U.S. patent application number 17/646897 was filed with the patent office on 2022-04-28 for malic enzyme inhibitors.
The applicant listed for this patent is Sun Pharma Advanced Research Company Ltd. Invention is credited to Umesh Vishnu Chaudhari, Sabbirhusen Yusufbhai Chimanwala, Trinadha Rao Chitturi, Aishwarya Hampiholi, Vaibhav Jain, Tushar Mukund Jarag, V.S.N Murty Kadiyala, Sairam VVM Kalapatapu, Saikat Maity, Gulamnizami Abdulsattar Qureshi, Prabal Sengupta, Gaurav Sanjivkumar Sheth, Raj Gopal Venkat.
Application Number | 20220127266 17/646897 |
Document ID | / |
Family ID | 1000006065964 |
Filed Date | 2022-04-28 |
View All Diagrams
United States Patent
Application |
20220127266 |
Kind Code |
A1 |
Sheth; Gaurav Sanjivkumar ;
et al. |
April 28, 2022 |
MALIC ENZYME INHIBITORS
Abstract
The present invention relates to novel compounds useful as malic
enzyme (ME) inhibitors, processes for their preparation and use of
these compounds for the therapeutic treatment of disorders mediated
by ME such as cancers (e.g. pancreatic ductal adenocarcinoma
(PDAC)) in humans.
Inventors: |
Sheth; Gaurav Sanjivkumar;
(Vadodara, IN) ; Chimanwala; Sabbirhusen Yusufbhai;
(Vadodara, IN) ; Jarag; Tushar Mukund; (Vadodara,
IN) ; Hampiholi; Aishwarya; (Pune, IN) ;
Maity; Saikat; (Medinipur District, IN) ; Sengupta;
Prabal; (Vadodara, IN) ; Qureshi; Gulamnizami
Abdulsattar; (Vadodara, IN) ; Chaudhari; Umesh
Vishnu; (Vadodara, IN) ; Venkat; Raj Gopal;
(Hyderabad, IN) ; Kadiyala; V.S.N Murty;
(Vadodara, IN) ; Kalapatapu; Sairam VVM;
(Hyderabad, IN) ; Jain; Vaibhav; (Sagar, IN)
; Chitturi; Trinadha Rao; (Vadodara, IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Sun Pharma Advanced Research Company Ltd |
Mumbai |
|
IN |
|
|
Family ID: |
1000006065964 |
Appl. No.: |
17/646897 |
Filed: |
January 4, 2022 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
17073017 |
Oct 16, 2020 |
11225480 |
|
|
17646897 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 209/18 20130101;
C07D 295/182 20130101; C07D 493/08 20130101; C07D 209/42 20130101;
C07D 401/14 20130101; C07D 401/12 20130101; C07D 209/08 20130101;
C07D 213/81 20130101; C07D 213/74 20130101; C07D 471/04 20130101;
C07D 409/12 20130101 |
International
Class: |
C07D 471/04 20060101
C07D471/04; C07D 209/08 20060101 C07D209/08; C07D 209/18 20060101
C07D209/18; C07D 209/42 20060101 C07D209/42; C07D 213/74 20060101
C07D213/74; C07D 213/81 20060101 C07D213/81; C07D 295/182 20060101
C07D295/182; C07D 401/12 20060101 C07D401/12; C07D 401/14 20060101
C07D401/14; C07D 409/12 20060101 C07D409/12; C07D 493/08 20060101
C07D493/08 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 17, 2019 |
IN |
201921033255 |
Claims
1. A compound of Formula I ##STR00510## or a pharmaceutically
acceptable salt, stereoisomer or deuterated analog thereof, wherein
X is CH; R.sub.1 is selected from hydrogen, --CH.sub.3, --COOH,
fluoro and --CN; R.sub.2 is selected from hydrogen, --CH.sub.3,
--COOH, fluoro and --CN; and Y is selected from: ##STR00511##
##STR00512## ##STR00513## ##STR00514## ##STR00515##
##STR00516##
2. The compound of claim 1, wherein Y is selected from:
##STR00517## ##STR00518## ##STR00519## ##STR00520##
##STR00521##
3. The compound of claim 2, wherein R.sub.1 and R.sub.2 are
hydrogen.
4. The compound of claim 1, wherein R.sub.1 and R.sub.2 both are
hydrogen; and Y is selected from: ##STR00522## ##STR00523##
##STR00524##
5. The compound of claim 1, wherein R.sub.1 and R.sub.2 both are
hydrogen; and Y is selected from: ##STR00525##
6. The compound of claim 1, wherein Y is selected from:
##STR00526##
7. The compound of claim 6, wherein R.sub.1 and R.sub.2 both are
hydrogen.
8. The compound of claim 1, wherein Y is selected from:
##STR00527##
9. The compound of claim 8, wherein R.sub.1 and R.sub.2 both are
hydrogen.
10. A compound selected from:
1-[4-(4-Hydroxyphenyl)piperazin-1-yl]-2-phenylethanone,
4-(4-Hydroxyphenyl)piperazin-1-yl]-(1H-indol-3-yl)-methanone,
1-[4-(4-Hydroxyphenyl)-piperazin-1-yl]-2-(3,4,5-trimethoxyphenyl)-ethanon-
e,
2-(4-Hydroxyphenyl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-ethanone,
1-[4-(4-Hydroxyphenyl)-piperazin-1-yl]-2-[4-(2-methoxyethoxy)-phenyl]-eth-
anone,
[4-(4-Hydroxyphenyl)-piperazin-1-yl]-[1-(2-methoxyethyl)-piperidin--
4-yl]-methanone,
[4-(4-Hydroxyphenyl)-piperazin-1-yl]-(1H-indazol-3-yl)-methanone,
Acridin-9-yl-[4-(4-hydroxy-phenyl)-piperazin-1-yl]-methanone,
[4-(4-Hydroxyphenyl)-piperazin-1-yl]-[5-(2-methoxyethoxy)-1H-indol-3-yl]--
methanone,
1-[4-(2-Fluoro-4-hydroxy-phenyl)-piperazin-1-yl]-2-phenyl ethanone,
3-(4-Butoxyphenyl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-propa-
n-1-one,
(5-Butoxy-1H-indol-3-yl)-[4-(4-hydroxyphenyl)-piperazin-1-yl]-met-
hanone,
(1-Benzyl-1H-indol-3-yl)-[4-(4-hydroxyphenyl)-piperazin-1-yl]-meth-
anone,
N-{(S)-1-Benzyl-2-[4-(4-hydroxyphenyl)-piperazin-1-yl]-2-oxoethyl}--
acetamide,
1-[4-(4-Hydroxyphenyl)-piperazin-1-yl]-2-phenyl-ethane-1,2-dion- e,
(1-Butyl-1H-indol-3-yl)-[4-(4-hydroxyphenyl)-piperazin-1-yl]-methanone,
N-{(1R)-2-[4-(4-Hydroxyphenyl)piperazin-1-yl]-2-oxo-1-phenylethyl}acetami-
de,
(2,6-diphenyl-4-pyridyl)-[4-(4-hydroxyphenyl)piperazin-1-yl]methanone,
Anthracen-9-yl-[4-(4-hydroxyphenyl)-piperazin-1-yl]-methanone,
[4-(4-Hydroxyphenyl)-piperazin-1-yl]-phenanthren-9-yl-methanone,
1-[4-(4-Hydroxyphenyl)-piperazin-1-yl]-3-naphthalen-2-yl-propan-1-one,
[4-(4-Hydroxyphenyl)-piperazin-1-yl]-quinolin-3-yl-methanone,
Anthracen-1-yl-[4-(4-hydroxyphenyl)-piperazin-1-yl]-methanone,
(1-Benzylindol-4-yl)-[4-(4-hydroxyphenyl)piperazin-1-yl]methanone,
(3,5-Diphenylphenyl)-[4-(4-hydroxyphenyl)piperazin-1-yl]methanone,
1-[4-(4-Hydroxyphenyl)-piperazin-1-yl]-2-(4-trifluoromethylphenyl)-ethano-
ne,
[4-(4-Hydroxyphenyl)-piperazin-1-yl]-imidazo[1,2-a]yridine-8-yl-methan-
one,
[4-(4-Hydroxyphenyl)-piperazin-1-yl]-(1H-indol-4-yl)-methanone,
[4-(4-Hydroxyphenyl)-piperazin-1-yl]-[3-(4-trifluoromethylphenyl)-imidazo-
[1,2-a]yridine-8-yl]-methanone,
2-Hydroxy-5-(4-phenylacetylpiperazin-1-yl)-benzoic acid,
[4-(4-Hydroxyphenyl)piperazin-1-yl]-(2-morpholino-6-phenyl-4-pyridyl)meth-
anone,
[4-(4-Hydroxyphenyl)piperazin-1-yl]-(2-phenyl-4-pyridyl)methanone,
[4-(4-Hydroxyphenyl)piperazin-1-yl]-(2-morpholino-4-pyridyl)methanone,
(2-Chloro-6-morpholino-4-pyridyl)-[4-(4-hydroxyphenyl)piperazin-1-yl]meth-
anone,
5-[4-(2,6-Diphenylpyridine-4-carbonyl)piperazin-1-yl]-2-hydroxy-ben-
zonitrile,
5-[4-(2,6-Diphenylpyridine-4-carbonyl)piperazin-1-yl]-2-hydroxy-
-benzoic acid,
3-[4-[4-(4-Hydroxyphenyl)piperazine-1-carbonyl]-2-pyridyl]benzoic
acid,
1-[4-(4-Hydroxyphenyl)piperazin-1-yl]-3,3-diphenyl-prop-2-en-1-one,
3-[4-[4-(4-Hydroxyphenyl)piperazine-1-carbonyl]-6-morpholino-2-pyridyl]be-
nzoic acid,
4-[4-[4-(4-Hydroxyphenyl)piperazine-1-carbonyl]-6-morpholino-2-pyridyl]be-
nzoic acid,
1-[4-(4-Hydroxyphenyl)-piperazin-1-yl]-3-naphthalen-1-yl-propan-1-one,
3-[4-(4-Hydroxyphenyl)piperazine-1-carbonyl]-1H-quinolin-4-one,
1-[4-(4-Hydroxyphenyl)piperazin-1-yl]-2-(2-phenoxyphenyl)ethanone,
[4-(4-Hydroxyphenyl)piperazin-1-yl]-[2-(1-piperidyl)-4-pyridyl]methanone,
1-[4-(4-Hydroxy-3-methyl-phenyl)-piperazin-1-yl]-2-phenylethanone,
3-Anthracen-9-yl-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-propan-1-one,
2-(3,5-Difluorophenyl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-ethanone,
2-(2,4-Difluorophenyl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-ethanone,
2-(5-Fluoro-1H-indol-3-yl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-ethanon-
e,
2-(2-Bromophenylsulfanyl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-ethano-
ne,
(2-Chloro-6-methylphenyl)-[4-(4-hydroxyphenyl)-piperazin-1-yl]-methano-
ne,
(5-Fluoro-1H-indol-3-yl)-[4-(4-hydroxyphenyl)-piperazin-1-yl]-methanon-
e,
1-[4-(4-Hydroxy-phenyl)-piperazin-1-yl]-2-(3,4,5-trifluoro-phenyl)-etha-
none,
1-[4-(4-Hydroxy-phenyl)-piperazin-1-yl]-3-methyl-3-phenyl-butan-1-on-
e, and pharmaceutically acceptable salts, stereoisomers, and/or
deuterated analogs thereof.
11. The compound of claim 10, selected from:
4-(4-Hydroxyphenyl)piperazin-1-yl]-(1H-indol-3-yl)-methanone,
2-(5-Fluoro-1H-indol-3-yl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-ethanon-
e,
2-(3,5-Difluorophenyl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-ethanone,
2-(2,4-Difluorophenyl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-ethanone,
and pharmaceutically acceptable salts, stereoisomers, and/or
deuterated analogs thereof.
12. The compound of claim 10, selected from:
[4-(4-Hydroxyphenyl)-piperazin-1-yl]-[1-(2-methoxyethyl)-piperidin-4-yl]--
methanone,
[4-(4-Hydroxyphenyl)-piperazin-1-yl]-(1H-indazol-3-yl)-methanon- e,
Acridin-9-yl-[4-(4-hydroxy-phenyl)-piperazin-1-yl]-methanone,
[4-(4-Hydroxyphenyl)-piperazin-1-yl]-[5-(2-methoxyethoxy)-1H-indol-3-yl]--
methanone,
1-[4-(2-Fluoro-4-hydroxy-phenyl)-piperazin-1-yl]-2-phenylethano-
ne,
3-(4-Butoxyphenyl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-propenone,
3-(4-Butoxyphenyl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-propan-1-one,
[4-(4-Hydroxyphenyl)-piperazin-1-yl]-phenanthren-9-yl-methanone,
[4-(4-Hydroxyphenyl)-piperazin-1-yl]-(1H-indol-4-yl)-methanone,
[4-(4-Hydroxyphenyl)piperazin-1-yl]-(2-morpholino-6-phenyl-4-pyridyl)meth-
anone,
[4-(4-Hydroxyphenyl)piperazin-1-yl]-(2-morpholino-4-pyridyl)methano-
ne,
(2-Chloro-6-morpholino-4-pyridyl)-[4-(4-hydroxyphenyl)piperazin-1-yl]m-
ethanone, and pharmaceutically acceptable salts, stereoisomers,
and/or deuterated analogs thereof.
13. The compound of claim 10, selected from:
1-[4-(4-Hydroxyphenyl)piperazin-1-yl]-2-phenylethanone,
4-(4-Hydroxyphenyl)piperazin-1-yl]-(1H-indol-3-yl)-methanone,
2-(4-Hydroxyphenyl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-ethanone,
1-[4-(4-Hydroxyphenyl)-piperazin-1-yl]-2-[4-(2-methoxyethoxy)-phenyl]-eth-
anone,
Anthracen-9-yl-[4-(4-hydroxyphenyl)-piperazin-1-yl]-methanone,
1-[4-(4-Hydroxyphenyl)-piperazin-1-yl]-2-(4-trifluoromethylphenyl)-ethano-
ne,
3-[4-[4-(4-Hydroxyphenyl)piperazine-1-carbonyl]-2-pyridyl]benzoic
acid,
1-[4-(4-Hydroxyphenyl)piperazin-1-yl]-3,3-diphenyl-prop-2-en-1-one,
3-[4-[4-(4-Hydroxyphenyl)piperazine-1-carbonyl]-6-morpholino-2-pyridyl]be-
nzoic acid,
4-[4-[4-(4-Hydroxyphenyl)piperazine-1-carbonyl]-6-morpholino-2-pyridyl]be-
nzoic acid,
1-[4-(4-Hydroxyphenyl)-piperazin-1-yl]-3-naphthalen-1-yl-propan-1-one,
3-[4-(4-Hydroxyphenyl)piperazine-1-carbonyl]-1H-quinolin-4-one,
1-[4-(4-Hydroxyphenyl)piperazin-1-yl]-2-(2-phenoxyphenyl)ethanone,
[4-(4-Hydroxyphenyl)piperazin-1-yl]-[2-(1-piperidyl)-4-pyridyl]methanone,
1-[4-(4-Hydroxy-3-methyl-phenyl)-piperazin-1-yl]-2-phenylethanone,
3-Anthracen-9-yl-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-propan-1-one,
2-(3,5-Difluorophenyl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-ethanone,
2-(2,4-Difluorophenyl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-ethanone,
2-(5-Fluoro-1H-indol-3-yl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-ethanon-
e,
2-(2-Bromophenylsulfanyl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-ethano-
ne,
(2-Chloro-6-methylphenyl)-[4-(4-hydroxyphenyl)-piperazin-1-yl]-methano-
ne,
(5-Fluoro-1H-indol-3-yl)-[4-(4-hydroxyphenyl)-piperazin-1-yl]-methanon-
e,
1-[4-(4-Hydroxy-phenyl)-piperazin-1-yl]-2-(3,4,5-trifluoro-phenyl)-etha-
none,
1-[4-(4-Hydroxy-phenyl)-piperazin-1-yl]-3-methyl-3-phenyl-butan-1-on-
e, and pharmaceutically acceptable salts, stereoisomers, and/or
deuterated analogs thereof.
14. A method of treating a subject having cancer, comprising
administering to the subject a malic enzyme inhibitor, wherein the
malic enzyme inhibitor is a compound of claim 1.
15. The method of claim 14, wherein the malic enzyme is malic
enzyme 3 (ME3), malic enzyme 2 (ME2) and/or malic enzyme 1
(ME1).
16. The method of claim 15, wherein the malic enzyme is malic
enzyme 3.
17. The method of claim 14, wherein the cancer is selected from
leukemia, brain cancer, bladder cancer, breast cancer, cervical
cancer, colorectal cancer, endometrial cancer, esophageal cancer,
head and neck cancer, liver cancer, lung cancer, lymphoma, ovarian
cancer, pancreatic cancer, prostate cancer, renal cancer, skin
cancer, stomach cancer, testis cancer, thyroid cancer, and
urothelial cancer.
18. A method of treating a subject having cancer, comprising
administering to the subject a malic enzyme inhibitor, wherein the
malic enzyme inhibitor is a compound of Formula I ##STR00528## or a
pharmaceutically acceptable salt, stereoisomer or deuterated analog
thereof, wherein X is CH; R.sub.1 is selected from hydrogen,
CH.sub.3, --COOH, fluoro and CN; R.sub.2 is selected from hydrogen,
CH.sub.3, --COOH, fluoro and CN; and Y is selected from substituted
or unsubstituted C.sub.1-5 alkyl, substituted or unsubstituted
C.sub.2-4 alkenyl, substituted or unsubstituted 5 to 14 membered
heteroaryl ring containing one, two or three heteroatoms each
independently selected from nitrogen, oxygen, and sulfur,
substituted or unsubstituted 5 to 14 membered heterocycloalkyl
group containing one, two or three heteroatoms each independently
selected from nitrogen and oxygen, substituted or unsubstituted
C.sub.3-15 cycloalkyl, substituted or unsubstituted C.sub.3-15
cycloalkylC.sub.1-6alkyl, substituted or unsubstituted C.sub.6-14
aryl, substituted or unsubstituted C.sub.6-14arylC.sub.1-6alkyl,
substituted or unsubstituted C.sub.6-14arylC.sub.2-5alkenyl,
substituted or unsubstituted 5 to 14 membered
heteroarylC.sub.1-6alkyl, and substituted or unsubstituted 5 to 14
membered heterocycloalkylC.sub.1-6alkyl.
19. The method of claim 18, wherein the malic enzyme is malic
enzyme 3 (ME3), malic enzyme 2 (ME2) and/or malic enzyme 1
(ME1).
20. The method of claim 19, wherein the malic enzyme is malic
enzyme 3.
21. The method of claim 18, wherein the cancer is selected from
leukemia, brain cancer, bladder cancer, breast cancer, cervical
cancer, colorectal cancer, endometrial cancer, esophageal cancer,
head and neck cancer, liver cancer, lung cancer, lymphoma, ovarian
cancer, pancreatic cancer, prostate cancer, renal cancer, skin
cancer, stomach cancer, testis cancer, thyroid cancer, and
urothelial cancer.
22. The compound of claim 1, for use in the treatment of a subject
having cancer by inhibiting the malic enzyme.
23. The compound of claim 22, wherein the malic enzyme is malic
enzyme 3 (ME3), malic enzyme 2 (ME2), and/or malic enzyme 1
(ME1).
24. The compound of claim 23, wherein the malic enzyme is malic
enzyme 3.
25. The compound of claim 22, wherein the cancer is selected from
leukemia, brain cancer, bladder cancer, breast cancer, cervical
cancer, colorectal cancer, endometrial cancer, esophageal cancer,
head and neck cancer, liver cancer, lung cancer, lymphoma, ovarian
cancer, pancreatic cancer, prostate cancer, renal cancer, skin
cancer, stomach cancer, testis cancer, thyroid cancer, and
urothelial cancer.
26. A compound of Formula I ##STR00529## or a pharmaceutically
acceptable salt, stereoisomer or deuterated analog thereof, wherein
X is CH; R.sub.1 is selected from hydrogen, CH.sub.3, --COOH,
fluoro and CN; R.sub.2 is selected from hydrogen, CH.sub.3, --COOH,
fluoro and CN; Y is selected from substituted or unsubstituted
C.sub.1-5 alkyl, substituted or unsubstituted C.sub.2-4 alkenyl,
substituted or unsubstituted 5 to 14 membered heteroaryl ring
containing one, two or three heteroatoms each independently
selected from nitrogen, oxygen, and sulfur, substituted or
unsubstituted 5 to 14 membered heterocycloalkyl group containing
one, two or three heteroatoms each independently selected from
nitrogen and oxygen, substituted or unsubstituted C.sub.3-15
cycloalkyl, substituted or unsubstituted C.sub.3-15
cycloalkylC.sub.1-6alkyl, substituted or unsubstituted C.sub.6-14
aryl, substituted or unsubstituted C.sub.6-14arylC.sub.1-6alkyl,
substituted or unsubstituted C.sub.6-14arylC.sub.2-5alkenyl,
substituted or unsubstituted 5 to 14 membered
heteroarylC.sub.1-6alkyl, and substituted or unsubstituted 5 to 14
membered heterocycloalkylC.sub.1-6alkyl, for use in the treatment
of a subject having cancer by inhibiting a malic enzyme.
27. The compound of claim 26, wherein the malic enzyme is malic
enzyme 3 (ME3), malic enzyme 2 (ME2), and/or malic enzyme 1
(ME1).
28. The compound of claim 27, wherein the malic enzyme is malic
enzyme 3.
29. The compound of claim 26, wherein the cancer is selected from
leukemia, brain cancer, bladder cancer, breast cancer, cervical
cancer, colorectal cancer, endometrial cancer, esophageal cancer,
head and neck cancer, liver cancer, lung cancer, lymphoma, ovarian
cancer, pancreatic cancer, prostate cancer, renal cancer, skin
cancer, stomach cancer, testis cancer, thyroid cancer, and
urothelial cancer.
30. A medicament comprising a compound according to claim 1 for
treating a subject having cancer by inhibiting a malic enzyme.
31. The medicament of claim 30, wherein the malic enzyme is malic
enzyme 3 (ME3), malic enzyme 2 (ME2), and/or malic enzyme 1
(ME1).
32. The medicament of claim 31, wherein the malic enzyme is malic
enzyme 3 (ME3).
33. The medicament of claim 30, wherein the cancer is selected from
leukemia, brain cancer, bladder cancer, breast cancer, cervical
cancer, colorectal cancer, endometrial cancer, esophageal cancer,
head and neck cancer, liver cancer, lung cancer, lymphoma, ovarian
cancer, pancreatic cancer, prostate cancer, renal cancer, skin
cancer, stomach cancer, testis cancer, thyroid cancer, and
urothelial cancer.
34. A pharmaceutical composition comprising a compound of claim 1
and a pharmaceutically acceptable carrier, diluent, or
excipient.
35. A method of inhibiting a malic enzyme in a subject comprising
administering to the subject in need thereof, a compound of claim
1.
36. The method of claim 35, wherein the subject has cancer.
37. The method of claim 36, wherein the cancer is selected from
leukemia, brain cancer, bladder cancer, breast cancer, cervical
cancer, colorectal cancer, endometrial cancer, esophageal cancer,
head and neck cancer, liver cancer, lung cancer, lymphoma, ovarian
cancer, pancreatic cancer, prostate cancer, renal cancer, skin
cancer, stomach cancer, testis cancer, thyroid cancer, and
urothelial cancer.
38. The method of claim 35, wherein the malic enzyme is malic
enzyme 3 (ME3), malic enzyme 2 (ME2), and/or malic enzyme 1
(ME1).
39. The method of claim 38, wherein the malic enzyme is malic
enzyme 3 (ME3).
40. A method of inhibiting a malic enzyme in a subject comprising
administering to the subject in need thereof, a compound of Formula
I ##STR00530## or a pharmaceutically acceptable salt, stereoisomer
or deuterated analog thereof, wherein X is CH; R.sub.1 is selected
from hydrogen, CH.sub.3, --COOH, fluoro and CN; R.sub.2 is selected
from hydrogen, CH.sub.3, --COOH, fluoro and CN; Y is selected from
substituted or unsubstituted C.sub.1-5 alkyl, substituted or
unsubstituted C.sub.2-4 alkenyl, substituted or unsubstituted 5 to
14 membered heteroaryl ring containing one, two or three
heteroatoms each independently selected from nitrogen, oxygen, and
sulfur, substituted or unsubstituted 5 to 14 membered
heterocycloalkyl group containing one, two or three heteroatoms
each independently selected from nitrogen and oxygen, substituted
or unsubstituted C.sub.3-15 cycloalkyl, substituted or
unsubstituted C.sub.3-15 cycloalkylC.sub.1-6alkyl, substituted or
unsubstituted C.sub.6-14 aryl, substituted or unsubstituted
C.sub.6-14arylC.sub.1-6alkyl, substituted or unsubstituted
C.sub.6-14arylC.sub.2-5alkenyl, substituted or unsubstituted 5 to
14 membered heteroarylC.sub.1-6alkyl, and substituted or
unsubstituted 5 to 14 membered heterocycloalkylC.sub.1-6alkyl.
41. The method of claim 40, wherein the subject has cancer.
42. The method of claim 41, wherein the cancer is selected from
leukemia, brain cancer, bladder cancer, breast cancer, cervical
cancer, colorectal cancer, endometrial cancer, esophageal cancer,
head and neck cancer, liver cancer, lung cancer, lymphoma, ovarian
cancer, pancreatic cancer, prostate cancer, renal cancer, skin
cancer, stomach cancer, testis cancer, thyroid cancer, and
urothelial cancer.
43. The method of claim 40, wherein the malic enzyme is malic
enzyme 3 (ME3), malic enzyme 2 (ME2), and/or malic enzyme 1
(ME1).
44. The method of claim 44, wherein the malic enzyme is malic
enzyme 3 (ME3).
Description
RELATED APPLICATIONS
[0001] This application is a divisional of 17/073,017, filed Oct.
16, 2020, which claims priority to Indian Provisional Patent
Application No. 201921033255 filed on Oct. 17, 2019, the contents
of which is hereby incorporated by reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to compounds useful as malic
enzyme (ME) inhibitors, process for their preparation, and use of
the compounds for the therapeutic treatment of disorders mediated
by ME, such as cancer (e.g., in humans).
BACKGROUND OF THE INVENTION
[0003] One hallmark of cancer is excessive growth and uncontrolled
proliferation. Cancer cells need energy and, using this energy,
cell membranes, nucleotides, and proteins grow in cells and
proliferate. Once cancer is initiated, alterations in key signaling
pathways accumulate and lead to loss of control over metabolism as
well as proliferation (Hanahan D, Weinberg R A., Hallmarks of
Cancer: the next generation. Cell, 2011; 144(5): 646-74).
[0004] Metabolic alterations provide the energetic and anabolic
demands of enhanced cell proliferation. In order to meet these
requirements, cancer cells use various metabolic approaches, such
as high aerobic glycolysis, glutaminolysis, and fatty acid
synthesis. Pyruvate, NAD, and NADPH have key roles in supporting
the advancement of glycolysis and fatty acid synthesis. Malic
enzyme is an important enzyme in metabolism that catalyzes the
conversion of malate to pyruvate with the concomitant regeneration
of NADPH. Malic enzyme, by producing pyruvate and NADPH, provides
abundant vital resources for glycolysis and fatty acid synthesis.
Malic enzyme expression is significantly up-regulated in different
types of human cancers.
[0005] Malic enzymes are oxidative decarboxylases that catalyze the
conversion of L-malate to pyruvate and CO.sub.2 and use NAD+ or
NAD(P)+ as a cofactor. In mammals, there are three malic enzyme
isoforms with different cofactor specificities: the cytosolic
NADP+-dependent malic enzyme 1 (ME1), the mitochondrial
NAD(P)+-dependent malic enzyme 2 (ME2), and the mitochondrial
NADP+-dependent malic enzyme 3 (ME3).
[0006] Cytoplasmic ME1 decarboxylates malate to form pyruvate and
ultimately NADPH. In cancer cells, pyruvate generated in this
manner is utilized for lactate fermentation. It has been reported
that wild-type p53 represses ME1 expression and hence ME1
overexpression is associated with cancers carrying mutated p53.
Malic enzyme 1 is the link to energy metabolism, redox status, and
EMT specifically in cancers of squamous cell (oral, head and neck),
nasopharynx, synovium, lung, pancreas, gastric, oesophageal, liver
and breast (see, e.g., Ruocen Liao et al., ME1 promotes basal-like
breast cancer progression and associates with poor prognosis, Sci.
Rep., 2018, 8:16743).
[0007] It has also been reported that ME2 enzyme activity increased
with progression to neoplasia in a rat tracheal epithelial line and
in Morris hepatomas (see, e.g., Jian-Guo Ren et al., Knockdown of
Malic Enzyme 2 Suppresses Lung Tumor Growth, Induces
Differentiation and Impacts PI3K/AKT Signaling, Sci. Rep., 2014,
4:5414). The first functional connection between ME2 expression and
cancer was reported in ME2 knockdown (KD) in K562 cells and this
led to erythroid differentiation in chronic myelogenous leukemia in
K562 cells. ME2 also plays a more important role in A549 cell
survival in tumor cells than in normal lung cells. ME2 depletion
also induced senescence and suppressed tumor growth in the p532/2
HCT116 xenograft model.
[0008] Genomic deletions are a key driver of virtually all cancers.
During cancer progression, many cancer cells delete
tumour-suppressor genes that block tumour development. This
deletion process often also removes some neighbouring genes. The
partial or complete loss of these neighbouring genes can make
cancer cells vulnerable to therapeutic targeting--a concept known
as collateral lethality.
[0009] In mammals, there is a third malic enzyme (ME3) which is
NADP+-dependent. Dey et al., (Nature, 2017 Feb. 2;
542(7639):119-123) report that silencing of ME3 when Smad4 and ME2
are co-deleted leads to collateral lethality. There could be
several possible unexplored independent functions of ME3 and whence
ME3 inhibitors can be useful in several cancers as well.
[0010] Pancreatic cancer is one of the leading causes of cancer
deaths in western societies, with the worst prognosis. It is the
third leading cause of cancer deaths in the United States (US)
alone (Lancet Oncol. 2017 June; 18(6):770-778) and is projected to
be the second leading cause of cancer-related deaths in US by 2030
(Endosc Ultrasound., 2017 December; 6 (Suppl 3): S58-S61). Even for
early-stage disease, recurrence is high. Although recent
combination therapies for metastatic pancreatic ductal
adenocarcinoma (PDAC) have improved the median overall survival
(mOS) by up to 5 months, the overall prognosis remains almost
unchanged, and novel therapies are desperately needed. The majority
of patients at diagnosis are unresectable, as the disease remains
symptomatically silent during the early stages, and no effective
screening test exists (Clin Cancer Res., 2017 Apr. 1; 23(7):
1670-1678).
[0011] Pancreatic cancer originates from exocrine cells of the
pancreas, and among all exocrine tumors, pancreatic ductal
adenocarcinoma (PDAC) is the most common type of pancreatic
neoplasm, accounting for more than 90% of pancreatic tumors (Prog.
Mol. Biol. Transl. Sci., 2016; 144:241-275). In spite of intense
research efforts and the development of numerous new cancer drugs
and treatment strategies over the past four decades, there has been
no significant improvement in overall patient survival, and death
rates are almost equivalent to incidence rates.
[0012] Pancreatic cancers are accompanied by activating mutations
in KRAS oncogene in >90% of cases, and subsequent loss of tumor
suppressors INK4A/ARF, TP53 and SMAD4 (Genes Dev., 2003 Dec. 15;
17(24):3112-26). Oncogenic Kras (KrasG12D) is a major driver in
PDAC initiation, with loss in tumor suppressor genes. Constitutive
KrasG12D signaling drives uncontrolled proliferation and enhances
survival of cancer cells through the activation of its downstream
signaling pathways, such as the MAPK and PI3K-mTOR pathways. To
meet the increased anabolic needs of enhanced proliferation, cancer
cells require both sufficient energy and biosynthetic precursors as
cellular building blocks to fuel cell growth. In cancer cells,
metabolic pathways are rewired in order to divert nutrients, such
as glucose and glutamine, into anabolic pathways to satisfy the
demand for cellular building blocks. It has been reported that the
reprogramming of tumor metabolism is under the control of various
oncogenic signals (J. Oral Maxillofac Pathol., 2017 May-August;
21(2):244-251). The Ras oncogene in particular has been shown to
promote glycolysis.
[0013] European Patent Publication No. EP 0595241 A2 discloses a
method for inhibiting the growth and proliferation of mammalian
tumor cells by examining the expression of specific isoforms of
malic enzyme and specifically inhibiting the malate enzyme isoform
which is overexpressed.
[0014] U.S. Pat. No. 9,539,323 discloses the use of a malic enzyme
2 inhibitor for treating a subject having cancer.
[0015] There is a continuing need for new compounds useful as malic
enzyme (especially ME3) inhibitors.
SUMMARY OF THE INVENTION
[0016] In one aspect, the present invention provides a method of
inhibiting a malic enzyme in a subject comprising administering to
the subject in need thereof a compound of Formula I
##STR00001## [0017] or a pharmaceutically acceptable salt,
stereoisomer or deuterated analog thereof, wherein [0018] X is CH
or nitrogen; [0019] R.sub.1 is selected from hydrogen, CH.sub.3,
--COOH, fluoro and CN; [0020] R.sub.2 is selected from hydrogen,
CH.sub.3, --COOH, fluoro and CN; and [0021] Y is selected from
substituted or unsubstituted C.sub.1-5 alkyl, substituted or
unsubstituted C.sub.2-4 alkenyl, substituted or unsubstituted 5 to
14 membered heteroaryl ring containing one, two or three
heteroatoms each independently selected from nitrogen, oxygen, and
sulfur, substituted or unsubstituted 5 to 14 membered
heterocycloalkyl group containing one, two or three heteroatoms
each independently selected from nitrogen and oxygen, substituted
or unsubstituted C.sub.3-15 cycloalkyl, substituted or
unsubstituted C.sub.3-15 cycloalkylC.sub.1-6alkyl, substituted or
unsubstituted C.sub.6-14 aryl, substituted or unsubstituted
C.sub.6-14arylC.sub.1-6alkyl, substituted or unsubstituted
C.sub.6-14arylC.sub.2-5alkenyl, substituted or unsubstituted 5 to
14 membered heteroarylC.sub.1-6alkyl, and substituted or
unsubstituted 5 to 14 membered heterocycloalkylC.sub.1-6alkyl.
[0022] In another aspect, the present invention provides a compound
of Formula I
##STR00002## [0023] or a pharmaceutically acceptable salt,
stereoisomer or deuterated analog thereof, wherein [0024] X is CH
or nitrogen; [0025] R.sub.1 is selected from hydrogen, CH.sub.3,
--COOH, fluoro and CN; [0026] R.sub.2 is selected from hydrogen,
CH.sub.3, --COOH, fluoro and CN;
[0027] Y is selected from substituted or unsubstituted C.sub.1-5
alkyl, substituted or unsubstituted C.sub.2-4 alkenyl, substituted
or unsubstituted 5 to 14 membered heteroaryl ring containing one,
two or three heteroatoms each independently selected from nitrogen,
oxygen, and sulfur, substituted or unsubstituted 5 to 14 membered
heterocycloalkyl group containing one, two or three heteroatoms
each independently selected from nitrogen and oxygen, substituted
or unsubstituted C.sub.3-15 cycloalkyl, substituted or
unsubstituted C.sub.3-15 cycloalkylC.sub.1-6alkyl, substituted or
unsubstituted C.sub.6-14 aryl, substituted or unsubstituted
C.sub.6-14arylC.sub.1-6alkyl, substituted or unsubstituted
C.sub.6-14arylC.sub.2-5alkenyl, substituted or unsubstituted 5 to
14 membered heteroarylC.sub.1-6alkyl, and substituted or
unsubstituted 5 to 14 membered heterocycloalkylC.sub.1-6alkyl;
[0028] with the proviso that (i) when X is CH, then Y is selected
from:
[0028] ##STR00003## ##STR00004## ##STR00005## ##STR00006##
##STR00007## ##STR00008## [0029] and (ii) when X is nitrogen, then
Y is selected from:
##STR00009## ##STR00010## ##STR00011## ##STR00012## ##STR00013##
##STR00014## ##STR00015## ##STR00016## ##STR00017## ##STR00018##
##STR00019## ##STR00020## ##STR00021##
[0030] The compounds of the present invention are potent ME
inhibitors and are useful in the treatment of diseases mediated by
ME such as cancer (e.g., a non-solid or a solid cancer)
particularly PDAC.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0031] The term "pharmaceutically acceptable salt" as used herein
includes acid addition salts formed with either organic or
inorganic acids. Suitable pharmaceutically acceptable salts
include, but not limited to, acid addition salts which may be salts
of inorganic acids such as hydrochloric acid, hydrobromic acid,
phosphoric acid, or of organic acids such as, for example, acetic
acid, benzenesulfonic acid, methanesulfonic acid, benzoic acid,
citric acid, glycolic acid, lactic acid, fumaric acid, succinic
acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic
acid, tartaric acid, and amino acids such as glutamic acid or
aspartic acid. The pharmaceutically acceptable acid addition salts
also include salts formed with the addition of one or more
equivalents of acids, for example, monohydrochloride, and
dihydrochloride salts.
[0032] The term "treating or treatment" as used herein refers to
completely or partially curing, alleviating, ameliorating,
improving, relieving, delaying the onset of, inhibiting progression
of, reducing severity of, and/or reducing incidence of one or more
symptoms or features of a particular disease, disorder, and/or
condition.
[0033] The term "subject" as used herein refer to either a human or
a non-human animal. These terms include mammals such as humans,
primates, livestock animals (e.g., bovines and porcines), companion
animals (e.g., canines and felines) and rodents (e.g., mice and
rats).
[0034] The term "deuterated analog" as used herein refers to
compounds described herein wherein at least one hydrogen atom has
been replaced by a deuterium atom. The deuterated analog may be a
fully or partially deuterium substituted derivative.
[0035] The term "alkyl" as used herein refers to a saturated
hydrocarbon chain radical that includes solely carbon and hydrogen
atoms in the backbone, either linear or branched, having from 1 to
6 carbon atoms, both inclusive unless defined otherwise and which
is attached to the rest of the molecule by a single bond. Suitable
non-limiting examples of alkyl groups include, e.g., methyl, ethyl,
n-propyl, 1-methylethyl (isopropyl), n-pentyl, n-hexyl, etc. Unless
set forth or recited to the contrary, all alkyl groups described
herein may be unsubstituted or substituted.
[0036] For example, an alkyl group can be substituted with one or
more groups independently selected from: [0037] C.sub.6-14 aryl
(for example, phenyl, naphthyl, anthracenyl) which is optionally
further substituted with one or more groups independently selected
from C.sub.1-4 alkoxy (for example, methoxy, propoxy and butoxy),
hydroxyl, C.sub.1-4 alkyl optionally substituted with C.sub.1-3
alkoxy, C.sub.1-3 haloalkyl (for example, trifluoromethyl),
NHC(O)Me, C(O), phenoxy, halogen (for example, chloro, fluoro, iodo
or bromo), N(Me).sub.2, COOH, COOMe and nitrile (CN); [0038] 6 to
14 membered heteroaryl (for example pyridine); [0039] COOH; [0040]
hydroxyl; [0041] benzenethiolyl, optionally substituted with one or
more halogen (for example, chloro, fluoro, iodo or bromo); [0042]
C.sub.3-14 cycloalkyl (for example, cyclopropyl, cyclobutyl,
cyclohexyl, tricyclo[3.3.1.1.sup.3,7] decane, 9H-fluorene), each of
which may be optionally further substituted with one or more groups
selected from hydroxyl; and [0043] amino group, optionally further
substituted with one or more groups selected from (a) C.sub.6-14
cycloalkyl (for example tricyclo[3.3.1.1.sup.3,7]decane), (b)
C.sub.1-4 alkyl optionally substituted with phenyl or C.sub.6-14
cycloalkyl (for example tricyclo[3.3.1.1.sup.3,7]decane) and (c)
--S(O).sub.2-heteroaryl(5-14)membered.
[0044] The numerical in phrases like "C.sub.1-4", refers to the
number of carbon atoms in the chain. For example, the phrase
"C.sub.1-4 alkyl" refers to an alkyl chain having 1 to 4 carbon
atoms.
[0045] The term "alkenyl" as used herein refers to a hydrocarbon
chain containing at least one carbon-carbon double bond, and may
have (E) or (Z) configuration. An alkenyl group may contain 2 to 8
carbon atoms unless specified otherwise. Unless set forth or
recited to the contrary, all alkenyl groups described herein may
form part of a straight or branched chain. Suitable non-limiting
examples of alkenyl groups include, e.g., ethylene, 2-propenyl
(allyl), 2-methyl-2-propenyl and 2-butenyl. Unless set forth or
recited to the contrary, all alkenyl groups described herein may be
unsubstituted or substituted. For example, an alkenyl group can be
substituted with one or more group selected from: [0046] C.sub.6-14
aryl (for example phenyl) optionally substituted with one or more
group independently selected from C.sub.1-4 alkoxy (for example
methoxy, propoxy, butoxy), and nitro; [0047] C.sub.6-14 cycloalkyl
(for example cyclopropane, cyclobutane, cyclohexane, 9H-fluorene);
and N(Me)S(O).sub.2 heteroaryl.
