U.S. patent application number 13/491480 was filed with the patent office on 2012-09-27 for compounds and methods for kinase modulation, and indications therefor.
This patent application is currently assigned to Plexxikon Inc.. Invention is credited to Hanna Cho, Prabha N. Ibrahim, Songyuan Shi, Wayne Spevak, Guoxian Wu.
Application Number | 20120245174 13/491480 |
Document ID | / |
Family ID | 42236712 |
Filed Date | 2012-09-27 |
United States Patent
Application |
20120245174 |
Kind Code |
A1 |
Ibrahim; Prabha N. ; et
al. |
September 27, 2012 |
COMPOUNDS AND METHODS FOR KINASE MODULATION, AND INDICATIONS
THEREFOR
Abstract
Compounds and salts thereof, formulations thereof, conjugates
thereof, derivatives thereof, forms thereof and uses thereof are
described. In certain aspects and embodiments, the described
compounds or salts thereof, formulations thereof, conjugates
thereof, derivatives thereof, and forms thereof are active on each
of BRaf and c-Raf-1 protein kinase, and may also be active on
either or both of A-Raf and B-Raf V600E protein kinase. Also
described are methods of use thereof to treat diseases and
conditions, including melanoma, colorectal cancer, thyroid cancer,
ovarian cancer, and biliary tract cancer.
Inventors: |
Ibrahim; Prabha N.;
(Mountain View, CA) ; Spevak; Wayne; (Berkeley,
CA) ; Cho; Hanna; (San Francisco, CA) ; Shi;
Songyuan; (Fremont, CA) ; Wu; Guoxian; (Foster
City, CA) |
Assignee: |
Plexxikon Inc.
|
Family ID: |
42236712 |
Appl. No.: |
13/491480 |
Filed: |
June 7, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12773798 |
May 4, 2010 |
8198273 |
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13491480 |
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61176054 |
May 6, 2009 |
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Current U.S.
Class: |
514/234.5 ;
514/256; 514/274; 514/275; 514/300; 544/122; 544/127; 544/316;
544/331; 544/333; 546/113 |
Current CPC
Class: |
A61P 43/00 20180101;
A61P 29/00 20180101; C07D 471/04 20130101; A61P 13/12 20180101;
A61P 35/02 20180101; A61P 35/00 20180101 |
Class at
Publication: |
514/234.5 ;
546/113; 514/300; 544/316; 514/274; 544/333; 514/256; 544/127;
544/122; 544/331; 514/275 |
International
Class: |
A61K 31/437 20060101
A61K031/437; A61P 35/00 20060101 A61P035/00; A61K 31/444 20060101
A61K031/444; A61K 31/5377 20060101 A61K031/5377; C07D 471/04
20060101 C07D471/04; A61K 31/506 20060101 A61K031/506 |
Claims
1. A compound having the chemical structure of Formula I,
##STR00333## or a salt, a prodrug, or a tautomer thereof, wherein:
R.sup.1 is selected from the group consisting of ##STR00334##
wherein ##STR00335## indicates the point of attachment of R.sup.1
to the S(O).sub.2 shown in Formula 1; R.sup.2 is hydrogen or
fluoro; R.sup.3 is hydrogen, chloro, methoxy or cyano; R.sup.4 is
selected from the group consisting of hydrogen, chloro, methyl,
methoxy, cyano, ##STR00336## ##STR00337## ##STR00338## ##STR00339##
wherein ##STR00340## indicates the point of attachment of R.sup.4
to the 5-position of the pyrrolo[2,3-b]pyridine ring shown in
Formula I; when R.sup.1 is ##STR00341## R.sup.3 is hydrogen and
R.sup.4 is cyano, R.sup.2 is hydrogen or fluoro; when R.sup.1 is
##STR00342## R.sup.2 is fluoro, and R.sup.3 is hydrogen, R.sup.4 is
methyl, methoxy, cyano, or ##STR00343## when R.sup.2 is fluoro,
R.sup.4 is hydrogen, and R.sup.3 is chloro, methoxy, or cyano,
R.sup.1 is ##STR00344## when R.sup.2 is hydrogen, R.sup.3 is
hydrogen, and R.sup.4 is cyano, R.sup.1 is ##STR00345## when
R.sup.1 is ##STR00346## R.sup.2 is fluoro, and R.sup.3 is hydrogen,
R.sup.4 is methyl or ##STR00347## when R.sup.1 is ##STR00348##
R.sup.2 is fluoro, and R.sup.3 is hydrogen, R.sup.4 is chloro,
methyl, cyano, or ##STR00349## when R.sup.1 is ##STR00350## R.sup.2
is fluoro, and R.sup.3 is hydrogen, R.sup.4 is chloro, methyl,
methoxy, or ##STR00351## and when R.sup.1 is ##STR00352## R.sup.2
is fluoro, and R.sup.3 is hydrogen, R.sup.4 is chloro, methyl, or
cyano.
2. A composition comprising a pharmaceutically acceptable carrier;
and a compound according to claim 1.
3. A kit comprising a compound according to claim 1.
4. A kit comprising a composition according to claim 2.
5. A method for treating a subject suffering from or at risk of a
disease or condition, comprising administering to the subject in
need thereof an effective amount of a compound according to claim
1, wherein the disease or condition is selected from the group
consisting of melanoma, glioma, glioblastoma multiforme, pilocytic
astrocytoma, colorectal cancer, thyroid cancer, lung cancer,
ovarian cancer, prostate cancer, liver cancer, gallbladder cancer,
gastrointestinal stromal tumors, and biliary tract cancer.
6. A method for treating a subject suffering from or at risk of a
disease or condition, comprising administering to the subject in
need thereof an effective amount of a compound according to claim
1, wherein the disease or condition is selected from the group
consisting of melanoma, liver cancer, biliary tract cancer,
colorectal cancer, lung cancer, bladder cancer, breast cancer,
pancreatic cancer, thyroid cancer, kidney cancer, ovarian cancer,
cervical cancer, endometrial cancer, and acute myeloid
leukemia.
7. A method for treating a subject suffering from or at risk of a
disease or condition, comprising administering to the subject in
need thereof an effective amount of a compound according to claim
1, wherein the disease or condition is selected from the group
consisting of melanoma, colorectal cancer, thyroid cancer, ovarian
cancer and biliary tract cancer.
8. A method for treating a subject suffering from or at risk of a
disease or condition, comprising administering to the subject in
need thereof an effective amount of a composition according to
claim 2, wherein the disease or condition is selected from the
group consisting of melanoma, glioma, glioblastoma multiforme,
pilocytic astrocytoma, colorectal cancer, thyroid cancer, lung
cancer, ovarian cancer, prostate cancer, liver cancer, gallbladder
cancer, gastrointestinal stromal tumors, and biliary tract
cancer.
9. A method for treating a subject suffering from or at risk of a
disease or condition, comprising administering to the subject in
need thereof an effective amount of a composition according to
claim 2, wherein the disease or condition is selected from the
group consisting of melanoma, liver cancer, biliary tract cancer,
colorectal cancer, lung cancer, bladder cancer, breast cancer,
pancreatic cancer, thyroid cancer, kidney cancer, ovarian cancer,
cervical cancer, endometrial cancer, and acute myeloid
leukemia.
10. A method for treating a subject suffering from or at risk of a
disease or condition, comprising administering to the subject in
need thereof an effective amount of a composition according to
claim 2, wherein the disease or condition is selected from the
group consisting of melanoma, colorectal cancer, thyroid cancer,
ovarian cancer and biliary tract cancer.
11. The compound according to claim 1, wherein the compound is
selected from the group consisting of:
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-2,5-difluoro-benzenesulfonamide (P-2002),
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-2,6-difluoro-benzenesulfonamide (P-2003),
N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-2-fluoro-benzenesulfonamide (P-2009),
N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-2,5-difluoro-benzenesulfonamide (P-2010),
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2-fluoro-benzenesulfonamide (P-2011),
N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-
-2-fluoro-benzenesulfonamide (P-2014),
N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-
-2,5-difluoro-benzenesulfonamide (P-2015),
N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-
-3-fluoro-benzenesulfonamide (P-2016),
N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-2-fluoro-benzenesulfonamide (P-2017),
N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-2,5-difluoro-benzenesulfonamide (P-2018),
N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-3-fluoro-benzenesulfonamide (P-2019),
N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2-fluoro-benzenesulfonamide (P-2020),
N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-2-fluoro-benzenesulfonamide (P-2021),
N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-2,5-difluoro-benzenesulfonamide (P-2022),
N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-3-fluoro-benzenesulfonamide (P-2023),
N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-
-2,6-difluoro-benzenesulfonamide (P-2024),
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2,6-difluoro-benzenesulfonamide (P-2029),
N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-2,6-difluoro-benzenesulfonamide (P-2033),
N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2,5-difluoro-benzenesulfonamide (P-2036),
N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2,6-difluoro-benzenesulfonamide (P-2037),
N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
3-fluoro-benzenesulfonamide (P-2039),
N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-
-3-carbonyl]-phenyl}-2-fluoro-benzenesulfonamide (P-2041),
N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-
-3-carbonyl]-phenyl}-2,5-difluoro-benzenesulfonamide (P-2042),
N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-
-3-carbonyl]-phenyl}-2,6-difluoro-benzenesulfonamide (P-2043),
N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-
-3-carbonyl]-phenyl}-3-fluoro-benzenesulfonamide (P-2045),
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
benzenesulfonamide (P-2046),
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-2-fl-
uoro-benzenesulfonamide (P-2051),
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-2,5--
difluoro-benzenesulfonamide (P-2052),
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-3-fl-
uoro-benzenesulfonamide (P-2053),
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-2,6--
difluoro-benzenesulfonamide (P-2054),
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-benz-
enesulfonamide (P-2056), Pyridine-3-sulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2069), Pyridine-3-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2071), Pyridine-3-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2072), Pyridine-3-sulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2073), Pyridine-3-sulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2074), Pyridine-3-sulfonic acid
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2077), Pyridine-3-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2086), and any salt, prodrug, or tautomer thereof.
Description
CROSS-REFERENCE TO RELATED PATENT APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 12/773,798 filed May 4, 2010, which claims the benefit of U.S.
Provisional Application No. 61/176,054, filed May 6, 2009, which
are incorporated herein by reference in their entireties and for
all purposes.
FIELD OF THE INVENTION
[0002] Disclosed are novel compounds and uses thereof. In certain
embodiments disclosed compounds are kinase inhibitors.
SUMMARY OF THE INVENTION
[0003] In certain aspects and embodiments disclosed herein,
compounds are provided, as well as various salts thereof,
formulations thereof, conjugates thereof, derivatives thereof,
forms thereof and uses thereof. In certain embodiments, the
compounds inhibit one or more Raf protein kinases, including one or
more of A-Raf, B-Raf, and c-Raf-1, and any mutations thereof. In
certain embodiments, the compounds inhibit each of c-Raf-1, B-Raf,
and B-Raf V600E protein kinase.
[0004] Also contemplated in accordance with the present invention
are methods for the use of the compounds in treating diseases and
conditions associated with regulation of the activity of one or
more Raf protein kinases, including one or more of A-Raf, B-Raf,
and c-Raf-1, and any mutations thereof. Thus, the use of compounds
for therapeutic methods involving modulation of protein kinases are
provided. In certain embodiments, the compounds inhibit the
activity on one or more Raf kinases, including A-Raf, B-Raf and/or
c-Raf-1, including any mutations thereof. In certain embodiments,
the compounds are used for therapeutic methods involving modulation
of one or more Raf protein kinases, including treatment of a
variety of indications, including, but not limited to, melanoma,
glioma, glioblastoma multiforme, pilocytic astrocytoma, colorectal
cancer, thyroid cancer, lung cancer, ovarian cancer, prostate
cancer, liver cancer, gallbladder cancer, gastrointestinal stromal
tumors, biliary tract cancer, cholangiocarcinoma, acute pain,
chronic pain and polycystic kidney disease. In certain embodiments,
the compounds are used for therapeutic methods involving modulation
of B-Raf V600E mutant protein kinase, including treatment of a
variety of indications, including, but not limited to, melanoma,
glioma, glioblastoma multiforme, pilocytic astrocytoma, colorectal
cancer, thyroid cancer, lung cancer, ovarian cancer, prostate
cancer, liver cancer, gallbladder cancer, gastrointestinal stromal
tumors, biliary tract cancer, and cholangiocarcinoma. In certain
embodiments, the compounds are used for therapeutic methods
involving modulation of c-Raf-1 protein kinase, including treatment
of a variety of indications, including, but not limited to, acute
pain, chronic pain and polycystic kidney disease.
[0005] In a first aspect, compounds having the structure according
to the following Formula I are provided:
##STR00001##
or a salt, a prodrug, or a tautomer thereof, [0006] wherein: [0007]
R.sup.1 is selected from the group consisting of
[0007] ##STR00002## wherein
##STR00003## indicates the point of attachment of R.sup.1 to the
S(O).sub.2 shown in Formula 1; [0008] R.sup.2 is hydrogen or
fluoro; [0009] R.sup.3 is hydrogen, chloro, methoxy or cyano;
[0010] R.sup.4 is selected from the group consisting of hydrogen,
chloro, methyl, methoxy, cyano,
[0010] ##STR00004## ##STR00005## ##STR00006## ##STR00007##
wherein
##STR00008## [0011] indicates the point of attachment of R.sup.4 to
the 5-position of the pyrrolo[2,3-b]pyridine ring shown in Formula
I; [0012] wherein: [0013] when R.sup.1 is
[0013] ##STR00009## R.sup.2 is fluoro, and R.sup.3 is hydrogen,
R.sup.4 is selected from the group consisting of
##STR00010## ##STR00011## ##STR00012## ##STR00013## [0014] when
R.sup.1 is
[0014] ##STR00014## R.sup.2 is hydrogen, and R.sup.3 is hydrogen,
R.sup.4 is
##STR00015## [0015] when R.sup.1 is
[0015] ##STR00016## R.sup.2 is fluoro, and R.sup.3 is hydrogen,
R.sup.4 is
##STR00017## [0016] when R.sup.1 is
[0016] ##STR00018## R.sup.3 is hydrogen and R.sup.4 is cyano,
R.sup.2 is hydrogen or fluoro; [0017] when R.sup.1 is
[0017] ##STR00019## R.sup.2 is fluoro, and R.sup.3 is hydrogen,
R.sup.4 is methyl, methoxy, cyano, or
##STR00020## [0018] when R.sup.2 is fluoro, R.sup.4 is hydrogen,
and R.sup.3 is chloro, methoxy, or cyano, R.sup.1 is
[0018] ##STR00021## [0019] when R.sup.2 is hydrogen, R.sup.3 is
hydrogen, and R.sup.4 is cyano, R.sup.1 is
[0019] ##STR00022## [0020] when R.sup.1 is
[0020] ##STR00023## R.sup.2 is fluoro, and R.sup.3 is hydrogen,
R.sup.4 is methyl or
##STR00024## [0021] when R.sup.1 is
[0021] ##STR00025## R.sup.2 is fluoro, and R.sup.3 is hydrogen,
R.sup.4 is chloro, methyl, cyano, or
##STR00026## [0022] when R.sup.1 is
[0022] ##STR00027## R.sup.2 is fluoro, and R.sup.3 is hydrogen,
R.sup.4 is chloro, methyl, methoxy, or
##STR00028## [0023] when R.sup.1 is
[0023] ##STR00029## R.sup.2 is fluoro, and R.sup.3 is hydrogen,
R.sup.4 is chloro, methyl, or cyano.
[0024] In one embodiment of compounds of Formula I, the compound is
selected from the group consisting of: [0025]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-2,5-difluoro-benzenesulfonamide (P-2002), [0026]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-2,6-difluoro-benzenesulfonamide (P-2003), [0027]
N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-2-fluoro-benzenesulfonamide (P-2009), [0028]
N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-2,5-difluoro-benzenesulfonamide (P-2010), [0029]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2-fluoro-benzenesulfonamide (P-2011), [0030]
N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-
-2-fluoro-benzenesulfonamide (P-2014), [0031]
N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-
-2,5-difluoro-benzenesulfonamide (P-2015), [0032]
N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-
-3-fluoro-benzenesulfonamide (P-2016), [0033]
N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-2-fluoro-benzenesulfonamide (P-2017), [0034]
N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-2,5-difluoro-benzenesulfonamide (P-2018), [0035]
N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-3-fluoro-benzenesulfonamide (P-2019), [0036]
N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2-fluoro-benzenesulfonamide (P-2020), [0037]
N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-2-fluoro-benzenesulfonamide (P-2021), [0038]
N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-2,5-difluoro-benzenesulfonamide (P-2022), [0039]
N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-3-fluoro-benzenesulfonamide (P-2023), [0040]
N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-
-2,6-difluoro-benzenesulfonamide (P-2024), [0041]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2,6-difluoro-benzenesulfonamide (P-2029), [0042]
N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-2,6-difluoro-benzenesulfonamide (P-2031), [0043]
N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-2,6-difluoro-benzenesulfonamide (P-2033), [0044]
N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2,5-difluoro-benzenesulfonamide (P-2036), [0045]
N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2,6-difluoro-benzenesulfonamide (P-2037), [0046]
N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
3-fluoro-benzenesulfonamide (P-2039), [0047]
N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-
-3-carbonyl]-phenyl}-2-fluoro-benzenesulfonamide (P-2041), [0048]
N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-
-3-carbonyl]-phenyl}-2,5-difluoro-benzenesulfonamide (P-2042),
[0049]
N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-
-3-carbonyl]-phenyl}-2,6-difluoro-benzenesulfonamide (P-2043),
[0050]
N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-
-3-carbonyl]-phenyl}-3-fluoro-benzenesulfonamide (P-2045), [0051]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
benzenesulfonamide (P-2046), [0052]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-2-fl-
uoro-benzenesulfonamide (P-2051), [0053]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-2,5--
difluoro-benzenesulfonamide (P-2052), [0054]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-3-fl-
uoro-benzenesulfonamide (P-2053), [0055]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-2,6--
difluoro-benzenesulfonamide (P-2054), [0056]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-benz-
enesulfonamide (P-2056), [0057] Pyridine-3-sulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2069), [0058] Pyridine-3-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2071), [0059] Pyridine-3-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2072), [0060] Pyridine-3-sulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2073), [0061] Pyridine-3-sulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2074), [0062] Pyridine-3-sulfonic acid
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2077), [0063] Pyridine-3-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2086), [0064]
5-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-pyridine-2-carboxylic acid ethylamide (P-2151),
[0065] Propane-1-sulfonic acid
{3-[5-(6-chloro-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-d-
ifluoro-phenyl}-amide (P-2154), [0066] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(6-fluoro-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-ca-
rbonyl]-phenyl}-amide (P-2155), [0067]
N-(4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-
-b]pyridin-5-yl}-phenyl)-acetamide (P-2161), [0068]
Propane-1-sulfonic acid
[2,4-difluoro-3-(5-pyrimidin-5-yl-1H-pyrrolo[2,3-b]pyridine-3-carbon-
yl)-phenyl]-amide (P-2162), [0069] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(4-methanesulfonylamino-phenyl)-1H-pyrrolo[2,3-b]pyrid-
ine-3-carbonyl]-phenyl}-amide (P-2165), [0070] Propane-1-sulfonic
acid
(2,4-difluoro-3-{5-[4-(morpholine-4-sulfonyl)-phenyl]-1H-pyrrolo[2,3-b]py-
ridine-3-carbonyl}-phenyl)-amide (P-2166), [0071]
4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-N-methyl-benzenesulfonamide (P-2167), [0072]
N-Cyclopropyl-4-{3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H--
pyrrolo[2,3-b]pyridin-5-yl}-benzenesulfonamide (P-2168), [0073]
Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(2-fluoro-6-methyl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyri-
dine-3-carbonyl]-phenyl}-amide (P-2172), [0074] Propane-1-sulfonic
acid
{2,4-difluoro-3-[5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl-
]-phenyl}-amide (P-2174), [0075] Propane-1-sulfonic acid
(2,4-difluoro-3-{5-[1-(2-morpholin-4-yl-ethyl)-1H-pyrazol-4-yl]-1H-pyrrol-
o[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2177), [0076]
Propane-1-sulfonic acid
(3-{5-[6-(3-dimethylamino-propoxy)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridin-
e-3-carbonyl}-2,4-difluoro-phenyl)-amide (P-2178), [0077]
5-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-pyridine-2-carboxylic acid methylamide (P-2180),
[0078]
5-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-pyridine-2-carboxylic acid cyclopropylamide (P-2181),
[0079] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(4-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2183), [0080] Propane-1-sulfonic acid
{3-[5-(2,6-dimethoxy-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]--
2,4-difluoro-phenyl}-amide (P-2184), [0081]
4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-N,N-dimethyl-benzenesulfonamide (P-2185), [0082]
Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(6-methylsulfanyl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyrid-
ine-3-carbonyl]-phenyl}-amide (P-2187), [0083] Propane-1-sulfonic
acid
{2,4-difluoro-3-[5-(5-methanesulfonyl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyri-
dine-3-carbonyl]-phenyl}-amide (P-2188), [0084] Propane-1-sulfonic
acid
{2,4-difluoro-3-[5-(2-methylsulfanyl-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyr-
idine-3-carbonyl]-phenyl}-amide (P-2189), [0085] Propane-1-sulfonic
acid
{3-[5-(1-benzyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,-
4-difluoro-phenyl}-amide (P-2190), [0086] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(2-fluoro-pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-ca-
rbonyl]-phenyl}-amide (P-2192), [0087]
N-(5-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-
-b]pyridin-5-yl}-pyridin-2-yl)-acetamide (P-2193), [0088]
4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-benzenesulfonamide (P-2194), [0089]
Propane-1-sulfonic acid
{3-[5-(2-dimethylamino-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbon-
yl]-2,4-difluoro-phenyl}-amide (P-2196), [0090] Propane-1-sulfonic
acid
{2,4-difluoro-3-[5-(2-morpholin-4-yl-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyr-
idine-3-carbonyl]-phenyl}-amide (P-2197), [0091] Propane-1-sulfonic
acid
{3-[5-(2,4-dimethoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl-
]-2,4-difluoro-phenyl}-amide (P-2199), [0092] Propane-1-sulfonic
acid
(3-{5-[2-(3-dimethylamino-propoxy)-pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyrid-
ine-3-carbonyl}-2,4-difluoro-phenyl)-amide (P-2203), [0093]
Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(2-methyl-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3--
carbonyl]-phenyl}-amide (P-2211), [0094] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(6-methyl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-ca-
rbonyl]-phenyl}-amide (P-2213), [0095] Propane-1-sulfonic acid
{3-[5-(6-amino-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-di-
fluoro-phenyl}-amide (P-2214), [0096] Propane-1-sulfonic acid
{3-[5-(4-ethanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-
-difluoro-phenyl}-amide (P-2218), [0097] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(2-pyrrolidin-1-yl-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]py-
ridine-3-carbonyl]-phenyl}-amide (P-2219), [0098]
5-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-pyridine-2-carboxylic acid amide (P-2220), [0099]
Propane-1-sulfonic acid
(3-{5-[6-(3-diethylamino-prop-1-ynyl)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyri-
dine-3-carbonyl}-2,4-difluoro-phenyl)-amide (P-2222), [0100]
Propane-1-sulfonic acid
(2,4-difluoro-3-{5-[4-(propane-2-sulfonyl)-phenyl]-1H-pyrrolo[2,3-b]pyrid-
ine-3-carbonyl}-phenyl)-amide (P-2223), [0101] Propane-1-sulfonic
acid
{2,4-difluoro-3-[5-(6-propyl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-ca-
rbonyl]-phenyl}-amide (P-2224), [0102] Propane-1-sulfonic acid
(2,4-difluoro-3-{5-[6-(3-methoxy-propyl)-pyridin-3-yl]-1H-pyrrolo[2,3-b]p-
yridine-3-carbonyl}-phenyl)-amide (P-2226), [0103]
Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2228), [0104] Propane-1-sulfonic acid
{3-[5-(6-dimethylamino-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl-
]-2,4-difluoro-phenyl}-amide (P-2229), [0105] Propane-1-sulfonic
acid
{2,4-difluoro-3-[5-(6-pyrrolidin-1-yl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyri-
dine-3-carbonyl]-phenyl}-amide (P-2231), [0106] Propane-1-sulfonic
acid
(2,4-difluoro-3-{5-[6-(2-morpholin-4-yl-ethoxy)-pyridin-3-yl]-1H-pyrrolo[-
2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2232), [0107]
Propane-1-sulfonic acid
(2,4-difluoro-3-{5-[6-(2-pyrrolidin-1-yl-ethoxy)-pyridin-3-yl]-1H-pyrrolo-
[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2233), [0108]
Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(6-hydroxy-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-c-
arbonyl]-phenyl}-amide (P-2234), [0109] Propane-1-sulfonic acid
(2,4-difluoro-3-{5-[6-(3-pyrrolidin-1-yl-propoxy)-pyridin-3-yl]-1H-pyrrol-
o[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2235), [0110]
Propane-1-sulfonic acid
(2,4-difluoro-3-{5-[6-(3-morpholin-4-yl-propoxy)-pyridin-3-yl]-1H-pyrrolo-
[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2236), [0111]
Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(3-methoxy-prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridine-3-ca-
rbonyl]-phenyl}-amide (P-2239), [0112] Propane-1-sulfonic acid
{3-[5-(3-diethylamino-prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]--
2,4-difluoro-phenyl}-amide (P-2241), [0113] Propane-1-sulfonic acid
[3-(5-ethynyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
amide (P-2260), [0114] 2-Methyl-propane-1-sulfonic acid
{2,4-difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2299), [0115] Propane-1-sulfonic acid
{2-fluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-car-
bonyl]-phenyl}-amide (P-2407), [0116] Propane-1-sulfonic acid
{3-[5-(2-dimethylamino-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbon-
yl]-2-fluoro-phenyl}-amide (P-2408), and a salt, prodrug, or
tautomer thereof.
[0117] In reference to compounds as described herein, including
compounds of Formula I and all embodiments thereof, unless clearly
indicated to the contrary, specification of a compound or group of
compounds includes salts of such compound(s) (including
pharmaceutically acceptable salts), formulations of such
compound(s) (including pharmaceutically acceptable formulations),
conjugates thereof, derivatives thereof, solid forms thereof, and
prodrugs thereof.
[0118] In a second aspect, methods are provided for treating any
Raf protein kinase mediated disease or condition in an animal
subject in need thereof, wherein the method involves administering
to the subject an effective amount of any one or more compound(s)
as described herein. In one embodiment, the method involves
administering to the subject an effective amount of any one or more
compound(s) as described herein in combination with one or more
other therapies for the disease or condition.
[0119] In a third aspect, methods are provided for treating any
A-Raf protein kinase mediated disease or condition, including any
A-Raf mutant kinase mediated disease or condition in an animal
subject in need thereof, wherein the method involves administering
to the subject an effective amount of any one or more compound(s)
as described herein. In certain embodiments, the method involves
administering to the subject an effective amount of any one or more
compound(s) as described herein in combination with one or more
other therapies for the disease or condition.
[0120] In a fourth aspect, methods are provided for treating any
B-Raf protein kinase mediated disease or condition, including any
B-Raf mutant kinase mediated disease or condition in an animal
subject in need thereof, wherein the method involves administering
to the subject an effective amount of any one or more compound(s)
as described herein. In certain embodiments, the method involves
administering to the subject an effective amount of any one or more
compound(s) as described herein in combination with one or more
other therapies for the disease or condition.
[0121] In a fifth aspect, methods are provided for treating any
B-Raf V600E mutant protein kinase mediated disease or condition in
an animal subject in need thereof, wherein the method involves
administering to the subject an effective amount of any one or more
compound(s) as described herein. In certain embodiments, the method
involves administering to the subject an effective amount of any
one or more compound(s) as described herein in combination with one
or more other therapies for the disease or condition.
[0122] In a sixth aspect, methods are provided for treating any
c-Raf-1 protein kinase mediated disease or condition, including any
c-Raf-1 mutant kinase mediated disease or condition in an animal
subject in need thereof, wherein the method involves administering
to the subject an effective amount of any one or more compound(s)
as described herein. In certain embodiments, the method involves
administering to the subject an effective amount of any one or more
compound(s) as described herein in combination with one or more
other therapies for the disease or condition.
[0123] In a seventh aspect, methods are provided for treating any
Ras mutant-activated Raf protein kinase mediated disease or
condition in an animal subject in need thereof, wherein the method
involves administering to the subject an effective amount of any
one or more compound(s) as described herein. In certain
embodiments, the method involves administering to the subject an
effective amount of any one or more compound(s) as described herein
in combination with one or more other therapies for the disease or
condition.
[0124] In an eighth aspect, a compound as described herein is a Raf
kinase inhibitor and has an IC.sub.50 of less than 500 nM, less
than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM,
less than 5 nM, or less than 1 nM as determined in a generally
accepted Raf kinase activity assay. In some embodiments, a compound
as described herein will have an IC.sub.50 of less than 500 nm,
less than 100 nM, less than 50 nM, less than 20 nM, less than 10
nM, less than 5 nM, or less than 1 nM with respect to A-Raf, B-Raf,
c-Raf-1, or B-Raf V600E mutant. In some embodiments, a compound as
described herein will selectively inhibit one Raf kinase relative
to one or more other non-Raf kinases.
[0125] In a ninth aspect, a compound as described herein is a pan
Raf inhibitor, i.e. inhibits at least each of B-Raf kinase and
c-Raf-1 kinase, with an IC.sub.50 of less than 100 nM, less than 50
nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than
1 nM as determined in each of a generally accepted B-Raf kinase
activity assay, and c-Raf-1 kinase activity assay. In some
embodiments, the compounds are approximately equipotent on each of
B-Raf and c-Raf-1, i.e. the ratio of IC.sub.50 for either of B-Raf
and c-Raf-1 divided by the IC.sub.50 for the other of B-Raf and
c-Raf-1 (e.g. B-Raf IC.sub.50 divided by c-Raf-1 IC.sub.50) is in
the range of 10 to 0.1, also 5 to 0.2. In some embodiments, the
compound is selective relative to other protein kinases, such that
the ratio of IC.sub.50 for another kinase assessed comparably,
divided by the IC.sub.50 for either of B-Raf and c-Raf-1 is >10,
also >20, also >30, also >40, also >50, also >60,
also >70, also >80, also >90, also >100, wherein the
other protein kinase includes, but is not limited to CSK, Insulin
receptor kinase, AMPK, PDGFR or VEGFR. In some embodiments, the pan
Raf inhibitor also inhibits A-Raf kinase. In some embodiments, the
compounds are approximately equipotent on each of B-Raf, c-Raf-1,
and A-Raf. In some embodiments, the pan Raf inhibitor also inhibits
B-Raf V600E mutant kinase. In some embodiments, the compounds are
approximately equipotent on each of B-Raf, c-Raf-1, and B-Raf
V600E. In some embodiments, the pan Raf inhibitor also inhibits
A-Raf and B-Raf V600E mutant kinase. In some embodiments, the
compounds are approximately equipotent on each of B-Raf, c-Raf-1,
A-Raf and B-Raf V600E. In some embodiments, the pan Raf inhibitor
also inhibits tumorigenic cell lines that are driven by Ras
mutations, i.e. the compounds inhibit proliferation of a Ras
mutation driven tumorigenic cell line with an IC.sub.50 of less
than 1 .mu.M, less than 500 nM, less than 200 nM, or less than 100
nM as determined in a generally accepted cell proliferation assay
(alternatively, >20%, >40%, >60%, or >80% inhibition at
1 .mu.M). In some embodiments, the pan Raf inhibitor also inhibits
IPC298 cells, i.e. the compounds inhibit proliferation of IPC298
cell line with an IC.sub.50 of less than 1 .mu.M, less than 500 nM,
less than 200 nM, or less than 100 nM as determined in a generally
accepted IPC298 cell proliferation assay (alternatively, >20%,
>40%, >60%, or >80% inhibition at 1 .mu.M).
