U.S. patent application number 13/318760 was filed with the patent office on 2012-05-17 for solid forms of sulfonamides and amino acids.
This patent application is currently assigned to Plexxikon, Inc.. Invention is credited to Hanna Cho, Prabha N. Ibrahim, Songyuan Shi, Wayne Spevak, Gary Conard Visor, Guoxian Wu.
Application Number | 20120122860 13/318760 |
Document ID | / |
Family ID | 42236712 |
Filed Date | 2012-05-17 |
United States Patent
Application |
20120122860 |
Kind Code |
A1 |
Visor; Gary Conard ; et
al. |
May 17, 2012 |
SOLID FORMS OF SULFONAMIDES AND AMINO ACIDS
Abstract
Solid forms of phenyl sulfonamide compounds of formula (I)
active on protein kinases, including Raf protein kinases, are
described, as well as methods of using such solid forms to treat
diseases and conditions associated with activity of protein
kinases, e.g. Raf protein kinases, including pain, polycystic
kidney disease, melanoma and colorectal cancer. ##STR00001##
Inventors: |
Visor; Gary Conard; (Castro
Valley, CA) ; 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.: |
13/318760 |
Filed: |
May 4, 2010 |
PCT Filed: |
May 4, 2010 |
PCT NO: |
PCT/US2010/033576 |
371 Date: |
January 6, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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61176054 |
May 6, 2009 |
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Current U.S.
Class: |
514/230.5 ;
514/234.5; 514/253.04; 514/274; 514/275; 514/300; 544/105; 544/122;
544/127; 544/316; 544/331; 544/362; 546/113 |
Current CPC
Class: |
A61P 35/02 20180101;
C07D 471/04 20130101; A61P 13/12 20180101; A61P 29/00 20180101;
A61P 43/00 20180101; A61P 35/00 20180101 |
Class at
Publication: |
514/230.5 ;
546/113; 514/300; 544/105; 544/316; 514/274; 544/127; 514/234.5;
544/331; 514/275; 544/122; 544/362; 514/253.04 |
International
Class: |
A61K 31/538 20060101
A61K031/538; A61K 31/437 20060101 A61K031/437; A61K 31/506 20060101
A61K031/506; A61P 13/12 20060101 A61P013/12; A61K 31/496 20060101
A61K031/496; C07D 495/04 20060101 C07D495/04; A61P 35/00 20060101
A61P035/00; A61P 29/00 20060101 A61P029/00; C07D 471/04 20060101
C07D471/04; A61K 31/5377 20060101 A61K031/5377 |
Claims
1. A solid form of a phenyl sulfonamide compound comprising a basic
amino acid and the phenyl sulfonamide compound of Formula I
##STR01435## wherein: Ar is heteroaryl; each R.sup.1, when present,
is independently selected from the group consisting of halogen,
lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl,
heterocycloalkyl, phenyl, heteroaryl, --CN, --NO.sub.2,
--O--R.sup.11, --N(R.sup.12)--R.sup.13,
--C(O)--N(R.sup.14)--R.sup.15, --C(O)--O--R.sup.16,
--S(O).sub.2--R.sup.17, and --N(H)--C(O)--R.sup.18, wherein lower
alkyl is optionally substituted with one or more R.sup.5, lower
alkenyl and lower alkynyl are optionally substituted with one or
more R.sup.6, heterocycloalkyl is optionally substituted with one
or more lower alkyl, phenyl is optionally substituted with one or
more R.sup.7, and heteroaryl is optionally substituted with one or
more R.sup.8; m is 0, 1, 2, or 3; R.sup.2 is hydrogen, fluoro or
chloro; R.sup.3 is hydrogen, fluoro, chloro, or methyl; R.sup.4 is
selected from the group consisting of lower alkyl, fluoro
substituted lower alkyl, mono-alkylamino, di-alkylamino,
cycloalkylamino, cycloalkyl, phenyl, and heteroaryl, wherein
cycloalkyl is optionally substituted with --C(O)OR.sup.16, phenyl
is optionally substituted with one or more R.sup.9, and heteroaryl
is optionally substituted with one or more R.sup.10; L is selected
from the group consisting of --NH--, --CH.sub.2--, --C(OH)H--,
--C(O)--, --S(O).sub.2--, --O--CH.sub.2--, --CH.sub.2--NH--,
--NH--CH.sub.2--, --C(O)--NH--, and --NH--C(O)--; each R.sup.5,
when present, is independently fluoro, --OH, lower alkoxy,
heteroaryl, chloro substituted heteroaryl, phenyl, chloro
substituted phenyl, mono-alkylamino, di-alkylamino,
cycloalkylamino, --C(O)--N(R.sup.14)--R.sup.19, or
--C(O)--O--R.sup.16; each R.sup.6, when present, is independently
--C(O)--O--R.sup.16, lower alkoxy, mono-alkylamino or
di-alkylamino; each R.sup.7, when present, is independently fluoro,
chloro, --CN, --OH, lower alkyl, lower alkenyl, --C(O)--O--R.sup.16
substituted lower alkenyl, lower alkoxy, lower alkoxy substituted
lower alkoxy, mono-alkylamino, di-alkylamino, cycloalkylamino,
--S(O).sub.2R.sup.20, --N(H)--S(O).sub.2--R.sup.20,
--N(H)--C(O)--R.sup.20, --C(O)--N(R.sup.21)--R.sup.22, or
--S(O).sub.2--N(R.sup.23), --R.sup.24, wherein lower alkyl is
optionally substituted with --C(O)--O--R.sup.16, mono-alkylamino,
di-alkylamino, or cycloalkylamino; each R.sup.8, when present, is
independently fluoro, chloro, --OH, --NH.sub.2, lower alkyl, lower
alkynyl, di-alkylamino substituted lower alkynyl, lower alkoxy,
lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkylamino,
phenyl, --C(O)--N(R.sup.25)--R.sup.26, or --N(H)--C(O)--R.sup.20,
wherein lower alkyl is optionally substituted with one or more
fluoro, alkoxy, mono-alkylamino, di-alkylamino, cycloalkylamino, or
phenyl, and wherein lower alkoxy is optionally substituted with
--OH, lower alkoxy, mono-alkylamino, di-alkylamino or
cycloalkylamino; each R.sup.9, when present, is independently
fluoro, chloro, --CN, --NO.sub.2, lower alkyl, fluoro substituted
lower alkyl, lower alkoxy, fluoro substituted lower alkoxy,
--C(O)--O--R.sup.16, --N(H)--C(O)--R.sup.20, heteroaryl optionally
substituted with one or more lower alkyl, or two R.sup.9 on
adjacent carbons combine to form a fused heterocycloalkyl
optionally substituted with one or more lower alkyl; each R.sup.10,
when present, is independently lower alkyl, fluoro substituted
lower alkyl, lower alkoxy, --C(O)--O--R.sup.16, or heteroaryl
optionally substituted with one or more lower alkyl; each R.sup.11,
when present, is independently hydrogen, lower alkyl, cycloalkyl,
or heterocycloalkyl, wherein lower alkyl is optionally substituted
with --OH, lower alkoxy, mono-alkylamino, di-alkylamino,
cycloalkylamino, phenyl, or heteroaryl; each R.sup.12, R.sup.14,
and R.sup.16, when present, are independently hydrogen or lower
alkyl; each R.sup.13, when present, is independently hydrogen,
lower alkyl, cycloalkyl, phenyl, heteroaryl or combined with the
nitrogen and R.sup.12 form cycloalkylamino, wherein lower alkyl is
optionally substituted with cycloalkylamino, phenyl, heteroaryl or
lower alkyl substituted heteroaryl; each R.sup.15, when present, is
independently hydrogen, lower alkyl, --OH substituted lower alkyl,
cycloalkyl or lower alkoxy; each R.sup.17, when present, is
independently lower alkyl, phenyl or lower alkyl substituted
phenyl; each R.sup.18, when present, is independently lower alkyl
or cycloalkylamino; each R.sup.19, when present, is independently
hydrogen, lower alkyl, or lower alkoxy; each R.sup.20, when
present, is independently lower alkyl; each R.sup.21 and R.sup.22,
when present, are independently hydrogen, lower alkyl, or combine
with the nitrogen to form cycloalkylamino; each R.sup.23 and
R.sup.24, when present, are independently hydrogen, lower alkyl
optionally substituted with --OH, cycloalkyl, or combine with the
nitrogen to form cycloalkylamino; and each R.sup.25 and R.sup.26,
when present, are independently hydrogen, lower alkyl, or
cycloalkyl.
2. The solid form of claim 1, wherein the sulfonamide compound is a
compound of Formula Ia ##STR01436## wherein: U and V are C--H, and
W is C--R.sup.27; or U and W are C--H, and V is C--R.sup.28; or U
is N, V is C--H, and W is C--R.sup.27; or U is N, V is C--R.sup.28,
and W is C--H; or U is C--H, V is N, and W is C--R.sup.27; or U is
C--H, V is C--R.sup.28, and W is N; L.sub.1 is --CH.sub.2--,
--C(OH)H--, or --C(O)--; R.sup.27 is selected from the group
consisting of hydrogen, halogen, lower alkyl, lower alkenyl, lower
alkynyl, cycloalkyl, heterocycloalkyl, phenyl, heteroaryl, --CN,
--O--R.sup.38, --N(R.sup.39)--R.sup.40,
--C(O)--N(R.sup.41)--R.sup.42, --C(O)--O--R.sup.43,
--S(O).sub.2--R.sup.44, and --N(H)--C(O)--R.sup.45, wherein lower
alkyl is optionally substituted with one or more R.sup.32, lower
alkenyl and lower alkynyl are optionally substituted with one or
more R.sup.33, heterocycloalkyl is optionally substituted with one
or more lower alkyl, phenyl is optionally substituted with one or
more R.sup.34, and heteroaryl is optionally substituted with one or
more R.sup.35; R.sup.28 is selected from the group consisting of
hydrogen, chloro, methyl, methoxy, --CN, and --C.ident.CH; R.sup.29
is hydrogen, fluoro or chloro; R.sup.30 is hydrogen, fluoro,
chloro, or methyl; R.sup.31 is selected from the group consisting
of lower alkyl, fluoro substituted lower alkyl, mono-alkylamino,
di-alkylamino, cycloalkylamino, cycloalkyl, phenyl, and heteroaryl,
wherein cycloalkyl is optionally substituted with --C(O)OR.sup.43,
phenyl is optionally substituted with one or more R.sup.36, and
heteroaryl is optionally substituted with one or more R.sup.37;
each R.sup.32, when present, is independently fluoro, --OH, lower
alkoxy, heteroaryl, chloro substituted heteroaryl, phenyl, chloro
substituted phenyl, mono-alkylamino, di-alkylamino,
cycloalkylamino, --C(O)--N(R.sup.41)--R.sup.46, or
--C(O)--O--R.sup.43; each R.sup.33, when present, is independently
--C(O)--O--R.sup.43, lower alkoxy, mono-alkylamino or
di-alkylamino; each R.sup.34, when present, is independently
fluoro, chloro, --CN, --OH, lower alkyl, lower alkenyl,
--C(O)--O--R.sup.43 substituted lower alkenyl, lower alkoxy, lower
alkoxy substituted lower alkoxy, mono-alkylamino, di-alkylamino,
cycloalkylamino, --S(O).sub.2R.sup.47,
--N(H)--S(O).sub.2--R.sup.47, --N(H)--C(O)--R.sup.47,
--C(O)--N(R.sup.48)--R.sup.49, or
--S(O).sub.2--N(R.sup.50)--R.sup.51, wherein lower alkyl is
optionally substituted with --C(O)--O--R.sup.43, mono-alkylamino,
di-alkylamino, or cycloalkylamino; each R.sup.35, when present, is
independently fluoro, chloro, --OH, --NH.sub.2, lower alkyl, lower
alkynyl, di-alkylamino substituted lower alkynyl, lower alkoxy,
lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkylamino,
phenyl, --C(O)--N(R.sup.52)--R.sup.53, or --N(H)--C(O)--R.sup.47,
wherein lower alkyl is optionally substituted with one or more
fluoro, alkoxy, mono-alkylamino, di-alkylamino, cycloalkylamino, or
phenyl, and wherein lower alkoxy is optionally substituted with
--OH, lower alkoxy, mono-alkylamino, di-alkylamino or
cycloalkylamino; each R.sup.36, when present, is independently
fluoro, chloro, --CN, --NO.sub.2, lower alkyl, fluoro substituted
lower alkyl, lower alkoxy, fluoro substituted lower alkoxy,
--C(O)--O--R.sup.43, --N(H)--C(O)--R.sup.47, heteroaryl optionally
substituted with one or more lower alkyl, or two R.sup.36 on
adjacent carbons combine to form a fused heterocycloalkyl
optionally substituted with one or more lower alkyl; each R.sup.37,
when present, is independently lower alkyl, fluoro substituted
lower alkyl, lower alkoxy, --C(O)--O--R.sup.43, or heteroaryl
optionally substituted with one or more lower alkyl; R.sup.38 is
hydrogen, lower alkyl, cycloalkyl, or heterocycloalkyl, wherein
lower alkyl is optionally substituted with --OH, lower alkoxy,
mono-alkylamino, di-alkylamino, cycloalkylamino, phenyl, or
heteroaryl; each R.sup.39, R.sup.41, and R.sup.43, when present,
are independently hydrogen or lower alkyl; R.sup.40 is hydrogen,
lower alkyl, cycloalkyl, phenyl, heteroaryl or combined with the
nitrogen and R.sup.39 form cycloalkylamino, wherein lower alkyl is
optionally substituted with cycloalkylamino, phenyl, heteroaryl or
lower alkyl substituted heteroaryl; R.sup.42 is hydrogen, lower
alkyl, --OH substituted lower alkyl, cycloalkyl or lower alkoxy;
R.sup.44 is lower alkyl, phenyl or lower alkyl substituted phenyl;
R.sup.45 is lower alkyl or cycloalkylamino; each R.sup.46, when
present, is independently hydrogen, lower alkyl, or lower alkoxy;
each R.sup.47, when present, is independently lower alkyl; each
R.sup.48 and R.sup.49, when present, are independently hydrogen,
lower alkyl, or combine with the nitrogen to form cycloalkylamino;
each R.sup.50 and R.sup.51, when present, are independently
hydrogen, lower alkyl optionally substituted with --OH, cycloalkyl,
or combine with the nitrogen to form cycloalkylamino; and each
R.sup.52 and R.sup.53, when present, are independently hydrogen,
lower alkyl, or cycloalkyl.
3. The solid form of claim 2, wherein the sulfonamide compound is a
compound selected from the group consisting of ##STR01437##
wherein: R.sup.54 is selected from the group consisting of chloro,
lower alkyl, phenyl, heteroaryl, --CN, --C.ident.CH, --O--R.sup.62,
--N(R.sup.63)--R.sup.64, --C(O)--N(R.sup.65)--R.sup.66,
--C(O)--O--R.sup.67, --S(O).sub.2--R.sup.68, and
--N(H)--C(O)--R.sup.69, wherein lower alkyl is optionally
substituted with one or more R.sup.57, phenyl is optionally
substituted with one or more R.sup.58, and heteroaryl is optionally
substituted with one or more R.sup.59; R.sup.78 is selected from
the group consisting of hydrogen, lower alkyl, phenyl, heteroaryl,
--CN, --C.ident.CH, --O--R.sup.62, --N(R.sup.63)--R.sup.64,
--C(O)--N(R.sup.65)--R.sup.66, --C(O)--O--R.sup.67,
--S(O).sub.2--R.sup.68, and --N(H)--C(O)--R.sup.69, wherein lower
alkyl is optionally substituted with one or more R.sup.57, phenyl
is optionally substituted with one or more R.sup.58, and heteroaryl
is optionally substituted with one or more R.sup.59; R.sup.79 is
selected from the group consisting of chloro, methyl, methoxy,
--CN, and --C.ident.H; R.sup.80 is hydrogen, methyl, methoxy, --CN,
or --C.ident.H; R.sup.55 is hydrogen or fluoro; R.sup.56 is
selected from the group consisting of lower alkyl, fluoro
substituted lower alkyl, mono-alkylamino, di-alkylamino,
cycloalkylamino, cycloalkyl, phenyl, and heteroaryl, wherein phenyl
is optionally substituted with one or more R.sup.60, and heteroaryl
is optionally substituted with one or more R.sup.61; each R.sup.57,
when present, is independently fluoro, --OH, lower alkoxy,
heteroaryl, chloro substituted heteroaryl, phenyl, chloro
substituted phenyl, mono-alkylamino, di-alkylamino,
cycloalkylamino, --C(O)--N(R.sup.65)--R.sup.70, or
--C(O)--O--R.sup.67; each R.sup.58, when present, is independently
fluoro, chloro, --CN, --OH, lower alkyl, lower alkenyl,
--C(O)--O--R.sup.67 substituted lower alkenyl, lower alkoxy, lower
alkoxy substituted lower alkoxy, mono-alkylamino, di-alkylamino,
cycloalkylamino, --S(O).sub.2R.sup.71,
--N(H)--S(O).sub.2--R.sup.71, --N(H)--C(O)--R.sup.71,
--C(O)--N(R.sup.72)--R.sup.73, or
--S(O).sub.2--N(R.sup.74)--R.sup.75, wherein lower alkyl is
optionally substituted with --C(O)--O--R.sup.67, mono-alkylamino,
di-alkylamino, or cycloalkylamino; each R.sup.59, when present, is
independently fluoro, chloro, --OH, --NH.sub.2, lower alkyl, lower
alkynyl, di-alkylamino substituted lower alkynyl, lower alkoxy,
lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkylamino,
phenyl, --C(O)--N(R.sup.76)--R.sup.77, or --N(H)--C(O)--R.sup.71,
wherein lower alkyl is optionally substituted with one or more
fluoro, alkoxy, mono-alkylamino, di-alkylamino, cycloalkylamino, or
phenyl, and wherein lower alkoxy is optionally substituted with
--OH, lower alkoxy, mono-alkylamino, di-alkylamino or
cycloalkylamino; each R.sup.60, when present, is independently
fluoro, chloro, --CN, --NO.sub.2, lower alkyl, fluoro substituted
lower alkyl, lower alkoxy, fluoro substituted lower alkoxy,
--C(O)--O--R.sup.67, --N(H)--C(O)--R.sup.71, heteroaryl optionally
substituted with one or more lower alkyl, or two R.sup.60 on
adjacent carbons combine to form a fused heterocycloalkyl
optionally substituted with one or more lower alkyl; each R.sup.61,
when present, is independently lower alkyl, fluoro substituted
lower alkyl, lower alkoxy, --C(O)--O--R.sup.67, or heteroaryl
optionally substituted with one or more lower alkyl; R.sup.62 is
hydrogen, lower alkyl, cycloalkyl, or heterocycloalkyl, wherein
lower alkyl is optionally substituted with --OH, lower alkoxy,
mono-alkylamino, di-alkylamino, cycloalkylamino, phenyl, or
heteroaryl; each R.sup.63, R.sup.65, and R.sup.67, when present,
are independently hydrogen or lower alkyl; R.sup.64 is hydrogen,
lower alkyl, cycloalkyl, phenyl, heteroaryl or combined with the
nitrogen and R.sup.63 form cycloalkylamino, wherein lower alkyl is
optionally substituted with cycloalkylamino, phenyl, heteroaryl or
lower alkyl substituted heteroaryl; R.sup.66 is hydrogen, lower
alkyl, --OH substituted lower alkyl, cycloalkyl or lower alkoxy;
R.sup.68 is lower alkyl, phenyl or lower alkyl substituted phenyl;
R.sup.69 is lower alkyl or cycloalkylamino; each R.sup.70, when
present, is independently hydrogen, lower alkyl, or lower alkoxy;
each R.sup.71, when present, is independently lower alkyl; each
R.sup.72 and R.sup.73, when present, are independently hydrogen,
lower alkyl, or combine with the nitrogen to form cycloalkylamino;
each R.sup.74 and R.sup.75, when present, are independently
hydrogen, lower alkyl optionally substituted with --OH, cycloalkyl,
or combine with the nitrogen to form cycloalkylamino; and each
R.sup.76 and R.sup.77, when present, are independently hydrogen,
lower alkyl, or cycloalkyl.
4. The solid form of claim 3, wherein the basic amino acid is
L-lysine or L-arginine
5. The solid form of claim 3, wherein the solid form is an
amorphous complex.
6. The solid form of claim 5, wherein R.sup.56 is lower alkyl,
di-alkylamino, cycloalkylamino, or phenyl substituted with one or
more fluoro, lower alkyl, or fluoro substituted lower alkyl.
7. The solid form of claim 6, wherein R.sup.56 is n-propyl,
di-methylamino, pyrrolidin-1-yl, 3-fluoro phenyl, or 2,5-di-fluoro
phenyl.
8. The solid form of claim 7, wherein the compound is
propane-1-sulfonic acid
{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-di-
fluoro-phenyl}-amide and the basic amino acid is L-lysine or
L-arginine.
9. (canceled)
10. The solid form of claim 7, wherein the compound is
propane-1-sulfonic acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyrid-
ine-3-carbonyl]-phenyl}-amide and the basic amino acid is L-lysine
or L-arginine.
11. (canceled)
12. The solid form of claim 6, wherein R.sup.56 is 4-t-butyl
phenyl, 3-trifluoromethyl phenyl or 4-trifluoromethyl phenyl.
13. The solid form of claim 12, wherein the compound is
N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-4-trifluoromethyl-benzenesulfonamide and the basic amino acid is
L-lysine or L-arginine.
14. (canceled)
15. The solid form of claim 12, wherein the compound is
N-[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
4-trifluoromethyl-benzenesulfonamide and the basic amino acid is
L-lysine or L-arginine.
16. (canceled)
17. A composition comprising the solid form of claim 1 and one or
more pharmaceutically acceptable excipients.
18. A method of making an amorphous complex comprising
propane-1-sulfonic acid
{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-di-
fluoro-phenyl}-amide and, said method comprising contacting
crystalline polymorph Form 1 of propane-1-sulfonic acid
{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluor-
o-phenyl}-amide with an amino acid selected from L-lysine or
L-arginine under conditions sufficient for the preparation of said
complex.
19. (canceled)
20. A method of making an amorphous complex comprising
propane-1-sulfonic acid
{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-di-
fluoro-phenyl}-amide and L-lysine, said method comprising
contacting crystalline polymorph Form 2 of propane-1-sulfonic acid
{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluor-
o-phenyl}-amide with an amino acid selected from L-lysine or
L-arginine under conditions sufficient for the preparation of said
complex.
21. (canceled)
22. A composition comprising the solid form of claim 8 and one or
more pharmaceutically acceptable excipients.
23. A composition comprising the solid form of claim 10 and one or
more pharmaceutically acceptable excipients.
24. A composition comprising the solid form of claim 12 and one or
more pharmaceutically acceptable excipients.
25. A composition comprising the solid form of claim 13 and one or
more pharmaceutically acceptable excipients.
26. A composition comprising the solid form of claim 15 and one or
more pharmaceutically acceptable excipients.
Description
FIELD OF THE INVENTION
[0001] Disclosed are novel compounds, and novel solid forms,
formulations, and uses thereof. In certain embodiments disclosed
compounds are kinase inhibitors.
SUMMARY OF THE INVENTION
[0002] In one aspect, solid forms of phenyl sulfonamide compounds,
preferably an
N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide or
similar sulfonamide compounds, are provided. Also contemplated in
accordance with the present invention are solid forms comprising a
phenyl sulfonamide compound, preferably an
N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide
compound and a basic amino acid, wherein the solid form provides
improved biopharmaceutical properties. Also contemplated in
accordance with the present invention are methods for the use of
the above-described solid forms and related compositions in
treating diseases and conditions associated with regulation of the
activity of one or more protein kinases, including, but not limited
to Raf protein kinases, including A-Raf, B-Raf, c-Raf-1 and any
mutations thereof. In certain embodiments, the solid forms that can
be 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, colorectal
cancer, thyroid cancer, ovarian cancer, cholangiocarcinoma, pain
and/or polycystic kidney disease.
[0003] In a second aspect, a solid form comprising a phenyl
sulfonamide compound, preferably an
N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide or
similar sulfonamide compound, and a basic amino acid is provided.
In one embodiment, the solid form comprising an
N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide or
similar sulfonamide compound and the basic amino acid provides
improved biopharmaceutical properties of the phenyl sulfonamide
compound relative to the free base, salt or other solid form of the
compound.
[0004] In one embodiment, the solid form comprising an
N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide or
similar sulfonamide compound and the basic amino acid provides
improved pharmacokinetics of the phenyl sulfonamide compound
relative to the free base, salt or other solid form of the
compound, wherein said improvement is an increase in the Cmax
and/or AUC for a given dose of the compound in a suitable animal
model, such as a mouse, rat, dog or monkey model. In one
embodiment, a composition comprising the solid form is provided. In
one embodiment, the solid form comprising an
N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide
compound and the basic amino acid is provided in a formulation that
further improves the biopharmaceutical properties of the
N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide
compound.
[0005] In a third aspect, a solid form comprising a phenyl
sulfonamide compound, preferably an
N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide or
similar sulfonamide compound, and arginine is provided. In one
embodiment, the solid form comprising an
N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide or
similar sulfonamide compound and arginine provides improved
biopharmaceutical properties of the phenyl sulfonamide compound
relative to the free base, salt or other solid form of the
compound. In one embodiment, the solid form comprising an
N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide or
similar sulfonamide compound and arginine provides improved
pharmacokinetics of the phenyl sulfonamide compound relative to the
free base, salt or other solid form of the compound, wherein said
improvement is an increase in the Cmax and/or AUC for a given dose
of the compound in a suitable animal model, such as a mouse, rat,
dog or monkey model. In one embodiment, a composition comprising
the solid form is provided. In one embodiment, the solid form
comprising an
N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide
compound and arginine is provided in a formulation that further
improves the biopharmaceutical properties of the
N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide
compound.
[0006] In a fourth aspect, a solid form comprising a phenyl
sulfonamide compound, preferably an
N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide or
similar sulfonamide compound and lysine is provided. In one
embodiment, the solid form comprising an
N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide or
similar sulfonamide compound and lysine provides with improved
biopharmaceutical properties of the phenyl sulfonamide compound
relative to the free base, salt or other solid form of the
compound. In one embodiment, the solid form comprising an
N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide or
similar sulfonamide compound and lysine provides improved
pharmacokinetics of the phenyl sulfonamide compound relative to the
free base, salt or other solid form of the compound, wherein said
improvement is an increase in the Cmax and/or AUC for a given dose
of the compound in a suitable animal model, such as a mouse, rat,
dog or monkey model. In one embodiment, a composition comprising
the solid form is provided. In one embodiment, the solid form
comprising an
N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide
compound and lysine is provided in a formulation that further
improves the biopharmaceutical properties of the
N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide
compound.
[0007] In a fifth aspect, a solid form is provided comprising a
basic amino acid and a phenyl sulfonamide compound of Formula I,
wherein Formula I is as follows:
##STR00002##
wherein: [0008] Ar is heteroaryl; [0009] each R.sup.1, when
present, is independently selected from the group consisting of
halogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl,
heterocycloalkyl, phenyl, heteroaryl, --CN, --NO.sub.2,
--O--R.sup.11, --N(R.sup.12)--R.sup.13,
--C(O)--N(R.sup.14)--R.sup.15, --C(O)--O--R.sup.16,
--S(O).sub.2--R.sup.17, and --N(H)--C(O)--R.sup.18, wherein lower
alkyl is optionally substituted with one or more R.sup.5, lower
alkenyl and lower alkynyl are optionally substituted with one or
more R.sup.6, heterocycloalkyl is optionally substituted with one
or more lower alkyl, phenyl is optionally substituted with one or
more R.sup.7, and heteroaryl is optionally substituted with one or
more R.sup.8; [0010] m is 0, 1, 2, or 3; [0011] R.sup.2 is
hydrogen, fluoro or chloro; [0012] R.sup.3 is hydrogen, fluoro,
chloro, or methyl; [0013] R.sup.4 is selected from the group
consisting of lower alkyl, fluoro substituted lower alkyl,
mono-alkylamino, di-alkylamino, cycloalkylamino, cycloalkyl,
phenyl, and heteroaryl, wherein cycloalkyl is optionally
substituted with --C(O)OR.sup.16, phenyl is optionally substituted
with one or more R.sup.9, and heteroaryl is optionally substituted
with one or more R.sup.10; [0014] L is selected from the group
consisting of --NH--, --CH.sub.2--, --C(OH)H--, --C(O)--,
--S(O).sub.2--, --O--CH.sub.2--, --CH.sub.2--NH--,
--NH--CH.sub.2--, --C(O)--NH--, and --NH--C(O)--; [0015] each
R.sup.5, when present, is independently fluoro, --OH, lower alkoxy,
heteroaryl, chloro substituted heteroaryl, phenyl, chloro
substituted phenyl, mono-alkylamino, dialkylamino, cycloalkylamino,
--C(O)--N(R.sup.14)--R.sup.19, or --C(O)--O--R.sup.16; [0016] each
R.sup.6, when present, is independently --C(O)--O--R.sup.16, lower
alkoxy, mono-alkylamino or dialkylamino;
[0017] each R.sup.7, when present, is independently fluoro, chloro,
--CN, --OH, lower alkyl, lower alkenyl, --C(O)--O--R.sup.16
substituted lower alkenyl, lower alkoxy, lower alkoxy substituted
lower alkoxy, mono-alkylamino, di-alkylamino, cycloalkylamino,
--S(O).sub.2R.sup.20, --N(H)--S(O).sub.2--R.sup.20,
--N(H)--C(O)--R.sup.20, --C(O)--N(R.sup.21)--R.sup.22, or
--S(O).sub.2--N(R.sup.23)R.sup.24, wherein lower alkyl is
optionally substituted with --C(O)--O--R.sup.16, mono-alkylamino,
di-alkylamino, or cycloalkylamino; [0018] each R.sup.8, when
present, is independently fluoro, chloro, --OH, --NH.sub.2, lower
alkyl, lower alkynyl, di-alkylamino substituted lower alkynyl,
lower alkoxy, lower alkylthio, monoalkylamino, di-alkylamino,
cycloalkylamino, phenyl, --C(O)--N(R.sup.25)--R.sup.26, or
--N(H)--C(O)--R.sup.20, wherein lower alkyl is optionally
substituted with one or more fluoro, alkoxy, mono-alkylamino,
di-alkylamino, cycloalkylamino, or phenyl, and wherein lower alkoxy
is optionally substituted with --OH, lower alkoxy, mono-alkylamino,
di-alkylamino or cycloalkylamino; [0019] each R.sup.9, when
present, is independently fluoro, chloro, --CN, --NO.sub.2, lower
alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro
substituted lower alkoxy, --C(O)--O--R.sup.16,
--N(H)--C(O)--R.sup.26, heteroaryl optionally substituted with one
or more lower alkyl, or two R.sup.9 on adjacent carbons combine to
form a fused heterocycloalkyl optionally substituted with one or
more lower alkyl; [0020] each R.sup.10, when present, is
independently lower alkyl, fluoro substituted lower alkyl, lower
alkoxy, --C(O)--O--R.sup.16, or heteroaryl optionally substituted
with one or more lower alkyl; [0021] each R.sup.11, when present,
is independently hydrogen, lower alkyl, cycloalkyl, or
heterocycloalkyl, wherein lower alkyl is optionally substituted
with --OH, lower alkoxy, mono-alkylamino, di-alkylamino,
cycloalkylamino, phenyl, or heteroaryl; [0022] each R.sup.12,
R.sup.14, and R.sup.16, when present, are independently hydrogen or
lower alkyl; [0023] each R.sup.11, when present, is independently
hydrogen, lower alkyl, cycloalkyl, phenyl, heteroaryl or combined
with the nitrogen and R.sup.11 form cycloalkylamino, wherein lower
alkyl is optionally substituted with cycloalkylamino, phenyl,
heteroaryl or lower alkyl substituted heteroaryl; [0024] each
R.sup.15, when present, is independently hydrogen, lower alkyl,
--OH substituted lower alkyl, cycloalkyl or lower alkoxy; [0025]
each R.sup.17, when present, is independently lower alkyl, phenyl
or lower alkyl substituted phenyl; [0026] each R.sup.18, when
present, is independently lower alkyl or cycloalkylamino; [0027]
each R.sup.19, when present, is independently hydrogen, lower
alkyl, or lower alkoxy; [0028] each R.sup.20, when present, is
independently lower alkyl; [0029] each R.sup.21 and R.sup.22, when
present, are independently hydrogen, lower alkyl, or combine with
the nitrogen to form cycloalkylamino; [0030] each R.sup.23 and
R.sup.24, when present, are independently hydrogen, lower alkyl
optionally substituted with --OH, cycloalkyl, or combine with the
nitrogen to form cycloalkylamino; and [0031] each R.sup.25 and
R.sup.26, when present, are independently hydrogen, lower alkyl, or
cycloalkyl.
[0032] In a sixth aspect, a solid form is provided comprising a
basic amino acid and an
N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide or
similar sulfonamide compound of Formula Ia, wherein Formula Ia is
as follows:
##STR00003##
wherein: [0033] U and V are C--H, and W is C--R.sup.27; [0034] or U
and W are C--H, and V is C--R.sup.28; [0035] or U is N, V is C--H,
and W is C--R.sup.27; [0036] or U is N, V is C--R.sup.28, and W is
C--H; [0037] or U is C--H, V is N, and W is C--R.sup.27; [0038] or
U is C--H, V is C--R.sup.28, and W is N; [0039] L.sub.1 is
--CH.sub.2--, --C(OH)H--, or --C(O)--; [0040] R.sup.27 is selected
from the group consisting of hydrogen, halogen, lower alkyl, lower
alkenyl, lower alkynyl, cycloalkyl, heterocycloalkyl, phenyl,
heteroaryl, --CN, --O--R.sup.38, --N(R.sup.39)--R.sup.40,
--C(O)--N(R.sup.41)--R.sup.42, --C(O)--O--R.sup.43,
--S(O).sub.2--R.sup.44, and --N(H)--C(O)--R.sup.45, wherein lower
alkyl is optionally substituted with one or more R.sup.32, lower
alkenyl and lower alkynyl are optionally substituted with one or
more R.sup.33, heterocycloalkyl is optionally substituted with one
or more lower alkyl, phenyl is optionally substituted with one or
more R.sup.34, and heteroaryl is optionally substituted with one or
more R.sup.35;
[0041] R.sup.28 is selected from the group consisting of hydrogen,
chloro, methyl, methoxy, --CN, and --C.ident.CH; [0042] R.sup.29 is
hydrogen, fluoro or chloro; [0043] R.sup.30 is hydrogen, fluoro,
chloro, or methyl; [0044] R.sup.31 is selected from the group
consisting of lower alkyl, fluoro substituted lower alkyl,
mono-alkylamino, di-alkylamino, cycloalkylamino, cycloalkyl,
phenyl, and heteroaryl, wherein cycloalkyl is optionally
substituted with --C(O)OR.sup.43, phenyl is optionally substituted
with one or more R.sup.36, and heteroaryl is optionally substituted
with one or more R.sup.37; [0045] each R.sup.32, when present, is
independently fluoro, --OH, lower alkoxy, heteroaryl, chloro
substituted heteroaryl, phenyl, chloro substituted phenyl,
mono-alkylamino, dialkylamino, cycloalkylamino,
--C(O)--N(R.sup.41)--R.sup.46, or --C(O)--O--R.sup.43; [0046] each
R.sup.33, when present, is independently --C(O)--O--R.sup.43, lower
alkoxy, mono-alkylamino or dialkylamino; [0047] each R.sup.34, when
present, is independently fluoro, chloro, --CN, --OH, lower alkyl,
lower alkenyl, --C(O)--O--R.sup.43 substituted lower alkenyl, lower
alkoxy, lower alkoxy substituted lower alkoxy, mono-alkylamino,
di-alkylamino, cycloalkylamino, --S(O).sub.2R.sup.47,
--N(H)--S(O).sub.2--R.sup.47, --N(H)--C(O)--R.sup.47,
--C(O)--N(R.sup.48)--R.sup.49, or
--S(O).sub.2--N(R.sup.50)--R.sup.51, wherein lower alkyl is
optionally substituted with --C(O)--O--R.sup.43, mono-alkylamino,
di-alkylamino, or cycloalkylamino;
[0048] each R.sup.35, when present, is independently fluoro,
chloro, --OH, --NH.sub.2, lower alkyl, lower alkynyl, di-alkylamino
substituted lower alkynyl, lower alkoxy, lower alkylthio,
monoalkylamino, di-alkylamino, cycloalkylamino, phenyl,
--C(O)--N(R.sup.52)--R.sup.53, or --N(H)--C(O)--R.sup.47, wherein
lower alkyl is optionally substituted with one or more fluoro,
alkoxy, mono-alkylamino, di-alkylamino, cycloalkylamino, or phenyl,
and wherein lower alkoxy is optionally substituted with --OH, lower
alkoxy, mono-alkylamino, di-alkylamino or cycloalkylamino; [0049]
each R.sup.36, when present, is independently fluoro, chloro, --CN,
--NO.sub.2, lower alkyl, fluoro substituted lower alkyl, lower
alkoxy, fluoro substituted lower alkoxy, --C(O)--O--R.sup.43,
--N(H)--C(O)--R.sup.47, heteroaryl optionally substituted with one
or more lower alkyl, or two R.sup.36 on adjacent carbons combine to
form a fused heterocycloalkyl optionally substituted with one or
more lower alkyl; [0050] each R.sup.37, when present, is
independently lower alkyl, fluoro substituted lower alkyl, lower
alkoxy, --C(O)--O--R.sup.43, or heteroaryl optionally substituted
with one or more lower alkyl; [0051] R.sup.38 is hydrogen, lower
alkyl, cycloalkyl, or heterocycloalkyl, wherein lower alkyl is
optionally substituted with --OH, lower alkoxy, mono-alkylamino,
di-alkylamino, cycloalkylamino, phenyl, or heteroaryl; [0052] each
R.sup.39, R.sup.41, and R.sup.43, when present, are independently
hydrogen or lower alkyl; [0053] R.sup.40 is hydrogen, lower alkyl,
cycloalkyl, phenyl, heteroaryl or combined with the nitrogen and
R.sup.39 form cycloalkylamino, wherein lower alkyl is optionally
substituted with cycloalkylamino, phenyl, heteroaryl or lower alkyl
substituted heteroaryl; [0054] R.sup.42 is hydrogen, lower alkyl,
--OH substituted lower alkyl, cycloalkyl or lower alkoxy; [0055]
R.sup.44 is lower alkyl, phenyl or lower alkyl substituted phenyl;
[0056] R.sup.45 is lower alkyl or cycloalkylamino; [0057] each
R.sup.46, when present, is independently hydrogen, lower alkyl, or
lower alkoxy; [0058] each R.sup.47, when present, is independently
lower alkyl; [0059] each R.sup.48 and R.sup.49, when present, are
independently hydrogen, lower alkyl, or combine with the nitrogen
to form cycloalkylamino; [0060] each R.sup.50 and R.sup.51, when
present, are independently hydrogen, lower alkyl optionally
substituted with --OH, cycloalkyl, or combine with the nitrogen to
form cycloalkylamino; and [0061] each R.sup.52 and R.sup.53, when
present, are independently hydrogen, lower alkyl, or
cycloalkyl.
[0062] In one embodiment of a solid form comprising a basic amino
acid and a compound of Formula Ia, U and V are C--H, W is
C--R.sup.27, and R.sup.27 is selected from the group consisting of
hydrogen, chloro, lower alkyl, phenyl, heteroaryl, --CN,
--C.ident.CH, --O--R.sup.38, --N(R.sup.39)--R.sup.40,
--C(O)--N(R.sup.41)--R.sup.42, --C(O)--O--R.sup.43,
--S(O).sub.2--R.sup.44, and --N(H)--C(O)--R.sup.45, wherein lower
alkyl is optionally substituted with one or more R.sup.32, phenyl
is optionally substituted with one or more R.sup.34, and heteroaryl
is optionally substituted with one or more R.sup.35. In one
embodiment, R.sup.27 is selected from the group consisting of
hydrogen, chloro, lower alkyl, phenyl, heteroaryl, --CN,
--C.ident.CH, --O--R.sup.38, --N(R.sup.39)--R.sup.40,
--C(O)--N(R.sup.41)--R.sup.42, --C(O)--O--R.sup.43,
--S(O).sub.2--R.sup.44, and --N(H)--C(O)--R.sup.45, wherein lower
alkyl is optionally substituted with one or more R.sup.32, phenyl
is optionally substituted with one or more R.sup.34, and heteroaryl
is optionally substituted with one or more R.sup.35 and R.sup.31 is
lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted
with one or more fluoro, lower alkyl, or fluoro substituted lower
alkyl. In one embodiment, R.sup.27 is chloro, methyl, --CN, chloro
substituted phenyl, or methoxy substituted pyrimidinyl, and
R.sup.31 is lower alkyl, dialkylamino, cycloalkylamino, or phenyl
substituted with one or more fluoro, lower alkyl, or
trifluoromethyl. In one embodiment, R.sup.27 is chloro, methyl,
--CN, chloro substituted phenyl, or methoxy substituted
pyrimidinyl, and R.sup.31 is n-propyl, di-methylamino,
pyrrolidin-1-yl, fluoro substituted phenyl, di-fluoro substituted
phenyl, t-butyl substituted phenyl or trifluoromethyl substituted
phenyl. In one embodiment, R.sup.27 is chloro, methyl, --CN, chloro
substituted phenyl, or methoxy substituted pyrimidinyl, and
R.sup.31 is n-propyl, di-methylamino, pyrrolidin-1-yl,
3-fluorophenyl, 2,5-di-fluoro-phenyl, 4-t-butyl-phenyl,
3-trifluoromethyl-phenyl or 4-trifluoromethylphenyl. In one
embodiment, R.sup.27 is chloro, methyl, --CN, chloro substituted
phenyl, or methoxy substituted pyrimidinyl, and R.sup.31 is
n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro-phenyl, or
2,5-di-fluoro-phenyl. In one embodiment, R.sup.27 is chloro,
methyl, --CN, chloro substituted phenyl, or methoxy substituted
pyrimidinyl, and R.sup.31 is 4-t-butyl-phenyl,
3-trifluoromethyl-phenyl or 4-trifluoromethyl-phenyl. In one
embodiment, R.sup.27 is chloro, --CN, chloro substituted phenyl, or
methoxy substituted pyrimidinyl, and R.sup.31 is n-propyl,
di-methylamino, pyrrolidin-1-yl, 3-fluorophenyl, or
2,5-di-fluoro-phenyl. In one embodiment, R.sup.27 is chloro,
methyl, or --CN, and R.sup.31 is 3-trifluoromethyl-phenyl or
4-trifluoromethyl-phenyl.
[0063] In one embodiment of a solid form comprising a basic amino
acid and a compound of Formula Ia, U and W are C--H, V is
C--R.sup.28, and R.sup.28 is selected from the group consisting of
hydrogen, chloro, methyl, methoxy, --CN, and --C.ident.CH. In one
embodiment, R.sup.28 is selected from the group consisting of
hydrogen, chloro, methyl, methoxy, --CN, and --C.ident.CH and
R.sup.31 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl
substituted with one or more fluoro, lower alkyl, or fluoro
substituted lower alkyl. In one embodiment, R.sup.28 is --CN, or
--C.ident.CH, and R.sup.31 is lower alkyl, di-alkylamino,
cycloalkylamino, or phenyl substituted with one or more fluoro,
lower alkyl, or trifluoromethyl. In one embodiment, R.sup.28 is
--CN, or --C.ident.CH, and R.sup.31 is n-propyl, dimethylamino,
pyrrolidin-1-yl, fluoro substituted phenyl, di-fluoro substituted
phenyl, t-butyl substituted phenyl or trifluoromethyl substituted
phenyl. In one embodiment, R.sup.28 is --CN, or --C.ident.CH, and
R.sup.31 is n-propyl, di-methylamino, pyrrolidin-1-yl,
3-fluoro-phenyl, or 2,5-di-fluoro-phenyl. In one embodiment,
R.sup.28 is --CN, or --C.ident.CH, and R.sup.31 is
4-t-butyl-phenyl, 3-trifluoromethyl-phenyl or
4-trifluoromethyl-phenyl. In one embodiment, R.sup.28 is --CN, or
--C.ident.CH, and R.sup.31 is 4-trifluoromethyl-phenyl.
[0064] In one embodiment of a solid form comprising a basic amino
acid and a compound of Formula Ia, U is C--H, V is N, W is
C--R.sup.27, and R.sup.27 is selected from the group consisting of
hydrogen, chloro, lower alkyl, phenyl, heteroaryl, --CN,
--C.ident.CH, --O--R.sup.38, --N(R.sup.39)--R.sup.40,
--C(O)--N(R.sup.41)--R.sup.42, --C(O)--O--R.sup.43,
--S(O).sub.2--R.sup.44, and --N(H)--C(O)--R.sup.45, wherein lower
alkyl is optionally substituted with one or more R.sup.32, phenyl
is optionally substituted with one or more R.sup.34, and heteroaryl
is optionally substituted with one or more R.sup.35. In one
embodiment, R.sup.27 is selected from the group consisting of
hydrogen, chloro, lower alkyl, phenyl, heteroaryl, --CN,
--C.ident.CH, --O--R.sup.38, --N(R.sup.39)--R.sup.40,
--C(O)--N(R.sup.41)--R.sup.42, --C(O)--O--R.sup.43,
C(O)--O--R.sup.43, --S(O).sub.2--R.sup.44, and
--N(H)--C(O)--R.sup.45, wherein lower alkyl is optionally
substituted with one or more R.sup.32, phenyl is optionally
substituted with one or more R.sup.34, and heteroaryl is optionally
substituted with one or more R.sup.35 and R.sup.31 is lower alkyl,
di-alkylamino, cycloalkylamino, or phenyl substituted with one or
more fluoro, lower alkyl, or fluoro substituted lower alkyl. In one
embodiment, R.sup.27 is hydrogen, chloro, methyl, --CN, chloro
substituted phenyl, or methoxy substituted pyrimidinyl, and
R.sup.31 is n-propyl, di-methylamino, pyrrolidin-1-yl,
3-fluoro-phenyl, or 2,5-di-fluoro-phenyl. In one embodiment,
R.sup.27 is hydrogen, chloro, methyl, --CN, chloro substituted
phenyl, or methoxy substituted pyrimidinyl, and R.sup.31 is
4-t-butyl-phenyl, 3-trifluoromethyl-phenyl or
4-trifluoromethyl-phenyl. In one embodiment, R.sup.27 is hydrogen
and R.sup.31 is lower alkyl, di-alkylamino, cycloalkylamino, or
phenyl substituted with one or more fluoro, lower alkyl, or
trifluoromethyl. In one embodiment, R.sup.27 is hydrogen and
R.sup.31 is n-propyl, di-methylamino, pyrrolidin-1-yl,
3-fluoro-phenyl, or 2,5-di-fluoro-phenyl. In one embodiment,
R.sup.27 is hydrogen and R.sup.31 is 4-t-butyl-phenyl,
3-trifluoromethyl-phenyl or 4-trifluoromethyl-phenyl. In one
embodiment, R.sup.27 is hydrogen and R.sup.31 is
4-trifluoromethyl-phenyl.
[0065] In one embodiment of a solid form comprising a basic amino
acid and a compound of Formula Ia, U is C--H, W is N, V is
C--R.sup.28, and R.sup.28 is selected from the group consisting of
hydrogen, chloro, methyl, methoxy, --CN, and --C.ident.CH. In one
embodiment, R.sup.28 is selected from the group consisting of
hydrogen, chloro, methyl, methoxy, --CN, and --C.ident.CH and
R.sup.31 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl
substituted with one or more fluoro, lower alkyl, or fluoro
substituted lower alkyl. In one embodiment, R.sup.28 is hydrogen,
chloro, methyl, methoxy, --CN, or --C.ident.CH and R.sup.31 is
n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro-phenyl, or
2,5-di-fluoro-phenyl. In one embodiment, R.sup.28 is hydrogen,
chloro, methyl, methoxy, --CN, or --C.ident.CH, and R.sup.31 is
4-t-butyl-phenyl, 3-trifluoromethyl-phenyl or
4-trifluoromethyl-phenyl. In one embodiment, R.sup.28 is hydrogen
or methoxy, and R.sup.31 is lower alkyl, di-alkylamino,
cycloalkylamino, or phenyl substituted with one or more fluoro,
lower alkyl, or trifluoromethyl. In one embodiment, R.sup.28 is
hydrogen or methoxy, and R.sup.31 is n-propyl, di-methylamino,
pyrrolidin-1-yl, 3-fluoro-phenyl, or 2,5-di-fluoro-phenyl. In one
embodiment, R.sup.28 is hydrogen or methoxy, and R.sup.31 is
4-t-butyl-phenyl, 3-trifluoromethyl-phenyl or
4-trifluoromethyl-phenyl. In one embodiment, R.sup.28 is hydrogen
or methoxy, and R.sup.31 is 4-t-butyl-phenyl or
4-trifluoromethyl-phenyl.
[0066] In one embodiment of a solid form comprising a basic amino
acid and a compound of Formula Ia, U is N, V is --CH, W is
C--R.sup.27, and R.sup.27 is selected from the group consisting of
hydrogen, chloro, lower alkyl, phenyl, heteroaryl, --CN,
--C.ident.CH, --O--R.sup.38, --N(R.sup.39)--R.sup.40,
--C(O)--N(R.sup.41)--R.sup.42, --C(O)--O--R.sup.43,
--S(O).sub.2--R.sup.44, and --N(H)--C(O)--R.sup.45, wherein lower
alkyl is optionally substituted with one or more R.sup.32, phenyl
is optionally substituted with one or more R.sup.34, and heteroaryl
is optionally substituted with one or more R.sup.35. In one
embodiment, R.sup.27 is selected from the group consisting of
hydrogen, chloro, lower alkyl, phenyl, heteroaryl, --CN,
--C.ident.CH, --O--R.sup.38, --N(R.sup.39)--R.sup.40,
--C(O)--N(R.sup.41)--R.sup.42, --C(O)--O--R.sup.43,
--S(O).sub.2--R.sup.44, and --N(H)--C(O)--R.sup.45, wherein lower
alkyl is optionally substituted with one or more R.sup.32, phenyl
is optionally substituted with one or more R.sup.34, and heteroaryl
is optionally substituted with one or more R.sup.35 and R.sup.31 is
lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted
with one or more fluoro, lower alkyl, or fluoro substituted lower
alkyl. In one embodiment, R.sup.27 is hydrogen, chloro, methyl,
--CN, chloro substituted phenyl, or methoxy substituted
pyrimidinyl, and R.sup.31 is n-propyl, di-methylamino,
pyrrolidin-1-yl, 3-fluoro-phenyl, or 2,5-di-fluoro-phenyl. In one
embodiment, R.sup.27 is hydrogen, chloro, methyl, --CN, chloro
substituted phenyl, or methoxy substituted pyrimidinyl, and
R.sup.31 is 4-t-butyl-phenyl, 3-trifluoromethyl-phenyl or
4-trifluoromethyl-phenyl.
[0067] In one embodiment of a solid form comprising a basic amino
acid and a compound of Formula Ia, U is N, W is --CH, V is
C--R.sup.28, and R.sup.28 is selected from the group consisting of
hydrogen, chloro, methyl, methoxy, --CN, and --C.ident.CH. In one
embodiment, R.sup.28 is selected from the group consisting of
hydrogen, chloro, methyl, methoxy, --CN, and --C.ident.CH and
R.sup.31 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl
substituted with one or more fluoro, lower alkyl, or fluoro
substituted lower alkyl. In one embodiment, R.sup.28 is hydrogen,
chloro, methyl, methoxy, --CN, or --C.ident.CH and R.sup.31 is
n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro-phenyl, or
2,5-di-fluoro-phenyl. In one embodiment, R.sup.28 is hydrogen,
chloro, methyl, methoxy, --CN, or --C.ident.CH, and R.sup.31 is
4-t-butyl-phenyl, 3-trifluoromethyl-phenyl or
4-trifluoromethyl-phenyl.
[0068] In one embodiment of a solid form comprising a basic amino
acid and a compound of Formula Ia, U and V are C--H, W is
C--R.sup.27, R.sup.27 is chloro, methyl or --CN, R.sup.29 is
fluoro, R.sup.30 is fluoro, and R.sup.31 is 3-trifluoromethyl
phenyl or 4-trifluoromethyl phenyl; or U and W are C--H, V is
C--R.sup.28, R.sup.28 is --CN or --C.ident.CH, R.sup.29 is fluoro,
R.sup.30 is fluoro, and R.sup.31 is 4-trifluoromethyl phenyl; or U
is C--H, W is N, V is C--R.sup.28, R.sup.28 is hydrogen or methoxy,
R.sup.29 is fluoro, R.sup.30 is fluoro, and R.sup.31 is
4-t-butyl-phenyl or 4-trifluoromethyl phenyl; or U is C--H, V is N,
W is C--R.sup.27, R.sup.27 is hydrogen, R.sup.29 is fluoro,
R.sup.30 is fluoro, and R.sup.31 is 4-trifluoromethyl-phenyl.
[0069] In one embodiment of a solid form comprising a basic amino
acid and a compound of Formula Ia, U and V are C--H, W is
C--R.sup.27, R.sup.27 is chloro, --CN, 4-chloro-phenyl, or
2-methoxy-pyrimidin-5-yl, R.sup.29 is hydrogen or fluoro, R.sup.30
is fluoro, and R.sup.31 is n-propyl, di-methylamino,
pyrrolidin-1-yl, 3-fluoro-phenyl, 2,5-di-fluoro-phenyl.
