U.S. patent application number 15/035438 was filed with the patent office on 2016-10-06 for combination therapy including an mdm2 inhibitor and one or more additional pharmaceutically active agents for the treatment of cancers.
This patent application is currently assigned to AMGEN INC.. The applicant listed for this patent is AMGEN INC.. Invention is credited to Sean CAENEPEEL, Jude CANON, Paul HUGHES, Jonathan D. OLINER, Richard J. RICKLES, Anne Y. SAIKI.
Application Number | 20160287569 15/035438 |
Document ID | / |
Family ID | 52001089 |
Filed Date | 2016-10-06 |
United States Patent
Application |
20160287569 |
Kind Code |
A1 |
CAENEPEEL; Sean ; et
al. |
October 6, 2016 |
COMBINATION THERAPY INCLUDING AN MDM2 INHIBITOR AND ONE OR MORE
ADDITIONAL PHARMACEUTICALLY ACTIVE AGENTS FOR THE TREATMENT OF
CANCERS
Abstract
The present invention provides combination therapy that includes
an MDM2 inhibitor and one or more additional pharmaceutically
active agents, particularly for the treatment of cancers. The
invention also relates to pharmaceutical compositions that contain
an MDM2 inhibitor and one or more additional pharmaceutically
active agents for the treatment of cancers.
Inventors: |
CAENEPEEL; Sean; (Thousand
Oaks, CA) ; CANON; Jude; (Marina Del Rey, CA)
; HUGHES; Paul; (Santa Monica, CA) ; OLINER;
Jonathan D.; (Garrett Park, MD) ; SAIKI; Anne Y.;
(Moorpark, CA) ; RICKLES; Richard J.; (Arlington,
MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AMGEN INC. |
Thousand Oaks |
CA |
US |
|
|
Assignee: |
AMGEN INC.
Thousand Oaks
CA
|
Family ID: |
52001089 |
Appl. No.: |
15/035438 |
Filed: |
November 11, 2014 |
PCT Filed: |
November 11, 2014 |
PCT NO: |
PCT/US2014/065034 |
371 Date: |
May 9, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61902717 |
Nov 11, 2013 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/44 20130101;
A61K 31/5025 20130101; A61K 31/706 20130101; A61P 1/16 20180101;
A61P 11/00 20180101; A61P 35/00 20180101; A61K 31/506 20130101;
A61P 13/10 20180101; A61K 31/496 20130101; A61K 31/704 20130101;
A61K 31/166 20130101; A61K 31/437 20130101; A61K 31/635 20130101;
A61K 31/519 20130101; A61P 1/00 20180101; A61K 31/451 20130101;
A61P 13/12 20180101; A61K 31/4045 20130101; A61P 43/00 20180101;
A61K 31/7068 20130101; A61P 35/02 20180101; A61K 31/365 20130101;
A61P 17/00 20180101; A61K 31/437 20130101; A61K 2300/00 20130101;
A61K 31/451 20130101; A61K 2300/00 20130101; A61K 31/506 20130101;
A61K 2300/00 20130101; A61K 31/519 20130101; A61K 2300/00 20130101;
A61K 31/7068 20130101; A61K 2300/00 20130101; A61K 31/7068
20130101; A61K 2300/00 20130101 |
International
Class: |
A61K 31/451 20060101
A61K031/451; A61K 31/437 20060101 A61K031/437; A61K 31/519 20060101
A61K031/519; A61K 31/5025 20060101 A61K031/5025; A61K 31/496
20060101 A61K031/496; A61K 31/365 20060101 A61K031/365; A61K 31/166
20060101 A61K031/166; A61K 31/635 20060101 A61K031/635; A61K
31/4045 20060101 A61K031/4045; A61K 31/706 20060101 A61K031/706;
A61K 31/7068 20060101 A61K031/7068; A61K 31/704 20060101
A61K031/704; A61K 31/506 20060101 A61K031/506; A61K 31/44 20060101
A61K031/44 |
Claims
1. A method of treating melanoma, the method comprising
administering to a patient in need thereof a therapeutically
effective amount of an MDM2 inhibitor and a BRAF inhibitor.
2. A method of treating colon cancer, the method comprising
administering to a patient in need thereof a therapeutically
effective amount of an MDM2 inhibitor and a BRAF inhibitor.
3. The method of claim 2 wherein the colon cancer has a BRAF V600E
or V600K mutation.
4. A method of treating liver cancer, the method comprising
administering to a patient in need thereof a therapeutically
effective amount of an MDM2 inhibitor and a BRAF inhibitor.
5. A method of treating melanoma, the method comprising
administering to a patient in need thereof a therapeutically
effective amount of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, dabrafenib and trametinib.
6. A method of treating melanoma, the method comprising
administering to a patient in need thereof a therapeutically
effective amount of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, and dabrafenib.
7. The method of any one of claims 1, 5 to 6 wherein the melanoma
has a BRAF V600E or V600K mutation.
8. The method of any one of claims 1-4 and 7, wherein the BRAF
inhibitor is dabrafenib.
9. The method of any one of claim 1-4 or 7, wherein the BRAF
inhibitor is AMG 2112819 or vemurafenib.
10. A method of treating melanoma, the method comprising
administering to a patient in need thereof a therapeutically
effective amount of an MDM2 inhibitor and a MEK inhibitor.
11. A method of treating colon cancer, the method comprising
administering to a patient in need thereof a therapeutically
effective amount of an MDM2 inhibitor and a MEK inhibitor.
12. A method of treating liver cancer, the method comprising
administering to a patient in need thereof a therapeutically
effective amount of an MDM2 inhibitor and a MEK inhibitor.
13. The method of claim 12 wherein the liver cancer has a BRAF
V600E or V600K mutation.
14. A method of treating bladder cancer, the method comprising
administering to a patient in need thereof a therapeutically
effective amount of an MDM2 inhibitor and a MEK inhibitor.
15. A method of treating AML, the method comprising administering
to a patient in need thereof a therapeutically effective amount of
an MDM2 inhibitor and a MEK inhibitor.
16. The method of claim 15 wherein the AML has a FLT3-ITD
mutation.
17. A method of treating NSCLC, the method comprising administering
to a patient in need thereof a therapeutically effective amount of
an MDM2 inhibitor and a MEK inhibitor.
18. The method of claim 17 wherein the NSCLC had a KRAS
mutation.
19. A method of treating kidney cancer, the method comprising
administering to a patient in need thereof a therapeutically
effective amount of an MDM2 inhibitor and a MEK inhibitor.
20. A method of treating stomach cancer, the method comprising
administering to a patient in need thereof a therapeutically
effective amount of an MDM2 inhibitor and a MEK inhibitor.
21. The method of any one of claims 10 to 20 wherein the MEK
inhibitor is trametinib.
22. The method of any one of claims 10 to 20 wherein the MEK
inhibitor is pimasertib, PD0325901, MEK162, TAK-733, GDC-0973 or
AZD8330.
23. The method of claim 20 wherein the stomach cancer has a KRAS
mutation.
24. A method of treating AML, the method comprising administering
to a patient in need thereof a therapeutically effective amount of
an MDM2 inhibitor and ponatinib.
25. The method of claim 24 wherein the AML has a FLT3 ITD
mutation.
26. A method of treating AML, the method comprising administering
to a patient in need thereof a therapeutically effective amount of
an MDM2 inhibitor and bosutinib.
27. The method of claim 26 wherein the AML has a FLT3 ITD
mutation
28. A pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; dabrafenib;
and a pharmaceutically acceptable excipient.
29. A pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; trametinib;
and a pharmaceutically acceptable excipient.
30. A pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; nilotinib; and
a pharmaceutically acceptable excipient.
31. A pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; pimasertinib;
and a pharmaceutically acceptable excipient.
32. A pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; PD0325901; and
a pharmaceutically acceptable excipient.
33. A pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; vemurafenib;
and a pharmaceutically acceptable excipient.
34. A pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; navitoclax;
and a pharmaceutically acceptable excipient.
35. A pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; dasatinib; and
a pharmaceutically acceptable excipient.
36. A pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; panobinostat;
and a pharmaceutically acceptable excipient.
37. A pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; decitabine;
and a pharmaceutically acceptable excipient.
38. A pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; cytarabine;
and a pharmaceutically acceptable excipient.
39. A pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; doxorubicin;
and a pharmaceutically acceptable excipient.
40. A pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; etoposide; and
a pharmaceutically acceptable excipient.
41. A pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; imatinib; and
a pharmaceutically acceptable excipient.
42. A pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; ponatinib; and
a pharmaceutically acceptable excipient.
43. A pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; bosutinib; and
a pharmaceutically acceptable excipient.
44. A pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; dabrafenib;
trametinib; and a pharmaceutically acceptable excipient.
45. The method of any one of claim 1-4, or 7-29 wherein the MDM2
inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
46. A combination of an MDM2 inhibitor medicament and a MEK
inhibitor medicament for treating a solid tumor.
47. A combination of an MDM2 inhibitor medicament and a MEK
inhibitor medicament for treating AML.
48. A combination of an MDM2 inhibitor medicament and a BRAF
inhibitor medicament for treating a solid tumor.
49. A combination of an MDM2 inhibitor medicament and a BRAF
inhibitor medicament for treating AML.
50. Use of an MDM2 inhibitor in combination with a BRAF inhibitor
for manufacture of a medicament for the management or treatment of
melanoma, liver cancer, AML or colon cancer in a subject.
51. Use of an MDM2 inhibitor in combination with a MEK inhibitor
for manufacture of a medicament for the management or treatment of
melanoma, liver cancer, AML or colon cancer in a subject.
Description
PRIORITY
[0001] This application claims the benefit of U.S. Provisional
Patent Application No. 61/902,717, filed on Nov. 11, 2013 which is
hereby incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention provides combination therapy that
includes an MDM2 inhibitor and one or more additional
pharmaceutically active agents, particularly for the treatment of
cancers. The invention also relates to pharmaceutical compositions
that contain an MDM2 inhibitor and one or more additional
pharmaceutically active agents for the treatment of cancers.
BACKGROUND OF THE INVENTION
[0003] p53 is a tumor suppressor and transcription factor that
responds to cellular stress by activating the transcription of
numerous genes involved in cell cycle arrest, apoptosis,
senescence, and DNA repair. Unlike normal cells, which have
infrequent cause for p53 activation, tumor cells are under constant
cellular stress from various insults including hypoxia and
pro-apoptotic oncogene activation. Thus, there is a strong
selective advantage for inactivation of the p53 pathway in tumors,
and it has been proposed that eliminating p53 function may be a
prerequisite for tumor survival. In support of this notion, three
groups of investigators have used mouse models to demonstrate that
absence of p53 function is a continuous requirement for the
maintenance of established tumors. When the investigators restored
p53 function to tumors with inactivated p53, the tumors
regressed.
[0004] p53 is inactivated by mutation and/or loss in 50% of solid
tumors and 10% of liquid tumors. Other key members of the p53
pathway are also genetically or epigenetically altered in cancer.
MDM2, an oncoprotein, inhibits p53 function, and it is activated by
gene amplification at incidence rates that are reported to be as
high as 10%. MDM2, in turn, is inhibited by another tumor
suppressor, p14ARF. It has been suggested that alterations
downstream of p53 may be responsible for at least partially
inactivating the p53 pathway in p53 .sup.WT tumors (p53 wild type).
In support of this concept, some p53.sup.WT tumors appear to
exhibit reduced apoptotic capacity, although their capacity to
undergo cell cycle arrest remains intact. One cancer treatment
strategy involves the use of small molecules that bind MDM2 and
neutralize its interaction with p53. MDM2 inhibits p53 activity by
three mechanisms: 1) acting as an E3 ubiquitin ligase to promote
p53 degradation; 2) binding to and blocking the p53 transcriptional
activation domain; and 3) exporting p53 from the nucleus to the
cytoplasm. All three of these mechanisms would be blocked by
neutralizing the MDM2-p53 interaction. In particular, this
therapeutic strategy could be applied to tumors that are p53
.sup.WT, and studies with small molecule MDM2 inhibitors have
yielded promising reductions in tumor growth both in vitro and in
vivo. Further, in patients with p53-inactivated tumors,
stabilization of wild type p53 in normal tissues by MDM2 inhibition
might allow selective protection of normal tissues from mitotic
poisons. As used herein, MDM2 means a human MDM2 protein and p53
means a human p53 protein. It is noted that human MDM2 can also be
referred to as HDM2 or hMDM2. Several MDM2 inhibitors are in human
clinical trials for the treatment of various cancers.
[0005] The present invention relates to combination therapy with an
MDM2 inhibitor and one or more additional pharmaceutically active
agents, which particular combinations show enhanced anti-cancer
activity in certain types of cancers over what is expected when the
individual members of the combination therapy are used alone.
SUMMARY OF THE INVENTION
[0006] In embodiment 1, the present invention provides a method of
treating melanoma, the method comprising administering to a patient
in need thereof a therapeutically effective amount of an MDM2
inhibitor and a BRAF inhibitor.
[0007] In embodiment 2, the present invention provides a method of
embodiment 1 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0008] In embodiment 3, the present invention provides a method of
embodiment 1 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof.
[0009] In embodiment 4, the present invention provides a method of
any one of embodiments 1 to 3 wherein the BRAF inhibitor is
dabrafenib.
[0010] In embodiment 5, the present invention provides a method of
any one of embodiments 1 to 3 wherein the BRAF inhibitor is AMG
2112819 or vemurafenib.
[0011] In embodiment 6, the present invention provides a method of
treating melanoma, the method comprising administering to a patient
in need thereof a therapeutically effective amount of an MDM2
inhibitor and a pan-Raf inhibitor.
[0012] In embodiment 7, the present invention provides a method of
embodiment 6 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0013] In embodiment 8, the present invention provides a method of
embodiment 6 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert
-butylsulfonyl)-1-cyclopropylethyl)-6-(4-chloro-3-fluorophenyl)-5-(3-chlo-
rophenyl)-3-methyl-2-oxopiperidin-3-yl)acetamido)-2-methoxybenzoic
acid, or a pharmaceutically acceptable salt thereof.
[0014] In embodiment 9, the present invention provides a method of
any one of embodiments 6 to 8 wherein the pan-RAF inhibitor is
RAF265 or MLN-2480.
[0015] In embodiment 10, the present invention provides a method of
treating melanoma, the method comprising administering to a patient
in need thereof a therapeutically effective amount of an MDM2
inhibitor and a MEK inhibitor.
[0016] In embodiment 11, the present invention provides a method of
embodiment 10 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0017] In embodiment 12, the present invention provides a method of
embodiment 10 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3
-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)ace-
tamido)-2-methoxybenzoic acid, or a pharmaceutically acceptable
salt thereof.
[0018] In embodiment 13, the present invention provides a method of
any one of embodiments 10 to 12 wherein the MEK inhibitor is
trametinib.
[0019] In embodiment 14, the present invention provides a method of
any one of embodiments 10 to 12 wherein the MEK inhibitor is
pimasertib, PD0325901, MEK162, TAK-733, GDC-0973 or AZD8330.
[0020] In embodiment 15, the present invention provides a method of
any one of embodiments 1 to 14 wherein the melanoma has a BRAF
V600E or V600K mutation.
[0021] In embodiment 16, the present invention provides a method of
treating colon cancer, the method comprising administering to a
patient in need thereof a therapeutically effective amount of an
MDM2 inhibitor and a BRAF inhibitor.
[0022] In embodiment 17, the present invention provides a method of
embodiment 16 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0023] In embodiment 18, the present invention provides a method of
embodiment 16 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof.
[0024] In embodiment 19, the present invention provides a method of
any one of embodiments 16 to 18 wherein the BRAF inhibitor is
dabrafenib.
[0025] In embodiment 20, the present invention provides a method of
any one of embodiments 16 to 18 wherein the BRAF inhibitor is AMG
2112819 or vemurafenib.
[0026] In embodiment 21, the present invention provides a method of
treating colon cancer, the method comprising administering to a
patient in need thereof a therapeutically effective amount of an
MDM2 inhibitor and a pan-Raf inhibitor.
[0027] In embodiment 22, the present invention provides a method of
embodiment 21 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0028] In embodiment 23, the present invention provides a method of
embodiment 21 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof.
[0029] In embodiment 24, the present invention provides a method of
any one of embodiments 21 to 23 wherein the pan-RAF inhibitor is
RAF265 or MLN-2480.
[0030] In embodiment 25, the present invention provides a method of
treating colon cancer, the method comprising administering to a
patient in need thereof a therapeutically effective amount of an
MDM2 inhibitor and a MEK inhibitor.
[0031] In embodiment 26, the present invention provides a method of
embodiment 25 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0032] In embodiment 27, the present invention provides a method of
embodiment 25 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3
-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)ace-
tamido)-2-methoxybenzoic acid, or a pharmaceutically acceptable
salt thereof.
[0033] In embodiment 28, the present invention provides a method of
any one of embodiments 25 to 27 wherein the MEK inhibitor is
trametinib.
[0034] In embodiment 29, the present invention provides a method of
any one of embodiments 25 to 27 wherein the MEK inhibitor is
pimasertib, PD0325901, MEK162, TAK-733, GDC-0973 or AZD8330.
[0035] In embodiment 30, the present invention provides a method of
any one of embodiments 16 to 29 wherein the colon cancer has a BRAF
V600E or V600K mutation.
[0036] In embodiment 31, the present invention provides a method of
treating liver cancer, the method comprising administering to a
patient in need thereof a therapeutically effective amount of an
MDM2 inhibitor and a BRAF inhibitor.
[0037] In embodiment 32, the present invention provides a method of
embodiment 31 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0038] In embodiment 33, the present invention provides a method of
embodiment 31 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof.
[0039] In embodiment 34, the present invention provides a method of
any one of embodiments 31 to 33 wherein the BRAF inhibitor is
dabrafenib, or a pharmaceutically acceptable salt thereof.
[0040] In embodiment 35, the present invention provides a method of
any one of embodiments 31 to 33 wherein the BRAF inhibitor is AMG
2112819 or vemurafenib.
[0041] In embodiment 36, the present invention provides a method of
treating liver cancer, the method comprising administering to a
patient in need thereof a therapeutically effective amount of an
MDM2 inhibitor and a pan-Raf inhibitor.
[0042] In embodiment 37, the present invention provides a method of
embodiment 36 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0043] In embodiment 38, the present invention provides a method of
embodiment 36 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof.
[0044] In embodiment 39, the present invention provides a method of
any one of embodiments 36 to 38 wherein the pan-RAF inhibitor is
RAF265 or MLN-2480.
[0045] In embodiment 40, the present invention provides a method of
treating liver cancer, the method comprising administering to a
patient in need thereof a therapeutically effective amount of an
MDM2 inhibitor and a MEK inhibitor.
[0046] In embodiment 41, the present invention provides a method of
embodiment 40 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0047] In embodiment 42, the present invention provides a method of
embodiment 40 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof.
[0048] In embodiment 43, the present invention provides a method of
any one of embodiments 40 to 42 wherein the MEK inhibitor is
trametinib.
[0049] In embodiment 44, the present invention provides a method of
any one of embodiments 40 to 42 wherein the MEK inhibitor is
pimasertib, PD0325901, MEK162, TAK-733, GDC-0973 or AZD8330.
[0050] In embodiment 45, the present invention provides a method of
any one of embodiments 31 to 44 wherein the liver cancer has a BRAF
V600E or V600K mutation.
[0051] In embodiment 46, the present invention provides a method of
treating bladder cancer, the method comprising administering to a
patient in need thereof a therapeutically effective amount of an
MDM2 inhibitor and a MEK inhibitor.
[0052] In embodiment 47, the present invention provides a method of
embodiment 46 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0053] In embodiment 48, the present invention provides a method of
embodiment 46 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof.
[0054] In embodiment 49, the present invention provides a method of
any one of embodiments 46 to 48 wherein the MEK inhibitor is
trametinib.
[0055] In embodiment 50, the present invention provides a method of
any one of embodiments 46 to 48 wherein the MEK inhibitor is
pimasertib, PD0325901, MEK162, TAK-733, GDC-0973 or AZD8330.
[0056] In embodiment 51, the present invention provides a method of
treating AML, the method comprising administering to a patient in
need thereof a therapeutically effective amount of an MDM2
inhibitor and a MEK inhibitor.
[0057] In embodiment 52, the present invention provides a method of
embodiment 51 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0058] In embodiment 53, the present invention provides a method of
embodiment 51 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof.
[0059] In embodiment 54, the present invention provides a method of
any one of embodiments 51 to 53 wherein the MEK inhibitor is
trametinib.
[0060] In embodiment 55, the present invention provides a method of
any one of embodiments 51 to 53 wherein the MEK inhibitor is
pimasertib, PD0325901, MEK162, TAK-733, GDC-0973 or AZD8330.
[0061] In embodiment 56, the present invention provides a method of
any one of embodiments 51 to 55 wherein the AML has a FLT3-ITD
mutation.
[0062] In embodiment 57, the present invention provides a method of
treating NSCLC, the method comprising administering to a patient in
need thereof a therapeutically effective amount of an MDM2
inhibitor and a pan-Raf inhibitor.
[0063] In embodiment 58, the present invention provides a method of
embodiment 57 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0064] In embodiment 59, the present invention provides a method of
embodiment 57 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof.
[0065] In embodiment 60, the present invention provides a method of
any one of embodiments 57 to 59 wherein the pan-RAF inhibitor is
RAF265 or MLN-2480.
[0066] In embodiment 61, the present invention provides a method of
treating NSCLC, the method comprising administering to a patient in
need thereof a therapeutically effective amount of an MDM2
inhibitor and a MEK inhibitor.
[0067] In embodiment 62, the present invention provides a method of
embodiment 61 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0068] In embodiment 63, the present invention provides a method of
embodiment 61 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3
-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)ace-
tamido)-2-methoxybenzoic acid, or a pharmaceutically acceptable
salt thereof.
[0069] In embodiment 64, the present invention provides a method of
any one of embodiments 61 to 63 wherein the MEK inhibitor is
trametinib.
[0070] In embodiment 65, the present invention provides a method of
any one of embodiments 61 to 63 wherein the MEK inhibitor is
pimasertib, PD0325901, MEK162, TAK-733, GDC-0973 or AZD8330, or a
pharmaceutically acceptable salt thereof.
[0071] In embodiment 66, the present invention provides a method of
any one of embodiments 57 to 65 wherein the NSCLC had a KRAS
mutation.
[0072] In embodiment 67, the present invention provides a method of
treating kidney cancer, the method comprising administering to a
patient in need thereof a therapeutically effective amount of an
MDM2 inhibitor and a MEK inhibitor.
[0073] In embodiment 68, the present invention provides a method of
embodiment 67 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0074] In embodiment 69, the present invention provides a method of
embodiment 67 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof.
[0075] In embodiment 70, the present invention provides a method of
any one of embodiments 67 to 69 wherein the MEK inhibitor is
trametinib.
[0076] In embodiment 71, the present invention provides a method of
any one of embodiments 67 to 69 wherein the MEK inhibitor is
pimasertib, PD0325901, MEK162, TAK-733, GDC-0973 or AZD8330, or a
pharmaceutically acceptable salt thereof.
[0077] In embodiment 72, the present invention provides a method of
treating stomach cancer, the method comprising administering to a
patient in need thereof a therapeutically effective amount of an
MDM2 inhibitor and a MEK inhibitor.
[0078] In embodiment 73, the present invention provides a method of
embodiment 72 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0079] In embodiment 74, the present invention provides a method of
embodiment 72 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yOaceta-
mido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof.
[0080] In embodiment 75, the present invention provides a method of
any one of embodiments 72 to 74 wherein the MEK inhibitor is
trametinib.
[0081] In embodiment 76, the present invention provides a method of
any one of embodiments 72 to 74 wherein the MEK inhibitor is
pimasertib, PD0325901, MEK162, TAK-733, GDC-0973 or AZD8330.
[0082] In embodiment 77, the present invention provides a method of
any one of embodiments 72 to 76 wherein the stomach cancer had a
KRAS mutation.
[0083] In embodiment 78, the present invention provides a method of
treating prostate cancer, the method comprising administering to a
patient in need thereof a therapeutically effective amount of an
MDM2 inhibitor and a PI3K pathway inhibitor.
[0084] In embodiment 79, the present invention provides a method of
embodiment 78 wherein the PI3K pathway inhibitor is a PI3K.alpha.
selective inhibitor.
[0085] In embodiment 80, the present invention provides a method of
embodiment 79 wherein the PI3K.alpha. selective inhibitor is AMG
511, AMG2520765 or BYL719.
[0086] In embodiment 81, the present invention provides a method of
embodiment 78 wherein the PI3K pathway inhibitor is a pan-PI3K
inhibitor.
[0087] In embodiment 82, the present invention provides a method of
embodiment 81 wherein the pan-PI3K inhibitor is BKM120 or
GDC-0941.
[0088] In embodiment 83, the present invention provides a method of
embodiment 78 wherein the PI3K pathway inhibitor is an AKT
inhibitor.
[0089] In embodiment 84, the present invention provides a method of
embodiment 83 wherein the AKT inhibitor is MK-2206, GDC-0068 or
AZD5363.
[0090] In embodiment 85, the present invention provides a method of
embodiment 78 wherein the PI3K pathway inhibitor is a dual
PI3K/mTOR inhibitor.
[0091] In embodiment 86, the present invention provides a method of
embodiment 85 wherein the dual PI3K/mTOR inhibitor is GDC-0980.
[0092] In embodiment 87, the present invention provides a method of
embodiment 78 wherein the PI3K pathway inhibitor is an mTOR
inhibitor.
[0093] In embodiment 88, the present invention provides a method of
embodiment 87 wherein the mTOR inhibitor is AZD2014 or MLN0128.
[0094] In embodiment 89, the present invention provides a method of
any one of embodiments 78 to 88 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0095] In embodiment 90, the present invention provides a method of
any one of embodiments 78 to 88 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof.
[0096] In embodiment 91, the present invention provides a method of
treating breast cancer, the method comprising administering to a
patient in need thereof a therapeutically effective amount of an
MDM2 inhibitor and a PI3K pathway inhibitor.
[0097] In embodiment 92, the present invention provides a method of
embodiment 91 wherein the PI3K pathway inhibitor is a PI3K.alpha.
selective inhibitor.
[0098] In embodiment 93, the present invention provides a method of
embodiment 92 wherein the PI3K.alpha. selective inhibitor is AMG
511, AMG2520765 or BYL719.
[0099] In embodiment 94, the present invention provides a method of
claim 91 wherein the PI3K pathway inhibitor is a pan-PI3K
inhibitor.
[0100] In embodiment 95, the present invention provides a method of
embodiment 94 wherein the pan-PI3K inhibitor is BKM120 or
GDC-0941.
[0101] In embodiment 96, the present invention provides a method of
embodiment 91 wherein the PI3K pathway inhibitor is an AKT
inhibitor.
[0102] In embodiment 97, the present invention provides a method of
embodiment 96 wherein the AKT inhibitor is MK-2206, GDC-0068 or
AZD5363.
[0103] In embodiment 98, the present invention provides a method of
embodiment 91 wherein the PI3K pathway inhibitor is a dual
PI3K/mTOR inhibitor.
[0104] In embodiment 99, the present invention provides a method of
embodiment 98 wherein the dual PI3K/mTOR inhibitor is GDC-0980.
[0105] In embodiment 100, the present invention provides a method
of embodiment 91 wherein the PI3K pathway inhibitor is an mTOR
inhibitor.
[0106] In embodiment 101, the present invention provides a method
of embodiment 100 wherein the mTOR inhibitor is AZD2014 or
MLN0128.
[0107] In embodiment 102, the present invention provides a method
of any one of embodiments 91 to 101 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0108] In embodiment 103, the present invention provides a method
of any one of embodiments 91 to 101 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof.
[0109] In embodiment 104, the present invention provides a method
of any one of embodiments 91 to 103 wherein the breast cancer has a
PI3K mutation.
[0110] In embodiment 105, the present invention provides a method
of treating endometrial cancer, the method comprising administering
to a patient in need thereof a therapeutically effective amount of
an MDM2 inhibitor and a PI3K pathway inhibitor.
[0111] In embodiment 106, the present invention provides a method
of embodiment 105 wherein the PI3K pathway inhibitor is a
PI3K.alpha. selective inhibitor.
[0112] In embodiment 107, the present invention provides a method
of embodiment 106 wherein the PI3K.alpha. selective inhibitor is
AMG 511, AMG252076 or BYL719.
[0113] In embodiment 108, the present invention provides a method
of embodiment 105 wherein the PI3K pathway inhibitor is a pan-PI3K
inhibitor.
[0114] In embodiment 109, the present invention provides a method
of embodiment 108 wherein the pan-PI3K inhibitor is BKM120 or
GDC-0941.
[0115] In embodiment 110, the present invention provides a method
of embodiment 105 wherein the PI3K pathway inhibitor is an AKT
inhibitor.
[0116] In embodiment 111, the present invention provides a method
of embodiment 110 wherein the AKT inhibitor is MK-2206, GDC-0068 or
AZD5363.
[0117] In embodiment 112, the present invention provides a method
of embodiment 105 wherein the PI3K pathway inhibitor is a dual
PI3K/mTOR inhibitor.
[0118] In embodiment 113, the present invention provides a method
of embodiment 112 wherein the dual PI3K/mTOR inhibitor is
GDC-0980.
[0119] In embodiment 114, the present invention provides a method
of embodiment 105 wherein the PI3K pathway inhibitor is an mTOR
inhibitor.
[0120] In embodiment 115, the present invention provides a method
of embodiment 114 wherein the mTOR inhibitor is AZD2014 or
MLN0128.
[0121] In embodiment 116, the present invention provides a method
of any one of embodiments 105 to 115 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0122] In embodiment 117, the present invention provides a method
of any one of embodiments 105 to 115 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof.
[0123] In embodiment 118, the present invention provides a method
of treating NSCLC, the method comprising administering to a patient
in need thereof a therapeutically effective amount of an MDM2
inhibitor and a PI3K pathway inhibitor.
[0124] In embodiment 119, the present invention provides a method
of embodiment 118 wherein the PI3K pathway inhibitor is a
PI3K.alpha. selective inhibitor.
[0125] In embodiment 120, the present invention provides a method
of embodiment 119 wherein the PI3K.alpha. selective inhibitor is
AMG 511, AMG2520765 or BYL719.
[0126] In embodiment 121, the present invention provides a method
of embodiment 118 wherein the PI3K pathway inhibitor is a pan-PI3K
inhibitor.
[0127] In embodiment 122, the present invention provides a method
of embodiment 121 wherein the pan-PI3K inhibitor is BKM120 or
GDC-0941.
[0128] In embodiment 123, the present invention provides a method
of embodiment 118 wherein the PI3K pathway inhibitor is an AKT
inhibitor.
[0129] In embodiment 124, the present invention provides a method
of embodiment 123 wherein the AKT inhibitor is MK-2206, GDC-0068 or
AZD5363.