[0126] In one embodiment of compounds of Formula I, the compound is
a pan Raf inhibitor selected from the group consisting of: [0127]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-2,5-difluoro-benzenesulfonamide (P-2002), [0128]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-2,6-difluoro-benzenesulfonamide (P-2003), [0129]
N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-2-fluoro-benzenesulfonamide (P-2009), [0130]
N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-2,5-difluoro-benzenesulfonamide (P-2010), [0131]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2-fluoro-benzenesulfonamide (P-2011), [0132]
N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-
-2-fluoro-benzenesulfonamide (P-2014), [0133]
N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-
-2,5-difluoro-benzenesulfonamide (P-2015), [0134]
N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-
-3-fluoro-benzenesulfonamide (P-2016), [0135]
N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-2-fluoro-benzenesulfonamide (P-2017), [0136]
N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-2,5-difluoro-benzenesulfonamide (P-2018), [0137]
N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-3-fluoro-benzenesulfonamide (P-2019), [0138]
N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2-fluoro-benzenesulfonamide (P-2020), [0139]
N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-2-fluoro-benzenesulfonamide (P-2021), [0140]
N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-2,5-difluoro-benzenesulfonamide (P-2022), [0141]
N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-3-fluoro-benzenesulfonamide (P-2023), [0142]
N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-
-2,6-difluoro-benzenesulfonamide (P-2024), [0143]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2,6-difluoro-benzenesulfonamide (P-2029), [0144]
N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-2,6-difluoro-benzenesulfonamide (P-2033), [0145]
N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2,5-difluoro-benzenesulfonamide (P-2036), [0146]
N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2,6-difluoro-benzenesulfonamide (P-2037), [0147]
N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
3-fluoro-benzenesulfonamide (P-2039), [0148]
N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-
-3-carbonyl]-phenyl}-2-fluoro-benzenesulfonamide (P-2041), [0149]
N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-
-3-carbonyl]-phenyl}-2,5-difluoro-benzenesulfonamide (P-2042),
[0150]
N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-
-3-carbonyl]-phenyl}-2,6-difluoro-benzenesulfonamide (P-2043),
[0151]
N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-
-3-carbonyl]-phenyl}-3-fluoro-benzenesulfonamide (P-2045), [0152]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
benzenesulfonamide (P-2046), [0153]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-2-fl-
uoro-benzenesulfonamide (P-2051), [0154]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-2,5--
difluoro-benzenesulfonamide (P-2052), [0155]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-3-fl-
uoro-benzenesulfonamide (P-2053), [0156]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-2,6--
difluoro-benzenesulfonamide (P-2054), [0157]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-benz-
enesulfonamide (P-2056), [0158] Pyridine-3-sulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2069), [0159] Pyridine-3-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2071), [0160] Pyridine-3-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2072), [0161] Pyridine-3-sulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2073), [0162] Pyridine-3-sulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2074), [0163] Pyridine-3-sulfonic acid
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2077), [0164] Pyridine-3-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2086), [0165]
5-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-pyridine-2-carboxylic acid ethylamide (P-2151),
[0166] Propane-1-sulfonic acid
{3-[5-(6-chloro-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-d-
ifluoro-phenyl}-amide (P-2154), [0167] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(6-fluoro-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-ca-
rbonyl]-phenyl}-amide (P-2155), [0168]
N-(4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-
-b]pyridin-5-yl}-phenyl)-acetamide (P-2161), [0169]
Propane-1-sulfonic acid
[2,4-difluoro-3-(5-pyrimidin-5-yl-1H-pyrrolo[2,3-b]pyridine-3-carbon-
yl)-phenyl]-amide (P-2162), [0170] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(4-methanesulfonylamino-phenyl)-1H-pyrrolo[2,3-b]pyrid-
ine-3-carbonyl]-phenyl}-amide (P-2165), [0171] Propane-1-sulfonic
acid
(2,4-difluoro-3-{5-[4-(morpholine-4-sulfonyl)-phenyl]-1H-pyrrolo[2,3-b]py-
ridine-3-carbonyl}-phenyl)-amide (P-2166), [0172]
4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-N-methyl-benzenesulfonamide (P-2167), [0173]
N-Cyclopropyl-4-{3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H--
pyrrolo[2,3-b]pyridin-5-yl}-benzenesulfonamide (P-2168), [0174]
Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(2-fluoro-6-methyl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyri-
dine-3-carbonyl]-phenyl}-amide (P-2172), [0175] Propane-1-sulfonic
acid
{2,4-difluoro-3-[5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl-
]-phenyl}-amide (P-2174), [0176] Propane-1-sulfonic acid
(2,4-difluoro-3-{5-[1-(2-morpholin-4-yl-ethyl)-1H-pyrazol-4-yl]-1H-pyrrol-
o[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2177), [0177]
Propane-1-sulfonic acid
(3-{5-[6-(3-dimethylamino-propoxy)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridin-
e-3-carbonyl}-2,4-difluoro-phenyl)-amide (P-2178), [0178]
5-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-pyridine-2-carboxylic acid methylamide (P-2180),
[0179]
5-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-pyridine-2-carboxylic acid cyclopropylamide (P-2181),
[0180] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(4-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2183), [0181] Propane-1-sulfonic acid
{3-[5-(2,6-dimethoxy-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]--
2,4-difluoro-phenyl}-amide (P-2184), [0182]
4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-N,N-dimethyl-benzenesulfonamide (P-2185), [0183]
Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(6-methylsulfanyl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyrid-
ine-3-carbonyl]-phenyl}-amide (P-2187), [0184] Propane-1-sulfonic
acid
{2,4-difluoro-3-[5-(5-methanesulfonyl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyri-
dine-3-carbonyl]-phenyl}-amide (P-2188), [0185] Propane-1-sulfonic
acid
{2,4-difluoro-3-[5-(2-methylsulfanyl-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyr-
idine-3-carbonyl]-phenyl}-amide (P-2189), [0186] Propane-1-sulfonic
acid
{3-[5-(1-benzyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,-
4-difluoro-phenyl}-amide (P-2190), [0187] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(2-fluoro-pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-ca-
rbonyl]-phenyl}-amide (P-2192), [0188]
N-(5-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-
-b]pyridin-5-yl}-pyridin-2-yl)-acetamide (P-2193), [0189]
4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-benzenesulfonamide (P-2194), [0190]
Propane-1-sulfonic acid
{3-[5-(2-dimethylamino-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbon-
yl]-2,4-difluoro-phenyl}-amide (P-2196), [0191] Propane-1-sulfonic
acid
{2,4-difluoro-3-[5-(2-morpholin-4-yl-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyr-
idine-3-carbonyl]-phenyl}-amide (P-2197), [0192] Propane-1-sulfonic
acid
{3-[5-(2,4-dimethoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl-
]-2,4-difluoro-phenyl}-amide (P-2199), [0193] Propane-1-sulfonic
acid
(3-{5-[2-(3-dimethylamino-propoxy)-pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyrid-
ine-3-carbonyl}-2,4-difluoro-phenyl)-amide (P-2203), [0194]
Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(2-methyl-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3--
carbonyl]-phenyl}-amide (P-2211), [0195] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(6-methyl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-ca-
rbonyl]-phenyl}-amide (P-2213), [0196] Propane-1-sulfonic acid
{3-[5-(6-amino-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-di-
fluoro-phenyl}-amide (P-2214), [0197] Propane-1-sulfonic acid
{3-[5-(4-ethanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-
-difluoro-phenyl}-amide (P-2218), [0198] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(2-pyrrolidin-1-yl-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]py-
ridine-3-carbonyl]-phenyl}-amide (P-2219), [0199]
5-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-pyridine-2-carboxylic acid amide (P-2220), [0200]
Propane-1-sulfonic acid
(3-{5-[6-(3-diethylamino-prop-1-ynyl)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyri-
dine-3-carbonyl}-2,4-difluoro-phenyl)-amide (P-2222), [0201]
Propane-1-sulfonic acid
(2,4-difluoro-3-{5-[4-(propane-2-sulfonyl)-phenyl]-1H-pyrrolo[2,3-b]pyrid-
ine-3-carbonyl}-phenyl)-amide (P-2223), [0202] Propane-1-sulfonic
acid
{2,4-difluoro-3-[5-(6-propyl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-ca-
rbonyl]-phenyl}-amide (P-2224), [0203] Propane-1-sulfonic acid
(2,4-difluoro-3-{5-[6-(3-methoxy-propyl)-pyridin-3-yl]-1H-pyrrolo[2,3-b]p-
yridine-3-carbonyl}-phenyl)-amide (P-2226), [0204]
Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2228), [0205] Propane-1-sulfonic acid
{3-[5-(6-dimethylamino-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl-
]-2,4-difluoro-phenyl}-amide (P-2229), [0206] Propane-1-sulfonic
acid
{2,4-difluoro-3-[5-(6-pyrrolidin-1-yl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyri-
dine-3-carbonyl]-phenyl}-amide (P-2231), [0207] Propane-1-sulfonic
acid
(2,4-difluoro-3-{5-[6-(2-morpholin-4-yl-ethoxy)-pyridin-3-yl]-1H-pyrrolo[-
2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2232), [0208]
Propane-1-sulfonic acid
(2,4-difluoro-3-{5-[6-(2-pyrrolidin-1-yl-ethoxy)-pyridin-3-yl]-1H-pyrrolo-
[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2233), [0209]
Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(6-hydroxy-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-c-
arbonyl]-phenyl}-amide (P-2234), [0210] Propane-1-sulfonic acid
(2,4-difluoro-3-{5-[6-(3-pyrrolidin-1-yl-propoxy)-pyridin-3-yl]-1H-pyrrol-
o[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2235), [0211]
Propane-1-sulfonic acid
(2,4-difluoro-3-{5-[6-(3-morpholin-4-yl-propoxy)-pyridin-3-yl]-1H-pyrrolo-
[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2236), [0212]
Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(3-methoxy-prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridine-3-ca-
rbonyl]-phenyl}-amide (P-2239), [0213] Propane-1-sulfonic acid
{3-[5-(3-diethylamino-prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]--
2,4-difluoro-phenyl}-amide (P-2241), [0214] Propane-1-sulfonic acid
[3-(5-ethynyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
amide (P-2260), [0215] 2-Methyl-propane-1-sulfonic acid
{2,4-difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2299), [0216] Propane-1-sulfonic acid
{2-fluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-car-
bonyl]-phenyl}-amide (P-2407), [0217] Propane-1-sulfonic acid
{3-[5-(2-dimethylamino-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbon-
yl]-2-fluoro-phenyl}-amide (P-2408), and a salt, prodrug, or
tautomer thereof.
[0218] In one embodiment of compounds of Formula I, the compound is
a pan Raf inhibitor selected from the group consisting of: [0219]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-2,5-difluoro-benzenesulfonamide (P-2002), [0220]
N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2-fluoro-benzenesulfonamide (P-2020), [0221]
N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2,5-difluoro-benzenesulfonamide (P-2036), [0222]
N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-
-3-carbonyl]-phenyl}-2-fluoro-benzenesulfonamide (P-2041), [0223]
N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-
-3-carbonyl]-phenyl}-2,5-difluoro-benzenesulfonamide (P-2042),
[0224]
N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-
-3-carbonyl]-phenyl}-2,6-difluoro-benzenesulfonamide (P-2043),
[0225]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
benzenesulfonamide (P-2046), [0226]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-3-fl-
uoro-benzenesulfonamide (P-2053), [0227] Pyridine-3-sulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2069), [0228] Pyridine-3-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2071), [0229] Pyridine-3-sulfonic acid
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2077), [0230] Pyridine-3-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2086), [0231]
5-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-pyridine-2-carboxylic acid ethylamide (P-2151),
[0232] Propane-1-sulfonic acid
{3-[5-(6-chloro-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-d-
ifluoro-phenyl}-amide (P-2154), [0233] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(6-fluoro-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-ca-
rbonyl]-phenyl}-amide (P-2155), [0234]
N-(4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-
-b]pyridin-5-yl}-phenyl)-acetamide (P-2161), [0235]
Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(4-methanesulfonylamino-phenyl)-1H-pyrrolo[2,3-b]-
pyridine-3-carbonyl]-phenyl}-amide (P-2165), [0236]
Propane-1-sulfonic acid
(2,4-difluoro-3-{5-[4-(morpholine-4-sulfonyl)-phenyl]-1H-pyrrolo[2,3-
-b]pyridine-3-carbonyl}-phenyl)-amide (P-2166), [0237]
4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-N-methyl-benzenesulfonamide (P-2167), [0238]
N-Cyclopropyl-4-{3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H--
pyrrolo[2,3-b]pyridin-5-yl}-benzenesulfonamide (P-2168), [0239]
Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl-
]-phenyl}-amide (P-2174), [0240] Propane-1-sulfonic acid
(2,4-difluoro-3-{5-[1-(2-morpholin-4-yl-ethyl)-1H-pyrazol-4-yl]-1H-pyrrol-
o[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2177), [0241]
Propane-1-sulfonic acid
(3-{5-[6-(3-dimethylamino-propoxy)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridin-
e-3-carbonyl}-2,4-difluoro-phenyl)-amide (P-2178), [0242]
5-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-pyridine-2-carboxylic acid methylamide (P-2180),
[0243]
5-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-pyridine-2-carboxylic acid cyclopropylamide (P-2181),
[0244] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(4-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2183), [0245]
4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-N,N-dimethyl-benzenesulfonamide (P-2185), [0246]
Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(6-methylsulfanyl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyrid-
ine-3-carbonyl]-phenyl}-amide (P-2187), [0247] Propane-1-sulfonic
acid
{2,4-difluoro-3-[5-(5-methanesulfonyl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyri-
dine-3-carbonyl]-phenyl}-amide (P-2188), [0248] Propane-1-sulfonic
acid
{2,4-difluoro-3-[5-(2-methylsulfanyl-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyr-
idine-3-carbonyl]-phenyl}-amide (P-2189), [0249] Propane-1-sulfonic
acid
{3-[5-(1-benzyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,-
4-difluoro-phenyl}-amide (P-2190), [0250] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(2-fluoro-pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-ca-
rbonyl]-phenyl}-amide (P-2192), [0251]
N-(5-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-
-b]pyridin-5-yl}-pyridin-2-yl)-acetamide (P-2193), [0252]
4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-benzenesulfonamide (P-2194), [0253]
Propane-1-sulfonic acid
{3-[5-(2-dimethylamino-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbon-
yl]-2,4-difluoro-phenyl}-amide (P-2196), [0254] Propane-1-sulfonic
acid
{2,4-difluoro-3-[5-(2-morpholin-4-yl-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyr-
idine-3-carbonyl]-phenyl}-amide (P-2197), [0255] Propane-1-sulfonic
acid
(3-{5-[2-(3-dimethylamino-propoxy)-pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyrid-
ine-3-carbonyl}-2,4-difluoro-phenyl)-amide (P-2203), [0256]
Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(2-methyl-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3--
carbonyl]-phenyl}-amide (P-2211), [0257] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(6-methyl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-ca-
rbonyl]-phenyl}-amide (P-2213), [0258] Propane-1-sulfonic acid
{3-[5-(6-amino-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-di-
fluoro-phenyl}-amide (P-2214), [0259] Propane-1-sulfonic acid
{3-[5-(4-ethanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-
-difluoro-phenyl}-amide (P-2218), [0260] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(2-pyrrolidin-1-yl-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]py-
ridine-3-carbonyl]-phenyl}-amide (P-2219), [0261]
Propane-1-sulfonic acid
(3-{5-[6-(3-diethylamino-prop-1-ynyl)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyri-
dine-3-carbonyl}-2,4-difluoro-phenyl)-amide (P-2222), [0262]
Propane-1-sulfonic acid
(2,4-difluoro-3-{5-[4-(propane-2-sulfonyl)-phenyl]-1H-pyrrolo[2,3-b]pyrid-
ine-3-carbonyl}-phenyl)-amide (P-2223), [0263] Propane-1-sulfonic
acid
{2,4-difluoro-3-[5-(6-propyl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-ca-
rbonyl]-phenyl}-amide (P-2224), [0264] Propane-1-sulfonic acid
(2,4-difluoro-3-{5-[6-(3-methoxy-propyl)-pyridin-3-yl]-1H-pyrrolo[2,3-b]p-
yridine-3-carbonyl}-phenyl)-amide (P-2226), [0265]
Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2228), [0266] Propane-1-sulfonic acid
(2,4-difluoro-3-{5-[6-(2-morpholin-4-yl-ethoxy)-pyridin-3-yl]-1H-pyrrolo[-
2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2232), [0267]
Propane-1-sulfonic acid
(2,4-difluoro-3-{5-[6-(2-pyrrolidin-1-yl-ethoxy)-pyridin-3-yl]-1H-pyrrolo-
[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2233), [0268]
Propane-1-sulfonic acid
(2,4-difluoro-3-{5-[6-(3-pyrrolidin-1-yl-propoxy)-pyridin-3-yl]-1H-pyrrol-
o[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2235), [0269]
Propane-1-sulfonic acid
(2,4-difluoro-3-{5-[6-(3-morpholin-4-yl-propoxy)-pyridin-3-yl]-1H-pyrrolo-
[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2236), [0270]
Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(3-methoxy-prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridine-3-ca-
rbonyl]-phenyl}-amide (P-2239), [0271] Propane-1-sulfonic acid
[3-(5-ethynyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
amide (P-2260), [0272] 2-Methyl-propane-1-sulfonic acid
{2,4-difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2299), and a salt, prodrug, or tautomer
thereof.
[0273] In one embodiment of compounds of Formula I, the compound is
a pan Raf inhibitor selected from the group consisting of: [0274]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-2,5-difluoro-benzenesulfonamide (P-2002), [0275]
N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2,5-difluoro-benzenesulfonamide (P-2036), [0276]
N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-
-3-carbonyl]-phenyl}-2-fluoro-benzenesulfonamide (P-2041), [0277]
N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-
-3-carbonyl]-phenyl}-2,5-difluoro-benzenesulfonamide (P-2042),
[0278]
N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-
-3-carbonyl]-phenyl}-2,6-difluoro-benzenesulfonamide (P-2043),
[0279]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
benzenesulfonamide (P-2046), [0280]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-3-fl-
uoro-benzenesulfonamide (P-2053), [0281] Pyridine-3-sulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2069), [0282] Pyridine-3-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2071), [0283]
5-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-pyridine-2-carboxylic acid ethylamide (P-2151),
[0284] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(6-fluoro-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-ca-
rbonyl]-phenyl}-amide (P-2155), [0285] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(4-methanesulfonylamino-phenyl)-1H-pyrrolo[2,3-b]pyrid-
ine-3-carbonyl]-phenyl}-amide (P-2165), [0286] Propane-1-sulfonic
acid
(2,4-difluoro-3-{5-[4-(morpholine-4-sulfonyl)-phenyl]-1H-pyrrolo[2,3-b]py-
ridine-3-carbonyl}-phenyl)-amide (P-2166), [0287]
4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-N-methyl-benzenesulfonamide (P-2167), [0288]
N-Cyclopropyl-4-{3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H--
pyrrolo[2,3-b]pyridin-5-yl}-benzenesulfonamide (P-2168), [0289]
Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl-
]-phenyl}-amide (P-2174), [0290] Propane-1-sulfonic acid
(2,4-difluoro-3-{5-[1-(2-morpholin-4-yl-ethyl)-1H-pyrazol-4-yl]-1H-pyrrol-
o[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2177), [0291]
Propane-1-sulfonic acid
(3-{5-[6-(3-dimethylamino-propoxy)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridin-
e-3-carbonyl}-2,4-difluoro-phenyl)-amide (P-2178), [0292]
Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(4-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2183), [0293]
4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-N,N-dimethyl-benzenesulfonamide (P-2185), [0294]
Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(6-methylsulfanyl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyrid-
ine-3-carbonyl]-phenyl}-amide (P-2187), [0295] Propane-1-sulfonic
acid
{2,4-difluoro-3-[5-(2-methylsulfanyl-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyr-
idine-3-carbonyl]-phenyl}-amide (P-2189), [0296] Propane-1-sulfonic
acid
{3-[5-(1-benzyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,-
4-difluoro-phenyl}-amide (P-2190), [0297]
N-(5-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-
-b]pyridin-5-yl}-pyridin-2-yl)-acetamide (P-2193), [0298]
Propane-1-sulfonic acid
{3-[5-(2-dimethylamino-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbon-
yl]-2,4-difluoro-phenyl}-amide (P-2196), [0299] Propane-1-sulfonic
acid
{2,4-difluoro-3-[5-(2-methyl-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3--
carbonyl]-phenyl}-amide (P-2211), [0300] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(6-methyl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-ca-
rbonyl]-phenyl}-amide (P-2213), [0301] Propane-1-sulfonic acid
{3-[5-(6-amino-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-di-
fluoro-phenyl}-amide (P-2214), [0302] Propane-1-sulfonic acid
(3-{5-[6-(3-diethylamino-prop-1-ynyl)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyri-
dine-3-carbonyl}-2,4-difluoro-phenyl)-amide (P-2222), [0303]
Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(6-propyl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-ca-
rbonyl]-phenyl}-amide (P-2224), [0304] Propane-1-sulfonic acid
(2,4-difluoro-3-{5-[6-(2-morpholin-4-yl-ethoxy)-pyridin-3-yl]-1H-pyrrolo[-
2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2232), [0305]
Propane-1-sulfonic acid
(2,4-difluoro-3-{5-[6-(2-pyrrolidin-1-yl-ethoxy)-pyridin-3-yl]-1H-pyrrolo-
[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2233), [0306]
Propane-1-sulfonic acid
(2,4-difluoro-3-{5-[6-(3-pyrrolidin-1-yl-propoxy)-pyridin-3-yl]-1H-pyrrol-
o[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2235), [0307]
Propane-1-sulfonic acid
(2,4-difluoro-3-{5-[6-(3-morpholin-4-yl-propoxy)-pyridin-3-yl]-1H-pyrrolo-
[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2236), [0308]
Propane-1-sulfonic acid
[3-(5-ethynyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
amide (P-2260), and a salt, prodrug, or tautomer thereof.
[0309] In one embodiment of compounds of Formula I, the compound is
a pan Raf inhibitor selected from the group consisting of: [0310]
5-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-pyridine-2-carboxylic acid ethylamide (P-2151),
[0311] Propane-1-sulfonic acid
{3-[5-(6-chloro-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-d-
ifluoro-phenyl}-amide (P-2154), [0312] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(6-fluoro-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-ca-
rbonyl]-phenyl}-amide (P-2155), [0313] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(2-fluoro-6-methyl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyri-
dine-3-carbonyl]-phenyl}-amide (P-2172), [0314] Propane-1-sulfonic
acid
(3-{5-[6-(3-dimethylamino-propoxy)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridin-
e-3-carbonyl}-2,4-difluoro-phenyl)-amide (P-2178), [0315]
5-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-pyridine-2-carboxylic acid methylamide (P-2180),
[0316]
5-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-pyridine-2-carboxylic acid cyclopropylamide (P-2181),
[0317] Propane-1-sulfonic acid
{3-[5-(2,6-dimethoxy-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]--
2,4-difluoro-phenyl}-amide (P-2184), [0318] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(6-methylsulfanyl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyrid-
ine-3-carbonyl]-phenyl}-amide (P-2187), [0319] Propane-1-sulfonic
acid
{2,4-difluoro-3-[5-(5-methanesulfonyl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyri-
dine-3-carbonyl]-phenyl}-amide (P-2188), [0320]
N-(5-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-
-b]pyridin-5-yl}-pyridin-2-yl)-acetamide (P-2193), [0321]
Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(6-methyl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-ca-
rbonyl]-phenyl}-amide (P-2213), [0322] Propane-1-sulfonic acid
{3-[5-(6-amino-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-di-
fluoro-phenyl}-amide (P-2214), [0323]
5-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-pyridine-2-carboxylic acid amide (P-2220), [0324]
Propane-1-sulfonic acid
(3-{5-[6-(3-diethylamino-prop-1-ynyl)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyri-
dine-3-carbonyl}-2,4-difluoro-phenyl)-amide (P-2222), [0325]
Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(6-propyl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-ca-
rbonyl]-phenyl}-amide (P-2224), [0326] Propane-1-sulfonic acid
(2,4-difluoro-3-{5-[6-(3-methoxy-propyl)-pyridin-3-yl]-1H-pyrrolo[2,3-b]p-
yridine-3-carbonyl}-phenyl)-amide (P-2226), [0327]
Propane-1-sulfonic acid
{3-[5-(6-dimethylamino-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl-
]-2,4-difluoro-phenyl}-amide (P-2229), [0328] Propane-1-sulfonic
acid
{2,4-difluoro-3-[5-(6-pyrrolidin-1-yl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyri-
dine-3-carbonyl]-phenyl}-amide (P-2231), [0329] Propane-1-sulfonic
acid
(2,4-difluoro-3-{5-[6-(2-morpholin-4-yl-ethoxy)-pyridin-3-yl]-1H-pyrrolo[-
2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2232), [0330]
Propane-1-sulfonic acid
(2,4-difluoro-3-{5-[6-(2-pyrrolidin-1-yl-ethoxy)-pyridin-3-yl]-1H-pyrrolo-
[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2233), [0331]
Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(6-hydroxy-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-c-
arbonyl]-phenyl}-amide (P-2234), [0332] Propane-1-sulfonic acid
(2,4-difluoro-3-{5-[6-(3-pyrrolidin-1-yl-propoxy)-pyridin-3-yl]-1H-pyrrol-
o[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2235), [0333]
Propane-1-sulfonic acid
(2,4-difluoro-3-{5-[6-(3-morpholin-4-yl-propoxy)-pyridin-3-yl]-1H-pyrrolo-
[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2236), and a salt,
prodrug, or tautomer thereof.
[0334] In one embodiment of compounds of Formula I, the compound is
a pan Raf inhibitor selected from the group consisting of: [0335]
Propane-1-sulfonic acid
[2,4-difluoro-3-(5-pyrimidin-5-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-p-
henyl]-amide (P-2162), [0336] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(2-methylsulfanyl-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyr-
idine-3-carbonyl]-phenyl}-amide (P-2189), [0337] Propane-1-sulfonic
acid
{3-[5-(2-dimethylamino-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbon-
yl]-2,4-difluoro-phenyl}-amide (P-2196), [0338] Propane-1-sulfonic
acid
{2,4-difluoro-3-[5-(2-morpholin-4-yl-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyr-
idine-3-carbonyl]-phenyl}-amide (P-2197), [0339] Propane-1-sulfonic
acid
{3-[5-(2,4-dimethoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl-
]-2,4-difluoro-phenyl}-amide (P-2199), [0340] Propane-1-sulfonic
acid
(3-{5-[2-(3-dimethylamino-propoxy)-pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyrid-
ine-3-carbonyl}-2,4-difluoro-phenyl)-amide (P-2203), [0341]
Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(2-methyl-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3--
carbonyl]-phenyl}-amide (P-2211), [0342] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(2-pyrrolidin-1-yl-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]py-
ridine-3-carbonyl]-phenyl}-amide (P-2219), [0343]
Propane-1-sulfonic acid
{2-fluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-car-
bonyl]-phenyl}-amide (P-2407), [0344] Propane-1-sulfonic acid
{3-[5-(2-dimethylamino-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbon-
yl]-2-fluoro-phenyl}-amide (P-2408), and a salt, prodrug, or
tautomer thereof.
[0345] In one embodiment of compounds of Formula I, the compound is
a pan Raf inhibitor selected from the group consisting of: [0346]
Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl-
]-phenyl}-amide (P-2174), [0347] Propane-1-sulfonic acid
(2,4-difluoro-3-{5-[1-(2-morpholin-4-yl-ethyl)-1H-pyrazol-4-yl]-1H-pyrrol-
o[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2177), [0348]
Propane-1-sulfonic acid
{3-[5-(1-benzyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,-
4-difluoro-phenyl}-amide (P-2190), [0349] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(2-fluoro-pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-ca-
rbonyl]-phenyl}-amide (P-2192), [0350] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(3-methoxy-prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridine-3-ca-
rbonyl]-phenyl}-amide (P-2239), [0351] Propane-1-sulfonic acid
{3-[5-(3-diethylamino-prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]--
2,4-difluoro-phenyl}-amide (P-2241), [0352] Propane-1-sulfonic acid
[3-(5-ethynyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
amide (P-2260), [0353] 2-Methyl-propane-1-sulfonic acid
{2,4-difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2299), and a salt, prodrug, or tautomer
thereof.
[0354] In one embodiment of compounds of Formula I, the compound is
a pan Raf inhibitor selected from the group consisting of: [0355]
N-(4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-
-b]pyridin-5-yl}-phenyl)-acetamide (P-2161), [0356]
Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(4-methanesulfonylamino-phenyl)-1H-pyrrolo[2,3-b]-
pyridine-3-carbonyl]-phenyl}-amide (P-2165), [0357]
Propane-1-sulfonic acid
(2,4-difluoro-3-{5-[4-(morpholine-4-sulfonyl)-phenyl]-1H-pyrrolo[2,3-
-b]pyridine-3-carbonyl}-phenyl)-amide (P-2166), [0358]
4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-N-methyl-benzene sulfonamide (P-2167), [0359]
N-Cyclopropyl-4-{3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H--
pyrrolo[2,3-b]pyridin-5-yl}-benzenesulfonamide (P-2168), [0360]
Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(4-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2183), [0361]
4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-N,N-dimethyl-benzene sulfonamide (P-2185), [0362]
4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-benzenesulfonamide (P-2194), [0363]
Propane-1-sulfonic acid
{3-[5-(4-ethanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-
-difluoro-phenyl}-amide (P-2218), [0364] Propane-1-sulfonic acid
(2,4-difluoro-3-{5-[4-(propane-2-sulfonyl)-phenyl]-1H-pyrrolo[2,3-b]pyrid-
ine-3-carbonyl}-phenyl)-amide (P-2223), [0365] Propane-1-sulfonic
acid
{2,4-difluoro-3-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2228), and a salt, prodrug, or tautomer
thereof.
[0366] In one embodiment of compounds of Formula I, the compound is
a pan Raf inhibitor selected from the group consisting of: [0367]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-2,6-difluoro-benzenesulfonamide (P-2003), [0368]
N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-
-2,6-difluoro-benzenesulfonamide (P-2024), [0369]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2,6-difluoro-benzenesulfonamide (P-2029), [0370]
N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-2,6-difluoro-benzenesulfonamide (P-2033), [0371]
N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2,6-difluoro-benzenesulfonamide (P-2037), [0372]
N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-
-3-carbonyl]-phenyl}-2,6-difluoro-benzenesulfonamide (P-2043),
[0373]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-2,6--
difluoro-benzenesulfonamide (P-2054), and a salt, prodrug, or
tautomer thereof.
[0374] In one embodiment of compounds of Formula I, the compound is
a pan Raf inhibitor selected from the group consisting of: [0375]
N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-
-3-fluoro-benzenesulfonamide (P-2016), [0376]
N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-3-fluoro-benzenesulfonamide (P-2019), [0377]
N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-3-fluoro-benzenesulfonamide (P-2023), [0378]
N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
3-fluoro-benzenesulfonamide (P-2039), [0379]
N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-
-3-carbonyl]-phenyl}-3-fluoro-benzenesulfonamide (P-2045), [0380]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-3-fl-
uoro-benzenesulfonamide (P-2053), and a salt, prodrug, or tautomer
thereof.
[0381] In one embodiment of compounds of Formula I, the compound is
a pan Raf inhibitor selected from the group consisting of: [0382]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-2,5-difluoro-benzenesulfonamide (P-2002), [0383]
N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-2,5-difluoro-benzenesulfonamide (P-2010), [0384]
N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-
-2,5-difluoro-benzenesulfonamide (P-2015), [0385]
N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-2,5-difluoro-benzenesulfonamide (P-2018), [0386]
N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-2,5-difluoro-benzenesulfonamide (P-2022), [0387]
N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2,5-difluoro-benzenesulfonamide (P-2036), [0388]
N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-
-3-carbonyl]-phenyl}-2,5-difluoro-benzene sulfonamide (P-2042),
[0389]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-2,5--
difluoro-benzenesulfonamide (P-2052), and a salt, prodrug, or
tautomer thereof.
[0390] In one embodiment of compounds of Formula I, the compound is
a pan Raf inhibitor selected from the group consisting of: [0391]
N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-2-fluoro-benzenesulfonamide (P-2009), [0392]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2-fluoro-benzenesulfonamide (P-2011), [0393]
N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-
-2-fluoro-benzenesulfonamide (P-2014), [0394]
N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-2-fluoro-benzenesulfonamide (P-2017), [0395]
N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2-fluoro-benzenesulfonamide (P-2020), [0396]
N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-2-fluoro-benzenesulfonamide (P-2021), [0397]
N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-
-3-carbonyl]-phenyl}-2-fluoro-benzenesulfonamide (P-2041), [0398]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-2-fl-
uoro-benzenesulfonamide (P-2051), and a salt, prodrug, or tautomer
thereof.
[0399] In one embodiment of compounds of Formula I, the compound is
a pan Raf inhibitor selected from the group consisting of: [0400]
Pyridine-3-sulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2069), [0401] Pyridine-3-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2071), [0402] Pyridine-3-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2072), [0403] Pyridine-3-sulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2073), [0404] Pyridine-3-sulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2074), [0405] Pyridine-3-sulfonic acid
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2077), [0406] Pyridine-3-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2086), and a salt, prodrug, or tautomer thereof.
[0407] In one embodiment of compounds of Formula I, the compound is
a pan Raf inhibitor selected from the group consisting of: [0408]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
benzene sulfonamide (P-2046), [0409]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-benz-
ene sulfonamide (P-2056), and a salt, prodrug, or tautomer
thereof.
[0410] In a tenth aspect, compositions are provided that include a
therapeutically effective amount of any one or more compound(s) as
described herein and at least one pharmaceutically acceptable
carrier, excipient, and/or diluent, including combinations of any
two or more compounds as described herein. The composition can
further include a plurality of different pharmacologically active
compounds, which can include a plurality of compounds as described
herein. In certain embodiments, the composition can include any one
or more compound(s) as described herein along with one or more
compounds that are therapeutically effective for the same disease
indication. In one embodiment, the composition includes any one or
more compound(s) as described herein along with one or more
compounds that are therapeutically effective for the same disease
indication, wherein the compounds have a synergistic effect on the
disease indication. In one embodiment, the composition includes any
one or more compound(s) as described herein effective in treating a
cancer and one or more other compounds that are effective in
treating the same cancer, further wherein the compounds are
synergistically effective in treating the cancer.
[0411] In an eleventh aspect, methods are provided for treating a
disease or condition mediated by one or more Raf kinases (including
A-Raf, B-Raf, and c-Raf-1) including mutations thereof, in a
subject in need thereof by administering to the subject an
effective amount of a composition including any one or more
compound(s) as described herein. In one embodiment, the invention
provides methods for treating a disease or condition mediated by
one or more Raf kinases, including mutations thereof, by
administering to the subject an effective amount of a composition
including any one or more compound(s) as described herein in
combination with one or more other suitable therapies for treating
the disease.
[0412] In a twelfth aspect, methods are provided for treating a
disease or condition mediated by A-Raf kinase, including any
mutations thereof, in a subject in need thereof by administering to
the subject an effective amount of a composition including any one
or more compound(s) as described herein. In one embodiment, the
invention provides methods for treating a disease or condition
mediated by A-Raf kinase, including any mutations thereof, by
administering to the subject an effective amount of a composition
including any one or more compound(s) as described herein in
combination with one or more other suitable therapies for treating
the disease.
[0413] In a thirteenth aspect, methods are provided for treating a
disease or condition mediated by B-Raf kinase, including any
mutations thereof, in a subject in need thereof by administering to
the subject an effective amount of a composition including any one
or more compound(s) as described herein. In one embodiment, the
invention provides methods for treating a disease or condition
mediated by B-Raf kinase, including any mutations thereof, by
administering to the subject an effective amount of a composition
including any one or more compound(s) as described herein in
combination with one or more other suitable therapies for treating
the disease.
[0414] In a fourteenth aspect, methods are provided for treating a
cancer disease or condition mediated by B-Raf V600E mutant kinase,
in a subject in need thereof by administering to the subject an
effective amount of a composition including any one or more
compound(s) of the invention as described herein. In one
embodiment, the invention provides methods for treating a disease
or condition mediated by B-Raf V600E mutant kinase, by
administering to the subject an effective amount of a composition
including any one or more compound(s) as described herein in
combination with one or more other suitable therapies for treating
the disease. In one embodiment, the invention provides methods for
treating a cancer mediated by B-Raf V600E mutant by administering
to the subject an effective amount of a composition including any
one or more compound(s) as described herein. In one embodiment, the
invention provides methods for treating a cancer mediated by B-Raf
V600E mutant by administering to the subject an effective amount of
a composition including any one or more compound(s) as described
herein in combination with one or more suitable anticancer
therapies, such as one or more chemotherapeutic drugs.
[0415] In a fifteenth aspect, methods are provided for treating a
disease or condition mediated by c-Raf-1 kinase, including any
mutations thereof, in a subject in need thereof by administering to
the subject an effective amount of a composition including any one
or more compound(s) as described herein. In one embodiment, the
invention provides methods for treating a disease or condition
mediated by c-Raf-1 kinase, including any mutations thereof, by
administering to the subject an effective amount of a composition
including any one or more compound(s) as described herein in
combination with one or more other suitable therapies for treating
the disease.
[0416] In a sixteenth aspect, methods are provided for treating a
disease or condition mediated by a Ras mutant-activated Raf kinase,
in a subject in need thereof by administering to the subject an
effective amount of a composition including any one or more
compound(s) as described herein. In one embodiment, the invention
provides methods for treating a disease or condition mediated by a
Ras mutant-activated Raf kinase, by administering to the subject an
effective amount of a composition including any one or more
compound(s) as described herein in combination with one or more
other suitable therapies for treating the disease.
[0417] In a seventeenth aspect, methods are provided for treating a
cancer in a subject in need thereof by administering to the subject
an effective amount of a composition including any one or more
compound(s) as described herein. In one embodiment, the invention
provides a method of treating a cancer in a subject in need thereof
by administering to the subject an effective amount of a
composition including any one or more compound(s) as described
herein in combination with one or more other therapies or medical
procedures effective in treating the cancer. Other therapies or
medical procedures include suitable anticancer therapy (e.g. drug
therapy, vaccine therapy, gene therapy, photodynamic therapy) or
medical procedure (e.g. surgery, radiation treatment, hyperthermia
heating, bone marrow or stem cell transplant). In one embodiment,
the one or more suitable anticancer therapies or medical procedures
is selected from treatment with a chemotherapeutic agent (e.g.
chemotherapeutic drug), radiation treatment (e.g. x-ray,
.gamma.-ray, or electron, proton, neutron, or a particle beam),
hyperthermia heating (e.g. microwave, ultrasound, radiofrequency
ablation), Vaccine therapy (e.g. AFP gene hepatocellular carcinoma
vaccine, AFP adenoviral vector vaccine, AG-858, allogeneic
GM-CSF-secretion breast cancer vaccine, dendritic cell peptide
vaccines), gene therapy (e.g. Ad5CMV-p53 vector, adenovector
encoding MDA7, adenovirus 5-tumor necrosis factor alpha),
photodynamic therapy (e.g. aminolevulinic acid, motexafin
lutetium), surgery, or bone marrow and stem cell
transplantation.