[0070] In a seventh aspect, a solid form is provided comprising a
basic amino acid and an
N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide
compound of Formula Ib, wherein Formula Ib is as follows:
##STR00004##
wherein: [0071] R.sup.54 is selected from the group consisting of
chloro, lower alkyl, phenyl, heteroaryl, --CN, --C.ident.CH,
--O--R.sup.62, --N(R.sup.63)--R.sup.64,
--C(O)--N(R.sup.65)--R.sup.66, --C(O)--O--R.sup.67,
--S(O).sub.2--R.sup.68, and --N(H)--C(O)--R.sup.69, wherein lower
alkyl is optionally substituted with one or more R.sup.57, phenyl
is optionally substituted with one or more R.sup.58, and heteroaryl
is optionally substituted with one or more R.sup.59; [0072]
R.sup.55 is hydrogen or fluoro; [0073] R.sup.56 is selected from
the group consisting of lower alkyl, fluoro substituted lower
alkyl, mono-alkylamino, di-alkylamino, cycloalkylamino, cycloalkyl,
phenyl, and heteroaryl, wherein phenyl is optionally substituted
with one or more R.sup.60, and heteroaryl is optionally substituted
with one or more R.sup.61; [0074] each R.sup.57, when present, is
independently fluoro, --OH, lower alkoxy, heteroaryl, chloro
substituted heteroaryl, phenyl, chloro substituted phenyl,
mono-alkylamino, di-alkylamino, cycloalkylamino,
--C(O)--N(R.sup.65)--R.sup.70, or --C(O)--O--R.sup.67;
[0075] each R.sup.58, when present, is independently fluoro,
chloro, --CN, --OH, lower alkyl, lower alkenyl, --C(O)--O--R.sup.67
substituted lower alkenyl, lower alkoxy, lower alkoxy substituted
lower alkoxy, mono-alkylamino, di-alkylamino, cycloalkylamino,
--S(O).sub.2R.sup.71, --N(H)--S(O).sub.2--R.sup.71,
--N(H)--C(O)--R.sup.71, --C(O)--N(R.sup.72)--R.sup.73, or
--S(O).sub.2--N(R.sup.74)--R.sup.75, wherein lower alkyl is
optionally substituted with --C(O)--O--R.sup.67, mono-alkylamino,
di-alkylamino, or cycloalkylamino; [0076] each R.sup.59, when
present, is independently fluoro, chloro, --OH, --NH.sub.2, lower
alkyl, lower alkynyl, di-alkylamino substituted lower alkynyl,
lower alkoxy, lower alkylthio, mono-alkylamino, di-alkylamino,
cycloalkylamino, phenyl, --C(O)--N(R.sup.76)--R.sup.77, or
--N(H)--C(O)--R.sup.71, wherein lower alkyl is optionally
substituted with one or more fluoro, alkoxy, mono-alkylamino,
di-alkylamino, cycloalkylamino, or phenyl, and wherein lower alkoxy
is optionally substituted with --OH, lower alkoxy, mono-alkylamino,
di-alkylamino or cycloalkylamino; [0077] each R.sup.60, when
present, is independently fluoro, chloro, --CN, --NO.sub.2, lower
alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro
substituted lower alkoxy, --C(O)--O--R.sup.67,
--N(H)--C(O)--R.sup.71, heteroaryl optionally substituted with one
or more lower alkyl, or two R.sup.60 on adjacent carbons combine to
form a fused heterocycloalkyl optionally substituted with one or
more lower alkyl; [0078] each R.sup.61, when present, is
independently lower alkyl, fluoro substituted lower alkyl, lower
alkoxy, --C(O)--O--R.sup.67, or heteroaryl optionally substituted
with one or more lower alkyl; [0079] R.sup.62 is hydrogen, lower
alkyl, cycloalkyl, or heterocycloalkyl, wherein lower alkyl is
optionally substituted with --OH, lower alkoxy, mono-alkylamino,
di-alkylamino, cycloalkylamino, phenyl, or heteroaryl; [0080] each
R.sup.63, R.sup.65, and R.sup.67, when present, are independently
hydrogen or lower alkyl; [0081] R.sup.64 is hydrogen, lower alkyl,
cycloalkyl, phenyl, heteroaryl or combined with the nitrogen and
R.sup.63 form cycloalkylamino, wherein lower alkyl is optionally
substituted with cycloalkylamino, phenyl, heteroaryl or lower alkyl
substituted heteroaryl; [0082] R.sup.66 is hydrogen, lower alkyl,
--OH substituted lower alkyl, cycloalkyl or lower alkoxy; [0083]
R.sup.68 is lower alkyl, phenyl or lower alkyl substituted phenyl;
[0084] R.sup.69 is lower alkyl or cycloalkylamino; [0085] each
R.sup.70, when present, is independently hydrogen, lower alkyl, or
lower alkoxy; [0086] each R.sup.71, when present, is independently
lower alkyl; [0087] each R.sup.72 and R.sup.73, when present, are
independently hydrogen, lower alkyl, or combine with the nitrogen
to form cycloalkylamino; [0088] each R.sup.74 and R.sup.75, when
present, are independently hydrogen, lower alkyl optionally
substituted with --OH, cycloalkyl, or combine with the nitrogen to
form cycloalkylamino; and [0089] each R.sup.76 and R.sup.77, when
present, are independently hydrogen, lower alkyl, or
cycloalkyl.
[0090] In one embodiment of a solid form comprising a basic amino
acid and a compound of Formula Ib, R.sup.56 is lower alkyl,
di-alkylamino, cycloalkylamino, or phenyl substituted with one or
more fluoro, lower alkyl, or fluoro substituted lower alkyl. In one
embodiment, R.sup.56 is lower alkyl, di-alkylamino,
cycloalkylamino, or phenyl substituted with one or more fluoro,
lower alkyl, or fluoro substituted lower alkyl and R.sup.55 is
fluoro. In one embodiment, R.sup.54 is chloro, methyl, --CN, chloro
substituted phenyl, or methoxy substituted pyrimidinyl, and
R.sup.56 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl
substituted with one or more fluoro, lower alkyl, or
trifluoromethyl. In one embodiment, R.sup.54 is chloro, methyl,
--CN, chloro substituted phenyl, or methoxy substituted
pyrimidinyl, R.sup.56 is lower alkyl, di-alkylamino,
cycloalkylamino, or phenyl substituted with one or more fluoro,
lower alkyl, or trifluoromethyl and R.sup.55 is fluoro. In one
embodiment, R.sup.54 is chloro, methyl, --CN, chloro substituted
phenyl, or methoxy substituted pyrimidinyl, and R.sup.56 is
n-propyl, di-methylamino, pyrrolidin-1-yl, fluoro substituted
phenyl, di-fluoro substituted phenyl, t-butyl substituted phenyl or
trifluoromethyl substituted phenyl. In one embodiment, R.sup.54 is
chloro, methyl, --CN, chloro substituted phenyl, or methoxy
substituted pyrimidinyl, R.sup.56 is n-propyl, di-methylamino,
pyrrolidin-1-yl, fluoro substituted phenyl, di-fluoro substituted
phenyl, t-butyl substituted phenyl or trifluoromethyl substituted
phenyl, and R.sup.55 is fluoro. In one embodiment, R.sup.54 is
chloro, methyl, --CN, chloro substituted phenyl, or methoxy
substituted pyrimidinyl, and R.sup.56 is n-propyl, di-methylamino,
pyrrolidin-1-yl, 3-fluoro phenyl, or 2,5-di-fluoro phenyl. In one
embodiment, R.sup.54 is chloro, methyl, --CN, chloro substituted
phenyl, or methoxy substituted pyrimidinyl, and R.sup.56 is
4-t-butyl phenyl, 3-trifluoromethyl phenyl or 4-trifluoromethyl
phenyl. In one embodiment, R.sup.54 is chloro, methyl, --CN, chloro
substituted phenyl, or methoxy substituted pyrimidinyl, R.sup.56 is
n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro phenyl, or
2,5-di-fluoro phenyl, and R.sup.55 is fluoro. In one embodiment,
R.sup.54 is chloro, methyl, --CN, chloro substituted phenyl, or
methoxy substituted pyrimidinyl, R.sup.56 is 4-t-butyl phenyl,
3-trifluoromethyl phenyl or 4-trifluoromethyl phenyl, and R.sup.55
is fluoro. In one embodiment, R.sup.54 is chloro, methyl or --CN,
R.sup.56 is 3-trifluoromethyl phenyl or 4-trifluoromethyl phenyl,
and R.sup.55 is fluoro. In one embodiment, R.sup.54 is chloro,
--CN, 4-chloro-phenyl, or 2-methoxy-pyrimidin-5-yl, R.sup.56 is
n-propyl, di-methylamino, pyrrolidin-1-yl, or 3-fluoro-phenyl,
2,5-di-fluoro-phenyl, and R.sup.55 is fluoro.
[0091] In an eighth aspect, a solid form is provided comprising a
basic amino acid and an
N-[3-(5H-pyrrolo[2,3-b]pyrazine-7-carbonyl)-phenyl]-sulfonamide
compound of Formula Ic, wherein Formula Ic is as follows:
##STR00005##
wherein [0092] R.sup.78 is selected from the group consisting of
hydrogen, lower alkyl, phenyl, heteroaryl, --CN, --C.ident.CH,
--O--R.sup.62, --N(R.sup.63)--R.sup.64,
--C(O)--N(R.sup.65)--R.sup.66, --C(O)--O--R.sup.67,
C(O)--O--R.sup.67, --S(O).sub.2--R.sup.68, and
--N(H)--C(O)--R.sup.69, wherein lower alkyl is optionally
substituted with one or more R.sup.57, phenyl is optionally
substituted with one or more R.sup.58, and heteroaryl is optionally
substituted with one or more R.sup.59; and [0093] R.sup.55,
R.sup.56, R.sup.57, R.sup.58, R.sup.59, R.sup.62, R.sup.63,
R.sup.64, R.sup.65, R.sup.66, R.sup.67, R.sup.68, and R.sup.69, are
as defined for Formula Ib.
[0094] In one embodiment of a solid form comprising a basic amino
acid and a compound of Formula Ic, R.sup.56 is lower alkyl,
di-alkylamino, cycloalkylamino, or phenyl substituted with one or
more fluoro, lower alkyl, or fluoro substituted lower alkyl. In one
embodiment, R.sup.56 is lower alkyl, di-alkylamino,
cycloalkylamino, or phenyl substituted with one or more fluoro,
lower alkyl, or fluoro substituted lower alkyl and R.sup.55 is
fluoro. In one embodiment, R.sup.78 is hydrogen, chloro, methyl,
--CN, chloro substituted phenyl, or methoxy substituted
pyrimidinyl, and R.sup.56 is lower alkyl, di-alkylamino,
cycloalkylamino, or phenyl substituted with one or more fluoro,
lower alkyl, or trifluoromethyl. In one embodiment, R.sup.78 is
hydrogen, chloro, methyl, --CN, chloro substituted phenyl, or
methoxy substituted pyrimidinyl, R.sup.56 is lower alkyl,
di-alkylamino, cycloalkylamino, or phenyl substituted with one or
more fluoro, lower alkyl, or trifluoromethyl and R.sup.55 is
fluoro. In one embodiment, R.sup.78 is hydrogen, chloro, methyl,
--CN, chloro substituted phenyl, or methoxy substituted
pyrimidinyl, and R.sup.56 is n-propyl, di-methylamino,
pyrrolidin-1-yl, fluoro substituted phenyl, di-fluoro substituted
phenyl, t-butyl substituted phenyl or trifluoromethyl substituted
phenyl. In one embodiment, R.sup.78 is hydrogen, chloro, methyl,
--CN, chloro substituted phenyl, or methoxy substituted
pyrimidinyl, R.sup.56 is n-propyl, di-methylamino, pyrrolidin-1-yl,
fluoro substituted phenyl, di-fluoro substituted phenyl, t-butyl
substituted phenyl or trifluoromethyl substituted phenyl, and
R.sup.55 is fluoro. In one embodiment, R.sup.78 is hydrogen,
chloro, methyl, --CN, chloro substituted phenyl, or methoxy
substituted pyrimidinyl, and R.sup.56 is n-propyl, di-methylamino,
pyrrolidin-1-yl, 3-fluoro phenyl, or 2,5-di-fluoro phenyl. In one
embodiment, R.sup.78 is hydrogen, chloro, methyl, --CN, chloro
substituted phenyl, or methoxy substituted pyrimidinyl, and
R.sup.56 is 4-t-butyl phenyl, 3-trifluoromethyl phenyl or
4-trifluoromethyl phenyl. In one embodiment, R.sup.78 is hydrogen,
chloro, methyl, --CN, chloro substituted phenyl, or methoxy
substituted pyrimidinyl, R.sup.56 is n-propyl, di-methylamino,
pyrrolidin-1-yl, 3-fluoro phenyl, or 2,5-di-fluoro phenyl, and
R.sup.55 is fluoro. In one embodiment, R.sup.78 is hydrogen,
chloro, methyl, --CN, chloro substituted phenyl, or methoxy
substituted pyrimidinyl, R.sup.56 is 4-t-butyl phenyl,
3-trifluoromethyl phenyl or 4-trifluoromethyl phenyl, and R.sup.55
is fluoro. In one embodiment, R.sup.78 is hydrogen, R.sup.56 is
4-trifluoromethyl phenyl, and R.sup.55 is fluoro.
[0095] In a ninth aspect, a solid form is provided comprising a
basic amino acid and an
N-[3-(1H-Pyrazolo[3,4-b]pyridine-3-carbonyl)-phenyl]-sulfonamide
compound of Formula Id, wherein Formula Id is as follows:
##STR00006##
[0096] wherein R.sup.54, R.sup.55, and R.sup.56 are as defined for
Formula Ib and R.sup.78 is as defined for Formula Ic.
[0097] In one embodiment of a solid form comprising a basic amino
acid and a compound of Formula Id, R.sup.56 is lower alkyl,
di-alkylamino, cycloalkylamino, or phenyl substituted with one or
more fluoro, lower alkyl, or fluoro substituted lower alkyl. In one
embodiment, R.sup.56 is lower alkyl, di-alkylamino,
cycloalkylamino, or phenyl substituted with one or more fluoro,
lower alkyl, or fluoro substituted lower alkyl and R.sup.55 is
fluoro. In one embodiment, R.sup.78 is hydrogen, chloro, methyl,
--CN, chloro substituted phenyl, or methoxy substituted
pyrimidinyl, and R.sup.56 is lower alkyl, di-alkylamino,
cycloalkylamino, or phenyl substituted with one or more fluoro,
lower alkyl, or trifluoromethyl. In one embodiment, R.sup.78 is
hydrogen, chloro, methyl, --CN, chloro substituted phenyl, or
methoxy substituted pyrimidinyl, R.sup.56 is lower alkyl,
di-alkylamino, cycloalkylamino, or phenyl substituted with one or
more fluoro, lower alkyl, or trifluoromethyl and R.sup.55 is
fluoro. In one embodiment, R.sup.78 is hydrogen, chloro, methyl,
--CN, chloro substituted phenyl, or methoxy substituted
pyrimidinyl, and R.sup.56 is n-propyl, di-methylamino,
pyrrolidin-1-yl, fluoro substituted phenyl, di-fluoro substituted
phenyl, t-butyl substituted phenyl or trifluoromethyl substituted
phenyl. In one embodiment, R.sup.78 is hydrogen, chloro, methyl,
--CN, chloro substituted phenyl, or methoxy substituted
pyrimidinyl, R.sup.56 is n-propyl, di-methylamino, pyrrolidin-1-yl,
fluoro substituted phenyl, di-fluoro substituted phenyl, t-butyl
substituted phenyl or trifluoromethyl substituted phenyl, and
R.sup.55 is fluoro. In one embodiment, R.sup.78 is hydrogen,
chloro, methyl, --CN, chloro substituted phenyl, or methoxy
substituted pyrimidinyl, and R.sup.56 is n-propyl, di-methylamino,
pyrrolidin-1-yl, 3-fluoro phenyl, or 2,5-di-fluoro phenyl. In one
embodiment, R.sup.78 is hydrogen, chloro, methyl, --CN, chloro
substituted phenyl, or methoxy substituted pyrimidinyl, and
R.sup.56 is 4-t-butyl phenyl, 3-trifluoromethyl phenyl or
4-trifluoromethyl phenyl. In one embodiment, R.sup.78 is hydrogen,
chloro, methyl, --CN, chloro substituted phenyl, or methoxy
substituted pyrimidinyl, R.sup.56 is n-propyl, di-methylamino,
pyrrolidin-1-yl, 3-fluoro phenyl, or 2,5-di-fluoro phenyl, and
R.sup.55 is fluoro. In one embodiment, R.sup.78 is hydrogen,
chloro, methyl, --CN, chloro substituted phenyl, or methoxy
substituted pyrimidinyl, R.sup.56 is 4-t-butyl phenyl,
3-trifluoromethyl phenyl or 4-trifluoromethyl phenyl, and R.sup.55
is fluoro. In one embodiment, R.sup.78 is hydrogen or --CN, and
R.sup.56 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro
phenyl, or 2,5-di-fluoro phenyl. In one embodiment, R.sup.78 is
hydrogen or --CN and R.sup.56 is 4-t-butyl phenyl,
3-trifluoromethyl phenyl or 4-trifluoromethyl phenyl. In one
embodiment, R.sup.78 is hydrogen or --CN, R.sup.56 is n-propyl,
di-methylamino, pyrrolidin-1-yl, 3-fluoro phenyl, or 2,5-di-fluoro
phenyl, and R.sup.55 is fluoro. In one embodiment, R.sup.78 is
hydrogen or --CN, R.sup.56 is 4-t-butyl phenyl, 3-trifluoromethyl
phenyl or 4-trifluoromethyl phenyl, and R.sup.55 is fluoro. In one
embodiment, R.sup.78 is hydrogen or --CN and R.sup.56 is n-propyl.
In one embodiment, R.sup.78 is hydrogen or --CN, R.sup.56 is
n-propyl, and R.sup.55 is fluoro.
[0098] In a tenth aspect, a solid form is provided comprising a
basic amino acid and an
N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide
compound of Formula Ie, wherein Formula Ie is as follows:
##STR00007##
wherein: [0099] R.sup.79 is selected from the group consisting of
chloro, methyl, methoxy, --CN, and --C.ident.CH; [0100] R.sup.55 is
hydrogen or fluoro; [0101] R.sup.56 is selected from the group
consisting of lower alkyl, fluoro substituted lower alkyl,
mono-alkylamino, di-alkylamino, cycloalkylamino, cycloalkyl,
phenyl, and heteroaryl, wherein phenyl is optionally substituted
with one or more R.sup.60, and heteroaryl is optionally substituted
with one or more R.sup.61; [0102] R.sup.60 is fluoro, chloro, --CN,
--NO.sub.2, lower alkyl, fluoro substituted lower alkyl, lower
alkoxy, fluoro substituted lower alkoxy, heteroaryl optionally
substituted with lower alkyl, --C(O)--O--R.sup.67,
--N(H)--C(O)--R.sup.71, or two R.sup.60 on adjacent carbons combine
to form a fused heterocycloalkyl optionally substituted with lower
alkyl; [0103] R.sup.61 is lower alkyl, fluoro substituted lower
alkyl, lower alkoxy, heteroaryl optionally substituted with lower
alkyl, or --C(O)--O--R.sup.67; [0104] R.sup.67 is hydrogen or lower
alkyl; and [0105] R.sup.71 is lower alkyl.
[0106] In one embodiment of a solid form comprising a basic amino
acid and a compound of Formula Ie, R.sup.56 is lower alkyl,
di-alkylamino, cycloalkylamino, or phenyl substituted with one or
more fluoro, lower alkyl, or fluoro substituted lower alkyl. In one
embodiment, R.sup.56 is lower alkyl, di-alkylamino,
cycloalkylamino, or phenyl substituted with one or more fluoro,
lower alkyl, or fluoro substituted lower alkyl and R.sup.55 is
fluoro. In one embodiment, R.sup.79 is --CN, or --C.ident.CH, and
R.sup.56 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl
substituted with one or more fluoro, lower alkyl, or
trifluoromethyl. In one embodiment, R.sup.79 is --CN, or
--C.ident.CH, R.sup.56 is lower alkyl, di-alkylamino,
cycloalkylamino, or phenyl substituted with one or more fluoro,
lower alkyl, or trifluoromethyl and R.sup.55 is fluoro. In one
embodiment, R.sup.79 is --CN, or --C.ident.CH, and R.sup.56 is
n-propyl, di-methylamino, pyrrolidin-1-yl, fluoro substituted
phenyl, di-fluoro substituted phenyl, t-butyl substituted phenyl or
trifluoromethyl substituted phenyl. In one embodiment, R.sup.79 is
--CN, or --C.ident.CH, R.sup.56 is n-propyl, di-methylamino,
pyrrolidin-1-yl, fluoro substituted phenyl, di-fluoro substituted
phenyl, t-butyl substituted phenyl or trifluoromethyl substituted
phenyl and R.sup.55 is fluoro. In one embodiment, R.sup.79 is --CN,
or --C.ident.CH, and R.sup.56 is n-propyl, di-methylamino,
pyrrolidin-1-yl, 3-fluoro phenyl, or 2,5-di-fluoro phenyl. In one
embodiment, R.sup.79 is --CN, or --C.ident.CH, R.sup.56 is
4-t-butyl phenyl, 3-trifluoromethyl phenyl or 4-trifluoromethyl
phenyl, and R.sup.55 is fluoro. In one embodiment, R.sup.79 is
--CN, or --C.ident.CH, R.sup.56 is n-propyl, di-methylamino,
pyrrolidin-1-yl, 3-fluoro phenyl, or 2,5-di-fluoro phenyl, and
R.sup.55 is fluoro. In one embodiment, R.sup.79 is --CN, or
--C.ident.CH, and R.sup.56 is 4-t-butyl phenyl, 3-trifluoromethyl
phenyl or 4-trifluoromethyl phenyl. In one embodiment, R.sup.79 is
--CN, or --C.ident.CH, R.sup.56 is 4-t-butyl phenyl,
3-trifluoromethyl phenyl or 4-trifluoromethyl phenyl, and R.sup.55
is fluoro. In one embodiment, R.sup.79 is --CN, or --C.ident.CH,
and R.sup.56 is 4-trifluoromethyl phenyl. In one embodiment,
R.sup.79 is --CN, or --C.ident.CH, R.sup.56 is 4-trifluoromethyl
phenyl and R.sup.55 is fluoro.
[0107] In an eleventh aspect, a solid form is provided comprising a
basic amino acid and an
N-[3-(7H-Pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-sulfonamide
compound of Formula If, wherein Formula If is as follows:
##STR00008##
[0108] wherein: [0109] R.sup.8.degree. is hydrogen, methyl,
methoxy, --CN, or --C.ident.CH; and [0110] R.sup.55 and R.sup.56
are as defined for Formula Ib.
[0111] In one embodiment of a solid form comprising a basic amino
acid and a compound of Formula If, R.sup.56 is lower alkyl,
di-alkylamino, cycloalkylamino, or phenyl substituted with one or
more fluoro, lower alkyl, or fluoro substituted lower alkyl. In one
embodiment, R.sup.56 is lower alkyl, di-alkylamino,
cycloalkylamino, or phenyl substituted with one or more fluoro,
lower alkyl, or fluoro substituted lower alkyl and R.sup.55 is
fluoro. In one embodiment, R.sup.80 is hydrogen or methoxy and
R.sup.56 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl
substituted with one or more fluoro, lower alkyl, or
trifluoromethyl. In one embodiment, R.sup.80 is hydrogen or
methoxy, and R.sup.56 is lower alkyl, di-alkylamino,
cycloalkylamino, or phenyl substituted with one or more fluoro,
lower alkyl, or trifluoromethyl and R.sup.55 is fluoro. In one
embodiment, R.sup.80 is hydrogen or methoxy, and R.sup.56 is
n-propyl, di-methylamino, pyrrolidin-1-yl, fluoro substituted
phenyl, di-fluoro substituted phenyl, t-butyl substituted phenyl or
trifluoromethyl substituted phenyl. In one embodiment, R.sup.80 is
hydrogen or methoxy, R.sup.56 is n-propyl, di-methylamino,
pyrrolidin-1-yl, fluoro substituted phenyl, di-fluoro substituted
phenyl, t-butyl substituted phenyl or trifluoromethyl substituted
phenyl and R.sup.55 is fluoro. In one embodiment, R.sup.80 is
hydrogen or methoxy, and R.sup.56 is n-propyl, di-methylamino,
pyrrolidin-1-yl, 3-fluoro phenyl, or 2,5-di-fluoro phenyl. In one
embodiment, R.sup.80 is hydrogen or methoxy, and R.sup.56 is
4-t-butyl phenyl, 3-trifluoromethyl phenyl or 4-trifluoromethyl
phenyl. In one embodiment, R.sup.80 is hydrogen or methoxy,
R.sup.56 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro
phenyl, or 2,5-di-fluoro phenyl, and R.sup.55 is fluoro. In one
embodiment, R.sup.80 is hydrogen or methoxy, R.sup.56 is 4-t-butyl
phenyl, 3-trifluoromethyl phenyl or 4-trifluoromethyl phenyl and
R.sup.55 is fluoro. In one embodiment, R.sup.80 is hydrogen or
methoxy, and R.sup.56 is 4-t-butyl-phenyl or 4-trifluoromethyl
phenyl. In one embodiment, R.sup.80 is hydrogen or methoxy,
R.sup.56 is 4-t-butyl-phenyl or 4-trifluoromethyl phenyl and
R.sup.55 is fluoro.
[0112] In a twelfth aspect, a solid form is provided comprising a
basic amino acid and an
N-[3-(1H-Pyrazolo[3,4-b]pyridine-3-carbonyl)-phenyl]-sulfonamide
compound of Formula Ig, wherein Formula Ig is as follows:
##STR00009##
wherein:
[0113] R.sup.55, and R.sup.56 are as defined for Formula Ib, and
R.sup.80 is as defined in Formula If.
[0114] In one embodiment of a solid form comprising a basic amino
acid and a compound of Formula Ig, R.sup.56 is lower alkyl,
di-alkylamino, cycloalkylamino, or phenyl substituted with one or
more fluoro, lower alkyl, or fluoro substituted lower alkyl. In one
embodiment, R.sup.56 is lower alkyl, di-alkylamino,
cycloalkylamino, or phenyl substituted with one or more fluoro,
lower alkyl, or fluoro substituted lower alkyl and R.sup.55 is
fluoro. In one embodiment, R.sup.80 is hydrogen, methoxy, --CN, or
--C.ident.CH, and R.sup.56 is lower alkyl, di-alkylamino,
cycloalkylamino, or phenyl substituted with one or more fluoro,
lower alkyl, or trifluoromethyl. In one embodiment, R.sup.80 is
hydrogen, methoxy, --CN, or --C.ident.CH, and R.sup.56 is lower
alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with
one or more fluoro, lower alkyl, or trifluoromethyl and R.sup.55 is
fluoro. In one embodiment, R.sup.80 is hydrogen, methoxy, --CN, or
--C.ident.CH, and R.sup.56 is n-propyl, di-methylamino,
pyrrolidin-1-yl, fluoro substituted phenyl, di-fluoro substituted
phenyl, t-butyl substituted phenyl or trifluoromethyl substituted
phenyl. In one embodiment, R.sup.80 is hydrogen, methoxy, --CN, or
--C.ident.CH, R.sup.56 is n-propyl, di-methylamino,
pyrrolidin-1-yl, fluoro substituted phenyl, di-fluoro substituted
phenyl, t-butyl substituted phenyl or trifluoromethyl substituted
phenyl and R.sup.55 is fluoro. In one embodiment, R.sup.80 is
hydrogen, methoxy, --CN, or --C.ident.CH, and R.sup.56 is n-propyl,
di-methylamino, pyrrolidin-1-yl, 3-fluoro phenyl, or 2,5-di-fluoro
phenyl. In one embodiment, R.sup.80 is hydrogen, methoxy, --CN, or
--C.ident.CH, and R.sup.56 is 4-t-butyl phenyl, 3-trifluoromethyl
phenyl or 4-trifluoromethyl phenyl. In one embodiment, R.sup.80 is
hydrogen, methoxy, --CN, or --C.ident.CH, R.sup.56 is n-propyl,
di-methylamino, pyrrolidin-1-yl, 3-fluoro phenyl, or 2,5-di-fluoro
phenyl, and R.sup.55 is fluoro. In one embodiment, R.sup.80 is
hydrogen, methoxy, --CN, or --C.ident.CH, R.sup.56 is 4-t-butyl
phenyl, 3-trifluoromethyl phenyl or 4-trifluoromethyl phenyl, and
R.sup.55 is fluoro.
[0115] In a thirteenth aspect, a solid form is provided comprising
arginine and a compound of Formula I, Ia, Ib, Ic, Id, Ie, If or Ig,
or any embodiment herein above.
[0116] In a fourteenth aspect, a solid form is provided comprising
lysine and a compound of Formula I, Ia, Ib, Ic, Id, Ie, If or Ig,
or any embodiment herein above.
[0117] In a fifteenth aspect, a solid form is provided comprising a
basic amino acid and a compound of Formula Ib, Ic, Id, Ie, If or
Ig, or any embodiments herein above. In certain embodiments, the
solid form comprises arginine and a compound of Formula Ib, Ic, Id,
Ie, If or Ig, or any embodiment herein above. In certain
embodiments, the solid form comprises lysine and a compound of
Formula Ib, Ic, Id, Ie, If or Ig, or any embodiment herein
above.
[0118] In a sixteenth aspect, a solid form is provided comprising a
complex of arginine and a compound of any of Formula I, Ia, Ib, Ic,
Id, Ie, If, or Ig. In one embodiment, a composition is provided
comprising said complex. In one embodiment, the composition is
effective as a pharmaceutical, for example in the treatment of pain
or polycystic kidney disease. In one embodiment, the composition is
effective as a pharmaceutical, for example in the treatment of
melanoma, thyroid cancer, ovarian cancer, cholangiocarcinoma or
colorectal cancer. In one embodiment, the complex is an amorphous
solid. In one embodiment, the composition comprises an amorphous
complex of arginine and the compound, and further comprises a
crystalline form of the compound, preferably crystalline free base
of the compound. In one embodiment, the composition comprises the
amorphous complex and 0-80% crystalline compound, also 0-50%,
0-20%, 0-10%, 0-5%, or 0-2% crystalline compound.
[0119] In a seventeenth aspect, a solid form is provided comprising
a complex of lysine and a compound of any of Formula I, Ia, Ib, Ic,
Id, Ie, If, or Ig. In one embodiment, a composition is provided
comprising said complex. In one embodiment, the composition is
effective as a pharmaceutical, for example in the treatment of pain
or polycystic kidney disease. In one embodiment, the composition is
effective as a pharmaceutical, for example in the treatment of
melanoma, thyroid cancer, ovarian cancer, cholangiocarcinoma or
colorectal cancer. In one embodiment, the complex is an amorphous
solid. In one embodiment, the composition comprises an amorphous
complex of lysine and the compound, and further comprises a
crystalline form of the compound, preferably crystalline free base
of the compound. In one embodiment, the composition comprises the
amorphous complex and 0-80% crystalline compound, also 0-50%,
0-20%, 0-10%, 0-5%, or 0-2% crystalline compound.
[0120] In an eighteenth aspect, a solid form is provided comprising
a ternary complex of arginine, a strong acid, and a compound of any
of Formula I, Ia, Ib, Ic, Id, Ie, If or Ig. In one embodiment, the
strong acid is hydrochloric acid. In one embodiment, the ternary
complex is an amorphous solid. In one embodiment, the ternary
complex is a ternary co-crystal. In one embodiment, a composition
is provided comprising said complex. In one embodiment, the
composition is effective as a pharmaceutical, for example in the
treatment of pain or polycystic kidney disease. In one embodiment,
the composition is effective as a pharmaceutical, for example in
the treatment of melanoma, thyroid cancer, ovarian cancer,
cholangiocarcinoma or colorectal cancer.
[0121] In a nineteenth aspect, a solid form is provided comprising
a ternary complex of lysine, a strong acid, and a compound of any
of Formula I, Ia, Ib, Ic, Id, Ie, If or Ig. In one embodiment, the
strong acid is hydrochloric acid. In one embodiment, the ternary
complex is an amorphous solid. In one embodiment, the ternary
complex is a ternary co-crystal. In one embodiment, a composition
is provided comprising said complex. In one embodiment, the
composition is effective as a pharmaceutical, for example in the
treatment of pain or polycystic kidney disease. In one embodiment,
the composition is effective as a pharmaceutical, for example in
the treatment of melanoma, thyroid cancer, ovarian cancer,
cholangiocarcinoma or colorectal cancer.
[0122] In a twentieth aspect, a solid form is provided comprising a
basic amino acid, preferably arginine or lysine, and a compound
selected from the group consisting of: [0123]
N-[3-(5-Bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
benzenesulfonamide (P-1001), [0124]
N-[2,4-Difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-p-
henyl]-benzenesulfonamide (P-1002), [0125]
N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-benzenes-
ulfonamide (P-1003), [0126]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-benzenesulfonamide (P-1012), [0127]
N-[2,4-Difluoro-3-(5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-
-benzenesulfonamide (P-1013), [0128]
N-{3-[(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-2,4-difluor-
o-phenyl}-benzenesulfonamide (P-1014), [0129]
N-{2,4-Difluoro-3-[(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methy-
l]-phenyl}-benzenesulfonamide (P-1015), [0130]
N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-benzenesulfonamide (P-1017), [0131]
N-[2,4-Difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-ph-
enyl]-benzenesulfonamide (P-1018), and [0132]
N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]benz-
enesulfonamide (P-1097).
[0133] In one embodiment, the solid form is a complex of the
compound and the basic amino acid. In one embodiment, the solid
form is a complex of the compound and arginine. In one embodiment,
the solid form is a complex of the compound and lysine. In one
embodiment, the complex is an amorphous solid.
[0134] In a twenty-first aspect, a solid form is provided
comprising a basic amino acid, preferably arginine or lysine, and a
compound selected from the group consisting of: [0135]
N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-methox-
y-benzenesulfonamide (P-1004), [0136]
N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-triflu-
oromethyl-benzenesulfonamide (P-1005), [0137]
4-Butoxy-N-[2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-
-benzenesulfonamide (P-1006), [0138]
4-Chloro-N-[2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-
-benzenesulfonamide (P-1007), [0139]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-4-methoxy-benzenesulfonamide (P-1016), [0140]
N-{3-[(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-2,4-difluo-
ro-phenyl}-4-trifluoromethyl-benzenesulfonamide (P-1019), [0141]
N-{2,4-Difluoro-3-[hydroxy-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-meth-
yl]-phenyl}-4-trifluoromethyl-benzenesulfonamide (P-1020), [0142]
N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-4-trifluoromethyl-benzenesulfonamide (P-1022), [0143]
N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-4-fluoro-benzenesulfonamide (P-1024), [0144]
N-{3-[5-(4-Chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-diflu-
oro-phenyl}-4-trifluoromethyl-benzenesulfonamide (P-1030), [0145]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-4-ethyl-benzenesulfonamide (P-1031), [0146]
N-[3-(5-Ethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
4-trifluoromethyl-benzenesulfonamide (P-1032), [0147]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-4-cyano-benzenesulfonamide (P-1033), [0148]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-4-isopropyl-benzenesulfonamide (P-1035), [0149]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-4-fluoro-benzenesulfonamide (P-1036), [0150]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-4-methyl-benzenesulfonamide (P-1038), [0151]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-4-oxazol-5-yl-benzenesulfonamide (P-1039), [0152]
N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-fluoro-
-benzenesulfonamide (P-1040), [0153]
N-{2,4-Difluoro-3-[5-(2-methoxy-ethoxy)-1H-pyrrolo[2,3-b]pyridine-3-carbo-
nyl]-phenyl}-4-fluoro-benzenesulfonamide (P-1042), [0154]
N-{2,4-Difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-
-3-carbonyl]-phenyl}-4-trifluoromethyl-benzenesulfonamide (P-1043),
[0155]
N-{2,4-Difluoro-3-[5-(2-methoxy-ethoxy)-1H-pyrrolo[2,3-b]pyridine-3-carbo-
nyl]-phenyl}-4-trifluoromethyl-benzenesulfonamide (P-1045), [0156]
N-{4-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phen-
ylsulfamoyl]-phenyl}-acetamide (P-1047), [0157]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-4-difluoromethoxy-benzenesulfonamide (P-1049), [0158]
N-{4-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenylsulfamo-
yl]-phenyl}-acetamide (P-1060), [0159]
N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-oxazol-
-5-yl-benzenesulfonamide (P-1066), [0160]
N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-isopro-
pyl-benzenesulfonamide (P-1069), [0161]
N-(2,4-Difluoro-3-{5-[4-(2-methoxy-ethoxy)-phenyl]-1H-pyrrolo[2,3-b]pyrid-
ine-3-carbonyl}-phenyl)-4-trifluoromethyl-benzenesulfonamide
(P-1071), [0162]
4-Butoxy-N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4--
difluoro-phenyl]-benzenesulfonamide (P-1073), [0163]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-4-pyrazol-1-yl-benzenesulfonamide (P-1074), [0164]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-4-isopropoxy-benzenesulfonamide (P-1075), [0165]
4-tert-Butyl-N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-dif-
luoro-phenyl]-benzenesulfonamide (P-1076), [0166]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-4-propyl-benzenesulfonamide (P-1077), [0167]
N-{2,4-Difluoro-3-[5-(2-methoxy-ethoxy)-1H-pyrrolo[2,3-b]pyridine-3-carbo-
nyl]-phenyl}-4-isopropyl-benzenesulfonamide (P-1079), [0168]
N-{2,4-Difluoro-3-[5-(4-methyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-
e-3-carbonyl]-phenyl}-4-isopropyl-benzenesulfonamide (P-1080),
[0169]
3-Difluoromethoxy-N-{2,4-difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrr-
olo[2,3-b]pyridine-3-carbonyl]-phenyl}-benzenesulfonamide (P-1081),
[0170]
N-{2,4-Difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-
-3-carbonyl]-phenyl}-4-propyl-benzenesulfonamide (P-1082), [0171]
N-{2,4-Difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-
-3-carbonyl]-phenyl}-4-isopropyl-benzenesulfonamide (P-1083),
[0172]
N-{2,4-Difluoro-3-[5-(5-methyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-
e-3-carbonyl]-phenyl}-4-propyl-benzenesulfonamide (P-1084), [0173]
N-{2,4-Difluoro-3-[5-(5-methyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-
e-3-carbonyl]-phenyl}-4-trifluoromethyl-benzenesulfonamide
(P-1086), [0174]
N-{2,4-Difluoro-3-[5-(1-methyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]-
pyridine-3-carbonyl]-phenyl}-4-propyl-benzenesulfonamide (P-1087),
[0175]
N-{3-[5-(1,5-Dimethyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbo-
nyl]-2,4-difluoro-phenyl}-4-propyl-benzenesulfonamide (P-1088),
[0176]
N-{2,4-Difluoro-3-[hydroxy-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methy-
l]-phenyl}-4-trifluoromethyl-benzenesulfonamide (P-1090), [0177]
(E)-3-{3-[2,6-Difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoyl-
]-1H-pyrrolo[2,3-b]pyridin-5-yl}-acrylic acid methyl ester
(P-1093), [0178]
3-{3-[2,6-Difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benz-
oyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-propionic acid methyl ester
(P-1094), [0179]
3-{3-[2,6-Difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benz-
oyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-propionic acid (P-1095), [0180]
3-{3-[2,6-Difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoyl]-1H-
-pyrrolo[2,3-b]pyridin-5-yl}-N-ethyl-propionamide (P-1096), [0181]
N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-4-fluoro-benzenesulfonamide (P-2026), [0182]
N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-4-fluoro-benzenesulfonamide (P-2027), [0183]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
4-fluoro-benzenesulfonamide (P-2028), [0184]
N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
4-fluoro-benzenesulfonamide (P-2035), [0185]
N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-
-3-carbonyl]-phenyl}-4-fluoro-benzenesulfonamide (P-2040), [0186]
N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-4-trifluoromethyl-benzenesulfonamide (P-2047), [0187]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-4-fl-
uoro-benzenesulfonamide (P-2050), [0188]
N-[2-Fluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4--
trifluoromethyl-benzenesulfonamide (P-2060), [0189]
N-[2,4-Difluoro-3-(5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-
-4-trifluoromethyl-benzenesulfonamide (P-2482), [0190]
N-[3-(5-Cyclopropyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-ph-
enyl]-4-trifluoromethyl-benzenesulfonamide (P-2483), [0191]
N-[3-(5-Ethynyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl-
]-4-trifluoromethyl-benzenesulfonamide (P-2484), [0192]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
4-propyl-benzenesulfonamide (P-2486), and [0193]
N-[3-(4-Ethynyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-4--
trifluoromethyl-benzenesulfonamide (P-2487). In one embodiment, the
solid form is a complex of the compound and the basic amino acid.
In one embodiment, the solid form is a complex of the compound and
arginine. In one embodiment, the solid form is a complex of the
compound and lysine. In one embodiment, the complex is an amorphous
solid.
[0194] In a twenty-second aspect, a solid form is provided
comprising a basic amino acid, preferably arginine or lysine, and a
compound selected from the group consisting of: [0195]
N-[2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl]-3-methoxy-
-benzenesulfonamide (P-1008), [0196]
N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-3-fluoro-benzenesulfonamide (P-1023), [0197]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-3-fluoro-benzenesulfonamide (P-1025), [0198]
N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenyl]-
-3-trifluoromethyl-benzenesulfonamide (P-1026), [0199]
N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-3-trifluoromethyl-benzenesulfonamide (P-1027), [0200]
N-[2,4-Difluoro-3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenyl]--
3-trifluoromethyl-benzenesulfonamide (P-1029), [0201]
N-{2,4-Difluoro-3-[5-(2-methoxy-ethoxy)-1H-pyrrolo[2,3-b]pyridine-3-carbo-
nyl]-phenyl}-3-fluoro-benzenesulfonamide (P-1041), [0202]
N-{2,4-Difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-
-3-carbonyl]-phenyl}-3-fluoro-benzenesulfonamide (P-1044), [0203]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-3-methoxy-benzenesulfonamide (P-1046), [0204]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-3-methyl-benzenesulfonamide (P-1055), [0205]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-3-cyano-benzenesulfonamide (P-1058), [0206]
N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-nitro--
benzenesulfonamide (P-1059), [0207]
N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-methyl-
-benzenesulfonamide (P-1065), [0208]
3-Cyano-N-[2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
benzenesulfonamide (P-1068), [0209]
N-{2,4-Difluoro-3-[5-(6-methoxy-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-3-fluoro-benzenesulfonamide (P-1070), [0210]
3-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyls-
ulfamoyl]-benzoic acid (P-1072), [0211]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-3-difluoromethoxy-benzenesulfonamide (P-1078), [0212]
3-Difluoromethoxy-N-{2,4-difluoro-3-[5-(5-methyl-1H-imidazol-2-yl)-1H-pyr-
rolo[2,3-b]pyridine-3-carbonyl]-phenyl}-benzenesulfonamide
(P-1085), [0213]
N-(2,4-Difluoro-3-{hydroxy-[5-(2-methoxy-ethoxy)-1H-pyrrolo[2,3-b]-
pyridin-3-yl]-methyl}-phenyl)-3-fluoro-benzenesulfonamide (P-1089),
[0214]
N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-
-3-fluoro-benzenesulfonamide (P-2016), [0215]
N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-3-fluoro-benzenesulfonamide (P-2019), [0216]
N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-3-fluoro-benzenesulfonamide (P-2023), [0217]
N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
3-fluoro-benzenesulfonamide (P-2039), [0218]
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), and
[0219]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-3-fl-
uoro-benzenesulfonamide (P-2053).
[0220] In one embodiment, the solid form is a complex of the
compound and the basic amino acid. In one embodiment, the solid
form is a complex of the compound and arginine. In one embodiment,
the solid form is a complex of the compound and lysine. In one
embodiment, the complex is an amorphous solid.
[0221] In a twenty-third aspect, a solid form is provided
comprising a basic amino acid, preferably arginine or lysine, and a
compound selected from the group consisting of: [0222]
N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3,4-dime-
thoxy-benzenesulfonamide (P-1009), [0223]
3,4-Dichloro-N-[2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phe-
nyl]-benzenesulfonamide (P-1010), [0224]
N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2,5-dime-
thoxy-benzenesulfonamide (P-1011), [0225]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-3-fluoro-4-methyl-benzenesulfonamide (P-1034), [0226]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-3,5-difluoro-benzenesulfonamide (P-1037), [0227]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-2-fluoro-benzenesulfonamide (P-1048), [0228]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-2,4-dimethoxy-benzenesulfonamide (P-1050), [0229]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-2-methyl-benzenesulfonamide (P-1051), [0230]
2,3-Dihydro-benzo[1,4]dioxine-6-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-1052), [0231]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-2,4-difluoro-benzenesulfonamide (P-1053), [0232]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-5-fluoro-2-methyl-benzenesulfonamide (P-1054), [0233]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-2,5-dimethoxy-benzenesulfonamide (P-1056), [0234]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-2-cyano-benzenesulfonamide (P-1057), [0235]
N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2,4-dime-
thoxy-benzenesulfonamide (P-1061), [0236]
N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2-methyl-
-benzenesulfonamide (P-1062), [0237]
2,3-Dihydro-benzo[1,4]dioxine-6-sulfonic acid
[2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-1063), [0238]
N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-5-fluoro-
-2-methyl-benzenesulfonamide (P-1064), [0239]
2-Cyano-N-[2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
benzenesulfonamide (P-1067), [0240]
4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2001), [0241]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-2,5-difluoro-benzenesulfonamide (P-2002), [0242]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-2,6-difluoro-benzenesulfonamide (P-2003), [0243]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-3,5-dimethyl-benzenesulfonamide (P-2004), [0244]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-3-fluoro-4-methoxy-benzenesulfonamide (P-2005), [0245]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-4-fluoro-2-methyl-benzenesulfonamide (P-2006), [0246]
2,3-Dihydro-benzofuran-5-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2007), [0247]
N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-2-fluoro-benzenesulfonamide (P-2009), [0248]
N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-2,5-difluoro-benzenesulfonamide (P-2010), [0249]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2-fluoro-benzenesulfonamide (P-2011), [0250]
N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-
-2-fluoro-benzenesulfonamide (P-2014), [0251]
N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-
-2,5-difluoro-benzenesulfonamide (P-2015), [0252]
N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-2-fluoro-benzenesulfonamide (P-2017), [0253]
N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-2,5-difluoro-benzenesulfonamide (P-2018), [0254]
N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2-fluoro-benzenesulfonamide (P-2020), [0255]
N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-2-fluoro-benzenesulfonamide (P-2021), [0256]
N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-2,5-difluoro-benzenesulfonamide (P-2022), [0257]
N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-
-2,6-difluoro-benzenesulfonamide (P-2024), [0258]
N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-
-2,4-difluoro-benzenesulfonamide (P-2025), [0259]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2,6-difluoro-benzenesulfonamide (P-2029), [0260]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2,4-difluoro-benzenesulfonamide (P-2030), [0261]
N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-2,6-difluoro-benzenesulfonamide (P-2031), [0262]
N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-2,4-difluoro-benzenesulfonamide (P-2032), [0263]
N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-2,6-difluoro-benzenesulfonamide (P-2033), [0264]
N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-2,4-difluoro-benzenesulfonamide (P-2034), [0265]
N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2,5-difluoro-benzenesulfonamide (P-2036), [0266]
N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2,6-difluoro-benzenesulfonamide (P-2037), [0267]
N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2,4-difluoro-benzenesulfonamide (P-2038), [0268]
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), [0269]
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),
[0270]
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),
[0271]
N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-
-3-carbonyl]-phenyl}-2,4-difluoro-benzenesulfonamide (P-2044),
[0272]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
benzenesulfonamide (P-2046), [0273]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-2-fl-
uoro-benzenesulfonamide (P-2051), [0274]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-2,5--
difluoro-benzenesulfonamide (P-2052), [0275]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-2,6--
difluoro-benzenesulfonamide (P-2054), [0276]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-2,4--
difluoro-benzenesulfonamide (P-2055), and [0277]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-benz-
enesulfonamide (P-2056).
[0278] In one embodiment, the solid form is a complex of the
compound and the basic amino acid. In one embodiment, the solid
form is a complex of the compound and arginine. In one embodiment,
the solid form is a complex of the compound and lysine. In one
embodiment, the complex is an amorphous solid.
[0279] In a twenty-fourth aspect, a solid form is provided
comprising a basic amino acid, preferably arginine or lysine, and a
compound selected from the group consisting of: [0280]
Thiophene-2-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-1098), [0281] Thiophene-3-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-1099), [0282] Thiophene-3-sulfonic acid
[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-1100), [0283] Benzo[b]thiophene-2-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-1101), [0284] 5-Pyridin-2-yl-thiophene-2-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-1102), [0285]
5-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyls-
ulfamoyl]-furan-2-carboxylic acid methyl ester (P-1103), [0286]
5-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyls-
ulfamoyl]-2-methyl-furan-3-carboxylic acid methyl ester (P-1104),
[0287] 1,2-Dimethyl-1H-imidazole-4-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-1105), [0288] 2,5-Dimethyl-thiophene-3-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-1106), [0289] 2,5-Dimethyl-furan-3-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-1107), [0290] 2,4-Dimethyl-thiazole-5-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-1108), [0291]
5-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenylsulfamoyl]-
-furan-2-carboxylic acid methyl ester (P-1109), [0292]
5-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenylsulfamoyl]-
-2-methyl-furan-3-carboxylic acid methyl ester (P-1110), [0293]
5-Oxazol-5-yl-thiophene-2-sulfonic acid
[2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-1111), [0294] 5-Isoxazol-5-yl-thiophene-2-sulfonic acid
[2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-1112), [0295] 2,5-Dimethyl-thiophene-3-sulfonic acid
[2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-1113), [0296] 2,5-Dimethyl-furan-3-sulfonic acid
[2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-1114), [0297] 2,4-Dimethyl-thiazole-5-sulfonic acid
[2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-1115), [0298] Benzothiazole-6-sulfonic acid
[2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-1116), [0299] Benzo[b]thiophene-3-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-1117), [0300] 5-Methyl-2-trifluoromethyl-furan-3-sulfonic
acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-1118), [0301] 5-Oxazol-5-yl-thiophene-2-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-1119), [0302] 2-Oxo-2H-chromene-6-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-1120), [0303] 5-Isoxazol-5-yl-thiophene-2-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-1121), [0304] Benzothiazole-6-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-1122), [0305]
1-Methyl-3-trifluoromethyl-1H-pyrazole-4-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phen-
yl]-amide (P-1123), [0306] Benzo[1,2,5]thiadiazole-5-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-1124), [0307] 5-Methyl-benzo[b]thiophene-2-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-1125), [0308] 5-Methyl-thiophene-2-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-1126), [0309] 1-Methyl-1H-pyrazole-3-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-1127), [0310] Pyridine-2-sulfonic acid
[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-1128), [0311] 2H-[1,2,4]Triazole-3-sulfonic acid
[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2061), [0312] 2H-[1,2,4]Triazole-3-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2062), [0313] Pyridine-2-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2063), [0314] 2H-[1,2,4]Triazole-3-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2064), [0315] 2H-[1,2,4]Triazole-3-sulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2065), [0316] 2H-[1,2,4]Triazole-3-sulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2066), [0317] Pyridine-2-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2067), [0318] 2H-[1,2,4]Triazole-3-sulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2068), [0319] Pyridine-3-sulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2069), [0320] Pyridine-2-sulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2070), [0321] Pyridine-3-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2071), [0322] Pyridine-3-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2072), [0323] Pyridine-3-sulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2073), [0324] Pyridine-3-sulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2074), [0325] Pyridine-2-sulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2075), [0326] Pyridine-2-sulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2076), [0327] Pyridine-3-sulfonic acid
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2077), [0328] Pyridine-2-sulfonic acid
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2078), [0329] Pyridine-2-sulfonic acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl-1H-pyrrolo[2,3-b]pyridine-3--
carbonyl]-phenyl}-amide (P-2079), [0330]
2H-[1,2,4]Triazole-3-sulfonic acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl-1H-pyrrolo[2,3-b]pyridi-
ne-3-carbonyl]-phenyl}-amide (P-2080), [0331]
5-Methyl-isoxazole-4-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2081), [0332] 1,5-Dimethyl-1H-pyrazole-4-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2082), [0333] 1-Ethyl-1H-pyrazole-4-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2083), [0334] 1-Methyl-1H-pyrazole-4-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2084), [0335] 6-Methoxy-pyridine-3-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2085), [0336] Pyridine-3-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2086), [0337] Pyridine-2-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2087), [0338] 5-Methyl-isoxazole-4-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2088), [0339] 1-Ethyl-1H-pyrazole-4-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2089), [0340] 1-Methyl-1H-pyrazole-4-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2090), [0341] 1,5-Dimethyl-1H-pyrazole-4-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2091), [0342] 6-Methoxy-pyridine-3-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2092), [0343] 6-Trifluoromethyl-pyridine-3-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2481), and [0344] 5-Trifluoromethyl-pyridine-2-sulfonic
acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2485). In one embodiment, the solid form is a complex of
the compound and the basic amino acid. In one embodiment, the solid
form is a complex of the compound and arginine. In one embodiment,
the solid form is a complex of the compound and lysine. In one
embodiment, the complex is an amorphous solid.
[0345] In a twenty-fifth aspect, a solid form is provided
comprising a basic amino acid, preferably arginine or lysine, and a
compound selected from the group consisting of: [0346]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
C-pyridin-2-yl-methanesulfonamide (P-2093), [0347]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
C-pyridin-3-yl-methanesulfonamide (P-2094), [0348]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
C-pyridin-4-yl-methanesulfonamide (P-2095), [0349]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-C-py-
ridin-3-yl-methanesulfonamide (P-2096), [0350]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-C-py-
ridin-4-yl-methanesulfonamide (P-2097), and [0351]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-C-py-
ridin-2-yl-methanesulfonamide (P-2098). In one embodiment, the
solid form is a complex of the compound and the basic amino acid.
In one embodiment, the solid form is a complex of the compound and
arginine. In one embodiment, the solid form is a complex of the
compound and lysine. In one embodiment, the complex is an amorphous
solid.
[0352] In a twenty-sixth aspect, a solid form is provided
comprising a basic amino acid, preferably arginine or lysine, and a
compound selected from the group consisting of: [0353]
4-Fluoro-N-{4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyr-
idine-3-carbonyl]-phenyl}-benzenesulfonamide (P-2100), [0354]
N-{4-Fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-c-
arbonyl]-phenyl}-4-trifluoromethyl-benzenesulfonamide (P-2104),
[0355]
4-Chloro-N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-ph-
enyl]-benzenesulfonamide (P-2106), [0356]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-4-f-
luoro-benzenesulfonamide (P-2107), [0357]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-4-t-
rifluoromethoxy-benzenesulfonamide (P-2109), [0358]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-4-t-
rifluoromethyl-benzenesulfonamide (P-2112), [0359]
4-Chloro-N-[4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-ben-
zenesulfonamide (P-2113),
4-Fluoro-N-[4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-ben-
zenesulfonamide (P-2114), [0360]
N-[4-Fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluorom-
ethoxy-benzenesulfonamide (P-2116), [0361]
N-[4-Fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluorom-
ethyl-benzenesulfonamide (P-2119), [0362]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-fluoro-ben-
zenesulfonamide (P-2121), [0363]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluorom-
ethoxy-benzenesulfonamide (P-2123), [0364]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluorom-
ethyl-benzenesulfonamide (P-2126), [0365]
4-Chloro-N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-ben-
zenesulfonamide (P-2128), [0366]
4-Chloro-N-{3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-c-
arbonyl]-phenyl}-benzenesulfonamide (P-2129), [0367]
4-Fluoro-N-{3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-c-
arbonyl]-phenyl}-benzenesulfonamide (P-2130), [0368]
N-{3-[5-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]--
phenyl}-4-trifluoromethoxy-benzenesulfonamide (P-2132), and [0369]
N-{3-[5-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]--
phenyl}-4-trifluoromethyl-benzenesulfonamide (P-2135). In one
embodiment, the solid form is a complex of the compound and the
basic amino acid. In one embodiment, the solid form is a complex of
the compound and arginine. In one embodiment, the solid form is a
complex of the compound and lysine. In one embodiment, the complex
is an amorphous solid.
[0370] In a twenty-seventh aspect, a solid form is provided
comprising a basic amino acid, preferably arginine or lysine, and a
compound selected from the group consisting of: [0371]
N-[4-Chloro-3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-f-
luoro-benzenesulfonamide (P-1129), [0372]
N-[4-Chloro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3--
fluoro-benzenesulfonamide (P-1130), [0373]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-3-f-
luoro-benzenesulfonamide (P-1131), [0374]
4-Cyano-N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-benzenesulfon-
amide (P-1132), [0375]
N-[3-(1H-Pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluoromethyl-ben-
zenesulfonamide (P-1133), [0376]
N-{2-Chloro-4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyr-
idine-3-carbonyl]-phenyl}-3-difluoromethoxy-benzenesulfonamide
(P-2099), [0377]
N-{4-Fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyrid-
ine-3-carbonyl]-phenyl}-3-trifluoromethyl-benzenesulfonamide
(P-2101), [0378]
N-{4-Fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyrid-
ine-3-carbonyl]-phenyl}-3-trifluoromethoxy-benzenesulfonamide
(P-2102), [0379]
3-Chloro-N-{4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,-
3-b]pyridine-3-carbonyl]-phenyl}-benzenesulfonamide (P-2103),
[0380]
3-Fluoro-N-{4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyr-
idine-3-carbonyl]-phenyl}-benzenesulfonamide (P-2105), [0381]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-3-t-
rifluoromethyl-benzenesulfonamide (P-2108), [0382]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-3-t-
rifluoromethoxy-benzenesulfonamide (P-2110), [0383]
3-Chloro-N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-ph-
enyl]-benzenesulfonamide (P-2111), [0384]
N-[4-Fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-trifluorom-
ethyl-benzenesulfonamide (P-2115), [0385]
N-[4-Fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-trifluorom-
ethoxy-benzenesulfonamide (P-2117), [0386]
3-Chloro-N-[4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-ben-
zenesulfonamide (P-2118), [0387]
3-Fluoro-N-[4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-ben-
zenesulfonamide (P-2120), [0388]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-trifluorom-
ethyl-benzenesulfonamide (P-2122), [0389]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-trifluorom-
ethoxy-benzenesulfonamide (P-2124), [0390]
3-Chloro-N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-ben-
zenesulfonamide (P-2125), [0391]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-fluoro-ben-
zenesulfonamide (P-2127), [0392]
N-{3-[5-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]--
phenyl}-3-trifluoromethyl-benzenesulfonamide (P-2131), [0393]
N-{3-[5-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]--
phenyl}-3-trifluoromethoxy-benzenesulfonamide (P-2133), [0394]
3-Chloro-N-{3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-c-
arbonyl]-phenyl}-benzenesulfonamide (P-2134), and [0395]
3-Fluoro-N-{3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-c-
arbonyl]-phenyl}-benzenesulfonamide (P-2136). In one embodiment,
the solid form is a complex of the compound and the basic amino
acid. In one embodiment, the solid form is a complex of the
compound and arginine. In one embodiment, the solid form is a
complex of the compound and lysine. In one embodiment, the complex
is an amorphous solid.