[0130] In embodiment 125, the present invention provides a method
of embodiment 118 wherein the PI3K pathway inhibitor is a dual
PI3K/mTOR inhibitor.
[0131] In embodiment 126, the present invention provides a method
of embodiment 125 wherein the dual PI3K/mTOR inhibitor is
GDC-0980.
[0132] In embodiment 127, the present invention provides a method
of embodiment 118 wherein the PI3K pathway inhibitor is an mTOR
inhibitor.
[0133] In embodiment 128, the present invention provides a method
of embodiment 127 wherein the mTOR inhibitor is AZD2014 or
MLN0128.
[0134] In embodiment 129, the present invention provides a method
of any one of embodiments 118 to 128 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0135] In embodiment 130, the present invention provides a method
of any one of embodiments 118 to 128 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof.
[0136] In embodiment 131, the present invention provides a method
of treating head and neck cancer, the method comprising
administering to a patient in need thereof a therapeutically
effective amount of an MDM2 inhibitor and a PI3K pathway
inhibitor.
[0137] In embodiment 132, the present invention provides a method
of embodiment 131 wherein the PI3K pathway inhibitor is a
PI3K.alpha. selective inhibitor.
[0138] In embodiment 133, the present invention provides a method
of embodiment 132 wherein the PI3K.alpha. selective inhibitor is
AMG 511, AMG2520765 or BYL719.
[0139] In embodiment 134, the present invention provides a method
of embodiment 131 wherein the PI3K pathway inhibitor is a pan-PI3K
inhibitor.
[0140] In embodiment 135, the present invention provides a method
of embodiment 134 wherein the pan-PI3K inhibitor is BKM120 or
GDC-0941.
[0141] In embodiment 136, the present invention provides a method
of embodiment 131 wherein the PI3K pathway inhibitor is an AKT
inhibitor.
[0142] In embodiment 137, the present invention provides a method
of embodiment 136 wherein the AKT inhibitor is MK-2206, GDC-0068 or
AZD5363.
[0143] In embodiment 138, the present invention provides a method
of embodiment 131 wherein the PI3K pathway inhibitor is a dual
PI3K/mTOR inhibitor.
[0144] In embodiment 139, the present invention provides a method
of embodiment 138 wherein the dual PI3K/mTOR inhibitor is
GDC-0980.
[0145] In embodiment 140, the present invention provides a method
of embodiment 131 wherein the PI3K pathway inhibitor is an mTOR
inhibitor.
[0146] In embodiment 141, the present invention provides a method
of embodiment 140 wherein the mTOR inhibitor is AZD2014 or
MLN0128.
[0147] In embodiment 142, the present invention provides a method
of any one of embodiments 131 to 141 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0148] In embodiment 143, the present invention provides a method
of any one of embodiments 131 to 141 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof.
[0149] In embodiment 144, the present invention provides a method
of treating DLBCL, the method comprising administering to a patient
in need thereof a therapeutically effective amount of an MDM2
inhibitor and a PI3K pathway inhibitor.
[0150] In embodiment 145, the present invention provides a method
of embodiment 144 wherein the PI3K pathway inhibitor is a
PI3K.alpha. selective inhibitor.
[0151] In embodiment 146, the present invention provides a method
of embodiment 145 wherein the PI3K.alpha. selective inhibitor is
AMG 511, AMG2520765 or BYL719.
[0152] In embodiment 147, the present invention provides a method
of embodiment 144 wherein the PI3K pathway inhibitor is a pan-PI3K
inhibitor.
[0153] In embodiment 148, the present invention provides a method
of embodiment 147 wherein the pan-PI3K inhibitor is BKM120 or
GDC-0941.
[0154] In embodiment 149, the present invention provides a method
of embodiment 144 wherein the PI3K pathway inhibitor is an AKT
inhibitor.
[0155] In embodiment 150, the present invention provides a method
of embodiment 149 wherein the AKT inhibitor is MK-2206, GDC-0068 or
AZD5363.
[0156] In embodiment 151, the present invention provides a method
of embodiment 144 wherein the PI3K pathway inhibitor is a dual
PI3K/mTOR inhibitor.
[0157] In embodiment 152, the present invention provides a method
of embodiment 151 wherein the dual PI3K/mTOR inhibitor is
GDC-0980.
[0158] In embodiment 153, the present invention provides a method
of embodiment 144 wherein the PI3K pathway inhibitor is an mTOR
inhibitor.
[0159] In embodiment 154, the present invention provides a method
of embodiment 153 wherein the mTOR inhibitor is AZD2014 or
MLN0128.
[0160] In embodiment 155, the present invention provides a method
of any one of embodiments 144 to 154 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0161] In embodiment 156, the present invention provides a method
of any one of embodiments 144 to 154 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof.
[0162] In embodiment 157, the present invention provides a method
of treating glioblastoma, the method comprising administering to a
patient in need thereof a therapeutically effective amount of an
MDM2 inhibitor and a PI3K pathway inhibitor.
[0163] In embodiment 158, the present invention provides a method
of embodiment 157 wherein the PI3K pathway inhibitor is a
PI3K.alpha. selective inhibitor.
[0164] In embodiment 159, the present invention provides a method
of embodiment 158 wherein the PI3K.alpha. selective inhibitor is
AMG 511, AMG2520765 or BYL719.
[0165] In embodiment 160, the present invention provides a method
of embodiment 157 wherein the PI3K pathway inhibitor is a pan-PI3K
inhibitor.
[0166] In embodiment 161, the present invention provides a method
of embodiment 160 wherein the pan-PI3K inhibitor is BKM120 or
GDC-0941.
[0167] In embodiment 162, the present invention provides a method
of embodiment 157 wherein the PI3K pathway inhibitor is an AKT
inhibitor.
[0168] In embodiment 163, the present invention provides a method
of embodiment 162 wherein the AKT inhibitor is MK-2206, GDC-0068 or
AZD5363.
[0169] In embodiment 164, the present invention provides a method
of embodiment 157 wherein the PI3K pathway inhibitor is a dual
PI3K/mTOR inhibitor.
[0170] In embodiment 165, the present invention provides a method
of embodiment 164 wherein the dual PI3K/mTOR inhibitor is
GDC-0980.
[0171] In embodiment 166, the present invention provides a method
of embodiment 157 wherein the PI3K pathway inhibitor is an mTOR
inhibitor.
[0172] In embodiment 167, the present invention provides a method
of embodiment 166 wherein the mTOR inhibitor is AZD2014 or
MLN0128.
[0173] In embodiment 168, the present invention provides a method
of any one of embodiments 157 to 167 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0174] In embodiment 169, the present invention provides a method
of any one of embodiments 157 to 167 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof.
[0175] In embodiment 170, the present invention provides a method
of treating bladder cancer, the method comprising administering to
a patient in need thereof a therapeutically effective amount of an
MDM2 inhibitor and a PI3K pathway inhibitor.
[0176] In embodiment 171, the present invention provides a method
of embodiment 170 wherein the PI3K pathway inhibitor is a
PI3K.alpha. selective inhibitor.
[0177] In embodiment 172, the present invention provides a method
of embodiment 171 wherein the PI3K.alpha. selective inhibitor is
AMG 511, AMG2520765 or BYL719.
[0178] In embodiment 173, the present invention provides a method
of embodiment 170 wherein the PI3K pathway inhibitor is a pan-PI3K
inhibitor.
[0179] In embodiment 174, the present invention provides a method
of embodiment 173 wherein the pan-PI3K inhibitor is BKM120 or
GDC-0941.
[0180] In embodiment 175, the present invention provides a method
of embodiment 170 wherein the PI3K pathway inhibitor is an AKT
inhibitor.
[0181] In embodiment 176, the present invention provides a method
of embodiment 175 wherein the AKT inhibitor is MK-2206, GDC-0068 or
AZD5363.
[0182] In embodiment 177, the present invention provides a method
of embodiment 170 wherein the PI3K pathway inhibitor is a dual
PI3K/mTOR inhibitor.
[0183] In embodiment 178, the present invention provides a method
of embodiment 177 wherein the dual PI3K/mTOR inhibitor is
GDC-0980.
[0184] In embodiment 179, the present invention provides a method
of embodiment 170 wherein the PI3K pathway inhibitor is an mTOR
inhibitor.
[0185] In embodiment 180, the present invention provides a method
of embodiment 179 wherein the mTOR inhibitor is AZD2014 or
MLN0128.
[0186] In embodiment 181, the present invention provides a method
of any one of embodiments 170 to 180 wherein the MDM2 inhibitor is
243R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulf-
onyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid,
or a pharmaceutically acceptable salt thereof.
[0187] In embodiment 182, the present invention provides a method
of any one of embodiments 170 to 180 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof.
[0188] In embodiment 183, the present invention provides a method
of treating AML, the method comprising administering to a patient
in need thereof a therapeutically effective amount of an MDM2
inhibitor and a PI3K pathway inhibitor.
[0189] In embodiment 184, the present invention provides a method
of embodiment 183 wherein the PI3K pathway inhibitor is a
PI3K.alpha. selective inhibitor.
[0190] In embodiment 185, the present invention provides a method
of embodiment 184 wherein the PI3K.alpha. selective inhibitor is
AMG 511, AMG2520765 or BYL719.
[0191] In embodiment 186, the present invention provides a method
of embodiment 183 wherein the PI3K pathway inhibitor is a pan-PI3K
inhibitor.
[0192] In embodiment 187, the present invention provides a method
of embodiment 186 wherein the pan-PI3K inhibitor is BKM120 or
GDC-0941.
[0193] In embodiment 188, the present invention provides a method
of embodiment 183 wherein the PI3K pathway inhibitor is an AKT
inhibitor.
[0194] In embodiment 189, the present invention provides a method
of embodiment 188 wherein the AKT inhibitor is MK-2206, GDC-0068 or
AZD5363.
[0195] In embodiment 190, the present invention provides a method
of embodiment 183 wherein the PI3K pathway inhibitor is a dual
PI3K/mTOR inhibitor.
[0196] In embodiment 191, the present invention provides a method
of embodiment 190 wherein the dual PI3K/mTOR inhibitor is
GDC-0980.
[0197] In embodiment 192, the present invention provides a method
of embodiment 183 wherein the PI3K pathway inhibitor is an mTOR
inhibitor.
[0198] In embodiment 193, the present invention provides a method
of embodiment 192 wherein the mTOR inhibitor is AZD2014 or
MLN0128.
[0199] In embodiment 194, the present invention provides a method
of any one of embodiments 183 to 193 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0200] In embodiment 195, the present invention provides a method
of any one of embodiments 183 to 193 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof.
[0201] In embodiment 196, the present invention provides a method
of any one of embodiments 183 to 195 wherein the AML has a FLT3 ITD
mutation.
[0202] In embodiment 197, the present invention provides a method
of treating bladder cancer, the method comprising administering to
a patient in need thereof a therapeutically effective amount of an
MDM2 inhibitor and a Bc12/Bc1xL inhibitor.
[0203] In embodiment 198, the present invention provides a method
of embodiment 197 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0204] In embodiment 199, the present invention provides a method
of embodiment 197 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof.
[0205] In embodiment 200, the present invention provides a method
of any one of embodiments 197 to 199 wherein the Bc12/Bc1xL
inhibitor is navitoclax.
[0206] In embodiment 201, the present invention provides a method
of treating glioblastoma, the method comprising administering to a
patient in need thereof a therapeutically effective amount of an
MDM2 inhibitor and a Bc12/Bc1xL inhibitor.
[0207] In embodiment 202, the present invention provides a method
of embodiment 201 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0208] In embodiment 203, the present invention provides a method
of embodiment 201 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof.
[0209] In embodiment 204, the present invention provides a method
of any one of embodiments 201 to 203 wherein the Bc12/Bc1xL
inhibitor is navitoclax.
[0210] In embodiment 205, the present invention provides a method
of treating head and neck cancer, the method comprising
administering to a patient in need thereof a therapeutically
effective amount of an MDM2 inhibitor and a Bc12/Bc1xL
inhibitor.
[0211] In embodiment 206, the present invention provides a method
of embodiment 205 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0212] In embodiment 207, the present invention provides a method
of embodiment 205 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof.
[0213] In embodiment 208, the present invention provides a method
of any one of embodiments 205 to 207 wherein the Bc12/Bc1xL
inhibitor is navitoclax.
[0214] In embodiment 209, the present invention provides a method
of treating kidney cancer, the method comprising administering to a
patient in need thereof a therapeutically effective amount of an
MDM2 inhibitor and a Bc12/Bc1xL inhibitor.
[0215] In embodiment 210, the present invention provides a method
of embodiment 209 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0216] In embodiment 211, the present invention provides a method
of embodiment 209 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof.
[0217] In embodiment 212, the present invention provides a method
of any one of embodiments 209 to 211 wherein the Bc12/Bc1xL
inhibitor is navitoclax.
[0218] In embodiment 213, the present invention provides a method
of treating liver cancer, the method comprising administering to a
patient in need thereof a therapeutically effective amount of an
MDM2 inhibitor and a Bc12/Bc1xL inhibitor.
[0219] In embodiment 214, the present invention provides a method
of embodiment 213 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0220] In embodiment 215, the present invention provides a method
of embodiment 213 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof.
[0221] In embodiment 216, the present invention provides a method
of any one of embodiments 213 to 215 wherein the Bc12/Bc1xL
inhibitor is navitoclax.
[0222] In embodiment 217, the present invention provides a method
of treating sarcoma, the method comprising administering to a
patient in need thereof a therapeutically effective amount of an
MDM2 inhibitor and a Bc12/Bc1xL inhibitor.
[0223] In embodiment 218, the present invention provides a method
of embodiment 217 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0224] In embodiment 219, the present invention provides a method
of embodiment 217 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof.
[0225] In embodiment 220, the present invention provides a method
of any one of embodiments 217 to 219 wherein the Bc12/Bc1xL
inhibitor is navitoclax.
[0226] In embodiment 221, the present invention provides a method
of treating AML, the method comprising administering to a patient
in need thereof a therapeutically effective amount of an MDM2
inhibitor and a Bc12/Bc1xL inhibitor.
[0227] In embodiment 222, the present invention provides a method
of embodiment 221 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0228] In embodiment 223, the present invention provides a method
of embodiment 221 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof.
[0229] In embodiment 224, the present invention provides a method
of any one of embodiments 221 to 223 wherein the Bc12/Bc1xL
inhibitor is navitoclax.
[0230] In embodiment 225, the present invention provides a method
of any one of embodiments 221 to 224 wherein the AML has a FLT3 ITD
mutation.
[0231] In embodiment 226, the present invention provides a method
of treating CML, the method comprising administering to a patient
in need thereof a therapeutically effective amount of an MDM2
inhibitor and a Bc12/Bc1xL inhibitor.
[0232] In embodiment 227, the present invention provides a method
of embodiment 226 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0233] In embodiment 228, the present invention provides a method
of embodiment 226 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof.
[0234] In embodiment 229, the present invention provides a method
of any one of embodiments 226 to 228 wherein the Bc12/Bc1xL
inhibitor is navitoclax.
[0235] In embodiment 230, the present invention provides a method
of any one of embodiments 226 to 229 where the CML has a BCR-ABL
mutation.
[0236] In embodiment 231, the present invention provides a method
of treating DLBCL, the method comprising administering to a patient
in need thereof a therapeutically effective amount of an MDM2
inhibitor and a Bc12/Bc1xL inhibitor.
[0237] In embodiment 32, the present invention provides a method of
embodiment 231 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0238] In embodiment 233, the present invention provides a method
of embodiment 231 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof.
[0239] In embodiment 234, the present invention provides a method
of any one of embodiments 231 to 233 wherein the Bc12/Bc1xL
inhibitor is navitoclax.
[0240] In embodiment 235, the present invention provides a method
of treating sarcoma, the method comprising administering to a
patient in need thereof a therapeutically effective amount of an
MDM2 inhibitor and a BCL2 inhibitor.
[0241] In embodiment 236, the present invention provides a method
of embodiment 235 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0242] In embodiment 237, the present invention provides a method
of embodiment 235 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof.
[0243] In embodiment 238, the present invention provides a method
of any one of embodiments 235 to 237 wherein the BCL2 inhibitor is
ABT-199.
[0244] In embodiment 239, the present invention provides a method
of treating AML, the method comprising administering to a patient
in need thereof a therapeutically effective amount of an MDM2
inhibitor and a BCL2 inhibitor.
[0245] In embodiment 240, the present invention provides a method
of embodiment 239 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0246] In embodiment 241, the present invention provides a method
of embodiment 239 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof.
[0247] In embodiment 242, the present invention provides a method
of any one of embodiments 239 to 241 wherein the BCL2 inhibitor is
ABT-199.
[0248] In embodiment 243, the present invention provides a method
of any one of embodiments 239 to 242 wherein the AML has a FLT3 ITD
mutation.
[0249] In embodiment 244, the present invention provides a method
of treating CML, the method comprising administering to a patient
in need thereof a therapeutically effective amount of an MDM2
inhibitor and a BCL2 inhibitor.
[0250] In embodiment 245, the present invention provides a method
of embodiment 244 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0251] In embodiment 246, the present invention provides a method
of embodiment 244 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof.
[0252] In embodiment 247, the present invention provides a method
of any one of embodiments 244 to 246 wherein the BCL2 inhibitor is
ABT-199.
[0253] In embodiment 248, the present invention provides a method
of any one of embodiments 244 to 247 where the CML has a BCR-ABL
mutation.
[0254] In embodiment 249, the present invention provides a method
of treating DLBCL, the method comprising administering to a patient
in need thereof a therapeutically effective amount of an MDM2
inhibitor and a BCL2 inhibitor.
[0255] In embodiment 250, the present invention provides a method
of embodiment 249 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0256] In embodiment 251, the present invention provides a method
of embodiment 249 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof.
[0257] In embodiment 252, the present invention provides a method
of any one of embodiments 249 to 251 wherein the BCL2 inhibitor is
ABT-199.
[0258] In embodiment 253, the present invention provides a method
of treating endometrial cancer, the method comprising administering
to a patient in need thereof a therapeutically effective amount of
an MDM2 inhibitor and a BCR-ABL inhibitor.
[0259] In embodiment 254, the present invention provides a method
of embodiment 253 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0260] In embodiment 255, the present invention provides a method
of embodiment 253 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof.
[0261] In embodiment 256, the present invention provides a method
of any one of embodiments 253 to 255 wherein the BCR-ABL inhibitor
is dasatinib.
[0262] In embodiment 257, the present invention provides a method
of treating glioblastoma, the method comprising administering to a
patient in need thereof a therapeutically effective amount of an
MDM2 inhibitor and a BCR-ABL inhibitor.
[0263] In embodiment 258, the present invention provides a method
of embodiment 257 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0264] In embodiment 259, the present invention provides a method
of embodiment 257 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof.
[0265] In embodiment 260, the present invention provides a method
of any one of embodiments 257 to 259 wherein the BCR-ABL inhibitor
is dasatinib.
[0266] In embodiment 261, the present invention provides a method
of treating CML, the method comprising administering to a patient
in need thereof a therapeutically effective amount of an MDM2
inhibitor and a BCR-ABL inhibitor.
[0267] In embodiment 262, the present invention provides a method
of embodiment 261 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0268] In embodiment 263, the present invention provides a method
of embodiment 261 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof.
[0269] In embodiment 264, the present invention provides a method
of any one of embodiments 261 to 263 wherein the BCR-ABL inhibitor
is dasatinib.
[0270] In embodiment 265, the present invention provides a method
of any one of embodiments 261 to 264 where the CML has a BCR-ABL
mutation.
[0271] In embodiment 266, the present invention provides a method
of treating endometrial cancer, the method comprising administering
to a patient in need thereof a therapeutically effective amount of
an MDM2 inhibitor and a BCR-ABL inhibitor.
[0272] In embodiment 267, the present invention provides a method
of embodiment 266 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0273] In embodiment 268, the present invention provides a method
of embodiment 266 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof.
[0274] In embodiment 269, the present invention provides a method
of any one of embodiments 266 to 268 wherein the BCR-ABL inhibitor
is dasatinib.
[0275] In embodiment 270, the present invention provides a method
of treating bladder cancer, the method comprising administering to
a patient in need thereof a therapeutically effective amount of an
MDM2 inhibitor and a BCR-ABL inhibitor.
[0276] In embodiment 271, the present invention provides a method
of embodiment 270 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0277] In embodiment 272, the present invention provides a method
of embodiment 270 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof.
[0278] In embodiment 273, the present invention provides a method
of any one of embodiments 270 to 272 wherein the BCR-ABL inhibitor
is dasatinib.
[0279] In embodiment 274, the present invention provides a method
of treating head and neck cancer, the method comprising
administering to a patient in need thereof a therapeutically
effective amount of an MDM2 inhibitor and a BCR-ABL inhibitor.
[0280] In embodiment 275, the present invention provides a method
of embodiment 274 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0281] In embodiment 276, the present invention provides a method
of embodiment 274 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof.
[0282] In embodiment 277, the present invention provides a method
of any one of embodiments 274 to 276 wherein the BCR-ABL inhibitor
is dasatinib.
[0283] In embodiment 278, the present invention provides a method
of treating kidney cancer, the method comprising administering to a
patient in need thereof a therapeutically effective amount of an
MDM2 inhibitor and a HDAC inhibitor.
[0284] In embodiment 279, the present invention provides a method
of embodiment 278 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0285] In embodiment 280, the present invention provides a method
of embodiment 278 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof.
[0286] In embodiment 281, the present invention provides a method
of any one of embodiments 278 to 280 wherein the HDAC inhibitor is
panobinostat.
[0287] In embodiment 282, the present invention provides a method
of treating liver cancer, the method comprising administering to a
patient in need thereof a therapeutically effective amount of an
MDM2 inhibitor and a HDAC inhibitor.
[0288] In embodiment 283, the present invention provides a method
of embodiment 282 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0289] In embodiment 284, the present invention provides a method
of embodiment 282 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof.
[0290] In embodiment 285, the present invention provides a method
of any one of embodiments 282 to 284 wherein the HDAC inhibitor is
panobinostat.
[0291] In embodiment 286, the present invention provides a method
of treating melanoma, the method comprising administering to a
patient in need thereof a therapeutically effective amount of an
MDM2 inhibitor and a HDAC inhibitor.
[0292] In embodiment 287, the present invention provides a method
of embodiment 286 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0293] In embodiment 288, the present invention provides a method
of embodiment 286 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof.
[0294] In embodiment 289, the present invention provides a method
of any one of embodiments 286 to 288 wherein the HDAC inhibitor is
panobinostat.
[0295] In embodiment 290, the present invention provides a method
of treating AML, the method comprising administering to a patient
in need thereof a therapeutically effective amount of an MDM2
inhibitor and decitabine.
[0296] In embodiment 291, the present invention provides a method
of embodiment 290 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0297] In embodiment 292, the present invention provides a method
of embodiment 290 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof.
[0298] In embodiment 293, the present invention provides a method
of any one of embodiments 290 to 292 wherein the AML has a FLT3 ITD
mutation.
[0299] In embodiment 294, the present invention provides a method
of treating AML, the method comprising administering to a patient
in need thereof a therapeutically effective amount of an MDM2
inhibitor and cytarabine.
[0300] In embodiment 295, the present invention provides a method
of embodiment 294 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0301] In embodiment 296, the present invention provides a method
of embodiment 294 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof.
[0302] In embodiment 297, the present invention provides a method
of any one of embodiments 294 to 296 wherein the AML has a FLT3 ITD
mutation.
[0303] In embodiment 298, the present invention provides a method
of treating AML, the method comprising administering to a patient
in need thereof a therapeutically effective amount of an MDM2
inhibitor and doxorubicin.
[0304] In embodiment 299, the present invention provides a method
of embodiment 298 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0305] In embodiment 300, the present invention provides a method
of embodiment 298 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof.
[0306] In embodiment 301, the present invention provides a method
of any one of embodiments 298 to 300 wherein the AML has a FLT3 ITD
mutation.
[0307] In embodiment 302, the present invention provides a method
of treating sarcoma, the method comprising administering to a
patient in need thereof a therapeutically effective amount of an
MDM2 inhibitor and etoposide.
[0308] In embodiment 303, the present invention provides a method
of embodiment 302 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0309] In embodiment 304, the present invention provides a method
of embodiment 302 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof.
[0310] In embodiment 305, the present invention provides a method
of treating breast cancer, the method comprising administering to a
patient in need thereof a therapeutically effective amount of an
MDM2 inhibitor and doxorubicin.
[0311] In embodiment 306, the present invention provides a method
of embodiment 305 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0312] In embodiment 307, the present invention provides a method
of embodiment 305 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof.
[0313] In embodiment 308, the present invention provides a method
of treating AML, the method comprising administering to a patient
in need thereof a therapeutically effective amount of an MDM2
inhibitor and imatinib.
[0314] In embodiment 309, the present invention provides a method
of embodiment 308 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0315] In embodiment 310, the present invention provides a method
of embodiment 308 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof.
[0316] In embodiment 311, the present invention provides a method
of any one of embodiments 308 to 310 wherein the AML has a FLT3 ITD
mutation.
[0317] In embodiment 312, the present invention provides a method
of treating AML, the method comprising administering to a patient
in need thereof a therapeutically effective amount of an MDM2
inhibitor and ponatinib.
[0318] In embodiment 313, the present invention provides a method
of embodiment 312 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0319] In embodiment 314, the present invention provides a method
of embodiment 312 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof.
[0320] In embodiment 315, the present invention provides a method
of any one of embodiments 312 to 314 wherein the AML has a FLT3 ITD
mutation.
[0321] In embodiment 316, the present invention provides a method
of treating AML, the method comprising administering to a patient
in need thereof a therapeutically effective amount of an MDM2
inhibitor and bosutinib.
[0322] In embodiment 317, the present invention provides a method
of embodiment 316 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0323] In embodiment 318, the present invention provides a method
of embodiment 316 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof.
[0324] In embodiment 319, the present invention provides a method
of any one of embodiments 316 to 318 wherein the AML has a FLT3 ITD
mutation
[0325] In embodiment 320, the present invention provides a method
of treating AML, the method comprising administering to a patient
in need thereof a therapeutically effective amount of an MDM2
inhibitor and nilotinib.
[0326] In embodiment 321, the present invention provides a method
of embodiment 320 wherein the MDM2 inhibitor is
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof.
[0327] In embodiment 322, the present invention provides a method
of embodiment 320 wherein the MDM2 inhibitor is
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof.
[0328] In embodiment 323, the present invention provides a method
of any one of embodiments 320 to 322 wherein the AML has a FLT3 ITD
mutation
[0329] In embodiment 324, the present invention provides a method
of treating melanoma, the method comprising administering to a
patient in need thereof a therapeutically effective amount of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, dabrafenib and trametinib.
[0330] In embodiment 325, the present invention provides a method
of treating melanoma, the method comprising administering to a
patient in need thereof a therapeutically effective amount of
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, dabrafenib and trametinib.
[0331] In embodiment 326, the present invention provides a method
of any one of embodiments 324 to 325 wherein the melanoma has a
BRAF V600E or V600K mutation.
[0332] In embodiment 327, the present invention provides a
pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; dabrafenib;
and a pharmaceutically acceptable excipient.
[0333] In embodiment 328, the present invention provides a
pharmaceutical composition comprising:
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof; dabrafenib; and a pharmaceutically acceptable
excipient.
[0334] In embodiment 329, the present invention provides a
pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; AMG 2112819;
and a pharmaceutically acceptable excipient.
[0335] In embodiment 330, the present invention provides a
pharmaceutical composition comprising:
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof; AMG 2112819; and a pharmaceutically acceptable
excipient.
[0336] In embodiment 331, the present invention provides a
pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; RAF265; and a
pharmaceutically acceptable excipient.
[0337] In embodiment 332, the present invention provides a
pharmaceutical composition comprising:
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof; RAF265; and a pharmaceutically acceptable excipient.
[0338] In embodiment 333, the present invention provides a
pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; MLN-2480; and
a pharmaceutically acceptable excipient.
[0339] In embodiment 334, the present invention provides a
pharmaceutical composition comprising:
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof; MLN-2480; and a pharmaceutically acceptable excipient.
[0340] In embodiment 335, the present invention provides a
pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; trametinib;
and a pharmaceutically acceptable excipient.
[0341] In embodiment 336, the present invention provides a
pharmaceutical composition comprising:
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof; trametinib; and a pharmaceutically acceptable
excipient.
[0342] In embodiment 337, the present invention provides a
pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; nilotinib; and
a pharmaceutically acceptable excipient.
[0343] In embodiment 338, the present invention provides a
pharmaceutical composition comprising:
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof; nilotinib; and a pharmaceutically acceptable
excipient.
[0344] In embodiment 339, the present invention provides a
pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; pimasertinib;
and a pharmaceutically acceptable excipient.
[0345] In embodiment 340, the present invention provides a
pharmaceutical composition comprising:
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof; pimasertinib; and a pharmaceutically acceptable
excipient.
[0346] In embodiment 341, the present invention provides a
pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; PD0325901; and
a pharmaceutically acceptable excipient.
[0347] In embodiment 342, the present invention provides a
pharmaceutical composition comprising:
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof; PD0325901; and a pharmaceutically acceptable
excipient.
[0348] In embodiment 343, the present invention provides a
pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; MEK 162; and a
pharmaceutically acceptable excipient.
[0349] In embodiment 344, the present invention provides a
pharmaceutical composition comprising:
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof; MEK 162; and a pharmaceutically acceptable excipient.
[0350] In embodiment 345, the present invention provides a
pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; TAK-733; and a
pharmaceutically acceptable excipient.
[0351] In embodiment 346, the present invention provides a
pharmaceutical composition comprising:
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof; TAK-733; and a pharmaceutically acceptable excipient.
[0352] In embodiment 347, the present invention provides a
pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; GDC-0973; and
a pharmaceutically acceptable excipient.
[0353] In embodiment 348, the present invention provides a
pharmaceutical composition comprising:
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof; GDC-0973; and a pharmaceutically acceptable excipient.
[0354] In embodiment 349, the present invention provides a
pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; AZD 8330; and
a pharmaceutically acceptable excipient.
[0355] In embodiment 350, the present invention provides a
pharmaceutical composition comprising:
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof; AZD 8330; and a pharmaceutically acceptable excipient.
[0356] In embodiment 351, the present invention provides a
pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; vemurafenib;
and a pharmaceutically acceptable excipient.
[0357] In embodiment 352, the present invention provides a
pharmaceutical composition comprising:
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof; vemurafenib; and a pharmaceutically acceptable
excipient.
[0358] In embodiment 353, the present invention provides a
pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; AMG 511; and a
pharmaceutically acceptable excipient.
[0359] In embodiment 354, the present invention provides a
pharmaceutical composition comprising:
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof; AMG 511; and a pharmaceutically acceptable excipient.