[0418] In an eighteenth aspect, methods are provided for treating a
cancer in a subject in need thereof by administering to the subject
an effective amount of a composition including any one or more
compound(s) as described herein, in combination with one or more
suitable chemotherapeutic agents. In one embodiment, the one or
more suitable chemotherapeutic agents is selected from an
alkylating agent, including, but not limited to, adozelesin,
altretamine, bendamustine, bizelesin, busulfan, carboplatin,
carboquone, carmofur, carmustine, chlorambucil, cisplatin,
cyclophosphamide, dacarbazine, estramustine, etoglucid,
fotemustine, hepsulfam, ifosfamide, improsulfan, irofulven,
lomustine, mannosulfan, mechlorethamine, melphalan, mitobronitol,
nedaplatin, nimustine, oxaliplatin, piposulfan, prednimustine,
procarbazine, ranimustine, satraplatin, semustine, streptozocin,
temozolomide, thiotepa, treosulfan, triaziquone,
triethylenemelamine, triplatin tetranitrate, trofosphamide, and
uramustine; an antibiotic, including, but not limited to,
aclarubicin, amrubicin, bleomycin, dactinomycin, daunorubicin,
doxorubicin, elsamitrucin, epirubicin, idarubicin, menogaril,
mitomycin, neocarzinostatin, pentostatin, pirarubicin, plicamycin,
valrubicin, and zorubicin; an antimetabolite, including, but not
limited to, aminopterin, azacitidine, azathioprine, capecitabine,
cladribine, clofarabine, cytarabine, decitabine, floxuridine,
fludarabine, 5-fluorouracil, gemcitabine, hydroxyurea,
mercaptopurine, methotrexate, nelarabine, pemetrexed, azathioprine,
raltitrexed, tegafur-uracil, thioguanine, trimethoprim,
trimetrexate, and vidarabine; an immunotherapy, including, but not
limited to, alemtuzumab, bevacizumab, cetuximab, galiximab,
gemtuzumab, panitumumab, pertuzumab, rituximab, tositumomab,
trastuzumab, 90 Y ibritumomab tiuxetan, ipilimumab, and
tremelimumab; a hormone or hormone antagonist, including, but not
limited to, anastrozole, androgens, buserelin, diethylstilbestrol,
exemestane, flutamide, fulvestrant, goserelin, idoxifene,
letrozole, leuprolide, magestrol, raloxifene, tamoxifen, and
toremifene; a taxane, including, but not limited to, DJ-927,
docetaxel, TPI 287, larotaxel, ortataxel, paclitaxel,
DHA-paclitaxel, and tesetaxel; a retinoid, including, but not
limited to, alitretinoin, bexarotene, fenretinide, isotretinoin,
and tretinoin; an alkaloid, including, but not limited to,
demecolcine, homoharringtonine, vinblastine, vincristine,
vindesine, vinflunine, and vinorelbine; an antiangiogenic agent,
including, but not limited to, AE-941 (GW786034, Neovastat),
ABT-510, 2-methoxyestradiol, lenalidomide, and thalidomide; a
topoisomerase inhibitor, including, but not limited to, amsacrine,
belotecan, edotecarin, etoposide, etoposide phosphate, exatecan,
irinotecan (also active metabolite SN-38
(7-ethyl-10-hydroxy-camptothecin)), lucanthone, mitoxantrone,
pixantrone, rubitecan, teniposide, topotecan, and
9-aminocamptothecin; a kinase inhibitor, including, but not limited
to, axitinib (AG 013736), dasatinib (BMS 354825), erlotinib,
gefitinib, flavopiridol, imatinib mesylate, lapatinib, motesanib
diphosphate (AMG 706), nilotinib (AMN107), seliciclib, sorafenib,
sunitinib malate, AEE-788, BMS-599626, UCN-01
(7-hydroxystaurosporine), and vatalanib; a targeted signal
transduction inhibitor including, but not limited to bortezomib,
geldanamycin, and rapamycin; a biological response modifier,
including, but not limited to, imiquimod, interferon-.alpha., and
interleukin-2; and other chemotherapeutics, including, but not
limited to 3-AP (3-amino-2-carboxyaldehyde thiosemicarbazone),
altrasentan, aminoglutethimide, anagrelide, asparaginase,
bryostatin-1, cilengitide, elesclomol, eribulin mesylate (E7389),
ixabepilone, lonidamine, masoprocol, mitoguanazone, oblimersen,
sulindac, testolactone, tiazofurin, mTOR inhibitors (e.g.
temsirolimus, everolimus, deforolimus), PI3K inhibitors (e.g.
BEZ235, GDC-0941, XL147, XL765), Cdk4 inhibitors (e.g. PD-332991),
Akt inhibitors, Hsp90 inhibitors (e.g. tanespimycin) and
farnesyltransferase inhibitors (e.g. tipifarnib). Preferably, the
method of treating a cancer involves administering to the subject
an effective amount of a composition including any one or more
compound(s) as described herein in combination with a
chemotherapeutic agent selected from capecitabine, 5-fluorouracil,
carboplatin, dacarbazine, gefitinib, oxaliplatin, paclitaxel,
SN-38, temozolomide, vinblastine, bevacizumab, cetuximab,
interferon-.alpha., interleukin-2, or erlotinib.
[0419] In a nineteenth aspect, methods are provided for treating a
disease or condition in a subject in need thereof, by administering
to the subject a therapeutically effective amount of any one or
more compound(s) as described herein, a prodrug of such compound,
or a pharmaceutically acceptable salt of such compound or prodrug,
or a pharmaceutically acceptable formulation of such compound or
prodrug. The compound can be alone or can be part of a composition.
In one embodiment, methods are provided for treating a disease or
condition in a subject, by administering to the subject a
therapeutically effective amount of any one or more compound(s) as
described herein, a prodrug of such compound, a pharmaceutically
acceptable salt of such compound or prodrug, or a pharmaceutically
acceptable formulation of such compound or prodrug in combination
with one or more other suitable therapies for the disease or
condition.
[0420] In a twentieth aspect, the invention provides kits that
include any one or more compound(s) or composition(s) thereof as
described herein. In some embodiments, the compound or composition
is packaged, e.g., in a vial, bottle, flask, which may be further
packaged, e.g., within a box, envelope, or bag; the compound or
composition is approved by the U.S. Food and Drug Administration or
similar regulatory agency for administration to a mammal, e.g., a
human; the compound or composition is approved for administration
to a mammal, e.g., a human, for a protein kinase mediated disease
or condition; the invention kit may include written instructions
for use and/or other indication that the compound or composition is
suitable or approved for administration to a mammal, e.g., a human,
for a Raf protein kinase-mediated disease or condition; and the
compound or composition may be packaged in unit dose or single dose
form, e.g., single dose pills, capsules, or the like.
[0421] In aspects and embodiments involving treatment of a disease
or condition with any one or more compound(s) as described herein,
the invention provides methods for treating an A-Raf-mediated,
B-Raf-mediated and/or c-Raf-1-mediated disease or condition in a
subject in need thereof, e.g., a disease or condition characterized
by abnormal A-Raf, B-Raf, and/or c-Raf-1 activity (e.g. kinase
activity). In some embodiments, invention methods may involve
administering to the subject suffering from or at risk of an
A-Raf-mediated, B-Raf-mediated and/or c-Raf-1-mediated disease or
condition an effective amount of any one or more Raf inhibitor(s)
as described herein. In one embodiment, the A-Raf-mediated,
B-Raf-mediated, and/or c-Raf-1-mediated disease is selected from
the group consisting of neurologic diseases, including, but not
limited to, multi-infarct dementia, head injury, spinal cord
injury, Alzheimer's disease (AD), Parkinson's disease, seizures and
epilepsy; neoplastic diseases including, but not limited to,
melanoma, glioma, glioblastoma multiforme, pilocytic astrocytoma,
sarcoma, carcinoma (e.g. gastrointestinal, liver, biliary tract
(e.g. bile duct, cholangiocarcinoma), colorectal, lung,
gallbladder, breast, pancreatic, thyroid, renal, ovarian,
adrenocortical, prostate), lymphoma (e.g. histiocytic lymphoma)
neurofibromatosis, gastrointestinal stromal tumors, acute myeloid
leukemia, myelodysplastic syndrome, leukemia, tumor angiogenesis,
neuroendocrine tumors such as medullary thyroid cancer, carcinoid,
small cell lung cancer, Kaposi's sarcoma, and pheochromocytoma;
pain of neuropathic or inflammatory origin, including, but not
limited to, acute pain, chronic pain, cancer-related pain, and
migraine; cardiovascular diseases including, but not limited to,
heart failure, ischemic stroke, cardiac hypertrophy, thrombosis
(e.g. thrombotic microangiopathy syndromes), atherosclerosis, and
reperfusion injury; inflammation and/or proliferation including,
but not limited to, psoriasis, eczema, arthritis and autoimmune
diseases and conditions, osteoarthritis, endometriosis, scarring,
vascular restenosis, fibrotic disorders, rheumatoid arthritis,
inflammatory bowel disease (IBD); immunodeficiency diseases,
including, but not limited to, organ transplant rejection, graft
versus host disease, and Kaposi's sarcoma associated with HIV;
renal, cystic, or prostatic diseases, including, but not limited
to, diabetic nephropathy, polycystic kidney disease,
nephrosclerosis, glomerulonephritis, prostate hyperplasia,
polycystic liver disease, tuberous sclerosis, Von Hippel Lindau
disease, medullary cystic kidney disease, nephronophthisis, and
cystic fibrosis; metabolic disorders, including, but not limited
to, obesity; infection, including, but not limited to Helicobacter
pylori, Hepatitis and Influenza viruses, fever, HIV and sepsis;
pulmonary diseases including, but not limited to, chronic
obstructive pulmonary disease (COPD) and acute respiratory distress
syndrome (ARDS); genetic developmental diseases, including, but not
limited to, Noonan's syndrome, Costello syndrome,
(faciocutaneoskeletal syndrome), LEOPARD syndrome,
cardio-faciocutaneous syndrome (CFC), and neural crest syndrome
abnormalities causing cardiovascular, skeletal, intestinal, skin,
hair and endocrine diseases; and diseases associated with muscle
regeneration or degeneration, including, but not limited to,
sarcopenia, muscular dystrophies (including, but not limited to,
Duchenne, Becker, Emery-Dreifuss, Limb-Girdle, Facioscapulohumeral,
Myotonic, Oculopharyngeal, Distal and Congenital Muscular
Dystrophies), motor neuron diseases (including, but not limited to,
amyotrophic lateral sclerosis, infantile progressive spinal
muscular atrophy, intermediate spinal muscular atrophy, juvenile
spinal muscular atrophy, spinal bulbar muscular atrophy, and adult
spinal muscular atrophy), inflammatory myopathies (including, but
not limited to, dermatomyositis, polymyositis, and inclusion body
myositis), diseases of the neuromuscular junction (including, but
not limited to, myasthenia gravis, Lambert-Eaton syndrome, and
congenital myasthenic syndrome), myopathies due to endocrine
abnormalities (including, but not limited to, hyperthyroid myopathy
and hypothyroid myopathy) diseases of peripheral nerve (including,
but not limited to, Charcot-Marie-Tooth disease, Dejerine-Sottas
disease, and Friedreich's ataxia), other myopathies (including, but
not limited to, myotonia congenita, paramyotonia congenita, central
core disease, nemaline myopathy, myotubular myopathy, and periodic
paralysis), and metabolic diseases of muscle (including, but not
limited to, phosphorylase deficiency, acid maltase deficiency,
phosphofructokinase deficiency, debrancher enzyme deficiency,
mitochondrial myopathy, carnitine deficiency, carnitine palmatyl
transferase deficiency, phosphoglycerate kinase deficiency,
phosphoglycerate mutase deficiency, lactate dehydrogenase
deficiency, and myoadenylate deaminase deficiency). In one
embodiment, the disease or condition is selected from the group
consisting of melanoma, glioma, glioblastoma multiforme, pilocytic
astrocytoma, sarcoma, liver cancer, biliary tract cancer,
colorectal cancer, lung cancer, gallbladder cancer, breast cancer,
pancreatic cancer, thyroid cancer, renal cancer, ovarian cancer,
adrenocortical cancer, prostate cancer, histiocytic lymphoma,
neurofibromatosis, gastrointestinal stromal tumors, acute myeloid
leukemia, myelodysplastic syndrome, leukemia, tumor angiogenesis,
medullary thyroid cancer, carcinoid, small cell lung cancer,
Kaposi's sarcoma, and pheochromocytoma. In one embodiment, the
disease or condition is selected from the group consisting of
melanoma, glioma, glioblastoma multiforme, pilocytic astrocytoma,
colorectal cancer, thyroid cancer, lung cancer, ovarian cancer,
prostate cancer, liver cancer, gallbladder cancer, gastrointestinal
stromal tumors, and biliary tract cancer. In one embodiment, the
disease or condition is selected from the group consisting of
melanoma, glioma, colorectal cancer, thyroid cancer, lung cancer,
ovarian cancer, prostate cancer, and biliary tract cancer. In one
embodiment, the disease or condition is selected from the group
consisting of melanoma, colorectal cancer, thyroid cancer, ovarian
cancer and biliary tract cancer.
[0422] In aspects and embodiments involving treatment of a disease
or condition with any one or more compound(s) as described herein,
the invention provides methods for treating a Ras mutant-activated
Raf-mediated disease or condition in a subject in need thereof,
e.g., a disease or condition characterized by Raf kinase activated
by a Ras mutation. In some embodiments, invention methods may
involve administering to the subject suffering from or at risk of
Ras mutant-activated Raf-mediated disease or condition an effective
amount of any one or more pan Raf inhibitor(s) as described herein.
In one embodiment, the Ras mutant-activated Raf-mediated disease or
condition is selected from the group consisting of melanoma, liver
cancer, biliary tract cancer, colorectal cancer, lung cancer,
bladder cancer, breast cancer, pancreatic cancer, thyroid cancer,
kidney cancer, ovarian cancer, cervical cancer, endometrial cancer,
and acute myeloid leukemia.
[0423] In aspects and embodiments involving treatment of a disease
or condition with any one or more compound(s) as described herein,
methods are provided for treating a disease or condition in a
subject in need thereof, wherein the disease or condition is
selected from the group consisting of polycystic kidney disease,
acute pain, and chronic pain.
[0424] In aspects and embodiments involving treatment of a disease
or condition with any one or more compound(s) as described herein,
methods are provided for treating a disease or condition in a
subject in need thereof, wherein the disease or condition is a
cancer. In one embodiment, the cancer is selected from the group
consisting of melanoma, glioma, glioblastoma multiforme, pilocytic
astrocytoma, colorectal cancer, thyroid cancer, lung cancer,
ovarian cancer, prostate cancer, liver cancer, gallbladder cancer,
gastrointestinal stromal tumors, and biliary tract cancer. In one
embodiment, the cancer is selected from the group consisting of
melanoma, liver cancer, biliary tract cancer, colorectal cancer,
lung cancer, bladder cancer, breast cancer, pancreatic cancer,
thyroid cancer, kidney cancer, ovarian cancer, cervical cancer,
endometrial cancer, and acute myeloid leukemia.
[0425] In aspects and embodiments involving treatment of a disease
or condition with any one or more compound(s) as described herein,
methods are provided for treating a cancer in a subject in need
thereof. In some embodiments, methods may involve administering to
the subject suffering from or at risk of a cancer an effective
amount of any one or more pan Raf inhibitor(s) as described herein,
wherein the cancer is selected from the group consisting of
melanoma, glioma, glioblastoma, pilocytic astrocytoma, liver
cancer, biliary tract cancer, colorectal cancer, lung cancer,
bladder cancer, gallbladder cancer, breast cancer, pancreatic
cancer, thyroid cancer, kidney cancer, ovarian cancer,
adrenocortical cancer, prostate cancer, cervical cancer,
endometrial cancer, gastrointestinal stromal tumors, medullary
thyroid cancer, tumor angiogenesis, acute myeloid leukemia, chronic
myelomonocytic leukemia, childhood acute lymphoblastic leukemia,
plasma cell leukemia, and multiple myeloma. In one embodiment, the
cancer is selected from the group consisting of melanoma, glioma,
glioblastoma multiforme, pilocytic astrocytoma, colorectal cancer,
thyroid cancer, lung cancer, ovarian cancer, prostate cancer, liver
cancer, gallbladder cancer, gastrointestinal stromal tumors, and
biliary tract cancer. In one embodiment, the cancer is selected
from the group consisting of melanoma, liver cancer, biliary tract
cancer, colorectal cancer, lung cancer, bladder cancer, breast
cancer, pancreatic cancer, thyroid cancer, kidney cancer, ovarian
cancer, cervical cancer, endometrial cancer, and acute myeloid
leukemia.
[0426] In a twenty-first aspect, compounds as described herein can
be used in the preparation of a medicament for the treatment of an
A-Raf-mediated, B-Raf-mediated or c-Raf-1-mediated disease or
condition selected from the group consisting of neurologic
diseases, including, but not limited to, multi-infarct dementia,
head injury, spinal cord injury, Alzheimer's disease (AD),
Parkinson's disease, seizures and epilepsy; neoplastic diseases
including, but not limited to, melanoma, glioma, glioblastoma
multiforme, pilocytic astrocytoma, sarcoma, carcinoma (e.g.
gastrointestinal, liver, biliary tract (e.g. bile duct,
cholangiocarcinoma), colorectal, lung, gallbladder, breast,
pancreatic, thyroid, renal, ovarian, adrenocortical, prostate),
lymphoma (e.g. histiocytic lymphoma) neurofibromatosis,
gastrointestinal stromal tumors, acute myeloid leukemia,
myelodysplastic syndrome, leukemia, tumor angiogenesis,
neuroendocrine tumors such as medullary thyroid cancer, carcinoid,
small cell lung cancer, Kaposi's sarcoma, and pheochromocytoma;
pain of neuropathic or inflammatory origin, including, but not
limited to, acute pain, chronic pain, cancer-related pain, and
migraine; cardiovascular diseases including, but not limited to,
heart failure, ischemic stroke, cardiac hypertrophy, thrombosis
(e.g. thrombotic microangiopathy syndromes), atherosclerosis, and
reperfusion injury; inflammation and/or proliferation including,
but not limited to, psoriasis, eczema, arthritis and autoimmune
diseases and conditions, osteoarthritis, endometriosis, scarring,
vascular restenosis, fibrotic disorders, rheumatoid arthritis,
inflammatory bowel disease (IBD); immunodeficiency diseases,
including, but not limited to, organ transplant rejection, graft
versus host disease, and Kaposi's sarcoma associated with HIV;
renal, cystic, or prostatic diseases, including, but not limited
to, diabetic nephropathy, polycystic kidney disease,
nephrosclerosis, glomerulonephritis, prostate hyperplasia,
polycystic liver disease, tuberous sclerosis, Von Hippel Lindau
disease, medullary cystic kidney disease, nephronophthisis, and
cystic fibrosis; metabolic disorders, including, but not limited
to, obesity; infection, including, but not limited to Helicobacter
pylori, Hepatitis and Influenza viruses, fever, HIV and sepsis;
pulmonary diseases including, but not limited to, chronic
obstructive pulmonary disease (COPD) and acute respiratory distress
syndrome (ARDS); genetic developmental diseases, including, but not
limited to, Noonan's syndrome, Costello syndrome,
(faciocutaneoskeletal syndrome), LEOPARD syndrome,
cardio-faciocutaneous syndrome (CFC), and neural crest syndrome
abnormalities causing cardiovascular, skeletal, intestinal, skin,
hair and endocrine diseases; and diseases associated with muscle
regeneration or degeneration, including, but not limited to,
sarcopenia, muscular dystrophies (including, but not limited to,
Duchenne, Becker, Emery-Dreifuss, Limb-Girdle, Facioscapulohumeral,
Myotonic, Oculopharyngeal, Distal and Congenital Muscular
Dystrophies), motor neuron diseases (including, but not limited to,
amyotrophic lateral sclerosis, infantile progressive spinal
muscular atrophy, intermediate spinal muscular atrophy, juvenile
spinal muscular atrophy, spinal bulbar muscular atrophy, and adult
spinal muscular atrophy), inflammatory myopathies (including, but
not limited to, dermatomyositis, polymyositis, and inclusion body
myositis), diseases of the neuromuscular junction (including, but
not limited to, myasthenia gravis, Lambert-Eaton syndrome, and
congenital myasthenic syndrome), myopathies due to endocrine
abnormalities (including, but not limited to, hyperthyroid myopathy
and hypothyroid myopathy) diseases of peripheral nerve (including,
but not limited to, Charcot-Marie-Tooth disease, Dejerine-Sottas
disease, and Friedreich's ataxia), other myopathies (including, but
not limited to, myotonia congenita, paramyotonia congenita, central
core disease, nemaline myopathy, myotubular myopathy, and periodic
paralysis), and metabolic diseases of muscle (including, but not
limited to, phosphorylase deficiency, acid maltase deficiency,
phosphofructokinase deficiency, debrancher enzyme deficiency,
mitochondrial myopathy, carnitine deficiency, carnitine palmatyl
transferase deficiency, phosphoglycerate kinase deficiency,
phosphoglycerate mutase deficiency, lactate dehydrogenase
deficiency, and myoadenylate deaminase deficiency). In one
embodiment, the disease or condition is selected from the group
consisting of melanoma, glioma, glioblastoma multiforme, pilocytic
astrocytoma, sarcoma, liver cancer, biliary tract cancer,
colorectal cancer, lung cancer, gallbladder cancer, breast cancer,
pancreatic cancer, thyroid cancer, renal cancer, ovarian cancer,
adrenocortical cancer, prostate cancer, histiocytic lymphoma,
neurofibromatosis, gastrointestinal stromal tumors, acute myeloid
leukemia, myelodysplastic syndrome, leukemia, tumor angiogenesis,
medullary thyroid cancer, carcinoid, small cell lung cancer,
Kaposi's sarcoma, and pheochromocytoma. In one embodiment, the
disease or condition is selected from the group consisting of
melanoma, glioma, glioblastoma multiforme, pilocytic astrocytoma,
colorectal cancer, thyroid cancer, lung cancer, ovarian cancer,
prostate cancer, liver cancer, gallbladder cancer, gastrointestinal
stromal tumors, and biliary tract cancer. In one embodiment, the
disease or condition is selected from the group consisting of
melanoma, glioma, colorectal cancer, thyroid cancer, lung cancer,
ovarian cancer, prostate cancer, and biliary tract cancer. In one
embodiment, the disease or condition is selected from the group
consisting of melanoma, colorectal cancer, thyroid cancer, ovarian
cancer and biliary tract cancer.
[0427] In a twenty-second aspect, compounds as described herein can
be used in the preparation of a medicament for the treatment of a
Ras mutant-activated Raf-mediated disease or condition selected
from the group consisting of melanoma, liver cancer, biliary tract
cancer, colorectal cancer, lung cancer, bladder cancer, breast
cancer, pancreatic cancer, thyroid cancer, kidney cancer, ovarian
cancer, cervical cancer, endometrial cancer, and acute myeloid
leukemia.
[0428] In a twenty-third aspect, compounds as described herein can
be used in the preparation of a medicament for the treatment of a
disease or condition selected from the group consisting of
polycystic kidney disease, acute pain, and chronic pain.
[0429] In a twenty-fourth aspect, compounds as described herein can
be used in the preparation of a medicament for the treatment of a
disease or condition selected from the group consisting of
melanoma, glioma, glioblastoma multiforme, pilocytic astrocytoma,
colorectal cancer, thyroid cancer, lung cancer, ovarian cancer,
prostate cancer, liver cancer, gallbladder cancer, gastrointestinal
stromal tumors, and biliary tract cancer. In one embodiment, the
disease or condition is selected from the group consisting of
melanoma, glioma, colorectal cancer, thyroid cancer, lung cancer,
ovarian cancer, prostate cancer, and biliary tract cancer.
[0430] In a twenty-fifth aspect, compounds as described herein can
be used in the preparation of a medicament for the treatment of a
disease or condition selected from the group consisting of
melanoma, liver cancer, biliary tract cancer, colorectal cancer,
lung cancer, bladder cancer, breast cancer, pancreatic cancer,
thyroid cancer, kidney cancer, ovarian cancer, cervical cancer,
endometrial cancer, and acute myeloid leukemia. In one embodiment,
the disease or condition is selected from the group consisting of
melanoma, colorectal cancer, thyroid cancer, ovarian cancer and
biliary tract cancer.
[0431] In a twenty-sixth aspect, there are provided compounds as
described herein for the treatment of an A-Raf-mediated,
B-Raf-mediated or c-Raf-1-mediated disease or condition selected
from the group consisting of neurologic diseases, including, but
not limited to, multi-infarct dementia, head injury, spinal cord
injury, Alzheimer's disease (AD), Parkinson's disease, seizures and
epilepsy; neoplastic diseases including, but not limited to,
melanoma, glioma, glioblastoma multiforme, pilocytic astrocytoma,
sarcoma, carcinoma (e.g. gastrointestinal, liver, biliary tract
(e.g. bile duct, cholangiocarcinoma), colorectal, lung,
gallbladder, breast, pancreatic, thyroid, renal, ovarian,
adrenocortical, prostate), lymphoma (e.g. histiocytic lymphoma)
neurofibromatosis, gastrointestinal stromal tumors, acute myeloid
leukemia, myelodysplastic syndrome, leukemia, tumor angiogenesis,
neuroendocrine tumors such as medullary thyroid cancer, carcinoid,
small cell lung cancer, Kaposi's sarcoma, and pheochromocytoma;
pain of neuropathic or inflammatory origin, including, but not
limited to, acute pain, chronic pain, cancer-related pain, and
migraine; cardiovascular diseases including, but not limited to,
heart failure, ischemic stroke, cardiac hypertrophy, thrombosis
(e.g. thrombotic microangiopathy syndromes), atherosclerosis, and
reperfusion injury; inflammation and/or proliferation including,
but not limited to, psoriasis, eczema, arthritis and autoimmune
diseases and conditions, osteoarthritis, endometriosis, scarring,
vascular restenosis, fibrotic disorders, rheumatoid arthritis,
inflammatory bowel disease (IBD); immunodeficiency diseases,
including, but not limited to, organ transplant rejection, graft
versus host disease, and Kaposi's sarcoma associated with HIV;
renal, cystic, or prostatic diseases, including, but not limited
to, diabetic nephropathy, polycystic kidney disease,
nephrosclerosis, glomerulonephritis, prostate hyperplasia,
polycystic liver disease, tuberous sclerosis, Von Hippel Lindau
disease, medullary cystic kidney disease, nephronophthisis, and
cystic fibrosis; metabolic disorders, including, but not limited
to, obesity; infection, including, but not limited to Helicobacter
pylori, Hepatitis and Influenza viruses, fever, HIV and sepsis;
pulmonary diseases including, but not limited to, chronic
obstructive pulmonary disease (COPD) and acute respiratory distress
syndrome (ARDS); genetic developmental diseases, including, but not
limited to, Noonan's syndrome, Costello syndrome,
(faciocutaneoskeletal syndrome), LEOPARD syndrome,
cardio-faciocutaneous syndrome (CFC), and neural crest syndrome
abnormalities causing cardiovascular, skeletal, intestinal, skin,
hair and endocrine diseases; and diseases associated with muscle
regeneration or degeneration, including, but not limited to,
sarcopenia, muscular dystrophies (including, but not limited to,
Duchenne, Becker, Emery-Dreifuss, Limb-Girdle, Facioscapulohumeral,
Myotonic, Oculopharyngeal, Distal and Congenital Muscular
Dystrophies), motor neuron diseases (including, but not limited to,
amyotrophic lateral sclerosis, infantile progressive spinal
muscular atrophy, intermediate spinal muscular atrophy, juvenile
spinal muscular atrophy, spinal bulbar muscular atrophy, and adult
spinal muscular atrophy), inflammatory myopathies (including, but
not limited to, dermatomyositis, polymyositis, and inclusion body
myositis), diseases of the neuromuscular junction (including, but
not limited to, myasthenia gravis, Lambert-Eaton syndrome, and
congenital myasthenic syndrome), myopathies due to endocrine
abnormalities (including, but not limited to, hyperthyroid myopathy
and hypothyroid myopathy) diseases of peripheral nerve (including,
but not limited to, Charcot-Marie-Tooth disease, Dejerine-Sottas
disease, and Friedreich's ataxia), other myopathies (including, but
not limited to, myotonia congenita, paramyotonia congenita, central
core disease, nemaline myopathy, myotubular myopathy, and periodic
paralysis), and metabolic diseases of muscle (including, but not
limited to, phosphorylase deficiency, acid maltase deficiency,
phosphofructokinase deficiency, debrancher enzyme deficiency,
mitochondrial myopathy, carnitine deficiency, carnitine palmatyl
transferase deficiency, phosphoglycerate kinase deficiency,
phosphoglycerate mutase deficiency, lactate dehydrogenase
deficiency, and myoadenylate deaminase deficiency). In one
embodiment, the disease or condition is selected from the group
consisting of melanoma, glioma, glioblastoma multiforme, pilocytic
astrocytoma, sarcoma, liver cancer, biliary tract cancer,
colorectal cancer, lung cancer, gallbladder cancer, breast cancer,
pancreatic cancer, thyroid cancer, renal cancer, ovarian cancer,
adrenocortical cancer, prostate cancer, histiocytic lymphoma,
neurofibromatosis, gastrointestinal stromal tumors, acute myeloid
leukemia, myelodysplastic syndrome, leukemia, tumor angiogenesis,
medullary thyroid cancer, carcinoid, small cell lung cancer,
Kaposi's sarcoma, and pheochromocytoma. In one embodiment, the
disease or condition is selected from the group consisting of
melanoma, glioma, glioblastoma multiforme, pilocytic astrocytoma,
colorectal cancer, thyroid cancer, lung cancer, ovarian cancer,
prostate cancer, liver cancer, gallbladder cancer, gastrointestinal
stromal tumors, and biliary tract cancer. In one embodiment, the
disease or condition is selected from the group consisting of
melanoma, glioma, colorectal cancer, thyroid cancer, lung cancer,
ovarian cancer, prostate cancer, and biliary tract cancer. In one
embodiment, the disease or condition is selected from the group
consisting of melanoma, colorectal cancer, thyroid cancer, ovarian
cancer and biliary tract cancer.
[0432] In a twenty-seventh aspect, there are provided compounds as
described herein for the treatment of a Ras mutant-activated
Raf-mediated disease or condition selected from the group
consisting of melanoma, liver cancer, biliary tract cancer,
colorectal cancer, lung cancer, bladder cancer, breast cancer,
pancreatic cancer, thyroid cancer, kidney cancer, ovarian cancer,
cervical cancer, endometrial cancer, and acute myeloid
leukemia.
[0433] In a twenty-eighth aspect, there are provided compounds as
described herein for the treatment of a disease or condition
selected from the group consisting of polycystic kidney disease,
acute pain, and chronic pain.
[0434] In a twenty-ninth aspect, there are provided compounds as
described herein for the treatment of a disease or condition
selected from the group consisting of melanoma, glioma,
glioblastoma multiforme, pilocytic astrocytoma, colorectal cancer,
thyroid cancer, lung cancer, ovarian cancer, prostate cancer, liver
cancer, gallbladder cancer, gastrointestinal stromal tumors, and
biliary tract cancer. In one embodiment, the disease or condition
is selected from the group consisting of melanoma, glioma,
colorectal cancer, thyroid cancer, lung cancer, ovarian cancer,
prostate cancer, and biliary tract cancer.
[0435] In a thirtieth aspect, there are provided compounds as
described herein for the treatment of a disease or condition
selected from the group consisting of melanoma, liver cancer,
biliary tract cancer, colorectal cancer, lung cancer, bladder
cancer, breast cancer, pancreatic cancer, thyroid cancer, kidney
cancer, ovarian cancer, cervical cancer, endometrial cancer, and
acute myeloid leukemia. In one embodiment, the disease or condition
is selected from the group consisting of melanoma, colorectal
cancer, thyroid cancer, ovarian cancer and biliary tract
cancer.
[0436] Any one or more of compounds as provided herein demonstrate
desirable inhibitory activity on Raf kinases, including desirable
activity profiles within the Raf kinases with selectivity relative
to other kinases. In some embodiments, compounds as provided herein
demonstrate inhibition of proliferation of tumorigenic cell lines
that are driven by a Ras mutation. Compounds further demonstrate
one or more desirable properties, including enhanced
pharmacokinetic properties, greater solubility, lesser Cyp
inhibition, and the like.
[0437] Additional aspects and embodiments will be apparent from the
following Detailed Description and from the claims.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0438] As used herein the following definitions apply unless
clearly indicated otherwise:
[0439] All atoms designated within a Formula or compound described
herein, either within a structure provided, or within the
definitions of variables related to the structure, is intended to
include any isotope thereof, unless clearly indicated to the
contrary. It is understood that for any given atom, the isotopes
may be present essentially in ratios according to their natural
occurrence, or one or more particular atoms may be enhanced with
respect to one or more isotopes using synthetic methods known to
one skilled in the art. Thus, hydrogen includes for example
.sup.1H, .sup.2H, .sup.3H; carbon includes for example .sup.11C,
.sup.12C, .sup.13C, .sup.14C; oxygen includes for example 16O,
.sup.17O, .sup.18O; nitrogen includes for example .sup.13N,
.sup.14N, .sup.15N; sulfur includes for example .sup.32S, .sup.33S,
.sup.34S, .sup.35S, .sup.36S, .sup.37S, .sup.38S; fluoro includes
for example .sup.17F, .sup.18F, .sup.19F; chloro includes for
example .sup.35Cl, .sup.36Cl, .sup.37Cl, .sup.38Cl, .sup.39Cl; and
the like.
[0440] "Halogen" refer to all halogens, that is, chloro (Cl),
fluoro (F), bromo (Br), or iodo (I).
[0441] "Hydroxyl" or "hydroxy" refer to the group --OH.
[0442] "Thiol" refers to the group --SH.
[0443] "Lower alkyl" alone or in combination means an
alkane-derived radical containing from 1 to 6 carbon atoms (unless
specifically defined) that includes a straight chain alkyl or
branched alkyl. The straight chain or branched lower alkyl group is
chemically feasible and attached at any available point to provide
a stable compound. In many embodiments, a lower alkyl is a straight
or branched alkyl group containing from 1-6, 1-4, or 1-2, carbon
atoms, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl,
and the like. A "lower alkyl" may be independently substituted as
described herein, unless indicated otherwise, with one or more,
preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents, wherein
the substituents are as indicated. For example "fluoro substituted
lower alkyl" denotes a lower alkyl group substituted with one or
more fluoro atoms, such as perfluoroalkyl, where preferably the
lower alkyl is substituted with 1, 2, 3, 4 or 5 fluoro atoms, also
1, 2, or 3 fluoro atoms. It is understood that any such
substitutions, or substitution of lower alkyl on another moiety,
are chemically feasible and attached at any available atom to
provide a stable compound.
[0444] "Lower alkenyl" alone or in combination means a straight or
branched hydrocarbon containing 2-6 carbon atoms (unless
specifically defined) and at least one, preferably 1-3, more
preferably 1-2, most preferably one, carbon to carbon double bond.
Carbon to carbon double bonds may be either contained within a
straight chain or branched portion. The straight chain or branched
lower alkenyl group is chemically feasible and attached at any
available point to provide a stable compound. Examples of lower
alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, and
the like. A "lower alkenyl" may be independently substituted as
described herein, unless indicated otherwise, with one or more,
preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents, wherein
the substituents are as indicated. For example "fluoro substituted
lower alkenyl" denotes a lower alkenyl group substituted with one
or more fluoro atoms, where preferably the lower alkenyl is
substituted with 1, 2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3
fluoro atoms. It is understood that any such substitutions, or
substitution of lower alkenyl on another moiety, are chemically
feasible and attached at any available atom to provide a stable
compound.
[0445] "Lower alkynyl" alone or in combination means a straight or
branched hydrocarbon containing 2-6 carbon atoms (unless
specifically defined) containing at least one, preferably one,
carbon to carbon triple bond. The straight chain or branched lower
alkynyl group is chemically feasible and attached at any available
point to provide a stable compound. Examples of alkynyl groups
include ethynyl, propynyl, butynyl, and the like. A "lower alkynyl"
may be independently substituted as described herein, unless
indicated otherwise, with one or more, preferably 1, 2, 3, 4 or 5,
also 1, 2, or 3 substituents, wherein the substituents are as
indicated. For example "fluoro substituted lower alkynyl" denotes a
lower alkynyl group substituted with one or more fluoro atoms,
where preferably the lower alkynyl is substituted with 1, 2, 3, 4
or 5 fluoro atoms, also 1, 2, or 3 fluoro atoms. It is understood
that any such substitutions, or substitution of lower alkynyl on
another moiety, are chemically feasible and attached at any
available atom to provide a stable compound
[0446] "Cycloalkyl" refers to saturated or unsaturated,
non-aromatic monocyclic, bicyclic or tricyclic carbon ring systems
of 3-10, also 3-8, more preferably 3-6, ring members per ring, such
as cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
A "cycloalkyl" may be independently substituted as described
herein, unless indicated otherwise, with one or more, preferably 1,
2, 3, 4 or 5, also 1, 2, or 3 substituents, wherein the
substituents are as indicated. It is understood that any such
substitutions, or substitutions of cycloalkyl on another moiety,
are chemically feasible and attached at any available atom to
provide a stable compound.