[0396] In a twenty-eighth aspect, a solid form is provided
comprising a basic amino acid, preferably arginine or lysine, and a
compound selected from the group consisting of: [0397]
Pyridine-3-sulfonic acid
[4-fluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2137), [0398] Pyridine-3-sulfonic acid
{4-fluoro-3-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-car-
bonyl]-phenyl}-amide (P-2138), [0399] Pyridine-3-sulfonic acid
{4-fluoro-3-[5-(3-methanesulfonylamino-phenyl)-1H-pyrrolo[2,3-b]pyridine--
3-carbonyl]-phenyl}-amide (P-2139), [0400] Pyridine-3-sulfonic
acid{4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2140), [0401] Pyridine-3-sulfonic acid
[3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2141), [0402] Pyridine-3-sulfonic acid
[3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2142), [0403] Pyridine-3-sulfonic acid
[3-(5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2143), [0404] Pyridine-3-sulfonic acid
{3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-ph-
enyl}-amide (P-2144), [0405] Pyridine-3-sulfonic acid
{3-[5-(3-methanesulfonylamino-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbony-
l]-phenyl}-amide (P-2145), [0406] Pyridine-3-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2146), [0407]
3-{3-[3-(Pyridine-3-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl-
}-benzamide (P-2147), [0408]
3-(3-{3-[3-(Pyridine-3-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-
-yl}-phenyl)-propionic acid (P-2148), [0409] Pyridine-3-sulfonic
acid
{3-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-ph-
enyl}-amide (P-2149), and [0410]
N-(6-Acetylamino-pyridin-3-yl)-3-benzenesulfonylamino-2,6-difluoro-benzam-
ide (P-2472). In one embodiment, the solid form is a complex of the
compound and the basic amino acid. In one embodiment, the solid
form is a complex of the compound and arginine. In one embodiment,
the solid form is a complex of the compound and lysine. In one
embodiment, the complex is an amorphous solid.
[0411] In a twenty-ninth aspect, a solid form is provided
comprising a basic amino acid, preferably arginine or lysine, and a
compound selected from the group consisting of: [0412]
N-[2,4-Difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-p-
henyl]-methanesulfonamide (P-1134), [0413]
N-{2,4-Difluoro-3-[5-(3-methanesulfonylamino-phenyl)-1H-pyrrolo[2,3-b]pyr-
idine-3-carbonyl]-phenyl}-methanesulfonamide (P-1135), [0414]
N-{2,4-Difluoro-3-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-
-3-carbonyl]-phenyl}-methanesulfonamide (P-1136), [0415]
N-[3-(5-Bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
methanesulfonamide (P-1137),
3-[3-(2,6-Difluoro-3-methanesulfonylamino-benzoyl)-1H-pyrrolo[2,3-b]pyrid-
in-5-yl]-benzamide (P-1138), [0416]
N-[2,4-Difluoro-3-(5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-
-methanesulfonamide (P-1139), [0417]
N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-methanes-
ulfonamide (P-1140), [0418]
N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenyl]-methanesu-
lfonamide (P-1141), [0419]
N-[2,4-Difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-ph-
enyl]-methanesulfonamide (P-1142), [0420]
N-[3-(5-Bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-chloro-2-fluoro-phe-
nyl]-methanesulfonamide (P-1249), [0421]
N-{4-Chloro-2-fluoro-3-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyr-
idine-3-carbonyl]-phenyl}-methanesulfonamide (P-1250), [0422]
N-[4-Chloro-2-fluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbon-
yl)-phenyl]-methanesulfonamide (P-1251), [0423]
N-{4-Chloro-2-fluoro-3-[5-(3-methanesulfonylamino-phenyl)-1H-pyrrolo[2,3--
b]pyridine-3-carbonyl]-phenyl}-methanesulfonamide (P-1252), [0424]
N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-methanesulfonamide (P-2288), [0425]
N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-
-methanesulfonamide (P-2289), [0426]
N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-methanesulfonamide (P-2290), [0427]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-methanesulfonamide (P-2291), [0428]
N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
methanesulfonamide (P-2292), [0429]
N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-methanesulfonamide (P-2293), [0430]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
methanesulfonamide (P-2294), and [0431]
N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-
-3-carbonyl]-phenyl}-methanesulfonamide (P-2295). In one
embodiment, the solid form is a complex of the compound and the
basic amino acid. In one embodiment, the solid form is a complex of
the compound and arginine. In one embodiment, the solid form is a
complex of the compound and lysine. In one embodiment, the complex
is an amorphous solid.
[0432] In a thirtieth aspect, a solid form is provided comprising a
basic amino acid, preferably arginine or lysine, and a compound
selected from the group consisting of: [0433] Ethanesulfonic acid
[2,4-difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phe-
nyl]-amide (P-1143), [0434] Propane-2-sulfonic acid
{3-[(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-2,4-difluoro--
phenyl}-amide (P-1144), [0435] Propane-2-sulfonic acid
{3-[(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-methoxy-methyl]-2,4-difluoro--
phenyl}-amide (P-1145), [0436] Propane-2-sulfonic acid
{2,4-difluoro-3-[methoxy-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-m-
ethyl]-phenyl}-amide (P-1146), [0437] Propane-2-sulfonic acid
[3-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-2,4-difluoro-phenyl]-ami-
de (P-1147), [0438] Propane-2-sulfonic acid
[2,4-difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phe-
nyl]-amide (P-1148), [0439] Propane-2-sulfonic acid
[2,4-difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phen-
yl]-amide (P-1149), [0440] Ethanesulfonic acid
[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2268), [0441] Ethanesulfonic acid
{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluor-
o-phenyl}-amide (P-2269), [0442] Ethanesulfonic acid
{2,4-difluoro-3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl-
]-phenyl}-amide (P-2270), [0443] Ethanesulfonic acid
{2,4-difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2271), [0444] Ethanesulfonic acid
[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2272), [0445] Propane-2-sulfonic acid
[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2273), [0446] Ethanesulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2274), [0447] Propane-2-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2275), [0448] Ethanesulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2276), [0449] Ethanesulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2277), [0450] Propane-2-sulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2278), [0451] Ethanesulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2279), [0452] Propane-2-sulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2280), [0453] Ethanesulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2281), [0454] Propane-2-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2282), [0455] Ethanesulfonic acid
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2283), [0456] Propane-2-sulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2284), [0457] Propane-2-sulfonic acid
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2285), [0458] Ethanesulfonic acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl-1H-pyrrolo[2,3-b]pyridine-3--
carbonyl]-phenyl}-amide (P-2286), [0459] Propane-2-sulfonic acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2287), [0460] Ethanesulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2410), and [0461] Propane-2-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2411). In one embodiment, the solid form is a complex of the
compound and the basic amino acid. In one embodiment, the solid
form is a complex of the compound and arginine. In one embodiment,
the solid form is a complex of the compound and lysine. In one
embodiment, the complex is an amorphous solid.
[0462] In a thirty-first aspect, a solid form is provided
comprising a basic amino acid, preferably arginine or lysine, and a
compound selected from the group consisting of: [0463]
Propane-1-sulfonic acid
[2,4-difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phe-
nyl]-amide (P-1150), [0464] Propane-1-sulfonic acid
[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-1151), [0465] Propane-1-sulfonic acid
[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-1152), [0466] Propane-1-sulfonic acid
[2,4-difluoro-3-(5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-1153), [0467] Propane-1-sulfonic acid
[2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-1154), [0468] Propane-1-sulfonic acid
{3-[(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-2,4-difluoro--
phenyl}-amide (P-1155), [0469] Propane-1-sulfonic acid
[3-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-2,4-difluoro-phenyl]-ami-
de (P-1156), [0470] Propane-1-sulfonic acid
[2,4-difluoro-3-(5-phenylamino-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pheny-
l]-amide (P-1157), [0471] Propane-1-sulfonic acid
[2,4-difluoro-3-(5-phenylamino-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phen-
yl]-amide (P-1158), [0472] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(4-methyl-piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridine-3--
carbonyl]-phenyl}-amide (P-1159), [0473] Propane-1-sulfonic acid
[2,4-difluoro-3-(5-morpholin-4-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-p-
henyl]-amide (P-1160), [0474] Propane-1-sulfonic acid
{2,4-difluoro-3-[hydroxy-(5-phenylamino-1H-pyrrolo[2,3-b]pyridin-3-yl)-me-
thyl]-phenyl}-amide (P-1161), [0475] Propane-1-sulfonic acid
{2,4-difluoro-3-[hydroxy-(5-morpholin-4-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-
-methyl]-phenyl}-amide (P-1162), [0476] Propane-1-sulfonic acid
{2,4-difluoro-3-[hydroxy-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-
-phenyl}-amide (P-1163), [0477] Propane-1-sulfonic acid
{2,4-difluoro-3-[methoxy-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-
-phenyl}-amide (P-1164), [0478] Propane-1-sulfonic acid
[2,4-difluoro-3-(5-morpholin-4-yl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-ph-
enyl]-amide (P-1165), [0479] Propane-1-sulfonic acid
[2,4-difluoro-3-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenyl]-am-
ide (P-1166), [0480] Propane-1-sulfonic acid
{3-[5-(4-dimethylamino-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4--
difluoro-phenyl}-amide (P-1168), [0481] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(4-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbony-
l]-phenyl}-amide (P-1169), [0482] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(4-trifluoromethyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-1170), [0483] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(3-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbony-
l]-phenyl}-amide (P-1171), [0484] Propane-1-sulfonic acid
{3-[5-(3-dimethylamino-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4--
difluoro-phenyl}-amide (P-1172), [0485] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(4-methyl-piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-y-
lmethyl]-phenyl}-amide (P-1173), [0486] Propane-1-sulfonic acid
[2,4-difluoro-3-(5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-1175), [0487] Propane-1-sulfonic acid
{3-[(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-methoxy-methyl]-2,4-difluoro--
phenyl}-amide (P-1176), [0488] Propane-1-sulfonic acid
{3-[(4-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-2,4-difluoro-
-phenyl}-amide (P-1177), [0489] Propane-1-sulfonic acid
{2,4-difluoro-3-[hydroxy-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl}--
amide (P-1178), [0490] Propane-1-sulfonic acid
{2,4-difluoro-3-[hydroxy-(5-isopropenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-me-
thyl]-phenyl}-amide (P-1179), [0491] Propane-1-sulfonic acid
[2,4-difluoro-3-(5-isopropenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phen-
yl]-amide (P-1180), [0492] Propane-1-sulfonic acid
[2,4-difluoro-3-(5-isopropyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-amide (P-1181), [0493] Propane-1-sulfonic acid
{2,4-difluoro-3-[hydroxy-(5-isopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-meth-
yl]-phenyl}-amide (P-1182), [0494] Propane-1-sulfonic acid
{2,4-difluoro-3-[hydroxy-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-
-phenyl}-amide (P-1183), [0495] Propane-1-sulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-1184), [0496] Propane-1-sulfonic acid
{2,4-difluoro-3-[methoxy-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-
-phenyl}-amide (P-1185), [0497] Propane-1-sulfonic acid
[2,4-difluoro-3-(5-isopropyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenyl]-
-amide (P-1186), [0498] Propane-1-sulfonic acid
{2,4-difluoro-3-[hydroxy-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl-
]-phenyl}-amide (P-1187), [0499] Propane-1-sulfonic acid
{2,4-difluoro-3-[methoxy-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl-
]-phenyl}-amide (P-1188), [0500] Propane-1-sulfonic acid
(2,4-difluoro-3-{hydroxy-[5-(4-methyl-piperazin-1-yl)-1H-pyrrolo[2,3-b]py-
ridin-3-yl]-methyl}-phenyl)-amide (P-1189), [0501]
Propane-1-sulfonic acid
[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenyl]-a-
mide (P-1190), [0502] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(4-methyl-piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine-3--
carbonyl]-phenyl}-amide (P-1191), [0503] Propane-1-sulfonic acid
(2,4-difluoro-3-{5-[2-(4-methyl-piperazin-1-yl)-ethylamino]-1H-pyrrolo[2,-
3-b]pyridin-3-ylmethyl}-phenyl)-amide (P-1192), [0504]
Propane-1-sulfonic acid
[3-(5-ethoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phen-
yl]-amide (P-1193), [0505] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(2-methoxy-ethoxy)-1H-pyrrolo[2,3-b]pyridine-3-carbony-
l]-phenyl}-amide (P-1194), [0506] Propane-1-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-2,4-difluoro-phenyl]-am-
ide (P-1195), [0507] Propane-1-sulfonic acid
[2,4-difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phen-
yl]-amide (P-1196), [0508] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(3-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl-
]-phenyl}-amide (P-1197), [0509] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl-
]-phenyl}-amide (P-1198), [0510] Propane-1-sulfonic acid
[2-fluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-
-amide (P-1199), [0511] Propane-1-sulfonic acid
[2,4-difluoro-3-(5-pyridin-4-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phe-
nyl]-amide (P-1200), [0512]
3-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-benzoic acid (P-1204), [0513]
3-3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]p-
yridin-5-yl-acrylic acid (P-1205), [0514]
3-3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]p-
yridin-5-yl-propionic acid (P-1206), [0515]
3-[2,6-difluoro-3-(propane-1-sulfonylamino)-phenyl]-hydroxy-methyl-1H-pyr-
rolo[2,3-b]pyridine-5-carboxylic acid methyl ester (P-1207), [0516]
4{-3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-benzamide (P-1208), [0517]
4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-N,N-dimethyl-benzamide (P-1209), [0518]
Propane-1-sulfonic acid
(2,4-difluoro-3-{5-[4-(morpholine-4-carbonyl)-phenyl]-1H-pyrrolo[2,3-
-b]pyridine-3-carbonyl}-phenyl)-amide (P-1210), [0519]
3-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-benzamide (P-1211), [0520]
3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyr-
idine-5-carboxylic acid methyl ester (P-1212), [0521]
3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyr-
idine-5-carboxylic acid (P-1213), [0522]
3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyr-
idine-5-carboxylic acid ethylamide (P-1214), [0523]
Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyrid-
ine-3-carbonyl]-phenyl}-amide (P-1215), [0524] Propane-1-sulfonic
acid
{2,4-difluoro-3-[5-(3-morpholin-4-yl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3--
carbonyl]-phenyl}-amide (P-1216), [0525] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(3-morpholin-4-ylmethyl-phenyl)-1H-pyrrolo[2,3-b]pyrid-
ine-3-carbonyl]-phenyl}-amide (P-1217), [0526] Propane-1-sulfonic
acid
{2,4-difluoro-3-[5-(6-methoxy-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-c-
arbonyl]-phenyl}-amide (P-1218), [0527] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(6-morpholin-4-yl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyrid-
ine-3-carbonyl]-phenyl}-amide (P-1219), [0528] Propane-1-sulfonic
acid
(2,4-difluoro-3-{5-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-1H-pyrrolo[-
2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-1220), [0529]
Propane-1-sulfonic acid
{3-[5-(4-cyano-3,5-dimethyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-
-2,4-difluoro-phenyl}-amide (P-1221), [0530] Propane-1-sulfonic
acid
(2,4-difluoro-3-{5-[4-(2-methoxy-ethoxy)-phenyl]-1H-pyrrolo[2,3-b]pyridin-
e-3-carbonyl}-phenyl)-amide (P-1222), [0531] Propane-1-sulfonic
acid
{2,4-difluoro-3-[5-(4-methyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine--
3-carbonyl]-phenyl}-amide (P-1223), [0532]
4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-2,N,N-trimethyl-benzamide (P-1224), [0533]
Propane-1-sulfonic acid
[3-(5-benzyloxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl-
]-amide (P-1225), [0534] Propane-1-sulfonic acid
[3-(5-cyclopentyloxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-p-
henyl]-amide (P-1226), [0535] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(2-morpholin-4-yl-ethoxy)-1H-pyrrolo[2,3-b]pyridine-3--
carbonyl]-phenyl}-amide (P-1227), [0536] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(tetrahydro-pyran-4-yloxy)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-1228), [0537] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-3-carbo-
nyl]-phenyl}-amide (P-1229), [0538]
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
(P-2150), [0539]
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),
[0540] Propane-1-sulfonic acid
{3-[5-(1,5-dimethyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbony-
l]-2,4-difluoro-phenyl}-amide (P-2152), [0541] Propane-1-sulfonic
acid
{2,4-difluoro-3-[5-(1-methyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine--
3-carbonyl]-phenyl}-amide (P-2153), [0542] 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), [0543] 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), [0544] Propane-1-sulfonic acid
{3-[5-(3,5-dimethyl-isoxazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]--
2,4-difluoro-phenyl}-amide (P-2156), [0545] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(I-isobutyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-
-3-carbonyl]-phenyl}-amide (P-2157), [0546] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyr-
idine-3-carbonyl]-phenyl}-amide (P-2158), [0547] Propane-1-sulfonic
acid
{2,4-difluoro-3-[5-(4-fluoro-3-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine--
3-carbonyl]-phenyl}-amide (P-2159), [0548] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(4-fluoro-3-trifluoromethyl-phenyl)-1H-pyrrolo[2,3-b]p-
yridine-3-carbonyl]-phenyl}-amide (P-2160), [0549]
N-(4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-
-b]pyridin-5-yl}-phenyl)-acetamide (P-2161), [0550]
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), [0551] 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), [0552] 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), [0553] 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), [0554]
4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-N-methyl-benzenesulfonamide (P-2167), [0555]
N-Cyclopropyl-4-{3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H--
pyrrolo[2,3-b]pyridin-5-yl}-benzenesulfonamide (P-2168), [0556]
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), [0557]
3-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-N-methyl-benzenesulfonamide (P-2170), [0558]
Propane-1-sulfonic acid
{3-[5-(4-chloro-3-trifluoromethyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-car-
bonyl]-2,4-difluoro-phenyl}-amide (P-2171), [0559]
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), [0560] Propane-1-sulfonic
acid
[2,4-difluoro-3-(5-methanesulfonyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)--
phenyl]-amide (P-2173), [0561] 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), [0562] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(2-methyl-2H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2175), [0563] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(2H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl-
]-phenyl}-amide (P-2176), [0564] Propane-1-sulfonic acid
(2,4-difluoro-3-{5-[I-(2-morpholin-4-yl-ethyl)-1H-pyrazol-4-yl]-1H-pyrrol-
o[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2177), [0565]
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), [0566]
Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(3-hydroxy-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbony-
l]-phenyl}-amide (P-2179), [0567]
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),
[0568]
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),
[0569] Propane-1-sulfonic acid
[2,4-difluoro-3-(5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)--
phenyl]-amide (P-2182), [0570] Propane-1-sulfonic acid
{2,4-difluoro-3-[hydroxy-(5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-3-yl-
)-methyl]-phenyl}-amide (P-2473), [0571] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(4-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2183), [0572] 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), [0573]
4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-N,N-dimethyl-benzenesulfonamide (P-2185), [0574]
Propane-1-sulfonic acid
(2,4-difluoro-3-{5-[4-(piperidine-1-sulfonyl)-phenyl]-1H-pyrrolo[2,3-b]py-
ridine-3-carbonyl}-phenyl)-amide (P-2186),
[0575] 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), [0576] 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), [0577] 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), [0578] 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), [0579] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-1H-pyrrolo[2,3-b]pyr-
idine-3-carbonyl]-phenyl}-amide (P-2191), [0580] 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), [0581]
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), [0582]
4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-benzenesulfonamide (P-2194), [0583]
Propane-1-sulfonic acid
{3-[5-(2,5-dimethyl-2H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl-
]-2,4-difluoro-phenyl}-amide (P-2195), [0584] 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), [0585] 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), [0586] Propane-1-sulfonic
acid
{2,4-difluoro-3-[5-(4-hydroxy-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbony-
l]-phenyl}-amide (P-2198), [0587] 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), [0588]
3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyr-
idine-5-carboxylic acid methylamide (P-2200), [0589]
3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyr-
idine-5-carboxylic acid cyclopropylamide (P-2201), [0590]
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), [0591]
Propane-1-sulfonic acid
[2,4-difluoro-3-(5-hydroxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2204), [0592]
3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyr-
idine-5-carboxylic acid ethyl ester (P-2207), [0593]
Propane-1-sulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phen-
yl]-amide (P-2208), [0594] Propane-1-sulfonic acid
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2209), [0595] Propane-1-sulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2210), [0596] 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), [0597] Propane-1-sulfonic acid
{3-[5-(2-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluor-
o-phenyl}-amide (P-2212), [0598] 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), [0599] 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), [0600] Propane-1-sulfonic acid
(2,4-difluoro-3-{5-[6-(2-hydroxy-ethoxy)-pyridin-3-yl]-1H-pyrrolo[2,3-b]p-
yridine-3-carbonyl}-phenyl)-amide (P-2215), [0601]
Propane-1-sulfonic acid
(3-{5-[6-(3-diethylamino-propoxy)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine-
-3-carbonyl}-2,4-difluoro-phenyl)-amide (P-2216), [0602]
3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyr-
idine-5-carboxylic acid (2-hydroxy-ethyl)-amide (P-2217), [0603]
Propane-1-sulfonic acid
{3-[5-(4-ethanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-
-difluoro-phenyl}-amide (P-2218), [0604] 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), [0605]
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), [0606]
4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-N-(2-hydroxy-ethyl)-benzenesulfonamide (P-2221),
[0607] 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), [0608]
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), [0609] 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), [0610]
(E)-3-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,-
3-b]pyridin-5-yl}-acrylic acid methyl ester (P-2225), [0611]
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), [0612]
Propane-1-sulfonic acid
(2,4-difluoro-3-{5-[4-(pyrrolidine-1-sulfonyl)-phenyl]-1H-pyrrolo[2,3-b]p-
yridine-3-carbonyl}-phenyl)-amide (P-2227), [0613]
Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2228), [0614] 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), [0615]
3-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-propionic acid methyl ester (P-2230), [0616]
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), [0617] 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), [0618]
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), [0619]
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), [0620] 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), [0621]
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), [0622]
3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyr-
idine-5-carboxylic acid dimethyl amide (P-2237), [0623]
3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyr-
idine-5-carboxylic acid methoxy-amide (P-2238), [0624]
Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(3-methoxy-prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridine-
-3-carbonyl]-phenyl}-amide (P-2239), [0625] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(3-methoxy-propyl)-1H-pyrrolo[2,3-b]pyridine-3-carbony-
l]-phenyl}-amide (P-2240), [0626] 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), Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(2H-tetrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbony-
l]-phenyl}-amide (P-2242), [0627]
3-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-N-methoxy-propionamide (P-2243), [0628]
Propane-1-sulfonic acid
[2,4-difluoro-3-(5-morpholin-4-ylmethyl-1H-pyrrolo[2,3-b]pyridine-3--
carbonyl)-phenyl]-amide (P-2244), [0629] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(3-morpholin-4-yl-propyl)-1H-pyrrolo[2,3-b]pyridine-3--
carbonyl]-phenyl}-amide (P-2247), [0630] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(3-pyrrolidin-1-yl-propyl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2248), [0631] Propane-1-sulfonic acid
[2,4-difluoro-3-(5-hydroxymethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-ph-
enyl]-amide (P-2250), [0632]
3-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-N,N-diethyl-propionamide (P-2255), [0633]
Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(4-methyl-piperazin-1-ylmethyl)-1H-pyrrolo[2,3-b]-
pyridine-3-carbonyl]-phenyl}-amide (P-2257), [0634]
Propane-1-sulfonic acid
[3-(5-diethylaminomethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-d-
ifluoro-phenyl]-amide (P-2258), [0635] Propane-1-sulfonic acid
[2,4-difluoro-3-(5-pyrrolidin-1-ylmethyl-1H-pyrrolo[2,3-b]pyridine-3-carb-
onyl)-phenyl]-amide (P-2259), [0636] Propane-1-sulfonic acid
[3-(5-ethynyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
amide (P-2260), and [0637] Propane-1-sulfonic acid
[3-(4-ethynyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
amide (P-2261).
[0638] In one embodiment, the solid form is a complex of the
compound and the basic amino acid. In one embodiment, the solid
form is a complex of the compound and arginine. In one embodiment,
the solid form is a complex of the compound and lysine. In one
embodiment, the complex is an amorphous solid.
[0639] In a thirty-second aspect, a solid form is provided
comprising a basic amino acid, preferably arginine or lysine, and a
compound selected from the group consisting of: [0640]
Propane-1-sulfonic acid
[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-1240), [0641] Propane-1-sulfonic acid
[2-fluoro-3-(5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-1241), [0642] Propane-1-sulfonic acid
{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-ph-
enyl}-amide (P-1242), [0643] Propane-1-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-1243), [0644] Propane-1-sulfonic acid
[2-fluoro-3-(5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-1244), [0645] Propane-1-sulfonic acid
[2-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-1245), [0646] Propane-1-sulfonic acid
[2-fluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-
-amide (P-1247), [0647] Propane-1-sulfonic acid
[2-fluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amid-
e (P-1248), [0648] Propane-1-sulfonic acid
[2-fluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2403), [0649]
3-[2-Fluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-
e-5-carboxylic acid methyl ester (P-2404), [0650]
3-[2-Fluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-
e-5-carboxylic acid ethyl ester (P-2406), [0651] 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), [0652] 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), [0653] Propane-1-sulfonic acid
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2409), and [0654] Propane-1-sulfonic acid
[2-fluoro-3-(5-iodo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2480).
[0655] In one embodiment, the solid form is a complex of the
compound and the basic amino acid. In one embodiment, the solid
form is a complex of the compound and arginine. In one embodiment,
the solid form is a complex of the compound and lysine. In one
embodiment, the complex is an amorphous solid.
[0656] In a thirty-third aspect, a solid form is provided
comprising a basic amino acid, preferably arginine or lysine, and a
compound selected from the group consisting of: [0657]
Butane-1-sulfonic acid
[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-1201), [0658] Butane-1-sulfonic acid
[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-1202), [0659] Butane-1-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-1203), [0660] Butane-1-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-1246), [0661] 2-Methyl-propane-1-sulfonic acid
[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2296), [0662] 2-Methyl-propane-1-sulfonic acid
{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluor-
o-phenyl}-amide (P-2297), [0663] 2-Methyl-propane-1-sulfonic acid
{2,4-difluoro-3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl-
]-phenyl}-amide (P-2298), [0664] 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), [0665] Butane-1-sulfonic acid
{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluor-
o-phenyl}-amide (P-2300), [0666] Butane-1-sulfonic acid
{2,4-difluoro-3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl-
]-phenyl}-amide (P-2301), [0667] Butane-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-2302), [0668]
2-Methyl-propane-1-sulfonic acid
[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2303), [0669] 2-Methyl-propane-1-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2304), [0670] 2-Methyl-propane-1-sulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2305), [0671] 2-Methyl-propane-1-sulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2306), [0672] 2-Methyl-propane-1-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2307), [0673] Butane-2-sulfonic acid
[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2308), [0674] Pentane-2-sulfonic acid
[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2309), [0675] Butane-2-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2310), [0676] Pentane-2-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2311), [0677] Butane-2-sulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2312), [0678] Butane-2-sulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2313), [0679] Pentane-2-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2314), [0680] Pentane-2-sulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2315), [0681] Pentane-2-sulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2316), [0682] Butane-2-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2317), [0683] 2-Methyl-propane-1-sulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2318), [0684] Butane-2-sulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2319), [0685] 2-Methyl-propane-1-sulfonic acid
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2320), [0686] Butane-2-sulfonic acid
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2321), [0687] 2-Methyl-propane-1-sulfonic acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2322), [0688] Butane-2-sulfonic acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2323), [0689]
2-Methyl-propane-1-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2412), and [0690] Butane-2-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2413). In one embodiment, the solid form is a complex of the
compound and the basic amino acid. In one embodiment, the solid
form is a complex of the compound and arginine. In one embodiment,
the solid form is a complex of the compound and lysine. In one
embodiment, the complex is an amorphous solid.
[0691] In a thirty-fourth aspect, a solid form is provided
comprising a basic amino acid, preferably arginine or lysine, and a
compound selected from the group consisting of: [0692]
3,3,3-Trifluoro-propane-1-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phen-
yl]-amide (P-2324), [0693] 3,3,3-Trifluoro-propane-1-sulfonic acid
{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluor-
o-phenyl}-amide (P-2325), [0694] 3,3,3-Trifluoro-propane-1-sulfonic
acid
{2,4-difluoro-3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl-
]-phenyl}-amide (P-2326), [0695] 3,3,3-Trifluoro-propane-1-sulfonic
acid
[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2327), [0696] 3,3,3-Trifluoro-propane-1-sulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2328), [0697] 3,3,3-Trifluoro-propane-1-sulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2329), [0698] 3,3,3-Trifluoro-propane-1-sulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2330), [0699] 3,3,3-Trifluoro-propane-1-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2331), [0700] 3,3,3-Trifluoro-propane-1-sulfonic acid
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2332), [0701] 3,3,3-Trifluoro-propane-1-sulfonic acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl-1H-pyrrolo[2,3-b]pyridine-3--
carbonyl]-phenyl}-amide (P-2333), [0702]
3,3,3-Trifluoro-propane-1-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2415), and [0703] 3,3,3-Trifluoro-propane-1-sulfonic acid
[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2478). In one embodiment, the solid form is a complex of the
compound and the basic amino acid. In one embodiment, the solid
form is a complex of the compound and arginine. In one embodiment,
the solid form is a complex of the compound and lysine. In one
embodiment, the complex is an amorphous solid.
[0704] In a thirty-fifth aspect, a solid form is provided
comprising a basic amino acid, preferably arginine or lysine, and a
compound selected from the group consisting of: [0705]
2,2,2-Trifluoro-ethanesulfonic acid
[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2334), [0706] 2,2,2-Trifluoro-ethanesulfonic acid
[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2335), [0707] 2,2,2-Trifluoro-ethanesulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2336), [0708] 2,2,2-Trifluoro-ethanesulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2337), [0709] 2,2,2-Trifluoro-ethanesulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2338), [0710] 2,2,2-Trifluoro-ethanesulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2339), [0711] 2,2,2-Trifluoro-ethanesulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2340), [0712] 2,2,2-Trifluoro-ethanesulfonic acid
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2341), [0713] 2,2,2-Trifluoro-ethanesulfonic acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2342), [0714]
2,2,2-Trifluoro-ethanesulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-a-
mide (P-2414). In one embodiment, the solid form is a complex of
the compound and the basic amino acid. In one embodiment, the solid
form is a complex of the compound and arginine. In one embodiment,
the solid form is a complex of the compound and lysine. In one
embodiment, the complex is an amorphous solid.
[0715] In a thirty-sixth aspect, a solid form is provided
comprising a basic amino acid, preferably arginine or lysine, and a
compound selected from the group consisting of: [0716]
N-{3-[5-(4-Chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-diflu-
oro-phenyl}-C,C,C-trifluoro-methanesulfonamide (P-2343), [0717]
N-{2,4-Difluoro-3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbon-
yl]-phenyl}-C,C,C-trifluoro-methanesulfonamide (P-2344), [0718]
N-{2,4-Difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-
-3-carbonyl]-phenyl}-C,C,C-trifluoro-methanesulfonamide (P-2345),
[0719]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-C,C,C-trifluoro-methanesulfonamide (P-2346), [0720]
N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-C,C,C-trifluoro-methanesulfonamide (P-2347), and [0721]
N-[3-(5-Bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
C,C,C-trifluoro-methanesulfonamide (P-2479). In one embodiment, the
solid form is a complex of the compound and the basic amino acid.
In one embodiment, the solid form is a complex of the compound and
arginine. In one embodiment, the solid form is a complex of the
compound and lysine. In one embodiment, the complex is an amorphous
solid.
[0722] In a thirty-seventh aspect, a solid form is provided
comprising a basic amino acid, preferably arginine or lysine, and a
compound selected from the group consisting of:
[0723] Cyclopropanesulfonic acid
[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2348), [0724]
1-[3-(5-Bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenylsu-
lfamoyl]-cyclopropanecarboxylic acid (P-2349), [0725]
Cyclopropanesulfonic acid
{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-di-
fluoro-phenyl}-amide (P-2350), [0726] Cyclopropanesulfonic acid
{2,4-difluoro-3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl-
]-phenyl}-amide (P-2351), [0727] Cyclopropanesulfonic acid
{2,4-difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2352), [0728] Cyclobutanesulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2353), [0729] Cyclobutanesulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2354), [0730] Cyclohexanesulfonic acid
[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2355), [0731] Cyclopentanesulfonic acid
[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2356), [0732] Cyclohexanesulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2357), [0733] Cyclopentanesulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2358), [0734] Cyclopentanesulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2359), [0735] Cyclohexanesulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2360), [0736] Cyclohexanesulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2361), [0737] Cyclobutanesulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2362), [0738] Cyclobutanesulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2363), [0739] Cyclobutanesulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2364), [0740] Cyclopentanesulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2365), [0741] Cyclohexanesulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2366), [0742] Cyclohexanesulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2367), [0743] Cyclopentanesulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2368), [0744] Cyclohexanesulfonic acid
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2369), [0745] Cyclobutanesulfonic acid
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2370), [0746] Cyclohexanesulfonic acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl-1H-pyrrolo[2,3-b]pyridine-3--
carbonyl]-phenyl}-amide (P-2371), [0747] Cyclopentanesulfonic acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2372), [0748] Cyclobutanesulfonic acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2373), [0749] Cyclohexanesulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2416), [0750] Cyclopentanesulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2417), and [0751] Cyclobutanesulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2418). In one embodiment, the solid form is a complex of the
compound and the basic amino acid. In one embodiment, the solid
form is a complex of the compound and arginine. In one embodiment,
the solid form is a complex of the compound and lysine. In one
embodiment, the complex is an amorphous solid.
[0752] In a thirty-eighth aspect, a solid form is provided
comprising a basic amino acid, preferably arginine or lysine, and a
compound selected from the group consisting of: [0753]
Dimethylamino-1-sulfonic acid
{2,4-difluoro-3-[hydroxy-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-m-
ethyl]-phenyl}-amide (P-1230), [0754] N,N-dimethylamino-1-sulfonic
acid
[2,4-difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phen-
yl]-amide (P-1231), [0755] N,N-diemethylamino-1-sulfonic acid
[3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phe-
nyl]-amide (P-1232), [0756] N,N-diemethylamino-1-sulfonic acid
[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide
(P-1233), [0757] N,N-diemethylamino-1-sulfonic acid
[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-1234), [0758] N,N-diemethylamino-sulfonic acid
[2,4-difluoro-3-(5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-1235), [0759] Piperidine-1-sulfonic acid
[2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-1236), [0760] Piperidine-1-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-1237), [0761] Dimethylamine-1-sulfonic acid
{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluor-
o-phenyl}-amide (P-1238), [0762] Dimethylamine-1-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-1239), [0763] Pyrrolidine-1-sulfonic acid
[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2374), [0764] Pyrrolidine-1-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2375), [0765] N,N-dimethylamino-sulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2376), [0766] Pyrrolidine-1-sulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2377), [0767] N,N-diethylamino-sulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2378), [0768] Pyrrolidine-1-sulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2379), [0769] N,N-dimethylamino-sulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2382), [0770] N,N-dimethylamino-sulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2383), [0771] N,N-diethylamino-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2384), [0772] N,N-diethylamino-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2385), [0773] N,N-diethylamino-sulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2386), [0774] N,N-diethylamino-sulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2387), [0775] N,N-diethylamino-sulfonic acid
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2388), [0776] N,N-diethylamino-sulfonic acid
[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2389), [0777] Morpholine-4-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2390), [0778] Morpholine-4-sulfonic acid
[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2391), [0779] Morpholine-4-sulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2392), [0780] Morpholine-4-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2393), [0781] Pyrrolidine-1-sulfonic acid
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2394), [0782] Morpholine-4-sulfonic acid
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2395), [0783] Morpholine-4-sulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2396), [0784] Morpholine-4-sulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2397), [0785] Pyrrolidine-1-sulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2398), [0786] N,N-dimethylamino-sulfonic acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2399), [0787] Pyrrolidine-1-sulfonic
acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl-1H-pyrrolo[2,3-b]pyridine-3--
carbonyl]-phenyl}-amide (P-2400), [0788] N,N-diethylamino-sulfonic
acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2401), [0789] Morpholine-4-sulfonic
acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2402), [0790]
N,N-dimethylamino-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2419), [0791] Pyrrolidine-1-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2420), [0792] Morpholine-4-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2421), [0793] Pyrrolidine-1-sulfonic acid
{2-fluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-car-
bonyl]-phenyl}-amide (P-2422), [0794] N,N-dimethylamino-sulfonic
acid
{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-ph-
enyl}-amide (P-2423), [0795] N,N-dimethylamino-sulfonic acid
{2-fluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-car-
bonyl]-phenyl}-amide (P-2424), [0796] Pyrrolidine-1-sulfonic acid
{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-ph-
enyl}-amide (P-2425), [0797] Pyrrolidine-1-sulfonic acid
[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2476), and [0798] N,N-dimethylamino-sulfonic acid
[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2477).
[0799] In one embodiment, the solid form is a complex of the
compound and the basic amino acid. In one embodiment, the solid
form is a complex of the compound and arginine. In one embodiment,
the solid form is a complex of the compound and lysine. In one
embodiment, the complex is an amorphous solid.
[0800] In a thirty-ninth aspect, a solid form is provided
comprising a basic amino acid, preferably arginine or lysine, and a
compound selected from the group consisting of: [0801]
Propane-1-sulfonic acid
[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-chloro-2-fluoro-pheny-
l]-amide (P-1253), [0802] Propane-1-sulfonic acid
[4-chloro-2-fluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl-
)-phenyl]-amide (P-1254), [0803] Propane-1-sulfonic acid
[4-chloro-2-fluoro-3-(5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phen-
yl]-amide (P-1255), [0804] Propane-1-sulfonic acid
[4-chloro-2-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-1256), [0805] Propane-1-sulfonic acid
[4-chloro-3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phen-
yl]-amide (P-1257), and [0806] Propane-1-sulfonic acid
{4-chloro-3-[(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-2-f-
luoro-phenyl}-amide (P-1258). In one embodiment, the solid form is
a complex of the compound and the basic amino acid. In one
embodiment, the solid form is a complex of the compound and
arginine. In one embodiment, the solid form is a complex of the
compound and lysine. In one embodiment, the complex is an amorphous
solid.
[0807] In a fortieth aspect, a solid form is provided comprising a
basic amino acid, preferably arginine or lysine, and a compound
selected from the group consisting of: [0808] Propane-1-sulfonic
acid
[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-amide
(P-1269), [0809] Propane-1-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-amide
(P-1270), [0810] Propane-1-sulfonic acid
{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-4-fluoro-ph-
enyl}-amide (P-1271), [0811] Propane-1-sulfonic acid
[4-fluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amid-
e (P-1272), [0812] Propane-1-sulfonic acid
[3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-1273), [0813] Propane-1-sulfonic acid
{3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-ami-
de (P-1274), [0814] Propane-1-sulfonic acid
[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-1275),
[0815] Propane-1-sulfonic acid
[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-1276), [0816] Propane-1-sulfonic acid
[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-chloro-4-fluoro-pheny-
l]-amide (P-2426), [0817] Propane-1-sulfonic acid
{2-chloro-3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-4--
fluoro-phenyl}-amide (P-2427), [0818] Propane-1-sulfonic acid
{2-chloro-4-fluoro-3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-car-
bonyl]-phenyl}-amide (P-2428), [0819] Propane-1-sulfonic acid
{2-chloro-4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyrid-
ine-3-carbonyl]-phenyl}-amide (P-2429), [0820] Propane-1-sulfonic
acid
{4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-car-
bonyl]-phenyl}-amide (P-2431), [0821] Propane-1-sulfonic acid
[4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2437), [0822] Propane-1-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2449), [0823] Propane-1-sulfonic acid
{3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-ph-
enyl}-amide (P-2454), and [0824] Propane-1-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-sulfonyl)-phenyl]-amide
(P-2467).
[0825] In one embodiment, the solid form is a complex of the
compound and the basic amino acid. In one embodiment, the solid
form is a complex of the compound and arginine. In one embodiment,
the solid form is a complex of the compound and lysine. In one
embodiment, the complex is an amorphous solid.
[0826] In a forty-first aspect, a solid form is provided comprising
a basic amino acid, preferably arginine or lysine, and a compound
selected from the group consisting of: [0827]
N-[3-(1H-Pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-methanesulfonamide
(P-1259), [0828]
N-[4-Fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-methanesulfo-
namide (P-1260), [0829]
N-[4-Fluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-pheny-
l]-methanesulfonamide (P-1261), [0830]
N-[4-Fluoro-3-(5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-met-
hanesulfonamide (P-1262), [0831]
N-{4-Fluoro-3-[5-(3-methanesulfonylamino-phenyl)-1H-pyrrolo[2,3-b]pyridin-
e-3-carbonyl]-phenyl}-methane sulfonamide (P-1263), [0832]
N-{4-Fluoro-3-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-c-
arbonyl]-phenyl}-methanesulfonamide (P-1264), [0833]
N-[3-(5-Bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-meth-
anesulfonamide (P-1265), [0834]
3-[3-(2-Fluoro-5-methanesulfonylamino-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-
-yl]-benzamide (P-1266), [0835]
(E)-3-{3-[3-(3-Methanesulfonylamino-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-y-
l]-phenyl}-acrylic acid methyl ester (P-1267), and [0836]
N-[3-(1H-Pyrrolo[2,3-b]pyridin-3-ylamino)-phenyl]-methanesulfonamide
(P-1268). In one embodiment, the solid form is a complex of the
compound and the basic amino acid. In one embodiment, the solid
form is a complex of the compound and arginine. In one embodiment,
the solid form is a complex of the compound and lysine. In one
embodiment, the complex is an amorphous solid.
[0837] In a forty-second aspect, a solid form is provided
comprising a basic amino acid, preferably arginine or lysine, and a
compound selected from the group consisting of: [0838]
Butane-1-sulfonic acid
{2-chloro-4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyrid-
ine-3-carbonyl]-phenyl}-amide (P-2430), [0839] Butane-1-sulfonic
acid
{4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-car-
bonyl]-phenyl}-amide (P-2432), [0840] Butane-1-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-amide
(P-2435), [0841] Butane-1-sulfonic acid
[4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2438), [0842] Butane-1-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2450), and [0843] Butane-1-sulfonic acid
{3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-ph-
enyl}-amide (P-2455).
[0844] In one embodiment, the solid form is a complex of the
compound and the basic amino acid. In one embodiment, the solid
form is a complex of the compound and arginine. In one embodiment,
the solid form is a complex of the compound and lysine. In one
embodiment, the complex is an amorphous solid.
[0845] In a forty-third aspect, a solid form is provided comprising
a basic amino acid, preferably arginine or lysine, and a compound
selected from the group consisting of: [0846] Cyclopropanesulfonic
acid
{4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-car-
bonyl]-phenyl}-amide (P-2433), [0847] Cyclohexanesulfonic acid
{4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-car-
bonyl]-phenyl}-amide (P-2434), [0848] Cyclopropanesulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-amide
(P-2436), [0849] Cyclopropanesulfonic acid
[4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2439), [0850] Cyclohexanesulfonic acid
[4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2441), [0851] Cyclopentanesulfonic acid
[4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2442), [0852] Cyclohexanesulfonic acid
[4-fluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2443), [0853] Cyclohexanesulfonic acid
{4-fluoro-3-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-car-
bonyl]-phenyl}-amide (P-2444), [0854] Cyclopentanesulfonic acid
{4-fluoro-3-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-car-
bonyl]-phenyl}-amide (P-2445), [0855] Cyclohexanesulfonic acid
{4-fluoro-3-[5-(3-methanesulfonylamino-phenyl)-1H-pyrrolo[2,3-b]pyridine--
3-carbonyl]-phenyl}-amide (P-2446), [0856] Cyclopentanesulfonic
acid
{4-fluoro-3-[5-(3-methanesulfonylamino-phenyl)-1H-pyrrolo[2,3-b]pyridine--
3-carbonyl]-phenyl}-amide (P-2447), [0857] Cyclopentanesulfonic
acid
[4-fluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2448), [0858] Cyclopropanesulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2451), [0859] Cyclohexanesulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2452), [0860] Cyclopentanesulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2453), [0861] Cyclopropanesulfonic acid
{3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-ph-
enyl}-amide (P-2456), [0862] Cyclohexanesulfonic acid
{3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-ph-
enyl}-amide (P-2457), [0863] Cyclohexanesulfonic acid
[3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2458), [0864] Cyclopentanesulfonic acid
[3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2459), [0865] Cyclohexanesulfonic acid
[3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2460), [0866] Cyclohexanesulfonic acid
{3-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-ph-
enyl}-amide (P-2461), [0867] Cyclohexanesulfonic acid
[3-(5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2462), [0868] Cyclopentanesulfonic acid
[3-(5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2463), [0869] Cyclopentanesulfonic acid
[3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2464), [0870] 3-{3-[3-(3-Cyclohexanesulfonyl
amino-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-propionic
acid (P-2465), and [0871]
3-{3-[3-(3-Cyclopentanesulfonylamino-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5--
yl]-phenyl}-propionic acid (P-2466). In one embodiment, the solid
form is a complex of the compound and the basic amino acid. In one
embodiment, the solid form is a complex of the compound and
arginine. In one embodiment, the solid form is a complex of the
compound and lysine. In one embodiment, the complex is an amorphous
solid.
[0872] In a forty-fourth aspect, a solid form is provided
comprising a basic amino acid, preferably arginine or lysine, and a
compound selected from the group consisting of: [0873]
Piperidine-1-sulfonic acid
[4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2440), [0874] Piperidine-1-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-amide
(P-2468), [0875] N,N-dimethylamino-sulfonic acid
[4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2469), [0876] N,N-dimethylamino-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2470), and [0877] Piperidine-1-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2471). In one embodiment, the solid form is a complex of the
compound and the basic amino acid. In one embodiment, the solid
form is a complex of the compound and arginine. In one embodiment,
the solid form is a complex of the compound and lysine. In one
embodiment, the complex is an amorphous solid.
[0878] In a forty-fifth aspect, a solid form is provided comprising
a basic amino acid, preferably arginine or lysine, and a compound
selected from the group consisting of: [0879]
N-[3-(5-Bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-methyl-phenyl]-meth-
anesulfonamide (P-1277), [0880]
N-[2-Methyl-3-(5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-met-
hanesulfonamide (P-1278), [0881]
N-[2-Methyl-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-pheny-
l]-methanesulfonamide (P-1279), [0882] Propane-1-sulfonic acid
{3-[(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-2-methyl-phen-
yl}-amide (P-1280), [0883] Propane-1-sulfonic acid
[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-methyl-phenyl]-amide
(P-1281), [0884] N,N-demethylamino-sulfonic acid
[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-methyl-phenyl]-amide
(P-1282), [0885] Propane-1-sulfonic acid
[2-methyl-3-(5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-1283), and [0886] Propane-1-sulfonic acid
[2-methyl-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-
-amide (P-1284). In one embodiment, the solid form is a complex of
the compound and the basic amino acid. In one embodiment, the solid
form is a complex of the compound and arginine. In one embodiment,
the solid form is a complex of the compound and lysine. In one
embodiment, the complex is an amorphous solid.
[0887] In a forty-sixth aspect, a solid form is provided comprising
a basic amino acid, preferably arginine or lysine, and a compound
selected from the group consisting of: [0888]
N-2,4-difluoro-3-[hydroxy-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methyl]-pheny-
l-4-trifluoromethyl-benzenesulfonamide (P-1426), [0889]
N-[2,4-Difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-2-fluo-
ro-benzenesulfonamide (P-1448), [0890]
N-[2,4-Difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-3-fluo-
ro-benzenesulfonamide (P-1449), [0891]
N-[2,4-Difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-2,5-di-
fluoro-benzenesulfonamide (P-1450), [0892]
N-[2,4-Difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-benzen-
esulfonamide (P-1451), [0893]
N-[2,4-Difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-4-isop-
ropyl-benzenesulfonamide (P-1452), [0894]
N-[2,4-Difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-4-prop-
yl-benzenesulfonamide (P-1453), [0895]
3-Difluoromethoxy-N-[2,4-difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbon-
yl)-phenyl]-benzenesulfonamide (P-1454), [0896]
4-Difluoromethoxy-N-[2,4-difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbon-
yl)-phenyl]-benzenesulfonamide (P-1455), [0897]
N-{2-Fluoro-3-[hydroxy-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methyl]-phenyl}--
4-trifluoromethyl-benzenesulfonamide (P-1457), [0898]
N-[2-Fluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-4-trifluor-
omethyl-benzenesulfonamide (P-1458), [0899]
4-Fluoro-N-[2-fluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-b-
enzenesulfonamide (P-1460), [0900]
2,5-Difluoro-N-[2-fluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-pheny-
l]-benzenesulfonamide (P-1463), [0901]
2,6-Difluoro-N-[2-fluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-pheny-
l]-benzenesulfonamide (P-1464), [0902]
2,4-Difluoro-N-[2-fluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-pheny-
l]-benzenesulfonamide (P-1465), [0903]
3-Fluoro-N-[2-fluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-b-
enzenesulfonamide (P-1467), [0904]
2-Fluoro-N-[2-fluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-b-
enzenesulfonamide (P-1475), [0905]
N-[2-Fluoro-3-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]--
4-trifluoromethyl-benzenesulfonamide (P-1481), [0906]
N-[2,4-Difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-4-fluo-
ro-benzenesulfonamide (P-1495), and [0907]
N-[3-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-2,4-difluoro--
phenyl]-4-trifluoromethyl-benzenesulfonamide (P-1505). In one
embodiment, the solid form is a complex of the compound and the
basic amino acid. In one embodiment, the solid form is a complex of
the compound and arginine. In one embodiment, the solid form is a
complex of the compound and lysine. In one embodiment, the complex
is an amorphous solid.
[0908] In a forty-seventh aspect, a solid form is provided
comprising a basic amino acid, preferably arginine or lysine, and a
compound selected from the group consisting of: [0909]
2H-[1,2,4]Triazole-3-sulfonic acid
[2,4-difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide
(P-1445), [0910] Thiazole-2-sulfonic acid
[2,4-difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide
(P-1446), [0911] Pyridine-2-sulfonic acid
[2,4-difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide
(P-1447), and [0912] Pyridine-3-sulfonic acid
[2-fluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide
(P-1462). In one embodiment, the solid form is a complex of the
compound and the basic amino acid. In one embodiment, the solid
form is a complex of the compound and arginine. In one embodiment,
the solid form is a complex of the compound and lysine. In one
embodiment, the complex is an amorphous solid.
[0913] In a forty-eighth aspect, a solid form is provided
comprising a basic amino acid, preferably arginine or lysine, and a
compound selected from the group consisting of: [0914]
Propane-1-sulfonic acid
{2,4-difluoro-3-[hydroxy-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methyl]-phenyl-
}-amide (P-1424), [0915] Propane-1-sulfonic acid
{2-fluoro-3-[hydroxy-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methyl]-phenyl}-am-
ide (P-1428), [0916] Propane-1-sulfonic acid
[2-fluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide
(P-1429), [0917] Propane-1-sulfonic acid
[2,4-difluoro-3-(4-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-
-amide (P-1479), [0918] Propane-1-sulfonic acid
[2,4-difluoro-3-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl-
]-amide (P-1480), [0919] Propane-1-sulfonic acid
[2-fluoro-3-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-am-
ide (P-1482), and [0920] Propane-1-sulfonic acid
[3-(4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-2,4-difluoro-ph-
enyl]-amide (P-1506).
[0921] In one embodiment, the solid form is a complex of the
compound and the basic amino acid. In one embodiment, the solid
form is a complex of the compound and arginine. In one embodiment,
the solid form is a complex of the compound and lysine. In one
embodiment, the complex is an amorphous solid.
[0922] In a forty-ninth aspect, a solid form is provided comprising
a basic amino acid, preferably arginine or lysine, and a compound
selected from the group consisting of: [0923]
N-[2,4-Difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-methan-
esulfonamide (P-1430), [0924] Ethanesulfonic acid
[2,4-difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide
(P-1431), [0925] Propane-2-sulfonic acid
[2,4-difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide
(P-1432), [0926] Butane-2-sulfonic acid
[2,4-difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide
(P-1433), [0927] 2-Methyl-propane-1-sulfonic acid
[2,4-difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide
(P-1434), [0928] Pentane-2-sulfonic acid
[2,4-difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide
(P-1435), [0929] Ethanesulfonic acid
[2-fluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide
(P-1459),
[0930] Propane-2-sulfonic acid
[2-fluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide
(P-1466), [0931] 2-Methyl-propane-1-sulfonic acid
[2-fluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide
(P-1470), [0932] Butane-2-sulfonic acid
[2-fluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide
(P-1471), [0933] Pentane-2-sulfonic acid
[2,4-difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide
(P-1474), and
[0934] Pentane-2-sulfonic acid
[2-fluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide
(P-1478).
[0935] In one embodiment, the solid form is a complex of the
compound and the basic amino acid. In one embodiment, the solid
form is a complex of the compound and arginine. In one embodiment,
the solid form is a complex of the compound and lysine. In one
embodiment, the complex is an amorphous solid.
[0936] In a fiftieth aspect, a solid form is provided comprising a
basic amino acid, preferably arginine or lysine, and a compound
selected from the group consisting of: [0937] Cyclopentanesulfonic
acid
[2,4-difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide
(P-1436), [0938] Cyclohexanesulfonic acid
[2,4-difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide
(P-1437), [0939] Cyclobutanesulfonic acid
[2-fluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide
(P-1472), [0940] Cyclohexanesulfonic acid
[2-fluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide
(P-1476), and [0941] Cyclopentanesulfonic acid
[2-fluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide
(P-1477). In one embodiment, the solid form is a complex of the
compound and the basic amino acid. In one embodiment, the solid
form is a complex of the compound and arginine. In one embodiment,
the solid form is a complex of the compound and lysine. In one
embodiment, the complex is an amorphous solid.
[0942] In a fifty-first aspect, a solid form is provided comprising
a basic amino acid, preferably arginine or lysine, and a compound
selected from the group consisting of: [0943]
N-[2,4-Difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-C,C,C--
trifluoro-methanesulfonamide (P-1438), [0944]
2,2,2-Trifluoro-ethanesulfonic acid
[2,4-difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide
(P-1439), [0945] 3,3,3-Trifluoro-propane-1-sulfonic acid
[2,4-difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide
(P-1440), and [0946] 2,2,2-Trifluoro-ethanesulfonic acid
[2-fluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide
(P-1461). In one embodiment, the solid form is a complex of the
compound and the basic amino acid. In one embodiment, the solid
form is a complex of the compound and arginine. In one embodiment,
the solid form is a complex of the compound and lysine. In one
embodiment, the complex is an amorphous solid.
[0947] In a fifty-second aspect, a solid form is provided
comprising a basic amino acid, preferably arginine or lysine, and a
compound selected from the group consisting of: [0948]
Dimethylamine-1-sulfonic acid
[3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-2,4-difluoro-phenyl]-amide
(P-1441), [0949] Diethylamine-1-sulfonic acid
[3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-2,4-difluoro-phenyl]-amide
(P-1442), [0950] Pyrrolidine-1-sulfonic acid
[2,4-difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide
(P-1443), [0951] Morpholine-4-sulfonic acid
[2,4-difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide
(P-1444), [0952] N,N-Dimethylamino-sulfonic acid
[2-fluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide
(P-1468), [0953] Pyrrolidine-1-sulfonic acid
[2-fluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide
(P-1469), and [0954] Morpholine-4-sulfonic acid
[2-fluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide
(P-1473). In one embodiment, the solid form is a complex of the
compound and the basic amino acid. In one embodiment, the solid
form is a complex of the compound and arginine. In one embodiment,
the solid form is a complex of the compound and lysine. In one
embodiment, the complex is an amorphous solid.