[0048] The term "cycloalkyl" as used herein refers to a
non-aromatic mono, multicyclic, bridged multicyclic or
spiromulticyclic ring system of 3 to 15 carbon atoms unless
specified otherwise. Monocyclic ring include, but are not limited
to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Examples
of simple multicyclic cycloalkyl groups include, but are not
limited to, perhydronapththyl, and perhydroindenyl. Bridged
multicyclic groups include, but are not limited to, adamantyl and
norbornyl. Spiromulticyclic groups include, but are not limited to,
spiro(4,4)non-2-yl. Unless set forth or recited to the contrary,
all cycloalkyl groups described herein may be unsubstituted or
substituted. For example, a cycloalkyl group can be substituted
with one or more groups selected from oxo (.dbd.O), hydroxyl, and
C.sub.6-14 aryl (for example, phenyl).
[0049] The term "aryl" as used herein refers to an aromatic radical
having 6 to 14 carbon atoms, including monocyclic, bicyclic or
tricyclic aromatic systems. A bicyclic aryl group includes an
aromatic ring fused to a saturated, partially unsaturated ring, or
aromatic ring. The bicyclic aryl group may be attached to the rest
of the molecule at any suitable position including the position on
the aromatic ring or saturated or partially unsaturated ring.
Typical aryl groups include, but are not limited to, phenyl,
naphthyl, indanyl (for e.g. 1-indanyl, 5-indanyl), indenyl,
anthracenyl and phenanthrenyl. Unless set forth or recited to the
contrary, all aryl groups described herein may be unsubstituted or
substituted. For example, an aryl group can be substituted with one
or more groups independently selected from: [0050] C.sub.1-4 alkyl
(for example, methyl, ethyl, propyl and butyl) optionally
substituted with one more halogen (for example, chloro, fluoro,
iodo or bromo); [0051] phenyl; [0052] halogen (for example, chloro,
fluoro, iodo or bromo); [0053] 5 to 10 membered heteroaryl ring
optionally substituted with one or more groups selected from
C.sub.1-4 alkyl; [0054] amino group, optionally further substituted
with a substituted heteroaryl group; and [0055] COOH.
[0056] The term "heteroaryl ring" refers to a 5 to 14 membered
aromatic heterocyclic ring containing one or more (such as 1, 2 or
3) heteroatoms, each independently selected from nitrogen, oxygen
and sulfur. The heteroaryl ring may be a mono-, bi- or tri-cyclic
ring system and includes fused ring systems (at least one of which
is aromatic). The heteroaryl ring radical may be attached to the
main structure at any heteroatom or carbon atom that results in the
creation of a stable structure. Suitable examples of heteroaryl
rings include, but are not limited to oxazolyl, isoxazolyl,
imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl,
triazinyl, tetrazoyl, thienyl, thiazolyl, isothiazolyl, pyridyl,
pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl,
benzoxazolyl, benzimidazolyl, benzothienyl, benzopyranyl,
carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, purinyl,
quinoxalinyl, quinolinyl, isoquinolinyl, thiadiazolyl, indolizinyl,
imidazo[1,2-a]pyridyl and phthalazinyl. Unless set forth or recited
to the contrary, all heteroaryl groups described or claimed herein
may be unsubstituted or substituted.
[0057] For example, a heteroaryl ring can be substituted with one
or more groups selected from: [0058] C.sub.1-4 alkoxy (for example,
methoxy, propoxy, butoxy) optionally substituted with one or more
C.sub.1-4 alkoxy or C.sub.1-4 alkyl, [0059] benzyl, [0060] phenyl,
wherein the phenyl may be optionally further substituted with one
or more C.sub.1-3 haloalkyl (for example trifluoromethyl), and/or
COOH and/or COOMe, [0061] hydroxyl, [0062] morpholinyl, [0063]
halogen (for example, chloro, fluoro, iodo or bromo), and [0064]
C.sub.6-14 heterocyclyl (for example piperidine).
[0065] The term "heterocycloalkyl" refers to a cycloalkyl ring
containing one, two or three heteroatoms, each independently
selected from nitrogen or oxygen. Suitable non-limiting examples of
heterocycloalkyl groups include, but are not limited to,
pyrrolidinyl, piperidine, piperazinyl, morpholinyl, thiomorpholine
and 1,3-oxazine. Unless set forth or recited to the contrary, a
heterocycloalkyl ring described herein may be unsubstituted or
substituted. For example, a heterocycloalkyl ring can be
substituted with one or more groups selected from: [0066] C.sub.1-4
alkoxy (for example, methoxy, propoxy, butoxy) optionally
substituted with one or more C.sub.1-4 alkoxy and/or C.sub.1-4
alkyl; [0067] benzyl; [0068] phenyl, wherein the phenyl group may
be optionally further substituted with one or more C.sub.1-3
haloalkyl (for example, trifluoromethyl) and/or COOH and/or COOMe;
[0069] C.sub.1-4 alkyl which may be optionally further substituted
with one or more groups selected from C.sub.1-4 alkoxy (for
example, methoxy, propoxy and butoxy), COOH, CONH.sub.2, CONHMe,
CONH(Me).sub.2, and C.sub.3-6 cycloalkyl (for example, cycloalkyl,
cyclopropyl, cyclobutyl); [0070] C.sub.3-4 alkenyl; [0071] oxo
(.dbd.O); [0072] C.sub.3-6 cycloalkyl (for example, cyclopropyl);
[0073] C.sub.1-4 alkanol (for example CH.sub.2CH.sub.2OH); [0074]
C(O)Me; [0075] COOMe; [0076] COOH; [0077] hydroxyl; [0078]
morpholinyl; [0079] halogen (for example, chloro, fluoro, iodo or
bromo); and [0080] 6 to 14 membered heterocyclyl ring (for example
piperidine).
[0081] Thus, in one aspect, the present invention relates to a
compound of Formula I
##STR00022## [0082] or a pharmaceutically acceptable salt,
stereoisomer or deuterated analog thereof, wherein [0083] X is CH
or nitrogen; [0084] R.sub.1 is selected from hydrogen, --CH.sub.3,
--COOH, fluoro and --CN; [0085] R.sub.2 is selected from hydrogen,
--CH.sub.3, --COOH, fluoro and --CN; [0086] Y is selected from
substituted or unsubstituted C.sub.1-5 alkyl, substituted or
unsubstituted C.sub.2-4 alkenyl, substituted or unsubstituted 5 to
14 membered heteroaryl ring containing one, two or three
heteroatoms each independently selected from nitrogen, oxygen, and
sulfur, substituted or unsubstituted 5 to 14 membered
heterocycloalkyl group containing one, two or three heteroatoms
each independently selected from nitrogen and oxygen, substituted
or unsubstituted C.sub.3-15 cycloalkyl, substituted or
unsubstituted C.sub.3-15 cycloalkylC.sub.1-6alkyl, substituted or
unsubstituted C.sub.6-14 aryl, substituted or unsubstituted
C.sub.6-14arylC.sub.1-6alkyl, substituted or unsubstituted
C.sub.6-14arylC.sub.2-5alkenyl, substituted or unsubstituted 5 to
14 membered heteroarylC.sub.1-6alkyl, and substituted or
unsubstituted 5 to 14 membered heterocycloalkylC.sub.1-6alkyl;
[0087] with the proviso that (i) when X is CH then Y is selected
from:
[0087] ##STR00023## ##STR00024## ##STR00025## ##STR00026##
##STR00027## ##STR00028## [0088] and (ii) when X is nitrogen then Y
is selected from:
##STR00029## ##STR00030## ##STR00031## ##STR00032## ##STR00033##
##STR00034## ##STR00035## ##STR00036## ##STR00037## ##STR00038##
##STR00039## ##STR00040## ##STR00041##
[0089] The compounds of Formula I may be described in one or more
embodiments. It is to be understood that the embodiments described
herein are illustrative of the present invention and are not
intended to be limiting. It is also to be understood that the
embodiments described herein may be used independently or in
conjunction with any definition, or any other embodiment defined
herein. Thus, the invention contemplates all possible combinations
and permutations of the various independently described
embodiments.
[0090] According to one embodiment, the present invention provides
a compound of Formula I or a pharmaceutically acceptable salt,
stereoisomer or deuterated analog thereof, wherein [0091] X is CH;
[0092] R.sub.1 is selected from hydrogen, --CH.sub.3, --COOH,
fluoro and --CN; [0093] R.sub.2 is selected from hydrogen,
--CH.sub.3, --COOH, fluoro and --CN; [0094] Y is selected from:
##STR00042## ##STR00043## ##STR00044## ##STR00045##
[0095] In another embodiment, the present invention provides a
compound of Formula I or a pharmaceutically acceptable salt,
stereoisomer or deuterated analog thereof, wherein [0096] X is
nitrogen; [0097] R.sub.1 is selected from hydrogen, --CH.sub.3,
--COOH, fluoro and --CN; [0098] R.sub.2 is selected from hydrogen,
--CH.sub.3, --COOH, fluoro and --CN; [0099] Y is selected from:
##STR00046## ##STR00047## ##STR00048## ##STR00049## ##STR00050##
##STR00051## ##STR00052## ##STR00053## ##STR00054##
[0100] In another embodiment, the present invention provides a
compound of Formula I wherein R.sub.1 and R.sub.2 are hydrogen.
[0101] In another embodiment, the present invention provides a
compound of Formula I, or a pharmaceutically acceptable salt,
stereoisomer or deuterated analog thereof, wherein [0102] R.sub.1
and R.sub.2 are hydrogen, [0103] X is CH or nitrogen, and [0104]
when X is CH then Y is selected from:
[0104] ##STR00055## ##STR00056## ##STR00057## [0105] and when X is
nitrogen then Y is selected from:
##STR00058##
[0106] In another embodiment, the present invention provides a
compound of Formula I, or a pharmaceutically acceptable salt,
stereoisomer or deuterated analog thereof, wherein [0107] R.sub.1
and R.sub.2 are hydrogen; and [0108] X is CH or nitrogen, [0109]
wherein when X is CH, Y is selected from:
[0109] ##STR00059## [0110] and when X is nitrogen, Y is selected
from:
##STR00060##
[0111] In another embodiment, the present invention provides a
compound of Formula I, or a pharmaceutically acceptable salt,
stereoisomer or deuterated analog thereof, wherein [0112] R.sub.1
is selected from hydrogen, CH.sub.3, --COOH, fluoro and CN (e.g.,
hydrogen); [0113] R.sub.2 is selected from hydrogen, CH.sub.3,
--COOH, fluoro and CN (e.g., hydrogen); [0114] X is CH, and [0115]
Y is selected from:
##STR00061##
[0116] In another embodiment, the present invention provides a
compound of Formula I, or a pharmaceutically acceptable salt,
stereoisomer or deuterated analog thereof, wherein [0117] R.sub.1
and R.sub.2 both are hydrogen, [0118] X is nitrogen and [0119] Y is
selected from the group consisting of:
##STR00062##
[0120] In another embodiment, the present invention provides a
compound of Formula I or a pharmaceutically acceptable salt,
stereoisomer or deuterated analog thereof, wherein [0121] R.sub.1
and R.sub.2 both are hydrogen, [0122] X is nitrogen and [0123] Y is
selected from:
##STR00063## ##STR00064## ##STR00065## ##STR00066##
[0124] In another embodiment, the present invention provides a
compound of Formula I or a pharmaceutically acceptable salt,
stereoisomer or deuterated analog thereof, wherein [0125] R.sub.1
is selected from hydrogen, CH.sub.3, --COOH, fluoro and CN (e.g.,
hydrogen); [0126] R.sub.2 is selected from hydrogen, CH.sub.3,
--COOH, fluoro and CN (e.g., hydrogen); [0127] X is CH; and [0128]
Y is selected from:
##STR00067## ##STR00068##
[0129] In another aspect, the present invention provides a compound
of Formula Ia
##STR00069## [0130] or a pharmaceutically acceptable salt,
stereoisomer or deuterated analog thereof, wherein [0131] R.sub.1
is selected from hydrogen, --CH.sub.3, --COOH, fluoro and --CN;
[0132] R.sub.2 is selected from hydrogen, --CH.sub.3, --COOH,
fluoro and --CN; and [0133] Y is selected from:
##STR00070## ##STR00071## ##STR00072## ##STR00073## ##STR00074##
##STR00075## ##STR00076## ##STR00077## ##STR00078## ##STR00079##
##STR00080## ##STR00081## ##STR00082## ##STR00083##
[0134] In another embodiment of the above aspect, the present
invention provides a compound of Formula Ia, or a pharmaceutically
acceptable salt, stereoisomer or deuterated analog thereof, wherein
[0135] R.sub.1 is selected from hydrogen, --CH.sub.3, --COOH,
fluoro and --CN; [0136] R.sub.2 is selected from hydrogen,
--CH.sub.3, --COOH, fluoro and --CN; and [0137] Y is selected
from:
##STR00084## ##STR00085## ##STR00086## ##STR00087## ##STR00088##
##STR00089## ##STR00090## ##STR00091## ##STR00092##
[0138] In another embodiment, the present invention provides a
compound of Formula Ia, or a pharmaceutically acceptable salt,
stereoisomer or deuterated analog thereof, wherein R.sub.1 and
R.sub.2 are hydrogen.
[0139] In another embodiment, the present invention provides a
compound of Formula Ia, or a pharmaceutically acceptable salt,
stereoisomer or deuterated analog thereof, wherein [0140] R.sub.1
and R.sub.2 are hydrogen; and [0141] Y is selected from:
##STR00093##
[0142] In another embodiment, the present invention provides a
compound of Formula Ia, or a pharmaceutically acceptable salt,
stereoisomer or deuterated analog thereof, wherein [0143] R.sub.1
and R.sub.2 are hydrogen; and [0144] Y is selected from:
##STR00094##
[0145] In another embodiment, the present invention provides a
compound of Formula Ia, or a pharmaceutically acceptable salt,
stereoisomer or deuterated analog thereof, wherein [0146] R.sub.1
and R.sub.2 are hydrogen, and [0147] Y is selected from:
##STR00095##
[0148] In another embodiment, the present invention provides a
compound of Formula Ia, or a pharmaceutically acceptable salt,
stereoisomer or deuterated analog thereof, wherein [0149] R.sub.1
and R.sub.2 are hydrogen, and [0150] Y is selected from:
##STR00096## ##STR00097## ##STR00098## ##STR00099##
[0151] In another aspect, the present invention relates to a
compound of Formula Ib
##STR00100## [0152] or a pharmaceutically acceptable salt,
stereoisomer or deuterated analog thereof, wherein [0153] R.sub.1
is selected from hydrogen, --CH.sub.3, --COOH, fluoro and --CN;
[0154] R.sub.2 is selected from hydrogen, --CH.sub.3, --COOH,
fluoro and --CN; [0155] Y is selected from:
##STR00101## ##STR00102## ##STR00103## ##STR00104## ##STR00105##
##STR00106##
[0156] According to one embodiment, the present invention provides
a compound of Formula Ib, or a pharmaceutically acceptable salt,
stereoisomer or deuterated analog thereof, wherein [0157] R.sub.1
is selected from hydrogen, CH.sub.3, --COOH, fluoro and CN; [0158]
R.sub.2 is selected from hydrogen, CH.sub.3, --COOH, fluoro and CN;
and [0159] Y is selected from:
##STR00107## ##STR00108## ##STR00109## ##STR00110##
##STR00111##
[0160] In another embodiment, the present invention provides a
compound of Formula Ib, or a pharmaceutically acceptable salt,
stereoisomer or deuterated analog thereof, wherein R.sub.1 and
R.sub.2 both are hydrogen.
[0161] In another embodiment, the present invention provides a
compound of Formula Ib, or a pharmaceutically acceptable salt,
stereoisomer or deuterated analog thereof, wherein [0162] R.sub.1
and R.sub.2 both are hydrogen, and [0163] Y is selected from:
##STR00112## ##STR00113## ##STR00114##
[0164] In another embodiment, the present invention provides a
compound of Formula Ib, or a pharmaceutically acceptable salt,
stereoisomer or deuterated analog thereof, wherein [0165] R.sub.1
and R.sub.2 both are hydrogen, and [0166] Y is selected from:
##STR00115##
[0167] In another embodiment, the present invention provides a
compound of Formula Ib, or a pharmaceutically acceptable salt,
stereoisomer or deuterated analog thereof, wherein [0168] R.sub.1
is selected from hydrogen, CH.sub.3, COOH, fluoro and CN; [0169]
R.sub.2 is selected from hydrogen, CH.sub.3, COOH, fluoro and CN;
and [0170] Y is selected from:
##STR00116##
[0171] In another embodiment the present invention provides a
compound of Formula Ib or a pharmaceutically acceptable salt,
stereoisomer or deuterated analog thereof, wherein [0172] R.sub.1
is selected from hydrogen, --CH.sub.3, --COOH, fluoro and --CN;
[0173] R.sub.2 is selected from hydrogen, --CH.sub.3, --COOH,
fluoro and --CN; and [0174] Y is selected from:
##STR00117## ##STR00118##
[0175] In another embodiment, the present invention relates to a
compound selected from: [0176]
1-[4-(4-Hydroxyphenyl)piperazin-1-yl]-2-phenylethanone, [0177]
4-(4-Hydroxyphenyl)piperazin-1-yl]-(1H-indol-3-yl)-methanone,
[0178]
1-[4-(4-Hydroxyphenyl)-piperazin-1-yl]-2-(3,4,5-trimethoxyphenyl)-ethanon-
e, [0179]
2-(4-Hydroxyphenyl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-ethan-
one, [0180]
1-[4-(4-Hydroxyphenyl)-piperazin-1-yl]-2-[4-(2-methoxyethoxy)-phenyl]-eth-
anone, [0181]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-2-phenylethanone,
[0182]
[4-(4-Hydroxyphenyl)-piperazin-1-yl]-[1-(2-methoxyethyl)-piperidin-4-yl]--
methanone, [0183]
[4-(4-Hydroxyphenyl)-piperazin-1-yl]-(1H-indazol-3-yl)-methanone,
[0184]
Acridin-9-yl-[4-(4-hydroxy-phenyl)-piperazin-1-yl]-methanone,
[0185]
[4-(4-Hydroxyphenyl)-piperazin-1-yl]-[5-(2-methoxyethoxy)-1H-indol-3-yl]--
methanone, [0186]
1-[4-(2-Fluoro-4-hydroxy-phenyl)-piperazin-1-yl]-2-phenylethanone,
[0187]
3-(4-Butoxyphenyl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-propenone,
[0188]
3-(4-Butoxyphenyl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-propan-1-
-one, [0189]
(5-Butoxy-1H-indol-3-yl)-[4-(4-hydroxyphenyl)-piperazin-1-yl]-methanone,
[0190]
(1-Benzyl-1H-indol-3-yl)-[4-(4-hydroxyphenyl)-piperazin-1-yl]-meth-
anone, [0191]
N-{(S)-1-Benzyl-2-[4-(4-hydroxyphenyl)-piperazin-1-yl]-2-oxoethyl}-acetam-
ide, [0192]
1-[4-(4-Hydroxyphenyl)-piperazin-1-yl]-2-phenyl-ethane-1,2-dione,
[0193]
(1-Butyl-1H-indol-3-yl)-[4-(4-hydroxyphenyl)-piperazin-1-yl]-methanone,
[0194]
N-{(1R)-2-[4-(4-Hydroxyphenyl)piperazin-1-yl]-2-oxo-1-phenylethyl}-
acetamide, [0195]
(2,6-diphenyl-4-pyridyl)-[4-(4-hydroxyphenyl)piperazin-1-yl]methanone,
[0196]
Anthracen-9-yl-[4-(4-hydroxyphenyl)-piperazin-1-yl]-methanone,
[0197]
[4-(4-Hydroxyphenyl)-piperazin-1-yl]-phenanthren-9-yl-methanone,
[0198]
1-[4-(4-Hydroxyphenyl)-piperazin-1-yl]-3-naphthalen-2-yl-propan-1--
one, [0199]
[4-(4-Hydroxyphenyl)-piperazin-1-yl]-quinolin-3-yl-methanone,
[0200]
Anthracen-1-yl-[4-(4-hydroxyphenyl)-piperazin-1-yl]-methanone,
[0201]
(1-Benzylindol-4-yl)-[4-(4-hydroxyphenyl)piperazin-1-yl]methanone,
[0202]
(3,5-Diphenylphenyl)-[4-(4-hydroxyphenyl)piperazin-1-yl]methanone,
[0203]
1-[4-(4-Hydroxyphenyl)-piperazin-1-yl]-2-(4-trifluoromethylphenyl)-
-ethanone, [0204]
[4-(4-Hydroxyphenyl)-piperazin-1-yl]-imidazo[1,2-a]yridine-8-yl-methanone-
, [0205]
[4-(4-Hydroxyphenyl)-piperazin-1-yl]-(1H-indol-4-yl)-methanone,
[0206]
[4-(4-Hydroxyphenyl)-piperazin-1-yl]-[3-(4-trifluoromethylphenyl)--
imidazo[1,2-a] yridine-8-yl]-methanone, [0207]
2-Hydroxy-5-(4-phenylacetylpiperazin-1-yl)-benzoic acid, [0208]
[4-(4-Hydroxyphenyl)piperazin-1-yl]-(2-morpholino-6-phenyl-4-pyridyl)meth-
anone, [0209]
[4-(4-Hydroxyphenyl)piperazin-1-yl]-(2-phenyl-4-pyridyl)methanone,
[0210]
[4-(4-Hydroxyphenyl)piperazin-1-yl]-(2-morpholino-4-pyridyl)methanone,
[0211]
(2-Chloro-6-morpholino-4-pyridyl)-[4-(4-hydroxyphenyl)piperazin-1--
yl]methanone, [0212]
5-[4-(2,6-Diphenylpyridine-4-carbonyl)piperazin-1-yl]-2-hydroxy-benzonitr-
ile, [0213]
5-[4-(2,6-Diphenylpyridine-4-carbonyl)piperazin-1-yl]-2-hydroxy-benzoic
acid, [0214]
3-[4-[4-(4-Hydroxyphenyl)piperazine-1-carbonyl]-2-pyridyl]benzoic
acid, [0215]
1-[4-(4-Hydroxyphenyl)piperazin-1-yl]-3,3-diphenyl-prop-2-en-1-one-
, [0216]
3-[4-[4-(4-Hydroxyphenyl)piperazine-1-carbonyl]-6-morpholino-2-py-
ridyl]benzoic acid, [0217]
4-[4-[4-(4-Hydroxyphenyl)piperazine-1-carbonyl]-6-morpholino-2-pyridyl]be-
nzoic acid, [0218]
[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-(1H-indol-3-yl)-methanone,
[0219]
Acridin-9-yl-[4-(5-hydroxy-pyridin-2-yl)-piperazin-1-yl]-methanone-
, [0220]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-phenyl-propan-1-on-
e, [0221]
1-[4-(4-Hydroxyphenyl)-piperazin-1-yl]-3-naphthalen-1-yl-propan--
1-one, [0222]
3-[4-(4-Hydroxyphenyl)piperazine-1-carbonyl]-1H-quinolin-4-one,
[0223]
1-[4-(5-Hydroxy-2-pyridyl)piperazin-1-yl]-2,2-diphenyl-ethanone,
[0224]
1-[4-(4-Hydroxyphenyl)piperazin-1-yl]-2-(2-phenoxyphenyl)ethanone,
[0225]
[4-(4-Hydroxyphenyl)piperazin-1-yl]-[2-(1-piperidyl)-4-pyridyl]methanone,
[0226]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-(1H-indol-3-yl)-pro-
pan-1-one, [0227]
1-[4-(4-Hydroxy-3-methyl-phenyl)-piperazin-1-yl]-2-phenylethanone,
[0228]
3-Anthracen-9-yl-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-propan-1-one,
[0229]
3-[4-(5-Hydroxy-2-pyridyl)piperazine-1-carbonyl]-1H-quinolin-4-one-
, [0230]
2-(1-Adamantyl)-1-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]ethanone-
, [0231]
2-(3-Hydroxy-1-adamantyl)-1-[4-(5-hydroxy-2-pyridyl)piperazin-1-y-
l]ethanone, [0232]
2-(1-Adamantylmethylamino)-1-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]ethan-
one, [0233]
2,2-Bis(4-chlorophenyl)-1-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]ethanone-
, [0234]
1-(Cyclopropylmethyl)-3-[4-(5-hydroxy-2-pyridyl)piperazine-1-carb-
onyl]quinolin-4-one, [0235]
2-Fluoren-9-ylidene-1-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]ethanone,
[0236]
2-(9H-Fluoren-9-yl)-1-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]ethan-
one, [0237]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-2-(1H-indol-3-yl)-ethanone,
[0238]
[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-(1H-pyrrolo[2,3-b]pyrid-
in-3-yl)-methanone, [0239]
Anthracen-9-yl-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-methanone,
[0240]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-4-phenylbutan-1-one,
[0241]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-pyridin-4-yl-propan-
-1-one, [0242]
[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-indan-2-yl-methanone,
[0243]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-5-phenylpentan-1-one,
[0244]
3-[4-(5-Hydroxy-2-pyridyl)piperazine-1-carbonyl]-1-methylquinolin-4-one,
[0245] 5-[4-(5-Hydroxy-2-pyridyl)piperazin-1-yl]-5-oxo-pentanoic
acid, [0246]
[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-(1-methyl-1H-indol-3-yl-
)-methanone, [0247]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-(3-trifluoromethyl-phenyl)-
-propan-1-one, [0248]
3-[4-(5-Hydroxy-2-pyridyl)piperazine-1-carbonyl]chromen-2-one,
[0249]
1-[4-(5-Hydroxy-2-pyridyl)piperazin-1-yl]-3,3-diphenyl-prop-2-en-1-one,
[0250]
1-[4-(5-Hydroxy-2-pyridyl)piperazin-1-yl]-3,3-diphenyl-propan-1-on-
e, [0251]
(5-Chlorothiophen-2-yl)-[4-(5-hydroxy-pyridin-2-yl)-piperazin-1--
yl]-methanone, [0252]
(E)-1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-(4-nitrophenyl)-propen-
one, [0253]
(E)-3-(4-Chlorophenyl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-prope-
none, [0254]
3-(3,4-Dichlorophenyl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-propa-
n-1-one, [0255]
(2-Chloro-6-methylphenyl)-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-meth-
anone, [0256]
[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-[3-(4-methylimidazol-1-yl)-5-t-
rifluoromethylphenyl]-methanone, [0257]
3-(4-Chlorophenyl)-1-[4-(5-hydroxy-pyridin-2-yl)-piperazin-1-yl]-propan-1-
-one, [0258]
2-(1-Adamantylamino)-1-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]ethanone,
[0259]
1-[4-(5-Hydroxy-2-pyridyl)piperazin-1-yl]-3,3-bis(4-methoxyphenyl)-
prop-2-en-1-one, [0260]
[[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-[4-methyl-3-(4-pyridin-3-yl-p-
yrimidin-2-ylamino)phenyl]methanone, [0261]
(1H-Benzoimidazol-2-yl)-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-methan-
one, [0262]
(5-Bromothiophen-2-yl)-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-methano-
ne, [0263]
[(5-Fluoro-1H-indol-2-yl)-[4-(5-hydroxypyridin-2-yl)-piperazin--
1-yl]-methanone, [0264] Quinoline-8-sulfonic acid
{2-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-2-oxo-ethyl}-methylamide,
[0265]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-(4-isobutylphenyl)--
propan-1-one, [0266]
2-(2,4-Difluorophenyl)-1-[4-(5-hydroxypyridine-2-yl)-piperazin-1-yl]-etha-
none, [0267]
3-(3-Fluorophenyl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-propan-1--
one, [0268]
1-[4-(5-Hydroxy-2-pyridyl)piperazin-1-yl]-3,3-bis(4-methoxyphenyl)propan--
1-one, [0269]
1-[4-(5-Hydroxy-2-pyridyl)piperazin-1-yl]-4,4-diphenyl-but-3-en-1-one,
[0270]
2-Cyclohexyl-2-hydroxy-1-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]-2-
-phenyl-ethanone, [0271]
2-[1-Adamantylmethyl(methyl)amino]-1-[4-(5-hydroxy-2-pyridyl)piperazin-1--
yl]ethanone, [0272]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-2-(5-nitropyridin-2-ylsulfan-
yl)-ethanone, [0273]
3-(1-Adamantyl)-1-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]propan-1-one,
[0274]
2-Cyclohexyl-1-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]-2-phenyl-et-
hanone, [0275]
3-(4-Hydroxyphenyl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-propan-1-
-one, [0276]
3-(4-Methoxyphenyl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-propan-1-
-one, [0277]
3-(2-Bromophenyl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-propan-1-o-
ne, [0278]
3-(4-Bromophenyl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]--
propan-1-one, [0279]
3-[4-(5-Hydroxypyridin-2-yl)-piperazine-1-carbonyl]-7-oxa-bicyclo[2.2.1]h-
eptane-2-carboxylic acid methyl ester, [0280]
3-[4-(5-Hydroxypyridin-2-yl)-piperazine-1-carbonyl]-7-oxa-bicyclo[2.2.1]h-
eptane-2-carboxylic acid, [0281]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-2-(1H-indol-3-yl)-ethane-1,2-
-dione, [0282]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-o-tolyl-propan-1-one,
[0283]
3-(4-Dimethylaminophenyl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-
-yl]-propan-1-one, [0284]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-(2-methoxyphenyl)-propan-1-
-one, [0285]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-p-tolyl-propan-1-one,
[0286] 2-[4-(5-Hydroxypyridin-2-yl)-piperazine-1-carbonyl]benzoic
acid, [0287]
1-[4-(5-Hydroxy-2-pyridyl)piperazin-1-yl]-4,4-diphenylbutan-1-one,
[0288]
[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-[3-(1H-indol-4-yl)pheny-
l]methanone, [0289]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-[4-(2-methoxyethoxy)phenyl-
]-propan-1-one, [0290]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-phenylbutan-1-one,
[0291]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-thiophen-2-yl-propan-1-one-
, [0292]
1-[4-(5-Hydroxy-2-pyridyl)piperazin-1-yl]-2-morpholino-2-phenylet-
hanone, [0293]
Cyclohexyl-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]methanone, [0294]
Cyclopropyl-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]methanone,
[0295]
(E)-3-Cyclohexyl-1-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]prop-2-en-1-one-
, [0296]
3-Cyclohexyl-1-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]propan-1-on-
e, [0297]
3-Benzo[b]thiophen-2-yl-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-
-yl]-propan-1-one, [0298]
[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-(5-phenylthiophen-2-yl)-methan-
one, [0299]
(3-Hydroxy-3-phenylcyclobutyl)-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-
-methanone, [0300]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-methyl-3-phenylbutan-1-one-
, [0301]
3-(4-Fluorophenyl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-p-
ropan-1-one, [0302]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-2-(2-methyl-1H-indol-3-yl)-e-
thanone, [0303]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-(2-trifluoromethylphenyl)--
propan-1-one, [0304]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-pyridin-2-yl-propan-1-one,
[0305]
3-Hydroxy-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-3-phenylpro-
pan-1-one, [0306]
2-(5-Fluoro-1H-indol-3-yl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-e-
thanone, [0307]
[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-(1,2,3,4-tetrahydronaphthalen--
1-yl)-methanone, [0308]
[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-((1R,2R)-2-phenylcyclopropyl)--
methanone, [0309]
[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-(3-phenylcyclobutyl)-methanone-
, [0310]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-indol-1-yl-propan--
1-one, [0311]
3-Benzoimidazol-1-yl-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-propan--
1-one, [0312]
2-Cyclopropyl-1-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]ethanone,
[0313]
3-(4-Cyanophenyl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-propan-1-o-
ne, [0314]
3-(4-Trifluoromethylphenyl)-1-[4-(5-hydroxypyridin-2-yl)-pipera-
zin-1-yl]-propan-1-one, [0315]
3-Cyclopropyl-1-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]propan-1-one,
[0316]
2-{3-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-oxopropyl}-benzo-
ic acid, [0317]
2-{3-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-oxo-propyl}-benzoic
acid methyl ester, [0318]
2-(2-Bromophenylsulfanyl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-et-
hanone, [0319]
2-Hydroxy-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-3-phenyl-propan-1--
one, [0320]
3-(4-Fluoro-2-methylphenyl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]--
propan-1-one, [0321]
3-(2,3-Dimethylphenyl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-propa-
n-1-one, [0322]
3-(2,6-Dimethylphenyl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-propa-
n-1-one, [0323]
2-(3,5-Difluorophenyl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-ethanone,
[0324]
2-(2,4-Difluorophenyl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-etha-
none, [0325]
2-(5-Fluoro-1H-indol-3-yl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-ethanon-
e, [0326]
2-(2-Bromophenylsulfanyl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-
-ethanone, [0327]
3-(2,4-Difluorophenyl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-propa-
n-1-one, [0328]
3-(3,4-Difluorophenyl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-propa-
n-1-one, [0329]
(2-Chloro-6-methylphenyl)-[4-(4-hydroxyphenyl)-piperazin-1-yl]-methanone,
[0330]
(5-Fluoro-1H-indol-3-yl)-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl-
]-methanone, [0331]
(5-Fluoro-1H-indol-3-yl)-[4-(4-hydroxyphenyl)-piperazin-1-yl]-methanone,
[0332]
3-(2,6-Difluorophenyl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl-
]-propan-1-one, [0333]
2-(6-Fluoro-1H-indol-3-yl)-1-[4-(5-hydroxy-pyridin-2-yl)-piperazin-1-yl]--
ethanone, [0334]
2-(5-Chloro-1H-indol-3-yl)-1-[4-(5-hydroxy-pyridin-2-yl)-piperazin-1-yl]--
ethanone, [0335]
2-(5,6-Difluoro-1H-indol-3-yl)-1-[4-(5-hydroxy-pyridin-2-yl)-piperazin-1--
yl]-ethanone, [0336]
3-(4-Fluoro-phenyl)-1-[4-(5-hydroxy-pyridin-2-yl)-piperazin-1-yl]-3-methy-
l-butan-1-one, [0337]
2-(2-Bromo-phenylsulfanyl)-1-[4-(5-hydroxy-pyridin-2-yl)-piperazin-1-yl]--
2-methyl-propan-1-one, [0338]
2-(4-Fluoro-phenylsulfanyl)-1-[4-(5-hydroxy-pyridin-2-yl)-piperazin-1-yl]-
-ethanone, [0339]
2-(4-Fluoro-phenoxy)-1-[4-(5-hydroxy-pyridin-2-yl)-piperazin-1-yl]-ethano-
ne, [0340]
2-(5-Fluoro-1-methyl-indol-3-yl)-1-[4-(5-hydroxy-pyridin-2-yl)--
piperazin-1-yl]-ethanone, [0341]
2-(5-Fluoro-2-methyl-1H-indol-3-yl)-1-[4-(5-hydroxy-pyridin-2-yl)-piperaz-
in-1-yl]-ethanone, [0342]
2-(5,7-Difluoro-1H-indol-3-yl)-1-[4-(5-hydroxy-pyridin-2-yl)-piperazin-1--
yl]-ethanone, [0343]
1-(5-Fluoro-1H-indol-3-yl)-2-[4-(5-hydroxy-pyridin-2-yl)-piperazin-1-yl]--
ethane-1,2-dione, [0344]
2-(5-Fluoro-1H-indol-3-yl)-1-[4-(5-hydroxy-pyridin-2-yl)-piperazin-1-yl]--
2-methyl-propan-1-one, [0345]
1-[4-(5-Hydroxy-pyridin-2-yl)-piperazin-1-yl]-3-(3,4,5-trifluoro-phenyl)--
propan-1-one, [0346]
1-[4-(4-Hydroxy-phenyl)-piperazin-1-yl]-2-(3,4,5-trifluoro-phenyl)-ethano-
ne, [0347]
N-{3-[4-(5-Hydroxy-pyridin-2-yl)-piperazin-1-yl]-3-oxo-1-phenyl-
-propyl}-acrylamide, [0348]
1-[4-(4-Hydroxy-phenyl)-piperazin-1-yl]-3-methyl-3-phenyl-butan-1-one,
[0349]
2-(5,6-Dichloro-1H-indol-3-yl)-1-[4-(5-hydroxy-pyridin-2-yl)-piper-
azin-1-yl]-ethanone, [0350]
2-(5-Chloro-2-methyl-1H-indol-3-yl)-1-[4-(5-hydroxy-pyridin-2-yl)-piperaz-
in-1-yl]-ethanone, [0351]
2-(5,6-Dichloro-2-methyl-1H-indol-3-yl)-1-[4-(5-hydroxy-pyridin-2-yl)-pip-
erazin-1-yl]-ethanone, [0352] and pharmaceutically acceptable
salts, stereoisomers, and/or deuterated analogs thereof.
[0353] In another embodiment, the present invention relates to a
compound selected from: [0354]
1-[4-(4-Hydroxyphenyl)piperazin-1-yl]-2-phenylethanone, [0355]
4-(4-Hydroxyphenyl)piperazin-1-yl]-(1H-indol-3-yl)-methanone,
[0356]
1-[4-(4-Hydroxyphenyl)-piperazin-1-yl]-2-(3,4,5-trimethoxyphenyl)-ethanon-
e, [0357]
2-(4-Hydroxyphenyl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-ethan-
one, [0358]
1-[4-(4-Hydroxyphenyl)-piperazin-1-yl]-2-[4-(2-methoxyethoxy)-phenyl]-eth-
anone, [0359]
[4-(4-Hydroxyphenyl)-piperazin-1-yl]-[1-(2-methoxyethyl)-piperidin-4-yl]--
methanone, [0360]
[4-(4-Hydroxyphenyl)-piperazin-1-yl]-(1H-indazol-3-yl)-methanone,
[0361]
Acridin-9-yl-[4-(4-hydroxy-phenyl)-piperazin-1-yl]-methanone,
[0362]
[4-(4-Hydroxyphenyl)-piperazin-1-yl]-[5-(2-methoxyethoxy)-1H-indol-3-yl]--
methanone, [0363]
1-[4-(2-Fluoro-4-hydroxy-phenyl)-piperazin-1-yl]-2-phenylethanone,
[0364]
3-(4-Butoxyphenyl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-propenone,
[0365]
3-(4-Butoxyphenyl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-propan-1-
-one, [0366]
(5-Butoxy-1H-indol-3-yl)-[4-(4-hydroxyphenyl)-piperazin-1-yl]-methanone,
[0367]
(1-Benzyl-1H-indol-3-yl)-[4-(4-hydroxyphenyl)-piperazin-1-yl]-meth-
anone, [0368]
N-{(S)-1-Benzyl-2-[4-(4-hydroxyphenyl)-piperazin-1-yl]-2-oxoethyl}-acetam-
ide, [0369]
1-[4-(4-Hydroxyphenyl)-piperazin-1-yl]-2-phenyl-ethane-1,2-dione,
[0370]
(1-Butyl-1H-indol-3-yl)-[4-(4-hydroxyphenyl)-piperazin-1-yl]-methanone,
[0371]
N-{(1R)-2-[4-(4-Hydroxyphenyl)piperazin-1-yl]-2-oxo-1-phenylethyl}-
acetamide, [0372]
(2,6-diphenyl-4-pyridyl)-[4-(4-hydroxyphenyl)piperazin-1-yl]methanone,
[0373]
Anthracen-9-yl-[4-(4-hydroxyphenyl)-piperazin-1-yl]-methanone,
[0374]
[4-(4-Hydroxyphenyl)-piperazin-1-yl]-phenanthren-9-yl-methanone,
[0375]
1-[4-(4-Hydroxyphenyl)-piperazin-1-yl]-3-naphthalen-2-yl-propan-1--
one, [0376]
[4-(4-Hydroxyphenyl)-piperazin-1-yl]-quinolin-3-yl-methanone,
[0377]
Anthracen-1-yl-[4-(4-hydroxyphenyl)-piperazin-1-yl]-methanone,
[0378]
(1-Benzylindol-4-yl)-[4-(4-hydroxyphenyl)piperazin-1-yl]methanone,
[0379]
(3,5-Diphenylphenyl)-[4-(4-hydroxyphenyl)piperazin-1-yl]methanone,
[0380]
1-[4-(4-Hydroxyphenyl)-piperazin-1-yl]-2-(4-trifluoromethylphenyl)-
-ethanone, [0381]
[4-(4-Hydroxyphenyl)-piperazin-1-yl]-imidazo[1,2-a]yridine-8-yl-methanone-
, [0382]
[4-(4-Hydroxyphenyl)-piperazin-1-yl]-(1H-indol-4-yl)-methanone,
[0383]
[4-(4-Hydroxyphenyl)-piperazin-1-yl]-[3-(4-trifluoromethylphenyl)--
imidazo[1,2-a] yridine-8-yl]-methanone, [0384]
2-Hydroxy-5-(4-phenylacetylpiperazin-1-yl)-benzoic acid, [0385]
[4-(4-Hydroxyphenyl)piperazin-1-yl]-(2-morpholino-6-phenyl-4-pyridyl)meth-
anone, [0386]
[4-(4-Hydroxyphenyl)piperazin-1-yl]-(2-phenyl-4-pyridyl)methanone,
[0387]
[4-(4-Hydroxyphenyl)piperazin-1-yl]-(2-morpholino-4-pyridyl)methanone,
[0388]
(2-Chloro-6-morpholino-4-pyridyl)-[4-(4-hydroxyphenyl)piperazin-1--
yl]methanone, [0389]
5-[4-(2,6-Diphenylpyridine-4-carbonyl)piperazin-1-yl]-2-hydroxy-benzonitr-
ile, [0390]
5-[4-(2,6-Diphenylpyridine-4-carbonyl)piperazin-1-yl]-2-hydroxy-benzoic
acid, [0391]
3-[4-[4-(4-Hydroxyphenyl)piperazine-1-carbonyl]-2-pyridyl]benzoic
acid, [0392]
1-[4-(4-Hydroxyphenyl)piperazin-1-yl]-3,3-diphenyl-prop-2-en-1-one-
, [0393]
3-[4-[4-(4-Hydroxyphenyl)piperazine-1-carbonyl]-6-morpholino-2-py-
ridyl]benzoic acid, [0394]
4-[4-[4-(4-Hydroxyphenyl)piperazine-1-carbonyl]-6-morpholino-2-pyridyl]be-
nzoic acid, [0395]
1-[4-(4-Hydroxyphenyl)-piperazin-1-yl]-3-naphthalen-1-yl-propan-1-one,
[0396]
3-[4-(4-Hydroxyphenyl)piperazine-1-carbonyl]-1H-quinolin-4-one,
[0397]
1-[4-(4-Hydroxyphenyl)piperazin-1-yl]-2-(2-phenoxyphenyl)ethanone,
[0398]
[4-(4-Hydroxyphenyl)piperazin-1-yl]-[2-(1-piperidyl)-4-pyridyl]met-
hanone, [0399]
1-[4-(4-Hydroxy-3-methyl-phenyl)-piperazin-1-yl]-2-phenylethanone,
[0400]
3-Anthracen-9-yl-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-propan-1-one,
[0401]
2-(3,5-Difluorophenyl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-etha-
none, [0402]
2-(2,4-Difluorophenyl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-ethanone,
[0403]
2-(5-Fluoro-1H-indol-3-yl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]--
ethanone, [0404]
2-(2-Bromophenylsulfanyl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-ethanone-
, [0405]
(2-Chloro-6-methylphenyl)-[4-(4-hydroxyphenyl)-piperazin-1-yl]-me-
thanone, [0406]
(5-Fluoro-1H-indol-3-yl)-[4-(4-hydroxyphenyl)-piperazin-1-yl]-methanone,
[0407]
1-[4-(4-Hydroxy-phenyl)-piperazin-1-yl]-2-(3,4,5-trifluoro-phenyl)-
-ethanone, [0408]
1-[4-(4-Hydroxy-phenyl)-piperazin-1-yl]-3-methyl-3-phenyl-butan-1-one,
[0409] and pharmaceutically acceptable salts, stereoisomers, and/or
deuterated analogs thereof.
