB |
Sodertalje |
|
SE |
|
|
Assignee: |
AstraZeneca AB
Sodertalje
SE
|
Family ID: |
41050276 |
Appl. No.: |
14/339981 |
Filed: |
July 24, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13000138 |
May 25, 2011 |
8901307 |
|
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PCT/GB2009/050773 |
Jul 2, 2009 |
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14339981 |
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61077639 |
Jul 2, 2008 |
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61183278 |
Jun 2, 2009 |
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Current U.S.
Class: |
514/210.2 ;
514/218; 514/254.02; 514/342; 540/575; 544/369; 546/209 |
Current CPC
Class: |
C07D 417/10 20130101;
C07D 417/12 20130101; C07D 277/34 20130101; A61P 35/00 20180101;
A61P 35/02 20180101; A61K 31/426 20130101; C07D 417/14 20130101;
A61P 43/00 20180101; A61K 31/427 20130101; C07D 417/06
20130101 |
Class at
Publication: |
514/210.2 ;
546/209; 514/342; 540/575; 514/218; 544/369; 514/254.02 |
International
Class: |
C07D 417/10 20060101
C07D417/10; C07D 417/12 20060101 C07D417/12 |
Claims
1. A method of treating or preventing cancer comprising, a)
providing a pharmaceutical composition comprising a compound of
formula I, ##STR00845## or salts thereof, functioning to inhibit a
PIM kinase, wherein R.sup.1 is selected from a carbocyclyl, aryl,
and heterocyclyl, wherein R.sup.1 is optionally substituted with
one or more, the same or different, R.sup.2; R.sup.2 is selected
from halogen, C.sub.1-6alkyl, halogenated C.sub.1-6alkyl, amino,
C.sub.1-6alkylamino, (C.sub.1-6alkyl).sub.2amino, and heterocyclyl,
wherein R.sup.2 is optionally substituted with one or more, the
same or different, R.sup.3; R.sup.3 is selected from
C.sub.1-6alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto,
formyl, carboxy, carbamoyl, C.sub.1-6alkoxy, C.sub.1-6alkylthio,
C.sub.1-6alkylamino, (C.sub.1-6alkyl).sub.2amino,
C.sub.1-6alkylsulfinyl, C.sub.1-6alkylsulfonyl, arylsulfonyl,
carbocyclyl, aryl, and heterocyclyl, wherein R.sup.3 is optionally
substituted with one or more, the same or different, R.sup.4;
R.sup.4 is selected from C.sub.1-6alkyl, halogen, nitro, cyano,
hydroxy, amino, mercapto, formyl, carboxy, carbamoyl,
C.sub.1-6alkoxy, C.sub.1-6alkylthio, C.sub.1-6alkylamino,
(C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkylsulfinyl,
C.sub.1-6alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, and
heterocyclyl, wherein R.sup.4 is optionally substituted with one or
more, the same or different, R.sup.5; and R.sup.5 is selected from
halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl,
amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl,
ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino,
dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino,
N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,
N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio,
ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl,
methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl,
N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl,
N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, and heterocyclyl; and
b) administering said pharmaceutical composition to a subject
diagnosed with, exhibiting symptoms of, or at risk for cancer.
2. A compound of formula IA, ##STR00846## or salts thereof,
wherein, --- is individually at each occurrence selected from a
single and double bond; n is selected from 0, 1, or 2; m is
selected from 0, 1, or 2; A is selected from N and CR.sup.7; X is
selected from O, S, CHR.sup.10 and NR.sup.11; Y is selected from N,
CH, and C; R.sup.5, R.sup.6, and R.sup.7 are each individually and
independently from hydrogen, C.sub.1-6alkyl, halogen, cyano, nitro,
hydroxy, amino, mercapto, formyl, carboxy, carbamoyl,
C.sub.1-6alkoxy, C.sub.1-6alkylthio, C.sub.1-6alkylamino,
(C.sub.1-6alkyl).sub.2amino, carbocyclyl, aryl, and heterocyclyl,
wherein R.sup.5, R.sup.6, and R.sup.7 are each optionally
substituted with one or more, the same or different, R.sup.12;
R.sup.8 and R.sup.9 are each individually and independently
selected from hydrogen, amino, hydroxyl, mercapto, C.sub.1-6alkyl,
C.sub.1-6alkylamino, carbocyclyl, aryl, and heterocyclyl wherein
R.sup.8 and R.sup.9 are each optionally substituted with one or
more, the same or different, R.sup.15; R.sup.10 is selected from
hydrogen, C.sub.1-6alkyl, halogen, nitro, cyano, hydroxy, amino,
mercapto, formyl, carboxy, carbamoyl, C.sub.1-6alkoxy,
C.sub.1-6alkylthio, C.sub.1-6alkylamino,
(C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkylsulfamoyl,
arylsulfamoyl, carbocyclyl, aryl, and heterocyclyl, wherein
R.sup.10 is optionally substituted with one or more, the same or
different, R.sup.12; R.sup.11 is selected from hydrogen, formyl,
C.sub.1-6alkyl, C.sub.1-6alkanoyl, C.sub.1-6alkylsulfinyl,
C.sub.1-6alkylsulfonyl, arylsulfonyl, C.sub.1-6alkoxycarbonyl,
carbocyclyl, aryl, and heterocyclyl, wherein R.sup.11 is optionally
substituted with one or more, the same or different, R.sup.12;
R.sup.12 is selected from halogen, nitro, cyano, hydroxy,
trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy,
carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy,
acetyl, acetoxy, methylamino, ethylamino, dimethylamino,
diethylamino, N-methyl-N-ethylamino, acetylamino,
N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,
N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio,
ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl,
methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl,
N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl,
N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, and heterocyclyl,
wherein R.sup.12 is optionally substituted with one or more, the
same or different, R.sup.16; R.sup.15 is selected from
C.sub.1-6alkyl, C.sub.1-6alkanoyl, C.sub.1-6alkylsulfinyl,
C.sub.1-6alkylsulfonyl, arylsulfonyl, and C.sub.1-6alkoxycarbonyl
wherein R.sup.15 is optionally substituted with one or more, the
same or different, R.sup.12; R.sup.16 is selected from halogen,
nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino,
formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl,
methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino,
dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino,
aminomethyl, aminoethyl, aminopropyl, aminobutyl,
N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,
N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio,
ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl,
methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl,
N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, and
N-methyl-N-ethylsulfamoyl; and provided that R.sup.5, R.sup.6, and
R.sup.7 are not all hydrogen and provided the compound is not
5-((5-nitro-2-(1-piperidinyl)phenyl)methylene)-2,4-thiazolidinedione
or
5-((2-(4-morpholinyl)-5-nitrophenyl)methylene)-2,4-thiazolidinedione.
3. A compound of formula IB, ##STR00847## or salts thereof,
wherein, n is selected from 0, 1, or 2; X is selected from O,
CHR.sup.10 and NR.sup.11; R.sup.5, R.sup.6, and R.sup.7 are each
individually and independently from hydrogen, halogen, cyano,
hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy,
carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy,
acetyl, acetoxy, methylamino, ethylamino, dimethylamino,
diethylamino, N-methyl-N-ethylamino, acetylamino,
N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,
N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio,
ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl,
methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl,
N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, and
N-methyl-N-ethylsulfamoyl; R.sup.8 and R.sup.9 are each
individually and independently selected from hydrogen, amino,
C.sub.1-6alkyl, C.sub.1-6alkylamino, wherein R.sup.8 and R.sup.9
are each optionally substituted with one or more, the same or
different, R.sup.15; R.sup.10 is selected from hydrogen,
C.sub.1-6alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto,
formyl, carboxy, carbamoyl, C.sub.1-6alkoxy, C.sub.1-6alkylthio,
C.sub.1-6alkylamino, (C.sub.1-6alkyl).sub.2amino,
C.sub.1-6alkylsulfamoyl, arylsulfamoyl, carbocyclyl, aryl, and
heterocyclyl, wherein R.sup.10 is optionally substituted with one
or more, the same or different, R.sup.12; R.sup.11 is selected from
hydrogen, C.sub.1-6alkyl, C.sub.1-6alkanoyl,
C.sub.1-6alkylsulfinyl, C.sub.1-6alkylsulfonyl, arylsulfonyl,
C.sub.1-6alkoxycarbonyl, carbocyclyl, aryl, and heterocyclyl,
wherein R.sup.11 is optionally substituted with one or more, the
same or different, R.sup.12; R.sup.12 is selected from halogen,
nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino,
formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl,
methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino,
dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino,
N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,
N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio,
ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl,
methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl,
N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl,
N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, and heterocyclyl,
wherein R.sup.12 is optionally substituted with one or more, the
same or different, R.sup.16; R.sup.15 is selected from
C.sub.1-6alkyl, C.sub.1-6alkanoyl, C.sub.1-6alkylsulfinyl,
C.sub.1-6alkylsulfonyl, arylsulfonyl, and C.sub.1-6alkoxycarbonyl
wherein R.sup.15 is optionally substituted with one or more, the
same or different, R.sup.12; R.sup.16 is selected from halogen,
nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino,
formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl,
methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino,
dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino,
N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,
N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio,
ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl,
methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl,
N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, and
N-methyl-N-ethylsulfamoyl.; and provided that said compound is not,
5-[[2-(4-methyl-1-piperazinyl)phenyl]methylene]-2,4-thiazolidinedione
or
5-[[2-[(2,6-dichloro-3-methylphenyl)amino]phenyl]methylene]-2,4-thiazolid-
inedione.
4. A compound of formula IC, ##STR00848## or salts thereof,
wherein, n is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8; X is
selected from O, S, CHR.sup.10 and NR.sup.11; Y is selected from O,
S, and NR.sup.13; R.sup.5, R.sup.6, and R.sup.7 are each
individually and independently from C.sub.1-6alkyl, halogen, nitro,
cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl,
C.sub.1-6alkoxy, C.sub.1-6alkylthio, C.sub.1-6alkylamino,
C.sub.1-6dialkylamino, carbocyclyl, aryl, and heterocyclyl, wherein
R.sup.5, R.sup.6, and R.sup.7 are each optionally substituted with
one or more, the same or different, R.sup.12; R.sup.10 is selected
from hydrogen, C.sub.1-6alkyl, halogen, nitro, cyano, hydroxy,
amino, mercapto, formyl, carboxy, carbamoyl, C.sub.1-6alkoxy,
C.sub.1-6alkylthio, C.sub.1-6alkylamino,
(C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkylsulfamoyl,
arylsulfamoyl, carbocyclyl, aryl, and heterocyclyl, wherein
R.sup.10 is optionally substituted with one or more, the same or
different, R.sup.12; R.sup.11, R.sup.13, and R.sup.14 are each
individually and independently selected from hydrogen,
C.sub.1-6alkyl, C.sub.1-6alkanoyl, C.sub.1-6alkylsulfinyl,
C.sub.1-6alkylsulfonyl, arylsulfonyl, and C.sub.1-6alkoxycarbonyl
wherein R.sup.11 is optionally substituted with one or more, the
same or different, R.sup.12; or R.sup.11 and R.sup.14, taken
together with the atoms to which they are attached form a five,
six, or seven membered heterocyclic ring optionally substituted
with one or more, the same or different, R.sup.12; R.sup.12 is
selected from halogen, nitro, cyano, hydroxy, trifluoromethoxy,
trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto,
sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy,
methylamino, ethylamino, dimethylamino, diethylamino,
N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl,
N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl,
N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl,
ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl,
ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl,
N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl,
N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, and heterocyclyl.
5. A compound of formula IC as defined in claim 4, or salts
thereof, wherein Y is NR.sup.13.
6. A compound of formula IA, IB, or IC, as defined in claims 2-4,
or salts thereof, wherein R.sup.5 is a halogenated
C.sub.1-6alkyl.
7. A compound of formula IA, IB, or IC, as defined in claims 2-4,
or salts thereof, wherein R.sup.7 is a halogen.
8. A compound of formula IX, ##STR00849## or salts thereof, wherein
R.sup.5 is selected from hydrogen, C.sub.1-6alkoxy, carbamoyl, and
halogenated C.sub.1-6alkyl; R.sup.6 is selected from hydrogen,
halogen, C.sub.1-6alkoxy, and 2-(1-piperidyl)ethoxy; R.sup.7 is
selected from hydrogen, halogen, and C.sub.1-6alkoxy; R.sup.17 is a
heterocarbocylcyl, wherein R.sup.17 is optionally substituted with
one or more, the same or different, R.sup.18; R.sup.18 is selected
from halogen, formyl, amino, C.sub.1-6alkyl, C.sub.1-6alkylamino,
(C.sub.1-6alkyl).sub.2amino, carbocyclyl, aryl, heterocyclyl,
wherein R.sup.18 is optionally substituted with one or more, the
same or different, R.sup.19; R.sup.19 is selected from amino,
C.sub.1-6alkyl, hydroxy, carbocyclyl, and heterocyclyl wherein
R.sup.19 is optionally substituted with one or more, the same or
different, R.sup.20; and R.sup.20 is selected from amino,
C.sub.1-6alkyl, and halogen.
9. The compound of claim 8, or salts thereof, wherein, R.sup.17 is
selected from (3R)-3-aminopyrrolidin-1-yl,
(3R)-3-dimethylaminopyrrolidin-1-yl,
(3S)-3-(3-aminopropylamino)pyrrolidin-1-yl,
(3S)-3-(5-aminopentanoylamino)pyrrolidin-1-yl,
(3S)-3-amino-1-piperidyl, (3S)-3-aminopyrrolidin-1-yl,
(3S)-3-dimethylaminopyrrolidin-1-yl,
(3S,5R)-3,5-dimethylpiperazin-1-yl, 1,4-diazepan-1-yl,
2-(1-piperidyl)ethoxy, 2-diethylaminoethoxy,
2-dimethylaminoethyl-methyl-amino, 2-hydroxyethoxy,
2-morpholinoethoxy, 3-(2-aminoethylamino)pyrrolidin-1-yl,
3-(2-hydroxyethylamino)pyrrolidin-1-yl,
3-(2-methylaminoethylamino)pyrrolidin-1-yl,
3-(3-aminopropanoylamino)pyrrolidin-1-yl,
3-(3-aminopropylamino)pyrrolidin-1-yl,
3-(3-methyl-1,2,4-oxadiazol-5-yl)-1-piperidyl,
3-(aminomethyl)-1-piperidyl, 3-(aminomethyl)pyrrolidin-1-yl,
3-acetamidopyrrolidin-1-yl, 3-aminopyrrolidin-1-yl,
3-dimethylaminopropoxy, 3-dimethylaminopropyl-methyl-amino,
3-dimethylaminopyrrolidin-1-yl, 3-hydroxypyrrolidin-1-yl,
3-pyridyl, 4-(1-methyl-4-piperidyl)piperazin-1-yl,
4-(1-piperidyl)-1-piperidyl, 4-(2-aminoethyl)piperazin-1-yl,
4-(2-hydroxyethyl)-1,4-diazepan-1-yl,
4-(2-hydroxyethyl)-1-piperidyl, 4-(2-hydroxyethyl)piperazin-1-yl,
4-(2-methylaminoethyl)piperazin-1-yl,
4-(2-morpholinoethyl)piperazin-1-yl,
4-(3-aminopropanoyl)-1,4-diazepan-1-yl,
4-(3-aminopropanoyl)piperazin-1-yl,
4-(3-aminopropyl)piperazin-1-yl, 4-(3-hydroxypropyl)piperazin-1-yl,
4-(3-methyl-1,2,4-oxadiazol-5-yl)-1-piperidyl,
4-(4-aminobutanoyl)-1,4-diazepan-1-yl,
4-(4-aminobutanoyl)piperazin-1-yl,
4-(4-chloro-2-fluoro-phenyl)piperazin-1-yl,
4-(4-fluorophenyl)piperazin-1-yl,
4-(4-pyridylmethyl)piperazin-1-yl,
4-(5-aminopentanoyl)-1,4-diazepan-1-yl,
4-(5-aminopentanoyl)piperazin-1-yl,
4-(azetidine-3-carbonyl)piperazin-1-yl,
4-(benzo[1,3]dioxol-5-ylmethyl)piperazin-1-yl,
4-(cyclopropylmethyl)piperazin-1-yl, 4-(hydroxymethyl)-1-piperidyl,
4-(piperidine-3-carbonyl)-1,4-diazepan-1-yl,
4-(piperidine-3-carbonyl)piperazin-1-yl,
4-(piperidine-4-carbonyl)piperazin-1-yl,
4-[(2-chlorophenyl)methyl]piperazin-1-yl,
4-[3-(aminomethyl)benzoyl]piperazin-1-yl,
4-[4-(piperazin-1-ylmethyl)benzoyl]piperazin-1-yl,
4-acetylpiperazin-1-yl, 4-amino-1-piperidyl,
4-butyl-1,4-diazepan-1-yl, 4-cyclopentylpiperazin-1-yl,
4-dimethylamino-1-piperidyl, 4-hydroxy-1-piperidyl,
4-isobutylpiperazin-1-yl, 4-isopropylpiperazin-1-yl,
4-methylpiperazin-1-yl, 4-morpholino-1-piperidyl, 4-pyridyl,
4-pyrrolidin-1-yl-1-piperidyl, 4-tert-butoxycarbonylpiperazin-1-yl,
4-tert-butylpiperazin-1-yl, morpholino, piperazin-1-yl, and
pyrrolidin-1-yl.
10. A compound selected from:
5-({2-[(3S)-3-aminopiperidin-1-yl]-3-chloro-5-(trifluoromethyl)phenyl}met-
hylidene)-1,3-thiazolidine-2,4-dione;
5-({2-[(3R)-3-aminopiperidin-1-yl]-3-chloro-5-(trifluoromethyl)phenyl}met-
hylidene)-1,3-thiazolidine-2,4-dione;
5-{[2-(4-aminopiperidin-1-yl)-3-chloro-5-(trifluoromethyl)phenyl]methylid-
ene}-1,3-thiazolidine-2,4-dione;
5-({2-[3-(aminomethyl)piperidin-1-yl]-3-chloro-5-(trifluoromethyl)phenyl}-
methylidene)-1,3-thiazolidine-2,4-dione;
5-{[3-chloro-2-(1,4-diazepan-1-yl)-5-(trifluoromethyl)phenyl]methylidene}-
-1,3-thiazolidine-2,4-dione;
5-{[3-chloro-2-(4-cyclopentylpiperazin-1-yl)-5-(trifluoromethyl)phenyl]me-
thylidene}-1,3-thiazolidine-2,4-dione;
5-({3-chloro-2-[4-(4-fluorophenyl)piperazin-1-yl]-5-(trifluoromethyl)phen-
yl}methylidene)-1,3-thiazolidine-2,4-dione;
5-({2-[4-(1,3-benzodioxol-5-ylmethyl)piperazin-1-yl]-3-chloro-5-(trifluor-
omethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
5-({3-chloro-2-[4-(3-methyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl]-5-(trifl-
uoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
5-{[3-chloro-2-(4-pyrrolidin-1-ylpiperidin-1-yl)-5-(trifluoromethyl)pheny-
l]methylidene}-1,3-thiazolidine-2,4-dione;
5-({3-chloro-2-[4-(1-methylethyl)piperazin-1-yl]-5-(trifluoromethyl)pheny-
l}methylidene)-1,3-thiazolidine-2,4-dione;
5-({3-chloro-2-[4-(2-methylpropyl)piperazin-1-yl]-5-(trifluoromethyl)phen-
yl}methylidene)-1,3-thiazolidine-2,4-dione;
5-({3-chloro-2-[4-(2-hydroxyethyl)piperidin-1-yl]-5-(trifluoromethyl)phen-
yl}methylidene)-1,3-thiazolidine-2,4-dione;
5-({3-chloro-2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-5-(trifluoromethyl-
)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
5-({3-chloro-2-[4-(4-chloro-2-fluorophenyl)piperazin-1-yl]-5-(trifluorome-
thyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
5-({3-chloro-2-[3-(3-methyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl]-5-(trifl-
uoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
5-({3-chloro-2-[4-(pyridin-4-ylmethyl)piperazin-1-yl]-5-(trifluoromethyl)-
phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
5-({3-chloro-2-[4-(2-chlorobenzyl)piperazin-1-yl]-5-(trifluoromethyl)phen-
yl}methylidene)-1,3-thiazolidine-2,4-dione;
5-({3-chloro-2-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-5-(trifluoromet-
hyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
5-({3-chloro-2-[4-(2-morpholin-4-ylethyl)piperazin-1-yl]-5-(trifluorometh-
yl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
5-({3-chloro-2-[4-(cyclopropylmethyl)piperazin-1-yl]-5-(trifluoromethyl)p-
henyl}methylidene)-1,3-thiazolidine-2,4-dione;
5-{[3-chloro-2-(4-morpholin-4-ylpiperidin-1-yl)-5-(trifluoromethyl)phenyl-
]methylidene}-1,3-thiazolidine-2,4-dione;
5-({3-chloro-2-[4-(3-hydroxypropyl)piperazin-1-yl]-5-(trifluoromethyl)phe-
nyl}methylidene)-1,3-thiazolidine-2,4-dione;
5-({3-chloro-2-[4-(dimethylamino)piperidin-1-yl]-5-(trifluoromethyl)pheny-
l}methylidene)-1,3-thiazolidine-2,4-dione;
5-{[3-chloro-2-{[3-(dimethylamino)propyl]
(methyl)amino}-5-(trifluoromethyl)phenyl]methylidene}-1,3-thiazolidine-2,-
4-dione;
5-({3-chloro-2-[4-(2-hydroxyethyl)-1,4-diazepan-1-yl]-5-(trifluor-
omethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
5-{[2-(4-butyl-1,4-diazepan-1-yl)-3-chloro-5-(trifluoromethyl)phenyl]meth-
ylidene}-1,3-thiazolidine-2,4-dione;
5-({3-chloro-2-[4-(2-hydroxyethyl)piperazin-1-yl]-5-(trifluoromethyl)phen-
yl}methylidene)-1,3-thiazolidine-2,4-dione;
5-{[3-chloro-2-morpholin-4-yl-5-(trifluoromethyl)phenyl]methylidene}-1,3--
thiazolidine-2,4-dione;
5-{[2-(4-tert-butylpiperazin-1-yl)-3-chloro-5-(trifluoromethyl)phenyl]met-
hylidene}-1,3-thiazolidine-2,4-dione;
5-{[2-(1,4'-bipiperidin-1'-yl)-3-chloro-5-(trifluoromethyl)phenyl]methyli-
dene}-1,3-thiazolidine-2,4-dione;
5-{[3-chloro-2-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl]methyli-
dene}-1,3-thiazolidine-2,4-dione;
5-({3-bromo-2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]phenyl}methylidene)--
1,3-thiazolidine-2,4-dione;
5-({2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-5-(trifluoromethyl)phenyl}meth-
ylidene)-1,3-thiazolidine-2,4-dione;
(5Z)-5-({2-[(3S)-3-aminopyrrolidin-1-yl]-3-chloro-5-(trifluoromethyl)phen-
yl}methylidene)-1,3-thiazolidine-2,4-dione;
(5Z)-5-({3-[3-(4-methylpiperazin-1-yl)propoxy]phenyl}methylidene)-1,3-thi-
azolidine-2,4-dione;
2-{3-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenoxy}acetamide;
(5Z)-5-{[3-(3-piperidin-1-ylpropoxy)phenyl]methylidene}-1,3-thiazolidine--
2,4-dione;
(5Z)-5-({3-[(4-methylpiperazin-1-yl)methyl]phenyl}methylidene)--
1,3-thiazolidine-2,4-dione;
N-[2-(dimethylamino)ethyl]-2'-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)m-
ethyl]-N-methylbiphenyl-4-sulfonamide;
5-({2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-5-methoxyphenyl}methylidene-
)-1,3-thiazolidine-2,4-dione;
5-({2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-5-(trifluoromethyl)phenyl}m-
ethylidene)-1,3-thiazolidine-2,4-dione;
5-({5-chloro-2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]phenyl}methylidene)-
-1,3-thiazolidine-2,4-dione;
5-({2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-4-methylphenyl}methylidene)-
-1,3-thiazolidine-2,4-dione;
5-({2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-5-fluorophenyl}methylidene)-
-1,3-thiazolidine-2,4-dione;
5-({2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-5-methylphenyl}methylidene)-
-1,3-thiazolidine-2,4-dione;
5-({5-bromo-2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]phenyl}methylidene)--
1,3-thiazolidine-2,4-dione;
5-({2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-3-fluorophenyl}methylidene)-
-1,3-thiazolidine-2,4-dione;
5-({2-chloro-6-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]phenyl}methylidene)-
-1,3-thiazolidine-2,4-dione;
(5Z)-5-({2-[(3R)-3-(aminomethyl)pyrrolidin-1-yl]-3-chlorophenyl}methylide-
ne)-1,3-thiazolidine-2,4-dione;
(5Z)-5-({2-[(3S)-3-(aminomethyl)pyrrolidin-1-yl]-3-chlorophenyl}methylide-
ne)-1,3-thiazolidine-2,4-dione;
(5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-chlorophenyl}methylidene)-1,3-t-
hiazolidine-2,4-dione;
(5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-methoxyphenyl}methylidene)-1,3--
thiazolidine-2,4-dione;
(5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-bromophenyl}methylidene)-1,3-th-
iazolidine-2,4-dione;
(5Z)-5-({2-[(3R)-3-aminopyrrolidin-1-yl]-3-chlorophenyl}methylidene)-1,3--
thiazolidine-2,4-dione;
(5Z)-5-({2-[(3S)-3-aminopyrrolidin-1-yl]-3-bromophenyl}methylidene)-1,3-t-
hiazolidine-2,4-dione;
(5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-ethoxyphenyl}methylidene)-1,3-t-
hiazolidine-2,4-dione;
(5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-(2-methylpropoxy)phenyl}methyli-
dene)-1,3-thiazolidine-2,4-dione;
(5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-(cyclohexylmethoxy)phenyl}methy-
lidene)-1,3-thiazolidine-2,4-dione;
(5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-(cyclohexyloxy)phenyl}methylide-
ne)-1,3-thiazolidine-2,4-dione;
(5Z)-5-({2-[(3R,4R)-3-amino-4-hydroxypiperidin-1-yl]-3-chlorophenyl}methy-
lidene)-1,3-thiazolidine-2,4-dione;
(5Z)-5-{[3-chloro-2-(1,4-diazepan-1-yl)phenyl]methylidene}-1,3-thiazolidi-
ne-2,4-dione;
(5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-(1-methylethoxy)phenyl}methylid-
ene)-1,3-thiazolidine-2,4-dione;
(5Z)-5-({2-[(3S)-3-aminopyrrolidin-1-yl]-3-(1-methylethoxy)phenyl}methyli-
dene)-1,3-thiazolidine-2,4-dione;
(5Z)-5-({2-[(3S)-3-aminopyrrolidin-1-yl]-3-ethoxyphenyl}methylidene)-1,3--
thiazolidine-2,4-dione;
(5Z)-5-({2-[(3R)-3-{[4-(aminomethyl)benzyl]amino}piperidin-1-yl]-3-chloro-
phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
(5Z)-5-({3-chloro-2-[(3R)-3-{[2-(methylamino)ethyl]amino}piperidin-1-yl]p-
henyl}methylidene)-1,3-thiazolidine-2,4-dione;
(5Z)-5-({2-[(3S,4S)-3-amino-4-hydroxypyrrolidin-1-yl]-3-chlorophenyl}meth-
ylidene)-1,3-thiazolidine-2,4-dione;
(5Z)-5-({3-chloro-2-[4-methyl-3-(methylamino)piperidin-1-yl]phenyl}methyl-
idene)-1,3-thiazolidine-2,4-dione;
(5Z)-5-{[2-(3-amino-4-methylpiperidin-1-yl)-3-chlorophenyl]methylidene}-1-
,3-thiazolidine-2,4-dione;
(5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]phenyl}methylidene)-1,3-thiazolidi-
ne-2,4-dione;
(5Z)-5-({2-[(3S)-3-aminopyrrolidin-1-yl]phenyl}methylidene)-1,3-thiazolid-
ine-2,4-dione;
(5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-(2,2,2-trifluoroethoxy)phenyl}m-
ethylidene)-1,3-thiazolidine-2,4-dione;
(5Z)-5-({2-[(3S)-3-aminopyrrolidin-1-yl]-3-(2,2,2-trifluoroethoxy)phenyl}-
methylidene)-1,3-thiazolidine-2,4-dione;
(5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-(2-methoxyethoxy)phenyl}methyli-
dene)-1,3-thiazolidine-2,4-dione;
(5Z)-5-({2-[(3S)-3-aminopyrrolidin-1-yl]-3-(2-methoxyethoxy)phenyl}methyl-
idene)-1,3-thiazolidine-2,4-dione;
(5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-(cyclopentyloxy)phenyl}methylid-
ene)-1,3-thiazolidine-2,4-dione;
(5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-(cyclobutyloxy)phenyl}methylide-
ne)-1,3-thiazolidine-2,4-dione;
4-[(3R)-3-aminopiperidin-1-yl]-3-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-yliden-
e)methyl]benzamide;
4-[(3S)-3-aminopiperidin-1-yl]-3-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-yliden-
e)methyl]benzamide;
4-[(3R)-3-aminopiperidin-1-yl]-3-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-yliden-
e)methyl]benzoic acid;
4-[(3S)-3-aminopyrrolidin-1-yl]-3-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylide-
ne)methyl]benzoic acid;
(5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]biphenyl-3-yl}methylidene)-1,3-thi-
azolidine-2,4-dione;
5-{[2-(3-aminopropoxy)-5-methoxyphenyl]methylidene}-1,3-thiazolidine-2,4--
dione;
N-{4-[3-(dimethylamino)pyrrolidin-1-yl]-3-[(Z)-(2,4-dioxo-1,3-thiaz-
olidin-5-ylidene)methyl]phenyl}acetamide;
(5Z)-5-[(3-chloro-2-{(3R)-3-[(2-hydroxyethyl)amino]piperidin-1-yl}phenyl)-
methylidene]-1,3-thiazolidine-2,4-dione;
(5Z)-5-[(3-chloro-2-{(3R)-3-[(3-hydroxypropyl)amino]piperidin-1-yl}phenyl-
)methylidene]-1,3-thiazolidine-2,4-dione;
N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]ph-
enyl}pyrrolidin-3-yl]-1-methyl-1H-imidazole-2-carboxamide;
N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]ph-
enyl}pyrrolidin-3-yl]-2-methoxyacetamide;
N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]ph-
enyl}pyrrolidin-3-yl]-1-methyl-1H-pyrazole-3-carboxamide;
N.sup.2-carbamoyl-N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-
-ylidene)methyl]phenyl}pyrrolidin-3-yl]glycinamide;
N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]ph-
enyl}pyrrolidin-3-yl]-2-pyridin-3-ylacetamide;
N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]ph-
enyl}pyrrolidin-3-yl]-2-pyridin-4-ylacetamide;
N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]ph-
enyl}pyrrolidin-3-yl]-1-methyl-1H-pyrazole-4-carboxamide;
N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]ph-
enyl}pyrrolidin-3-yl]-2-(1-oxidothiomorpholin-4-yl)acetamide;
N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]ph-
enyl}pyrrolidin-3-yl]-4-sulfamoylbutanamide;
N'-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]p-
henyl}pyrrolidin-3-yl]-N,N-dimethylbutanediamide;
N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]ph-
enyl}pyrrolidin-3-yl]-N.about.2.about.,N.about.2.about.-dimethylglycinamid-
e;
N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-
phenyl}pyrrolidin-3-yl]-2-cyanoacetamide;
N.sup.2-acetyl-N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-yl-
idene)methyl]phenyl}pyrrolidin-3-yl]glycinamide;
(5Z)-5-({3-chloro-2-[(3R)-3-(dipropylamino)piperidin-1-yl]phenyl}methylid-
ene)-1,3-thiazolidine-2,4-dione;
(5Z)-5-[(3-chloro-2-{(3R)-3-[(3,3,3-trifluoropropyl)amino]piperidin-1-yl}-
phenyl)methylidene]-1,3-thiazolidine-2,4-dione;
5-[(5-methoxy-2-{3-[(1-methylethyl)amino]propoxy}phenyl)methylidene]-1,3--
thiazolidine-2,4-dione;
(5Z)-5-({5-amino-2-[3-(dimethylamino)pyrrolidin-1-yl]phenyl}methylidene)--
1,3-thiazolidine-2,4-dione; and
5-[(2-amino-4,5-dimethoxyphenyl)methylidene]-1,3-thiazolidine-2,4-dione,
or salts thereof.
11. A pharmaceutical composition comprising a compound of formula
I, IA, IB, IC, or IX, as defined in claims 1-10, or a
pharmaceutically acceptable salt thereof.
12. A method of inhibiting a PIM kinase comprising, providing a
compound of formula I, IA, IB, IC, or IX, as defined in claims 1-10
comprising mixing a PIM kinase and said compound under conditions
such that PIM kinase phosphorylation is inhibited.
13. The use of a compound of the formula I, IA, IB, IC, or IX, or a
pharmaceutically acceptable salt thereof, as claimed in any one of
claims 1-10, for the manufacture of a medicament for the production
of an anti-cancer effect in a subject.
14. A method of making a compound of formula IA as defined in claim
2, ##STR00850## or salt thereof, comprising a) mixing a compound of
formula XI, ##STR00851## or salt thereof, wherein E is a halogen,
and R.sup.5, R.sup.6, and A are defined in claim 2, with a compound
of formula XII, ##STR00852## or salt thereof, wherein ---, R.sup.8,
R.sup.9, n, m, Y and X are defined in claim 2, if Y is N, then
R.sup.21 is hydrogen, if Y is C, then R.sup.21 is selected from
boronic acid and a boronic ester, and if Y is CH, then R.sup.21 is
selected from a metal halide, under conditions such that
composition comprising a compound of formula XIII, ##STR00853## or
salt thereof, is formed; and b) mixing the compound of formula XIII
and thiazolidine-2,4-dione under conditions such that a compound of
formula IA is formed.
15. A method of making a compound of formula IC, or salt thereof
comprising a) mixing a compound of formula V, ##STR00854## or salt
thereof, wherein R.sup.5, R.sup.6, and R.sup.7 are defined in claim
4, with a compound of formula VI, ##STR00855## or salt thereof,
wherein R.sup.14, n, X and Y are defined in claim 4, under
conditions such that a composition comprising a compound of formula
VIII, ##STR00856## or salt thereof, is formed; and b) mixing the
compound of formula VIII and thiazolidine-2,4-dione under
conditions such that a compound of formula IC is formed.
Description
[0001] This application is a continuation of U.S. application Ser.
No. 13/000,138, issuing, filed on May 25, 2011, which claims the
benefit under 35 U.S.C. .sctn.119(a)-(d) of International
Application No. PCT/GB2009/050773, filed on Jul. 2, 2009, which
claims the benefit of U.S. Application No. 61/183,278, filed Jun.
2, 2009 and U.S. Patent Application No. 61/077,639, filed Jul. 2,
2008. The contents of each of the foregoing applications are
incorporated herein by reference in their entirety.
FIELD OF INVENTION
[0002] The invention relates to chemical compounds of formula
I,
##STR00002##
and salts thereof. In some embodiments, the invention relates to
inhibitors or modulators of PIM-1 and/or PIM-2, and/or PIM-3
protein kinase activity or enzyme function. In still further
embodiments, the invention relates to pharmaceutical compositions
comprising compounds disclosed herein, and their use in the
prevention and treatment of PIM kinase related conditions and
diseases, preferably cancer.
BACKGROUND
[0003] PIM-1 gene was first identified as a proviral insertion site
in Moloney murine leukemia virus-induced T-cell lymphoma. PIM-1
gene translates a Ser/Thr protein kinase. The known PIM kinase
family also includes PIM-2 and PIM-3. Mice studies suggest that
physiologically the PIM kinases are involved in growth factor and
cytokine signaling. Deregulated PIM kinase expression occurs a in
large number of hematopoietic tumors, such as myeloid and
lymphoblastic leukemias and lyphomas. PIM kinases are also
expressed in solid tumors, such as prostate cancer and pancreatic
cancer, and transgenic mice which express PIM-1 develop T-cell
lymphoma. Dhanasekaran et al., (2001). Nature 412: 822-826 and Li
et al., (2006) Cancer Res 66: 6741-6747. Accordingly, it is
believed that PIM Kinase inhibitors will be useful in the treatment
and/or prevention of cancer. Thus, there is a need to identify
inhibitors of PIM kinases.
SUMMARY OF INVENTION
[0004] The invention relates to chemical compounds of formula
I,
##STR00003##
and salts thereof. In some embodiments, the invention relates to
inhibitors or modulators of PIM-1 and/or PIM-2, and/or PIM-3
protein kinase activity or enzyme function. In still further
embodiments, the invention relates to pharmaceutical compositions
comprising compounds disclosed herein, and their use in the
prevention and treatment of PIM kinase related conditions and
diseases, preferably cancer.
DETAILED DESCRIPTION
[0005] The invention relates to a method of treating or preventing
cancer comprising,
[0006] a) providing a pharmaceutical composition comprising a
compound of formula I,
##STR00004##
or pharmaceutically acceptable salts thereof, functioning to
inhibit a PIM kinase, wherein
[0007] R.sup.1 is selected from a carbocyclyl, aryl, and
heterocyclyl, wherein R.sup.1 is optionally substituted with one or
more, the same or different, R.sup.2;
[0008] R.sup.2 is selected from C.sub.1-6alkyl, halogen, nitro,
cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl,
C.sub.1-6alkoxy, C.sub.1-6alkylthio, C.sub.1-6alkylamino,
(C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkylsulfamoyl,
arylsulfamoyl, carbocyclyl, aryl, and heterocyclyl, wherein R.sup.2
is optionally substituted with one or more, the same or different,
R.sup.3;
[0009] R.sup.3 is selected from C.sub.1-6alkyl, halogen, nitro,
cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl,
C.sub.1-6alkoxy, C.sub.1-6alkylthio, C.sub.1-6alkylamino,
(C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkylsulfinyl,
C.sub.1-6alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, and
heterocyclyl,
[0010] wherein R.sup.3 is optionally substituted with one or more,
the same or different, R.sup.4;
[0011] R.sup.4 is selected from C.sub.1-6alkyl, halogen, nitro,
cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl,
C.sub.1-6alkoxy, C.sub.1-6alkylthio, C.sub.1-6alkylamino,
(C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkylsulfinyl,
C.sub.1-6alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, and
heterocyclyl, wherein R.sup.4 is optionally substituted with one or
more, the same or different, R.sup.5; and
[0012] R.sup.5 is selected from halogen, nitro, cyano, hydroxy,
trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy,
carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy,
acetyl, acetoxy, methylamino, ethylamino, dimethylamino,
diethylamino, N-methyl-N-ethylamino, acetylamino,
N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,
N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio,
ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl,
methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl,
N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl,
N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, and heterocyclyl;
and
[0013] b) administering said pharmaceutical composition to a
subject diagnosed with, exhibiting symptoms of, or at risk for
cancer with the proviso that said compound of formula I is not
5-[[2-[(2,6-dichloro-3-methylphenyl)amino]phenyl]methylene]-2,4-thiazolid-
inedione.