[0955] In a fifty-third aspect, a solid form is provided comprising
a basic amino acid, preferably arginine or lysine, and a compound
selected from the group consisting of: [0956] Propane-1-sulfonic
acid
[2,4-difluoro-3-(5H-pyrrolo[2,3-b]pyrazine-7-carbonyl)-phenyl]-amide
(P-1484), [0957] Propane-1-sulfonic acid
[3-(2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-1485), [0958] Propane-1-sulfonic acid
{2,4-difluoro-3-[2-(2-methoxy-pyrimidin-5-yl)-5H-pyrrolo[2,3-b]pyrazine-7-
-carbonyl]-phenyl}-amide (P-1486), [0959] Propane-1-sulfonic acid
{3-[2-(4-chloro-phenyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-2,4-difluor-
o-phenyl}-amide (P-1487), [0960] Propane-1-sulfonic acid
[3-(2-cyano-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-1488), [0961] Propane-1-sulfonic acid
{2,4-difluoro-3-[2-(1-methyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazine-7-
-carbonyl]-phenyl}-amide (P-1489), [0962] Propane-1-sulfonic acid
[2-fluoro-3-(5H-pyrrolo[2,3-b]pyrazine-7-carbonyl)-phenyl]-amide
(P-1490), and [0963]
N-[2-Fluoro-3-(5H-pyrrolo[2,3-b]pyrazine-7-carbonyl)-phenyl]-4-trifluorom-
ethyl-benzenesulfonamide (P-1492). In one embodiment, the solid
form is a complex of the compound and the basic amino acid. In one
embodiment, the solid form is a complex of the compound and
arginine. In one embodiment, the solid form is a complex of the
compound and lysine. In one embodiment, the complex is an amorphous
solid.
[0964] In a fifty-fourth aspect, a solid form is provided
comprising a basic amino acid, preferably arginine or lysine, and a
compound selected from the group consisting of: [0965]
Propane-1-sulfonic acid
[2,4-difluoro-3-(1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-phenyl]-amide
(P-1493), and [0966] Propane-1-sulfonic acid
[3-(5-cyano-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-1494). In one embodiment, the solid form is a complex of
the compound and the basic amino acid. In one embodiment, the solid
form is a complex of the compound and arginine. In one embodiment,
the solid form is a complex of the compound and lysine. In one
embodiment, the complex is an amorphous solid.
[0967] In a fifty-fifth aspect, a solid form is provided comprising
a basic amino acid, preferably arginine or lysine, and a compound
selected from the group consisting of: [0968]
6-Chloro-2-fluoro-3-(propane-1-sulfonylamino)-N-pyridin-3-yl-benzamide
(P-1285),
6-Chloro-2-fluoro-N-(6-methoxy-pyridin-3-yl)-3-(propane-1-sulfo-
nylamino)-benzamide (P-1287), [0969]
N-(2-Acetylamino-pyrimidin-5-yl)-6-chloro-2-fluoro-3-(propane-1-sulfonyla-
mino)-benzamide (P-1288), [0970]
6-Chloro-2-fluoro-N-(6-isopropylamino-pyridin-3-yl)-3-(propane-1-sulfonyl-
amino)-benzamide (P-1289), [0971] Pyrrolidine-1-carboxylic acid
{5-[6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoylamino]-pyridin-2-
-yl}-amide (P-1290), [0972]
6-Chloro-N-(3,5-dimethyl-isoxazol-4-yl)-2-fluoro-3-(propane-1-sulfonylami-
no)-benzamide (P-1291), [0973]
6-Chloro-N-(6-cyclopentylamino-pyridin-3-yl)-2-fluoro-3-(propane-1-sulfon-
ylamino)-benzamide (P-1292), [0974]
6-Chloro-N-[5-(4-chloro-phenyl)-2H-pyrazol-3-yl]-2-fluoro-3-(propane-1-su-
lfonylamino)-benzamide (P-1293), [0975]
6-Chloro-2-fluoro-N-[6-(5-methyl-thiazol-2-ylamino)-pyridin-3-yl]-3-(prop-
ane-1-sulfonylamino)-benzamide (P-1294), [0976]
6-Chloro-N-[5-(4-chloro-benzyl)-[1,3,4]thiadiazol-2-yl]-2-fluoro-3-(propa-
ne-1-sulfonylamino)-benzamide (P-1295), [0977]
6-Chloro-2-fluoro-3-(propane-1-sulfonylamino)-N-quinolin-3-yl-benzamide
(P-1296), [0978]
6-Chloro-N-(6-cyclopropylamino-pyridin-3-yl)-2-fluoro-3-(propane-1-sulfon-
ylamino)-benzamide (P-1298), [0979]
6-Chloro-2-fluoro-3-(propane-1-sulfonylamino)-N-{6-[(thiophen-2-ylmethyl)-
-amino]-pyridin-3-yl}-benzamide (P-1299), [0980]
N-(6-Benzylamino-pyridin-3-yl)-6-chloro-2-fluoro-3-(propane-1-sulfonylami-
no)-benzamide (P-1300), [0981]
6-Chloro-2-fluoro-N-imidazo[1,2-a]pyridin-3-yl-3-(propane-1-sulfonylamino-
)-benzamide (P-1301), and [0982]
2,6-Difluoro-3-(propane-1-sulfonylamino)-N-quinolin-3-yl-benzamide
(P-1312). In one embodiment, the solid form is a complex of the
compound and the basic amino acid. In one embodiment, the solid
form is a complex of the compound and arginine. In one embodiment,
the solid form is a complex of the compound and lysine. In one
embodiment, the complex is an amorphous solid.
[0983] In a fifty-sixth aspect, a solid form is provided comprising
a basic amino acid, preferably arginine or lysine, and a compound
selected from the group consisting of: [0984]
N-(6-Acetylamino-pyridin-3-yl)-6-chloro-2-fluoro-3-(propane-1-sulfonylami-
no)-benzamide (P-1286), [0985]
N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(propane-1-sulfonylamino)-b-
enzamide (P-1315), [0986]
N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(2-fluoro-benzenesulfonylam-
ino)-benzamide (P-1340), [0987]
N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(3-fluoro-benzenesulfonylam-
ino)-benzamide (P-1341), [0988]
N-(6-Acetylamino-pyridin-3-yl)-3-(2,6-difluoro-benzenesulfonylamino)-2,6--
difluoro-benzamide (P-1342), [0989]
N-(6-Acetylamino-pyridin-3-yl)-3-(2,4-difluoro-benzenesulfonylamino)-2,6--
difluoro-benzamide (P-1343), [0990]
N-(6-Acetylamino-pyridin-3-yl)-3-(2,5-difluoro-benzenesulfonylamino)-2,6--
difluoro-benzamide (P-1344), [0991]
6-Acetylamino-N-[2,6-difluoro-3-(3-fluoro-4-methoxy-benzenesulfonylamino)-
-phenyl]-nicotinamide (P-1345), [0992]
N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(4-trifluoromethyl-benzenes-
ulfonylamino)-benzamide (P-1346), [0993]
N-(6-Acetylamino-pyridin-3-yl)-3-(4-difluoromethoxy-benzenesulfonylamino)-
-2,6-difluoro-benzamide (P-1347), [0994]
N-(6-Acetylamino-pyridin-3-yl)-3-(3-difluoromethoxy-benzenesulfonylamino)-
-2,6-difluoro-benzamide (P-1348), [0995]
N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(4-isopropyl-benzenesulfony-
lamino)-benzamide (P-1349), [0996]
N-(6-Acetylamino-pyridin-3-yl)-3-(4-tert-butyl-benzenesulfonylamino)-2,6--
difluoro-benzamide (P-1350), [0997]
N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(4-propyl-benzenesulfonylam-
ino)-benzamide (P-1351), [0998]
N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(pyridine-2-sulfonylamino)--
benzamide (P-1352), [0999]
N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(pyridine-3-sulfonylamino)--
benzamide (P-1353), [1000]
N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(dimethylaminosulfonylamino-
)-benzamide (P-1354), [1001]
N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(piperidine-1-sulfonylamino-
)-benzamide (P-1355), [1002]
N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(morpholine-4-sulfonylamino-
)-benzamide (P-1356), [1003]
N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(tetrahydro-pyran-4-sulfony-
lamino)-benzamide (P-1357), [1004]
N-(6-Acetylamino-pyridin-3-yl)-3-cyclopentanesulfonylamino-2,6-difluoro-b-
enzamide (P-1358), [1005]
N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(pyrrolidine-1-sulfonylamin-
o)-benzamide (P-1359), [1006]
N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(3,3,3-trifluoro-propane-1--
sulfonylamino)-benzamide (P-1360), [1007]
N-(6-Acetylamino-pyridin-3-yl)-3-benzenesulfonylamino-2,6-difluoro-benzam-
ide (P-2474), and [1008]
6-Acetylamino-N-(3-benzenesulfonylamino-2,6-difluoro-phenyl)-nicotinamide
(P-2475). In one embodiment, the solid form is a complex of the
compound and the basic amino acid. In one embodiment, the solid
form is a complex of the compound and arginine. In one embodiment,
the solid form is a complex of the compound and lysine. In one
embodiment, the complex is an amorphous solid.
[1009] In a fifty-seventh aspect, a solid form is provided
comprising a basic amino acid, preferably arginine or lysine, and a
compound selected from the group consisting of: [1010]
Quinoline-3-carboxylic acid
[2,6-difluoro-3-(propane-1-sulfonylamino)-phenyl]-amide (P-1309),
[1011]
6-Acetylamino-N-[2,6-difluoro-3-(2-fluoro-benzenesulfonylamino)-phenyl]-n-
icotinamide (P-1317), [1012]
6-Acetylamino-N-[2,6-difluoro-3-(3-fluoro-benzenesulfonylamino)-phenyl]-n-
icotinamide (P-1318), [1013]
6-Acetylamino-N-[3-(2,6-difluoro-benzenesulfonylamino)-2,6-difluoro-pheny-
l]-nicotinamide (P-1319), [1014]
6-Acetylamino-N-[3-(2,4-difluoro-benzenesulfonylamino)-2,6-difluoro-pheny-
l]-nicotinamide (P-1320), [1015]
6-Acetylamino-N-[3-(2,5-difluoro-benzenesulfonylamino)-2,6-difluoro-pheny-
l]-nicotinamide (P-1321), [1016]
6-Acetylamino-N-[2,6-difluoro-3-(3-fluoro-4-methoxy-benzenesulfonylamino)-
-phenyl]-nicotinamide (P-1322), [1017]
6-Acetylamino-N-[2,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)--
phenyl]-nicotinamide (P-1323), [1018]
6-Acetylamino-N-[3-(4-difluoromethoxy-benzenesulfonylamino)-2,6-difluoro--
phenyl]-nicotinamide (P-1324), [1019]
6-Acetylamino-N-[3-(3-difluoromethoxy-benzenesulfonylamino)-2,6-difluoro--
phenyl]-nicotinamide (P-1325), [1020]
6-Acetylamino-N-[2,6-difluoro-3-(4-isopropyl-benzenesulfonylamino)-phenyl-
]-nicotinamide (P-1326), [1021]
6-Acetylamino-N-[3-(4-tert-butyl-benzenesulfonylamino)-2,6-difluoro-pheny-
l]-nicotinamide (P-1327), [1022]
6-Acetylamino-N-[2,6-difluoro-3-(4-propyl-benzenesulfonylamino)-phenyl]-n-
icotinamide (P-1328), [1023]
6-Acetylamino-N-[2,6-difluoro-3-(pyridine-2-sulfonylamino)-phenyl]-nicoti-
namide (P-1329), [1024]
6-Acetylamino-N-[2,6-difluoro-3-(pyridine-3-sulfonylamino)-phenyl]-nicoti-
namide (P-1330), [1025]
6-Acetylamino-N-[2,6-difluoro-3-(dimethylaminosulfonylamino)-phenyl]-nico-
tinamide (P-1331), [1026]
6-Acetylamino-N-[2,6-difluoro-3-(piperidine-1-sulfonylamino)-phenyl]-nico-
tinamide (P-1332), [1027]
6-Acetylamino-N-[2,6-difluoro-3-(morpholine-4-sulfonylamino)-phenyl]-nico-
tinamide (P-1333), [1028]
6-Acetylamino-N-[2,6-difluoro-3-(tetrahydro-pyran-4-sulfonylamino)-phenyl-
]-nicotinamide (P-1334), [1029]
6-Acetylamino-N-(3-cyclopentanesulfonylamino-2,6-difluoro-phenyl)-nicotin-
amide (P-1335), [1030]
6-Acetylamino-N-[2,6-difluoro-3-(pyrrolidine-1-sulfonylamino)-phenyl]-nic-
otinamide (P-1336), [1031]
6-Acetylamino-N-[2,6-difluoro-3-(3,3,3-trifluoro-propane-1-sulfonylamino)-
-phenyl]-nicotinamide (P-1337), and [1032]
6-Acetylamino-N-[2,6-difluoro-3-(propane-1-sulfonylamino)-phenyl]-nicotin-
amide (P-1361). In one embodiment, the solid form is a complex of
the compound and the basic amino acid. In one embodiment, the solid
form is a complex of the compound and arginine. In one embodiment,
the solid form is a complex of the compound and lysine. In one
embodiment, the complex is an amorphous solid.
[1033] In a fifty-eighth aspect, a solid form is provided
comprising a basic amino acid, preferably arginine or lysine, and a
compound selected from the group consisting of:
1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[2,6-difluoro-3-(2-fluoro-benzenesulfonylamino)-phenyl]-amide
(P-1362), [1034] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[2,6-difluoro-3-(3-fluoro-benzenesulfonylamino)-phenyl]-amide
(P-1363), [1035] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[3-(2,6-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide
(P-1364), [1036] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[3-(2,4-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide
(P-1365), [1037] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[3-(2,5-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide
(P-1366), [1038] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[2,6-difluoro-3-(3-fluoro-4-methoxy-benzenesulfonylamino)-phenyl]-amide
(P-1367), [1039] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[2,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-phenyl]-amide
(P-1368), [1040] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[3-(4-difluoromethoxy-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide
(P-1369), [1041] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[3-(3-difluoromethoxy-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide
(P-1370), [1042] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[2,6-difluoro-3-(4-isopropyl-benzenesulfonylamino)-phenyl]-amide
(P-1371), [1043] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[3-(4-tert-butyl-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide
(P-1372), [1044] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[2,6-difluoro-3-(4-propyl-benzenesulfonylamino)-phenyl]-amide
(P-1373), [1045] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[2,6-difluoro-3-(pyridine-2-sulfonylamino)-phenyl]-amide (P-1374),
[1046] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[2,6-difluoro-3-(pyridine-3-sulfonylamino)-phenyl]-amide (P-1375),
[1047] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[2,6-difluoro-3-(dimethylaminosulfonylamino)-phenyl]-amide
(P-1376), [1048] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[2,6-difluoro-3-(piperidine-1-sulfonylamino)-phenyl]-amide
(P-1377), [1049] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[2,6-difluoro-3-(morpholine-4-sulfonylamino)-phenyl]-amide
(P-1378), [1050] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[2,6-difluoro-3-(tetrahydro-pyran-4-sulfonylamino)-phenyl]-amide
(P-1379), [1051] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
(3-cyclopentanesulfonylamino-2,6-difluoro-phenyl)-amide (P-1380),
[1052] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[2,6-difluoro-3-(pyrrolidine-1-sulfonylamino)-phenyl]-amide
(P-1381), [1053] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[2,6-difluoro-3-(3,3,3-trifluoro-propane-1-sulfonylamino)-phenyl]-amide
(P-1382), and [1054] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[2,6-difluoro-3-(propane-1-sulfonylamino)-phenyl]-amide (P-1385).
In one embodiment, the solid form is a complex of the compound and
the basic amino acid. In one embodiment, the solid form is a
complex of the compound and arginine. In one embodiment, the solid
form is a complex of the compound and lysine. In one embodiment,
the complex is an amorphous solid.
[1055] In a fifty-ninth aspect, a solid form is provided comprising
a basic amino acid, preferably arginine or lysine, and a compound
selected from the group consisting of: [1056]
3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[2,6-difluoro-3-(2-fluoro-benzenesulfonylamino)-phenyl]-amide
(P-1386), [1057] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[2,6-difluoro-3-(3-fluoro-benzenesulfonylamino)-phenyl]-amide
(P-1387), [1058] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[3-(2,6-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide
(P-1388), [1059] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[3-(2,4-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide
(P-1389), [1060] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[3-(2,5-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide
(P-1390), [1061] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[2,6-difluoro-3-(3-fluoro-4-methoxy-benzenesulfonylamino)-phenyl]-amide
(P-1391), [1062] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[2,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-phenyl]-amide
(P-1392), [1063] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[3-(4-difluoromethoxy-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide
(P-1393), [1064] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[3-(3-difluoromethoxy-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide
(P-1394), [1065] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[2,6-difluoro-3-(4-isopropyl-benzenesulfonylamino)-phenyl]-amide
(P-1395), [1066] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[3-(4-tert-butyl-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide
(P-1396), [1067] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[2,6-difluoro-3-(4-propyl-benzenesulfonylamino)-phenyl]-amide
(P-1397), [1068] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[2,6-difluoro-3-(pyridine-2-sulfonylamino)-phenyl]-amide (P-1398),
[1069] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[2,6-difluoro-3-(pyridine-3-sulfonylamino)-phenyl]-amide (P-1399),
[1070] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[2,6-difluoro-3-(dimethylaminosulfonylamino)-phenyl]-amide
(P-1400), [1071] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[2,6-difluoro-3-(piperidine-1-sulfonylamino)-phenyl]-amide
(P-1401), [1072] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[2,6-difluoro-3-(morpholine-4-sulfonylamino)-phenyl]-amide
(P-1402), [1073] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[2,6-difluoro-3-(tetrahydro-pyran-4-sulfonylamino)-phenyl]-amide
(P-1403), [1074] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
(3-cyclopentanesulfonylamino-2,6-difluoro-phenyl)-amide (P-1404),
[1075] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[2,6-difluoro-3-(pyrrolidine-1-sulfonylamino)-phenyl]-amide
(P-1405), [1076] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[2,6-difluoro-3-(3,3,3-trifluoro-propane-1-sulfonylamino)-phenyl]-amide
(P-1406), and [1077] 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid
[2,6-difluoro-3-(propane-1-sulfonylamino)-phenyl]-amide (P-1407).
In one embodiment, the solid form is a complex of the compound and
the basic amino acid. In one embodiment, the solid form is a
complex of the compound and arginine. In one embodiment, the solid
form is a complex of the compound and lysine. In one embodiment,
the complex is an amorphous solid.
[1078] In a sixtieth aspect, a solid form is provided comprising a
basic amino acid, preferably arginine or lysine, and a compound
selected from the group consisting of: [1079] Propane-1-sulfonic
acid
(2,4-difluoro-3-{[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylami-
no]-methyl}-phenyl)-amide (P-1302), [1080] Propane-1-sulfonic acid
(3-{[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamino]--
methyl}-2,4-difluoro-phenyl)-amide (P-1303), [1081]
Propane-1-sulfonic acid
(2-fluoro-3-{[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylam-
ino]-methyl}-phenyl)-amide (P-1304), [1082] Propane-1-sulfonic acid
[2,4-difluoro-3-(quinolin-3-ylaminomethyl)-phenyl]-amide (P-1305),
[1083] Propane-1-sulfonic acid {3-[(6-chloro-pyridin-3-yl
amino)-methyl]-2,4-difluoro-phenyl}-amide (P-1306), [1084]
Propane-1-sulfonic acid
{2,4-difluoro-3-[(6-methoxy-pyridin-3-ylamino)-methyl]-phenyl}-amide
(P-1307), [1085] Propane-1-sulfonic acid
{2,4-difluoro-3-[(5-methyl-isoxazol-3-ylamino)-methyl]-phenyl}-amide
(P-1308), [1086] Propane-1-sulfonic acid
{2,4-difluoro-3-[(quinolin-3-ylmethyl)-amino]-phenyl}-amide
(P-1310), and [1087]
N-{5-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzyl
amino]-pyridin-2-yl}-acetamide (P-1316) In one embodiment, the
solid form is a complex of the compound and the basic amino acid.
In one embodiment, the solid form is a complex of the compound and
arginine. In one embodiment, the solid form is a complex of the
compound and lysine. In one embodiment, the complex is an amorphous
solid.
[1088] In a sixty-first aspect, a solid form is provided comprising
a basic amino acid, preferably arginine or lysine, and a compound
selected from the group consisting of: [1089] Propane-1-sulfonic
acid [2,4-difluoro-3-(quinolin-3-yloxymethyl)-phenyl]-amide
(P-1311), [1090] Propane-1-sulfonic acid
[3-(2-amino-pyridin-3-yloxymethyl)-2,4-difluoro-phenyl]-amide
(P-1313), [1091]
N-[3-(2-Amino-pyridin-3-yloxymethyl)-2,4-difluoro-phenyl]-4-triflu-
oromethyl-benzenesulfonamide (P-1314), [1092]
N-{5-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzyloxy]-pyridin-2-yl}-a-
cetamide (P-1338), [1093]
N-{5-[2,6-Difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzyloxy]--
pyridin-2-yl}-acetamide (P-1339), [1094] Propane-1-sulfonic acid
[2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridin-5-yloxymethyl)-phenyl]-amide
(P-1383), and [1095]
N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridin-5-yloxymethyl)-phenyl]-4-trif-
luoromethyl-benzenesulfonamide (P-1384). In one embodiment, the
solid form is a complex of the compound and the basic amino acid.
In one embodiment, the solid form is a complex of the compound and
arginine. In one embodiment, the solid form is a complex of the
compound and lysine. In one embodiment, the complex is an amorphous
solid.
[1096] In a sixty-second aspect, a solid form is provided
comprising a basic amino acid, preferably arginine or lysine, and a
compound selected from the group consisting of: [1097]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-4-tr-
ifluoromethyl-benzenesulfonamide (P-2057), [1098]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-4-t-
rifluoromethyl-benzenesulfonamide (P-2058), and [1099]
N-[2-Fluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-t-
rifluoromethyl-benzenesulfonamide (P-2059). In one embodiment, the
solid form is a complex of the compound and the basic amino acid.
In one embodiment, the solid form is a complex of the compound and
arginine. In one embodiment, the solid form is a complex of the
compound and lysine. In one embodiment, the complex is an amorphous
solid.
[1100] In a sixty-third aspect, a solid form is provided comprising
a basic amino acid, preferably arginine or lysine, and a compound
selected from the group consisting of: [1101]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-3-trifluoromethyl-benzenesulfonamide (P-1028), [1102]
N-[2,4-Difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-4-trif-
luoromethyl-benzenesulfonamide (P-1427), [1103]
4-tert-Butyl-N-[2,4-difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-p-
henyl]-benzenesulfonamide (P-1456), and [1104]
N-[2,4-Difluoro-3-(5H-pyrrolo[2,3-b]pyrazine-7-carbonyl)-phenyl]-4-triflu-
oromethyl-benzenesulfonamide (P-1491). In one embodiment, the solid
form is a complex of the compound and the basic amino acid. In one
embodiment, the solid form is a complex of the compound and
arginine. In one embodiment, the solid form is a complex of the
compound and lysine. In one embodiment, the complex is an amorphous
solid.
[1105] In a sixty-fourth aspect, a solid form is provided
comprising a basic amino acid, preferably arginine or lysine, and a
compound selected from the group consisting of: [1106]
N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-
-4-trifluoromethyl-benzenesulfonamide (P-1091), [1107]
N-[2,4-Difluoro-3-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phen-
yl]-4-trifluoromethyl-benzenesulfonamide (P-1483), [1108]
N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
4-trifluoromethyl-benzenesulfonamide (P-1503), and [1109]
N-[3-(4-Ethynyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl-
]-4-trifluoromethyl-benzenesulfonamide (P-1504). In one embodiment,
the solid form is a complex of the compound and the basic amino
acid. In one embodiment, the solid form is a complex of the
compound and arginine. In one embodiment, the solid form is a
complex of the compound and lysine. In one embodiment, the complex
is an amorphous solid.
[1110] In a sixty-fifth aspect, a solid form is provided comprising
a basic amino acid, preferably arginine or lysine, and a compound
selected from the group consisting of: [1111]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-4-trifluoromethyl-benzenesulfonamide (P-1021), and [1112]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
4-trifluoromethyl-benzenesulfonamide (P-1092). In one embodiment,
the solid form is a complex of the compound and the basic amino
acid. In one embodiment, the solid form is a complex of the
compound and arginine. In one embodiment, the solid form is a
complex of the compound and lysine. In one embodiment, the complex
is an amorphous solid.
[1113] In a sixty-sixth aspect, a solid form is provided comprising
a basic amino acid, preferably arginine or lysine, and a compound
selected from the group consisting of: [1114] Propane-1-sulfonic
acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-1174), [1115]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
3-fluoro-benzenesulfonamide (P-1498), [1116] Propane-1-sulfonic
acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-1499), [1117] Pyrrolidine-1-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-1500), and [1118] N,N-dimethylamino-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-1501). In one embodiment, the solid form is a complex of the
compound and the basic amino acid. In one embodiment, the solid
form is a complex of the compound and arginine. In one embodiment,
the solid form is a complex of the compound and lysine. In one
embodiment, the complex is an amorphous solid.
[1119] In a sixty-seventh aspect, a solid form is provided
comprising a basic amino acid, preferably arginine or lysine, and a
compound selected from the group consisting of: [1120]
Propane-1-sulfonic acid
{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluor-
o-phenyl}-amide (P-1167), [1121] Propane-1-sulfonic acid
[2,4-difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide
(P-1425), [1122] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-1496), [1123]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2,5-difluoro-benzenesulfonamide (P-1497), and [1124]
Propane-1-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-a-
mide (P-1502). In one embodiment, the solid form is a complex of
the compound and the basic amino acid. In one embodiment, the solid
form is a complex of the compound and arginine. In one embodiment,
the solid form is a complex of the compound and lysine. In one
embodiment, the complex is an amorphous solid.
[1125] In a sixty-eighth aspect, a complex of arginine and
N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-4-trifluoromethyl-benzenesulfonamide (P-1021) is provided. In one
embodiment, a composition is provided comprising said complex. In
one embodiment, the composition is effective as a pharmaceutical,
for example in the treatment of pain or polycystic kidney disease.
In one embodiment, the complex is an amorphous solid.
[1126] In a sixty-ninth aspect, a complex of lysine and
N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-4-trifluoromethyl-benzenesulfonamide (P-1021) is provided. In one
embodiment, a composition is provided comprising said complex. In
one embodiment, the composition is effective as a pharmaceutical,
for example in the treatment of pain or polycystic kidney disease.
In one embodiment, the complex is an amorphous solid.
[1127] In a seventieth aspect, a complex of arginine and
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
4-trifluoromethyl-benzenesulfonamide (P-1092) is provided. In one
embodiment, a composition is provided comprising said complex. In
one embodiment, the composition is effective as a pharmaceutical,
for example in the treatment of pain or polycystic kidney disease.
In one embodiment, the complex is an amorphous solid.
[1128] In a seventy-first aspect, a complex of lysine and
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
4-trifluoromethyl-benzenesulfonamide (P-1092) is provided. In one
embodiment, a composition is provided comprising said complex. In
one embodiment, the composition is effective as a pharmaceutical,
for example in the treatment of pain or polycystic kidney disease.
In one embodiment, the complex is an amorphous solid.
[1129] In a seventy-second aspect, a complex of arginine and
Propane-1-sulfonic acid
{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluor-
o-phenyl}-amide (P-1167) is provided. In one embodiment, a
composition is provided comprising said complex. In one embodiment,
the composition is effective as a pharmaceutical, for example in
the treatment of melanoma or colorectal cancer. In one embodiment,
the complex is an amorphous solid.
[1130] In a seventy-third aspect, a complex of lysine and
Propane-1-sulfonic acid
{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluor-
o-phenyl}-amide (P-1167) is provided. In one embodiment, a
composition is provided comprising said complex. In one embodiment,
the composition is effective as a pharmaceutical, for example in
the treatment of melanoma or colorectal cancer. In one embodiment,
the complex is an amorphous solid.
[1131] In a seventy-fourth aspect, a complex of arginine and
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2,5-difluoro-benzenesulfonamide (P-1497) is provided. In one
embodiment, a composition is provided comprising said complex. In
one embodiment, the composition is effective as a pharmaceutical,
for example in the treatment of melanoma or colorectal cancer. In
one embodiment, the complex is an amorphous solid.
[1132] In a seventy-fifth aspect, a complex of lysine and
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2,5-difluoro-benzenesulfonamide (P-1497) is provided. In one
embodiment, a composition is provided comprising said complex. In
one embodiment, the composition is effective as a pharmaceutical,
for example in the treatment of melanoma or colorectal cancer. In
one embodiment, the complex is an amorphous solid.
[1133] In a seventy-sixth aspect, a complex of arginine and
Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-1496 is provided. In one embodiment, a
composition is provided comprising said complex. In one embodiment,
the composition is effective as a pharmaceutical, for example in
the treatment of melanoma or colorectal cancer. In one embodiment,
the complex is an amorphous solid.
[1134] In a seventy-seventh aspect, a complex of lysine and
Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-1496) is provided. In one embodiment, a
composition is provided comprising said complex. In one embodiment,
the composition is effective as a pharmaceutical, for example in
the treatment of melanoma or colorectal cancer. In one embodiment,
the complex is an amorphous solid.
[1135] In a seventy-eighth aspect, a composition is provided
comprising an amorphous complex of arginine and any of the
above-referenced specific compounds, and further comprises a
crystalline form of the compound, preferably crystalline free base
of the compound. In one embodiment, the composition comprises the
amorphous complex and 0-80% crystalline compound, also 0-50%,
0-20%, 0-10%, 0-5%, or 0-2% crystalline compound.
[1136] In a seventy-ninth aspect, a composition is provided
comprising an amorphous complex of lysine and any of the
above-referenced specific compounds, and further comprises a
crystalline form of the compound, preferably crystalline free base
of the compound. In one embodiment, the composition comprises the
amorphous complex and 0-80% crystalline compound, also 0-50%,
0-20%, 0-10%, 0-5%, or 0-2% crystalline compound.
[1137] In an eightieth aspect, a compound is provided, where the
compound is selected from the group consisting of: [1138]
N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-4-fluoro-benzenesulfonamide (P-2026), [1139]
N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-4-fluoro-benzenesulfonamide (P-2027), [1140]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
4-fluoro-benzenesulfonamide (P-2028), [1141]
N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
4-fluoro-benzenesulfonamide (P-2035), [1142]
N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-
-3-carbonyl]-phenyl}-4-fluoro-benzenesulfonamide (P-2040), [1143]
N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-4-trifluoromethyl-benzenesulfonamide (P-2047), [1144]
N-[2,4-Difluoro-3-(5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-
-4-trifluoromethyl-benzenesulfonamide (P-2482), [1145]
N-[3-(5-Cyclopropyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-ph-
enyl]-4-trifluoromethyl-benzenesulfonamide (P-2483), [1146]
N-[3-(5-Ethynyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl-
]-4-trifluoromethyl-benzenesulfonamide (P-2484), [1147]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
4-propyl-benzenesulfonamide (P-2486), [1148]
N-[3-(4-Ethynyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-4--
trifluoromethyl-benzenesulfonamide (P-2487), and a salt, prodrug,
tautomer, or stereoisomer thereof. In one embodiment, the compound
is active on one or more Raf protein kinases, including A-Raf,
B-Raf, c-Raf-1 and any mutations thereof.
[1149] In an eighty-first aspect, a compound is provided, where the
compound is selected from the group consisting of: [1150]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-4-fl-
uoro-benzenesulfonamide (P-2050),
[1151]
N-[2-Fluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phen-
yl]-4-trifluoromethyl-benzenesulfonamide (P-2060), and
a salt, prodrug, tautomer, or stereoisomer thereof. In one
embodiment, the compound is active on one or more Raf protein
kinases, including A-Raf, B-Raf, c-Raf-1 and any mutations
thereof.
[1152] In an eighty-second aspect, a compound is provided, where
the compound is selected from the group consisting of: [1153]
N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-
-3-fluoro-benzenesulfonamide (P-2016), [1154]
N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-3-fluoro-benzenesulfonamide (P-2019), [1155]
N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-3-fluoro-benzenesulfonamide (P-2023), [1156]
N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
3-fluoro-benzenesulfonamide (P-2039), [1157]
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), [1158]
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, tautomer, or
stereoisomer thereof. In one embodiment, the compound is active on
one or more Raf protein kinases, including A-Raf, B-Raf, c-Raf-1
and any mutations thereof.
[1159] In an eighty-third aspect, a compound is provided, where the
compound is selected from the group consisting of: [1160]
4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2001), [1161]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-2,5-difluoro-benzenesulfonamide (P-2002), [1162]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-2,6-difluoro-benzenesulfonamide (P-2003), [1163]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-3,5-dimethyl-benzenesulfonamide (P-2004), [1164]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-3-fluoro-4-methoxy-benzenesulfonamide (P-2005), [1165]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-4-fluoro-2-methyl-benzenesulfonamide (P-2006), [1166]
2,3-Dihydro-benzofuran-5-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2007), [1167]
N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-2-fluoro-benzenesulfonamide (P-2009), [1168]
N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-2,5-difluoro-benzenesulfonamide (P-2010), [1169]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2-fluoro-benzenesulfonamide (P-2011), [1170]
N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-
-2-fluoro-benzenesulfonamide (P-2014), [1171]
N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-
-2,5-difluoro-benzenesulfonamide (P-2015), [1172]
N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-2-fluoro-benzenesulfonamide (P-2017), [1173]
N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-2,5-difluoro-benzenesulfonamide (P-2018), [1174]
N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2-fluoro-benzenesulfonamide (P-2020), [1175]
N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-2-fluoro-benzenesulfonamide (P-2021), [1176]
N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-2,5-difluoro-benzenesulfonamide (P-2022), [1177]
N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-
-2,6-difluoro-benzenesulfonamide (P-2024), [1178]
N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-
-2,4-difluoro-benzenesulfonamide (P-2025), [1179]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2,6-difluoro-benzenesulfonamide (P-2029), [1180]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2,4-difluoro-benzenesulfonamide (P-2030), [1181]
N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-2,6-difluoro-benzenesulfonamide (P-2031), [1182]
N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-2,4-difluoro-benzenesulfonamide (P-2032), [1183]
N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-2,6-difluoro-benzenesulfonamide (P-2033), [1184]
N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-2,4-difluoro-benzenesulfonamide (P-2034), [1185]
N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2,5-difluoro-benzenesulfonamide (P-2036), [1186]
N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2,6-difluoro-benzenesulfonamide (P-2037), [1187]
N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2,4-difluoro-benzenesulfonamide (P-2038), [1188]
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), [1189]
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),
[1190]
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),
[1191]
N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-
-3-carbonyl]-phenyl}-2,4-difluoro-benzenesulfonamide (P-2044),
[1192]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
benzenesulfonamide (P-2046), [1193]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-2-fl-
uoro-benzenesulfonamide (P-2051), [1194]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-2,5--
difluoro-benzenesulfonamide (P-2052), [1195]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-2,6--
difluoro-benzenesulfonamide (P-2054), [1196]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-2,4--
difluoro-benzenesulfonamide (P-2055), [1197]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-benz-
enesulfonamide (P-2056), and a salt, prodrug, tautomer, or
stereoisomer thereof. In one embodiment, the compound is active on
one or more Raf protein kinases, including A-Raf, B-Raf, c-Raf-1
and any mutations thereof.
[1198] In an eighty-fourth aspect, a compound is provided, where
the compound is selected from the group consisting of: [1199]
2H-[1,2,4]Triazole-3-sulfonic acid
[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2061), [1200] 2H-[1,2,4]Triazole-3-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2062), [1201] Pyridine-2-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2063), [1202] 2H-[1,2,4]Triazole-3-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2064), [1203] 2H-[1,2,4]Triazole-3-sulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2065), [1204] 2H-[1,2,4]Triazole-3-sulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2066), [1205] Pyridine-2-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2067), [1206] 2H-[1,2,4]Triazole-3-sulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2068), [1207] Pyridine-3-sulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2069), [1208] Pyridine-2-sulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2070), [1209] Pyridine-3-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2071), [1210] Pyridine-3-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2072), [1211] Pyridine-3-sulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2073), [1212] Pyridine-3-sulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2074), [1213] Pyridine-2-sulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2075), [1214] Pyridine-2-sulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2076), [1215] Pyridine-3-sulfonic acid
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2077), [1216] Pyridine-2-sulfonic acid
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2078), [1217] Pyridine-2-sulfonic acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2079), [1218]
2H-[1,2,4]Triazole-3-sulfonic acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyrid-
ine-3-carbonyl]-phenyl}-amide (P-2080), [1219]
5-Methyl-isoxazole-4-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2081), [1220] 1,5-Dimethyl-1H-pyrazole-4-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2082), [1221] 1-Ethyl-1H-pyrazole-4-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2083), [1222] 1-Methyl-1H-pyrazole-4-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2084), [1223] 6-Methoxy-pyridine-3-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2085), [1224] Pyridine-3-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2086), [1225] Pyridine-2-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2087), [1226] 5-Methyl-isoxazole-4-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2088), [1227] 1-Ethyl-1H-pyrazole-4-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2089), [1228] 1-Methyl-1H-pyrazole-4-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2090), [1229] 1,5-Dimethyl-1H-pyrazole-4-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2091), [1230] 6-Methoxy-pyridine-3-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2092), [1231] 6-Trifluoromethyl-pyridine-3-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2481), [1232] 5-Trifluoromethyl-pyridine-2-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2485), and a salt, prodrug, tautomer, or stereoisomer
thereof. In one embodiment, the compound is active on one or more
Raf protein kinases, including A-Raf, B-Raf, c-Raf-1 and any
mutations thereof.
[1233] In an eighty-fifth aspect, a compound is provided, where the
compound is selected from the group consisting of: [1234]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
C-pyridin-2-yl-methanesulfonamide (P-2093), [1235]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
C-pyridin-3-yl-methanesulfonamide (P-2094), [1236]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
C-pyridin-4-yl-methanesulfonamide (P-2095), [1237]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-C-py-
ridin-3-yl-methanesulfonamide (P-2096), [1238]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-C-py-
ridin-4-yl-methanesulfonamide (P-2097), [1239]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-C-py-
ridin-2-yl-methanesulfonamide (P-2098), and a salt, prodrug,
tautomer, or stereoisomer thereof. In one embodiment, the compound
is active on one or more Raf protein kinases, including A-Raf,
B-Raf, c-Raf-1 and any mutations thereof.
[1240] In an eighty-sixth aspect, a compound is provided, where the
compound is selected from the group consisting of: [1241]
4-Fluoro-N-{4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyr-
idine-3-carbonyl]-phenyl}-benzenesulfonamide (P-2100), [1242]
N-{4-Fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-c-
arbonyl]-phenyl}-4-trifluoromethyl-benzenesulfonamide (P-2104),
[1243]
4-Chloro-N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-ph-
enyl]-benzenesulfonamide (P-2106), [1244]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-4-f-
luoro-benzenesulfonamide (P-2107), [1245]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-4-t-
rifluoromethoxy-benzenesulfonamide (P-2109), [1246]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-4-t-
rifluoromethyl-benzenesulfonamide (P-2112), [1247]
4-Chloro-N-[4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-ben-
zenesulfonamide (P-2113), [1248]
4-Fluoro-N-[4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-ben-
zenesulfonamide (P-2114), [1249]
N-[4-Fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluorom-
ethoxy-benzenesulfonamide (P-2116), [1250]
N-[4-Fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluorom-
ethyl-benzenesulfonamide (P-2119), [1251]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-fluoro-ben-
zenesulfonamide (P-2121), [1252]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluorom-
ethoxy-benzenesulfonamide (P-2123), [1253]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluorom-
ethyl-benzenesulfonamide (P-2126), [1254]
4-Chloro-N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-ben-
zenesulfonamide (P-2128), [1255]
4-Chloro-N-{3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-c-
arbonyl]-phenyl}-benzenesulfonamide (P-2129), [1256]
4-Fluoro-N-{3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-c-
arbonyl]-phenyl}-benzenesulfonamide (P-2130), [1257]
N-{3-[5-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]--
phenyl}-4-trifluoromethoxy-benzenesulfonamide (P-2132), and [1258]
N-{3-[5-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]--
phenyl}-4-trifluoromethyl-benzenesulfonamide (P-2135), and a salt,
prodrug, tautomer, or stereoisomer thereof. In one embodiment, the
compound is active on one or more Raf protein kinases, including
A-Raf, B-Raf, c-Raf-1 and any mutations thereof.
[1259] In an eighty-seventh aspect, a compound is provided, where
the compound is selected from the group consisting of: [1260]
N-{2-Chloro-4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyr-
idine-3-carbonyl]-phenyl}-3-difluoromethoxy-benzenesulfonamide
(P-2099), [1261]
N-{4-Fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyrid-
ine-3-carbonyl]-phenyl}-3-trifluoromethyl-benzenesulfonamide
(P-2101), [1262]
N-{4-Fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyrid-
ine-3-carbonyl]-phenyl}-3-trifluoromethoxy-benzenesulfonamide
(P-2102), [1263]
3-Chloro-N-{4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,-
3-b]pyridine-3-carbonyl]-phenyl}-benzenesulfonamide (P-2103),
[1264]
3-Fluoro-N-{4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyr-
idine-3-carbonyl]-phenyl}-benzenesulfonamide (P-2105), [1265]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-3-t-
rifluoromethyl-benzenesulfonamide (P-2108), [1266]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-3-t-
rifluoromethoxy-benzenesulfonamide (P-2110), [1267]
3-Chloro-N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-ph-
enyl]-benzenesulfonamide (P-2111), [1268]
N-[4-Fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-trifluorom-
ethyl-benzenesulfonamide (P-2115), [1269]
N-[4-Fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-trifluorom-
ethoxy-benzenesulfonamide (P-2117), [1270]
3-Chloro-N-[4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-ben-
zenesulfonamide (P-2118), [1271]
3-Fluoro-N-[4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-ben-
zenesulfonamide (P-2120), [1272]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-trifluorom-
ethyl-benzenesulfonamide (P-2122), [1273]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-trifluorom-
ethoxy-benzenesulfonamide (P-2124), [1274]
3-Chloro-N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-ben-
zenesulfonamide (P-2125), [1275]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-fluoro-ben-
zenesulfonamide (P-2127), [1276]
N-{3-[5-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]--
phenyl}-3-trifluoromethyl-benzenesulfonamide (P-2131), [1277]
N-{3-[5-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]--
phenyl}-3-trifluoromethoxy-benzenesulfonamide (P-2133), [1278]
3-Chloro-N-{3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-c-
arbonyl]-phenyl}-benzenesulfonamide (P-2134), [1279]
3-Fluoro-N-{3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-c-
arbonyl]-phenyl}-benzenesulfonamide (P-2136), and a salt, prodrug,
tautomer, or stereoisomer thereof. In one embodiment, the compound
is active on one or more Raf protein kinases, including A-Raf,
B-Raf, c-Raf-1 and any mutations thereof.
[1280] In an eighty-eighth aspect, a compound is provided, where
the compound is selected from the group consisting of: [1281]
Pyridine-3-sulfonic acid
[4-fluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2137), [1282] Pyridine-3-sulfonic acid
{4-fluoro-3-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-car-
bonyl]-phenyl}-amide (P-2138), [1283] Pyridine-3-sulfonic acid
{4-fluoro-3-[5-(3-methanesulfonylamino-phenyl)-1H-pyrrolo[2,3-b]pyridine--
3-carbonyl]-phenyl}-amide (P-2139), [1284] Pyridine-3-sulfonic acid
{4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-car-
bonyl]-phenyl}-amide (P-2140), [1285] Pyridine-3-sulfonic acid
[3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2141), [1286] Pyridine-3-sulfonic acid
[3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2142), [1287] Pyridine-3-sulfonic acid
[3-(5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2143), [1288] Pyridine-3-sulfonic acid
{3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-ph-
enyl}-amide (P-2144), [1289] Pyridine-3-sulfonic acid
{3-[5-(3-methanesulfonylamino-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbony-
l]-phenyl}-amide (P-2145), [1290] Pyridine-3-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2146), [1291]
3-{3-[3-(Pyridine-3-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl-
}-benzamide (P-2147), [1292]
3-(3-{3-[3-(Pyridine-3-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-
-yl}-phenyl)-propionic acid (P-2148), [1293] Pyridine-3-sulfonic
acid
{3-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-ph-
enyl}-amide (P-2149), [1294]
N-(6-Acetylamino-pyridin-3-yl)-3-benzenesulfonylamino-2,6-difluoro-benzam-
ide (P-2472), and a salt, prodrug, tautomer, or stereoisomer
thereof. In one embodiment, the compound is active on one or more
Raf protein kinases, including A-Raf, B-Raf, c-Raf-1 and any
mutations thereof.
[1295] In an eighty-ninth aspect, a compound is provided, where the
compound is selected from the group consisting of: [1296]
N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-methanesulfonamide (P-2288), [1297]
N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-
-methanesulfonamide (P-2289), [1298]
N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-methanesulfonamide (P-2290), [1299]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-methanesulfonamide (P-2291), [1300]
N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
methanesulfonamide (P-2292), [1301]
N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-methanesulfonamide (P-2293), [1302]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
methanesulfonamide (P-2294), and [1303]
N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-
-3-carbonyl]-phenyl}-methanesulfonamide (P-2295), and
[1304] a salt, prodrug, tautomer, or stereoisomer thereof. In one
embodiment, the compound is active on one or more Raf protein
kinases, including A-Raf, B-Raf, c-Raf-1 and any mutations
thereof.
[1305] In a ninetieth aspect, a compound is provided, where the
compound is selected from the group consisting of: [1306]
Ethanesulfonic acid
[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2268), [1307] Ethanesulfonic acid
{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluor-
o-phenyl}-amide (P-2269), [1308] Ethanesulfonic acid
{2,4-difluoro-3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl-
]-phenyl}-amide (P-2270), [1309] Ethanesulfonic acid
{2,4-difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2271), [1310] Ethanesulfonic acid
[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2272), [1311] Propane-2-sulfonic acid
[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2273), [1312] Ethanesulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2274), [1313] Propane-2-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2275), [1314] Ethanesulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2276), [1315] Ethanesulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2277), [1316] Propane-2-sulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2278), [1317] Ethanesulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2279), [1318] Propane-2-sulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2280), [1319] Ethanesulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2281), [1320] Propane-2-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2282), [1321] Ethanesulfonic acid
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2283), [1322] Propane-2-sulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2284), [1323] Propane-2-sulfonic acid
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2285), [1324] Ethanesulfonic acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2286), [1325] Propane-2-sulfonic acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2287), [1326] Ethanesulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2410), [1327] Propane-2-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2411), and a salt, prodrug, tautomer, or stereoisomer thereof.
In one embodiment, the compound is active on one or more Raf
protein kinases, including A-Raf, B-Raf, c-Raf-1 and any mutations
thereof.
[1328] In a ninety-first aspect, a compound is provided, where the
compound is selected from the group consisting of: [1329]
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
(P-2150), [1330]
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),
[1331] Propane-1-sulfonic acid
{3-[5-(1,5-dimethyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbony-
l]-2,4-difluoro-phenyl}-amide (P-2152), [1332] Propane-1-sulfonic
acid
{2,4-difluoro-3-[5-(1-methyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine--
3-carbonyl]-phenyl}-amide (P-2153), [1333] 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), [1334] 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), [1335] Propane-1-sulfonic acid
{3-[5-(3,5-dimethyl-isoxazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]--
2,4-difluoro-phenyl}-amide (P-2156), [1336] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(I-isobutyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-
-3-carbonyl]-phenyl}-amide (P-2157), [1337] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyr-
idine-3-carbonyl]-phenyl}-amide (P-2158), [1338] Propane-1-sulfonic
acid
{2,4-difluoro-3-[5-(4-fluoro-3-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine--
3-carbonyl]-phenyl}-amide (P-2159), [1339] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(4-fluoro-3-trifluoromethyl-phenyl)-1H-pyrrolo[2,3-b]p-
yridine-3-carbonyl]-phenyl}-amide (P-2160), [1340]
N-(4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-
-b]pyridin-5-yl}-phenyl)-acetamide (P-2161), [1341]
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), [1342] 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), [1343] 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), [1344] 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), [1345]
4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-N-methyl-benzenesulfonamide (P-2167), [1346]
N-Cyclopropyl-4-{3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H--
pyrrolo[2,3-b]pyridin-5-yl}-benzenesulfonamide (P-2168), [1347]
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), [1348]
3-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-N-methyl-benzenesulfonamide (P-2170), [1349]
Propane-1-sulfonic acid
{3-[5-(4-chloro-3-trifluoromethyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-car-
bonyl]-2,4-difluoro-phenyl}-amide (P-2171), [1350]
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), [1351] Propane-1-sulfonic
acid
[2,4-difluoro-3-(5-methanesulfonyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)--
phenyl]-amide (P-2173), [1352] 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), [1353] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(2-methyl-2H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2175), [1354] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(2H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl-
]-phenyl}-amide (P-2176), [1355] Propane-1-sulfonic acid
(2,4-difluoro-3-{5-[I-(2-morpholin-4-yl-ethyl)-1H-pyrazol-4-yl]-1H-pyrrol-
o[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2177), [1356]
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), [1357]
Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(3-hydroxy-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbony-
l]-phenyl}-amide (P-2179), [1358]
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),
[1359]
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),
[1360] Propane-1-sulfonic acid
[2,4-difluoro-3-(5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)--
phenyl]-amide (P-2182), [1361] Propane-1-sulfonic acid
{2,4-difluoro-3-[hydroxy-(5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-3-yl-
)-methyl]-phenyl}-amide (P-2473), [1362] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(4-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2183), [1363] 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), [1364]
4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-N,N-dimethyl-benzenesulfonamide (P-2185), [1365]
Propane-1-sulfonic acid
(2,4-difluoro-3-{5-[4-(piperidine-1-sulfonyl)-phenyl]-1H-pyrrolo[2,3-b]py-
ridine-3-carbonyl}-phenyl)-amide (P-2186), [1366]
Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(6-methylsulfanyl-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridi-
ne-3-carbonyl]-phenyl}-amide (P-2187), [1367] Propane-1-sulfonic
acid
{2,4-difluoro-3-[5-(5-methanesulfonyl-pyridin-3-yl-1H-pyrrolo[2,3-b]pyrid-
ine-3-carbonyl]-phenyl}-amide (P-2188), [1368] 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), [1369] 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), [1370] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-1H-pyrrolo[2,3-b]pyr-
idine-3-carbonyl]-phenyl}-amide (P-2191), [1371] 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), [1372]
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), [1373]
4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-benzenesulfonamide (P-2194), [1374]
Propane-1-sulfonic acid
{3-[5-(2,5-dimethyl-2H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl-
]-2,4-difluoro-phenyl}-amide (P-2195), [1375] 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), [1376] 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), [1377] Propane-1-sulfonic
acid
{2,4-difluoro-3-[5-(4-hydroxy-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbony-
l]-phenyl}-amide (P-2198), [1378] 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), [1379]
3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyr-
idine-5-carboxylic acid methylamide (P-2200), [1380]
3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyr-
idine-5-carboxylic acid cyclopropylamide (P-2201), [1381]
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), [1382]
Propane-1-sulfonic acid
[2,4-difluoro-3-(5-hydroxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2204), [1383]
3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyr-
idine-5-carboxylic acid ethyl ester (P-2207), [1384]
Propane-1-sulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phen-
yl]-amide (P-2208), [1385] Propane-1-sulfonic acid
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2209), [1386] Propane-1-sulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2210), [1387] 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), [1388] Propane-1-sulfonic acid
{3-[5-(2-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluor-
o-phenyl}-amide (P-2212), [1389] 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), [1390] 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), [1391] Propane-1-sulfonic acid
(2,4-difluoro-3-{5-[6-(2-hydroxy-ethoxy)-pyridin-3-yl]-1H-pyrrolo[2,3-b]p-
yridine-3-carbonyl}-phenyl)-amide (P-2215), [1392]
Propane-1-sulfonic acid
(3-{5-[6-(3-diethylamino-propoxy)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine-
-3-carbonyl}-2,4-difluoro-phenyl)-amide (P-2216), [1393]
3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyr-
idine-5-carboxylic acid (2-hydroxy-ethyl)-amide (P-2217), [1394]
Propane-1-sulfonic acid
{3-[5-(4-ethanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-
-difluoro-phenyl}-amide (P-2218), [1395] 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), [1396]
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), [1397]
4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-N-(2-hydroxy-ethyl)-benzenesulfonamide (P-2221),
[1398] 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), [1399]
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), [1400] 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), [1401]
(E)-3-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,-
3-b]pyridin-5-yl}-acrylic acid methyl ester (P-2225), [1402]
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), [1403]
Propane-1-sulfonic acid
(2,4-difluoro-3-{5-[4-(pyrrolidine-1-sulfonyl)-phenyl]-1H-pyrrolo[2,3-b]p-
yridine-3-carbonyl}-phenyl)-amide (P-2227), [1404]
Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2228), [1405] 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), [1406]
3-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-propionic acid methyl ester (P-2230), [1407]
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), [1408] 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), [1409]
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), [1410]
Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(6-hydroxy-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-ca-
rbonyl]-phenyl}-amide (P-2234), [1411] 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), [1412]
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), [1413]
3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyr-
idine-5-carboxylic acid dimethyl amide (P-2237), [1414]
3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyr-
idine-5-carboxylic acid methoxy-amide (P-2238), [1415]
Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(3-methoxy-prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridine-
-3-carbonyl]-phenyl}-amide (P-2239), [1416] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(3-methoxy-propyl)-1H-pyrrolo[2,3-b]pyridine-3-carbony-
l]-phenyl}-amide (P-2240), [1417] 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), [1418] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(2H-tetrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbony-
l]-phenyl}-amide (P-2242), [1419]
3-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-N-methoxy-propionamide (P-2243), [1420]
Propane-1-sulfonic acid
[2,4-difluoro-3-(5-morpholin-4-ylmethyl-1H-pyrrolo[2,3-b]pyridine-3--
carbonyl)-phenyl]-amide (P-2244), [1421] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(3-morpholin-4-yl-propyl)-1H-pyrrolo[2,3-b]pyridine-3--
carbonyl]-phenyl}-amide (P-2247), [1422] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(3-pyrrolidin-1-yl-propyl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2248), [1423] Propane-1-sulfonic acid
[2,4-difluoro-3-(5-hydroxymethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-ph-
enyl]-amide (P-2250), [1424]
3-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-N,N-diethyl-propionamide (P-2255), [1425]
Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(4-methyl-piperazin-1-ylmethyl)-1H-pyrrolo[2,3-b]-
pyridine-3-carbonyl]-phenyl}-amide (P-2257), [1426]
Propane-1-sulfonic acid
[3-(5-diethylaminomethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-d-
ifluoro-phenyl]-amide (P-2258), [1427] Propane-1-sulfonic acid
[2,4-difluoro-3-(5-pyrrolidin-1-ylmethyl-1H-pyrrolo[2,3-b]pyridine-3-carb-
onyl)-phenyl]-amide (P-2259), [1428] Propane-1-sulfonic acid
[3-(5-ethynyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
amide (P-2260), [1429] Propane-1-sulfonic acid
[3-(4-ethynyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
amide (P-2261), and a salt, prodrug, tautomer, or stereoisomer
thereof. In one embodiment, the compound is active on one or more
Raf protein kinases, including A-Raf, B-Raf, c-Raf-1 and any
mutations thereof.