[0410] In another embodiment, the present invention relates to a
compound selected from: [0411]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-2-phenylethanone,
[0412]
[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-(1H-indol-3-yl)-methanone,
[0413]
Acridin-9-yl-[4-(5-hydroxy-pyridin-2-yl)-piperazin-1-yl]-methanone-
, [0414]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-phenyl-propan-1-on-
e, [0415]
1-[4-(5-Hydroxy-2-pyridyl)piperazin-1-yl]-2,2-diphenyl-ethanone,
[0416]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-(1H-indol-3-yl)-pro-
pan-1-one, [0417]
3-[4-(5-Hydroxy-2-pyridyl)piperazine-1-carbonyl]-1H-quinolin-4-one,
[0418]
2-(1-Adamantyl)-1-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]ethanone,
[0419]
2-(3-Hydroxy-1-adamantyl)-1-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl-
]ethanone, [0420]
2-(1-Adamantylmethylamino)-1-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]ethan-
one, [0421]
2,2-Bis(4-chlorophenyl)-1-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]ethanone-
, [0422]
1-(Cyclopropylmethyl)-3-[4-(5-hydroxy-2-pyridyl)piperazine-1-carb-
onyl]quinolin-4-one, [0423]
2-Fluoren-9-ylidene-1-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]ethanone,
[0424]
2-(9H-Fluoren-9-yl)-1-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]ethan-
one, [0425]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-2-(1H-indol-3-yl)-ethanone,
[0426]
[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-(1H-pyrrolo[2,3-b]pyrid-
in-3-yl)-methanone, [0427]
Anthracen-9-yl-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-methanone,
[0428]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-4-phenylbutan-1-one,
[0429]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-pyridin-4-yl-propan-
-1-one, [0430]
[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-indan-2-yl-methanone,
[0431]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-5-phenylpentan-1-one,
[0432]
3-[4-(5-Hydroxy-2-pyridyl)piperazine-1-carbonyl]-1-methylquinolin-4-one,
[0433] 5-[4-(5-Hydroxy-2-pyridyl)piperazin-1-yl]-5-oxo-pentanoic
acid, [0434]
[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-(1-methyl-1H-indol-3-yl-
)-methanone, [0435]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-(3-trifluoromethyl-phenyl)-
-propan-1-one, [0436]
3-[4-(5-Hydroxy-2-pyridyl)piperazine-1-carbonyl]chromen-2-one,
[0437]
1-[4-(5-Hydroxy-2-pyridyl)piperazin-1-yl]-3,3-diphenyl-prop-2-en-1-one,
[0438]
1-[4-(5-Hydroxy-2-pyridyl)piperazin-1-yl]-3,3-diphenyl-propan-1-on-
e, [0439]
(5-Chlorothiophen-2-yl)-[4-(5-hydroxy-pyridin-2-yl)-piperazin-1--
yl]-methanone, [0440]
(E)-1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-(4-nitrophenyl)-propen-
one, [0441]
(E)-3-(4-Chlorophenyl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-prope-
none, [0442]
3-(3,4-Dichlorophenyl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-propa-
n-1-one, [0443]
(2-Chloro-6-methylphenyl)-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-meth-
anone, [0444]
[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-[3-(4-methylimidazol-1-yl)-5-t-
rifluoromethylphenyl]-methanone, [0445]
3-(4-Chlorophenyl)-1-[4-(5-hydroxy-pyridin-2-yl)-piperazin-1-yl]-propan-1-
-one, [0446]
2-(1-Adamantylamino)-1-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]ethanone,
[0447]
1-[4-(5-Hydroxy-2-pyridyl)piperazin-1-yl]-3,3-bis(4-methoxyphenyl)-
prop-2-en-1-one, [0448]
[[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-[4-methyl-3-(4-pyridin-3-yl-p-
yrimidin-2-ylamino)phenyl]methanone, [0449]
(1H-Benzoimidazol-2-yl)-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-methan-
one, [0450]
(5-Bromothiophen-2-yl)-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-methano-
ne, [0451]
[(5-Fluoro-1H-indol-2-yl)-[4-(5-hydroxypyridin-2-yl)-piperazin--
1-yl]-methanone, [0452] Quinoline-8-sulfonic acid
{2-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-2-oxo-ethyl}-methylamide,
[0453]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-(4-isobutylphenyl)--
propan-1-one, [0454]
2-(2,4-Difluorophenyl)-1-[4-(5-hydroxypyridine-2-yl)-piperazin-1-yl]-etha-
none, [0455]
3-(3-Fluorophenyl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-propan-1--
one, [0456]
1-[4-(5-Hydroxy-2-pyridyl)piperazin-1-yl]-3,3-bis(4-methoxyphenyl)propan--
1-one, [0457]
1-[4-(5-Hydroxy-2-pyridyl)piperazin-1-yl]-4,4-diphenyl-but-3-en-1-one,
[0458]
2-Cyclohexyl-2-hydroxy-1-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]-2-
-phenyl-ethanone, [0459]
2-[1-Adamantylmethyl(methyl)amino]-1-[4-(5-hydroxy-2-pyridyl)piperazin-1--
yl]ethanone, [0460]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-2-(5-nitropyridin-2-ylsulfan-
yl)-ethanone, [0461]
3-(1-Adamantyl)-1-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]propan-1-one,
[0462]
2-Cyclohexyl-1-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]-2-phenyl-et-
hanone, [0463]
3-(4-Hydroxyphenyl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-propan-1-
-one, [0464]
3-(4-Methoxyphenyl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-propan-1-
-one, [0465]
3-(2-Bromophenyl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-propan-1-o-
ne, [0466]
3-(4-Bromophenyl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]--
propan-1-one, [0467]
3-[4-(5-Hydroxypyridin-2-yl)-piperazine-1-carbonyl]-7-oxa-bicyclo[2.2.1]h-
eptane-2-carboxylic acid methyl ester, [0468]
3-[4-(5-Hydroxypyridin-2-yl)-piperazine-1-carbonyl]-7-oxa-bicyclo[2.2.1]h-
eptane-2-carboxylic acid, [0469]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-2-(1H-indol-3-yl)-ethane-1,2-
-dione, [0470]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-o-tolyl-propan-1-one,
[0471]
3-(4-Dimethylaminophenyl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-
-yl]-propan-1-one, [0472]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-(2-methoxyphenyl)-propan-1-
-one, [0473]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-p-tolyl-propan-1-one,
[0474] 2-[4-(5-Hydroxypyridin-2-yl)-piperazine-1-carbonyl]benzoic
acid, [0475]
1-[4-(5-Hydroxy-2-pyridyl)piperazin-1-yl]-4,4-diphenylbutan-1-one,
[0476]
[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-[3-(1H-indol-4-yl)pheny-
l]methanone, [0477]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-[4-(2-methoxyethoxy)phenyl-
]-propan-1-one, [0478]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-phenylbutan-1-one,
[0479]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-thiophen-2-yl-propan-1-one-
, [0480]
1-[4-(5-Hydroxy-2-pyridyl)piperazin-1-yl]-2-morpholino-2-phenylet-
hanone, [0481]
Cyclohexyl-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]methanone, [0482]
Cyclopropyl-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]methanone,
[0483]
(E)-3-Cyclohexyl-1-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]prop-2-en-1-one-
, [0484]
3-Cyclohexyl-1-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]propan-1-on-
e, [0485]
3-Benzo[b]thiophen-2-yl-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-
-yl]-propan-1-one, [0486]
[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-(5-phenylthiophen-2-yl)-methan-
one, [0487]
(3-Hydroxy-3-phenylcyclobutyl)-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-
-methanone, [0488]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-methyl-3-phenylbutan-1-one-
, [0489]
3-(4-Fluorophenyl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-p-
ropan-1-one, [0490]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-2-(2-methyl-1H-indol-3-yl)-e-
thanone, [0491]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-(2-trifluoromethylphenyl)--
propan-1-one, [0492]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-pyridin-2-yl-propan-1-one,
[0493]
3-Hydroxy-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-3-phenylpro-
pan-1-one, [0494]
2-(5-Fluoro-1H-indol-3-yl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-e-
thanone, [0495]
[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-(1,2,3,4-tetrahydronaphthalen--
1-yl)-methanone, [0496]
[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-((1R,2R)-2-phenylcyclopropyl)--
methanone, [0497]
[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-(3-phenylcyclobutyl)-methanone-
, [0498]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-indol-1-yl-propan--
1-one, [0499]
3-Benzoimidazol-1-yl-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-propan--
1-one, [0500]
2-Cyclopropyl-1-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]ethanone,
[0501]
3-(4-Cyanophenyl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-propan-1-o-
ne, [0502]
3-(4-Trifluoromethylphenyl)-1-[4-(5-hydroxypyridin-2-yl)-pipera-
zin-1-yl]-propan-1-one, [0503]
3-Cyclopropyl-1-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]propan-1-one,
[0504]
2-{3-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-oxopropyl}-benzo-
ic acid, [0505]
2-{3-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-oxo-propyl}-benzoic
acid methyl ester, [0506]
2-(2-Bromophenylsulfanyl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-et-
hanone, [0507]
2-Hydroxy-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-3-phenyl-propan-1--
one, [0508]
3-(4-Fluoro-2-methylphenyl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]--
propan-1-one, [0509]
3-(2,3-Dimethylphenyl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-propa-
n-1-one, [0510]
3-(2,6-Dimethylphenyl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-propa-
n-1-one, [0511]
3-(2,4-Difluorophenyl-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-propan-
-1-one, [0512]
3-(3,4-Difluorophenyl-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-propan-
-1-one, [0513]
(5-Fluoro-1H-indol-3-yl)-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-metha-
none, [0514]
3-(2,6-Difluorophenyl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-propa-
n-1-one, [0515]
2-(6-Fluoro-1H-indol-3-yl)-1-[4-(5-hydroxy-pyridin-2-yl)-piperazin-1-yl]--
ethanone, [0516]
2-(5-Chloro-1H-indol-3-yl)-1-[4-(5-hydroxy-pyridin-2-yl)-piperazin-1-yl]--
ethanone, [0517]
2-(5,6-Difluoro-1H-indol-3-yl)-1-[4-(5-hydroxy-pyridin-2-yl)-piperazin-1--
yl]-ethanone, [0518]
3-(4-Fluoro-phenyl)-1-[4-(5-hydroxy-pyridin-2-yl)-piperazin-1-yl]-3-methy-
l-butan-1-one, [0519]
2-(2-Bromo-phenylsulfanyl)-1-[4-(5-hydroxy-pyridin-2-yl)-piperazin-1-yl]--
2-methyl-propan-1-one, [0520]
2-(4-Fluoro-phenylsulfanyl)-1-[4-(5-hydroxy-pyridin-2-yl)-piperazin-1-yl]-
-ethanone, [0521]
2-(4-Fluoro-phenoxy)-1-[4-(5-hydroxy-pyridin-2-yl)-piperazin-1-yl]-ethano-
ne, [0522]
2-(5-Fluoro-1-methyl-indol-3-yl)-1-[4-(5-hydroxy-pyridin-2-yl)--
piperazin-1-yl]-ethanone, [0523]
2-(5-Fluoro-2-methyl-1H-indol-3-yl)-1-[4-(5-hydroxy-pyridin-2-yl)-piperaz-
in-1-yl]-ethanone, [0524]
2-(5,7-Difluoro-1H-indol-3-yl)-1-[4-(5-hydroxy-pyridin-2-yl)-piperazin-1--
yl]-ethanone, [0525]
1-(5-Fluoro-1H-indol-3-yl)-2-[4-(5-hydroxy-pyridin-2-yl)-piperazin-1-yl]--
ethane-1,2-dione, [0526]
2-(5-Fluoro-1H-indol-3-yl)-1-[4-(5-hydroxy-pyridin-2-yl)-piperazin-1-yl]--
2-methyl-propan-1-one, [0527]
1-[4-(5-Hydroxy-pyridin-2-yl)-piperazin-1-yl]-3-(3,4,5-trifluoro-phenyl)--
propan-1-one, [0528]
N-{3-[4-(5-Hydroxy-pyridin-2-yl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl}-a-
crylamide, [0529]
2-(5,6-Dichloro-1H-indol-3-yl)-1-[4-(5-hydroxy-pyridin-2-yl)-piperazin-1--
yl]-ethanone, [0530]
2-(5-Chloro-2-methyl-1H-indol-3-yl)-1-[4-(5-hydroxy-pyridin-2-yl)-piperaz-
in-1-yl]-ethanone, [0531]
2-(5,6-Dichloro-2-methyl-1H-indol-3-yl)-1-[4-(5-hydroxy-pyridin-2-yl)-pip-
erazin-1-yl]-ethanone, [0532] and pharmaceutically acceptable
salts, stereoisomers, and/or deuterated analogs thereof.
[0533] In another embodiment, the present invention relates to a
compound selected from: [0534]
4-(4-Hydroxyphenyl)piperazin-1-yl]-(1H-indol-3-yl)-methanone,
[0535]
2-(5-Fluoro-1H-indol-3-yl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-ethanon-
e, [0536]
2-(3,5-Difluorophenyl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-et-
hanone, [0537]
2-(2,4-Difluorophenyl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-ethanone,
[0538]
2-(5-Fluoro-1H-indol-3-yl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin--
1-yl]-ethanone, [0539]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-phenyl-propan-1-one,
[0540]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-methyl-3-phenylbuta-
n-1-one, [0541]
2-(1-Adamantyl)-1-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]ethanone,
[0542]
2-(2-Bromophenylsulfanyl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-et-
hanone, [0543] and pharmaceutically acceptable salts,
stereoisomers, and/or deuterated analogs thereof.
[0544] In another embodiment, the present invention relates to a
compound selected from: [0545]
[4-(4-Hydroxyphenyl)-piperazin-1-yl]-[1-(2-methoxyethyl)-piperidin-4-yl]--
methanone, [0546]
[4-(4-Hydroxyphenyl)-piperazin-1-yl]-(1H-indazol-3-yl)-methanone,
[0547]
Acridin-9-yl-[4-(4-hydroxy-phenyl)-piperazin-1-yl]-methanone,
[0548]
[4-(4-Hydroxyphenyl)-piperazin-1-yl]-[5-(2-methoxyethoxy)-1H-indol-3-yl]--
methanone, [0549]
1-[4-(2-Fluoro-4-hydroxy-phenyl)-piperazin-1-yl]-2-phenylethanone,
[0550]
3-(4-Butoxyphenyl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-propenone,
[0551]
3-(4-Butoxyphenyl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-propan-1-
-one, [0552]
[4-(4-Hydroxyphenyl)-piperazin-1-yl]-phenanthren-9-yl-methanone,
[0553]
[4-(4-Hydroxyphenyl)-piperazin-1-yl]-(1H-indol-4-yl)-methanone,
[0554]
[4-(4-Hydroxyphenyl)piperazin-1-yl]-(2-morpholino-6-phenyl-4-pyridyl)meth-
anone, [0555]
[4-(4-Hydroxyphenyl)piperazin-1-yl]-(2-morpholino-4-pyridyl)methanone,
[0556]
(2-Chloro-6-morpholino-4-pyridyl)-[4-(4-hydroxyphenyl)piperazin-1--
yl]methanone, [0557] and pharmaceutically acceptable salts,
stereoisomers, and/or deuterated analogs thereof.
[0558] In another embodiment, the present invention relates to a
compound selected from: [0559]
Acridin-9-yl-[4-(5-hydroxy-pyridin-2-yl)-piperazin-1-yl]-methanone,
[0560]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-phenyl-propan-1-one-
, [0561]
1-[4-(5-Hydroxy-2-pyridyl)piperazin-1-yl]-2,2-diphenyl-ethanone,
[0562]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-(1H-indol-3-yl)-pro-
pan-1-one, [0563]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-thiophen-2-yl-propan-1-one-
, [0564]
3-(4-Fluorophenyl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-p-
ropan-1-one, [0565]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-indol-1-yl-propan-1-one,
[0566]
2-{3-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-oxo-propyl}-benz-
oic acid methyl ester, [0567]
2-Hydroxy-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-3-phenyl-propan-1--
one, [0568]
3-(4-Fluoro-2-methylphenyl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]--
propan-1-one, [0569]
(5-Fluoro-1H-indol-3-yl)-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-metha-
none, [0570] and pharmaceutically acceptable salts, stereoisomers,
and/or deuterated analogs thereof.
[0571] In another embodiment, the present invention relates to a
compound selected from: [0572]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-2-phenylethanone,
[0573]
3-[4-(5-Hydroxy-2-pyridyl)piperazine-1-carbonyl]-1H-quinolin-4-one,
[0574]
2-(1-Adamantyl)-1-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]ethanone,
[0575]
2,2-Bis(4-chlorophenyl)-1-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]e-
thanone, [0576]
1-(Cyclopropylmethyl)-3-[4-(5-hydroxy-2-pyridyl)piperazine-1-carbonyl]qui-
nolin-4-one, [0577]
2-(9H-Fluoren-9-yl)-1-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]ethanone,
[0578]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-2-(1H-indol-3-yl)-eth-
anone, [0579]
Anthracen-9-yl-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-methanone,
[0580]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-4-phenylbutan-1-one,
[0581]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-pyridin-4-yl-propan-
-1-one, [0582]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-5-phenylpentan-1-one,
[0583] 5-[4-(5-Hydroxy-2-pyridyl)piperazin-1-yl]-5-oxo-pentanoic
acid, [0584]
1-[4-(5-Hydroxy-2-pyridyl)piperazin-1-yl]-3,3-diphenyl-prop-2-en-1-one,
[0585]
3-(4-Chlorophenyl)-1-[4-(5-hydroxy-pyridin-2-yl)-piperazin-1-yl]-p-
ropan-1-one, [0586]
2-(1-Adamantylamino)-1-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]ethanone,
[0587]
[(5-Fluoro-1H-indol-2-yl)-[4-(5-hydroxypyridin-2-yl)-piperazin-1-y-
l]-methanone, [0588]
3-(3-Fluorophenyl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-propan-1--
one, [0589]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-o-tolyl-propan-1-one,
[0590]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-phenylbutan-1-one,
[0591]
3-Cyclohexyl-1-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]propan-1-one-
, [0592]
3-Benzo[b]thiophen-2-yl-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1--
yl]-propan-1-one, [0593]
(3-Hydroxy-3-phenylcyclobutyl)-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-
-methanone, [0594]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-2-(2-methyl-1H-indol-3-yl)-e-
thanone, [0595]
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-(2-trifluoromethylphenyl)--
propan-1-one, [0596]
3-Hydroxy-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-3-phenylpropan-1-o-
ne, [0597]
2-(5-Fluoro-1H-indol-3-yl)-1-[4-(5-hydroxypyridin-2-yl)-piperaz-
in-1-yl]-ethanone, [0598]
[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-((1R,2R)-2-phenylcyclopropyl)--
methanone, [0599]
2-Cyclopropyl-1-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]ethanone,
[0600]
3-(4-Cyanophenyl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-propan-1-o-
ne, [0601]
3-(4-Trifluoromethylphenyl)-1-[4-(5-hydroxypyridin-2-yl)-pipera-
zin-1-yl]-propan-1-one, [0602]
3-Cyclopropyl-1-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]propan-1-one,
[0603]
2-(2-Bromophenylsulfanyl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-
-yl]-ethanone, [0604]
3-(2,6-Dimethylphenyl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-propa-
n-1-one, [0605]
3-(2,4-Difluorophenyl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-propa-
n-1-one, [0606]
3-(3,4-Difluorophenyl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-propa-
n-1-one, [0607]
3-(2,6-Difluorophenyl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-propa-
n-1-one, [0608]
2-(6-Fluoro-1H-indol-3-yl)-1[4-(5-hydroxy-pyridin-2-yl)-piperazin-1-yl]-e-
thanone, [0609]
2-(5-Chloro-1H-indol-3-yl)-1-[4-(5-hydroxy-pyridin-2-yl)-piperazin-1-yl]--
ethanone, [0610]
2-(5,6-Difluoro-1H-indol-3-yl)-1-[4-(5-hydroxy-pyridin-2-yl)-piperazin-1--
yl]-ethanone, [0611]
3-(4-Fluoro-phenyl)-1-[4-(5-hydroxy-pyridin-2-yl)-piperazin-1-yl]-3-methy-
l-butan-1-one, [0612]
2-(2-Bromo-phenylsulfanyl)-1-[4-(5-hydroxy-pyridin-2-yl)-piperazin-1-yl]--
2-methyl-propan-1-one, [0613]
2-(4-Fluoro-phenylsulfanyl)-1-[4-(5-hydroxy-pyridin-2-yl)-piperazin-1-yl]-
-ethanone, [0614]
2-(5-Fluoro-2-methyl-1H-indol-3-yl)-1-[4-(5-hydroxy-pyridin-2-yl)-piperaz-
in-1-yl]-ethanone, [0615]
2-(5,7-Difluoro-1H-indol-3-yl)-1-[4-(5-hydroxy-pyridin-2-yl)-piperazin-1--
yl]-ethanone, [0616]
1-(5-Fluoro-1H-indol-3-yl)-2-[4-(5-hydroxy-pyridin-2-yl)-piperazin-1-yl]--
ethane-1,2-dione, [0617]
2-(5-Fluoro-1H-indol-3-yl)-1-[4-(5-hydroxy-pyridin-2-yl)-piperazin-1-yl]--
2-methyl-propan-1-one, [0618]
2-(5,6-Dichloro-1H-indol-3-yl)-1-[4-(5-hydroxy-pyridin-2-yl)-piperazin-1--
yl]-ethanone, [0619]
2-(5-Chloro-2-methyl-1H-indol-3-yl)-1-[4-(5-hydroxy-pyridin-2-yl)-piperaz-
in-1-yl]-ethanone, [0620]
2-(5,6-Dichloro-2-methyl-1H-indol-3-yl)-1-[4-(5-hydroxy-pyridin-2-yl)-pip-
erazin-1-yl]-ethanone, [0621] and pharmaceutically acceptable
salts, stereoisomers, and/or deuterated analogs thereof.
[0622] In another embodiment, the present invention relates to a
compound selected from: [0623]
1-[4-(4-Hydroxyphenyl)piperazin-1-yl]-2-phenylethanone, [0624]
4-(4-Hydroxyphenyl)piperazin-1-yl]-(1H-indol-3-yl)-methanone,
[0625]
2-(4-Hydroxyphenyl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-ethanone,
[0626]
1-[4-(4-Hydroxyphenyl)-piperazin-1-yl]-2-[4-(2-methoxyethoxy)-phen-
yl]-ethanone, [0627]
Anthracen-9-yl-[4-(4-hydroxyphenyl)-piperazin-1-yl]-methanone,
[0628]
1-[4-(4-Hydroxyphenyl)-piperazin-1-yl]-2-(4-trifluoromethylphenyl)-ethano-
ne, [0629]
3-[4-[4-(4-Hydroxyphenyl)piperazine-1-carbonyl]-2-pyridyl]benzo- ic
acid, [0630]
1-[4-(4-Hydroxyphenyl)piperazin-1-yl]-3,3-diphenyl-prop-2-en-1-one,
[0631]
3-[4-[4-(4-Hydroxyphenyl)piperazine-1-carbonyl]-6-morpholino-2-pyr-
idyl]benzoic acid, [0632]
4-[4-[4-(4-Hydroxyphenyl)piperazine-1-carbonyl]-6-morpholino-2-pyridyl]be-
nzoic acid, [0633]
1-[4-(4-Hydroxyphenyl)-piperazin-1-yl]-3-naphthalen-1-yl-propan-1-one,
[0634]
3-[4-(4-Hydroxyphenyl)piperazine-1-carbonyl]-1H-quinolin-4-one,
[0635]
1-[4-(4-Hydroxyphenyl)piperazin-1-yl]-2-(2-phenoxyphenyl)ethanone,
[0636]
[4-(4-Hydroxyphenyl)piperazin-1-yl]-[2-(1-piperidyl)-4-pyridyl]met-
hanone, [0637]
1-[4-(4-Hydroxy-3-methyl-phenyl)-piperazin-1-yl]-2-phenylethanone,
[0638]
3-Anthracen-9-yl-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-propan-1-one,
[0639]
2-(3,5-Difluorophenyl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-etha-
none, [0640]
2-(2,4-Difluorophenyl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-ethanone,
[0641]
2-(5-Fluoro-1H-indol-3-yl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]--
ethanone, [0642]
2-(2-Bromophenylsulfanyl)-1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-ethanone-
, [0643]
(2-Chloro-6-methylphenyl)-[4-(4-hydroxyphenyl)-piperazin-1-yl]-me-
thanone, [0644]
(5-Fluoro-1H-indol-3-yl)-[4-(4-hydroxyphenyl)-piperazin-1-yl]-methanone,
[0645]
1-[4-(4-Hydroxy-phenyl)-piperazin-1-yl]-2-(3,4,5-trifluoro-phenyl)-
-ethanone, [0646]
1-[4-(4-Hydroxy-phenyl)-piperazin-1-yl]-3-methyl-3-phenyl-butan-1-one,
[0647] and pharmaceutically acceptable salts, stereoisomers, and/or
deuterated analogs thereof.
[0648] The compounds of the present invention can also include all
isotopes of atoms occurring in the intermediates or final
compounds. Isotopes include those atoms having the same atomic
number but different mass numbers. For example, isotopes of
hydrogen include tritium and deuterium.
[0649] In another embodiment, the present invention provides
deuterated analogs of a compound of Formulae I, Ia or Ib, wherein
one or more hydrogen atoms are replaced with deuterium. Such
compounds can be synthesized by means well known in the art, for
example by employing starting materials in which one or more
hydrogen atoms have been replaced with deuterium. Deuterated
analogs may have improved drug metabolism and pharmacokinetics
properties, See, for example, Foster, "Deuterium Isotope Effects in
Studies of Drug Metabolism," Trends Pharmacol. Sci., 5(12):524-527
(1984).
[0650] The compounds described herein are potent malic enzyme
inhibitors and may be useful as medicaments, particularly for the
treatment of diseases or disorders that benefit from the inhibition
of malic enzyme. The compounds of the present invention may be
useful in the treatment of a number of tumors and/or cancers
including, but not limited to, leukemia, brain cancer, bladder
cancer, breast cancer, cervical cancer, colorectal cancer,
endometrial cancer, esophageal cancer, head and neck cancer, liver
cancer, lung cancer, lymphoma, ovarian cancer, pancreatic cancer,
prostate cancer, renal cancer, skin cancer, stomach cancer, testis
cancer, thyroid cancer, and urothelial cancer.
[0651] According to one embodiment, the compounds of the present
invention are inhibitors of malic enzyme 3 (ME3), malic enzyme 2
(ME2), and/or malic enzyme 1 (ME1).
[0652] In another embodiment, the compounds of the present
invention are inhibitors of ME3.
[0653] Thus, in another aspect, the present invention provides a
method of inhibiting a malic enzyme in a subject comprising
administering to the subject a compound of Formulae I, Ia, Ib, or a
pharmaceutically acceptable salt, stereoisomer or deuterated analog
thereof.
[0654] In one embodiment, the present invention provides a method
of inhibiting a malic enzyme in a subject comprising administering
to the subject a compound of Formula I
##STR00119## [0655] or a pharmaceutically acceptable salt,
stereoisomer or deuterated analog thereof, wherein [0656] X is CH
or nitrogen; [0657] R.sub.1 is selected from hydrogen, CH.sub.3,
--COOH, fluoro and CN; [0658] R.sub.2 is selected from hydrogen,
CH.sub.3, --COOH, fluoro and CN; [0659] Y is selected from
substituted or unsubstituted C.sub.1-5 alkyl, substituted or
unsubstituted C.sub.2-4 alkenyl, substituted or unsubstituted 5 to
14 membered heteroaryl ring containing one, two or three
heteroatoms each independently selected from nitrogen, oxygen, and
sulfur, substituted or unsubstituted 5 to 14 membered
heterocycloalkyl group containing one, two or three heteroatoms
each independently selected from nitrogen and oxygen, substituted
or unsubstituted C.sub.3-15 cycloalkyl, substituted or
unsubstituted C.sub.3-15 cycloalkylC.sub.1-6alkyl, substituted or
unsubstituted C.sub.6-14 aryl, substituted or unsubstituted
C.sub.6-14arylC.sub.1-6alkyl, substituted or unsubstituted
C.sub.6-14arylC.sub.2-5alkenyl, substituted or unsubstituted 5 to
14 membered heteroarylC.sub.1-6alkyl, and substituted or
unsubstituted 5 to 14 membered heterocycloalkylC.sub.1-6alkyl.
[0660] In another embodiment, the present invention provides a
method of inhibiting a malic enzyme in a subject comprising
administering to the subject a compound of Formula I, or a
pharmaceutically acceptable salt, stereoisomer or deuterated analog
thereof, wherein the malic enzyme is ME3, ME2, and/or ME1.
[0661] In another embodiment, the present invention provides a
method of inhibiting a malic enzyme in a subject comprising
administering to the subject a compound of Formula I, or a
pharmaceutically acceptable salt, stereoisomer or deuterated analog
thereof, wherein the malic enzyme is ME3.
[0662] In another embodiment, the present invention provides a
method of inhibiting a malic enzyme in a subject comprising
administering to the subject a compound of Formulae Ia or Ib, or a
pharmaceutically acceptable salt, stereoisomer or deuterated analog
thereof, wherein the malic enzyme is ME3, ME2, and/or ME1.
[0663] In another embodiment, the present invention provides a
method of inhibiting a malic enzyme in a subject comprising
administering to the subject a compound of Formulae Ia or Ib, or a
pharmaceutically acceptable salt, stereoisomer or deuterated analog
thereof, wherein the malic enzyme is ME3.
[0664] In another aspect, the present invention provides a method
of inhibiting a malic enzyme in a subject comprising administering
to the subject in need thereof, a compound of Formula I or a
pharmaceutically acceptable salt, stereoisomer or deuterated analog
thereof.
[0665] In one embodiment, the present invention provides a method
of inhibiting a malic enzyme in a subject comprising administering
to the subject in need thereof, a compound of Formula I
##STR00120## [0666] or a pharmaceutically acceptable salt,
stereoisomer or deuterated analog thereof, wherein [0667] X is CH
or nitrogen; [0668] R.sub.1 is selected from hydrogen, CH.sub.3,
--COOH, fluoro and CN; [0669] R.sub.2 is selected from hydrogen,
CH.sub.3, --COOH, fluoro and CN; [0670] Y is selected from
substituted or unsubstituted C.sub.1-5 alkyl, substituted or
unsubstituted C.sub.2-4 alkenyl, substituted or unsubstituted 5 to
14 membered heteroaryl ring containing one, two or three
heteroatoms each independently selected from nitrogen, oxygen, and
sulfur, substituted or unsubstituted 5 to 14 membered
heterocycloalkyl group containing one, two or three heteroatoms
each independently selected from nitrogen and oxygen, substituted
or unsubstituted C.sub.3-15 cycloalkyl, substituted or
unsubstituted C.sub.3-15 cycloalkylC.sub.1-6alkyl, substituted or
unsubstituted C.sub.6-14 aryl, substituted or unsubstituted
C.sub.6-14arylC.sub.1-6alkyl, substituted or unsubstituted
C.sub.6-14arylC.sub.2-5alkenyl, substituted or unsubstituted 5 to
14 membered heteroarylC.sub.1-6alkyl, and substituted or
unsubstituted 5 to 14 membered heterocycloalkylC.sub.1-6alkyl.
[0671] In another embodiment, the present invention provides a
method of inhibiting a malic enzyme in a subject comprising
administering to the subject in need thereof, a compound of Formula
I, or a pharmaceutically acceptable salt, stereoisomer or
deuterated analog thereof, wherein the malic enzyme is ME3, ME2,
and/or ME1.
[0672] In another embodiment, the present invention provides a
method of inhibiting a malic enzyme in a subject comprising
administering to the subject in need thereof, a compound of Formula
I, or a pharmaceutically acceptable salt, stereoisomer or
deuterated analog thereof, wherein the malic enzyme is ME3.
[0673] In another aspect, the present invention provides a method
of inhibiting a malic enzyme in a subject comprising administering
to the subject in need thereof, a compound of Formulae Ia, or Ib,
or a pharmaceutically acceptable salt, stereoisomer or deuterated
analog thereof.
[0674] In one embodiment, the present invention provides a method
of inhibiting a malic enzyme in a subject comprising administering
to the subject in need thereof, a compound of Formulae Ia, or Ib,
or a pharmaceutically acceptable salt, stereoisomer or deuterated
analog thereof, wherein the malic enzyme is ME3, ME2, and/or
ME1.
[0675] In one embodiment, the present invention provides a method
of inhibiting a malic enzyme in a subject comprising administering
to the subject in need thereof, a compound of Formulae Ia, or Ib,
or a pharmaceutically acceptable salt, stereoisomer or deuterated
analog thereof, wherein the malic enzyme is ME3, ME2, and/or
ME1.
[0676] In another embodiment, the present invention provides a
method of inhibiting a malic enzyme in a subject comprising
administering to the subject in need thereof, a compound of Formula
I, or a pharmaceutically acceptable salt, stereoisomer or
deuterated analog thereof, wherein the subject has cancer.
[0677] In another embodiment, the present invention provides a
method of inhibiting a malic enzyme in a subject comprising
administering to the subject in need thereof, a compound of Formula
Ia, or a pharmaceutically acceptable salt, stereoisomer or
deuterated analog thereof, wherein the subject has cancer.
[0678] In another embodiment, the present invention provides a
method of inhibiting a malic enzyme in a subject comprising
administering to the subject in need thereof, a compound of Formula
Ib, or a pharmaceutically acceptable salt, stereoisomer or
deuterated analog thereof, wherein the subject has cancer.
[0679] In one embodiment, the cancer is selected from leukemia,
brain cancer, bladder cancer, breast cancer, cervical cancer,
colorectal cancer, endometrial cancer, esophageal cancer, head and
neck cancer, liver cancer, lung cancer, lymphoma, ovarian cancer,
pancreatic cancer, prostate cancer, renal cancer, skin cancer,
stomach cancer, testis cancer, thyroid cancer, and urothelial
cancer.
[0680] In another aspect, the present invention provides a method
of treating a subject having cancer comprising administering to the
subject a malic enzyme inhibitor, wherein the malic enzyme
inhibitor is a compound of Formula I, or a pharmaceutically
acceptable salt, stereoisomer or deuterated analog thereof.
[0681] In one embodiment, the present invention provides a method
of treating a subject having cancer comprising administering to the
subject a malic enzyme inhibitor, wherein the malic enzyme
inhibitor is a compound of Formula I
##STR00121## [0682] or a pharmaceutically acceptable salt,
stereoisomer or deuterated analog thereof, wherein [0683] X is CH
or nitrogen; [0684] R.sub.1 is selected from hydrogen, CH.sub.3,
--COOH, fluoro and CN; [0685] R.sub.2 is selected from hydrogen,
CH.sub.3, --COOH, fluoro and CN; [0686] Y is selected from
substituted or unsubstituted C.sub.1-5 alkyl, substituted or
unsubstituted C.sub.2-4 alkenyl, substituted or unsubstituted 5 to
14 membered heteroaryl ring containing one, two or three
heteroatoms each independently selected from nitrogen, oxygen, and
sulfur, substituted or unsubstituted 5 to 14 membered
heterocycloalkyl group containing one, two or three heteroatoms
each independently selected from nitrogen and oxygen, substituted
or unsubstituted C.sub.3-15 cycloalkyl, substituted or
unsubstituted C.sub.3-15 cycloalkylC.sub.1-6alkyl, substituted or
unsubstituted C.sub.6-14 aryl, substituted or unsubstituted
C.sub.6-14arylC.sub.1-6alkyl, substituted or unsubstituted
C.sub.6-14arylC.sub.2-5alkenyl, substituted or unsubstituted 5 to
14 membered heteroarylC.sub.1-6alkyl, and substituted or
unsubstituted 5 to 14 membered heterocycloalkylC.sub.1-6alkyl.
[0687] In another aspect, the present invention provides a method
of treating a subject having cancer comprising administering to the
subject a malic enzyme inhibitor, wherein the malic enzyme
inhibitor is a compound of Formula Ia, or a pharmaceutically
acceptable salt, stereoisomer or deuterated analog thereof.
[0688] In another aspect, the present invention provides a method
of treating a subject having cancer comprising administering to the
subject a malic enzyme inhibitor, wherein the malic enzyme
inhibitor is a compound of Formula Ib, or a pharmaceutically
acceptable salt, stereoisomer or deuterated analog thereof.
[0689] In one embodiment, the cancer in any of the methods and/or
uses described herein is selected from leukemia, brain cancer,
bladder cancer, breast cancer, cervical cancer, colorectal cancer,
endometrial cancer, esophageal cancer, head and neck cancer, liver
cancer, lung cancer, lymphoma, ovarian cancer, pancreatic cancer,
prostate cancer, renal cancer, skin cancer, stomach cancer, testis
cancer, thyroid cancer, and urothelial cancer.
[0690] In another embodiment, the malic enzyme inhibitor is an
inhibitor of ME3, ME2, and/or ME1.
[0691] In another embodiment, the malic enzyme inhibitor is an
inhibitor of ME3.
[0692] The compounds of the present invention can be used either
alone or in combination with other malic enzyme inhibitors, or any
appropriate drugs for the treatment of disease mediated by malic
enzyme such as cancers, particularly in pancreatic ductal
adenocarcinoma (PDAC) in humans.
Pharmaceutical Compositions
[0693] Any of the compounds disclosed herein may be formulated into
a composition that additionally comprises one or more suitable
pharmaceutically acceptable carriers, including excipients and
other compounds that facilitate administration of the compound to a
subject. The pharmaceutical compositions may be formulated in a
conventional manner using one or more pharmaceutically acceptable
excipients. Such pharmaceutical compositions and the processes for
preparing the same are described, for example, in Remington: The
Science and Practice of Pharmacy (D. B. Troy, Editor, 21st Edition,
Lippincott, Williams & Wilkins, 2006), the contents of which
are incorporated herein by reference in their entirety.