[0360] In embodiment 355, the present invention provides a
pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; AMG 2520765;
and a pharmaceutically acceptable excipient.
[0361] In embodiment 356, the present invention provides a
pharmaceutical composition comprising:
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof; AMG 2520765; and a pharmaceutically acceptable
excipient.
[0362] In embodiment 357, the present invention provides a
pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; BYL719; and a
pharmaceutically acceptable excipient.
[0363] In embodiment 358, the present invention provides a
pharmaceutical composition comprising:
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof; BYL719; and a pharmaceutically acceptable excipient.
[0364] In embodiment 359, the present invention provides a
pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; BKM 120; and a
pharmaceutically acceptable excipient.
[0365] In embodiment 360, the present invention provides a
pharmaceutical composition comprising:
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof; BKM 120; and a pharmaceutically acceptable excipient.
[0366] In embodiment 361, the present invention provides a
pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; GDC-0941; and
a pharmaceutically acceptable excipient.
[0367] In embodiment 362, the present invention provides a
pharmaceutical composition comprising:
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof; GDC-0941; and a pharmaceutically acceptable excipient.
[0368] In embodiment 363, the present invention provides a
pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; MK-2206; and a
pharmaceutically acceptable excipient.
[0369] In embodiment 364, the present invention provides a
pharmaceutical composition comprising:
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof; MK-2206; and a pharmaceutically acceptable excipient.
[0370] In embodiment 365, the present invention provides a
pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; AZD 5363; and
a pharmaceutically acceptable excipient.
[0371] In embodiment 366, the present invention provides a
pharmaceutical composition comprising:
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof; AZD 5363; and a pharmaceutically acceptable excipient.
[0372] In embodiment 367, the present invention provides a
pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; GDC-0068; and
a pharmaceutically acceptable excipient.
[0373] In embodiment 368, the present invention provides a
pharmaceutical composition comprising:
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof; GDC-0068; and a pharmaceutically acceptable excipient.
[0374] In embodiment 369, the present invention provides a
pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; GDC-0980; and
a pharmaceutically acceptable excipient.
[0375] In embodiment 370, the present invention provides a
pharmaceutical composition comprising:
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof; GDC-0980; and a pharmaceutically acceptable excipient.
[0376] In embodiment 371, the present invention provides a
pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; AZD2014; and a
pharmaceutically acceptable excipient.
[0377] In embodiment 372, the present invention provides a
pharmaceutical composition comprising:
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof; AZD2014; and a pharmaceutically acceptable excipient.
[0378] In embodiment 373, the present invention provides a
pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; MLN0128; and a
pharmaceutically acceptable excipient.
[0379] In embodiment 374, the present invention provides a
pharmaceutical composition comprising:
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof; MLN0128; and a pharmaceutically acceptable excipient.
[0380] In embodiment 375, the present invention provides a
pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; navitoclax;
and a pharmaceutically acceptable excipient.
[0381] In embodiment 376, the present invention provides a
pharmaceutical composition comprising:
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chloropheny
1)-3-methyl-2-oxopiperidin-3-yl)acetamido)-2-methoxybenzoic acid,
or a pharmaceutically acceptable salt thereof; navitoclax; and a
pharmaceutically acceptable excipient.
[0382] In embodiment 377, the present invention provides a
pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; ABT-199; and a
pharmaceutically acceptable excipient.
[0383] In embodiment 378, the present invention provides a
pharmaceutical composition comprising:
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof; ABT-199; and a pharmaceutically acceptable excipient.
[0384] In embodiment 379, the present invention provides a
pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; dasatinib; and
a pharmaceutically acceptable excipient.
[0385] In embodiment 380, the present invention provides a
pharmaceutical composition comprising:
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof; dasatinib; and a pharmaceutically acceptable
excipient.
[0386] In embodiment 381, the present invention provides a
pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; panobinostat;
and a pharmaceutically acceptable excipient.
[0387] In embodiment 382, the present invention provides a
pharmaceutical composition comprising:
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof; panobinostat; and a pharmaceutically acceptable
excipient.
[0388] In embodiment 383, the present invention provides a
pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; decitabine;
and a pharmaceutically acceptable excipient.
[0389] In embodiment 384, the present invention provides a
pharmaceutical composition comprising:
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof; decitabine; and a pharmaceutically acceptable
excipient.
[0390] In embodiment 385, the present invention provides a
pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; cytarabine;
and a pharmaceutically acceptable excipient.
[0391] In embodiment 386, the present invention provides a
pharmaceutical composition comprising:
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof; cytarabine; and a pharmaceutically acceptable
excipient.
[0392] In embodiment 387, the present invention provides a
pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; doxorubicin;
and a pharmaceutically acceptable excipient.
[0393] In embodiment 388, the present invention provides a
pharmaceutical composition comprising:
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof; doxorubicin; and a pharmaceutically acceptable
excipient.
[0394] In embodiment 389, the present invention provides a
pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; etoposide; and
a pharmaceutically acceptable excipient.
[0395] In embodiment 390, the present invention provides a
pharmaceutical composition comprising:
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof; etoposide; and a pharmaceutically acceptable
excipient.
[0396] In embodiment 391, the present invention provides a
pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; imatinib; and
a pharmaceutically acceptable excipient.
[0397] In embodiment 392, the present invention provides a
pharmaceutical composition comprising:
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof; imatinib; and a pharmaceutically acceptable excipient.
[0398] In embodiment 393, the present invention provides a
pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; ponatinib; and
a pharmaceutically acceptable excipient.
[0399] In embodiment 394, the present invention provides a
pharmaceutical composition comprising:
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof; ponatinib; and a pharmaceutically acceptable
excipient.
[0400] In embodiment 395, the present invention provides a
pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; bosutinib; and
a pharmaceutically acceptable excipient.
[0401] In embodiment 396, the present invention provides a
pharmaceutical composition comprising:
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof; bosutinib; and a pharmaceutically acceptable
excipient.
[0402] In embodiment 397, the present invention provides a
pharmaceutical composition comprising:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, or a pharmaceutically acceptable salt thereof; dabrafenib;
trametinib; and a pharmaceutically acceptable excipient.
[0403] In embodiment 398, the present invention provides a
pharmaceutical composition comprising:
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoic acid, or a pharmaceutically acceptable salt
thereof; dabrafenib; trametinib; and a pharmaceutically acceptable
excipient.
[0404] In embodiment 399, the present invention provides a method
of treating melanoma comprising administering to a patient in need
thereof a therapeutically effective amount of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid, and dabrafenib.
[0405] In embodiment 400, the present invention provides a
combination of an MDM2 inhibitor medicament and a MEK inhibitor
medicament for treating a solid tumor.
[0406] In embodiment 401, the present invention provides a
combination of an MDM2 inhibitor medicament and a MEK inhibitor
medicament for treating AML.
[0407] In embodiment 402, the present invention provides a
combination of an MDM2 inhibitor medicament and a BRAF inhibitor
medicament for treating a solid tumor.
[0408] In embodiment 403, the present invention provides a
combination of an MDM2 inhibitor medicament and a BRAF inhibitor
medicament for treating AML.
[0409] In embodiment 404, the present invention provides a use of
an MDM2 inhibitor in combination with a BRAF inhibitor for
manufacture of a medicament for the management or treatment of
melanoma, liver cancer, AML or colon cancer in a subject.
[0410] In embodiment 405, the present invention provides a use of
an MDM2 inhibitor in combination with a MEK inhibitor for
manufacture of a medicament for the management or treatment of
melanoma, liver cancer, AML or colon cancer in a subject.
[0411] A further embodiment of the invention includes the use of a
combination comprising an MDM2 inhibitor with another therapeutic
agent selected from a RAF inhibitor, a MEK inhibitor, a Pi3K a
selective inhibitor, an mTOR inhibitor, an AKT inhibitor or an
Aurora kinase inhibitor. A further embodiment of the invention
includes the use of a combination for treatment of cancer, the
combination comprising an MDM2 inhibitor with another therapeutic
agent selected from a RAF inhibitor, an MEK inhibitor, a Pi3K a
selective inhibitor, an mTOR inhibitor, an AKT inhibitor or an
Aurora kinase inhibitor. A further embodiment of the invention
includes a method of using a combination comprising an MDM2
inhibitor with another therapeutic agent selected from a RAF
inhibitor, a MEK inhibitor, a Pi3K a selective inhibitor, an mTOR
inhibitor, an AKT inhibitor or an Aurora kinase inhibitor, for the
treatment of cancer. A further embodiment of the invention includes
the use of a combination for treatment of cancer, the combination
comprising an MDM2 inhibitor with another therapeutic agent
selected from a RAF inhibitor, an MEK inhibitor, a Pi3K a selective
inhibitor, an mTOR inhibitor, an AKT inhibitor or an Aurora kinase
inhibitor, wherein the use comprises self-administering the
combination.
[0412] A further embodiment of the invention includes a method of
treating cancer comprising prescribing a combination further
comprising an MDM2 inhibitor with another therapeutic agent
selected from a RAF inhibitor, a MEK inhibitor, a Pi3K a selective
inhibitor, an mTOR inhibitor, an AKT inhibitor or an Aurora kinase
inhibitor. A further embodiment of the invention includes a method
of treating cancer comprising prescribing to a subject in need
thereof, a combination further comprising an MDM2 inhibitor with
another therapeutic agent selected from a RAF inhibitor, a MEK
inhibitor, a Pi3K a selective inhibitor, an mTOR inhibitor, an AKT
inhibitor or an Aurora kinase inhibitor. A further embodiment of
the invention includes a method of treating cancer comprising
prescribing a combination containing an MDM2 inhibitor with another
therapeutic agent selected from a RAF inhibitor, a MEK inhibitor, a
Pi3K a selective inhibitor, an mTOR inhibitor, an AKT inhibitor or
an Aurora kinase inhibitor.
[0413] A further embodiment of the invention includes a method of
treating cancer using a combination comprising an MDM2 inhibitor
with another therapeutic agent selected from a RAF inhibitor, a MEK
inhibitor, a Pi3K a selective inhibitor, an mTOR inhibitor, an AKT
inhibitor or an Aurora kinase inhibitor, wherein such method
further comprises listing said combination in a formulary and
directing a patient in need of such cancer treatment to administer
the combination. A further embodiment of the invention includes a
method of treating cancer using a combination comprising an MDM2
inhibitor with another therapeutic agent selected from a RAF
inhibitor, a MEK inhibitor, a Pi3K a selective inhibitor, an mTOR
inhibitor, an AKT inhibitor or an Aurora kinase inhibitor, wherein
such method further comprises listing said combination in a
formulary and directing a patient in need of such cancer treatment
to self-administer the combination.
[0414] A further embodiment of the invention includes a method of
treating cancer using a combination comprising an MDM2 inhibitor
with another therapeutic agent selected from a RAF inhibitor, a MEK
inhibitor, a Pi3K a selective inhibitor, an mTOR inhibitor, an AKT
inhibitor or an Aurora kinase inhibitor, wherein such method
further comprises selling said combination for self-administration
to a patient in need of such cancer treatment.
[0415] A further embodiment of the invention includes a method of
using a combination comprising an MDM2 inhibitor with another
therapeutic agent selected from a RAF inhibitor, a MEK inhibitor, a
Pi3K a selective inhibitor, an mTOR inhibitor, an AKT inhibitor or
an Aurora kinase inhibitor, for the treatment of cancer, wherein
such method comprises purchasing said combination for
self-administration by a patient in need of such cancer treatment.
A further embodiment of the invention includes a method of using a
combination comprising an MDM2 inhibitor with another therapeutic
agent selected from a RAF inhibitor, a MEK inhibitor, a Pi3K a
selective inhibitor, an mTOR inhibitor, an AKT inhibitor or an
Aurora kinase inhibitor, for the treatment of cancer, wherein such
method comprises purchasing said combination for administration by
a patient in need of such cancer treatment.
[0416] A further embodiment of the invention includes a method of
treating cancer comprising instructing a subject in need of such
treatment to administer a combination comprising an MDM2 inhibitor
with another therapeutic agent selected from a RAF inhibitor, a MEK
inhibitor, a Pi3K a selective inhibitor, an mTOR inhibitor, an AKT
inhibitor or an Aurora kinase inhibitor. A further embodiment of
the invention includes a process of treating cancer comprising
[0417] A] prescribing
[0418] B] selling or advertising to sell,
[0419] C] purchasing,
[0420] D] instructing to self-administer, or
[0421] E] administering
[0422] of a combination described herein, wherein the combination
has been approved by a regulatory agency for the treatment of
cancer, to a subject in need of cancer treatment.
[0423] A further embodiment of the invention includes a method of
supplying a combination comprising an MDM2 inhibitor with another
therapeutic agent selected from a RAF inhibitor, a MEK inhibitor, a
Pi3K a selective inhibitor, an mTOR inhibitor, an AKT inhibitor or
an Aurora kinase inhibitor for treating cancer, said method
comprises reimbursing a physician, a formulary, a patient or an
insurance company for the sale of said combination.
[0424] For clarity, the term "instructing" is meant to include
information on a label approved by a regulatory agency, in addition
to its commonly understood definition.
BRIEF DESCRIPTION OF THE DRAWINGS
[0425] FIG. 1 shows data for the combination of compound 1 and
compound A with A204 cells.
[0426] FIG. 1a shows data for the combination of compound 1 and
compound A with A204 cells.
[0427] FIG. 2 shows data for the combination of compound 1 and
compound A with A375sq2 cells.
[0428] FIG. 2a shows data for the combination of compound 1 and
compound A with A375sq2 cells.
[0429] FIG. 3 shows data for the combination of compound 2 and
compound B with A-427 cells.
[0430] FIG. 3a shows data for the combination of compound 2 and
compound B with A-427 cells.
[0431] FIG. 4 shows data for the combination of compound 1 and
compound B with C32 cells.
[0432] FIG. 4a shows data for the combination of compound 1 and
compound B with C32 cells.
[0433] FIG. 5 shows data for the combination of compound 2 and
compound B with C32 cells.
[0434] FIG. 5a shows data for the combination of compound 2 and
compound B with C32 cells.
[0435] FIG. 6 shows data for the combination of compound 1 and
compound A with G-361 cells.
[0436] FIG. 6a shows data for the combination of compound 1 and
compound A with G-361 cells.
[0437] FIG. 7 shows data for the combination of compound 1 and
compound A with LS 174T cells.
[0438] FIG. 7a shows data for the combination of compound 1 and
compound A with LS 174T cells.
[0439] FIG. 8 shows data for the combination of compound 1 and
compound A with MCF7 cells.
[0440] FIG. 8a shows data for the combination of compound 1 and
compound A with MCF7 cells.
[0441] FIG. 9 shows data for the combination of compound 1 and
compound B with NCI-H1666 cells.
[0442] FIG. 9a shows data for the combination of compound 1 and
compound B with NCI-H1666 cells.
[0443] FIG. 10 shows data for the combination of compound 2 and
compound B with NCI-H1666 cells.
[0444] FIG. 10a shows data for the combination of compound 2 and
compound B with NCI-H1666 cells.
[0445] FIG. 11 shows data for the combination of compound 1 and
compound A with RKO cells.
[0446] FIG. 11 a shows data for the combination of compound 1 and
compound A with RKO cells.
[0447] FIG. 12 shows data for the combination of compound 2 and
compound B with RKO cells.
[0448] FIG. 12a shows data for the combination of compound 2 and
compound B with RKO cells.
[0449] FIG. 13 shows data for the combination of compound 1 and
compound B with RT4 cells.
[0450] FIG. 13a shows data for the combination of compound 1 and
compound B with RT4 cells.
[0451] FIG. 14 shows the data for the combination of compound 2 and
compound B with RT4 cells.
[0452] FIG. 14a shows data for the combination of compound 2 and
compound B with RT4 cells.
[0453] FIG. 15 shows data for the combination of compound 1 and
compound B with SH-4 cells.
[0454] FIG. 15a shows data for the combination of compound 1 and
compound B with SH-4 cells.
[0455] FIG. 16 shows data for the combination of compound 2 and
compound B with SH-4 cells.
[0456] FIG. 16a shows data for the combination of compound 2 and
compound B with SH-4 cells.
[0457] FIG. 17 shows data for the combination of compound 1 and
compound B with SK-HEP-1 cells.
[0458] FIG. 17a shows data for the combination of compound 1 and
compound B with SK-HEP-1 cells.
[0459] FIG. 18 shows data for the combination of compound 2 and
compound B with SK-HEP-1 cells.
[0460] FIG. 18a shows data for the combination of compound 2 and
compound B with SK-HEP-1 cells.
[0461] FIG. 19 shows data for the combination of compound 3 and
compound A with A204 cells.
[0462] FIG. 19a shows data for the combination of compound 3 and
compound A with A204 cells.
[0463] FIG. 20 shows data for the combination of compound 3 and
compound A with A375sq2 cells.
[0464] FIG. 20a shows data for the combination of compound 3 and
compound A with A375sq2 cells.
[0465] FIG. 21 shows data for the combination of compound 3 and
compound B with A-427 cells.
[0466] FIG. 21a shows data for the combination of compound 3 and
compound B with A-427 cells.
[0467] FIG. 22 shows data for the combination of compound 4 and
compound B with A-427 cells.
[0468] FIG. 22a shows data for the combination of compound 4 and
compound B with A-427 cells.
[0469] FIG. 23 shows data for the combination of compound 3 and
compound B with C32 cells.
[0470] FIG. 23a shows data for the combination of compound 3 and
compound B with C32 cells.
[0471] FIG. 24 shows data for the combination of compound 4 and
compound B with C32 cells.
[0472] FIG. 24a shows data for the combination of compound 4 and
compound B with C32 cells.
[0473] FIG. 25 shows data for the combination of compound 3 and
compound A with G-361cells.
[0474] FIG. 25a shows data for the combination of compound 3 and
compound A with G-361 cells. FIGS. 26 and 26a omitted.
[0475] FIG. 27 shows data for the combination of compound 3 and
compound A with LS 174T cells.
[0476] FIG. 27a shows data for the combination of compound 3 and
compound A with LS 174T cells.
[0477] FIG. 28 shows data for the combination of compound 3 and
compound A with MCF7 cells. FIG. 28a shows data for the combination
of compound 3 and compound A with MCF7 cells.
[0478] FIG. 29 shows data for the combination of compound 3 and
compound B with NCI-H1666 cells.
[0479] FIG. 29a shows data for the combination of compound 3 and
compound B with NCI-H1666 cells.
[0480] FIG. 30 shows data for the combination of compound 4 and
compound B with NCI-H1666 cells.
[0481] FIG. 30a shows data for the combination of compound 4 and
compound B with NCI-H1666 cells.
[0482] FIG. 31 shows data for the combination of compound 3 and
compound A with RKO cells.
[0483] FIG. 31 a shows data for the combination of compound 3 and
compound A with RKO cells.
[0484] FIG. 32 shows data for the combination of compound 4 and
compound B with RKO cells.
[0485] FIG. 32a shows data for the combination of compound 4 and
compound B with RKO cells.
[0486] FIG. 33 shows data for the combination of compound 3 and
compound B with RT4 cells.
[0487] FIG. 33a shows data for the combination of compound 3 and
compound B with RT4 cells.
[0488] FIG. 34 shows data for the combination of compound 4 and
compound B with RT4 cells.
[0489] FIG. 34a shows data for the combination of compound 4 and
compound B with RT4 cells.
[0490] FIG. 35 shows data for the combination of compound 3 and
compound B with SH-4 cells.
[0491] FIG. 35a shows data for the combination of compound 3 and
compound B with SH-4 cells.
[0492] FIG. 36 shows data for the combination of compound 4 and
compound B with SH-4 cells.
[0493] FIG. 36a shows data for the combination of compound 4 and
compound B with SH-4 cells.
[0494] FIG. 37 shows data for the combination of compound 3 and
compound B with SK-HEP-1 cells.
[0495] FIG. 37a shows data for the combination of compound 3 and
compound B with SK-HEP-1 cells.
[0496] FIG. 38 shows data for the combination of compound 4 and
compound B with SK-HEP-1 cells.
[0497] FIG. 38a shows data for the combination of compound 4 and
compound B with SK-HEP-1 cells.
[0498] FIG. 39 shows data for the combination of compound 5 and
compound A with A204 cells.
[0499] FIG. 39a shows data for the combination of compound 5 and
compound A with A204 cells.
[0500] FIG. 40 shows data for the combination of compound 5 and
compound A with A375sq2 cells.
[0501] FIG. 40a shows data for the combination of compound 5 and
compound A with A375sq2 cells.
[0502] FIG. 41 shows data for the combination of compound 5 and
compound B with CAL-51 cells.
[0503] FIG. 41a shows data for the combination of compound 5 and
compound B with CAL-51 cells.
[0504] FIG. 42 shows data for the combination of compound 5 and
compound A with G-361 cells.
[0505] FIG. 42a shows data for the combination of compound 5 and
compound A with G-361 cells.
[0506] FIG. 43 shows data for the combination of compound 5 and
compound B with HT-1197 cells.
[0507] FIG. 43a shows data for the combination of compound 5 and
compound B with HT-1197 cells.
[0508] FIG. 44 shows data for the combination of compound 5 and
compound A with LS 174T cells.
[0509] FIG. 44a shows data for the combination of compound 5 and
compound A with LS174T cells.
[0510] FIG. 45 shows data for the combination of compound 5 and
compound A with MCF7 cells.
[0511] FIG. 45a shows data for the combination of compound 5 and
compound A with MCF7 cells.
[0512] FIG. 46 shows data for the combination of compound 5 and
compound B with NCI-H460 cells.
[0513] FIG. 46a shows data for the combination of compound 5 and
compound B with NCI-H460 cells.
[0514] FIG. 47 shows data for the combination of compound 5 and
compound A with RKO cells.
[0515] FIG. 47a shows data for the combination of compound 5 and
compound A with RKO cells.
[0516] FIG. 48 shows data for the combination of compound 6 and
compound B with A204 cells.
[0517] FIG. 48a shows data for the combination of compound 6 and
compound B with A204 cells.
[0518] FIG. 49 shows data for the combination of compound 6 and
compound B with A2780 cells.
[0519] FIG. 49a shows data for the combination of compound 6 and
compound B with A2780 cells.
[0520] FIG. 50 shows data for the combination of compound 6 and
compound B with C32 cells.
[0521] FIG. 50a shows data for the combination of compound 6 and
compound B with C32 cells.
[0522] FIG. 51 shows data for the combination of compound 6 and
compound B with G-401 cells.
[0523] FIG. 51a shows data for the combination of compound 6 and
compound B with G-401 cells.
[0524] FIG. 52 shows data for the combination of compound 6 and
compound B with SK-HEP-1 cells.
[0525] FIG. 52a shows data for the combination of compound 6 and
compound B with SK-HEP-1 cells.
[0526] FIGS. 53-56 omitted.
[0527] FIG. 57 shows data for the combination of compound 8 and
compound B with BV-173 cells.
[0528] FIG. 57a shows data for the combination of compound 8 and
compound B with BV-173 cells.
[0529] FIG. 58 shows data for the combination of compound 8 and
compound B with CML-T1 cells.
[0530] FIG. 58a shows data for the combination of compound 8 and
compound B with CML-T1 cells.
[0531] FIG. 59 shows data for the combination of compound 9 and
compound B with KNS-81-FD cells.
[0532] FIG. 59a shows data for the combination of compound 9 and
compound B with KNS-81-FD cells.
[0533] FIG. 60 shows data for the combination of compound 9 and
compound B with SW48 cells.
[0534] FIG. 60a shows data for the combination of compound 9 and
compound B with SW48 cells.
[0535] FIG. 61 shows data for the combination of compound 10 and
compound B with MDA-MB-175 VII cells.
[0536] FIG. 61a shows data for the combination of compound 10 and
compound B with MDA-MB-175 VII cells.
[0537] FIG. 62 shows data for the combination of compound 10 and
compound B with UACC-812 cells.
[0538] FIG. 62a shows data for the combination of compound 10 and
compound B UACC-812 cells.
[0539] FIG. 63 shows data for the combination of compound 11 and
compound A with HCT-116 cells.
[0540] FIG. 63a shows data for the combination of compound 11 and
compound A HCT-116 cells.
[0541] FIG. 64 shows data for the combination of compound 13 and
compound B with GDM-1 cells.
[0542] FIG. 64a shows data for the combination of compound 13 and
compound B with GDM-1 cells.
[0543] FIG. 65 shows data for the combination of compound 13 and
compound B with ML-2 cells.
[0544] FIG. 65a shows data for the combination of compound 13 and
compound B ML-2 cells.
[0545] FIG. 66 shows data for the combination of compound 13 and
compound B with MOLM-13 cells.
[0546] FIG. 66a shows data for the combination of compound 13 and
compound B with MOLM-13 cells.
[0547] FIG. 67 shows data for the combination of compound 13 and
compound B with OCI-AML3 cells.
[0548] FIG. 67a shows data for the combination of compound 13 and
compound B with OCI-AML3 cells.
[0549] FIG. 68 shows data for the combination of compound 12 and
compound B with GDM-1 cells.
[0550] FIG. 68a shows data for the combination of compound 12 and
compound B with GDM-1 cells.
[0551] FIG. 69 shows data for the combination of compound 12 and
compound B with ML-2 cells.
[0552] FIG. 69a shows data for the combination of compound 12 and
compound B with ML-2 cells.
[0553] FIG. 70 shows data for the combination of compound 12 and
compound B with MOLM-13 cells.
[0554] FIG. 70a shows data for the combination of compound 12 and
compound B with MOLM-13 cells.
[0555] FIG. 71 shows data for the combination of compound 12 and
compound B with OCI-AML3 cells.
[0556] FIG. 71a shows data for the combination of compound 12 and
compound B with OCI-AML3 cells.
[0557] FIG. 72 shows data for combinations of AMG 232 and various
MAP kinase pathway inhibitors.
[0558] FIG. 73 shows data for combinations of AM-7209 and various
MAP kinase pathway inhibitors.
[0559] FIG. 74 shows data for combinations of RG7112 and various
MAP kinase pathway inhibitors.
[0560] FIG. 75 shows data for combinations of AMG 232 and various
PI3 kinase pathway inhibitors.
[0561] FIG. 76 shows data for combinations of AM-7209 and various
PI3 kinase pathway inhibitors.
[0562] FIG. 77 shows data for combinations of RG7112 and various
PI3 kinase pathway inhibitors.
[0563] FIG. 78 shows data for combinations of AMG 232 and various
compounds active in the intrinsic apoptosis pathway.
[0564] FIG. 79 shows data for combinations of AM-7209 and various
compounds active in the intrinsic apoptosis pathway.
[0565] FIG. 80 shows data for combinations of RG7112 and various
compounds active in the intrinsic apoptosis pathway.
[0566] FIG. 81 shows data for combinations of AMG 232 and various
chemotherapeutic compounds.
[0567] FIG. 82 shows data for combinations of AM-7209 and various
chemotherapeutic compounds.
[0568] FIG. 83 shows data for combinations of RG7112 and various
chemotherapeutic compounds.
[0569] FIG. 84 shows data for combinations of AMG 232 and various
chemotherapeutic compounds.
[0570] FIG. 85 shows data for combinations of AM-7209 and various
chemotherapeutic compounds.
[0571] FIG. 86 shows data for combinations of RG7112 and various
chemotherapeutic compounds.
[0572] FIG. 87 shows data for combinations of AMG 232 and various
compounds in hematopoietic cell lines.
[0573] FIG. 88 shows data for combinations of AM-7209 and various
compounds in hematopoietic cell lines.
[0574] FIG. 89 shows data for combinations of RG7112 and various
compounds in hematopoietic cell lines.
[0575] FIG. A shows tumor xenograft data for the combination of AMG
232 and cisplatin in an H460 tumor.
[0576] FIG. B shows tumor xenograft data for the combination of AMG
232 and cisplatin in an HCT 116 tumor.
[0577] FIG. C shows tumor xenograft data for the combination of AMG
232 and CPT-11(irinotecan) in an HCT116 tumor.
[0578] FIG. D shows tumor xenograft data for the combination of AMG
232 and doxorubicin in a SJSA-1 tumor.
[0579] FIG. E shows tumor xenograft data for the combination of AMG
232 and BRAF inhibitor AMG 2112819 or MEK inhibitor 1009089 in a
RKO tumor.
[0580] FIG. F shows tumor xenograft data for the combination of
RG7112 and PI3K inhibitor AMG 2520765 in a U87 tumor.
[0581] FIG. G shows tumor xenograft data for the combination of AMG
232 and MEK inhibitor AMG 1009089 in an A375 tumor.
[0582] FIG. H shows tumor xenograft data for the combination of AMG
232 and BRAF inhibitor AMG 2112819 in an A375sq2 tumor.
[0583] FIG. 1 shows tumor xenograft data for the combination of AMG
232, BRAF inhibitor AMG 2112819 and PI3K inhibitor 2539965 in a RKO
tumor.
[0584] FIG. J shows tumor xenograft data for various combinations
of AMG 232, BRAF inhibitor AMG 2112819 and PI3k inhibitor
AMG2539965 in a RKO tumor.
[0585] FIG. K shows tumor xenograft data for the combination of AMG
232 and doxorubicin in a MOLM13 tumor.
[0586] FIG. L shows tumor xenograft data for the combination of AMG
232 and MEK inhibitor AMG1009089 in a MOLM13 tumor.
[0587] FIG. M shows tumor xenograft data for the combination of AMG
232 and cytarabine in a MOLM13 tumor.
[0588] FIG. N shows tumor xenograft data for the combination of AMG
232 and decitabine in a MOLM13 tumor.
[0589] FIG. O shows tumor xenograft data for the combination of AMG
232 and Sorafanib in a MOLM13 tumor.
DETAILED DESCRIPTION OF THE INVENTION
[0590] The present invention provides combination therapy that
includes an MDM2 inhibitor and one or more additional
pharmaceutically active agents, particularly for the treatment of
cancers. The invention also relates to pharmaceutical compositions
that contain an MDM2 inhibitor and one or more additional
pharmaceutically active agents for the treatment of cancers.
[0591] The term "comprising" is meant to be open ended, including
the indicated component but not excluding other elements.
[0592] The term "therapeutically effective amount" means an amount
of a compound, or combination of compounds, that ameliorates,
attenuates or eliminates one or more symptom of a particular
disease or condition, or prevents or delays the onset of one of
more symptom of a particular disease or condition.
[0593] The terms "patient" and "subject" may be used
interchangeably and mean animals, such as dogs, cats, cows, horses,
sheep and humans. Particular patients are mammals. The term patient
includes males and females.
[0594] The term "pharmaceutically acceptable" means that the
referenced substance, such as a compound, or a salt of the
compound, or a formulation containing the compound, or a particular
excipient, are suitable for administration to a patient.
[0595] The terms "treating", "treat" or "treatment" and the like
include preventative (e.g., prophylactic) and palliative treatment.