[0014] In some embodiments, the invention relates to a method of
treating or preventing cancer comprising,
[0015] a) providing a pharmaceutical composition comprising a
compound of formula I,
##STR00005##
[0016] or salts thereof, functioning to inhibit a PIM kinase,
wherein
[0017] R.sup.1 is selected from a carbocyclyl, aryl, and
heterocyclyl, wherein R.sup.1 is optionally substituted with one or
more, the same or different, R.sup.2;
[0018] R.sup.2 is selected from halogen, C.sub.1-6alkyl,
halogenated C.sub.1-6alkyl, amino, C.sub.1-6alkylamino,
(C.sub.1-6alkyl).sub.2amino, and heterocyclyl, wherein R.sup.2 is
optionally substituted with one or more, the same or different,
R.sup.3;
[0019] R.sup.3 is selected from C.sub.1-6alkyl, halogen, nitro,
cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl,
C.sub.1-6alkoxy, C.sub.1-6alkylthio, C.sub.1-6alkylamino,
(C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkylsulfinyl,
C.sub.1-6alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, and
heterocyclyl, wherein R.sup.3 is optionally substituted with one or
more, the same or different, R.sup.4;
[0020] R.sup.4 is selected from C.sub.1-6alkyl, halogen, nitro,
cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl,
C.sub.1-6alkoxy, C.sub.1-6alkylthio, C.sub.1-6alkylamino,
(C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkylsulfinyl,
C.sub.1-6alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, and
heterocyclyl, wherein R.sup.4 is optionally substituted with one or
more, the same or different, R.sup.5; and
[0021] R.sup.5 is selected from halogen, nitro, cyano, hydroxy,
trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy,
carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy,
acetyl, acetoxy, methylamino, ethylamino, dimethylamino,
diethylamino, N-methyl-N-ethylamino, acetylamino,
N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,
N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio,
ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl,
methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl,
N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl,
N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, and heterocyclyl;
and
[0022] b) administering said pharmaceutical composition to a
subject diagnosed with, exhibiting symptoms of, or at risk for
cancer under conditions such that cancer is reduced or
prevented.
[0023] In further embodiments, the invention relates to a method of
treating cancer comprising administering to a subject in need
thereof a pharmaceutical composition comprising a compound of the
formula disclosed herein, wherein said cancer is selected from a
leukemia, lymphoma, prostate cancer, pancreatic cancer or other
solid tumors.
[0024] In further embodiments, the invention relates to a compound
of formula IA,
##STR00006##
or salts thereof, wherein,
[0025] --- is individually at each occurrence selected from a
single and double bond;
[0026] n is selected from 0, 1, or 2;
[0027] m is selected from 0, 1, or 2;
[0028] A is selected from N and CR.sup.7;
[0029] X is selected from O, S, CHR.sup.10 and NR.sup.11;
[0030] Y is selected from N, CH, and C;
[0031] R.sup.5, R.sup.6, and R.sup.7 are each individually and
independently from hydrogen, C.sub.1-6alkyl, halogen, cyano, nitro,
hydroxy, amino, mercapto, formyl, carboxy, carbamoyl,
C.sub.1-6alkoxy, C.sub.1-6alkylthio, C.sub.1-6alkylamino,
(C.sub.1-6alkyl).sub.2amino, carbocyclyl, aryl, and heterocyclyl,
wherein R.sup.5, R.sup.6, and R.sup.7 are each optionally
substituted with one or more, the same or different, R.sup.12;
[0032] R.sup.8 and R.sup.9 are each individually and independently
selected from hydrogen, amino, hydroxyl, mercapto, C.sub.1-6alkyl,
C.sub.1-6alkylamino, carbocyclyl, aryl, and heterocyclyl wherein
R.sup.8 and R.sup.9 are each optionally substituted with one or
more, the same or different, R.sup.15;
[0033] R.sup.10 is selected from hydrogen, C.sub.1-6alkyl, halogen,
nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl,
C.sub.1-6alkoxy, C.sub.1-6alkylthio, C.sub.1-6alkylamino,
(C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkylsulfamoyl,
arylsulfamoyl, carbocyclyl, aryl, and heterocyclyl, wherein
R.sup.10 is optionally substituted with one or more, the same or
different, R.sup.12;
[0034] R.sup.11 is selected from hydrogen, formyl, C.sub.1-6alkyl,
C.sub.1-6alkanoyl, C.sub.1-6alkylsulfinyl, C.sub.1-6alkylsulfonyl,
arylsulfonyl, C.sub.1-6alkoxycarbonyl, carbocyclyl, aryl, and
heterocyclyl, wherein R.sup.11 is optionally substituted with one
or more, the same or different, R.sup.12;
[0035] R.sup.12 is selected from halogen, nitro, cyano, hydroxy,
trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy,
carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy,
acetyl, acetoxy, methylamino, ethylamino, dimethylamino,
diethylamino, N-methyl-N-ethylamino, acetylamino,
N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,
N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio,
ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl,
methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl,
N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl,
N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, and heterocyclyl,
wherein R.sup.12 is optionally substituted with one or more, the
same or different, R.sup.16;
[0036] R.sup.15 is selected from C.sub.1-6alkyl, C.sub.1-6alkanoyl,
C.sub.1-6alkylsulfinyl, C.sub.1-6alkylsulfonyl, arylsulfonyl, and
C.sub.1-6alkoxycarbonyl wherein R.sup.15 is optionally substituted
with one or more, the same or different, R.sup.12;
[0037] R.sup.16 is selected from halogen, nitro, cyano, hydroxy,
trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy,
carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy,
acetyl, acetoxy, methylamino, ethylamino, dimethylamino,
diethylamino, N-methyl-N-ethylamino, acetylamino, aminomethyl,
aminoethyl, aminopropyl, aminobutyl, N-methylcarbamoyl,
N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl,
N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl,
ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl,
ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl,
N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, and
N-methyl-N-ethylsulfamoyl; and
[0038] provided that R.sup.5, R.sup.6, and R.sup.7 are not all
hydrogen and
[0039] provided the compound is not
5-((5-nitro-2-(1-piperidinyl)phenyl)methylene)-2,4-thiazolidinedione
or
5-((2-(4-morpholinyl)-5-nitrophenyl)methylene)-2,4-thiazolidinedione.
[0040] In some embodiments, the invention relates to a compound of
formula ID,
##STR00007##
or salts thereof, wherein,
[0041] n is selected from 0, 1, or 2;
[0042] A is selected from N and CR.sup.7;
[0043] X is selected from O, S, CHR.sup.10 and NR.sup.11;
[0044] R.sup.5, R.sup.6, and R.sup.7 are each individually and
independently from hydrogen, C.sub.1-6alkyl, halogen, cyano, nitro,
hydroxy, amino, mercapto, formyl, carboxy, carbamoyl,
C.sub.1-6alkoxy, C.sub.1-6alkylthio, C.sub.1-6alkylamino,
(C.sub.1-6alkyl).sub.2amino, carbocyclyl, aryl, and heterocyclyl,
wherein R.sup.5, R.sup.6, and R.sup.7 are each optionally
substituted with one or more, the same or different, R.sup.12;
[0045] R.sup.8 and R.sup.9 are each individually and independently
selected from hydrogen, amino, hydroxyl, mercapto, C.sub.1-6alkyl,
C.sub.1-6alkylamino, carbocyclyl, aryl, and heterocyclyl wherein
R.sup.8 and R.sup.9 are each optionally substituted with one or
more, the same or different, R.sup.15;
[0046] R.sup.10 is selected from hydrogen, C.sub.1-6alkyl, halogen,
nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl,
C.sub.1-6alkoxy, C.sub.1-6alkylthio, C.sub.1-6alkylamino,
(C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkylsulfamoyl,
arylsulfamoyl, carbocyclyl, aryl, and heterocyclyl, wherein
R.sup.10 is optionally substituted with one or more, the same or
different, R.sup.12;
[0047] R.sup.11 is selected from hydrogen, formyl, C.sub.1-6alkyl,
C.sub.1-6alkanoyl, C.sub.1-6alkylsulfinyl, C.sub.1-6alkylsulfonyl,
arylsulfonyl, C.sub.1-6alkoxycarbonyl, carbocyclyl, aryl, and
heterocyclyl, wherein R.sup.11 is optionally substituted with one
or more, the same or different, R.sup.12;
[0048] R.sup.12 is selected from halogen, nitro, cyano, hydroxy,
trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy,
carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy,
acetyl, acetoxy, methylamino, ethylamino, dimethylamino,
diethylamino, N-methyl-N-ethylamino, acetylamino,
N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,
N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio,
ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl,
methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl,
N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl,
N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, and heterocyclyl,
wherein R.sup.12 is optionally substituted with one or more, the
same or different, R.sup.16;
[0049] R.sup.15 is selected from C.sub.1-6alkyl, C.sub.1-6alkanoyl,
C.sub.1-6alkylsulfinyl, C.sub.1-6alkylsulfonyl, arylsulfonyl, and
C.sub.1-6alkoxycarbonyl wherein R.sup.15 is optionally substituted
with one or more, the same or different, R.sup.12;
[0050] R.sup.16 is selected from halogen, nitro, cyano, hydroxy,
trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy,
carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy,
acetyl, acetoxy, methylamino, ethylamino, dimethylamino,
diethylamino, N-methyl-N-ethylamino, acetylamino, aminomethyl,
aminoethyl, aminopropyl, aminobutyl, N-methylcarbamoyl,
N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl,
N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl,
ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl,
ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl,
N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, and
N-methyl-N-ethylsulfamoyl.
[0051] In some embodiments with regard to any of the compound
formula provided herein, R.sup.5, R.sup.6, and R.sup.7 are not all
hydrogen.
[0052] In some embodiments with regard to any of the compound
formula provided herein, R.sup.5, R.sup.6, and R.sup.7 are not
5-((5-nitro-2-(1-piperidinyl)phenyl)methylene)-2,4-thiazolidinedione
or
5-((2-(4-morpholinyl)-5-nitrophenyl)methylene)-2,4-thiazolidinedione.
[0053] In some embodiments, the invention relates to a compound of
formula IB,
##STR00008##
or salts thereof, wherein,
[0054] n is selected from 0, 1, or 2;
[0055] X is selected from O, CHR.sup.10 and NR.sup.11;
[0056] R.sup.5, R.sup.6, and R.sup.7 are each individually and
independently from hydrogen, halogen, cyano, hydroxy,
trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy,
carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy,
acetyl, acetoxy, methylamino, ethylamino, dimethylamino,
diethylamino, N-methyl-N-ethylamino, acetylamino,
N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,
N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio,
ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl,
methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl,
N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, and
N-methyl-N-ethylsulfamoyl;
[0057] R.sup.8 and R.sup.9 are each individually and independently
selected from hydrogen, amino, C.sub.1-6alkyl, C.sub.1-6alkylamino,
wherein R.sup.8 and R.sup.9 are each optionally substituted with
one or more, the same or different, R.sup.15;
[0058] R.sup.10 is selected from hydrogen, C.sub.1-6alkyl, halogen,
nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl,
C.sub.1-6alkoxy, C.sub.1-6alkylthio, C.sub.1-6alkylamino,
(C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkylsulfamoyl,
arylsulfamoyl, carbocyclyl, aryl, and heterocyclyl, wherein
R.sup.10 is optionally substituted with one or more, the same or
different, R.sup.12;
[0059] R.sup.11 is selected from hydrogen, C.sub.1-6alkyl,
C.sub.1-6alkanoyl, C.sub.1-6alkylsulfinyl, C.sub.1-6alkylsulfonyl,
arylsulfonyl, C.sub.1-6alkoxycarbonyl, carbocyclyl, aryl, and
heterocyclyl, wherein R.sup.11 is optionally substituted with one
or more, the same or different, R.sup.12;
[0060] R.sup.12 is selected from halogen, nitro, cyano, hydroxy,
trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy,
carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy,
acetyl, acetoxy, methylamino, ethylamino, dimethylamino,
diethylamino, N-methyl-N-ethylamino, acetylamino,
N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,
N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio,
ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl,
methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl,
N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl,
N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, and heterocyclyl,
wherein R.sup.12 is optionally substituted with one or more, the
same or different, R.sup.16;
[0061] R.sup.15 is selected from C.sub.1-6alkyl, C.sub.1-6alkanoyl,
C.sub.1-6alkylsulfinyl, C.sub.1-6alkylsulfonyl, arylsulfonyl, and
C.sub.1-6alkoxycarbonyl wherein R.sup.15 is optionally substituted
with one or more, the same or different, R.sup.12;
[0062] R.sup.16 is selected from halogen, nitro, cyano, hydroxy,
trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy,
carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy,
acetyl, acetoxy, methylamino, ethylamino, dimethylamino,
diethylamino, N-methyl-N-ethylamino, acetylamino,
N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,
N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio,
ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl,
methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl,
N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, and
N-methyl-N-ethylsulfamoyl.
[0063] In some embodiments, with regard to any of the compound
formula provided herein, said compound is not,
5-[[2-(4-methyl-1-piperazinyl)phenyl]methylene]-2,4-thiazolidinedione
or
5-[[2-[(2,6-dichloro-3-methylphenyl)amino]phenyl]methylene]-2,4-thiazolid-
inedione.
[0064] In further embodiments, the invention relates to a compound
of formula IC,
##STR00009##
or salts thereof, wherein,
[0065] n is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8;
[0066] X is selected from O, S, CHR.sup.10 and NR.sup.11;
[0067] Y is selected from O, S, and NR.sup.13;
[0068] R.sup.5, R.sup.6, and R.sup.7 are each individually and
independently from C.sub.1-6alkyl, halogen, nitro, cyano, hydroxy,
amino, mercapto, formyl, carboxy, carbamoyl, C.sub.1-6alkoxy,
C.sub.1-6alkylthio, C.sub.1-6alkylamino, C.sub.1-6dialkylamino,
carbocyclyl, aryl, and heterocyclyl, wherein R.sup.5, R.sup.6, and
R.sup.7 are each optionally substituted with one or more, the same
or different, R.sup.12;
[0069] R.sup.10 is selected from hydrogen, C.sub.1-6alkyl, halogen,
nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl,
C.sub.1-6alkoxy, C.sub.1-6alkylthio, C.sub.1-6alkylamino,
(C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkylsulfamoyl,
arylsulfamoyl, carbocyclyl, aryl, and heterocyclyl, wherein
R.sup.10 is optionally substituted with one or more, the same or
different, R.sup.12;
[0070] R.sup.11, R.sup.13, and R.sup.14 are each individually and
independently selected from hydrogen, C.sub.1-6alkyl,
C.sub.1-6alkanoyl, C.sub.1-6alkylsulfinyl, C.sub.1-6alkylsulfonyl,
arylsulfonyl, and C.sub.1-6alkoxycarbonyl wherein R.sup.11 is
optionally substituted with one or more, the same or different,
R.sup.12;
[0071] or R.sup.11 and R.sup.14, taken together with the atoms to
which they are attached form a five, six, or seven membered
heterocyclic ring optionally substituted with one or more, the same
or different, R.sup.12;
[0072] R.sup.12 is selected from halogen, nitro, cyano, hydroxy,
trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy,
carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy,
acetyl, acetoxy, methylamino, ethylamino, dimethylamino,
diethylamino, N-methyl-N-ethylamino, acetylamino,
N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,
N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio,
ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl,
methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl,
N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl,
N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, and heterocyclyl.
[0073] In some embodiments with regard to any of the compound
formula provided herein, Y is NR.sup.13, wherein R.sup.13 is a
C.sub.1-6alkyl.
[0074] In some embodiments with regard to any of the compound
formula provided herein, R.sup.5 is a halogenated
C.sub.1-6alkyl.
[0075] In some embodiments with regard to any of the compound
formula provided herein, R.sup.7 is a halogen.
[0076] In some embodiments, the invention relates to a compound of
formula IX,
##STR00010##
or salts thereof, wherein
[0077] R.sup.5 is selected from hydrogen, C.sub.1-6alkoxy,
carbamoyl, and halogenated C.sub.1-6alkyl;
[0078] R.sup.6 is selected from hydrogen, halogen, C.sub.1-6alkoxy,
and 2-(1-piperidyl)ethoxy;
[0079] R.sup.7 is selected from hydrogen, halogen, and
C.sub.1-6alkoxy;
[0080] R.sup.17 is a heterocarbocylcyl, wherein R.sup.17 is
optionally substituted with one or more, the same or different,
R.sup.18;
[0081] R.sup.18 is selected from halogen, formyl, amino,
C.sub.1-6alkyl, C.sub.1-6alkylamino, (C.sub.1-6alkyl).sub.2amino,
carbocyclyl, aryl, heterocyclyl, wherein R.sup.18 is optionally
substituted with one or more, the same or different, R.sup.19;
[0082] R.sup.19 is selected from amino, C.sub.1-6alkyl, hydroxy,
carbocyclyl, and heterocyclyl wherein R.sup.19 is optionally
substituted with one or more, the same or different, R.sup.20;
and
[0083] R.sup.20 is selected from amino, C.sub.1-6alkyl, and
halogen.
[0084] In further embodiments, R.sup.17 is selected from
(3R)-3-aminopyrrolidin-1-yl, (3R)-3-dimethylaminopyrrolidin-1-yl,
(3S)-3-(3-aminopropylamino)pyrrolidin-1-yl,
(3S)-3-(5-aminopentanoylamino)pyrrolidin-1-yl,
(3S)-3-amino-1-piperidyl, (3S)-3-aminopyrrolidin-1-yl,
(3S)-3-dimethylaminopyrrolidin-1-yl,
(3S,5R)-3,5-dimethylpiperazin-1-yl, 1,4-diazepan-1-yl,
2-(1-piperidyl)ethoxy, 2-diethylaminoethoxy,
2-dimethylaminoethyl-methyl-amino, 2-hydroxyethoxy,
2-morpholinoethoxy, 3-(2-aminoethylamino)pyrrolidin-1-yl,
3-(2-hydroxyethylamino)pyrrolidin-1-yl,
3-(2-methylaminoethylamino)pyrrolidin-1-yl,
3-(3-aminopropanoylamino)pyrrolidin-1-yl,
3-(3-aminopropylamino)pyrrolidin-1-yl,
3-(3-methyl-1,2,4-oxadiazol-5-yl)-1-piperidyl,
3-(aminomethyl)-1-piperidyl, 3-(aminomethyl)pyrrolidin-1-yl,
3-acetamidopyrrolidin-1-yl, 3-aminopyrrolidin-1-yl,
3-dimethylaminopropoxy, 3-dimethylaminopropyl-methyl-amino,
3-dimethylaminopyrrolidin-1-yl, 3-hydroxypyrrolidin-1-yl,
3-pyridyl, 4-(1-methyl-4-piperidyl)piperazin-1-yl,
4-(1-piperidyl)-1-piperidyl, 4-(2-aminoethyl)piperazin-1-yl,
4-(2-hydroxyethyl)-1,4-diazepan-1-yl,
4-(2-hydroxyethyl)-1-piperidyl, 4-(2-hydroxyethyl)piperazin-1-yl,
4-(2-methylaminoethyl)piperazin-1-yl,
4-(2-morpholinoethyl)piperazin-1-yl,
4-(3-aminopropanoyl)-1,4-diazepan-1-yl,
4-(3-aminopropanoyl)piperazin-1-yl,
4-(3-aminopropyl)piperazin-1-yl, 4-(3-hydroxypropyl)piperazin-1-yl,
4-(3-methyl-1,2,4-oxadiazol-5-yl)-1-piperidyl,
4-(4-aminobutanoyl)-1,4-diazepan-1-yl,
4-(4-aminobutanoyl)piperazin-1-yl,
4-(4-chloro-2-fluoro-phenyl)piperazin-1-yl,
4-(4-fluorophenyl)piperazin-1-yl,
4-(4-pyridylmethyl)piperazin-1-yl,
445-aminopentanoyl)-1,4-diazepan-1-yl,
4-(5-aminopentanoyl)piperazin-1-yl,
4-(azetidine-3-carbonyl)piperazin-1-yl,
4-(benzo[1,3]dioxol-5-ylmethyl)piperazin-1-yl,
4-(cyclopropylmethyl)piperazin-1-yl, 4-(hydroxymethyl)-1-piperidyl,
4-(piperidine-3-carbonyl)-1,4-diazepan-1-yl,
4-(piperidine-3-carbonyl)piperazin-1-yl,
4-(piperidine-4-carbonyl)piperazin-1-yl,
4-[(2-chlorophenyl)methyl]piperazin-1-yl,
4-[3-(aminomethyl)benzoyl]piperazin-1-yl,
4-[4-(piperazin-1-ylmethyl)benzoyl]piperazin-1-yl,
4-acetylpiperazin-1-yl, 4-amino-1-piperidyl,
4-butyl-1,4-diazepan-1-yl, 4-cyclopentylpiperazin-1-yl,
4-dimethylamino-1-piperidyl, 4-hydroxy-1-piperidyl,
4-isobutylpiperazin-1-yl, 4-isopropylpiperazin-1-yl,
4-methylpiperazin-1-yl, 4-morpholino-1-piperidyl, 4-pyridyl,
4-pyrrolidin-1-yl-1-piperidyl, 4-tert-butoxycarbonylpiperazin-1-yl,
4-tert-butylpiperazin-1-yl, morpholino, piperazin-1-yl, and
pyrrolidin-1-yl.
[0085] In further embodiments, the invention relates to a compound
selected from: [0086]
5-({2-[(3S)-3-aminopiperidin-1-yl]-3-chloro-5-(trifluoromethyl)phenyl}met-
hylidene)-1,3-thiazolidine-2,4-dione; [0087]
5-({2-[(3R)-3-aminopiperidin-1-yl]-3-chloro-5-(trifluoromethyl)phenyl}met-
hylidene)-1,3-thiazolidine-2,4-dione; [0088]
5-{[2-(4-aminopiperidin-1-yl)-3-chloro-5-(trifluoromethyl)phenyl]methylid-
ene}-1,3-thiazolidine-2,4-dione; [0089]
5-({2-[3-(aminomethyl)piperidin-1-yl]-3-chloro-5-(trifluoromethyl)phenyl}-
methylidene)-1,3-thiazolidine-2,4-dione; [0090]
5-{[3-chloro-2-(1,4-diazepan-1-yl)-5-(trifluoromethyl)phenyl]methylidene}-
-1,3-thiazolidine-2,4-dione; [0091]
5-{[3-chloro-2-(4-cyclopentylpiperazin-1-yl)-5-(trifluoromethyl)phenyl]me-
thylidene}-1,3-thiazolidine-2,4-dione; [0092]
5-({3-chloro-2-[4-(4-fluorophenyl)piperazin-1-yl]-5-(trifluoromethyl)phen-
yl}methylidene)-1,3-thiazolidine-2,4-dione; [0093]
5-({2-[4-(1,3-benzodioxol-5-ylmethyl)piperazin-1-yl]-3-chloro-5-(trifluor-
omethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione; [0094]
5-({3-chloro-2-[4-(3-methyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl]-5-(trifl-
uoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione; [0095]
5-{[3-chloro-2-(4-pyrrolidin-1-ylpiperidin-1-yl)-5-(trifluoromethyl)pheny-
l]methylidene}-1,3-thiazolidine-2,4-dione; [0096]
5-({3-chloro-2-[4-(1-methylethyl)piperazin-1-yl]-5-(trifluoromethyl)pheny-
l}methylidene)-1,3-thiazolidine-2,4-dione; [0097]
5-({3-chloro-2-[4-(2-methylpropyl)piperazin-1-yl]-5-(trifluoromethyl)phen-
yl}methylidene)-1,3-thiazolidine-2,4-dione; [0098]
5-({3-chloro-2-[4-(2-hydroxyethyl)piperidin-1-yl]-5-(trifluoromethyl)phen-
yl}methylidene)-1,3-thiazolidine-2,4-dione; [0099]
5-({3-chloro-2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-5-(trifluoromethyl-
)phenyl}methylidene)-1,3-thiazolidine-2,4-dione; [0100]
5-({3-chloro-2-[4-(4-chloro-2-fluorophenyl)piperazin-1-yl]-5-(trifluorome-
thyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione; [0101]
5-({3-chloro-2-[3-(3-methyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl]-5-(trifl-
uoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione; [0102]
5-({3-chloro-2-[4-(pyridin-4-ylmethyl)piperazin-1-yl]-5-(trifluoromethyl)-
phenyl}methylidene)-1,3-thiazolidine-2,4-dione; [0103]
5-({3-chloro-2-[4-(2-chlorobenzyl)piperazin-1-yl]-5-(trifluoromethyl)phen-
yl}methylidene)-1,3-thiazolidine-2,4-dione; [0104]
5-({3-chloro-2-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-5-(trifluoromet-
hyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione; [0105]
5-({3-chloro-2-[4-(2-morpholin-4-ylethyl)piperazin-1-yl]-5-(trifluorometh-
yl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione; [0106]
5-({3-chloro-2-[4-(cyclopropylmethyl)piperazin-1-yl]-5-(trifluoromethyl)p-
henyl}methylidene)-1,3-thiazolidine-2,4-dione; [0107]
5-{[3-chloro-2-(4-morpholin-4-ylpiperidin-1-yl)-5-(trifluoromethyl)phenyl-
]methylidene}-1,3-thiazolidine-2,4-dione; [0108]
5-({3-chloro-2-[4-(3-hydroxypropyl)piperazin-1-yl]-5-(trifluoromethyl)phe-
nyl}methylidene)-1,3-thiazolidine-2,4-dione; [0109]
5-({3-chloro-2-[4-(dimethylamino)piperidin-1-yl]-5-(trifluoromethyl)pheny-
l}methylidene)-1,3-thiazolidine-2,4-dione; [0110]
5-{[3-chloro-2-{[3-(dimethylamino)propyl](methyl)amino}-5-(trifluoromethy-
l)phenyl]methylidene}-1,3-thiazolidine-2,4-dione; [0111]
5-({3-chloro-2-[4-(2-hydroxyethyl)-1,4-diazepan-1-yl]-5-(trifluoromethyl)-
phenyl}methylidene)-1,3-thiazolidine-2,4-dione; [0112]
5-{[2-(4-butyl-1,4-diazepan-1-yl)-3-chloro-5-(trifluoromethyl)phenyl]meth-
ylidene}-1,3-thiazolidine-2,4-dione; [0113]
5-({3-chloro-2-[4-(2-hydroxyethyl)piperazin-1-yl]-5-(trifluoromethyl)phen-
yl}methylidene)-1,3-thiazolidine-2,4-dione; [0114]
5-{[3-chloro-2-morpholin-4-yl-5-(trifluoromethyl)phenyl]methylidene}-1,3--
thiazolidine-2,4-dione; [0115]
5-{[2-(4-tert-butylpiperazin-1-yl)-3-chloro-5-(trifluoromethyl)phenyl]met-
hylidene}-1,3-thiazolidine-2,4-dione; [0116]
5-{[2-(1,4'-bipiperidin-1'-yl)-3-chloro-5-(trifluoromethyl)phenyl]methyli-
dene}-1,3-thiazolidine-2,4-dione; [0117]
5-{[3-chloro-2-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl]methyli-
dene}-1,3-thiazolidine-2,4-dione; [0118]
5-({3-bromo-2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]phenyl}methylidene)--
1,3-thiazolidine-2,4-dione; and [0119]
5-({2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-5-(trifluoromethyl)phenyl}meth-
ylidene)-1,3-thiazolidine-2,4-dione; [0120]
(5Z)-5-({2-[(3S)-3-aminopyrrolidin-1-yl]-3-chloro-5-(trifluoromethyl)phen-
yl}methylidene)-1,3-thiazolidine-2,4-dione, [0121]
(5Z)-5-({3-[3-(4-methylpiperazin-1-yl)propoxy]phenyl}methylidene)-1,3-thi-
azolidine-2,4-dione; [0122]
2-{3-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenoxy}acetamide;
[0123]
(5Z)-5-{[3-(3-piperidin-1-ylpropoxy)phenyl]methylidene}-1,3-thiazo-
lidine-2,4-dione; [0124]
(5Z)-5-({3-[(4-methylpiperazin-1-yl)methyl]phenyl}methylidene)-1,3-thiazo-
lidine-2,4-dione; [0125]
N-[2-(dimethylamino)ethyl]-2'-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)m-
ethyl]-N-methylbiphenyl-4-sulfonamide; [0126]
5-({2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-5-methoxyphenyl}methylidene-
)-1,3-thiazolidine-2,4-dione; [0127]
5-({2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-5-(trifluoromethyl)phenyl}m-
ethylidene)-1,3-thiazolidine-2,4-dione; [0128]
5-({5-chloro-2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]phenyl}methylidene)-
-1,3-thiazolidine-2,4-dione; [0129]
5-({2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-4-methylphenyl}methylidene)-
-1,3-thiazolidine-2,4-dione; [0130]
5-({2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-5-fluorophenyl}methylidene)-
-1,3-thiazolidine-2,4-dione; [0131]
5-({2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-5-methylphenyl}methylidene)-
-1,3-thiazolidine-2,4-dione; [0132]
5-({5-bromo-2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]phenyl}methylidene)--
1,3-thiazolidine-2,4-dione; [0133]
5-({2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-3-fluorophenyl}methylidene)-
-1,3-thiazolidine-2,4-dione; [0134]
5-({2-chloro-6-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]phenyl}methylidene)-
-1,3-thiazolidine-2,4-dione; [0135]
(5Z)-5-({2-[(3R)-3-(aminomethyl)pyrrolidin-1-yl]-3-chlorophenyl}methylide-
ne)-1,3-thiazolidine-2,4-dione; [0136]
(5Z)-5-({2-[(3S)-3-(aminomethyl)pyrrolidin-1-yl]-3-chlorophenyl}methylide-
ne)-1,3-thiazolidine-2,4-dione; [0137]
(5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-chlorophenyl}methylidene)-1,3-t-
hiazolidine-2,4-dione; [0138]
(5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-methoxyphenyl}methylidene)-1,3--
thiazolidine-2,4-dione; [0139]
(5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-bromophenyl}methylidene)-1,3-th-
iazolidine-2,4-dione; [0140]
(5Z)-5-({2-[(3R)-3-aminopyrrolidin-1-yl]-3-chlorophenyl}methylidene)-1,3--
thiazolidine-2,4-dione; [0141]
(5Z)-5-({2-[(3S)-3-aminopyrrolidin-1-yl]-3-bromophenyl}methylidene)-1,3-t-
hiazolidine-2,4-dione; [0142]
(5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-ethoxyphenyl}methylidene)-1,3-t-
hiazolidine-2,4-dione; [0143]
(5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-(2-methylpropoxy)phenyl}methyli-
dene)-1,3-thiazolidine-2,4-dione; [0144]
(5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-(cyclohexylmethoxy)phenyl}methy-
lidene)-1,3-thiazolidine-2,4-dione; [0145]
(5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-(cyclohexyloxy)phenyl}methylide-
ne)-1,3-thiazolidine-2,4-dione; [0146]
(5Z)-5-({2-[(3R,4R)-3-amino-4-hydroxypiperidin-1-yl]-3-chlorophenyl}methy-
lidene)-1,3-thiazolidine-2,4-dione; [0147]
(5Z)-5-{[3-chloro-2-(1,4-diazepan-1-yl)phenyl]methylidene}-1,3-thiazolidi-
ne-2,4-dione; [0148]
(5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-(1-methylethoxy)phenyl}methylid-
ene)-1,3-thiazolidine-2,4-dione; [0149]
(5Z)-5-({2-[(3S)-3-aminopyrrolidin-1-yl]-3-(1-methylethoxy)phenyl}methyli-
dene)-1,3-thiazolidine-2,4-dione; [0150]
(5Z)-5-({2-[(3S)-3-aminopyrrolidin-1-yl]-3-ethoxyphenyl}methylidene)-1,3--
thiazolidine-2,4-dione; [0151]
(5Z)-5-({2-[(3R)-3-{[4-(aminomethyl)benzyl]amino}piperidin-1-yl]-3-chloro-
phenyl}methylidene)-1,3-thiazolidine-2,4-dione; [0152]
(5Z)-5-({3-chloro-2-[(3R)-3-{[2-(methylamino)ethyl]amino}piperidin-1-yl]p-
henyl}methylidene)-1,3-thiazolidine-2,4-dione; [0153]
(5Z)-5-({2-[(3S,4S)-3-amino-4-hydroxypyrrolidin-1-yl]-3-chlorophenyl}meth-
ylidene)-1,3-thiazolidine-2,4-dione; [0154]
(5Z)-5-({3-chloro-2-[4-methyl-3-(methylamino)piperidin-1-yl]phenyl}methyl-
idene)-1,3-thiazolidine-2,4-dione; [0155]
(5Z)-5-{[2-(3-amino-4-methylpiperidin-1-yl)-3-chlorophenyl]methylidene}-1-
,3-thiazolidine-2,4-dione; [0156]
(5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]phenyl}methylidene)-1,3-thiazolidi-
ne-2,4-dione; [0157]
(5Z)-5-({2-[(3S)-3-aminopyrrolidin-1-yl]phenyl}methylidene)-1,3-thiazolid-
ine-2,4-dione; [0158]
(5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-(2,2,2-trifluoroethoxy)phenyl}m-
ethylidene)-1,3-thiazolidine-2,4-dione; [0159]
(5Z)-5-({2-[(3S)-3-aminopyrrolidin-1-yl]-3-(2,2,2-trifluoroethoxy)phenyl}-
methylidene)-1,3-thiazolidine-2,4-dione; [0160]
(5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-(2-methoxyethoxy)phenyl}methyli-
dene)-1,3-thiazolidine-2,4-dione; [0161]
(5Z)-5-({2-[(3S)-3-aminopyrrolidin-1-yl]-3-(2-methoxyethoxy)phenyl}methyl-
idene)-1,3-thiazolidine-2,4-dione; [0162]
(5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-(cyclopentyloxy)phenyl}methylid-
ene)-1,3-thiazolidine-2,4-dione; [0163]
(5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-(cyclobutyloxy)phenyl}methylide-
ne)-1,3-thiazolidine-2,4-dione; [0164]
4-[(3R)-3-aminopiperidin-1-yl]-3-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-yliden-
e)methyl]benzamide; [0165]
4-[(3S)-3-aminopiperidin-1-yl]-3-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-yliden-
e)methyl]benzamide; [0166]
4-[(3R)-3-aminopiperidin-1-yl]-3-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-yliden-
e)methyl]benzoic acid; [0167]
4-[(3S)-3-aminopyrrolidin-1-yl]-3-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylide-
ne)methyl]benzoic acid; [0168]
(5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]biphenyl-3-yl}methylidene)-1,3-thi-
azolidine-2,4-dione; [0169]
5-{[2-(3-aminopropoxy)-5-methoxyphenyl]methylidene}-1,3-thiazolidine-2,4--
dione; [0170]
N-{4-[3-(dimethylamino)pyrrolidin-1-yl]-3-[(Z)-(2,4-dioxo-1,3-thiazolidin-
-5-ylidene)methyl]phenyl}acetamide; [0171]
(5Z)-5-[(3-chloro-2-{(3R)-3-[(2-hydroxyethyl)amino]piperidin-1-yl}phenyl)-
methylidene]-1,3-thiazolidine-2,4-dione; [0172]
(5Z)-5-[(3-chloro-2-{(3R)-3-[(3-hydroxypropyl)amino]piperidin-1-yl}phenyl-
)methylidene]-1,3-thiazolidine-2,4-dione; [0173]
N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]ph-
enyl}pyrrolidin-3-yl]-1-methyl-1H-imidazole-2-carboxamide; [0174]
N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]ph-
enyl}pyrrolidin-3-yl]-2-methoxyacetamide; [0175]
N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]ph-
enyl}pyrrolidin-3-yl]-1-methyl-1H-pyrazole-3-carboxamide; [0176]
N.sup.2-carbamoyl-N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-
-ylidene)methyl]phenyl}pyrrolidin-3-yl]glycinamide; [0177]
N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]ph-
enyl}pyrrolidin-3-yl]-2-pyridin-3-ylacetamide; [0178]
N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]ph-
enyl}pyrrolidin-3-yl]-2-pyridin-4-ylacetamide; [0179]
N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]ph-
enyl}pyrrolidin-3-yl]-1-methyl-1H-pyrazole-4-carboxamide; [0180]
N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]ph-
enyl}pyrrolidin-3-yl]-2-(1-oxidothiomorpholin-4-yl)acetamide;
[0181]
N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]ph-
enyl}pyrrolidin-3-yl]-4-sulfamoylbutanamide; [0182]
N'-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]p-
henyl}pyrrolidin-3-yl]-N,N-dimethylbutanediamide; [0183]
N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]ph-
enyl}pyrrolidin-3-yl]-N.about.2.about.,N.about.2.about.-dimethylglycinamid-
e; [0184]
N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)-
methyl]phenyl}pyrrolidin-3-yl]-2-cyanoacetamide; [0185]
N.sup.2-acetyl-N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-yl-
idene)methyl]phenyl}pyrrolidin-3-yl]glycinamide; [0186]
(5Z)-5-({3-chloro-2-[(3R)-3-(dipropylamino)piperidin-1-yl]phenyl}methylid-
ene)-1,3-thiazolidine-2,4-dione; [0187]
(5Z)-5-[(3-chloro-2-{(3R)-3-[(3,3,3-trifluoropropyl)amino]piperidin-1-yl}-
phenyl)methylidene]-1,3-thiazolidine-2,4-dione; [0188]
5-[(5-methoxy-2-{3-[(1-methylethyl)amino]propoxy}phenyl)methylidene]-1,3--
thiazolidine-2,4-dione; [0189]
(5Z)-5-({5-amino-2-[3-(dimethylamino)pyrrolidin-1-yl]phenyl}methylidene)--
1,3-thiazolidine-2,4-dione; and [0190]
5-[(2-amino-4,5-dimethoxyphenyl)methylidene]-1,3-thiazolidine-2,4-dione,
[0191] or salts thereof.