[0447] "Heterocycloalkyl" refers to a saturated or unsaturated
non-aromatic cycloalkyl group having from 5 to 10 atoms in which
from 1 to 3 carbon atoms in the ring are replaced by heteroatoms of
O, S or N, and are optionally fused with benzo or heteroaryl of 5-6
ring members. Heterocycloalkyl is also intended to include oxidized
S or N, such as sulfinyl, sulfonyl and N-oxide of a tertiary ring
nitrogen. Heterocycloalkyl is also intended to include compounds in
which a ring carbon may be oxo substituted, i.e. the ring carbon is
a carbonyl group, such as lactones and lactams. The point of
attachment of the heterocycloalkyl ring is at a carbon or nitrogen
atom such that a stable ring is retained. Examples of
heterocycloalkyl groups include, but are not limited to,
morpholino, tetrahydrofuranyl, dihydropyridinyl, piperidinyl,
pyrrolidinyl, pyrrolidonyl, piperazinyl, dihydrobenzofuryl, and
dihydroindolyl. A "heterocycloalkyl" may be independently
substituted as described herein, unless indicated otherwise, with
one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3
substituents, wherein the substituents are as indicated. It is
understood that any such substitutions, or substitutions of
heterocycloalkyl on another moiety, are chemically feasible and
attached at any available atom to provide a stable compound.
[0448] "Aryl" alone or in combination refers to a monocyclic or
bicyclic ring system containing aromatic hydrocarbons such as
phenyl or naphthyl, which may be optionally fused with a cycloalkyl
of preferably 5-7, more preferably 5-6, ring members. An "aryl" may
be independently substituted as described herein, unless indicated
otherwise, with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2,
or 3 substituents, wherein the substituents area as indicated. It
is understood that any such substitutions, or substitutions of aryl
on another moiety, are chemically feasible and attached at any
available atom to provide a stable compound.
[0449] "Heteroaryl" alone or in combination refers to a monocyclic
aromatic ring structure containing 5 or 6 ring atoms, or a bicyclic
aromatic group having 8 to 10 atoms, containing one or more,
preferably 1-4, more preferably 1-3, even more preferably 1-2,
heteroatoms independently selected from the group consisting of O,
S, and N. Heteroaryl is also intended to include oxidized S or N,
such as sulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen.
A carbon or nitrogen atom is the point of attachment of the
heteroaryl ring structure such that a stable compound is provided.
Examples of heteroaryl groups include, but are not limited to,
pyridinyl, pyridazinyl, pyrazinyl, quinoxalyl, indolizinyl,
benzo[b]thienyl, quinazolinyl, purinyl, indolyl, quinolinyl,
pyrimidinyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, thienyl,
isoxazolyl, oxathiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl,
triazolyl, furanyl, benzofuryl, and indolyl. A "heteroaryl" may be
independently substituted as described herein, unless indicated
otherwise, with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2,
or 3 substituents, wherein the substituents are as indicated. It is
understood that any such substitutions, or substitutions of
heteroaryl on another moiety, are chemically feasible and attached
at any available atom to provide a stable compound.
[0450] "Lower alkoxy" denotes the group --OR.sup.a, where R.sup.a
is lower alkyl. A "lower alkoxy" may be independently substituted,
i.e. R.sup.a is lower alkyl substituted with one or more
substituents as indicated herein. Preferably, substitution of lower
alkoxy is with 1, 2, 3, 4, or 5 substituents, also 1, 2, or 3
substituents. For example "fluoro substituted lower alkoxy" denotes
lower alkoxy in which the lower alkyl is substituted with one or
more fluoro atoms, where preferably the lower alkoxy is substituted
with 1, 2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3 fluoro atoms. It
is understood that substitutions on alkoxy, or alkoxy substitution
of other moieties, are chemically feasible and attached at any
available atom to provide a stable compound.
[0451] "Lower alkylthio" denotes the group --SR.sup.b, where
R.sup.b is lower alkyl. A "lower alkylthio" may be independently
substituted, i.e. R.sup.b is lower alkyl substituted with one or
more substituents as indicated herein. Preferably, substitution of
lower alkylthio is with 1, 2, 3, 4, or 5 substituents, also 1, 2,
or 3 substituents. For example "fluoro substituted lower alkylthio"
denotes lower alkylthio in which the lower alkyl is substituted
with one or more fluoro atoms, where preferably the lower alkylthio
is substituted with 1, 2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3
fluoro atoms. It is understood that substitutions on alkylthio, or
alkylthio substitution of other moieties, are chemically feasible
and attached at any available atom to provide a stable
compound.
[0452] "Mono-alkylamino" denotes the group --NHR.sup.c where
R.sup.c is lower alkyl. "Di-alkylamino" denotes the group
--NR.sup.cR.sup.d, where R.sup.c and R.sup.d are independently
lower alkyl. "Cycloalkylamino" denotes the group --NR.sup.eR.sup.f,
where R.sup.e and R.sup.f combine with the nitrogen to form a 5-7
membered heterocycloalkyl, where the heterocycloalkyl may contain
an additional heteroatom within the ring, such as O, N, or S, and
may also be further substituted with one or more lower alkyl.
Examples of 5-7 membered heterocycloalkyl include, but are not
limited to, piperidine, piperazine, 4-methylpiperazine, morpholine,
and thiomorpholine. It is understood that when mono-alkylamino,
di-alkylamino, or cycloalkylamino are substituents on other
moieties, these are chemically feasible and attached at any
available atom to provide a stable compound.
[0453] As used herein, the terms "treat", "treating", "therapy",
"therapies", and like terms refer to the administration of
material, e.g., any one or more compound(s) as described herein in
an amount effective to prevent, alleviate, or ameliorate one or
more symptoms of a disease or condition, i.e., indication, and/or
to prolong the survival of the subject being treated.
[0454] As used herein, the term "Raf protein kinase mediated
disease or condition" refers to a disease or condition in which the
biological function of a Raf protein kinase (also referred to as
Raf kinase, or Raf), including any of A-Raf protein kinase, B-Raf
protein kinase or c-Raf-1 protein kinase, or any mutation thereof,
affects the development, course, and/or symptoms of the disease or
condition, and/or in which modulation of Raf alters the
development, course, and/or symptoms of the disease or condition.
The Raf mediated disease or condition includes a disease or
condition for which Raf modulation provides a therapeutic benefit,
e.g. wherein treatment with Raf inhibitor(s), including one or more
compound(s) described herein, provides a therapeutic benefit to the
subject suffering from or at risk of the disease or condition.
[0455] As used herein, the term "A-Raf protein kinase mediated
disease or condition," and the like refer to a disease or condition
in which the biological function of an A-Raf protein kinase (also
referred to as A-Raf kinase, or A-Raf), including any mutations
thereof, affects the development, course, and/or symptoms of the
disease or condition, and/or in which modulation of A-Raf alters
the development, course, and/or symptoms of the disease or
condition. The A-Raf mediated disease or condition includes a
disease or condition for which A-Raf inhibition provides a
therapeutic benefit, e.g. wherein treatment with a compound that
inhibits A-Raf, including one or more compound(s) described herein,
provides a therapeutic benefit to the subject suffering from or at
risk of the disease or condition.
[0456] As used herein, the term "B-Raf protein kinase mediated
disease or condition," and the like refer to a disease or condition
in which the biological function of a B-Raf protein kinase (also
referred to as B-Raf kinase, or B-Raf), including any mutations
thereof, affects the development, course, and/or symptoms of the
disease or condition, and/or in which modulation of B-Raf alters
the development, course, and/or symptoms of the disease or
condition. The B-Raf mediated disease or condition includes a
disease or condition for which B-Raf inhibition provides a
therapeutic benefit, e.g. wherein treatment with a compound that
inhibits B-Raf, including one or more compound(s) described herein,
provides a therapeutic benefit to the subject suffering from or at
risk of the disease or condition.
[0457] As used herein, the term "B-Raf V600E mutant protein kinase
mediated disease or condition," and the like refer to a disease or
condition in which the biological function of B-Raf V600E mutant
protein kinase (also referred to as B-Raf V600E kinase, or B-Raf
V600E) affects the development, course, and/or symptoms of the
disease or condition, and/or in which modulation of B-Raf V600E
alters the development, course, and/or symptoms of the disease or
condition. The B-Raf V600E mediated disease or condition includes a
disease or condition for which B-Raf V600E inhibition provides a
therapeutic benefit, e.g. wherein treatment with a compound that
inhibits B-Raf V600E, including one or more compound(s) described
herein, provides a therapeutic benefit to the subject suffering
from or at risk of the disease or condition.
[0458] As used herein, the term "c-Raf-1 protein kinase mediated
disease or condition," and the like refer to a disease or condition
in which the biological function of a c-Raf-1 protein kinase (also
referred to as c-Raf-1 kinase, or c-Raf-1), including any mutations
thereof, affects the development, course, and/or symptoms of the
disease or condition, and/or in which modulation of c-Raf-1 alters
the development, course, and/or symptoms of the disease or
condition. The c-Raf-1 mediated disease or condition includes a
disease or condition for which c-Raf-1 inhibition provides a
therapeutic benefit, e.g. wherein treatment with a compound that
inhibits c-Raf-1, including one or more compound(s) described
herein, provides a therapeutic benefit to the subject suffering
from or at risk of the disease or condition.
[0459] As used herein, the term "Ras mutant-activated Raf protein
kinase mediated disease or condition," and the like refer to a
disease or condition in which the biological function of a Raf
protein kinase is activated by a mutation in Ras protein kinase,
such that the Ras mutation-activated Raf kinase affects the
development, course, and/or symptoms of the disease or condition.
The Ras mutant-activated Raf kinase-mediated disease or condition
includes a disease or condition for which a pan Raf inhibitor as
described herein provides a therapeutic benefit, e.g. wherein
treatment with a compound that inhibits A-Raf, B-Raf, B-Raf V600E,
and c-Raf-1 including one or more compound(s) described herein,
provides a therapeutic benefit to the subject suffering from or at
risk of the disease or condition.
[0460] As used herein, the term "Raf inhibitor" refers to a
compound that inhibits at least one of A-Raf, B-Raf, c-Raf-1, or
any mutations thereof, i.e. a compound having an IC.sub.50 of less
than 500 nM, less than 100 nM, less than 50 nM, less than 20 nM,
less than 10 nM, less than 5 nM, or less than 1 nM as determined in
a generally accepted Raf kinase activity assay. Such compounds are
preferably, but not necessarily, selective with respect to other
protein kinases, i.e. when compared to another protein kinase, the
IC.sub.50 for the other kinase divided by the IC.sub.50 for the Raf
kinase is >10, also >20, also >30, also >40, also
>50, also >60, also >70, also >80, also >90, also
>100. Preferably, the compounds are selective relative to other
protein kinases including, but not limited to, CSK, Insulin
receptor kinase, AMPK, PDGFR or VEGFR.
[0461] As used herein, the term "pan Raf inhibitor" refers to a
compound that inhibits at least each of B-Raf and c-Raf-1, i.e. a
compound having an IC.sub.50 of less than 100 nM, less than 50 nM,
less than 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM
as determined in a generally accepted B-Raf kinase activity assay,
and having an IC.sub.50 of less than 500 nM, less than 100 nM, less
than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or
less than 1 nM as determined in a comparable generally accepted
c-Raf-1 kinase activity assay. The pan Raf inhibitor may be, but is
not necessarily, approximately equipotent on each of B-Raf and
c-Raf-1. Compounds are considered approximately equipotent on each
of B-Raf and c-Raf-1 if the ratio of IC.sub.50 for either of B-Raf
and c-Raf-1 divided by the IC.sub.50 for the other of B-Raf and
c-Raf-1 (e.g. B-Raf IC.sub.50 divided by c-Raf-1 IC.sub.50) is in
the range of 10 to 0.1, also 5 to 0.2. Such compounds are
preferably, but not necessarily, selective with respect to other
protein kinases, i.e. when compared to another protein kinase, the
IC.sub.50 for the other kinase divided by the IC.sub.50 for either
of B-Raf and c-Raf-1 is >10, also >20, also >30, also
>40, also >50, also >60, also >70, also >80, also
>90, also >100. Preferably, the compounds are selective
relative to other protein kinases including, but not limited to,
CSK, Insulin receptor kinase, AMPK, PDGFR or VEGFR. The pan Raf
inhibitor may also inhibit either or both of A-Raf and B-Raf V600E,
where preferably the inhibition of A-Raf and/or B-Raf V600E is
approximately equipotent with the inhibition of B-Raf and c-Raf-1.
Preferred pan Raf inhibitors inhibit each of A-Raf, B-Raf, c-Raf-1
and B-Raf V600E with approximately equal potency, with an IC.sub.50
for each of A-Raf, B-Raf, c-Raf-1 and B-Raf V600E of less than 500
nM, less than 100 nM, less than 50 nM, less than 20 nM, less than
10 nM, less than 5 nM, or less than 1 nM as determined in a
generally accepted Raf kinase activity assay. While it is
understood that a pan Raf inhibitor may be used to treat any A-Raf,
B-Raf, c-Raf-1 or B-Raf V600E kinase mediated disease or condition,
the inhibition of each of A-Raf, B-Raf, c-Raf-1 and B-Raf V600E
provides beneficial effects in treating cancers, in particular
cancers having a Ras pathway mutation, such as a Ras mutation that
activates Raf kinase, e.g. cancers including, but not limited to,
melanoma, liver cancer, biliary tract cancer, colorectal cancer,
lung cancer, bladder cancer, breast cancer, pancreatic cancer,
thyroid cancer, kidney cancer, ovarian cancer, cervical cancer,
endometrial cancer, and acute myeloid leukemia. Such compounds are
also beneficial in treating B-Raf V600E mediated cancers that
become resistant to B-Raf V600E selective inhibitors.
[0462] As used herein, the term "solid form" refers to a solid
preparation (i.e. a preparation that is neither gas nor liquid) of
a pharmaceutically active compound that is suitable for
administration to an intended animal subject for therapeutic
purposes. The solid form includes any complex, such as a salt,
co-crystal or an amorphous complex, as well as any polymorph of the
compound. The solid form may be substantially crystalline,
semi-crystalline or substantially amorphous. The solid form may be
administered directly or used in the preparation of a suitable
composition having improved pharmaceutical properties. For example,
the solid form may be used in a formulation comprising at least one
pharmaceutically acceptable carrier or excipient.
[0463] As used herein, the term "substantially crystalline"
material embraces material which has greater than about 90%
crystallinity; and "crystalline" material embraces material which
has greater than about 98% crystallinity.
[0464] As used herein, the term "substantially amorphous" material
embraces material which has no more than about 10% crystallinity;
and "amorphous" material embraces material which has no more than
about 2% crystallinity.
[0465] As used herein, the term "semi-crystalline" material
embraces material which is greater than 10% crystallinity, but no
greater than 90% crystallinity; preferably "semi-crystalline"
material embraces material which is greater than 20% crystallinity,
but no greater than 80% crystallinity. In one aspect of the present
invention, a mixture of solid forms of a compound may be prepared,
for example, a mixture of amorphous and crystalline solid forms,
e.g. to provide a "semi-crystalline" solid form. Such a
"semi-crystalline" solid form may be prepared by methods known in
the art, for example by mixing an amorphous solid form with a
crystalline solid form in the desired ratio. In some instances, a
compound mixed with an acid or base forms an amorphous complex; a
semi-crystalline solid can be prepared employing an amount of
compound component in excess of the stoichiometry of the compound
and acid or base in the amorphous complex, thereby resulting in an
amount of the amorphous complex that is based on the stoichiometry
thereof, with excess compound in a crystalline form. The amount of
excess compound used in the preparation of the complex can be
adjusted to provide the desired ratio of amorphous complex to
crystalline compound in the resulting mixture of solid forms. For
example, where the amorphous complex of acid or base and compound
has a 1:1 stoichiometry, preparing said complex with a 2:1 mole
ratio of compound to acid or base will result in a solid form of
50% amorphous complex and 50% crystalline compound. Such a mixture
of solid forms may be beneficial as a drug product, for example, by
providing an amorphous component having improved biopharmaceutical
properties along with the crystalline component. The amorphous
component would be more readily bioavailable while the crystalline
component would have a delayed bioavailability. Such a mixture may
provide both rapid and extended exposure to the active
compound.
[0466] As used herein, the term "complex" refers to a combination
of a pharmaceutically active compound and an additional molecular
species that forms or produces a new chemical species in a solid
form. In some instances, the complex may be a salt, i.e. where the
additional molecular species provides an acid/base counter ion to
an acid/base group of the compound resulting in an acid:base
interaction that forms a typical salt. While such salt forms are
typically substantially crystalline, they can also be partially
crystalline, substantially amorphous, or amorphous forms. In some
instances, the additional molecular species, in combination with
the pharmaceutically active compound, forms a non-salt co-crystal,
i.e. the compound and molecular species do not interact by way of a
typical acid:base interaction, but still form a substantially
crystalline structure. Co-crystals may be formed from a salt of the
compound and an additional molecular species. In some instances,
the complex is a substantially amorphous complex, which may contain
salt-like acid:base interactions that do not form typical salt
crystals, but instead form a substantially amorphous solid, i.e. a
solid whose X-ray powder diffraction pattern exhibits no sharp
peaks (e.g. exhibits an amorphous halo).
[0467] As used herein, the term "stoichiometry" refers to the molar
ratio of a combination of two or more components, for example, the
molar ratio of acid or base to compound that form an amorphous
complex. For example, a 1:1 mixture of acid or base with compound
(i.e. 1 mole acid or base per mole of compound) resulting in an
amorphous solid form has a 1:1 stoichiometry.
[0468] As used herein, the term "composition" refers to a
pharmaceutical preparation suitable for administration to an
intended subject for therapeutic purposes that contains at least
one pharmaceutically active compound, including any solid form
thereof. The composition may include at least one pharmaceutically
acceptable component to provide an improved formulation of the
compound, such as a suitable carrier or excipient.
[0469] As used herein, the term "subject" refers to a living
organism that is treated with compounds as described herein,
including, but not limited to, any mammal, such as a human, other
primates, sports animals, animals of commercial interest such as
cattle, farm animals such as horses, or pets such as dogs and
cats.
[0470] As used herein, the term "biopharmaceutical properties"
refers to the pharmacokinetic action of a compound or complex of
the present invention, including the dissolution, absorption and
distribution of the compound on administration to animal subject.
As such, certain solid forms of compounds as described herein, such
as amorphous complexes of compounds as described herein are
intended to provide improved dissolution and absorption of the
active compound, which is typically reflected in improved C.sub.max
(i.e. the maximum achieved concentration in the plasma after
administration of the drug) and improved AUC (i.e. area under the
curve of drug plasma concentration vs. time after administration of
the drug).
[0471] The term "pharmaceutically acceptable" indicates that the
indicated material does not have properties that would cause a
reasonably prudent medical practitioner to avoid administration of
the material to a patient, taking into consideration the disease or
conditions to be treated and the respective route of
administration. For example, it is commonly required that such a
material be essentially sterile, e.g., for injectibles.
[0472] In the present context, the term "therapeutically effective"
or "effective amount" indicates that the materials or amount of
material is effective to prevent, alleviate, or ameliorate one or
more symptoms of a disease or medical condition, and/or to prolong
the survival of the subject being treated.
[0473] In the present context, the terms "synergistically
effective" or "synergistic effect" indicate that two or more
compounds that are therapeutically effective, when used in
combination, provide improved therapeutic effects greater than the
additive effect that would be expected based on the effect of each
compound used by itself.
[0474] By "assaying" is meant the creation of experimental
conditions and the gathering of data regarding a particular result
of the exposure to specific experimental conditions. For example,
enzymes can be assayed based on their ability to act upon a
detectable substrate. A compound can be assayed based on its
ability to bind to a particular target molecule or molecules.
[0475] As used herein, the term "modulating" or "modulate" refers
to an effect of altering a biological activity (i.e. increasing or
decreasing the activity), especially a biological activity
associated with a particular biomolecule such as a protein kinase.
For example, an inhibitor of a particular biomolecule modulates the
activity of that biomolecule, e.g., an enzyme, by decreasing the
activity of the biomolecule, such as an enzyme. Such activity is
typically indicated in terms of an inhibitory concentration
(IC.sub.50) of the compound for an inhibitor with respect to, for
example, an enzyme.
[0476] In the context of the use, testing, or screening of
compounds that are or may be modulators, the term "contacting"
means that the compound(s) are caused to be in sufficient proximity
to a particular molecule, complex, cell, tissue, organism, or other
specified material that potential binding interactions and/or
chemical reaction between the compound and other specified material
can occur.
[0477] "Pain" or a "pain condition" can be acute and/or chronic
pain, including, without limitation, arachnoiditis; arthritis (e.g.
osteoarthritis, rheumatoid arthritis, ankylosing spondylitis,
gout); back pain (e.g. sciatica, ruptured disc, spondylolisthesis,
radiculopathy); burn pain; cancer pain; dysmenorrhea; headaches
(e.g. migraine, cluster headaches, tension headaches); head and
facial pain (e.g. cranial neuralgia, trigeminal neuralgia);
hyperalgesia; hyperpathia; inflammatory pain (e.g. pain associated
with irritable bowel syndrome, inflammatory bowel disease,
ulcerative colitis, Crohn's disease, cystitis, pain from bacterial,
fungal or viral infection); keloid or scar tissue formation; labor
or delivery pain; muscle pain (e.g. as a result of polymyositis,
dermatomyositis, inclusion body myositis, repetitive stress injury
(e.g. writer's cramp, carpal tunnel syndrome, tendonitis,
tenosynovitis)); myofascial pain syndromes (e.g. fibromyalgia);
neuropathic pain (e.g. diabetic neuropathy, causalgia, entrapment
neuropathy, brachial plexus avulsion, occipital neuralgia, gout,
reflex sympathetic dystrophy syndrome, phantom limb or
post-amputation pain, postherpetic neuralgia, central pain
syndrome, or nerve pain resulting from trauma (e.g. nerve injury),
disease (e.g. diabetes, multiple sclerosis, Guillan-Barre Syndrome,
myasthenia gravis, neurodegenerative diseases such as Parkinson's
disease, Alzheimer's disease, amyotrophic lateral sclerosis, or
cancer treatment); pain associated with skin disorders (e.g.
shingles, herpes simplex, skin tumors, cysts, neurofibromatosis);
sports injuries (e.g. cuts, sprains, strains, bruises,
dislocations, fractures, spinal chord, head); spinal stenosis;
surgical pain; tactile allodynia; temporomandibular disorders;
vascular disease or injury (e.g. vasculitis, coronary artery
disease, reperfusion injury (e.g. following ischemia, stroke, or
myocardial infarcts)); other specific organ or tissue pain (e.g.
ocular pain, corneal pain, bone pain, heart pain, visceral pain
(e.g. kidney, gallbladder, gastrointestinal), joint pain, dental
pain, pelvic hypersensitivity, pelvic pain, renal colic, urinary
incontinence); other disease associated pain (e.g. sickle cell
anemia, AIDS, herpes zoster, psoriasis, endometriosis, asthma,
chronic obstructive pulmonary disease (COPD), silicosis, pulmonary
sarcoidosis, esophagitis, heart burn, gastroesophageal reflux
disorder, stomach and duodenal ulcers, functional dyspepsia, bone
resorption disease, osteoporosis, cerebral malaria, bacterial
meningitis); or pain due to graft v. host rejection or allograft
rejections.
Kinase Targets and Indications of the Invention
[0478] Protein kinases play key roles in propagating biochemical
signals in diverse biological pathways. More than 500 kinases have
been described, and specific kinases have been implicated in a wide
range of diseases or conditions (i.e., indications), including for
example without limitation, cancer, cardiovascular disease,
inflammatory disease, neurological disease, and other diseases. As
such, kinases represent important control points for small molecule
therapeutic intervention. Description of Raf target protein kinases
contemplated by the present invention follow:
[0479] A-Raf:
[0480] Target kinase A-Raf (i.e., v-raf murine sarcoma 3611 viral
oncogene homolog 1) is a 67.6 kDa serine/threonine kinase encoded
by chromosome Xp11.4-p11.2 (symbol: ARAF). The mature protein
comprises RBD (i.e., Ras binding domain) and phorbol-ester/DAG-type
zinc finger domain and is involved in the transduction of mitogenic
signals from the cell membrane to the nucleus. A-Raf inhibitors may
be useful in treating neurologic diseases such as multi-infarct
dementia, head injury, spinal cord injury, Alzheimer's disease
(AD), Parkinson's disease; neoplastic diseases including, but not
limited to, melanoma, glioma, sarcoma, carcinoma (e.g. colorectal,
lung, breast, pancreatic, thyroid, renal, ovarian), lymphoma (e.g.
histiocytic lymphoma), neurofibromatosis, myelodysplastic syndrome,
leukemia, tumor angiogenesis; pain of neuropathic or inflammatory
origin, including acute pain, chronic pain, cancer-related pain and
migraine; and diseases associated with muscle regeneration or
degeneration, including, but not limited to, vascular restenosis,
sarcopenia, muscular dystrophies (including, but not limited to,
Duchenne, Becker, Emery-Dreifuss, Limb-Girdle, Facioscapulohumeral,
Myotonic, Oculopharyngeal, Distal and Congenital Muscular
Dystrophies), motor neuron diseases (including, but not limited to,
amyotrophic lateral sclerosis, infantile progressive spinal
muscular atrophy, intermediate spinal muscular atrophy, juvenile
spinal muscular atrophy, spinal bulbar muscular atrophy, and adult
spinal muscular atrophy), inflammatory myopathies (including, but
not limited to, dermatomyositis, polymyositis, and inclusion body
myositis), diseases of the neuromuscular junction (including, but
not limited to, myasthenia gravis, Lambert-Eaton syndrome, and
congenital myasthenic syndrome), myopathies due to endocrine
abnormalities (including, but not limited to, hyperthyroid myopathy
and hypothyroid myopathy) diseases of peripheral nerve (including,
but not limited to, Charcot-Marie-Tooth disease, Dejerine-Sottas
disease, and Friedreich's ataxia), other myopathies (including, but
not limited to, myotonia congenita, paramyotonia congenita, central
core disease, nemaline myopathy, myotubular myopathy, and periodic
paralysis), and metabolic diseases of muscle (including, but not
limited to, phosphorylase deficiency, acid maltase deficiency,
phosphofructokinase deficiency, debrancher enzyme deficiency,
mitochondrial myopathy, carnitine deficiency, carnitine palmatyl
transferase deficiency, phosphoglycerate kinase deficiency,
phosphoglycerate mutase deficiency, lactate dehydrogenase
deficiency, and myoadenylate deaminase deficiency).
[0481] B-Raf:
[0482] Target kinase B-Raf (i.e., v-raf murine sarcoma viral
oncogene homolog B1) is a 84.4 kDa serine/threonine kinase encoded
by chromosome 7q34 (symbol: BRAF). The mature protein comprises RBD
(i.e., Ras binding domain), C1 (i.e., protein kinase C conserved
region 1) and STK (i.e., serine/threonine kinase) domains.
[0483] Target kinase B-Raf is involved in the transduction of
mitogenic signals from the cell membrane to the nucleus and may
play a role in the postsynaptic responses of hippocampal neurons.
As such, genes of the RAF family encode kinases that are regulated
by Ras and mediate cellular responses to growth signals. Indeed,
B-Raf kinase is a key component of the
RAS->Raf->MEK->ERK/MAP kinase signaling pathway, which
plays a fundamental role in the regulation of cell growth, division
and proliferation, and, when constitutively activated, causes
tumorigenesis. Among several isoforms of Raf kinase, the B-type, or
B-Raf, is the strongest activator of the downstream MAP kinase
signaling.
[0484] The BRAF gene is frequently mutated in a variety of human
tumors, especially in malignant melanoma and colon carcinoma. The
most common reported mutation was a missense thymine (T) to adenine
(A) transversion at nucleotide 1796 (T1796A; amino acid change in
the B-Raf protein is Val<600> to Glu<600>) observed in
80% of malignant melanoma tumors. Functional analysis reveals that
this transversion is the only detected mutation that causes
constitutive activation of B-Raf kinase activity, independent of
RAS activation, by converting B-Raf into a dominant transforming
protein. Based on precedents, human tumors develop resistance to
kinase inhibitors by mutating a specific amino acid in the
catalytic domain as the "gatekeeper". (Balak, et. al., Clin Cancer
Res. 2006, 12:6494-501). Mutation of Thr-529 in BRAF to Ile is thus
anticipated as a mechanism of resistance to BRAF inhibitors, and
this can be envisioned as a transition in codon 529 from ACC to
ATC.
[0485] Niihori et al., report that in 43 individuals with
cardio-facio-cutaneous (CFC) syndrome, they identified two
heterozygous KRAS mutations in three individuals and eight BRAF
mutations in 16 individuals, suggesting that dysregulation of the
RAS-RAF-ERK pathway is a common molecular basis for the three
related disorders (Niihori et al., Nat Genet. 2006,
38(3):294-6).
[0486] c-Raf-1:
[0487] Target kinase c-Raf-1 (i.e., v-raf murine sarcoma viral
oncogene homolog 1) is a 73.0 kDa STK encoded by chromosome 3p25
(symbol: RAF1). c-Raf-1 can be targeted to the mitochondria by BCL2
(i.e., oncogene B-cell leukemia 2) which is a regulator of
apoptotic cell death. Active c-Raf-1 improves BCL2-mediated
resistance to apoptosis, and c-Raf-1 phosphorylates BAD (i.e.,
BCL2-binding protein). c-Raf-1 is implicated in carcinomas,
including colorectal, ovarian, lung and renal cell carcinoma.
c-Raf-1 is also implicated as an important mediator of tumor
angiogenesis (Hood, J. D. et al., 2002, Science 296, 2404). C-Raf-1
inhibitors may also be useful for the treatment of acute myeloid
leukemia and myelodysplastic syndromes (Crump, Curr Pharm Des 2002,
8(25):2243-8). Raf-1 activators may be useful as treatment for
neuroendocrine tumors, such as medullary thyroid cancer, carcinoid,
small cell lung cancer and pheochromocytoma (Kunnimalaiyaan et al.,
Anticancer Drugs 2006, 17(2):139-42).
[0488] A-Raf, B-Raf and/or C-Raf-1 inhibitors may be useful in
treating A-Raf-mediated, B-Raf-mediated or c-Raf-1-mediated disease
or condition selected from the group consisting of neurologic
diseases, including, but not limited to, multi-infarct dementia,
head injury, spinal cord injury, Alzheimer's disease (AD),
Parkinson's disease seizures and epilepsy; neoplastic diseases
including, but not limited to, melanoma, glioma, glioblastoma
multiforme, pilocytic astrocytoma, sarcoma, carcinoma (e.g.
gastrointestinal, liver, biliary tract (e.g. bile duct,
cholangiocarcinoma), colorectal, lung, gallbladder, breast,
pancreatic, thyroid, renal, ovarian, adrenocortical, prostate),
lymphoma (e.g. histiocytic lymphoma) neurofibromatosis, acute
myeloid leukemia, myelodysplastic syndrome, leukemia, tumor
angiogenesis, gastrointestinal stromal tumors, neuroendocrine
tumors such as medullary thyroid cancer, carcinoid, small cell lung
cancer, Kaposi's sarcoma, and pheochromocytoma; pain of neuropathic
or inflammatory origin, including, but not limited to, acute pain,
chronic pain, cancer-related pain, and migraine; cardiovascular
diseases, including, but not limited to, heart failure, ischemic
stroke, cardiac hypertrophy, thrombosis (e.g. thrombotic
microangiopathy syndromes), atherosclerosis, and reperfusion
injury; inflammation and/or proliferation including, but not
limited to, psoriasis, eczema, arthritis and autoimmune diseases
and conditions, osteoarthritis, endometriosis, scarring, vascular
restenosis, fibrotic disorders, rheumatoid arthritis, inflammatory
bowel disease (IBD); immunodeficiency diseases, including, but not
limited to, organ transplant rejection, graft versus host disease,
and Kaposi's sarcoma associated with HIV; renal, cystic, or
prostatic diseases, including, but not limited to, diabetic
nephropathy, polycystic kidney disease, nephrosclerosis,
glomerulonephritis, prostate hyperplasia, polycystic liver disease,
tuberous sclerosis, Von Hippel Lindau disease, medullary cystic
kidney disease, nephronophthisis, and cystic fibrosis; metabolic
disorders, including, but not limited to, obesity; infection,
including, but not limited to, Helicobacter pylori, Hepatitis and
Influenza viruses, fever, HIV and sepsis; pulmonary diseases,
including, but not limited to, chronic obstructive pulmonary
disease (COPD) and acute respiratory distress syndrome (ARDS);
genetic developmental diseases, including, but not limited to,
Noonan's syndrome, Costello syndrome, (faciocutaneoskeletal
syndrome), LEOPARD syndrome, cardio-faciocutaneous syndrome (CFC),
and neural crest syndrome abnormalities causing cardiovascular,
skeletal, intestinal, skin, hair and endocrine diseases; and
diseases associated with muscle regeneration or degeneration,
including, but not limited to, sarcopenia, muscular dystrophies
(including, but not limited to, Duchenne, Becker, Emery-Dreifuss,
Limb-Girdle, Facioscapulohumeral, Myotonic, Oculopharyngeal, Distal
and Congenital Muscular Dystrophies), motor neuron diseases
(including, but not limited to, amyotrophic lateral sclerosis,
infantile progressive spinal muscular atrophy, intermediate spinal
muscular atrophy, juvenile spinal muscular atrophy, spinal bulbar
muscular atrophy, and adult spinal muscular atrophy), inflammatory
myopathies (including, but not limited to, dermatomyositis,
polymyositis, and inclusion body myositis), diseases of the
neuromuscular junction (including, but not limited to, myasthenia
gravis, Lambert-Eaton syndrome, and congenital myasthenic
syndrome), myopathies due to endocrine abnormalities (including,
but not limited to, hyperthyroid myopathy and hypothyroid myopathy)
diseases of peripheral nerve (including, but not limited to,
Charcot-Marie-Tooth disease, Dejerine-Sottas disease, and
Friedreich's ataxia), other myopathies (including, but not limited
to, myotonia congenita, paramyotonia congenita, central core
disease, nemaline myopathy, myotubular myopathy, and periodic
paralysis), and metabolic diseases of muscle (including, but not
limited to, phosphorylase deficiency, acid maltase deficiency,
phosphofructokinase deficiency, debrancher enzyme deficiency,
mitochondrial myopathy, carnitine deficiency, carnitine palmatyl
transferase deficiency, phosphoglycerate kinase deficiency,
phosphoglycerate mutase deficiency, lactate dehydrogenase
deficiency, and myoadenylate deaminase deficiency).
Kinase Activity Assays
[0489] A number of different assays for kinase activity can be
utilized for assaying for active modulators and/or determining
specificity of a modulator for a particular kinase or group or
kinases. In addition to the assay mentioned in the Examples below,
one of ordinary skill in the art will know of other assays that can
be utilized and can modify an assay for a particular application.
For example, numerous papers concerning kinases describe assays
that can be used.
[0490] Additional alternative assays can employ binding
determinations. For example, this sort of assay can be formatted
either in a fluorescence resonance energy transfer (FRET) format,
or using an AlphaScreen (amplified luminescent proximity
homogeneous assay) format by varying the donor and acceptor
reagents that are attached to streptavidin or the phosphor-specific
antibody.