The term" treating" and the like, in accordance with the present
invention, means reducing or eliminating cancers cells in a
patient.
[0596] The term "excipient" means any pharmaceutically acceptable
additive, carrier, diluent, adjuvant, or other ingredient, other
than the active pharmaceutical ingredient (API), which is typically
included for formulation and/or administration to a patient.
[0597] The phrase "compound(s) of the present invention" includes
MDM2 inhibitors and/or the one or more additional pharmaceutically
active agents according to the context of the use.
[0598] An "MDM2 inhibitor" is defined as a compound with a
molecular weight less than about 1000 that binds MDM2 as shown with
in vitro testing or by other means.
[0599] The compounds of the present invention are administered to a
patient in a therapeutically effective amount. The compounds can be
administered alone or as part of a pharmaceutically acceptable
composition or formulation. In addition, the compounds or
compositions can be administered all at once, as for example, by a
bolus injection, multiple times, such as by a series of tablets, or
delivered substantially uniformly over a period of time, as for
example, using transdermal delivery. It is also noted that the dose
of the compounds can be varied over time.
[0600] If the patient is to receive or is receiving multiple
pharmaceutically active compounds, the compounds can be
administered simultaneously or sequentially. For example, in the
case of tablets, the active compounds may be found in one tablet or
in separate tablets, which can be administered at once or
sequentially in any order. In addition, it should be recognized
that the compositions may be different forms. For example, one or
more compounds may be delivered via a tablet, while another is
administered via injection or orally as a syrup. All combinations,
delivery methods and administration sequences are contemplated.
[0601] The term "cancer" means a physiological condition in mammals
that is characterized by unregulated cell growth. General classes
of cancers include carcinomas, lymphomas, sarcomas, and
blastomas.
[0602] The compounds of the present invention can be used to treat
cancer. The methods of treating a cancer comprise administering to
a patient in need thereof a therapeutically effective amount of one
or more compounds, or pharmaceutically acceptable salts of any of
the compounds.
[0603] The compounds of the present invention can be used to treat
tumors. The methods of treating a tumor comprise administering to a
patient in need thereof a therapeutically effective amount of one
or more compounds of the present invention, or pharmaceutically
acceptable salts of any of the compounds.
[0604] The invention also concerns the use of the compounds in the
manufacture of a medicament for the treatment of a condition such
as a cancer.
[0605] Cancers which may be treated with compounds of the present
invention include, without limitation, carcinomas such as cancer of
the bladder, breast, colon, rectum, kidney, liver, lung (small cell
lung cancer, and non-small-cell lung cancer), esophagus,
gall-bladder, ovary, pancreas, stomach, cervix, thyroid, prostate,
and skin (including squamous cell carcinoma); hematopoietic tumors
of lymphoid lineage (including leukemia, acute lymphocytic
leukemia, chronic myelogenous leukemia, acute lymphoblastic
leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma,
non-Hodgkin's lymphoma, hairy cell lymphoma and Burkett's
lymphoma); hematopoietic tumors of myeloid lineage (including acute
and chronic myelogenous leukemias, myelodysplastic syndrome and
promyelocytic leukemia); tumors of mesenchymal origin (including
fibrosarcoma and rhabdomyosarcoma, and other sarcomas, e.g., soft
tissue and bone); tumors of the central and peripheral nervous
system (including astrocytoma, neuroblastoma, glioma and
schwannomas); and other tumors (including melanoma, seminoma,
teratocarcinoma, osteosarcoma, xenoderoma pigmentosum,
keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma).
Other cancers that can be treated with the compound of the present
invention include endometrial cancer, head and neck cancer,
glioblastoma, malignant ascites, and hematopoietic cancers.
[0606] Particular cancers that can be treated by the compounds of
the present invention include soft tissue sarcomas, bone cancers
such as osteosarcoma, breast tumors, bladder cancer, Li-Fraumeni
syndrome, brain tumors, rhabdomyosarcoma, adrenocortical carcinoma,
colorectal cancer, non-small cell lung cancer, and acute
myelogenous leukemia (AML).
[0607] In a particular embodiment of the invention that relates to
the treatment of cancers, the cancer is identified as p53wildtype
(p53.sup.WT). In another particular embodiment, the cancer is
identified as p53.sup.WT and CDKN2A mutant. In another aspect, the
present invention provides a diagnostic for determining which
patients should be administered a compound of the present
invention. For example, a sample of a patient's cancer cells may be
taken and analyzed to determine the status of the cancer cells with
respect to p53 and/or CDKN2A. In one aspect, a patient having a
cancer that is p53.sup.WT will be selected for treatment over
patients having a cancer that is mutated with respect to p53. In
another aspect, a patient having a cancer that is both p53.sup.WT
and has a mutant CDNK2A protein is selected over a patient that
does not have these characteristics. In still another aspect, the
patient has a cancer that is p53.sup.WT and exhibits MDM2
amplification. The taking of cancer cells for analyses is well
known to those skilled in the art. The term "p53.sup.WT" means a
protein encoded by genomic DNA sequence no. NC_000017 version 9
(7512445..7531642)(GenBank); a protein encoded by cDNA sequence no.
NM_000546 (GenBank); or a protein having the GenBank sequence no.
NP_000537.3. The term "CDNK2A mutant" means a CDNK2A protein that
in not wild type. The term "CDKN2A wild type" means a protein
encoded by genomic DNA sequence no. 9:21957751-21984490 (Ensembl
ID); a protein encoded by cDNA sequence no. NM_000077 (GenBank) or
NM_058195 9GenBank) or; or a protein having the GenBank sequence
no. NP_000068 or NP_478102.
[0608] The compounds of the present invention can also be used to
treat hyperproliferative disorders such as thyroid hyperplasia
(especially Grave's disease), and cysts (such as hypervascularity
of ovarian stroma, characteristic of polycystic ovarian syndrome
(Stein-Leventhal syndrome)).
[0609] The compounds of the present invention may be designated as
follows in the application and figures.
TABLE-US-00001 Compound A AMG 232 Compound B AMG 2653149 Compound C
AM-7209 Compound 1 AMG 2112819 Compound 2 dabrafenib Compound 3
PD0325901* Compound 4 trametinib Compound 5 AMG 511 Compound 6
panobinostat Compound 7 not used Compound 8 imatinib Compound 9
erlotinib Compound 10 lapatinib Compound 11 cisplatin Compound 12
cytarabine Compound 13 AMG 900 *AMG 1009089 (also called herein
1009089 or Compound 3) is PD0325901.
[0610] The MDM2 inhibitors of the present invention include those
disclosed in published PCT application WO2011/153,509. A particular
compound disclosed in the application is AMG 232 (Example 362)
having the structure and name shown below.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsul-
fonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00001##
[0612] A particular synthesis of AMG 232 is set forth in U.S.
provisional patent application number 61/833,196, filed June 10,
2013.
Procedures to Make Certain Intermediates and Starting Materials
Method for Making
##STR00002##
[0613] Step A. 2-(3-Chlorophenyl)-1-(4-chlorophenyl)ethanone
##STR00003##
[0615] Sodium bis(trimethylsilyl)amide (1 M in tetrahydrofuran, 117
mL) was slowly added to a -78.degree. C. solution of
2-(3-chlorophenyl) acetic acid (10 g, 58.6 mmol) in tetrahydrofuran
(58 mL) over 1 hour. After stirring at -78.degree. C. for 40
minutes, a solution of methyl 4-chlorobenzoate (10 g, 58.6 mmol) in
tetrahydrofuran (35 mL) was added over a period of 10 minutes. The
reaction was stirred at -78.degree. C. for 3 hours then allowed to
warm to 25.degree. C. After two hours at 25.degree. C., the
reaction was quenched with saturated aqueous ammonium chloride
solution, and most of the tetrahydrofuran was removed under reduced
pressure. The residue was extracted with ethyl acetate (2.times.100
mL). The combined organic layers were washed with saturated sodium
chloride solution, dried over sodium sulfate, filtered and the
filtrate was concentrated. The product was recrystallized from
ether/pentane to provide the title compound as a white solid.
.sup.1H NMR (500 MHz, DMSO-d.sub.6, .delta. ppm): 8.05 (m, 2H),
7.62 (m, 2H), 7.33 (m, 3H), 7.21 (br d, J=7.3 Hz, 1H), 4.45 (s,
2H). MS (ESI)=265.1 [M+H].sup.+.
Step B: Methyl
4-(3-chlorophenyl)-5-(4-chlorophenyl)-2-methyl-5-oxopentanoate
##STR00004##
[0617] Methyl methacrylate (12.65 mL, 119 mmol) was added to a
solution of 2-(3-chlorophenyl)-1-(4-chlorophenyl)ethanone (30 g,
113 mmol) in tetrahydrofuran (283 mL). Potassium tert-butoxide
(1.27 g, 11 3 mmol) was then added and the reaction was stirred at
room temperature for 2 days. The solvent was removed under a vacuum
and replaced with 300 mL of ethyl acetate. The organic phase was
washed with brine (50 mL), water (3.times.50 mL), and brine (50
mL). The organic phase was dried over magnesium sulfate, filtered
and concentrated under a vacuum to afford methyl
4-(3-chlorophenyl)-5-(4-chlorophenyl)-2-methyl-5-oxopentanoate as
an approximately 1:1 mixture of diastereomers. .sup.1H NMR (400
MHz, CDCl.sub.3, .delta. ppm): 7.87 (m, 2H), 7.38 (m, 2H),
7.27-7.14 (series of m, 4H), 4.61 (m, 1H), 3.69 (s, 1.5H), 3.60 (s,
1.5 H), 2.45 (m, 1H), 2.34 (m, 1H), 2.10 (ddd, J=13.9, 9.4, 5.5 Hz,
0.5H), 1.96 (ddd, J=13.7, 9.0, 4.3 Hz, 0.5H), 1.22 (d, J=7.0 Hz,
1.5H), 1.16 (d, J=7.0, 1.5 H). MS (ESI)=387.0 [M+23].sup.+.
Step C: (3S,
5R,6R)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahydro-2H-pyran--
2-one and (3R,
5R,6R)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahydro-2H-pyran--
2-one
##STR00005##
[0619] Methyl
4-(3-chlorophenyl)-5-(4-chlorophenyl)-2-methyl-5-oxopentanoate (40
g, 104.0 mmol) was dissolved in 200 mL of anhydrous toluene and
concentrated under a vacuum. The residue was placed under high
vacuum for 2 hours before use. The compound was split into
2.times.20 g batches and processed as follows: methyl
4-(3-chlorophenyl)-5-(4-chlorophenyl)-2-methyl-5-oxopentanoate (20
g, 52 0 mmol) in anhydrous 2-propanol (104 mL) was treated with
potassium tert-butoxide (2.33 g, 20.8 mmol) in a 250 mL glass
hydrogenation vessel. RuCl.sub.2(S-xylbinap)(S-DAIPEN) (0.191 g,
0.156 mmol, Strem Chemicals, Inc., Newburyport, Mass.) in 3.8 mL of
toluene was added. After 1.5 hours, the vessel was pressurized to
50 psi (344.7 kPa) and purged with hydrogen five times and allowed
to stir at room temperature. The reaction was recharged with
additional hydrogen as needed. After 3 days, the reactions were
combined and partitioned between 50% saturated ammonium chloride
solution and ethyl acetate. The aqueous layer was extracted with
ethyl acetate. The combined organic phases were washed with brine,
dried over magnesium sulfate, filtered, and concentrated.
[0620] The crude product (predominantly, (4R,5R)-isopropyl
4-(3-chlorophenyl)-5-(4-chlorophenyl)-5-hydroxy-2-methylpentanoate)
was dissolved in tetrahydrofuran (450 mL) and methanol (150 mL).
Lithium hydroxide (1.4 M, 149 mL, 208 mmol) was added, and the
solution was stirred at room temperature for 24 hours. The mixture
was concentrated under a vacuum and the residue was redissolved in
ethyl acetate. Aqueous 1N hydrochloric acid was added with stirring
until the aqueous layer had a pH of about 1. The layers were
separated and the organic phase was washed with brine, dried over
magnesium sulfate, filtered and concentrated. The material was
dissolved in 200 mL of anhydrous toluene and treated with
pyridinium p-toluenesulfonate (PPTS, 0.784 g, 3.12 mmol). The
reaction was heated to reflux under Dean-Stark conditions until the
seco-acid was consumed (about 2 hours). The reaction was cooled to
room temperature and washed with saturated sodium bicarbonate (50
mL) and brine (50 mL). The solution was dried over sodium sulfate,
filtered and concentrated. The crude material was purified by flash
chromatography on silica gel (120 g column; eluting with 100%
dichloromethane). The title compounds were obtained as a white
solid with an approximate 94:6 enantiomeric ratio and a 7:3 mixture
of methyl diastereomers. .sup.1H NMR (400 MHz, CDCl.sub.3, .delta.
ppm): 7.22-6.98 (series of m, 5H), 6.91 (dt, J=7.4, 1.2 Hz, 0.3H),
6.81 (m, 2H), 6.73 (dt, J=7.6, 1.4 Hz, 0.7H), 5.76 (d, J=4.1 Hz,
0.3 H), 5.69 (d, J=4.7 Hz, 0.7H), 3.67 (dt, J=6.6, 4.3 Hz, 0.3H),
3.55 (td, J=7.8, 4.7 Hz, 0.7 H), 2.96 (d of quintets, J=13.5, 6.7
Hz, 0.7 H), 2.81 (m, 0.3H), 2.56 (dt, J=14.3, 8.0 Hz, 0.7 H), 2.32
(dt, J=13.69, 7.0 Hz, 0.3 H), 2.06 (ddd, J=13.7, 8.4, 4.1, 0.3 H),
1.85 (ddd, J=14.1, 12.5, 7.4, 0.7 H), 1.42 (d, J=7.0 Hz, 0.9 H),
1.41 (d, J=6.7 Hz, 2.1H). MS (ESI)=357.0 [M+23].sup.+.
[.alpha.].sub.D (22.degree. C., c=1.0,
CH.sub.2Cl.sub.2)=-31.9.degree. ; m.p. 98-99.degree. C.
Step D.
(3S,5R,6R)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylt-
etrahydro-2H-pyran-2-one
##STR00006##
[0622] A solution of (3S,
5R,6R)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahydro-2H-pyran--
2-one and
(3R,5S,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahy-
dro-2H-pyran-2-one (4.5 g, 13.4 mmol) and allyl bromide (3.48 mL,
40 3 mmol) in tetrahydrofuran (22 mL) at -35.degree. C.
(acetonitrile/dry ice bath) was treated with a solution of lithium
bis(trimethylsilyl)amide in tetrahydrofuran (1.0 M, 17.45 mL, 17.45
mmol). The reaction was allowed to warm to -5.degree. C. over 1
hour and then was quenched with 50% saturated ammonium chloride.
The reaction was diluted with 100 mL of ethyl acetate and the
layers were separated. The organic phase was washed with brine,
dried over magnesium sulfate, filtered and concentrated under a
vacuum to afford the title compound as a white solid upon standing
under a vacuum. Chiral SFC (92% CO.sub.2, 8% methanol (20 mM
ammonia), 5 mL/min, Phenomenex Lux-2 column (Phenomenex, Torrance,
Calif.), 100 bar (10,000 kPa), 40.degree. C., 5 minute method) was
used to determine that the compound had an enantiomeric ratio of
96:4. (Major enantiomer: title compound, retention time=2.45
minutes, 96%; minor enantiomer (structure not shown, retention
time=2.12 min, 4%). The title compound was recrystallized by adding
to heptane (4.7 g slurried in 40 mL) at reflux and 1.5 mL of
toluene was added dropwise to solubilize. The solution was cooled
to 0.degree. C. The white solid was filtered and rinsed with 20 mL
of cold heptanes to afford a white powder. Chiral SFC (92%
CO.sub.2, 8% methanol, Phenomenex Lux-2 column, same method as
above) indicated an enantiomeric ratio of 99.2:0.8. (major
enantiomer, 2.45 min, 99.2%; minor enantiomer: 2.12 min, 0.8%).
.sup.1H NMR (400 MHz, CDCl.sub.3, .delta. ppm): 7.24 (ddd, J=8.0,
2.0, 1.2 Hz, 1H), 7.20-7.15 (series of m, 3H), 6.91 (t, J=2.0 Hz,
1H), 6.78 (br d, J=7.6 Hz, 1H), 6.60 (m, 2H), 5.84 (ddt, J=17.6,
10.2, 7.4 Hz, 1H), 5.70 (d, J=5.3 Hz, 1H), 5.21-5.13 (series of m,
2H), 3.82 (dt, J=11.7, 4.5 Hz, 1H), 2.62 (ABX J.sub.AB=13.7 Hz,
J.sub.AX=7.6 Hz, 1H), 2.53 (ABX, J.sub.AB=13.9 Hz, J.sub.BX=7.2 Hz,
1H). 1.99 (dd, J=14.1, 11.9 Hz, 1H), 1.92 (ddd, J=13.9, 3.9, 1.2
Hz, 1H). .sup.13C NMR (CDCl.sub.3, 100 MHz, .delta. ppm): 175.9,
140.2, 134.5, 134.3, 134.0, 132.2, 129.8, 128.6, 128.0, 127.9,
127.8, 126.4, 119.9, 83.9, 44.5, 42.4, 40.7, 31.8, 26.1. MS
(ESI)=375.2 [M+H].sup.+. IR=1730 cm.sup.-1. [.alpha.].sub.D
(24.degree. C., c=1.0, CH.sub.2Cl.sub.2)=-191.degree.. m.p.
111-114.degree. C.
Step E.
(S)-2-((2R,3R)-2-(3-Chlorophenyl)-3-(4-chlorophenyl)-3-hydroxyprop-
yl)-N-((S)-1-hydroxy-3-methylbutan-2-yl)-2-methylpent-4-enamide
##STR00007##
[0624]
(3S,5R,6R)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylte-
trahydro-2H-pyran-2-one (113 g, 300 0 mmol) was combined with
(S)-2-amino-3-methyllbutan-1-ol (93 g, 900.0 mmol) and the
suspension was heated at 100.degree. C. for 5 hours. The reaction
mixture was cooled to room temperature, diluted with ethyl acetate
(1000 mL) and washed with 1N hydrochloric acid (2.times.), water,
and brine. The organic layer was dried over magnesium sulfate and
concentrated under a vacuum to give the title compound as white
solid which was used in next step without further purification.
Step F.
(3S,5S,6R,8S)-8-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-isop-
ropyl-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium
trifluoromethanesulfonate
##STR00008##
[0626] Trifluoromethanesulfonic anhydride (57 mL, 339 mmol) was
added dropwise over 60 minutes via addition funnel to a solution of
(S)-2-((2R,3R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-3-hydroxypropyl)-N-(-
(S)-1-hydroxy-3-methylbutan-2-yl)-2-methylpent-4-enamide (73.7 g,
154 mmol) and 2,6-dimethylpyridine (78 mL, 678 mmol) in
dichloromethane (700 mL) at -50.degree. C. The reaction mixture was
stirred at -50.degree. C. for one additional hour and concentrated
under a vacuum to provide the title compound as a reddish solid
which was used in next step without further purification.
Step G.
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1--
(isopropylthio)-3-methylbutan-2-yl)-3-methylpiperidin-2-one
##STR00009##
[0628]
(3S,5S,6R,8S)-8-Allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-isopr-
opyl-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium
trifluoromethanesulfonate (736 mg, 1.242 mmol) was weighed into an
oven dried 50 mL pear-bottom flask and dissolved in 20 mL dry
toluene. The toluene was removed under a vacuum to remove trace
water in the solid. The process was repeated twice, and the
resulting residue was dried under a strong vacuum.
[0629] A solution of sodium isopropyl sulfide was prepared by
adding potassium 2-methylpropan-2-olate (3.0 mL, 3.00 mmol, 1 M
solution in tetrahydrofuran) to a solution of propane-2-thiol (331
mg, 4.35 mmol) in 8 mL dimethylformamide that had been prepared
under nitrogen and cooled to 0.degree. C. The sulfide solution was
allowed to stir at room temperature for five minutes and was cooled
to 0.degree. C. The dry
(3S,5S,6R,8S)-8-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-isopropyl-8-
-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium
trifluoromethanesulfonate (736 mg, 1.242 mmol) was dissolved in
dimethylformamide (8 mL total) and transferred (3 transfers total)
via syringe to the sulfide solution over the course of 5 minutes.
After 5 minutes, the ice bath was removed and the pale orange
solution was allowed to warm to room temperature.
[0630] After stirring overnight, the mixture was partitioned
between ethyl acetate and saturated ammonium chloride solution. The
aqueous phase was saturated in sodium chloride and back-extracted
three times. The combined organics were washed twice with saturated
sodium bicarbonate, twice with brine, dried over sodium sulfate,
filtered, and concentrated under a vacuum to provide a residue that
was purified by silica gel column chromatography (80 g column,
gradient elution of 0% to 50% ethyl acetate in hexanes).
[0631] Method for Making
##STR00010##
Step A.
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-
-hydroxy-3-methylbutan-2-yl)-3-methylpiperidin-2-one
##STR00011##
[0633] Lithium hydroxide hydrate (64.6 g, 1540 mmol) was added
portionwise, over a 5 minute period, to a solution of
(3S,5S,6R,8S)-8-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-isopropyl-8-
-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium
trifluoromethanesulfonate (Step F above) dissolved in
tetrahydrofuran (500 ml) and water (300 ml). The reaction mixture
was stirred at room temperature for 1 hour and concentrated under a
vacuum. The residue was dissolved in ethyl acetate (ca. 1.3 L) and
the layers were separated. The organic layer was washed with 1N
hydrochloric acid (ice cooled, with enough hydrochloric acid to
protonate and remove any remaining 2,6-dimethylpyridine (300
mL.times.2)), water and brine. The solvent was removed under a
vacuum to give a residue which was purified by silica gel column
chromatography (1500 g column, gradient elution of 0% to 50% ethyl
acetate in hexanes. The product was also crystallized from
cyclohexane.
Step B.
(3S,5S,6R,8S)-8-Allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-isop-
ropyl-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium
4-methylbenzenesulfonate
##STR00012##
[0635]
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-h-
ydroxy-3-methylbutan-2-yl)-3-methylpiperidin-2-one (49.77 g, 98
mmol) was transferred to a 1000 mL flask containing
4-methylbenzenesulfonic acid hydrate (19.27 g, 101 mmol) and a
stirring bar. The reactants were suspended in toluene (230 mL). The
flask was equipped with a Dean Stark trap and reflux condenser, and
the stirred mixture was heated at reflux in a preheated bath. After
1 hour, the solvent was carefully removed under a vacuum and the
resulting residue was further dried under high vacuum. The title
compound was taken to the next step without purification.
Step C.
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1--
(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methylpiperidin-2-one
##STR00013##
[0637]
(3S,5S,6R,8S)-8-Allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-isopr-
opyl-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium
4-methylbenzenesulfonate, dry, powdered potassium carbonate (26.9
g, 195 mmol) and propane-2-thiol (14 ml, 150 mmol) were added along
with 200 mL freshly sparged dimethylformamide. The mixture was
heated under argon at 50.degree. C. After about 21 hours, a
solution of meta-chloroperbenzoic acid (68.2 g, 77% pure by weight,
in 100 mL dimethylformamide) was transferred to a dropping funnel
and rapidly added to the stirred reaction mixture while the flask
was immersed in an ice bath. After 5 minutes, the resulting yellow
solution was allowed to warm to room temperature. After 10 minutes,
additional meta-chloroperbenzoic acid (12 g, 77% wt %) was added as
a solid and the mixture was stirred at room temperature. Upon
completion, the mixture was poured into ethyl acetate and washed
with 1 M sodium hydroxide (500 mL) that had been poured into ice.
The aqueous phase was back-extracted three times and washed with
additional 1 M NaOH ((500 mL, also poured into ice). The aqueous
layer was washed once with ethyl acetate and the organics were
combined. Sodium thiosulfate (1 M in water, 250 mL) was added to
the organics in a large Erlenmeyer flask, and the mixture was
stirred for twenty minutes. The organic phase was washed again with
sodium thiosulfate (1 M in water, 250 mL) and the mixture was
allowed to stand over the weekend. The organics were concentrated
to ca. 500 mL, then sequentially washed with 10% aqueous citric
acid, 1 M sodium hydroxide, and brine. The organics were dried over
sodium sulfate, filtered, and concentrated to give the crude
product. The residue was purified by flash column chromatography
(1.5 kg silica gel column, gradient elution of 0% to 50% ethyl
acetate in hexanes) to give the title compound as a white
solid.
Synthesis of Compound AMG 232 (Alternative 1)
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsul-
fonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00014##
[0639] Ruthenium(III) chloride trihydrate (22 mg, 0.084 mmol) and
sodium periodate (1.12 g, 5.24 mmol) were added to a mixture of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopro-
pylthio)-3-methylbutan-2-yl)-3-methylpiperidin-2-one (390 mg, 0.752
mmol) in acetonitrile (4.0 mL), carbon tetrachloride (4.0 mL),and
water (6.0 mL). The resulting dark brown mixture was vigorously
stirred at ambient temperature overnight. The mixture was filtered
through a pad of diatomaceous earth, washing with ethyl acetate.
The filtrate was partitioned between 2 M HCl and ethyl acetate. The
aqueous phase was back-extracted twice with ethyl acetate, and the
combined organics were washed with brine, dried over sodium
sulfate, filtered, and concentrated under a vacuum to a residue
that was purified by flash chromatography (40 g silica gel column,
gradient elution of 0% to 15% isopropanol in hexanes). Fractions
containing the desired product were combined, stripped of solvent,
redissolved in minimal ACN/water, frozen, and lyophilized to give a
white powder.
[0640] Subsequently, a mixture of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopro-
pylthio)-3-methylbutan-2-yl)-3-methylpiperidin-2-one (388 mg, 0.748
mmol), ruthenium(III) chloride trihydrate (19.56 mg, 0.075 mmol),
and sodium periodate (1.15 g, 5.38 mmol) in acetonitrile (4 mL),
carbon tetrachloride (4.00 mL), and water (4.00 mL) was vigorously
stirred at ambient temperature. After four hours, the mixture was
filtered through a pad of diatomaceous earth, and the filtrate was
partitioned between ethyl acetate and 2 M HCl. The aqueous phase
was back-extracted twice with ethyl acetate, and the combined
organics were washed with brine, dried over sodium sulfate,
filtered, and concentrated under a vacuum to a residue. The residue
was purified by flash chromatography (40 g silica gel column,
gradient elution of 0% to 15% isopropanol in hexanes). Fractions
containing the product were concentrated and combined with the
solid obtained in the prior experiment. The combined material was
dissolved in minimal acetonitrile/water, frozen, and lyophilized
overnight to give a white solid.
Synthesis of AMG 232 (Alternative 2)
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsul-
fonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00015##
[0642] Sodium periodate (2.85 g, 13.32 mmol) and ruthenium(III)
chloride trihydrate (0.049 g, 0.189 mmol) were added to a mixture
of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopro-
pylsulfonyl)-3-methylbutan-2-yl)-3-methylpiperidin-2-one (1.73 g,
3.14 mmol) in acetonitrile (18 mL), carbon tetrachloride (18 mL),
and water (27 mL). The mixture was stirred vigorously at room
temperature for 25 hours. The mixture was diluted with 2M HCl and
filtered through a pad of diatomaceous earth and rinsed with ethyl
acetate. The organic layer was separated, washed with brine, dried
over sodium sulfate, filtered, and concentrated under a vacuum. The
material was purified twice by flash chromatography (120g silica
gel, gradient elution of 0% to 20% isopropanol in hexanes; 120 g
column, gradient elution of 0% to 15% gradient isopropanol in
hexanes). It was purified once more by flash chromatography (220 g
silica gel; gradient elution 0% to 20% isopropanol in hexanes, 45
minutes) using a method in which the purest fractions were
concentrated and set aside and mixed fractions were pooled and
resubjected to the chromatography.
[0643] Subsequently, a mixture of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopro-
pylsulfonyl)-3-methylbutan-2-yl)-3-methylpiperidin-2-one (4.1 g,
7.45 mmol), ruthenium(III) chloride trihydrate (0.120 g, 0.459
mmol), and sodium periodate (6.73 g, 31.5 mmol) in acetonitrile (40
mL), carbon tetrachloride (40 mL), and water (60 mL) was vigorously
stirred at ambient temperature for 23 hours. The reaction was
diluted by addition of 2 M aqueous HCl and filtered through a
diatomaceous earth pad, washing with copious ethyl acetate. Most of
the organics were removed under a vacuum. The crude product was
extracted into ethyl acetate, washed with brine, dried over sodium
sulfate, filtered, and concentrated to a residue that was purified
twice by flash chromatography (330 g silica gel column, gradient
elution of 0% to 20% isopropanol in hexanes; 330 g silica gel
column, gradient elution of 0% to 20% isopropanol in hexanes) to
give an off-white foam. The material was purified by flash
chromatography three additional times (220 g silica gel column;
gradient elution 0% to 20% isopropanol in hexanes, 45 minutes)
using a method in which the purest fractions were concentrated and
set aside and mixed fractions were pooled and resubjected to the
chromatography.
[0644] Mixed fractions from both experiments were combined and
purified by flash chromatography twice more (220 g silica gel
column; gradient elution 0% to 20% isopropanol in hexanes, 45
minutes), and again the pure fractions were set aside.
All of the pure fractions were combined, concentrated under a
vacuum, dissolved in minimal acetonitrile/water and
lyophilized.
Synthesis of AMG 232 (Alternative 3)
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsul-
fonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00016##
[0646]
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(-
isopropylsulfonyl)-3-methylbutan-2-yl)-3-methylpiperidin-2-one
(5.05 g, 9.17 mmol) was weighed into a 500 mL round bottom flask
containing a large stir bar and 2.04 g sodium periodate (2.04 g).
The mixture was diluted with carbon tetrachloride (52 mL),
acetonitrile, (52 mL) and water (78 mL). The flask was immersed in
a room temperature water bath and the internal temperature was
monitored with a digital thermocouple.
[0647] Ruthenium chloride hydrate (approximately 50 mg) was added
in a single portion. The internal temperature rose to 22.degree.
C., then ice was added to the bath to cool the mixture. Additional
ruthenium chloride hydrate (25 mg) was added 3 minutes later. After
stirring for a total of thirty minutes, Three portions of sodium
periodate (2.08 g, 2.07 g and 2.08 g) were slowly added on 15
minute intervals. The temperature was kept below 19.degree. C., and
ice was quickly added to the bath if the internal temperature began
to rise. The mixture was stirred at ambient temperature overnight.
The mixture was filtered through a pad of diatomaceous earth and
the filter cake was washed copiously with ethyl acetate. The
filtrate was concentrated under a vacuum and partitioned between 2
M HCl (100 mL) and ethyl acetate (200 mL).