[0192] In some embodiments, the invention relates to any of the
compounds disclosed herein that are in the (Z) isomer.
[0193] In some embodiments, the invention relates to any of the
compounds disclosed herein that are in the (E) isomer.
[0194] In some embodiments, the invention relates to compositions
comprising a mixture of the (Z) and (E) isomers.
[0195] In some embodiments, the invention relates to a
pharmaceutical composition comprising a substituted
5-(3-halo-2-[piperidin-1-yl]phenylmethylidene)-1,3-thiazolidine-2,4-dione
functioning to inhibit a PIM kinase.
[0196] In further embodiments, the invention relates to a
pharmaceutical composition comprising a compound of formula I, IA,
IB, IC, ID, or IX or a pharmaceutically acceptable salt
thereof.
[0197] In further embodiments, the invention relates to a method of
inhibiting a PIM kinase comprising, providing a compound of formula
I, IA, IB, IC, ID, or IX, as defined herein, and mixing a PIM
kinase and said compound under conditions such that PIM kinase
phosphorylation is inhibited.
[0198] In further embodiments, said method is an in vitro
method.
[0199] In further embodiments, said method is an in vivo
method.
[0200] In further embodiments, the invention relates to a method of
inhibiting a PIM kinase in a subject comprising administering to
the subject a therapeutically effective amount of a compound of any
of the formula disclosed herein or a pharmaceutically acceptable
salt thereof.
[0201] In further embodiments, said PIM kinase is selected from
PIM-1, PIM-2, and PIM-3.
[0202] In further embodiments, the invention relates to the use of
a compound of the formula I, IA, IB, IC, ID, or IX, or a
pharmaceutically acceptable salt thereof, as defined herein, for
the manufacture of a medicament for the production of a PIM kinase
inhibitory effect in a subject.
[0203] In further embodiments, the invention relates to the use of
a compound of the formula I, IA, IB, IC, ID, or IX, or a
pharmaceutically acceptable salt thereof, as disclosed herein, for
the manufacture of a medicament for the production of an
anti-cancer effect in a subject.
[0204] In some embodiments, the invention relates to a method of
making a compound of formula IA as defined herein,
##STR00011##
[0205] or salt thereof, comprising
[0206] a) mixing a compound of formula XI,
##STR00012## [0207] or salt thereof, wherein E is a halogen, and
R.sup.5, R.sup.6, and A are defined herein, with a compound of
formula XII,
##STR00013##
[0208] or salt thereof, wherein [0209] ---, R.sup.8, R.sup.9, n, m,
Y and X are defined herein, [0210] if Y is N, then R.sup.21 is
hydrogen, [0211] if Y is C, then R.sup.21 is selected from boronic
acid and a boronic ester, and [0212] if Y is CH, then R.sup.21 is
selected from a metal halide,
[0213] under conditions such that composition comprising a compound
of formula XIII,
##STR00014##
or salt thereof, is formed; and
[0214] b) mixing the compound of formula XIII and
thiazolidine-2,4-dione under conditions such that a compound of
formula IA is formed.
[0215] In further embodiments, said metal halide is selected from
lithium chloride and magnesium bromide.
[0216] In further embodiments, said boronic ester is a dialkyl
boronic ester, such as diethyl boronic ester, or a cyclic boronic
ester, such as the boronic ester of 1,2-alkyldiols, such as
1,3,2-dioxaborolane, or cycloalkyldiols which may be optionally
substituted.
[0217] In further embodiments, the invention relates to a method of
making a compound of formula ID, or salt thereof comprising
[0218] a) mixing a compound of formula II,
##STR00015##
or salt thereof, wherein R.sup.5, R.sup.6, and A are defined
herein, with a compound of formula III,
##STR00016##
[0219] or salt thereof, wherein R.sup.8, R.sup.9, n, and X are
defined herein, under conditions such that composition comprising a
compound of formula IV,
##STR00017##
or salt thereof, is formed; and b) mixing the compound of formula
IV and thiazolidine-2,4-dione under conditions such that a compound
of formula ID is formed.
[0220] In further embodiments, the invention relates to a method of
making a compound of formula IC, or salt thereof comprising a)
mixing a compound of formula V,
##STR00018##
or salt thereof, wherein R.sup.5, R.sup.6, and R.sup.7 are defined
herein, with a compound of formula VI,
##STR00019##
[0221] or salt thereof, wherein R.sup.14, n, X and Y are defined
herein, under conditions such that a composition comprising a
compound of formula VIII,
##STR00020##
or salt thereof, is formed; and b) mixing the compound of formula
VIII and thiazolidine-2,4-dione under conditions such that a
compound of formula IC is formed.
[0222] In some embodiments, the invention relates to compounds of
formula I, IA, IB, IC, ID, or IX provided that they are not
selected from
5-((2-dipropylamino-5-nitrophenyl)methylene)-2,4-thiazolidinedione;
5-((5-nitro-2-(1-piperidinyl)phenyl)methylene)-2,4-thiazolidinedione;
5-((2-(4-morpholinyl)-5-nitrophenyl)methylene)-2,4-thiazolidinedione;
5-[[2-(4-methyl-1-piperazinyl)phenyl]methylene]-2,4-thiazolidinedione;
5-[[2-[(2,6-dichloro-3-methylphenyl)amino]phenyl]methylene]-2,4-thiazolid-
inedione;
[2S-[2.alpha.(Z),4.alpha.]]-1-([1,1'-biphenyl]-4-ylsulfonyl)-N-[-
2-[(2,4-dioxo-5-thiazolidinylidene)methyl]phenyl]-4-(methylthio)-2-pyrroli-
dinemethanamine; 1,1-dimethylethyl ester
[[2S-[2.alpha.(Z),4.alpha.]]-3-[[[1-([1,1'-biphenyl]-4-ylsulfonyl)-4-(met-
hylthio)-2-pyrrolidinyl]methyl]amino]-4-[(2,4-dioxo-5-thiazolidinylidene)m-
ethyl]phenyl]carbamic acid; and
[2S-[2.alpha.(Z),4.alpha.]]-N-[5-amino-2-[(2,4-dioxo-5-thiazolidinylidene-
)methyl]phenyl]-1-([1,1'-biphenyl]-4-ylsulfonyl)-4-(methylthio)-2-pyrrolid-
inemethanamine.
[0223] It is the Applicants understanding that WO 2001002377
discloses
5-((2-dipropylamino-5-nitrophenyl)methylene)-2,4-thiazolidinedione,
5-((5-nitro-2-(1-piperidinyl)phenyl)methylene)-2,4-thiazolidinedione,
and
5-((2-(4-morpholinyl)-5-nitrophenyl)methylene)-2,4-thiazolidinedione.
[0224] It is the Applicants understanding that WO 9814433 discloses
5-[[2-(4-methyl-1-piperazinyl)phenyl]methylene]-2,4-thiazolidinedione.
[0225] It is the Applicants understanding that U.S. Pat. No.
6,211,209 discloses,
5-[[2-[(2,6-dichloro-3-methylphenyl)amino]phenyl]methylene]-2,4-thiazolid-
inedione.
[0226] It is the Applicants understanding that WO 9705135
discloses,
[2S-[2.alpha.(Z),4.alpha.]]-1-([1,1'-biphenyl]-4-ylsulfonyl)-N-[2-[(2,4-d-
ioxo-5-thiazolidinylidene)methyl]phenyl]-4-(methylthio)-2-pyrrolidinemetha-
namine, 1,1-dimethylethyl ester
[[2S-[2.alpha.(Z),4.alpha.]]-3-[[[1-([1,1'-biphenyl]-4-ylsulfonyl)-4-(met-
hylthio)-2-pyrrolidinyl]methyl]amino]-4-[(2,4-dioxo-5-thiazolidinylidene)m-
ethyl]phenyl]-carbamic acid, and
[2S-[2.alpha.(Z),4.alpha.]]-N-[5-amino-2-[(2,4-dioxo-5-thiazolidinylidene-
)methyl]phenyl]-1-([1,1'-biphenyl]-4-ylsulfonyl)-4-(methylthio)-2-pyrrolid-
inemethanamine.
[0227] The preceding understandings are not intended to be
admissions.
[0228] In some embodiments, compounds disclosed herein could be
used in the clinic either as a single agent by itself or in
combination with other clinically relevant agents. This compound
could also prevent the potential cancer resistance mechanisms that
may arise due to mutations in a set of genes.
[0229] The anti-cancer treatment defined herein may be applied as a
sole therapy or may involve, in addition to the compound of the
invention, conventional surgery or radiotherapy or chemotherapy.
Such chemotherapy may include one or more of the following
categories of anti-tumour agents:
[0230] (i) antiproliferative/antineoplastic drugs and combinations
thereof, as used in medical oncology, such as alkylating agents
(for example cis-platin, carboplatin, cyclophosphamide, nitrogen
mustard, melphalan, chlorambucil, busulfan and nitrosoureas);
antimetabolites (for example antifolates such as fluoropyrimidines
like 5-fluorouracil and tegafur, raltitrexed, methotrexate,
cytosine arabinoside and hydroxyurea); antitumour antibiotics (for
example anthracyclines like adriamycin, bleomycin, doxorubicin,
daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and
mithramycin); antimitotic agents (for example vinca alkaloids like
vincristine, vinblastine, vindesine and vinorelbine and taxoids
like taxol and taxotere); and topoisomerase inhibitors (for example
epipodophyllotoxins like etoposide and teniposide, amsacrine,
topotecan and camptothecin); and proteosome inhibitors (for example
bortezomib [Velcade.RTM.]); and the agent anegrilide
[Agrylin.RTM.]; and the agent alpha-interferon
[0231] (ii) cytostatic agents such as antioestrogens (for example
tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene),
oestrogen receptor down regulators (for example fulvestrant),
antiandrogens (for example bicalutamide, flutamide, nilutamide and
cyproterone acetate), LHRH antagonists or LHRH agonists (for
example goserelin, leuprorelin and buserelin), progestogens (for
example megestrol acetate), aromatase inhibitors (for example as
anastrozole, letrozole, vorazole and exemestane) and inhibitors of
5.alpha.-reductase such as finasteride;
[0232] (iii) agents which inhibit cancer cell invasion (for example
metalloproteinase inhibitors like marimastat and inhibitors of
urokinase plasminogen activator receptor function);
[0233] (iv) inhibitors of growth factor function, for example such
inhibitors include growth factor antibodies, growth factor receptor
antibodies (for example the anti-erbb2 antibody trastuzumab
[Herceptin.TM.] and the anti-erbb1 antibody cetuximab [C225]),
farnesyl transferase inhibitors, tyrosine kinase inhibitors and
serine/threonine kinase inhibitors, for example inhibitors of the
epidermal growth factor family (for example EGFR family tyrosine
kinase inhibitors such as: [0234]
N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quina-
zolin-4-amine (gefitinib, AZD1839), [0235]
N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine
(erlotinib, OSI-774), and [0236]
6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazoli-
n-4-amine (CI 1033),
[0237] for example inhibitors of the platelet-derived growth factor
family and for example inhibitors of the hepatocyte growth factor
family, for example inhibitors or phosphotidylinositol 3-kinase
(PI3K) and for example inhibitors of mitogen activated protein
kinase kinase (MEK1/2) and for example inhibitors of protein kinase
B (PKB/Akt), for example inhibitors of Src tyrosine kinase family
and/or Abelson (Abl) tyrosine kinase family such as AZD0530 and
dasatinib (BMS-354825) and imatinib mesylate (Gleevec.TM.); and any
agents that modify STAT signaling.
[0238] (v) antiangiogenic agents such as those which inhibit the
effects of vascular endothelial growth factor, (for example the
anti-vascular endothelial cell growth factor antibody bevacizumab
[Avastin.TM.], compounds such as those disclosed in International
Patent Applications WO 97/22596, WO 97/30035, WO 97/32856 and WO
98/13354) and compounds that work by other mechanisms (for example
linomide, inhibitors of integrin .alpha.v.beta.3 function and
angiostatin);
[0239] (vi) vascular damaging agents such as Combretastatin A4 and
compounds disclosed in International Patent Applications WO
99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO
02/08213;
[0240] (vii) antisense therapies, for example those which are
directed to the targets listed above, such as ISIS 2503, an
anti-ras antisense;
[0241] (viii) gene therapy approaches, including for example
approaches to replace aberrant genes such as aberrant p53 or
aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug
therapy) approaches such as those using cytosine deaminase,
thymidine kinase or a bacterial nitroreductase enzyme and
approaches to increase patient tolerance to chemotherapy or
radiotherapy such as multi-drug resistance gene therapy; and
[0242] (ix) immunotherapy approaches, including for example ex-vivo
and in-vivo approaches to increase the immunogenicity of patient
tumour cells, such as transfection with cytokines such as
interleukin 2, interleukin 4 or granulocyte-macrophage colony
stimulating factor, approaches to decrease T-cell anergy,
approaches using transfected immune cells such as
cytokine-transfected dendritic cells, approaches using
cytokine-transfected tumour cell lines and approaches using
anti-idiotypic antibodies, and approaches using the
immunomodulatory drugs thalidomide and lenalidomide
[Revlimid.RTM.].
[0243] Such conjoint treatment may be achieved by way of the
simultaneous, sequential or separate dosing of the individual
components of the treatment. Such combination products employ the
compounds of this invention, or pharmaceutically acceptable salts
thereof, within the dosage range described hereinbefore and the
other pharmaceutically-active agent within its approved dosage
range.
[0244] The invention relates to phosphorylation inhibitors of PIM
kinases. In still further embodiments, the invention relates to
pharmaceutical composition comprising compounds disclosed herein
and their use in the prevention and treatment of cancer.
[0245] It is understood the compositions disclosed herein may exist
in solid and solution form tautomers. For example, imidazole and
imidazole containing heterocycles may be drawn in a formula such
that one or the other of the nitrogens contain a hydrogen atom.
However, as provided herein, embodiments of such a formula are
considered to encompass alternative tautomeric forms.
[0246] As used herein, "alkyl" means a noncyclic straight chain or
branched, unsaturated or saturated hydrocarbon such as those
containing from 1 to 10 carbon atoms, while the term "lower alkyl"
or "C.sub.1-6alkyl" has the same meaning as alkyl but contains from
1 to 6 carbon atoms. The term "higher alkyl" has the same meaning
as alkyl but contains from 7 to 10 carbon atoms. Representative
saturated straight chain alkyls include methyl, ethyl, n-propyl,
n-butyl, n-pentyl, n-hexyl, n-septyl, n-octyl, n-nonyl, and the
like; while saturated branched alkyls include isopropyl, sec-butyl,
isobutyl, tert-butyl, isopentyl, and the like. Unsaturated alkyls
contain at least one double or triple bond between adjacent carbon
atoms (referred to as an "alkenyl" or "alkynyl", respectively).
Representative straight chain and branched alkenyls include
ethylenyl, propylenyl, 1-butenyl, 2-butenyl, isobutylenyl,
1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl,
2,3-dimethyl-2-butenyl, and the like; while representative straight
chain and branched alkynyls include acetylenyl, propynyl,
1-butyryl, 2-butyryl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl,
and the like.
[0247] A "halogenated alkyl" refers to an alkyl group where one or
more or all of the hydrogen(s) are substituted with halogen(s). A
representative halogenated alkyl includes trifluoromethyl (i.e.,
--CF.sub.3).
[0248] Non-aromatic mono or polycyclic alkyls are referred to
herein as "carbocycles" or "carbocyclyl" groups. Representative
saturated carbocycles include cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, and the like; while unsaturated carbocycles include
cyclopentenyl and cyclohexenyl, aryls and the like.
[0249] "Heterocarbocycles" or heterocarbocyclyl" groups are
carbocycles which contain from 1 to 4 heteroatoms independently
selected from nitrogen, oxygen and sulfur which may be saturated or
unsaturated (but not aromatic), monocyclic or polycyclic, and
wherein the nitrogen and sulfur heteroatoms may be optionally
oxidized, and the nitrogen heteroatom may be optionally
quaternized. Heterocarbocycles include morpholinyl, pyrrolidinonyl,
pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl,
oxetanyl, tetrahydrofuranyl, tetrahydropyranyl,
tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl,
tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl,
tetrahydrothiopyranyl, and the like.
[0250] "Aryl" means an aromatic carbocyclic monocyclic or
polycyclic ring such as phenyl or naphthyl.
[0251] As used herein, "heteroaryl" refers an aromatic
heterocarbocycle having 1 to 4 heteroatoms selected from nitrogen,
oxygen and sulfur, and containing at least 1 carbon atom, including
both mono- and polycyclic ring systems. Polycyclic ring systems
may, but are not required to, contain one or more non-aromatic
rings, as long as one of the rings is aromatic. Representative
heteroaryls are furyl, benzofuranyl, thiophenyl, benzothiophenyl,
pyrrolyl, indolyl, isoindolyl, azaindolyl, pyridyl, quinolinyl,
isoquinolinyl, oxazolyl, isooxazolyl, benzoxazolyl, pyrazolyl,
imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl,
isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,
cinnolinyl, phthalazinyl, and quinazolinyl. It is contemplated that
the use of the term "heteroaryl" includes N-alkylated derivatives
such as a 1-methylimidazol-5-yl substituent.
[0252] As used herein, "heterocycle" or "heterocyclyl" refers to
mono- and polycyclic ring systems having 1 to 4 heteroatoms
selected from nitrogen, oxygen and sulfur, and containing at least
1 carbon atom. The mono- and polycyclic ring systems may be
aromatic, non-aromatic or mixtures of aromatic and non-aromatic
rings. Heterocycle includes heterocarbocycles, heteroaryls, and the
like.
[0253] "Alkylthio" refers to an alkyl group as defined above with
the indicated number of carbon atoms attached through a sulfur
bridge. An example of an alkylthio is methylthio, (i.e.,
--S--CH.sub.3).
[0254] "Alkoxy" refers to an alkyl group as defined above with the
indicated number of carbon atoms attached through an oxygen bridge.
Examples of alkoxy include, but are not limited to, methoxy,
ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy,
n-pentoxy, and s-pentoxy. Preferred alkoxy groups are methoxy,
ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy.
[0255] "Alkylamino" refers an alkyl group as defined above with the
indicated number of carbon atoms attached through an amino bridge.
An example of an alkylamino is methylamino, (i.e.,
--NH--CH.sub.3).
[0256] "Alkanoyl" refers to an alkyl as defined above with the
indicated number of carbon atoms attached through a carbonyl bride
(i.e., --(C.dbd.O)alkyl).
[0257] "Alkylsulfonyl" refers to an alkyl as defined above with the
indicated number of carbon atoms attached through a sulfonyl bridge
(i.e., --S(.dbd.O).sub.2alkyl) such as mesyl and the like, and
"Arylsulfonyl" refers to an aryl attached through a sulfonyl bridge
(i.e., --S(.dbd.O).sub.2aryl).
[0258] "Alkylsulfamoyl" refers to an alkyl as defined above with
the indicated number of carbon atoms attached through a sulfamoyl
bridge (i.e., --NHS(.dbd.O).sub.2alkyl), and an "Arylsulfamoyl"
refers to an alkyl attached through a sulfamoyl bridge (i.e.,
(i.e., --NHS(.dbd.O).sub.2aryl).
[0259] "Alkylsulfinyl" refers to an alkyl as defined above with the
indicated number of carbon atoms attached through a sulfinyl bridge
(i.e. --S(.dbd.O)alkyl).
[0260] The term "substituted" refers to a molecule wherein at least
one hydrogen atom is replaced with a substituent. When substituted,
one or more of the groups are "substituents." The molecule may be
multiply substituted. In the case of an oxo substituent (".dbd.O"),
two hydrogen atoms are replaced. Example substituents within this
context may include halogen, hydroxy, alkyl, alkoxy, nitro, cyano,
oxo, carbocyclyl, carbocycloalkyl, heterocarbocyclyl,
heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, --NR.sub.aR.sub.b, --NR.sub.aC(.dbd.O)R.sub.b,
--NR.sub.aC(.dbd.O)NR.sub.aNR.sub.b, --NR.sub.aC(.dbd.O)OR.sub.b,
--NR.sub.aSO.sub.2R.sub.b, --C(.dbd.O)R.sub.a, --C(.dbd.O)OR.sub.a,
--C(.dbd.O)NR.sub.aR.sub.b, --OC(.dbd.O)NR.sub.aR.sub.b,
--OR.sub.a, --SR.sub.a, --SOR.sub.a, --S(.dbd.O).sub.2R.sub.a,
--OS(.dbd.O).sub.2R.sub.a and --S(.dbd.O).sub.2OR.sub.a. R.sub.a
and R.sub.b in this context may be the same or different and
independently hydrogen, halogen hydroxyl, alkyl, alkoxy, alkyl,
amino, alkylamino, dialkylamino, carbocyclyl, carbocycloalkyl,
heterocarbocyclyl, heterocarbocycloalkyl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl.
[0261] The term "optionally substituted," as used herein, means
that substitution is optional and therefore it is possible for the
designated atom to be unsubstituted.
[0262] As used herein, the terms "prevent" and "preventing" include
the prevention of the recurrence, spread or onset. It is not
intended that the present invention be limited to complete
prevention. In some embodiments, the onset is delayed, or the
severity of the disease is reduced.
[0263] As used herein, the terms "treat" and "treating" are not
limited to the case where the subject (e.g. patient) is cured and
the disease is eradicated. Rather, embodiments, of the present
invention also contemplate treatment that merely reduces symptoms,
and/or delays disease progression.
[0264] As used herein, "salts" refer to derivatives of the
disclosed compounds where the parent compound is modified making
acid or base salts thereof. Examples of salts include, but are not
limited to, mineral or organic acid salts of basic residues such as
amines, alkylamines, or dialkylamines; alkali or organic salts of
acidic residues such as carboxylic acids; and the like. In
preferred embodiment the salts are conventional non-toxic
pharmaceutically acceptable salts including the quaternary ammonium
salts of the parent compound formed, and non-toxic inorganic or
organic acids. Preferred salts include those derived from inorganic
acids such as hydrochloric, hydrobromic, sulfuric, sulfamic,
phosphoric, nitric and the like; and the salts prepared from
organic acids such as acetic, propionic, succinic, glycolic,
stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic,
hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,
sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic,
methanesulfonic, ethane disulfonic, oxalic, isethionic, and the
like.
[0265] The pharmaceutically acceptable salts of the present
invention can be synthesized from the parent compound that contains
a basic or acidic moiety by conventional chemical methods.
Generally, such salts can be prepared by reacting the free acid or
base forms of these compounds with a stoichiometric amount of the
appropriate base or acid in water or in an organic solvent, or in a
mixture of the two; generally, nonaqueous media like ether, ethyl
acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists
of suitable salts are found in Remington's Pharmaceutical Sciences,
17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the
disclosure of which is hereby incorporated by reference.
[0266] "Subject" means any animal, preferably a human patient,
livestock, or domestic pet.
[0267] "Cancer" refers any of various cellular diseases with
malignant neoplasms characterized by the proliferation of cells. It
is not intended that the diseased cells must actually invade
surrounding tissue and metastasize to new body sites. Cancer can
involve any tissue of the body and have many different forms in
each body area. Within the context of certain embodiments, whether
"cancer is reduced" may be identified by a variety of diagnostic
manners known to one skill in the art including, but not limited
to, observation the reduction in size or number of tumor masses or
if an increase of apoptosis of cancer cells observed, e.g., if more
than a 5% increase in apoptosis of cancer cells is observed for a
sample compound compared to a control without the compound. It may
also be identified by a change in relevant biomarker or gene
expression profile, such as PSA for prostate cancer, her2 for
breast cancer, or others.
[0268] The present pharmaceutical compositions can take the form of
solutions, suspensions, emulsion, tablets, pills, pellets,
capsules, capsules containing liquids, powders, sustained-release
formulations, suppositories, emulsions, aerosols, sprays,
suspensions, or any other form suitable for use.
[0269] Administration may be topical, i.e., substance is applied
directly where its action is desired, enteral or oral, i.e.,
substance is given via the digestive tract, parenteral, i.e.,
substance is given by other routes than the digestive tract such as
by injection.
[0270] In a preferred embodiment, the active compound and
optionally another therapeutic or prophylactic agent are formulated
in accordance with routine procedures as pharmaceutical
compositions adapted for intravenous administration to human
beings. Typically, the active compound for intravenous
administration are solutions in sterile isotonic aqueous buffer.
Where necessary, the compositions can also include a solubilizing
agent. Compositions for intravenous administration can optionally
include a local anesthetic such as lignocaine to ease pain at the
site of the injection. Generally, the ingredients are supplied
either separately or mixed together in unit dosage form, for
example, as a dry lyophilized powder or water free concentrate in a
hermetically sealed container such as an ampoule. Where the active
compound is to be administered by infusion, it can be dispensed,
for example, with an infusion bottle containing sterile
pharmaceutical grade water or saline. Where the active compound is
administered by injection, an ampoule of sterile water for
injection or saline can be provided so that the ingredients can be
mixed prior to administration.
[0271] Compositions for oral delivery can be in the form of
tablets, lozenges, aqueous or oily suspensions, granules, powders,
emulsions, capsules, syrups, or elixirs, for example. Orally
administered compositions can contain one or more optional agents,
for example, sweetening agents such as fructose, aspartame or
saccharin; flavoring agents such as peppermint, oil of wintergreen,
or cherry; coloring agents; and preserving agents, to provide a
pharmaceutically palatable preparation. A time delay material such
as glycerol monostearate or glycerol stearate can also be used.
Oral compositions can include standard vehicles such as mannitol,
lactose, starch, magnesium stearate, sodium saccharine, cellulose,
magnesium carbonate, and the like. Such vehicles are preferably of
pharmaceutical grade.
[0272] Compositions for use in accordance with the present
invention can be formulated in conventional manner using one or
more physiologically acceptable carriers or excipients. Thus, the
compound and optionally another therapeutic or prophylactic agent
and their physiologically acceptable salts and solvates can be
formulated into pharmaceutical compositions for administration by
inhalation or insufflation (either through the mouth or the nose)
or oral, parenteral or mucosol (such as buccal, vaginal, rectal,
sublingual) administration. In one embodiment, local or systemic
parenteral administration is used.
[0273] For oral administration, the compositions can take the form
of, for example, tablets or capsules prepared by conventional means
with pharmaceutically acceptable excipients such as binding agents
(e.g., pregelatinised maize starch, polyvinylpyrrolidone or
hydroxypropyl methylcellulose); fillers (e.g., lactose,
microcrystalline cellulose or calcium hydrogen phosphate);
lubricants (e.g., magnesium stearate, talc or silica);
disintegrants (e.g., potato starch or sodium starch glycolate); or
wetting agents (e.g., sodium lauryl sulfate). The tablets can be
coated by methods well known in the art. Liquid preparations for
oral administration can take the form of, for example, solutions,
syrups or suspensions, or they can be presented as a dry product
for constitution with water or other suitable vehicle before use.
Such liquid preparations can be prepared by conventional means with
pharmaceutically acceptable additives such as suspending agents
(e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible
fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous
vehicles (e.g., almond oil, oily esters, ethyl alcohol or
fractionated vegetable oils); and preservatives (e.g., methyl or
propyl-p-hydroxybenzoates or sorbic acid). The preparations can
also contain buffer salts, flavoring, coloring and sweetening
agents as appropriate.
EXPERIMENTAL
[0274] The following is intended to provide examples on methods of
making and using embodiments of the invention. It is not intended
to limit the scope.
Example 1
##STR00021##
[0275]
(S,Z)-5-(2-(3-aminopiperidin-1-yl)-3-chloro-5-(trifluoromethyl)benz-
ylidene)thiazolidine-2,4-dione trifluoroacetate
[0276] A 40 mL vial was charged with a magnetic stir bar,
3-chloro-2-fluoro-5-(trifluoromethyl)benzaldehyde (0.134 ml, 1.10
mmol), acetonitrile (2.76 ml), (S)-tert-butyl
piperidin-3-ylcarbamate (0.221 g, 1.10 mmol), and K.sub.2CO.sub.3
(0.229 g, 1.66 mmol). The vial was heated to 70.degree. C. with
stirring for 2 h. The vessel was cooled to rt and the mixture was
diluted with DCM and filtered. The filtrate was conc. in vacuo to
afford the substituted aldehyde which was dissolved in EtOH (2.76
ml). Thiazolidine-2,4-dione (0.155 g, 1.32 mmol) and piperidine
(9.40 mg, 0.11 mmol) were then added. The mixture was heated to
reflux for 4 h before being allowed to cool to rt and the mixture
was conc. in vacuo. The product was dissolved DCM (2 mL) and TFA (1
mL) and stirred at rt for 1 h before being conc. in vacuo. The
residue was dissolved in DMSO (.about.2 mL) and purified via
reverse phase HPLC to afford
(S,Z)-5-(2-(3-aminopiperidin-1-yl)-3-chloro-5-(trifluoromethyl)benzyliden-
e)thiazolidine-2,4-dione trifluoroacetate (0.214 g, 37.3%). .sup.1H
NMR (300 MHz, DMSO-D6) .delta. ppm 12.78 (s, 1H) 7.95 (m, 3H) 7.79
(s, 1H) 7.62 (s, 1H) 3.40-3.20 (s, 5H) 2.12-2.06 (m, 1H) 1.79-1.70
(m 1H) 1.65-1.60 (m, 1H) 1.52-1.41 (m, 1H); m/z 406.
[0277] The following examples were prepared by the procedure of
Example 1, using the appropriate starting materials. The following
parent compounds obtained after chromatography may be converted to
their corresponding hydrochloride salts using the procedure in
Example 6, or a similar procedure.
TABLE-US-00001 Ex. Compound .sup.1H NMR (300 MHz) m/z SM 2
(R,Z)-5-(2-(3- 12.79 (s, 1 H) 7.98 (s, 2 406 (R)-tert-butyl
piperidin- aminopiperidin-1-yl)- H) 7.95 (s, 1 H) 7.79 (s, 1
3-ylcarbamate 3-chloro-5-(trifluoromethyl)
benzylidene)thiazolidine- 2,4-dione trifluoroacetate ##STR00022##
H) 7.62 (s, 1 H) 3.31- 3.20 (m, 5 H) 2.12-2.09 (m, 1 H) 1.85-1.77
(m, 1 H) 1.66-1.63 (m, 1 H) 1.45-1.40 (m, 1 H) ##STR00023## 3
(Z)-5-(2-(4- 12.76 (s, 1 H) 7.99 (s, 1 406 tert-butyl piperidin-4-
aminopiperidin-1-yl)- H) 7.91 (s, 2 H) 7.78 (s, 1 ylcarbamate
3-chloro-5-(trifluoromethyl) benzylidene)thiazolidine- 2,4-dione
trifluoroacetate ##STR00024## H) 7.60 (s, 1 H) 3.33- 3.18 (m, 5 H)
1.94 (d, 2 H) 1.71-1.60 (m, 2 H) ##STR00025## 4 (Z)-5-(2-(3- 12.78
(s, 1 H) 7.93 (s, 1 421 tert-butyl piperidin-3- (aminomethyl) H)
7.84 (s, 1 H) 7.75 (s, 1 ylmethylcarbamate
piperidin-1-yl)-3-chloro-5- (trifluoromethyl)
benzylidene)thiazolidine- 2,4-dione trifluoroacetate ##STR00026##
H) 7.61 (s, 1 H) 3.31- 3.05 (m, 6 H) 2.79-2.71 (m, 1 H) 1.95-1.89
(m, 2 H) 1.72-1.55 (m, 2 H) 1.29-1.10 (m, 1 H) ##STR00027## 5A
(Z)-5-(3-chloro-2- 12.83 (brs, 1 H) 9.20 405 tert-butyl
1,4-diazepane- (1,4-diazepan-1-yl)- (brs, 2 H) 8.05 (d, 1 H)
1-carboxylate 5-(trifluoromethyl) benzylidene)thiazolidine-
2,4-dione hydrochloride ##STR00028## 7.90 (s, 1 H) 7.66 (d, 1 H)
3.51 (brs, 2 H) 3.35 (d, 2 H) 3.26-3.03 (m, 4 H) 2.27-1.99 (m, 2 H)
##STR00029## 5B (S,Z)-5-(2-(3- 12.73 (brs, 1 H) 8.29 392 tert-butyl
(3S)- aminopyrrolidin-1- (brs, 3 H) 7.93 (s, 1 H)
pyrrolidin-3-ylcarbamate yl)-3-chloro-5-(trifluoromethyl)
benzylidene)thiazolidine-2,4-dione ##STR00030## 7.83 (s, 1 H) 7.66
(s, 1 H) 3.88 (brs, 1 H) 3.66 (dd, 1 H), 3.52-3.27 (m, 3 H)
2.42-2.19 (m, 1 H) 2.12- 1.88 (m, 1 H) ##STR00031##
Example 6
##STR00032##
[0278]
(Z)-5-(3-chloro-2-(4-cyclopentylpiperazin-1-yl)-5-(trifluoromethyl)-
benzylidene)thiazolidine-2,4-dione hydrochloride
[0279] A 40 mL vial was charged with a magnetic stir bar,
3-chloro-2-fluoro-5-(trifluoromethyl)benzaldehyde (0.134 ml, 1.10
mmol), acetonitrile (2.76 ml), 1-cyclopentylpiperazine (0.213 g,
1.38 mmol), and K.sub.2CO.sub.3 (0.229 g, 1.66 mmol). The vial was
heated to 70.degree. C. with stirring for 2 h. The vessel was then
cooled to rt and the mixture was diluted with DCM and filtered. The
filtrate was conc. in vacuo to afford the substituted aldehyde
which was dissolved in EtOH (2.76 ml). Thiazolidine-2,4-dione
(0.155 g, 1.32 mmol) and piperidine (9.40 mg, 0.11 mmol) were then
added and the mixture was heated to reflux for 4 h before being
allowed to cool to rt. The mixture was then conc. in vacuo to
afford the product which was dissolved in DMSO (.about.2 mL) and
purified via reverse phase HPLC to afford fractions that were conc.
in vacuo, suspended in methanol (.about.5 mL) and 1N HCl in diethyl
ether (.about.2 mL). This mixture was conc. in vacuo to afford
(Z)-5-(3-chloro-2-(4-cyclopentylpiperazin-1-yl)-5-(trifluoromethyl)benzyl-
idene)thiazolidine-2,4-dione hydrochloride (0.215 g, 39.3%).
.sup.1H NMR (300 MHz, DMSO-D6) .delta. ppm 12.78 (s, 1H) 7.96 (s,
1H) 7.83 (s, 1H) 7.63 (s, 1H) 3.77-3.50 (m, 5H) 3.30-3.22 (m, 2H)
3.08-2.99 (m, 2H) 2.03-1.99 (m, 2H) 1.84-1.61 (m, 4H) 1.60-1.50 (m,
2H); m/z 461.
[0280] The following examples were prepared by the procedure of
Example 6, using the appropriate starting materials. The following
parent compounds obtained after chromatography may be converted to
their corresponding hydrochloride salt in a manner similar as
described in example 6.