Organic Synthetic Techniques
[0491] A wide array of organic synthetic techniques exist in the
art to facilitate the construction of potential modulators. Many of
these organic synthetic methods are described in detail in standard
reference sources utilized by those skilled in the art. One example
of such a reference is March, 1994, Advanced Organic Chemistry;
Reactions, Mechanisms and Structure, New York, McGraw Hill. Thus,
the techniques useful to synthesize a potential modulator of kinase
function are readily available to those skilled in the art of
organic chemical synthesis.
Alternative Compound Forms or Derivatives
[0492] Compounds contemplated herein are described with reference
to both generic formulae and specific compounds. In addition,
compounds as described herein may exist in a number of different
forms or derivatives, all within the scope of the present
invention. Alternative forms or derivatives, include, for example,
(a) prodrugs, and active metabolites (b) tautomers, isomers
(including stereoisomers and regioisomers), and racemic mixtures
(c) pharmaceutically acceptable salts and (d) solid forms,
including different crystal forms, polymorphic or amorphous solids,
including hydrates and solvates thereof, and other forms.
[0493] (a) Prodrugs and Metabolites
[0494] In addition to the present formulae and compounds described
herein, the invention also includes prodrugs (generally
pharmaceutically acceptable prodrugs), active metabolic derivatives
(active metabolites), and their pharmaceutically acceptable
salts.
[0495] Prodrugs are compounds or pharmaceutically acceptable salts
thereof which, when metabolized under physiological conditions or
when converted by solvolysis, yield the desired active compound.
Prodrugs include, without limitation, esters, amides, carbamates,
carbonates, ureides, solvates, or hydrates of the active compound.
Typically, the prodrug is inactive, or less active than the active
compound, but may provide one or more advantageous handling,
administration, and/or metabolic properties. For example, some
prodrugs are esters of the active compound; during metabolysis, the
ester group is cleaved to yield the active drug. Esters include,
for example, esters of a carboxylic acid group, or S-acyl or O-acyl
derivatives of thiol, alcohol, or phenol groups. In this context, a
common example is an alkyl ester of a carboxylic acid. Prodrugs may
also include variants wherein an --NH group of the compound has
undergone acylation, such as the 1-position of the
pyrrolo[2,3-b]pyridine ring or the nitrogen of the sulfonamide
group of compounds as described herein, where cleavage of the acyl
group provides the free --NH group of the active drug. Some
prodrugs are activated enzymatically to yield the active compound,
or a compound may undergo further chemical reaction to yield the
active compound. Prodrugs may proceed from prodrug form to active
form in a single step or may have one or more intermediate forms
which may themselves have activity or may be inactive.
[0496] As described in The Practice of Medicinal Chemistry, Ch.
31-32 (Ed. Wermuth, Academic Press, San Diego, Calif., 2001),
prodrugs can be conceptually divided into two non-exclusive
categories, bioprecursor prodrugs and carrier prodrugs. Generally,
bioprecursor prodrugs are compounds that are inactive or have low
activity compared to the corresponding active drug compound, that
contain one or more protective groups and are converted to an
active form by metabolism or solvolysis. Both the active drug form
and any released metabolic products should have acceptably low
toxicity. Typically, the formation of active drug compound involves
a metabolic process or reaction that is one of the following
types:
[0497] Oxidative Reactions:
[0498] Oxidative reactions are exemplified without limitation by
reactions such as oxidation of alcohol, carbonyl, and acid
functionalities, hydroxylation of aliphatic carbons, hydroxylation
of alicyclic carbon atoms, oxidation of aromatic carbon atoms,
oxidation of carbon-carbon double bonds, oxidation of
nitrogen-containing functional groups, oxidation of silicon,
phosphorus, arsenic, and sulfur, oxidative N-dealkylation,
oxidative O- and S-dealkylation, oxidative deamination, as well as
other oxidative reactions.
[0499] Reductive Reactions:
[0500] Reductive reactions are exemplified without limitation by
reactions such as reduction of carbonyl functionalities, reduction
of alcohol functionalities and carbon-carbon double bonds,
reduction of nitrogen-containing functional groups, and other
reduction reactions.
[0501] Reactions without Change in the Oxidation State:
[0502] Reactions without change in the state of oxidation are
exemplified without limitation by reactions such as hydrolysis of
esters and ethers, hydrolytic cleavage of carbon-nitrogen single
bonds, hydrolytic cleavage of non-aromatic heterocycles, hydration
and dehydration at multiple bonds, new atomic linkages resulting
from dehydration reactions, hydrolytic dehalogenation, removal of
hydrogen halide molecule, and other such reactions.
[0503] Carrier prodrugs are drug compounds that contain a transport
moiety, e.g., that improves uptake and/or localized delivery to a
site(s) of action. Desirably for such a carrier prodrug, the
linkage between the drug moiety and the transport moiety is a
covalent bond, the prodrug is inactive or less active than the drug
compound, the prodrug and any release transport moiety are
acceptably non-toxic. For prodrugs where the transport moiety is
intended to enhance uptake, typically the release of the transport
moiety should be rapid. In other cases, it is desirable to utilize
a moiety that provides slow release, e.g., certain polymers or
other moieties, such as cyclodextrins. (See, e.g., Cheng et al.,
U.S. Patent Publ. No 20040077595, application Ser. No. 10/656,838,
incorporated herein by reference.) Such carrier prodrugs are often
advantageous for orally administered drugs. In some instances, the
transport moiety provides targeted delivery of the drug, for
example the drug may be conjugated to an antibody or antibody
fragment. Carrier prodrugs can, for example, be used to improve one
or more of the following properties: increased lipophilicity,
increased duration of pharmacological effects, increased
site-specificity, decreased toxicity and adverse reactions, and/or
improvement in drug formulation (e.g., stability, water solubility,
suppression of an undesirable organoleptic or physiochemical
property). For example, lipophilicity can be increased by
esterification of hydroxyl groups with lipophilic carboxylic acids,
or of carboxylic acid groups with alcohols, e.g., aliphatic
alcohols. Wermuth, supra.
[0504] Metabolites, e.g., active metabolites, overlap with prodrugs
as described above, e.g., bioprecursor prodrugs. Thus, such
metabolites are pharmacologically active compounds or compounds
that further metabolize to pharmacologically active compounds that
are derivatives resulting from metabolic processes in the body of a
subject. Of these, active metabolites are such pharmacologically
active derivative compounds. For prodrugs, the prodrug compound is
generally inactive or of lower activity than the metabolic product.
For active metabolites, the parent compound may be either an active
compound or may be an inactive prodrug. For example, in some
compounds, one or more alkoxy groups can be metabolized to hydroxyl
groups while retaining pharmacologic activity and/or carboxyl
groups can be esterified, e.g., glucuronidation. In some cases,
there can be more than one metabolite, where an intermediate
metabolite(s) is further metabolized to provide an active
metabolite. For example, in some cases a derivative compound
resulting from metabolic glucuronidation may be inactive or of low
activity, and can be further metabolized to provide an active
metabolite.
[0505] Metabolites of a compound may be identified using routine
techniques known in the art, and their activities determined using
tests such as those described herein. See, e.g., Bertolini et al.,
1997, J. Med. Chem., 40:2011-2016; Shan et al., 1997, J Pharm Sci
86(7):756-757; Bagshawe, 1995, Drug Dev. Res., 34:220-230; Wermuth,
supra.
[0506] (b) Tautomers, Stereoisomers, and Regioisomers
[0507] It is understood that some compounds may exhibit
tautomerism. In such cases, the formulae provided herein expressly
depict only one of the possible tautomeric forms. It is therefore
to be understood that the formulae provided herein are intended to
represent any tautomeric form of the depicted compounds and are not
to be limited merely to the specific tautomeric form depicted by
the drawings of the formulae.
[0508] Likewise, some of the compounds as described herein may
exist as stereoisomers, i.e. having the same atomic connectivity of
covalently bonded atoms yet differing in the spatial orientation of
the atoms. For example, compounds may be optical stereoisomers,
which contain one or more chiral centers, and therefore, may exist
in two or more stereoisomeric forms (e.g. enantiomers or
diastereomers). Thus, such compounds may be present as single
stereoisomers (i.e., essentially free of other stereoisomers),
racemates, and/or mixtures of enantiomers and/or diastereomers. As
another example, stereoisomers include geometric isomers, such as
cis- or trans-orientation of substituents on adjacent carbons of a
double bond. All such single stereoisomers, racemates and mixtures
thereof are intended to be within the scope of the present
invention. Unless specified to the contrary, all such
stereoisomeric forms are included within the formulae provided
herein.
[0509] In some embodiments, a chiral compound as described herein
is in a form that contains at least 80% of a single isomer (60%
enantiomeric excess ("e.e.") or diastereomeric excess ("d.e.")), or
at least 85% (70% e.e. or d.e.), 90% (80% e.e. or d.e.), 95% (90%
e.e. or d.e.), 97.5% (95% e.e. or d.e.), or 99% (98% e.e. or d.e.).
As generally understood by those skilled in the art, an optically
pure compound having one chiral center is one that consists
essentially of one of the two possible enantiomers (i.e., is
enantiomerically pure), and an optically pure compound having more
than one chiral center is one that is both diastereomerically pure
and enantiomerically pure. In some embodiments, the compound is
present in optically pure form, such optically pure form being
prepared and/or isolated by methods known in the art (e.g. by
recrystallization techniques, chiral synthetic techniques
(including synthesis from optically pure starting materials), and
chromatographic separation using a chiral column.
[0510] (c) Pharmaceutically Acceptable Salts
[0511] Unless specified to the contrary, specification of a
compound herein includes pharmaceutically acceptable salts of such
compound. Thus, compounds as described herein can be in the form of
pharmaceutically acceptable salts, or can be formulated as
pharmaceutically acceptable salts. Contemplated pharmaceutically
acceptable salt forms include, without limitation, mono, bis, tris,
tetrakis, and so on. Pharmaceutically acceptable salts are
non-toxic in the amounts and concentrations at which they are
administered. The preparation of such salts can facilitate the
pharmacological use by altering the physical characteristics of a
compound without preventing it from exerting its physiological
effect. Useful alterations in physical properties include lowering
the melting point to facilitate transmucosal administration and
increasing the solubility to facilitate administering higher
concentrations of the drug. A compound as described herein may
possess a sufficiently acidic, a sufficiently basic, or both
functional groups, and accordingly can react with any of a number
of inorganic or organic bases, and inorganic and organic acids, to
form a pharmaceutically acceptable salt.
[0512] Pharmaceutically acceptable salts include acid addition
salts such as those containing chloride, bromide, iodide,
hydrochloride, acetate, phenylacetate, acrylate, ascorbate,
aspartate, benzoate, 2-phenoxybenzoate, 2-acetoxybenzoate,
dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate,
bicarbonate, butyne-1,4 dioate, hexyne-1,6-dioate, caproate,
caprylate, chlorobenzoate, cinnamate, citrate, decanoate, formate,
fumarate, glycolate, gluconate, glucarate, glucuronate,
glucose-6-phosphate, glutamate, heptanoate, hexanoate, isethionate,
isobutyrate, gamma-hydroxybutyrate, phenylbutyrate, lactate,
malate, maleate, hydroxymaleate, methylmaleate, malonate,
mandelate, nicotinate, nitrate, isonicotinate, octanoate, oleate,
oxalate, pamoate, phosphate, monohydrogenphosphate,
dihydrogenphosphate, orthophosphate, metaphosphate, pyrophosphate,
2-phosphoglycerate, 3-phosphoglycerate, phthalate, propionate,
phenylpropionate, propiolate, pyruvate, quinate, salicylate,
4-aminosalicylate, sebacate, stearate, suberate, succinate,
sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, sulfamate,
sulfonate, benzenesulfonate (i.e. besylate), ethanesulfonate (i.e.
esylate), ethane-1,2-disulfonate, 2-hydroxyethanesulfonate (i.e.
isethionate), methanesulfonate (i.e. mesylate),
naphthalene-1-sulfonate, naphthalene-2-sulfonate (i.e. napsylate),
propanesulfonate, p-toluenesulfonate (i.e. tosylate),
xylenesulfonates, cyclohexylsulfamate, tartrate, and
trifluoroacetate. These pharmaceutically acceptable acid addition
salts can be prepared using the appropriate corresponding acid.
[0513] When acidic functional groups, such as carboxylic acid or
phenol are present, pharmaceutically acceptable salts also include
basic addition salts such as those containing benzathine,
chloroprocaine, choline, ethanolamine, diethanolamine,
triethanolamine, t-butylamine, dicyclohexylamine, ethylenediamine,
N,N'-dibenzylethylenediamine, meglumine, hydroxyethylpyrrolidine,
piperidine, morpholine, piperazine, procaine, aluminum, calcium,
copper, iron, lithium, magnesium, manganese, potassium, sodium,
zinc, ammonium, and mono-, di-, or tri-alkylamines (e.g.
diethylamine), or salts derived from amino acids such as
L-histidine, L-glycine, L-lysine, and L-arginine. For example, see
Remington's Pharmaceutical Sciences, 19.sup.th ed., Mack Publishing
Co., Easton, Pa., Vol. 2, p. 1457, 1995. These pharmaceutically
acceptable base addition salts can be prepared using the
appropriate corresponding base.
[0514] Pharmaceutically acceptable salts can be prepared by
standard techniques. For example, the free-base form of a compound
can be dissolved in a suitable solvent, such as an aqueous or
aqueous-alcohol solution containing the appropriate acid and then
isolated by evaporating the solution. In another example, a salt
can be prepared by reacting the free base and acid in an organic
solvent. If the particular compound is an acid, the desired
pharmaceutically acceptable salt may be prepared by any suitable
method, for example, treatment of the free acid with an appropriate
inorganic or organic base.
[0515] (d) Other Compound Forms
[0516] In the case of agents that are solids, it is understood by
those skilled in the art that the compounds and salts may exist in
different crystal or polymorphic forms, or may be formulated as
co-crystals, or may be in an amorphous form, or may be any
combination thereof (e.g. partially crystalline, partially
amorphous, or mixtures of polymorphs) all of which are intended to
be within the scope of the present invention and specified
formulae. Whereas salts are formed by acid/base addition, i.e. a
free base or free acid of the compound of interest forms an
acid/base reaction with a corresponding addition base or addition
acid, respectively, resulting in an ionic charge interaction,
co-crystals are a new chemical species that is formed between
neutral compounds, resulting in the compound and an additional
molecular species in the same crystal structure.
[0517] In some instances, compounds as described herein are
complexed with an acid or a base, including base addition salts
such as ammonium, diethylamine, ethanolamine, ethylenediamine,
diethanolamine, t-butylamine, piperazine, meglumine; acid addition
salts, such as acetate, acetylsalicylate, besylate, camsylate,
citrate, formate, fumarate, glutarate, hydrochlorate, maleate,
mesylate, nitrate, oxalate, phosphate, succinate, sulfate,
tartrate, thiocyanate and tosylate; and amino acids such as
alanine, arginine, asparagine, aspartic acid, cysteine, glutamine,
glutamic acid, glycine, histidine, isoleucine, leucine, lysine,
methionine, phenylalanine, proline, serine, threonine, tryptophan,
tyrosine or valine. In combining compounds as described herein with
the acid or base, an amorphous complex is preferably formed rather
than a crystalline material such as a typical salt or co-crystal.
In some instances, the amorphous form of the complex is facilitated
by additional processing, such as by spray-drying, mechanochemical
methods such as roller compaction, or microwave irradiation of the
parent compound mixed with the acid or base. Such amorphous
complexes provide several advantages. For example, lowering of the
melting temperature relative to the free base facilitates
additional processing, such as hot melt extrusion, to further
improve the biopharmaceutical properties of the compound. Also, the
amorphous complex is readily friable, which provides improved
compression for loading of the solid into capsule or tablet
form.
[0518] Additionally, compounds as described herein may include
hydrated or solvated as well as unhydrated or unsolvated forms of
the identified compound. For example, the indicated compounds
include both hydrated and non-hydrated forms. Other examples of
solvates include compounds as described herein in combination with
a suitable solvent, such as isopropanol, ethanol, methanol, DMSO,
ethyl acetate, acetic acid, or ethanolamine.
Formulations and Administration
[0519] Compounds as described herein will typically be used in
therapy for human subjects. However, compounds as described herein
may also be used to treat similar or identical indications in other
animal subjects, and can be administered by different routes,
including injection (i.e. parenteral, including intravenous,
intraperitoneal, subcutaneous, and intramuscular), oral,
transdermal, transmucosal, rectal, or inhalant. Such dosage forms
should allow the compound to reach target cells. Other factors are
well known in the art, and include considerations such as toxicity
and dosage forms that retard the compound or composition from
exerting its effects. Techniques and formulations generally may be
found in Remington: The Science and Practice of Pharmacy, 21.sup.st
edition, Lippincott, Williams and Wilkins, Philadelphia, Pa., 2005
(hereby incorporated by reference herein).
[0520] In some embodiments, compositions will comprise
pharmaceutically acceptable carriers or excipients, such as
fillers, binders, disintegrants, glidants, lubricants, complexing
agents, solubilizers, and surfactants, which may be chosen to
facilitate administration of the compound by a particular route.
Examples of carriers include calcium carbonate, calcium phosphate,
various sugars such as lactose, glucose, or sucrose, types of
starch, cellulose derivatives, gelatin, lipids, liposomes,
nanoparticles, and the like. Carriers also include physiologically
compatible liquids as solvents or for suspensions, including, for
example, sterile solutions of water for injection (WFI), saline
solution, dextrose solution, Hank's solution, Ringer's solution,
vegetable oils, mineral oils, animal oils, polyethylene glycols,
liquid paraffin, and the like. Excipients may also include, for
example, colloidal silicon dioxide, silica gel, talc, magnesium
silicate, calcium silicate, sodium aluminosilicate, magnesium
trisilicate, powdered cellulose, macrocrystalline cellulose,
carboxymethyl cellulose, cross-linked sodium
carboxymethylcellulose, sodium benzoate, calcium carbonate,
magnesium carbonate, stearic acid, aluminum stearate, calcium
stearate, magnesium stearate, zinc stearate, sodium stearyl
fumarate, syloid, stearowet C, magnesium oxide, starch, sodium
starch glycolate, glyceryl monostearate, glyceryl dibehenate,
glyceryl palmitostearate, hydrogenated vegetable oil, hydrogenated
cotton seed oil, castor seed oil mineral oil, polyethylene glycol
(e.g. PEG 4000-8000), polyoxyethylene glycol, poloxamers, povidone,
crospovidone, croscarmellose sodium, alginic acid, casein,
methacrylic acid divinylbenzene copolymer, sodium docusate,
cyclodextrins (e.g. 2-hydroxypropyl-.delta.-cyclodextrin),
polysorbates (e.g. polysorbate 80), cetrimide, TPGS
(d-alpha-tocopheryl polyethylene glycol 1000 succinate), magnesium
lauryl sulfate, sodium lauryl sulfate, polyethylene glycol ethers,
di-fatty acid ester of polyethylene glycols, or a polyoxyalkylene
sorbitan fatty acid ester (e.g., polyoxyethylene sorbitan ester
Tween.RTM.), polyoxyethylene sorbitan fatty acid esters, sorbitan
fatty acid ester, e.g. a sorbitan fatty acid ester from a fatty
acid such as oleic, stearic or palmitic acid, mannitol, xylitol,
sorbitol, maltose, lactose, lactose monohydrate or lactose spray
dried, sucrose, fructose, calcium phosphate, dibasic calcium
phosphate, tribasic calcium phosphate, calcium sulfate, dextrates,
dextran, dextrin, dextrose, cellulose acetate, maltodextrin,
simethicone, polydextrosem, chitosan, gelatin, HPMC (hydroxypropyl
methyl celluloses), HPC (hydroxypropyl cellulose), hydroxyethyl
cellulose, and the like.
[0521] In some embodiments, oral administration may be used.
Pharmaceutical preparations for oral use can be formulated into
conventional oral dosage forms such as capsules, tablets, and
liquid preparations such as syrups, elixirs, and concentrated
drops. Compounds as described herein may be combined with solid
excipients, optionally grinding a resulting mixture, and processing
the mixture of granules, after adding suitable auxiliaries, if
desired, to obtain, for example, tablets, coated tablets, hard
capsules, soft capsules, solutions (e.g. aqueous, alcoholic, or
oily solutions) and the like. Suitable excipients are, in
particular, fillers such as sugars, including lactose, glucose,
sucrose, mannitol, or sorbitol; cellulose preparations, for
example, corn starch, wheat starch, rice starch, potato starch,
gelatin, gum tragacanth, methyl cellulose,
hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose (CMC),
and/or polyvinylpyrrolidone (PVP: povidone); oily excipients,
including vegetable and animal oils, such as sunflower oil, olive
oil, or codliver oil. The oral dosage formulations may also contain
disintegrating agents, such as cross-linked polyvinylpyrrolidone,
agar, or alginic acid, or a salt thereof such as sodium alginate; a
lubricant, such as talc or magnesium stearate; a plasticizer, such
as glycerol or sorbitol; a sweetening agent such as sucrose,
fructose, lactose, or aspartame; a natural or artificial flavoring
agent, such as peppermint, oil of wintergreen, or cherry flavoring;
or dye-stuffs or pigments, which may be used for identification or
characterization of different doses or combinations. Also provided
are dragee cores with suitable coatings. For this purpose,
concentrated sugar solutions may be used, which may optionally
contain, for example, gum arabic, talc, poly-vinylpyrrolidone,
carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer
solutions, and suitable organic solvents or solvent mixtures.
[0522] Pharmaceutical preparations that can be used orally include
push-fit capsules made of gelatin ("gelcaps"), as well as soft,
sealed capsules made of gelatin, and a plasticizer, such as
glycerol or sorbitol. The push-fit capsules can contain the active
ingredients in admixture with filler such as lactose, binders such
as starches, and/or lubricants such as talc or magnesium stearate
and, optionally, stabilizers. In soft capsules, the active compound
may be dissolved or suspended in suitable liquids, such as fatty
oils, liquid paraffin, or liquid polyethylene glycols.
[0523] In some embodiments, injection (parenteral administration)
may be used, e.g., intramuscular, intravenous, intraperitoneal,
and/or subcutaneous. Compounds as described herein for injection
may be formulated in sterile liquid solutions, preferably in
physiologically compatible buffers or solutions, such as saline
solution, Hank's solution, or Ringer's solution. Dispersions may
also be prepared in non-aqueous solutions, such as glycerol,
propylene glycol, ethanol, liquid polyethylene glycols, triacetin,
and vegetable oils. Solutions may also contain a preservative, such
as methylparaben, propylparaben, chlorobutanol, phenol, sorbic
acid, thimerosal, and the like. In addition, the compounds may be
formulated in solid form, including, for example, lyophilized
forms, and redissolved or suspended prior to use.
[0524] In some embodiments, transmucosal, topical or transdermal
administration may be used. In such formulations of compounds as
described herein, penetrants appropriate to the barrier to be
permeated are used. Such penetrants are generally known in the art,
and include, for example, for transmucosal administration, bile
salts and fusidic acid derivatives. In addition, detergents may be
used to facilitate permeation. Transmucosal administration, for
example, may be through nasal sprays or suppositories (rectal or
vaginal). Compositions of compounds as described herein for topical
administration may be formulated as oils, creams, lotions,
ointments, and the like by choice of appropriate carriers known in
the art. Suitable carriers include vegetable or mineral oils, white
petrolatum (white soft paraffin), branched chain fats or oils,
animal fats and high molecular weight alcohol (greater than
C.sub.12). In some embodiments, carriers are selected such that the
active ingredient is soluble. Emulsifiers, stabilizers, humectants
and antioxidants may also be included as well as agents imparting
color or fragrance, if desired. Creams for topical application are
preferably formulated from a mixture of mineral oil,
self-emulsifying beeswax and water in which mixture the active
ingredient, dissolved in a small amount of solvent (e.g., an oil),
is admixed. Additionally, administration by transdermal means may
comprise a transdermal patch or dressing such as a bandage
impregnated with an active ingredient and optionally one or more
carriers or diluents known in the art. To be administered in the
form of a transdermal delivery system, the dosage administration
will be continuous rather than intermittent throughout the dosage
regimen.
[0525] In some embodiments, compounds are administered as
inhalants. Compounds as described herein may be formulated as dry
powder or a suitable solution, suspension, or aerosol. Powders and
solutions may be formulated with suitable additives known in the
art. For example, powders may include a suitable powder base such
as lactose or starch, and solutions may comprise propylene glycol,
sterile water, ethanol, sodium chloride and other additives, such
as acid, alkali and buffer salts. Such solutions or suspensions may
be administered by inhaling via spray, pump, atomizer, or
nebulizer, and the like. The compounds as described herein may also
be used in combination with other inhaled therapies, for example
corticosteroids such as fluticasone proprionate, beclomethasone
dipropionate, triamcinolone acetonide, budesonide, and mometasone
furoate; beta agonists such as albuterol, salmeterol, and
formoterol; anticholinergic agents such as ipratropium bromide or
tiotropium; vasodilators such as treprostinal and iloprost; enzymes
such as DNAase; therapeutic proteins; immunoglobulin antibodies; an
oligonucleotide, such as single or double stranded DNA or RNA,
siRNA; antibiotics such as tobramycin; muscarinic receptor
antagonists; leukotriene antagonists; cytokine antagonists;
protease inhibitors; cromolyn sodium; nedocril sodium; and sodium
chromoglycate.
[0526] The amounts of compounds as described herein to be
administered can be determined by standard procedures taking into
account factors such as the compound activity (in vitro, e.g. the
compound IC.sub.50 vs. target, or in vivo activity in animal
efficacy models), pharmacokinetic results in animal models (e.g.
biological half-life or bioavailability), the age, size, and weight
of the subject, and the disorder associated with the subject. The
importance of these and other factors are well known to those of
ordinary skill in the art. Generally, a dose will be in the range
of about 0.01 to 50 mg/kg, also about 0.1 to 20 mg/kg of the
subject being treated. Multiple doses may be used.
[0527] The compounds as described herein may also be used in
combination with other therapies for treating the same disease.
Such combination use includes administration of the compounds and
one or more other therapeutics at different times, or
co-administration of the compound and one or more other therapies.
In some embodiments, dosage may be modified for one or more of the
compounds as described herein or other therapeutics used in
combination, e.g., reduction in the amount dosed relative to a
compound or therapy used alone, by methods well known to those of
ordinary skill in the art.
[0528] It is understood that use in combination includes use with
other therapies, drugs, medical procedures etc., where the other
therapy or procedure may be administered at different times (e.g.
within a short time, such as within hours (e.g. 1, 2, 3, 4-24
hours), or within a longer time (e.g. 1-2 days, 2-4 days, 4-7 days,
1-4 weeks)) than a compound as described herein, or at the same
time as a compound as described herein. Use in combination also
includes use with a therapy or medical procedure that is
administered once or infrequently, such as surgery, along with a
compound as described herein administered within a short time or
longer time before or after the other therapy or procedure. In some
embodiments, the present invention provides for delivery of a
compound as described herein and one or more other drug
therapeutics delivered by a different route of administration or by
the same route of administration. The use in combination for any
route of administration includes delivery of a compound as
described herein and one or more other drug therapeutics delivered
by the same route of administration together in any formulation,
including formulations where the two compounds are chemically
linked in such a way that they maintain their therapeutic activity
when administered. In one aspect, the other drug therapy may be
co-administered with a compound as described herein. Use in
combination by co-administration includes administration of
co-formulations or formulations of chemically joined compounds, or
administration of two or more compounds in separate formulations
within a short time of each other (e.g. within an hour, 2 hours, 3
hours, up to 24 hours), administered by the same or different
routes. Co-administration of separate formulations includes
co-administration by delivery via one device, for example the same
inhalant device, the same syringe, etc., or administration from
separate devices within a short time of each other. Co-formulations
of a compound as described herein and one or more additional drug
therapies delivered by the same route includes preparation of the
materials together such that they can be administered by one
device, including the separate compounds combined in one
formulation, or compounds that are modified such that they are
chemically joined, yet still maintain their biological activity.
Such chemically joined compounds may have a linkage that is
substantially maintained in vivo, or the linkage may break down in
vivo, separating the two active components.
EXAMPLES
[0529] Examples related to the synthesis and use of compounds as
described herein are provided below. In most cases, alternative
synthetic and analysis techniques can be used. Additional synthetic
methods may be used in the synthesis of compounds as described in
the following examples, such as methods found, for example, in U.S.
patent application Ser. No. 11/473,347 (see also, PCT publication
WO2007002433), U.S. patent application Ser. No. 11/960,590
(Publication number 2008/0167338), U.S. patent application Ser. No.
11/961,901 (Publication number 2008/0188514), U.S. patent
application Ser. No. 11/986,667 (see also, PCT publication
WO2008064265), US Provisional Patent Application Ser. No.
61/060,418, U.S. Provisional Patent Application Ser. No.
61/054,445, and PCT patent application PCT/US2008/070124, the
disclosures of which are hereby incorporated by reference regarding
methods of making compounds. The examples are intended to be
illustrative and are not limiting or restrictive to the scope of
the invention. For example, where additional compounds are prepared
following a protocol of a Scheme for a particular compound, it is
understood that conditions may vary, for example, any of the
solvents, reaction times, reagents, temperatures, work up
conditions, or other reaction parameters may be varied employing
alternate solvents, reagents, reaction times, temperatures, work up
conditions, and the like, as are readily available to one skilled
in the art. In some examples, the mass spectrometry result
indicated for a compound may have more than one value due to the
isotope distribution of an atom in the molecule, such as a compound
having a bromo or chloro substituent.
[0530] Ring numbering for the 1H-pyrrolo[2,3-b]pyridine in the
following Examples is as follows:
##STR00030##
Example 1
Synthesis of
(3-amino-2,6-difluoro-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone
compounds
[0531]
(3-amino-2,6-difluoro-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-metha-
none compounds substituted at the 4 or 5 position were prepared by
the following schemes.
##STR00031##
Step 1--Preparation of (2,4-difluoro-phenyl)-carbamic acid benzyl
ester (3)
[0532] To 2,4-difluoro-phenylamine (1, 7.0 mL, 70.0 mmol) in 100 mL
of dichloromethane, pyridine (11 mL, 140.0 mmol) and benzyl
chloroformate (2, 11.9 mL, 83.4 mmol) were added. The reaction
mixture was stirred at room temperature for 1.5 hours. The reaction
mixture was concentrated under vacuum and the residue was
partitioned between ethyl acetate and potassium bisulfate solution.
The organic layer was dried with magnesium sulfate, filtered and
the filtrate concentrated under vacuum and crystallized from
hexanes to give the desired compound (3, 15.6 g, 85%).
Step 2--Preparation of (2,4-difluoro-3-formyl-phenyl)-carbamic acid
benzyl ester (4)
[0533] Into a round bottom flask was added
(2,4-difluoro-phenyl)-carbamic acid benzyl ester (3, 3.83 g, 14.5
mmol) in 148 mL of tetrahydrofuran. The solution was chilled to
-78.degree. C. and n-butyllithium (1.60 M in hexane, 19.1 mL, 30.0
mmol) was added over 30 minutes followed by the addition of 1.12 mL
of N,N-dimethylformamide. The reaction mixture was allowed to warm
to room temperature and stirred overnight. The reaction mixture was
poured into water and extracted with ethyl acetate and the organic
layer was washed with brine, dried over sodium sulfate, filtered
and the filtrate concentrated under vacuum and crystallized from
ether to give the desired compound (4, 3.0 g, 71%).
Step 3--Preparation of
{3-[(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-2,4-difluoro-
-phenyl}-carbamic acid benzyl ester (6)
[0534] Into a round bottom flask was added
5-chloro-1H-pyrrolo[2,3-b]pyridine (5, 0.524 g, 3.43 mmol) in 5.00
mL of methanol. Potassium hydroxide (0.800 g, 14.2 mmol) and
(2,4-difluoro-3-formyl-phenyl)-carbamic acid benzyl ester (4, 1.02
g, 3.5 mmol) were added and the reaction mixture was stirred
overnight. The reaction mixture was poured into 1N hydrochloric
acid and extracted with ethyl acetate. The organic layer was washed
with brine, dried over sodium sulfate, filtered and the filtrate
concentrated under vacuum and crystallized from ethyl acetate to
give the desired compound (6, 710 mg, 46%). MS (ESI)
[M+H.sup.+].sup.+=444.
Step 4--Preparation of
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-c-
arbamic acid benzyl ester (7)
[0535] Into a round bottom flask was added
{3-[(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-2,4-difluoro-
-phenyl}-carbamic acid benzyl ester (6, 1.01 g, 2.28 mmol) in 5.00
mL of tetrahydrofuran. Dess-Martin periodinane (1.20 g, 2.89 mmol)
was added in portions. The reaction mixture was stirred at room
temperature for 10 minutes, then poured into water and extracted
with ethyl acetate. The organic layer was washed with brine, dried
over sodium sulfate, filtered and the filtrate concentrated under
vacuum and purified by silica gel chromatography to give the
desired compound (7, 914 mg, 91%). MS (ESI)
[M+H.sup.+].sup.+=442.
Step 5--Preparation of
(3-amino-2,6-difluoro-phenyl)-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-me-
thanone (8)
[0536]
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phe-
nyl]-carbamic acid benzyl ester (7, 800 mg, 1.81 mmol) was added to
15.00 mL of 10 M sodium hydroxide and warmed to reflux overnight.
The reaction mixture was diluted with 30 mL of water and extracted
with ethyl acetate. The organic layer was separated, dried,
filtered and the filtrate concentrated under vacuum to give the
desired compound (8, 450 mg, 81%).
[0537]
3-(3-Amino-2,6-difluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridine-5-carbon-
itrile 9,
(3-amino-2,6-difluoro-phenyl)-(4-methoxy-1H-pyrrolo[2,3-b]pyridi-
n-3-yl)-methanone 10, and
(3-amino-2,6-difluoro-phenyl)-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-m-
ethanone 11,
##STR00032##
were prepared similarly to the protocol of Scheme 1, replacing
5-chloro-1H-pyrrolo[2,3-b]pyridine 5 with
1H-pyrrolo[2,3-b]pyridine-5-carbonitrile,
4-methoxy-1H-pyrrolo[2,3-b]pyridine, and
5-methoxy-1H-pyrrolo[2,3-b]pyridine, respectively, in Step 3.
[0538]
3-(3-Amino-2,6-difluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridine-4-carbon-
itrile 13
##STR00033##
was prepared similarly, replacing
5-chloro-1H-pyrrolo[2,3-b]pyridine 5 with
1H-pyrrolo[2,3-b]pyridine-4-carbonitrile in Step 3, resulting in
the methyl ester of the carbamic acid along with the benzyl ester.
The methyl ester is carried through Step 4 and the resulting
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-ca-
rbamic acid methyl ester (12) was reacted by the following Step
5a:
##STR00034##
Step 5a--Preparation of
3-(3-amino-2,6-difluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile
(13)
[0539] To
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-p-
henyl]-carbamic acid methyl ester (12, 0.290 g, 0.814 mmol) in 3.0
mL of acetonitrile at 25.degree. C. under an atmosphere of
nitrogen, iodotrimethylsilane (0.431 mL, 3.03 mmol) was added. The
reaction was stirred at room temperature overnight, then
concentrated and washed with ethyl acetate and hexane to give a
brown solid, which was used without further purification (13, 245
mg, 79.1% purity) or further purified. MS (ESI)
[M+H.sup.+].sup.+=299.0.
[0540]
(3-Amino-2,6-difluoro-phenyl)-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3--
yl)-methanone 17 was prepared in two steps from
2,6-difluoro-3-nitro-benzoyl chloride 14 and
5-methyl-1H-pyrrolo[2,3-b]pyridine 15 as shown in Scheme 1a.