[0694] Thus, in one embodiment, the present invention provides a
pharmaceutical composition comprising a compound of Formula I, or a
pharmaceutically acceptable salt or deuterated analog thereof, and
a pharmaceutically acceptable carrier, diluent, or excipient.
[0695] In another embodiment, the present invention provides a
pharmaceutical composition comprising a compound of Formula Ia, or
a pharmaceutically acceptable salt or deuterated analog thereof,
and a pharmaceutically acceptable carrier, diluent, or
excipient.
[0696] In another embodiment, the present invention provides a
pharmaceutical composition comprising a compound of Formula Ib, or
a pharmaceutically acceptable salt or deuterated analog thereof,
and a pharmaceutically acceptable carrier, diluent, or
excipient.
[0697] Suitable doses of the compounds for use in treating any of
the diseases, disorders and/or conditions described herein can be
determined by those skilled in the relevant art. Therapeutic doses
are generally identified through a dose ranging study in humans
based on preliminary evidence derived from animal studies. Doses
must be sufficient to result in a desired therapeutic benefit
without causing unwanted side effects. The mode of to
administration, dosage forms, and suitable pharmaceutical
excipients can also be understood and adjusted by those skilled in
the art.
General Synthetic Methods for the Preparation of Compounds of
Formula I
[0698] In one embodiment, the compounds of Formula I can be
prepared by following the process as shown in Scheme 1 below:
##STR00122##
[0699] Variables R.sub.1, R.sub.2, X and Y in the compounds
depicted in Scheme 1 are as defined in the any of the embodiments
described herein. Step-I involves condensation of a suitably
protected and substituted amine compound of Formula 1.1 (where P is
a hydroxy protecting group such as benzyl, benzoyl, etc.) with a
compound of Formula 1.2 (wherein L is a leaving group such as
halogen) to obtain a suitably substituted and protected compound
1.3. Preferably, the condensation reaction is carried out in the
presence of an inert base such as triethylamine or
di-isopropylethylamine and/or a suitable catalyst in an inert
solvent such as tetrahydrofuran, dichloromethane,
N,N-dimethylformamide, dimethylacetamide, etc. The starting
compound of Formula 1.1 can be obtained commercially or can be
prepared by methods known in the art.
[0700] The compound of the Formula 1.2 which is in activated form
(i.e. --C(O)-L) is preferably an acid halide, an ester, an
anhydride or a cyclic imide and can be prepared from the
corresponding acid (L is --OH) by general methods known to those
skilled in the art. For example, a compound of the Formula 1.2
wherein L is a halide can be obtained by treatment of the
corresponding acid (L is --OH) of Formula 1.2 with a halogenating
agent such as thionyl chloride, phosphorus pentachloride or oxalyl
chloride. The compound of Formula 1.2 in activated form can
alternatively be generated in-situ from the corresponding acid
(when L=OH), for example, reactive esters formed by using
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) or
1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
3-oxide hexafluorophosphate (HATU); and then condensed with the
compound of Formula 1.1 to generate the compound of Formula
1.3.
[0701] The compound of Formula 1.2 in activated form is preferably
generated in situ from the corresponding acid (i.e. when L=OH). For
example, N,N'-disubstituted amidino esters can be formed in situ by
reacting a mixture of the acid of Formula 1.2 (i.e., when L=OH) and
the compound of Formula 1.1 in the presence of a suitable
condensation agent, such as, for example
N,N'-dicyclohexylcarbodiimide. Reactive mixed anhydrides of the
acid may also be generated with an organic phosphonic acid in situ
by reaction with propylphosphonic anhydride or
diethylcyanophosphonate in the presence of suitable base for e.g.
triethylamine or 4-(N,N-dimethylamino)pyridine.
[0702] The reaction may be carried out in a manner known in the
art, the reaction conditions being dependent on how the acid group
of Formula 1.2 has been activated, usually in the presence of a
suitable solvent or diluent or of a mixture thereof and, if
necessary, in the presence of a condensation agent. Condensation
agents include, for example, (i) carbodiimides such as
N,N'-diethyl-,N,N'-diisopropyl, N,N'-dicyclohexyl- or
N-ethyl-N'-(3-diethylaminopropyl)-carbodiimide, (ii) carbonyl
compounds, for example, carbonyldiimidazole, (iii) 1,2-oxazolium
compounds, for example, 2-ethyl-5-phenyl-1,2-oxazolium 3'-sulfonate
and 2-tert-butyl-5-methyl-isoxazolium perchlorate, and (iv) an
acylamino compound, for example,
2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline. The bases normally
used for aiding the condensation are either inorganic bases such as
sodium or potassium carbonate, or organic bases, such as pyridine,
triethyamine, N,N-diisopropylethylamine or
4-(dimethylamino)pyridine.
[0703] The subsequent Step-II involves deprotection of the
substituted amide 1.3 with suitable deprotecting agents known in
art to obtain the desired compounds of Formula I.
[0704] Alternatively, the compounds of Formula I can also be
prepared by reacting a compound of Formula 2.1 with a compound of
Formula 1.2, using similar condensation methods as described above
(for Scheme 1-Step I). The method is as shown in Scheme 2 below,
wherein R.sub.1, R.sub.2, X, L and Y are as defined according to
any of the embodiments herein. The starting compound of Formula 2.1
can be obtained commercially or can be prepared by methods known in
the art.
##STR00123##
[0705] The compounds of Formula I can be converted into salts
thereof by methods known in the art, such as, for example,
dissolving the compound of Formula I in a suitable solvent and
treating it with an appropriate acid.
[0706] Alternatively, the starting materials, i.e. a compound of
Formula 1.1 or a compound of Formula 2.1 used in Scheme 1 or Scheme
2, respectively, can be prepared as depicted in synthetic Scheme 3
below:
##STR00124##
[0707] Variables R.sub.1, R.sub.2, and X in the compounds of Scheme
3 are as defined in any of the embodiments described herein. Step 1
in Scheme 3 involves protection of the hydroxyl group of compound
3.1 (wherein L.sub.1 is leaving group such as a halide) to obtain
compound 3.2 (wherein P is a hydroxy protecting group such as
benzyl, benzoyl, etc.). Compound 3.2 can be coupled with compound
3.3, wherein Pi is a nitrogen protecting group, such as
tert-butyloxycarbonyl (Boc), fluorenylmethyloxycarbonyl (Fmoc),
etc.; by known methods such as Buchwald coupling to obtain compound
3.4. The compound 3.4 on selective deprotection of P.sub.1 group
using an acid or base can give compound 1.1. Compound 1.1 on
further deprotection of protecting group P by using known methods,
such as debenzylation using catalytic hydrogenation, can give
compound 2.1.
[0708] Similarly, the compounds of Formulae Ia or Ib, can be
prepared by following the processes described above.
[0709] Similarly, the compounds of Formulae Ia, or Ib, can be
converted into their pharmaceutically acceptable salts by treating
them with an appropriate acid in a suitable solvent.
[0710] Representative compounds of Formula I are as shown in Table
1 below:
TABLE-US-00001 TABLE 1 Formula I ##STR00125## Compound No. Y
R.sub.1 R.sub.2 X I.1 ##STR00126## H H CH I.2 ##STR00127## H H CH
I.3 ##STR00128## H H CH I.4 ##STR00129## H H CH I.5 ##STR00130## H
H CH I.6 ##STR00131## H H N I.7 ##STR00132## H H CH I.8
##STR00133## H H CH I.9 ##STR00134## H H CH I.10 ##STR00135## H H
CH I.11 ##STR00136## F H CH I.12 ##STR00137## H H CH I.13
##STR00138## H H CH I.14 ##STR00139## H H CH I.15 ##STR00140## H H
CH I.16 ##STR00141## H H CH I.17 ##STR00142## H H CH I.18
##STR00143## H H CH I.19 ##STR00144## H H CH I.20 ##STR00145## H H
CH I.21 ##STR00146## H H CH I.22 ##STR00147## H H CH I.23
##STR00148## H H CH I.24 ##STR00149## H H CH I.25 ##STR00150## H H
CH I.26 ##STR00151## H H CH I.27 ##STR00152## H H CH I.28
##STR00153## H H CH I.29 ##STR00154## H H CH I.30 ##STR00155## H H
CH I.31 ##STR00156## H H CH I.32 ##STR00157## H COOH CH I.33
##STR00158## H H CH I.34 ##STR00159## H H CH I.35 ##STR00160## H H
CH I.36 ##STR00161## H H CH I.37 ##STR00162## H CN CH I.38
##STR00163## H --COOH CH I.39 ##STR00164## H H CH I.40 ##STR00165##
H H CH I.41 ##STR00166## H H CH I.42 ##STR00167## H H CH I.43
##STR00168## H H N I.44 ##STR00169## H H N I.45 ##STR00170## H H N
I.46 ##STR00171## H H CH I.47 ##STR00172## H H CH I.48 ##STR00173##
H H N I.49 ##STR00174## H H CH I.50 ##STR00175## H H CH I.51
##STR00176## H H N I.52 ##STR00177## H CH.sub.3 CH I.53
##STR00178## H H CH I.54 ##STR00179## H H N I.55 ##STR00180## H H N
I.56 ##STR00181## H H N I.57 ##STR00182## H H N I.58 ##STR00183## H
H N I.59 ##STR00184## H H N I.60 ##STR00185## H H N I.61
##STR00186## H H N I.62 ##STR00187## H H N I.63 ##STR00188## H H N
I.64 ##STR00189## H H N I.65 ##STR00190## H H N I.66 ##STR00191## H
H N I.67 ##STR00192## H H N I.68 ##STR00193## H H N I.69
##STR00194## H H N I.70 ##STR00195## H H N I.71 ##STR00196## H H N
I.72 ##STR00197## H H N I.73 ##STR00198## H H N I.74 ##STR00199## H
H N I.75 ##STR00200## H H N I.76 ##STR00201## H H N I.77
##STR00202## H H N I.78 ##STR00203## H H N I.79 ##STR00204## H H N
I.80 ##STR00205## H H N I.81 ##STR00206## H H N I.82 ##STR00207## H
H N I.83 ##STR00208## H H N I.84 ##STR00209## H H N I.85
##STR00210## H H N I.86 ##STR00211## H H N I.87 ##STR00212## H H N
I.88 ##STR00213## H H N I.89 ##STR00214## H H N I.90 ##STR00215## H
H N I.91 ##STR00216## H H N I.92 ##STR00217## H H N I.93
##STR00218## H H N I.94 ##STR00219## H H N I.95 ##STR00220## H H N
I.96 ##STR00221## H H N I.97 ##STR00222## H H N I.98 ##STR00223## H
H N I.99 ##STR00224## H H N I.100 ##STR00225## H H N I.101
##STR00226## H H N I.102 ##STR00227## H H N I.103 ##STR00228## H H
N I.104 ##STR00229## H H N I.105 ##STR00230## H H N I.106
##STR00231## H H N I.107 ##STR00232## H H N I.108 ##STR00233## H H
N I.109 ##STR00234## H H N I.110 ##STR00235## H H N I.111
##STR00236## H H N I.112 ##STR00237## H H N I.113 ##STR00238## H H
N I.114 ##STR00239## H H N I.115 ##STR00240## H H N I.116
##STR00241## H H N I.117 ##STR00242## H H N I.118 ##STR00243## H H
N I.119 ##STR00244## H H N I.120 ##STR00245## H H N I.121
##STR00246## H H N I.122 ##STR00247## H H N
I.123 ##STR00248## H H N I.124 ##STR00249## H H N I.125
##STR00250## H H N I.126 ##STR00251## H H N I.127 ##STR00252## H H
N I.128 ##STR00253## H H N I.129 ##STR00254## H H N I.130
##STR00255## H H N I.131 ##STR00256## H H N I.132 ##STR00257## H H
N I.133 ##STR00258## H H N I.134 ##STR00259## H H N I.135
##STR00260## H H N I.136 ##STR00261## H H N I.137 ##STR00262## H H
N I.138 ##STR00263## H H N I.139 ##STR00264## H H N I.140
##STR00265## H H N I.141 ##STR00266## H H N I.142 ##STR00267## H H
N I.143 ##STR00268## H H N I.144 ##STR00269## H H N I.145
##STR00270## H H N I.146 ##STR00271## H H N I.147 ##STR00272## H H
N I.148 ##STR00273## H H CH I.149 ##STR00274## H H CH I.150
##STR00275## H H CH I.151 ##STR00276## H H CH I.152 ##STR00277## H
H N I.153 ##STR00278## H H N I.154 ##STR00279## H H CH I.155
##STR00280## H H N I.156 ##STR00281## H H CH I.157 ##STR00282## H H
N I.158 ##STR00283## H H N I.159 ##STR00284## H H N I.160
##STR00285## H H N I.161 ##STR00286## H H N I.162 ##STR00287## H H
N I.163 ##STR00288## H H N I.164 ##STR00289## H H N I.165
##STR00290## H H N I.166 ##STR00291## H H N I.167 ##STR00292## H H
N I.168 ##STR00293## H H N I.169 ##STR00294## H H N I.170
##STR00295## H H N I.171 ##STR00296## H H CH I.172 ##STR00297## H H
N I.173 ##STR00298## H H CH I.174 ##STR00299## H H N I.175
##STR00300## H H N I.176 ##STR00301## H H N
[0711] The present invention is further illustrated in detail with
reference to the following examples. It is desired that the
examples be considered in all respect as illustrative and are not
intended to limit the scope of the claimed invention.
EXAMPLES
[0712] The compounds of Formulae I, Ia and Ib may be prepared as
described below. All solvents and reagents were used as obtained
from commercial sources unless otherwise indicated. .sup.1H-NMR
spectra were recorded with a Bruker.RTM. spectrometer operating at
500 MHz in deuterated DMSO.
List of Abbreviations:
[0713] EDC.HCl: N-Ethyl-N'-(3-dimethylaminopropyl)carbodiimide
hydrochloride. [0714] HATU:
1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
3-oxide hexafluorophosphate. [0715] NBS: N-Bromosuccinimide. [0716]
AIBN: Azobisisobutyronitrile. [0717] THF: Tetrahydrofuran.
Preparation of Intermediate: 4-piperazin-1-yl-phenol (1D)
##STR00302##
[0718] Step-I: To a solution of 4-chlorophenol (2 g, 1 eq) in
N,N-dimethylformamide (10 ml) was added potassium carbonate (3.2 g,
1.5 eq) and benzyl bromide (1.9 ml, 1.05 eq). The resultant
reaction mixture was heated to 40.degree. C. for 18 hours. The
reaction was monitored by thin layer chromatography (TLC). On
completion of reaction, the reaction mixture was quenched with
water and extracted with ethyl acetate. The combined organic layers
were washed with saturated sodium chloride solution, dried over
anhydrous sodium sulfate and concentrated under reduced pressure.
The resultant residue was purified using column chromatography on
silica gel (230-400 mesh) using an ethyl acetate hexane mixture as
eluent to afford pure compound 1A.
[0719] Step-II: To a solution of t-butyl piperazine-1-carboxylate
(1.7 g, 1.0 eq) in toluene (40 ml) was added compound 1A (2.0 g,
1.0 eq), Pd.sub.2(dba).sub.3 (0.42 g, 0.05 eq) and S-Phos (0.37 g,
0.1 eq) at room temperature and heated to 50.degree. C. for 15
minutes under nitrogen atmosphere. Sodium t-butoxide (2.6 g, 3.0
eq) was added to the reaction mixture and the reaction mixture was
heated at 100.degree. C. for 6 hours. On completion of reaction,
the reaction mixture was filtered through celite bed and washed
with ethyl acetate. The combined organic layers were washed with
water, dried over anhydrous sodium sulfate and concentrated under
reduced pressure. The resultant residue was purified using column
chromatography on silica gel (230-400 mesh) using an ethyl acetate
hexane mixture as eluent to afford the pure compound 1B.
[0720] Step-III: A solution of compound 1B (1.0 g) in
dichloromethane (10 ml) was treated with trifluoroacetic acid (5
ml) and stirred for 2 hours. On completion of reaction, the
residual solvents were evaporated under reduced pressure. The
resultant residue was dissolved in water, basified with saturated
sodium bicarbonate solution and extracted with ethyl acetate. The
combined organic layers were dried over anhydrous sodium sulfate
and concentrated under reduced pressure to afford compound 1C.
[0721] Step-IV: To a solution of compound 1C (1.0 g) in
methanol-tetrahydrofuran (1:1) (30 ml) was added 10% Palladium on
activated carbon (0.1 g) and the suspension was stirred under
hydrogen atmosphere for 2 hours at room temperature. On completion
of reaction, the reaction mixture was filtered off from the
catalyst and the solution was evaporated under reduced pressure to
afford compound 1D which was used in the next step without further
purification.
Example 1
Preparation of
1-[4-(4-hydroxyphenyl)piperazin-1-yl]-2-phenylethanone (I.1)
##STR00303##
[0723] To a solution of phenyl acetic acid (1 g, 1.0 eq) in
N,N-dimethylacetamide (10 ml) was added HATU (3.07 g, 1.2 eq) and
triethylamine (1.88 ml, 2.0 eq). The reaction mixture was stirred
for 10 minutes and then compound 1D (1.2 g, 1.0 eq) was added and
further stirred at room temperature for 3 hours. On completion of
reaction, the reaction mixture was quenched with water and
extracted with ethyl acetate. The combined organic layer was washed
with saturated sodium chloride solution, dried over anhydrous
sodium sulfate and concentrated under reduced pressure. The
resultant residue was purified using column chromatography on
silica gel (230-400 mesh) using an ethyl acetate hexane mixture as
eluent to afford pure compound I.1.
Example 2
Preparation of 2-hydroxy-5-(4-phenylacetyl-piperazin-1-yl)-benzoic
acid (I.32)
##STR00304##
[0725] Step-I: A solution of 5-bromo-2-hydroxybenzoic acid (2.0 g,
1.0 eq) in N,N-dimethylformamide (10 ml) was added K.sub.2CO.sub.3
(2.8 g, 2.2 eq) and benzyl bromide (3.1 g, 2.0 eq) and the
resultant reaction mixture was stirred at room temperature for 2
hours. On completion of reaction, the reaction mixture was quenched
with water and extracted with ethyl acetate. The combined organic
layers were washed with saturated aq. sodium chloride solution,
dried over anhydrous sodium sulfate and concentrated under reduced
pressure to afford compound 2A.
[0726] Step-II: To a solution of tent-butyl
piperazine-1-carboxylate (0.63 g, 1.3 eq) in toluene (40 ml) was
added compound 2A (1.0 g, 1.0 eq), cesium carbonate (2.5 g, 3.0 eq)
and S-Phos (0.10 g, 0.1 eq) at room temperature and purged with
nitrogen for 5 min. Pd.sub.2(dba).sub.3 (0.12 g, 0.05 eq) was then
added and the resultant reaction mixture was heated at 100.degree.
C. for 6 hours. On completion of reaction, the reaction mixture was
filtered through celite bed and washed with ethyl acetate. The
combined organic layers were washed with water, dried over
anhydrous sodium sulfate and concentrated under reduced pressure.
The resultant residue was purified using column chromatography on
silica gel (230-400 mesh) using an ethyl acetate-hexane mixture as
eluent to afford protected piperazine intermediate.
[0727] The protected piperazine intermediate (0.9 g) was dissolved
in dichloromethane (9 ml), treated with trifluoroacetic acid (4.5
ml) and the resultant solution was stirred for 2 hours. On
completion of reaction, the solvents were evaporated under reduced
pressure and the resultant residue was dissolved in water. The
above solution was basified with saturated sodium bicarbonate
solution and extracted with ethyl acetate. The combined organic
layers were dried over anhydrous sodium sulfate and concentrated
under reduced pressure to afford compound 2B.
[0728] Step-III: To a cooled solution (0-5.degree. C.) of
phenylacetic acid (0.25 g, 1.0 eq) in N,N-dimethylformamide (5 ml)
was added HATU (0.90 gm, 1.3 eq) followed by diisopropylethylamine
(0.37 ml, 1.3 eq). After stirring the reaction mixture for 10
minutes, compound 2B (0.67 g, 0.9 eq) was added and stirring was
continued for 1 hour at 0-5.degree. C. On completion of reaction,
the reaction mixture was quenched with water and extracted with
ethyl acetate. The combined organic layers were washed with
saturated sodium chloride solution, dried over anhydrous sodium
sulfate and concentrated under reduced pressure. The resultant
residue was purified using column chromatography on silica gel
(230-400 mesh) using an ethyl acetate hexane mixture as eluent to
afford pure compound 2C.
[0729] Step-IV: A solution of compound 2C (0.2 g) in
methanol:tetrahydrofuran (1:1) (20 ml) was added 10% Palladium on
activated carbon (0.2 g) and the resultant suspension was stirred
under hydrogen atmosphere for 6 hours at room temperature. On
completion of reaction, the reaction mixture was filtered off from
the catalyst and the filtrate was evaporated under reduced pressure
to obtain a residue. The residue was stirred with diethyl ether (5
ml) for 30 minutes. The resultant suspension was filtered, washed
with diethyl ether (1 ml) and dried to afford pure Compound
1.32.
Example 3
Preparation of
1-[4-(4-hydroxyphenyl)piperazin-1-yl]-3,3-diphenylprop-2-en-1-one
(I.40)
##STR00305##
[0731] Step-I: Sodium hydride (0.24 g, 1.1 eq) was charged to
tetrahydrofuran (10 ml) under stirring and cooled to -20.degree. C.
under argon atmosphere. Trimethylphosphonoacetate (1.0 g, 1 eq)
dissolved in tetrahydrofuran (2 ml) was added drop wise and the
resultant reaction mixture was stirred at ambient temperature for
30 minutes. The reaction mixture was again cooled to -20.degree. C.
and a tetrahydrofuran (3 ml) solution of compound 3 (1 g, 1 eq) was
added dropwise and then heated to 65.degree. C. for 18 hours. Then
the reaction mixture was cooled to ambient temperature, quenched
with water and extracted with ethyl acetate. The organic layer was
separated, washed with brine, dried over anhydrous Na.sub.2SO.sub.4
and the solvent was removed under reduced pressure. The resultant
crude residue was purified by flash column chromatography with
hexane and ethylacetate as gradient eluent to obtain compound
3A.
[0732] Step-II: Compound 3A (1 gm, 1 eq) was dissolved in dioxane :
water (1:2) (5 ml) and potassium hydroxide (0.6 g, 2 eq) was then
added. The resultant reaction mixture was then heated to 65.degree.
C. for 2 hours until TLC analysis showed completion of the
reaction. The reaction mixture was then acidified to pH 5 using
sulphuric acid (10N) and the resultant white solid precipitate was
filtered and washed with water and hexanes to get pure compound
3B.
[0733] Step-III: Synthesis of compound 1.40: Compound 3B (0.05 g,
1.0 eq) was dissolved in N,N-dimethylformamide (3 ml) and to this
solution was added EDC.HCl (0.07 g, 1.5 eq) and HOBt (0.05 g, 1.5
eq). The resultant reaction mixture was stirred for 30 minutes at
room temperature under nitrogen atmosphere. A solution of compound
1D (0.04 gm, 1.0 eq) in N,N-dimethylformamide (1 ml) was then added
drop wise to the above reaction mixture and the resultant reaction
mixture was stirred at room temperature for 3 hours. After
completion of reaction, the reaction mixture was quenched with
water (20 ml). Precipitated solids were filtered and washed with
water (10 ml) followed by diethylether (5 ml) to obtain compound
1.40.
Example 4
Preparation of 1-[4-(4-hydroxyphenyl) piperazin-1-yl]-2-(2-phenoxy
phenyl)ethanone (I.49)
##STR00306##
[0735] Step-I: Methyl 2-(2-hydroxyphenyl)acetate (0.25 g, 1.0 eq)
was dissolved in N,N-dimethylformamide (5 ml) at ambient
temperature and to this solution was added potassium carbonate (0.7
g, 3 eq), bromobenzene (0.17 ml, 1.1 eq), copper (I) iodide (0.06
g, 0.2 eq), and N,N-dimethylglycine hydrochloride (0.09 g, 0.4 eq)
under stirring and nitrogen atmosphere. The resultant reaction
mixture was heated to 120.degree. C. for 3 hours until the reaction
was completed. The reaction was quenched with water, extracted with
ethyl acetate and washed with brine. The organic layer was
separated, dried over anhydrous sodium sulfate, and concentrated
under reduced pressure to obtain a crude material which was
purified by column chromatography to obtain compound 4A.
[0736] Step-II: To a solution of compound 4A (0.5 g, 1.0 eq) in
methanol:water (4:1) (5 ml) was added sodium hydroxide (0.24 g, 3
eq) and the resultant reaction mixture was stirred for 3 hours.
After completion of reaction, the solvent was removed under reduced
pressure, acidified with 1N HCl and extracted with ethyl acetate.
The organic layer was washed with brine. The organic layer was
separated, dried over anhydrous Na.sub.2SO.sub.4 and concentrated
under reduced pressure to obtain almost pure compound 4B in
quantitative yields which was used without further purification in
the next step.
[0737] Step-III: Synthesis of compound 1.50: Compound 4B (0.250 g,
1.0 eq) was dissolved in N,N-dimethylformamide (3 ml) and to this
solution was added EDC.HCl (0.32 g, 1.5 eq) and HOBt (0.22 g, 1.5
eq). The resultant reaction mixture was stirred for 30 minutes at
room temperature under nitrogen atmosphere. A solution of compound
1D (0.22 g, 1.1 eq) in N,N-dimethylformamide (1 ml) was added
dropwise to the above reaction mixture and the resultant reaction
mixture was then stirred for 3 hours till reaction was completed.
The reaction was quenched with water, extracted with ethyl acetate
and washed with brine. The organic layer was dried over anhydrous
Na.sub.2SO.sub.4, concentrated under reduced pressure and purified
by flash column chromatography using hexane and ethyl acetate as
gradient eluent to obtain compound 1.49.
Example 5
Preparation of
4-(4-hydroxyphenyl)piperazin-1-yl]-(1H-indol-3-yl)-methanone
(I.2)
##STR00307##
[0739] To a solution of indole-3-carboxylic acid (1 g, 1.0 eq) in
N,N-dimethylacetamide (5 ml) was added EDC.HCl (1.78 g, 1.5 eq).
The reaction mixture was stirred for 15 minutes and then compound
1D (1.10 g, 1.0 eq) was added and the reaction mixture was further
stirred at room temperature for 3 hours. On completion of reaction,
the reaction mixture was quenched with water and extracted with
ethyl acetate. The combined organic layers were washed with
saturated aq. sodium chloride solution, dried over anhydrous sodium
sulfate and concentrated under reduced pressure. The resultant
residue was purified using column chromatography on silica gel
(230-400 mesh) using dichloromethane:methanol (9:1) as eluent to
afford the pure compound as a pale pink solid.
Example 6
Preparation of
1-[4-(4-hydroxyphenyl)-piperazin-1-yl]-2-phenyl-ethane-1,2-dione
(I.17)
##STR00308##
[0741] To a solution of phenylglyoxylic acid (1 g, 1.0 eq) in
N,N-dimethylacetamide (5 ml) was added EDC.HCl (1.91 g, 1.5 eq).
The reaction mixture was stirred for 15 minutes and then compound
1D (1.18 g, 1.0 eq) was added. The resultant reaction mixture was
further stirred at room temperature for 3 hours. On completion of
reaction, the reaction mixture was quenched with water and
extracted with ethyl acetate. The combined organic layer was washed
with saturated aq. sodium chloride solution, dried over anhydrous
sodium sulfate and concentrated under reduced pressure. The
resultant residue was purified using column chromatography on
silica gel (230-400 mesh) using dichloromethane:methanol (9:1) as
eluent to afford the pure compound as an off white solid.
Example 7
Preparation of
2-(3,5-difluoro-phenyl)-1-[4-(4-hydroxy-phenyl)-piperazin-1-yl]ethanone
(I.148)
##STR00309##
[0743] To a solution of 3,5-difluorophenylacetic acid (1 g, 1.0 eq)
in N,N-dimethylacetamide (5 ml) was added EDC.HCl (1.67 g, 1.5 eq).
The reaction mixture was stirred for 15 minutes and then compound
1D (1.03 g, 1.0 eq) was added. The resultant reaction mixture was
then further stirred at room temperature for 3 hours. On completion
of reaction, the reaction mixture was quenched with water and
extracted with ethyl acetate. The combined organic layers were
washed with saturated aq. sodium chloride solution, dried over
anhydrous sodium sulfate and concentrated under reduced pressure.
The resultant residue was purified using column chromatography on
silica gel (230-400 mesh) using dichloromethane:methanol (9:1) as
eluent to afford pure compound 1.148 as an off white solid
Example 8
Preparation of
2-(2,4-difluoro-phenyl)-1-[4-(4-hydroxy-phenyl)-piperazin-1-yl]-ethanone
(I.149)
##STR00310##
[0745] To a solution of 2,4-difluorophenylacetic acid (1 g, 1.0 eq)
in N,N-dimethylacetamide (5 ml) was added EDC.HCl (1.67 gm, 1.5
eq). The reaction mixture was stirred for 15 minutes and then
compound 1D (1.03 g, 1.0 eq) was added. The resultant reaction
mixture was then further stirred at room temperature for 3 hours.
On completion of reaction, the reaction mixture was quenched with
water and extracted with ethyl acetate. The combined organic layers
were washed with saturated aq. sodium chloride solution, dried over
anhydrous sodium sulfate and concentrated under reduced pressure.
The resultant residue was purified using column chromatography on
silica gel (230-400 mesh) using dichloromethane:methanol (9:1) as
eluent to afford pure compound 1.149 as an off white solid.
Example 9
Preparation of
2-(5-fluoro-1H-indol-3-yl)-1-[4-(4-hydroxy-phenyl)-piperazin-1-yl]-ethano-
ne (I.150)
##STR00311##
[0747] To a solution of 5-fluoroindole-3-acetic acid (1 g, 1.0 eq)
in N,N-dimethylacetamide (5 ml) was added EDC.HCl (1.48 g, 1.5 eq).
The reaction mixture was stirred for 15 minutes and then compound
1D (0.92 g, 1.0 eq) was added and the reaction mixture was further
stirred at room temperature for 3 hours. On completion of reaction,
the reaction mixture was quenched with water and extracted with
ethyl acetate. The combined organic layers were washed with
saturated aq. sodium chloride solution, dried over anhydrous sodium
sulfate and concentrated under reduced pressure. The resultant
residue was purified using column chromatography on silica gel
(230-400 mesh) using dichloromethane:methanol (9:1) as eluent to
afford the pure compound as an off white solid.
Example 10
Preparation of
2-(2-bromo-phenylsulfanyl)-1-[4-(4-hydroxy-phenyl)-piperazin-1-yl]-ethano-
ne (I.151)
##STR00312##
[0749] Step-I: Synthesis of compound 10B: To a solution of 2-bromo
thiophenol (10A) (2.0 to g, 1.0 eq) in acetone (40 ml) was added
cesium carbonate (5.17 g, 1.5 eq) and ethyl bromoacetate (2.12 g,
1.0 eq). The resultant reaction mixture was stirred at room
temperature for 3 hours. On completion of reaction, the reaction
mixture was quenched with water (50 ml) and extracted with ethyl
acetate (2.times.30 ml). The combined organic layers were washed
with saturated aq. sodium chloride solution (10 ml), dried over
anhydrous sodium sulfate and concentrated under reduced pressure.
The resultant residue was purified using column chromatography on
silica gel (230-400 mesh) using an ethyl acetate-hexane mixture as
eluent to afford pure compound 10B (2.72 g, yield: 93%) as an off
white solid.
[0750] Step-II: Synthesis of compound 10C: To a solution of
compound 10B (2.72 g, 1.0 eq) in methanol:tetrahydrofuran (1:1) (30
ml) was added a solution of sodium hydroxide (0.79 g, 2.0 eq) in
water (5 ml) and the resultant suspension was stirred for 2 hours
at 90.degree. C. On completion of reaction, reaction mixture was
evaporated under reduced pressure at 50.degree. C. Aqueous layer
washed with diethyl ether (50 ml). The aqueous layer was acidified
with hydrochloric acid (1N). Precipitated solid was filtered and
dried under reduced pressure at 55.degree. C. for 5 hours to afford
compound 10C (1.3 g, yield: 53%) as an off white solid.
[0751] Step-III: Synthesis of
2-(2-bromo-phenylsulfanyl)-1-[4-(4-hydroxy-phenyl)-piperazin-1-yl]-ethano-
ne (I.151)
[0752] To a cooled solution (0-5.degree. C.) of compound 10C (0.3
g, 1.0 eq) in N,N-dimethylacetamide (5 ml) was added HATU (0.6 g,
1.3 eq) followed by triethylamine (0.260 ml, 1.5 eq). After
stirring the reaction mixture for 10 minutes, compound 1D (0.194 g,
0.9 eq) was added and stirring was continued for 2 hours at 0 to
5.degree. C. On completion of reaction, the reaction mixture was
quenched with water (50 ml) and extracted with ethyl acetate
(2.times.30 ml). The combined organic layers were washed with
saturated aq. sodium chloride solution (10 ml), dried over
anhydrous sodium sulfate and concentrated under reduced pressure.
The resultant residue was purified using column chromatography on
silica gel (230-400 mesh) using a dichloromethane: methanol mixture
as eluent to afford pure compound (0.125 g, yield: 25%) as an off
white solid.
Example 11
Preparation of
[4-(4-hydroxy-phenyl)-piperazin-1-yl]-[3-(4-trifluoromethyl-phenyl)-imida-
zo[1,2-a]pyridin-8-yl]-methanone (I.31)
##STR00313##
[0754] Step-I: Synthesis of compound 11A
(imidazo[1,2-a]pyridine-8-carboxylic acid ethyl ester):
Bromoacetaldehyde dimethyl acetal (1.3 ml, 2.1 eq) was added in 40%
HBr in water (5 ml) and the resultant reaction mixture was stirred
for 30 min. The reaction mixture was then diluted with ethanol (30
ml) and basified with sodium bicarbonate (3 g) under vigorous
stirring. Ethyl 2-aminonicotinate (0.9 g, 1.0eq) was then added and
the resultant reaction mixture was then heated at 70.degree. C. for
16 hrs. On completion of reaction, the reaction mixture was
concentrated, quenched with water (50 ml) and extracted with
dichloromethane (2.times.30 ml). The combined organic layers were
dried over anhydrous sodium sulfate and concentrated under reduced
pressure. The resultant residue was crystalized with diethyl ether,
filtered and dried to obtain compound 11A (0.6 g, yield: 58%) as an
off white solid.
[0755] Step-II: Synthesis of compound 11B
(3-iodo-imidazo[1,2-a]pyridine-8-carboxylic acid ethyl ester): To a
solution of compound 11A (0.6 g, 1.0 eq) in acetonitrile (20 ml)
was added N-iodo succinimide (0.7 g, 1.0 eq) and the resultant
reaction mixture was stirred under nitrogen atmosphere for 2 hours
at room temperature. On completion of reaction, the reaction
mixture was quenched with 10% sodium thiosulfate solution (50 ml)
and extracted with ethyl acetate (2.times.30 ml). The combined
organic layers were dried over anhydrous sodium sulfate and
concentrated under reduced pressure. The resultant residue was
purified using column chromatography on silica gel (230-400 mesh)
using a dichloromethane:methanol mixture as eluent to afford pure
compound 11B (0.70g, yield: 70.7%) as a pale yellow solid.
[0756] Step-III: Synthesis of Compound 11C
(3-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine-8-carboxylic
acid): A mixture of compound 11B (0.9 g, 1.0 eq),
4-(trifluoromethyl) phenyl boronic acid (0.39 g, 1.3 eq) and sodium
carbonate (0.5 g, 3.0 eq) in ethanol (20 ml), toluene (20 ml) and
water (5 ml) was degassed at room temperature for 10 minutes then
added tetrakis(triphenylphosphine) palladium (0.09 g, 0.05 eq). The
resultant reaction mixture was heated at 90.degree. C. for 18
hours. On completion of reaction, the reaction mixture was cooled
to room temperature, diluted with ethyl acetate (30 ml) and
quenched with cold water (20 ml). The suspension was filtered over
a pad of celite. The aqueous layer was acidified with hydrochloric
acid (6N) (5 ml) and extracted with ethyl acetate (2.times.30 ml).
The combined organic layers were dried over anhydrous sodium
sulfate and concentrated under reduced pressure to afford compound
11C (0.15 g, yield: 29%) as a brown solid.
[0757] Step-IV: Synthesis of
4-(4-hydroxy-phenyl)-piperazin-1-yl]-[3-(4-trifluoromethyl-phenyl)-imidaz-
o[1,2-a]pyridin-8-yl]-methanone (I.31)
[0758] To a cooled solution (0-5.degree. C.) of compound 11C (0.15
g, 1.0 eq) in N,N-dimethylformamide (5 ml) was added HATU (0.24 gm,
1.3 eq) followed by N,N-diisopropylethylamine (0.260 ml, 1.5 eq).
After stirring the reaction mixture for 10 minutes, compound 1D
(0.096 g, 1.1 eq) was added and stirring continued for 2 hours at
0-5.degree. C. On completion of reaction, the reaction mixture was
quenched with aqueous sodium bicarbonate solution (30 ml) and
extracted with dichloromethane (2.times.30 ml). The combined
organic layers were dried over anhydrous sodium sulfate and
concentrated under reduced pressure. The resultant residue was
purified using column chromatography on silica gel (230-400 mesh)
using a dichloromethane: methanol mixture as eluent to obtain pure
compound (0.070 g, yield: 30%) as an off white solid.
Example 12
Preparation of
(2,6-diphenyl-4-pyridyl)-[4-(4-hydroxyphenyl)piperazin-1-yl]methanone
(I.20)
##STR00314##
[0760] Step-I: To a solution of compound 1C (0.294 g, 1.1 eq) in
methylene chloride (2 ml) was added triethylamine (0.3 mL, 2.7 eq).
The resultant reaction mixture was stirred at 0.degree. C. under
nitrogen atmosphere for 15 minutes and then compound 12A (0.2 g,
1.0 eq) was added in portions. The resultant reaction mixture was
stirred at ambient temperature for 2 hours. After completion of
reaction, the reaction mixture was quenched with aqueous saturated
sodium bicarbonate solution and extracted with methylene chloride
(2.times.10 ml). The combined organic layers were dried over
anhydrous sodium sulfate and concentrated under reduced pressure.
The resultant residue was purified by silica gel column
chromatography to afford pure compound 12B (0.15 g).
[0761] Step-II: Compound 12B (0.15 g) was dissolved in methanol (10
ml) and 10% by weight of palladium on carbon (0.05 g) was added to
it. The resultant reaction mixture was stirred under hydrogen
atmosphere created using hydrogen balloon at ambient temperature
for 3 hours. After completion of reaction, the reaction mixture was
filtered on celite and washed with methanol (2.times.10 ml). The
organic layer was concentrated under reduced pressure and the
resultant crude product was purified by silica gel column
chromatography to get pure title compound (0.07 g) as an off white
solid.
Example 13
Preparation of
(1-benzylindol-4-yl)-[4-(4-hydroxyphenyl)piperazin-1-yl]methanone
(I.26)
##STR00315##
[0763] Step-I: To a solution of compound 13A (2.0 g, 1.0 eq) in
N,N-dimethylformamide (20 ml), was added sodium hydride (0.36 g,
1.3 eq) at ambient temperature. Benzyl bromide (2.53 g, 1.3 eq) was
then added drop wise to the above reaction mixture. The resultant
reaction mixture was stirred for 1 h and then quenched with water
(10 ml) and extracted with ethyl acetate (3.times.15 ml). The
combined organic layers were dried over anhydrous sodium sulfate
and concentrated under reduced pressure to afford the crude
product. The crude product was then purified with silica gel column
chromatography to afford compound 13B.
[0764] Step-II: To a solution of compound 13B (2.9 g, 1.0 eq) in
tetrahydrofuran:water (4:1) (20 ml) was added lithium hydroxide
(0.87 g, 2.0 eq). The resultant reaction mixture was heated to
90.degree. C. for 15 hours. On completion of reaction, it was
quenched with hydrochloric acid (1N) (20 ml) and extracted with
ethyl acetate (3.times.20 ml). The organic layer was dried-over
anhydrous sodium sulfate and the crude product was purified by
silica gel column chromatography to get pure compound 13C (0.9
g).
[0765] Step-III: To a cooled (0.degree. C.) solution of compound
13C (0.4 g, 1.0 eq) in N,N-dimethylformamide (5 ml) was added HATU
(0.78 g, 1.2 eq) and N,N-diisopropylethylamine (0.80 ml, 3.0 eq).
The resultant reaction mixture was allowed to attain room
temperature, and then compound 1D (0.07 g, 1.0 eq) was added into
it. The resultant reaction mixture was further stirred for 2 hours.