[1430] In a ninety-second aspect, a compound is provided, where the
compound is selected from the group consisting of: [1431]
Propane-1-sulfonic acid
[2-fluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2403), [1432]
3-[2-Fluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-
e-5-carboxylic acid methyl ester (P-2404), [1433]
3-[2-Fluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-
e-5-carboxylic acid ethyl ester (P-2406), [1434] 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), [1435] 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), [1436] Propane-1-sulfonic acid
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2409), [1437] Propane-1-sulfonic acid
[2-fluoro-3-(5-iodo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2480), and a salt, prodrug, tautomer, or stereoisomer thereof.
In one embodiment, the compound is active on one or more Raf
protein kinases, including A-Raf, B-Raf, c-Raf-1 and any mutations
thereof.
[1438] In a ninety-third aspect, a compound is provided, where the
compound is selected from the group consisting of: [1439]
2-Methyl-propane-1-sulfonic acid
[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2296), [1440] 2-Methyl-propane-1-sulfonic acid
{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluor-
o-phenyl}-amide (P-2297), [1441] 2-Methyl-propane-1-sulfonic acid
{2,4-difluoro-3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl-
]-phenyl}-amide (P-2298), [1442] 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), [1443] Butane-1-sulfonic acid
{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluor-
o-phenyl}-amide (P-2300), [1444] Butane-1-sulfonic acid
{2,4-difluoro-3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl-
]-phenyl}-amide (P-2301), [1445] Butane-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-2302), [1446]
2-Methyl-propane-1-sulfonic acid
[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2303), [1447] 2-Methyl-propane-1-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2304), [1448] 2-Methyl-propane-1-sulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2305), [1449] 2-Methyl-propane-1-sulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2306), [1450] 2-Methyl-propane-1-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2307), [1451] Butane-2-sulfonic acid
[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2308), [1452] Pentane-2-sulfonic acid
[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2309), [1453] Butane-2-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2310), [1454] Pentane-2-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2311), [1455] Butane-2-sulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2312), [1456] Butane-2-sulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2313), [1457] Pentane-2-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2314), [1458] Pentane-2-sulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2315), [1459] Pentane-2-sulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2316), [1460] Butane-2-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2317), [1461] 2-Methyl-propane-1-sulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2318), [1462] Butane-2-sulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2319), [1463] 2-Methyl-propane-1-sulfonic acid
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2320), [1464] Butane-2-sulfonic acid
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2321), [1465] 2-Methyl-propane-1-sulfonic acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2322), [1466] Butane-2-sulfonic acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2323), [1467]
2-Methyl-propane-1-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2412), [1468] Butane-2-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2413), and a salt, prodrug, tautomer, or stereoisomer thereof.
In one embodiment, the compound is active on one or more Raf
protein kinases, including A-Raf, B-Raf, c-Raf-1 and any mutations
thereof.
[1469] In a ninety-fourth aspect, a compound is provided, where the
compound is selected from the group consisting of: [1470]
3,3,3-Trifluoro-propane-1-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2324), [1471] 3,3,3-Trifluoro-propane-1-sulfonic acid
{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluor-
o-phenyl}-amide (P-2325), [1472] 3,3,3-Trifluoro-propane-1-sulfonic
acid
{2,4-difluoro-3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl-
]-phenyl}-amide (P-2326), [1473] 3,3,3-Trifluoro-propane-1-sulfonic
acid
[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2327), [1474] 3,3,3-Trifluoro-propane-1-sulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2328), [1475] 3,3,3-Trifluoro-propane-1-sulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2329), [1476] 3,3,3-Trifluoro-propane-1-sulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2330), [1477] 3,3,3-Trifluoro-propane-1-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2331), [1478] 3,3,3-Trifluoro-propane-1-sulfonic acid
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2332), [1479] 3,3,3-Trifluoro-propane-1-sulfonic acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl-1H-pyrrolo[2,3-b]pyridine-3--
carbonyl]-phenyl}-amide (P-2333), [1480]
3,3,3-Trifluoro-propane-1-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2415), [1481] 3,3,3-Trifluoro-propane-1-sulfonic acid
[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2478), and a salt, prodrug, tautomer, or stereoisomer
thereof. In one embodiment, the compound is active on one or more
Raf protein kinases, including A-Raf, B-Raf, c-Raf-1 and any
mutations thereof.
[1482] In a ninety-fifth aspect, a compound is provided, where the
compound is selected from the group consisting of: [1483]
2,2,2-Trifluoro-ethanesulfonic acid
[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2334), [1484] 2,2,2-Trifluoro-ethanesulfonic acid
[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2335), [1485] 2,2,2-Trifluoro-ethanesulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2336), [1486] 2,2,2-Trifluoro-ethanesulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2337), [1487] 2,2,2-Trifluoro-ethanesulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2338), [1488] 2,2,2-Trifluoro-ethanesulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2339), [1489] 2,2,2-Trifluoro-ethanesulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2340), [1490] 2,2,2-Trifluoro-ethanesulfonic acid
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2341), [1491] 2,2,2-Trifluoro-ethanesulfonic acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2342), [1492]
2,2,2-Trifluoro-ethanesulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-a-
mide (P-2414), and a salt, prodrug, tautomer, or stereoisomer
thereof. In one embodiment, the compound is active on one or more
Raf protein kinases, including A-Raf, B-Raf, c-Raf-1 and any
mutations thereof.
[1493] In a ninety-sixth aspect, a compound is provided, where the
compound is selected from the group consisting of: [1494]
N-{3-[5-(4-Chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-diflu-
oro-phenyl}-C,C,C-trifluoro-methanesulfonamide (P-2343), [1495]
N-{2,4-Difluoro-3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbon-
yl]-phenyl}-C,C,C-trifluoro-methanesulfonamide (P-2344), [1496]
N-{2,4-Difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-
-3-carbonyl]-phenyl}-C,C,C-trifluoro-methanesulfonamide (P-2345),
[1497]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-C,C,C-trifluoro-methanesulfonamide (P-2346), [1498]
N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-C,C,C-trifluoro-methanesulfonamide (P-2347), [1499]
N-[3-(5-Bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
C,C,C-trifluoro-methanesulfonamide (P-2479), and a salt, prodrug,
tautomer, or stereoisomer thereof. In one embodiment, the compound
is active on one or more Raf protein kinases, including A-Raf,
B-Raf, c-Raf-1 and any mutations thereof.
[1500] In a ninety-seventh aspect, a compound is provided, where
the compound is selected from the group consisting of: [1501]
Cyclopropanesulfonic acid
[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2348), [1502]
I-[3-(5-Bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenylsu-
lfamoyl]-cyclopropanecarboxylic acid (P-2349), [1503]
Cyclopropanesulfonic acid
{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-di-
fluoro-phenyl}-amide (P-2350), [1504] Cyclopropanesulfonic acid
{2,4-difluoro-3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl-
]-phenyl}-amide (P-2351), [1505] Cyclopropanesulfonic acid
{2,4-difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2352), [1506] Cyclobutanesulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2353), [1507] Cyclobutanesulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2354), [1508] Cyclohexanesulfonic acid
[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2355), [1509] Cyclopentanesulfonic acid
[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2356), [1510] Cyclohexanesulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2357), [1511] Cyclopentanesulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2358), [1512] Cyclopentanesulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2359), [1513] Cyclohexanesulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2360), [1514] Cyclohexanesulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2361), [1515] Cyclobutanesulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2362), [1516] Cyclobutanesulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2363), [1517] Cyclobutanesulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2364), [1518] Cyclopentanesulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2365), [1519] Cyclohexanesulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2366), [1520] Cyclohexanesulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2367), [1521] Cyclopentanesulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2368), [1522] Cyclohexanesulfonic acid
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2369), [1523] Cyclobutanesulfonic acid
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2370), [1524] Cyclohexanesulfonic acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl-1H-pyrrolo[2,3-b]pyridine-3--
carbonyl]-phenyl}-amide (P-2371), [1525] Cyclopentanesulfonic acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl-1H-pyrrolo[2,3-b]pyridine-3--
carbonyl]-phenyl}-amide (P-2372), [1526] Cyclobutanesulfonic acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl-1H-pyrrolo[2,3-b]pyridine-3--
carbonyl]-phenyl}-amide (P-2373), [1527] Cyclohexanesulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2416), [1528] Cyclopentanesulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2417), [1529] Cyclobutanesulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2418), and a salt, prodrug, tautomer, or stereoisomer thereof.
In one embodiment, the compound is active on one or more Raf
protein kinases, including A-Raf, B-Raf, c-Raf-1 and any mutations
thereof.
[1530] In a ninety-eighth aspect, a compound is provided, where the
compound is selected from the group consisting of: [1531]
Pyrrolidine-1-sulfonic acid
[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2374), [1532] Pyrrolidine-1-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2375), [1533] N,N-dimethylamino-sulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2376), [1534] Pyrrolidine-1-sulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2377), [1535] N,N-diethylamino-sulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2378), [1536] Pyrrolidine-1-sulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2379), [1537] N,N-dimethylamino-sulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2382), [1538] N,N-dimethylamino-sulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2383), [1539] N,N-diethylamino-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2384), [1540] N,N-diethylamino-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2385), [1541] N,N-diethylamino-sulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2386), [1542] N,N-diethylamino-sulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2387), [1543] N,N-diethylamino-sulfonic acid
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2388), [1544] N,N-diethylamino-sulfonic acid
[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2389), [1545] Morpholine-4-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2390), [1546] Morpholine-4-sulfonic acid
[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2391), [1547] Morpholine-4-sulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2392), [1548] Morpholine-4-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2393), [1549] Pyrrolidine-1-sulfonic acid
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2394), [1550] Morpholine-4-sulfonic acid
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2395), [1551] Morpholine-4-sulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2396), [1552] Morpholine-4-sulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2397), [1553] Pyrrolidine-1-sulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2398), [1554] N,N-dimethylamino-sulfonic acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2399), [1555] Pyrrolidine-1-sulfonic
acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl-1H-pyrrolo[2,3-b]pyridine-3--
carbonyl]-phenyl}-amide (P-2400), [1556] N,N-diethylamino-sulfonic
acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2401), [1557] Morpholine-4-sulfonic
acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2402), [1558]
N,N-dimethylamino-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2419), [1559] Pyrrolidine-1-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2420), [1560] Morpholine-4-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2421), [1561] Pyrrolidine-1-sulfonic acid
{2-fluoro-3-[5-(2-methoxy-pyrimidin-5-yl-1H-pyrrolo[2,3-b]pyridine-3-carb-
onyl]-phenyl}-amide (P-2422), [1562] N,N-dimethylamino-sulfonic
acid
{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-ph-
enyl}-amide (P-2423), [1563] N,N-dimethylamino-sulfonic acid
{2-fluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-car-
bonyl]-phenyl}-amide (P-2424), [1564] Pyrrolidine-1-sulfonic acid
{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-ph-
enyl}-amide (P-2425), [1565] Pyrrolidine-1-sulfonic acid
[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2476), [1566] N,N-dimethylamino-sulfonic acid
[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2477), and a salt, prodrug, tautomer, or stereoisomer thereof.
In one embodiment, the compound is active on one or more Raf
protein kinases, including A-Raf, B-Raf, c-Raf-1 and any mutations
thereof.
[1567] In a ninety-ninth aspect, a compound is provided, where the
compound is selected from the group consisting of: [1568]
Propane-1-sulfonic acid
[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-chloro-4-fluoro-pheny-
l]-amide (P-2426), [1569] Propane-1-sulfonic acid
{2-chloro-3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-4--
fluoro-phenyl}-amide (P-2427), [1570] Propane-1-sulfonic acid
{2-chloro-4-fluoro-3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-car-
bonyl]-phenyl}-amide (P-2428), [1571] Propane-1-sulfonic acid
{2-chloro-4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyrid-
ine-3-carbonyl]-phenyl}-amide (P-2429), [1572] Propane-1-sulfonic
acid
{4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-car-
bonyl]-phenyl}-amide (P-2431), [1573] Propane-1-sulfonic acid
[4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2437), [1574] Propane-1-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2449), [1575] Propane-1-sulfonic acid
{3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-ph-
enyl}-amide (P-2454), [1576] Propane-1-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-sulfonyl)-phenyl]-amide
(P-2467), and a salt, prodrug, tautomer, or stereoisomer thereof.
In one embodiment, the compound is active on one or more Raf
protein kinases, including A-Raf, B-Raf, c-Raf-1 and any mutations
thereof.
[1577] In a one hundredth aspect, a compound is provided, where the
compound is selected from the group consisting of: [1578]
Butane-1-sulfonic acid
{2-chloro-4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyrid-
ine-3-carbonyl]-phenyl}-amide (P-2430), [1579] Butane-1-sulfonic
acid
{4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-car-
bonyl]-phenyl}-amide (P-2432), [1580] Butane-1-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-amide
(P-2435), [1581] Butane-1-sulfonic acid
[4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2438), [1582] Butane-1-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2450), Butane-1-sulfonic acid
{3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-ph-
enyl}-amide (P-2455), and a salt, prodrug, tautomer, or
stereoisomer thereof. In one embodiment, the compound is active on
one or more Raf protein kinases, including A-Raf, B-Raf, c-Raf-1
and any mutations thereof.
[1583] In a one hundred and first aspect, a compound is provided,
where the compound is selected from the group consisting of: [1584]
Cyclopropanesulfonic acid
{4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-car-
bonyl]-phenyl}-amide (P-2433), [1585] Cyclohexanesulfonic acid
{4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-car-
bonyl]-phenyl}-amide (P-2434), [1586] Cyclopropanesulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-amide
(P-2436), [1587] Cyclopropanesulfonic acid
[4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2439), [1588] Cyclohexanesulfonic acid
[4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2441), [1589] Cyclopentanesulfonic acid
[4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2442), [1590] Cyclohexanesulfonic acid
[4-fluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2443), [1591] Cyclohexanesulfonic acid
{4-fluoro-3-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-car-
bonyl]-phenyl}-amide (P-2444), [1592] Cyclopentanesulfonic acid
{4-fluoro-3-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-car-
bonyl]-phenyl}-amide (P-2445), [1593] Cyclohexanesulfonic acid
{4-fluoro-3-[5-(3-methanesulfonylamino-phenyl)-1H-pyrrolo[2,3-b]pyridine--
3-carbonyl]-phenyl}-amide (P-2446), [1594] Cyclopentanesulfonic
acid
{4-fluoro-3-[5-(3-methanesulfonylamino-phenyl)-1H-pyrrolo[2,3-b]pyridine--
3-carbonyl]-phenyl}-amide (P-2447), [1595] Cyclopentanesulfonic
acid
[4-fluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2448), [1596] Cyclopropanesulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2451), [1597] Cyclohexanesulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2452), [1598] Cyclopentanesulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2453), [1599] Cyclopropanesulfonic acid
{3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-ph-
enyl}-amide (P-2456), [1600] Cyclohexanesulfonic acid
{3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-ph-
enyl}-amide (P-2457), [1601] Cyclohexanesulfonic acid
[3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2458), [1602] Cyclopentanesulfonic acid
[3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2459), [1603] Cyclohexanesulfonic acid
[3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2460), [1604] Cyclohexanesulfonic acid
{3-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-ph-
enyl}-amide (P-2461), [1605] Cyclohexanesulfonic acid
[3-(5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2462), [1606] Cyclopentanesulfonic acid
[3-(5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2463), [1607] Cyclopentanesulfonic acid
[3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2464), [1608] 3-{3-[3-(3-Cyclohexanesulfonyl
amino-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-propionic
acid (P-2465), [1609]
3-{3-[3-(3-Cyclopentanesulfonylamino-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5--
yl]-phenyl}-propionic acid (P-2466), and a salt, prodrug, tautomer,
or stereoisomer thereof. In one embodiment, the compound is active
on one or more Raf protein kinases, including A-Raf, B-Raf, c-Raf-1
and any mutations thereof.
[1610] In a one hundred and second aspect, a compound is provided,
where the compound is selected from the group consisting of: [1611]
Piperidine-1-sulfonic acid
[4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2440), [1612] Piperidine-1-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-amide
(P-2468), [1613] N,N-dimethylamino-sulfonic acid
[4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2469), [1614] N,N-dimethylamino-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2470), [1615] Piperidine-1-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2471), and a salt, prodrug, tautomer, or stereoisomer thereof.
In one embodiment, the compound is active on one or more Raf
protein kinases, including A-Raf, B-Raf, c-Raf-1 and any mutations
thereof.
[1616] In a one hundred and third aspect, a compound is provided,
where the compound is selected from the group consisting of: [1617]
N-(6-Acetylamino-pyridin-3-yl)-3-benzenesulfonylamino-2,6-difluoro-benzam-
ide (P-2474), and [1618]
6-Acetylamino-N-(3-benzenesulfonylamino-2,6-difluoro-phenyl)-nicotinamide
(P-2475), and a salt, prodrug, tautomer, or stereoisomer thereof.
In one embodiment, the compound is active on one or more Raf
protein kinases, including A-Raf, B-Raf, c-Raf-1 and any mutations
thereof.
[1619] In a one hundred and fourth aspect, a compound is provided,
where the compound is selected from the group consisting of: [1620]
5-(2-Oxo-hexahydro-thieno[3,4-d]imidazol-6-yl)-pentanoic acid
[5-(3-{3-[2,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoyl-
]-1H-pyrrolo[2,3-b]pyridin-5-yl}-propionylamino)-pentyl]-amide
(P-2008), [1621]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-pheny-
l]-4-trifluoromethyl-benzenesulfonamide (P-2057), [1622]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-4-t-
rifluoromethyl-benzenesulfonamide (P-2058), [1623]
N-[2-Fluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-t-
rifluoromethyl-benzenesulfonamide (P-2059), and a salt, prodrug,
tautomer, or stereoisomer thereof. In one embodiment, the compound
is active on one or more Raf protein kinases, including A-Raf,
B-Raf, c-Raf-1 and any mutations thereof.
[1624] In a one hundred and fifth aspect, the compound
5-(2-Oxo-hexahydro-thieno[3,4-d]imidazol-6-yl)-pentanoic acid
[5-(3-{3-[2,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoyl-
]-1H-pyrrolo[2,3-b]pyridin-5-yl}-propionylamino)-pentyl]-amide
(P-2008) is provided. In one embodiment, P-2008 may be used as a
probe for binding to one or more of A-Raf, B-Raf, and c-Raf-1,
including any mutations of these kinases, in order to assess
whether such kinase is present in a biological sample, and in some
instances, to assess the amounts of such kinase in a biological
sample.
[1625] In reference to compounds herein, unless clearly indicated
to the contrary, specification of a compound or group of compounds
includes salts or solid forms of such compound(s) (including
pharmaceutically acceptable salts and solid forms), formulations of
such compound(s) (including pharmaceutically acceptable
formulations), conjugates thereof, derivatives thereof, prodrugs
thereof, and all stereoisomers thereof. In reference to
compositions, kits, methods of use, etc. of compounds of Formula I
described herein, it is understood (unless indicated otherwise)
that a compound of Formula I includes all sub-embodiments thereof
(e.g. including Formulae Ia-Ig, and all embodiments as described
above).
[1626] In a one hundred and sixth aspect, methods are provided for
treating a protein kinase mediated disease or condition in an
animal subject, wherein the method involves administering to the
subject an effective amount of any one or more compound(s) of the
invention as described herein. The terms "treat," "therapy," and
like terms refer to the administration of material, e.g., one or
more compound(s) of the invention 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. The term "protein kinase
mediated disease or condition" "kinase mediated disease or
condition" and the like refers to a disease or condition in which
the biological function of a protein kinase affects the
development, course, and/or symptoms of the disease or condition,
and/or in which modulation of the protein kinase alters the
development, course, and/or symptoms of the disease or condition. A
protein kinase mediated disease or condition includes a disease or
condition for which modulation provides a therapeutic benefit, e.g.
wherein treatment with protein kinase inhibitors, including
compounds of the invention as described herein, provides a
therapeutic benefit to the subject suffering from or at risk of the
disease or condition. In certain embodiments, the method involves
administering to the subject an effective amount of a compound of
the invention as described herein in combination with one or more
other therapies for the disease or condition.
[1627] In a one hundred and seventh aspect, the invention provides
methods for treating a Raf protein kinase mediated disease or
condition in an animal subject, wherein the method involves
administering to the subject an effective amount of any one or more
compound(s) of the invention as described herein. The terms "Raf
protein kinase mediated disease or condition," "Raf kinase mediated
disease or condition," "Raf mediated disease or condition," and the
like refer to a disease or condition in which the biological
function of a Raf protein kinase, including any mutations thereof,
affects the development, course, and/or symptoms of the disease or
condition, and/or in which modulation of the Raf protein kinase
alters the development, course, and/or symptoms of the disease or
condition. The Raf protein kinase includes, but is not limited to,
A-Raf, mutations of A-Raf, B-Raf, mutations of B-Raf, c-Raf-1 and
mutations of c-Raf-1. In some embodiments, the Raf protein kinase
is B-Raf mutation V600E. In some embodiments, the Raf protein
kinase is B-Raf mutation V600E/T5291. In some embodiments, the
disease or condition is a cancer that is amenable to treatment by
an inhibitor of the V600E mutant B-Raf. In some embodiments, the
disease or condition is a cancer that is amenable to treatment by
an inhibitor of the V600E/T5291 mutant B-Raf. The Raf protein
kinase mediated disease or condition includes a disease or
condition for which Raf inhibition provides a therapeutic benefit,
e.g. wherein treatment with Raf inhibitors, including compounds
described herein, provides a therapeutic benefit to the subject
suffering from or at risk of the disease or condition. In one
embodiment, the method involves administering to the subject an
effective amount of any one or more compound(s) of the invention as
described herein in combination with one or more other therapies
for the disease or condition. Similarly, the terms "A-Raf, B-Raf or
c-Raf-1 protein kinase mediated disease or condition," "A-Raf,
B-Raf or c-Raf-1 kinase mediated disease or condition," "A-Raf,
B-Raf or c-Raf-1 mediated disease or condition," and the like refer
to a disease or condition in which the biological function of an
A-Raf, B-Raf or c-Raf-1 kinase, respectively, including any
mutations thereof, affects the development, course and/or symptoms
of the disease or condition, and/or in which modulation of the
A-Raf, B-Raf or c-Raf-1 protein kinase, respectively, alters the
development, course, and/or symptoms of the disease or
condition.
[1628] In a one hundred and eighth aspect, a compound of the
invention as described herein is an inhibitor of a Raf kinase 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, the compound 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 one or more of A-Raf, B-Raf, c-Raf-1, B-Raf V600E mutant, or
B-Raf V600E/T529I mutant. In some embodiments, the compound will
selectively inhibit one Raf kinase relative to one or more other
Raf kinases. In some embodiments, the compound will selectively
inhibit a mutation of the Raf kinase relative to the wild type
kinase, for example B-Raf V600E mutant relative to wild type
B-Raf.
[1629] Further to any of the above mentioned aspects and
embodiments, a compound of the invention as described herein may
selectively inhibit one kinase relative to one or more other
kinases, where preferably inhibition is selective with respect to
any of the other kinases, whether a kinase discussed herein, or
other kinases. In some embodiments, the compound may selectively
inhibit the effects of a mutation of the kinase relative to the
wild type kinase, for example B-Raf V600E mutant relative to wild
type B-Raf. In some embodiments, the compound may selectively
inhibit Fms relative to Kit. Selective inhibition of one kinase
relative to another is such that the IC.sub.50 for the one kinase
may be at least about 2-fold, also 5-fold, also 10-fold, also
20-fold, also 50-fold, or at least about 100-fold less than the
IC.sub.50 for any of the other kinases as determined in a generally
accepted kinase activity assay.
[1630] In a one hundred and ninth aspect, compositions are provided
that include a therapeutically effective amount of any one or more
compound(s) of the invention as described herein and at least one
pharmaceutically acceptable carrier, excipient, and/or diluent. In
certain embodiments, the composition can include any one or more
compound(s) of the invention 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) of the invention 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) of the
invention 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.
[1631] In a one hundred and tenth aspect, the invention provides
methods for treating a disease or condition mediated by A-Raf,
B-Raf, c-Raf-1, B-Raf V600E mutant, or B-Raf V600E/T529I mutant 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 A-Raf, B-Raf, c-Raf-1,
B-Raf V600E mutant, or B-Raf V600E/T529I 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 other suitable therapies for treating the disease. In one
embodiment, the invention provides methods for treating a cancer
mediated by B-Raf V600E mutant or B-Raf V600E/T529I mutant 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 combination with one or more suitable anticancer
therapies, such as one or more chemotherapeutic drugs.
[1632] In a one hundred and eleventh aspect, the invention provides
a method of treating a cancer 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 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 .alpha. 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.
[1633] In a one hundred and twelfth aspect, the invention provides
a method of treating a cancer 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 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, and 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) of the invention 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.
[1634] In a one hundred and thirteenth aspect, the invention
provides a method of treating or prophylaxis of a disease or
condition in a mammal, by administering to the mammal a
therapeutically effective amount of any one or more compound(s) of
the invention as described herein, a prodrug of such compound, or a
pharmaceutically acceptable salt of such compound or prodrug. The
compound can be alone or can be part of a composition. In another
aspect, the invention provides a method of treating or prophylaxis
of a disease or condition in a mammal, by administering to the
mammal a therapeutically effective amount of one or more compounds
as described herein, a prodrug of such compound, or a
pharmaceutically acceptable salt of such compound or prodrug in
combination with one or more other suitable therapies for the
disease or condition.
[1635] In a one hundred and fourteenth aspect, the invention
provides kits that include any one or more compound(s) or the
invention or composition thereof as described herein. In some
embodiments, the composition is packaged, e.g., in a vial, bottle,
flask, which may be further packaged, e.g., within a box, envelope,
or bag; the 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 composition is approved for
administration to a mammal, e.g., a human, for a protein kinase
mediated disease or condition; the invention kit includes written
instructions for use and/or other indication that the composition
is suitable or approved for administration to a mammal, e.g., a
human, for a protein kinase-mediated disease or condition; and the
composition is packaged in unit dose or single dose form, e.g.,
single dose pills, capsules, or the like.
[1636] In aspects and embodiments involving treatment or
prophylaxis of a disease or condition with the compounds 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 an animal subject (e.g. a 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), 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 compounds 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, sarcoma,
carcinoma (e.g. gastrointestinal, liver, bile duct
(cholangiocarcinoma), colorectal, lung, breast, pancreatic,
thyroid, renal, ovarian, prostate), lymphoma (e.g. histiocytic
lymphoma) neurofibromatosis, 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, sarcoma, gastrointestinal cancer,
liver cancer, cholangiocarcinoma, colorectal cancer, lung cancer,
breast cancer, pancreatic cancer, thyroid cancer, renal cancer,
ovarian cancer, prostate cancer, histiocytic lymphoma,
neurofibromatosis, acute myeloid leukemia, myelodysplastic
syndrome, leukemia, tumor angiogenesis, medullary thyroid cancer,
carcinoid, small cell lung cancer, Kaposi's sarcoma,
pheochromocytoma, pain, and polycystic kidney disease. In a
preferred embodiment, the disease or condition is selected from the
group consisting of melanoma, colorectal cancer, thyroid cancer,
ovarian cancer, cholangiocarcinoma, pain, and polycystic kidney
disease.
[1637] In a one hundred and fifteenth 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, sarcoma, carcinoma (e.g. gastrointestinal, liver,
bile duct (cholangiocarcinoma), colorectal, lung, breast,
pancreatic, thyroid, renal, ovarian, prostate), lymphoma (e.g.
histiocytic lymphoma) neurofibromatosis, 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, sarcoma, gastrointestinal cancer,
liver cancer, cholangiocarcinoma, colorectal cancer, lung cancer,
breast cancer, pancreatic cancer, thyroid cancer, renal cancer,
ovarian cancer, prostate cancer, histiocytic lymphoma,
neurofibromatosis, acute myeloid leukemia, myelodysplastic
syndrome, leukemia, tumor angiogenesis, medullary thyroid cancer,
carcinoid, small cell lung cancer, Kaposi's sarcoma,
pheochromocytoma, pain, and polycystic kidney disease. In a
preferred embodiment, the disease or condition is selected from the
group consisting of melanoma, colorectal cancer, thyroid cancer,
ovarian cancer, cholangiocarcinoma, pain, and polycystic kidney
disease.
[1638] Additional aspects and embodiments will be apparent from the
following Detailed Description and from the claims.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[1639] As used herein the following definitions apply unless
clearly indicated otherwise:
[1640] 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.14C; oxygen includes for example .sup.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.
[1641] "Halogen" refer to all halogens, that is, chloro (Cl),
fluoro (F), bromo (Br), or iodo (I).
[1642] "Hydroxyl" or "hydroxy" refer to the group --OH.
[1643] "Thiol" refers to the group --SH.
[1644] "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 "substituted lower alkyl" denotes lower alkyl that
is independently substituted, unless indicated otherwise, with one
or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents.
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 substitutions are chemically feasible and
attached at any available atom to provide a stable compound.
[1645] "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 I-3, more
preferably I-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 "substituted lower alkenyl" denotes lower alkenyl that
is independently substituted, unless indicated otherwise, with one
or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents.
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
substitutions are chemically feasible and attached at any available
atom to provide a stable compound.
[1646] "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 "substituted
lower alkynyl" denotes lower alkynyl that is independently
substituted, unless indicated otherwise, with one or more,
preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents. 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 substitutions
are chemically feasible and attached at any available atom to
provide a stable compound
[1647] "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, adamantyl, and the like. A
"substituted cycloalkyl" is a cycloalkyl that is independently
substituted, unless indicated otherwise, with one or more,
preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents. It is
understood that substitutions are chemically feasible and attached
at any available atom to provide a stable compound.
[1648] "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 "substituted heterocycloalkyl" is a
heterocycloalkyl that is independently substituted, unless
indicated otherwise, with one or more, preferably 1, 2, 3, 4 or 5,
also 1, 2, or 3 substituents. It is understood that substitutions
are chemically feasible and attached at any available atom to
provide a stable compound.
[1649] "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. A
"substituted aryl" is an aryl that is independently substituted,
unless indicated otherwise, with one or more, preferably 1, 2, 3, 4
or 5, also 1, 2, or 3 substituents. It is understood that
substitutions are chemically feasible and attached at any available
atom to provide a stable compound.
[1650] "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, quinaoxalyl, 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 "substituted
heteroaryl" is a heteroaryl that is independently substituted,
unless indicated otherwise, with one or more, preferably 1, 2, 3, 4
or 5, also 1, 2, or 3 substituents. It is understood that
substitutions are chemically feasible and attached at any available
atom to provide a stable compound.
[1651] "Lower alkoxy" denotes the group --OR.sup.a, where R.sup.a
is lower alkyl. "Substituted lower alkoxy" denotes lower alkoxy in
which R.sup.a is lower alkyl substituted with one or more
substituents as indicated herein, for example, in the description
of compounds of Formula I, including descriptions of substituted
cycloalkyl, heterocycloalkyl, aryl and heteroaryl, attached at any
available atom to provide a stable compound. 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 are chemically feasible and attached at any available atom
to provide a stable compound.
[1652] "Lower alkylthio" denotes the group --SR.sup.b, where
R.sup.b is lower alkyl. "Substituted lower alkylthio" denotes lower
alkylthio in which R.sup.b is lower alkyl substituted with one or
more substituents as indicated herein, for example, in the
description of compounds of Formula I, including descriptions of
substituted cycloalkyl, heterocycloalkyl, aryl and heteroaryl,
attached at any available atom to provide a stable compound.
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 are chemically feasible and attached at
any available atom to provide a stable compound.
[1653] "Amino" or "amine" denotes the group --NH.sub.2.
"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.
[1654] 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.
[1655] 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.
[1656] 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.
[1657] 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. Alternatively, the
complex of the compound and arginine or lysine may be prepared with
an amount of compound component in excess of the stoichiometry of
the complex, thereby resulting in an amount of the complex that is
based on the stoichiometry of the complex, 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
arginine and compound has a 1:1 stoichiometry, preparing said
complex with a 2:1 mole ratio of compound to arginine 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
bioavailablity. Such a mixture may provide both rapid and extended
exposure to the active compound.
[1658] 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. In some instances, the pharmaceutically
active compound and two additional molecular species may form a
ternary complex, where the ternary complex could be amorphous,
partially amorphous, or crystalline, such as a co-crystal. For
example, 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).
[1659] As used herein, the term "stoichiometry" refers to the molar
ratio of two or more reactants that combine to form a complex, for
example, the molar ratio of arginine to compound that form an
amorphous complex. For example, a 1:1 mixture of arginine with
compound (i.e. 1 mole arginine per mole of compound) resulting in
an amorphous solid form has a 1:1 stoichiometry.
[1660] As used herein, the term "composition" refers to a
pharmaceutical preparation suitable for administration to an
intended animal 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.
[1661] As used herein, the term "biopharmaceutical properties"
refers to the pharmacokinetic action of a pharmaceutical (e.g. a
compound or complex of the present invention), including the
dissolution, absorption and distribution of the compound on
administration to an animal. As such, the amorphous complexes of
compounds of the invention 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).
[1662] 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.
[1663] 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.
[1664] 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.
[1665] As used herein, the term "modulating" or "modulate" refers
to an effect of altering a biological activity, especially a
biological activity associated with a particular biomolecule such
as a protein kinase. For example, an agonist or antagonist of a
particular biomolecule modulates the activity of that biomolecule,
e.g., an enzyme, by either increasing (e.g. agonist, activator), or
decreasing (e.g. antagonist, inhibitor) the activity of the
biomolecule, such as an enzyme. Such activity is typically
indicated in terms of an inhibitory concentration (IC.sub.50) or
excitation concentration (EC.sub.50) of the compound for an
inhibitor or activator, respectively, with respect to, for example,
an enzyme.
[1666] "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, gall bladder, 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.
[1667] The present invention concerns compounds and compositions as
disclosed herein that are modulators of protein kinases, for
example without limitation, the compounds are modulators,
preferably inhibitors, of at least one of the kinases selected from
the group consisting of Ab1, Akt1, Akt2, Akt3, ALK, Alk5, B-Raf,
Brk, Btk, Cdk2, CDK4, CDK5, CDK6, CHK1, c-Raf-1, Csk, EGFR, EphA1,
EphA2, EphB2, EphB4, Erk2, Fak, FGFR1, FGFR2, FGFR3, FGFR4, Flt1,
Flt3, Flt4, Fms, Frk, Fyn, Gsk3.alpha., Gsk3.beta., HCK,
Her2/Erbb2, Her4/Erbb4, IGF1R, IKK beta, Irak4, Itk, Jak1, Jak2,
Jak3, Jnk1, Jnk2, Jnk3, Kdr, Kit, Lck, Lyn, MAP2K1, MAP2K2, MAP4K4,
MAPKAPK2, Met, Mnk1, MLK1, mTOR, p38, PDGFRA, PDGFRB, PDPK1,
PI3K.alpha., PI3K.beta., PI3K.delta., PI3K.gamma., Pim1, Pim2,
Pim3, PKC alpha, PKC beta, PKC theta, Plk1, Pyk2, Ret, ROCK1,
ROCK2, Ron, Src, Stk6, Syk, TEC, Tie2, TrkA, TrkB, Yes, and Zap70,
and the use of such compounds in the treatment of diseases or
conditions.
[1668] The compounds of the invention with kinase inhibitory
activity IC.sub.50 less than 10 .mu.M as determined in a standard
assay known in the art can be used to treat protein kinase mediated
diseases and conditions related to the following protein kinases,
including any mutations thereof, for example without limitation:
[1669] Ab1, related to chronic myeloid leukemia (CML), acute
lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML);
[1670] Akt1, related to gastric, prostate, colorectal, ovarian,
pancreatic and breast cancer, glioblastoma and leukemia, as well as
schizophrenia and bipolar disorders, and also use in combination
with other chemotherapeutic drugs; [1671] Akt2, related to
hyperglycemia due to peripheral insulin resistance and
nonsuppressible hepatic glucose production accompanied by
inadequate compensatory hyperinsulinemia, also related to
pancreatic, ovarian and breast cancer; [1672] Akt3, related to
melanoma, prostate and breast cancer; [1673] ALK, related to
non-Hodgkin lymphomas such as diffuse large B-cell lymphoma and
anaplastic large cell lymphoma; [1674] Alk5, related to pancreatic
and biliary cancers, and cutaneous T-cell lymphoma; [1675] A-Raf,
related to 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); [1676] B-Raf or
c-Raf-1, related to neurologic diseases, including, but not limited
to, 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,
acute myeloid leukemia, myelodysplastic syndrome, leukemia, tumor
angiogenesis, neuroendocrine tumors such as medullary thyroid
cancer, carcinoid, small cell lung cancer 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,
reperfusion injury; inflammation including, but not limited to,
psoriasis, 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;
renal or prostatic diseases, including, but not limited to,
diabetic nephropathy, polycystic kidney disease, nephrosclerosis,
glomerulonephritis, prostate hyperplasia; metabolic disorders,
including, but not limited to, obesity; infection, including, but
not limited to, Helicobacter pylori, Hepatitis and Influenza
viruses, fever, 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; [1677] Brk, related
to breast and colon cancer, and head and neck squamous cell
carcinoma; [1678] Btk, related to X-linked agammaglobulinemia,
acute lymphocytic leukemia, autoimmune diseases such as multiple
sclerosis, systemic lupus erythematosis, rheumatoid arthritis, and
Graves' disease, immune suppression in organ transplant, and drug
sensitivity of B-lineage cells; [1679] Cdk2, related to prostate,
breast, colorectal and ovarian cancer; [1680] Cdk4, related to
glioblastoma (e.g. glioblastoma multiforme), anaplastic
astrocytoma, and breast cancer; [1681] Cdk5, related to Alzheimer's
disease, amyotrophic lateral sclerosis and Lewy body disease;
[1682] Cdk6, related to glioblastoma multiforme, non-Hodgkin's
lymphoma, splenic marginal zone lymphoma, T-cell lymphoblastic
lymphoma (T-LBL) and T-cell acute lymphoblastic leukemia (T-ALL);
[1683] CHK1, related to DNA damage repair, sensitizes cells to
chemotherapeutic agents; [1684] Csk, related to colon and
pancreatic carcinomas and autoimmune pathology such as type 1
diabetes, rheumatoid arthritis and systemic lupus erythematosus;
[1685] EGFR, related to breast, colorectal, bladder, prostate and
non small cell lung cancer, squamous cell carcinomas of the head
and neck cancer, oral cavity, and esophagus, and glioblastoma
multiforme; [1686] EphA1, related to head and neck squamous cell
carcinoma, hepatoma and lung cancer; [1687] EphA2, related to
aberrant short-range contact-mediated axonal guidance, bladder,
breast, prostate, colon, skin, cervical, ovarian, pancreatic and
lung cancers, and metastatic melanoma; [1688] EphB2, related to
angiogenesis disorder (e.g. ocular angiogenesis disease such as
retinopathy), and cancer (e.g. glioblastoma, breast and liver
cancer); [1689] EphB4, related to colorectal cancer (CRC), head and
neck squamous cell carcinoma, and tumours of the prostate, breast,
endometrium, and bladder; [1690] Erk2, related to aberrant
proliferation, differentiation, transcription regulation and
development, and may be useful in treating inflammation, for
example inflammation associated with Lyme neuroborreliosis, and in
treating cancers, such as gastric cancer; [1691] Fak, related to
colon and breast tumors, and is also related to esophageal squamous
cell carcinoma, melanoma, anaplastic astrocytoma, glioblastoma,
ductal carcinoma in situ, prostate and hepatocellular carcinoma,
and tumor metastases, and may also provide synergistic effects when
used with other chemotherapeutic drugs; [1692] FGFR1, related to 8
.mu.l myeloproliferative syndrome; [1693] FGFR2, related to Crouzon
Syndrome, Jackson-Weiss Syndrome, Apert Syndrome, craniosynostosis,
Pfeiffer Syndrome, acrocephalo syndactyl)-type V, and
Beare-Stevenson Cutis Gyrata Syndrome; [1694] FGFR3, related to
angiogenesis, wound healing, achondroplasia, Muenke
craniosynostosis, Crouzon syndrome, acanthosis nigricans,
thanatophoric dysplasia, bladder carcinomas, and multiple myeloma;
[1695] FGFR4, related to cancer of the breast, lung, colon,
medullary thyroid, pancreas, ovary, prostate, endometrium, and
fallopian tube, head and neck squamous cell carcinomas and
leiomyosarcoma; [1696] Flt1, related to non-small cell lung
carcinoma, prostate carcinoma, and colorectal cancer; [1697] Flt3,
related to acute myeloid leukemia, myelodysplastic syndrome, acute
lymphoblastic leukemia; [1698] Flt4, related to primary
lymphoedema; [1699] Fms, related to immune disorders, including
rheumatoid arthritis, systemic lupus erythematosis (SLE), and
transplant rejection, inflammatory diseases including inflammatory
bowel syndrome, ulcerative colitis, Crohn's disease, chronic
obstructive pulmonary disease (COPD), emphysema, and
atherosclerosis, metabolic disorders, including Type I diabetes,
Type II diabetes, insulin resistance, hyperglycemia, and lipolysis,
disorders of bone structure, mineralization and bone formation and
resorption, including osteoporosis, increased risk of fracture,
Paget's disease, hypercalcemia, and metastasis of cancer to bone,
kidney diseases, including nephritis (e.g. glomerulonephritis,
interstitial nephritis, Lupus nephritis), tubular necrosis,
diabetes-associated renal complications (e.g. diabetic
nephropathy), and hypertrophy, disorders of the central nervous
system, including multiple sclerosis, stroke, Alzheimer's disease
and Parkinson's disease; inflammatory and chronic pain, including
bone pain; and cancers, including multiple myeloma, acute myeloid
leukemia, chronic myeloid leukemia (CML), prostate cancer, breast
cancer, ovarian cancer, and metastasis of tumors to other tissues;
[1700] Frk, related to acute myeloid leukemia and type 1 diabetes;
[1701] Fyn, related to Alzheimer's disease, schizophrenia and
prevention of metastases, e.g. in melanoma and squamous cell
carcinoma; [1702] GSK3 (Gsk3.alpha. and/or Gsk3.beta.), related to
CNS disorders such as Alzheimer's disease, Parkinson's disease,
amyotrophic lateral sclerosis, diabetes type II, bipolar disorders,
stroke, cancer, chronic inflammatory disease, leucopenia,
schizophrenia, chronic pain, neuropathic pain, and traumatic head
injury; [1703] HCK, related to chronic myelogenous leukemia and
acute lymphocytic leukemia; [1704] Her2/Erbb2, related to prostate
and breast cancer; [1705] Her4/Erbb4, related to childhood
medulloblastoma; [1706] IGF1R, related to prostate cancer,
hepatocellular carcinoma; [1707] IKK beta, related to leukemia of
T-cells, necrosis, insulin resistance, and malignant neoplasms;
[1708] Irak4, related to bacterial infections, immunodeficiency
syndrome, Crohn's disease, ulcerative colitis, asthma, chronic
bronchitis, cardio hypertrophy, and kidney hypertension; [1709]
Itk, related to allergic asthma; [1710] Jak1, related to Hepatitis
C virus infection; [1711] Jak2, related to myeloproliferative
disorders such as polycythaemia vera, myelofibrosis, essential
thrombocythemia, myeloid metaplasia and leukemias, including acute
lymphoblastic leukemia, chronic neutrophilic leukemia, juvenile
myelomonocytic leukemia, CMML, Philadelphia chromosome-negative
CML, megakaryocytic leukemia, and acute erythroid leukemia; [1712]
Jak3, related to X-linked severe combined immunodeficiency,
myeloproliferative disorders, transplant rejection and autoimmune
diseases such as rheumatoid arthritis, inflammatory bowel syndrome,
Crohn's disease, systemic lupus erythematosis, ulcerative colitis,
psoriasis and multiple sclerosis; [1713] Jnk (Jnk1, Jnk2, Jnk3),
related to metabolic diseases including type 1 diabetes, type 2
diabetes, metabolic syndrome, obesity, and hepatic steatosis;
cardiovascular diseases such as atherosclerosis, ischemia (e.g.
cerebrovascular ischemia, liver ischemia), reperfusion injury,
cardiac hypertrophy; renal diseases such as chronic renal failure;
neoplastic diseases and associated complications, including
chemotherapy-induced hypoxia, prostate tumors, myeloid leukemia and
cancers of the liver, bone, skin, brain, pancreas, lung breast,
colon, prostate and ovary; transplant rejection; pain of
neuropathic or inflammatory origin including acute and chronic
pain; inflammatory and autoimmune diseases including age-related
macular degeneration, rheumatoid arthritis, inflammatory bowel
disease, ulcerative colitis, Crohn's disease, systemic lupus
erythematosis, Sjogren's Syndrome, psoriasis, scleroderma, chronic
thyroiditis, Grave's disease, myasthenia gravis, and multiple
sclerosis, and inflammation in other organs including CNS
inflammation, pancreatitis, nephritis, atopic dermatitis, and
hepatitis; airway inflammatory diseases such as asthma, allergy,
bronchitis, pulmonary fibrosis, chronic obstructive pulmonary
disease; neurologic diseases such as stroke, cerebrovascular
ischemia, neurodegenerative diseases such as Parkinson's disease,
Alzheimer's disease, amyotrophic lateral sclerosis, dementia,
senile chorea, head and spinal cord trauma, and Huntington's
disease. More particularly, Jnk1 is related to type 1 diabetes,
type 2 diabetes, metabolic syndrome, obesity and hepatic steatosis,
Jnk2 is related to atherosclerosis, and Jnk3 is related to
inflammatory diseases including autoimmune diseases such as
rheumatoid arthritis, inflammatory bowel syndrome, Crohn's disease,
systemic lupus erythematosis, Sjogren's Syndrome, psoriasis and
multiple sclerosis, airway inflammatory diseases such as asthma,
allergy, pulmonary fibrosis, and chronic obstructive pulmonary
disease, and inflammation in other organs, such as CNS
inflammation, pancreatitis, nephritis, and hepatitis; neurologic
diseases such as stroke, cerebrovascular ischemia, and
neurodegenerative diseases such as Parkinson's disease, Alzheimer's
disease, and Huntington's disease; and neoplastic diseases such as
prostate tumors and myeloid leukemia; [1714] Kdr, related to
anti-angiogenesis for treating solid tumor growth (e.g. ovarian,
lung, breast, prancreatic, prostate, colon, gastrointestinal
stromal tumor, non small cell lung cancer, and epidermoid cancer),
metastasis, psoriasis, rheumatoid arthritis, diabetic retinopathy
and age related macular degeneration; [1715] Kit, related to
malignancies, including mast cell tumors, small cell lung cancer,
testicular cancer, gastrointestinal stromal tumors (GISTS),
glioblastoma, astrocytoma, neuroblastoma, carcinomas of the female
genital tract, sarcomas of neuroectodermal origin, colorectal
carcinoma, carcinoma in situ, Schwann cell neoplasia associated
with neurofibromatosis, acute myelocytic leukemia, acute
lymphocytic leukemia, chronic myelogenous leukemia, mastocytosis,
melanoma, and canine mast cell tumors, and inflammatory diseases,
including asthma, rheumatoid arthritis, allergic rhinitis, multiple
sclerosis, inflammatory bowel syndrome, transplant rejection, and
hypereosinophilia;
[1716] Lck, related to acute lymphoblastic leukemia, T-cell
lymphoma, lymphopenia, renal carcinoma, colon carcinoma, severe
combined immunodeficiency, multiple sclerosis, inflammatory bowel
and type I diabetes; [1717] Lyn, related to [1718] MAP2K1, related
to acute myeloid leukemia, breast, ovarian and liver cancer; [1719]
MAP2K2, related to cancer and inflammation; [1720] MAP4K4, related
to metabolic indications, including re-sensitizing fat and muscle
cells to insulin, ameliorating the pathology in adipocytes,
ameliorating the pathology in muscle cells, metabolic syndrome, and
type II diabetes; a broad range of oncology indications, including
blocking the migration, invasion and metastasis in many different
tumor types; and T-cell mediated autoimmune diseases; [1721]
MAPKAPK2, cancer (e.g. prostate, breast), stroke, menengitis, and
inflammatory disorders; [1722] Met, related to kidney, breast,
bladder, non-small-cell lung, colorectal, and bladder cancers, and
hepatocellular carcinoma; [1723] Mnk1, related to conditions
associated with heat shock, nutrient deprivation, oxidative or
osmotic stress, and infection of mammalian cells (e.g. with viruses
such as adenovirus (Ad) or influenza virus), and autoimmune
diseases; [1724] MLK1, related to neurodegenerative diseases such
as Alzheimer's disease and Parkinson's disease, and inflammatory
disorders; [1725] mTOR, related to neuronal tumors, breast cancer,
prostate cancer, acute myelogenous leukemia, lung cancer,
pancreatic cancer, colon cancer, renal cancer and myeloma; [1726]
p38, related to acute coronary syndrome, stroke, atherosclerosis,
and inflammatory autoimmune diseases such as rheumatoid arthritis,
inflammatory bowel disease, and Crohn's disease; [1727]
PDGFR(PDGFRA, PDGFRB), related to idiopathic hypereosinophilic
syndrome, chronic eosinophilic leukemia, glioma, gastrointestinal
stromal tumors (GISTS), juvenile myelomonocytic leukemia,
metastatic medulloblastoma, atherogenesis, and restenosis. More
particularly, PDGFRA related to idiopathic hypereosinophilic
syndrome, chronic eosinophilic leukemia, glioma, gastrointestinal
stromal tumors (GISTS), juvenile myelomonocytic leukemia,
metastatic medulloblastoma, atherogenesis, and restenosis, and
PDGFRB related to idiopathic hypereosinophilic syndrome, chronic
eosinophilic leukemia, juvenile myelomonocytic leukemia, and
metastatic medulloblastoma; [1728] PDPK1, related to cancer and
diabetes; [1729] PI3K (including PI3K.alpha., PI3K.beta.,
PI3K.delta. and PI3K.gamma.), related to inflammatory disease,
including asthma, chronic obstructive pulmonary disease,
bronchitis, emphysema, eosinophilia, lung fibrosis, osteoarthritis,
ankylosing spondylitis, sepsis, septic shock, inflammatory
myopathies, meningitis, encephalitis, lacrimal parotid gland
syndrome, acute respiratory distress syndrome and pancreatitis,
graft vs. host disease; allergies, including allergic rhinitis,
type I hypersensitivity reactions, atopic dermatitis, contact
dermatitis, and eczema; cardiovascular disease, including
atherosclerosis, pulmonary hypertension, deep venous thrombosis,
stroke, myocardial infarction, myocardial contractility disorders,
ischemia, thromoemolism, pulmonary embolism, acute arterial
ischemia, peripheral thrombotic occlusions, coronary artery disease
and acute coronary syndrome; autoimmune disease, including systemic
lupus erythematosus, rheumatoid arthritis, multiple sclerosis,
glomerulonephritis, scleroderma, chronic thyroiditis, Graves'
disease, autoimmune gastritis, type I diabetes, autoimmune
hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic
dermatitis, myasthenia gravis, inflammatory bowel disease,
ulcerative colitis, Crohn's disease, psoriasis, and Sjogren's
syndrome; cancers, including ovarian cancer, cervical cancer,
breast cancer, colorectal cancer, endometrial cancer, gastric
carcinomas, hepatocellular carcinoma, pancreatic cancer, small and
non-small cell lung cancer, thyroid carcinoma, lymphomas, multiple
myelomas, leukemias (e.g. acute myelogenous leukemia, chronic
myelogenous leukemia), neuroblastomas and glioblastomas; [1730]
Pim1, related to cancers such as hematopoietic (e.g. acute myeloid
and acute lymphoid leukemias) and prostate cancers, and
non-Hodgkin's lymphomas; [1731] Pim2, related to lymphomas; [1732]
Pim3, related to hepatocellular carcinoma; [1733] PKC alpha,
related to pituitary tumors and prefrontal cortical dysfunction
such as distractibility, impaired judgment, impulsivity, and
thought disorder, also may be used to sensitize chemotherapy in
breast, colon, and non small cell lung cancers; [1734] PKC beta,
related to diabetic retinopathy; [1735] PKC-theta, related to
insulin resistance, T-cell lymphoma; [1736] Plk1, related to
cancers (e.g. lymphoma of the thyroid, non-Hodgkin's lymphomas,
colorectal cancers, leukemias and melanoma), also useful as
sensitizer in chemotherapy; [1737] Pyk2, related to inflammation
(e.g. osteoporosis, polycystic kidney disease, rheumatoid arthritis
and inflammatory bowel disease), CNS disease (e.g. Parkinson's
disease and Alzheimer's disease), stroke and cancers (e.g. gliomas,
breast cancer, and pancreatic cancer); [1738] Ret, related to
cancer of the thyroid, neuroblastoma, familial medullary thyroid
carcinoma (FMTC), multiple endocrine neoplasia type IIA and IIB
(MEN2A, MEN2B), and neurodegenerative disorders (e.g.
Hirschsprung's disease, Parkinson's disease, Alzheimer's disease,
and amyotrophic lateral sclerosis); [1739] ROCK (ROCK-1, ROCK-2),
related to cancers (e.g. ovarian cancer, hepatocellular carcinoma,
pancreatic cancer), ocular disease (e.g. glaucoma), cardiac
hypertrophy, improved renal perfusion, transplant rejection, and
acute respiratory distress syndrome; [1740] Ron, related to cancer
and inflammation; [1741] Src, related to cancer and osteoporosis;
[1742] Stk6, related to gastric, bladder, breast, lung, CNS,
ovarian, kidney, colon, prostate, pancreas, and cervical cancers,
melanoma, leukemia, and neuroblastoma; [1743] Syk, related to
lymphomas (e.g. mantle cell lymphoma); [1744] TEC, related to
sepsis, septic shock, inflammation, rheumatoid arthritis, Crohn's
disease, irritable bowel disease (IBD), and ulcerative colitis;
[1745] Tie2 (TEK), related to cancer, arthritis (e.g. rheumatoid
arthritis), and atherosclerosis; [1746] TrkA, related to pain (e.g.
chronic pain, neuropathic pain), cancer (e.g. prostate cancer, lung
cancer, pancreatic cancer), allergic disorders (e.g. asthma),
arthritis, diabetic retinopathy, macular degeneration and
psoriasis; [1747] TrkB, related to obesity, hyperphagia,
developmental delays, cancer (e.g. prostate cancer, lung cancer,
Wilms tumors, neuroblastoma, pancreatic cancer), various
neuropathies (e.g. stroke, multiple sclerosis, transverse myelitis,
and encephalitis), and diabetes. [1748] Yes, related to various
cancers including esophageal squamous cell carcinoma; and [1749]
Zap70, related to AIDS, systemic lupus erythematosus, myasthenia
gravis, atherosclerosis, rejection of transplanted organs or
tissues, allograft rejection including acute and chronic allograft
rejection, graft versus host disease, rheumathoid arthritis,
psoriasis, systemic sclerosis, atopic dermatitis, eczematous
dermatitis, alopecia, and inflammation of the nasal mucus membrane,
including all forms of rhinitis.
Kinase Targets and Indications of the Invention
[1750] 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. Specific target protein kinases
contemplated by the present invention are described in the art,
including, without limitation, protein kinases as described in U.S.
patent application Ser. No. 11/473,347 (see also, PCT publication
WO2007002433), the disclosure of which is hereby incorporated by
reference in regards to such target protein kinases. Additional
description of Raf target protein kinases contemplated by the
present invention follow:
[1751] A-Raf: Target kinase A-Raf (i.e., v-raf murine sarcoma 3611
viral oncogene homolog I) 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).
[1752] B-Raf: Target kinase B-Raf (i.e., v-raf murine sarcoma viral
oncogene homolog BI) is a 84.4 kDa serine/threonine kinase encoded
by chromosome 7q34 (symbol: BRAF). The mature protein comprises RBD
(i.e., Ras binding domain), Cl (i.e., protein kinase C conserved
region 1) and STK (i.e., serine/threonine kinase) domains.
[1753] 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.
[1754] 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.
[1755] 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).
[1756] c-Raf-1: 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).