##STR00035##
Step 1--Preparation of
(2,6-difluoro-3-nitro-phenyl)-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-me-
thanone (16)
[0541] To 5-methyl-1H-pyrrolo[2,3-b]pyridine (15, 2.00 g, 15.1
mmol) and aluminum trichloride (11.6 g, 87.2 mmol), nitromethane
(63.1 mL, 1.16 mol) was added, followed by the addition of
2,6-difluoro-3-nitro-benzoyl chloride (14, 3.22 g, 14.5 mmol). The
reaction was placed in an oil bath at 45.degree. C. and stirred for
3 days, then cooled to room temperature and 30 mL of methanol was
added. The reaction was then diluted with 200 mL of ethyl acetate
and 100 mL each of water and 1N hydrochloric acid, resulting in a
precipitate that was collected to provide the desired compound (16,
2.761 g). Additional compound was recovered from the organic layer,
removing the solvent and purifying by silica gel column
chromatography eluting with a gradient of 5 to 70% ethyl acetate in
hexanes to provide another 126 mg of compound. MS (ESI)
[M+H.sup.+].sup.+=317.9.
Step 2--Preparation of
(3-amino-2,6-difluoro-phenyl)-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-me-
thanone (17)
[0542] To
(2,6-difluoro-3-nitro-phenyl)-(5-methyl-1H-pyrrolo[2,3-b]pyridin-
-3-yl)-methanone (16, 1.165 g, 3.672 mmol), 80 mL of ethyl acetate
was added, followed by stannous chloride, dihydrate (2.86 g, 12.6
mmol). The suspension was stirred in an oil bath at 65.degree. C.
for 18 hours, then poured into a beaker with 200 mL each of water
and saturated bicarbonate. The resulting milky suspension was
treated with celite, then vacuum filtered through a thin pad of
celite. The resulting clear layers of the filtrate were separated
and the solvents were removed from the ethyl acetate layer. The
resulting material was purified by silica gel column chromatography
eluting with a gradient from 30 to 100% ethyl acetate in hexanes to
give the desired compound with some impurities. This material was
re-purified by silica gel column chromatography eluting with a
gradient from 1 to 60% methanol in dichloromethane to give the
desired compound (17, 760 mg). .sup.1H NMR was consistent with the
desired compound structure. MS (ESI) [M+H.sup.+].sup.+=288.5.
[0543]
(3-Amino-2,6-difluoro-phenyl)-(4-chloro-1H-pyrrolo[2,3-b]pyridin-3--
yl)-methanone 18
##STR00036##
was prepared similarly to the protocol of Scheme 1a, replacing
5-methyl-1H-pyrrolo[2,3-b]pyridine 15 with
4-chloro-1H-pyrrolo[2,3-b]pyridine in Step 1, and in Step 1a, the
nitro compound is reduced in ethanol using iron instead of stannous
chloride, and the reaction is carried out at 85.degree. C. MS (ESI)
[M+H.sup.+].sup.+=308.4.
[0544]
(3-Amino-2,6-difluoro-phenyl)-(5-iodo-1H-pyrrolo[2,3-b]pyridin-3-yl-
)-methanone 19
##STR00037##
was prepared similarly to the protocol of Scheme 1a, replacing
5-methyl-1H-pyrrolo[2,3-b]pyridine 15 with
5-iodo-1H-pyrrolo[2,3-b]pyridine in Step 1. MS (ESI)
[M+H.sup.+].sup.+=399.9. This was reacted further to provide
(3-amino-2,6-difluoro-phenyl)-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,-
3-b]pyridin-3-yl]-methanone 21 via the following Step 3a:
##STR00038##
Step 3a--Preparation of
(3-amino-2,6-difluoro-phenyl)-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,-
3-b]pyridin-3-yl]-methanone (21)
[0545] In a microwave vial,
(3-amino-2,6-difluoro-phenyl)-(5-iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)-meth-
anone (19, 1.36 g, 3.41 mmol), 2-methoxy-pyrimidine-5-boronic acid
(20, 1.05 g, 6.81 mmol), and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.25
g, 0.34 mmol) were mixed in 22 mL of 1.00 M potassium carbonate in
water and 18 mL of acetonitrile. The resulting mixture was heated
at 160.degree. C. in the microwave for 15 minutes. The resulting
mixture was filtered through a thin layer of celite, and the celite
bed was washed with a mixture of water and ethyl acetate. The two
layers of the filtrate were separated, and the aqueous layer was
extracted with ethyl acetate. The combined organic layers were
washed with brine, dried over sodium sulfate, filtered, and the
filtrate concentrated under vacuum. The residue was purified by
flash silica gel chromatography eluting with ethyl acetate and
dichloromethane to provide the desired compound (21, 0.567 g). MS
(ESI) [M+H.sup.+].sup.+=382.1.
[0546]
(3-Amino-2-fluoro-phenyl)-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-m-
ethanone 22
##STR00039##
was prepared similarly to the protocol of Scheme 1a, replacing
5-methyl-1H-pyrrolo[2,3-b]pyridine 15 with
5-bromo-1H-pyrrolo[2,3-b]pyridine and replacing
2,6-difluoro-3-nitro-benzoyl chloride 14 with
2-fluoro-3-nitro-benzoyl chloride in Step 1. MS (ESI)
[M+H.sup.+].sup.+=334.3 and 336.3. This was reacted further to
provide
(3-amino-2-fluoro-phenyl)-(5-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)-methano-
ne 23 via the following Step 3b:
##STR00040##
Step 3--Preparation of
(3-amino-2-fluoro-phenyl)-(5-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)-methano-
ne (23)
[0547] To
(3-amino-2-fluoro-phenyl)-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl-
)-methanone (22, 1.080 g, 3.232 mmol) in a vial,
N,N-dimethylacetamide (2.90 mL, 31.2 mmol) was added. The
suspension was degassed by bubbling with argon and zinc powder
(0.032 g, 0.48 mmol), 1,1'-bis(diphenylphosphino)ferrocene (0.0568
g, 0.102 mmol), zinc cyanide (0.223 g, 1.90 mmol), and
tris(dibenzylideneacetone)dipalladium (0) (0.053 g, 0.052 mmol)
were added at room temperature under argon. The mixture was heated
to 120.degree. C., resulting in most of the solid dissolving, and
the mixture was heated at 120.degree. C. for 2 hours, then cooled
to 100.degree. C. and 8 mL of water was added and the reaction
mixture cooled to room temperature. The reaction mixture was
extracted with ethyl acetate and saturated sodium chloride in
water. The organic layer was washed with water and brine, then
dried with magnesium sulfate, filtered and the filtrate
concentrated under vacuum. The residue was suspended in
acetonitrile and sonicated for 30 minutes, after which the
precipitated material was collected by filtration to provide the
desired compound as a tan solid (23, 613 mg). Additional material
was recovered from the filtrate by silica gel chromatography
eluting with ethyl acetate and hexanes, the appropriate fractions
were combined and the solvent removed to provide an additional 42
mg. MS (ESI) [M+H.sup.+].sup.+=280.9.
Example 2
Synthesis of 5-ethynyl-1H-pyrrolo[2,3-b]pyridine 27
[0548] 5-Ethynyl-1H-pyrrolo[2,3-b]pyridine 27 was synthesized in
two steps from 5-iodo-1H-pyrrolo[2,3-b]pyridine 24 as shown in
Scheme 2.
##STR00041##
Step 1--Preparation of
5-trimethylsilanylethynyl-1H-pyrrolo[2,3-b]pyridine (26)
[0549] 5-Iodo-1H-pyrrolo[2,3-b]pyridine (24, 0.303 g, 1.22 mmol),
(trimethylsilyl)acetylene (25, 0.210 mL, 1.46 mmol),
bis(triphenylphosphine)palladium(II) chloride (0.039 g, 0.055
mmol), and copper(I) iodide (0.0019 g, 0.010 mmol) were dissolved
in triethylamine (19 mL, 0.14 mol) under an atmosphere of nitrogen.
The resulting mixture was heated to 60.degree. C. and stirred under
an atmosphere of nitrogen for 16 hours. The triethylamine was
removed under vacuum, 30 mL of water was added to the residue, and
it was extracted with 2.times.20 mL with ether. The combined
organic layers were washed with brine and dried over sodium
sulfate. Solids were filtered out and the filtrate was concentrated
under vacuum. The crude material was purified by silica gel flash
chromatography, eluting with ethyl acetate and dichloromethane. The
appropriate fractions were combined and the solvents removed under
vacuum to provide the desired compound as a solid (26, 0.237 g). MS
(ESI) [M+H.sup.+].sup.+=215.3.
Step 2--Preparation of 5-ethynyl-1H-pyrrolo[2,3-b]pyridine (27)
[0550] 5-Trimethylsilanylethynyl-1H-pyrrolo[2,3-b]pyridine (26,
0.235 g, 1.10 mmol) was dissolved in 16 mL of methanol, and
potassium carbonate (0.0152 g, 0.110 mmol) was added. The reaction
was stirred for 2 hours at room temperature, then concentrated
under vacuum, and the residue was dissolve in dichloromethane,
dried over sodium sulfate. Solids were filtered out and the
filtrate was concentrated under vacuum. The crude material was
purified by silica gel flash chromatography, eluting with ethyl
acetate and hexane. The appropriate fractions were combined and the
solvents removed under vacuum to provide the desired compound as a
solid (27, 0.155 g). MS (ESI) [M+H.sup.+].sup.+=143.3.
Example 3
Synthesis of 5-(3-methoxy-prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridine
32
[0551] 5-(3-Methoxy-prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridine 32 was
synthesized in three steps from 5-iodo-1H-pyrrolo[2,3-b]pyridine 24
as shown in Scheme 3.
##STR00042##
Step 1--Preparation of
1-benzenesulfonyl-5-iodo-1H-pyrrolo[2,3-b]pyridine (29)
[0552] 5-Iodo-1H-pyrrolo[2,3-b]pyridine (24, 0.521 g, 2.13 mmol),
tetra-N-butylammonium bromide (0.0689 g, 0.214 mmol), and 5.00 M
sodium hydroxide in water (5.50 mL, 0.0275 mol) were combined in a
round bottom flask. Benzenesulfonyl chloride (28, 0.327 mL, 2.56
mmol) in 5.0 mL of tetrahydrofuran was added dropwise at room
temperature. The reaction was stirred at room temperature overnight
and the two layers were separated. The aqueous layer was washed
with ethyl acetate and the combined organic layers were washed with
1M aqueous sodium bicarbonate followed by water. The organic layer
was washed with brine and dried over anhydrous sodium sulfate, then
filtered and the filtrate concentrated. The crude material was
purified by silica gel flash chromatography eluting with ethyl
acetate and dichloromethane. The appropriate fractions were
combined and the solvents removed under vacuum to provide the
desired compound (29, 0.702 g).
Step 2--Preparation of
1-benzenesulfonyl-5-(3-methoxy-prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridine
(31)
[0553] 1-Benzenesulfonyl-5-iodo-1H-pyrrolo[2,3-b]pyridine (29,
0.482 g, 1.23 mmol), 3-methoxy-propyne (30, 0.127 mL, 1.48 mmol),
bis(triphenylphosphine)palladium(II) chloride (0.039 g, 0.056
mmol), and copper(I) iodide (0.0020 g, 0.010 mmol) were dissolved
in 19 mL of triethylamine under an atmosphere of nitrogen. The
resulting mixture was heated to 60.degree. C. and stirred under an
atmosphere of nitrogen for 16 hours. The triethylamine was removed
under vacuum and 30 mL of water was added to the residue, and
extracted with 2.times.20 mL of ether. The combined organic layers
were washed with brine and dried over sodium sulfate, filtered and
the filtrate concentrated under vacuum. The crude material was
purified by silica gel flash chromatography eluting with ethyl
acetate and dichloromethane. The appropriate fractions were
combined and the solvents removed under vacuum to provide the
desired compound.
Step 3--Preparation of
5-(3-methoxy-prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridine (32)
[0554] Under an atmosphere of nitrogen
1-benzenesulfonyl-5-(3-methoxy-prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridine
(31, 0.541 g, 1.66 mmol) was dissolved in 13 mL of tetrahydrofuran
and 1.00 M tetra-n-butylammonium fluoride in 9.12 mL of
tetrahydrofuran was added. The resulting solution was stirred for
three hours at room temperature under an atmosphere of nitrogen.
The reaction was quenched with water and the two layers were
separated. The aqueous layer was extracted with ethyl acetate and
the combined organic layers were washed with brine and dried over
anhydrous sodium sulfate, then filtered and the filtrate
concentrated under vacuum. The crude material was purified by
silica gel flash chromatography eluting with ethyl acetate and
dichloromethane. The appropriate fractions were combined and the
solvents removed under vacuum to provide the desired compound (32,
0.215 g).
[0555] Diethyl-[3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-prop-2-ynyl]amine
33
##STR00043##
was prepared similarly to the protocol of Scheme 3, replacing
3-methoxy-propyne 30 with diethyl-prop-2-ynyl-amine in Step 2.
Example 4
Synthesis of
5-(1H-pyrrolo[2,3-b]pyridin-5-yl)-pyridine-2-carboxylic acid
ethylamide 38
[0556] 5-(1H-Pyrrolo[2,3-b]pyridin-5-yl)-pyridine-2-carboxylic acid
ethylamide 38 was synthesized in two steps from
5-bromo-pyridine-2-carboxylic acid 34 as shown in Scheme 4.
##STR00044##
Step 1--Preparation of 5-bromo-pyridine-2-carboxylic acid
ethylamide (36) 5-Bromo-pyridine-2-carboxylic acid (34, 0.417 g,
2.06 mmol) was dissolved in 19 mL of tetrahydrofuran.
N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.633
g, 3.30 mmol), N,N-diisopropylethylamine (1.81 mL, 10.4 mmol), and
1-hydroxybenzotriazole (0.363 g, 2.68 mmol) were added, followed by
2.00 M ethylamine in tetrahydrofuran (35, 1.20 mL, 2.40 mmol). The
reaction mixture was stirred overnight at room temperature, after
which 1.5 mL of dimethylformamide was added and stirred for another
4 hours. The resulting mixture was poured into water and extracted
with ethyl acetate. The combined organic layers were washed with
brine, dried over anhydrous sodium sulfate and filtered. The
filtrate was concentrated under vacuum. The crude material was
purified by silica gel flash chromatography. The appropriate
fractions were combined and the solvents removed under vacuum to
provide the desired compound (36, 163 mg). MS (ESI)
[M+H.sup.+].sup.+=229.29, 231.3.
Step 2--Preparation of
5-(1H-pyrrolo[2,3-b]pyridin-5-yl)-pyridine-2-carboxylic acid
ethylamide (38)
[0557]
5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]p-
yridine (37, 0.424 g, 1.74 mmol), 5-bromo-pyridine-2-carboxylic
acid ethylamide (36, 0.159 g, 0.694 mmol), and
tetrakis(triphenylphosphine)palladium(0) (0.016 g, 0.014 mmol) were
mixed in 1.00 M potassium carbonate in water (4.2 mL, 4.2 mmol).
The reaction mixture was heated at 80.degree. C. overnight. The two
layers were separated, and the aqueous layer was extracted with
ethyl acetate. The combined organic layers were washed with brine,
dried over anhydrous sodium sulfate and filtered. The filtrate was
concentrated under vacuum. The crude material was purified by
silica gel flash chromatography. The appropriate fractions were
combined and the solvents removed under vacuum to provide the
desired compound (38, 200 mg). MS (ESI)
[M+H.sup.+].sup.+=267.2.
[0558] 5-(1H-Pyrrolo[2,3-b]pyridin-5-yl)-pyridine-2-carboxylic acid
methylamide 39, and
5-(1H-pyrrolo[2,3-b]pyridin-5-yl)-pyridine-2-carboxylic acid
cyclopropylamide 40,
##STR00045##
were prepared following the protocol of Scheme 4, replacing
ethylamine 35 with methylammonium chloride and cycloalkylamine,
respectively in Step 1. MS (ESI) [M+H.sup.+].sup.+=253.1 (39), and
279.1 (40).
Example 5
Synthesis of
5-[6-(3-methoxy-propyl)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine
44
[0559]
5-[6-(3-Methoxy-propyl)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine 44
was synthesized in three steps from 2,5-dibromo-pyridine 41 as
shown in Scheme 5.
##STR00046##
Step 1--Preparation of 5-bromo-2-(3-methoxy-prop-1-ynyl)-pyridine
(108)
[0560] A solution of 2,5-dibromo-pyridine (41, 4.64 g, 19.6 mmol),
3-methoxy-propyne (30, 1.66 mL, 19.7 mmol), and copper(I) iodide
(0.084 g, 0.44 mmol) in 61.6 mL of triethylamine was purged with
nitrogen, and bis(triphenylphosphine)palladium(II) chloride (0.31
g, 0.44 mmol) was added at 0.degree. C. The resulting mixture was
stirred at 0.degree. C. for 1 hour, then at room temperature for 1
hour. The reaction mixture was diluted with ethyl acetate, then
washed with water and brine. The organic layer was dried with
anhydrous sodium sulfate, filtered and the filtrate concentrated
under vacuum. The crude material was purified by silica gel flash
chromatography eluting with ethyl acetate and hexane. The
appropriate fractions were combined and the solvents removed under
vacuum to provide the desired compound (42, 2.64 g).
Step 2--Preparation of
5-[6-(3-methoxy-prop-1-ynyl)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine
(43)
[0561]
5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]p-
yridine (37, 0.998 g, 4.09 mmol),
5-bromo-2-(3-methoxy-prop-1-ynyl)-pyridine (42, 0.616 g, 2.72
mmol), and tetrakis(triphenylphosphine)palladium(0) (0.157 g, 0.136
mmol) were mixed in 8.2 mL of 1.00 M potassium carbonate in water
(8.2 mmol) and 22 mL of tetrahydrofuran. The resulting mixture was
heated at 80.degree. C. Ethyl acetate and water were added, and the
two layers were separated. The aqueous layer was extracted with
ethyl acetate. The combined organic layers were washed with brine,
dried over sodium sulfate, filtered, and the filtrate concentrated
under vacuum. The crude material was purified by silica gel flash
chromatography. The appropriate fractions were combined and the
solvents removed under vacuum to provide the desired compound (43,
565 mg). MS (ESI) [M+H.sup.+].sup.+=264.3.
Step 3--Preparation of
5-[6-(3-methoxy-propyl)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine
(44)
[0562]
5-[6-(3-Methoxy-prop-1-ynyl)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridin-
e (43, 0.534 g, 2.03 mmol) was dissolved in 8.1 mL of methanol.
Palladium hydroxide (0.028 g, 0.20 mmol) was added, and the
resulting mixture was stirred under an atmosphere of hydrogen for a
few hours, then filtered through a bed of celite. The filtrate was
concentrated under vacuum. The crude material was purified by
silica gel flash chromatography eluting with ethyl acetate and
hexane. The appropriate fractions were combined and the solvents
removed under vacuum to provide the desired compound (44, 419 g).
MS (ESI) [M+H.sup.+].sup.+=268.3.
[0563]
Diethyl-{3-[5-(1H-pyrrolo[2,3-b]pyridin-5-yl)-pyridin-2-yl]-prop-2--
ynyl}-amine 45
##STR00047##
was prepared following the protocol of Scheme 5, steps 1 and 2,
replacing 3-methoxy-propyne 30 with diethyl-prop-2-ynyl-amine in
step 1. MS (ESI) [M+H.sup.+].sup.+=305.3.
Example 6
Synthesis of
dimethyl-{3-[5-(1H-pyrrolo[2,3-b]pyridin-5-yl)-pyrimidin-2-yloxy]-propyl}-
-amine 49
[0564]
Dimethyl-{3-[5-(1H-pyrrolo[2,3-b]pyridin-5-yl)-pyrimidin-2-yloxy]-p-
ropyl}-amine 49 was synthesized in two steps from
5-bromo-2-chloro-pyrimidine 46 as shown in Scheme 6.
##STR00048##
Step 1--Preparation of
[3-(5-bromo-pyrimidin-2-yloxy)-propyl]-dimethyl-amine (48)
[0565] To a solution of 3-(dimethylamino)-1-propanol (47, 3.45 mL,
2.84 mmol) in 10 mL of dry tetrahydrofuran, sodium hydride (0.0784
g, 3.10 mmol) was added at room temperature. After 15 minutes,
5-bromo-2-chloro-pyrimidine (46, 0.500 g, 2.58 mmol) was added and
the mixture was stirred at room temperature for 16 hours. To this,
.about.500 .mu.L of saturated ammonium chloride was added and the
reaction was treated with ethyl acetate and filtered. The solvents
were removed from the filtrate under vacuum, then added diethyl
ether, removed solvent under vacuum and repeated twice. The
resulting residue was taken up with tetrahydrofuran/acetonitrile
and filtered. Silica gel was added to the filtrate and solvents
removed under vacuum, then purified by silica gel chromatography
eluting with 1 to 6% methanol in dichloromethane, followed with 20%
methanol in dichloromethane. The appropriate fractions were
combined and the solvents removed under vacuum to provide the
desired compound (48, 259 mg). MS (ESI)
[M+H.sup.+].sup.+=261.9.
Step 2--Preparation of
dimethyl-{3-[5-(1H-pyrrolo[2,3-b]pyridin-5-yl)-pyrimidin-2-yloxy]-propyl}-
-amine (49)
[0566] Into a round bottom flask,
[3-(5-bromo-pyrimidin-2-yloxy)-propyl]-dimethyl-amine (48, 259 mg,
0.996 mmol),
5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]-
pyridine (37, 364 mg, 1.49 mmol),
tetrakis(triphenylphosphine)palladium(0) (57.5 mg, 0.0498 mmol),
and tetra-n-butylammonium iodide (37 mg, 0.10 mmol) were mixed in 6
mL of 1.00 M potassium carbonate in water (6.0 mmol) and 12 mL of
tetrahydrofuran. The resulting mixture was heated at 70.degree. C.
overnight. The two layers were separated and the aqueous layer was
extracted with ethyl acetate. The organic layers were washed with
saturated aqueous sodium bicarbonate, water, and brine, dried over
anhydrous sodium sulfate, filtered, and the filtrate concentrated
under vacuum. The crude material was purified by silica gel
chromatography, eluting with up to 30% methanol in dichloromethane.
The appropriate fractions were combined and concentrated under
vacuum, then further purified on a new column eluting with 15%
methanol in ethyl acetate with 8% triethylamine. The appropriate
fractions were combined and concentrated under vacuum to provide
the desired compound as an off-white solid (49, 76 mg). MS (ESI)
[M+H.sup.+].sup.+=298.0.
Example 7
Synthesis of propane-1-sulfonic acid
[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide 56
[0567] Propane-1-sulfonic acid
[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide 56 was synthesized in five steps from 2,4-difluoro-phenylamine
1 as shown in Scheme 7.
##STR00049##
Step 1--Preparation of 3-amino-2,6-difluoro-benzoic acid benzyl
ester (50)
[0568] To 2,4-difluoro-phenylamine (1, 5.11 mL, 50.7 mmol) in
tetrahydrofuran (250 mL), cooled with dry ice/acetone bath under an
atmosphere of nitrogen, was added n-butyllithium (1.60 M in hexane,
34.0 mL, 54.4 mmol) slowly. After 30 minutes,
1,2-Bis-(chloro-dimethyl-silanyl)-ethane (11.5 g, 53.4 mmol)
dissolved in tetrahydrofuran (40.0 mL) was added to the reaction
slowly. After 1 hour, n-butyllithium (1.60 M in hexane, 31.9 mL,
51.0 mmol) was added slowly to the reaction. The reaction was
stirred at -78.degree. C. for 30 minutes and then allowed to warm
to room temperature over 40 minutes. The reaction was cooled to
-78.degree. C., followed by addition of n-butyllithium (1.60 M in
hexane, 35.1 mL, 56.2 mmol) slowly. After 70 minutes, benzyl
chloroformate (7.97 mL, 55.8 mmol) was added to the reaction. The
reaction mixture was stirred at -78.degree. C. overnight followed
by addition of 2 N HCl (120 mL). The reaction was allowed to warm
to room temperature for 2 hours. The organic layer was separated.
The aqueous layer was basified with potassium carbonate and
extracted with ethyl acetate. The organic layers were combined and
washed with brine, dried over anhydrous sodium sulfate, filtrated
and concentrated. The desired compound was isolated by silica gel
column chromatography (ethyl acetate/hexane 20%) to give a
colorless oil (50, 10.6 g, 79.7%). MS (ESI)
[M+H.sup.+].sup.+=264.1.
Step 2--Preparation of
2,6-difluoro-3-(propane-1-sulfonylamino)-benzoic acid benzyl ester
(52)
[0569] To 3-amino-2,6-difluoro-benzoic acid benzyl ester (50, 6.00
g, 22.8 mmol) in methylene chloride (150 mL) was added pyridine
(2.76 mL, 34.2 mmol) and propane-1-sulfonyl chloride (51, 3.80 mL,
33.8 mmol). The reaction was stirred at room temperature overnight.
Then the reaction was poured into water, and extracted with ethyl
acetate. The organic layer was washed with brine, dried over
anhydrous sodium sulfate, filtrated and concentrated. The desired
compound was isolated with silica gel column chromatography to give
a colorless oil (52, 7.0 g, 83.1%). MS (ESI)
[M+H.sup.+].sup.+=370.1.
Step 3--Preparation of
2,6-difluoro-3-(propane-1-sulfonylamino)-benzoic acid (53)
[0570] To 2,6-difluoro-3-(propane-1-sulfonylamino)-benzoic acid
benzyl ester (52, 2.0 g, mmol) in methanol (30 mL) was added 20%
palladium hydroxide on carbon (100 mg). The reaction was stirred
under hydrogen at 1 atm for 15 minutes. The reaction was filtered
and the filtrate concentrated under vacuum to provide the desired
compound.
Step 4--Preparation of
2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl chloride (54)
[0571] To 2,6-difluoro-3-(propane-1-sulfonylamino)-benzoic acid
(53, 1.50 g, 5.4 mmol) was added toluene (7.0 mL) and thionyl
chloride (15.0 mL, 0.21 mmol). The reaction was heated to reflux
for 3 hours. The reaction was concentrated to give crude compound
that was used in the next step.
Step 5--Preparation of propane-1-sulfonic acid
[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (56)
[0572] To aluminum trichloride (8.89 g, 66.7 mmol) was added
methylene chloride (150 mL) under an atmosphere of nitrogen below
5.degree. C. Into this, 5-bromo-1H-pyrrolo[2,3-b]pyridine (55, 1.64
g, 8.34 mmol) in methylene chloride (20 mL) was added. The reaction
was stirred for 60.0 minutes and
2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl chloride (54, 3.50
g, 11.8 mmol) in methylene chloride (20 mL) was added. The reaction
was stirred for 6 hours and warmed to room temperature overnight.
The reaction mixture was poured into water and extracted with ethyl
acetate. The organic layer was dried over anhydrous sodium sulfate,
filtrated and concentrated. The desired compound was isolated by
silica gel column chromatography (methylene chloride/methanol 5%)
to give a white solid (56, 1.2 g, 31.4%). MS (ESI)
[M+H.sup.+].sup.+=460.0, 462.0.
Example 8
Synthesis of propane-1-sulfonic acid
(2,4-difluoro-3-formyl-phenyl)-amide 58
[0573] Propane-1-sulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide
58 was synthesized in two steps from 2,4-difluorophenylamine 1 as
shown in Scheme 8.
##STR00050##
Step 1--Preparation of propane-1-sulfonic acid
(2,4-difluoro-phenyl)-amide (57)
[0574] To 2,4-difluoro-phenylamine (1, 3.0 mL, 29.8 mmol) in
tetrahydrofuran (50 mL) were added triethylamine (9.13 mL, 65.5
mmol) and propane-1-sulfonyl chloride (51, 2.90 mL, 25.8 mmol)
under an atmosphere of nitrogen. The reaction was stirred at room
temperature overnight. The reaction was poured into 1 M HCl and
extracted with ethyl acetate. The organic layer was washed with
brine, dried over anhydrous sodium sulfate and filtered. The
filtrate was concentrated to give the compound (57, 2.0 g, 28%)
that was used in the next step.
Step 2--Preparation of propane-1-sulfonic acid
(2,4-difluoro-3-formyl-phenyl)-amide (58)
[0575] To propane-1-sulfonic acid (2,4-difluoro-phenyl)-amide (57,
1.5 g, 6.38 mmol) in tetrahydrofuran (10 mL) under an atmosphere of
nitrogen, cooled in a -78.degree. C. acetone/dry ice bath was added
lithium diisopropylamide (0.80 M in tetrahydrofuran, 24 mL, freshly
prepared from n-butyllithium and diisopropylamine). After 30
minutes, N,N-dimethyl-formamide (542 .mu.L, 7.018 mmol) was added
dropwise to the reaction. The reaction was stirred for 30 minutes
at -78.degree. C. and then allowed to warm to room temperature for
40 minutes. The reaction was poured into water and extracted with
ethyl acetate. The organic layer was washed with brine, dried over
anhydrous sodium sulfate and filtered. The filtrate was
concentrated and purified by silica gel column chromatography
eluting with 5% ethyl acetate in hexane to give a light yellow
solid (58, 300 mg, 18%). MS (ESI) [M-H.sup.+].sup.-=262.3.
[0576] 2-Methyl-propane-1-sulfonic acid
(2,4-difluoro-3-formyl-phenyl)-amide 59
##STR00051##
was prepared similarly to the protocol of Scheme 8, replacing
propane-1-sulfonyl chloride 51 with 2-methyl-propane-1-sulfonyl
chloride in Step 1.
Example 9
Synthesis of propane-1-sulfonic acid
(2-fluoro-3-formyl-phenyl)-amide 67
[0577] Propane-1-sulfonic acid (2-fluoro-3-formyl-phenyl)-amide 67
was synthesized in seven steps from 4-chloro-2-fluoro-phenylamine
60 as shown in Scheme 9.
##STR00052## ##STR00053##
Step 1--Preparation of 3-Amino-6-chloro-2-fluoro-benzoic acid
benzyl ester (61)
[0578] To 4-chloro-2-fluoro-phenylamine (60, 6.30 mL, 57.0 mmol) in
tetrahydrofuran (300 mL), cooled with dry ice/acetone bath under an
atmosphere of nitrogen, n-butyllithium (2.50 M in hexane, 24.4 mL)
was added slowly. After 20 minutes,
1,2-Bis-(chloro-dimethyl-silanyl)-ethane (12.9 g, 60.0 mmol)
dissolved in tetrahydrofuran (40.0 mL) was added slowly to the
reaction. After 1 hour, n-butyllithium (2.50 M in hexane, 25.0 mL)
was added slowly to the reaction. The reaction was stirred at
-78.degree. C. for 20 minutes and then allowed to warm to room
temperature over 60 minutes. The reaction was cooled to -78.degree.
C., followed by addition of n-butyllithium (2.50 M in hexane, 26.0
mL) slowly. After 80 minutes, benzyl chloroformate (10.0 mL, 70.0
mmol) was added to the reaction. The reaction mixture was stirred
at -78.degree. C. overnight followed by addition of water (80 mL)
and concentrated hydrochloric acid (25 mL). The reaction was
allowed to warm to room temperature for 2 hours. The organic layer
was separated. The aqueous layer was basified with potassium
carbonate and extracted with ethyl acetate. The organic layers were
combined and washed with brine, dried over anhydrous sodium
sulfate, filtered and concentrated. The desired compound was
isolated by silica gel column chromatography (ethyl acetate/hexane
20%) to give a colorless oil (61, 12.5 g, 78.3%). MS (ESI)
[M+H.sup.+].sup.+=280.0.
Step 2--Preparation of
6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoic acid benzyl
ester (62)
[0579] To 3-amino-6-chloro-2-fluoro-benzoic acid benzyl ester (61,
1.20 g, 4.3 mmol) in methylene chloride (28 mL) was added pyridine
(0.52 mL, 6.4 mmol) and propane-1-sulfonyl chloride (51, 0.685 g,
4.8 mmol). The reaction was stirred at room temperature overnight,
then poured into water, and extracted with ethyl acetate. The
organic layer was washed with brine, dried over anhydrous sodium
sulfate, filtered and concentrated. The desired compound was
isolated with silica gel column chromatography to give a colorless
oil (62, 960 mg, 58.0%). MS (ESI) [M-H.sup.+].sup.-=384.1.
Step 3--Preparation of
6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoic acid (63)
[0580] To 6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoic
acid benzyl ester (62, 6.00 g, 15.6 mmol) in tetrahydrofuran (100
mL) was added 1.0 M aqueous potassium hydroxide (100 mL). The
reaction was heated to reflux overnight. The reaction was poured
into water, acidified to pH 2 with 1 N hydrochloric acid and
extracted with ethyl acetate. The organic portion was dried over
anhydrous sodium sulfate, filtered and concentrated to give a white
solid (63, 3.95 g, 85.8%).
Step 4--Preparation of 2-fluoro-3-(propane-1-sulfonylamino)-benzoic
acid (64)
[0581] To 6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoic
acid (63, 0.69 g, 2.3 mmol) in methanol (10 mL) was added 20%
palladium hydroxide on carbon (200 mg). The reaction was stirred
under hydrogen at 50 psi for 2 hours. The reaction was filtered and
concentrated to give the desired compound. MS (ESI)
[M-H.sup.+].sup.-=260.1.
Step 5--Preparation of 2-fluoro-3-(propane-1-sulfonylamino)-benzoic
acid methyl ester (65)
[0582] To a 2-fluoro-3-(propane-1-sulfonylamino)-benzoic acid (64,
5.05 g, 0.0193 mol) in methylene chloride (100 mL) was added
N,N-dimethylformamide (0.075 mL, 0.97 mmol) under an atmosphere of
nitrogen. The reaction was cooled with ice/water, followed by slow
addition of Oxalyl chloride (2.00 M of in methylene chloride, 10.8
mL, 21.6 mmol). The reaction mixture was stirred at room
temperature for 3.0 hours. The reaction was cooled with ice/water,
followed by addition of methanol (36.0 mL, 0.89 mol) slowly. The
reaction was stirred at room temperature overnight. The reaction
was concentrate and purified with silica gel column chromatography
eluting with 30% ethyl acetate in hexane to give a crude white
solid 4.0 g.
Step 6--Preparation of Propane-1-sulfonic acid
(2-fluoro-3-hydroxymethyl-phenyl)-amide (66)
[0583] To 2-fluoro-3-(propane-1-sulfonylamino)-benzoic acid methyl
ester (65, 3.80 g, 13.8 mmol) in tetrahydrofuran (133 mL) was added
lithium tetrahydroaluminate (1.00 M in tetrahydrofuran, 20.0 mL,
20.0 mmol) under an atmosphere of nitrogen at room temperature. The
reaction was stirred at room temperature for 8 hours, followed by
addition of 10 g of NaSO.sub.4.10H.sub.2O. After 12 hours, the
reaction was filtered, concentrated and purified with silica gel
column chromatography eluting with 5% methanol in methylene
chloride to give a white solid (66, 3.0 g, 87.9%).
Step 7--Preparation of propane-1-sulfonic acid
(2-fluoro-3-formyl-phenyl)-amide (67)
[0584] To propane-1-sulfonic acid
(2-fluoro-3-hydroxymethyl-phenyl)-amide (66, 0.20 g, 0.81 mmol) in
tetrahydrofuran (5.0 mL) was added Dess-Martin periodinane (0.377
g, 0.89 mmol). The reaction was stirred at room temperature for 10
minutes, then poured into water and extracted with ethyl acetate.
The organic layer was dried over anhydrous sodium sulfate, and
filtered. The filtrate was concentrated and purified by silica gel
column chromatography eluting with 20% ethyl acetate in hexane to
give a white solid (67, 100 mg, 50.0%). MS (ESI)
[M-H.sup.+].sup.+=244.1.
Example 10
Synthesis of 2-methyl-propane-1-sulfonic acid
[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide 69
[0585] 2-Methyl-propane-1-sulfonic acid
[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide 69 was synthesized in two steps from
5-bromo-1H-pyrrolo[2,3-b]pyridine 55 as shown in Scheme 10.