On completion of reaction, the reaction mixture was quenched with
water (10 ml) and extracted with ethyl acetate (3.times.10 ml). The
combined organic layers were dried over sodium sulfate and
concentrated under reduced pressure. The crude residue was purified
by flash column chromatography using hexane and ethyl acetate as
gradient eluent to afford pure compound as an off white solid.
Example 14
Preparation
2-chloro-6-morpholino-4-pyridyl)-[4-(4-hydroxyphenyl)piperazin-1-yl]metha-
none (I.36)
##STR00316##
[0767] Step-I: To a solution of 2,6-dichloroisonicotinic acid (1.0
gm, 1.0 eq) in N,N-dimethylacetamide (5 ml) was added
N,N-diisopropylethylamine (1.8 ml, 2 eq) and morpholine (0.49 g,
1.1 eq). The resultant reaction mixture was heated to 120.degree.
C. for 20 hours. On completion of reaction, reaction mixture was
neutralised using hydrochloric acid to pH 6. Precipitated brown
solid was filtered and washed with diethyl ether to afford pure
compound 14B (0.650 g)
[0768] Step-II: To a solution of compound 14B (0.4 g, 1.0 eq) in
N,N-dimethylformamide (5 ml), was added EDC.HCl (0.36 g 1.5 eq) and
HOBt (0.25 g, 1.8 mmol, 1.5 eq). The resultant reaction mixture was
stirred at room temperature for 30 minutes under nitrogen
atmosphere. To the reaction mixture was then added compound 1D
(0.23 g, 1.0 eq) and the mixture was stirred for 3 hours. On
completion, the reaction mixture was quenched with water (10 ml)
and extracted with ethyl acetate (3.times.20 ml).The combined
organic layers were dried over anhydrous sodium sulfate and
concentrated under reduced pressure. The crude residue was purified
by flash column chromatography using hexane and ethyl acetate as
gradient eluent to afford pure title compound (0.4 g) as an off
white solid
Example 15
Preparation of
5-[4-(2,6-diphenylpyridine-4-carbonyl)piperazin-1-yl]-2-hydroxy-benzonitr-
ile (I.37)
##STR00317##
[0770] Step-I: Compound 15A (2 g, 1.0 eq) was dissolved in
N,N-dimethylformamide (20 ml) and to it was added potassium
carbonate (2.1 g, 1.5 eq) followed by benzyl bromide (1.3 ml, 1.1
eq). The resultant reaction mixture was stirred at ambient
temperature under nitrogen atmosphere for 1 hour. On completion of
reaction, the reaction mixture was quenched with water.
Precipitated solid was filtered, dried and purified by flash column
chromatography using hexane and ethyl acetate as gradient eluent to
afford pure compound 15B (2.6 g) as a white solid.
[0771] Step-II: Compound 15B (2.5 g, 1.0 eq) was dissolved in
1,4-dioxane (20 ml) and to it was added 1-Boc-piperazine (1.62 g,
1.0 eq), Xantphos (0.37 g, 0.0065 mol, 0.75 eq),
tris(dibenzylideneacetone)dipalladium(0) (0.39 g, 0.05 eq) and
sodium tert-butoxide (3.6 g, 6.0 eq). The resultant reaction
mixture was refluxed for 2 hours. On completion of the reaction,
reaction mixture was quenched with water (20 ml) and extracted with
ethyl acetate (3.times.20 ml). The combined organic layers were
washed with water, dried over anhydrous sodium sulfate and
concentrated under reduced pressure. The resultant crude product
was purified by silica gel column chromatography to get
Boc-protected intermediate (0.91 g) as yellow solid. The obtained
Boc-protected intermediate was then dissolved in 1,4-dioxane (10
ml) and hydrochloric acid (4M in dioxane) (20 ml) was added to it.
The resultant reaction mixture was then stirred at room
temperature. On completion of reaction, solvent was removed on
rotavapour and co-distilled with methanol. The crude product was
triturated with diethyl ether (25 ml) to obtain pure product
compound 15C (0.5 g) as a brown solid in the form of a
hydrochloride salt.
[0772] Step-III:--Compound 15D (0.4 g, 1.0 eq) was dissolved in
N,N-dimethylformamide (20 ml) and was added triethylamine (0.36 ml,
2.0 eq), EDC.HCl (0.37 g, 1.5 eq) and HOBt (0.26 g, 1.5 eq). The
resultant reaction mixture was stirred under nitrogen atmosphere
for 10 minutes and then added compound 15C (0.46 g, 1.0 eq) and the
reaction was further stirred for 1 hour. On completion of reaction,
reaction mixture was quenched with sodium bicarbonate (20 ml) and
extracted with ethyl acetate (3.times.20 ml). The combined organic
layers were washed with water, dried over sodium sulfate and
concentrated under reduced pressure to get crude product, which was
triturated with diethyl ether (25 ml) to afford pure compound 15E
(0.258 g) as a brown solid.
[0773] Step-IV: Compound 15E (0.258 g, 1.0 eq) was dissolved in THF
(10 ml) and added palladium on carbon (0.0025 g, 10% by weight, 50%
wet) and stirred under hydrogen atmosphere created using balloon
for 5 hours. On completion of reaction, the reaction mixture was
filtered through celite bed and washed with tetrahydrofuran
(3.times.10 ml). The combined organic layers were concentrated
under reduced pressure to get a brown solid. The obtained brown
solid was triturated with diethyl ether (25 ml) and filtered to get
the pure title product (0.038 g) as a brown solid.
Preparation of Intermediate: 6-Piperazin-1-yl-pyridin-3-ol (5D)
##STR00318##
[0775] Step-I: To a solution of 2-chloro-5-hydroxypyridine (100 g)
in N,N-dimethylformamide (500 ml) was added potassium carbonate
(159.7 g, 1.5 eq) and benzyl bromide (96.3 ml, 1.05 eq) drop wise
and stirred at room temperature for 4 hours. On completion of
reaction, the reaction mixture was quenched with water (2000 ml)
and extracted with ethyl acetate (2.times.100 ml). The combined
organic layers were dried over anhydrous sodium sulfate and
concentrated under reduced pressure. The resultant residue was
purified using column chromatography on silica gel using an ethyl
acetate-hexane mixture as eluent to afford compound 5A.
[0776] Step-II: To a solution of compound 5A (100 g, 1 eq) in
toluene (500 ml) was added 1-Boc-piperazine (84.8 g, 1 eq),
tris(dibenzylideneacetone)dipalladium(0) (20.84 g, 0.05 eq) and
S-phos (18.6 g, 0.1 eq) at room temperature. The resultant reaction
mixture was heated to 50.degree. C. for 10 minutes and then added
sodium tert-butoxide (131.2 g, 3 eq) portion wise and further
heated at 110.degree. C. for 3 hours. On completion of reaction,
water (200 ml) and ethyl acetate (100 ml) was added to the reaction
mixture and mixture was stirred. The resulting mixture was passed
through celite bed and washed with ethyl acetate (2.times.200 ml).
To filtrate was added brine solution (300 ml) and stirred for 15
minutes. The aqueous layer was separated and extracted in ethyl
acetate (500 ml). The combined organic layers were dried over
anhydrous sodium sulphate and concentrated under reduced pressure.
The resultant residue was purified using column chromatography on
silica gel using an ethyl acetate-hexane mixture as eluent to
afford 5B.
[0777] Step-III: To a solution of compound 5B (100 g) in
1,4-dioxane (200 ml) was added hydrochloric acid (200 ml) drop wise
and the resultant reaction mixture was stirred for 3 hours after
completion of addition. After completion of reaction, the reaction
mixture was quenched in saturated aqueous sodium bicarbonate
solution (1.5 liter). Precipitated solid was filtered, washed with
water (2.times.100 ml) and dried to afford compound 5C.
[0778] Step-IV: To a solution of compound 5C (100 g) in methanol:
tetrahydrofuran (1:1) (1000 ml) was added palladium on activated
carbon (5.0 g, 10% by weight, 50% wet). The suspension was stirred
under hydrogen atmosphere created using hydrogen balloon for 8
hours at room temperature. On completion of reaction, the reaction
mixture was filtered off from the catalyst and the solution was
evaporated under reduced pressure to afford compound 5D, which was
used in the next step without any further purification.
Example 16
Preparation of
1-[4-(5-hydroxy-pyridin-2-yl)-piperazin-1-yl]-3-phenyl-propan-1-one
(I.45)
##STR00319##
[0780] To a solution of 3-phenylpropanoic acid (1 g, 1.0 eq) in
N,N-dimethylacetamide (5 ml) was added EDC.HCl (1.91 g, 1.5 eq).
The reaction mixture was stirred for 15 minutes, then added
compound 5D (1.19 g, 1.0 eq). The reaction mixture was further
stirred at room temperature for 3 hours. On completion of reaction,
the reaction mixture was quenched with water and extracted with
ethyl acetate. The combined organic layers were washed with
saturated aq. sodium chloride solution, dried over anhydrous sodium
sulfate and concentrated under reduced pressure. The resultant
residue was purified using column chromatography on silica gel
(230-400 mesh) using dichloromethane:methanol (9:1) as eluent to
afford the compound 1.45 as an off white solid.
Example 17
Preparation of
1-[4-(5-Hydroxy-pyridin-2-yl)-piperazin-1-yl]-3-methyl-3-phenyl-butan-1-o-
ne (I.125)
##STR00320##
[0782] Step-I: To a cooled (0-5.degree. C.) solution of
3,3-dimethylacrylic acid (10 g, 1.0 eq) in dry benzene (50 ml) was
added anhydrous aluminum chloride (16 g, 1.2 eq) in small portions
and the temperature was kept below 5.degree. C. The reaction
mixture was stirred for 20 minutes and then allowed to attain to
room temperature. After completion of reaction, diethyl ether (50
ml) was added to reaction mixture and it was then cooled to
0.degree. C. Hydrochloric acid (1N) was added to the reaction
mixture until all of the solid dissolved and pH was less than 2.
The aqueous layer was extracted with diethyl ether (3.times.50 ml).
The organic layer was concentrated to reduce the volume to 50 ml
and then extracted with saturated aq. sodium bicarbonate solution
(6.times.30 ml). The combined aqueous layers were acidified with
hydrochloric acid until the pH was less than 2. The aqueous layer
was extracted with diethyl ether (3.times.50 ml). The combined
organic layers were dried over anhydrous sodium sulfate and
distilled to afford compound 17A (17.5 g, yield: 98%) as a low
melting off white solid.
[0783] Step-II: To a solution of 3-methyl-3-phenyl-butyric acid (1
g, 1.0 eq) in N,N dimethylacetamide (5 ml) was added EDC.HCl (1.61
g, 1.5 eq). The resultant reaction mixture was stirred for 15
minutes, then added compound 5D (1 g, 1.0 eq) and further stirred
at room temperature for 3 hours. On completion of reaction, the
reaction mixture was quenched with water and extracted with ethyl
acetate. The combined organic layers were washed with saturated aq.
sodium chloride solution, dried over anhydrous sodium sulfate and
concentrated under reduced pressure. The resultant residue was
purified using column chromatography on silica gel (230-400 mesh)
using dichloromethane:methanol (9:1) as eluent to afford compound
1.125 as an off white solid.
Example 18
Preparation of
[4-(5-hydroxy-pyridin-2-yl)-piperazin-1-yl]-[4-methyl-3-(4-pyridin-3-yl-p-
yrimidin-2-ylamino)-phenyl]-methanone (I.85)
##STR00321##
[0785] To a cooled solution (0-5.degree. C.) of
4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzoic acid (0.312
g, 1.1 eq) in N,N-dimethylformamide (5 ml) was added HATU (0.423 g,
1.2 eq) followed by triethylamine (0.17 ml, 1.2 eq). After stirring
the reaction mixture for 10 minutes, compound 5D (0.2 g, 1.0 eq)
was added and stirring was continued for 1 hour at 0-5.degree. C.
On completion of reaction, the reaction mixture was quenched with
water (50 ml) and extracted with ethyl acetate (2.times.30 ml). The
combined organic layers were washed with saturated aq. sodium
chloride solution (10 ml), dried over anhydrous sodium sulfate and
concentrated under reduced pressure. The resultant residue was
purified using column chromatography over silica gel (230-400 mesh)
using a dichloromethane: methanol mixture as eluent to afford pure
compound 1.85 (0.10 g, yield: 20%) as an off white solid.
Example 19
Preparation of
1-[4-(5-hydroxy-pyridin-2-yl)-piperazin-1-yl]-2-(5-nitro-pyridin-2-ylsulf-
anyl)-ethanone (I.97)
##STR00322##
[0787] Step-I: To a cooled solution (0-5.degree. C.) of compound 5D
(0.7 g, 1.0 eq) in dichloromethane (10 ml) was added
N,N-diisopropylethylamine (0.926 g, 3.0 eq). The resultant reaction
mixture was stirred 10 minutes, then added chloroacetylchloride
(0.206 ml, 1.1 eq). After addition, the reaction mixture was
allowed to attain room temperature and then further stirred for 2
hours. On completion of reaction, the reaction mixture was quenched
with saturated aq. sodium bicarbonate solution (20 ml) and
extracted with dichloromethane (2.times.20 ml). The combined
organic layers were washed with saturated aq. sodium chloride
solution (10 ml), dried over anhydrous sodium sulfate and
concentrated under reduced pressure to afford pure compound 19A
(0.380 g, yield: 40%) as an off white solid.
[0788] Step-II: A solution of compound 19A (0.38 g, 1.0 eq) in
ethanol (25 ml) was added to 5-nitropyridine-2-thiol (0.232 g, 1.0
eq) at room temperature and the resultant reaction mixture was
heated to 95.degree. C. for 15 hours. On completion of reaction,
the reaction mixture was cooled to 0-5.degree. C. Precipitated
solid was filtered and washed with diethyl ether (2.times.10 ml).
The solid obtained was dried under reduced pressure at 55.degree.
C. for 3 hours to afford pure compound (I.97) (0.35 g, yield: 66%)
as a red brown colored solid.
Example 20
Preparation of
2-(2-Bromo-phenylsulfanyl)-1-[4-(5-hydroxy-pyridin-2-yl)-piperazin-1-yl]e-
thanone (I.143)
##STR00323##
[0790] To a cooled solution (0-5.degree. C.) of compound 10C (0.25
g, 1.0 eq) in N,N-dimethylformamide (5 ml) was added HATU (0.5 g,
1.3 eq) followed by triethylamine (0.21 ml, 1.5 eq). After stirring
the reaction mixture for 10 minutes, compound 5D (0.199 g, 1.1 eq)
was added and stirring was continued for 2 hours at 0-5.degree. C.
On completion of reaction, the reaction mixture was quenched with
water (50 ml) and extracted with ethyl acetate (2.times.30 ml). The
combined organic layers were washed with saturated aq. sodium
chloride solution (10 ml), dried over anhydrous sodium sulfate and
concentrated under reduced pressure. The resultant residue was
purified using column chromatography on silica gel (230-400 mesh)
using a dichloromethane: methanol mixture as eluent to afford the
pure compound (I.143) (0.15 g, yield: 45%) as a yellow solid.
Example 21
Preparation of
2-(5-fluoro-1H-indol-3-yl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-e-
thanone (I.131)
##STR00324##
[0792] To a solution of 5-fluoroindole-3-acetic acid (1 g, 1.0 eq)
in N,N-dimethylacetamide (5 ml) was added EDC.HCl (1.49 g, 1.5 eq).
The resultant reaction mixture was stirred for 15 minutes, and
added compound 5D (0.93 g, 1.0 eq) and then further stirred at room
temperature for 3 hours. On completion of reaction, the reaction
mixture was quenched with water and extracted with ethyl acetate.
The combined organic layers were washed with saturated aq. sodium
chloride solution, dried over anhydrous sodium sulfate and
concentrated under reduced pressure. The resultant residue was
purified using column chromatography on silica gel (230-400 mesh)
using dichloromethane:methanol (9:1) as eluent to afford the pure
compound (I.131) as an off white solid.
Example 22
Preparation of
[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-((1R,2R)-2-phenylcyclopropyl)--
methanone (I.133)
##STR00325##
[0794] A solution of (1R,2R)-2-phenyl-cyclopropanecarboxylic acid
(0.207 g, 1.0 eq) in N,N-dimethylacetamide (10 ml) was added
EDC.HCl (0.363 g, 1.7 eq). After stirring the reaction mixture for
10 minutes, compound 5D (0.2 g, 1.1 eq) was added and stirring
continued for 2 hours at room temperature. On completion of
reaction, the reaction mixture was quenched with water (50 ml) and
extracted with ethyl acetate (2.times.30 ml). The combined organic
layers were washed with saturated aq. sodium chloride solution (10
ml) and concentrated. The resultant residue was purified using
column chromatography on silica gel (230-400 mesh) using a
dichloromethane:methanol (9:1) mixture as eluent to afford the to
pure compound (1.133) (0.100 g, yield: 27%) as a white solid.
Example 23
Preparation of quinoline-8-sulfonic acid
{2-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-2-oxo-ethyl}-methylamide
(I.89)
##STR00326##
[0796] Step-I: To a cooled solution (0-5.degree. C.) of sarcosine
methyl ester hydrochloride (10 g, 1.0 eq) and quinolone-8-sulfonyl
chloride (17.94 g, 1.1 eq) in dichloromethane (100 ml), was added
N,N-diisopropylethylamine (37.43 ml, 3.0 eq) drop wise over 10 min.
The resultant reaction mixture was stirred at room temperature for
16 hours. After completion of reaction, the reaction mixture was
quenched with saturated aq. sodium bicarbonate solution (300 ml)
under stirring. The organic layer was separated, dried on anhydrous
sodium sulfate and concentrated in vacuum. The resultant residue
was purified by column chromatography, eluting with ethyl
acetate:hexane (7:3) to afford pure compound 23A as an orange
solid.
[0797] Step-II: Compound 23A (12 g) was dissolved in methanol (120
ml) and added aqueous sodium hydroxide solution (2N) (120 ml). The
resultant reaction mixture was stirred at room temperature for 2
hours. After completion of reaction, the reaction mixture was
acidified with hydrochloric acid (1N) and extracted with ethyl
acetate (120 ml). The organic layer was dried over anhydrous sodium
sulfate and concentrated in vacuum to afford compound 23B as an off
yellow solid, which was taken forward without further
purification.
[0798] Step-III: To a solution of compound 23B (1 g, 1.0 eq) in
N,N-dimethylacetamide (10 ml) was added EDC.HCl (1.02 g, 1.5 eq).
The resultant reaction mixture was stirred for 15 minutes, then
added compound 5D (0.693 g, 1.0 eq) and further stirred the
reaction at room temperature for 3 hours. On completion of
reaction, the reaction mixture was quenched with water and
extracted with ethyl acetate. The combined organic layers were
washed with saturated aq. sodium chloride solution, dried over
anhydrous sodium sulfate and concentrated under reduced pressure.
The resultant residue was purified using column chromatography on
silica gel (230-400 mesh) using dichloromethane:methanol (9:1) as
eluent to afford the pure compound (1.89) as an off white
solid.
Example 24
Preparation of
[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-[3-(1H-indol-4-yl)
phenyl]methanone (I.113)
##STR00327##
[0800] Step-I: To a mixture of 4-bromoindole (11.81 g, 1.0 eq) and
3-carboxyphenylboronic acid (10.0 g, 1.0 eq) in acetonitrile (100
ml) and N,N-dimethylformamide (100 ml) were added palladium
catalyst Pd(PPh.sub.3).sub.4 (2.09 g, 0.03 eq) and freshly prepared
sodium hydroxide (9.64 g, 4.0 eq) solution in 80 ml water. The
resultant reaction mixture was stirred under nitrogen at
100.degree. C. for 4 hours. After completion of coupling reaction,
the reaction mixture was cooled to room temperature and filtered
through celite bed. The filtrate was diluted with ethyl acetate and
separated from the water layer. The organic layer was washed with
brine, dried over anhydrous sodium sulfate and concentrated under
reduced pressure. The resultant crude product was purified by a
silica gel column eluting with dichloromethane:methanol to afford
compound 24A.
[0801] Step-II: To a solution of compound 24A (1 g, 1.0 eq) in
N,N-dimethylacetamide (10 ml) was added EDC.HCl (1.21 g, 1.5 eq).
The reaction mixture was stirred for 15 minutes and then added
compound 5D (0.755 g, 1.0 eq) and further stirred at room
temperature for 3 hours. On completion of reaction, the reaction
mixture was quenched with water and extracted with ethyl acetate.
The combined organic layers were washed with saturated aq. sodium
chloride solution, dried over anhydrous sodium sulfate and
concentrated under reduced pressure. The resultant residue was
purified by column chromatography on silica gel (230-400 mesh)
using dichloromethane:methanol (9:1) as eluent to afford the pure
compound (I.113) as an off white solid.
Example 25
Preparation of
2-(1-adamantyl)-1-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]ethanone
(I.55)
##STR00328##
[0803] Step-I: To a solution of compound 25A (0.30 g, 1.0 eq) in
N,N-dimethylformamide (5 ml), was added EDC.HCl (0.44 g, 1.5 eq)
and HOBt (0.31 g, 1.5 eq). The resultant reaction mixture was
stirred for 30 minutes at room temperature, then added compound 5C
(0.42 g, 1.0 eq) and further stirred at room temperature for 3
hours. On completion of reaction, the reaction mixture was quenched
with water (25 ml) under vigorous stirring. Precipitated yellow
solid was filtered, washed with diethyl ether and dried under
vacuum to afford pure compound 25B in quantitative yield.
[0804] Step-II: To a solution of compound 25B (0.56 g) in
methanol:dichloromethane (4:1) (10 ml), was added palladium on
carbon (0.18 g, 10% by weight, 50% wet) and stirred under hydrogen
atmosphere created using balloon for 3 hours at room temperature.
After completion of reaction mixture, the reaction mixture was
filtered through celite bed and the filtrate was concentrated under
reduced pressure. The obtained yellow solid was leached with
diethyl ether and filtered to afford pure product (1.55) in
quantitative yield.
Example 26
Preparation of
2-(1-adamantylmethylamino)-1-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]ethan-
one (I.57)
##STR00329##
[0806] Step-I: To a solution of 1-adamantanemethylamine (0.048 g,
1.0 eq) in tetrahydrofuran, was added potassium carbonate (0.04 g,
1.0 eq). The resultant reaction mixture was stirred at room
temperature for 10 minutes, then added compound 26A (0.1 g, 1.0 eq)
and further stirred under nitrogen atmosphere for 3 hours. After
completion of reaction, the reaction mixture was quenched with
water and extracted with ethyl acetate (3.times.20 ml). The
combined organic layers were washed with water, dried over
anhydrous sodium sulfate and concentrated under reduced pressure.
The resultant residue was purified by column chromatography on
silica gel (230-400 mesh) to afford pure compound 26B (0.1 g).
[0807] Step-II: Compound 26B (0.1 g) was dissolved in methanol (5
ml) and palladium on carbon (0.01 g, 10% by weight, 50% wet) was
added to it. The resultant reaction mixture was stirred under
hydrogen atmosphere created using hydrogen balloon for 3 hours at
room temperature. On completion of reaction, the reaction mixture
was filtered through celite bed and the filtrate was concentrated
under reduced pressure. The resultant crude product was purified by
column chromatography on silica gel (230-400 mesh) to afford pure
product (1.57) (0.04 g).
Example 27
Preparation of
5-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]-5-oxo-pentanoic acid
(I.70)
##STR00330##
[0809] Step-I: To a solution of compound 5C (1 g, 1.0 eq) in
tetrahydrofuran (10 ml), was added glutaric anhydride (0.71 g, 1.7
eq) and the resultant reaction mixture was heated to 65.degree. C.
for 16 hours. On completion of reaction, the reaction mixture was
concentrated under reduced pressure. The resultant residue was
triturated with diethyl ether (5 ml) and filtered to afford
compound 27A (0.9 g) as an off white solid.
[0810] Step-II: Compound 27A (0.9 g) was dissolved in methanol (10
ml) and palladium on carbon (0.05 g, 10% by weight, 50% wet) was
added to it. The resultant reaction mixture was stirred under
hydrogen atmosphere created using hydrogen balloon for 3 hours at
room temperature. On completion of reaction, the reaction mixture
was filtered through celite bed and concentrated under reduced
pressure. The resultant crude product was purified by column
chromatography on silica gel (230-400 mesh) to afford pure product
(I.70) (0.58 g) in quantitative yield.
Example 28
Preparation of
2-cyclohexyl-2-hydroxy-1-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]-2-phenyl-
-ethanone (I.95)
##STR00331##
[0812] Step-I: To a solution of 2-cyclohexyl-2-phenylglycolic acid
(0.3g, 1.0 eq) in N,N-dimethylformamide (5 ml), was added EDC.HCl
(0.36 g, 1.5 eq) and HOBt (0.26 g, 1.5 eq). The resultant reaction
mixture was stirred for 15 minutes at room temperature and then
added compound 5C (0.34 g, 1.0 eq) and further stirred for 2 hours.
After completion of reaction, the reaction mixture was quenched
with a saturated aq. sodium bicarbonate solution (5 ml) and
extracted with ethyl acetate (3.times.20 ml). The organic layer was
dried over anhydrous sodium sulfate and concentrated under reduced
pressure to afford crude product. The crude product was purified by
column chromatography on silica gel (230-400 mesh) to get compound
28A as a white solid (0.314 g).
[0813] Step-II: To a solution of compound 28A (0.314 g) in
methanol:dichloromethane (1:1) (10 ml), was added 10% by weight
palladium on carbon (0.15 g) and stirred under hydrogen atmosphere
created by hydrogen balloon for 2 hours. After completion of
reaction, the reaction mixture was filtered through celite bed and
the filtrate was concentrated under reduced pressure. The crude
product was triturated with diethyl ether (5 ml) and filtered to
afford pure product (I.95) as a white solid (0.19 g).
Example 29
Preparation of
1-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]-2-morpholino-2-phenyl-ethanone
(I.117)
##STR00332##
[0815] Step-I: To a solution of phenylacetic acid (5 g, 1.0 eq) in
carbon tetrachloride (50 ml), was added NBS (7.18 g, 1.1 eq) and
AIBN (0.3 g, 0.05 eq). The resultant reaction mixture was heated to
reflux and stirred for 19 hours under nitrogen atmosphere. After
completion of the reaction, the reaction mixture was cooled to room
temperature, diluted with n-hexane (50 ml) and filtered through
celite bed. The filtrate was concentrated under reduced pressure
and the residue was purified by column chromatography on silica gel
(230-400 mesh) to afford compound 29A (8.0 g) as a light yellow
liquid.
[0816] Step-II: To a solution of compound 29A (7.5 g, 1.0 eq) in
methanol (70 ml), was added sulfuric acid (0.1 ml, 0.05 eq) slowly
under stirring. The resultant reaction mixture was refluxed for 24
hours. After completion of the reaction, the reaction mixture was
cooled to room temperature, quenched with water (30 ml) and
extracted with ethyl acetate (4.times.20 ml). The combined organic
layers were washed with water, dried over anhydrous sodium sulfate
and concentrated under reduced pressure to afford compound 29B
(6.65 g) as a light brown liquid, which was used directly in next
step without further purification.
[0817] Step-III: To a solution of compound 29B (5.65 g, 1 eq) in
acetonitrile (30 ml), was added N,N-diisopropylethylamine (4.3 ml,
1 eq) and morpholine (2.55 ml, 1.2 eq). The resultant reaction
mixture was stirred at room temperature for 4 hours. On completion
of reaction, the reaction mixture was quenched with water and
extracted with ethyl acetate (3.times.20 ml). The combined organic
layers were washed with water, dried over anhydrous sodium sulfate
and concentrated under reduced pressure. The resultant crude
product was purified by column chromatography on silica gel
(230-400 mesh) to obtain pure ester intermediate (4.0 g) as a light
brown liquid. The ester intermediate (4.0 g, 1 eq) was dissolved in
1,4-dioxane (40 ml) and to it was added hydrochloric acid (14.88
ml, 10.0 eq). The resultant reaction mixture was heated at
110.degree. C. for 24 hours. On completion of reaction, the
reaction mixture was concentrated under reduced pressure and the
resulting residue was triturated with diethyl ether (50 ml).
Precipitated solid was filtered to afford compound 29C (4.1 g) as
an off white solid in the form of a hydrochloride salt.
[0818] Step-IV: To a solution of compound 29C (0.43 g, 1.0 eq) in
N,N-dimethylformamide (10 ml), was added triethylamine (0.23 ml,
1.0 eq), EDC.HCl (0.48 g, 1.5 eq) and HOBt (0.34 g, 1.5 eq). The
resultant reaction mixture was stirred at room temperature for 15
minutes, then added compound 5C (0.45 g, 1.0 eq) and further
stirred for 2 hours. On completion of reaction, the reaction
mixture was quenched with saturated aq. sodium bicarbonate solution
(20 ml) and extracted with ethyl acetate (3.times.20 ml). The
combined organic layers were washed with water, dried over sodium
sulfate and concentrated under reduced pressure to get the crude
product. The crude obtained was triturated with diethyl ether (5
ml). The resultant solid was filtered to afford compound 29D (0.55
g) as an off white solid.
[0819] Step-V: To a solution of compound 29D (0.5 g) in
methanol:dichloromethane (1:1) (10 ml), was added 10% by weight
palladium on carbon (0.15 g) and the resultant reaction mixture was
stirred under hydrogen atmosphere created by hydrogen balloon for 2
hours. After completion of reaction, the reaction mixture was
filtered through celite bed and the filtrate was concentrated under
reduced pressure to afford the crude product. The crude product was
purified by column chromatography on silica gel (230-400 mesh) to
afford pure compound (I.117) (0.160 g) as a light brown solid.
[0820] Table 2 set forth below provides characterizing data
(.sup.1H NMR spectral data) for the compounds of the instant
invention. The compounds for which data is provided below but for
which a description of the synthesis is not explicitly provided
above were made in an analogous manner to the synthetic procedures
provided above.
TABLE-US-00002 TABLE 2 Chemical Name and .sup.1H NMR Data for
Compound of Formula I Com- pound .sup.1H NMR (.delta. ppm) in
DMSO-d.sub.6 as No. IUPAC Name solvent, 500 MHz I.1 ##STR00333##
1-[4-(4- Hydroxyphenyl)pip- erazin-1-yl]-2- phenylethanone 2.88 (t,
2H, J = 4.47 Hz), 2.93 (t, 2H, J = 4.68 Hz), 3.65 (t, 4H, J = 4.91
Hz), 6.69 (d, 2H, J = 8.77 Hz), 6.82 (d, 2H, J = 8.78 Hz), 7.26-
7.30 (m, 3H), 7.36 (t, 2H, J = 7.51 Hz), 8.93 (s, 1H) I.2
##STR00334## 4-(4- Hydroxyphenyl)pip- erazin-1-yl]-(1H-
indol-3-yl)- methanone 2.99 (t, 4H, J = 4.67 Hz), 3.74 (t, 4H, J =
4.73 Hz), 6.66 (d, 2H, J = 8.82 Hz), 6.82 (d, 2H, J = 8.85 Hz),
7.10 (t, 1H, J = 7.40 Hz), 7.16 (t, 1H, J = 7.41 Hz), 7.44 (d, 1H,
J = 8.03 Hz), 7.69 (d, 1H, J = 7.86 Hz), 7.72 (d, 1H, J = 2.63 Hz),
8.89 (s, 1H), 11.61 (s, 1H) I.3 ##STR00335## 1-[4-(4-
Hydroxyphenyl)- piperazin-1-yl]-2- (3,4,5- trimethoxyphenyl)-
ethanone 2.90-2.95 (m, 4H), 3.65-3.66 (m, 4H), 3.68 (s, 3H), 3.73
(s, 2H), 3.79 (s, 6H), 6.59 (s, 2H), 6.70 (d, 2H, J = 8.85 Hz),
6.83 (d, 2H, J = 8.86 Hz), 8.94 (s, 1H) I.4 ##STR00336## 2-(4-
Hydroxyphenyl)-1- [4-(4- hydroxyphenyl)- piperazin-1-yl]- ethanone
2.86 (t, 2H, J = 4.38 Hz), 2.91 (t, 2H, J = 4.68 Hz), 3.62 (t, 4H,
J = 4.68 Hz), 3.66 (s, 2H), 6.69 (d, 2H, J = 8.81 Hz), 6.73 (d, 2H,
J = 8.34 Hz), 6.82 (d, 2H, J = 8.82 Hz), 7.08 (d, 2H, J = 8.31 Hz),
8.93 (s, 1H), 9.30 (s, 1H) I.5 ##STR00337## 1-[4-(4-
Hydroxyphenyl)- piperazin-1-yl]-2- [4-(2- methoxyethoxy)-
phenyl]-ethanone 2.88 (t, 2H, J = 4.38 Hz), 2.92 (t, 2H, J = 4.68
Hz), 3.35 (s, 3H), 3.63 (t, 4H, J = 4.68 Hz), 3.69 (t, 2H, J = 4.53
Hz), 3.72 (s, 2H), 4.10 (t, 2H, J = 4.54 Hz), 6.69 (d, 2H, J = 8.83
Hz), 6.82 (d, 2H, J = 8.86 Hz), 6.92 (d, 2H, J = 8.56 Hz), 7.19 (d,
2H, J = 8.52 Hz), 8.93 (s, 1H) I.6 ##STR00338## 1-[4-(5-
Hydroxypyridin-2- yl)-piperazin-1-yl]- 2-phenylethanone 3.25 (m,
2H), 3.30 (m, 2H), 3.62- 3.63 (m, 4H), 3.81 (s, 2H), 6.78 (d, 1H, J
= 8.98 Hz), 7.10-7.13 (m, 1H), 7.26-7.30 (m, 3H), 7.34- 7.37 (m,
2H), 7.78 (d, 1H, J = 2.74 Hz), 9.09 (s, 1H) I.7 ##STR00339##
[4-(4- Hydroxyphenyl)- piperazin-1-yl]-[1- (2-methoxyethyl)-
piperidin-4-yl]- methanone 1.66 (br-s, 4H), 2.42 (m, 2H), 2.93 (m,
3H), 2.98 (m, 4H), 3.29 (m, 4H), 3.50 (br-s, 2H), 3.62 (s, 3H),
3.64 (br-s, 2H), 6.70-6.71 (d, 2H, J = 5.96 Hz), 6.84 (d, 2H), 8.94
(s, 1H) I.8 ##STR00340## [4-(4- Hydroxyphenyl)- piperazin-1-yl]-
(1H-indazol-3-yl)- methanone 3.07 (m, 4H), 3.90 (m, 2H), 4.19 (m,
2H), 6.72 (d, 2H, J = 8.81 Hz), 6.89 (d, 2H, J = 8.84 Hz), 7.28 (t,
1H, J = 7.51 Hz), 7.47 (t, 1H, J = 7.61 Hz), 7.67 (d, 1H, J = 8.40
Hz), 8.04 (d, 1H, J = 8.15 Hz), 8.93 (s, 1H), 13.59 (s, 1H) I.9
##STR00341## Acridin-9-yl-[4-(4- hydroxy-phenyl)- piperazin-l-yl]-
methanone 2.94 (s, 2H), 3.12 (s, 2H), 3.53 (s, 2H), 4.16 (s, 2H),
6.69 (d, 2H, J = 8.81 Hz), 6.83 (d, 2H, J = 8.85 Hz), 7.76 (t, 2H,
J = 7.69 Hz), 7.97 (d, 2H, J = 7.76 Hz), 8.01 (d, 2H, J = 7.90 Hz),
8.27 (d, 2H, J = 6.72 Hz), 8.95 (s, 1H). I.10 ##STR00342## [4-(4-
Hydroxyphenyl)- piperazin-1-yl]-[5- (2-methoxyethoxy)-
1H-indol-3-yl]- methanone 3.05 (s, 4H), 3.37 (s, 3H), 3.71- 3.73
(m, 2H), 3.80 (s, 4H), 4.13 (t, 2H, J = 4.66 Hz), 6.72 (d, 2H, J =
9.06 Hz), 6.85 (d, 1H, J = 2.35 Hz), 6.88 (d, 2H, J = 8.38 Hz),
7.21 (d, 1H, J = 1.98 Hz), 7.38 (d, 1H, J = 8.78 Hz), 7.73 (d, 1H,
J = 2.63 Hz), 8.94 (s, 1H), 11.55 (s, 1H). I.11 ##STR00343##
1-[4-(2-Fluoro-4- hydroxy-phenyl)- piperazin-1-yl]-2-
phenylethanone 2.81 (t, 2H, J = 4.58 Hz), 2.85 (t, 2H, J = 4.82
Hz), 3.65-3.67 (m, 4H), 3.80 (s, 2H), 6.56 (dd, 1H, J.sub.1 = 8.52
Hz, J2 = 2.7 Hz), 6.60 (dd, 1H, J.sub.1 = 13.7 Hz, J.sub.2 = 2.59
Hz), 6.89 (t, 1H, J = 9.39 Hz), 7.26-7.30 (m, 3H), 7.35-7.38 (t,
2H, J = 7.44 Hz), 9.52 (s, 1H) I.12 ##STR00344## 3-(4-
Butoxyphenyl)-1- [4-(4- hydroxyphenyl)- piperazin-1-yl]- propenone
1.00 (t, 3H, J = 7.38 Hz), 1.45- 1.53 (m, 2H), 1.72-1.78 (m, 2H),
3.01 (m, 4H), 3.74 (m, 2H), 3.88 (m, 2H), 4.06 (t, 2H, J = 6.47
Hz), 6.72 (d, 2H, J = 8.84 Hz), 6.88 (d, 2H, J = 8.81 Hz), 7.00 (d,
2H, J = 8.64 Hz), 7.20 (d, 1H, J = 15.33 Hz), 6.52 (d, 1H, J =
15.22 Hz), 7.72 (d, 2H, J = 8.62 Hz), 8.94 (s, 1H) I.13
##STR00345## 3-(4- Butoxyphenyl)-1- [4-(4- hydroxyphenyl)-
piperazin-1-yl]- propan-1-one 0.97 (t, 3H, J = 7.39 Hz), 1.42- 1.50
(m, 2H), 1.68-1.74 (m, 2H), 2.65 (t, 2H, J = 7.59 Hz), 2.80 (t, 2H,
J = 7.60 Hz), 2.86 (t, 2H, J = 4.81 Hz), 2.90 (t, 2H, J = 4.99 Hz),
3.56 (t, 2H, J = 4.81 Hz), 3.61 (t, 2H, J = 4.94 Hz), 3.94 (t, 2H,
J = 6.49 Hz), 6.70 (d, 2H, J = 8.93 Hz), 6.83 (d, 2H, J = 8.94 Hz),
6.87 (d, 2H, J = 8.60 Hz), 7.18 (d, 2H, J = 8.61 Hz), 8.93 (s, 1H)
I.14 ##STR00346## (5-Butoxy-1H- indol-3-yl)-[4-(4- hydroxyphenyl)-
piperazin-1-yl]- methanone 0.99 (t, 3H, J = 7.40 Hz), 1.46-1.54 (m,
2H), 1.73-1.79 (m, 2H), 3.05 (s, 4H), 3.80 (s, 4H), 4.00 (t, 2H, J
= 6.46 Hz), 6.72 (d, 2H, J = 8.83 Hz), 6.83-6.85 (m, 1H), 6.86 (d,
2H, J = 8.79 Hz), 7.21 (d, 1H, J = 2.12 Hz), 7.37 (d, 1H, J = 8.78
Hz), 7.72 (d, 1H, J = 2.71 Hz), 8.94 (s, 1H), 11.55 (s, 1H). I.15
##STR00347## (1-Benzyl-1H- indol-3-yl)-[4-(4- hydroxyphenyl)-
piperazin-1-yl]- methanone 3.05 (s, 4H), 3.80 (s, 4H), 5.53 (s,
2H), 6.72 (d, 2H, J = 8.85 Hz), 6.88 (d, 2H, J = 8.87 Hz),
7.17-7.24 (m, 2H), 7.32 (d, 3H, J = 7.37 Hz), 7.38 (d, 2H, J = 7.17
Hz), 7.56 (d, 1H, J = 7.38 Hz), 7.78 (d, 1H, J = 7.58 Hz), 8.02 (s,
1H), 8.94 (s, 1H). I.16 ##STR00348## N-{(S)-1-Benzyl-2- [4-(4-
hydroxyphenyl)- piperazin-1-yl]-2- oxoethyl}- acetamide 1.98 (s,
3H), 2.56 (m, 1H), 2.65- 2.70 (m, 1H), 2.71-2.82 (m, 3H), 2.95-3.15
(m, 1H), 3.49-3.52 (m, 1H), 3.52-3.65 (m, 3H), 5.02 (q, 1H, J.sub.1
= 8.08 Hz, J.sub.2 = 7.60 Hz), 6.69 (d, 2H, J = 8.87 Hz), 6.78 (d,
2H, J = 8.92 Hz), 7.20-7.25 (m, 1H), 7.27- 7.34 (m, 4H), 8.41 (d,
1H, J = 8.34 Hz), 8.94 (s, 1H) . I.17 ##STR00349## 1-[4-(4-
Hydroxyphenyl)- piperazin-1-yl]-2- phenyl-ethane-1,2- dione 2.95
(t, 2H, J = 5.04 Hz), 3.13 (t, 2H, J = 5.14 Hz), 3.45 (t, 2H, J =
5.01 Hz), 3.82 (t, 2H, J = 5.14 Hz), 6.72 (d, 2H, J = 8.92 Hz),
6.86 (d, 2H, J = 8.93 Hz), 7.69 (t, 2H, J = 7.80 Hz), 7.82-7.85 (m,
1H), 7.98 (dd, 2H, J.sub.1 = 8.32 Hz, J.sub.2 = 1.19 Hz), 8.98 (s,
1H) I.18 ##STR00350## (1-Butyl-1H-indol- 3-yl)-[4-(4-
hydroxyphenyl)- piperazin-1-yl]- methanone 0.95 (t, 3H, J = 7.32
Hz), 1.29- 1.34 (m, 2H), 1.80-1.83 (m, 2H), 3.00-3.08 (m, 4H), 3.80
(m, 4H), 4.28 (t, 2H, J = 6.89 Hz), 6.71 (d, 2H, J = 8.60 Hz), 6.88
(d, 2H, J = 8.52 Hz), 7.18 (t, 1H, J = 7.27 Hz), 7.26 (t, 1H, J =
7.49 Hz), 7.60 (d, 1H, J = 8.11 Hz), 7.77 (d, 1H, J = 7.92 Hz),
7.85 (s, 1H), 8.94 (s, 1H) I.19 ##STR00351## N-{(1R)-2-[4-(4-
Hydroxyphenyl)pip- erazin-1-yl]-2-oxo- 1- phenylethyl} acetamide
1.92 (s, 3H), 2.81-2.97 (m, 4H), 3.43-3.64 (m, 4H), 5.96 (d, 1H, J
= 7.90 Hz), 6.68 (d, 2H, J = 8.89 Hz), 6.78 (d, 2H, J = 8.93 Hz),
7.35- 7.37 (m, 1H), 7.40-7.44 (m, 4H), 8.57 (d, 1H, J = 7.87 Hz),
8.92 (s, 1H) I.20 ##STR00352## (2,6-Diphenyl-4- pyridyl)-[4-(4-
hydroxyphenyl)pip- erazin-1- yl]methanone 3.03 (m, 2H), 3.15 (m,
2H), 3.54 (m, 2H), 3.88 (m, 2H), 6.71 (d, J = 8.75 Hz, 2H), 6.87
(d, J = 8.68 Hz, 2H), 7.54-7.56 2H), 7.59-7.62 (m, 4H), 8.01 (s,
2H), 8.33 (d, J = 7.45 Hz, 4H), 8.95 (s, 1H). I.21 ##STR00353##
Anthracen-9-yl[4- (4-hydroxyphenyl)- piperazin-1-yl]- methanone
2.77 (t, 2H, J = 4.56 Hz), 3.11 (t, 2H, J = 4.73 Hz), 3.27 (t, 2H,
J = 4.78 Hz), 4.15 (t, 2H, J = 4.75 Hz), 6.69 (d, 2H, J = 8.75 Hz),
6.82 (d, 2H, J = 8.80 Hz), 7.61-7.68 (m, 4H), 7.94 (d, 2H, J = 8.39
Hz), 8.22 (d, 2H, J = 8.17 Hz), 8.75 (s, 1H), 8.94 (s, 1H) I.22
##STR00354## [4-(4- Hydroxyphenyl)- piperazin-1-yl-
phenanthren-9-yl- methanone 2.81-2.82 (m, 1H), 2.95 (m, 1H), 3.19
(m, 2H), 3.33 (m, 2H), 3.93- 3.95 (m, 1H), 4.05-4.07 (m, 1H), 6.70
(d, 2H, J = 8.68 Hz), 6.84 (d, 2H, J = 8.72 Hz), 7.74-7.78 (m,
2H),7.81 (t, 2H, J = 7.49 Hz), 7.91 (d, 1H, J = 7.67 Hz), 7.92 (s,
1H), 8.11 (d, 1H, J = 7.83 Hz), 8.93 (d, 1H, J = 8.26 Hz), 8.97 (s,
1H), 8.98 (d, 1H, J = 8.43 Hz) I.23 ##STR00355## 1-[4-(4-
Hydroxyphenyl)- piperazin-1-yl]-3- naphthalen-2-yl- propan-l-one
2.81 (t, 2H, J = 7.69 Hz), 2.87 (t, 2H, J = 4.61 Hz), 2.90 (t, 2H,
J = 4.84 Hz), 3.06 (t, 2H, J = 7.65 Hz), 3.60 (t, 2H, J = 4.58 Hz),
3.62 (t, 2H, J = 5.00 Hz), 6.69 (d, 2H, J = 8.82 Hz), 6.79 (d, 2H,
J = 8.85 Hz), 7.48-7.54 (m, 3H), 7.79 (s, 1H), 7.87-7.92 (m, 3H),
8.93 (s, 1H) I.24 ##STR00356## [4-(4- Hydroxyphenyl)-
piperazin-1-yl]- quinolin-3-yl- methanone 3.03-3.13 (m, 4H), 3.61
(s, 2H), 3.88 (s, 2H), 6.67 (d, 2H, J = 8.78 Hz), 6.87 (d, 2H, J =
8.82 Hz), 7.57 (t, 1H, J = 7.79 Hz), 7.91 (t, 1H, J = 7.70 Hz),
8.13 (d, 2H, J = 8.61 Hz), 8.56 (s, 1H), 8.96 (s, 1H), 9.00 (d, 1H,
J = 1.54 Hz). I.25 ##STR00357## Anthracen-1-yl[4-
(4-hydroxyphenyl)- piperazin-1-yl]- methanone 2.80 (m, 1H), 2.91
(m, 1H), 3.22- 3.33 (m, 4H), 3.98 (m, 1H), 4.10 (m, 1H), 6.69 (d,
2H, J = 8.79 Hz), 6.84 (d, 2H, J = 8.78 Hz), 7.54 (d, 1H, J = 6.59
Hz), 7.58-7.63 (m, 3H), 8.17 (d, 1H, J = 7.83 Hz), 8.22- 8.23 (m,
2H), 8.50 (s, 1H), 8.73 (s, 1H), 8.94 (s, 1H) I.26 ##STR00358##
(1-Benzylindol-4- yl)-[4-(4- hydroxyphenyl) piperazin-1-
yl]methanone 7.20-7.50 (m, 6H), 7.13-7.25 (m, 1H), 7.11 (d, J = 7
.08 Hz, 2H), 6.84 (d, J = 8.86 Hz, 2H), 6.76 (d, J = 8.85 Hz, 2H),
6.57 (d, J = 3.09 Hz, 1H), 5.35 (s, 2H), 4.58-4.49 (bs, 1H),
3.90-4.10 (m, 2H), 3.40- 3.60 (m, 2H), 3.10-3.20 (m, 2H), 2.90-3.00
(m, 2H). I.27 ##STR00359## (3,5- Diphenylphenyl)- [4-(4-
hydroxyphenyl) piperazin-1- yl]methanone 2.98-3.05 (m, 2H),
3.07-3.15 (m, 2H), 3.61 (s, 2H), 3.86 (s, 2H), 6.71 (d, J = 8.76
Hz, 2H), 6.87 (d, J = 8.81 Hz, 2H), 7.46-7.49 (m, 2H), 7.56 (t, J =
7.65 Hz, 4H), 7.73 (s, 2H), 7.87 (d, J = 7.52 Hz, 4H), 8.05 (s,
1H), 8.95 (s, 1H). I.28 ##STR00360## 1-[4-(4- Hydroxyphenyl)-
piperazin-l-yl]-2- (4- trifluoromethyl- phenyl)- ethanone 2.95 (m,
4H), 3.65-3.68 (m, 4H), 3.94 (s, 2H), 6.70 (d, 2H, J = 8.79 Hz),
6.84 (d, 2H, J = 8.81 Hz), 7.51 (d, 2H, J = 7.97 Hz), 7.72 (d, 2H,
J = 8.01 Hz), 8.94 (s, 1H) I.29 ##STR00361## [4-(4- Hydroxyphenyl)-
piperazin-l-yl]- imidazo[1,2- a]126yridine-8-yl- methanone 2.95 (s,
2H), 2.99-3.12 (m, 2H), 3.32-3.33 (m, 2H), 3.87 (s, 2H), 6.71 (d,
2H, J = 8.80 Hz), 6.85 (d, 2H, J = 8.82 Hz), 7.03 (t, 1H, J = 6.81
Hz), 7.32 (d, 1H, J = 7.42 Hz), 7.68 (s, 1H), 8.10 (s, 1H), 8.68
(d, 1H, J = 6.74 Hz), 8.94 (s, 1H). I.30 ##STR00362## [4-(4-
Hydroxyphenyl)- piperazin-l-yl]- (1H-indol-4-yl)- methanone
2.92-3.09 (m, 4H), 3.87 (m, 4H), 6.44 (s, 1H), 6.70 (d, 2H, J =
8.79 Hz), 6.84 (d, 2H, J = 8.83 Hz), 7.06 (d, 1H, J = 7.11 Hz),
7.20 (t, 1H, J = 7.65 Hz), 7.48 (t, 1H, J = 2.56 Hz), 7.53 (d, 1H,
J = 8.13 Hz), 8.93 (s, 1H), 11.38 (s, 1H) I.31 ##STR00363## [4-(4-
Hydroxyphenyl)- piperazin-l-yl]-[3- (4- trifluoromethylphenyl)-
imidazo [1,2- a]126yridine-8-yl]- methanone 2.95 (s, 2H), 2.99-3.12
(m, 2H), 3.32-3.33 (m, 2H), 3.87 (s, 2H), 6.71 (d, 2H, J = 8.80
Hz), 6.85 (d, 2H, J = 8.82 Hz), 7.03 (m, 1H), 7.32 (m, 1H),
8.13-8.25 (m, 5H), 8.68 (d, 1H, J = 6.74 Hz), 8.94 (s, 1H). I.32
##STR00364## 2-Hydroxy-5-(4- phenylacetylpiperazin- 1-yl)-benzoic
acid 2.95 (s, 2H), 3.00 (s, 2H), 3.66 (m, 4H), 3.67 (s, 2H),
6.90-6.92 (m, 1H), 7.26-7.30 (m, 5H), 7.35-7.38 (m, 2H). I.33
##STR00365## [4-(4- Hydroxyphenyl)pip- erazin-1-yl]-(2-
morpholino-6- phenyl-4- pyridyl)methanone 2.99-3.03 (m, 2H),
3.08-3.12 (m, 2H), 3.47-3.52 (m, 2H), 3.63-3.67 (m, 4H),3.77-3.84
(m, 6H), 6.71 (d, J = 8.76 Hz, 2H), 6.84-6.87 (m, 3H), 7.30 (s,
1H), 7.46-7.53 (m, 3H), 8.14 (d, J = 7.39 Hz, 2H), 8.94 (s, 1H).