TABLE-US-00002 Ex. Compound .sup.1H NMR m/z SM 7
(Z)-5-(3-chloro-2-(4- 12.74 (s, 1 H) 7.89-8.01 486 1-(4-
(4-fluorophenyl)piperazin- (m, 2 H) 7.62 (s, 1 H)
fluorophenyl)piperazine 1-yl)-5-(trifluoromethyl)
benzylidene)thiazolidine-2,4-dione ##STR00033## 6.99-7.13 (m, 4 H)
3.34- 3.23 (m, 8 H) ##STR00034## 8
(Z)-5-(2-(4-(benzo[d][1,3]dioxol- 12.77 (s, 1 H) 7.97 (d, 1 526
1-(benzo[d][1,3]dioxol- 5-ylmethyl)piperazin- H) 7.97 (s, 1 H) 7.77
(s, 1 5-ylmethyl)piperazine 1-yl)-3-chloro-5-(trifluoromethyl)
benzylidene)thiazolidine- 2,4-dione trifluoroacetate ##STR00035##
H) 7.63 (s, 1 H) 7.10 (s, 1 H) 7.02 (s, 2 H) 6.08 (s, 2 H) 4.34 (s,
2 H) 3.58- 3.11 (m, 8 H) ##STR00036## 9
(Z)-5-(3-chloro-2-(4-(3-methyl-1,2,4- 12.72 (s, 1 H) 7.91 (s, 1 473
3-methyl-5-(piperidin-4- oxadiazol-5-yl)piperidin-1-yl)-5- H) 7.84
(s, 1 H) 7.61 (s, 1 yl)-1,2,4-oxadiazole
(trifluoromethyl)benzylidene) thiazolidine-2,4-dione ##STR00037##
H) 3.33-3.18 (m, 4 H) 2.79-2.71 (m, 1 H) 2.33 (s, 3 H) 2.06 (d, 2
H) 1.98-1.80 (m, 2 H) ##STR00038## 10
(Z)-5-(3-chloro-2-(4-(pyrrolidin-1- 12.78 (s, 1 H) 7.92 (s, 1 461
4-(pyrrolidin-1- yl)piperidin-1-yl)-5-(trifluoromethyl) H) 7.79 (s,
1 H) 7.60 (s, 1 yl)piperidine benzylidene)thiazolidine- 2,4-dione
hydrochloride ##STR00039## H) 3.33-3.20 (m, 5 H) 3.12-3.03 (m, 4 H)
2.09 (d, 2 H) 1.97-1.78 (m, 6 H) ##STR00040## 11
(Z)-5-(3-chloro-2-(4- 12.80 (s, 1 H) 7.96 (s, 1 434
1-isopropylpiperazine isopropylpiperazin-1- yl)-5-(trifluoromethyl)
benzylidene)thiazolidine- 2,4-dione hydrochloride ##STR00041## H)
7.82 (s, 1 H) 7.62 (s, 1 H) 3.85 (t, 2 H) 3.55-3.52 (m, 1 H) 3.41
(d, 2 H) 3.26 (d, 2 H) 3.10-3.06 (m, 2 H) 1.32 (d, 6 H)
##STR00042## 12 (Z)-5-(3-chloro-2-(4- 12.80 (s, 1 H) 7.96 (d, 1 450
1-isobutylpiperazine isobutylpiperazin-1- yl)-5-(trifluoromethyl)
benzylidene)thiazolidine- 2,4-dione hydrochloride ##STR00043## H)
7.80 (s, 1 H) 7.63 (s, 1 H) 3.87 (brs, 2 H) 3.52 (d, 2 H) 3.27
(brs, 2 H) 3.11-3.00 (m, 4 H) 2.10 (qq, 1 H) 1.00 (d, 6 H)
##STR00044## 13 (Z)-5-(3-chloro-2-(4- 12.73 (s, 1 H) 7.87 (s, 1 437
2-(piperidin-4-yl)ethanol (2-hydroxyethyl)piperidin-
1-yl)-5-(trifluoromethyl) benzylidene)thiazolidine-2,4-dione
##STR00045## H) 7.83 (s, 1 H) 7.59 (s, 1 H) 3.46 (t, 2 H) 3.23 (t,
2 H) 3.07 (brs, 2 H) 1.70 (d, 2 H) 1.61-1.52 (m, 1 H) 1.42 (q, 2 H)
1.33- 1.20 (m, 2 H) ##STR00046## 14
(S,Z)-5-(3-chloro-2-(3-(dimethylamino) 12.65 (s, 1 H) 7.82 (s, 1
421 (S)-N,N- pyrrolidin-1-yl)-5-(trifluoromethyl) H) 7.72 (s, 1 H)
7.53 (s, 1 dimethylpyrrolidin-3- benzylidene)thiazolidine- H)
3.59-3.50 (m, 1 H) amine 2,4-dione hydrochloride ##STR00047##
3.38-3.30 (m, 4 H) 2.56 (s, 6 H) 2.31-2.28 (m, 1 H) 2.09-2.01 (m, 1
H) ##STR00048## 15 (Z)-5-(3-chloro-2-(4-(4-chloro-2- 12.75 (brs, 1
H) 8.06- 520 1-(4-chloro-2- fluorophenyl)piperazin-1-yl)-5- 7.90
(m, 2 H) 7.64 (d, 1 fluorophenyl)piperazine (trifluoromethyl)
benzylidene)thiazolidine- 2,4-dione hydrochloride ##STR00049## H)
7.38 (dd, 1 H) 7.23 (dd, 1 H) 7.11 (t, 1 H) 3.42 (m, 4 H) 3.15 (d,
4 H) ##STR00050## 16 (Z)-5-(3-chloro-2-(3-(3-methyl-1,2,4- 471
3-methyl-5-(piperidin-3- oxadiazol-5-yl)piperidin-1-yl)-5-
yl)-1,2,4-oxadiazole (trifluoromethyl) benzylidene)thiazolidine-
2,4-dione hydrochloride ##STR00051## ##STR00052## 17
(Z)-5-(3-chloro-2-(4-(pyridin-4- 12.75 (brs, 1H) 8.78 (d, 2 483
1-(pyridin-4- ylmethyl)piperazin-1- H) 7.98 (s, 1 H) 7.74
ylmethyl)piperazine yl)-5-(trifluoromethyl)
benzylidene)thiazolidine- 2,4-dione hydrochloride ##STR00053##
(brs, 1 H) 7.71 (s, 1 H) 7.64 (s, 1 H) 4.44 (brs, 2 H) 3.44 (brs, 4
H) 3.17 (s, 4 H) ##STR00054## 18
(Z)-5-(3-chloro-2-(4-(2-chlorobenzyl) 7.98 (d, 1 H) 7.73 (dd, 1 517
1-(2- piperazin-1-yl)-5-(trifluoromethyl) H) 7.68-7.59 (m, 2 H)
chlorobenzyl)piperazine benzylidene)thiazolidine- 2,4-dione
hydrochloride ##STR00055## 7.58-7.42 (m, 3 H) 4.53 (brs, 2 H)
3.75-3.30 (m, 8 H) ##STR00056## 19 (Z)-5-(3-chloro-2-(4- 10.68
(brs, 1 H) 7.92 (d, 489 1-(1-methylpiperidin-4-
(1-methylpiperidin-4- 1 H) 7.78 (brs, 1 H) 7.58 yl)piperazine
yl)piperazin-1-yl)-5-(trifluoromethyl) benzylidene)thiazolidine-
2,4-dione hydrochloride ##STR00057## (s, 1 H) 3.73-3.63 (m, 1 H)
3.61-3.41 (m, 6 H) 3.10 (brs, 3 H) 2.93 (brs, 3 H) 2.67 (s, 3 H)
2.39- 2.18 (m, 2 H) 2.07 (brs, 2 H) ##STR00058## 20
(Z)-5-(3-chloro-2-(4-(2-morpholinoethyl) 11.12 (brs, 1 H) 7.91 (d,
505 4-(2-(piperazin-1- piperazin-1-yl)-5-(trifluoromethyl) 1 H)
7.79 (brs, 1 H) 7.59 yl)ethyl)morpholine benzylidene)thiazolidine-
2,4-dione hydrochloride ##STR00059## (s, 1 H) 3.80-2.81 (m, 20 H)
##STR00060## 21 (Z)-5-(3-chloro-2-(4-(cyclopropylmethyl) 12.59
(brs, 1 H) 7.76 (d, 447 1-(cyclopropylmethyl)
piperazin-1-yl)-5-(trifluoromethyl) 1 H) 7.61 (brs, 1 H) 7.43
piperazine benzylidene)thiazolidine- 2,4-dione hydrochloride
##STR00061## (s, 1 H) 3.62 (brs, 2 H) 3.44-3.24 (m, 2 H) 3.10 (brs,
2 H) 2.87 (d, 4 H) 0.94 (brs, 1 H) 0.54- 0.31 (m, 2 H) 0.32-0.08
(m, 2 H) ##STR00062## 22 (Z)-5-(3-chloro-2-(4-morpholinopiperidin-
12.92 (brs, 1 H) 8.08 (d, 476 4-(piperidin-4-
1-yl)-5-(trifluoromethyl) 1 H) 7.95 (brs, 1 H) 7.76 yl)morpholine
benzylidene)thiazolidine- 2,4-dione hydrochloride ##STR00063## (s,
1 H) 4.14 (brs, 3 H) 3.98 (brs, 2 H) 3.58 (brs, 3 H) 3.53-3.34 (m,
3 H) 3.28 (brs, 2 H) 2.32 (brs, 2 H) 1.92 (d, 2 H) ##STR00064## 23
(Z)-5-(3-chloro-2-(4-(3-hydroxypropyl) 12.90 (brs, 1 H) 10.52 450
3-(piperazin-1-yl)propan- piperazin-1-yl)-5-(trifluoromethyl) (brs,
1 H) 7.98 (d, 1 H) 1-ol benzylidene)thiazolidine- 2,4-dione
hydrochloride ##STR00065## 7.84 (brs, 1 H) 7.65 (s, 1 H) 3.90-3.65
(m, 2 H) 3.57-3.41 (m, 5 H) 3.30-3.06 (m, 5 H) 1.96-1.73 (m, 2 H)
##STR00066## 24 (Z)-5-(3-chloro-2-(4-(dimethylamino) 12.79 (brs, 1
H) 7.94 (d, 434 N,N-dimethylpiperidin-4-
piperidin-1-yl)-5-(trifluoromethyl) 1 H) 7.82 (s, 1 H) 7.61 (s,
amine benzylidene)thiazolidine- 2,4-dione hydrochloride
##STR00067## 1 H) 3.84 (brs, 1 H) 3.46- 3.18 (m, 4 H) 2.75 (d, 6 H)
2.10 (d, 2 H) 1.74 (dd, 2 H) ##STR00068## 25
(Z)-5-(3-chloro-2-((3-(dimethylamino) 12.81 (brs, 1 H) 7.98 (d, 422
N1,N1,N3- propyl)(methyl)amino)-5-(trifluoromethyl) 1 H) 7.81 (s, 1
H) 7.65 trimethylpropane-1,3- benzylidene)thiazolidine- (d, 1 H)
3.15 (t, 2 H) 3.02 diamine 2,4-dione hydrochloride ##STR00069##
(brs, 2 H) 2.89 (s, 3 H) 2.72 (d, 6 H) 1.99-1.74 (m, 2 H)
##STR00070## 26 (Z)-5-(3-chloro-2-(4-(2-hydroxyethyl)-1,4- 8.04
(brs, 1 H) 7.79 (d, 1 451 2-(1,4-diazepan-1-
diazepan-1-yl)-5-(trifluoromethyl) H) 7.63 (s, 1 H) 3.83 (t, 3
yl)ethanol benzylidene)thiazolidine- 2,4-dione hydrochloride
##STR00071## H) 3.71 (m, 2 H) 3.56 (m, 3 H) 3.33 (m, 6 H) 2.21 (m,
2 H) ##STR00072## 27 (Z)-5-(2-(4-butyl-1,4-diazepan-1-yl)-3- 10.76
(brs, 1 H) 8.06 (d, 463 1-butyl-1,4-diazepane
chloro-5-(trifluoromethyl) benzylidene)thiazolidine- 2,4-dione
hydrochloride ##STR00073## 1 H) 7.91 (brs, 1 H) 7.66 (d, 1 H) 3.69
(m, 3 H) 3.57 (brs, 1 H) 3.46 (m, 3 H) 3.14 (m, 3 H) 2.34 (brs, 1
H) 2.16 (brs, 1 H) 1.73 (d, 2 H) 1.32 (m, 2 H) 0.93 (t, 3 H)
##STR00074## 28 (Z)-5-(3-chloro-2-(4-(2-hydroxyethyl) 7.98 (d, 1 H)
7.82 (brs, 1 436 2-(piperazin-1-yl)ethanol
piperazin-1-yl)-5-(trifluoromethyl) benzylidene)thiazolidine-
2,4-dione hydrochloride ##STR00075## H) 7.64 (d, 1 H) 5.40 (brs, 1
H) 3.74 (m, 4 H) 3.56 (m, 3 H) 3.27 (m, 3 H) 3.18 (brs, 1 H) 3.11
(brs, 1 H) ##STR00076## 29 (Z)-5-(3-chloro-2-morpholino-5- 12.76
(brs, 1 H) 7.94 (m, 394 morpholine (trifluoromethyl)
benzylidene)thiazolidine-2,4-dione ##STR00077## 2 H) 7.63 (d, 1 H)
3.71 (t, 4 H) 3.20 (brs, 4 H) ##STR00078## 30
(Z)-5-(2-(4-tert-butylpiperazin-1-yl)- 12.80 (brs, 1 H) 8.00 (d,
449 1-tert-butylpiperazine 3-chloro-5-(trifluoromethyl)
benzylidene)thiazolidine- 2,4-dione hydrochloride ##STR00079## 1 H)
7.85 (brs, 1 H) 7.65 (d, 1 H) 3.82 (m, 2 H) 3.56 (d, 2 H) 3.29 (dd,
2 H) 3.04 (m, 2 H) 1.39 (s, 9 H) ##STR00080## 31
(Z)-5-(2-(1,4'-bipiperidin-1'-yl)-3- 9.75 (brs, 1 H) 7.94 (d, 1 474
1,4'-bipiperidine chloro-5-(trifluoromethyl)
benzylidene)thiazolidine- 2,4-dione hydrochloride ##STR00081## H)
7.81 (brs, 1 H) 7.62 (s, 1 H) 3.29 (m, 7 H) 2.96 (m, 2 H) 2.14 (d,
2 H) 1.78 (m, 7 H) 1.44 (brs, 1 H) ##STR00082## 32
(Z)-5-(3-chloro-2-(4-methylpiperazin-1- 7.94 (brs, 1 H) 7.75 406
1-methylpiperazine yl)-5-(trifluoromethyl)
benzylidene)thiazolidine- 2,4-dione hydrochloride ##STR00083## (d,
1 H) 7.63 (s, 1 H) 3.56-3.38 (m, 3 H) 3.31- 3.21 (m, 5 H) 2.92 (s,
3 H) ##STR00084##
Example 33
##STR00085##
[0281]
(S,Z)-5-(3-bromo-2-(3-(dimethylamino)pyrrolidin-1-yl)benzylidene)th-
iazolidine-2,4-dione hydrochloride
[0282] A 100 mL round bottom flask was charged with a magnetic stir
bar, (S)-3-bromo-2-(3-(dimethylamino)pyrrolidin-1-yl)benzaldehyde
(Method 1) (0.370 g, 1.24 mmol), thiazolidine-2,4-dione (0.146 g,
1.24 mmol), and ethanol (4.15 ml). Piperidine (0.012 ml, 0.12 mmol)
was then added and the reaction was heated to reflux for 2 h. Once
the reaction was judged to be complete by LCMS, it was allowed to
cool to rt and was conc. in vacuo to afford the product which was
purified on 40 g of silica gel using ethyl acetate/methanol (3:1)
as eluent to afford the free base which was suspended in methanol
(.about.5 mL) and 1N HCl in diethyl ether (2 mL) and conc. in vacuo
to afford
(S,Z)-5-(3-bromo-2-(3-(dimethylamino)pyrrolidin-1-yl)benzylidene)thiazoli-
dine-2,4-dione hydrochloride (0.141 g, 26.2%). .sup.1H NMR (300
MHz, DMSO-D6) .delta. ppm 12.68 (s, 1H) 7.91 (s, 1H) 7.77 (d, 1H)
7.48 (d, 1H) 7.33 (t, 1H) 4.10-4.02 (m, 1H) 3.62 (t, 2H) 3.50-3.45
(m, 2H) 2.81 (s, 6H) 2.42-2.38 (m, 1H) 2.31-2.21 (m, 1H); m/z
398.
[0283] The following examples were prepared by the procedure of
Example 33, using the appropriate starting materials. The following
parent compounds obtained after chromatography (normal or reverse
phase) may be converted to its corresponding hydrochloride salt as
described in example 33, or similar procedure.
TABLE-US-00003 Ex. Compound .sup.1H NMR m/z SM 34
(Z)-5-(2-((3S,5R)-3,5- dimethylpiperazin-1- yl)-5-
(trifluoromethyl) benzylidene) thiazolidine- 2,4-dione
hydrochloride ##STR00086## 12.63 (s, 1 H) 8.99-8.94 (m, 1 H) 7.77
(d, 1 H) 7.72 (s, 2 H) 7.40 (d, 1 H) 3.49-3.43 (m, 2 H) 3.32 (d, 2
H) 2.92 (t, 2 H) 1.25 (d, 6 H) 387 2-((3S,5R)-3,5-
dimethylpiperazin-1-yl)- 5-(trifluoromethyl) benzaldehyde Method 2
##STR00087## 35 (Z)-5-(2-((3S,5R)-3,5- dimethylpiperazin-1- yl)-3-
methoxybenzylidene) thiazolidine-2,4- dione ##STR00088## 7.87 (brs,
1 H) 7.24 (t, 1 H) 7.20-7.10 (m, 1 H) 7.02 (d, 1 H) 3.81 (s, 3 H)
3.48-3.23 (m, 2 H) 3.17 (t, 2 H) 2.89 (d, 2 H) 1.30-1.09 (m, 6 H)
348 2-((3S,5R)-3,5- dimethylpiperazin-1-yl)- 3-methoxybenzaldehyde
Method 3 ##STR00089## 36 (S,Z)-5-(2-(3- (dimethylamino)
pyrrolidin-1-yl)-3- methoxybenzylidene) thiazolidine-2,4- dione
##STR00090## 7.89 (s, 1 H) 7.26 (m, 1 H) 7.10 (m, 2 H) 3.84 (s, 3
H) 3.41-3.29 (m, 7 H) 3.24-3.13 (m, 4 H) 2.18 (m, 1 H) 1.99 (m, 1
H) 348 (S)-2-(3- (dimethylamino) pyrrolidin-1-yl)-3-
methoxybenzaldehyde Method 4 ##STR00091## 37 (Z)-5-(3-chloro-2-
((3S,5R)-3,5- dimethylpiperazin-1- yl)benzylidene)
thiazolidine-2,4-dione ##STR00092## 7.80 (s, 1 H) 7.50 (brs, 1 H)
7.38 (d, 1 H) 7.30 (brs, 1 H) 3.34-3.02 (m, 6 H) 1.26-1.09 (m, 6 H)
352 3-chloro-2-((3S,5R)-3,5- dimethylpiperazin-1- yl)benzaldehyde
Method 5 ##STR00093## 38 (S,Z)-5-(3-chloro-2- (3- (dimethylamino)
pyrrolidin-1- yl)benzylidene) thiazolidine-2,4-dione ##STR00094##
7.73 (s, 1 H) 7.52-7.47 (m, 2 H) 7.47 (s, 1 H) 7.33-7.31 (m, 1 H)
3.58- 3.52 (m, 1 H) 3.48 (m, 1 H) 3.37-3.27 (m, 3 H) 2.56 (s, 6 H)
2.26-2.35 (m, 1 H) 2.08 (m, 1 H) 352 (S)-3-chloro-2-(3-
(dimethylamino) pyrrolidin-1-yl) benzaldehyde Method 6 ##STR00095##
39 (R,Z)-5-(2-(3- (dimethylamino) pyrrolidin-1-yl)-4,5-
dimethoxybenzylidene) thiazolidine-2,4- dione ##STR00096## 7.75 (s,
1 H) 6.98 (s, 1 H) 6.68 (s, 1 H) 3.83 (s, 3 H) 3.72 (s, 3 H)
3.24-3.06 (m, 4 H) 2.50 (m, 1 H) 2.32 (s, 6 H) 2.12 (m, 1 H) 1.84
(m, 1 H) 378 (R)-2-(3- (dimethylamino) pyrrolidin-1-yl)-4,5-
dimethoxybenzaldehyde Method 7 ##STR00097## 40 (S,Z)-5-(2-(3-
(dimethylamino) pyrrolidin-1-yl)-4,5- dimethoxybenzylidene)
thiazolidine-2,4- dione ##STR00098## 7.76 (s, 1 H) 6.98 (s, 1 H)
6.68 (s, 1 H) 3.83 (s, 3 H) 3.72 (s, 3 H) 3.26-3.01 (m, 5 H) 2.32
(s, 6 H) 2.15-2.09 (m, 1 H) 1.90- 1.81 (m, 1 H) 378 (S)-2-(3-
(dimethylamino) pyrrolidin-1-yl)-4,5- dimethoxybenzaldehyde Method
8 ##STR00099## 41 (5Z)-5-{2-[4- (hydroxymethyl)
piperidin-1-yl]-4,5- dimethoxybenzylidene}- 1-,3-thiazolidine-
2,4-dione ##STR00100## 12.44 (brs, 1 H) 7.94 (s, 1 H) 7.05-6.87 (m,
1 H) 6.80 (s, 1 H) 4.54 (t, 1 H) 3.85 (s, 3H) 3.76 (s, 3 H) 3.17
(d, 1 H) 3.03 (d, 2 H) 2.71 (t, 2 H) 1.75 (brs, 2 H) 1.56-1.26 (m,
3 H) 379 2-(4- (hydroxymethyl) piperidin-1-yl)-4,5-
dimethoxybenzaldehyde Method 9 ##STR00101## 42 (5Z)-5-[2-(4-
hydroxypiperidin-1- dimethoxybenzylidene]- 1,3-thiazolidine-
2,4-dione ##STR00102## 12.50 (brs, 1 H) 8.02 (s, 1 H) 6.99 (s, 1 H)
6.92- 6.82 (m, 1 H) 4.79 (d, 1 H) 3.90 (s, 3 H) 3.82 (s, 3 H)
3.74-3.58 (m, 1 H) 3.13-2.96 (m, 2 H) 2.88- 2.71 (m, 2 H) 2.01-
1.81 (m, 2 H) 1.78-1.58 (m, 2 H) 365 2-(4-hydroxypiperidin-1-
yl)-4,5- dimethoxybenzaldehyde Method 10 ##STR00103## 43
(5Z)-5-{2-[3- (dimethylamino) pyrrolidin-1-yl]-5-
methoxybenzylidene]- 1,3-thiazolidine-2,4- dione ##STR00104## 7.51
(s, 1 H) 7.03 (d, 1 H) 6.99 (d, 1 H) 6.84 (dd, 1 H) 3.72 (s, 3 H)
3.09- 3.21 (m, 1 H) 2.82-3.09 (m, 4 H) 2.23 (s, 6 H) 2.06 (d, 1 H)
1.73-1.85 (m, 1 H) 348 2-(3- (dimethylamino) pyrrolidin-1-yl)-5-
methoxybenzaldehyde Method 11 ##STR00105## 44 (5Z)-5-{2-[4-
(dimethylamino) piperidin-1-yl]-5- methoxybenzylidene]
1,3-thiazolidine-2,4- dione ##STR00106## 7.59 (s, 1 H) 7.11-6.99
(m, 2 H) 6.85 (dd, 1 H) 3.75 (s, 3 H) 3.03 (m, 2 H) 2.64-2.54 (m, 2
H) 2.44-2.33 (m, 7 H) 1.91 (s, 2 H) 1.62 (dd, 2 H) 362 2-(4-
(dimethylamino)piperidin- 1-yl)-5- methoxybenzaldehyde Method 12
##STR00107## 45 (5Z)-5-[2-(3- hydroxypyrrolidin-1- yl)-4,5-
dimethoxybenzylidene]- 1,3-thiazolidine- 2,4-dione ##STR00108##
12.32 (brs, 1 H) 7.88 (s, 1 H) 6.93 (s, 1 H) 6.66 (s, 1 H) 4.34
(brs, 1 H) 3.83 (s, 3 H) 3.72 (s, 3 H) 3.55- 3.29 (m, 3 H) 3.22
(brs, 1 H) 2.90 (d, 1 H) 2.16- 1.94 (m, 1 H) 1.84 (d, 1 H) 351
2-(3-hydroxypyrrolidin- 1-yl)-4,5- dimethoxybenzaldehyde Method 13
##STR00109## 46 (5Z)-5-(4,5- dimethoxy-2- pyrrolidin-1-
ylbenzylidene)-1,3- thiazolidine-2,4- dione ##STR00110## 12.21
(brs, 1 H) 7.86 (s, 1 H) 6.94 (s, 1 H) 6.65 (s, 1 H) 3.83 (s, 3 H)
3.72 (s,3 H) 3.12 (brs, 4 H) 1.90 (brs, 4 H) 335 4,5-dimethoxy-2-
(pyrrolidin-1- yl)benzaldehyde Method 14 ##STR00111## 47
(5Z)-5-{2-[[2- (dimethylamino)ethyl] (methyl)amino]
benzylidene}-1,3- thiazolidine-2,4- dione ##STR00112## 7.62 (s, 1
H) 7.48 (d, 1 H) 7.32 (t, 1 H) 7.17 (d, 1 H) 7.10 (t, 1 H) 3.06 (t,
2 H) 2.86-2.62 (m, 5 H) 2.36 (s, 6 H) 306 2-((2-
(dimethylamino)ethyl) (methyl)amino) benzaldehyde Method 15
##STR00113## 48 (5Z)-5-{2-[3- (dimethylamino) pyrrolidin-1-
yl]benzylidene}-1,3- thiazolidine-2,4- dione ##STR00114## 7.52 (s,
1 H) 7.27-7.21 (m, 1 H) 7.14-7.05 (m, 1 H) 6.84 (d, 1 H) 6.77 (t, 1
H) 3.17 (s, 1 H) 3.16- 3.09 (m, 1 H) 3.06-2.94 (m, 2 H) 2.86-2.77
(m, 1 H) 2.16-2.11 (m, 6 H) 2.03-1.92 (m, 1 H) 1.66 (dd, 1 H) 318
2-(3- (dimethylamino)pyrrolidin- 1-yl)benzaldehyde Method 16
##STR00115## 49 (5Z)-5-{2-[4- (dimethylamino) piperidin-1-
yl]benzylidene}-1,3- thiazolidine-2,4- dione ##STR00116## 7.64 (s,
1 H) 7.50 (d, 1 H) 7.35-7.27 (m, 1 H) 7.12 (t, 2 H) 3.22 (m, 2 H)
2.88 (m, 1 H) 2.68 (t, 2 H) 2.63 (s, 6 H) 2.04 (s, 2 H) 1.73 (td, 2
H) 332 2-(4- (dimethylamino)piperidin- 1-yl)benzaldehyde Method 17
##STR00117## 50 (5Z)-5-[2-(4- isopropylpiperazin-1-
yl)benzylidene]-1,3- thiazolidine-2,4- dione ##STR00118## 7.80 (s,
1 H) 7.49-7.43 (m, 1 H) 7.43-7.39 (m, 1 H) 7.22-7.13 (m, 2 H)
2.99-2.88 (m, 5 H) 2.80 (s, 4 H) 1.13-1.04 (m, 6 H) 332
2-(4-isopropylpiperazin- 1-yl)benzaldehyde Method 18 ##STR00119##
51 (5Z)-5-{2-[[2- (dimethylamino)ethyl] (methyl)amino]-4,5-
dimethoxybenzylidene}- 1,3-thiazolidine- 2,4-dione ##STR00120##
7.78 (s, 1 H) 7.02 (s, 1 H) 6.85 (s, 1 H) 3.83 (s, 3 H) 3.76 (s, 3
H) 3.11-2.98 (m, 2 H) 2.76-2.65 (m, 5 H) 2.37 (s, 6 H) 364 2-((2-
(dimethylamino)ethyl) (methyl)amino)-4,5- dimethoxybenzaldehyde
Method 19 ##STR00121## 52 (5Z)-5-{2-[3- (dimethylamino)
pyrrolidin-1-yl]-4,5- dimethoxybenzylidone- 1,3-thiazolidine-
2,4-dione ##STR00122## 7.76 (s, 1 H), 6.98 (s, 1 H), 6.68 (s, 1 H),
3.83 (s, 3 H), 3.72 (s, 3 H), 3.25 (m, 1 H), 3.13 (m, 2 H), 3.06
(m, 2 H), 2.32 (s, 6 H), 2.15-2.09 (m, 1 H) 1.90-1.81 (m, 1 H) 378
2-(3- (dimethylamino) pyrrolidin-1-yl)-4,5- dimethoxybenzaldehyde
Method 20 ##STR00123## 53 (5Z)-5-{2-(4- isopropylpiperazin-1-
yl)-4,5- dimethoxybenzylidene}- thiazolidine-2,4- dione
##STR00124## 7.86 (s, 1 H) 6.95 (s, 1 H) 6.77 (s, 1 H) 3.81 (s, 3
H) 3.76-3.67 (m, 3 H) 2.91- 2.79 (m, 5 H) 2.71 (s, 4 H) 1.08-1.00
(m, 6 H) 392 2-(4-isopropylpiperazin- 1-yl)-4,5-
dimethoxybenzaldehyde Method 21 ##STR00125## 54 (5Z)-5-{2-(4-
(dimethylamino) piperidin-1-yl)-4,5- dimethoxybenzylidene}-
thiazolidine-2,4- dione ##STR00126## 7.48 (s, 1 H) 6.82 (s, 1 H)
6.51 (s, 1 H) 3.58 (s, 3 H) 3.51 (s, 3 H) 2.87 (d, 2 H) 2.47 (m, 3
H) 2.35 (s, 6 H) 1.79 (d, 2 H) 1.49 (d, 2 H) 392 2-(4-
(dimethylamino)piperidin- 1-yl)-4,5- dimethoxybenzaldehyde Method
22 ##STR00127## 55 (Z)-tert-butyl 4-(2- ((2,4- dioxothiazolidin-5-
ylidene)methyl)-4- (trifluoromethyl) phenyl)piperazine-1-
carboxylate ##STR00128## 12.65 (s, 1 H) 7.82 (s, 1 H) 7.72 (s, 1 H)
7.53 (s, 1 H) 3.59-3.50 (m, 1 H) 3.38-3.30 (m, 4 H) 2.56 (s, 6 H)
2.31-2.28 (m, 1 H) 2.09-2.01 (m, 1 H) 458 tert-butyl 4-(2-formyl-4-
(trifluoromethyl)phenyl) piperazine-1-carboxylate Method 23
##STR00129## 56 (Z)-5-(2-(3- (dimethylamino) pyrrolidin-1-yl)-5-
nitrobenzylidene) thiazolidine-2,4-dione hydrochloride ##STR00130##
12.64 (s, 1 H) 8.22 (d, 1 H) 8.12 (d, 1 H) 7.95 (d, 1 H) 7.04 (d, 1
H) 3.95- 3.90 (m, 1 H) 3.70-3.65 (m, 2 H) 3.56-3.51 (m, 2 H) 2.79
(s, 6 H) 2.41- 2.35 (m, 1 H) 2.34-2.22 (m, 1 H) 363 2-(3-
(dimethylamino) pyrrolidin-1-yl)-5- nitrobenzaldehyde Method 24
##STR00131## 57 (Z)-4-(3- (dimethylamino) pyrrolidin-1-yl)-3-((2,4-
dioxothiazolidin-5- ylidene)methyl) benzamide hydrochloride
##STR00132## 12.47 (s, 1 H) 7.92-7.84 (m, 4 H) 7.23 (s, 1 H) 7.03
(d, 1 H) 3.98-3.91 (m, 1 H) 3.53-3.49 (m, 2 H) 3.46-3.39 (m, 2 H)
2.79 (s, 6 H) 2.34-2.19 (m, 2 H) 361 4-(3- (dimethylamino)
pyrrolidin-1-yl)-3- formylbenzamide Method 25 ##STR00133## 58
(Z)-tert-butyl 4-(2- ((2,4- dioxothiazolidin-5- ylidene)methyl)
phenyl)piperazine-1- carboxylate ##STR00134## 12.55 (s, 1 H) 7.92
(s, 1 H) 7.46-7.44 (m, 2 H) 7.21-7.18 (m, 2 H) 3.48 (brs, 4 H) 2.86
(brs, 4 H) 1.43 (s, 9 H) 389 tert-butyl 4-(2-
formylphenyl)piperazine- 1-carboxylate Method 26 ##STR00135## 59
(Z)-5-(3-methoxy-4- (2-(piperidin-1- yl)ethoxy)benzylidene)
thiazolidine-2,4- dione ##STR00136## 7.78 (s, 1 H) 7.27 (s, 1 H)
7.21 (s, 2 H) 4.47 (t, 2 H) 3.84 (s, 3 H) 3.49 (t, 4 H) 3.04 (brs,
2H) 1.80 (d, 4 H) 1.64 (brs, 1 H) 1.43 (brs, 1 H) 363
3-methoxy-4-(2- (piperidin-1- yl)ethoxy)benzaldehyde Commercial
##STR00137## 60 (Z)-5-(2-(2- hydroxyethoxy) benzylidene)
thiazolidine- 2,4-dione ##STR00138## 12.58 (brs, 1 H) 8.06 (s, 1 H)
7.57-7.32 (m, 2 H) 7.26-7.03 (m, 2 H) 4.95 (brs, 1 H) 4.13 (t, 2 H)
3.77 (brs, 2 H) 266 2-(2- hydroxyethoxy) benzaldehyde Commercial
##STR00139## 61 (Z)-5-(5-methoxy-2- (2-(piperidin-1- yl)ethoxy)
benzylidene) thiazolidine-2,4- dione ##STR00140## 7.80 (s, 1 H)
7.10 (d, 1 H) 7.04-6.95 (m, 2 H) 4.22 (t, 2 H) 3.75 (s, 3 H) 3.07
(t, 2 H) 2.84 (s, 4 H) 1.62 (dq, 4 H) 1.46 (d, 2 H) 363
5-methoxy-2-(2- (piperidin-1- yl)ethoxy)benzaldehyde Method 27
##STR00141## 62 (Z)-5-(5-methoxy-2- (2- morpholinoethoxy)
benzylidene) thiazolidine-2,4-dione ##STR00142## 7.99 (s, 1 H)
7.22-7.10 (m, 1 H) 7.09-6.97 (m, 1 H) 6.91 (d, 1 H) 4.17 (t, 2 H)
3.76 (s, 3 H) 3.64- 3.51 (m, 4 H) 2.75 (t, 2 H) 2.51-2.62 (m, 4 H)
365 5-methoxy-2-(2- morpholinoethoxy) benzaldehyde Method 28
##STR00143## 63 (Z)-5-(2-(2- (diethylamino)ethoxy)-
5-methoxybenzylidene) thiazolidine-2,4- dione ##STR00144## 7.77 (s,
1 H) 7.08-7.05 (m, 1 H) 7.03-6.95 (m, 2 H) 4.19 (t, 2 H) 3.75 (s, 3
H) 3.25-3.14 (m, 2 H) 2.95 (q, 4 H) 1.17-1.08 (m, 6 H) 352 2-(2-
(diethylamino)ethoxy)-5 methoxybenzaldehyde Method 29 ##STR00145##
64 (Z)-5-(2-(2- (diethylamino) ethoxy)benzylidene)
thiazolidine-2,4-dione ##STR00146## 7.84 (s, 1 H) 7.47 (d, 1 H)
7.43-7.35 (m, 1 H) 7.14-7.04 (m, 2 H) 4.24 (t, 2 H) 3.20 (m, 2 H)
2.90 (q, 4 H) 1.13 (t, 6 H) 321 2-(2- (diethylamino)ethoxy)
benzaldehyde Method 30 ##STR00147## 65 (Z)-5-(4,5- dimethoxy-2-
(pyridin-3- yl)benzylidene) thiazolidine-2,4-dione ##STR00148##
12.55 (brs, 1 H) 8.73- 8.61 (m, 1 H) 8.58 (brs, 1 H) 7.81 (dd, 1 H)
7.53 (dd, 1 H) 7.46 (s, 1 H) 7.13 (d, 2 H) 3.89 (d, 6 H) 343
4,5-dimethoxy-2- (pyridin-3- yl)benzaldehyde Method 31 ##STR00149##
66 (Z)-5-(4,5- dimethoxy-2- (pyridin-4- yl)benzylidene)
thiazolidine-2,4-dione ##STR00150## 12.58 (brs, 1 H) 8.67 (d, 2 H)
7.48 (d, 1 H) 7.41 (d, 2 H) 7.12 (d, 2 H) 3.89 (s, 6 H) 343
4,5-dimethoxy-2- (pyridin-4- yl)benzaldehyde Method 32 ##STR00151##
67 (Z)-5-((1H-indol-3- yl)methylene) thiazolidine-2,4-dione
##STR00152## 7.21 (dddd, 2 H) 7.50 (d, 1 H) 7.71 (d, 1 H) 7.87 (d,
1 H) 7.99 (s, 1 H) 12.07 (brs, 2 H) 245 1H-indole-3- carbaldehyde
Commercial ##STR00153## 68 (Z)-5-((1H-indazol-3- yl)methylene)
thiazolidine-2,4-dione ##STR00154## 7.28 (t, 1 H) 7.52-7.39 (m, 1
H) 7.64 (d, 1 H) 8.22-8.03 (m, 2 H) 12.41 (d, 1 H) 13.96 (s, 1 H)
246 1H-indazole-3- carbaldehyde Commercial ##STR00155## 69
(Z)-5-((6-oxo-1,6- dihydropyridin-3- yl)methylene)
thiazolidine-2,4-dione ##STR00156## 11.99 (brs, 1 H) 7.74 (brs, 1
H) 7.69-7.58 (m, 1 H) 7.27 (s, 1 H) 6.43 (d, 1 H) 223 6-oxo-1,6-
dihydropyridine-3- carbaldehyde Commercial ##STR00157## 70
(Z)-5-((2-oxo-1,2- dihydropyridin-3- yl)methylene)
thiazolidine-2,4-dione ##STR00158## 12.43 (brs, 1 H) 12.16 (brs, 1
H) 7.73 (s, 1 H) 7.69 (dd, 1 H) 7.57 (d, 1 H) 6.38 (t, 1 H) 223
2-oxo-1,2- dihydropyridine-3- carbaldehyde Commercial ##STR00159##
71 (Z)-5-((1H-pyrazol-4- yl)methylene) thiazolidine-2,4-dione
##STR00160## 13.51 (brs, 1 H) 12.37 (brs, 1 H) 8.20 (s, 1 H) 7.82
(s, 1 H) 7.74 (s, 1 H) 196 1H-pyrazole-4- carbaldehyde Commercial
##STR00161## 72 (Z)-5-(pyridin-4- ylmethylene)
thiazolidine-2,4-dione ##STR00162## 12.61 (brs, 1 H) 8.71 (d, 2 H)
7.74 (s, 1 H) 7.53 (d, 2 H) 207 4- pyridinecarboxaldehyde
Commercial ##STR00163## 73 (5Z)-5-[(1-methyl- 1H-1,2,3-
benzotriazol-5- yl)methylene]-1,3- thiazolidine-2,4- dione
##STR00164## 12.65 (brs, 1 H) 8.28 (s, 1 H) 8.00-7.98 (m, 2 H) 7.76
(d, 1 H) 4.33 (s, 3 H) 259 1-methyl-1H- benzo[d][1,2,3]triazole-
5-carbaldehyde Commercial ##STR00165## 74 (5Z)-5-(3,4-
dimethoxybenzylidene)- 1,3-thiazolidine- 2,4-dione ##STR00166##
12.51 (brs, 1 H) 7.74 (s, 1 H) 7.19-7.09 (m, 3 H) 3.82 (s,
3 H) 3.80 (s, 3 H) 266 3,4- dimethoxybenzaldehyde Commercial
##STR00167## 75 (5Z)-5-[(1-methyl- 1H-indol-6- yl)methylene]-1,3-
thiazolidine-2,4- dione ##STR00168## 12.49 (brs, 1 H) 7.92 (s, 1 H)
7.68 (d, 1 H) 7.54 (s 1 H) 7.25 (d, 1 H) 6.50 (s, 1 H) 3.84 (s, 3
H) 1-methyl-1H-indole-6- carbaldehyde Commercial ##STR00169## 76
(5Z)-5-[(1-methyl- 1H-indol-5- yl)methylene]-1,3- thiazolidine-2,4-
dione ##STR00170## 12.45 (brs, 1 H) 7.90 (s, 1 H) 7.84 (d, 1 H)
7.59 (d, 1 H) 7.44 (d, 1 H) 7.38 (d 1 H) 6.57 (d, 1 H) 3.82 (s, 3
H) 259 1-methyl-1H-indole-5- carbaldehyde Commercial ##STR00171##
77 (5Z)-5-(quinolin-6- ylmethylene)-1,3- thiazolidine-2,4- dione
trifluoroacetate ##STR00172## 12.70 (brs, 1 H) 8.97 (d, 1 H) 8.51
(d, 1 H) 8.24 (s, 1 H) 8.12 (d, 1 H) 7.96-7.93 (m, 2 H) 7.64- 7.61
(m, 1 H) 257 quinoline-6-carbaldehyde Commercial ##STR00173## 78
(5Z)-5-(1H-indol-5- ylmethylene)-1,3- thiazolidine-2,4- dione
##STR00174## 12.43 (brs, 1 H) 11.44 (brs, 1 H) 7.85 (d, 1 H)
7.53-7.51 (m, 2 H) 7.45- 7.44 (m, 1 H) 7.33 (d, 1 H) 6.56 (s, 1 H)
245 1H-indole-5- carbaldehyde Commercial ##STR00175## 79
(5Z)-5-(1H-indol-6- ylmethylene)-1,3- thiazolidine-2,4- dione
trifluoroacetate ##STR00176## 12.47 (brs, 1 H) 11.48 (brs, 1 H)
7.90 (s, 1 H) 7.69-7.66 (m, 2 H) 7.55- 7.52 (m, 1 H) 7.23 (d, 1 H)
6.51 (s, 1 H) 245 1H-indole-6- carbaldehyde Commercial ##STR00177##
80 (5Z)-5-(1H- pyrrolo[2,3- b]pyridin-5- ylmethylene)-1,3-
thiazolidine-2,4- dione ##STR00178## 12.02 (brs, 1 H) 8.49 (d, 1 H)
8.15 (d, 1 H) 7.92 (s, 1 H) 7.58 (t, 1 H) 6.59 (brs, 1 H) 246
1H-pyrrolo[2,3- b]pyridine-5- carbaldehyde Commercial ##STR00179##
81 (5Z)-5-{2-[3- (dimethylamino) propoxy]benzylidene}-
1,3-thiazolidine-2,4- dione ##STR00180## 8.16 (s, 1 H) 7.76 (s, 1
H) 7.48 (d, 1 H) 7.34 (s, 1 H) 7.08 (d, 1 H) 4.11 (t, 2 H) 2.86 (1,
2 H) 2.53 (s, 6 H) 2.10-1.98 (m, 2 H) 307 2-[3- (dimethylamino)
propoxy]benzaldehyde Commercial ##STR00181## 82
(5Z)-5-(2-morpholin- 4-ylbenzylidene)-1,3- thiazolidine-2,4- dione
##STR00182## 7.89 (s, 1 H) 7.46 (d, 1 H) 7.45-7.41 (m, 1 H)
7.22-7.14 (m, 2 H) 3.80- 3.69 (m, 4 H) 2.93- 2.82 (m, 4 H) 291
2-morpholin-4- ylbenzaldehyde Commercial ##STR00183## 83
(5Z)-5-(3-morpholin- 4-ylbenzylidene)-1,3- thiazolidine-2,4- dione
trifluoroacetate ##STR00184## 12.58 (brs, 1 H) 7.74 (s, 1 H) 7.37
(t, 1 H) 7.12 (s, 1 H) 7.07 (dd, 1 H) 7.00 (d, 1 H) 3.79-3.69 (m, 4
H) 3.20-3.09 (m, 4 H) 290 3-morpholin-4- ylbenzaldehyde Commercial
##STR00185## 84A (5Z)-5-[2-(4- methylpiperazin-1-
yl)benzylidene]-1,3- thiazolidine-2,4- dione ##STR00186## 7.78 (s,
1 H) 7.46 (d, 1 H) 7.42-7.35 (m, 1 H) 7.19-7.11 (m, 2 H) 2.94 (t, 4
H) 2.70 (brs, 4 H) 2.40 (s, 3 H) 304 2-(4-methylpiperazin-1-
yl)benzaldehyde Commercial ##STR00187## 84B (Z)-5-(3-(3-(4-
methylpiperazin-1- yl)propoxy)benzylidene) thiazolidine-2,4- dione
##STR00188## 11.37 (brs, 1 H) 7.54 (s, 1 H) 7.38 (t, 1 H) 7.12 (m,
2 H), 6.96 (m, 1 H) 4.58 (s, 3 H) 4.05 (t, 2 H) 3.00- 2.55 (m, 10
H) 1.93 (m, 2 H) 362 3-(3-(4-methylpiperazin- 1-
yl)propoxy)benzaldehyde hydrochloride ##STR00189## 84C
(Z)-2-(3-((2,4- dioxothiazolidin-5- ylidene)methyl)
phenoxy)acetamide ##STR00190## 12.62 (s, 1 H) 7.73 (s, 1 H) 7.60
(s, 1 H) 7.44 (t, 1 H) 7.41 (s, 1 H) 7.19 (d, 1 H) 7.14 (m, 1 H)
7.05 (dd, 1 H) 4.48 (s, 2 H) 279 2-(3- formylphenoxy)acetamide
##STR00191## 84D (Z)-5-(3-(3- (piperidin-1- yl)propoxy)benzylidene)
thiazolidine-2,4- dione ##STR00192## 7.30 (t, 1 H) 7.24 (s, 1 H)
7.08 (m, 2 H) 6.85 (dd, 1 H) 4.01 (t, 2 H) 2.45 (t, 2 H) 2.40 (m, 4
H) 1.88 (m, 2H) 1.50 (m, 4 H) 1.38 (m, 2 H) 347 3-(3-(piperidin-1-
yl)propoxy)bcnzaldehyde hydrochloride ##STR00193## 84E
(Z)-5-(3-((4- methylpiperazin-1- yl)methyl)benzylidene)
thiazolidine-2,4- dione ##STR00194## 7.59 (s, 1 H) 7.51 (s, 1 H)
7.46 (m, 2 H) 7.34 (m, 1 H) 3.59 (s, 2 H) 2.96 (m, 4 H) 2.59 (m, 4
H) 2.58 (s, 3 H) 318 3-((4-methylpiperazin-1-
yl)methyl)benzaldehyde ##STR00195## 84F (Z)-N-(2- (dimethylamino)
ethyl)-2'-((2,4- dioxothiazolidin-5- ylidene)methyl)-N-
methylbiphenyl-4- sulfonamide ##STR00196## 7.90 (d, 2 H) 7.69 (d, 1
H) 7.65-7.49 (m, 4 H) 7.49-7.40 (m, 1 H) 7.31 (s, 1 H) 3.24 (t, 2
H) 2.83 (t, 2 H) 2.78 (s, 3 H) 2.48 (s, 6 H) 445 N-(2-
(dimethylamino)ethyl)- 2'-formyl-N- methylbiphenyl-4- sulfonamide
Method 32B ##STR00197## 84G (S)-5-(2-(3- (dimethylamino)
pyrrolidin-1-yl)-5- methoxybenzylidene) thiazolidine-2,4- dione
##STR00198## 348 (S)-2-(3- (dimethylamino) pyrrolidin-1-yl)-5-
methoxybenzaldehyde Method 104 ##STR00199## 84H (S)-5-(2-(3-
(dimethylamino) pyrrolidin-1-yl)-5- (trifluoromethyl)
benzylidene)thiazolidine- 2,4-dione ##STR00200## 12.55 (s, 1 H)
11.25 (brs, 1 H) 7.95 (s, 1 H) 7.78 (s, 1 H) 7.60 (m, 1 H), 7.15
(m, 1 H) 4.00 (m, 1 H) 3.65 (m, 2 H) 3.40 (m, 1 H) 3.32 (m, 1 H)
2.80 (s, 6 H) 2.35 (m, 1 H) 2.20 (m, 1 H) 386 (S)-2-(3-
(dimethylamino) pyrrolidin-1-yl)-5- (trifluoromethyl) benzaldehyde
Method 105 ##STR00201## 84I (S)-5-(5-chloro-2-(3- (dimethylamino)
pyrrolidin-1- yl)benzylidene) thiazolidine-2,4-dione ##STR00202##
12.55 (s, 1 H) 7.81 (s, 1H), 7.93 (m, 2H), 7.12 (m, 1H), 3.90 (m,
1H), 3.45-3.30 (m, 2H), 3.29 (m, 1H), 3.15 (m, 1H), 2.80 (s, 6H),
2.35 (m, 1H), 2.20 (m, 1H) 352 (S)-5-chloro-2-(3- (dimcthylamino)
pyrrolidin-1- yl)benzaldehyde Method 106 ##STR00203## 84J
(S)-5-(2-(3- (dimethylamino) pyrrolidin-1-yl)-4- methylbenzylidene)
thiazolidine-2,4-dione ##STR00204## 332 (S)-2-(3- (dimethylamino)
pyrrolidin-1-yl)-4- methylbenzaldehyde Method 107 ##STR00205## 84K
(S)-5-(2-(3- (dimethylamino) pyrrolidin-1-yl)-5- fluorobenzylidene)
thiazolidine-2,4-dione ##STR00206## 12.55 (s, 1 H) 11.40 (s, 1 H)
7.80 (s, 1 H) 7.30- 7.15 (m, 3 H) 3.92 (m, 1 H) 3.45 (m, 1 H) 3.35
(m, 1 H) 3.18 (m, 1 H) 3.15 (m, 1 H) 3.80 (d, 6 H) 2.30 (m, 1 H),
2.20 (m, 1H) 336 (S)-2-(3- (dimethylamino) pyrrolidin-1-yl)-5-
fluorobenzaldehyde Method 108 ##STR00207## 84L (S)-5-(2-(3-
(dimethylamino) pyrrolidin-1-yl)-5- methylbenzylidene)
thiazolidine-2,4-dione ##STR00208## 332 (S)-2-(3- (dimethylamino)
pyrrolidin-1-yl)-5- methylbenzaldehyde Method 109 ##STR00209## 84M
(S)-5-(5-bromo-2-(3- (dimethylamino) pyrrolidin-1- yl)benzylidene)
thiazolidine-2,4-dione ##STR00210## 397 (S)-5-bromo-2-(3-
(dimethylamino) pyrrolidin-1-yl) benzaldehyde Method 110
##STR00211## 84N (S)-5-(2-(3- (dimethylamino) pyrrolidin-1-yl)-3-
fluorobenzylidene) thiazolidine-2,4-dione ##STR00212## 12.55 (s, 1
H) 10.34 (s, 1 H) 7.87 (d, 1H) 7.33-7.21 (m, 3 H) 3.93 (m, 1 H)
3.40 (m, 2 H) 3.25 (m, 1 H) 3.18 (m, 1 H) 2.79 (s, 6 H) 2.26 (m,
1H) 2.12 (m, 1H) 336 (S)-2-(3- (dimethylamino) pyrrolidin-1-yl)-3-
fluorobenzaldehyde Method 111 ##STR00213## 84O
(S)-5-(2-chloro-6-(3- (dimethylamino) pyrrolidin-1- yl)benzylidene)
thiazolidine-2,4-dione ##STR00214## 352 (S)-2-chloro-6-(3-
(dimethylamino) pyrrolidin-1-yl) benzaldehyde Method 112
##STR00215##
Example 85
##STR00216##
[0284]
(S,Z)-5-(2-(3-aminopyrrolidin-1-yl)-4-chlorobenzylidene)thiazolidin-
e-2,4-dione hydrochloride
[0285] A 100 mL round bottom flask was charged with a magnetic stir
bar, (S,Z)-tert-butyl
1-(5-chloro-2-((2,4-dioxothiazolidin-5-ylidene)methyl)phenyl)pyrrolidin-3-
-ylcarbamate (Method 33) (1.300 g, 3.07 mmol), MeOH (10.22 ml), and
a 1N sol'n of HCl in diethyl ether (2.294 ml, 46.00 mmol). The
reaction mixture was allowed to stir overnight at rt before being
conc. in vacuo to afford the product as its hydrochloride salt.