##STR00054##
Step 1--Preparation of 2-methyl-propane-1-sulfonic acid
{3-[(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-2,4-difluoro--
phenyl}-amide (68)
[0586] In a reaction vial, 5-bromo-1H-pyrrolo[2,3-b]pyridine (55,
287 mg, 1.46 mmol), 2-methyl-propane-1-sulfonic acid
(2,4-difluoro-3-formyl-phenyl)-amide (59, 445 mg, 1.60 mmol) and
potassium hydroxide (246 mg, 4.38 mmol) are combined with 7 mL of
methanol and stirred at room temperature overnight. The reaction
was combined with ethyl acetate and aqueous saturated sodium
chloride, and extracted. The organic layer was washed with water,
brine, and dried over magnesium sulfate, filtered and the filtrate
concentrated under vacuum. The residue was treated with 75 mL of
acetonitrile:water 4:1 with 5% trifluoroacetic acid and stirred
overnight at room temperature. The reaction was combined with ethyl
acetate and aqueous saturated sodium chloride, and extracted. The
organic layer was washed with water, brine, and dried over
magnesium sulfate, filtered and the filtrate concentrated under
vacuum to provide the desired compound (68, 618 mg).
Step 2--Preparation of 2-methyl-propane-1-sulfonic acid
[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (69)
[0587] In a round bottom flask, 2-methyl-propane-1-sulfonic acid
{3-[(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-2,4-difluoro--
phenyl}-amide (68, 618 mg, 1.30 mmol) was dissolved in 20 mL of
tetrahydrofuran, and Dess-Martin periodinane (555 mg, 1.31 mmol)
was added. The reaction was stirred at room temperature for 30
minutes, then quenched with water and extracted with ethyl acetate.
The organic layer was washed with sodium bicarbonate, water, and
brine, then dried with magnesium sulfate, filtered and concentrated
under vacuum. The resulting material was purified by silica gel
column chromatography, eluting with dichloromethane and methanol.
Appropriate fractions were collected and concentrated under vacuum
to provide the desired compound (69, 257 mg). MS (ESI)
[M-H.sup.+].sup.-=469.9, 471.9.
[0588] Propane-1-sulfonic acid
[2-fluoro-3-(5-iodo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
70
##STR00055##
was prepared similarly to the protocol of Scheme 10, replacing
5-bromo-1H-pyrrolo[2,3-b]pyridine 55 with
5-iodo-1H-pyrrolo[2,3-b]pyridine 24 and 2-methyl-propane-1-sulfonic
acid (2,4-difluoro-3-formyl-phenyl)-amide 59 with
propane-1-sulfonic acid (2-fluoro-3-formyl-phenyl)-amide 67 in step
1.
Example 11
Synthesis of
N-[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-
-3-fluoro-benzenesulfonamide P-2016
[0589]
N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-p-
henyl]-3-fluoro-benzenesulfonamide P-2016 was synthesized in one
step from
(3-amino-2,6-difluoro-phenyl)-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-me-
thanone 17 as shown in Scheme 11.
##STR00056##
Step 1--Preparation of
N-[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-
-3-fluoro-benzenesulfonamide (P-2016)
[0590] To
(3-amino-2,6-difluoro-phenyl)-(5-methyl-1H-pyrrolo[2,3-b]pyridin-
-3-yl)-methanone (17, 20 mg, 0.07 mmol) in 0.5 mL of
tetrahydrofuran and pyridine (50 .mu.L, 0.62 mmol),
4-fluoro-benzenesulfonyl chloride (71, 20.4 mg, 0.105 mmol) was
added and the reaction was stirred at room temperature overnight.
The mixture was concentrated under vacuum and the crude dry
material was dissolved in 0.5 mL of dimethylsulfoxide and purified
by reverse phase HPLC, eluting with 0.1% trifluoroacetic acid in
water and 0.1% trifluoroacetic acid in acetonitrile, 20-100%
acetonitrile over 40 minutes at 20 mL per minute. Appropriate
fractions were combined and the solvent removed under reduced
pressure to provide the desired compound. MS (ESI)
[M+H.sup.+].sup.+=445.9.
[0591] Additional compounds were prepared similarly to the protocol
of Scheme 11, where optimal reaction conditions may have varied in
terms of time and temperature of the reaction, and in
chromatography conditions for purification of the desired
compounds. The reactions were performed optionally replacing
(3-amino-2,6-difluoro-phenyl)-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-me-
thanone 17 with 5-(2-methoxy-pyrimidin-5-yl), 5-chloro, 5-cyano,
5-methoxy, 4-methoxy, 4-cyano, or
4-chloro(3-amino-2,6-difluoro-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-met-
hanone (prepared as described in Example 1) and/or replacing
4-fluoro-benzenesulfonyl chloride 71 with an appropriate sulfonyl
chloride. The following compounds were prepared by this procedure:
[0592]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-2,5-difluoro-benzenesulfonamide (P-2002), [0593]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-2,6-difluoro-benzenesulfonamide (P-2003), [0594]
N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-2-fluoro-benzenesulfonamide (P-2009), [0595]
N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-2,5-difluoro-benzenesulfonamide (P-2010), [0596]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2-fluoro-benzenesulfonamide (P-2011), [0597]
N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-
-2-fluoro-benzenesulfonamide (P-2014), [0598]
N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-
-2,5-difluoro-benzenesulfonamide (P-2015), [0599]
N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-2-fluoro-benzenesulfonamide (P-2017), [0600]
N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-2,5-difluoro-benzenesulfonamide (P-2018), [0601]
N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-3-fluoro-benzenesulfonamide (P-2019), [0602]
N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2-fluoro-benzenesulfonamide (P-2020), [0603]
N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-2-fluoro-benzenesulfonamide (P-2021), [0604]
N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-2,5-difluoro-benzenesulfonamide (P-2022), [0605]
N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-3-fluoro-benzenesulfonamide (P-2023), [0606]
N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-
-2,6-difluoro-benzenesulfonamide (P-2024), [0607]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2,6-difluoro-benzenesulfonamide (P-2029), [0608]
N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-2,6-difluoro-benzenesulfonamide (P-2031), [0609]
N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-2,6-difluoro-benzenesulfonamide (P-2033), [0610]
N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2,5-difluoro-benzenesulfonamide (P-2036), [0611]
N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2,6-difluoro-benzenesulfonamide (P-2037), [0612]
N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
3-fluoro-benzenesulfonamide (P-2039), [0613]
N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-
-3-carbonyl]-phenyl}-2-fluoro-benzenesulfonamide (P-2041), [0614]
N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-
-3-carbonyl]-phenyl}-2,5-difluoro-benzenesulfonamide (P-2042),
[0615]
N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-
-3-carbonyl]-phenyl}-2,6-difluoro-benzenesulfonamide (P-2043),
[0616]
N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-
-3-carbonyl]-phenyl}-3-fluoro-benzenesulfonamide (P-2045), [0617]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
benzenesulfonamide (P-2046), [0618]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-2-fl-
uoro-benzenesulfonamide (P-2051), [0619]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-2,5--
difluoro-benzenesulfonamide (P-2052), [0620]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-3-fl-
uoro-benzenesulfonamide (P-2053), [0621]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-2,6--
difluoro-benzenesulfonamide (P-2054), [0622]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-benz-
enesulfonamide (P-2056), [0623] Pyridine-3-sulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2069), [0624] Pyridine-3-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2071), [0625] Pyridine-3-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2072), [0626] Pyridine-3-sulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2073), [0627] Pyridine-3-sulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2074), [0628] Pyridine-3-sulfonic acid
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2077), and [0629] Pyridine-3-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2086).
[0630] The following table indicates the 1H-pyrrolo[2,3-b]pyridine
(column 2) and sulfonyl chloride (column 3) used to afford the
desired compound (column 4). The compound number is provided in
column 1, and the observed mass is in column 5.
TABLE-US-00001 MS(ESI) 1H-pyrrolo[2,3- Sulfonyl [M + H.sup.+].sup.+
b]pyridine chloride Compound observed P-2002 ##STR00057##
##STR00058## ##STR00059## 483.9 P-2003 ##STR00060## ##STR00061##
##STR00062## 483.9 P-2009 ##STR00063## ##STR00064## ##STR00065##
461.9 P-2010 ##STR00066## ##STR00067## ##STR00068## 479.9 P-2011
##STR00069## ##STR00070## ##STR00071## 457.1 P-2014 ##STR00072##
##STR00073## ##STR00074## 445.9 P-2015 ##STR00075## ##STR00076##
##STR00077## 463.9 P-2017 ##STR00078## ##STR00079## ##STR00080##
465.9 P-2018 ##STR00081## ##STR00082## ##STR00083## 483.9 P-2019
##STR00084## ##STR00085## ##STR00086## 465.9 P-2020 ##STR00087##
##STR00088## ##STR00089## 457.1 P-2021 ##STR00090## ##STR00091##
##STR00092## 461.9 P-2022 ##STR00093## ##STR00094## ##STR00095##
479.9 P-2023 ##STR00096## ##STR00097## ##STR00098## 461.9 P-2024
##STR00099## ##STR00100## ##STR00101## 463.9 P-2029 ##STR00102##
##STR00103## ##STR00104## 474.7 P-2031 ##STR00105## ##STR00106##
##STR00107## 479.9 P-2033 ##STR00108## ##STR00109## ##STR00110##
483.9 P-2036 ##STR00111## ##STR00112## ##STR00113## 475.1 P-2037
##STR00114## ##STR00115## ##STR00116## 474.7 P-2039 ##STR00117##
##STR00118## ##STR00119## 457.1 P-2041 ##STR00120## ##STR00121##
##STR00122## 539.9 P-2042 ##STR00123## ##STR00124## ##STR00125##
558.0 P-2043 ##STR00126## ##STR00127## ##STR00128## 558.0 P-2045
##STR00129## ##STR00130## ##STR00131## 539.9 P-2046 ##STR00132##
##STR00133## ##STR00134## 437.5 P-2051 ##STR00135## ##STR00136##
##STR00137## 439.1 P-2052 ##STR00138## ##STR00139## ##STR00140##
457.1 P-2053 ##STR00141## ##STR00142## ##STR00143## 438.7 P-2054
##STR00144## ##STR00145## ##STR00146## 457.7 P-2056 ##STR00147##
##STR00148## ##STR00149## 420.9 P-2069 ##STR00150## ##STR00151##
##STR00152## 429.1 P-2071 ##STR00153## ##STR00154## ##STR00155##
448.8 P-2072 ##STR00156## ##STR00157## ##STR00158## 439.9 P-2073
##STR00159## ##STR00160## ##STR00161## 445.1 P-2074 ##STR00162##
##STR00163## ##STR00164## 448.7 P-2077 ##STR00165## ##STR00166##
##STR00167## 439.9 P-2086 ##STR00168## ##STR00169## ##STR00170##
421.9
Example 12
Synthesis of propane-1-sulfonic acid
{3-[5-(6-chloro-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-d-
ifluoro-phenyl}-amide P-2154
[0631] Propane-1-sulfonic acid
{3-[5-(6-chloro-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-d-
ifluoro-phenyl}-amide P-2154 was synthesized in one step from
propane-1-sulfonic acid
[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide 56 as shown in Scheme 12.
##STR00171##
Step 1--Preparation of propane-1-sulfonic acid
{3-[5-(6-chloro-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-d-
ifluoro-phenyl}-amide (P-2154)
[0632] Propane-1-sulfonic acid
[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (56, 10 mg, 0.022 mmol) was weighed into a 5 mL microwave vial
and combined with 6-chloro-pyridine-3-boronic acid (72, 4.4 mg,
0.028 mmol), followed by the addition of 600 .mu.L of acetonitrile
and 500 .mu.L of 1M potassium carbonate and a spatula tip
(.apprxeq.1 mg) of
[1,1''-bis(diphenylphosphino)-ferrocene]dichloropalladium(II). The
reaction mixture was irradiated in a microwave at 160.degree. C.
for 5 minutes. The solution was neutralized with 100 .mu.L of
acetic acid and all material was transferred to a 4 mL vial and the
solvents were removed under vacuum. The crude material was
dissolved in 400 .mu.L of dimethylsulfoxide and purified by reverse
phase HPLC, eluting with 0.1% trifluoroacetic acid in water and
0.1% trifluoroacetic acid in acetonitrile, 20-100% acetonitrile
over 16 minutes at 6 mL per minute. Appropriate fractions were
combined and the solvent removed under reduced pressure to provide
the desired compound. MS (ESI) [M+H.sup.+].sup.+=491.1.
[0633] Additional compounds were prepared similarly to the protocol
of Scheme 12, where optimal reaction conditions may have varied in
terms of time and temperature of the reaction, or alternatively,
tetrakis(triphenylphosphine)palladium(0) was used as a catalyst,
and in chromatography conditions for purification of the desired
compounds. The reactions were performed optionally substituting
6-chloro-pyridine-3-boronic acid 72 with an appropriate boronic
acid and/or propane-1-sulfonic acid
[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide 56 with an appropriate 5-bromo-1H-pyrrolo[2,3-b]pyridine
derivative. The following compounds were prepared by this
procedure: [0634] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(6-fluoro-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-ca-
rbonyl]-phenyl}-amide (P-2155), [0635]
N-(4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-
-b]pyridin-5-yl}-phenyl)-acetamide (P-2161), [0636]
Propane-1-sulfonic acid
[2,4-difluoro-3-(5-pyrimidin-5-yl-1H-pyrrolo[2,3-b]pyridine-3-carbon-
yl)-phenyl]-amide (P-2162), [0637] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(2-fluoro-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-ca-
rbonyl]-phenyl}-amide (P-2164), [0638] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(4-methanesulfonylamino-phenyl)-1H-pyrrolo[2,3-b]pyrid-
ine-3-carbonyl]-phenyl}-amide (P-2165), [0639] Propane-1-sulfonic
acid
(2,4-difluoro-3-{5-[4-(morpholine-4-sulfonyl)-phenyl]-1H-pyrrolo[2,3-b]py-
ridine-3-carbonyl}-phenyl)-amide (P-2166), [0640]
4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-N-methyl-benzenesulfonamide (P-2167), [0641]
N-Cyclopropyl-4-{3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H--
pyrrolo[2,3-b]pyridin-5-yl}-benzenesulfonamide (P-2168), [0642]
Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(3-methanesulfonylamino-phenyl)-1H-pyrrolo[2,3-b]pyrid-
ine-3-carbonyl]-phenyl}-amide (P-2169), [0643] Propane-1-sulfonic
acid
{2,4-difluoro-3-[5-(2-fluoro-6-methyl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyri-
dine-3-carbonyl]-phenyl}-amide (P-2172), [0644] Propane-1-sulfonic
acid
{2,4-difluoro-3-[5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl-
]-phenyl}-amide (P-2174), [0645] Propane-1-sulfonic acid
(2,4-difluoro-3-{5-[1-(2-morpholin-4-yl-ethyl)-1H-pyrazol-4-yl]-1H-pyrrol-
o[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2177), [0646]
Propane-1-sulfonic acid
(3-{5-[6-(3-dimethylamino-propoxy)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridin-
e-3-carbonyl}-2,4-difluoro-phenyl)-amide (P-2178), [0647]
Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(4-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2183), [0648] Propane-1-sulfonic acid
{3-[5-(2,6-dimethoxy-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]--
2,4-difluoro-phenyl}-amide (P-2184), [0649]
4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-N,N-dimethyl-benzenesulfonamide (P-2185), [0650]
Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(6-methylsulfanyl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyrid-
ine-3-carbonyl]-phenyl}-amide (P-2187), [0651] Propane-1-sulfonic
acid
{2,4-difluoro-3-[5-(5-methanesulfonyl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyri-
dine-3-carbonyl]-phenyl}-amide (P-2188), [0652] Propane-1-sulfonic
acid
{2,4-difluoro-3-[5-(2-methylsulfanyl-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyr-
idine-3-carbonyl]-phenyl}-amide (P-2189), [0653] Propane-1-sulfonic
acid
{3-[5-(1-benzyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,-
4-difluoro-phenyl}-amide (P-2190), [0654] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(2-fluoro-pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-ca-
rbonyl]-phenyl}-amide (P-2192), [0655]
N-(5-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-
-b]pyridin-5-yl}-pyridin-2-yl)-acetamide (P-2193), [0656]
4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-benzenesulfonamide (P-2194), [0657]
Propane-1-sulfonic acid
{3-[5-(2-dimethylamino-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbon-
yl]-2,4-difluoro-phenyl}-amide (P-2196), [0658] Propane-1-sulfonic
acid
{2,4-difluoro-3-[5-(2-morpholin-4-yl-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyr-
idine-3-carbonyl]-phenyl}-amide (P-2197), [0659] Propane-1-sulfonic
acid
{3-[5-(2,4-dimethoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl-
]-2,4-difluoro-phenyl}-amide (P-2199), [0660] Propane-1-sulfonic
acid
{2,4-difluoro-3-[5-(2-methyl-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3--
carbonyl]-phenyl}-amide (P-2211), [0661] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(6-methyl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-ca-
rbonyl]-phenyl}-amide (P-2213), [0662] Propane-1-sulfonic acid
{3-[5-(6-amino-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-di-
fluoro-phenyl}-amide (P-2214), [0663] Propane-1-sulfonic acid
{3-[5-(4-ethanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-
-difluoro-phenyl}-amide (P-2218), [0664] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(2-pyrrolidin-1-yl-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]py-
ridine-3-carbonyl]-phenyl}-amide (P-2219), [0665]
5-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-pyridine-2-carboxylic acid amide (P-2220), [0666]
Propane-1-sulfonic acid
(2,4-difluoro-3-{5-[4-(propane-2-sulfonyl)-phenyl]-1H-pyrrolo[2,3-b]pyrid-
ine-3-carbonyl}-phenyl)-amide (P-2223), [0667] Propane-1-sulfonic
acid
{2,4-difluoro-3-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2228), [0668] Propane-1-sulfonic acid
{3-[5-(6-dimethylamino-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl-
]-2,4-difluoro-phenyl}-amide (P-2229), [0669] Propane-1-sulfonic
acid
{2,4-difluoro-3-[5-(6-pyrrolidin-1-yl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyri-
dine-3-carbonyl]-phenyl}-amide (P-2231), [0670] Propane-1-sulfonic
acid
(2,4-difluoro-3-{5-[6-(2-morpholin-4-yl-ethoxy)-pyridin-3-yl]-1H-pyrrolo[-
2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2232), [0671]
Propane-1-sulfonic acid
(2,4-difluoro-3-{5-[6-(2-pyrrolidin-1-yl-ethoxy)-pyridin-3-yl]-1H-pyrrolo-
[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2233), [0672]
Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(6-hydroxy-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-c-
arbonyl]-phenyl}-amide (P-2234), [0673] Propane-1-sulfonic acid
(2,4-difluoro-3-{5-[6-(3-pyrrolidin-1-yl-propoxy)-pyridin-3-yl]-1H-pyrrol-
o[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2235), [0674]
Propane-1-sulfonic acid
(2,4-difluoro-3-{5-[6-(3-morpholin-4-yl-propoxy)-pyridin-3-yl]-1H-pyrrolo-
[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2236), [0675]
2-Methyl-propane-1-sulfonic acid
{2,4-difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2299), [0676] Propane-1-sulfonic acid
{2-fluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-car-
bonyl]-phenyl}-amide (P-2407), and [0677] Propane-1-sulfonic acid
{3-[5-(2-dimethylamino-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbon-
yl]-2-fluoro-phenyl}-amide (P-2408).
[0678] The following table indicates the 1H-pyrrolo[2,3-b]pyridine
(column 2) and boronic acid (column 3) used to afford the desired
compound (column 4). The compound number is provided in column 1,
and the observed mass is in column 5.
TABLE-US-00002 MS (ESI) [M + H.sup.+].sup.+ 1H-pyrrolo[2,3- Boronic
ob- b]pyridine acid Compound served P-2155 ##STR00172##
##STR00173## ##STR00174## 475.1 P-2161 ##STR00175## ##STR00176##
##STR00177## 513.1 P-2162 ##STR00178## ##STR00179## ##STR00180##
458.3 P-2164 ##STR00181## ##STR00182## ##STR00183## 475.1 P-2165
##STR00184## ##STR00185## ##STR00186## 549.1 P-2166 ##STR00187##
##STR00188## ##STR00189## 605.2 P-2167 ##STR00190## ##STR00191##
##STR00192## 549.1 P-2168 ##STR00193## ##STR00194## ##STR00195##
575.2 P-2169 ##STR00196## ##STR00197## ##STR00198## 549.1 P-2172
##STR00199## ##STR00200## ##STR00201## P-2174 ##STR00202##
##STR00203## ##STR00204## 446.0 P-2177 ##STR00205## ##STR00206##
##STR00207## 459.0 P-2178 ##STR00208## ##STR00209## ##STR00210##
458.2 P-2183 ##STR00211## ##STR00212## ##STR00213## 533.9 P-2184
##STR00214## ##STR00215## ##STR00216## 517.1 P-2185 ##STR00217##
##STR00218## ##STR00219## 563.2 P-2187 ##STR00220## ##STR00221##
##STR00222## 503.1 P-2188 ##STR00223## ##STR00224## ##STR00225##
535.1 P-2189 ##STR00226## ##STR00227## ##STR00228## 503.9 P-2190
##STR00229## ##STR00230## ##STR00231## 536.3 P-2192 ##STR00232##
##STR00233## ##STR00234## 475.1 P-2193 ##STR00235## ##STR00236##
##STR00237## 514.3 P-2194 ##STR00238## ##STR00239## ##STR00240##
535.1 P-2196 ##STR00241## ##STR00242## ##STR00243## 501.1 P-2197
##STR00244## ##STR00245## ##STR00246## 543.1 P-2199 ##STR00247##
##STR00248## ##STR00249## 517.9 P-2211 ##STR00250## ##STR00251##
##STR00252## 472.0 P-2213 ##STR00253## ##STR00254## ##STR00255##
471.0 P-2214 ##STR00256## ##STR00257## ##STR00258## 472.5 P-2218
##STR00259## ##STR00260## ##STR00261## 546.5 [M - H.sup.+].sup.-
P-2219 ##STR00262## ##STR00263## ##STR00264## 527.7 P-2220
##STR00265## ##STR00266## ##STR00267## 500.2 P-2223 ##STR00268##
##STR00269## ##STR00270## 562.3 P-2228 ##STR00271## ##STR00272##
##STR00273## 532.3 [M - H.sup.+].sup.- P-2229 ##STR00274##
##STR00275## ##STR00276## 500.4 P-2231 ##STR00277## ##STR00278##
##STR00279## 526.4 P-2232 ##STR00280## ##STR00281## ##STR00282##
586.1 P-2233 ##STR00283## ##STR00284## ##STR00285## 570.5 P-2234
##STR00286## ##STR00287## ##STR00288## 473.1 P-2235 ##STR00289##
##STR00290## ##STR00291## 584.1 P-2236 ##STR00292## ##STR00293##
##STR00294## 600.1 P-2299 ##STR00295## ##STR00296## ##STR00297##
P-2407 ##STR00298## ##STR00299## ##STR00300## 470.1 P-2408
##STR00301## ##STR00302## ##STR00303## 483.6
Example 13
Synthesis of
5-{3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1,1-pyrrolo[2,3-b-
]pyridin-5-yl}-pyridine-2-carboxylic acid ethylamide P-2151
[0679]
5-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[-
2,3-b]pyridin-5-yl}-pyridine-2-carboxylic acid ethylamide P-2151
was synthesized in two steps from
5-(1H-pyrrolo[2,3-b]pyridin-5-yl)-pyridine-2-carboxylic acid
ethylamide 38 as shown in Scheme 13.
##STR00304##
Step 1--Preparation of
5-(3-{[2,6-difluoro-3-(propane-1-sulfonylamino)-phenyl]-hydroxy-methyl}-1-
H-pyrrolo[2,3-b]pyridin-5-yl)-pyridine-2-carboxylic acid ethylamide
(73)
[0680] In a round bottom flask,
5-(1H-pyrrolo[2,3-b]pyridin-5-yl)-pyridine-2-carboxylic acid
ethylamide (38, 71 mg, 0.27 mmol), propane-1-sulfonic acid
(2,4-difluoro-3-formyl-phenyl)-amide (58, 84.2 mg, 0.32 mmol) and
potassium hydroxide (44.9 mg, 0.80 mmol) were combined with 1.1 mL
of methanol. The reaction was stirred for 2 hours at room
temperature. The reaction solution was neutralized with 0.1 N
hydrochloric acid, then extracted 3.times. with ethyl acetate. The
organic layer was washed with brine, dried over sodium sulfate,
filtered and the filtrate concentrated under vacuum. The resulting
residue was purified by silica gel column chromatography to provide
the desired compound (73, 55 mg). MS (ESI)
[M+H.sup.+].sup.+=530.1.
Step 2--Preparation of
5-{3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-pyridine-2-carboxylic acid ethylamide (P-2151)
[0681] To
5-(3-{[2,6-difluoro-3-(propane-1-sulfonylamino)-phenyl]-hydroxy--
methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-pyridine-2-carboxylic acid
ethylamide (73, 50 mg, 0.094 mmol) dissolved in 0.76 mL of
tetrahydrofuran, Dess-Martin periodinane (48 mg, 0.113 mmol) was
added, followed by 1 mL of dimethylformamide. The reaction was
allowed to stir at room temperature for 1 hour, then quenched with
water and the aqueous layer extracted with ethyl acetate. The
organic layer was washed with brine, dried over sodium sulfate,
filtered and the filtrate concentrated under vacuum. The resulting
residue was purified by silica gel column chromatography to provide
the desired compound (P-2151, 30.6 mg). MS (ESI)
[M+H.sup.+].sup.+=528.2.
[0682] Additional compounds were prepared similarly to the protocol
of Scheme 13, where optimal reaction conditions may have varied in
terms of time and temperature of the reaction, and in
chromatography conditions for purification of the desired
compounds. The reactions were performed optionally substituting
5-(1H-pyrrolo[2,3-b]pyridin-5-yl)-pyridine-2-carboxylic acid
ethylamide 38 with an appropriate 1H-pyrrolo[2,3-b]pyridine and/or
propane-1-sulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide 58
with an appropriate aldehyde in step 1. The following compounds
were prepared by this procedure: [0683]
5-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-pyridine-2-carboxylic acid methylamide (P-2180),
[0684]
5-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-pyridine-2-carboxylic acid cyclopropylamide (P-2181),
[0685] Propane-1-sulfonic acid
(3-{5-[2-(3-dimethylamino-propoxy)-pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyrid-
ine-3-carbonyl}-2,4-difluoro-phenyl)-amide (P-2203), [0686]
Propane-1-sulfonic acid
(3-{5-[6-(3-diethylamino-prop-1-ynyl)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyri-
dine-3-carbonyl}-2,4-difluoro-phenyl)-amide (P-2222), [0687]
Propane-1-sulfonic acid
(2,4-difluoro-3-{5-[6-(3-methoxy-propyl)-pyridin-3-yl]-1H-pyrrolo[2,3-b]p-
yridine-3-carbonyl}-phenyl)-amide (P-2226), [0688]
Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(3-methoxy-prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridine-3-ca-
rbonyl]-phenyl}-amide (P-2239), [0689] Propane-1-sulfonic acid
{3-[5-(3-diethylamino-prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]--
2,4-difluoro-phenyl}-amide (P-2241), and [0690] Propane-1-sulfonic
acid
[3-(5-ethynyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
amide (P-2260).
[0691] The following table indicates the 1H-pyrrolo[2,3-b]pyridine
(column 2) and aldehyde (column 3) used to afford the desired
compound (column 4). The compound number is provided in column 1,
and the observed mass is in column 5.
TABLE-US-00003 MS (ESI) [M + 1H- H.sup.+].sup.+ pyrrolo[2,3- ob-
b]pyridine Aldehyde Compound served P-2151 ##STR00305##
##STR00306## ##STR00307## 528.2 P-2180 ##STR00308## ##STR00309##
##STR00310## 512.1 ([M - H.sup.+].sup.-) P-2181 ##STR00311##
##STR00312## ##STR00313## 538.1 ([M - H.sup.+].sup.-) P-2203
##STR00314## ##STR00315## ##STR00316## 559.1 P-2222 ##STR00317##
##STR00318## ##STR00319## 566.7 P-2226 ##STR00320## ##STR00321##
##STR00322## 529.6 P-2239 ##STR00323## ##STR00324## ##STR00325##
448.1 P-2241 ##STR00326## ##STR00327## ##STR00328## 489.3 P-2260
##STR00329## ##STR00330## ##STR00331## 404.2
Example 14
Synthesis of propane-1-sulfonic acid
{2,4-difluoro-3-[5-(6-propyl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-ca-
rbonyl]-phenyl}-amide P-2224
[0692] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(6-propyl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-ca-
rbonyl]-phenyl}-amide P-2224 was synthesized in one step from
propane-1-sulfonic acid
(3-{5-[6-(3-diethylamino-prop-1-ynyl)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyri-
dine-3-carbonyl}-2,4-difluoro-phenyl)-amide P-2222 as shown in
Scheme 14.
##STR00332##
Step 1--Preparation of propane-1-sulfonic acid
{2,4-difluoro-3-[5-(6-propyl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-ca-
rbonyl]-phenyl}-amide (P-2224)
[0693] Propane-1-sulfonic acid
(3-{5-[6-(3-diethylamino-prop-1-ynyl)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyri-
dine-3-carbonyl}-2,4-difluoro-phenyl)-amide (P-2222, 20.3 mg,
0.0359 mmol) was dissolved in 0.14 mL of methanol. Platinum dioxide
(0.81 mg, 0.0036 mmol) was added and the resulting mixture was
stirred under an atmosphere of hydrogen for 1 hour. The mixture was
filtered through a bed of celite and the filtrate was concentrated.
The crude material was purified by flash silica gel chromatography,
eluting with a gradient of 15% methanol in dichloromethane to 1%
methanol in dichloromethane. The appropriate fractions were
combined and concentrated to provide the desired compound as a
solid. MS (ESI) [M+H.sup.+].sup.+=499.4.
Example 15
Compound Properties
[0694] While the inhibitory activity of the compounds on any Raf
kinase is important to their activity in treating of disease, the
compounds described herein show favorable properties that provide
advantages as a pharmaceutical as well. In addition to
demonstrating kinase inhibitory activity against each of B-Raf,
c-Raf-1 and B-Raf V600E in either biochemical or cell based assays,
compounds may show favorable solubility, favorable pharmacokinetic
properties, and low Cyp inhibition. The compounds are assessed in
the following assays or similar assays available to one skilled in
the art.
[0695] Assays for biochemical and cell based activity are known in
the art, for example, as described in PCT publication WO
2007/002433, the disclosure of which is hereby incorporated by
reference as it relates to such assays. For example, the
biochemical activity IC.sub.50 values are determined with respect
to inhibition of A-Raf kinase activity, B-Raf kinase activity,
c-Raf-1 kinase activity, or B-Raf V600E kinase activity, where
inhibition of phosphorylation of a peptide substrate is measured as
a function of compound concentration. Compounds to be tested are
diluted in dimethyl sulfoxide to a concentration of 0.1 mM. These
are serially diluted 15 .mu.L into 30 .mu.L of dimethyl sulfoxide
seven times in 96 well plates for a total of 8 dilution points, and
for each dilution point 1 .mu.L is added to a well of an assay
plate. Plates are prepared such that each well in a 384 well plate
contains 1 .mu.L of compound in 10 .mu.L volume with 0.1 ng Raf
enzyme (i.e. any of A-Raf, B-Raf, c-Raf-1 or B-Raf V600E, Upstate
Biotechnology or prepared by methods known to one of skill in the
art), 50 mM HEPES, pH 7.0, 50 mM NaCl, 2 mM MgCl.sub.2, 1 mM
MnCl.sub.2, 0.01% Tween-20, 1 mM DTT, and 100 nM biotin-MEK1 as
substrate. The reaction is started with addition of 10 .mu.L of 200
.mu.M ATP (i.e. final 100 .mu.M ATP). After incubation of the
kinase reaction for 45 minutes at room temperature, 5 .mu.L/well of
Stop Solution is added (25 mM Hepes pH 7.5, 100 mM EDTA, 0.01% BSA
with donor beads (Streptavidin coated beads, Perkin Elmer),
acceptor beads (Protein A coated, Perkin Elmer), and anti phosphor
MEK1/2 antibody (CellSignal), each at final concentration 10
.mu.g/mL). The plates are incubated for 3 hours at room temperature
and read on Envision reader (Perkin Elmer). Phosphorylation of Mek1
results in binding of the anti-phosphor-MEK1/2 antibody and
association of the donor and acceptor beads such that signal
correlates with kinase activity. The signal vs. compound
concentration is used to determine the IC.sub.50.
[0696] Compounds are assessed in a variety of cell based assays.
For example human cell lines with B-Raf V600E mutation (A375
melanoma, SKMEL3 melanoma, and COLO205 colon adenocarcinoma), as
well as tumorigenic cell lines with wild-type B-RAF (SW620 colon
adenocarcinoma) or with Ras mutations (SKMEL2 melanoma and IPC298
melanoma). Similar assays may be used to assess additional
tumorigenic cell lines with Ras mutations, including, but not
limited to, M202, M207, M243, M244, M296, S117, HCT116, HCT15,
DLD1, MiaPaCa, A549, NCI-H23, NCI-H460, HOP62, MDA-MB231, Hs-578T,
HL60, MOLT-4, and CCRF-CEM.
[0697] On day 1, cells are counted, then centrifuged in a conical
tube for 5 minutes at 1000 rpm. The supernatant is removed and
cells are re-suspended as follows: [0698] SW620 (ATCC catalog
#CCL-27): resuspend in Leibovitz's L-15 medium, 2 mM L-glutamine,
10% fetal bovine serum to 6.times.10.sup.4 cells/mL. [0699] A375
(ATCC catalog #CRL-1619): resuspend in Dulbecco's modified Eagle's
medium, 4 mM L-glutamine, 4.5 g/L D-glucose, 10% fetal bovine serum
to 6.times.10.sup.4 cells/mL. [0700] COLO205 (ATCC catalog
#CCL-222): resuspend in RPMI 1640, 2 mM L-glutamine, 1.5 g/L sodium
bicarbonate, 4.5 g/L D-glucose, 10 mM HEPES, 1.0 mM sodium
pyruvate, 10% fetal bovine serum to 6.times.10.sup.4 cells/mL.
[0701] SKMEL2 (ATCC catalog #HTB-68): resuspend in Minimum Eagle
essential medium, 2 mM L-glutamine, 1.5 g/L sodium bicarbonate, 0.1
mM non-essential amino acids, 1.0 mM sodium pyruvate, 10% fetal
bovine serum to 6.times.10.sup.4 cells/mL. [0702] SKMEL3 (ATCC
catalog #HTB-69): resuspend in McCoy's 5A medium, 1.5 mM
L-glutamine, 15% fetal bovine serum to 6.times.10.sup.4 cells/mL.
[0703] IPC298 (DSMZ catalog #ACC 251): resuspend in RPMI 1640, 2 mM
L-glutamine, 10% fetal bovine serum to 6.times.10.sup.4
cells/mL.
[0704] The cells are plated, 50 .mu.L in each well of a 96-well
dish (Corning 3610) and incubated at 37.degree. C. in 5% CO.sub.2
overnight, cells plated to a final concentration of cells as
follows: [0705] SW620: 5,000 cells per well. [0706] A375: 2,000
cells per well. [0707] COLO205: 2,000 cells per well. [0708]
SKMEL2: 2,000 cells per well. [0709] SKMEL3: 3,000 cells per well.
[0710] IPC298: 2,000 cells per well.
[0711] On day 2, compound at a maximum concentration of 5 mM is
serially diluted 1:3 for a total of 8 point titration with DMSO as
a control. A 1 .mu.L aliquot of each dilution point and control is
added to 249 .mu.L growth media and 50 .mu.L is added to a well
containing cells, providing 10 .mu.M compound at the maximum
concentration point. The cells are incubated for 3 days at
37.degree. C. in 5% CO.sub.2.