I.34 ##STR00366## [4-(4- Hydroxyphenyl)pip- erazin-1-yl]-(2-
phenyl-4- pyridyl)methanone 2.94-3.00 (m, 2H), 3.12-3.19 (m, 2H),
3.42-3.48 (m, 2H), 3.84-3.94 (m, 2H), 6.70-6.74 (m, 2H), 6.85- 6.90
(m, 2H), 7.40-7.44 (s, 1H), 7.50-7.70 (m, 3H), 8.04 (s, 1H),
8.19-8.21 (m, 2H), 8.81-8.82 (m, 1H), 8.95 (s, 1H). I.35
##STR00367## [4-(4- Hydroxyphenyl)pip- erazin-1-yl]-(2-
morpholino-4- pyridyl)methanone 2.97-2.98 (m, 2H), 3.07-3.10 (m,
2H), 3.43-3.46 (m, 2H), 3.53 (t, J = 4.80 Hz, 4H), 3.74 (t, J =
4.80 Hz, 4H), 3.77-3.82 (m, 2H), 6.70-6.74 (m, 3H), 6.86-6.90 (m,
3H), 8.24 (d, J = 4.85 Hz, 1H), 8.97 (s, 1H). I.36 ##STR00368##
(2-Chloro-6- morpholino-4- pyridyl)-[4-(4- hydroxyphenyl)pip-
erazin-1- yl]methanone 2.95-3.01 (m, 2H), 3.05-3.09 (m, 2H),
3.43-3.48 (m, 2H), 3.53-3.57 (m, 4H), 3.70-3.75 (m, 4H), 3.75- 3.78
(m, 2H), 6.70-6.72 (m, 2H), 6.76 (s, 1H), 6.84 (s, 1H), 6.85-6.87
(m, 2H), 8.95 (s, 1H). I.37 ##STR00369## 5-[4-(2,6-
Diphenylpyridine- 4- carbonyl)piperazin- 1-yl]-2-hydroxy-
benzonitrile 3.10-3.14 (m, 2H), 3.22-3.25 (m, 2H), 3.52-3.57 (m,
2H), 3.86-3.90 (m, 2H), 6.96-6.70 (m, 1H), 7.18- 7.29 (m, 2H),
7.52-7.64 (m, 6H), 8.02 (s, 2H), 8.29-8.36 (m, 4H) 10.54 (s, 1H).
I.38 ##STR00370## 5-[4-(2,6- Diphenylpyridine- 4-
carbonyppiperazin- 1-yl]-2-hydroxy- benzoic acid 3.09-3.14 (m, 2H),
3.20-3.24 (m, 2H), 3.54-3.53 (m, 2H), 3.87-3.93 (m, 2H), 6.94 (d, J
= 8.90 Hz, 1H), 7.31-7.36 (m, 2H), 7.54-7.56 (m, 2H), 7.59-7.62 (m,
4H), 8.02 (s, 2H), 8.33 (d, J = 7.30 Hz, 4H). I.39 ##STR00371##
3-[4-[4-(4- Hydroxyphenyl)pip- erazine-1- carbonyl]-2-
pyridyl]benzoic acid 2.98-3.01 (m, 2H), 3.11-3.15 (m, 2H),
3.47-3.51 (m, 2H), 3.83-3.87 (m, 2H), 6.71 (d, J= 8.90 Hz, 2H),
6.86 (d, J = 8.95 Hz, 2H), 7.47 (dd, J.sub.1 = 1.15 Hz, J.sub.2 =
4.85 Hz, 1H), 7.66 (t, J = 7.72 Hz, 1H), 8.08 (d, J = 7.65 Hz, 1H),
8.10 (s, 1H), 8.39 (d, J = 7.65 Hz, 1H), 8.77 (s, 1H), 8.84 (d, J =
4.85 Hz, 1H), 8.98 br s, 1H). I.40 ##STR00372## 1-[4-(4-
Hydroxyphenyl)pip- erazin-1-yl]-3,3- diphenyl-prop-2-en- 1-one 2.51
(t, J = 4.72 Hz, 2H), 2.78 (t, J = 4.55 Hz, 2H), 3.44 (t, J = 4.80
Hz, 2H), 3.53 (t, J = 4.85 Hz, 2H), 6.55 (s, 1H), 6.67 (d, J = 8.95
Hz, 2H), 6.73 (d, J = 9.00 Hz, 2H), 7.22-7.24 (m,
2H), 7.35-7.38 (m, 2H), 7.40- 7.46 (m, 6H), 8.93 (s, 1H). I.41
##STR00373## 3-[4-[4-(4- Hydroxyphenyl)pip- erazine-1- carbonyl]-6-
morpholino-2- pyridyl]benzoic acid 2.99-3.01 (m, 2H), 3.09-3.13 (m,
2H), 3.49-3.52 (m, 2H), 3.64-3.68 (m, 4H), 3.79-3.85 (m, 6H), 6.71
(d, J = 8.90 Hz, 2H), 6.89 (d, J = 8.90 Hz, 2H), 6.89 (s, 1H), 7.35
(s, 1H), 7.65 (t, J = 7.75 Hz, 1H), 8.04 (d, J = 7.60 Hz, 1H), 8.37
(d, J = 7.95 Hz, 1H), 8.65 (s, 1H), 8.95 (s, 1H). I.42 ##STR00374##
4-[4-[4-(4- Hydroxyphenyl)pip- erazine-1- carbonyl]-6-
morpholino-2- pyridyl]benzoic acid 3.00 (m, 1H), 3.10 (m, 1H),
3.43- 3.47 (m, 1H), 3.49 (m, 1H), 3.66- 3.70 (m, 5.5H), 3.80-3.90
(m, 6.5H), 6.71 (d, J = 8.88, 1H), 6.87 (d, J= 8.90, 1H), 6.91,
7.39 (s, 1H), 7.31 (s, 1H), 7.68-7.78 (m, 1H), 8.05-8.10 (m, 3H),
8.23-8.29 (m, 3H), 8.95 (s, 1H). I.43 ##STR00375## [4-(5-
Hydroxypyridin-2- yl)-piperazin-1-yl]- (1H-indol-3-yl)- methanone
3.42 (t, 4H, J = 4.84 Hz), 3.78 (t, 4H, J = 4.89 Hz), 6.81 (d, 1H,
J = 8.97 Hz), 7.13-7.17 (m, 2H), 7.21 (t, 1H, J = 7.50 Hz), 7.49
(d, 1H, J = 8.06 Hz), 7.75 (d, 1H, J = 7.89 Hz), 7.80 (dd, 2H,
J.sub.1 = 14.37 Hz, J.sub.2 = 2.66 Hz), 9.10 (s, 1H), 11.66 (s, 1H)
I.44 ##STR00376## Acridin-9-yl[4-(5- hydroxy-pyndm-2-
yl)-piperazin-1-yl]- methanone 3.14-3.17 (m, 4H), 3.67 (t, 2H, J =
4.9 Hz), 4.12 (t, 2H, J = 4.95 Hz), 6.78 (d, 1H, J = 8.99 Hz), 7.12
(dd, 1H, J.sub.1 = 8.95 Hz, J.sub.2 = 2.87 Hz), 7.75 (t, 2H, J =
7.55 Hz), 7.78 (d, 1H, J = 2.81 Hz), 7.96 (t, 2H, J = 7.60 Hz),
8.02 (d, 2H, J = 8.6 Hz), 8.28 (d, 2H, J = 8.77 Hz), 9.13 (s, 1H)
I.45 ##STR00377## 1-[4-(5- Hydroxypyridin-2- yl)-piperazin-1-yl]-
3-phenyl-propan-1- one 2.71 (t, 2H, J = 7.75 Hz), 2.88 (t, 2H, J =
7.70 Hz), 3.29 (m, 4H), 3.55- 3.60 (m, 4H), 6.78 (d, 1H, J = 8.98
Hz), 7.12 (dd, 1H, J.sub.1 = 8.93 Hz, J.sub.2 = 2.86 Hz), 7.22 (t,
1H, J = 6.63 Hz), 7.29-7.34 (m, 4H), 7.79 (d, 1H, J = 2.75 Hz),
9.08 (s, 1H) I.46 ##STR00378## 1-[4-(4- Hydroxyphenyl)-
piperazin-1-yl]-3- naphthalen-l-yl- propan-l-one 2.80-2.83 (m, 4H),
2.90 (t, 2H, J = 4.82 Hz), 3.36 (t, 2H, J = 7.77 Hz), 3.51-3.64 (m,
4H), 6.70 (d, 2H, J = 8.82 Hz), 6.81 (d, 2H, J = 8.86 Hz),
7.46-7.50 (m, 2H), 7.57 (t, 1H, J = 7.36 Hz), 7.62 (t, 1H, J = 7.45
Hz), 7.82-7.84 (m, 1H), 7.98 (d, 1H, J = 7.95 Hz), 8.12 (d, 1H, J =
8.35 Hz), 8.96 (s, 1H) I.47 ##STR00379## 3-[4-(4-
Hydroxyphenyl)pip- erazine-1- carbonyl]-1H- quinolin-4-one
2.98-3.08 (m, 4H), 3.44-3.48 (br s, 2H), 3.76-3.82 (br s, 2H), 6.71
(d, J = 8.85 Hz, 2H), 6.86 (d, J = 8.45 Hz, 2H), 7.42-7.45 (m, 1H),
7.66 (d, J = 8.20 Hz, 1H), 7.73-7.77 (m, 1H), 8.20-8.21 (m, 2H),
8.13 (s, 1H), 12.29 (d, J = 6.10 Hz, 1H). I.48 ##STR00380##
1-[4-(5-Hydroxy-2- pyridyl)piperazin-1- yl]-2,2-diphenyl- ethanone
3.03-3.08 (m, 2H), 3.28-3.32 (m, 2H), 3.62-3.70 (m, 4H), 5.64 (s,
1H), 6.75 (d, J = 8.85 Hz, 1H), 7.10 (dd, J.sub.1 = 2.72 Hz,
J.sub.2 = 8.95 Hz, 1H), 7.26-7.38 (m, 10H), 7.76 (d, J = 2.70 Hz,
1H), H 9.10 (s, 1H). I.49 ##STR00381## 1-[4-(4- Hydroxyphenyl)pip-
erazin-1-yl]-2-(2- phenoxyphenyl) ethanone 2.69 (m, 1H), 2.85-2.90
(m, 3H), 3.58-3.62 (m, 4H), 3.76 (s, 2H), 6.69 (d, J = 8.83 Hz,
2H), 6.80 (d, J = 8.87 Hz, 2H), 6.89 (d, J = 7.58 Hz, 1H), 6.98 (d,
J = 7.77 Hz, 2H), 7.13-7.19 (m, 2H), 7.29-7.32 (m, 1H), 7.36-7.41
(m, 3H), 8.93 (s, 1H). I.50 ##STR00382## [4-(4- Hydroxyphenyl)pip-
erazin-1-yl]-[2-(1- piperidyl)-4- pyridyl]methanone 1.50-1.60 (m,
4H), 1.63-1.68 (m, 2H), 2.95-3.00 (m, 2H), 3.05-3.10 (m, 2H),
3.40-3.45 (m, 2H), 3.58- 3.60 (m, 4H), 3.75-3.80 (m, 2H), 6.58-6.60
(m, 1H), 6.71 (d, J = 7.58 Hz, 2H), 6.80 (s, 1H), 6.86 (d, J = 8.90
Hz, 2H), 8.19 (d, J = 4.97 Hz, 1H), 8.95 (s, 1H). I.51 ##STR00383##
1-[4-(5- Hydroxypyridin-2- yl)-piperazin-1-yl]- 3-(1H-indol-3-yl)-
propan-l-one 2.76 (t, 2H, J = 7.74 Hz), 2.94- 3.00 (m, 2H),
3.22-3.29 (m, 4H), 3.55 (t, 2H, J = 4.88 Hz), 3.61 (t, 2H, J = 4.97
Hz), 6.77 (d, 1H, J = 9.00 Hz), 7.02 (t, 1H, J = 7.04 Hz),
7.09-07.13 (m, 2H), 7.20 (d, 1H, J = 2.06 Hz), 7.37 (d, 1H, J =
8.04 Hz), 7.57 (d, 1H, J = 7.81 Hz), 7.79 (d, 1H, J = 2.89 Hz),
9.10 (s, 1H), 10.84 (s, 1H) I.52 ##STR00384## 1-[4-(4-Hydroxy-3-
methyl-phenyl)- piperazin-1-yl]-2- phenylethanone 2.12 (s, 3H),
2.87-2.92 (m, 4H), 3.64 (m, 4H), 3.80 (s, 2H), 6.62 (d, 1H, J =
8.29 Hz), 6.68 (d, 1H, J = 8.52 Hz), 6.74 (s, 1H), 7.28-7.30 (m,
3H), 7.35-7.37 (m, 2H), 8.78 (s, 1H) I.53 ##STR00385##
3-Anthracen-9-yl-1- [4-(4- hydroxyphenyl)- piperazin-l-yl]-
propan-l-one 2.65 (t, 2H, J = 4.80 Hz), 2.81- 2.86 (m, 4H), 3.37
(t, 2H, J = 4.89 Hz), 3.63 (t, 2H, J = 5.03 Hz), 3.92 (t, 2H, J =
7.93 Hz), 6.68 (d, 2H, J = 8.95 Hz), 6.77 (d, 2H, J = 9.00 Hz),
7.55-7.58 (m, 2H), 7.61- 7.64 (m, 2H), 8.14 (d, 2H, J = 8.28 Hz),
8.35 (d, 2H, J = 8.87 Hz), 8.56 (s, 1H), 8.94 (s, 1H) I.54
##STR00386## 3-[4-(5-Hydroxy-2- pyridyl)piperazine- 1-carbonyl1-1H-
quinolin-4-one 3.35-3.44 (m, 6H), 3.74-3.78 (br s, 2H), 6.82 (d, J
= 9.00 Hz, 1H), 7.15 (dd, J.sub.1 = 2.85 Hz, J.sub.2 = 8.95 Hz,
1H), 7.44 (t, J = 7.50 Hz, 1H), 7.67 (d, J = 8.20 Hz, 1H), H
7.73-7.77 (m, 1H), 7.80 (d, J = 2.80 Hz, 1H), 8.20-8.22 (m, 2H),
9.15 (s, 1H), 12.32 (d, J = 6.05 Hz, 1H). I.55 ##STR00387##
2-(1-Adamantyl)-1- [4-(5-hydroxy-2- pyridyl)piperazin-1-
yl]ethanone 1.63-1.71 (m, 12H), 1.96 (s, 3H), 2.19 (s, 2H),
3.28-3.31 (m, 2H), 3.33-3.36 (m, 2H), 3.61-3.67 (m, 4H), 6.80 (d, J
= 8.95 Hz, 1H), 7.13 (dd, J.sub.1 = 2.97 Hz, J.sub.2 = 9.00 Hz,
1H), 7.80 (d, J = 2.85 Hz, 1H), 9.11 (s, 1H). I.56 ##STR00388##
2-(3-Hydroxy-1- adamantyl)-1-[4-(5- hydroxy-2- pyridyl)piperazin-1-
yl]ethanone 1.48-1.62 (m, 12H), 2.09-2.15 (bs, 2H), 2.24 (s, 2H),
3.27-3.33 (m, 2H), 3.59-3.68 (m, 4H), 4.41 (s, 1H), 6.80 (d, J =
8.99 Hz, 1H), 7.10 (dd, J.sub.1 = 8.98 Hz, J.sub.2 = 2.99 Hz, 1H),
7.80 (d, J = 2.90 Hz, 1H), 9.11 (s, 1H). I.57 ##STR00389## 2-(1-
Adamantylmethyl amino)-1-[4-(5- hydroxy-2- pyridyl)piperazin-1-
yl]ethanone 1.39 (m, 1H), 1.54 (m, 6H), 1.65 (d, J = 11.68 Hz, 3H),
1.72 (d, J = 11.96 Hz, 3H), 1.96-1.98 (m, 3H), 2.23 (m, 2H),
3.32-3.33 (m, 2H), 3.45 (m, 2H), 3.55-3.60 (m, 6H), 6.80 (d, J =
8.92 Hz, 1H), 7.13 (dd, J.sub.1 = 8.92 Hz, J.sub.2 = 2.90 Hz, 1H),
7.79 (d, J = 2.75 Hz, 1H), 9.10 (s, 1H). I.58 ##STR00390##
2,2-bis(4- Chlorophenyl)-1-[4- (5-hydroxy-2- pyridyl)piperazine-
yl]ethanone 3.07-3.13 (m, 2H), 3.28-3.34 (m, 2H), 3.60-3.64 (m,
2H), 3.65-3.70 (m, 2H), 5.73 (s, 1H), 6.76 (d, J = 9 Hz, 1H), 7.10
(dd, J.sub.1 = 8.97 Hz, J.sub.2 = 2.96 Hz, 1H), 7.30-7.35 (m, 4H),
7.42-7.47 (m, 4H), 7.77 (d, J = 2.88 Hz, 1H), 9.09 (s, 1H). I.59
##STR00391## 1- (Cyclopropylmethyl)- 3-[4-(5-hydroxy- 2-
pyridyl)piperazine- 1- carbonyl]iquinolin- 4-one 0.50-0.51 (m, 2H),
0.58-0.60 (m, 2H), 1.30-1.60 (m, 1H), 3.30-3.40 (m, 2H), 3.41-3.55
(m, 4H), 3.70- 3.90 (m, 2H), 4.27 (d, J = 7.08 Hz, 2H), 6.80 (d, J
= 8.99 Hz, 1H), 7.14 (dd, J.sub.1 = 2.94 Hz, J.sub.2 = 8.96 Hz,
1H), 7.51-7.54 (m, 1H), 7.78-7.82 (m, 1H), 7.83-7.89 (m, 1H), 7.96-
8.01 (m, 1H), 8.29-8.34 (m, 1H), 8.36 (s, 1H), 9.10 (s, 1H). I.60
##STR00392## 2-Fluoren-9- ylidene-1-[4-(5- hydroxy-2-
pyridyl)piperazin-1- yl]ethanone 9.11 (s, 1H), 7.99-8.05 (m, 1H),
7.88-7.94 (m, 2H), 7.78 -7.84 (m, 2H), 7.32-7.53 (m, 5H), 7.11-7.16
(m, 1H), 6.75-6.85 (m, 1H), 3.85- 3.90 (m, 2H), 3.64-3.70 (m, 2H),
3.45-3.55 (m, 2H), 3.27-3.35 (m, 2H). I.61 ##STR00393##
2-(9H-Fluoren-9- yl)-1-[4-(5- hydroxy-2- pyridyl)piperazin-1-
yl]ethanone 9.10 (s, 1H), 7.90-7.95 (m, 2H), 7.78-7.82 (m, 1H),
7.65-7.69 (m, 2H), 7.40-7.46 (m, 2H), 7.32-7.38 (m, 2H), 7.11-7.16
(m, 1H), 6.57- 6.58 (m, 1H), 4.51 (t, J = 6.96 HZ, 1H), 3.75-3.85
(m, 2H), 3.40-3.60 (m, 4H), 3.25-3.35 (m, 2H), 2.90 (d, J = 7.06
Hz, 2H). I.62 ##STR00394## 1-[4-(5- Hydroxypyridin-2-
yl)-piperazin-1-yl]- 2-(1H-indol-3-yl)- ethanone 3.20 (t, 2H, J =
4.94 Hz), 3.27 (t, 2H, J = 5.12 Hz), 3.62 (t, 2H, J = 5.05 Hz),
3.66 (t, 2H, J = 4.93 Hz), 3.86 (s, 2H), 6.76 (d, 1H, J = 8.90 Hz),
7.00-7.03 (m, 1H), 7.09- 7.13 (m, 2H), 7.27 (d, 1H, J = 2.27 Hz),
7.38 (d, 1H, J = 8.08 Hz), 7.62 (d, 1H, J = 7.90 Hz), 7.77 (d, 1H,
J = 2.84 Hz), 9.08 (s, 1H), 10.95 (s, 1H) I.63 ##STR00395## [4-(5-
Hydroxypyridin-2- yl)-piperazin-1-yl]- (1H-pyrrolo[2,3-
b]pyridin-3-yl)- methanone 3.43 (t, 4H, J = 4.83 Hz), 3.80 (t, 4H,
J = 5.05 Hz), 6.81 (d, 1H, J = 8.99 Hz), 7.14 (dd, 1H, J.sub.1 =
8.95 Hz, J.sub.2 = 2.98 Hz), 7.22 (dd, 1H, J.sub.1 = 7.91 Hz,
J.sub.2 = 4.64 Hz), 7.81 (d, 1H, J = 2.90 Hz), 7.93 (s, 1H), 8.16
(dd, 1H, J.sub.1 = 7.91 Hz, J.sub.2 = 1.48 Hz), 8.34 (dd, 1H,
J.sub.1 = 4.62 Hz, J.sub.2 = 1.47 Hz), 9.11 (s, 1H), 12.25 (s, 1H)
I.64 ##STR00396## Anthracen-9-yl[4- (5-hydroxypyridin-
2-yl)-piperazin-1- yl]-methanone 3.09-3.13 (m, 4H), 3.65 (t, 2H, J
= 5.02 Hz), 4.12 (t, 2H, J = 5.06 Hz), 6.77 (d, 1H, J = 9.01 Hz),
7.12 (dd, 1H, J.sub.1 = 8.98 Hz, J.sub.2 = 2.95 Hz), 7.61-7.66 (m,
4H), 7.77 (d, 1H, J = 2.87 Hz), 7.94 (d, 2H, J = 8.09 Hz), 8.22 (d,
2H, J = 7.43 Hz), 8.75 (s, 1H), 9.12 (s, 1H) I.65 ##STR00397##
1-[4-(5- Hydroxypyridin-2- yl)-piperazin-1-yl]- 4-phenylbutan-1-
-one 1.83-1.89 (m, 2H), 2.41 (t, 2H, J = 7.39 Hz), 2.65 (t, 2H, J =
7.70 Hz), 3.30 (t, 2H, J = 4.96 Hz), 3.35 (t, 2H, J = 5.07 Hz),
3.55 (t, 2H, J = 5.21 Hz), 3.60 (t, 2H, J = 4.94 Hz), 6.80 (d, 1H,
J = 8.98 Hz), 7.12 (dd, 1H, J.sub.1 = 8.93 Hz, J.sub.2 = 2.98 Hz),
7.21- 7.26 (m, 3H), 7.33 (t, 2H, J = 7.50 Hz), 7.79 (d, 1H, J =
2.91 Hz), 9.10 (s, 1H) I.66 ##STR00398## 1-[4-(5- Hydroxypyridin-2-
yl)-piperazin-1-yl]- 3-pyridin-4-yl- propan-l-one 2.78 (t, 2H, J =
7.5 Hz), 2.89 (t, 2H, J = 7.5 Hz), 3.30 (t, 2H, J = 4.9 Hz), 3.33
(t, 2H, J = 4.75 Hz), 3.57- 3.61 (m, 4H), 6.79 (d, 1H, J = 8.9 Hz),
7.12 (dd, 1H, J.sub.1 = 8.93 Hz, J.sub.2 = 2.86 Hz), 7.34 (d, 2H, J
= 5.39 Hz), 7.79 (d, 1H, J = 2.84 Hz), 8.49 (d, 2H, J = 5.48 Hz),
9.1 (s, 1H) I.67 ##STR00399## [4-(5- Hydroxypyridin-2-
yl)-piperazin-1-yl]- indan-2-yl- methanone 3.18 (d, 4H, J = 8.32
Hz), 3.34 (t, 2H, J = 5.00 Hz), 3.42 (t, 2H, J = 4.98 Hz), 3.65 (t,
2H, J = 5.00 Hz), 3.69-3.78 (m, 3H), 6.83 (d, 1H, J = 8.96 Hz),
7.13-7.20 (m, 3H), 7.23-7.26 (m, 2H), 7.81 (d, 1H, J = 2.92 Hz),
9.16 (s, 1H) I.68 ##STR00400## 1-[4-(5- Hydroxypyridin-2-
yl)-piperazin-1-yl]- 5-phenylpentan-1- one hydrochloride 1.55-1.60
(m, 2H), 1.62-1.68 (m, 2H), 2.43 (t, 2H, J = 7.3 Hz), 2.65 (t, 2H,
J = 7.4 Hz), 3.65 (m, 8H), 7.20-7.28 (m, 3H), 7.31-7.34 (m, 3H),
7.65 (m, 2H), 10.20 (br-s, 1H) I.69 ##STR00401## 3-[4-(5-Hydroxy-2-
pyridyl)piperazine- 1-carbonyl]-1- methylquinolin-4- one 3.35-3.39
br s, 2H), 3.41-3.45 (br s, 4H), 3.76-3.79 (br s, 2H), 3.95 (s,
3H), 6.82 (d, J = 5.00 Hz, 1H), 7.16 (dd, J.sub.1 = 2.45 Hz,
J.sub.2 = 8.87 Hz, 1H), 7.53 (t, J = 7.40 Hz, 1H), 7.77-7.81 (m,
2H), 7.85-7.89 (m, 1H), 8.30 (dd, J.sub.1 = 1.15 Hz, J.sub.2 = 8.00
Hz 1H), 8.35 (s, 1H), 9.15 (s, 1H). I.70 ##STR00402##
5-[4-(5-hHydroxy- 2-pyridyl)piperazin- 1-yl-5-oxo- pentanoic acid
12.10 (bs, 1H), 9.10 (bs, 1H), 7.80 (d, J = 2.92 Hz, 1H), 7.13 (dd,
J.sub.1 = 5.90 Hz, J.sub.2 = 2.98 Hz, 1H), 6.80 (d, J = 8.99 Hz,
1H), 3.55-3.65 (m, 4H), 3.25-3.45 (m, 4H), 2.42 (t, J = 7.42 Hz,
2H), 2.31 (m, 2H), 1.77 (m, 2H). I.71 ##STR00403## [4-(5-
Hydroxypyridin-2- yl)-piperazin-1-yl]- (1-methyl-1H- indol-3-yl)-
methanone 3.42 (t, 4H, J = 5.09 Hz), 3.78 (t, 4H, J = 5.11 Hz),
3.89 (s, 3H), 6.82 (d, 1H, J = 8.98 Hz), 7.14 (dd, 1H, J.sub.1 =
8.96 Hz, J.sub.2 = 3.00 Hz), 7.19- 7.22 (m, 1H), 7.27-7.30 (m, 1H),
7.55 (d, 1H, J = 8.22 Hz), 7.78 (d, 1H, J = 7.91 Hz), 7.81 (d, 1H,
J = 2.9 Hz), 7.82 (s, 1H), 9.10 (s, 1H) I-72 ##STR00404## 1-[4-(5-
Hydroxypyridin-2- yl)-piperazin-1-yl]- 3-(3- trifluoromethyl-
phenyl)-propan-1- one 2.78 (t, 2H, J = 7.65 Hz), 2.98 (t, 2H, J =
7.61 Hz), 3.28-3.31 (m, 4H), 3.56-3.61 (m, 4H), 6.78 (d, 1H, J =
8.99 Hz), 7.12 (dd, 1H, J.sub.1 = 8.96 Hz, J2 = 2.99 Hz), 7.54-7.59
(m, 2H), 7.63 (d, 1H, J = 7.10 Hz), 7.68 (s, 1H), 7.79 (d, 1H, J =
2.90 Hz), 9.09 (s, 1H) I-73 ##STR00405## 3-[4-(5-Hydroxy-2-
pyridyl)piperazine- 1- carbonyl]chromen- 2-one 3.34-3.38 (m, 2H),
3.44-3.47 (m, 2H), 3.53-3.56 (m, 2H), 3.75-3.77 (m, 2H), 6.82 (d, J
= 9.00 Hz, 1H), 7.14 (dd, J.sub.1 = 3.00 Hz, J.sub.2 = 9.00 Hz,
1H), 7.45-7.48 (m, 1H), 7.52 (d, J = 8.25 Hz, 1H), 7.74 (td,
J.sub.1 = 1.55 Hz, J.sub.2 = 7.86 Hz, 1H), 7.80 (d, J = 2.90 Hz,
1H), 7.83 (dd, J.sub.1 = 1.55 Hz, J.sub.2 = 7.86 Hz, 1H), 8.29 (s,
1H), 9.13 (s, 1H). I.74 ##STR00406## 1-[4-(5-Hydroxy-2-
pyridyl)piperazin-1- yl]-3,3-diphenyl- prop-2-en-1-one 2.91-2.93
(m, 2H), 3.15-3.17 (m, 2H), 3.40-3.42 (m, 2H), 3.49-3.51 (m, 2H),
6.56 (s, 1H), 6.70 (d, J = 9.05 Hz, 1H), 7.11 (dd, J.sub.1 = 3.00
Hz, J.sub.2 = 8.95 Hz, 1H), 7.22-7.24 (m, 2H), 7.35-7.39 (m, 3H),
7.41- 7.46 (m, 5H), 7.76 (d, J = 2.85 Hz, 1H), 9.07 (s, 1H). I.75
##STR00407## 1-[4-(5-Hydroxy-2- pyridyppiperazin-1-
yl]-3,3-diphenyl- propan-1-one 3.18-3.20 (m, 3H), 3.22-3.24 (m,
3H), 3.50-3.52 (m, 2H), 3.62-3.65 (m, 2H), 4.56 (t, J = 7.45 Hz,
1H), 6.76 (d, J = 9.00 Hz, 1H), 7.12 (dd, J.sub.1 = 2.95 Hz,
J.sub.2 = 9.00 Hz, 1H), 7.17-7.20 (m, 2H), 7.30 (t, J = 7.62 Hz,
4H), 7.37-7.39 (m, 4H), 7.79 (d, J = 2.90 Hz, 1H), 9.08 (s, 1H).