This material was dissolved in DMSO and purified via reverse phase
HPLC to afford fractions that were conc. in vacuo, suspended in
methanol (.about.5 mL) and 1N HCl in diethyl ether (.about.2 mL).
This mixture was conc. in vacuo to afford
(S,Z)-5-(2-(3-aminopyrrolidin-1-yl)-4-chlorobenzylidene)thiazolidine-2,4--
dione hydrochloride (0.710 g, 64.3%). .sup.1H NMR (300 MHz,
DMSO-D6) .delta. ppm 12.51 (s, 1H) 8.36 (s, 2H) 7.85 (s, 1H) 7.35
(d, 1H) 6.96 (dd, 2H) 3.90-3.75 (m, 1H) 3.55-3.47 (m, 1H) 3.40 (dd,
1H) 3.31-3.21 (m, 1H) 3.18-3.10 (m, 1H) 2.29-2.18 (m, 1H) 2.10-1.96
(m, 1H); m/z 325.
[0286] The following examples were prepared by the procedure of
Example 85, using the appropriate starting materials. The following
parent compounds obtained after chromatography may be converted to
their corresponding hydrochloride salt in a manner similar as
described in example 85, or similar procedure.
TABLE-US-00004 Ex. Compound .sup.1H NMR m/z SM 86 (S,Z)-5-(2-(3-
aminopyrrolidin-1- yl)-3- chlorobenzylidene) thiazolidine-2,4-dione
hydrochloride ##STR00217## 12.69 (s, 1 H) 8.35 (brs, 2 H) 7.94 (s 1
H) 7.57 (d, 1 H) 7.41-7.35 (m, 2 H) 3.95-3.88 (m, 1 H) 3.53- 3.26
(m, 4 H) 2.37- 2.31 (m, 1 H) 2.08-2.01 (m, 1 H) 324
(S,Z)-tert-butyl 1-(2- chloro-6-((2,4- dioxothiazolidin-5-
ylidene)methyl)phenyl) pyrrolidin-3-ylcarbamate Method 34
##STR00218## 87 (Z)-5-(2-(piperazin-1- yl)-5- (trifluoromethyl)
benzylidene) thiazolidine- 2,4-dione hydroehloride ##STR00219##
12.69 (s, 1 H) 9.32 (brs, 2 H) 7.79 (d, 1 H) 7.71 (d, 2 H) 7.37 (d,
1 H) 3.23 (s, 8 H) 358 (Z)-tert-butyl 4-(2-((2,4-
dioxothiazolidin-5- ylidene)methyl)-4- (trifluoromethyl)phenyl)
piperazine-1-carboxylate Method 35 ##STR00220## 88 (S,Z)-5-(2-(3-
aminopyrrolidin-1- yl)-5- (trifluoromethyl) benzylidene)
thiazolidine- 2,4-dione hydrochloride ##STR00221## 12.53 (s, 1 H)
8.17 (brs, 2 H) 7.95 (s, 1 H) 7.65 (s, 1 H) 7.59 (d 1 H) 7.05 (d, 1
H) 3.90-3.81 (m, 1 H) 3.56 (q, 1 H) 3.47-3.35 (m, 2 H) 3.18 (dd, 1
H) 2.33-2.18 (m, 1 H) 2.09- 1.99 (m, 1 H) 358 (S,Z)-tert-butyl
1-(2- ((2,4-dioxothiazolidin-5- ylidene)methyl)-4-
(trifluoromethyl)phenyl) pyrrolidin-3-ylcarbamate Method 36
##STR00222## 89 (Z)-5-((2-(piperazin- 1-yl)pyridin-3- yl)methylene)
thiazolidine-2,4-dione hydrochloride ##STR00223## 12.65 (s, 1 H)
8.39 (s, 1 H) 8.33 (d, 1 H) 7.83 (d, 1 H) 7.63 (s, 1 H) 7.15 (dd, 1
H) 3.41 (brs, 4 H) 3.17 (brs, 4 H) 291 (Z)-tert-butyl 4-(3-((2,4-
dioxothiazolidin-5- ylidene)methyl)pyridin- 2-yl)piperazine-1-
carboxylate Method 37 ##STR00224## 90 (Z)-5-((2-(4-(3-
aminopropanoyl) piperazin-1-yl)pyridin-3- yl )methylene)
thiazolidine-2,4-dione trifluoroacetate ##STR00225## 12.60 (s, 1 H)
8.32 (d, 1 H) 7.82 (s, 1 H) 7.68 (s, 1 H) 7.63 (brs, 2 H) 7.12 (dd,
1 H) 3.57 (d, 4 H) 3.17 (d, 4 H) 3.00 (q, 2 H) 2.70 (t, 2 H) 362
(Z)-tert-butyl 3-(4-(3- ((2,4-dioxothiazolidin-5-
ylidene)methyl)pyridin- 2-yl)piperazin-1-yl)-3- oxopropylcarbamate
Method 38 ##STR00226## 91 (Z)-5-(2-(4- (piperidine-4-
carbonyl)piperazin-1- yl)benzylidene) thiazolidine-2,4-dione
##STR00227## 9.00 (brs, 1 H) 8.67 (brs, 1 H) 8.18 (s, 1 H) 7.57-
7.52 (m, 1 H) 7.30-7.16 (m, 1 H) 3.71 (s, 1 H) 3.63 (s, 1 H) 3.34
(s, 3 H) 3.31-3.22 (m, 2 H) 3.13 (s, 3 H) 3.01-2.87 (m, 5 H)
1.85-1.77 (m, 4 H) 401 (Z)-tert-butyl 4-(4-(2-
((2,4-dioxothiazolidin-5- ylidene)methyl)phenyl) piperazine-1-
carbonyl)piperidine-1- carboxylate Method 39 ##STR00228## 92
(Z)-5-(2-(4- (piperidine-3- carbonyl)piperazin-1- yl)-5-
(trifluoromethyl) benzylidene) thiazolidine- 2,4-dione
hydrochloride ##STR00229## 12.68 (s, 1 H) 8.87 (s, 1 H) 7.78-7.69
(m, 3 H) 7.32 (d, 1 H) 3.68-3.64 (m, 8 H) 3.38 (tt, 1 H) 3.13-2.98
(m, 4 H) 1.75- 1.56 (m, 4 H) 469 (Z)-tert-butyl 3-(4-(2-
((2,4-dioxothiazolidin-5- ylidene)methyl)-4-
(trifluoromethyl)phenyl) piperazine-1- carbonyl)piperidine-1-
carboxylate Method 40 ##STR00230## 93 (Z)-5-(2-(4-(3-
aminopropanoyl) piperazin-1-yl)-5- (trifluoromethyl) benzylidene)
thiazolidine- 2,4-dione hydrochloride ##STR00231## 12.67 (s 1 H)
7.93 (brs, 2 H) 7.78-7.68 (m, 3 H) 7.32 (d, 1 H) 3.69-3.59 (m, 8 H)
3.00-2.74 (m, 4 H) 429 (Z)-tert-butyl 3-(4-(2-
((2,4-dioxothiazolidin-5- ylidene)methyl)-4-
(trifluoromethyl)phenyl) piperazin-1-yl)-3- oxopropylcarbamate
Method 41 ##STR00232## 94 (Z)-5-(2-(4-(3- aminopropanoyl)
piperazin-1-yl)-3- methoxybenzylidene) thiazolidine-2,4- dione
hydrochloride ##STR00233## 12.53 (brs, 1 H) 8.21 (s, 1 H), 7.58
(brs, 3 H), 7.24 (t, 1 H) 7.11 (d, 1 H) 7.00 (d, 1 H) 3.75 (s, 3 H)
3.35 (brs, 4 H) 3.09- 2.85 (m, 4 H) 2.65 (brs, 2 H) 391
(Z)-tert-butyl 3-(4-(2- ((2,4-dioxothiazolidin-5-
ylidene)methyl)-6- methoxyphenyl) piperazin-1-yl)-3-
oxopropylcarbamate Method 42 ##STR00234## 95 (Z)-5-(2-(4-(3-
aminopropanoyl) piperazin-1-yl)-3- chlorobenzylidene)
thiazolidine-2,4-dione hydrochloride ##STR00235## 12.69 (brs, 1 H)
8.12 (s, 1 H) 7.67 (brs, 2 H) 7.55 (dd, 1 H) 7.49-7.40 (m, 1 H)
7.35 (t, 1 H) 4.17 (brs, 1 H) 3.75 (brs, 1 H) 3.35 (brs, 3 H) 3.13-
2.84 (m, 5 H) 2.74 (brs, 2 H) 395 (Z)-tert-butyl 3-(4-(2-
chloro-6-((2,4- dioxothiazolidin-5- ylidene)methyl)phenyl)
piperazin-1-yl)-3- oxopropylcarbamate Method 43 ##STR00236## 96
(S,Z)-5-(2-(3- aminopyrrolidin-1- yl)-3- methoxybenzylidene)
thiazolidine-2.4- dione hydrochloride ##STR00237## 12.43 (s, 1 H)
7.94 (s, 1 H) 7.86 (brs, 1 H) 7.16 (t, 1 H) 7.05 (d, 1 H) 6.91 (d,
1 H) 3.71 (s, 3 H) 3.30 (dd, 1 H) 3.17-3.08 (m, 1 H) 3.08-2.91 (m,
2 H) 2.23-2.06 (m, 2 H), 1.80-1.75 (m, 1 H) 320 (S,Z)-tert-butyl
1-(2- ((2,4-dioxothiazolidin-5- ylidene)methyl)-6- methoxyphenyl)
pyrrolidin-3-ylcarbamate Method 44 ##STR00238## 97
(Z)-5-(3-methoxy-2- (piperazin-1- yl)benzylidene)
thiazolidine-2,4-dione hydrochloride ##STR00239## 12.45 (brs, 1 H)
8.59 (brs, 1 H) 7.99 (s, 1 H) 7.15 (t, 1 H) 7.02 (d, 1 H) 6.89 (d,
1 H) 3.67 (s, 3 H) 3.17-2.99 (m, 8 H) 320 (Z)-tert-butyl
4-(2-((2,4- dioxothiazolidin-5- ylidene)methyl)-6- methoxyphenyl)
piperazine-1-carboxylate Method 45 ##STR00240## 98
(Z)-5-(3-chloro-2- (piperazin-1- yl)benzylidene)
thiazolidine-2,4-dione hydrochloride ##STR00241## 12.72 (brs, 1 H)
9.19 (brs, 1 H) 8.01 (s, 1 H) 7.57 (dd, 1 H) 7.50-7.40 (m, 1 H)
7.36 (t, 1 H) 3.60 (brs, 2 H), 3.51- 3.29 (m, 1 H) 3.29-3.12 (m, 2
H) 3.06 (brs, 3 H) 324 (Z)-tert-butyl 4-(2- chloro-6-((2,4-
dioxothiazolidin-5- ylidene)methyl)phenyl) piperazine-1-carboxylate
Method 46 ##STR00242## 99 (Z)-5-(2-(3- (aminomethyl)pyrrolidin-
1-yl)-4,5- dimethoxybenzylidene) thiazolidine-2,4- dione
hydrochloride ##STR00243## 12.40 (s, 1 H) 9.25 (s, 1 H) 7.88 (s, 1
H) 6.97 (s, 1 H) 6.73 (s, 1 H) 3.85 (s, 3 H) 3.81 (m, 1 H) 3.74 (s,
3 H) 3.40-3.31 (m, 2 H) 3.25-3.13 (m, 2 H) 2.59 (t, 3 H) 2.31 (dd,
1 H) 2.08 (d, 1 H) 364 (Z)-tert-butyl (1-(2-((2,4-
dioxothiazolidin-5- ylidene)methyl)-4,5- dimethoxyphenyl)
pyrrolidin-3- yl)methylcarbamate Method 47 ##STR00244## 100
(R,Z)-5-(2-(3- aminopyrrolidin-1- yl)-4,5- dimethoxybenzylidene)
thiazolidine-2,4- dione hydrochloride ##STR00245## 12.39 (s, 1 H)
8.06 (s, 2 H) 7.89 (s, 1 H) 6.96 (s, 1 H) 6.65 (s, 1 H) 3.84 (s, 4
H) 3.73 (s, 3 H) 3.35 (d, 2 H) 3.20 (s, 1 H) 3.07 (d, 1 H) 2.28 (s,
1 H) 1.97 (s, 1 H) 350 (R,Z)-tert-butyl 1-(2-
((2,4-dioxothiazolidin-5- ylidene)methyl)-4,5- dimethoxyphenyl)
pyrrolidin-3-ylcarbamate Method 48 ##STR00246## 101 (S,Z)-5-(2-(3-
aminopyrrolidin-1- yl)-4,5- dimethoxybenzylidene) thiazolidine-2,4-
dione hydrochloride ##STR00247## 12.39 (s, 1 H) 8.08 (s, 2 H) 7.89
(s, 1 H) 6.96 (s, 1 H) 6.65 (s, 1 H) 3.84 (s, 4 H) 3.73 (s, 3 H)
3.45- 3.30 (m, 2 H) 3.24-3.14 (m, 1 H) 3.12-3.00 (m, 1 H) 2.28 (s,
1 H) 1.98 (s, 1H) 350 (S,Z)-tert-butyl 1-(2-
((2,4-dioxothiazolidin-5- ylidene)methyl)-4,5- dimethoxyphenyl)
pyrrolidin-3- ylcarbamate Method 49 ##STR00248## 102 (Z)-5-(2-(4-
(piperidine-3- carbonyl)-1,4- diazepan-1- yl)benzylidene)
thiazolidine-2,4-dione hydrochloride ##STR00249## 12.49 (s, 1 H)
8.47 (s, 1 H) 7.82 (d, 1 H) 7.39- 7.30 (m, 2 H) 7.16 (dd, 1 H) 7.06
(td, 1 H) 3.63- 3.54 (m, 4 H) 3.29-3.06 (m, 9 H) 1.88-1.48 (m, 6H)
415 (Z)-tert-butyl 3-(4-(2- ((2,4-dioxothiazolidin-5-
ylidene)methyl)phenyl)- 1,4-diazepane-1- carbonyl)piperidine-1-
carboxylate Method 50 ##STR00250## 103 (Z)-5-(2-(4-(5-
aminopentanoyl)-1,4- diazepan-1- yl)benzylidene)
thiazolidine-2,4-dione hydrochloride ##STR00251## 12.57 (s, 1 H)
7.90 (d, 1 H) 7.76 (s, 2 H) 7.47- 7.36 (m, 2 H) 7.22 (t, 1 H) 7.12
(d, 1 H) 3.63 (d, 4 H) 3.22 (s, 1 H) 3.17 (s, 1 H) 3.05 (s, 2 H)
2.80 (s, 2 H) 2.41 (s, 1 H) 2.34 (s, 1 H) 1.91 (s, 1 H) 1.85 (s, 1
H) 1.57 (d, 4 H) 403 (Z)-tert-butyl 5-(4-(2-
((2,4-dioxothiazolidin-5- ylidene)methyl)phenyl)-
1,4-diazepan-1-yl)-5- oxopentylcarbamate Method 51 ##STR00252## 104
(Z)-5-(2-(4-(4- aminobutanoyl)-1,4- diazepan-1- yl)benzylidene)
thiazolidine-2,4-dione hydrochloride ##STR00253## 12.49 (s, 1 H)
7.83 (d, 1 H) 7.65 (s, 2 H) 7.39- 7.30 (m, 2 H) 7.20-7.12 (m, 1 H)
7.09-7.01 (m, 1 H) 3.61-3.50 (m, 4 H) 3.18-3.07 (m, 2 H) 2.98 (d, 2
H) 2.77 (ddd, 2 H) 2.37 (t, 2 H) 1.85-1.66 (m, 4 H). 389
(Z)-tert-butyl 4-(4-(2- ((2,4-dioxothiazolidin-5-
ylidene)methyl)phenyl)- 1,4-diazepan-1-yl)-4- oxobutylcarbamate
Method 52 ##STR00254## 105 (Z)-5-(2-(4-(3- aminopropanoyl)-1,4-
diazepan-1- yl)benzylidene) thiazolidine-2,4-dione hydrochloride
##STR00255## 12.50 (s, 1 H) 7.83 (s, 1 H) 7.63 (s, 2 H) 7.39- 7.31
(m, 2 H) 7.16 (dd, 1 H) 7.10-7.01 (m, 1 H) 3.64-3.52 (m, 4 H) 3.20-
3.09 (m, 2 H) 2.97 (dt, 4 H) 2.65 (dt, 2 H) 1.87- 1.81 (m, 2 H) 375
(Z)-tert-butyl 3-(4-(2- ((2,4-dioxothiazolidin-5-
ylidene)methyl)phenyl)- 1,4-diazepan-1-yl)-3- oxopropylcarbamate
Method 53 ##STR00256## 106 (Z)-5-(2-(1,4- diazepan-1-
yl)benzylidene) thiazolidine-2,4-dione hydrochloride ##STR00257##
12.57 (s, 1 H) 9.31 (s, 1 H) 7.91 (s, 1 H) 7.46- 7.40 (m, 2 H) 7.26
(d, 1 H) 7.18-7.09 (m, 1 H) 3.36 (d, 2 H) 3.27 (d, 4 H) 3.19 (dd, 2
H) 2.10- 2.01 (m, 2 H) 304 (Z)-tert-butyl 4-(2-((2,4-
dioxothiazolidin-5- ylidene)methyl)phenyl)- 1,4-diazepane-1-
carboxylate Method 54 ##STR00258## 107 (Z)-5-(2-(4-(4-
aminobutanoyl) piperazin-1- yl)benzylidene) thiazolidine-2,4-dione
hydrochloride ##STR00259## 12.60 (s, 1 H) 7.95 (s, 4 H) 7.53-7.44
(m, 2 H) 7.26-7.17 (m, 2 H) 3.66- 3.57 (m, 5 H) 2.89 (m, 4 H)
2.85-2.76 (m, 3 H) 1.85-1.76 (m, 2 H) 375 (Z)-tert-butyl 4-(4-(2-
((2,4-dioxothiazolidin-5- ylidene)methyl)phenyl) piperazin-1-yl)-4-
oxobutylcarbamate Method 55 ##STR00260## 108 (Z)-5-(2-(4-(5-
aminopentanoyl) piperazin-1- yl)benzylidene) thiazolidine-2,4-dione
hydrochloride ##STR00261## 12.66 (s, 1 H) 8.10 (s, 2 H) 7.99 (s, 1
H) 7.52 (s, 1 H) 7.51-7.47 (m, 1 H) 7.25 (t, 2 H) 3.67 (s, 4 H)
2.92-2.81 (m, 6 H) 2.44 (t, 2 H) 1.62 (s, 4 H) 389 (Z)-tert-butyl
5-(4-(2- ((2,4-dioxothiazolidin-5- ylidene)methyl)phenyl)
piperazin-1-yl)-5- oxopentylcarbamate Method 56 ##STR00262## 109
(Z)-5-(2-(4-(4- (piperazin-1- ylmethyl)benzoyl) piperazin-1-
yl)benzylidene) thiazolidine-2,4-dione hydrochloride ##STR00263##
12.57 (brs, 1 H) 9.70 (brs, 1 H) 7.94 (s, 1 H) 7.75 (d, 2 H) 7.52
(m, 2 H) 7.49-7.41 (m, 2 H) 7.21 (t, 2 H) 4.45 (brs, 2 H) 3.81
(brs, 2 H) 3.54- 3.35 (m, 8 H) 3.27 (brs, 2 H) 2.89 (brs, 4 H) 492
(Z)-tert-butyl 4-(4-(4-(2- ((2,4-dioxothiazolidin-5-
ylidene)methyl)phenyl) piperazine-1- carbonyl)benzyl)piperazine-
1-carboxylate Method 57 ##STR00264## 110 (Z)-5-(2-(4-(3-
(aminomethyl) benzoyl)piperazin-1- yl)benzylidene)
thiazolidine-2,4-dione hydrochloride ##STR00265## 12.56 (s, 1 H)
8.18 (brs, 2 H) 7.95 (s, 1 H) 7.64- 7.38 (m, 6 H) 7.36-7.11 (m, 2
H) 4.19-4.02 (m, 2 H) 3.82 (brs, 2 H) 3.52 (brs, 2 H) 2.92 (brs, 4
H) 423 (Z)-tert-butyl 3-(4-(2- ((2,4-dioxothiazolidin-5-
ylidene)methyl)phenyl) piperazine-1- carbonyl)benzylcarbamate
Method 58 ##STR00266## 111 (Z)-5-(2-(3-(2- aminoethylamino)
pyrrolidin-1-yl)-4,5- dimethoxybenzylidene) thiazolidine-2,4- dione
hydrochloride ##STR00267## 12.38 (s, 1 H) 9.99 (s, 1 H) 8.44 (s, 2
H) 7.86 (s, 1 H) 6.96 (s, 1 H) 6.76 (s, 1 H) 3.93 (s, 1 H) 3.84 (s,
3 H) 3.73 (s, 3 H) 3.45- 3.33 (m, 2 H) 3.28-3.16 (m, 6 H) 2.32 (s,
1 H) 2.15 (s, 1 H) 393 (Z)-tert-butyl 2-(1-(2-
((2,4-dioxothiazolidin-5- ylidene)methyl)-4,5- dimethoxyphenyl)
pyrrolidin-3- ylamino)ethylcarbamate Method 59 ##STR00268## 112
(Z)-5-(2-(4-(2- aminoethyl)piperazin- 1-yl)benzylidene)
thiazolidine-2,4-dione hydrochloride ##STR00269## 12.70 (s, 1 H)
11.43 (s, 1 H) 8.38 (s, 3 H) 7.86 (s, 1 H) 7.49 (m, 2 H) 7.25 (m, 2
H) 3.67 (m, 2 H) 3.42- 3.30 (m, 8 H) 333 (Z)-tert-butyl 2-(4-(2-
((2,4-dioxothiazolidin-5- ylidene)methyl)phenyl) piperazin-1-
yl)ethylcarbamate Method 60 ##STR00270## 113 (Z)-5-(4,5-
dimethoxy-2-(3-(2- (methylamino) ethylamino)pyrrolidin-1-
yl)benzylidene) thiazolidine-2,4-dione hydrochloride ##STR00271##
12.39 (s, 1 H) 9.93 (brs, 1 H) 9.42 (brs, 1 H) 7.87 (s, 1 H) 6.98
(s, 1 H) 6.77 (s, 1 H) 4.00-3.91 (m, 1 H) 3.85 (s, 3 H) 3.74 (s, 3
H) 3.44-3.16 (m, 8 H) 2.62 (s, 3H) 2.40-2.31 (m, 1 H) 2.20-2.14 (m,
1 H) 407 (Z)-tert-butyl 2-(1-(2- ((2,4-dioxothiazolidin-5-
ylidene)methyl)-4,5- dimethoxyphenyl) pyrrolidin-3-
ylamino)ethyl)methyl) carbamate Method 61 ##STR00272## 114
(Z)-5-(2-(4-(2- (methylamino)ethyl) piperazin-1- yl)benzylidene)
thiazolidine-2,4-dione hydrochloride ##STR00273## 12.62 (s, 1 H)
11.28 (s, 1 H) 9.28 (s, 1 H) 7.87 (s, 1 H) 7.50 (t, 1 H) 7.26 (t, 1
H) 3.71 (m, 4 H) 3.57 (m, 2 H) 3.45 (m, 2 H) 3.26 (m, 4 H) 2.62 (s,
3 H) 347 (Z)-tert-butyl 2-(4-(2- ((2,4-dioxothiazolidin-5-
ylidene)methyl)phenyl) piperazin-1- yl)ethyl)methyl)carbamate
Method 62 ##STR00274## 115 (5Z)-5-(2-piperazin-
1-ylbenzylidene)-1,3- thiazolidine-2,4- dione hydrochloride
##STR00275## 12.61 (s, 1 H) 9.21 (s, 1 H) 7.86 (s, 1 H) 7.49 (t, 2
H) 7.24 (t, 2 H), 3.25 (s, 4 H) 3.12 (s, 4 H) 290
tert-butyl-4-{2-[(Z)-(2,4- dioxo-1,3-thiazolidin-5-
ylidene)methyl]phenyl} piperazine-1-carboxylate Example 58
##STR00276## 116 5-(2-(4-(piperidine-3- carbonyl)piperazin-1-
yl)benzylidene) thiazolidine-2,4-dione hydrochloride ##STR00277##
12.60 (s, 1 H) 9.10 (s, 1 H) 8.90 (s, 1 H) 7.94 (s, 1 H) 7.51-7.43
(m, 1 H) 7.21 (t, 2 H) 5.14 (m, 4 H) 3.67 (m, 3 H) 3.17 (m, 2 H)
2.91-2.88 (m, 4 H) 1.86 (s, 1 H) 1.81-1.71 (m, 2 H) 1.57 (d, 1 H)
401 tert-butyl 3-(4-(2-((2,4- dioxothiazolidin-5-
ylidene)methyl)phenyl) piperazine-1- carbonyl)piperidine-1-
carboxylate Method 63 ##STR00278## 117 (5Z)-5-{2-[4- (azetidin-3-
ylcarbonyl)piperazin- 1-yl]benzylidene}- 1,3-thiazolidine-2,4-
dione hydrochloride ##STR00279## 12.59 (s, 1 H) 9.15 (s, 1 H) 8.86
(s, 1 H) 7.93 (s, 1 H) 7.47 (ddd, 2 H) 7.25- 7.16 (m, 1 H)
4.15-4.05 (m, 4 H) 4.01-3.91 (m, 1 H) 3.71 (m, 2 H) 3.42 (s, 2 H)
2.89 (d, 4 H) 373 tert-butyl 3-(4-(2-((2,4- dioxothiazolidin-5-
ylidene)methyl)phenyl) piperazine-1- carbonyl)azetidine-1-
carboxylate Method 64 ##STR00280##
118 (5Z)-5-[2-(3- aminopyrrolidin-1- yl)-4,5-
dimethoxybenzylidene]- 1,3-thiazolidine- 2,4-dione hydrochloride
##STR00281## 12.38 (s, 1 H) 8.34 (s, 2 H) 7.90 (s, 1 H) 6.96 (s, 1
H) 6.68 (s, 1 H) 3.89- 3.80 (m, 4 H) 3.73 (s, 3 H) 3.46-3.34 (m, 2
H) 3.23-3.13 (m, 1 H) 3.10 (dd, 1 H) 2.28 (dd, 1 H) 2.01 (d, 1 H)
351 tert-butyl 1-(2-((2,4- dioxothiazolidin-5- ylidene)methyl)-4,5-
dimethoxyphenyl) pyrrolidin-3-ylcarbamate Method 65 ##STR00282##
119 (R,Z)-5-amino-N-(1- (2-((2,4- dioxothiazolidin-5-
ylidene)methyl)-4,5- dimethoxyphenyl) pyrrolidin-3- yl)pentanamide
hydrochloride ##STR00283## 12.24 (s, 1 H) 8.07 (d, 1 H) 7.79 (s, 1
H) 7.60 (brs, 2 H) 6.88 (s, 1 H) 6.55 (s, 1 H) 4.22 (d, 1 H) 3.76
(s, 3 H) 3.65 (s, 3 H) 3.30-3.15 (m, 2 H) 3.15-2.98 (m, 1 H) 2.86
(dd, 1 H) 2.70 (d, 2 H) 2.17-1.92 (m, 3 H) 1.76 (brs, 1 H)
1.52-1.25 (m, 4 H) 449 (R,Z)-tert-butyl 5-(1-(2-
((2,4-dioxothiazolidin-5- ylidene)methyl)-4,5- dimethoxyphenyl)
pyrrolidin-3-ylamino)-5- oxopentylcarbamate Method 66 ##STR00284##
120 (S,Z)-5-amino-N-(1- (2-((2,4- dioxothiazolidin-5-
ylidene)methyl)-4,5- dimethoxyphenyl) pyrrolidin-3- yl)pentanamide
hydrochloride ##STR00285## 12.24 (s, 1 H) 8.07 (d, 1 H) 7.79 (s, 1
H) 7.60 (brs, 2 H) 6.88 (s, 1 H) 6.55 (s, 1 H) 4.22 (d, 1 H) 3.76
(s, 3 H) 3.65 (s, 3 H) 3.30-3.15 (m, 2 H) 3.15-2.98 (m, 1 H) 2.86
(dd, 1 H) 2.70 (d, 2 H) 2.17-1.92 (m, 3 H) 1.76 (brs, 1 H)
1.52-1.25 (m, 4 H) 449 (S,Z)-tert-butyl 5-(1-(2-
((2,4-dioxothiazolidin-5- ylidene)methyl)-4,5- dimethoxyphenyl)
pyrrolidin-3-ylamino)-5- oxopentylcarbamate Method 67 ##STR00286##
121 (S,Z)-5-(2-(3-(3- aminopropylamino) pyrrolidin-1-yl)-4,5-
dimethoxybenzylidene) thiazolidine-2,4- dione hydrochloride
##STR00287## 12.50 (s, 1 H) 9.78 (s, 1 H) 7.92 (s, 1 H) 7.05 (s, 1
H) 6.85 (s, 1 H) 4.21- 4.11 (m, 1 H) 3.93 (s, 3 H) 3.83 (s, 3 H)
3.42- 3.25 (m, 8 H) 2.45 (m, 1 H) 2.20 (m, 1 H) 1.32 (m, 2 H) 407
(S,Z)-tert-butyl 3-(1-(2- ((2,4-dioxothiazolidin-5-
ylidene)methyl)-4,5- dimethoxyphenyl) pyrrolidin-3-
ylamino)propylcarbamate Method 68 ##STR00288## 122A
(R,Z)-5-(2-(3-(3- aminopropylamino) pyrrolidin-1-yl)-4,5-
dimethoxybenzylidene) thiazolidine-2,4- dione hydrochloride
##STR00289## 12.44 (s, 1 H) 9.78 (s, 1 H) 7.92 (s, 1 H) 7.05 (s, 1
H) 6.85 (s, 1 H) 4.21- 4.11 (m, 1 H) 3.93 (s, 3 H) 3.83 (s, 3 H)
3.42- 3.25 (m, 8 H) 2.45 (m, 1 H) 2.20 (m, 1 H) 1.32 (m, 2 H) 407
(R,Z)-tert-butyl 3-(1-(2- ((2,4-dioxothiazolidin-5-
ylidene)methyl)-4,5- dimethoxyphenyl) pyrrolidin-3-
ylamino)propylcarbamate Method 69 ##STR00290## 122B (R,Z)-5-(2-(3-
(aminomethyl) pyrrolidin-1-yl)-3- chlorobenzylidene)
thiazolidine-2,4-dione ##STR00291## (400 MHz, MeOD) ppm 8.08 (s, 1
H) 7.49 (dd, 2 H) 7.31 (t, 1 H) 3.56 (t, 1 H) 3.42-3.51 (m, 1 H)
3.38 (td, 1 H) 3.09-3.15 (m, 2 H) 2.71-2.78 (m, 1 H) 2.26-2.36 (m,
1 H) 1.86-1.96 (m, 1 H) 1.31 (dd, 1 H) 338 (R,Z)-tert-butyl (1-(2-
chloro-6-((2,4- dioxothiazolidin-5- ylidene)methyl)phenyl)
pyrrolidin-3- yl)methylcarbamate Method 132 ##STR00292## 122C
(S,Z)-5-(2-(3- (aminomethyl) pyrrolidin-1-yl)-3- chlorobenzylidene)
thiazolidine-2,4-dione ##STR00293## (400 MHz, MeOD) ppm 8.07 (s, 1
H) 7.49 (dd, 2 H) 7.31 (t, 1 H) 3.56 (t, 1 H) 3.42-3.51 (m, 2 H)
3.38 (td, 1 H) 3.07-3.16 (m, 2 H) 2.67-2.79 (m, 1 H) 2.24-2.36 (m,
1 H) 1.90 (dd, 1 H) 338 (S,Z)-tert-butyl (1-(2- chloro-6-((2,4-
dioxothiazolidin-5- ylidene)mcthyl)phenyl) pyrrolidin-3-
yl)methylcarbamate Method 133 ##STR00294## 122D (R,Z)-5-(2-(3-
aminopiperidin-1-yl)- 3-chlorobenzylidene) thiazolidine-2,4-dione
hydrochloride ##STR00295## 12.70 (s, 1 H) 8.17 (brs, 3 H) 8.01 (s,
1 H) 7.52 (d, 1 H) 7.41-7.31 (m, 2 H) 3.40-3.10 (m, 4 H) 2.84- 2.81
(m, 1 H) 2.12-2.10 (m, 1 H) 1.80-1.58 (m, 3 H) 338 (R,Z)-tert-butyl
1-(2- chloro-6-((2,4- dioxothiazolidin-5- ylidene)methyl)phenyl)
piperidin-3-ylcarbamate Method 134 ##STR00296## 122E (R,Z)-5-(2-(3-
aminopiperidin-1-yl)- 3-methoxybenzylidene) thiazolidine-2,4- dione
hydrochloride ##STR00297## 12.60 (s, 1 H) 8.12 (brs, 4 H) 7.28-7.02