[1757] Raf inhibitors (A-Raf and/or B-Raf and/or C-Raf-1, and/or
mutations thereof) 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; 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, acute myeloid leukemia, myelodysplastic
syndrome, leukemia, tumor angiogenesis, neuroendocrine tumors such
as medullary thyroid cancer, carcinoid, small cell lung cancer 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
including, but not limited to, psoriasis, 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; renal or prostatic diseases, including, but
not limited to, diabetic nephropathy, polycystic kidney disease,
nephrosclerosis, glomerulonephritis, prostate hyperplasia;
metabolic disorders, including, but not limited to, obesity;
infection, including, but not limited to, Helicobacter pylori,
Hepatitis and Influenza viruses, fever, 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.
Kinase Activity Assays
[1758] 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.
[1759] 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
[1760] 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
[1761] Compounds contemplated herein are described with reference
to both generic formulae and specific compounds. In addition,
invention compounds 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.
[1762] (a) Prodrugs and Metabolites
[1763] 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.
[1764] 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 of the present invention, 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.
[1765] 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:
[1766] Oxidative reactions: 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.
[1767] Reductive reactions: Reductive reactions are exemplified
without limitation by reactions such as reduction of carbonyl
functionalitites, reduction of alcohol functionalities and
carbon-carbon double bonds, reduction of nitrogen-containing
functional groups, and other reduction reactions.
[1768] Reactions without change in the oxidation state: Reactions
without change in the state of oxidation are exemplified without
limitation to 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.
[1769] 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 maybe 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.
[1770] 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.
[1771] 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.
[1772] (b) Tautomers, Stereoisomers, and Regioisomers
[1773] 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.
[1774] Likewise, some of the compounds according to the present
invention 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 steroisomeric forms are included within the formulae provided
herein.
[1775] In some embodiments, a chiral compound of the present
invention 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.
[1776] (c) Pharmaceutically Acceptable Salts
[1777] Unless specified to the contrary, specification of a
compound herein includes pharmaceutically acceptable salts of such
compound. Thus, compounds of the invention 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 of the invention 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.
[1778] 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.
[1779] 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.
[1780] 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.
[1781] (d) Other Compound Forms
[1782] 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.
[1783] In some instances, compounds of the invention are complexed
with a basic amino acid, such as L-histidine, L-lysine, or
L-arginine, preferably L-lysine or L-arginine. In some instances,
the complex of the compound and basic amino acid further comprises
a strong acid, such as hydrochloric acid. In such instances, the
resulting ternary complex can be amorphous, partially amorphous, or
crystalline (e.g. a co-crystal). In combining the compound of the
invention with the basic amino acid, 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 basic
amino acid. Such amorphous complexes provide several advantages.
For example, lowering of the melting temperature relative to the
free base facilitiates 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.
[1784] Additionally, the formulae are intended to cover hydrated or
solvated as well as unhydrated or unsolvated forms of the
identified structures. For example, the indicated compounds include
both hydrated and non-hydrated forms. Other examples of solvates
include the structures in combination with a suitable solvent, such
as isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic
acid, or ethanolamine.
Formulations and Administration
[1785] The methods and compounds will typically be used in therapy
for human subjects. However, they may also be used to treat similar
or identical indications in other animal subjects. Compounds of the
invention 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).
[1786] 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, hypromellose, and the like.
[1787] 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 of the invention 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 the 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
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.
[1788] 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
compounds may be dissolved or suspended in suitable liquids, such
as fatty oils, liquid paraffin, or liquid polyethylene glycols.
[1789] In some embodiments, injection (parenteral administration)
may be used, e.g., intramuscular, intravenous, intraperitoneal,
and/or subcutaneous. Compounds of Formula I 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.
[1790] In some embodiments, transmucosal, topical or transdermal
administration may be used. In such formulations of compounds of
Formula I, 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 of Formula I 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.
[1791] In some embodiments, compounds are administered as
inhalants. Compounds of Formula I 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 of Formula I 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 ipratroprium 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
cromoglycate.
[1792] The amounts of various compounds 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.
[1793] The compounds of Formula I 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 of the
invention 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.
[1794] 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. I-2 days, 2-4 days, 4-7 days,
I-4 weeks)) than a compound of Formula I, or at the same time as a
compound of Formula I. 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 of Formula I
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 of Formula I 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 of Formula I 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 of Formula I.
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 of Formula I 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
[1795] Examples related to the present invention are described
below. In most cases, alternative techniques can be used. The
examples are intended to be illustrative and are not limiting or
restrictive to the scope of the invention. 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.
Synthesis of known starting materials in the following examples, or
known compounds for formation of solid forms can be 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), U.S. 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.
Example 1
Synthesis of
(3-amino-2,6-difluoro-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone
compounds
[1796]
(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.
##STR00010##
Step 1--Preparation of (2,4-difluoro-phenyl)-carbamic acid benzyl
ester (3):
[1797] 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):
[1798] 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-methy]-2,4-difluoro--
phenyl}-carbamic acid benzyl ester (6):
[1799] 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 IN 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.+=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):
[1800] 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):
[1801]
[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%).
[1802]
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,
##STR00011##
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.
[1803]
3-(3-Amino-2,6-difluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridine-4-carbon-
itrile 13
##STR00012##
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:
##STR00013##
Step 5a --Preparation of
3-(3-amino-2,6-difluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile
(13):
[1804] 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.
[1805]
(3-Amino-2-chloro-6-fluoro-phenyl)-[5-(1-methyl-1H-pyrazol-4-yl)-1H-
-pyrrolo[2,3-b]pyridin-3-yl]-methanone 71
##STR00014##
was prepared similarly to the protocol used for
3-(3-Amino-2,6-difluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile
13, replacing 2,4-difluoro-phenylamine 1 with
2-chloro-4-fluoro-phenylamine in step 1 and replacing
5-chloro-1H-pyrrolo[2,3-b]pyridine 5 with
5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine in Step 3.
MS (ESI) [M+H.sup.+].sup.+=369.7 and 371.4.
##STR00015##
Step 1--Preparation of
(2,6-difluoro-3-nitro-phenyl)-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-me-
thanone (16):
[1806] 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 IN hydrochloric acid, resulting in a
precipitate that was collected to provide the desired compound (16,
2.761 g). Additonal 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):
[1807] 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 dichloromethante 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.
[1808]
(3-Amino-2,6-difluoro-phenyl)-(4-chloro-1H-pyrrolo[2,3-b]pyridin-3--
yl)-methanone
##STR00016##
was prepared similarly to the protocol of Scheme 2, 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 2, 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.
[1809]
(3-Amino-2-fluoro-phenyl)-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-m-
ethanone 69
##STR00017##
was prepared similarly to the protocol of Scheme 2, 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 70 as follows:
##STR00018##
Step 3--Preparation of
(3-amino-2-fluoro-phenyl)-(5-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)-methano-
ne (70):
[1810] To
(3-amino-2-fluoro-phenyl)-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl-
)-methanone (69, 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 (70, 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.
[1811]
(3-Amino-2,6-difluoro-phenyl)-(5-iodo-1H-pyrrolo[2,3-b]pyridin-3-yl-
)-methanone 19
##STR00019##
was prepared similarly to the protocol of Scheme 2, 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:
##STR00020##
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):
[1812] 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 seperated, 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.
##STR00021##
[1813] Step 1--Preparation of
(3-nitro-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone
(24):
[1814] Into a round bottom flask under an atmosphere of nitrogen,
aluminum trichloride (2.8 g, 21.0 mmol) was added to 40 mL of
dichloromethane. 1H-Pyrrolo[2,3-b]pyridine (23, 0.5 g, 4.0 mmol)
was then added and the solution was stirred under nitrogen at room
temperature. After 1 hour, 3-nitro-benzoyl chloride (22, 2.0 g,
10.0 mmol) was added dropwise. The mixture was stirred at room
temperature for 2.5 hours, then quenched with methanol. The
solvents were removed under vacuum and ethyl acetate and water were
added. The resulting solid was filtered out and stirred with hot
methanol for 30 minutes, filtered and dried under vacuum to provide
the desired compound (24, 150 mg).
[1815] Step 2--Preparation of
(3-amino-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone
(25):
[1816] Into a round bottom flask, under an atmosphere of nitrogen,
(3-nitro-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (24, 26
mg, 0.097 mmol) was combined with 2 mL of 6 M hydrochloric acid in
water and 0.44 mL of ethanol, resulting in a clear solution. Iron
(95 mg, 1.7 mmol) was added to the mixture and the reaction was
refluxed for 3.5 hours, then cooled and the solvents removed under
vacuum. The resulting solid was dissolved into ethyl acetate and
washed with sodium bicarbonate. The ethyl acetate layer was dried
over sodium sulfate, filtered and the filtrate was concentrated
under vacuum. The desired compound was purified with preparative
TLC plate eluting with 5% methanol/dichloromethane with some
triethylamine drops added. The desired band was extracted to
provide the desired compound (25, 14.3 mg) of white solid after
lyophilization.
[1817]
(3-Amino-phenyl)-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone
26,
(3-amino-phenyl)-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyrid-
in-3-yl]-methanone 27,
(5-amino-2-fluoro-phenyl)-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-methan-
one 28,
(5-amino-2-fluoro-phenyl)-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo-
[2,3-b]pyridin-3-yl]-methanone 29, and
(5-amino-2-fluoro-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone
200,
##STR00022##
were prepared similarly to the protocol of Scheme 2a, where
1H-pyrrolo[2,3-b]pyridine 23 was replaced with
5-chloro-1H-pyrrolo[2,3-b]pyridine (26, 28) or
5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine (27, 29) in
Step 1 and optionally replacing 3-nitro-benzoyl chloride 22 with
2-fluoro-5-nitro-benzoyl chloride in Step 1 (28, 29, 200).
##STR00023##
Step 1--Preparation of
(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-(3-nitro-phenyl)-methanone
(31): [1818] 5-Methyl-1H-pyrrolo[2,3-b]pyridine (30, 198 mg, 1.5
mmol) was dissolved in 2 mL of dichloromethane, followed by
addition of aluminum trichloride (1.2 g, 9 mmol). After stirring at
room temperature under nitrogen for 30 minutes, 3-nitro-benzoyl
chloride (22, 555 mg, 3 mmol) was added. The reaction mixture was
stirred at room temperature overnight, then poured into ice water
and acetic acid was added to neutralize the pH. The mixture was
extracted with ethyl acetate and the organic layer was washed with
brine, dried over magnesium sulfate and concentrated in vacuum to
provide the desired compound as an off white solid (31, 321 mg,
76%). Step 2--Preparation of
(3-amino-phenyl)-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone
(32):
[1819]
(5-Methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-(3-nitro-phenyl)-methanone
(31, 321 mg, 1.14 mmol) was dissolved in 10 mL of ethanol and 1.5
mL of concentrated hydrochloric acid and iron dust (1.28 g, 23
mmol) was added. The reaction mixture was refluxed for 2 hours, the
iron dust was filtered off and washed with ethanol. Combined
filtrates were evaporated under vacuum and the residue was
dissolved in ethyl acetate and washed with bicarbonate, then brine,
and dried over anhydrous magnesium sulfate, filtered and the
filtrate concentrated under vacuum to provide the desired compound
as a yellow solid (32, 120 mg, 42%).
[1820]
(5-Amino-2-fluoro-phenyl)-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)--
methanone 33,
3-[3-(5-amino-2-fluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzamide
34, (5-amino-2-fluoro-phenyl)-[5-(3-methane
sulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone 35, and
N-{3-[3-(5-amino-2-fluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-
-methanesulfonamide 36,
##STR00024##
were prepared similarly to the protocol of Scheme 2b, replacing
3-nitro-benzoyl chloride 22 with 2-fluoro-5-nitro-benzoyl chloride
in Step 1 and optionally replacing
5-methyl-1H-pyrrolo[2,3-b]pyridine 30 with
3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-benzamide (34),
5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine (35), and
N-[3-(1H-Pyrrolo[2,3-b]pyridin-5-yl)-phenyl]-methanesulfonamide
(36) in Step 1.
##STR00025##
Step 1--Preparation of
(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-(3-nitro-phenyl)-methanol
(39):
[1821] To a solution of 5-methoxy-1H-pyrrolo[2,3-b]pyridine (38,
592 mg, 4 mmol) and 3-nitrobenzaldehyde (37, 1.2 g, 8 mmol) in 5 mL
of dioxane, potassium hydroxide (448 mg, 8 mmol) was added. The
reaction mixture was heated at 50.degree. C. for 30 minutes. The
resulting precipitate was isolated by filtration and washed with
water. This solid was dissolved in ethyl acetate, and the organic
layer was washed with brine, dried over anhydrous magnesium
sulfate, filtered and the filtrate concentrated under vacuum to
provide the desired compound as a white solid (39, 938 mg,
78%).
Step 2--Preparation of
(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-(3-nitro-phenyl)-methanone
(40):
[1822] To a solution of
(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-(3-nitro-phenyl)-methanol
(39, 450 mg, 1.5 mmol) in 5 mL of dichloromethane, pyridinium
chlorochromate (390 mg, 1.8 mmol) was added. The reaction mixture
was stirred at room temperature overnight. The resulting
precipitate was isolated by filtration and washed with
dichloromethane and used in the next step without further
purification.
Step 3--Preparation of
(3-Amino-phenyl)-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone
(41):
[1823] The crude
(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-(3-nitro-phenyl)-methanone
(40) was treated according to the protocol of Scheme 2b Step 2 to
provide the desired compound.
[1824]
(3-Amino-phenyl)-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone
42, (3-amino-phenyl)-[5-(3-methane
sulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone 43,
N-{3-[3-(3-amino-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-methane
sulfonamide 44, and
(3-amino-phenyl)-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone
45,
##STR00026##
were prepared similarly to the protocol of Scheme 3, replacing
5-methoxy-1H-pyrrolo[2,3-b]pyridine 38 with
5-fluoro-1H-pyrrolo[2,3-b]pyridine (42),
5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine (43),
N-[3-(1H-Pyrrolo[2,3-b]pyridin-5-yl)-phenyl]-methanesulfonamide
(44), and 5-bromo-1H-pyrrolo[2,3-b]pyridine (45), in Step 1.
Example 2
Synthesis of benzo[b]thiophene-3-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide P-1117
[1825] Benzo[b]thiophene-3-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide P-1117 was synthesized in one step from
(3-amino-2,6-difluoro-phenyl)-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-me-
thanone 8 as shown in Scheme 4.
##STR00027##
Step 1--Preparation of benzo[b]thiophene-3-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-1117):
[1826] To
(3-amino-2,6-difluoro-phenyl)-(5-chloro-1H-pyrrolo[2,3-b]pyridin-
-3-yl)-methanone (8, 10 mg, 0.033 mmol) and
I-benzothiophene-3-sulfonyl chloride (46, 23 mg, 0.1 mmol)
dissolved in 1 mL of tetrahydrofuran in a 2 mL microwave vial, 100
.mu.L of pyridine was added and the solution was irradiated in
microwave for 10 minutes at 130.degree. C. The reaction mixture was
transferred to a 5 mL vial and the solvents were removed under
reduced pressure. The crude dry material was dissolved in 300 .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.+=503.9.
[1827] N-(6-Acetyl
amino-pyridin-3-yl)-3-benzenesulfonylamino-2,6-difluoro-benzamide
P-2474 and
6-acetylamino-N-(3-benzenesulfonylamino-2,6-difluoro-phenyl)-nicotina-
mide P-2475,
##STR00028##
were prepared similarly to the protocol of Scheme 4, replacing
(3-amino-2,6-difluoro-phenyl)-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-me-
thanone 8 with
N-(6-acetylamino-pyridin-3-yl)-3-amino-2,6-difluoro-benzamide (64)
and 6-acetylamino-N-(3-amino-2,6-difluoro-phenyl)-nicotinamide
(68), respectively, and replacing I-benzothiophene-3-sulfonyl
chloride 46 with benzenesulfonyl chloride. MS
(ESI)[M+H.sup.+].sup.+=447.1 (P-2474) and 447.1 (P-2475).
[1828] Additional compounds were prepared similarly to the protocol
of Scheme 4, 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-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-me-
thanone 8 with 5-(2-methoxy-pyrimidin-5-yl), 5-methyl, 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)-methanone
(prepared as described in Example 1) and/or replacing
1-benzothiophene-3-sulfonyl chloride 46 with an appropriate
sulfonyl chloride. The following compounds were prepared by this
procedure: [1829]
4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2001), [1830]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-2,5-difluoro-benzenesulfonamide (P-2002), [1831]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-2,6-difluoro-benzenesulfonamide (P-2003), [1832]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-3,5-dimethyl-benzenesulfonamide (P-2004), [1833]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-3-fluoro-4-methoxy-benzenesulfonamide (P-2005), [1834]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-4-fluoro-2-methyl-benzenesulfonamide (P-2006), [1835]
2,3-Dihydro-benzofuran-5-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2007), [1836]
N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-2-fluoro-benzenesulfonamide (P-2009), [1837]
N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-2,5-difluoro-benzenesulfonamide (P-2010), [1838]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2-fluoro-benzenesulfonamide (P-2011), [1839]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2,5-difluoro-benzenesulfonamide (P-1497), [1840]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
3-fluoro-benzenesulfonamide (P-1498), [1841]
N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-
-2-fluoro-benzenesulfonamide (P-2014), [1842]
N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-
-2,5-difluoro-benzenesulfonamide (P-2015), [1843]
N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-
-3-fluoro-benzenesulfonamide (P-2016), [1844]
N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-2-fluoro-benzenesulfonamide (P-2017), [1845]
N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-2,5-difluoro-benzenesulfonamide (P-2018), [1846]
N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-3-fluoro-benzenesulfonamide (P-2019), [1847]
N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2-fluoro-benzenesulfonamide (P-2020), [1848]
N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-2-fluoro-benzenesulfonamide (P-2021), [1849]
N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-2,5-difluoro-benzenesulfonamide (P-2022), [1850]
N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-3-fluoro-benzenesulfonamide (P-2023), [1851]
N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-
-2,6-difluoro-benzenesulfonamide (P-2024), [1852]
N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-
-2,4-difluoro-benzenesulfonamide (P-2025), [1853]
N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-4-fluoro-benzenesulfonamide (P-2026), [1854]
N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-4-fluoro-benzenesulfonamide (P-2027), [1855]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
4-fluoro-benzenesulfonamide (P-2028), [1856]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2,6-difluoro-benzenesulfonamide (P-2029), [1857]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2,4-difluoro-benzenesulfonamide (P-2030), [1858]
N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-2,6-difluoro-benzenesulfonamide (P-2031), [1859]
N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-2,4-difluoro-benzenesulfonamide (P-2032), [1860]
N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-2,6-difluoro-benzenesulfonamide (P-2033), [1861]
N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-2,4-difluoro-benzenesulfonamide (P-2034), [1862]
N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
4-fluoro-benzenesulfonamide (P-2035), [1863]
N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2,5-difluoro-benzenesulfonamide (P-2036), [1864]
N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2,6-difluoro-benzenesulfonamide (P-2037), [1865]
N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
2,4-difluoro-benzenesulfonamide (P-2038), [1866]
N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
3-fluoro-benzenesulfonamide (P-2039), [1867]
N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-
-3-carbonyl]-phenyl}-4-fluoro-benzenesulfonamide (P-2040), [1868]
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), [1869]
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),
[1870]
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),
[1871]
N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-
-3-carbonyl]-phenyl}-2,4-difluoro-benzenesulfonamide (P-2044),
[1872]
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), [1873]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
benzenesulfonamide (P-2046), [1874]
N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-4-trifluoromethyl-benzenesulfonamide (P-2047), [1875]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-4-fl-
uoro-benzenesulfonamide (P-2050), [1876]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-2-fl-
uoro-benzenesulfonamide (P-2051), [1877]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-2,5--
difluoro-benzenesulfonamide (P-2052), [1878]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-3-fl-
uoro-benzenesulfonamide (P-2053), [1879]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-2,6--
difluoro-benzenesulfonamide (P-2054), [1880]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-2,4--
difluoro-benzenesulfonamide (P-2055), [1881]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-benz-
enesulfonamide (P-2056), [1882] 2H-[1,2,4]Triazole-3-sulfonic acid
[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2061), [1883] 2H-[1,2,4]Triazole-3-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2062), [1884] Pyridine-2-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2063), [1885] 2H-[1,2,4]Triazole-3-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2064), [1886] 2H-[1,2,4]Triazole-3-sulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2065), [1887] 2H-[1,2,4]Triazole-3-sulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2066), [1888] Pyridine-2-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2067), [1889] 2H-[1,2,4]Triazole-3-sulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2068), [1890] Pyridine-3-sulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2069), [1891] Pyridine-2-sulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2070), [1892] Pyridine-3-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2071), [1893] Pyridine-3-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2072), [1894] Pyridine-3-sulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2073), [1895] Pyridine-3-sulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2074), [1896] Pyridine-2-sulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2075), [1897] Pyridine-2-sulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2076), [1898] Pyridine-3-sulfonic acid
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2077), [1899] Pyridine-2-sulfonic acid
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2078), [1900] Pyridine-2-sulfonic acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl-1H-pyrrolo[2,3-b]pyridine-3--
carbonyl]-phenyl}-amide (P-2079), [1901]
2H-[1,2,4]Triazole-3-sulfonic acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl-1H-pyrrolo[2,3-b]pyridi-
ne-3-carbonyl]-phenyl}-amide (P-2080), [1902]
5-Methyl-isoxazole-4-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2081), [1903] 1,5-Dimethyl-1H-pyrazole-4-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2082), [1904] 1-Ethyl-1H-pyrazole-4-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2083), [1905] 1-Methyl-1H-pyrazole-4-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2084), [1906] 6-Methoxy-pyridine-3-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2085), [1907] Pyridine-3-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2086), [1908] Pyridine-2-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2087), [1909] 5-Methyl-isoxazole-4-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2088), [1910] 1-Ethyl-1H-pyrazole-4-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2089), [1911] 1-Methyl-1H-pyrazole-4-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2090), [1912] 1,5-Dimethyl-1H-pyrazole-4-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2091), [1913] 6-Methoxy-pyridine-3-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2092), [1914]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
C-pyridin-2-yl-methanesulfonamide (P-2093), [1915]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
C-pyridin-3-yl-methanesulfonamide (P-2094), [1916]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
C-pyridin-4-yl-methanesulfonamide (P-2095), [1917]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-C-py-
ridin-3-yl-methanesulfonamide (P-2096), [1918]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-C-py-
ridin-4-yl-methanesulfonamide (P-2097), [1919]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-C-py-
ridin-2-yl-methanesulfonamide (P-2098), [1920]
N-{2-Chloro-4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyr-
idine-3-carbonyl]-phenyl}-3-difluoromethoxy-benzenesulfonamide
(P-2099), [1921]
4-Fluoro-N-{4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,-
3-b]pyridine-3-carbonyl]-phenyl}-benzenesulfonamide (P-2100),
[1922]
N-{4-Fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-c-
arbonyl]-phenyl}-3-trifluoromethyl-benzenesulfonamide (P-2101),
[1923]
N-{4-Fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-c-
arbonyl]-phenyl}-3-trifluoromethoxy-benzenesulfonamide (P-2102),
[1924]
3-Chloro-N-{4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyr-
idine-3-carbonyl]-phenyl}-benzenesulfonamide (P-2103), [1925]
N-{4-Fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-c-
arbonyl]-phenyl}-4-trifluoromethyl-benzenesulfonamide (P-2104),
[1926]
3-Fluoro-N-{4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyr-
idine-3-carbonyl]-phenyl}-benzenesulfonamide (P-2105), [1927]
4-Chloro-N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-ph-
enyl]-benzenesulfonamide (P-2106), [1928]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-4-f-
luoro-benzenesulfonamide (P-2107), [1929]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-3-t-
rifluoromethyl-benzenesulfonamide (P-2108), [1930]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-4-t-
rifluoromethoxy-benzenesulfonamide (P-2109), [1931]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-3-t-
rifluoromethoxy-benzenesulfonamide (P-2110), [1932]
3-Chloro-N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-ph-
enyl]-benzenesulfonamide (P-2111), [1933]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-4-t-
rifluoromethyl-benzenesulfonamide (P-2112), [1934]
4-Chloro-N-[4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-ben-
zenesulfonamide (P-2113), [1935]
4-Fluoro-N-[4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-ben-
zenesulfonamide (P-2114), [1936]
N-[4-Fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-trifluorom-
ethyl-benzenesulfonamide (P-2115), [1937]
N-[4-Fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluorom-
ethoxy-benzenesulfonamide (P-2116), [1938]
N-[4-Fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-trifluorom-
ethoxy-benzenesulfonamide (P-2117), [1939]
3-Chloro-N-[4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-ben-
zenesulfonamide (P-2118), [1940]
N-[4-Fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluorom-
ethyl-benzenesulfonamide (P-2119), [1941]
3-Fluoro-N-[4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-ben-
zenesulfonamide (P-2120), [1942]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-fluoro-ben-
zenesulfonamide (P-2121), [1943]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-trifluorom-
ethyl-benzenesulfonamide (P-2122), [1944]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluorom-
ethoxy-benzenesulfonamide (P-2123),
[1945]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-tri-
fluoromethoxy-benzenesulfonamide (P-2124), [1946]
3-Chloro-N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-ben-
zenesulfonamide (P-2125), [1947]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluorom-
ethyl-benzenesulfonamide (P-2126), [1948]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-fluoro-ben-
zenesulfonamide (P-2127), [1949]
4-Chloro-N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-ben-
zenesulfonamide (P-2128), [1950]
4-Chloro-N-{3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-c-
arbonyl]-phenyl}-benzenesulfonamide (P-2129), [1951]
4-Fluoro-N-{3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-c-
arbonyl]-phenyl}-benzenesulfonamide (P-2130), [1952]
N-{3-[5-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]--
phenyl}-3-trifluoromethyl-benzenesulfonamide (P-2131), [1953]
N-{3-[5-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]--
phenyl}-4-trifluoromethoxy-benzenesulfonamide (P-2132), [1954]
N-{3-[5-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]--
phenyl}-3-trifluoromethoxy-benzenesulfonamide (P-2133), [1955]
3-Chloro-N-{3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-c-
arbonyl]-phenyl}-benzenesulfonamide (P-2134), [1956]
N-{3-[5-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]--
phenyl}-4-trifluoromethyl-benzenesulfonamide (P-2135), [1957]
3-Fluoro-N-{3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-c-
arbonyl]-phenyl}-benzenesulfonamide (P-2136), [1958]
Pyridine-3-sulfonic acid
[4-fluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2137), [1959] Pyridine-3-sulfonic acid
{4-fluoro-3-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-car-
bonyl]-phenyl}-amide (P-2138), [1960] Pyridine-3-sulfonic acid
{4-fluoro-3-[5-(3-methanesulfonylamino-phenyl)-1H-pyrrolo[2,3-b]pyridine--
3-carbonyl]-phenyl}-amide (P-2139), [1961] Pyridine-3-sulfonic acid
{4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-car-
bonyl]-phenyl}-amide (P-2140), [1962] Pyridine-3-sulfonic acid
[3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2141), [1963] Pyridine-3-sulfonic acid
[3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2142), [1964] Pyridine-3-sulfonic acid
[3-(5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2143), [1965] Pyridine-3-sulfonic acid
{3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-ph-
enyl}-amide (P-2144), [1966] Pyridine-3-sulfonic acid
{3-[5-(3-methanesulfonylamino-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbony-
l]-phenyl}-amide (P-2145), [1967] Pyridine-3-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2146), [1968] Pyridine-3-sulfonic acid
{3-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-ph-
enyl}-amide (P-2149), [1969] Ethanesulfonic acid
[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2272), [1970] Propane-2-sulfonic acid
[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2273), [1971] Ethanesulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2274), [1972] Propane-2-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2275), [1973] Ethanesulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2276), [1974] Ethanesulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2277), [1975] Propane-2-sulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2278), [1976] Ethanesulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2279), [1977] Propane-2-sulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2280), [1978] Ethanesulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2281), [1979] Propane-2-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2282), [1980] Ethanesulfonic acid
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2283), [1981] Propane-2-sulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2284), [1982] Propane-2-sulfonic acid
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2285), [1983] Ethanesulfonic acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2286), [1984] Propane-2-sulfonic acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2287), [1985]
N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-methanesulfonamide (P-2288), [1986]
N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-
-methanesulfonamide (P-2289), [1987]
N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-methanesulfonamide (P-2290), [1988]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-methanesulfonamide (P-2291), [1989]
N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
methanesulfonamide (P-2292), [1990]
N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-methanesulfonamide (P-2293), [1991]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
methanesulfonamide (P-2294), [1992]
N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-
-3-carbonyl]-phenyl}-methanesulfonamide (P-2295), [1993]
2-Methyl-propane-1-sulfonic acid
[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2303), [1994] 2-Methyl-propane-1-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2304), [1995] 2-Methyl-propane-1-sulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2305), [1996] 2-Methyl-propane-1-sulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2306), [1997] 2-Methyl-propane-1-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2307), [1998] Butane-2-sulfonic acid
[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2308), [1999] Pentane-2-sulfonic acid
[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2309), [2000] Butane-2-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2310), [2001] Pentane-2-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2311), [2002] Butane-2-sulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2312), [2003] Butane-2-sulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2313), [2004] Pentane-2-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2314), [2005] Pentane-2-sulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2315), [2006] Pentane-2-sulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2316), [2007] Butane-2-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2317), [2008] 2-Methyl-propane-1-sulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2318), [2009] Butane-2-sulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2319), [2010] 2-Methyl-propane-1-sulfonic acid
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2320), [2011] Butane-2-sulfonic acid
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2321), [2012] 2-Methyl-propane-1-sulfonic acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2322), [2013] Butane-2-sulfonic acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2323), [2014]
3,3,3-Trifluoro-propane-1-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2324), [2015] 3,3,3-Trifluoro-propane-1-sulfonic acid
[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2327), [2016] 3,3,3-Trifluoro-propane-1-sulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2328), [2017] 3,3,3-Trifluoro-propane-1-sulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2329), [2018] 3,3,3-Trifluoro-propane-1-sulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2330), [2019] 3,3,3-Trifluoro-propane-1-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2331), [2020] 3,3,3-Trifluoro-propane-1-sulfonic acid
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2332), [2021] 3,3,3-Trifluoro-propane-1-sulfonic acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl-1H-pyrrolo[2,3-b]pyridine-3--
carbonyl]-phenyl}-amide (P-2333), [2022]
2,2,2-Trifluoro-ethanesulfonic acid
[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phe-
nyl]-amide (P-2335), [2023] 2,2,2-Trifluoro-ethanesulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2336), [2024] 2,2,2-Trifluoro-ethanesulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2337), [2025] 2,2,2-Trifluoro-ethanesulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2338), [2026] 2,2,2-Trifluoro-ethanesulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2339), [2027] 2,2,2-Trifluoro-ethanesulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2340), [2028] 2,2,2-Trifluoro-ethanesulfonic acid
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2341), [2029] 2,2,2-Trifluoro-ethanesulfonic acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2342), [2030]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-C,C,C-trifluoro-methanesulfonamide (P-2346), [2031]
N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl-
]-C,C,C-trifluoro-methanesulfonamide (P-2347), [2032]
Cyclobutanesulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-pheny-
l]-amide (P-2353), [2033] Cyclobutanesulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2354), [2034] Cyclohexanesulfonic acid
[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2355), [2035] Cyclopentanesulfonic acid
[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2356), [2036] Cyclohexanesulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2357), [2037] Cyclopentanesulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2358), [2038] Cyclopentanesulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2359), [2039] Cyclohexanesulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2360), [2040] Cyclohexanesulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2361), [2041] Cyclobutanesulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2362), [2042] Cyclobutanesulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2363), [2043] Cyclobutanesulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2364), [2044] Cyclopentanesulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2365), [2045] Cyclohexanesulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2366), [2046] Cyclohexanesulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2367), [2047] Cyclopentanesulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2368), [2048] Cyclohexanesulfonic acid
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2369), [2049] Cyclobutanesulfonic acid
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2370), [2050] Cyclohexanesulfonic acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2371), [2051] Cyclopentanesulfonic acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2372), [2052] Cyclobutanesulfonic acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2373), [2053] Pyrrolidine-1-sulfonic
acid
[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2374), [2054] Pyrrolidine-1-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2375), [2055] N,N-dimethylamino-sulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2376), [2056] Pyrrolidine-1-sulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2377), [2057] N,N-diethylamino-sulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2378), [2058] Pyrrolidine-1-sulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2379), [2059] Pyrrolidine-1-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-1500), [2060] N,N-dimethylamino-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-1501), [2061] N,N-dimethylamino-sulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2382), [2062] N,N-dimethylamino-sulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2383), [2063] N,N-diethylamino-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2384), [2064] N,N-diethylamino-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2385), [2065] N,N-diethylamino-sulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2386), [2066] N,N-diethylamino-sulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2387),
[2067] N,N-diethylamino-sulfonic acid
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2388), [2068] N,N-diethylamino-sulfonic acid
[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2389), [2069] Morpholine-4-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2390), [2070] Morpholine-4-sulfonic acid
[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2391), [2071] Morpholine-4-sulfonic acid
[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a-
mide (P-2392), [2072] Morpholine-4-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2393), [2073] Pyrrolidine-1-sulfonic acid
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2394), [2074] Morpholine-4-sulfonic acid
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2395), [2075] Morpholine-4-sulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2396), [2076] Morpholine-4-sulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2397), [2077] Pyrrolidine-1-sulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2398), [2078] N,N-dimethylamino-sulfonic acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2399), [2079] Pyrrolidine-1-sulfonic
acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl-1H-pyrrolo[2,3-b]pyridine-3--
carbonyl]-phenyl}-amide (P-2400), [2080] N,N-diethylamino-sulfonic
acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2401), [2081] Morpholine-4-sulfonic
acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2402), [2082] Ethanesulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2410), [2083] Propane-2-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2411), [2084] 2-Methyl-propane-1-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2412), [2085] Butane-2-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2413), [2086] 2,2,2-Trifluoro-ethanesulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2414), [2087] 3,3,3-Trifluoro-propane-1-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2415), [2088] Cyclohexanesulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2416), [2089] Cyclopentanesulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2417), [2090] Cyclobutanesulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2418), [2091] N,N-dimethylamino-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2419), [2092] Pyrrolidine-1-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2420), [2093] Morpholine-4-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2421), [2094] Propane-1-sulfonic acid
{4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-car-
bonyl]-phenyl}-amide (P-2431), [2095] Butane-1-sulfonic acid
{4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-car-
bonyl]-phenyl}-amide (P-2432), [2096] Cyclopropanesulfonic acid
{4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-car-
bonyl]-phenyl}-amide (P-2433), [2097] Cyclohexanesulfonic acid
{4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-car-
bonyl]-phenyl}-amide (P-2434), [2098] Butane-1-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-amide
(P-2435), [2099] Cyclopropanesulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-amide
(P-2436), [2100] Propane-1-sulfonic acid
[4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2437), [2101] Butane-1-sulfonic acid
[4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2438), [2102] Cyclopropanesulfonic acid
[4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2439), [2103] Piperidine-1-sulfonic acid
[4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2440), [2104] Cyclohexanesulfonic acid
[4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2441), [2105] Cyclopentanesulfonic acid
[4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2442), [2106] Cyclohexanesulfonic acid
[4-fluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2443), [2107] Cyclohexanesulfonic acid
{4-fluoro-3-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-car-
bonyl]-phenyl}-amide (P-2444), [2108] Cyclopentanesulfonic acid
{4-fluoro-3-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-car-
bonyl]-phenyl}-amide (P-2445), [2109] Cyclohexanesulfonic acid
{4-fluoro-3-[5-(3-methanesulfonylamino-phenyl)-1H-pyrrolo[2,3-b]pyridine--
3-carbonyl]-phenyl}-amide (P-2446), [2110] Cyclopentanesulfonic
acid
{4-fluoro-3-[5-(3-methanesulfonylamino-phenyl)-1H-pyrrolo[2,3-b]pyridine--
3-carbonyl]-phenyl}-amide (P-2447), [2111] Cyclopentanesulfonic
acid
[4-fluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2448), [2112] Propane-1-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2449), [2113] Butane-1-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2450), [2114] Cyclopropanesulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2451), [2115] Cyclohexanesulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2452), [2116] Cyclopentanesulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2453), [2117] Propane-1-sulfonic acid
{3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-ph-
enyl}-amide (P-2454), [2118] Butane-1-sulfonic acid
{3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-ph-
enyl}-amide (P-2455), [2119] Cyclopropanesulfonic acid
{3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-ph-
enyl}-amide (P-2456), [2120] Cyclohexanesulfonic acid
{3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-ph-
enyl}-amide (P-2457), [2121] Cyclohexanesulfonic acid
[3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2458), [2122] Cyclopentanesulfonic acid
[3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2459), [2123] Cyclohexanesulfonic acid
[3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2460), [2124] Cyclohexanesulfonic acid
{3-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-ph-
enyl}-amide (P-2461), [2125] Cyclohexanesulfonic acid
[3-(5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2462), [2126] Cyclopentanesulfonic acid
[3-(5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2463), [2127] Cyclopentanesulfonic acid
[3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2464), [2128]
3-{3-[3-(3-Cyclohexanesulfonylamino-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-y-
l]-phenyl}-propionic acid (P-2465), [2129]
3-{3-[3-(3-Cyclopentanesulfonylamino-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5--
yl]-phenyl}-propionic acid (P-2466), [2130] Piperidine-1-sulfonic
acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-amide
(P-2468), [2131] N,N-dimethylamino-sulfonic acid
[4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2469), [2132] N,N-dimethylamino-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2470), [2133] Piperidine-1-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2471), [2134] Pyridine-3-sulfonic acid
[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]amide
(P-2472), [2135] Pyrrolidine-1-sulfonic acid
[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2476), [2136] N,N-dimethylamino-sulfonic acid
[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2477), [2137] 6-Trifluoromethyl-pyridine-3-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2481), [2138] 5-Trifluoromethyl-pyridine-2-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a-
mide (P-2485), and [2139]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
4-propyl-benzenesulfonamide (P-2486).
[2140] 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-2001 ##STR00029##
##STR00030## ##STR00031## 519.1 P-2002 ##STR00032## ##STR00033##
##STR00034## 483.9 P-2003 ##STR00035## ##STR00036## ##STR00037##
483.9 P-2004 ##STR00038## ##STR00039## ##STR00040## 475.9 P-2005
##STR00041## ##STR00042## ##STR00043## 495.9 P-2006 ##STR00044##
##STR00045## ##STR00046## 479.9 P-2007 ##STR00047## ##STR00048##
##STR00049## 490.3 P-2009 ##STR00050## ##STR00051## ##STR00052##
461.9 P-2010 ##STR00053## ##STR00054## ##STR00055## 479.9 P-2011
##STR00056## ##STR00057## ##STR00058## 457.1 P-1497 ##STR00059##
##STR00060## ##STR00061## 475.1 P-1498 ##STR00062## ##STR00063##
##STR00064## 457.1 P-2014 ##STR00065## ##STR00066## ##STR00067##
445.9 P-2015 ##STR00068## ##STR00069## ##STR00070## 463.9 P-2016
##STR00071## ##STR00072## ##STR00073## 445.9 P-2017 ##STR00074##
##STR00075## ##STR00076## 465.9 P-2018 ##STR00077## ##STR00078##
##STR00079## 483.9 P-2019 ##STR00080## ##STR00081## ##STR00082##
465.9 P-2020 ##STR00083## ##STR00084## ##STR00085## 457.1 P-2021
##STR00086## ##STR00087## ##STR00088## 461.9 P-2022 ##STR00089##
##STR00090## ##STR00091## 479.9 P-2023 ##STR00092## ##STR00093##
##STR00094## 461.9 P-2024 ##STR00095## ##STR00096## ##STR00097##
463.9 P-2025 ##STR00098## ##STR00099## ##STR00100## 463.9 P-2026
##STR00101## ##STR00102## ##STR00103## 465.9 P-2027 ##STR00104##
##STR00105## ##STR00106## 461.9 P-2028 ##STR00107## ##STR00108##
##STR00109## 457.1 P-2029 ##STR00110## ##STR00111## ##STR00112##
474.7 P-2030 ##STR00113## ##STR00114## ##STR00115## 475.1 P-2031
##STR00116## ##STR00117## ##STR00118## 479.9 P-2032 ##STR00119##
##STR00120## ##STR00121## 479.9 P-2033 ##STR00122## ##STR00123##
##STR00124## 483.9 P-2034 ##STR00125## ##STR00126## ##STR00127##
483.9 P-2035 ##STR00128## ##STR00129## ##STR00130## 457.1 P-2036
##STR00131## ##STR00132## ##STR00133## 475.1 P-2037 ##STR00134##
##STR00135## ##STR00136## 474.7 P-2038 ##STR00137## ##STR00138##
##STR00139## 475.1 P-2039 ##STR00140## ##STR00141## ##STR00142##
457.1 P-2040 ##STR00143## ##STR00144## ##STR00145## 540.3 P-2041
##STR00146## ##STR00147## ##STR00148## 539.9 P-2042 ##STR00149##
##STR00150## ##STR00151## 558.0 P-2043 ##STR00152## ##STR00153##
##STR00154## 558.0 P-2044 ##STR00155## ##STR00156## ##STR00157##
558.0 P-2045 ##STR00158## ##STR00159## ##STR00160## 539.9 P-2046
##STR00161## ##STR00162## ##STR00163## 437.5 P-2047 ##STR00164##
##STR00165## ##STR00166## 512.4 P-2050 ##STR00167## ##STR00168##
##STR00169## 439.1 P-2051 ##STR00170## ##STR00171## ##STR00172##
439.1 P-2052 ##STR00173## ##STR00174## ##STR00175## 457.1 P-2053
##STR00176## ##STR00177## ##STR00178## 438.7 P-2054 ##STR00179##
##STR00180## ##STR00181## 457.7 P-2055 ##STR00182## ##STR00183##
##STR00184## 457.1 P-2056 ##STR00185## ##STR00186## ##STR00187##
420.9 P-2061 ##STR00188## ##STR00189## ##STR00190## 435.1 P-2062
##STR00191## ##STR00192## ##STR00193## 439.1 P-2063 ##STR00194##
##STR00195## ##STR00196## 439.9 P-2064 ##STR00197## ##STR00198##
##STR00199## 429.9 P-2065 ##STR00200## ##STR00201## ##STR00202##
419.1 P-2066 ##STR00203## ##STR00204## ##STR00205## 439.1 P-2067
##STR00206## ##STR00207## ##STR00208## 448.7 P-2068 ##STR00209##
##STR00210## ##STR00211## 435.1 P-2069 ##STR00212## ##STR00213##
##STR00214## 429.1 P-2070 ##STR00215## ##STR00216## ##STR00217##
429.1 P-2071 ##STR00218## ##STR00219## ##STR00220## 448.8 P-2072
##STR00221## ##STR00222## ##STR00223## 439.9 P-2073 ##STR00224##
##STR00225## ##STR00226## 445.1 P-2074 ##STR00227## ##STR00228##
##STR00229## 448.7 P-2075 ##STR00230## ##STR00231## ##STR00232##
448.7 P-2076 ##STR00233## ##STR00234## ##STR00235## 445.1 P-2077
##STR00236## ##STR00237## ##STR00238## 439.9 P-2078 ##STR00239##
##STR00240## ##STR00241## 439.9 P-2079 ##STR00242## ##STR00243##
##STR00244## P-2080 ##STR00245## ##STR00246## ##STR00247## 513.1
P-2081 ##STR00248## ##STR00249## ##STR00250## 444.3 P-2082
##STR00251## ##STR00252## ##STR00253## 457.1 P-2083 ##STR00254##
##STR00255## ##STR00256## 457.1 P-2084 ##STR00257## ##STR00258##
##STR00259## 443.1 P-2085 ##STR00260## ##STR00261## ##STR00262##
469.9 P-2086 ##STR00263## ##STR00264## ##STR00265## 421.9 P-2087
##STR00266## ##STR00267## ##STR00268## 421.9 P-2088 ##STR00269##
##STR00270## ##STR00271## 425.8 P-2089 ##STR00272## ##STR00273##
##STR00274## 439.0 P-2090 ##STR00275## ##STR00276## ##STR00277##
425.1 P-2091 ##STR00278## ##STR00279## ##STR00280## 439.1 P-2092
##STR00281## ##STR00282## ##STR00283## 451.9 P-2093 ##STR00284##
##STR00285## ##STR00286## 453.9 P-2094 ##STR00287## ##STR00288##
##STR00289## 453.9 P-2095 ##STR00290## ##STR00291## ##STR00292##
453.9 P-2096 ##STR00293## ##STR00294## ##STR00295## 436.0 P-2097
##STR00296## ##STR00297## ##STR00298## 436.0 P-2098 ##STR00299##
##STR00300## ##STR00301## 436.3 P-2098 ##STR00302## ##STR00303##
##STR00304## 436.3 P-2099 ##STR00305## ##STR00306## ##STR00307##
575.7 577.5 P-2101 ##STR00308## ##STR00309## ##STR00310## 544.3
P-2102 ##STR00311## ##STR00312## ##STR00313## 560.0 P-2103
##STR00314## ##STR00315## ##STR00316## 510.3 P-2104 ##STR00317##
##STR00318## ##STR00319## 544.3 P-2105 ##STR00320## ##STR00321##
##STR00322## 493.9 P-2106 ##STR00323## ##STR00324## ##STR00325##
463.9 P-2107 ##STR00326## ##STR00327## ##STR00328## 447.9 P-2108
##STR00329## ##STR00330## ##STR00331## 498.3 P-2109 ##STR00332##
##STR00333## ##STR00334## 514.3 P-2110 ##STR00335## ##STR00336##
##STR00337## 513.9 P-2111 ##STR00338## ##STR00339## ##STR00340##
563.9 P-2112 ##STR00341## ##STR00342## ##STR00343## 498.3 P-2113
##STR00344## ##STR00345## ##STR00346## 430.3 P-2114 ##STR00347##
##STR00348## ##STR00349## 414.3 P-2115 ##STR00350## ##STR00351##
##STR00352## 463.9 P-2116 ##STR00353## ##STR00354## ##STR00355##
479.9 P-2117 ##STR00356## ##STR00357## ##STR00358## 479.9 P-2118
##STR00359## ##STR00360## ##STR00361## 430.3 P-2119 ##STR00362##
##STR00363## ##STR00364## 463.9 P-2120 ##STR00365## ##STR00366##
##STR00367## 413.9 P-2121 ##STR00368## ##STR00369## ##STR00370##
430.3 P-2122 ##STR00371## ##STR00372## ##STR00373## 479.9 P-2123
##STR00374## ##STR00375## ##STR00376## 496.3 P-2124 ##STR00377##
##STR00378## ##STR00379## 496.3 P-2125 ##STR00380## ##STR00381##
##STR00382## 445.9 P-2126 ##STR00383## ##STR00384## ##STR00385##
479.9 P-2127 ##STR00386## ##STR00387## ##STR00388## 430.3 P-2128
##STR00389## ##STR00390## ##STR00391## 445.9 P-2129 ##STR00392##
##STR00393## ##STR00394## 491.9 P-2130 ##STR00395## ##STR00396##
##STR00397## 475.9
P-2131 ##STR00398## ##STR00399## ##STR00400## 526.3 P-2132
##STR00401## ##STR00402## ##STR00403## 541.9 P-2133 ##STR00404##
##STR00405## ##STR00406## 542.3 P-2134 ##STR00407## ##STR00408##
##STR00409## 492.3 P-2135 ##STR00410## ##STR00411## ##STR00412##
525.9 P-2136 ##STR00413## ##STR00414## ##STR00415## 475.9 P-2137
##STR00416## ##STR00417## ##STR00418## 411.1 P-2138 ##STR00419##
##STR00420## ##STR00421## 551.1 P-2139 ##STR00422## ##STR00423##
##STR00424## 566.4 P-2140 ##STR00425## ##STR00426## ##STR00427##
477.1 P-2141 ##STR00428## ##STR00429## ##STR00430## 393.1 P-2142
##STR00431## ##STR00432## ##STR00433## 409.1 P-2143 ##STR00434##
##STR00435## ##STR00436## 397.1 P-2144 ##STR00437## ##STR00438##
##STR00439## 459.1 P-2145 ##STR00440## ##STR00441## ##STR00442##
547.9 P-2146 ##STR00443## ##STR00444## ##STR00445## 413.1 P-2149
##STR00446## ##STR00447## ##STR00448## 533.1 P-2272 ##STR00449##
##STR00450## ##STR00451## 395.9 P-2273 ##STR00452## ##STR00453##
##STR00454## 410.3 P-2274 ##STR00455## ##STR00456## ##STR00457##
399.9 P-2275 ##STR00458## ##STR00459## ##STR00460## 413.9 P-2276
##STR00461## ##STR00462## ##STR00463## 399.9 P-2277 ##STR00464##
##STR00465## ##STR00466## 379.9 P-2278 ##STR00467## ##STR00468##
##STR00469## 393.9 P-2279 ##STR00470## ##STR00471## ##STR00472##
395.9 P-2280 ##STR00473## ##STR00474## ##STR00475## 409.9 P-2281
##STR00476## ##STR00477## ##STR00478## 391.1 P-2282 ##STR00479##
##STR00480## ##STR00481## 405.1 P-2283 ##STR00482## ##STR00483##
##STR00484## 391.1 P-2284 ##STR00485## ##STR00486## ##STR00487##
413.9 P-2285 ##STR00488## ##STR00489## ##STR00490## 405.1 P-2286
##STR00491## ##STR00492## ##STR00493## 474.6 P-2287 ##STR00494##
##STR00495## ##STR00496## 487.9 P-2288 ##STR00497## ##STR00498##
##STR00499## 381.9 P-2289 ##STR00500## ##STR00501## ##STR00502##
365.9 P-2290 ##STR00503## ##STR00504## ##STR00505## 385.9 P-2291
##STR00506## ##STR00507## ##STR00508## 385.9 P-2292 ##STR00509##
##STR00510## ##STR00511## 377.1 P-2293 ##STR00512## ##STR00513##
##STR00514## 381.9 P-2294 ##STR00515## ##STR00516## ##STR00517##
377.1 P-2295 ##STR00518## ##STR00519## ##STR00520## 459.9 P-2303
##STR00521## ##STR00522## ##STR00523## 423.9 P-2304 ##STR00524##
##STR00525## ##STR00526## 427.9 P-2305 ##STR00527## ##STR00528##
##STR00529## 408.3 P-2306 ##STR00530## ##STR00531## ##STR00532##
423.9 P-2307 ##STR00533## ##STR00534## ##STR00535## 419.1 P-2308
##STR00536## ##STR00537## ##STR00538## 423.9 P-2309 ##STR00539##
##STR00540## ##STR00541## 438.3 P-2310 ##STR00542## ##STR00543##
##STR00544## 427.9 P-2311 ##STR00545## ##STR00546## ##STR00547##
442.3 P-2312 ##STR00548## ##STR00549## ##STR00550## 409.1 P-2313
##STR00551## ##STR00552## ##STR00553## 423.9 P-2314 ##STR00554##
##STR00555## ##STR00556## 433.1 P-2315 ##STR00557## ##STR00558##
##STR00559## 421.9 P-2316 ##STR00560## ##STR00561## ##STR00562##
437.9 P-2317 ##STR00563## ##STR00564## ##STR00565## 419.1 P-2318
##STR00566## ##STR00567## ##STR00568## 427.9 P-2319 ##STR00569##
##STR00570## ##STR00571## 427.9 P-2320 ##STR00572## ##STR00573##
##STR00574## 419.1 P-2321 ##STR00575## ##STR00576## ##STR00577##
419.1 P-2322 ##STR00578## ##STR00579## ##STR00580## 501.9 P-2323
##STR00581## ##STR00582## ##STR00583## 501.9 P-2324 ##STR00584##
##STR00585## ##STR00586## 467.9 P-2327 ##STR00587## ##STR00588##
##STR00589## 463.9 P-2328 ##STR00590## ##STR00591## ##STR00592##
447.9 P-2329 ##STR00593## ##STR00594## ##STR00595## 467.9 P-2330
##STR00596## ##STR00597## ##STR00598## 463.9 P-2331 ##STR00599##
##STR00600## ##STR00601## 459.1 P-2332 ##STR00602## ##STR00603##
##STR00604## 459.1 P-2333 ##STR00605## ##STR00606## ##STR00607##
P-2335 ##STR00608## ##STR00609## ##STR00610## 449.9 P-2336
##STR00611## ##STR00612## ##STR00613## 445.1 P-2337 ##STR00614##
##STR00615## ##STR00616## 433.9 P-2338 ##STR00617## ##STR00618##
##STR00619## 453.9 P-2339 ##STR00620## ##STR00621## ##STR00622##
453.9 P-2340 ##STR00623## ##STR00624## ##STR00625## 449.9 P-2341
##STR00626## ##STR00627## ##STR00628## 445.1 P-2342 ##STR00629##
##STR00630## ##STR00631## P-2346 ##STR00632## ##STR00633##
##STR00634## 439.9 P-2347 ##STR00635## ##STR00636## ##STR00637##
435.9 P-2353 ##STR00638## ##STR00639## ##STR00640## 417.1 P-2354
##STR00641## ##STR00642## ##STR00643## 426.7 P-2355 ##STR00644##
##STR00645## ##STR00646## 449.9 P-2356 ##STR00647## ##STR00648##
##STR00649## 436.3 P-2357 ##STR00650## ##STR00651## ##STR00652##
453.9 P-2358 ##STR00653## ##STR00654## ##STR00655## 439.9 P-2359
##STR00656## ##STR00657## ##STR00658## 431.1 P-2360 ##STR00659##
##STR00660## ##STR00661## 433.9 P-2361 ##STR00662## ##STR00663##
##STR00664## 449.9 P-2362 ##STR00665## ##STR00666## ##STR00667##
406.3 P-2363 ##STR00668## ##STR00669## ##STR00670## 425.9 P-2364
##STR00671## ##STR00672## ##STR00673## 421.9 P-2365 ##STR00674##
##STR00675## ##STR00676## 419.9 P-2366 ##STR00677## ##STR00678##
##STR00679## 445.1 P-2367 ##STR00680## ##STR00681## ##STR00682##
453.9 P-2368 ##STR00683## ##STR00684## ##STR00685## 439.9 P-2369
##STR00686## ##STR00687## ##STR00688## 445.1 P-2370 ##STR00689##
##STR00690## ##STR00691## 417.5 P-2371 ##STR00692## ##STR00693##
##STR00694## 527.9 P-2372 ##STR00695## ##STR00696## ##STR00697##
P-2373 ##STR00698## ##STR00699## ##STR00700## 499.9 P-2374
##STR00701## ##STR00702## ##STR00703## 437.1 P-2375 ##STR00704##
##STR00705## ##STR00706## 441.1 P-2376 ##STR00707## ##STR00708##
##STR00709## 411.1 P-2377 ##STR00710## ##STR00711## ##STR00712##
437.1 P-2378 ##STR00713## ##STR00714## ##STR00715## 439.1 P-2379
##STR00716## ##STR00717## ##STR00718## 421.1 P-1500 ##STR00719##
##STR00720## ##STR00721## 432.3 P-1501 ##STR00722## ##STR00723##
##STR00724## 407.1 P-2382 ##STR00725## ##STR00726## ##STR00727##
395.1 P-2383 ##STR00728## ##STR00729## ##STR00730## 415.1 P-2384
##STR00731## ##STR00732## ##STR00733## 443.1 P-2385 ##STR00734##
##STR00735## ##STR00736## 433.9 P-2386 ##STR00737## ##STR00738##
##STR00739## 422.7 P-2387 ##STR00740## ##STR00741## ##STR00742##
443.1 P-2388 ##STR00743## ##STR00744## ##STR00745## 433.9 P-2389
##STR00746## ##STR00747## ##STR00748## 439.1 P-2390 ##STR00749##
##STR00750## ##STR00751## 457.1 P-2391 ##STR00752## ##STR00753##
##STR00754## 452.7 P-2392 ##STR00755## ##STR00756## ##STR00757##
437.1 P-2393 ##STR00758## ##STR00759## ##STR00760## 447.9 P-2394
##STR00761## ##STR00762## ##STR00763## 431.9 P-2395 ##STR00764##
##STR00765## ##STR00766## 447.9 P-2396 ##STR00767## ##STR00768##
##STR00769## 453.1 P-2397 ##STR00770## ##STR00771## ##STR00772##
457.1
P-2398 ##STR00773## ##STR00774## ##STR00775## 441.1 P-2399
##STR00776## ##STR00777## ##STR00778## 489.1 P-2400 ##STR00779##
##STR00780## ##STR00781## 515.1 P-2401 ##STR00782## ##STR00783##
##STR00784## 517.1 P-2402 ##STR00785## ##STR00786## ##STR00787##
531.1 P-2410 ##STR00788## ##STR00789## ##STR00790## 373.1 P-2411
##STR00791## ##STR00792## ##STR00793## 387.1 P-2412 ##STR00794##
##STR00795## ##STR00796## 401.1 P-2413 ##STR00797## ##STR00798##
##STR00799## 401.1 P-2414 ##STR00800## ##STR00801## ##STR00802##
427.1 P-2415 ##STR00803## ##STR00804## ##STR00805## 441.1 P-2416
##STR00806## ##STR00807## ##STR00808## 427.1 P-2417 ##STR00809##
##STR00810## ##STR00811## 413.1 P-2418 ##STR00812## ##STR00813##
##STR00814## 399.1 P-2419 ##STR00815## ##STR00816## ##STR00817##
388.3 P-2420 ##STR00818## ##STR00819## ##STR00820## 413.9 P-2421
##STR00821## ##STR00822## ##STR00823## 429.9 P-2431 ##STR00824##
##STR00825## ##STR00826## 442.3 P-2432 ##STR00827## ##STR00828##
##STR00829## 455.9 P-2433 ##STR00830## ##STR00831## ##STR00832##
440.3 P-2434 ##STR00833## ##STR00834## ##STR00835## 481.9 P-2435
##STR00836## ##STR00837## ##STR00838## 410.3 P-2436 ##STR00839##
##STR00840## ##STR00841## 393.9 P-2437 ##STR00842## ##STR00843##
##STR00844## 362.3 P-2438 ##STR00845## ##STR00846## ##STR00847##
376.3 P-2439 ##STR00848## ##STR00849## ##STR00850## 359.9 P-2440
##STR00851## ##STR00852## ##STR00853## 403.1 P-2441 ##STR00854##
##STR00855## ##STR00856## 402.3 P-2442 ##STR00857## ##STR00858##
##STR00859## 388.3 P-2443 ##STR00860## ##STR00861## ##STR00862##
416.3 P-2444 ##STR00863## ##STR00864## ##STR00865## 556.0 P-2445
##STR00866## ##STR00867## ##STR00868## 542.3 P-2446 ##STR00869##
##STR00870## ##STR00871## 571.2 P-2447 ##STR00872## ##STR00873##
##STR00874## 557.2 P-2448 ##STR00875## ##STR00876## ##STR00877##
402.3 P-2449 ##STR00878## ##STR00879## ##STR00880## 378.3 P-2450
##STR00881## ##STR00882## ##STR00883## 391.9 P-2451 ##STR00884##
##STR00885## ##STR00886## 376.3 P-2452 ##STR00887## ##STR00888##
##STR00889## 418.3 P-2453 ##STR00890## ##STR00891## ##STR00892##
404.3 P-2454 ##STR00893## ##STR00894## ##STR00895## 423.9 P-2455
##STR00896## ##STR00897## ##STR00898## 438.3 P-2456 ##STR00899##
##STR00900## ##STR00901## 421.9 P-2457 ##STR00902## ##STR00903##
##STR00904## 463.9 P-2458 ##STR00905## ##STR00906## ##STR00907##
398.3 P-2459 ##STR00908## ##STR00909## ##STR00910## 384.3 P-2460
##STR00911## ##STR00912## ##STR00913## 414.3 P-2461 ##STR00914##
##STR00915## ##STR00916## 538.3 P-2462 ##STR00917## ##STR00918##
##STR00919## 402.3 P-2463 ##STR00920## ##STR00921## ##STR00922##
388.3 P-2464 ##STR00923## ##STR00924## ##STR00925## 399.9 P-2465
##STR00926## ##STR00927## ##STR00928## 531.9 P-2466 ##STR00929##
##STR00930## ##STR00931## 518.3 P-2468 ##STR00932## ##STR00933##
##STR00934## 437.1 P-2469 ##STR00935## ##STR00936## ##STR00937##
363.1 P-2470 ##STR00938## ##STR00939## ##STR00940## 379.1 P-2471
##STR00941## ##STR00942## ##STR00943## 419.1 P-2472 ##STR00944##
##STR00945## ##STR00946## P-2476 ##STR00947## ##STR00948##
##STR00949## 465.5 467.4 [M - H.sup.+].sup.- P-2477 ##STR00950##
##STR00951## ##STR00952## 439.4 441.4 [M - H.sup.+].sup.- P-2481
##STR00953## ##STR00954## ##STR00955## 517 519 P-2485 ##STR00956##
##STR00957## ##STR00958## 516.9 P-2486 ##STR00959## ##STR00960##
##STR00961## 481.2
##STR00962##
##STR00963##
Example 3
Synthesis of propane-1-sulfonic acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide P-1496
[2141] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide P-1496 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 47 as shown in Scheme 5.