I.76 ##STR00408## (5-Chlorothiophen- 2-yl)-[4-(5-
hydroxy-pyridin-2- yl)-piperazin-l-yl]- methanone 3.44 (t, 4H, J =
5.22 Hz), 3.79 (m, 4H), 6.81 (d, 1H, J = 8.86 Hz), 7.15 (dd, 1H,
J.sub.1 = 8.95 Hz, J.sub.2 = 3.00 Hz), 7.23 (d, 1H, J = 3.99 Hz),
7.42 (d, 1H, J = 3.99 Hz), 7.80 (s, 1H), 7.81 (s, 1H), 9.11 (s, 1H)
I.77 ##STR00409## (E)-1-[4-(5- Hydroxypyridin-2-
yl)-piperazin-l-yl]- 3-(4-nitrophenyl)- propenone 3.36 (m, 4H),
3.69 (m, 2H), 3.83 (m, 2H), 6.78 (d, 1H, J = 8.94 Hz), 7.09 (dd,
1H, J.sub.1 = 8.93 Hz, J.sub.2 = 2.99 Hz), 7.55 (d, 1H, J = 15.48
Hz), 7.60 (d, 1H, J = 15.47 Hz), 7.75 (d, 1H, J = 2.7 Hz), 8.03 (d,
2H, J = 8.85 Hz), 8.25 (d, 2H, J = 8.84 Hz), 9.05 (s, 1H) I.78
##STR00410## (E)-3-(4- Chlorophenyl)-1-[4- (5-hydroxypyridin-
2-yl)-piperazin-1- yl]-propenone 3.39 (m, 4H), 3.72 (m, 2H), 3.86
(m,
2H), 6.83 (d, 1H, J = 8.99 Hz), 7.14 (dd, 1H, J.sub.1 = 8.96 Hz,
J.sub.2 = 2.99 Hz), 7.40 (d, 1H, J = 15.40 Hz), 7.52 (d, 2H, J =
8.52 Hz), 7.56 (d, 1H, J = 15.5 Hz), 7.82 (d, 1H, J = 2.9 Hz), 7.84
(d, 2H, J = 8.49 Hz), 9.10 (s, 1H) I.79 ##STR00411## 3-(3,4-
Dichlorophenyl)-1- [4-(5- hydroxypyridin-2- yl)-piperazin-l-yl]-
propan-l-one 2.74 (t, 2H, J = 7.76 Hz), 2.88 (t, 2H, J = 7.42 Hz),
3.28-3.34 (m, 4H), 3.56-3.59 (m, 4H), 6.79 (d, 1H, J = 8.99 Hz),
7.12 (dd, 1H, J.sub.1 = 8.95 Hz, J.sub.2 = 2.96 Hz), 7.31 (d, 1H, J
= 7.53 Hz), 7.57 (d, 1H, J = 8.23 Hz), 7.61 (d, 1H, J = 1.9 Hz),
7.79 (d, 1H, J = 2.74 Hz), 9.09 (s, 1H) I.80 ##STR00412##
(2-Chloro-6- methylphenyl)-[4- (5-hydroxypyridin-
2-yl)-piperazin-1- yl]-methanone 2.28 (s, 3H), 3.26-3.31 (m, 4H),
3.46 (m, 2H), 3.82 (m, 2H), 6.80 (d, 1H, J = 8.05 Hz), 7.14 (d, 1H,
J = 7.60 Hz), 7.34-7.40 (m, 3H), 7.80 (s, 1H), 9.13 (s, 1H) I.81
##STR00413## [4-(5- Hydroxypyridin-2- yl)-piperazin-1-yl]- [3-(4-
methylimidazol-1- yl)-5- trifluoromethylphen yl]-methanone 2.22 (s,
3H), 3.49 (m, 6H), 3.81 (m, 2H), 6.80-6.82 (d, 1H, J = 8.90 Hz),
7.13-7.15 (m 1H, J = 8.71 Hz), 7.75-7.76 (d, 2H J = 2.40 Hz), 7.80-
7.81 (d,1H, J= I.97 Hz), 8.08 (m, 1H), 8.17 (m, 1H), 8.44 (s, 1H),
9.12 (s,1H) I.82 ##STR00414## 3-(4-Chlorophenyl)- 1-[4-(5-hydroxy-
pyridin-2-yl)- piperazin-1-yl]- propan-l-one 2.71 (t, 2H, J = 7.64
Hz), 2.87 (t, 2H, J = 7.61 Hz), 3.28-3.34 (m, 4H), 3.56 (t, 2H, J =
5.01 Hz), 3.59 (t, 2H, J = 5.1 Hz), 6.79 (d, 1H, J = 8.83 Hz), 7.12
(dd, 1H, J.sub.1 = 8.96 Hz, J.sub.2 = 3.00 Hz), 7.31-7.34 (m, 2H),
7.36-7.38 (m, 2H), 7.79 (d, 1H, J = 2.55 Hz), 9.08 (s, 1H) I.83
##STR00415## 2-(1- Adamantylamino)- 1-[4-(5-hydroxy-2-
pyridyl)piperazin-1- yl]ethanone 1.28-1.35 (m, 6H), 1.39 (s, 1H),
1.62-1.76 (m, 3H), 1.76-1.84 (m, 3H), 2.08-2.15 (m, 2H), 3.29 (m,
2H), 3.42-3.44 (m, 2H), 3.53-3.55 (m, 4H), 3.71 (m, 2H), 6.78 (d, J
= 8.90 Hz, 1H), 7.12 (dd, J.sub.1 = 8.86 Hz, J.sub.2 = 2.90 Hz,
1H), 7.79 (d, J = 2.83 Hz, 1H), 9.09 (s, 1H). I.84 ##STR00416##
1-[4-(5-Hydroxy-2- pyridyl)piperazin-1- yl]-3,3-bis(4-
methoxyphenyl)prop- 2-en-1-one 2.92-2.97 (m, 2H), 3.18-3.22 (m,
2H), 3.5-3.38 (m, 2H), 3.49-3.53 (m, 2H), 3.77 (s, 3H), 3.83 (s,
3H), 6.34 (s, 1H), 6.71 (d, J = 8.95 Hz, 1H), 6.98-6.99 (m, 4H),
7.09 (dd, J.sub.1 = 2.80 Hz, J.sub.2 = 9.00 Hz, 1H), 7.14 (d, J =
8.45 Hz, 2H), 7.29 (d, J = 8.55 Hz, 2H),7.76 (d, J = 2.65 Hz, 1H),
9.08 (s, 1H). I.85 ##STR00417## [[4-(5- Hydroxypyridin-2-
yl)-piperazin-1-yl]- [4-methyl-3-(4- pyridin-3-yl- pyrimidin-2-
ylamino)phenyl] methanone 2.37 (s, 3H), 3.51-3.72 (m, 8H), 6.76 (d,
1H, J = 8.96 Hz), 7.12- 7.14 (m, 2H), 7.19 (d ,1H, J = 7.60 Hz),
7.37-7.59 (m, 2H), 7.75-7.80 (m, 2H), 8.46 (d, 1H , J= 7.88 Hz),
8.59 (d, 1H, J = 5.05 Hz), 8.74 (d, 1H, J = 3.99 Hz) 9.11 (s, 1H),
9.22 (s, 1H), 9.31 (s, 1H) I.86 ##STR00418## (1H- Benzoimidazol-2-
yl)-[4-(5- hydroxypyridin-2- yl)-piperazin-1-yl]- methanone 3.5 (m,
4H), 3.8 (t, 2H, J = 4.8 Hz), 4.6 (t, 2H, J = 4.5 Hz), 6.8 (d, 1H,
J = 8.9 Hz), 7.15 (dd, 1H, J.sub.1 = 8.92 Hz, J.sub.2 = 2.79 Hz),
7.35 (m, 2H), 7.59 (s, 1H), 7.8 (m, 2H), 9.11 (s, 1H), 13.21 (s,
1H) I.87 ##STR00419## (5-Bromothiophen- 2-yl)-[4-(5-
hydroxypyridin-2- yl)-piperazin-1-yl]- methanone 3.38-3.39 (m, 4H),
3.73 (m, 4H), 6.76 (d, 1H, J = 8.96 Hz), 7.08 (dd, 1H, J.sub.1 =
8.92 Hz, J.sub.2 = 2.89 Hz), 7.3 (d, 1H, J = 3.89 Hz), 7.2 ( d, 1H,
J = 3.89 Hz), 7.75 (d, 1H, J = 2.83 Hz), 9.05 (s, 1H) I.88
##STR00420## [(5-Fluoro-1H- indol-2-yl)44-(5- hydroxypyridin-2-
yl)-piperazin-1-yl]- methanone 3.45-3.47 (m, 4H), 3.90 (m, 4H),
6.83 (d, 1H, J = 8.93 Hz), 6.88 (s, 1H), 7.16-7.10 (m, 2H),
7.42-7.44 (m, 1H), 7.46-7.49 (m, 1H), 7.81 (d, 1H, J = 2.88 Hz),
9.12 (s, 1H) I.89 ##STR00421## Quinoline-8- sulfonic acid {2-[4-
(5-hydroxypyridin- 2-yl)-piperazin-1- yl]-2-oxo-ethyl}- methylamide
2.90 (s, 3H), 3.32-3.34 (m, 2H), 3.45 (t, 2H, J = 5.35 Hz),
3.51-3.52 (m, 2H), 3.63 (m, 2H), 4.5 (s, 2H), 6.82 (d, 1H, J = 8.9
Hz), 7.15 (dd, 1H, J.sub.1 = 8.96 Hz, J.sub.2 = 3 .0 Hz), 7.73-
7.75 (m, 1H), 7.81-7.82 (m, 2H), 8.36 (dd, 1H, J.sub.1 = 8.23 Hz,
J.sub.2 = 1.34 Hz), 8.45 (dd, 1H, J.sub.1 = 7.34 Hz, J.sub.2 = 1.41
Hz), 8.58 (dd, 1H, J 1= 8.4 Hz, J.sub.2 = 1.75 Hz), 9.10 (s, 1H),
9.14 (dd, 1H, J.sub.1 = 4.18 Hz, J.sub.2 = 1.78 Hz) I.90
##STR00422## 1-[4-(5- Hydroxypyridin-2- yl)-piperazin-1-yl]- 3-(4-
isobutylphenyl)- propan-l-one 0.82 (m, 6H), 1.27 (d, 3H, J = 6.72
Hz) 1.78 (m, 1H), 2.38 (m, 2H), 2.60 (m, 1H), 3.00 (m, 1H) 3.22 (m,
1H), 3.43 (m, 2H), 3.49-3.50 (m, 1H), 3.69-3.70 (m, 1H), 4.08- 4.09
(m, 1H), 6.64 (d, 1H, J = 8.98 Hz), 7.02 (dd, 1H, J.sub.1 = 8.93
Hz, J.sub.2 = 2.74 Hz), 7.08 (d, 2H, J = 7.83 Hz), 7.16 (d, 2H, J =
7.83 Hz), 7.69 (d, 1H, J = 2.81 Hz), 9.0 (s, 1H) I.91 ##STR00423##
2-(2,4- Difluorophenyl)-1- [4-(5- hydroxypyridine-2-
yl)-piperazin-1-yl]- ethanone 3.33 (t, 2H, J = 4.77 Hz), 3.40- 3.41
(m, 2H), 3.62 (t, 2H, J = 4.78 Hz), 3.68-3.69 (m, 2H), 3.82 (s,
2H), 6.82 (d, 1H, J = 8.98 Hz), 7.06- 7.10 (m, 1H), 7.13 (dd, 1H,
J.sub.1 = 8.90 Hz, J.sub.2 = 2.86 Hz), 7.21-7.24 (m, 1H), 7.37 (q,
1H, J.sub.1 = 15.53 Hz, J.sub.2 = 8.40 Hz), 7.81 (d, 1H, J = 2.84
Hz), 9.10 (s, 1H) I.92 ##STR00424## 3-(3-Fluorophenyl)- 1-[4-(5-
hydroxypyridin-2- yl)-piperazin-1-yl]- propan-l-one 2.74 (t, 2H, J
= 7.7 Hz), 2.90 (t, 2H, J = 7.7 Hz), 3.30 (m, 4H), 3.59 (m, 4H),
6.79 (d, 1H, J = 8.98 Hz), 7.05 (t, 1H, J = 7.54 Hz), 7.14 (m, 3H),
7.36 (q, 1H, J.sub.1 = 14.54 Hz, J.sub.2 = 7.52 Hz), 7.8 (d, 1H, J
= 2.84 Hz), 9.09 (s, 1H) I.93 ##STR00425## 1-[4-(5-Hydroxy-2-
pyridyl)piperazin-1- yl]-3,3-bis(4- methoxyphenyl) propan-1-one
3.12 (br d, J = 7.45 Hz, 2H), 3.20 (br s, 4H), 3.50-3.53 (m, 2H),
3.60- 3.63 (m, 2H), 3.72 (s, 6H), 4.44 (t, J = 7.37 Hz, 1H), 6.76
(d, J = 9.00 Hz, 1H), 6.86 (d, J = 8.30 Hz, 4H), 7.12 (dd, J.sub.1
= 2.55 Hz, J.sub.2 = 8.92 Hz, 1H), 7.25 (d, J = 8.35 Hz, 4H), 7.79
(d, J = 2.45 Hz, 1H), 9.09 (s, 1H). I.94 ##STR00426##
1-[4-(5-Hydroxy-2- pyridyl)piperazin-1- yl]-4,4-diphenyl-
but-3-en-1-one 2.27-2.37 (m, 4H), 3.23-3.32 (m, 4H), 3.57-3.62 (m,
2H), 4.20 (t, J = 7.20 Hz, 1H), 6.78 (d, J = 9.00 Hz, 1H),
7.13-7.16 (m, 1H), 7.20-7.24 (m, 2H), 7.32-7.38 (m, 8H), 7.73 (d, J
= 2.60 Hz, 1H), 9.09 (s, 1H). I.95 ##STR00427## 2-Cyclohexyl-2-
hydroxy-1-[4-(5- hydroxy-2- pyridyl)piperazin-l- yl]-2-phenyl-
ethanone 0.9-1.3 (m, 6H), 1.58-1.64 (m, 2H), 1.70-1.80 (m, 1H),
1.90-2.00 (m, 1H), 2.20-2.30 (m, 1H), 2.90-3.20 (m, 2H), 3.40-3.60
(m, 4H), 3.70- 3.90 (m, 2H), 5.85 (s, 1H), 6.65 (d, J = 2.90 Hz,
1H), 7.04-7.08 (m, 1H), 7.24-7.29 (m, 1H), 7.36- 7.41 (m, 4H), 7.72
(d, J = 2.80 Hz, 1H), 9.04 (s, 1H). I.96 ##STR00428## 2-[1-
Adamantylmethyl( methyl)amino]-1- [4-(5-hydroxy-2-
pyridyl)piperazin-1- yl]ethanone 1.40-1.58 (m, 6H), 1.55-1.67 (m,
3H), 1.67-1.80-2.10 (m, 3H), 2.10- 2.25 (m, 2H), 2.36 (s, 3H),
3.25- 3.44 (m, 6H), 3.52-3.62 (m, 2H), 3.63 = 3.80 (m, 2H), 6.81
(d, J = 8.96 Hz, 1H), 7.13 (dd, J.sub.1 = 8.87 Hz, J.sub.2 = 2.58
Hz, 1H), 7.79 (d, J = 2.67 Hz, 1H), 9.10 (s, 1H). I.97 ##STR00429##
1-[4-(5- Hydroxypyridin-2- yl)-piperazin-1-yl]-
2-(5-nitropyridin-2- ylsulfanyl)- ethanone 3.34-3.36 (m, 2H),
3.45-3.47 (m, 2H), 3.62-3.64 (m, 2H), 3.75-3.78 (m, 2H), 4.44 (s,
2H), 6.83 (d, 1H, J = 8.97 Hz), 7.14 (dd, 1H, J.sub.1 = 8.95 Hz,
J.sub.2 = 3.00 Hz), 7.69 (dd, 1H, J.sub.1 = 8.94 Hz, J2 = 0.49 Hz),
7.81 (d, 1H, J = 2.79 Hz), 8.45 (dd, 1H, J.sub.1 = 8.93 Hz, J.sub.2
= 2.72 Hz), 9.12 (s, 1H), 9.24 (dd, 1H, J.sub.1 = 2.68 Hz, J.sub.2
= 0.5 Hz) I.98 ##STR00430## 3-(1-Adamantyl)-1- [4-(5-hydroxy-2-
pyridyl)piperazin-1- yl]propan-l-one 1.32-1.37 (m, 2H), 1.51 (s,
6H), 1.65 (d, J = 11.80 Hz, 3H), 1.72 (d, J = 11.80 Hz, 3H), 1.98
(s, 3H), 2.30-2.34 (m, 2H), 3.28-3.32 (m, 2H), 3.35-3.37 (m, 2H),
3.57-3.60 (m, 4H), 6.80 (d, J = 8.95 Hz, 1H), 7.14 (dd, J.sub.1 =
2.25 Hz, J.sub.2 = 8.80 Hz, 1H), 7.80 (d, J = 2.15 Hz, 1H), 9.24
(s, 1H). I.99 ##STR00431## 2-Cyclohexyl-1-[4- (5-hydroxy-2-
pyridyl)piperazin-1- yl]-2-phenyl- ethanone 0.81-0.88 (m, 1H),
0.97-1.05 (m, 1H), 1.07-1.18 (m, 3H), 1.221I.31 (m, 1H), 1.62 (s,
2H), 1.70-1.72 (m, 1H), 1.82-1.84 (m, 1H), 2.02-2.09 (m, 1H),
2.89-2.94 (m, 1H), 3.12- 3.18 (m, 1H), 3.21-3.26 (m, 2H), 3.54-3.67
(m, 3H), 3.78 (d, J = 10.10 Hz, 1H), 3.80-3.86 (m, 1H), 6.73 (d, J
= 9.00 Hz, 1H), 7.10 (dd, J.sub.1 = 2.70 Hz, J.sub.2 = 8.90 Hz,
1H), 7.25 (t, J = 7.12 Hz, 1H), 7.34 (t, J = 7.52 Hz, 2H), 7.39 (d,
J = 7.70 Hz, 2H), 7.76 (d, J = 2.70 Hz, 1H), 1.09 (s, 1H). I.100
##STR00432## 3-(4- Hydroxyphenyl)-1- [4-(5- hydroxypyridin-2-
yl-piperazin-1-yl]- propan-l-one 2.63 (t, 2H, J = 7.35 Hz), 2.76
(t, 2H, J = 7.53 Hz), 3.29 (m 4H), 3.54- 3.59 (m, 4H), 6.70 (d, 2H,
J = 8.00 Hz), 6.78 (d, 1H, J = 8.97 Hz), 7.07 (d, 2H, J = 7.90 Hz),
7.13 (d, 1H, J = 8.90 Hz), 7.79 (s, 1H), 9.19 (s, 1H) I.101
##STR00433## 3-(4- Methoxyphenyl)-1- [4-(5- hydroxypyridin-2-
yl)-piperazin-1-yl]- propan-l-one hydrochloride 2.68 (t, 2H, J =
7.62 Hz), 2.81 (t, 2H, J = 7.58 Hz), 3.59 (m, 4H), 3.65 (m, 4H),
3.75 (s, 3H), 6.87 (d, 2H, J = 8.27 Hz), 7.19 (d, 2H, J = 8.3 Hz),
7.34 (d, 1H, J = 9.63 Hz), 7.63 (d, 1H, J = 2.38 Hz), 7.75 (d, 1H,
J = 8.95 Hz), 10.37 (s, 1H) I.102 ##STR00434## 3-(2-Bromophenyl)-
1-[4-(5- hydroxypyridin-2- yl)-piperazin-1-yl]- propan-1-one
2.70-2.72 (m, 2H), 2.99 (m, 2H), 3.31 (m, 4H), 3.58-3.61 (m, 4H),
6.79 (d, 1H, J = 8.28 Hz), 7.12 (d, 1H, J = 7.12 Hz), 7.20-7.22 (m,
1H), 7.37-7.56 (m, 2H), 7.64 (d, 1H, J = 7.68), 7.79 (s, 1H), 9.09
(s, 1H) I.103 ##STR00435## 3-(4-Bromophenyl)- 1-[4-(5-
hydroxypyridin-2- yl)-piperazin-l-yl]- propan-l-one 2.72 (m, 2H),
2.85 (m, 2H), 3.30 (m, 4H), 3.58 (m, 4H), 6.79 (d, 1H, J = 8.96
Hz), 7.12 (d, 1H, J = 6.88 Hz), 7.28 (d, 2H, J = 7.16 Hz), 7.50 (d,
2H, J = 7.60 Hz), 7.79 (s, 1H), 9.09 (s, 1H) I.104 ##STR00436##
3-[4-(5- Hydroxypyridin-2- yl)-piperazine-1- carbonyl]-7-oxa-
bicyclo[2.2.1]heptane- 2-carboxylic acid methyl ester 1.66 (s, 4H),
3.15 (br-s, 4H), 3.39 (s, 2H), 3.63 (s, 3H), 3.71 (br-s, 3H), 4.82
(s, 1H), 4.93 (s, 1H), 7.00 (d, 1H, J = 9.05 Hz), 7.41 (d, 1H, J =
8.05 Hz), 7.95 (s, 1H) I.105 ##STR00437## 3-[4-(5-
Hydroxypyridin-2- yl)-piperazine-1- carbonyl]-7-oxa-
bicyclo[2.2.1]heptane- 2-carboxylic acid 1.49-1.57 (m, 4H),
2.81-2.87 (m, 2H), 3.21 (m, 4H), 3.61-3.66 (m, 4H), 4.63 (d, 1H, J
= 11.11 Hz), 4.74 (d,1H, J = 11.85 Hz), 6.69- 6.79 (m, 1H), 7.12
(d, 1H, J = 8.02 Hz), 7.77 (s, 1H), 9.42 (br-s, 1H) I.106
##STR00438## 1-[4-(5- Hydroxypyridin-2- yl)-piperazin-l-yl]-
2-(1H-indol-3-yl)- ethane-1,2-dione 3.28 (d, 2H, J = 4.68 Hz),
3.70- 3.72 (m, 4H), 4.10 (d, 2H, J = 4.20 Hz), 6.75 (d, 1H, J =
8.98 Hz), 7.06- 7.09 (m, 1H), 7.24-7.30 (m, 2H), 7.53 (d, 1H, J =
7.80 Hz), 7.75 (d, 1H, J = 2.65 Hz), 8.13 (d, 1H, J = 7.30 Hz),
8.20 (s, 1H), 9.06 (s, 1H), 12.13 (s, 1H) I.107 ##STR00439##
1-[4-(5- Hydroxypyridin-2- yl)-piperazin-1-yl]- 3-o-tolyl-propan-1-
one 2.28 (s, 3H), 2.59 (t, 2H, J = 7.86 Hz) 2.80 (t, 2H, J = 7.81
Hz), 3.24 (m, 4H), 3.49-3.55 (m, 4H), 6.73 (d, 1H, J = 8.98 Hz),
7.05-7.13 (m, 4H), 7.16 (d, 1H, J= 7.21 Hz), 7.73 (d, 1H, J = 2.37
Hz), 9.03 (s, 1H) I.108 ##STR00440## 3-(4- Dimethylaminophenyl)-
1-[4-(5- hydroxypyridin-2- yl)-piperazin-1-yl]- propan-l-one 2.57
(t, 2H, J = 7.66 Hz), 2.70 (t, 2H, J = 7.63 Hz), 3.21-3.22 (m, 4H),
3.48-3.53 (m, 4H), 6.63 (d, 2H, J = 8.24 Hz), 6.71 (d, 1H, J = 8.97
Hz), 7.04 (d, 2H, J = 8.45 Hz), 7.07 (d, 1H, J = 2.63 Hz), 7.73 (d,
1H, J = 2.59 Hz), 9.02 (s, 1H) I.109 ##STR00441## 1-[4-(5-
Hydroxypyridin-2- yl)-piperazin-1-yl]- 3-(2- methoxyphenyl)-
propan-l-one 2.56 (t, 2H, J = 7.88 Hz), 2.77 (t, 2H, J = 7.82 Hz),
3.24 (m, 4H), 3.50- 3.54 (m, 4H), 3.79 (s, 3H), 6.73 (d, 1H, J =
8.98 Hz), 6.85 (t, 1H, J = 7.35 Hz), 6.94 (d, 1H, J = 8.06 Hz),
7.06 (dd, 1H, J.sub.1 = 8.89 Hz, J.sub.2 = 2.61 Hz), 7.15-7.19 (m,
2H), 7.73 (d, 1H, J = 2.55 Hz), 9.03 (s, 1H) I.110 ##STR00442##
1-[4-(5- Hydroxypyridin-2- yl)-piperazin-1-yl]- 3-p-tolyl-propan-1-
one 2.23 (s, 3H), 2.61 (t, 2H, J = 7.71 Hz), 2.77 (t, 2H, J = 7.68
Hz), 3.22- 3.23 (m, 4H), 3.49-3.54 (m, 4H), 6.72 (d, 1H, J = 8.98
Hz), 7.05- 7.07 (m, 3H), 7.12 (d, 2H, J = 7.77 Hz), 7.73 (d, 1H, J
= 2.76 Hz), 9.03 (s, 1H) I.111 ##STR00443## 2-[4-(5-
Hydroxypyridin-2- yl)-piperazine-1- carbonyl]benzoic acid 3.15-3.23
(m, 4H), 3.38 (m, 2H), 3.68 (m, 2H), 6.73 (d, 1H, J = 8.98 Hz) 7.07
(dd, 1H, J.sub.1 = 8.90 Hz, J.sub.2 = 2.66 Hz), 7.32 (d, 1H, J =
7.52 Hz), 7.53 (t, 1H, J = 7.60 Hz), 7.65 (t, 1H, J = 7.48 Hz),
7.73 (d, 1H, J = 2.66 Hz), 7.93 (d, 1H, J = 7.79 Hz), 9.05 (s, 1H)
I.112 ##STR00444## 1-[4-(5-Hydroxy-2- pyridyl)piperazin-1- yl]-4,4-
diphenylbutan-1- one 2.26-2.36 (m, 4H), 3.23-3.29 (m, 4H),
3.38-3.43 (m, 2H), 3.54-3.60 (m. 2H), 4.02 (t, J = 7.25 Hz, 1H),
6.77 (d, J= 9.00 Hz, 1H), 7.12 (dd, J.sub.1 = 2.70 Hz, J.sub.1 =
8.90 Hz, 1H), 7.21 (t, J = 6.70 Hz, 2H), 7.31-7.36 (m, 8H), 7.79
(d, J = 2.70 Hz, 1H), 9.08 (s, 1H). I.113 ##STR00445## [4-(5-
Hydroxypyridin-2- yl)-piperazin-1-yl]- [3(1H-indol-4-
yl)phenylimethanone 3.43-3.46 (m, 4H), 3.60 (m, 2H), 3.80 (m, 2H),
6.60 (s, 1H), 6.81 (d, 1H, J = 9.01 Hz), 7.13 (dd, 1H, J.sub.1 =
8.96 Hz, J.sub.2 = 2.98 Hz), 7.17 (d, 1H, J = 7.21 Hz), 7.25 (t,
1H, J = 7.66 Hz), 7.47-7.50 (m, 3H), 7.64 (t, 1H, J = 7.65 Hz),
7.72 (s, 1H), 7.80 (d, 1H, J = 2.96 Hz), 7.82 (d, 1H, J = 8.03 Hz),
9.12 (s, 1H), 11.37 (s, 1H) I.114 ##STR00446## 1-[4-(5-
Hydroxypyridin-2- yl)-piperazin-l-yl]- 3-[4-(2-
methoxyethoxy)phenyl]- propan-1-one dihydrochloride 2.63 (t, 2H, J
= 7.58 Hz), 2.76 (t, 2H, J = 7.55 Hz), 3.29 (s, 3H), 3.54- 3.60 (m,
4H), 3.61-3.63 (m, 6H), 4.02(t, 2H, J = 4.47 Hz), 6.84(d, 2H, J =
8.32 Hz), 7.15 (d, 2H, J = 8.32 Hz), 7.29 (d, 1H, J = 9.66 Hz),
7.59 (d, 1H, J = 2.44 Hz), 7.70 (d, 1H, J = 9.04 Hz), 10.36 (s, 1H)
I.115 ##STR00447## 1-[4-(5- Hydroxypyridin-2- yl)-piperazin-1-yl]-
3-phenylbutan-1- one dihydrochloride 1.27 (d, 3H, J = 6.88 Hz),
2.66-
2.76 (m, 2H), 3.22-3.29 (m, 1H), 3.43-3.49 (m, 2H), 3.57-3.70 (m,
6H), 7.20-7.23 (m, 1H), 7.30- 7.33 (m, 5H), 7.66 (s, 1H), 7.72 (d,
1H, J = 8.96 Hz), 10.35 (s, 1H) I.116 ##STR00448## 1-[4-(5-
Hydroxypyridin-2- yl)-piperazin-1-yl]- 3-thiophen-2-yl-
propan-1-one 2.70 (t, 2H, J = 6.99 Hz), 3.04 (t, 2H, J = 6.81 Hz),
3.25-3.27 (m, 4H), 3.25-3.27 (m, 4H), 6.74 (d, 1H, J = 8.78 Hz),
6.89-6.92 (m, 2H), 7.07 (d, 1H, J = 7.95 Hz), 7.29 (d, 1H, J = 4.33
Hz), 7.74 (s, 1H), 9.03 (s, 1H) I.117 ##STR00449##
1-[4-(5-Hydroxy-2- pyridyl)piperazin-1- yl]-2-morpholino-2-
phenylethanone 2.46-2.50 (m, 4H), 2.94-2.97 (m, 1H), 3.17-3.28 (m,
3H), 3.59-3.64 (m, 7H), 3.79-3.83 (m, 1H), 4.62 (s, 1H), 6.74 (d J
= 9.00 Hz, 1H), 7.10 (dd, J.sub.1 = 2.60 Hz, J.sub.2 = 8.95 Hz,
1H), 7.34 (t, J = 7.20 Hz, 1H), 7.40 (t, J = 7.40 Hz, 2H) 7.48 (d,
J = 7.50 Hz, 2H), 7.76 (d, J = 2.60 Hz, 1H), 9.09 (s, 1H). I.118
##STR00450## Cyclohexyl-[4-(5- hydroxy-2- pyridyppiperazin-1-
yl]methanone 1.07-1.237 (m, 1H), 1.25-1.45 (m, 4H), 1.63-1.70 (m,
3H), 1.70-1.75 (m, 2H), 2.58-2.62 (m, 1H), 3.23- 3.30 (m, 4H),
3.53-3.57 (m, 4H), 6.74 (d, J = 8.96 Hz, 1H), 7.07 (dd, J.sub.1 =
8.93 Hz, J.sub.2 = 2.82 Hz, 1H), 7.74 (d, J = 2.77 Hz, 1H), 9.04
(s, 1H). I.119 ##STR00451## Cyclopropyl-[4-(5- hydroxy-2-
pyridyl)ppiperazin-1- yl]methanone 0.69-0.76 (m, 4H), 2.00-2.03 (m,
1H), 3.25 (m, 2H), 3.35 (m, 2H), 3.55 (m, 2H), 3.76 (m, 2H), 6.75
(d, J = 8.95 Hz, 1H), 7.07 (dd, J.sub.1 = 8.92 Hz, J.sub.2 = 2.83
Hz, 1H), 7.74 (d, J = 2.71 Hz, 1H), 9.04 (s, 1H). I.120
##STR00452## (E)-3-Cyclohexyl- 1-[4-(5-hydroxy-2-
pyridyl)piperazin-1- yl]prop-2-en-1-one 1.14-1.27 (m, 3H),
1.29-1.38 (m, 2H), 1.67-1.72 (m, 1H), 1.74-1.78 (m, 4H), 2.17-2.26
(m, 1H), 3.34- 3.38 (m, 4H), 3.65-3.72 (m, 4H), 6.48 (dd, J.sub.1 =
1.20 Hz, J.sub.2 = 15.12 Hz, 1H), 6.71 (dd, J.sub.1 = 7.00 Hz,
J.sub.2 = 15.10 Hz, 1H), 6.80 (d, J = 8.95 Hz, 1H), 7.13 (dd,
J.sub.1 = 3.00 Hz, J.sub.2 = 8.95 Hz, 1H), 7.80 (d, J = 2.70 Hz,
1H), 9.09 (s, 1H) I.121 ##STR00453## 3-Cyclohexyl-1-[4-
(5-hydroxy-2- pyridyl)piperazin-l- yl]propan-l-one 0.88-0.95 (m,
2H), 1.13-1.29 (m, 4H), 1.45 (q, J = 7.48 Hz, 1H), 1.65-1.73 (m,
5H), 2.38 (t, J = 7.87 Hz, 2H), 3.28-3.30 (m, 2H), 3.35- 3.37 (m,
2H), 3.57-3.59 (m, 4H), 6.80 (d, J = 8.95 Hz, 1H), 7.13 (dd,
J.sub.1 = 3.00 Hz, J.sub.2 = 8.95 Hz, 1H), 7.80 (d, J = 2.75 Hz,
1H), 9.15 (s, 1H). I.122 ##STR00454## 3- Benzo[b]thiophen-
2-yl-1-[4-(5- hydroxypyridin-2- yl)-piperazin-1-yl]- propan-l-one
2.87 (t, 2H, J = 7.22 Hz), 3.20 (t, 2H, J = 7.12 Hz), 3.32-3.35 (m,
4H), 3.62-3.63 (m, 4H), 6.79 (d, 1H, J = 8.96 Hz), 7.11-7.13 (m,
1H), 7.26 (s, 1H), 7.32 (t, 1H, J = 7.40 Hz), 7.37 (t, 1H, J = 7.35
Hz), 7.77 (d, 1H, J = 9.89 Hz), 7.79 (d, 1H, J = 2.06 Hz), 7.91 (d,
1H, J = 7.83 Hz), 9.10 (s, 1H) I.123 ##STR00455## [4-(5-
Hydroxypyridin-2- yl)-piperazin-1-yl]- (5-phenylthiophen-
2-yl)-methanone 3.46-3.47 (m, 4H), 3.83 (m, 4H), 6.82 (d, 1H, J =
8.95 Hz), 7.14- 7.16 (m, 1H), 7.42 (t, 1H, J = 7.30 Hz), 7.49-7.53
(m, 3H), 7.58 (d, 1H, J = 3.62 Hz), 7.77 (d, 2H, J = 7.66 Hz), 7.83
(d, 1H, J = 2.29 Hz), 9.12 (s, 1H) I.124 ##STR00456## (3-Hydroxy-3-
phenylcyclobutyl)- [4-(5- hydroxypyridin-2- yl)-piperazin-1-yl]-
methanone 2.54-2.58 (m, 2H), 2.60-2.62 (m, 2H), 2.95-2.98 (m, 1H),
3.26 (t, 4H, J = 4.75 Hz), 3.56 (m, 2H), 3.57 (m, 2H), 5.61 (s,
1H), 6.73 (d, 1H, J = 8.98 Hz), 7.06-7.08 (m, 1H), 7.25 (t, 1H, J =
7.24 Hz), 7.36 (t, 2H, J = 7.52 Hz), 7.56 (d, 2H, J = 4.87 Hz),
7.74 (d, 1H, J = 2.69 Hz), 9.04 (s, 1H) I.125 ##STR00457## 1-[4-(5-
Hydroxypyridin-2- yl)-piperazin-1-yl]- 3-methyl-3-
phenylbutan-1-one 9.08 (s, 1H), 7.77 (d, 1H, J = 2.59 Hz), 7.43 (d,
2H, J = 7.94 Hz), 7.32 (t, 2H, J = 7.4 Hz), 7.19 (t, 1H, J = 7.21
Hz), 7.10 (dd, 1H, J.sub.1 = 8.9 Hz, J.sub.2 = 2.6 Hz), 6.73 (d,
1H, J = 8.9 Hz), 3.48 (m, 2H), 3.36 (m, 2H), 3.18 (m, 2H), 3.09 (m,
2H), 2.73 (m, 2H), 1.46 (s, 6H) I.126 ##STR00458##
3-(4-Fluorophenyl)- 1-[4-(5- hydroxypyridin-2- yl)-piperazin-1-yl]-
propan-l-one 9.04 (s, 1H), 7.73 (d, 1H, J = 2.64 Hz), 7.28 (m, 2H),
7.06 (m, 3H), 6.73 (d, 1H, J = 8.9 Hz), 3.53 (m, 4H), 3.23 (m, 4H),
2.81 (t, 2H, J = 7.57 Hz), 2.65 (t, 2H, J = 7.61 Hz) I.127
##STR00459## 1-[4-(5- Hydroxypyridin-2- yl)-piperazin-1-yl]-
2-(2-methyl-1H- indol-3-yl)- ethanone 2.38 (s, 3H), 3.13 (m, 2H),
3.24 (m, 2H), 3.60 (m, 4H), 3.79 (s, 2H), 6.74 (d, 1H, J = 8.91
Hz), 6.94- 6.95 (m, 1H), 7.00-7.03 (m, 1H), 7.09 (d, 1H, J = 6.95
Hz), 7.27 (d, 1H, J = 7.79 Hz), 7.47 (d, 1H, J = 7.58 Hz), 7.76 (s,
1H), 9.08 (s, 1H), 10.85 (s, 1H) I.128 ##STR00460## 1-[4-(5-
Hydroxypyridin-2- yl)-piperazin-1-yl]- 3-(2-
trifluoromethylphenyl)- propan-1-one 9.1 (s, 1H), 7.79 (d, 1H, J =
2.62 Hz), 7.73 (d, 1H, J = 7.88 Hz), 7.67 (t, 1H, J = 7.52 Hz),
7.60 (d, 1H, J = 7.69 Hz), 7.47 (t, 1H, J = 7.57 Hz), 7.13 (dd, 1H,
J.sub.1 = 8.92 Hz, J.sub.2 = 2.69 Hz), 6.8 (d, 1H, J = 8.9 Hz),
3.62 (t, 2H, J = 4.71 Hz), 3.56 (t, 2H, J = 4.47 Hz), 3.32-3.33 (m,
4H), 3.05 (t, 2H, J = 7.93 Hz), 2.73 (t, 2H, J = 7.98 Hz) I.129
##STR00461## 1-[4-(5- Hydroxypyridin-2- yl)-piperazin-1-yl]-
3-pyridin-2-yl- propan-l-one 2.84 (t, 2H, J = 7.46 Hz), 3.03 (t,
2H, J = 7.61 Hz), 3.21-3.36 (m, 4H), 3.56-3.59 (m, 4H), 6.79 (d,
1H, J = 8.71 Hz), 7.15 (dd, 1H, J.sub.1 = 8.85 Hz, J.sub.2 = 2.42
Hz), 7.24 (t, 1H, J = 5.94 Hz), 7.34 (d, 1H, J = 8.03 Hz), 7.73 (t,
1H, J = 7.20 Hz), 7.80 (d, 1H, J = 2.16 Hz), 8.51 (d, 1H, J = 4.56
Hz), 9.22 (s, 1H) I.130 ##STR00462## 3-Hydroxy-1-[4-(5-
hydroxypyridin-2- yl)-piperazin-1-yl]- 3-phenylpropan-1- one 2.63
(dd, 1H, J.sub.1 = 14.88 Hz, J.sub.2 = 4.68 Hz), 2.83 (dd, 1H,
J.sub.1 = 14.81 Hz, J.sub.2 = 8.48 Hz), 3.20 (m, 1H), 3.26-3.30 (m,
3H), 3.43-3.53 (m, 1H), 3.59-3.60 (m, 3H), 5.02- 5.04 (m, 1H), 5.40
(d, 1H, J = 4.2 Hz), 6.77 (d, 1H, J = 8.9 Hz), 7.12 (dd, 1H,
J.sub.1 = 8.9 Hz, J.sub.2 = 3 Hz), 7.27 (t, 1H, J = 7.2 Hz),7.37
(t, 2H, J = 7.5 Hz), 7.43 (d, 2H, J = 7.08 Hz), 7.78 (d, 1H, J =
2.8 Hz), 9.08 (s, 1H) I.131 ##STR00463## 2-(5-Fluoro-1H-
indol-3-yl)-1-[4-(5- hydroxypyridin-2- yl)-piperazin-1-yl]-
ethanone 3.22 (t, 2H, J = 4.6 Hz), 3.27 (t, 2H, J = 5.16 Hz),
3.62-3.66 (m, 4H), 3.84 (s, 2H), 6.76 (d, 1H, J = 9.0 Hz), 6.95
(td, 1H, J.sub.1 = 15.8 Hz, J.sub.2 = 4.6 Hz), 7.11 (dd, 1H,
J.sub.1 = 8.9 Hz, J.sub.2 = 3 Hz), 7.37 (m, 3H), 7.77 (d, 1H, J =
2.8 Hz), 9.08 (s, 1H), 11.05 (s, 1H) I.132 ##STR00464## [4-(5-
Hydroxypyridin-2- yl)-piperazin-1-yl]- (1,2,3,4-
tetrahydronaphthalen- 1-yl)-methanone 1.85 (m, 1H), 1.87 (m, 1H),
1.93 (m, 1H), 1.98 (m, 1H), 3.69 (m, 2H), 3.76 (m, 2H), 3.80 (m,
2H), 3.87 (m, 1H), 4.16 (m, 1H), 4.30 (t, 1H, J = 6.66 Hz), 6.83
(d, 2H, J = 8.96 Hz), 6.95 (d, 1H, J = 7.0 Hz), 7.14 (m, 4H), 7.81
(s, 1H), 9.11 (s, 1H) I.133 ##STR00465## [4-(5- Hydroxypyridin-2-
yl)-piperazin-1-yl]- ((1R, 2R)-2- phenylcyclopropyl)- methanone
1.27 (br-s, 1H), 1.48 (br-s, 1H), 2.38 (d, 2H, J = 5.04 Hz), 3.65
(s, 4H), 3.76 (br-s, 2H), 3.80 (br-s, 2H), 6.80 (d, 1H, J = 8.92
Hz), 7.12 (d, 1H, J = 6.05 Hz), 7.24 (d, 3H, J = 7.24 Hz),
7.31-7.34 (m, 2H), 7.80 (s, 1H), 9.09 (s, 1H) I.134 ##STR00466##
[4-(5- Hydroxypyridin-2- yl)-piperazin-1-yl]- (3-
phenylcyclobutyl)- methanone 2.27-2.35 (m, 2H), 2.58 (br-s, 1H),
3.31-3.38 (m, 1H), 3.41-3.45 (m, 2H), 3.46-3.48 (m, 1H), 3.50-3.52
(m, 3H), 3.55-3.60 (m, 4H), 6.80 (d, 1H, J = 8.92 Hz), 7.13 (d, 1H,
J = 6.90 Hz), 7.23-7.27 (m, 2H), 7.33-7.37 (m, 3H), 7.80 (s, 1H),
9.13 (s, 1H) I.135 ##STR00467## 1-[4-(5- Hydroxypyridin-2-
yl)-piperazin-1-yl]- 3-indol-1-yl- propan-l-one 2.93 (t, 2H, J =
6.92 Hz), 3.20- 3.26 (m, 4H), 3.43-3.57 (m, 4H), 4.48 (t, 2H, J =
6.90 Hz), 6.45 (d, 1H, J = 3.13 Hz), 6.75 (d, 1H, J = 9.00 Hz),
7.05 (t, 1H, J = 7.46 Hz), 7.11 (dd, 1H, J.sub.1 = 8.96 Hz, J.sub.2
= 3.00 Hz), 7.18 (t, 1H, J = 7.12 Hz), 7.43 (d, 1H, J = 3.12 Hz),
7.55 (dd, 2H, J.sub.1 = 15.66 Hz, J.sub.2 = 8.02 Hz), 7.78 (d, 1H,
J = 2.8 Hz), 9.07 (s, 1H) I.136 ##STR00468## 3-Benzoimidazol-1-
yl-1-[4-(5- hydroxypyridin-2- yl)-piperazin-1-yl]- propan-l-one
3.02 (t, 2H, J = 6.78 Hz), 3.22- 3.27 (m, 4H), 3.47-3.58 (m, 4H),
4.54 (t, 2H, J = 6.78 Hz), 6.76 (d, 1H, J = 9.01 Hz), 7.12 (dd, 1H,
J.sub.1 = 8.96 Hz, J.sub.2 = 3.00 Hz), 7.24 (t, 1H, J = 7.02 Hz),