(m, 3 H) 3.82 (s, 3 H) 3.18-2.87 (m, 5 H) 2.10-2.07 (m, 1 H)
1.75-1.38 (m, 3 H) 334 (R,Z)-tert-butyl 1-(2-
((2,4-dioxothiazolidin-5- ylidene)methyl)-6-
methoxyphenyl)piperidin- 3-ylcarbamate Method 135 ##STR00298## 122F
(R,Z)-5-(2-(3- aminopiperidin-1-yl)- 3-bromobenzylidene)
thiazolidine-2,4-dione hydrochloride ##STR00299## 12.70 (s, 1 H)
8.15 (brs, 3 H) 8.01 (s, 1 H) 7.74- 7.69 (m, 1 H) 7.46 (d, 1 H)
7.26 (t, 1 H) 3.27-2.99 (m, 4 H) 2.82-2.80 (m, 1 H) 2.12-2.10 (m, 1
H) 1.76-1.40 (m, 3 H) 383 (R,Z)-tert-butyl 1-(2- bromo-6-((2,4-
dioxothiazolidin-5- ylidene)methyl)phenyl) piperidin-3-ylcarbamate
Method 136 ##STR00300## 122G (R,Z)-5-(2-(3- aminopyrrolidin-1-
yl)-3- chlorobrnzylidene) thiazolidine-2,4-dione hydrochloride
##STR00301## 12.67 (brs, 1 H) 8.30 (brs, 3 H) 7.93 (s, 1 H) 7.55
(d, 1 H) 7.41-7.31 (m, 2 H) 3.87 (brs, 1 H) 3.50-3.27 (m, 4 H)
2.40- 2.28 (m, 1 H) 2.08-1.95 (m, 1 H) 324 (R,Z)-tert-butyl 1-(2-
chloro-6-((2,4- dioxothiazolidin-5- ylidene)methyl)phenyl)
pyrrolidin-3-ylcarbamate Method 137 ##STR00302## 122H
(S,Z)-5-(2-(3- aminopyrrolidin-1- yl)-3- bromobenzylidene)
thiazolidine-2,4-dione hydrochloride ##STR00303## 12.68 (brs, 1 H)
8.31 (brs, 3 H) 7.90 (s, 1 H) 7.75 (d, 1 H) 7.46 (d, 1 H) 7.29 (t,
1 H) 3.75 (brs, 1 H) 3.55 (t, 1 H) 3.38- 3.25 (m, 3 H) 2.40-2.32
(m, 1 H) 2.12-2.02 (m, 1 H) 370 (S,Z)-tert-butyl 1-(2-
bromo-6-((2,4- dioxothiazolidin-5- ylidene)methyl)phenyl)
pyrrolidin-3-ylcarbamate Method 138 ##STR00304## 122I
(R,Z)-5-(2-(3- aminopiperidin-1-yl)- 3-ethoxybenzylidene)
thiazolidine-2,4-dione hydrochloride ##STR00305## 12.58 (s, 1 H)
8.13-8.09 (m, 4 H) 7.26-7.24 (m, 1 H) 7.16-7.14 (m, 1 H) 7.03-7.01
(m, 1 H) 4.07 (q, 2 H) 3.78-3.67 (m, 2 H) 3.22-3.07 (m, 3 H)
2.10-2.07 (m, 1 H) 1.76- 1.55 (m, 3 H) 1.38 (t, 3 H) 348
(R,Z)-tert-butyl 1-(2- ((2,4-dioxothiazolidin-5- ylidene)methyl)-6-
ethoxyphenyl)piperidin- 3-ylcarbamate Method 139 ##STR00306## 122J
(R,Z)-tert-butyl 1-(2- ((2,4- dioxothiazolidin-5-
ylidene)methyl)-6- isobutoxyphenyl) piperidin-3-ylcarbamate
hydrochloride ##STR00307## 12.60 (s, 1 H) 8.18 (brs, 3 H) 8.15 (s,
1 H) 7.26 (t, 1 H) 7.15 (d, 1 H) 7.02 (d, 1 H) 3.84-3.74 (m, 2 H)
3.20-3.02 (m, 4 H) 2.74 (d, 1 H) 2.14-2.07 (m, 2 H) 1.73-1.21 (m, 3
H) 1.03 (d, 6 H) 376 (R,Z)-tert-butyl 1-(2-
((2,4-dioxothiazolidin-5- ylidene)methyl)-6- isobutoxyphenyl)
piperidin-3-ylcarbamate Method 140 ##STR00308## 122K (R,Z)-5-(2-(3-
aminopiperidin-1-yl)- 3-(cyclohexylmethoxy) benzylidene)
thiazolidine-2,4-dione hydrochloride ##STR00309## 12.60 (s, 1 H)
8.14 (brs, 4 H) 7.25 (t, 1 H) 7.14 (d, 1 H) 7.00 (d, 1 H) 3.82
(brs, 2 H) 3.29-3.00 (m, 4 H) 2.75-2.72 (m, 1 H) 2.12-2.10 (m, 1 H)
1.86- 1.50 (m, 8 H) 1.35-1.03 (m, 6 H) 416 (R,Z)-tert-butyl 1-(2-
(cyclohexylmethoxy)-6- ((2,4-dioxothiazolidin-5-
ylidene)methyl)phenyl) piperidin-3-ylcarbamate Method 141
##STR00310## 122L (R,Z)-5-(2-(3- aminopiperidin-1-yl)-
3-(cyclohexyloxy) benzylidene)thiazolidine- 2,4-dione hydrochloride
##STR00311## 402 (R,Z)-tert-butyl 1-(2- (cyclohexyloxy)-6-((2,4-
dioxothiazolidin-5- ylidene)methyl)phenyl) piperidin-3-ylcarbamate
Method 142 ##STR00312## 122M (.+-.)-(Z)-5-(2-3-amino-
4-hydroxypiperidin- 1-yl)-3- chlorobenzylidene)
thiazolidine-2,4-dione hydrochloride ##STR00313## 12.68 (s, 1 H)
8.01 (brs, 4 H) 7.53 (d, 1 H) 7.44- 7.42 (m, 1 H) 7.35 (t, 1 H)
5.72-5.70 (m, 1 H) 3.32-3.22 (m, 2 H) 3.20- 3.11 (m, 3 H) 1.96-1.94
(m, 1 H) 1.40-1.37 (m, 1 H) 354 (.+-.)-tert-butyl-1-(2-
chloro-6-((Z)-(2,4- dioxothiazolidin-5- ylidene)methyl)phenyl)-
4-hydroxypiperidin-3- ylcarbamate Method 143 ##STR00314## 122N
(Z)-5-(3-chloro-2- (1,4-diazepan-1- yl)benzylidene)
thiazolidine-2,4-dione hydrochloride ##STR00315## 12.73 (brs, 1 H),
9.18 (brs, 2 H), 8.04 (s, 1 H), 7.62 (d, 1 H), 7.41 (dt, 2 H), 3.65
(brs, 1 H), 3.34- 3.30 (m, 5 H), 3.04 (brs, 2 H), 2.14 (brs, 2 H)
338 (Z)-tert-butyl 4-(2- chloro-6-((2,4- dioxothiazolidin-5-
ylidene)methyl)phenyl)- 1,4-diazepane-1- carboxylate Method 144
##STR00316## 122O (R,Z)-5-(2-(3- aminopiperidin-1-yl)-
3-isopropoxybenzylidene) thiazolidine-2,4- dione hydrochloride
##STR00317## 12.61 (brs, 1 H) 8.33 (brs, 3 H) 8.15 (brs, 1 H)
7.34-7.09 (m, 2 H) 6.99 (d, 1 H) 4.67 (ddd 1 H) 3.28 (brs, 1 H)
3.07 (brs, 3 H) 2.70 (brs, 1 H) 2.12 (brs, 1 H) 1.73 (brs, 1 H)
1.57 (brs, 1 H) 1.51- 1.21 (m, 7 H) 362 (R,Z)-tert-butyl 1-(2-
((2,4-dioxothiazolidin-5- ylidene)methyl)-6- isopropoxyphenyl)
piperidin-3-ylcarbamate Method 145 ##STR00318## 122P (S,Z)-5-(2-(3-
aminopyrrolidin-1- yl)-3- isopropoxybenzylidene) thiazolidine-2,4-
dione hydrochloride ##STR00319## 12.58 (brs, 1 H) 8.52 (brs, 3 H)
8.08 (s, 1 H) 7.39-7.10 (m, 2 H) 6.99 (d, 1 H) 4.70 (d, 1 H) 3.78
(brs, 1 H) 3.52-3.33 (m, 1 H) 3.33-3.03 (m, 3 H) 2.28 (brs, 1 H)
2.00 (d, 1 H) 1.32 (d, 6 H) 348 (S,Z)-tert-butyl 1-(2-
((2,4-dioxothiazolidin-5- ylidene)methyl)-6- isopropoxyphenyl)
pyrrolidin-3-ylcarbamate Method 146 ##STR00320## 122Q
(S,Z)-5-(2-(3- aminopyrrolidin-1- yl)-3- ethoxybenzylidene)
thiazolidine-2,4-dione hydrochloride ##STR00321## 12.58 (brs, 1 H)
8.48 (brs, 3 H) 8.09 (s, 1 H) 7.26 (t, 1 H) 7.16 (d, 1 H) 7.02 (d,
1 H) 4.09 (q, 2 H) 3.80 (d, 1 H) 3.47 (dd, 1 H) 3.28 (m, 1 H) 3.21
(dd, 1 H) 2.29 (d, 1 H) 2.01 (dd, 1 H) 1.40 (t, 3 H) 334
(S,Z)-tert-butyl 1-(2- ((2,4-dioxothiazolidin-5- ylidene)methyl)-6-
ethoxyphenyl)pyrrolidin- 3-ylcarbamate Method 147 ##STR00322## 122R
(R,Z)-5-(2-(3-(4- (aminomethyl) benzylamino)piperidin-1- yl)-3-
chlorobenzylidene) thiazolidine-2,4-dione hydrochloride
##STR00323## 9.62 (brs, 1 H) 8.46 (brs, 3 H) 7.66-7.49 (m, 5 H)
7.47-7.34 (m, 2 H) 4.26- 4.12 (m, 2 H) 4.09-3.94 (m, 2 H) 3.42-3.25
(m, 4 H) 2.83 (brs, 1 H) 2.36 (s, 1 H) 1.85 (m, 1 H) 1.62 (d, 2 H)
457 (R,Z)-tert-butyl 4-((1-(2- chloro-6-((2,4- dioxothiazolidin-5-
ylidene)methyl)phenyl) piperidin-3- ylamino)methyl) benzylcarbamate
Example 167 ##STR00324## 122S (R,Z)-5-(3-chloro-2- (3-(2-
(methylamino) ethylamino)piperidin-1- yl)benzylidene)
thiazolidine-2,4-dione hydrochloride ##STR00325## 12.68 (brs, 1 H)
9.68 (brs, 2H) 9.21 (brs, 2 H) 8.05 (s, 1 H) 7.56 (d, 1 H)
7.50-7.42 (m, 1 H) 7.37 (t, 1 H) 3.75-3.65 (m, 5 H) 3.63-3.57 (m, 2
H) 3.16 (d, 1 H) 2.82 (brs, 1 H) 2.60 (brs, 3 H) 2.37-2.28 (m, 1 H)
1.80 (d, 1 H) 1.65 (m, 1H) 1.54 (brs, 1 H) 395 (R,Z)-tert-butyl
2-(1-(2- chloro-6-((2,4- dioxothiazolidin-5- ylidene)methyl)phenyl)
piperidin-3- ylamino)ethyl)methyl) carbamate Example 168
##STR00326## 122T (Z)-5-(2-((3S,4S)-3- amino-4-
hydroxypyrrolidin-1- yl)-3- chlorobenzylidene)
thiazolidine-2,4-dione hydrochloride ##STR00327## 12.68 (brs, 1 H)
8.50 (brs, 3 H) 8.10-7.81 (m, 1 H) 7.58 (dd, 1 H) 7.51- 7.27 (m, 2
H) 4.56-4.28 (m, 1 H) 3.84 (brs, 1 H) 3.66-3.40 (m, 4 H) 3.39- 3.23
(m, 1 H) 339 tert-butyl (3S,4S)-1-(2- chloro-6-((Z)-(2,4-
dioxothiazolidin-5- ylidene)methyl)phenyl)- 4-hydroxypyrrolidin-3-
ylcarbamate Method 151 ##STR00328## 122U (Z)-5-(3-chloro-2-(4-
methyl-3- (methylamino) piperidin-1- yl)benzylidene)
thiazolidine-2,4-dione hydrochloride ##STR00329## 12.69 (brs, 1 H)
8.63 (brs, 2 H) 8.02 (s, 1 H) 7.57 (d, 1 H) 7.47-7.31 (m, 2 H) 3.58
(m, 1 H) 3.07 (m, 1 H) 2.67 (brs, 1 H) 2.58 (brs, 3 H) 2.40 (m, 1
H) 1.87 (m, 1 H) 1.68 (m, 1 H) 1.29 (m, 1 H) 1.07 (d, 3 H) 0.87 (d,
1 H) 365 (Z)-tert-butyl 1-(2- chloro-6-((2,4- dioxothiazolidin-5-
ylidene)methyl)phenyl)- 4-methylpiperidin-3- yl)methyl)carbamate
Method 152 ##STR00330## 122V (Z)-5-(2-(3-amino-4-
methylpiperidin-1- yl)-3- chlorobenzylidene) thiazolidine-2,4-dione
hydrochloride ##STR00331## 351 (Z)-tert-butyl 1-(2- chloro-6-((2,4-
dioxothiazolidin-5- ylidene)methyl)phenyl)- 4-methylpiperidin-3-
ylcarbamate Method 153 ##STR00332## 122W (R,Z)-5-(2-(3-
aminopiperidin-1- yl)benzylidene) thiazolidine-2,4-dione
hydrochloride ##STR00333## 12.58 (s, 1 H), 8.44 (brs, 3 H) 7.89 (s,
1 H) 7.54- 7.34 (m, 2 H) 7.27-7.05 (m, 2 H) 3.26 (d, 2 H) 2.94 (d,
1 H), 2.87-2.61 (m, 2 H) 2.05 (brs, 1 H) 1.85 (brs, 1 H) 1.75-1.47
(m, 2 H) 304 (R,Z)-tert-butyl 1-(2- ((2,4-dioxothiazolidin-5-
ylidene)methyl)phenyl) piperidin-3-ylcarbamate Method 154 122X
(S,Z)-5-(2-(3- aminopyrrolidin-1- yl)benzylidene)
thiazolidine-2,4-dione hydrochloride ##STR00334## 12.49 (s, 1 H)
8.50 (brs, 3 H) 7.91 (s, 1 H) 7.44- 7.22 (m, 2 H) 7.07-6.79 (m, 2
H) 3.83 (d, 1 H) 3.51-3.29 (m, 2 H) 3.28- 3.17 (m, 2 H) 2.27 (dd, 1
H), 2.11-1.94 (m, 1 H) 290 (S,Z)-tert-butyl 1-(2-
((2,4-dioxothiazolidin-5- ylidene)methyl)phenyl)
pyrrolidin-3-ylcarbamate Method 155 ##STR00335## 122Y
(R,Z)-5-(2-(3- aminopiperidin-1-yl)- 3-(2,2,2- trifluoroethoxy)
benzylidene) thiazolidine- 2,4-dione hydrochloride ##STR00336##
12.57 (brs, 1 H) 8.03 (brs, 1 H) 7.90 (brs, 3 H) 7.36-7.13 (m, 2 H)
7.07 (d, 1 H) 4.85-4.55 (m, 2 H) 2.98 (brs, 4 H) 2.74 (brs, 1 H)
2.02 (d, 1 H) 1.69 (d, 1 H) 1.54 (d, 1 H) 1.30 (brs, 1 H) 402
(R,Z)-tert-butyl 1-(2- ((2,4-dioxothiazolidin-5-
ylidene)methyl)-6-(2,2,2- trifluoroethoxy)phenyl)
piperidin-3-ylcarbamate Method 156 ##STR00337## 122Z (S,Z)-5-(2-(3-
aminopyrrolidin-1- yl)-3-(2,2,2- trifluoroethoxy)
benzylidene)thiazolidine- 2,4-dione hydrochloride ##STR00338##
12.52 (brs, 1 H) 8.21- 7.91 (m, 4 H) 7.34-7.14 (m, 2 H) 7.07 (d, 1
H) 4.88-4.72 (m, 2 H) 3.74 (d, 1 H) 3.40 (dd, 1 H) 3.22 (td, 1 H)
3.18-3.10 (m, 1 H) 3.06 (dd, 1 H) 2.30-2.10 (m, 1 H) 1.90 (dd, 1 H)
388 (S,Z)-tert-butyl 1-(2- ((2,4-dioxothiazolidin-5-
ylidene)methyl)-6-(2,2,2- trifluoroethoxy)phenyl)
pyrrolidin-3-ylcarbamate Method 157 ##STR00339## 122AA
(R,Z)-5-(2-(3- aminopiperidin-1-yl)- 3-(2- methoxyethoxy)
benzylidene)thiazolidine- 2,4-dione hydrochloride ##STR00340##
12.67 (brs, 1 H) 8.30 (brs, 3 H) 8.20 (brs, 1 H) 7.33 (brs, 1 H)
7.25 (brs, 1 H) 7.10 (d, 1 H) 4.68 (brs, 3 H) 4.22 (t, 2 H)
3.91-3.65 (m, 2 H) 3.42 (s, 3 H) 3.29 (brs, 1 H) 2.80 (brs, 1 H)
2.18 (brs, 1 H) 1.81 (brs, 1 H) 1.68 (brs, 1 H) 1.48 (brs, 1 H) 378
(R,Z)-tert-butyl 1-(2- ((2,4-dioxothiazolidin-5-
ylidene)methyl)-6-(2- methoxyethoxy)phenyl) piperidin-3-ylcarbamate
Method 158 ##STR00341##
122AB (S,Z)-5-(2-(3- aminopyrrolidin-1- yl)-3-(2- methoxyethoxy)
benzylidene)thiazolidine- 2,4-dione hydrochloride ##STR00342##
12.58 (brs, 1 H) 8.42 (brs, 3 H) 8.10 (s, 1 H) 7.28 (t, 1 H)
7.23-7.11 (m, 1 H) 7.04 (d, 1 H) 4.27-3.97 (m, 2 H) 3.85 (d, 1 H)
3.78-3.63 (m, 2 H) 3.49 (dd, 1 H) 3.34 (s, 3 H) 3.27 (td, 1 H)
3.22- 3.06 (m, 2 H) 2.30 (dd, 1 H) 2.02 (dd, 1 H) 364
(S,Z)-tert-butyl 1-(2- ((2,4-dioxothiazolidin-5-
ylidene)methyl)-6-(2- methoxyethoxy)phenyl)
pyrrolidin-3-ylcarbamate Method 159 ##STR00343## 122AC
(R,Z)-5-(2-(3- aminopiperidin-1-yl)- 3-(cyclopentyloxy)
benzylidene)thiazolidine- 2,4-dione hydrochloride ##STR00344##
12.37 (brs, 1 H) 8.00 (brs, 3H) 7.93 (s, 1 H) 7.02 (d, 1 H) 6.91
(d, 1 H) 6.77 (d, 1 H) 3.02- 2.91 (m, 1 H) 2.82 (d, 3 H) 2.48 (brs,
1 H) 1.89- 1.40 (m, 12 H) 1.16 (brs, 1 H) 388 (R,Z)-ten-butyl 1-(2-
(cyclopentyloxy)-6-((2,4- dioxothiazolidin-5-
ylidene)methyl)phenyl) piperidin-3-ylcarbamate Method 160
##STR00345## 122AD (R,Z)-5-(2-(3- aminopiperidin-1-yl)-
3-cyclobutoxybenzylidene) thiazolidine-2,4- dione hydrochloride
##STR00346## 12.60 (brs, 1 H) 8.14 (brs, 4 H) 7.23 (d, 1 H) 7.00
(dd, 2 H), 4.86-4.67 (m, 1 H) 3.25 (m, 1 H) 3.05 (m, 2 H) 2.74
(brs, 1 H) 2.49-2.35 (m, 2 H) 2.21-1.95 (m, 3 H) 1.93- 1.76 (m, 2
H) 1.67 (td, 3 H) 1.42 (brs, 1 H) 374 (R,Z)-tert-butyl 1-(2-
cyclobutoxy-6-((2,4- dioxothiazolidin-5- ylidene)methyl)phenyl)
piperidin-3-ylcarbamate Method 161 ##STR00347## 122AE (R,Z)-4-(3-
aminopipcridin-1-yl)- 3-((2,4- dioxothiazolidin-5- ylidene)methyl)
benzamide hydrochloride ##STR00348## 347 (R,Z)-tert-butyl 1-(4-
carbamoyl-2-((2,4- dioxothiazolidin-5- ylidene)methyl)phenyl)
piperidin-3-ylcarbamate Method 162 ##STR00349## 122AF (S,Z)-4-(3-
aminopiperidin-1-yl)- 3-((2,4- dioxothiazolidin-5- ylidene)methyl)
benzamide hydrochloride ##STR00350## 347 (S,Z)-tert-butyl 1-(4-
carbamoyl-2-((2,4- dioxothiazolidin-5- ylidene)methyl)phenyl)
piperidin-3-ylcarbamate Method 163 ##STR00351## 122AG (R,Z)-4-(3-
aminopiperidin-1-yl)- 3-((2,4- dioxothiazolidin-5- ylidene)methyl)
benzoic acid hydrochloride ##STR00352## 348 (R,Z)-4-(3-(tert-
butoxycarbonylamino) piperidin-1-yl)-3-((2,4- dioxothiazolidin-5-
ylidene)methyl)benzoic acid Method 164 ##STR00353## 122AH
(S,Z)-4-(3- aminopyrrolidin-1- yl)-3-((2,4- dioxothiazolidin-5-
ylidene)methyl) benzoic acid ##STR00354## 333 (S,Z)-4-(3-(tert-
butoxycarbonylamino) pyrrolidin-1-yl)-3-((2,4- dioxothiazolidin-5-
ylidene)methyl) benzoic acid Method 165 ##STR00355## 122AI
(R,Z)-5-((2-(3- aminopiperidin-1- yl)biphenyl-3- yl)methylene)
thiazolidine-2,4- dione ##STR00356## 12.64 (brs, 1 H) 8.09 (brs, 3
H) 7.92 (s, 1 H) 7.56-7.36 (m, 4 H) 7.36- 7.16 (m, 4 H) 3.06 (brs,
1 H) 3.00 (brs, 1 H) 2.72 (d, 1 H) 2.35 (brs, 2 H) 2.05 (brs, 1 H)
1.58 (brs, 2 H) 1.32-1.15 (m, 1 H) 380 (R,Z)-tert-butyl 1-(3-
((2,4-dioxothiazolidin-5- ylidene)methyl)biphenyl-
2-yl)piperidin-3- ylcarbamate Method 166 ##STR00357##
Example 123
##STR00358##
[0287]
(S,Z)-5-(2-(3-(3-aminopropylamino)pyrrolidin-1-yl)-5-(trifluorometh-
yl)benzylidene)thiazolidine-2,4-dione hydrochloride
[0288] A 25 mL round bottom flask was charged with a magnetic stir
bar,
(S,Z)-5-(2-(3-(3-(1,3-dioxoisoindolin-2-yl)propylamino)pyrrolidin-1-yl)-5-
-(trifluoromethyl)benzylidene)thiazolidine-2,4-dione (Method 70)
(0.271 g, 0.50 mmol), EtOH (2.488 ml), and hydrazine (0.023 ml,
0.75 mmol). The reaction was stirred at rt for 30 min and then
filtered through a bed of Celite. The filtrate was conc. in vacuo
and purified via reverse phase HPLC (MeCN/water) to afford
fractions that were conc. in vacuo, suspended in methanol (.about.5
mL) and 1N HCl in diethyl ether (.about.2 mL) and conc. in vacuo to
afford
(S,Z)-5-(2-(3-(3-aminopropylamino)pyrrolidin-1-yl)-5-(trifluoromethyl)ben-
zylidene)thiazolidine-2,4-dione hydrochlride (0.071 g, 29.3%).
.sup.1H NMR (300 MHz, DMSO-D6) .delta. ppm 12.52 (s, 1H) 9.49 (s,
1H) 8.08 (brs, 2H) 7.93 (s, 1H) 7.67 (s, 1H) 7.61 (d, 1H) 7.08 (d,
1H) 3.88-3.81 (m, 1H) 3.53-3.33 (m, 4H) 3.08-3.05 (m, 2H) 2.92-2.89
(m, 2H) 2.33-2.19 (m, 2H) 2.04-1.96 (m, 2H); m/z 415.
[0289] The following examples were prepared by the procedure of
Example 123, using the appropriate starting materials. The
following parent compounds obtained after chromatography may be
converted to their corresponding hydrochloride salt in a manner
similar as described in example 123.
TABLE-US-00005 Ex. Compound .sup.1H NMR m/z SM 124 ##STR00359##
12.59 (brs, 1 H) 9.30 (brs, 1 H) 8.09 (s, 1 H) 8.07 (brs, 1 H) 7.32
(t, 1 H) 7.21 (d, 1 H) 7.08 (d, 1 H) 3.87 (s, 3 H) 3.46-3.44 (m, 1
H) 3.39-3.25 (m, 2 H) 3.17-2.99 (m, 4 H) 2.96-2.91 (m 2 H)
2.19-2.10 (m, 2 H) 2.08-1.99 (m, 2 H) 377 ##STR00360## 125
##STR00361## 12.72 (brs, 1 H) 9.50 (brs, 1 H) 8.10 (brs, 2 H) 7.96
(s, 1 H) 7.60 (d, 1 H) 7.46-7.39 (m, 2 H) 3.95-3.91 (m, 1 H)
3.51-3.20 (m, 4 H) 2.99- 2.92 (m, 2 H) 2.44-2.38 (m, 2 H) 2.21-2.11
(m, 2 H) 2.08-1.99 (m, 2 H) 382 ##STR00362## 126 ##STR00363## 12.40
(s, 1 H) 9.78 (s, 1 H) 7.92 (s, 1 H) 7.05 (s, 1 H) 6.85 (s, 1 H)
4.21-4.11 (m, 1 H) 3.93 (s, 3 H) 3.83 (s, 3 H) 3.42-3.25 (m, 8 H)
2.45 (m, 1 H) 2.20 (m, 1 H) 1.32 (m, 2 H) 407 ##STR00364## 127
##STR00365## 12.64 (s, 1 H) 11.50 (s, 1 H) 8.27 (s, 1 H) 7.85 (s, 1
H) 7.49 (t, 2 H) 7.24 (t, 2 H) 3.55 (d, 2 H) 3.32- 3.16 (m, 8 H)
2.93 (d, 2 H) 2.18-2.07 (m, 2 H) 347 ##STR00366## 128 ##STR00367##
12.34 (s, 1 H) 8.46 (d, 1 H) 7.86 (s, 3 H) 6.95 (s, 1 H) 6.63 (s, 1
H) 4.36-4.26 (m, 1 H) 3.84 (s, 3 H) 3.72 (s, 3 H), 3.32-3.21 (m, 3
H) 3.02-2.93 (m, 3 H) 2.18 (dd, 2 H) 1.86 (dd, 1 H) 421
##STR00368## 129A ##STR00369## 12.59 (s, 1 H) 7.94 (s, 1 H) 7.82
(s, 2 H) 7.51- 7.44 (m, 2 H) 7.26-7.17 (m, 2 H) 3.66 (m, 2 H) 3.59
(m, 2 H) 3.08-2.97 (m, 2 H) 2.96-2.86 (m, 4 H) 2.74 (m, 2 H) 361
##STR00370## 129B ##STR00371## 12.69 (brs, 1 H) 9.31 (brs, 1 H)
8.05 (s, 3 H) 7.56 (d, 1 H) 7.49-7.41 (m, 1 H) 7.37 (t, 1 H)
3.76-3.65 (m, 3 H) 3.16 (brs, 1 H) 3.04 (brs, 2 H) 2.94-2.75 (m, 3
H) 2.33 (brs, 1 H) 2.04-1.92 (m, 2 H) 1.78 (d, 1 H) 1.65 (m, 1 H),
1.50 (m, 1 H) 395 ##STR00372## 129C ##STR00373## 12.64 (brs, 1 H)
7.94 (brs, 4 H) 7.11 (m, 2 H) 6.93 (s, 1 H) 4.13 (m, 2 H) 3.77 (s,
3 H) 2.97 (m, 2 H) 2.06 (m, 2 H) 309 ##STR00374##
Example 130
##STR00375##
[0291]
(5Z)-5-[2-(4-acetylpiperazin-1-yl)benzylidene]-1,3-thiazolidine-2,4-
-dione: To a mixture of
(57)-5-(2-piperazin-1-ylbenzylidene)-1,3-thiazolidine-2,4-dione
(Example 115) and acetyl chloride (36.1 mg, 0.46 mmol) was added
triethylamine (93 mg, 0.92 mmol) at room temperature. The reaction
mixture was stirred at room temperature overnight and was then
treated with sat'd aqueous NaHCO.sub.3 (.about.25 mL). This mixture
was allowed to stir at room temperature for 10 min, and was then
extracted with DCM (3.times.25 mL). The combined organic extract
was dried over anhydrous Na.sub.2SO.sub.4, filtered through a bed
of Celite, and the filtrate was conc. in vacuo to afford the
product which was purified via reverse phase HPLC
(acetonitrile:water: 0.1% TFA=5% to 70%) to afford the title
compound as a pale yellow solid (40.0 mg, 35.4%). .sup.1H NMR (300
MHz, DMSO-D6) .delta. ppm 12.58 (brs, 1H) 7.94 (s, 1H) 7.47 (d, 2H)
7.30-7.07 (m, 2H) 3.60 (brs, 4H) 2.90 (brs, 2H) 2.85 (brs, 2H) 2.04
(s, 3H); m/z 331.
[0292] The following examples were prepared by the procedure of
Example 130, using the appropriate starting materials.
TABLE-US-00006 Ex. Compound .sup.1H NMR m/z SM 131A ##STR00376##
12.29 (brs, 1 H) 8.13 (d, 1 H) 7.85 (s, 1 H) 6.94 (s, 1 H) 6.61 (s,
1 H) 4.27 (d, 1 H) 3.83 (s, 3 H) 3.72 (s, 3 H) 3.43-3.14 (m, 4 H)
2.94 (dd, 1 H) 2.30-2.05 (m, 1 H) 1.82 (s, 3 H) 392 ##STR00377##
131B ##STR00378## 9.86 (s, 1 H) 7.68 (s, 1 H) 7.56 (s, 1 H)
7.49-7.47 (d, 1 H) 6.96-6.94 (d, 1 H) 3.23 (m, 1 H) 3.00 (m, 4 H)
2.51 (s, 6 H) 2.15 (m, 1 H) 2.01 (s, 3 H) 1.55 (m, 1 H) 375
##STR00379##
Example 132
##STR00380##
[0293]
(Z)-5-(2-(3-(2-hydroxyethylamino)pyrrolidin-1-yl)-4,5-dimethoxybenz-
ylidene)thiazolidine-2,4-dione
[0294] A mixture of
(Z)-5-(2-(3-(2-(tert-butyldimethylsilyloxy)ethylamino)pyrrolidin-1-yl)-4,-
5-dimethoxybenzylidene)thiazolidine-2,4-dione (Method 77) (120 mg,
0.24 mmol) in 5 mL of 1.25 M HCl in methanol was stirred at room
temperature for 30 min. The mixture was then conc. in vacuo to
afford the product which was purified via reverse phase HPLC
(acetonitrile:water: 0.1% NH.sub.4OAc=5% to 55%) to yield the title
compound as a yellow solid (45.0 mg, 48.4%). .sup.1H NMR (300 MHz,
DMSO-D6) .delta. ppm 7.40 (s, 1H) 7.07 (s, 1H) 6.57 (s, 1H) 3.78
(s, 3H) 3.70 (s, 3H) 3.45 (m, 2H) 3.27-3.15 (m, 4H) 2.92 (m, 1H)
2.59 (m, 2H) 2.08 (m, 1H) 1.66 (m, 1H); m/z 394.
[0295] The following examples were prepared by the procedure of
Example 132 using the appropriate starting materials.