[0648] Two rounds of flash column chromatography (330 g silica gel,
then 220 g silica gel, gradient elution of 0% to 20% isopropanol in
hexanes) provided the title compound. A portion of this material
was lyophilized from acetonitrile and water. The less pure
fractions were repurified by two additional rounds of flash column
chromatography (220 g then 330 g silica gel columns, gradient
elution of 0% to 20% isopropanol in hexanes). The most pure
fractions from both runs were combined, concentrated under a vacuum
and lyophilized from acetonitrile and water to give the title
compound.
[0649] Another particular MDM2 inhibitor is AM-7209 (Compound C
herein), which is disclosed in U.S. provisional patent application
number 61/770,901, filed February 28, 2013. (See Example No. 5
therein and below). AM-7209 has the following chemical name and
structure:
4-(2-43R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-ch-
loro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)aceta-
mido)-2-methoxybenzoic acid
##STR00017##
EXAMPLE 1
2-((3R,5R,6S)-1-((S)-2-(tert-Butylsulfonyl)-1-cyclopropylethyl)-5-(3-chlor-
ophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid (Example 351 of WO2011/153509 (Amgen Inc.), published Dec. 8,
2011.
##STR00018##
[0650] Step A. 2-(3-Chlorophenyl)-1-(4-chlorophenyl)ethanone
##STR00019##
[0652] Sodium bis(trimethylsilyl)amide (1 M in tetrahydrofuran, 117
mL) was slowly added to a -78.degree. C. solution of
2-(3-chlorophenyl) acetic acid (10 g, 58 6 mmol) in tetrahydrofuran
(58 mL) over 1 hour. After stirring at -78.degree. C. for 40
minutes, a solution of methyl 4-chlorobenzoate (10 g, 58.6 mmol) in
tetrahydrofuran (35 mL) was added over a period of 10 minutes. The
reaction was stirred at -78.degree. C. for 3 hours then allowed to
warm to 25.degree. C. After two hours at 25.degree. C., the
reaction was quenched with saturated aqueous ammonium chloride
solution, and most of the tetrahydrofuran was removed under reduced
pressure. The residue was extracted with ethyl acetate (2.times.100
mL). The combined organic layers were washed with saturated sodium
chloride solution, dried over sodium sulfate, filtered and the
filtrate was concentrated. The product was recrystallized from
ether/pentane to provide the title compound as a white solid.
.sup.1H NMR (500 MHz, DMSO-d.sub.6, .delta. ppm): 8.05 (m, 2H),
7.62 (m, 2H), 7.33 (m, 3H), 7.21 (br d, J=7.3 Hz, 1H), 4.45 (s,
2H). MS (ESI)=265.1 [M+H].sup.+.
Step B: Methyl
4-(3-chlorophenyl)-5-(4-chlorophenyl)-2-methyl-5-oxopentanoate
##STR00020##
[0654] Methyl methacrylate (12.65 mL, 119 mmol) was added to a
solution of 2-(3-chlorophenyl)-1-(4-chlorophenyl)ethanone (30 g,
113 mmol, Example 1, Step A) in tetrahydrofuran (283 mL). Potassium
tert-butoxide (1.27 g, 11 3 mmol) was then added and the reaction
was stirred at room temperature for 2 days. The solvent was removed
under a vacuum and replaced with 300 mL of ethyl acetate. The
organic phase was washed with brine (50 mL), water (3.times.50 mL),
and brine (50 mL). The organic phase was dried over magnesium
sulfate, filtered and concentrated under a vacuum to afford methyl
4-(3-chlorophenyl)-5-(4-chlorophenyl)-2-methyl-5-oxopentanoate as
an approximately 1:1 mixture of diastereomers. .sup.1H NMR (400
MHz, CDCl.sub.3, .delta. ppm): 7.87 (m, 2H), 7.38 (m, 2H),
7.27-7.14 (series of m, 4H), 4.61 (m, 1H), 3.69 (s, 1.5H), 3.60 (s,
1.5 H), 2.45 (m, 1H), 2.34 (m, 1H), 2.10 (ddd, J=13.9, 9.4, 5.5 Hz,
0.5H), 1.96 (ddd, J=13.7, 9.0, 4.3 Hz, 0.5H), 1.22 (d, J=7.0 Hz,
1.5H), 1.16 (d, J=7.0, 1.5 H). MS (ESI)=387.0 [M+23].sup.+.
Step C: (3S,
5R,6R)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahydro-2H-pyran--
2-one and (3R,
5R,6R)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahydro-2H-pyran--
2-one
##STR00021##
[0656] Methyl
4-(3-chlorophenyl)-5-(4-chlorophenyl)-2-methyl-5-oxopentanoate (40
g, 104 0 mmol, Example 1, Step B) was dissolved in 200 mL of
anhydrous toluene and concentrated under a vacuum. The residue was
placed under high vacuum for 2 hours before use. The compound was
split into 2.times.20 g batches and processed as follows: methyl
4-(3-chlorophenyl)-5-(4-chlorophenyl)-2-methyl-5-oxopentanoate (20
g, 52 0 mmol) in anhydrous 2-propanol (104 mL) was treated with
potassium tert-butoxide (2.33 g, 20 8 mmol) in a 250 mL glass
hydrogenation vessel. RuCl.sub.2(S-xylbinap)(S-DAIPEN) (0.191 g,
0.156 mmol, Strem Chemicals, Inc., Newburyport, Mass.) in 3.8 mL of
toluene was added. After 1.5 hours, the vessel was pressurized to
50 psi (344.7 kPa) and purged with hydrogen five times and allowed
to stir at room temperature. The reaction was recharged with
additional hydrogen as needed. After 3 days, the reactions were
combined and partitioned between 50% saturated ammonium chloride
solution and ethyl acetate. The aqueous layer was extracted with
ethyl acetate. The combined organic phases were washed with brine,
dried over magnesium sulfate, filtered, and concentrated. The crude
product (predominantly, (4R,5R)-isopropyl
4-(3-chlorophenyl)-5-(4-chlorophenyl)-5-hydroxy-2-methylpentanoate)
was dissolved in tetrahydrofuran (450 mL) and methanol (150 mL).
Lithium hydroxide (1.4 M, 149 mL, 208 mmol) was added, and the
solution was stirred at room temperature for 24 hours. The mixture
was concentrated under a vacuum and the residue was redissolved in
ethyl acetate. Aqueous 1N hydrochloric acid was added with stirring
until the aqueous layer had a pH of about 1. The layers were
separated and the organic phase was washed with brine, dried over
magnesium sulfate, filtered and concentrated. The material was
dissolved in 200 mL of anhydrous toluene and treated with
pyridinium p-toluenesulfonate (PPTS, 0.784 g, 3.12 mmol). The
reaction was heated to reflux under Dean-Stark conditions until the
seco-acid was consumed (about 2 hours). The reaction was cooled to
room temperature and washed with saturated sodium bicarbonate (50
mL) and brine (50 mL). The solution was dried over sodium sulfate,
filtered and concentrated. The crude material was purified by flash
chromatography on silica gel (120 g column; eluting with 100%
dichloromethane). The title compounds were obtained as a white
solid with an approximate 94:6 enantiomeric ratio and a 7:3 mixture
of methyl diastereomers. .sup.1H NMR (400 MHz, CDCl.sub.3, .delta.
ppm): 7.22-6.98 (series of m, 5H), 6.91 (dt, J=7.4, 1.2 Hz, 0.3H),
6.81 (m, 2H), 6.73 (dt, J=7.6, 1.4 Hz, 0.7H), 5.76 (d, J=4.1 Hz,
0.3 H), 5.69 (d, J=4.7 Hz, 0.7H), 3.67 (dt, J=6.6, 4.3 Hz, 0.3H),
3.55 (td, J=7.8, 4.7 Hz, 0.7 H), 2.96 (d of quintets, J=13.5, 6.7
Hz, 0.7 H), 2.81 (m, 0.3 H), 2.56 (dt, J=14.3, 8.0 Hz, 0.7 H), 2.32
(dt, J=13.69, 7.0 Hz, 0.3 H), 2.06 (ddd, J=13.7, 8.4, 4.1, 0.3 H),
1.85 (ddd, J=14.1, 12.5, 7.4, 0.7 H), 1.42 (d, J=7.0 Hz, 0.9 H),
1.41 (d, J=6.7 Hz, 2.1H). MS (ESI)=357.0 [M+23].sup.+.
[.alpha.].sub.D (22.degree. C., c=1.0,
CH.sub.2Cl.sub.2)=-31.9.degree.; m.p. 98-99.degree. C.
Step D.
(3S,5R,6R)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylt-
etrahydro-2H-pyran-2-one
##STR00022##
[0658] A solution of (3S,
5R,6R)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahydro-2H-pyran--
2-one and
(3R,5S,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahy-
dro-2H-pyran-2-one (4.5 g, 13.4 mmol, Example 1, Step C) and allyl
bromide (3.48 mL, 40.3 mmol) in tetrahydrofuran (22 mL) at
-35.degree. C. (acetonitrile/dry ice bath) was treated with a
solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran
(1.0 M, 17.45 mL, 17.45 mmol). The reaction was allowed to warm to
-5.degree. C. over 1 hour and then was quenched with 50% saturated
ammonium chloride. The reaction was diluted with 100 mL of ethyl
acetate and the layers were separated. The organic phase was washed
with brine, dried over magnesium sulfate, filtered and concentrated
under a vacuum to afford the title compound as a white solid upon
standing under a vacuum. Chiral SFC (92% CO.sub.2, 8% methanol (20
mM ammonia), 5 mL/min, Phenomenex Lux-2 column (Phenomenex,
Torrance. Calif.), 100 bar (10,000 kPa), 40.degree. C., 5 minute
method) was used to determine that the compound had an enantiomeric
ratio of 96:4. (Major enantiomer: title compound, retention
time=2.45 minutes, 96%; minor enantiomer (structure not shown,
retention time=2.12 min, 4%). The title compound was recrystallized
by adding to heptane (4.7 g slurried in 40 mL) at reflux and 1.5 mL
of toluene was added dropwise to solubilize. The solution was
cooled to 0.degree. C. The white solid was filtered and rinsed with
20 mL of cold heptanes to afford a white powder. Chiral SFC (92%
CO.sub.2, 8% methanol, Phenomenex Lux-2 column, same method as
above) indicated an enantiomeric ratio of 99.2:0.8. (major
enantiomer, 2.45 min, 99.2%; minor enantiomer: 2.12 min, 0.8%).
.sup.1H NMR (400 MHz, CDCl.sub.3, .delta. ppm): 7.24 (ddd, J=8.0,
2.0, 1.2 Hz, 1H), 7.20-7.15 (series of m, 3H), 6.91 (t, J=2.0 Hz,
1H), 6.78 (br d, J=7.6 Hz, 1H), 6.60 (m, 2H), 5.84 (ddt, J=17.6,
10.2, 7.4 Hz, 1H), 5.70 (d, J=5.3 Hz, 1H), 5.21-5.13 (series of m,
2H), 3.82 (dt, J=11.7, 4.5 Hz, 1H), 2.62 (ABX J.sub.AB=13.7 Hz,
J=7.6 Hz, 1H), 2.53 (ABX, J.sub.AB=13.9 Hz, J.sub.BX=7.2 Hz, 1H).
1.99 (dd, J=14.1, 11.9 Hz, 1H), 1.92 (ddd, J=13.9, 3.9, 1.2 Hz,
1H). .sup.13C NMR (CDCl.sub.3, 100 MHz, .delta. ppm): 175.9, 140.2,
134.5, 134.3, 134.0, 132.2, 129.8, 128.6, 128.0, 127.9, 127.8,
126.4, 119.9, 83.9, 44.5, 42.4, 40.7, 31.8, 26.1. MS (ESI)=375.2
[M+H].sup.+. IR=1730 cm.sup.-1. [.alpha.].sub.D (24.degree. C.,
c=1.0, CH.sub.2Cl.sub.2)=-191.degree.. m.p. 111-114.degree. C.
Step E.
(2S)-2-((2R)-2-(3-Chlorophenyl)-3-(4-chlorophenyl)-3-hydroxypropyl-
)-NAS)-1-cyclopropyl-2-hydroxyethyl)-2-methylpent-4-enamide
##STR00023##
[0660]
(3S,5R,6R)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylte-
trahydro-2H-pyran-2-one (125.0 g, 333 mmol, Example 1, Step D) was
added to (S)-2-amino-2-cyclopropylethanol (101 g, 999 mmol) and the
reaction mixture was heated at 110.degree. C. under argon for 25
hours. The reaction mixture was diluted with isopropyl acetate,
cooled to room temperature, and 3 M hydrochloric acid (400 mL) was
added slowly. The mixture was stirred at room temperature for 20
minutes, and the layers were separated. The organic layer was
washed with 1 M hydrochloric acid (200 mL) and brine, then dried
over magnesium sulfate, filtered and concentrated under a vacuum to
provide the desired product as a brown oil (159 g).
Step F.
(3S,5S,6R,8S)-8-Allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-cycl-
opropyl-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium
4-methylbenzenesulfonate
##STR00024##
[0661] A 2 L 4-necked round-bottomed flask equipped with a magnetic
stir bar, addition funnel, septa and internal temperature sensor
was charged withp-toluenesulfonic anhydride (240 g, 734 mmol) and
anhydrous dichloromethane (600 mL). The internal temperature was
adjusted to 14.degree. C. and the mixture was stirred for 10
minutes. A solution of
(S)-2-((2R,3R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-3-hydroxypropyl)-N-(-
(S)-1-cyclopropyl-2-hydroxyethyl)-2-methylpent-4-enamide (159.0 g,
334 mmol, Example 1, Step E) in anhydrous dichloromethane (400 mL)
was added to the reaction mixture. The temperature increased to
17.degree. C. before returning to 14.degree. C. The reaction
mixture was cooled to 7.degree. C. and 2,6-lutidine (160 mL, 1372
mmol) (dried over activated 4 A molecular sieves) was added
dropwise via addition funnel to the reaction mixture. The addition
was complete after 1 hour. The reaction mixture was removed from
the water bath and stirred at room temperature for 1 hour. The
reaction mixture was heated at reflux for 16 hours. LCMS indicated
that some intermediate remained. Additional p-toluenesulfonic
anhydride (0.25 equiv) and lutidine (0.5 equiv) were added and the
reaction mixture was heated at reflux for 8 hours. LCMS indicated
that the reaction was complete. The reaction mixture was cooled to
room temperature and added via addition funnel to 1 M aqueous
sulfuric acid (764 mL, 764 mmol) with stirring. The addition took
30 minutes, and the solution was stirred at room temperature for 30
minutes thereafter. The layers were separated and the organic layer
was dried over magnesium sulfate, filtered and concentrated under a
vacuum to provide a brown syrup. To remove any dichloromethane from
the syrup it was taken up in ethyl acetate and concentrated under a
vacuum twice to provide a thick brown syrup. Ethyl acetate (2 L)
was added and the mixture was heated at 60.degree. C. until all of
the syrup was dissolved (about 45 minutes). The solution was
stirred while cooling to room temperature. Crystals had formed
after 2 hours and the mixture was cooled to 10.degree. C. for 1
hour before collecting the solid by vacuum filtration and washing
with cold (10.degree. C.) ethyl acetate. This provided 70 g of the
desired product as an off-white crystalline solid. The filtrate was
concentrated under a vacuum to 1.5 L and the mixture was stirred at
10.degree. C. for 1.5 hours. The mixture was filtered under vacuum
to provide a light brown crystalline solid that was shown to be
lutidinium tosylate by NMR. The filtrate was concentrated under
vacuum to provide a brown syrup (161g). Heptane was added to the
syrup and the mixture was heated. A minimal amount of ethyl acetate
was added until the material dissolved. The solution was cooled to
room temperature and then placed in the freezer. The resulting
solid was collected by vacuum filtration and washed with cold
(0.degree. C.) ethyl acetate to provide the desired product as an
off-white crystalline solid (34g). The filtrate was concentrated to
provide a dark brown oil and purified by flash chromatography on
silica gel (1.5 kg SiO.sub.2 column, gradient elution of 20% to
100% acetone in hexanes) to provide the desired product as a light
brown syrup (73 g). .sup.1H NMR (500 MHz, CDCk.sub.3, .delta. ppm):
-0.3 to -0.2 (m, 2H), 0.06-0.11 (m, 1H), 0.31-0.36 (m, 1H),
0.38-0.43 (m, 1H), 1.57 (s, 3H), 1.91 (dd, J=3.7 and 13.9 Hz, 1H),
2.36 (s, 3H), 2.64 (dd, J=7.3 and 13.7 Hz, 1H), 2.72 (dd, J=7.6 and
13.7 Hz, 1H), 2.95 (t, J=13.9 Hz, 1H), 3.32 (dt, J=3.7 and 10.8 Hz,
1H), 4.47 (t, J=8.6 Hz, 1H), 4.57-4.62 (m, 1H), 5.32 (d, J=16.9 Hz,
1H), 5.35 (d, J=10.3 Hz, 1H), 5.46 (t, J=9.5 Hz, 1H), 5.82 (d,
J=10.5 Hz, 1H), 5.84-5.93 (m, 1H), 6.94 (br s, 1H), 7.04 (s, 1H),
7.14-7.20 (m, 5H), 7.28-7.40 (m, 3H), 7.88 (d, J=8.1 Hz, 2H)). MS
(ESI) 440.1 [M+H].sup.+.
Step G.
(3S,5R,6S)-3-Allyl-1-((S)-2-(tert-butylthio)-1-cyclopropylethyl)-5-
-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one
##STR00025##
[0663] 2-Methyl-2-propanethiol (0.195 mL, 1.796 mmol, dried over
activated 4 A molecular sieves) was added to a solution of lithium
bis(trimethylsilyl)amide in tetrahydrofuran (1.0 M, 1.8 mL, 1.8
mmol) in anhydrous tetrahydrofuran (4 mL) at room temperature. The
reaction mixture was heated at 60.degree. C. After 15 minutes at
60.degree. C.,
(3S,5S,6R,8S)-8-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-cyclopropyl-
-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium
4-methylbenzenesulfonate (1.00 g, 1.632 mmol, Example 1, Step F)
was added as a solid. The reaction mixture was heated at 60.degree.
C. for 12 hours and then cooled to room temperature and diluted
with water. The solution was extracted with ethyl acetate thrice
and the organics were pooled, washed with brine, dried over sodium
sulfate, decanted and concentrated under a vacuum to provide a
brown oil. Purification by flash chromatography (80 g SiO.sub.2
column, gradient elution of 10 to 60% ethyl acetate in hexanes
provided the desired product as a colorless syrup. .sup.1H NMR (500
MHz, CDCl.sub.3, .delta. ppm): -0.88 to -0.85 (m, 1H), -0.16 to
-0.13 (m, 1H), 0.22-0.27 (m, 1H), 0.39-0.44 (m, 1H), 1.28 (s, 3H),
1.35 (s, 9H), 1.66-1.71 (m, 1H), 1.86 (dd, J=3.2 and 13.5 Hz, 1H),
2.16 (t, J=13.7, 1H), 2.21-2.27 (m, 1H), 2.60 (dd, J=4.4 and 12.0
Hz, 1H), 2.65 (d, J=7.6 Hz, 2H), 3.12 (dt, J=3.2 and 10.3 Hz, 1H),
3.60 (t, J=11.3 Hz, 1H), 4.68 (d, J=10.3 Hz, 1H), 5.16-5.19 (m,
2H), 5.83-5.92 (m, 1H), 6.79 (d, J=7.6 Hz, 1H), 6.93-7.04 (m, 3H),
7.09-7.16 (m, 2H), 7.19-7.24 (m, 2H). MS (ESI) 530.2
[M+H].sup.+.
Step H.
2-((3R,5R,6S)-1-((S)-2-(tert-Butylsulfonyl)-1-cyclopropylethyl)-5--
(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00026##
[0665] Ruthenium(III) chloride hydrate (30.0 mg, 0.135 mmol) was
added to a solution of
(3S,5R,6S)-3-allyl-1-((S)-2-(tert-butylthio)-1-cyclopropylethyl)-5-(3-chl-
orophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one (3.25 g, 6.13
mmol, Example 1, Step H) and sodium periodate (1.33 g) in ethyl
acetate (12 mL), acetonitrile (12 mL) and water (18 mL) at
18.degree. C. The temperature rose to 25.degree. C. upon addition.
Additional sodium periodate was added in five 1.33 g portions over
30 minutes while maintaining the temperature below 22.degree. C.
LCMS after 1.5 hours indicated that the reaction was incomplete,
and sodium periodate (1 equivalent) was added. After 1.5 hours the
reaction mixture was vacuum filtered, washed with ethyl acetate,
and the layers were separated. The aqueous layer was extracted with
ethyl acetate and the organics were combined, washed with brine,
dried over magnesium sulfate, filtered and concentrated under a
vacuum to provide a green oil. Purification by flash chromatography
(330 g SiO.sub.2 column, gradient elution of 0% to 20% isopropanol
in hexanes provided the title compound as a white solid. .sup.1H
NMR (500 MHz, CDCl.sub.3, .delta. ppm): -1.15 to -1.05 (m, 1H),
-0.35 to -0.25 (m, 1H), 0.18-0.28 (m, 1H), 0.33-0.40 (m, 1H), 1.45
(s, 9H), 1.51 (s, 3H), 1.86 (dd, J=2.7 and 13.7 Hz, 1H), 1.87-1.93
(m, 1H), 2.47 (t, J=13.9, 1H), 2.72-2.76 (m, 1H), 2.76 (d, J=15.5
Hz, 1H), 2.93 (d, J=13.7 Hz, 1H), 3.12 (d, J=15.1 Hz, 1H), 3.12
(dt, J=2.7 and 12.5 Hz, 1H), 4.29 (t, J=11.5 Hz, 1H), 4.95 (d,
J=10.8 Hz, 1H), 6.86-6.89 (m, 1H), 6.96 (br s, 1H), 7.08-7.14 (m,
3H), 7.15-7.35 (m, 3H). MS (ESI) 580.2 [M+H].sup.+.
EXAMPLE 2
2-((3R,5R,6S)-1-((S)-2-(tert-Butylsulfonyl)-1-cyclopropylethyl)-5-(3-chlor-
ophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetamide
##STR00027##
[0667] Oxalyl chloride (0.033 mL, 0.379 mmol) was added to a
solution of
2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-5-(3-chlo-
rophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid (0.200 g, 0.344 mmol, Example 1, Step H) in anhydrous
dichloromethane (1.5 mL) at room temperature. The reaction mixture
was stirred at room temperature for 1 hour and then concentrated
under a vacuum to provide the acid chloride as a white foam (206
mg). Lithium bis(trimethylsilyl)amide (1.0 M in tetrahydrofuran,
0.516 mL, 0.516 mmol) and anhydrous tetrahydrofuran (0.5 mL) were
added at room temperature. The reaction mixture was stirred at room
temperature for 5.5 hours and was then diluted with 1 N
hydrochloric acid and extracted with ethyl acetate thrice. The
organics were pooled, washed with brine, dried over sodium sulfate,
decanted and concentrated under a vacuum to provide a yellow foam.
Purification by flash chromatography (12 g SiO.sub.2 column;
gradient elution of 35% to 100% ethyl acetate) provided the title
compound as an off-white foam. .sup.1H NMR (500 MHz, CDCl.sub.3,
.delta. ppm): -1.10 to -1.00 (m, 1H), -0.38 to -0.325 (m, 1H),
0.17-0.26 (m, 1H), 0.30-0.38 (m, 1H), 1.43 (s, 3H), 1.44 (s, 9H),
1.85-1.92 (m, 1H), 2.00 (dd, J=2.7 and 13.5 Hz, 1H), 2.39 (t,
J=13.7, 1H), 2.65-2.75 (m, 1H), 2.73-2.80 (m, 2H), 2.90-2.96 (m,
1H), 3.31 (dt, J=2.9 and 10.8 Hz, 1H), 4.30-4.38 (m, 1H), 4.96 (d,
J=10.8 Hz, 1H), 5.63 (br s, 1H), 6.64 (br s, 1H), 6.90-6.91 (m,
1H), 7.00 (s, 2H), 7.06-7.11 (m, 3H), 7.12-7.29 (m, 2H). MS (ESI)
579.2 [M+H].sup.+.
EXAMPLE 3
2-((3R,5R,6S)-1-((S)-2-(tert-Butylsulfonyl)-1-cyclopropylethyl)-5-(3-chlor-
ophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)-N-phenylacetamid-
e
##STR00028##
[0669] N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride
(EDC, 0.117 g, 0.612 mmol) was added to a solution of
2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-5-(3-chlo-
rophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid (0.118 g, 0.204 mmol, Example 1, Step H) and aniline (0.020
mL, 0.225 mmol) at 0.degree. C. After the addition was complete,
the reaction mixture was removed from the ice bath and stirred at
room temperature for 19 hours. The reaction mixture was diluted
with ice-cold 1 M hydrochloric acid to adjust the pH to 1 and the
solution was extracted twice with ether. The combined organic layer
was washed with brine, dried over sodium sulfate, decanted and
concentrated under a vacuum to provide an orange oil. Purification
by flash chromatography (12 g SiO.sub.2 column, gradient elution of
15% to 100% ethyl acetate in hexanes provided the title compound as
a white foam. .sup.1H NMR (500 MHz, CDCl.sub.3, .delta. ppm): -1.32
to -1.20 (m, 1H), -0.40 to -0.28 (m, 1H), -0.28 to -0.10 (m, 1H),
0.30-0.40 (m, 1H), 1.45 (s, 9H), 1.47 (s, 3H), 1.94 (br s, 1H),
2.07 (dd, J=2.7 and 13.7 Hz, 1H), 2.39 (t, J=13.7, 1H), 2.67-2.73
(m, 2H), 2.95 (t, J=13.5 Hz, 2H), 3.30 (dt, J=2.7 and 11.0 Hz, 1H),
4.31 (br t, J=11.7 Hz, 1H), 4.94 (d, J=10.8 Hz, 1H), 6.86-6.89 (m,
1H), 6.99 (s, 1H), 7.02-7.09 (m, 6 H), 7.17 (t, J=7.3 Hz, 1H), 7.38
(t, J=8.3 Hz, 2H), 7.66 (d, J=7.8 Hz, 2H). MS (ESI) 655.3
[M+H].sup.+.
EXAMPLE 4
2-((3R,5R,6S)-1-((S)-2-(tert-Butylsulfonyl)-1-cyclopropylethyl)-6-(4-chlor-
o-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00029##
[0670] Step A. Methyl -4-chloro-3-fluorobenzoate
##STR00030##
[0672] A solution of 4-chloro-3-fluoro benzoic acid (450.0 g, 2.586
mol, Fluorochem, Derbyshire, UK) in methanol (4.5 L) was cooled to
0.degree. C. and thionyl chloride (450.0 mL) was added over 30
minutes. The reaction mixture was stirred for 12 hours at ambient
temperature. The reaction was monitored by TLC. Upon completion,
the solvent was removed under reduced pressure and the residue was
quenched with 1.0 M sodium bicarbonate solution (500 mL). The
aqueous layer was extracted with dichloromethane (2.times.5.0 L).
The combined organic layer was washed with brine (2.5 L), dried
over anhydrous sodium sulfate and concentrated under reduced
pressure afforded the title compound as light brown solid. The
crude compound was used in the next step without further
purification. .sup.1H NMR (400 MHz, CDCl.sub.3, .delta. ppm):
7.82-7.74 (m, 2H), 7.46 (dd, J=8.2, 7.5 Hz, 1H), 3.92 (s, 3H).
Step B. 1-(4-chloro-3-fluorophenyl)-2-(3-chlorophenyl)ethanone
##STR00031##
[0674] Sodium bis(trimethylsilyl)amide (1 M in tetrahydrofuran, 4
L, 4000 mmol) was added over 1 hour to a solution of 3-chlorophenyl
acetic acid (250.0 g, 1465 mmol) in anhydrous tetrahydrofuran (1.75
L) at -78.degree. C. under nitrogen. The resulting reaction mixture
was stirred for an additional hour at -78.degree. C. Then, a
solution of methyl-4-chloro-3-fluorobenzoate (221.0 g, 1175 mmol,
Example 4, Step A) in tetrahydrofuran (500 mL) was added over 1
hour at -78.degree. C., and the resulting reaction mixture was
stirred at the same temperature for 2 hours. The reaction was
monitored by TLC. On completion, reaction mixture was quenched with
2 N hydrochloric acid (2.5 L) and aqueous phase was extracted with
ethyl acetate (2.times.2.5 L). The combined organic layer was
washed with brine (2.5 L), dried over anhydrous sodium sulfate and
concentrated under reduced pressure to provide the crude material
which was purified by flash column chromatography (silica gel: 100
to 200 mesh, product eluted in 2% ethyl acetate in hexane) to
afford the title compound as a white solid. .sup.1H NMR (400 MHz,
CDCl.sub.3, .delta. ppm): 7.74 (ddd, J=10.1, 8.9, 1.8 Hz, 2H),
7.56-7.48 (m, 1H), 7.26 (t, J=6.4 Hz, 3H), 7.12 (d, J=5.7 Hz, 1H),
4.22 (s, 2H). MS (ESI) 282.9 [M+H].sup.+.
Step C. Methyl
5-(4-chloro-3-fluorophenyl)-4-(3-chlorophenyl)-2-methyl-5-oxopentanoate
##STR00032##
[0676] Methyl methacrylate (125.0 g, 1097 mmol) and potassium
tert-butoxide (1 M in tetrahydrofuran, 115 mL, 115 mmol) were
sequentially added to a solution of
1-(4-chloro-3-fluorophenyl)-2-(3-chlorophenyl)ethanone (327.0 g,
1160 mmol, Example 4, Step B) in anhydrous tetrahydrofuran (2.61
L), at 0.degree. C. The reaction mixture was stirred for 1 hour at
0.degree. C. and then warmed to ambient temperature and stirred for
12 hours. On completion, the reaction was quenched with water (1.0
L) and extracted with ethyl acetate (2.times.2.5 L). The combined
organic layer was washed with brine, dried over anhydrous sodium
sulfate and concentrated under reduced pressure to get the crude
material which was purified by flash column chromatography (silica
gel: 60 to 120 mesh, product eluted in 4% ethyl acetate in hexane)
affording the title compound (mixture of diastereomers) as light
yellow liquid. .sup.1H NMR (400 MHz, CDCl.sub.3, .delta. ppm):
7.74-7.61 (m, 4H), 7.47-7.40 (m, 2H), 7.28-7.18 (m, 6H), 7.16-7.10
(m, 2H), 4.56 (m, 2H), 3.68 (s, 3H), 3.60 (s, 3H), 2.50-2.39 (m,
2H), 2.37-2.25 (m, 2H), 2.10-2.02 (m, 1H), 1.94 (ddd, J=13.6, 9.1,
4.2 Hz, 1H), 1.21 (d, J=7.0 Hz, 3H), 1.15 (d, J=7.0 Hz, 3H). MS
(ESI) 383.0 [M+H].sup.+.