##STR00964##
[2142] Step 1--Preparation of propane-1-sulfonic acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-1496):
[2143] Propane-1-sulfonic acid
[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (47, 10 mg, 0.022 mmol) was weighed into a 5 mL microwave vial
and combined with 2-methoxypyrimidine-5-boronic acid (48, 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 dimtheylsulfoxide 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.+]=487.9.
[2144] Additional compounds were prepared similarly to the protocol
of Scheme 5, 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
2-methoxypyrimidine-5-boronic acid 48 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 47 with an appropriate 5-bromo-1H-pyrrolo[2,3-b]pyridine
derivative. The following compounds were prepared by this
procedure: [2145]
3-{3-[3-(Pyridine-3-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl-
}-benzamide (P-2147), [2146]
3-(3-{3-[3-(Pyridine-3-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-
-yl}-phenyl)-propionic acid (P-2148), [2147] 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), [2148] 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), [2149] Propane-1-sulfonic acid
{3-[5-(3,5-dimethyl-isoxazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]--
2,4-difluoro-phenyl}-amide (P-2156), [2150] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(1-isobutyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-
-3-carbonyl]-phenyl}-amide (P-2157), [2151] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyr-
idine-3-carbonyl]-phenyl}-amide (P-2158), [2152] Propane-1-sulfonic
acid
{2,4-difluoro-3-[5-(4-fluoro-3-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine--
3-carbonyl]-phenyl}-amide (P-2159), [2153] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(4-fluoro-3-trifluoromethyl-phenyl)-1H-pyrrolo[2,3-b]p-
yridine-3-carbonyl]-phenyl}-amide (P-2160), [2154]
N-(4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-
-b]pyridin-5-yl}-phenyl)-acetamide (P-2161), [2155]
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), [2156] 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), [2157] 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), [2158] 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), [2159]
4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-N-methyl-benzenesulfonamide (P-2167), [2160]
N-Cyclopropyl-4-{3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H--
pyrrolo[2,3-b]pyridin-5-yl}-benzenesulfonamide (P-2168), [2161]
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), [2162]
3-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-N-methyl-benzenesulfonamide (P-2170), [2163]
Propane-1-sulfonic acid
{3-[5-(4-chloro-3-trifluoromethyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-car-
bonyl]-2,4-difluoro-phenyl}-amide (P-2171), [2164]
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), [2165] 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), [2166] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(2-methyl-2H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2175), [2167] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(2H-pyrazol-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-
-phenyl}-amide (P-2176), [2168] 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), [2169]
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), [2170]
Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(3-hydroxy-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbony-
l]-phenyl}-amide (P-2179), [2171] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(4-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2183), [2172] 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), [2173]
4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-N,N-dimethyl-benzenesulfonamide (P-2185), [2174]
Propane-1-sulfonic acid
(2,4-difluoro-3-{5-[4-(piperidine-1-sulfonyl)-phenyl]-1H-pyrrolo[2,3-b]py-
ridine-3-carbonyl}-phenyl)-amide (P-2186), [2175]
Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(6-methylsulfanyl-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridi-
ne-3-carbonyl]-phenyl}-amide (P-2187), [2176] Propane-1-sulfonic
acid
{2,4-difluoro-3-[5-(5-methanesulfonyl-pyridin-3-yl-1H-pyrrolo[2,3-b]pyrid-
ine-3-carbonyl]-phenyl}-amide (P-2188), [2177] 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), [2178] 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), [2179] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-1H-pyrrolo[2,3-b]pyr-
idine-3-carbonyl]-phenyl}-amide (P-2191), [2180] 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), [2181]
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), [2182]
4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-benzenesulfonamide (P-2194), [2183]
Propane-1-sulfonic acid
{3-[5-(2,5-dimethyl-2H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl-
]-2,4-difluoro-phenyl}-amide (P-2195), [2184] 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), [2185] 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), [2186] Propane-1-sulfonic
acid
{2,4-difluoro-3-[5-(4-hydroxy-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbony-
l]-phenyl}-amide (P-2198), [2187] 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), [2188] 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), [2189] Propane-1-sulfonic acid
{3-[5-(2-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluor-
o-phenyl}-amide (P-2212), [2190] 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), [2191] 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), [2192] Propane-1-sulfonic acid
(2,4-difluoro-3-{5-[6-(2-hydroxy-ethoxy)-pyridin-3-yl]-1H-pyrrolo[2,3-b]p-
yridine-3-carbonyl}-phenyl)-amide (P-2215), [2193]
Propane-1-sulfonic acid
(3-{5-[6-(3-diethylamino-propoxy)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine-
-3-carbonyl}-2,4-difluoro-phenyl)-amide (P-2216), [2194]
Propane-1-sulfonic acid
{3-[5-(4-ethanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-
-difluoro-phenyl}-amide (P-2218), [2195] 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), [2196]
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), [2197]
4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-N-(2-hydroxy-ethyl)-benzenesulfonamide (P-2221),
[2198] 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), [2199] Propane-1-sulfonic
acid
(2,4-difluoro-3-{5-[4-(pyrrolidine-1-sulfonyl)-phenyl]-1H-pyrrolo[2,3-b]p-
yridine-3-carbonyl}-phenyl)-amide (P-2227), [2200]
Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2228), [2201] 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), [2202] 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), [2203] 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), [2204]
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), [2205]
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), [2206] 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), [2207]
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), [2208]
Ethanesulfonic acid
{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-di-
fluoro-phenyl}-amide (P-2269), [2209] Ethanesulfonic acid
{2,4-difluoro-3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl-
]-phenyl}-amide (P-2270), [2210] Ethanesulfonic acid
{2,4-difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2271), [2211]
2-Methyl-propane-1-sulfonic acid
{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluor-
o-phenyl}-amide (P-2297), [2212] 2-Methyl-propane-1-sulfonic acid
{2,4-difluoro-3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl-
]-phenyl}-amide (P-2298), [2213] 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), [2214] Butane-1-sulfonic acid
{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluor-
o-phenyl}-amide (P-2300), [2215] Butane-1-sulfonic acid
{2,4-difluoro-3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl-
]-phenyl}-amide (P-2301), [2216] Butane-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-2302), [2217]
3,3,3-Trifluoro-propane-1-sulfonic acid
{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluor-
o-phenyl}-amide (P-2325), [2218] 3,3,3-Trifluoro-propane-1-sulfonic
acid
{2,4-difluoro-3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl-
]-phenyl}-amide (P-2326), [2219]
N-{3-[5-(4-Chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-diflu-
oro-phenyl}-C,C,C-trifluoro-methanesulfonamide (P-2343), [2220]
N-{2,4-Difluoro-3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbon-
yl]-phenyl}-C,C,C-trifluoro-methanesulfonamide (P-2344), [2221]
N-{2,4-Difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-
-3-carbonyl]-phenyl}-C,C,C-trifluoro-methanesulfonamide (P-2345),
[2222] Cyclopropanesulfonic acid
{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluor-
o-phenyl}-amide (P-2350), [2223] Cyclopropanesulfonic acid
{2,4-difluoro-3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl-
]-phenyl}-amide (P-2351), [2224] Cyclopropanesulfonic acid
{2,4-difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2352), [2225] 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), [2226] 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), [2227] Pyrrolidine-1-sulfonic
acid
{2-fluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-car-
bonyl]-phenyl}-amide (P-2422), [2228] N,N-dimethylamino-sulfonic
acid
{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-ph-
enyl}-amide (P-2423), [2229] N,N-dimethylamino-sulfonic acid
{2-fluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-car-
bonyl]-phenyl}-amide (P-2424), [2230] Pyrrolidine-1-sulfonic acid
{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-ph-
enyl}-amide (P-2425), [2231] Propane-1-sulfonic acid
{2-chloro-3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-4--
fluoro-phenyl}-amide (P-2427), [2232] Propane-1-sulfonic acid
{2-chloro-4-fluoro-3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-car-
bonyl]-phenyl}-amide (P-2428), and [2233] Propane-1-sulfonic acid
{2-chloro-4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyrid-
ine-3-carbonyl]-phenyl}-amide (P-2429).
[2234] 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- 2147 ##STR00965##
##STR00966## ##STR00967## 498.3 P- 2148 ##STR00968## ##STR00969##
##STR00970## 527.1 P- 2154 ##STR00971## ##STR00972## ##STR00973##
491.1 P- 2155 ##STR00974## ##STR00975## ##STR00976## 475.1 P- 2156
##STR00977## ##STR00978## ##STR00979## 475.1 P- 2157 ##STR00980##
##STR00981## ##STR00982## 502.3 P- 2158 ##STR00983## ##STR00984##
##STR00985## 488.3 P- 2159 ##STR00986## ##STR00987## ##STR00988##
503.9 P- 2160 ##STR00989## ##STR00990## ##STR00991## 541.9 P- 2161
##STR00992## ##STR00993## ##STR00994## 513.1 P- 2162 ##STR00995##
##STR00996## ##STR00997## 458.3 P- 2164 ##STR00998## ##STR00999##
##STR01000## 475.1 P- 2165 ##STR01001## ##STR01002## ##STR01003##
549.1 P- 2166 ##STR01004## ##STR01005## ##STR01006## 605.2 P- 2167
##STR01007## ##STR01008## ##STR01009## 549.1 P- 2168 ##STR01010##
##STR01011## ##STR01012## 575.2 P- 2169 ##STR01013## ##STR01014##
##STR01015## 549.1 P- 2170 ##STR01016## ##STR01017## ##STR01018##
549.1 P- 2171 ##STR01019## ##STR01020## ##STR01021## P- 2172
##STR01022## ##STR01023## ##STR01024## P- 2174 ##STR01025##
##STR01026## ##STR01027## 446.0 P- 2175 ##STR01028## ##STR01029##
##STR01030## 460.4 P- 2176 ##STR01031## ##STR01032## ##STR01033##
446.0 P- 2177 ##STR01034## ##STR01035## ##STR01036## 459.0 P- 2178
##STR01037## ##STR01038## ##STR01039## 458.2 P- 2179 ##STR01040##
##STR01041## ##STR01042## 472.1 P- 2183 ##STR01043## ##STR01044##
##STR01045## 533.9 P- 2184 ##STR01046## ##STR01047## ##STR01048##
517.1 P- 2185 ##STR01049## ##STR01050## ##STR01051## 563.2 P- 2186
##STR01052## ##STR01053## ##STR01054## 603.2 P- 2187 ##STR01055##
##STR01056## ##STR01057## 503.1 P- 2188 ##STR01058## ##STR01059##
##STR01060## 535.1 P- 2189 ##STR01061## ##STR01062## ##STR01063##
503.9 P- 2190 ##STR01064## ##STR01065## ##STR01066## 536.3 P- 2191
##STR01067## ##STR01068## ##STR01069## 537.5 P- 2192 ##STR01070##
##STR01071## ##STR01072## 475.1 P- 2193 ##STR01073## ##STR01074##
##STR01075## 514.3 P- 2194 ##STR01076## ##STR01077## ##STR01078##
535.1 P- 2195 ##STR01079## ##STR01080## ##STR01081## 474.3 P- 2196
##STR01082## ##STR01083## ##STR01084## 501.1 P- 2197 ##STR01085##
##STR01086## ##STR01087## 543.1 P- 2198 ##STR01088## ##STR01089##
##STR01090## 472.1 P- 2199 ##STR01091## ##STR01092## ##STR01093##
517.9 P- 2211 ##STR01094## ##STR01095## ##STR01096## 472.0 P- 2212
##STR01097## ##STR01098## ##STR01099## 490.0 492.0 P- 2213
##STR01100## ##STR01101## ##STR01102## 471.0 P- 2214 ##STR01103##
##STR01104## ##STR01105## 472.5 P- 2215 ##STR01106## ##STR01107##
##STR01108## 517.0 P- 2216 ##STR01109## ##STR01110## ##STR01111##
586.5 P- 2218 ##STR01112## ##STR01113## ##STR01114## 546.5 [M -
H.sup.+].sup.- P- 2219 ##STR01115## ##STR01116## ##STR01117## 527.7
P- 2220 ##STR01118## ##STR01119## ##STR01120## 500.2 P- 2221
##STR01121## ##STR01122## ##STR01123## 579.6 P- 2223 ##STR01124##
##STR01125## ##STR01126## 562.3 P- 2227 ##STR01127## ##STR01128##
##STR01129## 589.6 P- 2228 ##STR01130## ##STR01131## ##STR01132##
532.3 [M - H.sup.+].sup.- P- 2229 ##STR01133## ##STR01134##
##STR01135## 500.4 P- 2231 ##STR01136## ##STR01137## ##STR01138##
526.4 P- 2232 ##STR01139## ##STR01140## ##STR01141## 586.1 P- 2233
##STR01142## ##STR01143## ##STR01144## 570.5 P- 2234 ##STR01145##
##STR01146## ##STR01147## 473.1 P- 2235 ##STR01148## ##STR01149##
##STR01150## 584.1 P- 2236 ##STR01151## ##STR01152## ##STR01153##
600.1 P- 2269 ##STR01154## ##STR01155## ##STR01156## P- 2270
##STR01157## ##STR01158## ##STR01159## P- 2271 ##STR01160##
##STR01161## ##STR01162## P- 2297 ##STR01163## ##STR01164##
##STR01165## P- 2298 ##STR01166## ##STR01167## ##STR01168## P- 2299
##STR01169## ##STR01170## ##STR01171## P- 2300 ##STR01172##
##STR01173## ##STR01174## 503.9 P- 2301 ##STR01175## ##STR01176##
##STR01177## 488.3 P- 2302 ##STR01178## ##STR01179## ##STR01180##
474.3 P- 2325 ##STR01181## ##STR01182## ##STR01183## 544.3 P- 2326
##STR01184## ##STR01185## ##STR01186## 529.1 P- 2343 ##STR01187##
##STR01188## ##STR01189## 516.3 P- 2344 ##STR01190## ##STR01191##
##STR01192## 500.3 P- 2345 ##STR01193## ##STR01194## ##STR01195##
486.3 P- 2350 ##STR01196## ##STR01197## ##STR01198## P- 2351
##STR01199## ##STR01200## ##STR01201## P- 2352 ##STR01202##
##STR01203## ##STR01204## P- 2407 ##STR01205## ##STR01206##
##STR01207## 470.1 P- 2408 ##STR01208## ##STR01209## ##STR01210##
483.6 P- 2422 ##STR01211## ##STR01212## ##STR01213## 597.1 P- 2423
##STR01214## ##STR01215## ##STR01216## 471.5 473.5 [M -
H.sup.+].sup.- P- 2424 ##STR01217## ##STR01218## ##STR01219## 469.6
[M - H.sup.+].sup.- P- 2425 ##STR01220## ##STR01221## ##STR01222##
499.1 501.1 P- 2427 ##STR01223## ##STR01224## ##STR01225## P- 2428
##STR01226## ##STR01227## ##STR01228## P- 2429 ##STR01229##
##STR01230## ##STR01231## P- 1496 ##STR01232## ##STR01233##
##STR01234## 487.9
Example 4
Synthesis of propane-1-sulfonic acid
[2,4-difluoro-3-(5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)--
phenyl]-amide P-2182
[2235] Propane-1-sulfonic acid
[2,4-difluoro-3-(5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)--
phenyl]-amide P-2182 was synthesized in two steps from
5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine 49 as shown in Scheme
6.
##STR01235##
Step 1--Preparation of propane-1-sulfonic acid
{2,4-difluoro-3-[hydroxy-(5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-3-yl-
)-methy]-phenyl}-amide (P-2473):
[2236] 5-Trifluoromethyl-1H-pyrrolo[2,3-b]pyridine (49, 100 mg,
0.537 mmol), propane-1-sulfonic acid
(2,4-difluoro-3-formyl-phenyl)-amide (50, 170 mg, 0.645 mmol) and
potassium hydroxide (90.4 mg, 1.61 mmol), were combined in a vial
with 2 mL of methanol. The reaction was stirred for 3 hours at room
temperature. The reaction solution was extracted with 20 mL of
ethyl acetate and 20 mL water (with 1N hydrochloric acid added to
pH.about.1). The organic layer was separated and the solvents
removed under vacuum, and the resulting residue was taken up in 4:1
acetonitrile:water with 5% TFA. This was allowed to stir over the
weekend at room temperature, then extracted with ethyl acetate and
water. The organic layer was washed with brine and then dried over
magnesium sulfate, filtered, and the solvents were removed from the
filtrate under vacuum. The resulting material was purified by
silica gel column chromatography eluting with a gradient of ethyl
acetate in hexanes to provide the desired compound (P-2473, 135
mg). MS (ESI) [M+H.sup.+].sup.+=449.9.
Step 2--Preparation of propane-1-sulfonic acid
[2,4-difluoro-3-(5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)--
phenyl]-amide (P-2182):
[2237] To propane-1-sulfonic acid
{2,4-difluoro-3-[hydroxy-(5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-3-yl-
)-methyl]-phenyl}-amide (P-2473, 135 mg, 0.300 mmol) dissolved in 2
mL of dichloromethane and 2 mL of tetrahydrofuran, Dess-Martin
periodinane (127 mg, 0.300 mmol) was added as a solid. The reaction
was a suspension, which was allowed to stir at room temperature for
15 minutes, then quenched with 60 mL of 5:1 saturated sodium
bicarbonate:saturated sodium bisulfite and 20 mL of ethyl acetate.
The mixture was stirred for 10 minutes, and the layers were
separated. The organic layer was washed with brine, dried over
anhydrous magnesium sulfate and filtered. The solvents were removed
from the filtrate under vacuum, and the resulting residue was
purified by silica gel column chromatography eluting with a
gradient from 1% to 5% methanol in dichloromethane to provide the
desired compound (P-2182, 53 mg). MS (ESI)
[M-H.sup.+].sup.-=446.0.
[2238] Additional compounds were prepared similarly to the protocol
of Scheme 6, 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-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine 49 with an appropriate
1H-pyrrolo[2,3-b]pyridine and/or propane-1-sulfonic acid
(2,4-difluoro-3-formyl-phenyl)-amide 50 with an appropriate
aldehyde in step 1. The following compounds were prepared by this
procedure: [2239]
N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-p-
henyl]-4-trifluoromethyl-benzenesulfonamide (P-1503), [2240]
N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-4-tr-
ifluoromethyl-benzenesulfonamide (P-2057), [2241]
N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-4-t-
rifluoromethyl-benzenesulfonamide (P-2058), [2242]
N-[2-Fluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-t-
rifluoromethyl-benzenesulfonamide (P-2059), [2243]
N-[2-Fluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4--
trifluoromethyl-benzenesulfonamide (P-2060), [2244]
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
(P-2150), [2245]
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),
[2246] Propane-1-sulfonic acid
{3-[5-(1,5-dimethyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbony-
l]-2,4-difluoro-phenyl}-amide (P-2152), [2247] Propane-1-sulfonic
acid
{2,4-difluoro-3-[5-(1-methyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine--
3-carbonyl]-phenyl}-amide (P-2153), [2248] Propane-1-sulfonic acid
[2,4-difluoro-3-(5-methanesulfonyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)--
phenyl]-amide (P-2173), [2249]
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),
[2250]
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),
[2251]
3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyr-
idine-5-carboxylic acid methylamide (P-2200), [2252]
3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyr-
idine-5-carboxylic acid cyclopropylamide (P-2201), [2253]
Propane-1-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-1499), [2254] 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), [2255]
Propane-1-sulfonic acid
[2,4-difluoro-3-(5-hydroxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2204), [2256]
3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyr-
idine-5-carboxylic acid ethyl ester (P-2207), [2257]
Propane-1-sulfonic acid
[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phen-
yl]-amide (P-2208), [2258] Propane-1-sulfonic acid
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2209), [2259] Propane-1-sulfonic acid
[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2210), [2260] 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), [2261]
(E)-3-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,-
3-b]pyridin-5-yl}-acrylic acid methyl ester (P-2225), [2262]
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), [2263]
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), [2264] 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), [2265] Propane-1-sulfonic acid
[2,4-difluoro-3-(5-morpholin-4-ylmethyl-1H-pyrrolo[2,3-b]pyridine-3-carbo-
nyl)-phenyl]-amide (P-2244), [2266] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(3-morpholin-4-yl-propyl)-1H-pyrrolo[2,3-b]pyridine-3--
carbonyl]-phenyl}-amide (P-2247), [2267] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(3-pyrrolidin-1-yl-propyl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide (P-2248), [2268] Propane-1-sulfonic acid
[2,4-difluoro-3-(5-hydroxymethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-ph-
enyl]-amide (P-2250), [2269]
3-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-N,N-diethyl-propionamide (P-2255), [2270]
Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(4-methyl-piperazin-1-ylmethyl)-1H-pyrrolo[2,3-b]-
pyridine-3-carbonyl]-phenyl}-amide (P-2257), [2271]
Propane-1-sulfonic acid
[3-(5-diethylaminomethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-d-
ifluoro-phenyl]-amide (P-2258), [2272] Propane-1-sulfonic acid
[2,4-difluoro-3-(5-pyrrolidin-1-ylmethyl-1H-pyrrolo[2,3-b]pyridine-3-carb-
onyl)-phenyl]-amide (P-2259), [2273] Propane-1-sulfonic acid
[3-(5-ethynyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
amide (P-2260), [2274] Propane-1-sulfonic acid
[3-(4-ethynyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
amide (P-2261), [2275] Ethanesulfonic acid
[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2268), [2276] 2-Methyl-propane-1-sulfonic acid
[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2296), [2277] Cyclopropanesulfonic acid
[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2348), [2278]
1-[3-(5-Bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenylsu-
lfamoyl]-cyclopropanecarboxylic acid (P-2349), [2279]
Propane-1-sulfonic acid
[2-fluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]--
amide (P-2403), [2280]
3-[2-Fluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-
e-5-carboxylic acid methyl ester (P-2404), [2281]
Propane-1-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-1502), [2282]
3-[2-Fluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-
e-5-carboxylic acid ethyl ester (P-2406), [2283] Propane-1-sulfonic
acid
[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide
(P-2409), [2284] Propane-1-sulfonic acid
[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-chloro-4-fluoro-pheny-
l]-amide (P-2426), [2285] Butane-1-sulfonic acid
{2-chloro-4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyrid-
ine-3-carbonyl]-phenyl}-amide (P-2430), [2286]
N-[3-(4-Ethynyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl-
]-4-trifluoromethyl-benzenesulfonamide (P-1504), [2287]
3,3,3-Trifluoro-propane-1-sulfonic acid
[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2478), [2288]
N-[3-(5-Bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
C,C,C-tri fluoro-methanesulfonamide (P-2479), and [2289]
Propane-1-sulfonic acid
[2-fluoro-3-(5-iodo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide
(P-2480), [2290]
N-[2,4-Difluoro-3-(5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-
-4-trifluoromethyl-benzenesulfonamide (P-2482), [2291]
N-[3-(5-Cyclopropyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-ph-
enyl]-4-trifluoromethyl-benzenesulfonamide (P-2483), [2292]
N-[3-(5-Ethynyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl-
]-4-trifluoromethyl-benzenesulfonamide (P-2484), and [2293]
N-[3-(4-Ethynyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-4--
trifluoromethyl-benzenesulfonamide (P-2487). 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 [2293] MS (ESI) [M + 1H- H.sup.+].sup.+ pyrrolo[2,3-
ob- b]pyridine Aldehyde Compound served P- 1503 ##STR01236##
##STR01237## ##STR01238## 505.5 ([M - H.sup.+].sup.-) P- 2057
##STR01239## ##STR01240## ##STR01241## 487.7 ([M - H.sup.+].sup.-)
P- 2058 ##STR01242## ##STR01243## ##STR01244## 496.4 498.4 ([M -
H.sup.+].sup.-) P- 2059 ##STR01245## ##STR01246## ##STR01247##
478.2 P- 2060 ##STR01248## ##STR01249## ##STR01250## 494.1 P- 2150
Iso- late after step 1 ##STR01251## ##STR01252## ##STR01253## 530.1
P- 2151 ##STR01254## ##STR01255## ##STR01256## 528.2 P- 2152
##STR01257## ##STR01258## ##STR01259## 474.2 P- 2153 ##STR01260##
##STR01261## ##STR01262## 460.2 P- 2173 ##STR01263## ##STR01264##
##STR01265## 456.0 ([M - H.sup.+].sup.-) P- 2180 ##STR01266##
##STR01267## ##STR01268## 512.1 ([M - H.sup.+].sup.-) P- 2181
##STR01269## ##STR01270## ##STR01271## 538.1 ([M - H.sup.+].sup.-)
P- 2200 ##STR01272## ##STR01273## ##STR01274## 437.1 P- 2201
##STR01275## ##STR01276## ##STR01277## 462.8 P- 1499 ##STR01278##
##STR01279## ##STR01280## 403.2 ([M - H.sup.+].sup.-) P- 2203
##STR01281## ##STR01282## ##STR01283## 559.1 P- 2204 ##STR01284##
##STR01285## ##STR01286## 396.3 P- 2207 ##STR01287## ##STR01288##
##STR01289## 450.3 ([M - H.sup.+].sup.-) P- 2208 ##STR01290##
##STR01291## ##STR01292## 414.1 P- 2209 ##STR01293## ##STR01294##
##STR01295## 403.3 ([M - H.sup.+].sup.-) P- 2210 ##STR01296##
##STR01297## ##STR01298## 410.2 ([M - H.sup.+].sup.-) P- 2222
##STR01299## ##STR01300## ##STR01301## 566.7 P- 2225 ##STR01302##
##STR01303## ##STR01304## 464.2 P- 2226 ##STR01305## ##STR01306##
##STR01307## 529.6 P- 2239 ##STR01308## ##STR01309## ##STR01310##
448.1 P- 2241 ##STR01311## ##STR01312## ##STR01313## 489.3 P- 2244
##STR01314## ##STR01315## ##STR01316## 479.7 P- 2247 ##STR01317##
##STR01318## ##STR01319## 507.1 P- 2248 ##STR01320## ##STR01321##
##STR01322## 491.4 P- 2250 ##STR01323## ##STR01324## ##STR01325##
410.0 P- 2255 ##STR01326## ##STR01327## ##STR01328## 507.0 P- 2257
##STR01329## ##STR01330## ##STR01331## 492.5 P- 2258 ##STR01332##
##STR01333## ##STR01334## P- 2259 ##STR01335## ##STR01336##
##STR01337## 463.1 P- 2260 ##STR01338## ##STR01339## ##STR01340##
404.2 P- 2261 ##STR01341## ##STR01342## ##STR01343## 404.0 P- 2268
##STR01344## ##STR01345## ##STR01346## 441.9 443.9 [M -
H.sup.+].sup.- P- 2296 ##STR01347## ##STR01348## ##STR01349## 469.9
471.9 [M - H.sup.+].sup.- P- 2348 ##STR01350## ##STR01351##
##STR01352## 453.9 455.9 [M - H.sup.+].sup.- P- 2349* ##STR01353##
##STR01354## ##STR01355## 497.9 499.9 [M - H.sup.+].sup.- P- 2403
##STR01356## ##STR01357## ##STR01358## 376.2 P- 2404 ##STR01359##
##STR01360## ##STR01361## 418.4 [M - H.sup.+].sup.- P- 1502
##STR01362## ##STR01363## ##STR01364## 385.4 [M - H.sup.+].sup.- P-
2406 ##STR01365## ##STR01366## ##STR01367## 432.3 [M -
H.sup.+].sup.- P- 2409 ##STR01368## ##STR01369## ##STR01370## 387.2
P- 2426 ##STR01371## ##STR01372## ##STR01373## 474.0 [M -
H.sup.+].sup.- P- 2430 ##STR01374## ##STR01375## ##STR01376## 490.7
P- 1504 ##STR01377## ##STR01378## ##STR01379## 506 P- 2478
##STR01380## ##STR01381## ##STR01382## P- 2479 ##STR01383##
##STR01384## ##STR01385## P- 2480 ##STR01386## ##STR01387##
##STR01388## 486.4 [M - H.sup.+].sup.- P- 2482 ##STR01389##
##STR01390## ##STR01391## 499.6 P- 2483 ##STR01392## ##STR01393##
##STR01394## 522.4 P- 2484 ##STR01395## ##STR01396## ##STR01397##
506.0 P- 2487 ##STR01398## ##STR01399## ##STR01400## 487.9
*isolated by-product of reaction for P-2348.
Example 5
Synthesis of
5-(2-oxo-hexahydro-thieno[3,4-d]imidazol-6-yl)-pentanoic acid
[5-(3-{3-[2,6-difluoro-3-(4-trifluoromethyl-benzene
sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-propionylamino)-pe-
ntyl]-amide P-2008
[2294] 5-(2-Oxo-hexahydro-thieno[3,4-d]imidazol-6-yl)-pentanoic
acid
[5-(3-{3-[2,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoyl-
]-1H-pyrrolo[2,3-b]pyridin-5-yl}-propionylamino)-pentyl]-amide
P-2008 was synthesized in one step from
3-{3-[2,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoyl]-1H-
-pyrrolo[2,3-b]pyridin-5-yl}-propionic acid P-1095 as shown in
Scheme 7.
##STR01401##
Step 1--Preparation of
5-(2-oxo-hexahydro-thieno[3,4-d]imidazol-6-yl)-pentanoic acid
[5-(3-{3-[2,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoyl-
]-1H-pyrrolo[2,3-b]pyridin-5-yl}-propionylamino)-pentyl]-amide
(P-2008):
[2295] In a vial,
3-{3-[2,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoyl]-1H-
-pyrrolo[2,3-b]pyridin-5-yl}-propionic acid (P-1095, 278 mg, 0.502
mmol) was dissolved in 20 mL of tetrahydrofuran, followed by the
addition of
5-(2-oxo-hexahydro-thieno[3,4-d]imidazol-6-yl)-pentanoic acid
(5-amino-pentyl)-amide (150.0 mg, 0.457 mmol). To the resulting
suspension, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide
hydrochloride (175 mg, 0.913 mmol) was added and the reaction was
stirred at room temperature overnight. This resulted in a solid
material to which 10 mL of dimethylformamide was added in order to
dissolve most of the solid, and the reaction was stirred at room
temperature for another 24 hours. 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. The solvents were removed under
vacuum and the resulting crude material was purified by silica gel
chromatography eluting with ethyl acetate with 4% acetic acid,
gradient of 0-15% with methanol in dichloromethane. The appropriate
fractions were combined and concentrated under vacuum. This was
found to have some impurity, and was further purified by
preparitive HPLC. Lyophilization of the appropriate fractions
provided the desired compound as a white fluffy solid (P-2008, 57
mg). MS (ESI) [M+H.sup.+].sup.+=864.3.
Example 6
Synthesis of
3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1,1-pyrrolo[2,3-b]py-
ridine-5-carboxylic acid (2-hydroxy-ethyl)-amide P-2217
[2296]
3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-
-b]pyridine-5-carboxylic acid (2-hydroxy-ethyl)-amide P-2217 was
synthesized in one step from
3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyr-
idine-5-carboxylic acid P-1213 as shown in Scheme 8.
##STR01402##
[2297] Step 1--Preparation of
3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyr-
idine-5-carboxylic acid (2-hydroxy-ethyl)-amide (P-2217):
[2298]
3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-
-b]pyridine-5-carboxylic acid (P-1213, 0.206 g, 0.486 mmol) was
dissolved in 3.9 mL of tetrahydrofuran and
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.149
g, 0.778 mmol), N,N-diisopropylethylamine (0.426 mL, 2.44 mmol),
and 1-hydroxybenzotriazole (0.0855 g, 0.632 mmol) were added,
followed by addition of ethanolamine (52, 0.0341 mL, 0.564 mmol).
The reaction mixture was stirred overnight at room temperature,
then 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 and the crude material was purified by
silica gel flash chromatography to provide the desired compound
(P-2217, 6 mg). MS (ESI) [M+H.sup.+].sup.+=467.5.
[2299]
3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-
-b]pyridine-5-carboxylic acid dimethyl amide P-2237, P-2238, and
P-2243,
##STR01403##
were prepared following the protocol of Scheme 8, replacing
ethanolamine 52 with dimethylamine (P-2237), replacing ethanolamine
52 with methoxylamine hydrochloride, using N,N-dimethylformamide in
place of tetrahydrofuran, and using 1-methylpyrrolidine in place of
N,N-diisopropylethylamine (P-2238), or replacing ethanolamine 52
with methoxylamine hydrochloride, using N,N-dimethylformamide in
place of tetrahydrofuran, using 1-methylpyrrolidine in place of
N,N-diisopropylethylamine and replacing
3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyr-
idine-5-carboxylic acid P-1213 with
3-{3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]-
pyridin-5-yl}-propionic acid P-1206 (P-2243). P-2237 MS (ESI)
[M+H.sup.+].sup.+=451.2, P-2238 MS (ESI) [M+H.sup.+].sup.+=453.2,
and P-2243 MS (ESI) [M+H.sup.+].sup.30 =481.8.
Example 7
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
[2300] 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 9.
##STR01404##
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):
[2301] 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.
[2302]
3-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[-
2,3-b]pyridin-5-yl}-propionic acid methyl ester P-2230, and
propane-1-sulfonic acid
{2,4-difluoro-3-[5-(3-methoxy-propyl)-1H-pyrrolo[2,3-b]pyridine-3-carbony-
l]-phenyl}-amide P-2240,
##STR01405##
were prepared similarly by hydrogenation following the protocol of
Scheme 9, using palladium hydroxide 20% on carbon in place of
platinum dioxide and replacing 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 with either
(E)-3-{3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,-
3-b]pyridin-5-yl}-acrylic acid methyl ester P-2225 or
propane-1-sulfonic acid
{2,4-difluoro-3-[5-(3-methoxy-prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridine-
-3-carbonyl]-phenyl}-amide P-2239, respectively. P-2230 MS (ESI)
[M+H.sup.+].sup.+=466.0, P-2240 MS (ESI)
[M+H.sup.+].sup.+=452.2.
Example 8
Synthesis of propane-1-sulfonic acid
{2,4-difluoro-3-[5-(2H-tetrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbony-
l]-phenyl}-amide P-2242
[2303] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(2H-tetrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbony-
l]-phenyl}-amide P-2242 was synthesized in one step from
propane-1-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide P-1499 as shown in Scheme 10.
##STR01406##
Step 1--Preparation of propane-1-sulfonic acid
{2,4-difluoro-3-[5-(2H-tetrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbony-
l]-phenyl}-amide (P-2242):
[2304] In a vial, propane-1-sulfonic acid
[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-1499, 0.217 g, 0.537 mmol) was combined with
azidotrimethylsilane (53, 356 .mu.L, 2.68 mmol) and
dibutyloxostannane (24 mg, 0.096 mmol) in 1.5 mL of toluene. The
mixture was heated at 110.degree. C. for 24 hours, and remained as
a suspension. 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 some acetonitrile and sonicated for 10 minutes.
The precipitated material was collected by filtration and dried
under vacuum to provide the desired compound as an off-white solid
(P-2242, 98 mg). .sup.1H-NMR (dmso-d6) was consistent with the
desired compound structure. MS (ESI) [M+H.sup.+].sup.+=448.0.
Example 9
Synthesis of 2,2,2-trifluoro-ethanesulfonic acid
[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide P-2334
[2305] 2,2,2-Trifluoro-ethanesulfonic acid
[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide P-2334 was synthesized in one step from
5-bromo-1H-pyrrolo[2,3-b]pyridine 54 as shown in Scheme 11.
##STR01407##
Step 1--Preparation of 2,2,2-trifluoro-ethanesulfonic acid
[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-am-
ide (P-2334):
[2306] To
2,6-difluoro-3-(2,2,2-trifluoro-ethanesulfonylamino)-benzoic acid
(55, 0.520 g, 1.63 mmol) 2 mL of dichloromethane and 2 mL of
tetrahydrofuran were added, followed by thionyl chloride (297
.mu.L, 4.07 mmol). The reaction was placed in a 50.degree. C. oil
bath. After 45 minutes, the reaction had turned clear and solvent
was removed and the solid dried under vacuum for 1 hour. In a
separate reaction flask, 5-bromo-1H-pyrrolo[2,3-b]pyridine (54,
0.267 g, 1.36 mmol) and aluminum trichloride (0.905 g, 6.79 mmol)
in 10 mL of dichloromethane was stirred at room temperature for 1
hour, becoming a cloudy orange colored solution. The dried acid
chloride reaction was added to this reaction as a solution in
dichloromethane and the reaction was allowed to stir overnight. The
reaction was quenched with methanol, providing a clear solution.
Solvent was removed under vacuum to reduce the volume, and the
crude reaction mixture was purified by silica gel column
chromatography. Appropriate fractions were combined and the
solvents removed to provide the desired compound as a solid
(P-2334, 6 mg). MS (ESI) [M-H.sup.+].sup.-=496.0, 498.0.
Example 10
Synthesis of propane-1-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-sulfonyl)-phenyl]-amide
P-2467
[2307] Propane-1-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-sulfonyl)-phenyl]-amide
P-2467 was synthesized in four steps from
5-chloro-1H-pyrrolo[2,3-b]pyridine 5 as shown in Scheme 12.
##STR01408##
Step 1--Preparation of
5-chloro-3-(3-nitro-phenylsulfanyl)-1H-pyrrolo[2,3-b]pyridine
(57):
[2308] Into a round bottom flask,
5-chloro-1H-pyrrolo[2,3-b]pyridine (5, 0.200 g, 1.31 mmol) was
dissolved in 10 mL of N,N-dimethylformamide at 0.degree. C. and
sodium hydride (63 mg, 1.6 mmol) was added to the flask in one
portion. The reaction was allowed to stir for 15 minutes, then
3-nitrophenyl disulfide (56, 490 mg, 1.6 mmol) was added in one
portion to the flask. The reaction was stirred at room temperature
overnight. The reaction was diluted with 3 volumes of water, and
extracted 3.times. with ethyl acetate. The combined organic layers
were washed 2.times. with water, 2.times. with brine, dried over
sodium sulfate, filtered and the filtrate concentrated under vacuum
to provide an orange solid. The solid was triturated with
dichloromethane and collected by filtration to provide the desired
compound as a yellow solid. MS (ESI) [M-H.sup.+].sup.-=305.9.
Step 2--Preparation of
5-chloro-3-(3-nitro-benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine
(58):
[2309] Into a round bottom flask,
5-chloro-3-(3-nitro-phenylsulfanyl)-1H-pyrrolo[2,3-b]pyridine (57,
0.100 g, 0.326 mmol) was dissolved in 3 mL of
N,N-dimethylformamide, m-chloroperbenzoic acid (0.1 g, 0.6 mmol)
was added, and the reaction was stirred at room temperature for 3
hours, after which an additional 100 mg of m-chloroperbenzoic acid
was added and the reaction stirred for another 16 hours. The
reaction was diluted with water: saturated sodium bicarbonate
solution (1:1), and extracted 4.times. with ethyl acetate. The
combined organic layers were washed 3.times. with brine, dried over
sodium sulfate, filtered and the filtrate concentrated under
vacuum. This crude material was taken on to the next step without
further purification (approximately 50% purity by MS analysis).
Step 3--Preparation of
3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-sulfonyl)-phenylamine
(59):
[2310] To
5-chloro-3-(3-nitro-benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine (58,
0.14 g, 0.41 mmol), 30 mL of ethanol was added, followed by tin
dichloride (0.39 g, 2.1 mmol). The reaction was stirred at
58.degree. C. overnight, then diluted with brine, and extracted
3.times. with ethyl acetate. The combined organic layers were
washed 3.times. with brine, dried over sodium sulfate, and
evaporated under reduced pressure to provide a yellow solid. This
was treated further with 50 mL of water and 50 mL of saturated
sodium bicarbonate, 100 mL of ethyl acetate was added and the milky
suspension was treated with celite and mixed well before filtering.
Brine was added to give clear layers that were separated and the
organic layer was dried with magnesium sulfate, filtered and the
filtrate concentrated under vacuum. The residue was purified by
silica gel chromatography eluting with ethyl acetate/hexane. The
appropriate fractions were combined and concentrated under vacuum
to provide the desired compound as a yellow solid (59, 466 mg).
.sup.1H-NMR (dmso-d6) was consistent with the desired compound
structure. MS (ESI) [M-H.sup.+].sup.-=306.5 and 308.5.
[2311] Step 4--Preparation of propane-1-sulfonic acid
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-sulfonyl)-phenyl]-amide
(P-2467):
[2312] Into a round bottom flask,
3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-sulfonyl)-phenylamine (59,
0.1 g, 0.2 mmol) was dissolved in 1 mL of tetrahydrofuran and 1 mL
of pyridine. Propane-1-sulfonyl chloride (60, 0.044 mL, 0.39 mmol)
was added in one portion, and the reaction was allowed to stir at
room temperature for 3 days, after which the reaction was warmed at
35.degree. C. overnight. The reaction was diluted with water, and
extracted 3.times. with ethyl acetate. The combined organic layers
were washed with 2.times. brine, dried over sodium sulfate,
filtered and the filtrate concentrated under vacuum to provide a
solid. The solid was purified using reverse phase chromatography to
provide the desired compound (P-2467, 15 mg),along with an impurity
that runs close to the product (difficult to isolate). .sup.1H-NMR
was consistent with the desired compound structure. MS (ESI)
[M-H.sup.+].sup.-=412.38.
Example 11
Synthesis of
N-(6-acetylamino-pyridin-3-yl)-3-amino-2,6-difluoro-benzamide
64
[2313]
N-(6-Acetylamino-pyridin-3-yl)-3-amino-2,6-difluoro-benzamide 64
was synthesized in two steps from
N-(5-amino-pyridin-2-yl)-acetamide 61 as shown in Scheme 13.
##STR01409##
Step 1--Preparation of
N-(6-acetylamino-pyridin-3-yl)-2,6-difluoro-3-nitro-benzamide
(63):
[2314] To N-(5-amino-pyridin-2-yl)-acetamide (61, 1.53 g, 10.1
mmol), 20 mL of tetrahydrofuran was added followed by pyridine
(0.900 mL, 11.1 mmol). To this suspension a solution of
2,6-difluoro-3-nitro-benzoyl chloride (62, 2.24 g, 10.1 mmol) in 10
mL of tetrahydrofuran was added, the reaction was stirred at room
temperature overnight, then extracted with addition of ethyl
acetate and water (with added hydrochloric acid). The organic layer
was washed with brine, and the combined aqueous layers were
extracted with ethyl acetate. The combined organic layers were
dried over anhydrous magnesium sulfate, filtered and the filtrate
concentrated under vacuum and this material was purified by silica
gel column chromatography eluting with a gradient of 1 to 6%
methanol in dichloromethane to provide the desired compound (63,
1.527 g). MS (ESI) [M+H.sup.+].sup.+=336.9.
Step 2--Preparation of
N-(6-acetylamino-pyridin-3-yl)-3-amino-2,6-difluoro-benzamide
(64):
[2315] To
N-(6-acetylamino-pyridin-3-yl)-2,6-difluoro-3-nitro-benzamide (63,
0.500 g, 1.49 mmol) in 30 mL of ethanol and 85 mL of
tetrahydrofuran, .about.3 cc of raney nickle slurry in water was
added. Then, the reaction was placed in a parr hydrogenator under
hydrogen (0.0718 g, 35.5 mmol) at 35 psi. The reaction was left
over the weekend, after which it was filtered through celite and
all volatile solvents removed from the filtrate to give crude
material that was purified by silica gel column chromatography
eluting with 1 to 6% methanol in dichloromethane to provide the
desired product (64, 345 mg). MS (ESI) [M+H.sup.+].sup.+=306.9.
Example 12
Synthesis of
6-acetylamino-N-(3-amino-2,6-difluoro-phenyl)-nicotinamide 68
[2316] 6-Acetylamino-N-(3-amino-2,6-difluoro-phenyl)-nicotinamide
68 was synthesized in two steps from 6-acetylamino-nicotinic acid
65 as shown in Scheme 14.
##STR01410##
Step 1--Preparation of
6-acetylamino-N-(2,6-difluoro-3-nitro-phenyl)-nicotinamide
(67):
[2317] In a vial, 6-acetylamino-nicotinic acid (65, 0.362 g, 2.01
mmol) and cyanuric chloride (0.371 g, 2.01 mmol) were mixed in 10
mL of tetrahydrofuran, followed by the addition of pyridine (162
.mu.L, 2.01 mmol) dropwise at room temperature. The reaction
mixture was stirred at room temperature for 5 hours, after which
2,6-difluoro-3-nitro-phenylamine (66, 0.200 g, 1.15 mmol) in 2 mL
of tetrahydrofuran and pyridine (320 .mu.L, 4.0 mmol) were added
and the reaction stirred at room temperature for 4 days. Water
(with 1N hydrochloric acid) was added the mixture extracted with
ethyl acetate. The organic layer was washed with water and brine,
then dried over magnesium sulfate. The volatile solvents were
removed under vacuum and the residue was purified by silica gel
chromatography eluting with ethyl acetate/hexane. The appropriate
fractions were combined and concentrated under vacuum to provide
the desired compound (67, 225 mg). .sup.1H-NMR (dmso-d6) was
consistent with the desired compound. MS (ESI)
[M+H.sup.+].sup.+=337.1.
Step 2--Preparation of
6-acetylamino-N-(3-amino-2,6-difluoro-phenyl)-nicotinamide
(68):
[2318] To
6-acetylamino-N-(2,6-difluoro-3-nitro-phenyl)-nicotinamide (67,
0.431 g, 1.28 mmol) in 20 mL of ethanol and 75 mL of
tetrahydrofuran, .about.3 cc of raney nickle slurry in water. The
reaction was placed in a flask under hydrogen (0.0619 g, 30.6 mmol)
with a balloon. After 4 hours, the reaction was filtered through
celite and all volatile solvents removed from the filtrate to give
crude material that was purified by silica gel chromatography
eluting with ethyl acetate/hexane. The appropriate fractions were
combined and concentrated under vacuum to provide the desired
compound as a white solid (68, 310 mg). .sup.1H-NMR (dmso-d6) was
consistent with the desired compound. MS (ESI)
[M+H.sup.+].sup.+=307.1.
Example 13
Synthesis of 5-ethynyl-1H-pyrrolo[2,3-b]pyridine 72
[2319] 5-Ethynyl-1H-pyrrolo[2,3-b]pyridine 72 was synthesized in
two steps from 5-iodo-1H-pyrrolo[2,3-b]pyridine 69 as shown in
Scheme 15.
##STR01411##
Step 1--Preparation of
5-trimethylsilanylethynyl-1,1-pyrrolo[2,3-b]pyridine (71):
[2320] 5-Iodo-1H-pyrrolo[2,3-b]pyridine (69, 0.303 g, 1.22 mmol),
(trimethylsilyl)acetylene (70, 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 (71, 0.237 g). MS
(ESI) [M+H.sup.+].sup.+=215.3.
Step 2--Preparation of 5-ethynyl-1H-pyrrolo[2,3-b]pyridine
(72):
[2321] 5-Trimethylsilanylethynyl-1H-pyrrolo[2,3-b]pyridine (71,
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 (72, 0.155 g). MS (ESI) [M+H.sup.+].sup.+=143.3.
Example 14
Synthesis of 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl
ester 74
[2322] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester 74
was synthesized in one step from
1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid 73 as shown in Scheme
16.
##STR01412##
Step 1--Preparation of 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid
ethyl ester (74):
[2323] To 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (73, 0.511 g,
3.15 mmol) in 18 mL of ethanol, sulfuric acid (2.5 mL, 0.047 mol)
was added. The resulting mixture was refluxed overnight. The
solvents were reduced under vacuum, and the residue was poured into
5% aqueous sodium bicarbonate 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 and the crude material was purified by
silica gel flash chromatography. The appropriate fractions were
combined to provide the desired compound as a white solid. MS (ESI)
[M+H.sup.+].sup.+=191.2.
Example 15
Synthesis of 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid
methylamide 75
[2324] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid methylamide 75
was synthesized in one step from
1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid 73 as shown in Scheme
17.
##STR01413##
Step 1--Preparation of 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid
methylamide (75):
[2325] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid (73, 0.441 g,
2.72 mmol) was dissolved in 22 mL of tetrahydrofuran.
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.834
g, 4.35 mmol), N,N-diisopropylethylamine (2.37 mL, 13.6 mmol), and
1-hydroxybenzotriazole (0.478 g, 3.54 mmol) were added, followed by
a mixture of methylammonium chloride (0.213 g, 3.15 mmol) and
triethylamine (0.455 mL, 3.26 mmol) in 2 mL of tetrahydrofuran. The
resulting mixture was very cloudy, and 1.5 ml of dimethylformamide
was added. The reaction was stirred overnight at room temperature.
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 and the crude material was purified by
silica gel flash chromatography. The appropriate fractions were
combined and solvents removed under vacuum to provide the desired
compound as a white solid (75, 198 mg). MS (ESI)
[M+H.sup.+].sup.+=176.0.
[2326] 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid cyclopropylamide
76,
##STR01414##
was prepared following the protocol of Scheme 17, replacing
methylammonium chloride and triethylamine with cyclopropylamine. MS
(ESI) [M+H.sup.+].sup.+=202.0.
Example 16
Synthesis of 5-morpholin-4-ylmethyl-1H-pyrrolo[2,3-b]pyridine
79
[2327] 5-Morpholin-4-ylmethyl-1H-pyrrolo[2,3-b]pyridine-79 was
synthesized in one step from
1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde 77 as shown in Scheme
18.
##STR01415##
Step 1--Preparation of
5-morpholin-4-ylmethyl-1H-pyrrolo[2,3-b]pyridine (79):
[2328] To 1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (77, 0.303 g,
2.07 mmol), 20 mL of dichloromethane was added followed by
morpholine (78, 181 .mu.L, 2.07 mmol) and then acetic acid (354
.mu.L, 6.22 mmol). This suspension was stirred at room temperature
for 30 minutes, then sodium triacetoxyborohydride (1.32 g, 6.22
mmol) was added. The reaction was stirred over the weekend, then
was quenched with methanol and all volatile solvents were removed
under vacuum. The solid was treated with .about.50 mL of
tetrahydrofuran and the white precipitate was removed by
filtration. Solvents were removed under vacuum from the filtrate to
give crude solid that was purified by silica gel column
chromatography eluting with a gradient of 1 to 10% methanol in
dichloromethane. The appropriate fractions were combined and the
solvents removed under vacuum to provide the desired compound (79,
395 mg). MS (ESI) [M+H.sup.+].sup.+=218.1.
[2329] 5-Pyrrolidin-1-ylmethyl-1H-pyrrolo[2,3-b]pyridine 80,
5-(4-methyl-piperazin-1-ylmethyl)-1H-pyrrolo[2,3-b]pyridine 81, and
diethyl-(1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)-amine 82,
##STR01416##
were prepared following the protocol of Scheme 18, replacing
morpholine 78 with pyrrolidine, 1-methyl-piperazine and
diethyl-amine, respectively. MS (ESI) [M+H.sup.+].sup.+=202.4 (80),
231.2 (81), and 204.9 (82).
Example 17
Synthesis of
N,N-diethyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-propionamide 87
[2330] N,N-Diethyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-propionamide
87 was synthesized in three steps from
(E)-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-acrylic acid methyl ester 83
as shown in Scheme 19.