TABLE-US-00007 133 ##STR00381## 8.81 (brs, 2 H) 7.96 (s, 1 H) 7.48
(d, 1 H) 7.40-7.32 (m, 1 H) 7.31-7.25 (m, 1 H) 3.63-3.55 (m, 2 H)
3.46-3.38 (m, 2 H) 3.08 (brs, 2 H) 2.96 (d, 2 H) 2.75 (brs, 1 H)
2.20 (m, 1H) 1.72 (brs, 1 H) 1.56 (brs, 1 H) 1.44 (brs, 1 H) 382
##STR00382## 134 ##STR00383## 12.69 (brs, 1 H) 8.84 (brs, 1 H) 8.04
(s, 1 H) 7.56 (d, 1 H) 7.49-7.39 (m, 1 H) 7.36 (t, 1 H) 3.69 (dd, 2
H) 3.17 (brs, 2 H) 3.00 (brs, 2 H) 2.83 (brs, 1 H) 2.26 (brs, 1 H)
1.93-1.72 (m, 4 H) 1.66 (brs, 1 H) 1.50 (brs, 1 H) ##STR00384##
Example 135
##STR00385##
[0296]
(S,Z)--N-(1-(2-chloro-6-((2,4-dioxothiazolidin-5-ylidene)methyl)phe-
nyl)pyrrolidin-3-yl)-1-methyl-1H-imidazole-2-carboxamide
[0297] To a 50 mL vial charged with a magnetic stir bar was added
(S,Z)-5-(2-(3-aminopyrrolidin-1-yl)-3-chlorobenzylidene)thiazolidine-2,4--
dione (75 mg, 0.23 mmol) (Example 86),
1-methyl-1H-imidazole-2-carboxylic acid (87 mg, 0.69 mmol), HATU
(220 mg, 0.58 mmol) and dichloromethane (5 mL). Hunig's base (0.202
mL, 1.16 mmol) was then added and the mixture was stirred at rt for
4 h. The reaction was then diluted with dichloromethane and washed
with water. The mixture was separated with a phase separator tube
and the organic phase was evaporated to dryness. The residue was
purified by reverse phase chromatography to afford the title
compound as a yellow solid (21 mg, 21%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 7.89 (s, 1H) 7.51 (dd, 1H) 7.41 (dd, 1H)
7.18-7.27 (m, 2H) 7.01 (s, 1H) 4.67-4.77 (m, 1H) 4.00 (s, 3H)
3.63-3.75 (m, 2H) 3.47-3.54 (m, 1H) 3.36-3.47 (m, 1H) 2.39-2.51 (m,
1H) 2.14 (dd, 1H); m/z 432.
[0298] The following examples were prepared by the procedure of 135
using the appropriate starting materials.
TABLE-US-00008 136 ##STR00386## 7.89 (s, 1 H) 7.52 (dd, 1 H) 7.41
(dd, 1 H) 7.25 (t, 1 H) 4.58-4.67 (m, 1 H) 3.93 (s, 2 H) 3.65 (dd,
1 H) 3.36- 3.46 (m, 5 H) 3.13 (dd, 1 H) 2.38 (dd, 1 H) 2.01-2.13
(m, 1 H) 396 ##STR00387## ##STR00388## 137 ##STR00389## 7.93 (s, 1
H) 7.61 (d, 1 H) 7.52 (dd, 1 H) 7.42 (dd, 1 H) 7.25 (t, 1 H) 6.73
(d, 1 H) 4.73-4.83 (m, 1 H) 3.92-3.99 (m, 3 H) 3.71 (dd, 1 H)
3.38-3.50 (m, 2 H) 3.23 (dd, 1 H) 2.38-2.50 (m, 1 H) 2.09-2.21 (m,
1 H) 432 ##STR00390## ##STR00391## 138 ##STR00392## 7.93 (s, 1 H)
7.52 (dd, 1 H) 7.41 (dd, 1 H) 7.25 (t, 1 H) 4.53 (ddd, 1 H)
3.83-3.92 (m, 2 H) 3.65-3.70 (m, 1 H) 3.42-3.49 (m, 1 H) 3.35-3.42
(m, 1 H) 3.07 (dd, 1 H) 2.37 (dt, 1 H) 1.98- 2.10 (m, 1 H) 424
##STR00393## ##STR00394## 139 ##STR00395## 8.44 (br. S., 2 H) 8.02
(s, 1 H) 7.83 (d, 1 H) 7.50 (dd, 1 H) 7.34-7.46 (m, 3 H) 7.25 (t, 1
H) 4.51 (t, 1 H) 3.60-3.69 (m, 3 H) 3.37-3.48 (m, 2 H) 3.08 (dd, 1
H) 2.31-2.43 (m, 1 H) 2.03 (dd, 1 H) 443 ##STR00396## ##STR00397##
140 ##STR00398## 8.47 (br. S., 1 H) 7.98 (s, 1 H) 7.53 (dd, 1 H)
7.41 (dd, 3 H) 7.25 (t, 1 H) 4.53 (t, 1 H) 3.64-3.71 (m, 3 H)
3.39-3.48 (m, 2 H) 3.07 (dd, 1 H) 2.32-2.44 (m, 1 H) 2.03 (dd, 1 H)
443 ##STR00399## ##STR00400## 141 ##STR00401## 8.17 (s, 1 H) 8.07
(s, 1 H) 7.94 (s, 1 H) 7.47 (ddd, 2 H) 7.27 (t, 1 H) 4.67-4.78 (m,
1 H) 3.89-3.97 (m, 3 H) 3.73 (dd, 1 H) 3.44 (t, 2 H) 3.19 (dd, 1 H)
2.42 (dd, 1 H) 2.14 (dd, 1 H) 432 ##STR00402## ##STR00403## 142
##STR00404## 7.91 (s, 1 H) 7.56 (dd, 1 H) 7.43 (dd, 1 H) 7.27 (t, 1
H) 4.62 (t, 1 H) 3.67- 3.78 (m, 2 H) 3.41-3.48 (m, 2 H) 3.19-3.22
(m, 2 H) 3.10-3.17 (m, 5 H) 2.92-2.98 (m, 2 H) 2.81-2.86 (m, 1 H)
2.37-2.48 (m, 1 H) 2.02-2.13 (m, 1 H) 483 ##STR00405## ##STR00406##
143 ##STR00407## 7.18 (s, 1 H) 6.70 (dd, 1 H) 6.62 (dd, 1 H) 6.45
(t, 1 H) 3.71 (s, 1 H) 2.84 (dd, 1 H) 2.56- 2.66 (m, 2 H) 2.29-2.36
(m, 2 H) 2.26 (dd, 1 H) 1.64 (t, 2 H) 1.57 (d, 1 H) 1.25-1.37 (m, 2
H) 1.20 (d, 1 H) 473 ##STR00408## ##STR00409## 144 ##STR00410##
8.01 (s, 1 H) 7.50 (d, 1 H) 7.44 (d, 1 H) 7.26 (t, 1 H) 4.47-4.58
(m, 1 H) 3.62 (t, 1 H) 3.42 (t, 2 H) 3.02-3.15 (m, 4 H) 2.92 (s, 3
H) 2.67 (d, 2 H) 2.56 (t, 2 H) 2.36 (dd, 1 H) 2.02 (dd, 1 H) 451
##STR00411## ##STR00412## 145 ##STR00413## 7.07 (s, 1 H) 6.69-6.74
(m, 1 H) 6.59 (dd, 1 H) 6.43 (t, 1 H) 3.76 (br. S., 1 H) 2.85-2.94
(m, 2 H) 2.84 (d, 1 H) 2.36 (br. S., 1 H) 2.29 (dd, 2 H) 1.52-1.64
(m, 7 H) 1.18-1.28 (m, 1 H) 409 ##STR00414## ##STR00415## 146
##STR00416## 7.95 (s, 1 H) 7.52 (dd, 1 H) 7.42 (dd, 1 H) 7.26 (t, 1
H) 4.50 (ddd, 1 H) 3.68-3.78 (m, 1 H) 3.64 (dd, 1 H) 3.44- 3.50 (m,
1 H) 3.40 (t, 1 H) 3.22 (q, 1 H) 3.09 (dd, 1 H) 2.39 (dt, 1 H) 2.03
(d, 1 H) 391 ##STR00417## ##STR00418## 147 ##STR00419## 7.89 (s, 1
H) 7.54 (dd, 1 H) 7.39 (dd, 1 H) 7.24 (t, 1 H) 4.49- 4.60 (m, 1 H)
3.86- 3.98 (m, 1 H) 3.65 (dd, 1 H) 3.36-3.48 (m, 2 H) 3.17- 3.25
(m, 1 H) 3.07-3.16 (m, 1 H) 2.31-2.43 (m, 1 H) 1.96-2.09 (m, 4 H)
423 ##STR00420## ##STR00421##
Example 148
##STR00422##
[0299]
(R,Z)-5-(3-chloro-2-(3-(dipropylamino)piperidin-1-yl)benzylidene)th-
iazolidine-2,4-dione
[0300] A mixture of
(R,Z)-5-(2-(3-aminopiperidin-1-yl)-3-chlorobenzylidene)thiazolidine-2,4-d-
ione (122D) (100 mg, 0.27 mmol) and propionaldehyde (20.17 mg, 0.35
mmol) in CH.sub.2Cl.sub.2 (15 mL) was stirred at 50.degree. C. for
20 min. before sodium triacetoxyborohydride (170 mg, 0.80 mmol) was
added. The mixture was then stirred at 50.degree. C. for 4 h.
before sat'd aqueous K.sub.2CO.sub.3 (.about.50 mL) was added to
the mixture. This solution was poured into a separatory funnel and
extracted with CHCl.sub.3/isopropanol (5/1) (2.times.50 mL). The
combined organic extract was dried over anhydrous Na.sub.2SO.sub.4,
filtered, and conc. in vacuo affording the product. It was purified
with Gilson (0.1% TFA in water:0.1% TFA in CAN=30% to 80%; UV
absorption at 322) to yield the title compound as a yellow solid
(94 mg, 77%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.96
(s, 1H) 7.48 (d, 1H) 7.41-7.34 (m, 1H) 7.29 (t, 1H) 3.67-3.58 (m,
2H) 3.44-3.37 (m, 2H) 3.03-2.78 (m, 5H) 2.21 (brs, 1H), 1.79 (d,
1H) 1.61 (d, 6H) 0.84-0.79 (m, 6H). m/z 422.
[0301] He following examples were prepared by the procedure of 148,
using the appropriate starting materials.
TABLE-US-00009 149 ##STR00423## 12.65 (brs, 1 H) 9.35 (brs, 1H)
8.05 (s, 1 H) 7.56 (d, 1 H) 7.44 (brs, 1 H) 7.37 (t, 1 H) 3.75-3.63
(m, 2 H) 3.53-3.45 (m, 2 H) 3.23 (m, 1 H) 2.85- 2.65 (m, 4 H) 2.30
(brs, 1 H) 1.85-1.76 (m, 1 H) 1.67 (brs, 1 H) 1.49 (brs, 1 H) 433
##STR00424## ##STR00425## 150 ##STR00426## 12.65 (s, 1H), 8.91 (s,
br, 2H), 7.91 (s, 1H), 7.10 (m, 2H), 7.85 (s, 1H), 4.17 (m, 2H),
3.65 (m, 4H), 3.05 (m, 2H), 2.14 (m, 2H), 1.22 (m, 6H) 351
##STR00427## ##STR00428##
Example 151
##STR00429##
[0302]
(Z)-5-(5-amino-2-(3-(dimethylamino)pyrrolidin-1-yl)benzylidene)thia-
zolidine-2,4-dione
[0303] To a mixture of
(Z)-5-(2-(3-(dimethylamino)pyrrolidin-1-yl)-5-nitrobenzylidene)thiazolidi-
ne-2,4-dione (100 mg, 0.28 mmol) (Method 149) and iron (154 mg,
2.76 mmol) chip in MeOH (10 mL) was added 5 drops of conc. HCl and
5 drops of water. The mixture was stirred at 80.degree. C. for 1
hr. The mixture was loaded into silica gel, purified with ISCO
(100% ethyl acetate to methanol/ethyl acetate=50%) to yield a red
solid which was repurified with Gilson (acetonitrile:water:0.1%
TFA=0% to 50% fro 7 min) to yield a yellow solid as
(Z)-5-(5-amino-2-(3-(dimethylamino)pyrrolidin-1-yl)benzylidene)thiazol-
idine-2,4-dione (51.0 mg, 38.6%). .sup.1H NMR (400 MHz, DMSO-d6) d
ppm 12.55 (brs, 1H), 11.32 (brs, 1H), 10.30 (brs, 2H), 7.80 (s,
1H), 7.42 (m, 2H), 7.19 (m, 1H), 3.95 (m, 1H), 3.39-3.27 (m, 4H),
2.78 (s, 6H), 2.30-2.10 (m, 2H); m/z 333.
[0304] The following intermediates were prepared by the procedure
of Example 151 using the appropriate starting materials.
TABLE-US-00010 Ex Compound .sup.1H NMR m/z SM 152 ##STR00430##
12.45 (brs, 1 H) 7.87 (s, 1 H) 6.80 (s, 1H) 6.79 (s, 1 H) 3.78 (s,
3 H) 3.73 (s, 3 H) 280 ##STR00431##
Methods Section
##STR00432##
[0305] Method 1
(S)-3-bromo-2-(3-(dimethylamino)pyrrolidin-1-yl)benzaldehyde
[0306] A 50 mL round bottom flask was charged with a magnetic stir
bar, 3-bromo-2-fluorobenzaldehyde (0.555 g, 2.73 mmol),
(S)--N,N-dimethylpyrrolidin-3-amine (0.312 g, 2.73 mmol), DMSO
(5.47 ml), and potassium carbonate (0.378 g, 2.73 mmol). The
mixture was heated to 85.degree. C. overnight with stirring. The
reaction was allowed to cool to ambient temperature, was diluted
with water, and extracted into methylene chloride. The combined
organic extract was dried with MgSO.sub.4, filtered, and conc. in
vacuo to provide the product which was purified via silica gel
chromatography (40 g) using ethyl acetate/MeOH (10:1) as eluent to
afford (S)-3-bromo-2-(3-(dimethylamino)pyrrolidin-1-yl)benzaldehyde
(0.369 g, 45.4%).
[0307] The following intermediates were prepared by the procedure
of Method 1, using the appropriate starting materials.
TABLE-US-00011 Method Compound .sup.1H NMR m/z SM 2 ##STR00433##
287 ##STR00434## 3 ##STR00435## 249 ##STR00436## 4 ##STR00437## 249
##STR00438## 5 ##STR00439## 254 ##STR00440## 6 ##STR00441## 253
##STR00442## 7 ##STR00443## 279 ##STR00444## 8 ##STR00445## 279
##STR00446## 9 ##STR00447## 280 ##STR00448## 10 ##STR00449## 266
##STR00450## 11 ##STR00451## 249 ##STR00452## 12 ##STR00453## 263
##STR00454## 13 ##STR00455## 253 ##STR00456## 14 ##STR00457## 236
##STR00458## 15 ##STR00459## 207 ##STR00460## 16 ##STR00461## 219
##STR00462## 17 ##STR00463## 233 ##STR00464## 18 ##STR00465## 233
##STR00466## 19 ##STR00467## 267 ##STR00468## 20 ##STR00469## 279
##STR00470## 21 ##STR00471## 293 ##STR00472## 22 ##STR00473## 293
##STR00474## 23 ##STR00475## 359 ##STR00476## 24 ##STR00477## 264
##STR00478## 25 ##STR00479## 262 ##STR00480## 26 ##STR00481## 291
##STR00482## 79 ##STR00483## 326 ##STR00484## 80 ##STR00485## 359
##STR00486## 81 ##STR00487## 359 ##STR00488## 82 ##STR00489## 292
##STR00490## 83 ##STR00491## 322 ##STR00492## 84 ##STR00493## 321
##STR00494## 85 ##STR00495## 326 ##STR00496## 86 ##STR00497## 365
##STR00498## 87 ##STR00499## 351 ##STR00500## 88 ##STR00501## 351
##STR00502## 89 ##STR00503## 305 ##STR00504## 90 ##STR00505## 351
##STR00506## 91 ##STR00507## 339 ##STR00508## 92 ##STR00509## 339
##STR00510## 93 ##STR00511## 339 ##STR00512## 94 ##STR00513## 335
##STR00514## 95 ##STR00515## 385 ##STR00516## 96 ##STR00517## 325
##STR00518## 97 ##STR00519## 371 ##STR00520## 98 ##STR00521## 349
##STR00522## 99 ##STR00523## 377 ##STR00524## 100 ##STR00525## 417
##STR00526## 101 ##STR00527## 403 ##STR00528## 102 ##STR00529## 354
##STR00530## 103 ##STR00531## 10.49 (s, 1 H), 7.75 (d, 1 H), 7.63
(d, 1 H), 7.25 (t, 1 H), 3.37 (brs, 4 H), 1.88 (brs, 2 H), 1.53 (s,
9 H) 339 ##STR00532## 104 ##STR00533## 249 ##STR00534## 105
##STR00535## 287 ##STR00536## 106 ##STR00537## 253 ##STR00538## 107
##STR00539## 233 ##STR00540## 108 ##STR00541## 237 ##STR00542## 109
##STR00543## 233 ##STR00544## 110 ##STR00545## 298 ##STR00546## 111
##STR00547## 237 ##STR00548## 112 ##STR00549## 253 ##STR00550## 113
##STR00551## 363 ##STR00552## 114 ##STR00553## 349 ##STR00554## 115
##STR00555## 334 ##STR00556## 116 ##STR00557## 263 ##STR00558## 117
##STR00559## 10.30 (s, 1 H) 7.76 (dd, 1 H) 7.65 (dd, 1 H) 7.29-7.24
(m, 1 H) 5.05 (brs, 1 H) 4.41 (brs, 1 H) 4.20 (brs, 1 H) 3.87 (dd,
1 H) 3.78 (dd, 1 H) 3.64-3.47 (m, 1 H) 3.36 (brs, 1 H) 3.21 (dd, 1
H) 1.50 (s, 9 H) 341 ##STR00560## 118 ##STR00561## 367 ##STR00562##
119 ##STR00563## 310 ##STR00564## 120 ##STR00565## 305 ##STR00566##
121 ##STR00567## 291 ##STR00568## 122 ##STR00569## 403 ##STR00570##
123 ##STR00571## 389 ##STR00572## 124 ##STR00573## 379 ##STR00574##
125 ##STR00575## 365 ##STR00576## 126 ##STR00577## 389 ##STR00578##
127 ##STR00579## 375 ##STR00580## 128 ##STR00581## 348 ##STR00582##
129 ##STR00583## 348 ##STR00584## 130 ##STR00585## 348 ##STR00586##
131 ##STR00587## 334 ##STR00588##
##STR00589##
Method 27
5-methoxy-2-(2-(piperidin-1-yl)ethoxy)benzaldehyde
[0308] A mixture of 2-hydroxy-5-methoxybenzaldehyde (0.761 g, 5
mmol), 1-(2-chloroethyl)piperidine hydrochloride (0.921 g, 5.00
mmol), K.sub.2CO.sub.3 (2.07 g, 14.99 mmol), and sodium iodide
(0.075 g, 0.50 mmol) in acetonitrile (40 mL) was stirred at
100.degree. C. overnight. The reaction was allowed to cool to
ambient temperature and sat'd aqueous K.sub.2CO.sub.3 was added to
the reaction mixture. The mixture was poured into a reparatory
funnel and extracted with EtOAc. The organic phase was dried over
anhydrous MgSO.sub.4, filtered through a bed of Celite, and conc.
in vacuo to yield the product which was purified via silica gel
chromatography (80 g) using EtOAc/hexanes (4:1) as eluent to yield
the title compound as a brown oil (0.551 g, 42%); m/z 264.
[0309] The following intermediates were prepared by the procedure
of Method 27, using the appropriate starting materials.
TABLE-US-00012 Method Compound .sup.1H NMR m/z SM 28
5-methoxy-2-(2- 266 2-hydroxy-5- morpholinoethoxy) methoxy-
benzaldehyde benzaldehyde ##STR00590## ##STR00591## and 4-(2-
chloroethyl)morpholine hydrochloride ##STR00592## 29 2-(2- 252
2-hydroxy-5- (diethylamino) methoxy- ethoxy)-5- benzaldehyde
methoxybenzaldehyde ##STR00593## ##STR00594## and 2-chloro-N,N-
diethylethanamine ##STR00595## 30A 2-(2- 222 Salicylaldehyde
(diethylamino)ethoxy) benzaldehyde ##STR00596## ##STR00597## and
2-chloro-N,N- diethylethanamine ##STR00598## 30B 2-(3-(1,3- 10.18
(s, 1 H) 7.69 (m, 4 340 2-hydroxy-5- dioxoisoindolin-2- H) 7.11 (m,
2 H) 6.97 (d, methoxybenzaldehyde yl)propoxy)-5- 1 H) 4.05 (m, 2 H)
3.83 methoxybenzaldehyde (m, 2 H) 3.67 (s, 3 H) 2.12 (m, 2 H)
##STR00599## ##STR00600## and 2-(3- bromopropyl)
isoindoline-1,3-dione ##STR00601##
##STR00602##
Method 31
4,5-dimethoxy-2-(pyridin-3-yl)benzaldehyde
[0310] A mixture of 2-bromo-4,5-dimethoxybenzaldehyde (0.368 g, 1.5
mmol), pyridin-3-ylboronic acid (0.246 g, 2.0 mmol),
Pd(PPh.sub.3).sub.4 (0.173 g, 0.150 mmol), and cesium carbonate
(0.977 g, 3 mmol) were suspended in dioxane (4 mL) and water (1
mL). The mixture was heated to 140.degree. C. in a microwave for 1
h. The reaction vessel was allowed to cool to ambient temperature,
diluted with ethyl acetate (.about.25 mL), filtered through a bed
of Celite, and conc. in vacuo to afford the aldehyde which was
purified via SiO.sub.2 chromatography (40 g) using ethyl
acetate/hexanes (5:1) as eluent to afford the title compound as a
white solid (0.340 g, 93%); m/z 244.
[0311] The following intermediates were prepared by the procedure
of Method 31, using the appropriate starting materials.
TABLE-US-00013 Method Compound .sup.1H NMR m/z SM 32A
4,5-dimethoxy-2- 244 2-bromo-4,5- (pyridin-4- dimethoxy-
yl)benzaldehyde benzaldehyde ##STR00603## ##STR00604## and
pyridin-4-ylboronic acid ##STR00605## 32B N-(2- 9.95 (s, 1 H), 8.05
(d, 1 346 N-(2- (dimethylamino)ethyl)- H), 7.96 (d, 2 H), 7.72-
(dimethylamino)ethyl)- 2'-formyl-N- 7.83 (m, 1 H), 7.57-
N-methyl-4-(4,4,5,5- methylbiphenyl-4- 7.72 (m, 3 H), 7.53 (d, 1
tetramethyl-1,3,2- sulfonamide H), 3.24 (t, 2 H), 2.79-
dioxaborolan-2- 2.91 (m, 3 H), 2.65 (t, 2 yl)benzenesulfonamide H),
2.37 (s, 6 H) ##STR00606## ##STR00607## And 2-bromobenzaldehyde
##STR00608##
##STR00609##
Method 33
(S,Z)-tert-butyl
1-(5-chloro-2-((2,4-dioxothiazolidin-5-ylidene)methyl)phenyl)pyrrolidin-3-
-ylcarbamate
[0312] A 100 mL round bottom flask was charged with a magnetic stir
bar, (S)-tert-butyl
1-(5-chloro-2-formylphenyl)pyrrolidin-3-ylcarbamate (Method 78)
(1.100 g, 3.39 mmol), thiazolidine-2,4-dione (0.397 g, 3.39 mmol),
and ethanol (11.29 ml). Piperidine (0.034 mL, 0.34 mmol) was added
and the reaction was heated to reflux for 2 h. Once the reaction
was judged to be complete by LCMS, it was allowed to cool to
ambient temperature and conc. in vacuo to afford the title compound
(1.310 g, 91%) which was used in the next step without further
purification.; m/z 425.
[0313] The following intermediates were prepared by the procedure
of Method 33, using the appropriate starting materials.
TABLE-US-00014 Method Compound .sup.1H NMR m/z SM 34
(S,Z)-tert-butyl 1-(2- 425 tent-butyl [(3S)-1-(2- chloro-6-((2,4-
chloro-6- dioxothiazolidin-5- formylphenyl)pyrrolidin-
ylidene)methyl)phenyl) 3-yl]carbamate pyrrolidin-3-ylcarbamate
Method 79 ##STR00610## ##STR00611## 35 (Z)-tert-butyl 4-(2-((2,4-
459 tert-butyl4-[2-formyl-4- dioxothiazolidin-5-
(trifluoromethyl)phenyl] ylidene)methyl)-4-
piperazine-1-carboxylate (trifluoromethyl)phenyl) Method 80
piperazine-1-carboxylate ##STR00612## ##STR00613## 36
(S,Z)-tert-butyl 1-(2- 459 tert-butyl {(3S)-1-[2-
((2,4-dioxothiazolidin-5- formyl-4- ylidene)methyl)-4-
(trifluoromethyl)phenyl] (trifluoromethyl)phenyl) pyrrolidin-3-yl}
carbamate pyrrolidin-3-ylcarbamate Method 81 ##STR00614##
##STR00615## 37 (Z)-tert-butyl 4-(3-((2,4- 391 tert-butyl 4-(3-
dioxothiazolidin-5- formylpyridin-2- ylidene)methyl)pyridin-
yl)piperazine-1- 2-yl)piperazine-1- carboxylate carboxylate Method
82 ##STR00616## ##STR00617## 44 (S,Z)-tert-butyl 1-(2- 421
tert-butyl [(3S)-1-(2- ((2,4-dioxothiazolidin-5- formyl-6-
ylidene)methyl)-6- methoxyphenyl) methoxyphenyl)
pyrrolidin-3-yl]carbamate pyrrolidin-3-ylcarbamate Method 83
##STR00618## ##STR00619## 45 (Z)-tert-butyl 4-(2-((2,4- 421
tert-butyl 4-(2-formyl-6- dioxothiazolidin-5-
methoxyphenyl)piperazine- ylidene)methyl)-6- 1-caboxylate
methoxyphenyl)piperazine- Method 84 1-carboxylate ##STR00620##
##STR00621## 46 (Z)-tert-butyl 4-(2- 425 tert-butyl 4-(2-chloro-6-
chloro-6-((2,4- formylphenyl)piperazine- dioxothiazolidin-5-
1-carboxylate ylidene)methyl)phenyl) Method 85
piperazine-1-carboxylate ##STR00622## ##STR00623## 47
(Z)-tert-butyl (1-(2-((2,4- 465 tert-butyl (1-(2-formyl-
dioxothiazolidin-5- 4,5- ylidene)methyl)-4,5- dimethoxyphenyl)
dimethoxyphenyl) pyrrolidin-3- pyrrolidin-3- yl)methylcarbamate
yl)methylcarbamate Method 86 ##STR00624## ##STR00625## 48
(R,Z)-tert-butyl 1-(2- 451 (R)-tert-butyl 1-(2-
((2,4-dioxothiazolidin-5- formyl-4,5- ylidene)methyl)-4,5-
dimethoxyphenyl) dimethoxyphenyl) pyrrolidin-3-ylcarbamate
pyrrolidin-3-ylcarbamate Method 87 ##STR00626## ##STR00627## 49
(S,Z)-tert-butyl 1-(2- 451 (S)-tert-butyl 1-(2-
((2,4-dioxothiazolidin-5- formyl-4,5- ylidene)methyl)-4,5-
dimethoxyphenyl) dimethoxyphenyl) pyrrolidin-3-ylcarbamate
pyrrolidin-3-ylcarbamate Method 88 ##STR00628## ##STR00629## 54
(Z)-tert-butyl 4-(2-((2,4- 404 tert-butyl 4-(2- dioxothiazolidin-5-
formylphenyl)-1,4- ylidene)methyl)phenyl)- diazepane-1-carboxylate
1,4-diazepane-1- Method 89 carboxylate ##STR00630## ##STR00631## 65
tert-butyl 1-(2-((2,4- 451 tert-butyl 1-(2-formyl-
dioxothiazolidin-5- 4,5- ylidene)methyl)-4,5- dimethoxyphenyl)
dimethoxyphenyl) pyrrolidin-3-carbamate pyrrolidin-3-ylcarbamate
Method 90 ##STR00632## ##STR00633## 132 (R,Z)-tert-butyl (1-(2- 439
(R)-tert-butyl (1-(2- chloro-6-((2,4- chloro-6- dioxothiazolidin-5-
formylphenyl)pyrrolidin- ylidene)methyl)phenyl)
3-yl)methylcarbamate pyrrolidin-3-yl) Method 91 methylcarbamate
##STR00634## ##STR00635## 133 (S,Z)-tert-butyl (1-(2- 439
(S)-tert-butyl (1-(2- chloro-6-((2,4- chloro-6- dioxothiazolidin-5-
formylphenyl)pyrrolidin- ylidene)methyl)phenyl)
3-yl)methylcarbamate pyrrolidin-3-yl)methylcarbamate Method 92
##STR00636## ##STR00637## 134 (R,Z)-tert-butyl 1-(2- 438
(R)-tert-butyl 1-(2- chloro-6-((2,4- chloro-6- dioxothiazolidin-5-
formylphenyl)piperidin- ylidene)methyl)phenyl) 3-ylcarbamate
piperidin-3-ylcarbamate Method 93 ##STR00638## ##STR00639## 135
(R,Z)-tert-butyl 1-(2- 434 (R)-tert-butyl 1-(2-
((2,4-dioxothiazolidin-5- formyl-6- ylidene)methyl)-6-
methoxyphenyl)piperidin- methoxyphenyl) 3-ylcarbamate
pyrrolidin-3-ylcarbamate Method 94 ##STR00640## ##STR00641## 136
(R,Z)-tert-butyl 1-(2- 484 (R)-tert-butyl bromo-6-((2,4- bromo-6-
dioxothiazolidin-5- formylphenyl)piperidin- ylidene)methyl)phenyl)
3-ylcarbamate piperidin-3-ylcarbamate Method 95 ##STR00642##
##STR00643## 137 (R,Z)-tert-butyl 1-(2- 424 (R)-tert-butyl 1-(2-
chloro-6-((2,4- chloro-6- dioxothiazolidin-5-
formylphenyl)pyrrolidin- ylidene)methyl)phenyl) 3-ylcarbamate
pyrrolidin-3-ylcarbamate Method 96 ##STR00644## ##STR00645## 138
(S,Z)-tert-butyl 1-(2- 470 (S)-tert-butyl 1-(2- bromo-6-((2,4-
bromo-6- dioxothiazolidin-5- formylphenyl)pyrrolidin-
ylidene)methyl)phenyl) 3-ylcarbamate pyrrolidin-3-ylcarbamate
Method 97 ##STR00646## ##STR00647## 139 (R,Z)-tert-butyl 1-(2- 448
(R)-tert-butyl 1-(2- ((2,4-dioxothiazolidin-5- ethoxy-6-
ylidene)methyl)-6- formylphenyl)piperidin- ethoxyphenyl)
3-ylcarbamate piperidin-3-ylcarbamate Method 98 ##STR00648##
##STR00649## 140 (R,Z)-tert-butyl 1-(2- 476 (R)-tert-butyl 1-(2-
((2,4-dioxothiazolidin-5- formyl-6- ylidene)methyl)-6-
isobutoxyphenyl)piperidin- isobutoxyphenyl) 3-ylcarbamate
piperidin-3-ylcarbamate Method 99 ##STR00650## ##STR00651## 141
(R,Z)-tert-butyl 1-(2- 516 (R)-tert-butyl 1-(2-
(cyclohexylmethoxy)-6- (cyclohexylmethoxy)-6-
((2,4-dioxothiazolidin-5- formylphenyl)piperidin-
ylidene)methyl)phenyl) 3-ylcarbamate piperidin-3-ylcarbamate Method
100 ##STR00652## ##STR00653## 142 (R,Z)-tert-butyl 1-(2- 501
(R)-tert-butyl 1-(2- (cyclohexyloxy)-6-((2,4- (cyclohexyloxy)-6-
dioxothiazolidin-5- formylphenyl)piperidin- ylidene)methyl)phenyl)
3-ylcarbamate piperidin-3-ylcarbamate Method 101 ##STR00654##
##STR00655## 143 (.+-.)-tert-butyl 1-(2- 454
(.+-.)-tert-butyl-1-(2- chloro-6-((Z)-((2,4-
chloro-6-formylphenyl)- dioxothiazolidin-5- 4-hydroxypiperidin-3-
ylidene)methyl)phenyl)- ylcarbamate 4-hydroxypiperidin-3- Method
102 ylcarbamate ##STR00656## ##STR00657## 144 (Z)-tert-butyl 4-(2-
8.66 (brs, 438 tert-butyl 4-(2-chloro-6- chloro-6-((2,4- 1 H), 8.36
formylphenyl)-1,4- dioxothiazolidin-5- (brs, 1 H),
diazepane-1-carboxylate ylidene)methyl)phenyl)- 7.47 (d, 1 Method
103 1,4-diazepane-1- H), 7.39 carboxylate (d, 1 H), 7.22 (t, 1 H),
3.61 (brs, 3 H), 3.52 (brs, 2 H), 3.27 (brs, 3 H), 1.91 (brs, 2 H),
1.52 (s, 9 H) ##STR00658## ##STR00659## 145 (R,Z)-tert-butyl 1-(2-
462 (R)-tert-butyl 1-(2- ((2,4-dioxothiazolidin-5- formyl-6-
ylidene)methyl)-6- isopropoxyphenyl) isopropoxyphenyl)
piperidin-3-ylcarbamate piperidin-3-ylcarbamate Method 113
##STR00660## ##STR00661## 146 (S,Z)-tert-butyl 1-(2- 448
(S)-tert-butyl 1-(2- ((2,4-dioxothiazolidin-5- formyl-6-
ylidene)methyl)-6- isopropoxyphenyl) isopropoxyphenyl)
pyrrolidin-3-ylcarbamate pyrrolidin-3-ylcarbamate Method 114
##STR00662## ##STR00663## 147 (S,Z)-tert-butyl 1-(2- 334
(S)-tert-butyl 1-(2- ((2,4-dioxothiazolidin-5- ethoxy-6-
ylidene)methyl)-6- formylphenyl)pyrrolidin- ethoxyphenyl)
3-tlcarbamate pyrrolidin-3-ylcarbamate Method 115 ##STR00664##
##STR00665## 148 5-(2-(3-(1,3- 12.54 (s, 438 2-(3-(1,3-
dioxoisoindolin-2- 1 H) 7.83- dioxoisoindolin-2- yl)propoxy)-5-
7.79 (m, 5 yl)propoxy)-5- methoxybenzylidene) H) 7.04 (s,
methoxybenzaldehyde thiazolidine-2,4-dione 2 H) 6.86 Method 30B (s,
1 H) 4.08 (m, 2 H) 3.80- 3.75 (m,
5 H) 2.11 (m, 2 H) ##STR00666## ##STR00667## 149 5-(2-(3- 8.20 (s,
1 363 2-(3- (dimethylamino)pyrrolidin- H) 8.07 (d,
(dimethylamino)pyrrolidin- 1-yl)-5- 1 H) 7.82 1-yl)-5-
nitrobenzylidene) (s, 1 H) nitrobenzaldehyde thiazolidine-2,4-dione
6.96 (d, Method 116 1H) 3.58- 3.51 (m, 3H) 3.36 (m, 1 H) 3.04 (m, 1
H) 2.51 (s, 6 H), 2.40 (m, 1 H), 1.86 (m, 1 H) ##STR00668##
##STR00669## 150 (Z)-5-(4,5-dimethoxy-2- 8.32 (s, 1 309
4,5-dimethoxy-2- nitrobenzylidene) H) 8.25 nitrobenzaldehyde
thiazolidene-2,4-dione (brs, 1 H) 7.79 (s, 1 H) 7.02 (s, 1 H) 4.03
(s, 6 H) ##STR00670## ##STR00671## 151 tert-butyl (3S,4S)-1-(2-
8.30 (s, 1 H) 439 tert-butyl (3S,4S)-1-(2- chloro-6-((Z)-(2,4- 7.49
(d, chloro-6-formylphenyl)- dioxothiazolidin-5- 1 H) 7.42
4-hydroxypyrrolidin-3- ylidene)methyl)phenyl)- (d, 1 H) ylcarbamate
4-hydroxypyrrolidin-3- 7.28-7.20 Method 117 ylcarbamate (m, 1 H)
5.01 (d, 1 H) 4.39 (brs, 1 H) 4.27 (brs, 1 H) 4.05 (s, 1 H) 3.83
(dd, 1 H) 3.69 (dd, 1 H) 3.27 (brs, 1 H) 3.19 (dd, 1 H), 1.50 (s, 9
H) ##STR00672## ##STR00673## 152 (Z)-tert-butyl 1-(2- 465
tert-butyl 1-(2-chloro-6- chloro-6-(2,4- formylphenyl)-4-
dioxothiazolidin-5- methylpiperidin-3- ylidene)methyl)phenyl)-
yl(methyl)carbamate 4-methylpiperidin-3- Method 118
yl(methyl)carbamate ##STR00674## ##STR00675## 153 (Z)-tert-butyl
1-(2- 451 tert-butyl 1-(2-chloro-6- chloro-6-((2,4-
formylphenyl)-4- dioxothiazolidin-5- methylpiperidin-3-
ylidene)methyl)phenyl)- ylcarbamate 4-methylpiperidin-3- Method 119
ylcarbamate ##STR00676## ##STR00677## 154 (R,Z)-tert-butyl 1-(2-
404 (R)-tert-butyl 1-(2- ((2,4-dioxothiazolidin-5-
formylphenyl)piperidin- ylidene)methyl)phenyl)- 3-ylcarbamate
piperidin-3-ylcarbamate Method 120 ##STR00678## ##STR00679## 155
(S,Z)-tert-butyl 1-(2- 390 (S)-tert-butyl 1-(2-
((2,4-dioxothiazolidin-5- formylphenyl)pyrrolidin-
ylidene)methyl)phenyl)- 3-ylcarbamate pyrrolidin-3-ylcarbamate
Method 121 ##STR00680## ##STR00681## 156 (R,Z)-tert-butyl 1-(2- 502
(R)-tert-butyl 1-(2- ((2,4-dioxothiazolidin-5- formyl-6-(2,2,2-
ylidene)methyl)-6-(2,2,2- trifluoroethoxy)phenyl)
trifluoroethoxy)phenyl) piperidin-3-ylcarbamate
piperidin-3-ylcarbamate Method 122 ##STR00682## ##STR00683## 157
(S,Z)-tert-butyl 1-(2- 488 (S)-tert-butyl 1-(2-
((2,4-dioxothiazolidin-5- formyl-6-(2,2,2-
ylidene)methyl)-6-(2,2,2- trifluoroethoxy)phenyl)
trifluoroethoxy)phenyl) pyrrolidin-3-ylcarbamate
pyrrolidin-3-ylcarbamate Method 123 ##STR00684## ##STR00685## 158
(R,Z)-tert-butyl 1-(2- 478 (R)-tert-butyl 1-(2-
((2,4-dioxothiazolidin-5- formyl-6-(2- ylidene)methyl)-6-(2-
methoxyethoxy)phenyl) methoxyethoxy)phenyl) piperidin-3-ylcarbamate
piperidin-3-ylcarbamate Method 124 ##STR00686## ##STR00687## 159
(S,Z)-tert-butyl 1-(2- 464 (S)-tert-butyl 1-(2-
((2,4-dioxothiazolidin-5- formyl-6-(2- ylidene)methyl)-6-(2-
methoxyethoxy)phenyl) methoxyethoxy)phenyl)
pyrrolidin-3-ylcarbamate pyrrolidin-3-ylcarbamate Method 125
##STR00688## ##STR00689## 160 (R,Z)-tert-butyl 1-(2- 488
(R)-tert-butyl 1-(2- (cyclopentyloxy)-6-((2,4- (cyclopentyloxy)-6-
dioxothiazolidin-5- formylphenyl)piperidin- ylidene)methyl)phenyl)
3-ylcarbamate piperidin-3-ylcarbamate Method 126 ##STR00690##
##STR00691## 161 (R,Z)-tert-butyl 1-(2- 474 (R)-tert-butyl 1-(2-
cyclobutoxy)-6-((2,4- cyclobutoxy-6- dioxothiazolidin-5-
formylphenyl) ylidene)methyl)phenyl) piperidin-3-ylcarbamate
piperidin-3-ylcarbamate Method 127 ##STR00692## ##STR00693## 162
(R,Z)-tert-butyl 1-(2- 447 (R)-tert-butyl 1-(4- carbamoyl-2-((2,4-
carbamoyl-2- dioxothiazolidin-5- formylphenyl)
ylidene)methyl)phenyl) piperidin-3-ylcarbamate
piperidin-3-ylcarbamate Method 128 ##STR00694## ##STR00695## 163
(S,Z)-tert-butyl 1-(4- 447 (S)-tert-butyl 1-(4- carbamoyl-2-((2,4-
carbamoyl-2- dioxothiazolidin-5- formylphenyl)
ylidene)methyl)phenyl) piperidin-3-ylcarbamate
piperidin-3-ylcarbamate Method 129 ##STR00696## ##STR00697## 164
(R,Z)-4-(3-(tert- 447 (R)-4-(3-(tert- butoxycarbonylamino)
butoxycarbonylamino) piperidin-1-yl)-3-((2,4- piperidin-1-yl)-3-
dioxothiazolidin-5- formylbenzoic acid ylidene)methyl)benzoic
Method 130 acid ##STR00698## ##STR00699## 165 (S,Z)-4-(3-(tert- 433
(S)-4-(3-(tert- butoxycarbonylamino) butoxycarbonylamino)
pyrrolidin-1-yl)-3-((2,4- pyrrolidin-1-yl)-3- dioxothiazolidin-5-
formylbenzoic acid ylidene)methyl)benzoic Method 131 acid
##STR00700## ##STR00701## 166 (R,Z)-tert-butyl 1-(3- 480
(R)-tert-butyl 1-(3- ((2,4-dioxothiazolidin-5- formylbiphenyl-2-
ylidene)methyl)biphenyl- yl)piperidin-3- 2-yl)piperidin-3-
ylcarbamate ylcarbamate Method 201 ##STR00702## ##STR00703##
##STR00704##
Method 38
(Z)-tert-butyl
3-(4-(3-((2,4-dioxothiazolidin-5-ylidene)methyl)pyridin-2-yl)piperazin-1--
yl)-3-oxopropylcarbamate
[0314] A 50 mL vial was charged with a magnetic spin bar,
(Z)-5-((2-(piperazin-1-yl)pyridin-3-yl)methylene)thiazolidine-2,4-dione
hydrochloride (Example 89) (0.125 g, 0.38 mmol),
3-(tert-butoxycarbonylamino)propanoic acid (0.109 g, 0.57 mmol),
DMF (1.912 ml), and diisopropylethylamine (0.334 ml, 1.91 mmol).