Step D.
(3S,5R,6R)-6-(4-Chloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-
tetrahydro-2H-pyran-2-one and
(3R,5R,6R)-6-(4-chloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyltetrahy-
dro-2H-pyran-2-one
##STR00033##
[0678] In a 2000 mL reaction vessel charged with methyl
5-(4-chloro-3-fluorophenyl)-4-(3-chlorophenyl)-2-methyl-5-oxopentanoate
(138.0 g, 360 mmol, Example 4, Step C) (which was cooled on ice for
10 minutes before transferring to a glove bag) anhydrous 2-propanol
(500 mL), and potassium tert-butoxide (16.16 g, 144 mmol) were
sequentially added while in a sealed glove bag under argon. This
mixture was allowed to stir for 30 minutes.
RuCl.sub.2(S-xylbinap)(S-DAIPEN) (1.759 g, 1.440 mmol, Strem
Chemicals, Inc., Newburyport, Mass., weighed in the glove bag) in
30.0 mL toluene was added. The reaction was vigorously stirred at
room temperature for 2 hours. The vessel was set on a hydrogenation
apparatus, purged with hydrogen 3 times and pressurized to 50 psi
(344.7 kPa). The reaction was allowed to stir overnight at room
temperature. On completion, the reaction was quenched with water
(1.5 L) and extracted with ethyl acetate (2.times.2.5 L). The
organic layer was washed with brine (1.5 L), dried over anhydrous
sodium sulfate and concentrated under reduced pressure to get crude
material which was purified by flash column chromatography (silica
gel; 60-120 mesh; product eluted in 12% ethyl acetate in hexane) to
provide a dark colored liquid as a mixture of diastereomers.
[0679] The product was dissolved in (240.0 g, 581 mmol) in
tetrahydrofuran (1.9 L) and methanol (480 mL), and lithium
hydroxide monohydrate (2.5 M aqueous solution, 480.0 mL) was added.
The reaction mixture was stirred at ambient temperature for 12
hours. On completion, the solvent was removed under reduced
pressure and the residue was acidified with 2 N hydrochloric acid
to a pH between 5 and 6. The aqueous phase was extracted with ethyl
acetate (2.times.1.0 L). The combined organic layer was washed with
brine (750 mL), dried over anhydrous sodium sulfate, filtered, and
concentrated under reduced pressure to provide a dark colored
liquid, which was used without further purification.
[0680] A portion of the crude intermediate (25.4 g, predominantly
seco acid) was added to a 500 mL round bottom flask, equipped with
a Dean-Stark apparatus. Pyridiniump-toluenesulfonate (0.516 g,
2.053 mmol) and toluene (274 mL) were added, and the mixture was
refluxed for 1 hour (oil bath temperature about 150.degree. C.).
The reaction was cooled to room temperature and concentrated under
reduced pressure. The reaction was diluted with saturated aqueous
sodium bicarbonate (150 mL), extracted with diethyl ether
(2.times.150 mL), and washed with brine (150 mL). The combined
organic layer was dried over magnesium sulfate, filtered and
concentrated under reduced pressure. Purification by flash column
chromatography (divided into 3 portions, 330 g Si0.sub.2/each,
gradient elution of 0% to 30% acetone in hexanes, 35 minutes)
provided the title compounds as a pale yellow solid and a 1:1.6
mixture of diastereomers at C2. MS (ESI) 353.05 [M+H].sup.+.
Step E.
(3S,5R,6R)-3-Allyl-6-(4-chloro-3-fluorophenyl)-5-(3-chlorophenyl)--
3-methyltetrahydro-2H-pyran-2-one
##STR00034##
[0682]
(3S,5R,6R)-6-(4-Chloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methylt-
etrahydro-2H-pyran-2-one and
(3R,5R,6R)-6-(4-chloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyltetrahy-
dro-2H-pyran-2-one (18 g, 51 0 mmol, Example 4, Step D) was added
to an oven dried 500 mL round-bottom flask. The solid was dissolved
in anhydrous toluene and concentrated to remove adventitious water.
3-Bromoprop-1-ene (11.02 mL, 127 mmol, passed neat through basic
alumina prior to addition) in tetrahydrofuran (200 mL) was added
and the reaction vessel was evacuated and refilled with argon three
times. Lithium bis(trimethylsilyl)amide (1.0 M, 56.1 mL, 56 1 mmol)
was added dropwise at -40.degree. C. (dry ice/acetonitrile bath)
and stirred under argon. The reaction was allowed to gradually warm
to -10.degree. C. and stirred at -10.degree. C. for 3 hours. The
reaction was quenched with saturated ammonium chloride (10 mL),
concentrated, and the crude product was diluted in water (150 mL)
and diethyl ether (200 mL). The layers were separated and the
aqueous layer was washed twice more with diethyl ether (200
mL/each). The combined organic layer was washed with brine (100
mL), dried over magnesium sulfate, filtered, and concentrated under
reduced pressure to a residue. The residue was purified by flash
chromatography (2.times.330 g silica gel columns, gradient elution
of 0% to 30% acetone in hexanes) to provide the title compound as a
white solid. The product can alternatively be crystallized from a
minimum of hexanes in dichloromethane. Enantiomeric excess was
determined to be 87% by chiral SFC (90% CO.sub.2, 10% methanol (20
mM ammonia), 5 0 mL/min, 100 bar (10,000 kPa), 40.degree. C., 5
minute method, Phenomenex Lux-2 (Phenomenex, Torrance, Calif.) (100
mm.times.4.6 mm, 5 !um column), retention times: 1.62 min. (minor)
and 2.17 min. (major)). The purity could be upgraded to >98%
through recrystallization in hexanes and dichloromethane. .sup.1H
NMR (400 MHz, CDCl.sub.3, .delta. ppm): 7.24-7.17 (m, 3H), 6.94 (s,
1H), 6.80 (d, J=7.5 Hz, 1H), 6.48 (dd, J=10.0, 1.9 Hz, 1H), 6.40
(d, J=8.3 Hz, 1H), 5.90-5.76 (m, 1H), 5.69 (d, J=5.2 Hz, 1H),
5.20-5.13 (m, 2H), 3.81 (dd, J=13.9, 6.9 Hz, 1H), 2.62 (dd, J=13.8,
7.6 Hz, 1H), 2.50 (dd, J=13.8, 7.3 Hz, 1H), 1.96 (d, J=8.4 Hz, 2H),
1.40 (s, 3H). MS (ESI) 393.1 [M+H].sup.+.
Step F.
(2S)-2-((2R)-3-(4-Chloro-3-fluorophenyl)-2-(3-chlorophenyl)-3-hydr-
oxypropyl)-N-((S)-1-cyclopropyl-2-hydroxyethyl)-2-methylpent-4-enamide
##STR00035##
[0684] Sodium methoxide (25% in methanol, 60.7 ml, 265 mmol) was
added to a solution of (S)-2-amino-2-cyclopropylethanol
hydrochloride (36.5 g, 265 mmol, NetChem Inc., Ontario, Canada) in
methanol (177 mL) at 0.degree. C. A precipitate formed during the
addition. After the addition was complete, the reaction mixture was
removed from the ice bath and warmed to room temperature. The
reaction mixture was filtered under a vacuum and the solid was
washed with dichloromethane. The filtrate was concentrated under a
vacuum to provide a cloudy brown oil.
[0685] The oil was taken up in dichloromethane (150 mL), filtered
under a vacuum and the solid phase washed with dichloromethane to
provide the filtrate as a clear orange solution. The solution was
concentrated under a vacuum to provide
(S)-2-amino-2-cyclopropylethanol as a light brown liquid.
[0686]
(3S,5R,6R)-3-Allyl-6-(4-chloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-
-methyltetrahydro-2H-pyran-2-one (32 g, 81 mmol, Example 4, Step E)
was combined with (S)-2-amino-2-cyclopropylethanol (26.7 g, 265
mmol) and the suspension was heated at 100.degree. C. overnight.
The reaction mixture was cooled to room temperature, diluted with
ethyl acetate and washed with 1 N hydrochloric acid (2X), water,
and brine. The organic layer was dried over magnesium sulfate and
concentrated under vacuum to provide the title compound as a white
solid. .sup.1H NMR (500 MHz, CDCl.sub.3, .delta. ppm): 0.23-0.30
(m, 2H), 0.45-0.56 (m, 2H), 0.81 (m, 1H), 1.12 (s, 3H), 1.92-2.09
(m, 3H), 2.39 (dd, J=13.6, 7.2 Hz, 1H), 2.86 (br s, 1H), 2.95 (dtd,
J=9.5, 6.3, 6.3, 2.9 Hz, 1H), 3.44 (dd, J=11.0, 5.6 Hz, 1H), 3.49
(m, 1H), 3.61 (dd, J=11.0, 2.9 Hz, 1H), 4.78 (d, J=5.6 Hz, 1H),
4.95-5.13 (m, 2H), 5.63 (m, 1H), 5.99 (d, J=6.4 Hz, 1H), 6.94-7.16
(m, 3H), 7.16-7.32 (m, 4H). MS (ESI) 494 [M+H].sup.+.
Step G.
(3S,5R,6S)-3-Allyl-6-(4-chloro-3-fluorophenyl)-5-(3-chlorophenyl)--
1-((S)-1-cyclopropyl-2-hydroxyethyl)-3-methylpiperidin-2-one
##STR00036##
[0688] A solution of
(2S)-2-((2R)-3-(4-chloro-3-fluorophenyl)-2-(3-chlorophenyl)-3-hydroxyprop-
yl)-N-((S)-1-cyclopropyl-2-hydroxyethyl)-2-methylpent-4-enamide
(40.2 g, 81 mmol, Example 4, Step F) in dichloromethane (80 mL) was
addedp-toluenesulfonic anhydride (66.3 g, 203 mmol) in
dichloromethane (220 mL) at 0.degree. C. ,and the reaction mixture
was stirred for 10 minutes at same the temperature. 2,6-Lutidine
(43.6 mL, 374 mmol, Aldrich, St. Louis, Mo.) was added dropwise via
addition funnel at 0.degree. C. The reaction mixture was slowly
warmed to room temperature, and then it was stirred at reflux.
After 24 hours, sodium bicarbonate (68.3 g, 814 mmol) in water (600
mL) and 1,2-dichloroethane (300 mL) were added in succession. The
reaction mixture was heated at reflux for an hour and then cooled
to room temperature. The layers were separated and the aqueous
layer was extracted with dichloromethane. The combined organic
layer was washed with 1 N hydrochloric acid, water, and brine, then
concentrated under reduced pressure. The residue was purified by
flash chromatography (1.5 kg SiO.sub.2 column, gradient elution of
10% to 50% ethyl acetate in hexanes) to provide the title compound
as a white solid. .sup.1H NMR (500 MHz, CDCl.sub.3, .delta. ppm):
0.06 (m, 1H), 0.26 (m, 1H), 0.57-0.67 (m, 2H), 0.85 (m, 1H), 1.25
(s, 3H), 1.85-2.20 (m, 2H), 2.57-2.65 (m, 2H), 3.09 (ddd, J=11.8,
9.8, 4.8 Hz, 1H), 3.19 (t, J=10.0 Hz, 1H), 3.36 (td, J=10.3, 4.6
Hz, 1H), 3.63 (dd, J=11.0, 4.6 Hz, 1H), 4.86 (d, J=10.0 Hz, 1H),
5.16-5.19 (m, 2H), 5.87 (m, 1H), 6.77 (dd, J=7.7, 1.6 Hz, 1H),
6.80-6.90 (m, 2H), 7.02 (t, J=2.0 Hz, 1H), 7,16 (dd, J=10.0, 7.7
Hz, 1H), 7.21 (dd, J=10.0, 1.6 Hz, 1H), 7.29 (t, J=10.0 Hz, 1H). MS
(ESI) 476 [M+H].sup.+.
Step H.
(3S,5S,6R,85)-8-Allyl-5-(4-chloro-3-fluorophenyl)-6-(3-chloropheny-
l)-3-cyclopropyl-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium
4-methylbenzenesulfonate
##STR00037##
[0689] p-Toluenesulfonic acid monohydrate (30.3 g, 159 mmol,
Aldrich, St. Louis, Mo.) was added to a solution of
(3S,5R,6S)-3-allyl-6-(4-chloro-3-fluorophenyl)-5-(3-chlorophenyl)-1-((S)--
1-cyclopropyl-2-hydroxyethyl)-3-methylpiperidin-2-one (73.6 g, 154
mmol) in toluene (386 mL). The reaction mixture was heated at
reflux using a Dean-Stark apparatus. After 4 hours, the reaction
was cooled and concentrated under reduced pressure to provide the
title compound as a pale yellow syrup. The crude product was used
in next step without further purification. .sup.1H NMR (500 MHz,
CDCl.sub.3, .delta. ppm): -0.25 to -0.10 (m, 2H), 0.08-0.18 (m,
1H), 0.33-0.50 (m, 2H), 1.57 (s, 3H), 1.92 (dd, J=3.7 and 13.9 Hz,
1H), 2.37 (s, 3H), 2.63 (dd, J=7.3 and 13.7 Hz, 1H), 2.72 (dd,
J=7.6 and 13.7 Hz, 1H), 2.93 (t, J=13.7 Hz, 1H), 3.29 (m, 1H), 4.51
(t, J=8.6 Hz, 1H), 4.57-4.63 (m, 1H), 5.33 (d, J=17.1 Hz, 1H), 5.37
(d, J=10.5 Hz, 1H), 5.47 (dd, J=9.1 and 10.0 Hz, 1H), 5.75-5.93 (m,
2H), 6.80 (br s, 1H), 7.08 (s, 1H), 7.16-7.20 (m, 5H), 7.25-7.32
(m, 2H), 7.87 (d, J=8.3 Hz, 2H). MS (ESI) 458 [M+H].sup.+.
Step I.
(3S,5R,6S)-3-Allyl-1-((S)-2-(tert-butylthio)-1-cyclopropylethyl)-6-
-(4-chloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methylpiperidin-2-one
##STR00038##
[0691] 2-Methyl-2-propanethiol (15.25 mL, 135 mmol, dried over
activated 4 A molecular sieves) was added to a solution of lithium
bis(trimethylsilyl)amide in tetrahydrofuran (1.0 M, 135 mL, 135
mmol) at room temperature under argon in a 500 mL round-bottomed
flask. The reaction mixture was heated to 60.degree. C. After 30
minutes, a solution of
(3S,5S,6R,8S)-8-allyl-5-(4-chloro-3-fluorophenyl)-6-(3-chlorophenyl)-3-
-cyclopropyl-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium
4-methylbenzenesulfonate (78 g, 123 mmol, Example 4, Step H) in
anhydrous tetrahydrofuran (100 mL) was added via cannula. The
reaction mixture was heated at 60.degree. C. for 3 hours and then
cooled to room temperature. The reaction mixture was quenched with
water and extracted thrice with ethyl acetate. The organics were
pooled, washed with brine, dried over magnesium sulfate, filtered
and concentrated under a vacuum to provide a yellow foam.
Purification by flash column chromatography (1.5 kg SiO.sub.2
column, gradient elution with 5% to 30% ethyl acetate in hexanes
provided the title compound as an off-white foam. .sup.1H NMR (400
MHz, CDCl.sub.3, .delta. ppm): -0.89 to -0.80 (m, 1H), -0.15 to
-0.09 (m, 1H), 0.27-0.34 (m, 1H), 0.41-0.48 (m, 1H), 1.28 (s, 3H),
1.35 (s, 9H), 1.70-1.77 (m, 1H), 1.86 (dd, J=3.1 and 13.5 Hz, 1H),
2.16 (t, J=13.7, 1H), 2.17-2.23 (m, 1H), 2.60-2.63 (m, 3H), 3.09
(dt, J=3.1 and 10.4 Hz, 1H), 3.62 (t, J=11.1 Hz, 1H), 4.70 (d,
J=10.1 Hz, 1H), 5.16 (s, 1H), 5.19-5.21 (m, 1H), 5.82-5.93 (m, 1H),
6.65-6.80 (m, 1H), 6.80-6.83 (m, 1H), 6.84-6.98 (m, 1H), 7.05-7.07
(m, 1H), 7.12-7.18 (m, 2H), 7.19-7.26 (m, 1H). MS (ESI) 548.2
[M+H].sup.+.
Step J.
2-((3R,5R,6S)-1-((S)-2-(tert-Butylsulfonyl)-1-cyclopropylethyl)-6--
(4-chloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)-
acetic acid
##STR00039##
[0693] Ruthenium(III) chloride hydrate (0.562 mg, 2.493 mmol) was
added to a mixture of
(3S,5R,6S)-3-allyl-1-((S)-2-(tert-butylthio)-1-cyclopropylethyl)-6-(4-chl-
oro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methylpiperidin-2-one
(62.17 g, 113 mmol, Example 4, Step I) and sodium periodate (24.67
g) in ethyl acetate (216 mL), acetonitrile (216 mL) and water (324
mL) at 20.degree. C. The temperature quickly rose to 29.degree. C.
The reaction mixture was cooled to 20.degree. C. and the remaining
equivalents of sodium periodate were added in five 24.67 g portions
over 2 hours, being careful to maintain an internal reaction
temperature below 25.degree. C. The reaction was incomplete, so
additional sodium periodate (13 g) was added. The temperature
increased from 22.degree. C. to 25.degree. C. After stirring for an
additional 1.5 hours, the reaction mixture was filtered under a
vacuum and washed with ethyl acetate. The layers were separated and
the aqueous layer was extracted with ethyl acetate. The organics
were pooled, washed with brine, dried over magnesium sulfate,
filtered and concentrated under a vacuum to provide a dark green
foam. Purification by flash column chromatography (1.5 kg SiO.sub.2
column, gradient elution of 0% to 20% isopropanol in hexanes)
provided an off-white foam. 15% Ethyl acetate in heptanes (970 mL)
was added to the foam, and the mixture was heated at 80.degree. C.
until the foam dissolved. The solution was then cooled slowly, and
at 60.degree. C. the solution was seeded with previously obtained
crystalline material. The mixture was cooled to room temperature
and then allowed to stand at room temperature for 2 hours before
collecting the solid by vacuum filtration to provide a white solid
with a very pale pink hue (57.1 g). The mother liquor was
concentrated under a vacuum to provide a pink foam (8.7 g). 15%
ethyl acetate in heptanes (130 mL) was added to the foam, and it
was heated at 80.degree. C. to completely dissolve the material.
The solution was cooled, and at 50.degree. C., it was seeded with
crystalline material. After cooling to room temperature the solid
was collected by vacuum filtration to provide a white crystalline
solid with a very pale pink hue. .sup.1H NMR (500 MHz, CDCl.sub.3,
.delta. ppm): -1.10 to -1.00 (m, 1H), -0.30 to -0.22 (m, 1H),
0.27-0.37 (m, 1H), 0.38-0.43 (m, 1H), 1.45 (s, 9H), 1.50 (s, 3H),
1.87 (dd, J=2.7 and 13.7 Hz, 1H), 1.89-1.95 (m, 1H), 2.46 (t,
J=13.7, 1H), 2.69-2.73 (m, 1H), 2.78 (d, J=14.9 Hz, 1H), 2.93 (dd,
J=2.0 and 13.7 Hz, 1H), 3.07 (d, J=14.9 Hz, 1H), 3.11 (dt, J=2.7
and 11.0 Hz, 1H), 4.30 (t, J=13.5 Hz, 1H), 4.98 (d, J=10.8 Hz, 1H),
6.75-6.87 (m, 1H), 6.88-6.90 (m, 1H), 6.98 (br s, 1H), 7.02-7.09
(m, 1H), 7.11-7.16 (m, 2H), 7.16-7.25 (m, 1H). MS (ESI) 598.1
[M+H].sup.+.
EXAMPLE 5
4-(2-((3R,5R,6S)-1-((S)-2-(tert-Butylsulfonyl)-1-cyclopropylethyl)-6-(4-ch-
loro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yOacetam-
ido)-2-methoxybenzoic acid
##STR00040##
[0694] Step A. Methyl
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoate
##STR00041##
[0696] N-(3-Dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride
(EDC, 76 g, 398 mmol) was added to a mixture of
2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-chlo-
ro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid (79.4 g, 133 mmol, Example 4, Step J) and methyl
4-amino-2-methoxybenzoate (26.4 g, 146 mmol) in pyridine (332 mL)
at 3.degree. C. The mixture was allowed to warm to room temperature
and was stirred at room temperature for 16 hours. The reaction
mixture was cooled to 0.degree. C. and added to an ice-cold
solution of 1 M hydrochloric acid (1 L). Ether (1 L) was added and
the layers were agitated and then separated. The organic layer was
washed with 1 M hydrochloric acid (6.times.500 mL), saturated
aqueous sodium bicarbonate (500 mL), brine (500 mL), dried over
magnesium sulfate, filtered and concentrated under a vacuum to
provide an off-white foam. .sup.1H NMR (400 MHz, CDCl.sub.3,
.delta. ppm): -1.20 to -1.12 (m, 1H), -0.35 to -0.20 (m, 1H),
0.05-0.20 (m, 1H), 0.32-0.45 (m, 1H), 1.45 (s, 9H), 1.48 (s, 3H),
1.86-1.98 (m, 1H), 2.03 (dd, J=2.7 and 13.7 Hz, 1H), 2.43 (t,
J=13.7, 1H), 2.64-2.75 (m, 1H), 2.80 (d, J=14.3 Hz, 1H), 2.89-2.96
(m, 2H), 3.24 (dt, J=2.5 and 10.8 Hz, 1H), 3.89 (s, 3H), 3.96 (s,
3H), 4.28-4.36 (m, 1H), 4.98 (d, J=10.8 Hz, 1H), 6.85-6.93 (m, 3H),
6.99 (br s, 1H), 7.06-7.18 (m, 4 H), 7.82 (br s, 1H), 7.85 (d,
J=8.4 Hz, 1H), 8.81 (br s, 1H). MS (ESI) 761.2 [M+H].sup.+.
Step B.
4-(2-((3R,5R,6S)-1-((S)-2-(tert-Butylsulfonyl)-1-cyclopropylethyl)-
-6-(4-chloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3--
yl)acetamido)-2-methoxybenzoic acid
##STR00042##
[0698] A solution of lithium hydroxide monohydrate (18.2 g, 433
mmol) in water (295 mL) was added to a solution of methyl
4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-c-
hloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
amido)-2-methoxybenzoate (164.9 g, 217 mmol, Example 5, Step A) in
tetrahydrofuran (591 mL) and methanol (197 mL) at room temperature.
After stirring for 15 hours at room temperature, a trace amount of
the ester remained, so the reaction mixture was heated at
50.degree. C. for 1 hour. When the reaction was complete, the
mixture was concentrated under a vacuum to remove the
tetrahydrofuran and methanol. The thick mixture was diluted with
water (1 L) and 1 M hydrochloric acid (1 L) was added. The
resulting white solid was collected by vacuum filtration in a
Buchner funnel The vacuum was removed, and water (1 L) was added to
the filter cake. The material was stirred with a spatula to suspend
it evenly in the water. The liquid was then removed by vacuum
filtration. This washing cycle was repeated three more times to
provide a white solid. The solid was dried under vacuum at
45.degree. C. for 3 days to provide the title compound as a white
solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm -1.30 to
-1.12 (m, 1H), -0.30 to -0.13 (m, 1H), 0.14-0.25 (m, 1H), 0.25-0.38
(m, 1H), 1.30 (s, 3H), 1.34 (s, 9H), 1.75-1.86 (m, 1H), 2.08-2.18
(m, 2H), 2.50-2.60 (m, 1H), 2.66 (d, J=13.7, 1H), 3.02-3.16 (m,
2H), 3.40-3.50 (m, 1H), 3.77 (s, 3H), 4.05-4.20 (m, 1H), 4.89 (d,
J=10.5 Hz, 1H), 6.90-6.93 (m, 3H), 7.19 (d, J=8.8 Hz, 1H),
7.22-7.26 (m, 3H), 7.40-7.50 (m, 1H), 7.54 (br s, 1H), 7.68 (d,
J=8.6 Hz, 1H) 10.44 (s, 1H), 12.29 (br s, 1H). MS (ESI) 747.2
[M+H].sup.+.
[0699] Another particular MDM2 inhibitor is Compound B (also known
as AMG 2653149 or 2653149), which is Example 256 of published PCT
application WO2011/153,509. Other MDM2 inhibitors that can be used
in the combinations of the present invention include those
disclosed in published PCT application WO2013/049250; U.S.
provisional patent application number 61/766,635; and U.S.
provisional patent application number 61/784,230. Still other MDM2
inhibitors that can be used in the combinations of the present
invention include RG7112 (also known as RO504337), RG7388 (also
known as idasanutin, and RO5503781), SAR405838 (also known as
MI-773), SAR299155, MK-8242 (also known as SCH 900242), CGM097 and
DS 3032. The structures of RG7112 and SAR299155 as well as other
inhibitors of MDM2 that can be used in the present invention are
shown in Bioorganic & Medicinal Chemistry Letters 23 (2013)
2480-2485, which summarizes pathways to the clinic for MDM2
inhibitors. Still other MDM2 inhibitors that can be used in the
combinations of the present invention include RG7775 and Novartis
CGM097.
[0700] The MDM2 inhibitors of the present invention can be used in
combination with Aurora kinase inhibitors, such as those found in
published PCT application WO2011/031842. A particular compound is
AMG 900 (Example 1).
[0701] The MDM2 inhibitors of the present invention can be used in
combination with MAP kinase pathway inhibitors. Examples of
proteins in the MAP kinase pathway that can be inhibited and the
inhibitors of such proteins used in combination with an MDM2
inhibitors are BRAF inhibitors, Pan-RAF inhibitors, and MEK
inhibitors. There are three main RAF isoforms: ARAF, BRAF and CRAF.
A pan-RAF inhibitor shows inhibitory activity on more than one RAF
isoform. In contrast, a BRAF inhibitor exhibits more inhibitor
activity (or selectivity) towards BRAF than the other RAF
proteins.
[0702] The MDM2 inhibitors of the present invention can be used in
combination with MEK inhibitors, such as those found in published
PCT application WO2002/006213. A particular compound is
N-(((2R)-2,3-dihydroxypropyl)oxy)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)-
amino)benzamide, also known as AMG 1009089 or 1009089, (Example
39).
[0703] The MDM2 inhibitors of the present invention can be used in
combination with BRAF inhibitors, such as those found in published
PCT application WO2008/153,947. A particular compound is AMG
2112819 (also known as 2112819) (Example 56). Another particular
BRAF inhibitor that can be used in the combinations of the present
invention is dabrafenib. Another BRAF inhibitor that can be used in
the combinations of the present invention is vemurafenib.
[0704] Pan-RAF inhibitors can also be used along with MDM2
inhibitors in the combinations of the present invention. Particular
Pan--Raf inhibitor include RAF265 and MLN-2480.
[0705] The MDM2 inhibitors of the present invention can be used in
combination with MEK inhibitors. Particular MEK inhibitors that can
be used in the combinations of the present invention include
PD0325901, trametinib, pimasertib, MEK162 [also known as
binimetinin TAK-733, GDC-0973 and AZD8330. A particular MEK
inhibitor that can be used along with MDM2 inhibitor in the
combinations of the present invention is trametinib (also called
AMG 2712849 or 2712849). Another particular MEK inhibitor is
N-(((2R)-2,3-dihydroxypropyl)oxy)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)-
amino)benzamide, also known as AMG 1009089, 1009089 or PD0325901.
Another particular MEK inhibitor that can be used in the
combinations of the present invention includes cobimetinib.
[0706] In another aspect, the present invention relates to the use
of the compound of the present invention in combination with one or
more pharmaceutical agent that is an inhibitor of a protein in the
phosphatidylinositol 3-kinase (PI3K) pathway. Examples of proteins
in the PI3K pathway include PI3K, mTOR and PKB (also known as Akt
or AKT). The PI3K protein exists in several isoforms including
.alpha., .beta., .delta., or .gamma.. It is contemplated that a
PI3K inhibitor that can be used in the present invention can be
selective for one or more isoform. By selective it is meant that
the compounds inhibit one or more isoform more than other isoforms.
Selectivity is a concept well known to those is the art and can be
measured with well-known in vitro or cell-based activity assays.
Preferred selectivity includes greater than 2-fold, preferably
10-fold, or more preferably 100-fold greater selectivity for one or
more isoform over the other isoforms. In one aspect, the PI3K
inhibitors that can be used in combination with compounds of the
present invention are PI3K .alpha. selective inhibitors. In another
aspect the compound is a PI3K .delta. selective inhibitor. In still
another aspect the compound is a PI3K .beta. selective
inhibitor.
[0707] Examples of PI3K inhibitors that can be used in combination
with one or more compounds of the present invention include those
disclosed in the following: PCT published application no.
WO2010/151791; PCT published application no. WO2010/151737; PCT
published application no.WO2010/151735; PCT published application
no. WO2010151740; PCT published application no. WO2008/118455; PCT
published application no. WO2008/118454; PCT published application
no. WO2008/118468; U.S. published application no. US20100331293;
U.S. published application no. US20100331306; U.S. published
application no. US20090023761; U.S. published application no.
US20090030002; U.S. published application no. US20090137581;U.S.
published application no. US2009/0054405; U.S. published
application no. U.S. 2009/0163489; U.S. published application no.
US 2010/0273764; U.S. published application no. U.S. 2011/0092504;
or PCT published application no. WO2010/108074.
[0708] Preferred PI3K inhibitors for use in combination with the
compound of the present invention include:
##STR00043##
or a pharmaceutically acceptable salt thereof.
[0709] Also preferred is a compound of Formula IIa below, or a
pharmaceutically acceptable salt thereof,
##STR00044##
wherein X.sup.1 is fluorine or hydrogen;Y.sup.1 is hydrogen or
methyl; and Z.sup.1 is hydrogen or methyl. A particular PI3K
inhibitor that can be used in the combinations of the present
invention is AMG 511 (also known as AMG 2539965 or 2539965), which
is Example 148 of published PCT application WO2010/126895.
[0710] Other PI3K inhibitors that can be used in combination with
MDM2 inhibitors in the combinations of the present invention
include Pan-PI3K inhibitors such as BKM120 and GDC-0941;
PI3K.alpha. selective inhibitors such as AMG 511 and BYL719; and
PI3K 13 selective inhibitors such as GSK-2636771.
[0711] Compounds that inhibit both PI3K and mTOR (dual inhibitors)
are known. In still another aspect, the present invention provides
the use of dual PI3K and mTOR inhibitors for use in combination
with MDM2 inhibitors. An example of a particular dual inhibitor is
GDC-0980.