7.30 (t, 1H, J = 7.08 Hz), 7.68 (dd, 2H, J.sub.1 = 7.88 Hz, J.sub.2
= 2.92 Hz), 7.78 (d, 1H, J = 2.84 Hz), 8.27 (s, 1H), 9.08 (s, 1H)
I.137 ##STR00469## 2-Cyclopropyl-1-[4- (5-hydroxy-2-
pyridyl)piperazin-1- yl]ethanone 0.17-0.18 (m, 2H), 0.49-0.51 (m,
2H), 1.01 (m, 1H), 2.34 (d, J = 6.72 Hz, 2H), 3.30-3.55 (m, 4H),
3.56- 3.58 (m, 4H), 6.80 (d, J = 8.92 Hz, 1H), 7.12 ((d, J.sub.1 =
8.92 Hz, J.sub.2 = 2.80 Hz, 1H), 7.79 (d, J = 2.64 Hz, 1H), 9.09
(s, 1H). I.138 ##STR00470## 3-(4-Cyanophenyl)- 1-[4-(5-
hydroxypyridin-2- yl)-piperazin-1-yl]- propan-l-one 2.77 (t, 2H, J
= 7.60 Hz), 2.97 (t, 2H, J = 7.55 Hz), 3.29-3.31 (m, 4H), 3.57-3.59
(m, 4H), 6.79 (d, 1H, J = 9.00 Hz), 7.13 (dd, 1H, J.sub.1 = 9.0 Hz,
J.sub.2 = 3.0 Hz), 7.53 (d, 2H, J = 8.31 Hz), 7.79 (d, 2H, J = 7.65
Hz), 7.79 (s, 1H), 9.09 (s, 1H) I.139 ##STR00471## 3-(4-
Trifluoromethylphenyl)- 1-[4-(5- hydroxypyridin-2-
yl)-piperazin-1-yl]- propan-l-one 2.77 (t, 2H, J = 7.40 Hz), 2.97
(t, 2H, J = 7.42 Hz), 3.30 (m, 4H), 3.58 (m, 4H), 6.79 (d, 1H, J =
9.00 Hz), 7.12 (d, 1H, J = 8.96 Hz), 7.54 (d, 2H, J = 7.85 Hz),
7.69 (d, 2H, J = 7.45 Hz), 7.79 (s, 1H), 9.08 (s, 1H) I.140
##STR00472## 3-Cyclopropyl-1[4- (5-hydroxy-2- pyridyl)piperazin-1-
yl]propan-l-one 0.07-.011 (m, 2H), 0.40-0.45 (m, 2H), 0.76-0.80 (m,
1H), 1.43-1.50 (m. 2H), 2.47(t, J = 7.64 Hz, 2H), 3.28-3.32 (m,
2H), 3.33-3.36 (m, 2H), 3.55-3.65 (m, 4H), 6.80 (d, J = 8.96 Hz,
1H), 7.12 ((d, J.sub.1 = 8.96 Hz, J.sub.2 = 3.00 Hz, 1H), 7.79 (d,
J = 2.84 Hz, 1H), 9.09 (s, 1H). I.141 ##STR00473## 2-{3-[4-(5-
Hydroxypyridin-2- yl)-piperazin-l-yl]- 3-oxopropyl}- benzoic acid
2.68 (t, 2H, J = 7.94 Hz), 3.18 (t, 2H, J = 7.92 Hz), 3.28-3.30 (m,
4H), 3.56-3.60 (m, 4H), 6.78 (d, 1H, J = 8.92 Hz), 7.12 (dd, 1H,
J.sub.1 = 8.96 Hz, J.sub.2 = 3.0 Hz), 7.35 (t, 1H, J = 7.52 Hz),
7.40 (d, 1H, J = 6.96 Hz), 7.52 (t, 1H, J = 6.82 Hz), 7.79 (d, 1H,
J = 2.84 Hz), 7.84 (d, 1H, J = 6.56 Hz), 9.09 (s, 1H), 13.0 (s, 1H)
I.142 ##STR00474## 2-{3-[4-(5- Hydroxypyridin-2-
yl)-piperazin-l-yl]- 3-oxo-propyl}- benzoic acid methyl ethanone
2.68 (t, 2H, J = 7.84 Hz), 3.16 (t, 2H, J = 7.78 Hz), 3.29 (m, 4H),
3.54 (m, 2H), 3.59-3.60 (m, 2H), 3.88 (s, 3H), 6.78 (d, 1H, J =
8.96 Hz), 7.12 (dd, 1H, J1= 8.92 Hz, J.sub.2 = 2.92 Hz), 7.37 (t,
1H, J = 7.5 Hz), 7.44 (d, 1H, J = 7.56 Hz), 7.55 (d, 1H, J = 7.5
Hz), 7.8 (d, 1H, J = 2.29 Hz), 7.84 (d, 1H, J = 7.76 Hz), 9.09 (s,
1H) I.143 ##STR00475## 2-(2- Bromophenylsulfanyl)- 1-[4-(5-
hydroxypyridin-2- yl)-piperazin-l-yl- ethanone 3.34 (t, 2H, J =
5.00 Hz), 3.43 (t, 2H, J = 4.84 Hz), 3.62 (t, 2H, J = 4.96 Hz),
3.71 (t, 2H, J = 4.90 Hz), 4.18 (s, 2H), 6.83 (d, 1H, J = 8.96 Hz),
7.12-7.18 (m, 2H), 7.40-7.44 (m, 1H), 7.52 (dd, 1H, J.sub.1 = 8.00
Hz, J.sub.2 = 1.40 Hz), 7.65 (dd, 1H, J.sub.1 = 7.94 Hz, J.sub.2 =
1.22 Hz), 7.81 (d, 1H, 2.84 Hz), 9.11 (s, 1H) I.144 ##STR00476##
2-Hydroxy-1-[4-(5- hydroxypyridin-2- yl)-piperazin-l-yl-
3-phenyl-propan-1- one 2.82 (dd, 1H, J.sub.1 = 13.56 Hz, J.sub.2 =
7.92 Hz), 2.97 (dd, 1H, J.sub.1 = 13.58 Hz, J.sub.2 = 5.26 Hz),
3.22-3.35 (m, 4H), 3.50-3.67 (m, 4H), 4.59- 4.64 (m, 1H), 5.18 (d,
1H, J = 7.92 Hz), 6.78 (d, 1H, J = 8.96 Hz), 7.12 (dd, 1H, J.sub.1
= 8.96 Hz, J.sub.2 = 3 Hz), 7.21-7.26 (m, 1H), 7.29-7.35 (m, 4H),
7.79 (d, 1H, J = 2.8 Hz), 9.10 (s, 1H) I.145 ##STR00477##
3-(4-Fluoro-2- methylphenyl)-1-[4- (5-hydroxypyridin-
2-yl)-piperazin-1- yl]-propan-1-one 2.34 (s, 3H), 2.64 (t, 2H, J =
7.78 Hz), 2.84 (t, 2H, J = 7.76 Hz), 3.30 (t, 4H, J = 5.12 Hz),
3.54-3.60 (m, 4H), 6.78 (d, 1H, J = 8.96 Hz), 6.96 (td, 1H, J.sub.1
= 14.4 Hz, J.sub.2 = 4.3 Hz), 7.04 (dd, 1H, J.sub.1 = 10.06 Hz,
J.sub.2 = 2.66 Hz), 7.13 (dd, 1H, J.sub.1 = 8.96 Hz, J.sub.2 = 3.00
Hz), 7.25 (dd, 1H, J.sub.1 = 8.4 Hz, J.sub.2 = 6.2 Hz), 7.80 (d,
1H, J = 2.92 Hz), 9.08 (s, 1H) I.146 ##STR00478## 3-(2,3-
Dimethylphenyl)-1- [4-(5- hydroxypyridin-2- yl)-piperazin-1-yl]-
propan-l-one 2.22 (s, 3H), 2.27 (s, 3H), 2.61 (t, 2H, J = 7.9 Hz),
2.88 (t, 2H, J = 7.9 Hz), 3.28-3.31 (m, 4H), 3.53 (t, 2H, J = 4.96
Hz), 3.60 (t, 2H, J = 5.06 Hz), 6.78 (d, 1H, J = 8.96 Hz),
7.02-7.08 (m, 3H), 7.13 (dd, 1H, J.sub.1 = 8.96 Hz, J.sub.2 = 3.00
Hz), 7.79 (d, 1H, J = 2.68 Hz), 9.08 (s, 1H) I.147 ##STR00479##
3-(2,6- Dimethylphenyl)-1- [4 -(5- hydroxypyridin-2-
yl)-piperazin-1-yl]- propan-l-one 2.33 (s, 6H), 2.52-2.53 (m, 2H),
2.88 (t, 2H, J = 8.26 Hz), 3.30- 3.33 (m, 4H), 3.41-3.63 (m, 4H),
6.78 (d, 1H, J = 9.00 Hz), 7.03 (s, 3H), 7.13 (dd, 1H, J.sub.1 =
8.96 Hz, J.sub.2 = 3.00 Hz), 7.79 (d, 1H, J = 2.84 Hz), 9.06 (s,
1H) I.148 ##STR00480## 2-(3,5- Difluorophenyl)-1- [4-(4-
hydroxyphenyl)- piperazin-1-yl]- ethanone 2.95 (m, 4H), 3.67 (m,
4H), 3.87 (s, 2H), 6.70-6.72 (m, 2H), 6.84- 6.86 (m, 2H), 7.03 (dd,
2H, J.sub.1 = 8.62 Hz, J.sub.2 = 2.1 Hz), 7.14 (tt, 1H, J.sub.1 =
9.48 Hz, J.sub.2 = 2.34 Hz), 8.93 (s, 1H) I.149 ##STR00481##
2-(2,4- Difluorophenyl)-1- [4-(4- hydroxyphenyl)- piperazin-1-yl]-
ethanone 2.96 (m, 2H), 3.02-3.33 (m, 2H), 3.64 (m, 2H), 3.71 (m,
2H), 3.82 (s, 2H), 6.72 (d, 2H, J = 8.8 Hz), 6.87 (d, 2H, J = 8.9
Hz), 7.08 (t, 1H, J = 7.54 Hz), 7.24 (td, 1H, J.sub.1 = 9.84 Hz,
J.sub.2 = 2.41 Hz), 7.37 (q, 1H, J.sub.1 = 15.44 Hz, J.sub.2 = 8.64
Hz), 8.93 (s, 1H) I.150 ##STR00482## 2-(5-Fluoro-1H-
indol-3-yl)-1-[4-(4- hydroxyphenyl)- piperazin-1-yl] ethanone 2.86
(m, 2H), 2.91 (m, 2H), 3.64 (m, 2H), 3.68 (m, 2H), 3.83 (s, 2H),
6.68 (d, 2H, J = 8.93 Hz), 6.8 (d, 2H, J = 8.9 Hz), 6.96 (td, 1H,
J.sub.1 = 9.14 Hz, J.sub.2 = 2.53 Hz), 7.35-7.40 (m, 3H), 8.9 (s,
1H), 11.05 (s, 1H) I.151 ##STR00483## 2-(2- Bromophenylsulfanyl)-
1-[4-(4- hydroxyphenyl)- piperazin-1-yl]- ethanone 2.97 (t, 2H),
3.06 (t, 2H), 3.65 (t, 2H), 3.74 (t, 2H), 4.17 (s, 2H), 6.72 (d,
2H, J = 8.84 Hz), 6.87 (d, 2H, J = 8.84 Hz), 7.16 (t, 1H, J = 7.60
Hz), 7.42 (t, 1H, J = 7.62 Hz), 7.52 (d, 1H, J = 7.96 Hz), 7.65 (d,
1H, J = 7.88 Hz), 8.92 (s, 1H)
I.152 ##STR00484## 3-(2,4 -Difluorophenyl)-1- [4-(5-
hydroxypyridin-2- yl)-piperazin-1-yl]- propan-l-one 2.70 (t, 2H, J
= 7.56 Hz), 2.88 (t, 2H, J = 7.74 Hz), 3.20-3.34 (m, 4H), 3.42-3.61
(m, 4H), 6.79 (d, 1H, J = 8.96 Hz), 7.04-7.08 (m, 1H), 7.12 (dd,
1H, J.sub.1 = 8.9 Hz, J.sub.2 = 3.00 Hz), 7.19-7.25 (m, 1H), 7.42-
7.48 (m, 1H), 7.8 (d, 1H, J = 2.80 Hz), 9.08 (s, 1H) I.153
##STR00485## 3-(3,4- Difluorophenyl)-1- [4-(5- hydroxypyridin-2-
yl)-piperazin-1-yl]- propan-l-one 2.73 (t, 2H, J = 7.56 Hz), 2.88
(t, 2H, J = 7.58 Hz), 3.28-3.33 (m, 4H), 3.56-3.61 (t, 4H), 6.80
(d, 1H, J = 9.0 Hz), 7.12-7.15 (m, 2H), 7.33-7.43 (m, 2H), 7.8 (d,
1H, J = 2.72 Hz), 9.10 (s, 1H) I.154 ##STR00486## (2-Chloro-6-
methylphenyl)-[4- (4-hydroxyphenyl)- piperazin-1-yl]- methanone
2.29 (s, 3H), 2.89-2.95 (m, 1H), 2.97-3.03 (m, 1H), 3.08 (t, 2H, J
= 5.27 Hz), 3.24-3.29 (m, 2H), 3.81- 3.89 (m, 2H), 6.71 (d, 2H, J =
8.96 Hz), 6.86 (d, 2H, J = 8.96 Hz), 7.32- 7.36 (m, 1H), 7.39 (t,
2H, J = 3.32 Hz), 8.93 (s, 1H) I.155 ##STR00487##
(5-Fluoro-1H-indol- 3-yl)-[4-(4- hydroxypyridin-2-
yl)-piperazin-1-yl]- methanone 3.43 (t, 4H, J = 5.08 Hz), 3.79 (t,
4H, J = 5.08 Hz), 6.81 (d, 1H, J = 8.96 Hz), 7.04-7.09 (m, 1H),
7.13- 7.16 (m, 1H), 7.47-7.51 (m, 2H), 7.81 (d, 2H, J = 2.84 Hz),
7.87 (s, 1H), 9.08 (s, 1H), 11.78 (s, 1H) I.156 ##STR00488##
(5-Fluoro-1H-indol- 3-yl)-[4-(4- hydroxyphenyl)- piperazin-1-yl]-
methanone 3.05 (t, 4H, J = 4.94 Hz), 3.81 (t, 4H, J = 4.94 Hz),
6.72 (d, 2H, J = 8.92 Hz), 6.87 (d, 2H, J = 8.92 Hz),7.04-709 (m,
1H), 7.46-7.52 2H), 8.50 (s, 1H), 8.92 (s, 1H), 11.78 (s, 1H) I.157
##STR00489## 3-(2,6- Difluorophenyl)-1- [4-(5- hydroxypyridin-2-
yl)-piperazin-1-yl]- propan-l-one 2.67 (t, 2H, J = 7.94 Hz), 2.91
(t, 2H, J = 7.90 Hz), 3.32-3.38 (m, 4H), 3.55 (t, 2H, J = 4.98 Hz),
3.60 (t, 2H, J = 5.06 Hz), 6.79 (d, 1H, J = 8.96 Hz), 7.08-7.14 (m,
3H), 7.32-7.39 (m, 1H), 7.79 (d, 1H, J = 2.88 Hz), 9.08 (s, 1H)
I.158 ##STR00490## 2-(6-Fluoro-1H- indol-3-yl)-1-[4-(5-
hydroxy-pyridin-2- yl)-piperazin-1-yl]- ethanone 3.34 (m, 4H),
3.65-3.69 (m, 4H), 3.93 (s, 2H), 6.73 (q, 1H, J.sub.1 = 11.4 Hz,
J.sub.2 = 7.72 Hz), 6.80 (d, 1H, J = 8.96 Hz), 7.04-7.09 (m, 1H),
7.12 (dd, 1H, J.sub.1 = 8.98 Hz, J.sub.2 = 2.98 Hz), 7.21 (t, 2H, J
= 7.62 Hz), 7.8 (d, 1H, J = 2.92 Hz), 9.1 (s, 1H), 11.19 (s, 1H)
I.159 ##STR00491## 2-(5-Chloro-1H- indol-3-yl)-1-[4-(5-
hydroxy-pyridin-2- yl)-piperazin-1-yl]- ethanone 3.23-3.28 (m, 4H),
3.62-3.67 (m, 4H), 3.86 (s, 2H), 6.78 (d, 1H, J = 8.96 Hz),
7.09-7.12 (m, 2H), 7.37- 7.41 (m, 2H), 7.66 (d, 1H, J = 2.04 Hz),
7.77 (d, 1H, J = 2.76 Hz), 9.09 (s, 1H), 11.16 (s, 1H) I.160
##STR00492## 2-(5,6-Difluoro-1H- indol-3-yl)-1-[4-(5-
hydroxy-pyridin-2- yl)-piperazin-1-yl]- ethanone 3.34-3.35 (m, 4H),
3.65-3.71 (m, 4H), 3.93 (s, 2H), 6.81 (d, 1H, , J = 9.0 Hz),
7.08-7.21 (m, 3H), 7.28 (d, 2H, J = 2.08 Hz), 7.81 (d, 1H, J = 2.88
Hz), 9.11 (s, 1H), 11.25 (s, 1H) I.161 ##STR00493## 3-(4-Fluoro-
phenyl)-1-[4-(5- hydroxy-pyridin-2- yl)-piperazin-1-yl]-
3-methyl-butan-1- one 1.45 (s, 6H), 2.56 (s, 2H), 2.73 (m, 4H),
3.48 (m, 4H), 6.75 (d, 1H, J = 9.0 Hz), 7.09-7.15 (m, 3H), 7.43-
7.47 (m, 2H), 7.77 (d, 1H, J = 2.76 Hz), 9.09 (s, 1H) I.162
##STR00494## 2-(2-Bromo- phenylsulfanyl)-1- [4-(5-hydroxy-
pyridin-2-yl)- piperazin-1-yl]-2- methyl-propan-1- one 1.59 (s,
6H), 3.31 (m, 4H), 3.91 (m, 4H), 6.79 (d, 1H, J = 8.96 Hz), 7.12
(dd, 1H, J.sub.1 = 8.94 Hz, J.sub.2 = 2.94 Hz), 7.25-7.29 (m, 1H),
7.39-7.47 (m, 2H), 7.74 (d, 1H, J = 7.88 Hz), 7.78 (d, 1H, J = 2.84
Hz), 9.11 (s, 1H) I.163 ##STR00495## 2-(4-Fluoro-
phenylsulfanyl)-1- [4-(5-hydroxy- pyridin-2-yl)- piperazin-1-yl]-
ethanone 3.31-3.39 (m, 4H), 3.59-3.63 (m, 4H), 4.05 (s, 2H), 6.81
(d, 1H, J = 8.96 Hz), 7.14 (dd, 1H, J.sub.1 = 8.9 Hz, J.sub.2 =
2.78 Hz), 7.23 (t, 2H, J = 8.78 Hz), 7.52 (q, 1H, J.sub.1 = 8.44
Hz, J.sub.2 = 5.36 Hz), 7.80 (d, 1H, J = 2.68 Hz), 9.11 (s, 1H)
I.164 ##STR00496## 2-(4-Fluoro- phenoxy)-1-[4-(5-
hydroxy-pyridin-2- yl)-piperazin-1-yl]- ethanone 3.34 (m, 2H), 3.39
(m, 2H), 3.60 (t, 4H, J = 5.10 Hz), 4.90 (s, 2H), 6.82 (d, 1H, J =
9.0 Hz), 6.98-7.02 (m, 2H), 7.12-7.19 (m, 3H), 7.80 (d, 1H, J =
2.84 Hz), 9.11 (s, 1H) I.165 ##STR00497## 2-(5-Fluoro-1-
methyl-indol-3-yl)- 1-[4-(5-hydroxy- pyridin-2-yl)-
piperazin-1-yl]- ethanone 3.27-3.31 (m, 4H), 3.61-3.66 (m, 4H),
3.83 (s, 3H), 3.96 (s, 2H), 6.78 (d, 1H, J = 8.99 Hz), 7.03 (td,
1H, J.sub.1 = 15.79 Hz, J.sub.2 = 4.59 Hz), 7.11 (dd, 1H, J.sub.1 =
8.96 Hz, J.sub.2 = 3.00 Hz), 7.34 (s, 1H), 7.39 (dd, 1H, J.sub.1 =
10.08 Hz, J.sub.2 = 2.48 Hz), 7.45 (dd, 1H, J.sub.1 = 8.87 Hz,
J.sub.2 = 4.42 Hz), 7.78 (d, 1H, J = 2.87 Hz), 9.07 (s, 1H) I.166
##STR00498## 2-(5-Fluoro-2- methyl-1H-indol-3- yl)-1-[4-(5-
hydroxy-pyridin-2- yl)-piperazin-l-yl]- ethanone 2.38 (s, 3H), 3.16
(m, 2H), 3.25 (m, 2H), 3.60 (t, 4H, J = 5.01 Hz), 3.77 (s, 2H),
6.75 (d, 1H, J = 8.99 Hz), 6.82-6.86 (m, 1H), 7.10 (dd, 1H, J.sub.1
= 8.96 Hz, J.sub.2 = 2.96 Hz), 7.23- 7.26 (m, 2H), 7.77 (d, 1H, J =
2.87 Hz), 9.09 (s, 1H), 10.97 (s, 1H) I.167 ##STR00499##
2-(5,7-Difluoro-1H- indol-3-yl)-1-[4-(5- hydroxy-pyridin-2-
yl)-piperazin-1-yl]- ethanone 3.24-3.28 (m, 4H), 3.61 (m, 2H), 3.67
(m, 2H), 3.85 (m, 2H), 6.77 (d, 1H, J = 8.98 Hz), 6.97-7.02 (m,
1H), 7.11 (dd, 1H, J.sub.1 = 8.94 Hz, J.sub.2 = 2.92 Hz), 7.26 (dd,
1H, J.sub.1 = 9.58 Hz, J.sub.2 = 1.90 Hz), 7.44 (d, 1H, J = 1.88
Hz), 7.78 (d, 1H, J = 2.84 Hz), 9.09 (s, 1H), 11.59 (s, 1H) I.168
##STR00500## 1-(5-Fluoro-1H- indol-3-yl)-2-[4-(5-
hydroxy-pyridin-2- yl)-piperazin-l-yl]- ethane-1,2-dione 3.32-3.34
(m, 2H), 3.49-3.51 (m, 4H), 3.76-3.77 (m, 2H), 6.80 (d, 1H, J =
8.98 Hz), 7.14 (dd, 1H, J.sub.1 = 8.94 Hz, J.sub.2 = 2.89 Hz),
7.19-7.23 (m, 1H), 7.59-7.62 (m, 1H), 7.80 (d, 1H, J = 2.79 Hz),
7.85 (d, 1H, J = 7.64 Hz), 8.32 (s, 1H), 9.11 (s, 1H), 12.46 (s,
1H) I.169 ##STR00501## 2-(5-Fluoro-1H- indol-3-yl)-1-[4-(5-
hydroxy-pyridin-2- yl)-piperazin-l-yl]- 2-methyl-propan-1- one 1.59
(s, 6H), 3.42 (s, 8H), 6.59 (d, 1H, J = 8.98 Hz), 6.92 (t, 1H, J =
9.06 Hz), 6.98-7.03 (m, 2H), 7.38- 7.41 (m, 2H), 7.68 (d, 1H, J =
2.8 Hz), 9.01 (s, 1H), 11.16 (s, 1H) I.170 ##STR00502##
1-[4-(5-Hydroxy- pyridin-2-yl)- piperazin-1-yl]-3-
(3,4,5-trifluoro- phenyl)-propan-1- one 2.75 (t, 2H, J = 7.58 Hz),
2.87 (t, 2H, J = 7.63 Hz), 3.29 (t, 2H, J = 5.17 Hz), 3.34 (t, 2H,
J = 5.12 Hz), 3.57-3.61 (m, 4H), 6.80 (d, 1H, J = 8.95 Hz), 7.13
(dd, 1H, J.sub.1 = 8.96 Hz, J.sub.2 = 3.00 Hz), 7.29-7.33 (m, 2H),
7.79 (d, 1H, J = 2.55 Hz), 9.09 (s, 1H) I.171 ##STR00503##
1-[4-(4-Hydroxy- phenyl)-piperazin- 1-yl]-2-(3,4,5-
trifluoro-phenyl)- ethanone 2.95-2.99 (m, 4H), 3.64-3.68 (m, 4H),
3.84 (s, 2H), 6.71 (d, 2H, J = 8.68 Hz), 6.85 (d, 2H, J = 8.72 Hz),
7.25 (t, 2H, J = 7.86 Hz), 8.99 (s, 1H) I.172 ##STR00504##
N-{3-[4-(5- Hydroxy-pyridin-2- yl)-piperazin-l-yl]- 3-oxo-1-phenyl-
propyl}-acrylamide 2.87 (dd, 1H, J.sub.1 = 15.40 Hz, J.sub.2 = 6.44
Hz), 2.95 (dd, 1H, J.sub.1 = 15.39 Hz, J.sub.2 = 7.75 Hz),
3.23-3.34 (m, 4H), 3.42-3.58 (m, 4H), 5.37 (q, 1H, J.sub.1 = 14.58
Hz, J.sub.2 = 7.65 Hz), 5.64 (dd, 1H, J.sub.1 = 10.2 Hz, J.sub.2 =
2.12 Hz), 6.13 (dd, 1H, J.sub.1 = 17.07 Hz, J.sub.2 = 2.11 Hz),
6.29-6.34 (m, 1H), 6.78 (d, 1H, J = 8.98 Hz), 7.12 (dd, 1H, J.sub.1
= 8.95 Hz, J.sub.2 = 3.00 Hz), 7.26- 7.29 (m, 1H), 7.35-7.40 (m,
4H), 7.79 (d, 1H, J = 2.85 Hz), 8.57 (d, 1H, J = 8.13 Hz), 9.08 (s,
1H) I.173 ##STR00505## 1-[4-(4-Hydroxy- phenyl)-piperazin-
1-yl1-3-methyl-3- phenyl-butan-l-one hydrochloride salt 1.47 (s,
6H), 2.78 (s, 2H), 3.18 (m, 2H), 3.75-3.94 (m, 6H), 6.90 (d, 2H, J
= 8.09 Hz), 7.22 (t, 1H, J = 7.24 Hz), 7.36 (t, 2H, J = 7.68 Hz),
7.45 (d, 2H, J = 7.6 Hz), 7.49-7.50 (m, 2H), 9.97 (br-s, 1H) I.174
##STR00506## 2-(5,6-Dichloro-1H- indol-3-yl)-1-[4-(5-
hydroxy-pyridin-2- yl)-piperazin-1-yl]- ethanone 3.25-3.28 (m, 4H),
3.61-3.67 (m, 4H), 3.87 (s, 2H), 6.78 (d, 1H, J = 8.98 Hz), 7.10
(dd, 1H, J.sub.1 = 8.93 Hz, J.sub.2 = 2.88 Hz), 7.42 (s, 1H), 7.64
(s, 1H), 7.78 (d, 1H, J = 2.79 Hz), 7.86 (s, 1H), 9.09 (s, 1H),
11.24 (s, 1H) I.175 ##STR00507## 2-(5-Chloro-2- methyl-1H-indol-3-
yl)-1-[4-(5- hydroxy-pyridin-2- yl)-piperazin-1-yl]- ethanone 2.38
(s, 3H), 3.19 (m, 2H), 3.26 (m, 2H), 3.61 (m, 4H), 3.79 (s, 2H),
6.77 (d, 1H, J = 9.01 Hz), 7.01 (dd, 1H, J.sub.1 = 8.47 Hz, J.sub.2
= 1.84 Hz), 7.10 (dd, 1H, J.sub.1 = 8.93 Hz, J.sub.2 = 2.92 Hz),
7.28 (d, 1H, J = 8.49 Hz), 7.52 (d, 1H, J = 1.51 Hz), 7.77 (d, 1H,
J = 2.83 Hz), 9.07 (s, 1H), 11.07 (s, 1H) I.176 ##STR00508##
2-(5,6-Dichloro-2- methyl-1H-indol-3- yl)-1-[4-(5-
hydroxy-pyridin-2- yl)-piperazin-l-yl]- ethanone 2.37 (s, 3H), 3.22
(m, 2H), 3.27 (m, 2H), 3.61 (m, 4H), 3.80 (s, 2H), 6.77 (d, 1H, J =
8.98 Hz), 7.11 (dd, 1H, J.sub.1 = 8.92 Hz, J.sub.2 = 2.86 Hz), 7.50
(s, 1H), 7.72 (s, 1H), 7.77 (d, 1H, J = 2.75 Hz), 9.08 (s, 1H),
11.21 (s, 1H) ##STR00509##
Biological Data
In-Vitro Enzyme Assay
ME3 Inhibition Assay
[0821] ME3 catalyzes the oxidative decarboxylation of malate to
pyruvate with conversion of the co-factor .beta.-NADP+ to NADPH. In
the fluorescence assay, a coupled reaction is set up wherein an
enzyme, Diaphorase, utilizes NADPH generated by ME3, to convert the
dye resazurin to a fluorescent molecule resorufin. Resorufin has a
characteristic fluorescence with excitation/emission at 540/600 nm
(SLAS Discov., 2017 Apr. 1: 2472555217706649).
[0822] The enzyme activity inhibition assay is set up in a 200
.mu.L final reaction volume in a 96-well plate. As per the
experimental design, 2 .mu.L of the test compounds at 100.times.
the desired concentration (10 .mu.M) in DMSO were added to the
respective wells with 178 .mu.L of assay buffer (50 mM Tris-HCl pH
7.5, 10 mM MnCl.sub.2, 3 mM L-malate, 50 .mu.M Resazurin and 0.025
mg/ml Diapharose). The 96-well plate was incubated on a plate
shaker at room temperature for 15 minutes protected from light. The
well contents were gently mixed by adding 10 .mu.L of 20 nM human
ME3 enzyme to the wells and the plate was incubated on a shaker at
room temperature for 5 minutes protected from light. Suitable
enzyme only and no enzyme controls were included in the experiment.
The enzyme reaction was started by adding 10 .mu.L of 1 mM
.beta.-NADP+. The reaction was gently mixed and the plate was
initially left on a shaker at room temperature for 7 minutes
protected from light. Later, the plate was incubated without
shaking at room temperature for 3 hours. At the end of 3 hours, the
fluorescence of the wells was measured at excitation 540 nm and
emission 600 nm. The % enzyme activity of the compounds is obtained
by normalizing the data with enzyme only (100%) and no enzyme
controls (0%) using GraphPad Prism software 7.04.
ME2 Inhibition Assay
[0823] ME2 catalyzes the oxidative decarboxylation of malate to
pyruvate with conversion of the co-factor .beta.-NAD.sup.+ to
.beta.-NADH. In the fluorescence assay, a coupled reaction is set
up where in an enzyme, Diaphorase, utilizes NADH generated by ME2,
to convert the dye resazurin to a fluorescent molecule resorufin.
Resorufin has a characteristic fluorescence with
excitation/emission at 540/600 nm (SLAS Discov., 2017 Apr. 1:
2472555217706649).
[0824] The enzyme activity inhibition assay is set up in a 200
.mu.L final reaction volume in a 96-well plate. As per the
experimental design, 2 .mu.L of the compounds at 100.times. the
desired concentration (10 .mu.M) in DMSO were added to the
respective wells with 178 .mu.L of assay buffer (50 mM Tris-HCl pH
7.5, 10 mM MnCl.sub.2, 7 mM L-malate, 50 .mu.M Resazurin and 0.025
mg/ml Diapharose). The 96-well plate was incubated on a plate
shaker at room temperature for 15 minutes protected from light. The
well contents were gently mixed by adding 10 .mu.L of 60 nM human
ME2 enzyme to the wells and the plate was incubated on a shaker at
room temperature for 5 minutes protected from light. Suitable
`enzyme only` and `no enzyme` controls were included in the
experiment. The enzymatic reaction was started by adding 10 .mu.L
of 2 mM .beta.-NAD.sup.+. The reaction was gently mixed and the
plate was initially left on a shaker at room temperature for 7
minutes protected from light. Later, the plate was incubated
without shaking at room temperature for 2 hours. At the end of 2
hours, the fluorescence of the wells was measured at excitation 540
nm and emission 600 nm. The % enzyme activity of the compounds is
obtained by normalizing the data with enzyme only (100%) and no
enzyme controls (0%) using GraphPad Prism software 7.04.
ME1 Inhibition Assay
[0825] ME1 catalyzes the oxidative decarboxylation of malate to
pyruvate with conversion of the co-factor .beta.-NADP.sup.+ to
.beta.-NADPH. In the fluorescence assay, a coupled reaction is set
up where in an enzyme, Diaphorase, utilizes NADPH generated by MEL
to convert the dye resazurin to a fluorescent molecule resorufin.
Resorufin has a characteristic fluorescence with
excitation/emission at 540/600 nm (SLAS Discov., 2017 Apr. 1:
2472555217706649).
[0826] The enzyme activity inhibition assay is set up in a 200
.mu.L, final reaction volume in a 96-well plate. As per the
experimental design, 2 .mu.L of the compounds at 100.times. the
desired concentration (10 .mu.M) in DMSO were added to the
respective wells with 178 .mu.L, of assay buffer (50 mM Tris-HCl pH
7.5, 10 mM MnCl.sub.2, 2 mM L-malate, 10 .mu.M Resazurin and 0.01
mg/ml Diapharose). The 96-well plate was incubated on a plate
shaker at room temperature for 15 minutes protected from light. The
well contents were gently mixed by adding 10 .mu.L, of 20 nM human
ME1 enzyme to the wells and the plate was incubated on a shaker at
room temperature for 5 minutes protected from light. Suitable
`enzyme only` and `no enzyme` controls were included in the
experiment. The enzymatic reaction was started by adding 10 .mu.L,
of 0.3 mM .beta.-NADP.sup.+. The reaction was gently mixed and the
plate was initially left on a shaker at room temperature for 7
minutes protected from light. Later, the plate was incubated
without shaking at room temperature for 2 hours. At the end of 2
hours, the fluorescence of the wells was measured at excitation 540
nm and emission 600 nm. The % enzyme activity of the compounds is
obtained by normalizing the data with enzyme only (100%) and no
enzyme controls (0%) using GraphPad Prism software 7.04.
[0827] Results for representative compounds of the instant
invention at 10 .mu.M concentration are provided in Table 3
below.
TABLE-US-00003 TABLE 3 Malic Enzyme Inhibition (%) at 10 .mu.M
Concentration Malic Enzyme 3 Malic Enzyme 1 Malic Enzyme 2 Compound
% inhibition % inhibition % inhibition No. (10 .mu.M) (10 .mu.M)
(10 .mu.M) I.1 A A A I.2 A A A I.3 A A -- I.4 A A -- I.5 A A A I.6
A A A I.7 A -- -- I.8 A -- -- I.9 A A A I.10 A -- -- I.11 A A B
I.12 A -- -- I.13 A -- -- I.14 A -- -- I.15 A -- -- I.16 A -- --
I.17 A -- -- I.18 A -- -- I.19 A -- -- I.20 A -- -- I.21 A A A I.22
A -- -- I.23 A -- -- I.24 A -- -- I.25 A -- -- I.26 A -- -- I.27 A
-- -- I.28 A A -- I.29 A -- -- I.30 A -- -- I.31 A -- -- I.32 B --
-- I.33 A -- -- I.34 A -- -- I.35 A -- -- I.36 A -- -- I.37 C -- --
I.38 A -- -- I.39 A A A I.40 A A A I.41 A A A I.42 A A A I.43 A A C
I.44 A A C I.45 A A B I.46 A A A I.47 A A A I.48 A B B I.49 A A A
I.50 A A A I.51 A B B I.52 A A A I.53 A A A I.54 A B C I.55 A A B
I.56 A C B I.57 A B B I.58 A B C I.59 A B B I.60 A B B I.61 A B B
I.62 A B B I.63 A B B I.64 A B C I.65 A B B I.66 A B B I.67 A A C
I.68 A A B I.69 A B B I.70 A B B I.71 A A B I.72 A A B I.73 A B B
I.74 A A B I.75 A A B I.76 A -- -- I.77 A -- -- I.78 A -- -- I.79 A
A A I.80 A A A I.81 A I.82 A A A I.83 A C C I.84 A B B I.85 A -- --
I.86 A -- -- I.87 A -- -- I.88 A A B I.89 A -- -- I.90 A -- -- I.91
A -- -- I.92 A A A I.93 A B B I.94 A B B I.95 A B B I.96 A B B I.97
A -- -- I.98 A -- -- I.99 A -- -- I.100 A -- -- I.101 A -- -- I.102
A -- -- I.103 A -- -- I.104 B -- -- I.105 A -- -- I.106 A -- --
I.107 A A A I.108 A -- -- I.109 A -- -- I.110 A -- -- I.111 A -- --
I.112 A -- -- I.113 A -- -- I.114 A -- -- I.115 A A A I.116 A A A
I.117 A -- -- I.118 A -- -- I.119 A -- -- I.120 A -- -- I.121 A A A
I.122 A A A I.123 A B B I.124 A A A I.125 A A A I.126 A A A I.127 A
A A I.128 A A A I.129 A B B I.130 A B A I.131 A A A I.132 A B A
I.133 A A A I.134 A A A I.135 A B A I.136 A B A I.137 A A A I.138 A
A A I.139 A A A I.140 A A A I.141 A B A I.142 A B A I.143 A A A
I.144 A C A I.145 A A A I.146 A A A I.147 A A A I.148 A A A I.149 A
A A I.150 A A A I.151 A A A I.152 A A A I.153 A A A I.154 A A A
I.155 A A A I.156 A A A I.157 A A A I.158 A A A I.159 A A A I.160 A
A A I.161 A A A I.162 A A A I.163 A A A I.164 A A A I.165 A A A
I.166 A A A I.167 A A A I.168 A A A I.169 A A A I.170 A A A I.171 A
A A I.172 A C A I.173 A B A I.174 A A A I.175 A A A I.176 A A A A =
greater than 90% inhibition at the tested concentration B = 70-89%
inhibition at the tested concentration C = 50-69% inhibition at the
tested concentration.
* * * * *