With stirring, HATU (0.291 g, 0.76 mmol) was added and the reaction
was warmed to 50.degree. C. for 3 h. The reaction was then diluted
with water and extracted with ethyl acetate (3.times.50 mL). The
combined organic extract was dried with MgSO.sub.4, filtered
through a bed of Celite, and conc. in vacuo to yield the product
which was purified via silica gel chromatography (80 g) using ethyl
acetate/hexanes (1:1) as eluent to provide the title compound as an
off white solid. (0.080 g, 45.3%); m/z 462.
[0315] The following intermediates were prepared by the procedure
of Method 38, using the appropriate starting materials.
TABLE-US-00015 Method Compound .sup.1H NMR m/z SM 39 (Z)-tert-butyl
4-(4-(2- 502 (5Z)-5-(2-piperazin-1- ((2,4-dioxothiazolidin-5-
ylbenzylidene)-1,3- ylidene)methyl)phenyl) thiazolidine-2,4-dione
piperazine-1- carbonyl)piperidine-1- carboxylate ##STR00705##
##STR00706## Example 115 and 1-(tert- butoxycarbonyl)piperidine-
4-carboxylic acid ##STR00707## 40 (Z)-tert-butyl 3-(4-(2- 560
(Z)-5-(2-(piperazin-1-yl)- ((2,4-dioxothiazolidin-5-
5-(trifluoromethyl) ylidene)methyl)-4- benzylidene)
(trifluoromethyl)phenyl) thiazolidine-2,4- piperazine-1- dione
carbonyl)piperidine-1- carboxylate ##STR00708## ##STR00709##
Example 87 and 1-(tert- butoxycarbonyl)piperidine- 3-carboxylic
acid ##STR00710## 41 (Z)-tert-butyl 3-(4-(2- 530
(Z)-5-(2-(piperazin-1-yl)- ((2,4-dioxothiazolidin-5-
5-(trifluoromethyl) ylidene)methyl)-4- benzylidene)
(trifluoromethyl)phenyl) thiazolidine-2,4- piperazin-1-yl)-3- dione
oxopropylcarbamate ##STR00711## ##STR00712## Example 87 and
3-[(tert- butoxycarbonyl)amino] propanoic acid ##STR00713## 42
(Z)-tert-butyl 3-(4-(2- 492 (Z)-5-(3-methoxy-2-
((2,4-dioxothiazolidin-5- (piperazin-1-yl)- ylidene)methyl)-6-
benzylidene) methoxyphenyl)piperazin- thiazolidine-2,4- 1-yl)-3-
dione oxopropylcarbamate ##STR00714## ##STR00715## Example 97 and
3-[(tert- butoxycarbonyl)amino] propanoic acid ##STR00716## 43
(Z)-tert-butyl 3-(4-(2- 496 (Z)-5-(3-chloro-2- chloro-6-((2,4-
(piperazin-1-yl)- dioxothiazolidin-5- benzylidene)
ylidene)methyl)phenyl) thiazolidine-2,4- piperazin-1-yl)-3- dione
oxopropylcarbamate ##STR00717## ##STR00718## Example 98 and
3-[(tert- butoxycarbonyl)amino] propanoic acid ##STR00719## 50
(Z)-tert-butyl 3-(4-(2- 516 (Z)-5-(2-(1,4-diazepan-1-
((2,4-dioxothiazolidin-5- yl)benzylidene) ylidene)methyl)phenyl)-
thiazolidine-2,4-dione 1,4-diazepane-1- carbonyl)piperidine-1-
carboxylate ##STR00720## ##STR00721## Example 106 and 1-(tert-
butoxycarbonyl)piperidine- 3-carboxylic acid ##STR00722## 51
(Z)-tert-butyl 5-(4-(2- 504 (Z)-5-(2-(1,4-diazepan-1-
((2,4-dioxothiazolidin-5- yl)benzylidene) ylidene)methyl)phenyl)-
thiazolidine-2,4-dione 1,4-diazepan-1-yl)-5- oxopentylcarbamate
##STR00723## ##STR00724## Example 106 and 5-[(tert-
butoxycarbonyl)amino] pentanoic acid ##STR00725## 52 (Z)-tert-butyl
4-(4-(2- 490 (Z)-5-(2-(1,4-diazepan-1- ((2,4-dioxothiazolidin-5-
yl)benzylidene) ylidene)methyl)phenyl)- thiazolidine-2,4-dione
1,4-diazepan-1-yl)-4- oxobutylcarbamate ##STR00726## ##STR00727##
Example 106 and 4-[(tert- butoxycarbonyl)amino] butanoic acid
##STR00728## 53 (Z)-tert-butyl 3-(4-(2- 475
(Z)-5-(2-(1,4-diazepan-1- ((2,4-dioxothiazolidin-5- yl)benzylidene)
ylidene)methyl)phenyl)- thiazolidine-2,4-dione
1,4-diazepan-1-yl)-3- oxopropylcarbamate ##STR00729## ##STR00730##
Example 106 and 3-[(tert- butoxycarbonyl)amino] propanoic acid
##STR00731## 55 (Z)-tert-butyl 4-(4-(2- 476 (5Z)-5-(2-piperazin-1-
((2,4-dioxothiazolidin-5- yl)benzylidene)-1,3-
ylidene)methyl)phenyl) thiazolidine-2,4-dione piperazin-1-yl)-4-
oxobutylcarbamate ##STR00732## ##STR00733## Example 115 and
4-[(tert- butoxycarbonyl)amino] butanoic acid ##STR00734## 56
(Z)-tert-butyl 5-(4-(2- 490 (5Z)-5-(2-piperazin-1-
((2,4-dioxothiazolidin-5- ylbenzylidene)-1,3-
ylidene)methyl)phenyl) thiazolidine-2,4-dione piperazin-1-yl)-5-
oxopentylcarbamate ##STR00735## ##STR00736## Example 115 and nd
5-[(tert- butoxycarbonyl)amino] pentanoic acid ##STR00737## 57
(Z)-tert-butyl 4-(4-(4-(2- 593 (5Z)-5-(2-piperazin-1-
((2,4-dioxothiazolidin-5- ylbenzylidene)-1,3-
ylidene)methyl)phenyl) thiazolidine-2,4-dione piperazine-1-
carbonyl)benzyl) piperazine-1-carboxylate ##STR00738## ##STR00739##
Example 115 and 4-{[4-(tert- butoxycarbonyl)piperazin-
1-yl]methyl}benzoic acid ##STR00740## 58 (Z)-tert-butyl 3-(4-(2-
524 (5Z)-5-(2-piperazin-1- ((2,4-dioxothiazolidin-5-
yl)benzylidene)-1,3- ylidene)methyl)phenyl) thiazolidine-2,4-dione
piperazine-1- carbonyl)benzylcarbamate ##STR00741## ##STR00742##
Example 115 and 3-{[(tert- butoxycarbonyl)amino) methyl}benzoic
acid ##STR00743## 63 tert-butyl 3-(4-(2- 501 (5Z)-5-(2-piperazin-1-
((2,4-dioxothiazolidin-5- ylbenzylidene)-1,3-
ylidene)methyl)phenyl) thiazolidine-2,4-dione piperazine-1-
carbonyl)piperidine-1- carboxylate ##STR00744## ##STR00745##
Example 115 And 1-(tert- butoxycarbonyl)piperidine- 3-carboxylic
acid ##STR00746## 64 tert-butyl 3-(4-(2- 473 (5Z)-5-(2-piperazin-1-
((2,4-dioxothiazolidin-5- ylbenzylidene)-1,3-
ylidene)methyl)phenyl) thiazolidine-2,4-dione piperazine-1-
carbonyl)azetidine-1- carboxylate ##STR00747## ##STR00748## Example
115 And 1-(tert- butoxycarbonyl)azetidine- 3-carboxylic acid
##STR00749## 66 (R,Z)-tert-butyl 5-(1-(2- 550 (R,Z)-5-(2-(3-
((2,4-dioxothiazolidin-5- aminopyrrolidin-1-yl)-
ylidene)methyl)-4,5- 4,5- dimethoxyphenyl) dimethoxybenzylidene)
pyrrolidin-3-ylamino)-5- thiazolidine-2,4-dione oxopentylcarbamate
##STR00750## ##STR00751## Example 100 And 5-[(tert-
butoxycarbonyl)amino] pentanoic acid ##STR00752## 67
(S,Z)-tert-butyl 5-(1-(2- 550 (S,Z)-5-(2-(3-
((2,4-dioxothiazolidin-5- aminopyrrolidin-1-yl)-
ylidene)methyl)-4,5- 4,5- dimethoxyphenyl) dimethoxybenzylidene)
pyrrolidin-3-ylamino)-5- thiazolidine-2,4-dione oxopentylcarbamate
##STR00753## ##STR00754## Example 101 And 5-[(tert-
butoxycarbonyl)amino] pentanoic acid ##STR00755## 75 (Z)-3-(1,3-
552 (5Z)-5-[2-(3- dioxoisoindolin-2-yl)-N- aminopyrrolidin-1-yl)-
(1-(2-((2,4- 4,5- dioxothiazolidin-5- dimethoxybenzylidene]-
ylidene)methyl)-4,5- 1,3-thiazolidine-2,4-dione dimethoxyphenyl)
pyrrolidin-3-yl) propanamide ##STR00756## ##STR00757## Example 118
and 3-(1,3-dioxo-1,3- dihydro-2H-isoindol-2- yl)propanoic acid
##STR00758## 76 5Z)-(2-(4-(3-(1,3- (5Z)-5-(2-piperazin-1-
dioxoisoindolin-2- ylbenzylidene)-1,3- yl)propanoyl)piperazin-1-
thiazolidine-2,4-dione yl)benzylidene) thiazolidine-2,4-dione
##STR00759## ##STR00760## Example 115 and 3-(1,3-dioxo-1,3-
dihydro-2H-isoindol-2- yl)propanoic acid ##STR00761##
##STR00762##
Method 59
(Z)-tert-butyl
2-(1-(2-((2,4-dioxothiazolidin-5-ylidene)methyl)-4,5-dimethoxyphenyl)pyrr-
olidin-3-ylamino)ethylcarbamate
[0316] A mixture of
(5Z)-5-{2-[3-(dimethylamino)pyrrolidin-1-yl]-4,5-dimethoxybenzylidene}-1,-
3-thiazolidine-2,4-dione (Example 52) (120 mg, 0.31 mmol) and
tert-butyl 2-oxoethylcarbamate (198 mg, 1.24 mmol) in
CH.sub.2Cl.sub.2 (20 mL) were heated to reflux for 15 min followed
by the addition of sodium triacetoxyhydroborate (65.9 mg, 0.31
mmol). The reaction mixture was refluxed overnight before being
allowed to cool to ambient temperature. Water (.about.0.5 mL) was
added and the mixture was allowed to stir for 15 min before being
loaded onto a silica gel column which was eluted with ethyl
acetate/hexane (10:1) to yield the title compound as an orange
solid as (60.0 mg, 39.2%); m/z 493.
[0317] The following intermediates were prepared by the procedure
of Method 59, using the appropriate starting materials.
TABLE-US-00016 Method Compound .sup.1H NMR m/z SM 60 ##STR00763##
433 ##STR00764## 61 ##STR00765## 507 ##STR00766## 62 ##STR00767##
448 ##STR00768## 68 ##STR00769## 507 ##STR00770## 69 ##STR00771##
507 ##STR00772## 70 ##STR00773## 545 ##STR00774## 71 ##STR00775##
508 ##STR00776## 72 ##STR00777## 512 ##STR00778## 73 ##STR00779##
507 ##STR00780## 74 ##STR00781## 477 ##STR00782## 77 ##STR00783##
509 ##STR00784## 167 ##STR00785## 557 ##STR00786## 168 ##STR00787##
496 ##STR00788## 169 ##STR00789## 496 ##STR00790## 170 ##STR00791##
510 ##STR00792## 171 ##STR00793## 525 ##STR00794##
##STR00795##
Method 172
3-ethoxy-2-fluorobenzaldehyde
[0318] A 200 mL round bottom flask was charged with a magnetic stir
bar, 3-ethoxy-2-fluorobenzonitrile (1.000 g, 6.05 mmol), and
anhydrous toluene (12.92 ml). The sol'n was placed under argon and
cooled to 0.degree. C. with an ice bath. DIBAL-H (7.27 ml, 7.27
mmol) (1M in PhMe) was then added drop wise via syringe and the
reaction was allowed to stir to rt overnight. To this mixture was
added 10% HCl until the sol'n reached a pH of .about.2. The
resulting mixture was then left to stir for 0.5 h. and was then
poured into a separatory funnel and extracted with ethyl acetate
(2.times.200 mL). The combined organic extract was dried with
MgSO.sub.4, filtered, and conc. in vacuo to yield the crude product
which was purified via silica gel chromatography (80 g) using ethyl
acetate/hexanes (1:4) as eluent to provide pure
3-ethoxy-2-fluorobenzaldehyde (0.810 g, 80%). m/z 196.
[0319] The following intermediates were prepared by the procedure
of Method 172, using the appropriate starting materials.
TABLE-US-00017 173 ##STR00796## 197 ##STR00797## 174 ##STR00798##
237 ##STR00799## 175 ##STR00800## 223 ##STR00801## 176 ##STR00802##
183 ##STR00803## 177 ##STR00804## 223 ##STR00805## 178 ##STR00806##
10.32 (s, 1 H) 7.56- 7.35 (m, 2 H) 7.13- 6.96 (m, 1 H) 4.33- 4.22
(m, 2 H) 3.84- 3.77 (m, 2 H) 3.42 (s, 3 H) 199 ##STR00807## 179
##STR00808## 195 ##STR00809## 180 ##STR00810## 10.31 (s, 1 H) 7.41-
7.36 (m, 2 H) 7.05- 7.03 (m, 1 H) 4.94- 4.85 (m, 1 H) 2.01- 1.83
(m, 8 H) 209 ##STR00811##
Method 181
##STR00812##
[0321] A 100 mL round bottom flask was charged with a magnetic stir
bar, 2-fluoro-3-hydroxybenzonitrile (0.500 g, 3.65 mmol), MeCN
(13.89 ml), 1-bromo-2-methylpropane (0.699 ml, 7.29 mmol), and
K.sub.2CO.sub.3 (1.008 g, 7.29 mmol). The mixture was then placed
in an oil bath and heated to 60.degree. C. with stirring overnight.
This mixture was then cooled to rt, filtered through a bed of
Celite, and conc. In vacuo. The crude material was purified via
silica gel chromatography (40 g) using ethyl acetate/hexanes (1:4)
as eluent to afford pure 2-fluoro-3-isobutoxybenzonitrile (0.610 g,
87%) as a colorless oil. M/z 194.
[0322] The following intermediates were prepared by the procedure
of Method 181, using the appropriate starting materials.
TABLE-US-00018 182 ##STR00813## 234 ##STR00814## 183 ##STR00815##
220 ##STR00816## 184 ##STR00817## 179 ##STR00818## 185 ##STR00819##
196 ##STR00820## 186 ##STR00821## 192 ##STR00822## 187 ##STR00823##
##STR00824##
Method 188
##STR00825##
[0323] (.+-.)-tert-butyl-4-hydroxypyrrolidin-3-ylcarbamate
[0324] A racemic mixture of trans-benzyl
3-(tert-butoxycarbonylamino)-4-hydroxypyrrolidine-1-carboxylate
(3.36 g, 9.99 mmol) (Method 190) in MeOH (40 mL) was degassed, then
10 wt % Pd/C (3.19 g, 3.00 mmol) was added. The mixture was
degassed, charged with H.sub.2, and stirred overnight. The mixture
was filtered through a bed of Celite, washed with methanol, the
filtrate was dried over anhydrous Na.sub.2SO.sub.4, filtered and
conc. in vacuo to yield a white solid as racemic
tert-butyl-4-hydroxypyrrolidin-3-ylcarbamate (2.020 g, 100%).
.sup.1H NMR (400 MHz, MeOD) .delta. .quadrature.ppm 4.13 (dt, 1H),
3.89-3.75 (m, 1H), 3.35 (brs, 1H), 3.14 (dd, 1H), 2.93-2.73 (m,
2H), 1.46 (s, 10H); m/z 203.
[0325] The following intermediates were prepared by the procedure
of Method 188, using the appropriate starting materials.
TABLE-US-00019 Method Compound .sup.1H NMR m/z SM 189 ##STR00826##
216 ##STR00827##
Method 190
##STR00828##
[0326] (.+-.)-benzyl
3-(tert-butoxycarbonylamino)-4-hydroxypyrrolidine-1-carboxylate
[0327] To a mixture of racemic trans-benzyl
3-amino-4-hydroxypyrrolidine-1-carboxylate (2.67 g, 11.30 mmol)
(Method 193) and di-tert-butyl dicarbonate (3.70 g, 16.95 mmol) in
CH.sub.2Cl.sub.2 (50 mL) was added Et.sub.3N (4.73 mL, 33.90 mmol)
at 0.degree. C. The mixture was then stirred at rt for 48 h. The
reaction mixture was then conc. in vacuo giving a residue which was
purified via silica gel chromatography (40% to 90% ethyl
acetate/hexane) to yield a white solid as (.+-.)-benzyl
3-(tert-butoxycarbonylamino)-4-hydroxypyrrolidine-1-carboxylate
(3.36 g, 88%). .sup.1H NMR (400 MHz, Dichloromethane-d2) .delta.
.quadrature.ppm 7.48-7.32 (m, 5H), 5.21-5.00 (m, 2H), 4.78 (brs,
1H), 4.29-4.18 (m, 1H), 3.84 (dd, 1H), 3.74 (d, 1H), 3.41-3.12 (m,
2H), 1.49-1.33 (m, 9H); m/z 337
[0328] The following starting materials were prepared by the
procedure of Method 190 using the appropriate starting
materials.
TABLE-US-00020 Method Compound .sup.1H NMR m/z SM 191 ##STR00829##
350 ##STR00830## 192 ##STR00831## 352 ##STR00832##
Method 193
##STR00833##
[0329] (.+-.)-benzyl 3-amino-4-hydroxypyrrolidine-1-carboxylate
[0330] A mixture of racemic trans-benzyl
3-azido-4-hydroxypyrrolidine-1-carboxylate (2.96 g, 11.29 mmol)
(Method 195) and triphenylphosphine (3.11 g, 11.85 mmol) in THF (25
mL) was stirred at rt for 7 h. Water (2 mL, 111 mmol) was then
added and the mixture then stirred at 50.degree. C. overnight. The
mixture was then concentrated under reduced pressure, and the
residue was purified via silica gel chromatography (100% DCM to
37:3:60/methanol:Et.sub.3N:DCM) to yield the title compound (2.96
g, 11.29 mmol) as an oil. .sup.1H NMR (400 MHz, Dichloromethane-d2)
.delta. ppm 7.38-7.19 (m, 5H), 5.02 (s, 2H), 3.89 (brs, 1H), 3.62
(dd, 2H), 3.29-3.15 (m, 2H), 3.12-3.01 (m, 1H); m/z 236.
[0331] The following starting materials were prepared by the
procedure of Method 193 using the appropriate starting
materials.
TABLE-US-00021 Method Compound .sup.1H NMR m/z SM 194 ##STR00834##
250 ##STR00835##
Method 195
##STR00836##
[0332] (.+-.)-benzyl 3-azido-4-hydroxypyrrolidine-1-carboxylate
[0333] To a stirred mixture of benzyl
6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (5.2 g, 23.72 mmol)
(Method 197) in DMF (30 mL) was added sodium azide (2.313 g, 35.58
mmol) in a mixture of acetone (20.00 mL) and water (10.00 mL). The
resulting mixture was stirred at 80.degree. C. for 24 h. The
mixture was then diluted with water and ether, separated, and the
organic layer was washed with brine, dried and conc. invacuo. The
resulting material was purified via silica gel chromatography
(eluted with 15% to 35% ethyl acetate/hexane), yielding the title
compound as a yellow solid (4.10 g, 65.9%). .sup.1H NMR (400 MHz,
dichloromethane-d2) .delta. .quadrature.ppm 7.50-7.25 (m, 5H),
5.43-5.25 (m, 2H), 4.31 (brs, 1H), 4.00 (brs, 1H), 3.77 (dd, 1H),
3.69 (dd, 1H), 3.53 (d, 1H), 3.44 (dd, 1H), 2.17 (brs, 1H); m/z
263.
[0334] The following starting materials were prepared by the
procedure of Method 195 using the appropriate starting
materials.
TABLE-US-00022 Method Compound .sup.1H NMR m/z SM 196 ##STR00837##
276 ##STR00838##
Method 197
##STR00839##
[0335] benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate
[0336] To a stirred mixture of benzyl
2,5-dihydro-1H-pyrrole-1-carboxylate (5 g, 24.60 mmol) in DCM (80
mL) was added 3-chlorobenzoperoxoic acid (6.89 g, 30.75 mmol) at
0.degree. C. The mixture was then stirred at rt overnight. The
reaction mixture was then filtered through a bed of Celite and the
filtrate was washed with sat'd aqueous Na.sub.2CO.sub.3 and brine.
The organic was then separated and dried over anhydrous
Na.sub.2SO.sub.4, filtered, and conc. in vacuo to yield the title
compound that was used for next step without further
purification.
[0337] The following starting materials were prepared by the
procedure of Method 197 using the appropriate starting
materials.
TABLE-US-00023 Method Compound .sup.1H NMR m/z SM 198 ##STR00840##
217 ##STR00841##
Method 199
##STR00842##
[0338] 2-(3-amino-4-methylpiperidin-1-yl)-3-chlorobenzaldehyde
[0339] To a stirred solution of methyl
1-(2-chloro-6-formylphenyl)-4-methylpiperidin-3-ylcarbamate (220
mg, 0.71 mmol) (Method 119) in MeOH (3 ml) was added 40% aqueous
solution of KOH (10 ml) drop wise, and the resulting mixture was
heated at reflux for 16 h. The mixture was allowed to cool to rt,
diluted with water, and extracted with DCM. The combined organic
extract was dried over anhydrous Na.sub.2SO.sub.4, filtered, and
conc. in vacuo. The resulting residue was purified via silica gel
chromatography (100% ethyl acetate to 10% methanol in ethyl
acetate) to yield the title compound as a light yellow gum (0.057
g, 31.9%). .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 8.44 (s,
1H), 7.40 (t, 2H), 7.07 (t, 1H), 4.29 (d, 1H), 3.58 (ddd, 1H), 3.38
(dd, 1H), 3.11 (td, 1H), 2.81 (d, 1H), 2.20-1.91 (m, 1H), 1.31-1.14
(m, 1H), 1.08 (d, 3H), 0.63-0.37 (m, 1H).
Method 200
##STR00843##
[0340] 2-fluoro-3-(2,2,2-trifluoroethoxy)benzonitrile
[0341] A stirred solution of 2-fluoro-3-hydroxybenzonitrile (800
mg, 5.83 mmol) in DMF (10 mL) at 0.degree. C. was treated
portionwise with NaH (280 mg, 7.00 mmol) (60% oil dispersion). The
reaction mixture was then stirred for 0.5 h and
2,2,2-trifluoroethyl trifluoromethanesulfonate (1490 mg, 6.42 mmol)
was added. The reaction was allowed to warm to rt overnight with
stirring. The reaction mixture was then treated with water (40 mL)
and brine (5 mL) and extracted with ethyl acetate (.about.50 mL).
The organic extract was washed with water, dried over anhydrous
Na.sub.2SO.sub.4, filtered and conc. in vacuo to afford a residue
which was purified via silica gel chromatography (10% to 30% ethyl
acetate/hexanes) to yield the title compound as a white solid (1040
mg, 81%). .sup.1H NMR (400 MHz, MeOD) .delta. ppm 7.56 (td, 1H),
7.47-7.38 (m, 1H), 7.38-7.24 (m, 1H), 4.73 (q, 2H); m/z 220.
Method 201
(R)-tert-butyl 1-(3-formylbiphenyl-2-yl)piperidin-3-ylcarbamate
##STR00844##
[0343] A mixture of (R)-tert-butyl
1-(2-bromo-6-formylphenyl)piperidin-3-yl carbamate (Method 95) (300
mg, 0.78 mmol), phenylboronic acid (143 mg, 1.17 mmol),
1,1'-bis(di-tert-butyllphosphino)ferrocenedichloro palladium (II)
complex (40.8 mg, 0.06 mmol), and Na.sub.2CO.sub.3 (124 mg, 1.17
mmol) was suspended in dioxane (5 mL) and water (1.50 mL) and
stirred at 110.degree. C. for overnight under an atmosphere of
nitrogen. The reaction was cooled to rt and water (.about.50 mL)
and ethyl acetate (.about.50 mL) was added to the mixture. The
organic phase was separated, dried over anhydrous MgSO.sub.4,
filtered, and conc. in vacuo affording a residue purified with via
silica gel chromatography (40 g) using a gradient of 5% to 30%
ethyl acetate/hexanes to yield the title compound as a low melting
solid (168 mg, 56.4%); m/z 381.
[0344] One may purify examples provided above by reverse-phase HPLC
in a solvent contain varying concentrations of trifluoroacetic acid
or hydrochloric acid. Thus the examples above may be isolated as,
the freebase, hydrochloride salt, or trifluoroacetate salt.
[0345] PIM 1 and 2 enzyme assay descriptions:
PIM1 In-Vitro Mobility Shift Assay
[0346] One may determine the activity of purified human His-PIM1
[2-313] enzyme in-vitro using a mobility shift assay on a Caliper
LC3000 reader (Caliper, Mass.), which measures fluorescence of a
phosphorylated and unphosphorylated FL-Ahx-Bad
(FITC-(AHX)RSRHSSYPAGT-COOH, Primm 200606-00289, Primm Biotech, MA)
and calculates a ratiometric value to determine percent turnover.
One may express PIM1 (University of Dundee, Scotland) in
baculovirus system with a typical yield of >85% purity.
[0347] One determines phosphorylation of the FL-Ahx-Bad in the
presence and absence of the compound of interest. One preincubates
5 ul of Enzyme/Substrate/adenosine triphosphate (ATP) mix
consisting of 2.4 nM PIM1, 3.6 uM FL-Ahx-Bad, and 240 uM ATP in
1.2.times. buffer with 2 ul of compound for 20 minutes at
25.degree. C. One initiates reactions with 5 ul of Metal mix
consisting of 24 mM MgCl.sub.2 in 1.2.times. buffer and incubated
at 25.degree. C. for 90 minutes and stops the reactions by addition
of 5 ul of Stop mix consisting of 100 mM HEPES, 121 mM
ethylenediamine tetraacetic acid, 0.8% Coatin Reagent 3 (Caliper,
Mass.), and 0.01% Tween. One detects phosphorylated and
unphosphorylated substrate by a Caliper LC3000 reader (Caliper,
Mass.) in the presence of separation buffer consisting of 100 mM
HEPES, 16 mM ethylenediamine tetraacetic acid, 0.1% Coatin Reagent
3 (Caliper, Mass.), 0.015% Brij-35, 5% DMSO, and 5.6 mM MgCl.sub.2.
One may use the following separation conditions for a Caliper
LC3000: -1.0 PSI, -2000 V upstream voltage, -400 V downstream
voltage, 0.2 second sample sip, 45 second post sip, 10% laser
strength.
PIM2 In-Vitro Mobility Shift Assay
[0348] One may determine the activity of purified human His-PIM2
[23-299] enzyme in-vitro using a mobility shift assay on a Caliper
LC3000 reader (Caliper, Mass.), which measures fluorescence of a
phosphorylated and unphosphorylated FL-Ahx-Bad
(FITC-(AHX)RSRHSSYPAGT-COOH, Primm 200606-00289, Primm Biotech, MA)
and calculates a ratiometric value to determine percent turnover.
One may express PIM2 (produced at AstraZeneca, R&D Boston) in
E. coli cells with a typical yield of >90% purity.
[0349] One determines phosphorylation of the FL-Ahx-Bad in the
presence and absence of the compound of interest. One preincubates
5 uL of Enzyme/Substrate/adenosine triphosphate (ATP) mix
consisting of 2.4 nM PIM1, 3.6 uM FL-Ahx-Bad, and 12 uM ATP in
1.2.times. buffer with 2 ul of compound for 20 minutes at
25.degree. C. One initiates reactions with 5 uL of Metal mix
consisting of 24 mM MgCl.sub.2 in 1.2.times. buffer and incubates
at 25.degree. C. for 90 minutes. One stops reactions by addition of
5 uL of Stop mix consisting of 100 mM HEPES, 121 mM ethylenediamine
tetraacetic acid, 0.8% Coatin Reagent 3 (Caliper, Mass.), and 0.01%
Tween. One detects phosphorylated and unphosphorylated substrate by
a Caliper LC3000 reader (Caliper, Mass.) in the presence of
separation buffer consisting of 100 mM HEPES, 16 mM ethylenediamine
tetraacetic acid, 0.1% Coatin Reagent 3 (Caliper, Mass.), 0.015%
Brij-35, 5% DMSO, and 5.6 mM MgCl.sub.2. One may use the following
separation conditions for a Caliper LC3000: -1.0 PSI, -2000 V
upstream voltage, -400 V downstream voltage, 0.2 second sample sip,
45 second post sip, 10% laser strength.
[0350] Using the above described assays, or appropriate
modifications thereof, preferred compounds disclosed herein
generally have an IC.sub.50 for PIM1 of less that 5 micromolar
(uM), and even more preferred of less than 1 micromolar. The table
1 below provides the percent inhibition of PIM1 at 0.3 micromolar
for Examples provided herein. Several examples were tested more
than once. Variations in the experimental outcomes, negative
values, or values over 100% inhibition are presumably due to
experimental error inherent in the assay.
TABLE-US-00024 TABLE 1 Example number PIM1 % I at 0.3 uM PIM2 % I
at 0.3 uM 1 >95 77.7 2 >95 >95 3 >95 58.0 4 >95 79.6
5A >95 79.9 5B >95 >95 6 79.4 9.5 7 5.4 <5 8 16.3 <5
9 6.9 <5 10 >95 50.1 11 89.4 17.9 12 80.2 <5 13 <5
<5 14 >95 69.9 15 12.9 <5 16 13.9 <5 17 29.8 <5 18
<5 <5 19 >95 38.3 20 86.5 19.1 21 82.9 15.8 22 81.9 8.5 23
87.6 19.7 24 >95 44.3 25 >95 68.4 26 >95 49.6 27 90.8 25.1
28 90.0 27.4 29 92.8 30 90.8 15.6 31 92.8 23.3 32 94.0 31.9 33
>95 >95 34 >95 39.3 35 <5 <5 36 >95 >95 37
89.7 69.4 38 >95 92.9 39 89.4 57.3 40 >95 89.8 41 74.0 25.1
42 58.8 23.3 43 55.4 14.7 44 83.8 46.7 45 40.1 14.3 46 13.4 15.7 47
50.0 26.3 48 84.4 41.3 49 >95 86.3 50 93.7 45.4 51 85.5 80.6 52
>95 93.5 53 92.3 82.1 54 88.1 73.1 55 11.0 <5 56 90.7 33.5 57
53.3 42.6 58 16.0 7.1 59 <5 6.6 60 35.4 11.3 61 81.8 28.1 62
62.1 17.5 63 79.2 21.5 64 86.5 25.7 65 45.3 18.9 66 50.3 20.9 67
<5 68 41.9 9.0 69 <5 16.3 70 <5 <5 71 <5 <5 72
<5 <5 73 <5 <5 74 75 >95 69.5 76 59.6 27.6 77 51.2
22.7 78 71.4 30.0 79 90.0 60.7 80 <5 81 <5 82 87.4 58.2 83
34.0 84A 92.9 54.3 84B 84C 47.8 29.6 84D 27.8 <5 84E 11.7 6.1
84F 87.4 52.4 84G 92.0 63.0 84H >95 67.0 84I >95 82.7 84J
93.3 40.4 84K >95 90.8 84L >95 55.2 84M >95 80.9 84N 92.8
81.4 84O <5 <5 85 >95 82.4 86 >95 >95 87 >95 84.2
88 >95 88.4 89 48.4 21.5 90 78.2 86.3 91 6.6 16.4 92 >95 81.5
93 >95 66.3 94 >95 >95 95 >95 >95 96 >95 >95
97 >95 86.4 98 >95 81.4 99 >95 >95 100 93.0 93.9 101
>95 >95 102 93.3 91.9 103 >95 88.7 104 >95 92.4 105
>95 92.4 106 >95 92.8 107 >95 >95 108 >95 >95 109
64.2 65.8 110 90.9 90.7 111 >95 >95 112 >95 >95 113
>95 >95 114 >95 >95 115 93.3 76.1 116 >95 >95 117
>95 >95 118 >95 >95 119 56.2 20.1 120 58.9 22.2 121
>95 87.4 122A 88.2 55.0 122B >95 92.3 122C >95 >95 122D
>95 >95 122E >95 >95 122F >95 >95 122G >95
92.1 122H >95 >95 122I >95 >95 122J >95 >95 122K
>95 >95 122L >95 >95 122M >95 >95 122N >95
>95 1220 >95 >95 122P >95 >95 122Q >95 >95
122R >95 89.6 122S >95 >95 122T >95 >95 122U >95
>95 122V >95 >95 122W >95 >95 122X >95 67.1 122Y
>95 >95 122Z >95 >95 122AA >95 >95 122AB >95
>95 122AC >95 >95 122AD >95 >95 122AE >95 >95
122AF 83.9 87.9 122AG 68.9 86.7 122AH 19.0 14.0 122AI >95 >95
123 >95 >95 124 >95 >95 125 >95 >95 126 >95
>95 127 >95 >95 128 81.2 49.0 129A >95 >95 129B
>95 >95 129C 85.0 52.1 130 66.2 45.5 131A 27.1 <5 131B
<5 <5 132 93.0 88.1 133 >95 93.4 134 >95 85.2 135 42.5
10.8 136 82.8 44.6 137 55.1 18.6 138 87.9 63.2 139 58.1 15.1 140
73.3 52.0 141 34.9 <5 142 86.1 75.2 143 85.9 49.8 144 63.2 21.2
145 >95 80.1 146 88.9 48.5 147 74.3 36.4 148 91.5 60.8 149
>95 75.4 150 79.8 31.7 151 31.5 13.5 152 10.8 16.7
* * * * *