[0712] On day 5, ATPlite 1 step Luminescence Assay System (Perkin
Elmer #6016739) is brought to room temperature along with the cell
cultures. ATPlite is added 25 .mu.L to each well, shake for 2
minutes, and the cells are incubated at room temperature for 10
minutes, then luminescence is read on Safire reader. The measured
luminescence correlates directly with cell number, such that the
reading as a function of compound concentration is used to
determine the IC.sub.50 value.
[0713] It is understood that the results of these assays may vary
as assay conditions are varied. Inhibition levels determined under
the conditions described herein represent a relative activity for
the compounds tested under the specific conditions employed. The
cell based assays are likely to show variability due to the
complexity of the system and the sensitivity thereof to any changes
in the assay conditions. As such, some level of inhibition in the
cell based assays is indicative of the compounds having some
inhibitory activity for those cells, whereas lack of inhibition
below the threshold of the highest concentration tested does not
necessarily indicate that the compound has no inhibitory activity
on the cells, only that under the conditions tested, no inhibition
is observed. Results for compounds that are tested and show
substantially no inhibition below the highest tested concentration
are represented as "-" in the tables below. In some instances, the
compounds were not tested in all of the assays, or assay results
were not valid, as indicated by NA in the tables below.
[0714] The following table provides data indicating the A-Raf,
B-Raf, B-Raf V600E and c-Raf-1 biochemical inhibitory activity for
compounds as described herein:
TABLE-US-00004 Biochemical Inhibition IC.sub.50 (.mu.M) Compound
B-Raf number A-Raf B-Raf V600E c-RAf-1 P-2002 <0.01 <0.01
<0.01 <0.01 P-2003 NA <0.1 <0.1 <0.01 P-2009
<0.01 <0.1 <0.01 NA P-2010 <0.01 <0.1 <0.01
<0.01 P-2011 <0.01 <0.1 <0.01 NA P-2014 <0.01
<0.1 <0.01 NA P-2015 <0.01 <0.1 <0.01 <0.01
P-2016 <0.01 <0.1 <0.01 NA P-2017 <0.01 <0.1
<0.01 NA P-2018 <0.01 <0.01 <0.01 NA P-2019 <0.01
<0.01 <0.01 NA P-2020 <0.01 <0.01 <0.01 <0.01
P-2021 NA <0.1 <0.1 <0.01 P-2022 <0.1 <0.1 <0.01
<0.01 P-2023 NA <0.01 <0.01 <0.01 P-2024 NA <0.1
<0.1 <0.01 P-2029 NA <0.1 <0.01 <0.01 P-2031 NA
<1 <0.1 <0.1 P-2033 NA <0.1 <0.01 <0.01 P-2036
<0.01 <0.01 <0.01 <0.01 P-2037 <0.01 <0.1
<0.01 <0.01 P-2039 <0.01 <0.01 <0.01 <0.01 P-2041
NA <0.01 <0.01 <0.01 P-2042 NA <0.01 <0.01 <0.01
P-2043 NA <0.01 <0.01 <0.01 P-2045 NA <0.01 <0.1
<0.01 P-2046 <0.01 <0.01 <0.01 <0.01 P-2051 NA
<0.1 <0.01 <0.1 P-2052 NA <0.1 <0.01 <0.01 P-2053
NA <0.01 <0.01 <0.01 P-2054 NA <0.1 <0.01 <0.1
P-2056 <0.01 <0.1 <0.01 <0.01 P-2069 <0.1 <0.01
<0.01 <0.01 P-2071 <0.1 <0.01 <0.01 <0.01 P-2072
NA <0.01 <0.01 <0.01 P-2073 NA <0.1 <0.1 <0.01
P-2074 NA <0.01 <0.01 <0.01 P-2077 <0.01 <0.01
<0.01 <0.01 P-2086 NA <0.01 <0.01 <0.01 P-2151 NA
<0.01 <0.01 <0.01 P-2154 NA <0.01 <0.1 <0.01
P-2155 NA <0.01 <0.01 <0.01 P-2161 NA NA <0.01 NA
P-2162 NA <0.1 <0.01 <0.01 P-2165 <0.01 <0.01
<0.01 <0.01 P-2166 NA <0.01 <0.01 <0.01 P-2167 NA
<0.01 <0.01 <0.01 P-2168 NA <0.01 <0.01 <0.01
P-2172 NA <0.1 <0.1 NA P-2174 NA <0.01 <0.01 <0.01
P-2177 NA <0.01 <0.01 NA P-2178 NA <0.01 <0.01 <0.01
P-2180 NA <0.01 <0.01 NA P-2181 NA <0.01 <0.01 NA
P-2183 NA <0.01 <0.01 NA P-2184 NA <0.1 <0.1 NA P-2185
NA <0.01 <0.01 <0.01 P-2187 NA <0.01 <0.01 NA P-2188
NA <0.01 <0.01 NA P-2189 NA <0.01 <0.01 <0.01 P-2190
NA <0.01 <0.01 NA P-2192 NA <0.01 <0.01 NA P-2193 NA
<0.01 <0.01 <0.01 P-2194 NA <0.01 <0.01 <0.01
P-2196 <0.01 <0.01 <0.01 <0.01 P-2197 NA <0.01
<0.01 NA P-2199 NA <0.1 <0.01 <0.01 P-2203 NA <0.01
<0.01 NA P-2211 NA <0.01 <0.01 <0.01 P-2213 NA <0.01
<0.01 <0.01 P-2214 NA <0.01 <0.01 <0.01 P-2218 NA
<0.1 <0.1 <0.1 P-2219 NA <0.1 <0.1 <0.1 P-2220
<0.01 <0.1 <0.1 <0.1 P-2222 NA <0.01 <0.01
<0.01 P-2223 NA <0.01 <0.01 <0.01 P-2224 <0.01
<0.01 <0.01 <0.01 P-2226 NA <0.01 <0.01 <0.1
P-2228 NA <0.01 <0.01 <0.01 P-2229 NA <0.1 <0.1
<0.1 P-2231 <0.01 <0.01 <0.01 <0.1 P-2232 <0.01
<0.01 <0.01 <0.01 P-2233 <0.01 <0.01 <0.01
<0.01 P-2234 <0.01 <0.01 <0.01 <0.01 P-2235 <0.01
<0.01 <0.01 <0.01 P-2236 <0.01 <0.01 <0.01
<0.01 P-2239 <0.01 <0.1 <0.01 <0.01 P-2260 <0.01
<0.01 <0.01 <0.01 P-2299 NA <0.01 <0.01 NA P-2407
<0.01 <0.1 <0.01 <0.01 P-2408 <0.01 <0.01
<0.01 <0.1
[0715] The following table provides data indicating the SW620,
A375, COLO205, SK-MEL-2, SK-MEL-3, and IPC298 cell growth
inhibitory activity for compounds as described herein:
TABLE-US-00005 Com- pound Cell Inhibition IC.sub.50 (.mu.M) number
SW620 A375 COLO205 SKMEL2 SKMEL3 IPC298 P-2002 <20 <1 <1
-- NA NA P-2003 NA <1 <5 NA NA NA P-2009 -- <1 <5 -- NA
NA P-2010 -- <1 <1 -- NA NA P-2011 -- <1 <1 -- NA NA
P-2014 -- <1 <5 -- NA NA P-2015 -- <1 <1 -- NA NA
P-2016 -- <1 <5 -- NA NA P-2017 -- <1 <5 -- NA NA
P-2018 -- <1 <5 -- NA NA P-2019 -- <5 <5 -- NA NA
P-2020 -- <5 NA -- NA NA P-2021 -- <1 <5 NA NA NA P-2022
-- <5 <5 -- NA NA P-2023 NA <1 <5 NA NA NA P-2024 NA
<5 <5 NA NA NA P-2029 -- <5 <5 -- NA NA P-2031 -- <5
<5 -- NA NA P-2033 -- <5 <10 -- NA NA P-2036 -- <5
<1 -- NA NA P-2037 -- <5 NA -- NA NA P-2039 -- <5 <5 --
NA NA P-2041 -- <1 <1 NA <1 <1 P-2042 -- <1 <0.1
NA <1 <1 P-2043 -- <5 <1 NA NA NA P-2045 -- <5 <1
NA <5 NA P-2046 <5 <1 <1 -- NA NA P-2051 -- <1 NA --
NA NA P-2052 -- <1 <1 -- NA NA P-2053 -- <5 <1 -- NA NA
P-2054 -- <5 NA NA NA NA P-2056 <5 <5 <5 -- NA NA
P-2069 NA <5 <1 NA NA NA P-2071 -- <1 <1 -- NA NA
P-2072 -- <5 <5 -- NA NA P-2073 -- <10 <10 -- NA NA
P-2074 -- <5 <10 -- NA NA P-2077 -- <10 NA -- NA NA P-2086
-- <10 NA -- NA NA P-2151 NA <1 <1 NA NA NA P-2154 --
<1 <1 -- NA NA P-2155 -- <1 <1 <20 NA NA P-2161 --
<1 <1 <10 NA NA P-2162 -- <1 <1 <10 NA NA P-2165
<10 <1 <1 <10 NA NA P-2166 <10 <1 <0.1 <5
NA NA P-2167 <10 <1 <0.1 <5 NA NA P-2168 <5 <1
<0.1 <5 NA NA P-2172 <10 <1 <1 <5 NA NA P-2174 --
<1 <1 <10 NA NA P-2177 <20 <1 <0.1 <10 NA NA
P-2178 -- <0.1 <0.1 <5 NA NA P-2180 NA <1 NA NA NA NA
P-2181 NA <1 NA NA NA NA P-2183 <20 <0.1 <0.1 -- NA NA
P-2184 NA <1 NA NA NA NA P-2185 -- <0.1 <0.1 -- NA NA
P-2187 -- <1 <1 NA NA NA P-2188 NA <10 NA NA NA NA P-2189
-- <1 <1 <10 NA <10 P-2190 <10 <1 <1 NA NA NA
P-2192 -- <1 NA NA NA NA P-2193 -- <1 <1 -- NA NA P-2194
NA <5 NA NA NA NA P-2196 -- <1 <1 -- <1 <10 P-2197
NA <1 NA NA NA NA P-2199 NA <5 NA NA NA NA P-2203 -- <1 NA
NA NA NA P-2211 -- <1 <1 -- NA NA P-2213 <20 <1 <1
-- NA NA P-2214 <20 <1 <1 -- NA NA P-2218 <20 <0.1
<0.1 -- NA NA P-2219 -- <0.1 <0.1 -- <5 NA P-2220 --
<1 <1 NA NA NA P-2222 -- <0.1 <0.1 NA NA NA P-2224 --
<1 <1 NA NA NA P-2226 -- <0.1 <0.1 NA NA NA P-2228 --
<1 NA NA NA NA P-2229 -- <0.1 <0.1 NA NA NA P-2231 <5
<0.1 <1 NA NA NA P-2232 -- <0.1 <0.1 NA NA NA P-2233 --
<0.1 <0.1 NA NA NA P-2234 -- <5 <5 -- NA NA P-2235 --
<0.1 <0.1 NA NA NA P-2236 -- <0.1 <0.1 NA NA NA P-2239
-- <1 <1 <20 NA NA P-2260 -- <1 <1 NA NA NA P-2299
-- <1 <1 -- NA NA P-2407 -- <1 <1 <20 NA NA P-2408
NA <0.1 <1 NA NA NA
[0716] Compounds also demonstrate in vivo activity in a xenograft
mouse model for Colo205. Female nu/nu mice are implanted with
Colo-205 trocar fragments from donor mice, sub-cutaneous and high
in the axilla. Tumor growth is monitored to approximately 100 mg
size, and mice are distributed to treatment groups such that the
mean tumor burden within a group is within 10% of the overall mean
tumor burden. Mice are treated with vehicle control, positive
control or compound (8 mice per group) in 5% DMSO and 95% CMC (1%),
with compound dosed at 10 mg/kg daily for fourteen days. Mice are
observed daily, with tumor burden and body weights measured twice a
week. Animals with tumor burden above 1500-2000 mg and any animals
in moribund condition are euthanized. The average tumor growth of
vehicle control group mice is compared to the average tumor growth
of the test compound mice. Percent tumor growth inhibition is
calculated as 100.times.[(tumor growth control-tumor growth test
compound)/tumor growth control].
[0717] The following table provides data indicating the percent
tumor growth inhibition for compounds as described herein in the
Colo205 xenograft mouse model:
TABLE-US-00006 Compound % Tumor growth number inhibition P-2011 72
P-2015 67 P-2021 35 P-2046 70 P-2056 66 P-2069 29 P-2071 59 P-2162
17 P-2178 0 P-2196 71 P-2211 0 P-2219 39 P-2232 54 P-2239 4 P-2260
79
[0718] As an indication of relative solubility, the turbidity of
compounds in aqueous solutions is assessed. To assess possible
compound properties in different physiological compartments, such
as stomach, intestine, and blood, a series of aqueous buffers with
varying pH is used. Thus each compound is diluted into four
different physiologically relevant buffers and solution turbidity
is measured by spectrophotometry. The concentration of compound
that demonstrates turbidity by forming enough insoluble suspension
to raise the average optical density above 0.01 at three
wavelengths (490, 535, and 650 nm) is used to define the limit of
the compound solubility in that buffer.
[0719] Compounds are dissolved at a concentration of 25 mM in
dimethyl sulfoxide, then serially diluted 1:1 into a 96 well plate,
diluting 10 times in pure dimethyl sulfoxide, with the final well
of each row a dimethyl sulfoxide blank. In an assay plate, 99 .mu.L
of appropriate buffer is added to each well, and 1 .mu.L of each
sample dilution is added to the buffer, achieving a range of final
total concentrations in aqueous solutions having different pH. The
buffers used are Simulated Gastric Fluid (SGF-pH 1.5) 0.5M NaCl, pH
1.5; Simulated Intestinal fluid (SIF-pH 4.5 and pH 6.8) 0.05M
NaH.sub.2PO.sub.4, pH 4.5 and 6.8; and Hepes Buffer (HEPES-pH 7.4)
10 mM HEPES, 150 mM NaCl, pH 7.4. Control compounds pyrene, estriol
and propranolol HCl are also assessed. Plates are spun and then
mixed for 1 minute, and the absorbance is read using a Tecan Safire
II to read wavelengths in the visible range (490, 535, and 650 nm)
at four locations per well, reflecting the degree of turbidity
present. The average optical density for each wavelength in each
well is graphed vs. compound concentration, and the concentration
at which the curve crosses a threshold O.D. of 0.01 for each
wavelength is reported as the endpoint turbidity assay result. The
average of the three wavelengths is used to compare turbidity of
compounds. Compounds are considered to have low solubility if the
threshold concentration is <31.3 .mu.M, moderate solubility if
the threshold concentration is 31.3 .mu.M to 250 .mu.M, and high
solubility if the threshold concentration is >250 .mu.M.
[0720] The following table provides data indicating the relative
solubility (L=low, M=moderate, H=high) based on turbidity threshold
concentration at each pH for compounds as described herein:
TABLE-US-00007 Compound turbidity threshold (L, M, H) number 1.4
4.5 6.8 7.4 P-2002 L L M M P-2003 M M M H P-2009 L L L M P-2010 L L
M M P-2011 M M M M P-2014 L M M M P-2015 M L M M P-2016 H L M M
P-2017 M M M M P-2018 L M M M P-2019 L M M M P-2020 M M M M P-2021
H M M M P-2022 H M M H P-2023 H M M M P-2024 M L M M P-2041 L L L L
P-2042 L L L L P-2043 L L L M P-2045 L L L M P-2046 L L M M P-2051
M M M M P-2052 L L M M P-2053 L L M M P-2056 L L M M P-2069 H M M H
P-2071 M M M M P-2086 M M M H P-2151 L L L L P-2155 L L L L P-2162
M M M M P-2165 L L L L P-2166 L L L L P-2168 L L L L P-2174 L L L L
P-2177 H M L L P-2178 H M L L P-2180 L L L L P-2181 L L L L P-2183
L L L L P-2184 L L L L P-2185 L L L L P-2188 M L L M P-2189 L L L L
P-2190 L L L L P-2192 L L L L P-2193 M L L L P-2194 L L L L P-2196
M L L L P-2197 M L L L P-2211 M M M M P-2213 H M L L P-2219 M L L L
P-2222 L L L L P-2226 H L L L P-2229 M L M M P-2231 L L L L P-2232
M M L L P-2233 L M L M P-2235 L M L L P-2236 M M L L P-2239 L M L M
P-2260 L L L L P-2407 L L L L P-2408 L L L L
[0721] CYP (Cytochrome P450) enzymes are the major drug
metabolizing enzymes present in the liver. The inhibition of CYP
enzyme activity (IC.sub.50) for each of CYP1A2, CYP2C19, CYP2C9,
CYP2D6, CYP3A4(BFC) and CYP3A4(BQ) is determined for compounds,
where inhibition of metabolism of a known substrate leads to a
decrease in the fluorescence of the metabolized product. The
fluorescence of the product is monitored as a function of compound
concentration.
[0722] Compounds are dissolved in dimethyl sulfoxide to a
concentration of 100 mM. These are diluted 1 .mu.L into 82 .mu.L of
acetonitrile. An 11 .mu.L aliquot of this solution is then added to
204 .mu.L of cofactor mix (1.3% NADPH Regeneration system Solution
A, 1.04% NADPH Regeneration system Solution B from BD Biosciences,
5% acetonitrile and 0.05% dimethyl sulfoxide). These are then
serially diluted 1:1 (160 .mu.L to 160 .mu.L co-factor mix) for a
total of 10 points. A 10 .mu.L aliquot of this final mixture is
dispensed into 384 well assay plates and incubated for 10 minutes
at 37.degree. C. Enzyme and substrate mix (10 .mu.L; 0.5 pmol
CYP1A2/5 .mu.M CEC; 1.0 pmol CYP2C9/75 .mu.M MFC; 0.5 pmol
CYP2C19/25 .mu.M CEC; 1.5 pmol CYP2D6/1.5 .mu.M AMMC; 1.0 pmol
CYP3A4/50 .mu.M BFC; or 1.0 pmol CYP3A4/40 .mu.M BQ) is added to
these assay plates. Assay plates are incubated at 37.degree. C.
(CYP1A2-15 min; CYP2C9-45 min; CYP2C19, 2D6 and 3A4-30 min) and
read in a Tecan Safire 2 plate reader (CYP1A2, 2C19 and 3A4 409
ex/460 em; CYP2C9 and 2D6 409 ex/530 em). The signal versus
compound concentration is used to determine the IC.sub.50. The
enzymes and substrates for this assay are obtained from BD
Biosciences. While other factors are involved in determining CYP
effects in vivo, compounds preferably have IC.sub.50 values of
>5 .mu.M, more preferably IC.sub.50 values of >10 .mu.M.
[0723] The following table provides data indicating the Cyp
inhibitory activity for compounds as described herein:
TABLE-US-00008 Compound Cyp IC.sub.50 (.mu.M) number 1A2 2C19 2C9
2D6 3A4(BFC) 3A4(BQ) P-2002 >10 5-10 5-10 >10 >10 >10
P-2003 >10 >10 >10 >10 >10 >10 P-2009 >10
>10 >10 >10 >10 >10 P-2010 >10 >10 >10
>10 >10 >10 P-2011 >10 >10 >10 >10 >10
>10 P-2014 >10 >10 >10 >10 >10 >10 P-2015
>10 5-10 >10 >10 >10 >10 P-2016 >10 >10 <5
>10 >10 5-10 P-2017 >10 >10 >10 >10 >10 >10
P-2018 >10 >10 >10 >10 5-10 >10 P-2019 >10 >10
>10 >10 5-10 >10 P-2020 >10 >10 >10 >10 >10
>10 P-2021 >10 >10 >10 >10 >10 >10 P-2022
>10 >10 5-10 >10 5-10 5-10 P-2023 >10 >10 5-10
>10 5-10 <5 P-2024 >10 >10 >10 >10 >10 >10
P-2029 >10 >10 >10 >10 >10 >10 P-2031 >10
>10 >10 >10 >10 >10 P-2033 >10 >10 >10
>10 >10 >10 P-2036 >10 >10 >10 >10 >10
>10 P-2037 >10 >10 >10 >10 >10 >10 P-2039
>10 >10 >10 >10 >10 >10 P-2041 >10 >10
>10 >10 >10 >10 P-2042 >10 >10 5-10 >10 >10
>10 P-2043 >10 >10 >10 5-10 >10 >10 P-2045 >10
>10 >10 >10 >10 >10 P-2046 >10 <5 <5 >10
>10 >10 P-2051 >10 >10 5-10 >10 >10 >10 P-2052
>10 >10 <5 >10 5-10 >10 P-2053 >10 >10 5-10
>10 >10 >10 P-2054 >10 >10 >10 >10 >10
>10 P-2056 >10 >10 5-10 >10 >10 >10 P-2069 >10
>10 <5 >10 <5 <5 P-2071 >10 >10 >10 >10
<5 <5 P-2072 >10 >10 >10 >10 5-10 <5 P-2073
>10 >10 >10 >10 5-10 <5 P-2074 >10 >10 >10
>10 >10 >10 P-2077 >10 >10 5-10 >10 5-10 5-10
P-2086 >10 >10 >10 >10 >10 >10 P-2151 >10
>10 5-10 >10 >10 >10 P-2154 >10 5-10 5-10 >10
>10 >10 P-2155 >10 5-10 >10 >10 >10 >10 P-2162
<5 >10 5-10 >10 5-10 <5 P-2165 >10 5-10 5-10 >10
>10 >10 P-2166 >10 >10 >10 >10 >10 >10
P-2167 >10 5-10 5-10 >10 >10 5-10 P-2168 >10 5-10 <5
>10 >10 5-10 P-2174 >10 5-10 <5 5-10 >10 <5
P-2177 >10 5-10 <5 >10 <5 >10 P-2178 >10 5-10
5-10 >10 >10 <5 P-2180 >10 5-10 <5 >10 >10
>10 P-2181 >10 >10 <5 >10 >10 >10 P-2183
>10 5-10 5-10 >10 >10 >10 P-2184 >10 >10 5-10
>10 >10 >10 P-2185 >10 >10 <5 >10 >10
>10 P-2187 >10 >10 >10 >10 >10 >10 P-2188
>10 >10 5-10 >10 >10 >10 P-2189 >10 5-10 <5
>10 >10 <5 P-2190 >10 5-10 <5 >10 >10 >10
P-2192 >10 >10 5-10 >10 >10 >10 P-2193 >10 5-10
>10 >10 5-10 >10 P-2194 >10 >10 >10 >10 >10
>10 P-2196 >10 >10 5-10 >10 <5 >10 P-2197 >10
>10 >10 >10 >10 >10 P-2199 >10 >10 >10
>10 >10 >10 P-2211 >10 5-10 >10 >10 >10 >10
P-2213 >10 >10 <5 >10 >10 >10 P-2214 >10 5-10
>10 >10 >10 >10 P-2218 >10 NA >10 >10 >10
>10 P-2219 >10 <5 >10 >10 5-10 >10 P-2222 >10
<5 5-10 5-10 >10 5-10 P-2223 >10 >10 >10 >10
>10 >10 P-2224 >10 5-10 5-10 >10 >10 >10 P-2226
>10 >10 <5 >10 >10 >10 P-2228 >10 >10
>10 >10 >10 >10 P-2229 >10 >10 5-10 >10 >10
>10 P-2231 <5 5-10 5-10 >10 >10 >10 P-2232 >10
>10 5-10 >10 >10 >10 P-2233 >10 5-10 >10 >10
>10 >10 P-2235 >10 <5 >10 >10 >10 >10
P-2236 >10 <5 <5 >10 <5 5-10 P-2239 >10 5-10 5-10
>10 5-10 5-10 P-2260 >10 5-10 5-10 >10 <5 5-10 P-2407
>10 <5 >10 >10 >10 >10 P-2408 >10 >10 5-10
>10 >10 >10
[0724] Pharmacokinetic properties of compounds (including any solid
forms or formulations thereof) are assessed in male Sprague Dawley
rats or male Beagle dogs. Rats are dosed daily with compound either
by IV injections via surgically implanted jugular catheters or by
oral gavage (PO). Each compound is prepared as a 20 mg/mL stock
solution in dimethyl sulfoxide, which is further diluted to provide
the dosing stock at the desired concentration for the IV or PO
formulations. For IV dosing, the dosing stock is diluted into a
1:1:8 mixture of Solutol.RTM.:ethanol:water. For PO dosing, the
dosing stock is diluted into 1% methylcellulose. In a cassette
format (or each compound, solid form thereof or formulation thereof
is done individually), compounds are diluted to 0.5 mg/mL each for
IV dosing and 0.4 mg/mL each for PO dosing and dosed at 1 mg/kg (2
mL/kg) or 2 mg/kg (5 mL/kg), respectively. For IV dosed animals,
tail vein blood samples are collected with lithium heparin
anticoagulant at 5, 15, 30, and 60 minutes and 4, 8, and 24 hours
post dosing each day. For PO dosed animals, tail vein blood samples
are collected with lithium heparin anticoagulant at 30 minutes, 1,
2, 4, 8 and 24 hours post dosing each day. Dogs are dosed daily by
oral capsules in a suitable formulation at 50 mg/mL. Cephalic vein
blood samples are collected with lithium heparin anticoagulant at
30 minutes, 1, 2, 4, 8 and 24 hours post dosing each day. All
samples are processed to plasma and frozen for later analysis of
each compound by LC/MS/MS. Plasma levels as a function of time are
plotted to assess the AUC (ng*hr/mL). Compounds according to the
present invention preferably show improved pharmacokinetic
properties relative to previously described compounds, i.e. they
have substantially higher values for one or more of AUC, C.sub.max
and half-life relative to previously described compounds.
Example 16
Efficacy of Compounds in Combination with Standard-of-Care
Chemotherapeutic Agents in Four Human Cancer Cell Lines
[0725] Compounds as described herein, in combination with a
standard chemotherapeutic agent, such as 5-fluorouracil,
carboplatin, dacarbazine, gefitinib, oxaliplatin, paclitaxel,
SN-38, temozolomide, or vinblastine, can be assessed for their
effectiveness in killing human tumor cells. Human tumor cell lines,
such as A-375 (malignant melanoma), SK-MEL-2 (malignant melanoma,
skin metastasis), COLO 205 (colorectal adenocarcinoma, ascites
metastasis) or SW-620 (colorectal adenocarcinoma, lymph node
metastasis) can be treated with compounds as described herein
alone, or in combination with one of the above-mentioned
chemotherapeutic agents.
[0726] Tumor cells are grown as a monolayer at 37.degree. C. in a
humidified atmosphere (5% CO.sub.2, 95% air). Cells are grown in a
suitable culture medium, e.g. RPMI 1640 (Ref BE12-702F, Cambrex,
Verviers, Belgium) containing 2 mM L-glutamine and supplemented
with 10% fetal bovine serum (Ref DE14-801E, Cambrex). For
experimental use, the tumor cells are detached from the culture
flask by a 5-minute treatment with trypsin-versene (Ref 02-007E,
Cambrex), diluted in Hanks' medium without calcium or magnesium
(Ref BE10-543F, Cambrex). Trypsin treatment is neutralized by
culture medium addition. The cells are counted in a hemocytometer
and their viability assessed by 0.25% trypan blue exclusion. The
cell lines are checked for mycoplasma contamination with the
Mycotect assay kit (Ref 15672-017, Invitrogen, Cergy-Pontoise,
France) in accordance with the manufacturer's instructions. The
mycoplasma test is assayed from the culture supernatants of the
cell lines and compared to negative and positive controls.
[0727] The tumor cells (10,000 per well) are plated in 96-well
flat-bottom microtitration plates (Ref 055260, Nunc, Dutscher,
Brumath, France) and incubated at 37.degree. C. for 24 hours before
treatment in 100 .mu.l of drug-free culture medium supplemented
with 10% FBS. In order to assess the IC.sub.50 of each compound to
be used for each cell line, the tumor cells are incubated in a 200
.mu.l final volume of RPMI 1640 supplemented with 10% FBS and
containing either compounds as described herein, or one of
5-fluorouracil, carboplatin, dacarbazine, gefitinib, oxaliplatin,
paclitaxel, SN-38, temozolomide, or vinblastine. The compounds are
tested in a suitable concentration range, such as 10.sup.-8 to
10.sup.-3 M for compounds as described herein, 5-fluorouracil,
dacarbazine or gefitinib, 10.sup.-9 to 10.sup.-4 M for carboplatin,
oxaliplatin, or temozolomide, 10.sup.-11 to 10.sup.-6 M for
paclitaxel or SN-38, and 10.sup.-15 to 10.sup.-10 M for
vinblastine. Compounds as described herein are dissolved in DMSO
and diluted with culture medium to the desired concentrations.
5-fluorouracil (50 mg/ml, Dakota Pharm, LePlessis Robinson,
France), carboplatin (10 mg/ml, Aguettant, Lyon, France), and
paclitaxel (6 mg/ml, Bristol-Myers Squibb SpA, Rueil Malmaison,
France), are diluted with culture medium to the desired
concentrations. Dacarbazine (Sigma, Saint Quentin Fallavier,
France) and vinblastine (Lilly France S.A., Saint Cloud, France)
are dissolved in NaCl 0.9% and diluted with culture medium to the
desired concentrations. Gefitinib is dissolved in a mixed solution
of RPMI 1640 and DMSO and diluted with culture medium to the
desired concentrations (maximum final DMSO of 0.1% v/v). SN-38 (LKT
Laboratories, Inc., St. Paul, Minn.) is dissolved in DMSO and
diluted with culture medium to the desired concentrations (maximum
final DMSO of 0.1% v/v). Temozolomide (LKT Laboratories, Inc., St.
Paul, Minn.) is dissolved in water for injection and diluted with
culture medium to the desired concentrations. Cells are incubated
for 96 hours in the presence of test substances at 37.degree. C.
under 5% CO.sub.2. At the end of treatments, the cytotoxic activity
is evaluated by an MTT assay.
[0728] For the MTT assay, at the end of the cells treatment, 20
.mu.l of a 5 mg/ml solution 0.22 .mu.m filtered tetrazolium reagent
(MTT, Ref M2128, Sigma) in Phosphate Buffered Saline (PBS, Ref
BE17-517Q, Cambrex), is added in each well. Culture plates are
incubated for 2 h at 37.degree. C. The resulting supernatant is
removed and formazan crystals dissolved with 200 .mu.l of DMSO per
well. Absorbency (OD) is measured at 570 nm in each well using
VICTOR.sup.3.TM. 1420 multilabeled counter (Wallac, PerkinElmer,
Courtaboeuf, France).
[0729] The IC.sub.50 for each compound on each cell line is
determined from the OD measurements of each sample. The dose
response inhibition of cell proliferation is expressed as:
IC=(OD of drug exposed cells/OD of drug free wells).times.100.
[0730] The mean of multiple measurements for each concentration is
plotted vs. the drug concentration. The dose-response curves are
plotted using XLFit 3 (IDBS, United Kingdom). The IC.sub.50 (drug
concentration to obtain 50% inhibition of cell proliferation)
determination values are calculated using the XLFit 3 from semi-log
curves. The IC.sub.50 value determined for each compound in each
cell line is used to determine the concentration of compounds as
described herein, and of the standard chemotherapeutic to be used
in combination.
[0731] The cells are treated with a combination of five
concentrations of compounds as described herein and five
concentrations of one of 5-fluorouracil, carboplatin, dacarbazine,
gefitinib, oxaliplatin, paclitaxel, SN-38, temozolomide, or
vinblastine, based on the IC.sub.50 results. The compounds and
cells are treated per the IC50 determination described above and
assayed by the MTT assay.
[0732] The results are assessed to determine whether the
combination is synergistic or antagonistic. The compound
interactions are calculated by multiple drug effect analysis and
are performed by the median equation principle according to the
methodology described by Chou and Talalay (Adv. Enzyme Regul. 1984,
22: 27-55).
[0733] The combination index (CI) will be calculated by the Chou et
al. equation (Adv. Enzyme Regul. 1984, 22: 27-55; Encyclopaedia of
human biology, Academic Press, 1991, 2: 371-9; Synergism and
Antagonism in Chemotherapy, Academic Press, 1991, 61-102) which
takes into account both the potency (D.sub.m or IC.sub.50) and the
shape of the dose-effect curve (the m value). The general equation
for the CI of the two compounds is given by:
CI = ( D ) 1 ( D x ) 1 + ( D ) 2 ( D x ) 2 + ( D ) 1 ( D ) 2 ( D x
) 1 ( D x ) 2 ##EQU00001##
where: (D.sub.x).sub.1 and (D.sub.x).sub.2 in the denominators are
the doses (or concentrations) for compound 1 and compound 2 alone
which demonstrate x % of inhibition, whereas (D).sub.1 and
(D).sub.2 in the numerators are doses of both compounds (1 and 2)
in combination that also inhibit x % (iso-effective). CI<1, =1,
and >1 indicate synergism, additive effect and antagonism,
respectively.
[0734] The (D.sub.x).sub.1 and (D.sub.x).sub.2 can be calculated
from the median-effect equation of Chou et al. (J. Natl. Cancer
Inst. 1994, 86: 1517-24):
D x = D m ( f a ( 1 - f a ) ) 1 / m ##EQU00002##
where: D.sub.m is the median-effect dose that is obtained from the
anti-log of x-intercept of the median-effect plot, x=log(D) versus
y=log {f.sub.a/(1-f.sub.a)}, or D.sub.m=10.sup.-(y-intercept)/m;
and m is the slope of the median-effect plot and f.sub.a is the
fraction of cells affected by the treatment. Each CI will be
calculated with CalcuSyn software (Biosoft, UK) from the mean
affected fraction at each drug ratio concentration.
[0735] All patents and other references cited in the specification
are indicative of the level of skill of those skilled in the art to
which the invention pertains, and are incorporated by reference in
their entireties, including any tables and figures, to the same
extent as if each reference had been incorporated by reference in
its entirety individually.
[0736] One skilled in the art would readily appreciate that the
present invention is well adapted to obtain the ends and advantages
mentioned, as well as those inherent therein. The methods,
variances, and compositions described herein as presently
representative of preferred embodiments are exemplary and are not
intended as limitations on the scope of the invention. Changes
therein and other uses will occur to those skilled in the art,
which are encompassed within the spirit of the invention, are
defined by the scope of the claims.
[0737] It will be readily apparent to one skilled in the art that
varying substitutions and modifications may be made to the
invention disclosed herein without departing from the scope and
spirit of the invention. Thus, such additional embodiments are
within the scope of the present invention and the following
claims.
[0738] The invention illustratively described herein suitably may
be practiced in the absence of any element or elements, limitation
or limitations which is not specifically disclosed herein. Thus,
for example, in each instance herein any of the terms "comprising",
"consisting essentially of" and "consisting of" may be replaced
with either of the other two terms. Thus, for an embodiment of the
invention using one of the terms, the invention also includes
another embodiment wherein one of these terms is replaced with
another of these terms. In each embodiment, the terms have their
established meaning. Thus, for example, one embodiment may
encompass a method "comprising" a series of steps, another
embodiment would encompass a method "consisting essentially of" the
same steps, and a third embodiment would encompass a method
"consisting of" the same steps. The terms and expressions which
have been employed are used as terms of description and not of
limitation, and there is no intention that in the use of such terms
and expressions of excluding any equivalents of the features shown
and described or portions thereof, but it is recognized that
various modifications are possible within the scope of the
invention claimed. Thus, it should be understood that although the
present invention has been specifically disclosed by preferred
embodiments and optional features, modification and variation of
the concepts herein disclosed may be resorted to by those skilled
in the art, and that such modifications and variations are
considered to be within the scope of this invention as defined by
the appended claims.
[0739] In addition, where features or aspects of the invention are
described in terms of Markush groups or other grouping of
alternatives, those skilled in the art will recognize that the
invention is also thereby described in terms of any individual
member or subgroup of members of the Markush group or other
group.
[0740] Also, unless indicated to the contrary, where various
numerical values are provided for embodiments, additional
embodiments are described by taking any 2 different values as the
endpoints of a range. Such ranges are also within the scope of the
described invention.
[0741] Thus, additional embodiments are within the scope of the
invention and within the following claims.
* * * * *