[0712] mTOR is a protein in the PI3K pathway. It is another aspect
of the present invention to use an mTOR inhibitor in combination
with MDM2 inhibitors. mTOR inhibitors that can be used in
combination with the compound of the present invention include
those disclosed in the following documents: PCT published
application no. WO2010/132598 and PCT published application no.
WO2010/096314. mTOR inhibitors that can be used in combination with
MDM2 inhibitors in the combinations of the present invention
include AZD2014 and MLN0128.
[0713] PKB (AKT) is also a protein in the PI3K pathway. It is
another aspect of the present invention to use an AKT inhibitor in
combination with an MDM2 inhibitor. AKT inhibitors that can be used
in combination with the compound of the present invention include
those disclosed in the following documents: U.S. Pat. No.
7,354,944; U.S. Pat. No. 7,700,636; U.S. Pat. No. 7,919,514; U.S.
Pat. No. 7,514,566; U.S. patent application publication no. US
2009/0270445 A1; U.S. Pat. No. 7,919,504; U.S. Pat. No. 7,897,619;
or PCT published application no. WO 2010/083246 Al. Particular AKT
inhibitors that can be used in combination with MDM2 inhibitors in
the combinations of the present invention include MK-2206, GDC-0068
and AZD5363.
[0714] MDM2 inhibitors can also be used in combination with CDK4
and/or 6 inhibitors in the present invention CDK 4 and/or 6
inhibitors that can be used in the present combinations include
those disclosed in the following documents: PCT published
application no. WO 2009/085185 or U.S. patent application
publication no. US2011/0097305.
[0715] Other compounds that can be used in combination with MDM2
inhibitors in the combinations of the present invention include
compounds that inhibit proteins that are part of the intrinsic
apoptosis pathway. Examples of such compounds include Bc12/Bc1xL
inhibitors such as navitoclax and Bc12 inhibitors as such as
ABT-199.
[0716] Other compounds that can be used in combination with MDM2
inhibitors in the combinations of the present invention include
BCR-ABL inhibitors such as dasatinib and HDAC inhibitors such as
panobinostat.
[0717] Other compounds that can be used in combination with MDM2
inhibitors in the combinations of the present invention include
platinums, such as Cisplatin, Carboplatin and Oxaliplatin;
Topoisomerase II inhibitors, typically of the anthracycline class,
such as doxorubicin, daunorubicin, idarubicin, epirubicin,
pegylated liposomal doxorubicin hydrochloride, myocet and
etoposide; Topoisomerase I inhibitors such as irinotecan (CPT-11);
DNA alkylation agents such as temozolomide; and nucleoside analogs
such as cytarabine and decitabine.
[0718] Other compounds that can be used in combination with MDM2
inhibitors in the combinations of the present invention include
receptor and non-receptor kinase inhibitors including tyrosine
kinase inhibitors. Example of such compounds include imatinib,
dasatinib, ponatinib, bosutinib, nilotininb, quizartinib,
midostaurin, erlotinib and lapatinib.
[0719] The compound of the present invention can also be used in
combination with pharmaceutically active agents that treat nausea.
Examples of agents that can be used to treat nausea include:
dronabinol; granisetron; metoclopramide; ondansetron; and
prochlorperazine; or a pharmaceutically acceptable salt
thereof.
[0720] The compound of the present invention may also be used in
combination with radiation therapy, hormone therapy, surgery and
immunotherapy, which therapies are well known to those skilled in
the art.
[0721] Since one aspect of the present invention contemplates the
treatment of the disease/conditions with a combination of
pharmaceutically active compounds that may be administered
separately, the invention further relates to combining separate
pharmaceutical compositions in kit form. The kit comprises two
separate pharmaceutical compositions: the compound of the present
invention, and a second pharmaceutical compound. The kit comprises
a container for containing the separate compositions such as a
divided bottle or a divided foil packet. Additional examples of
containers include syringes, boxes and bags. Typically, the kit
comprises directions for the use of the separate components. The
kit form is particularly advantageous when the separate components
are preferably administered in different dosage forms (e.g., oral
and parenteral), are administered at different dosage intervals, or
when titration of the individual components of the combination is
desired by the prescribing physician or veterinarian.
[0722] An example of such a kit is a so-called blister pack.
Blister packs are well known in the packaging industry and are
being widely used for the packaging of pharmaceutical unit dosage
forms (tablets, capsules, and the like). Blister packs generally
consist of a sheet of relatively stiff material covered with a foil
of a preferably transparent plastic material. During the packaging
process recesses are formed in the plastic foil. The recesses have
the size and shape of the tablets or capsules to be packed. Next,
the tablets or capsules are placed in the recesses and the sheet of
relatively stiff material is sealed against the plastic foil at the
face of the foil which is opposite from the direction in which the
recesses were formed. As a result, the tablets or capsules are
sealed in the recesses between the plastic foil and the sheet.
Preferably the strength of the sheet is such that the tablets or
capsules can be removed from the blister pack by manually applying
pressure on the recesses whereby an opening is formed in the sheet
at the place of the recess. The tablet or capsule can then be
removed via said opening.
[0723] It may be desirable to provide a memory aid on the kit,
e.g., in the form of numbers next to the tablets or capsules
whereby the numbers correspond with the days of the regimen which
the tablets or capsules so specified should be ingested. Another
example of such a memory aid is a calendar printed on the card,
e.g., as follows "First Week, Monday, Tuesday, . . . . etc . . .
Second Week, Monday, Tuesday, . . . " etc. Other variations of
memory aids will be readily apparent. A "daily dose" can be a
single tablet or capsule or several pills or capsules to be taken
on a given day. Also, a daily dose of a compound of the present
invention can consist of one tablet or capsule, while a daily dose
of the second compound can consist of several tablets or capsules
and vice versa. The memory aid should reflect this and aid in
correct administration of the active agents.
[0724] In another specific embodiment of the invention, a dispenser
designed to dispense the daily doses one at a time in the order of
their intended use is provided. Preferably, the dispenser is
equipped with a memory-aid, so as to further facilitate compliance
with the regimen. An example of such a memory-aid is a mechanical
counter which indicates the number of daily doses that has been
dispensed. Another example of such a memory-aid is a
battery-powered micro-chip memory coupled with a liquid crystal
readout, or audible reminder signal which, for example, reads out
the date that the last daily dose has been taken and/or reminds one
when the next dose is to be taken.
[0725] The compounds of the present invention and other
pharmaceutically active compounds, if desired, can be administered
to a patient either orally, rectally, parenterally, (for example,
intravenously, intramuscularly, or subcutaneously)
intracisternally, intravaginally, intraperitoneally,
intravesically, locally (for example, powders, ointments or drops),
or as a buccal or nasal spray. All methods that are used by those
skilled in the art to administer a pharmaceutically active agent
are contemplated.
[0726] Compositions suitable for parenteral injection may comprise
physiologically acceptable sterile aqueous or nonaqueous solutions,
dispersions, suspensions, or emulsions, and sterile powders for
reconstitution into sterile injectable solutions or dispersions.
Examples of suitable aqueous and nonaqueous carriers, diluents,
solvents, or vehicles include water, ethanol, polyols (propylene
glycol, polyethylene glycol, glycerol, and the like), suitable
mixtures thereof, vegetable oils (such as olive oil) and injectable
organic esters such as ethyl oleate. Proper fluidity can be
maintained, for example, by the use of a coating such as lecithin,
by the maintenance of the required particle size in the case of
dispersions, and by the use of surfactants.
[0727] These compositions may also contain adjuvants such as
preserving, wetting, emulsifying, and dispersing agents.
Microorganism contamination can be prevented by adding various
antibacterial and antifungal agents, for example, parabens,
chlorobutanol, phenol, sorbic acid, and the like. It may also be
desirable to include isotonic agents, for example, sugars, sodium
chloride, and the like. Prolonged absorption of injectable
pharmaceutical compositions can be brought about by the use of
agents delaying absorption, for example, aluminum monostearate and
gelatin.
[0728] Solid dosage forms for oral administration include capsules,
tablets, powders, and granules. In such solid dosage forms, the
active compound is admixed with at least one inert customary
excipient (or carrier) such as sodium citrate or dicalcium
phosphate or (a) fillers or extenders, as for example, starches,
lactose, sucrose, mannitol, and silicic acid; (b) binders, as for
example, carboxymethylcellulose, alginates, gelatin,
polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, as for
example, glycerol; (d) disintegrating agents, as for example,
agar-agar, calcium carbonate, potato or tapioca starch, alginic
acid, certain complex silicates, and sodium carbonate; (a) solution
retarders, as for example, paraffin; (f) absorption accelerators,
as for example, quaternary ammonium compounds; (g) wetting agents,
as for example, cetyl alcohol and glycerol monostearate; (h)
adsorbents, as for example, kaolin and bentonite; and (i)
lubricants, as for example, talc, calcium stearate, magnesium
stearate, solid polyethylene glycols, sodium lauryl sulfate, or
mixtures thereof. In the case of capsules, and tablets, the dosage
forms may also comprise buffering agents.
[0729] Solid compositions of a similar type may also be used as
fillers in soft and hard filled gelatin capsules using such
excipients as lactose or milk sugar, as well as high molecular
weight polyethylene glycols, and the like.
[0730] Solid dosage forms such as tablets, dragees, capsules,
pills, and granules can be prepared with coatings and shells, such
as enteric coatings and others well known in the art. They may also
contain opacifying agents, and can also be of such composition that
they release the active compound or compounds in a certain part of
the intestinal tract in a delayed manner. Examples of embedding
compositions that can be used are polymeric substances and waxes.
The active compound can also be in micro-encapsulated form, if
appropriate, with one or more of the above-mentioned
excipients.
[0731] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups, and elixirs. In addition to the active compounds, the
liquid dosage form may contain inert diluents commonly used in the
art, such as water or other solvents, solubilizing agents and
emulsifiers, as for example, ethyl alcohol, isopropyl alcohol,
ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in
particular, cottonseed oil, groundnut oil, corn germ oil, olive
oil, castor oil, and sesame seed oil, glycerol, tetrahydrofurfuryl
alcohol, polyethylene glycols and fatty acid esters of sorbitan, or
mixtures of these substances, and the like.
[0732] Besides such inert diluents, the composition can also
include adjuvants, such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compound, may contain
suspending agents, as for example, ethoxylated isostearyl alcohols,
polyoxyethylene sorbitol and sorbitan esters, microcrystalline
cellulose, aluminum metahydroxide, bentonite, agar-agar, and
tragacanth, or mixtures of these substances, and the like.
[0733] Compositions for rectal administration are preferable
suppositories, which can be prepared by mixing the compounds of the
present invention with suitable non-irritating excipients or
carriers such as cocoa butter, polyethylene glycol or a suppository
wax, which are solid at ordinary room temperature, but liquid at
body temperature, and therefore, melt in the rectum or vaginal
cavity and release the active component.
[0734] Dosage forms for topical administration of the compound of
the present invention include ointments, powders, sprays and
inhalants. The active compound or compounds are admixed under
sterile condition with a physiologically acceptable carrier, and
any preservatives, buffers, or propellants that may be required.
Ophthalmic formulations, eye ointments, powders, and solutions are
also contemplated as being within the scope of this invention.
[0735] The compounds of the present invention can be administered
to a patient at dosage levels in the range of about 0.1 to about
3,000 mg per day. For a normal adult human having a body weight of
about 70 kg, a dosage in the range of about 0.01 to about 100 mg
per kilogram body weight is typically sufficient. The specific
dosage and dosage range that can be used depends on a number of
factors, including the requirements of the patient, the severity of
the condition or disease being treated, and the pharmacological
activity of the compound being administered. A particular dosage of
a compound of the present invention is the FDA approved dosage, if
the compound has been approved.
[0736] The compounds of the present invention can be administered
as pharmaceutically acceptable salts, esters, amides or prodrugs.
The term "salts" refers to inorganic and organic salts of compounds
of the present invention. The salts can be prepared in situ during
the final isolation and purification of a compound, or by
separately reacting a purified compound in its free base or acid
form with a suitable organic or inorganic base or acid and
isolating the salt thus formed. Representative salts include the
hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate,
oxalate, palmitiate, stearate, laurate, borate, benzoate, lactate,
phosphate, tosylate, citrate, maleate, fumarate, succinate,
tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and
laurylsulphonate salts, and the like. The salts may include cations
based on the alkali and alkaline earth metals, such as sodium,
lithium, potassium, calcium, magnesium, and the like, as well as
non-toxic ammonium, quaternary ammonium, and amine cations
including, but not limited to, ammonium, tetramethylammonium,
tetraethylammonium, methylamine, dimethylamine, trimethylamine,
triethylamine, ethylamine, and the like. See, for example, S. M.
Berge, et al., "Pharmaceutical Salts," J Pharm Sci, 66: 1-19
(1977).
[0737] Examples of pharmaceutically acceptable esters of the
compound of the present invention include C.sub.1-C.sub.8 alkyl
esters. Acceptable esters also include C.sub.5-C.sub.7 cycloalkyl
esters, as well as arylalkyl esters such as benzyl. C.sub.1-C.sub.4
alkyl esters are commonly used. Esters of compounds of the present
invention may be prepared according to methods that are well known
in the art.
[0738] Examples of pharmaceutically acceptable amides of the
compound of the present invention include amides derived from
ammonia, primary C.sub.1-C.sub.8 alkyl amines, and secondary
C.sub.1-C.sub.8 dialkyl amines. In the case of secondary amines,
the amine may also be in the form of a 5 or 6 membered
heterocycloalkyl group containing at least one nitrogen atom.
Amides derived from ammonia, C.sub.1-C.sub.3 primary alkyl amines
and C.sub.1-C.sub.2 dialkyl secondary amines are commonly used.
Amides of the compound of the present invention may be prepared
according to methods well known to those skilled in the art.
[0739] The term "prodrug" means compounds that are transformed in
vivo to yield a compound of the present invention. The
transformation may occur by various mechanisms, such as through
hydrolysis in blood. A discussion of the use of prodrugs is
provided by T. Higuchi and W. Stella, "Prodrugs as Novel Delivery
Systems," Vol. 14 of the A.C.S. Symposium Series, and in
Bioreversible Carriers in Drug Design, ed. Edward B. Roche,
American Pharmaceutical Association and Pergamon Press, 1987.
[0740] To illustrate, because the compound of the invention
contains a carboxylic acid functional group, a prodrug can comprise
an ester formed by the replacement of the hydrogen atom of the acid
group with a group such as (C.sub.1-C.sub.8 alkyl,
(C.sub.2-Cl.sub.2)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having
from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)ethyl having from
5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6
carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon
atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8
carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9
carbon atoms, 1-(N-(alkoxycarbonyl)aminomethyl having from 4 to 10
carbon atoms, 3-phthalidyl, 4-crotonolactonyl,
gamma-butyrolacton-4-yl,
di-N,N-(C.sub.1-C.sub.2)alkylamino(C.sub.2-C.sub.3)alkyl (such as
.beta.-dimethylaminoethyl), carbamoyl-(C.sub.1-C.sub.2)alkyl,
N,N-di(C.sub.1-C.sub.2)alkylcarbamoyl-(C.sub.1-C.sub.2)alkyl and
piperidino-, pyrrolidino- or morpholino(C.sub.2-.sub.3)alkyl.
[0741] The compounds of the present invention may contain
asymmetric or chiral centers, and therefore, exist in different
stereoisomeric forms. It is contemplated that all stereoisomeric
forms of the compound as well as mixtures thereof, including
racemic mixtures, form part of the present invention. In addition,
the present invention contemplates all geometric and positional
isomers. For example, if the compound contains a double bond, both
the cis and trans forms (designated as Z and E, respectively), as
well as mixtures, are contemplated.
[0742] Mixture of stereoisomers, such as diastereomeric mixtures,
can be separated into their individual stereochemical components on
the basis of their physical chemical differences by known methods
such as chromatography and/or fractional crystallization.
Enantiomers can also be separated by converting the enantiomeric
mixture into a diastereomeric mixture by reaction with an
appropriate optically active compound (e.g., an alcohol),
separating the diastereomers and converting (e.g., hydrolyzing) the
individual diastereomers to the corresponding pure enantiomers.
Also, some compounds may be atropisomers (e.g., substituted
biaryls).
[0743] The compounds of the present invention may exist in
unsolvated as well as solvated forms with pharmaceutically
acceptable solvents such as water (hydrate), ethanol, and the like.
The present invention contemplates and encompasses both the
solvated and unsolvated forms.
[0744] It is also possible that the compounds of the present
invention may exist in different tautomeric forms. All tautomers of
the compound of the present invention are contemplated. For
example, all of the tautomeric forms of the tetrazole moiety are
included in this invention. Also, for example, all keto-enol or
imine-enamine forms of the compounds are included in this
invention.
[0745] Those skilled in the art will recognize that the compound
names and structures contained herein may be based on a particular
tautomer of a compound. While the name or structure for only a
particular tautomer may be used, it is intended that all tautomers
are encompassed by the present invention, unless stated
otherwise.
[0746] It is also intended that the present invention encompass
compounds that are synthesized in vitro using laboratory
techniques, such as those well known to synthetic chemists; or
synthesized using in vivo techniques, such as through metabolism,
fermentation, digestion, and the like. It is also contemplated that
the compounds of the present invention may be synthesized using a
combination of in vitro and in vivo techniques.
[0747] The present invention also includes isotopically-labelled
compounds, which are identical to those recited herein, but for the
fact that one or more atoms are replaced by an atom having an
atomic mass or mass number different from the atomic mass or mass
number usually found in nature. Examples of isotopes that can be
incorporated into compounds of the invention include isotopes of
hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and
chlorine, such as .sup.2H, .sup.3H, .sup.13C, .sup.14C, .sup.15N,
.sup.16O, .sup.17O, .sup.18O, .sup.31P, .sup.32P, .sup.35S,
.sup.18F and .sup.36Cl. In one aspect, the present invention
relates to compounds wherein one or more hydrogen atom is replaced
with deuterium (.sup.2H) atoms.
[0748] The compounds of the present invention that contains the
aforementioned isotopes and/or other isotopes of other atoms are
within the scope of this invention. Certain isotopically-labelled
compounds of the present invention, for example those into which
radioactive isotopes such as .sup.3H and .sup.14C are incorporated,
are useful in drug and/or substrate tissue distribution assays.
Tritiated, i.e., .sup.3H, and carbon-14, i.e., .sup.14C, isotopes
are particularly preferred for their ease of preparation and
detection. Further, substitution with heavier isotopes such as
deuterium, i.e., .sup.2H, can afford certain therapeutic advantages
resulting from greater metabolic stability, for example increased
in vivo half-life or reduced dosage requirements and, hence, may be
preferred in some circumstances. Isotopically labelled compounds of
this invention can generally be prepared by substituting a readily
available isotopically labelled reagent for a non-isotopically
labelled reagent.
[0749] The compounds of the present invention may exist in various
solid states including crystalline states and as an amorphous
state. The different crystalline states, also called polymorphs,
and the amorphous states of the present compounds are contemplated
as part of this invention.
[0750] In synthesizing the compounds of the present invention, it
may be desirable to use certain leaving groups. The term "leaving
groups" ("LG") generally refer to groups that are displaceable by a
nucleophile. Such leaving groups are known in the art. Examples of
leaving groups include, but are not limited to, halides (e.g., I,
Br, F, Cl), sulfonates (e.g., mesylate, tosylate), sulfides (e.g.,
SCH.sub.3), N-hydroxysuccinimide, N-hydroxybenzotriazole, and the
like. Examples of nucleophiles include, but are not limited to,
amines, thiols, alcohols, Grignard reagents, anionic species (e.g.,
alkoxides, amides, carbanions) and the like.
[0751] All patents, patent applications and other documents recited
herein are hereby incorporated by reference in their entirety.
[0752] The examples presented below illustrate specific embodiments
of the present invention. These examples are meant to be
representative and are not intended to limit the scope of the
claims in any manner
[0753] The following abbreviations may be used herein:
TABLE-US-00002 932 or 2705932 AMG 232 ADD additivity AML acute
myelogenous leukemia ATP adenosine triphosphate Cispl cisplatin CML
chronic myelogenous leukemia CPT-11 irinotecan DIC drug in capsules
DLBCL diffuse large B-cell lymphoma Dox doxorubicin GBM
glioblastoma HP.beta.CD hydroxypropyl beta cyclodextrin HPMC
hydroxypropyl methylcellulose MDS myelodysplastic syndrome mpk
milligrams per kilogram NHL non-Hodgkin's lymphoma NMR nuclear
magnetic resonance NSCLC non-small cell lung cancer PBS phosphate
buffered saline PCT patent cooperation treaty RTK receptor tyrosine
kinase TGI tumor growth inhibition Tx begins treatment begins Cell
Culture Reagents Tween .RTM. 80 polyoxyethylene (20) sorbitan
monooleate (Uniqema Americas, Inc., Wilmington, DE) Pluronic .RTM.
F68 polyoxyethylene-polyoxypropylene block co- polymer (BASF Corp.,
Mount Olive, NJ)
EXAMPLES
[0754] In Vitro Cell-Based Combination Studies
[0755] Cell lines were purchased from American Type Culture
Collection (ATCC), German Collection of Microorganisms and Cell
Cultures (DSMZ), and Japanese Collection of Research Bioresources
(JCRB). Each line was cultured in its recommended growth medium.
Cell line A375sq2 was made in accordance with the procedure set
forth in J. Med. Chem. 2009, 52, 6189-6192, footnote 13.
[0756] For Examples 1 to 71, cells were seeded into 384-well cell
culture plates at initial densities ranging from 300 to 7500 cells
per well in a 30 .mu.L volume, depending on the growth rate of the
cell line, so that adherent cells would remain at subconfluent
densities by the end of the 72-hour treatment period. In order to
determine the appropriate concentration range to test in subsequent
combination experiments, 10 .mu.L of a 19-point, two-fold serial
titration of compound starting at a high final concentration of 20
.mu.M, as well as a 0.25% dimethyl sulfoxide (DMSO) control were
added to the cells 16 hours after seeding. CellTiter-Glo.RTM.
Luminescent Cell Viability Assay (Promega; Madison, Wis.) was used
to determine the number of viable cells based on quantitation of
the amount of ATP present, an indicator of metabolically active
cells. Luminescence was measured with an EnVision.RTM. Multilabel
Reader (Perkin Elmer; Waltham, Mass.) for each cell line at time
zero (V.sub.0) before the addition of compounds, as well as after
72 hours of compound treatment (T.sub.72). Growth inhibition (GI)
was calculated according to the following equations, where V.sub.72
was luminescence of DMSO control at 72 hours and T.sub.72 was
luminescence of the compound-treated sample: if
T.sub.72.gtoreq.V.sub.0, then
GI=100.times.(1-((T.sub.72-V.sub.0)/(V.sub.72-V.sub.0))); if
T.sub.72<V.sub.0, then
GI=100.times.(1-((T.sub.72-V.sub.0)/V.sub.0)). This formula is
derived from the growth inhibition calculation used in the National
Cancer Institute's NCI-60 high throughput screen. On a scale of 0
to 200 percent growth inhibition, a value of 0 represents
uninhibited growth (i.e. DMSO control), 100 typically represents
stasis (signal equivalent at time zero reading), and 200 represents
complete cell killing. Sigmoidal dose response curves were plotted
using a 4-parameter logistic model. For all combinations tested in
any given cell line, the starting high concentration and dilution
factor of each compound was chosen to well-define the curve
maximum, curve minimum, and slope over a range of 9 doses.
[0757] Two-way combination experiments were conducted essentially
as described above, with the following exceptions. To each well, 5
.mu.L of a 9-point serial titration of the first compound (starting
high final concentration and dilution factor determined as
previously described) along with DMSO control was added to the
cells in 10 identical rows (x-axis) of a 384-well plate. Then, 5
.mu.L of a 9-point serial titration of the second compound
(starting high final concentration and dilution factor determined
as previously described) along with DMSO control were added to the
cells in 10 identical columns (y-axis). The final concentration of
DMSO in each well was 0.25%. Duplicate 100-well (10x10) matrices
were run on each 384-well plate. Growth inhibition for each well of
the matrix was calculated as previously described, and the data
were analyzed for synergistic interactions using Chalice.TM.
Analyzer software (Zalicus; Cambridge, Mass.) which generated
synergy scores based on the Loewe Additivity model (Lehar, J., et
al. (2009). "Synergistic drug combinations tend to improve
therapeutically relevant selectivity." Nat Biotech 27(7): 659-666)
and Rickles, et al (2012) "Adenosine A2A and Beta-2 Adrenergic
Receptor Agonists: Novel Selective and Synergistic Multiple Myeloma
Targets Discovered through Systematic Combination Screening" Mol
Cancer Therapeutics 11 (7): 1432.
[0758] The Loewe ADD (additivity) model quantifies combination
effects. Combinations were ranked initially by Additivity Excess
Volume, which is defined as ADD Volume=.SIGMA.C.sub.X,C.sub.Y
(I.sub.data-I.sub.Loewe), where I.sub.Loewe(C.sub.X,C.sub.Y) is the
inhibition that satisfies (C.sub.X/EC.sub.X)+(C.sub.Y/EC.sub.Y)=1,
and EC.sub.X,Y are the effective concentrations at I.sub.Loewe for
the single agent curves. A "Synergy Score" was also used, where the
Synergy Score S=log f.sub.X log f.sub.Y .SIGMA. I.sub.data
(I.sub.data-I.sub.Lowee), summed over all non-single-agent
concentration pairs, and where log f.sub.X,Y is the natural
logarithm of the dilution factors used for each single agent. This
effectively calculates a volume between the measured and Loewe
additive response surfaces, weighted towards high inhibition and
corrected for varying dilution factors. An uncertainty
.sigma..sub.S was calculated for each synergy score, based on the
measured errors for the I.sub.data values and standard error
propagation.
[0759] In the examples shown, the Growth Inhibition (%) matrices
contain the consensus growth inhibition values calculated from the
luminescence data using the formulas described above; the ADD Model
Growth Inhibition (%) matrices contain the predicted growth
inhibition values based on the Loewe additivity model, which was
derived from the modeled single agent growth inhibition curves; and
the ADD Excess Growth Inhibition (%) matrices contain the values of
growth inhibition in excess of the additivity model. The additivity
model serves as a "null-hypothesis" and assumes no synergistic
interaction between the two agents. Any activity observed after
subtraction of the ADD model from the Growth Inhibition dose
response matrix (=ADD Excess Growth Inhibition) is indicative of
synergy.
[0760] For Examples 72-89, two-way combination experiments were
carried out in a similar manner as described above, but using a
high-throughput screening format. Cells were thawed from a liquid
nitrogen preserved state. Screening began after the cells were
expanded and were dividing at their expected doubling times. Cells
were seeded in growth media in either black 1536-well or 384-well
tissue culture treated plates at the cell densities as listed in
the table below.
TABLE-US-00003 Cell Line Plate Format Cell Density RT4 384 500
SJSA-1 1536 100 KS-1 1536 100 MCF7 384 500 RKO 1536 100 SNG-M 1536
100 RPMI-2650 1536 200 G-401 1536 100 CML-T1 1536 100 EOL-1 384 500
MOLM-13 384 500 SK-HEP-1 1536 100 A427 1536 100 DOHH-2 1536 100
22RV1 1536 100 A375 1536 100 C32 384 500 MKN45 1536 100 NOI-SNJ-1
1536 100 SW982 1536 100 HT-29 1536 100 PC-3 1536 100
[0761] Cells were equilibrated in assay plates via centrifugation
and placed in incubators attached to the Dosing Modules at
37.degree. C. for 24 hours before treatment. At the time of
treatment, a set of untreated assay plates were collected and ATP
levels were measured by adding ATPLite lstep Luminescent Assay
reagent (Perkin Elmer; Waltham, Mass.). These Tzero (T.sub.o)
plates were read using ultrasensitive luminescence on an
EnVision.RTM. Multilabel Reader (Perkin Elmer; Waltham, Mass.).
Treated assay plates were incubated with compound for 72 hours and
were assayed for viable cell number at the endpoint. All data
points were collected via automated processes; quality controlled;
and analyzed using Chalice.TM. Analyzer software (Zalicus;
Cambridge, Mass.) which generated synergy scores based on the Loewe
Additivity model (Lehar et al., supra). Assay plates were accepted
if they passed the following quality control standards: relative
luciferase values were consistent throughout the entire experiment,
Z-factor scores were greater than 0.6, and untreated/vehicle
controls behaved consistently on the plate. The synergistic
interaction of each experimental combination was evaluated for
statistical significance. The synergy scores calculated for
individual replicates of heterologous combinations (A.times.B) were
compared to the synergy scores of individual replicates of the
component self-crosses (A.times.A and B.times.B) using two sample
Student's t-test with unequal variance. Only those combinations in
which the synergy score of A.times.B was statistically significant
(p-value <0.05) when compared to both A.times.A and B.times.B
were considered synergistic.
[0762] Three-way combination experiments were conducted essentially
as described above, with the following exceptions. Ten identical
384-well plates each containing duplicate 100-well two-way
combinations were set-up as before, except that 3.3 .mu.L of
3.times. final concentration of each compound were added. Then 3.3
.mu.L of a single fixed concentration of the third compound were
added to all of the wells of the matrix on a given plate. Thus the
ten plates comprised the 9-point serial titration of the third
compound (z-axis; starting high final concentration and dilution
factor determined as previously described), along with a DMSO
control (i.e. no compound 3 added) plate. Growth inhibition for
each well of the matrix was calculated as previously described.
Examples of cell lines used in the above-identified experiments are
set forth in the table below. The tissue column of the table
indicate the type of tissue from which the cells were obtained, and
the mutation column indicates certain mutations identified in the
particular cell line.
TABLE-US-00004 Cell Line Tissue Mutation HT-1197 Bladder NRAS, PI3K
RT4 Bladder TSC1 KNS-81-FD Brain; CNS EGFR CAL-51 Breast PI3K MCF7
Breast PI3K MDA-MB-175-VII Breast HER2 autocrine loop UACC-812
Breast HER2 amplified HCT116 Colon KRAS, PI3K LS 174T Colon KRAS,
PI3K RKO Colon BRAF, PI3K SW48 Colon EGFR BV-173 Haematopoietic and
lymphoid BCR-ABL (CML) CML-T1 Haematopoietic and lymphoid BCR-ABL
(CML) GDM-1 Haematopoietic and lymphoid None identified (AML) ML-2
Haematopoietic and lymphoid KRAS (AML) MOLM-13 Haematopoietic and
lymphoid FLT3 ITD (AML) OCI-AML3 Haematopoietic and lymphoid Not
known (AML) CAL-54 Kidney MET amplified SK-HEP-1 Liver BRAF A427
Lung (NSCLC) KRAS A549 Lung KRAS NCI-H1666 Lung (NSCLC) BRAF (not
V600E) NCI-H460 Lung (NSCLC) KRAS, PI3K A2780 Ovary PTEN A375sq2
Skin (Melanoma) BRAF A375 Skin (Melanoma) BRAF C32 Skin (Melanoma)
BRAF, PTEN G-361 Skin (Melanoma) BRAF SH-4 Skin (Melanoma) BRAF
A204 Soft tissue None identified (rhabdomyosarcoma) G-401 Soft
tissue (kidney) None identified MKN45 Stomach MET amplified
[0763] The results of the in vitro cell-based combination studies
are shown in FIGS. 1 to 89. In FIGS. 1 to 71, the Growth Inhibition
(%) matrices represent the consensus growth inhibition values from
multiple experimental replicates for a given combination calculated
according to formulas described above. For example, in FIG. 1, the
growth inhibition obtained when 2.5 .mu.M Compound A and 3 .mu.M
Compound 1 were combined was 114%. The ADD Model Growth Inhibition
(%) matrices represent the predicted growth inhibition values for
an additive interaction between two compounds based on the Loewe
additivity model and was derived from the experimental growth
inhibition activities of each of the agents alone. The ADD Excess
Growth Inhibition (%) matrices represent the growth inhibition
values in excess of the additivity model. For example, in FIG. 1a,
when 2.5 .mu.M Compound A was combined with 3 .mu.M Compound 1, the
growth inhibition in excess of the additivity model was 26% (114%
experimental growth inhibition-88% model=26%). The shading of the
matrices corresponds to the degree of growth inhibition, with
darker shading/positive growth inhibition values representing
larger effects; negative growth inhibition values were excluded
from synergy score calculations. Synergy scores were calculated
based on the sum of the excess growth inhibition values for a given
combination, with normalization factors for the concentration
ranges of the component agents tested and additional weighting
given to synergistic interactions that occur at high effect levels
(Lehar et al., supra). For example, in FIG. 1 a, the synergy score
for the combination of Compound A.times.Compound 1 was 0.532; the
synergy score for the self-cross combination of Compound
A.times.Compound A was 0.621; and the synergy score for the
self-cross combination of Compound 1.times.Compound 1 was
0.432.
[0764] In FIGS. 72 to 89, the first label on the Y axis indicates
the target of the compound tested in combination with the
particular MDM2 inhibitor. For example, in FIG. 72, the first
target is BRAF (the compound tested is vemurafenib) and the last is
MEK (the compound tested is AZD8330). The next section on the Y
axis indicates the exact combination. For example, in FIG. 72, AMG
232.times.Vemurafenib means that the combination tested was AMG 232
and Vemurafenib. On the X axis, at the top of the grid, the cancer
cell line that was tested is indicated. Above the cancer cell line,
mutational status is indicated For example, in FIG. 72, KRAS and
BRAF indicates that the particular cell lines below these
designations contain a KRAS or BRAF mutation as indicated (mutation
data obtained from the literature or the Sanger (Cosmic) or Broad
Institute (Cancer Cell Line Encyclopedia) cancer genomics
databases). It should be noted that the cell lines used in these
experiments are known to those skilled in the art, and the various
mutations associated with those cells lines may be readily
determined by one skilled in the art. Also, on FIG. 72, TP53
indicates that the designated cell lines contain a mutation in
TP53. As mentioned above, MDM2 inhibitors show activity in cancer
having wild type TP53. The shading in each box of the grid
indicates the level of synergy identified, with darker indicating
higher synergy. The number in the box is the synergy score, and if
a number is underlined it indicates that the experiment showed
statistical significance.
In Vivo Tumor Xenograft Combination Studies
[0765] In vivo tumor xenograft studies were conducted following
these general procedures: Tumor cells (Table 1) were cultured,
harvested and implanted subcutaneously into the right flank of
female athymic nude mice. When tumors reached about 200mm.sup.3,
mice were randomized into treatment groups (n=10/group) and
treatment was initiated (on days indicated on graphs). Compound
names, dosing frequency, and routes of administration are listed in
Table 2. Tumor sizes and body weights were measured 2 to 3 times
per week. Tumor volume was measured by digital calipers, calculated
as L.times.W.times.H and expressed in mm.sup.3 Statistical
significance of observed differences between growth curves was
evaluated by repeated measures analysis of covariance (RMANOVA) of
the log transformed tumor volume data with Dunnett adjusted
multiple comparisons comparing the control group to the treatment
groups. For combination studies, RMANOVA was run with the
combination group compared one to one with each single agent
treatment group.
[0766] BD Matrigel.TM. Basement Membrane Matrix is a solubilized
basement membrane preparation extracted from the
Engelbreth-Holm-Swarm (EHS) mouse sarcoma (BD Biosciences, San
Jose, Calif.)
All studies were measured in a blinded manner.
TABLE-US-00005 TABLE 1 Matrigel Cell Line Tumor Type Cells/mouse
Source # (cells:matrigel) RKO Colon 5 .times. 10.sup.6 (ATCC)
CRL-2577 1:1 SJSA-1 Osteosarcoma 5 .times. 10.sup.6 (ATCC) CRL-2098
2:1 HCT116 Colorectal 2 .times. 10.sup.6 (ATCC) CCL-247 2:1 A375sq2
Melanoma 5 .times. 10.sup.6 See Reference above 2:1 NCI-H460
Non-small cell lung 5 .times. 10.sup.6 (ATCC) HTB-177 no U87
Glioblastoma 5 .times. 10.sup.6 (ATCC) HTB-14 no Molm13 Acute
myelogenous 2.5 .times. 10.sup.6 (DSMZ) AC-554 1:1 leukemia
TABLE-US-00006 TABLE 2 Treatment Route Frequency AMG 232 PO QD
1009089 (MEK) PO QD cisplatin IP 1x/wk CPT-11 IP 1x/wk doxorubicin
IV 1x/wk 2112819 (BRAF) PO QD RG7112 (MDM2) PO QD 2520765 (PI3K) PO
QD cytarabine IP 5 days on, 2 days off decitabine IP 3x/wk
Definition of abbreviations: PO: oral gavage IP: intraperitoneal
IV: intravenous QD: once per day wk: week
In vivo combination studies conducted:
[0767] 1. AMG 232+MEK (RKO),
[0768] 2. AMG 232+BRAF (RKO)
[0769] 3. AMG 232+cisplatin (H460)
[0770] 4. AMG 232+cisplatin (HCT-116)
[0771] 5. AMG 232+doxorubicin (SJSA-1)
[0772] 6. AMG 232+irinotecan (HCT116)
[0773] 7. AMG 232+MEK (A375sq2)
[0774] 8. AMG 232+BRAF (A375sq2)
[0775] 9. AMG 232+BRAF+PI3K (RKO, triple combination)
[0776] 10. AMG 232+doxorubicin (Molm-13)
[0777] 11. AMG 232+MEK (Molm-13)
[0778] 12. AMG 232+cytarabine (Molm-13)
[0779] 13. AMG 232+decitabine (Molm-13)
[0780] 14. AMG 232+sorafenib (Molm-13)
The results of the in vivo tumor xenograft combination studies are
shown in FIGS. A to O.
[0781] Table A below illustrates specific combinations of an MDM2
inhibitor with one or more additional pharmaceutically active
agents for particular cancers types. The data obtained and
summarized in the Figures indicates that the combinations set forth
in Table A show enhanced anti-cancer activity over what is expected
when the individual members of the combination therapy are used
alone. It is noted that the magnitude of the therapeutic synergy
that is seen can vary depending on the type of cancer treated and
agent used.
TABLE-US-00007 TABLE A Additional Pharmaceutically MDM2 Inhibitor
Active Agent Cancer Type AMG 232 vemurafenib melanoma AMG 232
vemurafenib colon AMG 232 vemurafenib liver AMG 232 vemurafenib
sarcoma AMG 232 vemurafenib AML AMG 232 vemurafenib CML AMG 232
vemurafenib DLBCL AMG 232 vemurafenib kidney AMG 232 dabrafenib
melanoma AMG 232 dabrafenib colon AMG 232 dabrafenib liver AMG 232
dabrafenib sarcoma AMG 232 dabrafenib glioblastoma AMG 232
dabrafenib head and neck AMG 232 dabrafenib AML AMG 232 dabrafenib
CML AMG 232 dabrafenib DLBCL AMG 232 RAF265 melanoma AMG 232 RAF265
colon AMG 232 RAF265 liver AMG 232 RAF265 sarcoma AMG 232 RAF265
NSCLC AMG 232 RAF265 stomach AMG 232 RAF265 endometrium AMG 232
RAF265 glioblastoma AMG 232 RAF265 head and neck AMG 232 RAF265
bladder AMG 232 RAF265 AML AMG 232 RAF265 CML AMG 232 RAF265 DLBCL
AMG 232 MLN2480 melanoma AMG 232 MLN2480 colon AMG 232 MLN2480
liver AMG 232 MLN2480 NSCLC AMG 232 MLN2480 endometrium AMG 232
MLN2480 bladder AMG 232 MLN2480 AML AMG 232 MLN2480 CML AMG 232
MLN2480 DLBCL AMG 232 trametinib melanoma AMG 232 trametinib colon
AMG 232 trametinib liver AMG 232 trametinib sarcoma AMG 232
trametinib NSCLC AMG 232 trametinib stomach AMG 232 trametinib
prostate AMG 232 trametinib kidney AMG 232 trametinib glioblastoma
AMG 232 trametinib breast AMG 232 trametinib head and neck AMG 232
trametinib bladder AMG 232 trametinib AML AMG 232 trametinib CML
AMG 232 trametinib DLBCL AMG 232 pimasertib melanoma AMG 232
pimasertib colon AMG 232 pimasertib liver AMG 232 pimasertib NSCLC
AMG 232 pimasertib stomach AMG 232 pimasertib prostate AMG 232
pimasertib kidney AMG 232 pimasertib glioblastoma AMG 232
pimasertib breast AMG 232 pimasertib head and neck AMG 232
pimasertib AML AMG 232 pimasertib CML AMG 232 pimasertib DLBCL AMG
232 pimasertib bladder AMG 232 MEK162 melanoma AMG 232 MEK162 colon
AMG 232 MEK162 liver AMG 232 MEK162 NSCLC AMG 232 MEK162 stomach
AMG 232 MEK162 prostate AMG 232 MEK162 glioblastoma AMG 232 MEK162
bladder AMG 232 MEK162 AML AMG 232 MEK162 CML AMG 232 MEK162 DLBCL
AMG 232 TAK-733 melanoma AMG 232 TAK-733 colon AMG 232 TAK-733
liver AMG 232 TAK-733 sarcoma AMG 232 TAK-733 NSCLC AMG 232 TAK-733
stomach AMG 232 TAK-733 prostate AMG 232 TAK-733 kidney AMG 232
TAK-733 glioblastoma AMG 232 TAK-733 breast AMG 232 TAK-733 head
and neck AMG 232 TAK-733 bladder AMG 232 TAK-733 AML AMG 232
TAK-733 CML AMG 232 TAK-733 DLBCL AMG 232 GDC-0973 melanoma AMG 232
GDC-0973 colon AMG 232 GDC-0973 liver AMG 232 GDC-0973 NSCLC AMG
232 GDC-0973 stomach AMG 232 GDC-0973 prostate AMG 232 GDC-0973
kidney AMG 232 GDC-0973 glioblastoma AMG 232 GDC-0973 breast AMG
232 GDC-0973 bladder AMG 232 GDC-0973 head and neck AMG 232
GDC-0973 sarcoma AMG 232 GDC-0973 AML AMG 232 GDC-0973 CML AMG 232
GDC-0973 DLBCL AMG 232 AZD8330 melanoma AMG 232 AZD8330 colon AMG
232 AZD8330 liver AMG 232 AZD8330 sarcoma AMG 232 AZD8330 NSCLC AMG
232 AZD8330 stomach AMG 232 AZD8330 prostate AMG 232 AZD8330 kidney
AMG 232 AZD8330 glioblastoma AMG 232 AZD8330 breast AMG 232 AZD8330
head and neck AMG 232 AZD8330 bladder AMG 232 AZD8330 AML AMG 232
AZD8330 CML AMG 232 AZD8330 DLBCL AMG 232 BKM120 prostate AMG 232
BKM120 breast AMG 232 BKM120 melanoma AMG 232 BKM120 NSCLC AMG 232
BKM120 kidney AMG 232 BKM120 stomach AMG 232 BKM120 head and neck
AMG 232 BKM120 bladder AMG 232 BKM120 sarcoma AMG 232 BKM120 AML
AMG 232 BKM120 CML AMG 232 GDC-0941 prostate AMG 232 GDC-0941
breast AMG 232 GDC-0941 endometrium AMG 232 GDC-0941 melanoma AMG
232 GDC-0941 NSCLC AMG 232 GDC-0941 kidney AMG 232 GDC-0941
glioblastoma AMG 232 GDC-0941 stomach AMG 232 GDC-0941 head and
neck AMG 232 GDC-0941 bladder AMG 232 GDC-0941 sarcoma AMG 232
GDC-0941 AML AMG 232 GDC-0941 CML AMG 232 GDC-0941 DLBCL AMG 232
BYL719 prostate AMG 232 BYL719 breast AMG 232 BYL719 endometrium
AMG 232 BYL719 melanoma AMG 232 BYL719 NSCLC AMG 232 BYL719 kidney
AMG 232 BYL719 glioblastoma AMG 232 BYL719 stomach AMG 232 BYL719
head and neck AMG 232 BYL719 bladder AMG 232 BYL719 sarcoma AMG 232
BYL719 AML AMG 232 BYL719 DLBCL AMG 232 GSK-2636771 AML AMG 232
GSK-2636771 DLBCL AMG 232 MK-2206 prostate AMG 232 MK-2206 breast
AMG 232 MK-2206 melanoma AMG 232 MK-2206 endometrium AMG 232
MK-2206 head and neck AMG 232 MK-2206 sarcoma AMG 232 MK-2206 AML
AMG 232 MK-2206 DLBCL AMG 232 GDC-0068 prostate AMG 232 GDC-0068
breast AMG 232 GDC-0068 endometrium AMG 232 GDC-0068 melanoma AMG
232 GDC-0068 glioblastoma AMG 232 GDC-0068 head and neck AMG 232
GDC-0068 sarcoma AMG 232 GDC-0068 AML AMG 232 GDC-0068 DLBCL AMG
232 AZD5363 prostate AMG 232 AZD5363 breast AMG 232 AZD5363
endometrium AMG 232 AZD5363 melanoma AMG 232 AZD5363 glioblastoma
AMG 232 AZD5363 head and neck AMG 232 AZD5363 sarcoma AMG 232
AZD5363 AML AMG 232 AZD5363 CML AMG 232 AZD5363 DLBCL AMG 232
GDC-0980 prostate AMG 232 GDC-0980 breast AMG 232 GDC-0980 melanoma
AMG 232 GDC-0980 kidney AMG 232 GDC-0980 glioblastoma AMG 232
GDC-0980 stomach AMG 232 GDC-0980 head and neck AMG 232 GDC-0980
bladder AMG 232 GDC-0980 liver AMG 232 GDC-0980 sarcoma AMG 232
GDC-0980 AML AMG 232 GDC-0980 DLBCL AMG 232 AZD2014 prostate AMG
232 AZD2014 breast AMG 232 AZD2014 endometrium AMG 232 AZD2014
melanoma AMG 232 AZD2014 NSCLC AMG 232 AZD2014 kidney AMG 232
AZD2014 glioblastoma AMG 232 AZD2014 stomach AMG 232 AZD2014 head
and neck AMG 232 AZD2014 bladder AMG 232 AZD2014 liver AMG 232
AZD2014 sarcoma AMG 232 AZD2014 AML AMG 232 AZD2014 DLBCL AMG 232
MLN0128 prostate AMG 232 MLN0128 breast AMG 232 MLN0128 endometrium
AMG 232 MLN0128 melanoma AMG 232 MLN0128 NSCLC AMG 232 MLN0128
glioblastoma AMG 232 MLN0128 stomach AMG 232 MLN0128 head and neck
AMG 232 MLN0128 bladder AMG 232 MLN0128 liver AMG 232 MLN0128
sarcoma AMG 232 MLN0128 AML AMG 232 MLN0128 DLBCL AMG 232 dasatinib
bladder AMG 232 dasatinib colon AMG 232 dasatinib endometium AMG
232 dasatinib glioblastoma AMG 232 dasatinib head and neck AMG 232
dasatinib kidney AMG 232 dasatinib NSCLC AMG 232 dasatinib melanoma
AMG 232 dasatinib sarcoma AMG 232 dasatinib AML AMG 232 dasatinib
CML AMG 232 dasatinib DLBCL AMG 232 panobinostat kidney AMG 232
panobinostat head and neck AMG 232 panobinostat melanoma
AMG 232 panobinostat sarcoma AMG 232 panobinostat stomach AMG 232
panobinostat AML AMG 232 panobinostat DLBCL AMG 232 panobinostat
liver AMG 232 doxorubicin breast AMG 232 doxorubicin AML AMG 232
etoposide sarcoma AMG 232 cytarabine AML AMG 232 decitabine AML AMG
232 navitoclax bladder AMG 232 navitoclax breast AMG 232 navitoclax
endometrium AMG 232 navitoclax glioblastoma AMG 232 navitoclax head
and neck AMG 232 navitoclax kidney AMG 232 navitoclax liver AMG 232
navitoclax melanoma AMG 232 navitoclax sarcoma AMG 232 navitoclax
stomach AMG 232 navitoclax AML AMG 232 navitoclax CML AMG 232
navitoclax DLBCL AMG 232 ABT-199 glioblastoma AMG 232 ABT-199 head
and neck AMG 232 ABT-199 kidney AMG 232 ABT-199 sarcoma AMG 232
ABT-199 AML AMG 232 ABT-199 CML AMG 232 ABT-199 DLBCL AMG 232
imatinib CML AMG 232 ponatinib CML AMG 232 bosutinb CML AMG 232
nilotinib CML AMG 232 quizartinib AML AMG 232 midostaurin AML AMG
232 cisplatin Ovarian AMG 232 cisplatin Colon AMG 232 cisplatin
NSCLC AMG 232 cisplatin esophageal/stomach AMG 232 cispaltin Breast
AMG 232 doxorubicin Breast AMG 232 doxorubicin stomach AMG 232
doxorubicin ovarian AMG 232 doxorubicin AML AMG 232 doxorubicin ALL
AMG 232 doxorubicin MDS AMG 232 doxorubicin NHL AMG 232 doxorubicin
Hodgkin's lymphoma AMG 232 decitabine MDS AMG 232 sorafenib kidney
AMG 232 sorafenib liver AMG 232 sorafenib AML AM-7209 vemurafenib
melanoma AM-7209 vemurafenib colon AM-7209 vemurafenib liver
AM-7209 vemurafenib sarcoma AM-7209 vemurafenib AML AM-7209
vemurafenib CML AM-7209 vemurafenib DLBCL AM-7209 dabrafenib
melanoma AM-7209 dabrafenib colon AM-7209 dabrafenib liver AM-7209
dabrafenib sarcoma AM-7209 dabrafenib glioblastoma AM-7209
dabrafenib stomach AM-7209 dabrafenib head and neck AM-7209
dabrafenib AML AM-7209 dabrafenib CML AM-7209 dabrafenib DLBCL
AM-7209 dabrafenib prostate AM-7209 dabrafenib endometrium AM-7209
RAF265 melanoma AM-7209 RAF265 colon AM-7209 RAF265 liver AM-7209
RAF265 sarcoma AM-7209 RAF265 NSCLC AM-7209 RAF265 stomach AM-7209
RAF265 endometrium AM-7209 RAF265 kidney AM-7209 RAF265
glioblastoma AM-7209 RAF265 head and neck AM-7209 RAF265 bladder
AM-7209 RAF265 AML AM-7209 RAF265 CML AM-7209 RAF265 DLBCL AM-7209
MLN2480 melanoma AM-7209 MLN2480 colon AM-7209 MLN2480 liver
AM-7209 MLN2480 sarcoma AM-7209 MLN2480 NSCLC AM-7209 MLN2480
breast AM-7209 MLN2480 AML AM-7209 MLN2480 CML AM-7209 MLN2480
DLBCL AM-7209 trametinib melanoma AM-7209 trametinib colon AM-7209
trametinib liver AM-7209 trametinib sarcoma AM-7209 trametinib
NSCLC AM-7209 trametinib stomach AM-7209 trametinib endometrium
AM-7209 trametinib prostate AM-7209 trametinib kidney AM-7209
trametinib glioblastoma AM-7209 trametinib breast AM-7209
trametinib head and neck AM-7209 trametinib bladder AM-7209
trametinib AML AM-7209 trametinib CML AM-7209 trametinib DLBCL
AM-7209 pimasertib melanoma AM-7209 pimasertib colon AM-7209
pimasertib liver AM-7209 pimasertib NSCLC AM-7209 pimasertib
stomach AM-7209 pimasertib endometrium AM-7209 pimasertib prostate
AM-7209 pimasertib kidney AM-7209 pimasertib glioblastoma AM-7209
pimasertib breast AM-7209 pimasertib head and neck AM-7209
pimasertib bladder AM-7209 pimasertib AML AM-7209 pimasertib CML
AM-7209 pimasertib sarcoma AM-7209 MEK162 melanoma AM-7209 MEK162
colon AM-7209 MEK162 liver AM-7209 MEK162 NSCLC AM-7209 MEK162
stomach AM-7209 MEK162 prostate AM-7209 MEK162 kidney AM-7209
MEK162 glioblastoma AM-7209 MEK162 head and neck AM-7209 MEK162
bladder AM-7209 MEK162 AML AM-7209 MEK162 CML AM-7209 TAK-733
melanoma AM-7209 TAK-733 colon AM-7209 TAK-733 liver AM-7209
TAK-733 sarcoma AM-7209 TAK-733 NSCLC AM-7209 TAK-733 stomach
AM-7209 TAK-733 endometrium AM-7209 TAK-733 prostate AM-7209
TAK-733 kidney AM-7209 TAK-733 glioblastoma AM-7209 TAK-733 breast
AM-7209 TAK-733 head and neck AM-7209 TAK-733 bladder AM-7209
TAK-733 AML AM-7209 TAK-733 CML AM-7209 TAK-733 DLBCL AM-7209
GDC-0973 melanoma AM-7209 GDC-0973 colon AM-7209 GDC-0973 liver
AM-7209 GDC-0973 sarcoma AM-7209 GDC-0973 NSCLC AM-7209 GDC-0973
stomach AM-7209 GDC-0973 endometrium AM-7209 GDC-0973 prostate
AM-7209 GDC-0973 kidney AM-7209 GDC-0973 glioblastoma AM-7209
GDC-0973 breast AM-7209 GDC-0973 head and neck AM-7209 GDC-0973
bladder AM-7209 GDC-0973 AML AM-7209 GDC-0973 CML AM-7209 GDC-0973
DLBCL AM-7209 AZD8330 melanoma AM-7209 AZD8330 colon AM-7209
AZD8330 liver AM-7209 AZD8330 sarcoma AM-7209 AZD8330 NSCLC AM-7209
AZD8330 stomach AM-7209 AZD8330 prostate AM-7209 AZD8330 kidney
AM-7209 AZD8330 glioblastoma AM-7209 AZD8330 breast AM-7209 AZD8330
head and neck AM-7209 AZD8330 bladder AM-7209 AZD8330 AML AM-7209
AZD8330 CML AM-7209 AZD8330 DLBCL AM-7209 BKM120 prostate AM-7209
BKM120 breast AM-7209 BKM120 melanoma AM-7209 BKM120 NSCLC AM-7209
BKM120 kidney AM-7209 BKM120 glioblastoma AM-7209 BKM120 stomach
AM-7209 BKM120 head and neck AM-7209 BKM120 bladder AM-7209 BKM120
sarcoma AM-7209 BKM120 AML AM-7209 BKM120 CML AM-7209 GDC-0941
prostate AM-7209 GDC-0941 breast AM-7209 GDC-0941 colon AM-7209
GDC-0941 endometrium AM-7209 GDC-0941 melanoma AM-7209 GDC-0941
NSCLC AM-7209 GDC-0941 kidney AM-7209 GDC-0941 glioblastoma AM-7209
GDC-0941 stomach AM-7209 GDC-0941 head and neck AM-7209 GDC-0941
bladder AM-7209 GDC-0941 sarcoma AM-7209 GDC-0941 AML AM-7209
GDC-0941 DLBCL AM-7209 GDC-0941 liver AM-7209 BYL719 prostate
AM-7209 BYL719 breast AM-7209 BYL719 colon AM-7209 BYL719 melanoma
AM-7209 BYL719 NSCLC AM-7209 BYL719 kidney AM-7209 BYL719
glioblastoma AM-7209 BYL719 stomach AM-7209 BYL719 head and neck
AM-7209 BYL719 bladder AM-7209 BYL719 liver AM-7209 BYL719 sarcoma
AM-7209 BYL719 AML AM-7209 BYL719 DLBCL AM-7209 GSK-2636771 breast
AM-7209 GSK-2636771 NSCLC AM-7209 GSK-2636771 liver AM-7209
GSK-2636771 sarcoma AM-7209 GSK-2636771 AML AM-7209 GSK-2636771
DLBCL AM-7209 MK-2206 prostate AM-7209 MK-2206 breast AM-7209
MK-2206 colon AM-7209 MK-2206 endometrium AM-7209 MK-2206 melanoma
AM-7209 MK-2206 NSCLC AM-7209 MK-2206 glioblastoma AM-7209 MK-2206
stomach AM-7209 MK-2206 head and neck AM-7209 MK-2206 sarcoma
AM-7209 MK-2206 liver AM-7209 MK-2206 AML AM-7209 MK-2206 CML
AM-7209 MK-2206 DLBCL AM-7209 GDC-0068 prostate AM-7209 GDC-0068
breast AM-7209 GDC-0068 colon AM-7209 GDC-0068 endometrium AM-7209
GDC-0068 melanoma
AM-7209 GDC-0068 NSCLC AM-7209 GDC-0068 glioblastoma AM-7209
GDC-0068 stomach AM-7209 GDC-0068 head and neck AM-7209 GDC-0068
liver AM-7209 GDC-0068 sarcoma AM-7209 GDC-0068 AML AM-7209
GDC-0068 DLBCL AM-7209 AZD5363 prostate AM-7209 AZD5363 breast
AM-7209 AZD5363 colon AM-7209 AZD5363 endometrium AM-7209 AZD5363
NSCLC AM-7209 AZD5363 glioblastoma AM-7209 AZD5363 stomach AM-7209
AZD5363 head and neck AM-7209 AZD5363 liver AM-7209 AZD5363 sarcoma
AM-7209 AZD5363 AML AM-7209 AZD5363 CML AM-7209 AZD5363 DLBCL
AM-7209 GDC0980 prostate AM-7209 GDC0980 breast AM-7209 GDC0980
colon AM-7209 GDC0980 endometrium AM-7209 GDC0980 melanoma AM-7209
GDC0980 NSCLC AM-7209 GDC0980 kidney AM-7209 GDC0980 glioblastoma
AM-7209 GDC0980 stomach AM-7209 GDC0980 head and neck AM-7209
GDC0980 bladder AM-7209 GDC0980 sarcoma AM-7209 GDC0980 AML AM-7209
GDC0980 DLBCL AM-7209 AZD2014 prostate AM-7209 AZD2014 breast
AM-7209 AZD2014 colon AM-7209 AZD2014 melanoma AM-7209 AZD2014
NSCLC AM-7209 AZD2014 kidney AM-7209 AZD2014 stomach AM-7209
AZD2014 head and neck AM-7209 AZD2014 bladder AM-7209 AZD2014 liver
AM-7209 AZD2014 sarcoma AM-7209 AZD2014 AML AM-7209 AZD2014 DLBCL
AM-7209 MLN0128 prostate AM-7209 MLN0128 breast AM-7209 MLN0128
colon AM-7209 MLN0128 endometrium AM-7209 MLN0128 melanoma AM-7209
MLN0128 NSCLC AM-7209 MLN0128 glioblastoma AM-7209 MLN0128 stomach
AM-7209 MLN0128 head and neck AM-7209 MLN0128 bladder AM-7209
MLN0128 liver AM-7209 MLN0128 sarcoma AM-7209 MLN0128 AML AM-7209
MLN0128 DLBCL AM-7209 navitoclax bladder AM-7209 navitoclax breast
AM-7209 navitoclax colon AM-7209 navitoclax endometrium AM-7209
navitoclax glioblastoma AM-7209 navitoclax head and neck AM-7209
navitoclax kidney AM-7209 navitoclax liver AM-7209 navitoclax NSCLC
AM-7209 navitoclax melanoma AM-7209 navitoclax sarcoma AM-7209
navitoclax stomach AM-7209 navitoclax AML AM-7209 navitoclax CML
AM-7209 navitoclax DLBCL AM-7209 ABT-199 glioblastoma AM-7209
ABT-199 head and neck AM-7209 ABT-199 liver AM-7209 ABT-199 sarcoma
AM-7209 ABT-199 AML AM-7209 ABT-199 CML AM-7209 ABT-199 DLBCL
AM-7209 doxorubicin AML AM-7209 etoposide sarcoma AM-7209 etoposide
stomach AM-7209 Irinotecan colon AM-7209 cytarabine AML AM-7209
decitabine AML AM-7209 dasatinib bladder AM-7209 dasatinib colon
AM-7209 dasatinib endometrium AM-7209 dasatinib glioblastoma
AM-7209 dasatinib head and neck AM-7209 dasatinib kidney AM-7209
dasatinib liver AM-7209 dasatinib NSCLC AM-7209 dasatinib melanoma
AM-7209 dasatinib prostate AM-7209 dasatinib sarcoma AM-7209
dasatinib AML AM-7209 dasatinib CML AM-7209 dasatinib DLBCL AM-7209
panobinostat endometrium AM-7209 panobinostat head and neck AM-7209
panobinostat kidney AM-7209 panobinostat liver AM-7209 panobinostat
melanoma AM-7209 panobinostat sarcoma AM-7209 panobinostat stomach
AM-7209 panobinostat AML AM-7209 panobinostat CML AM-7209
panobinostat DLBCL AM-7209 ponatinib CML AM-7209 imatinib CML
AM-7209 bosutinib CML AM-7209 nilotinib CML AM-7209 quizartinib AML
AM-7209 midostaurin AML AM-7209 cisplatin Ovarian AM-7209 cisplatin
Colon AM-7209 cisplatin NSCLC AM-7209 cisplatin esophageal/stomach
AM-7209 cispaltin Breast AM-7209 doxorubicin Breast AM-7209
doxorubicin stomach AM-7209 doxorubicin ovarian AM-7209 doxorubicin
AML AM-7209 doxorubicin ALL AM-7209 doxorubicin MDS AM-7209
doxorubicin NHL AM-7209 doxorubicin Hodgkin's lymphoma AM-7209
decitabine MDS AM-7209 sorafenib kidney AM-7209 sorafenib liver
AM-7209 sorafenib AML
* * * * *