##STR01417##
Step 1--Preparation of 3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-propionic
acid methyl ester (84):
[2331] Into a 1-neck round-bottom flask,
(E)-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-acrylic acid methyl ester
(4.615 g, 22.82 mmol) was dissolved in 150 mL of methanol and 200
mL of tetrahydrofuran. This solution was degassed with nitrogen gas
for 5 minutes and 465 mg of 10% Pd/C was added to the solution. The
mixture was hydrogenation with a hydrogen balloon and stirred at
room temperature overnight. The Pd/C was removed by filtration and
solvents removed from the filtrates under vacuum to provide the
desired compound 84. MS (ESI) [M+H.sup.+].sup.+=205.2.
Step 2--Preparation of 3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-propionic
acid (85):
[2332] Into a round bottom flask,
3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-propionic acid methyl ester (84,
4.21 g, 20.6 mmol) was dissolved in 150 mL of tetrahydrofuran and a
solution of lithium hydroxide (3550 mg, 0.0845 mol, dissolved in 84
mL of deionized water) was added. The mixture was heated at
50.degree. C. for 2 hours, then the reaction mixture was acidified
to pH-1-2 with 6 N hydrochloric acid and extracted with ethyl
acetate and water. The aqueous layer was adjusted pH.about.3-4
resulting in a precipitate, which was collected with filtration to
provided 1.051 g of the desired compound. MS (ESI)
[M+H.sup.+].sup.+=191.4. The aqueous layer was then extracted with
ethyl acetate and the combined organic layers was washed with water
and brine, and dried with magnesium sulfate and filtered. The
filtrate was concentrated under vacuum to provide an additional
1.67 g of the desired compound.
Step 3--Preparation of
N,N-diethyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-propionamide
(87):
[2333] In a vial, 3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-propionic acid
(85, 401 mg, 2.11 mmol) was dissolved in 20 mL of tetrahydrofuran
and diethyl-amine (86, 436 .mu.L, 4.22 mmol) was added.
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (808
mg, 4.22 mmol) was added and the reaction was stirred at room
temperature overnight. The reaction mixture was extracted with
ethyl acetate and water saturated with sodium chloride. The organic
layer was washed with water and brine, then dried over magnesium
sulfate and filtered. The filtrate was concentrated under vacuum
and the crude material was purified by silica gel column
chromatography eluting with methanol/dichloromethane. The
appropriate fractions were combined and solvents removed under
vacuum to provide the desired compound as an oily material (87, 267
mg). MS (ESI) [M+H.sup.+].sup.+=246.5.
[2334]
1-Pyrrolidin-1-yl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-propan-1-one
88, and
1-morpholin-4-yl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-propan-1-one
89,
##STR01418##
were prepared following the protocol of Scheme 19, replacing
diethyl-amine 86 with pyrrolidine, and morpholine, respectively in
Step 3. MS (ESI) [M+H.sup.+].sup.+=244.5 (88), and 260.5 (89).
[2335]
1-Pyrrolidin-1-yl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-propan-1-one 88
was reacted according to the following step 4 to provide
5-(3-pyrrolidin-1-yl-propyl)-1H-pyrrolo[2,3-b]pyridine 90:
##STR01419##
Step 4--Preparation of
5-(3-pyrrolidin-1-yl-propyl)-1H-pyrrolo[2,3-b]pyridine (90):
[2336] To 1.0 M lithium tetrahydroaluminate in tetrahydrofuran
(2.65 mL, 2.66 mmol) 50 mL of tetrahydrofuran was added and the
mixture cooled to 0.degree. C. in an ice-water bath. A solution of
1-pyrrolidin-1-yl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-propan-1-one
(88, 431 mg, 1.77 mmol) in 10 mL of tetrahydrofuran was added
dropwise and kept at 0.degree. C. for 15 minutes. The reaction
mixture was allowed to warm to room temperature. After 2 hours, the
reaction mixture was diluted with 20 mL of tetrahydrofuran and
added .about.4 grams of sodium sulfate and stirred at room
temperature for 30 minutes. The reaction was filtered to remove
solid material and the filtrate was concentrated under vacuum. The
crude material was purified by silica gel chromatography eluting
with ethyl acetate and hexanes. The appropriate fractions were
combined and concentrated under vacuum to provide the desired
compound (90, 235 mg). MS (ESI) [M+H.sup.+].sup.+=230.5.
[2337] 5-(3-Morpholin-4-yl-propyl)-1H-pyrrolo[2,3-b]pyridine 91
##STR01420##
was prepared following the protocol of Scheme 19, step 4, replacing
1-pyrrolidin-1-yl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-propan-1-one 88
with
1-morpholin-4-yl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-propan-1-one 89.
MS (ESI) [M+H.sup.+].sup.+=246.5.
Example 18
Synthesis of 5-methanesulfonyl-1H-pyrrolo[2,3-b]pyridine 93
[2338] 5-Methanesulfonyl-1H-pyrrolo[2,3-b]pyridine 93 was
synthesized in one step from 5-bromo-1H-pyrrolo[2,3-b]pyridine 54
as shown in Scheme 20.
##STR01421##
Step 1--Preparation of 5-methanesulfonyl-1H-pyrrolo[2,3-b]pyridine
(93):
[2339] To 5-bromo-1H-pyrrolo[2,3-b]pyridine (54, 1.00 g, 5.08 mmol)
in 15 mL of dimethyl sulfoxide, sodium methanesulfinate (92, 0.6218
g, 6.090 mmol), L-proline (0.117 g, 1.02 mmol), copper(I) iodide
(0.200 g, 1.05 mmol) and sodium hydroxide (0.0406 g, 1.02 mmol)
were added. The reaction was stirred at 120.degree. C. overnight,
then poured into aqueous ammonia and extracted with ethyl acetate.
The organic layer was dried over anhydrous sodium sulfate, then
filtered and the filtrate was concentrated and purified by silica
gel column chromatography eluting with 20% to 100% ethyl acetate in
hexane to provide the desired compound as a white solid (93, 0.50
g). MS (ESI) [M-H.sup.+].sup.-=195.1.
Example 19
Synthesis of 5-(3-methoxy-prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridine
98
[2340] 5-(3-Methoxy-prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridine 98 was
synthesized in three steps from 5-iodo-1H-pyrrolo[2,3-b]pyridine 69
as shown in Scheme 21.
##STR01422##
Step 1--Preparation of
1-benzenesulfonyl-5-iodo-1H-pyrrolo[2,3-b]pyridine (95):
[2341] 5-Iodo-1H-pyrrolo[2,3-b]pyridine (69, 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 (94, 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 seperated. 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 (95, 0.702 g).
Step 2--Preparation of
1-benzenesulfonyl-5-(3-methoxy-prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridine
(97):
[2342] 1-Benzenesulfonyl-5-iodo-1H-pyrrolo[2,3-b]pyridine (95,
0.482 g, 1.23 mmol), 3-methoxy-propyne (96, 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 (98):
[2343] Under an atmosphere of nitrogen
1-benzenesulfonyl-5-(3-methoxy-prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridine
(97, 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
seperated. 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 (98,
0.215 g).
Example 20
Synthesis of
5-(1H-pyrrolo[2,3-b]pyridin-5-yl)-pyridine-2-carboxylic acid
ethylamide 101
[2344] 5-(1H-Pyrrolo[2,3-b]pyridin-5-yl)-pyridine-2-carboxylic acid
ethylamide 101 was synthesized in two steps from
5-bromo-pyridine-2-carboxylic acid 99 as shown in Scheme 22.
##STR01423##
Step 1--Preparation of 5-bromo-pyridine-2-carboxylic acid
ethylamide (101): 5-Bromo-pyridine-2-carboxylic acid (99, 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 Methylamine in tetrahydrofuran (100, 1.20 mL, 2.40 mmol). The
reaction mixture was stirred for 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 (101, 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 (103):
[2345]
5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]p-
yridine (102, 0.424 g, 1.74 mmol), 5-bromo-pyridine-2-carboxylic
acid ethylamide (101, 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 seperated, 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 (103, 200 mg). MS (ESI)
[M+H.sup.+].sup.+=267.2.
[2346] 5-(1H-Pyrrolo[2,3-b]pyridin-5-yl)-pyridine-2-carboxylic acid
methylamide 104, and
5-(1H-pyrrolo[2,3-b]pyridin-5-yl)-pyridine-2-carboxylic acid
cyclopropylamide 105,
##STR01424##
were prepared following the protocol of Scheme 22, replacing
ethylamine 100 with methylammonium chloride and cycloalkylamine,
respectively in Step 1. MS (ESI) [M+H.sup.+].sup.+=253.1 (104), and
279.1 (105).
Example 21
Synthesis of
5-[6-(3-methoxy-propyl)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine
110
[2347]
5-[6-(3-Methoxy-propyl)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine 110
was synthesized in three steps from 2,5-dibromo-pyridine 106 as
shown in Scheme 23.
##STR01425##
Step 1--Preparation of 5-bromo-2-(3-methoxy-prop-1-ynyl)-pyridine
(108):
[2348] A solution of 2,5-dibromo-pyridine (106, 4.64 g, 19.6 mmol),
3-methoxy-propyne (107, 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 (108, 2.64 g).
Step 2--Preparation of
5-[6-(3-methoxy-prop-1-ynyl)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine
(109):
[2349]
5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]p-
yridine (102, 0.998 g, 4.09 mmol),
5-bromo-2-(3-methoxy-prop-1-ynyl)-pyridine (108, 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 seperated. 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 (109,
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
(110):
[2350]
5-[6-(3-Methoxy-prop-1-ynyl)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridin-
e (109, 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 (110, 419 g).
MS (ESI) [M+H.sup.+].sup.+=268.3.
[2351]
Diethyl-{3-[5-(1H-pyrrolo[2,3-b]pyridin-5-yl)-pyridin-2-yl]-prop-2--
ynyl}-amine 111
##STR01426##
was prepared following the protocol of Scheme 23, steps 1 and 2,
replacing 3-methoxy-propyne 107 with diethyl-prop-2-ynyl-amine in
step 1. MS (ESI) [M+H.sup.+].sup.+=305.3.
Example 22
Synthesis of
dimethyl-{3-[5-(1H-pyrrolo[2,3-b]pyridin-5-yl)-pyrimidin-2-yloxy]-propyl}-
-amine 115
[2352]
Dimethyl-{3-[5-(1H-pyrrolo[2,3-b]pyridin-5-yl)-pyrimidin-2-yloxy]-p-
ropyl}-amine-115 was synthesized in two steps from
5-bromo-2-chloro-pyrimidine 112 as shown in Scheme 24.
##STR01427##
Step 1--Preparation of
[3-(5-bromo-pyrimidin-2-yloxy)-propyl]-dimethyl-amine (114):
[2353] To a solution of 3-(dimethylamino)-1-propanol (113, 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 (112, 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 (113, 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 (115):
[2354] Into a round bottom flask,
[3-(5-bromo-pyrimidin-2-yloxy)-propyl]-dimethyl-amine (114, 259 mg,
0.996 mmol),
5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]-
pyridine (102, 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 (115, 76 mg). MS (ESI)
[M+H.sup.+].sup.+=298.0.
Example 23
Synthesis of Aldehyde Reactants
[2355] Propane-1-sulfonic acid (2-fluoro-3-formyl-phenyl)-amide
124, was synthesized in seven steps from
4-chloro-2-fluoro-phenylamine 116 as shown in Scheme 25.
##STR01428## ##STR01429##
Step 1--Preparation of 3-amino-6-chloro-2-fluoro-benzoic acid
benzyl ester (118):
[2356] To 4-chloro-2-fluoro-phenylamine (116, 6.30 mL, 57.0 mmol)
in 300 mL of tetrahydrofuran 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 (117, 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 80 mL of
water and 25 mL of concentrated hydrochloric acid. 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 the filtrate concentrated under vacuum. The
desired compound was isolated by silica gel column chromatography
(ethyl acetate/hexane 20%) to give a colorless oil (3, 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 (119):
[2357] To 3-amino-6-chloro-2-fluoro-benzoic acid benzyl ester (118,
1.20 g, 4.3 mmol) in 28 mL of dichloromethane, pyridine (0.52 mL,
6.4 mmol) and propane-1-sulfonyl chloride (60, 0.685 g, 4.8 mmol)
were added. 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 the filtrate concentrated under vacuum. The
desired compound was isolated with silica gel column chromatography
to give a colorless oil (119, 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
(120):
[2358] To 6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoic
acid benzyl ester (119, 6.00 g, 15.6 mmol) in 100 mL of
tetrahydrofuran, 100 mL of 1.0 M aqueous potassium hydroxide was
added. The reaction was heated to reflux overnight, then poured
into water, acidified to pH 2 with 1N aqueous hydrochloric acid and
extracted with ethyl acetate. The organic portion was dried over
anhydrous sodium sulfate, filtered and the filtrate concentrated
under vacuum to give the desired compound as a white solid (120,
3.95 g, 85.8%).
Step 4--Preparation of 2-fluoro-3-(propane-1-sulfonylamino)-benzoic
acid (121):
[2359] To 6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoic
acid (120, 0.69 g, 2.3 mmol) in 10 mL of methanol, 20% palladium
hydroxide on carbon (200 mg) was added. The reaction was stirred
under hydrogen at 50 psi for 2 hours. The reaction was filtered and
the filtrate concentrated under vacuum to give the desired compound
(121) as a white solid that was used in the next step without
further purification. MS (ESI) [M-H.sup.+].sup.-=260.1.
Step 5--Preparation of 2-fluoro-3-(propane-1-sulfonylamino)-benzoic
acid methyl ester (122):
[2360] To a 2-fluoro-3-(propane-1-sulfonylamino)-benzoic acid (121,
5.05 g, 19.3 mmol) in 100 mL of dichloromethane,
N,N-dimethylformamide (0.075 mL, 0.97 mmol) was added under an
atmosphere of nitrogen. The reaction was cooled with ice/water,
followed by slow addition of oxalyl chloride (2.00 M in
dichloromethane, 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 concentrated under vacuum and purified
with silica gel column chromatography eluting with 30% ethyl
acetate in hexane to give the desired compound as a crude white
solid (122, 4.0 g), used in the next step without further
purification.
Step 6--Preparation of propane-1-sulfonic acid
(2-fluoro-3-hydroxymethyl-phenyl)-amide (123):
[2361] To 2-fluoro-3-(propane-1-sulfonylamino)-benzoic acid methyl
ester (122, 3.80 g, 13.8 mmol) in 133 mL of tetrahydrofuran,
lithium tetrahydroaluminate (1.00 M in tetrahydrofuran, 20.0 mL,
20.0 mmol) was added 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 sodium sulfate decahydrate.
After 12 hours, the reaction was filtered, the filtrate
concentrated under vacuum and purified with silica gel column
chromatography eluting with 5% methanol in dichloromethane to give
the desired compound as a white solid (123, 3.0 g, 87.9%).
[2362] Step 7--Preparation of propane-1-sulfonic acid
(2-fluoro-3-formyl-phenyl)-amide (124):
[2363] To propane-1-sulfonic acid
(2-fluoro-3-hydroxymethyl-phenyl)-amide (123, 0.20 g, 0.81 mmol) in
5.0 mL of tetrahydrofuran, Dess-Martin periodinane (0.377 g, 0.89
mmol) was added. 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 under vacuume and
purified by silica gel column chromatography eluting with 20% ethyl
acetate in hexane to give the desired compound as a white solid
(124, 100 mg, 50.0%). MS (ESI) [M-H.sup.+].sup.-=244.1.
[2364]
N-(2-Fluoro-3-formyl-phenyl)-4-trifluoromethyl-benzenesulfonamide
125
##STR01430##
was prepared following the protocol of scheme 25, replacing
propane-1-sulfonyl chloride 60 with
4-trifluoromethyl-benzenesulfonyl chloride in step 2. MS (ESI)
[M-H.sup.+].sup.-=346.4.
[2365] Propane-1-sulfonic acid
(2-chloro-4-fluoro-3-formyl-phenyl)-amide (127) was synthesized in
two steps from 2-chloro-4-fluoro-phenylamine 125 as shown in Scheme
26.
##STR01431##
[2366] Step 1--Preparation of propane-1-sulfonic acid
(2-chloro-4-fluoro-phenyl)-amide (127):
[2367] To 2-chloro-4-fluoro-phenylamine (126, 1.226 g, 8.422 mmol)
in 10 mL of dichloromethane, pyridine (0.759 mL, 9.26 mmol) and
propane-1-sulfonyl chloride (60, 1.04 mL, 9.26 mmol) were added and
the reaction was stirred at room temperature for 3-4 hours. The
reaction was quenched with 1M aqueous hydrochloric acid, the
aqueous layer was separated and extracted with ethyl acetate. The
organic layers were combined and washed with brine, dried over
anhydrous sodium sulfate, filtered and the filtrate concentrated
under vacuum. The crude material was purified by silica gel column
chromatography to provide the desired compound (127, 1.59 g). MS
(ESI) [M-H.sup.+].sup.-=250.03, 252.03.
Step 2--Preparation of propane-1-sulfonic acid
(2-chloro-4-fluoro-3-formyl-phenyl)-amide (128):
[2368] To N,N-diisopropylamin (2.74 mL, 19.6 mmol) in 51 mL of
tetrahydrofuran, n-butyllithium (7.83 mL, 2.50 M in hexane, 19.6
mmol) was added at 78.degree. C. under an atmosphere of nitrogen.
After 30 minutes, propane-1-sulfonic acid
(2-chloro-4-fluoro-phenyl)-amide (127, 1.59 g, 6.32 mmol) was added
under nitrogen, maintaining the temperature at 78.degree. C. After
1 hour, N,N-dimethylformamide (1.7 mL, 22 mmol) was added under
nitrogen, maintaining the temperature at 78.degree. C. with
stirring for 30 minutes, then allowing to warm to room temperature
for one hour. The reaction was quenched with saturated aqueous
ammonium chloride, the aqueous layer separated and extracted
3.times. with ethyl acetate. All organic layers were combined,
washed with brine, dried over anhydrous sodium sulfate, filtered
and the filtrate concentrated under vacuum. The crude material was
purified by silica gel column chromatography to provide the desired
compound (127, 398 mg). MS (ESI) [M-H.sup.+].sup.-=278.1.
[2369] Butane-1-sulfonic acid
(2-chloro-4-fluoro-3-formyl-phenyl)-amide 129
##STR01432##
was prepared following the protocol of scheme 26, replacing
propane-1-sulfonyl chloride 60 with butane-1-sulfonyl chloride in
step 1. MS (ESI) [M-H.sup.+].sup.-=291.9.
[2370] Ethanesulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide
130, 2-methyl-propane-1-sulfonic acid
(2,4-difluoro-3-formyl-phenyl)-amide 131, 3,3,3-tri
fluoro-propane-1-sulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide
132,
N-(2,4-difluoro-3-formyl-phenyl)-C,C,C-trifluoro-methanesulfonamide
133, and cyclopropanesulfonic acid
(2,4-difluoro-3-formyl-phenyl)-amide 134,
##STR01433##
were prepared following the protocol of scheme 26, replacing
2-chloro-4-fluoro-phenylamine 126 with 2,4-difluoro-phenylamine and
propane-1-sulfonyl chloride 60 with ethanesulfonyl chloride,
2-methyl-propane-1-sulfonyl chloride,
3,3,3-trifluoro-propane-1-sulfonyl chloride,
trifluoro-methanesulfonyl chloride, and cyclopropanesulfonyl
chloride, respectively, in step 1. MS (ESI) [M-H.sup.+].sup.+=248.1
(130), 276.1 (131), 288.0 (133).
Example 24
Synthesis of 5-cyclopropyl-1H-pyrrolo[2,3-b]pyridine 136
[2371] 5-Cyclopropyl-1H-pyrrolo[2,3-b]pyridine 136 was synthesized
in one step from 5-iodo-1H-pyrrolo[2,3-b]pyridine 69 as shown in
Scheme 27.
##STR01434##
Step 2--Preparation of 5-Cyclopropyl-1H-pyrrolo[2,3-b]pyridine
(136):
[2372] In a reaction vessel, 5-Iodo-1H-pyrrolo[2,3-b]pyridine (69,
0.343 g, 1.40 mmol), cyclopropylzinc bromide (135, 12.6 mL of 0.500
M in tetrahydrofuran, 6.32 mmol), and
[1,3-bis(diphenylphosphino)propane]nickel(II) chloride (0.0762 g,
0.140 mmol) were combined with 5.37 mL of 1,4-dioxane. The reaction
was heated at 100.degree. C. overnight. Methanol was added, and the
mixture was concentrated under vacuum. Ethyl acetate and water were
added to the residue, and the resulting mixture was filtered
through a bed of celite. The celite bed was washed with ethyl
acetate. The combined filtrate was separated and the aqueous layer
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
silica gel column chromatography, eluting with ethyl acetate and
hexane. The appropriate fractions were combined and the solvents
removed under vacuum to provide the desired compound. MS (ESI)
[M+H.sup.+].sup.+=159.0.
Example 25
Propane-1-sulfonic acid
{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluor-
o-phenyl}-amide (P-1167) polymorphs
[2373] Propane-1-sulfonic acid
{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluor-
o-phenyl}-amide (P-1167) may be prepared according to methods known
in the art, for example, using methods described in U.S. patent
application Ser. No. 11/473,347 (see also, PCT publication
WO2007002433), the disclosure of which is hereby incorporated by
reference. Compound P-1167 can exist in polymorphic forms, for
example as polymorphic forms 1 or 2, where such polymorphic forms
may be isolated as the substantially pure polymorph. The desired
polymorphic form may be prepared, for example, by using appropriate
crystallization conditions. For example, Form 1 was isolated by
recrystallization from acetone/absolute ethanol (e.g. 1:1 to 5:1,
preferably 2:1 by volume). Form 2 is the more stable polymorph, and
can be formed under a variety of recrystallization conditions, for
example, recrystallization from methyl-t-butyl
ether/tetrahydrofuran, ethyl acetate, or acetone, or may be formed
by heating/melting and re-solidifying. The substantially pure
isolated polymorphic forms were characterized by X-Ray Powder
Diffraction (XRPD), differential scanning calorimetry (DSC) and
infrared spectroscopy.
[2374] To demonstrate the formation of polymorphic form 1,
propane-1-sulfonic acid
{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluor-
o-phenyl}-amide (P-1167) was treated with about 2.4 w/w of an
acetone:absolute ethanol mixture (1:4 by volume) and agitated at
20.degree. C. 5.degree. C. for at least 6 hours. The contents were
filtered and the solids were washed with acetone:absolute ethanol
(1:4 by volume) mixture. Solids were treated with about 3.4 w/w
tetrahydrofuran, and the suspension was heated to 60.degree. C.
5.degree. C. for at least 30 minutes and agitated. The mixture was
cooled to 55.degree. C. 5.degree. C. and about 11.8 w/w
methyl-t-butyl ether was added. The resulting suspension was cooled
to 20.degree. C. 5.degree. C. for at least 1 hour. The contents
were filtered and the solids were washed with methyl-t-butyl ether
and dried. The solid was treated with acetone:absolute ethanol (2:1
by volume). The contents were agitated and the suspension was
heated at 60.degree. C. until a solution was achieved. The solution
was filtered through a polish filter to remove any residual solid
from the methyl-t-butyl ether treatment step. The filtrate was
concentrated under vacuum, stirred at 20.degree. C. 5.degree. C.
for at least 30 minutes and filtered. The solids were washed with
pre-cooled (0.degree. C. to 5.degree. C.) ethanol and dried at
45.degree. C. followed by drying at 75.degree. C. under vacuum
until a constant weight was achieved, to provide pure P-1167
polymorphic form 1. Form 1 was also prepared treating a sample with
acetone:ethanol (1:1 by volume) at reflux, then filtering hot and
removing solvent from the filtrate under vacuum until solid
precipitates out.
[2375] The propane-1-sulfonic acid
{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluor-
o-phenyl}-amide polymorphic form 1 and form 2 were characterized by
X-ray powder diffraction, infra-red spectrometry, and differential
scanning calorimetry. Samples were analyzed by X-ray powder
diffraction (XRPD) using a ShimadzuXRD-6000 X-ray powder
diffractometer using Cu K.alpha. radiation. The tube voltage and
amperage were set to 40 kV and 40 mA, respectively. The divergence
and scattering slits were set at 1.degree. and the receiving slit
was set at 0.15 mm. Diffracted radiation was detected by a NaI
scintillation detector. A .theta.-2.theta. continuous scan at
3.degree./min (0.4 sec/0.02.degree. step) from 2.5.degree. to
40.degree. 2.theta. was used. A silicon standard was analyzed to
check the instrument alignment. Data were collected and analyzed
using XRD-6100/7000 v.5.0. Sample was prepared for analysis by
placing it in an aluminum holder with silicon insert. The results
are provided in the following Table 1.
TABLE-US-00004 TABLE 1 XRPD 2.theta. values for P-1167 polymorphic
Form 1 and Form 2. 2.theta. value (+/-0.2) Form 1 Form 2 4.7 6.7
8.8 9.4 9.2 10.0 11.0 12.5 13.5 14.2 14.1 14.5 14.9 15.0 15.4 16.1
16.2 17.0 17.3 17.7 18.6 18.3 19.0 19.1 19.7 20.6 20.0 20.9 21.2
21.4 21.6 22.0 22.2 22.2 23.2 23.9 23.8 24.1 24.4 25.1 25.7 26.1
26.6 26.8 28.1 28.8 29.2 29.3 30.1 31.1 31.7 34.5 34.9 35.9 39.2
41.3
[2376] The propane-1-sulfonic acid
{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluor-
o-phenyl}-amide polymorphic form 1 and form 2 were analyzed by
infra-red spectrometry. The results are provided in the following
Table 2, which provides the characteristic wavenumbers observed for
each sample.
TABLE-US-00005 TABLE 2 IR absorption spectrum wavenumber values for
P-1167 polymorphic Form 1 and Form 2. Wavenumber cm.sup.-1 Form 1
Form 2 3238 3266 3121 2969 2879 2880 1709 1645 1639 1590 1589 1519
1519 1485 1487 1417 1417 1331 1322 1305 1306 1280 1287 1246 1246
1211 1215 1149 1143 1102 1096 1022 1027 1013 1012 965 968 915 916
891 893 857 825 825 796 798 773 767 717 685 683 651 662 631 607 587
585 564 558 550 532 532 516 508 503
[2377] The propane-1-sulfonic acid
{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluor-
o-phenyl}-amide polymorphic form 1 and form 2 were analyzed by
differential scanning calorimetry, scanning at 10.00.degree. C. per
minute. The DSC thermogram for form 1 shows an exothermic shift at
approximately 152-164.degree. C. and an endothermic peak at
268.0.degree. C. The DSC thermogram for form 2 shows an endothermic
peak at 271.2.degree. C.
Example 26
N-[3-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]sulfonamide and
related compounds, acidic and basic addition salts and
complexes
[2378]
N-[3-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]sulfonamide and
related compounds, such as compounds of Formula I are characterized
as having functionalities providing both weakly basic and weakly
acidic centers which can form organic salt complexes, resulting in
improved solubility. For example, the N-7 of the azaindole portion
is weakly basic (pKa approximately 4-5) while the sulfonamide
nitrogen is weakly acidic (pKa approximately 7). An organic salt
complex reflects the potential for multiple sites of interaction
between the guest and host. Attempts to make inorganic salts, e.g.
using sodium or potassium, resulted in material that was difficult
to isolate and was hygroscopic in some instances. In other
instances, while the material may be non-hygroscopic, isolated
material may exhibit multiple polymorphic forms. In contrast, the
basic amino acids arginine and lysine were found to form
non-crystalline complexes readily in a stoichiometric manner, and
the resulting materials demonstrated enhanced solubility and
bioavailability (exposure in pharmacokinetic analysis) relative to
the free base form as well as other standard salt forms.
Demonstrating additional unexpected advantages, such complexes were
isolated as amorphous forms rather than typical crystalline salt
forms, were non-hygroscopic, and chemically stable.
[2379] Organic base complexes, including arginine, nicotinamide and
lysine complexes are typically formed by dissolving
N-[3-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]sulfonamide and
related compounds in 20-50 solvent volumes of an alcohol,
preferably methanol, with moderate heating (30-35.degree. C.). The
milky suspension is stirred, and 1 equivalent of the L-form of
arginine or lysine that has been triturated in a separate portion
of the alcohol is added. The mixture is stirred under an inert
atmosphere until a clear yellowish solution is formed. The solution
is filtered and the solvent removed from the filtrate under reduced
pressure. The resulting yellow film forms a friable solid upon
vacuum drying. Alternatively, the complex may be precipitated by
addition of cold solvent such as heptane, methyl t-butyl ether,
ethyl acetate or the like to the alcohol solution, the resulting
solid filtered and vacuum dried to isolate the friable solid. The
resulting solid is typically amorphous with some degree (<30%)
of crystallinity, preferably the complex is substantially
amorphous, and is less than 10%, also less than 5%, also less than
1% crystalline. In some instances, the resulting solid may be
prepared to have some degree of crystalline material, where the
method above is modified by using an excess amount of the
N-[3-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]sulfonamide
relative to the arginine or lysine. For example, 0.5 equivalent of
the L-form of arginine or lysine may be added to the suspension of
compound in methanol. The resulting solid that is isolated will
comprise a mixture of the amorphous complex and crystalline
compound. The amount of L-arginine or L-lysine used may be adjusted
appropriately to provide a solid that has any level of crystalline
material, for example, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or
90% crystalline, with 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20% or 10%
amorphous solid, respectively. The relative amount of crystalline
material and amorphous material in a solid can be readily
determined by one skilled in the art, for example as described in
Shah et al., J Pharm Sci 2006, 95:1641-1665.
[2380] Acid addition salts, including sulfonic acid series of
organic anions such as tosylate, besylate or mesylate, of
N-[3-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide and
related compounds are preferably formed using acetone, which
provides solubility of the free base and is a non-solvent once the
salt is formed. Typically,
N-[3-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide is
added to 20-50 solvent volumes of acetone with stirring and heating
(30-35.degree. C.), followed by the addition of 1 equivalent of the
desired acid counter ion. The solution is slowly cooled to
2-8.degree. C. and the solid is isolated by either filtration or
centrifugation, followed by vacuum drying. The resulting solid may
be amorphous, partially amorphous or crystalline, and can be
recrystallized as needed from alcohol:acetone:ethyl acetate or
alcohol alone to obtain the desired solid in crystalline form.
[2381] Organic acid complexes, including citric acid, tartaric
acid, succinic acid, glutaric acid and acetylsalicylic acid
complexes of
N-[3-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide and
related compounds are preferably formed in 1:1 or 1:2 compound:acid
ratios in a suitable solvent such as methanol. Typically,
N-[3-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide is
added to 15-20 solvent volumes of methanol, with the desired solid
isolated by either spray drying or by addition of non-solvent such
as heptane followed by filtration and vacuum drying. The resulting
solid is preferably an amorphous complex.
[2382] Mineral acids, including sulfate, phosphate and hydrochloric
acid salts of
N-[3-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide and
related compounds are prepared from methanol or ethyl acetate
solutions.
[2383] The resulting complexes or salts may also be processed
through spray-drying techniques to provide the preferred form
directly, or with suitable excipient materials to provide for a
directly compressible or encapsulated dosage form. Salts or
complexes may also be achieved by mechanochemical (e.g. roller
compaction) or microwave irradiation of the parent compound with
the appropriate selection of charge transfer partner. Such an
approach is used to minimize solvent utilization, increase yield,
purity and throughput, as well as achieve constructs not attainable
using conventional solvent techniques.
[2384] The arginine complex of
N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-4-trifluoromethyl-benzenesulfonamide P-1021 was prepared by
suspending 5 g (9.7 mmol) of the free base in 100 mL of methanol,
mixing with heating 30-35.degree. C. L-arginine (1.70 g, 9.7 mmol)
as a triturated dispersion in 5.1 mL of methanol. The milky white
suspension is stirred with heating until a clear yellowish solution
is formed. The solution was filtered and the solvent removed from
the filtrate under reduced pressure, or processed by spray-drying
to provide the complex as a friable yellow solid.
[2385] The arginine complexes of
N-[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
4-trifluoromethyl-benzenesulfonamide P-1092, propane-1-sulfonic
acid
{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluor-
o-phenyl}-amide P-1167, and propane-1-sulfonic acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide P-1496 were prepared similarly, as were
the lysine or nicotinamide complexes of
N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-4-trifluoromethyl-benzenesulfonamide P-1021 and the lysine complex
of propane-1-sulfonic acid
{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluor-
o-phenyl}-amide P-1167.
[2386] Any of these arginine or lysine complexes may be prepared as
a ternary complex comprising a strong acid, such as hydrochloric
acid, for example by addition of 1 equivalent of hydrochloric acid
(or other suitable acid) to the suspension of compound in methanol
and mixing with the L-arginine or L-lysine.
[2387] The mesylate salt of
N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-4-trifluoromethyl-benzenesulfonamide P-1021 was prepared by
suspending 5 g (9.7 mmol) in 100 mL of acetone, mixing with heating
30-35.degree. C. Methanesulfonic acid (0.63 mL, 9.7 mmol) was added
and the solution cooled to 5.degree. C. over 30 minutes. The
resulting solid was isolated by filtration, washed and dried under
vacuum to provide the desired salt.
[2388] The besylate and tosylate salts of
N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-4-trifluoromethyl-benzenesulfonamide P-1021 were prepared
similarly.
Example 27
Physical Properties of Solid Forms
[2389] Propane-1-sulfonic acid
{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluor-
o-phenyl}-amide P-1167 complexed with either lysine or arginine was
compared to the free base polymorph form 2 from which the complexes
were formed. The XRPD comparison of these materials indicate that
the lysine complex is essentially amorphous (some peaks associated
with the free base having much reduced intensity), and the arginine
complex is substantially amorphous (no clear peaks associated with
the free base). The 2-theta values and intensities are provide in
the following Table 3.
TABLE-US-00006 TABLE 3 XRPD 2.theta. values for P-1167 polymorphic
Form 2 and the lysine or arginine complex thereof. Peak intensity
(cps) Arginine Lysine 2.theta. value (+/-0.2) Form 2 complex
complex 6.7 240 48.3 39.6 8.8 229 119 27.4 9.2 2141 564 66.3 13.5
341 103 22 14.1 185 64.6 14.1 14.5 272 101 18 15.0 887 218 37.1
17.7 106 43.5 17 18.3 253 220 20.1 19.1 442 267 72.4 19.7 310 96.7
47.5 20.9 165 79.6 16.5 21.4 205 181 20.8 24.1 200 149 43.4 24.4
591 373 78.1 25.1 163 115 34.1 28.1 121 97.4 32.7 30.1 116 68.9
22.2
[2390] It is clear from this data that the lysine complex is
amorphous, with the lack of any clear structure in the XRPD sprecta
and the intensity of the peaks corresponding to the two largest
peaks in form 2 (20 values of about 9.2 and 15.0) reduced to less
than 5% of the form 2 intensity. The arginine complex is
substantially amorphous, showing some residual level of
crystallinity in the XRPD spectra, with the intensity of these
peaks at less than 30% of the form 2 intensity. The amount of
crystalline material in such complexes can be readily reduced
further in processing, for example, by spray drying techniques such
that an amorphous complex with arginine or lysine is provided.
[2391] The DSC of these samples shows that the arginine and lysine
complexes lack a characteristic transition and have completely
melted before the free base crystalline transition at 271.degree.
C., further supporting that these complexes are amorphous.
[2392] The intrinsic dissolution rate of a similarly prepared
substantially amorphous arginine complex of P-1167 was compared to
that of the form 2 polymorph in simulated gastric fluid (SGF)
without enzyme and in simulated intestinal fluid (SIF). A pellet of
test sample was dissolved in the appropriate fluid, and the UV
absorbance as a function of time was measured at 254 nm (SGF) or
310 nm (SIF) and plotted. The results demonstrate a maximum
absorbance in SGF at approximately 200 minutes that is
substantially greater than the free base, and a substantially
higher absorbance in SIF than the free base. As such, significant
improvement of dissolution of the arginine complex is shown, which
is likely to be improved further by processing the complex to a
completely amorphous form.
[2393] Propane-1-sulfonic acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide P-1496 complexed with arginine was
compared to the free base from which the complex was formed. The
XRPD comparison of these materials indicate that the arginine
complex is amorphous, demonstrating the characteristic amorphous
halo.
[2394] Similarly, the DSC shows that the arginine complex has a
very broad transition from about 56.degree. C. to about 120.degree.
C. and lacks the characteristic transition of the free base at
approximately 275.degree. C.
[2395]
N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-p-
henyl]-4-trifluoromethyl-benzenesulfonamide P-1021 lot number 14
complexed with arginine was compared to the free base from which
the complex was formed. The XRPD comparison of these materials
indicate that the arginine complex is amorphous, demonstrating
essentially the characteristic amorphous halo with some minor peaks
associated with the free base. Similarly, the DSCshows that the
arginine complex has a broad transition at lower temperatures and a
very minor transition at about 140.degree. C. and lacks the
characteristic transition of the free base at approximately
276.degree. C. Finally, the solid state NMR was also compared,
where .sup.13C cross polarization magic angle spinning was acquired
at room temperature using a Varian .sup.UnityINOVA-400 spectrometer
(Larmor frequencies: .sup.13C=100.542 MHz, .sup.1H=399.790 MHz).
Samples were packed into 4 mm PENCIL type zirconia rotors and
rotated at 12 kHz at the magic angle. The spectra were acquired
with phase modulated SPINAL-64 high power .sup.1H decoupling during
the acquisition time using a .sup.1H pulse width of 2.2
.mu.s(90.degree.), a ramped amplitude cross polarization contact
time of 3-8 ms, a 30 ms acquisition time, a 10-30 second delay
between scans, a spectral width of 45 kHz with 2700 data points,
and 100 or 400 co-added scans. Each free induction decay was
processed using Varian VNMR 6.1C software3 with 32768 points and an
exponential line broadening factor of 10 or 100 Hz to improve the
signal-to-noise ratio. The first three data points of the free
induction decay were back predicted using VNMR linear prediction
algorithm to produce a flat baseline. The chemical shifts of the
spectral peaks were externally referenced to the carbonyl carbon
resonance of glycine at 176.5 ppm. The results show that the
complex has no ordered structure as compared to either the free
base or L-arginine, clearly demonstrating the amorphous nature of
the complex. This amorphous complex, in addition to providing
preferable biopharmaceutical properties, is readily friable and
compressible, and therefor is advantageous in preparation of solid
capsules, as more material can be compressed into a tablet than
with the free base.
[2396]
N-[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-ph-
enyl]-4-trifluoromethyl-benzenesulfonamide P-1092 lot number 2
complexed with arginine was compared to the free base from which
the complex was formed. The XRPD comparison of these materials
indicate that the arginine complex is amorphous, demonstrating
essentially the characteristic amorphous halo. Similarly, the DSC
show that the arginine complex has a broad transition at lower
temperatures and a very minor transition at about 140.degree. C.
and lacks the characteristic transition of the free base at
approximately 276.degree. C.
Example 28
Pharmacokinetic Evaluation of Solid Forms
[2397] Pharmacokinetic properties of various compositions prepared
from the complexes may be assessed in male Sprague Dawley rats or
male Beagle dogs, and compared to the properties of the free base
compound. 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, 5 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).
[2398] The arginine complex of
N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-
-4-trifluoromethyl-benzenesulfonamide P-1021 was analyzed in a
number of dog PK studies following the above or similar protocols.
These were done primarily at Bridge Laboratories, Beijing, China,
with one study done at Seventh Wave Laboratories LLC, Chesterfield,
Mo. Plasma samples were analyzed to determine the plasma
concentration (PPD Development, Madison, Wis.) at each time point
from which the Cmax and AUC.infin. were determined. The dosing
formulations and results for these studies are given in the
following tables. In some instances, the materials are combined in
the solvents indicated, and the solvent is removed by evaporation,
or by spray drying where indicated. In these tables, unless
indicated otherwise, the dose is mg/dog, and the Cmax/dose
((ng/mL)/(mg/kg)) and the AUC.infin./dose ((ng*hr/mL)/(mg/kg)) are
calculated assuming a 10 kg weight for the dogs.
TABLE-US-00007 TABLE 4A Solid forms and formulations for dog PK
study comparing P-1021 arginine complex to the free base, a sulfate
salt or a nicotinamide complex. Amoung (g) per Component 7.4 gram
batch W/W% P-1021 arginine complex Micronized P-1021 free base 2.68
36.2 Crystalline spray dried 2.32 31.4 mannitol Polyplasdone XL
0.400 5.40 Poloxamer F-68 2.00 27.0 P-1021 free base P-1021
arginine complex 2.00 27.0 Crystalline spray dried 3.00 40.5
mannitol Polyplasdone XL 0.400 5.40 Poloxamer F-68 2.00 27.0 P-1021
sulfate salt P-1021 sulfate salt 2.38 32.2 Crystalline spray dried
2.62 35.4 mannitol Polyplasdone XL 0.400 5.40 Poloxamer F-68 2.00
27.0 P-1021 nicotinamide complex P-1021 nicotinamide 1:2 2.31 39.0
Polyplasdone XL 0.20 6.25 Poloxamer F-68 1.00 15.6
TABLE-US-00008 TABLE 4B Cmax/dose and AUC.infin./dose comparing
P-1021 arginine complex to free base, sulfate salt and nicotinamide
complex. Dose Test article (mg/dog) Cmax/dose AUC.infin./dose
Arginine complex 100 830.5 16,850 Free base 100 581.3 8,031 Sulfate
100 181.5 5,067 Nicotinamide 100 110.7 2,043
TABLE-US-00009 TABLE 5A Solid forms and formulations for dog PK
study comparing P-1021 arginine complex to the free base, an
amorphous form of the free base, or mesylate salt. P-1021 arginine
complex Amoung (g) per 10 gram Component batch W/W % P-1021
arginine complex 5.00 free base 50.0 1.70 L-arginine 17.0 Mannitol
1.70 17.0 Polyplasdone XL 0.40 4.0 Mg-Al-silicate 1.00 10.0
Poloxamer F127 0.40 4.0 In methanol solvent (~50 mg/mL) removed
during processing P-1021 free base Amoung (g) per 7.4 gram
Component batch W/W % Micronized P-1021 free base 5.00 50.0
Mannitol 2.22 22.0 D-Sorbitol 2.00 20.0 Polyplasdone XL 0.40 4.0
Poloxamer F127 0.40 4.0 Dry blended with simulation of roller
compaction P-1021 amorphous free base Amoung (g) per 7.4 gram
Component batch W/W % P-1021 amorphous free base 5.00 50.0 Mannitol
1.20 12.0 D-Sorbitol 2.00 20.0 Polyplasdone XL 0.40 4.0
Mg-Al-silicate 1.00 10.0 Poloxamer F127 0.40 4.0 In acetone solvent
(~100 mg/mL) removed during processing P-1021 mesylate salt Amoung
(g) per 10 gram Component batch W/W % Micronized P-1021 free base
5.00 50.0 Methane-sulfonic acid 1.00 10.0 Mannitol 0.70 7.0
D-Sorbitol 1.50 15.0 Polyplasdone XL 0.40 4.0 Mg-Al-Silicate 1.00
10.0 Poloxamer F127 0.40 4.0
TABLE-US-00010 TABLE 5B Cmax/dose and AUC.infin./dose comparing
P-1021 arginine complex to free base, amorphous free base and
mesylate salt. Dose Test article (mg/dog) Cmax/dose AUC.infin./dose
Arginine complex 150 810 34,693 Free base 150 482 5,270 Amorphous
free base 150 33 482 Mesylate 150 116 2,849
TABLE-US-00011 TABLE 6A Solid forms and formulations for dog PK
study comparing arginine complex of P-1021, mixed formulation vs.
spray dried formulation. Component W/W % P-1021 Arginine complex
P-10 P-1021 arginine complex 30.0 PEG400 55.0 Propylene Glycol 5.00
Polysorbate 20 5.00 TPGS 5.00 P-1021 arginine complex spray dried
P-11* P-1021 arginine complex 50.0 Poloxamer 188 40.0 Mannitol 10.0
In acetone: ethanol 80:20, removed on spray drying onto Poloxamer
F68 P-1021 arginine complex P-18 P-1021 arginine complex 26.8
Propylene Glycol 25.0 Polysorbate 20 5.00 TPGS 5.00 Capryol 90 38.2
In acetone: ethanol 80:20, removed during processing
TABLE-US-00012 TABLE 6B Cmax/dose and AUC.infin./dose comparing
various formulations. Dose Test article (mg/dog) Cmax/dose
AUC.infin./dose P-10 400 808 13,787 P-10 800 824 16,881 P-11 200
1,525 37,211 P-18 200 1,030 18,324
TABLE-US-00013 TABLE 7A Solid forms and formulations for dog PK
study comparing arginine complex at 200 or 400 mg per dog dose.
P-1021 arginine complex spray dried P-11 Component W/W % P-1021
arginine complex 50.0 Poloxamer 407 35.0 Mannitol 15.0 Methanol
removed during processing
TABLE-US-00014 TABLE 7B Cmax/dose and AUC.infin./dose for P-1021
arginine complex dosed at 200 or 400 mg perdog. Dose AUC.infin./
Test article (mg/dog) Cmax/dose dose Arginine complex 200 960
22,480 Arginine complex 400 455 12,120
TABLE-US-00015 TABLE 8A Solid forms and formulations for dog PK
study comparing arginine complex at increasesing doses (mg/kg).
P-1021 arginine complex Component W/W % P-1021 arginine complex
54.3% P-1021 18.5% L-arginine Poloxamer 407 27.2
This study was done at Seventh Wave, containers were provided with
13.259 g, 39.776 g or 66.301 g of this formulation and suspended in
360 mL of 1.5% Polysorbate 20 vehicle and dosed by oral gavage.
TABLE-US-00016 TABLE 8B Cmax/dose and AUC.infin./dose for P-1021
arginine complex dosed at the indicated mg/kg. Dose AUC.infin./
Test article (mg/kg) Cmax/dose dose Arginine complex 249 208 11,247
Arginine complex 795 107 7,457 Arginine complex 965 178 3,883
[2399]
N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-p-
henyl]-4-trifluoromethyl-benzenesulfonamide P-1021 was analyzed in
a dog PK study wherein the arginine complex of
N-[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]--
4-trifluoromethyl-benzenesulfonamide P-1092 was also assessed.
Formulations and results are provided in the following Tables 9A
and 9B.
TABLE-US-00017 TABLE 9A Solid forms and formulations for dog PK
study of P-1021 arginine mixed in formulation (non-complex) and
P-1092 arginine complex. P-1092 arginine complex Component Amoung
(g) per 5.00 g batch W/W % P-1092 arginine complex 2.50 50.0
Poloxamer 407 1.75 35.0 Mannitol 0.75 15.0 P-1021 non-complex
arginine formulation Component Amoung (g) per 15.00 g batch W/W %
P-1021 5.00 33.33 L-arginine 3.38 22.53 Poloxamer 407 5.25 35.0
Mannitol 1.37 9.13
TABLE-US-00018 TABLE 9B Cmax/dose and AUC.infin./dose for P-1021
non-complexed with arginine, or P-1092 arginine complex. Dose Cmax/
Test article (mg/dog) dose AUC.infin./dose P-1021 non-complex 400
392.5 8,092 P-1092 arginine complex 200 550 11,720 P-1092 arginine
complex 400 617.5 12,580
[2400] These dog PK studies demonstrate favorable biopharmaceutical
properties of the compounds as an arginine complex. For example,
P-1021 shows favorable Cmax and AUC compared to free base and other
formulations (Table 4B, Table 5B), and Table 6B demonstrates
further improvement of these properties with spray drying of the
formulations. The arginine complex, and not just the presence of an
equivalent amount of arginine, is favorable, as typically, the
AUC/dose of the complex dosed at 400 mg per dog is greater than
12,000 (Table 6B, Table 7B), whereas the AUC/dose for a
non-complexed formulation with arginine is approximately 8,000
(Table 9B). The P-1092 arginine complex shows similar exposure as
the P-1021 complex (Table 9B).
[2401] A PK study was carried out in Sprague-Dawley rats on the
arginine or lysine complex of propane-1-sulfonic acid
{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonyl]-phenyl}-amide P-1496 (Murigenics, Berkeley, Calif.),
dosing via tail vein injection, with sampling of approximately 250
.mu.L of blood via jugular veing in Lithium heparin tubes at 30
minutes, 1, 3, 6, 8, 12, 24, 36 and 48 hours. Blood samples were
centrifuged at 4.degree. C. for 10 minutes at RCF of 1,000, plasma
was stored at 80.degree. C. and shipped frozen for analytical
analysis (Integrated Analytical Solutions, Inc., Berkeley, Calif.).
The results demonstrate improved biopharmaceutical properties for
either the arginine or the lysine comples. The solid form and
formulations are provided in Table 10A, with the results provided
in Table 10B.
TABLE-US-00019 TABLE 10A Solid forms and formulations for rat PK
study of P-1496 arginine or lysine complex. Amoung (g) per 2.00 g
Component batch W/W % P-1496 free base P-1496 free base 1.00 50.0
Poloxamer 407 1.00 50.0 Methanol removed in processing P-1496
arginine complex P-1496 1.00 50.00 L-arginine 0.36 18.00 Poloxamer
407 0.64 32.0 Acetone removed in processing P-1496 lysine complex
P-1496 1.00 50.00 L-lysine 0.30 15.00 Poloxamer 407 0.70 35.0
Acetone removed in processing
Solid formulations were taken up in PEG400:water at 200 mg/cc for
free base, arginine, and lysine complexes, and also at 400 mg/cc
for lysine complex and dosed by oral gavage 10 mL/kg to provide the
P-1496 doses indicated in Table 10B.
TABLE-US-00020 TABLE 10B Cmax/dose and AUC.infin./dose for P-1496
free base, arginine complex and lysine complex in rats. Cmax/dose
AUC.infin./ Test article Dose (mg/kg) dose P-1496 free base 100 106
1,970 P-1496 arginine complex 100 159 3,620 P-1496 lysine complex
100 283 3,210 P-1496 lysine complex 200 155 2,750
Example 29
Kinase Activity Assays
[2402] Assays for the activity of Raf kinases, including, but not
limited to, B-Raf, B-Raf V600E, B-Raf V600E/T529I and c-Raf-1, as
well as for other kinases are known in the art, for example as
described in U.S. patent application Ser. No. 11/473,347 (see also,
PCT publication WO2007002433), the disclosure of which is hereby
incorporated by reference in its entirety. The activity of
compounds for Raf kinases and other kinases is summarized in the
following tables. Compounds having IC.sub.50 of less than 10 .mu.M
with respect to the indicated kinase are shown in tables 11a
(A-Raf), 11b (B-Raf), 11c (B-Raf V600E), 11d (C-Raf), 11e (Btk),
11f (Fms), 11 g (Kdr), 11 h (Kit), 11i (Src), 11j (TEC), 11k
(TrkA), 11m (MAP4K4), 11n (Flt1), 11o (PI3K.alpha.), 11p
(PI3K.delta.), and 11q (PI3K.gamma.).
TABLE-US-00021 TABLE 11a Compounds with activity toward kinase
A-Raf with IC.sub.50 .ltoreq. 10 .mu.M. A-Raf P-2002, P-2009,
P-2010, P-2011, P-2014, P-2015, P-2016, P-2017, P-2018, P-2019,
P-2020, P-2022, P-2035, P-2036, P-2037, P-2038, P-2039, P-2046,
P-2047, P-2056, P-2057, P-2061, P-2062, P-2063, P-2064, P-2065,
P-2066, P-2067, P-2069, P-2071, P-2075, P-2076, P-2077, P-2078,
P-2113, P-2115, P-2116, P-2117, P-2119, P-2165, P-2182, P-2196,
P-2208, P-2209, P-2210, P-2220, P-2224, P-2230, P-2231, P-2232,
P-2233, P-2234, P-2235, P-2236, P-2238, P-2239, P-2240, P-2243,
P-2244, P-2247, P-2248, P-2250, P-2255, P-2257, P-2258, P-2259,
P-2260, P-2261, P-2272, P-2273, P-2274, P-2275, P-2276, P-2277,
P-2278, P-2283, P-2284, P-2285, P-2288, P-2289, P-2290, P-2291,
P-2292, P-2297, P-2303, P-2304, P-2305, P-2314, P-2315, P-2316,
P-2317, P-2318, P-2319, P-2320, P-2321, P-2327, P-2328, P-2329,
P-2332, P-2335, P-2336, P-2337, P-2338, P-2339, P-2341, P-2343,
P-2346, P-2347, P-2353, P-2354, P-2362, P-2363, P-2364, P-2365,
P-2366, P-2367, P-2368, P-2369, P-2370, P-2374, P-2375, P-2379,
P-2384, P-2385, P-2386, P-2387, P-2388, P-2389, P-2390, P-2391,
P-2392, P-2393, P-2394, P-2395, P-2396, P-2397, P-2398, P-2407,
P-2408, P-2420, P-2437
TABLE-US-00022 TABLE 11b Compounds with activity toward kinase
B-Raf with IC.sub.50 .ltoreq. 10 .mu.M. B-Raf P-2001, P-2002,
P-2003, P-2004, P-2005, P-2006, P-2007, P-2008, P-2009, P-2010,
P-2011, P-2014, P-2015, P-2016, P-2017, P-2018, P-2019, P-2020,
P-2021, P-2022, P-2023, P-2024, P-2025, P-2026, P-2027, P-2028,
P-2029, P-2030, P-2031, P-2032, P-2033, P-2034, P-2035, P-2036,
P-2037, P-2038, P-2039, P-2040, P-2041, P-2042, P-2043, P-2044,
P-2045, P-2046, P-2047, P-2050, P-2051, P-2052, P-2053, P-2054,
P-2055, P-2056, P-2057, P-2058, P-2059, P-2060, P-2063, P-2066,
P-2067, P-2069, P-2070, P-2071, P-2072, P-2073, P-2074, P-2075,
P-2076, P-2077, P-2078, P-2079, P-2080, P-2084, P-2085, P-2086,
P-2087, P-2090, P-2099, P-2101, P-2102, P-2103, P-2104, P-2105,
P-2106, P-2108, P-2109, P-2110, P-2112, P-2113, P-2116, P-2117,
P-2119, P-2123, P-2126, P-2127, P-2128, P-2139, P-2140, P-2142,
P-2144, P-2145, P-2147, P-2148, P-2149, P-2150, P-2151, P-2152,
P-2153, P-2154, P-2155, P-2162, P-2165, P-2166, P-2167, P-2168,
P-2171, P-2172, P-2173, P-2174, P-2175, P-2176, P-2177, P-2178,
P-2179, P-2180, P-2181, P-2182, P-2183, P-2184, P-2185, P-2186,
P-2187, P-2188, P-2189, P-2190, P-2191, P-2192, P-2193, P-2194,
P-2195, P-2196, P-2197, P-2198, P-2199, P-2200, P-2201, P-2203,
P-2204, P-2207, P-2208, P-2209, P-2210, P-2211, P-2212, P-2213,
P-2214, P-2215, P-2216, P-2217, P-2218, P-2219, P-2220, P-2222,
P-2223, P-2224, P-2225, P-2226, P-2227, P-2228, P-2229, P-2230,
P-2231, P-2232, P-2233, P-2234, P-2235, P-2236, P-2237, P-2238,
P-2239, P-2240, P-2243, P-2244, P-2247, P-2248, P-2250, P-2255,
P-2257, P-2258, P-2259, P-2260, P-2261, P-2268, P-2269, P-2270,
P-2271, P-2272, P-2273, P-2274, P-2275, P-2276, P-2277, P-2278,
P-2279, P-2280, P-2281, P-2282, P-2283, P-2285, P-2286, P-2287,
P-2290, P-2295, P-2297, P-2298, P-2299, P-2300, P-2301, P-2302,
P-2303, P-2304, P-2305, P-2306, P-2307, P-2310, P-2313, P-2317,
P-2318, P-2320, P-2321, P-2322, P-2323, P-2324, P-2325, P-2326,
P-2327, P-2328, P-2329, P-2330, P-2331, P-2332, P-2333, P-2334,
P-2335, P-2336, P-2338, P-2339, P-2340, P-2341, P-2342, P-2343,
P-2344, P-2345, P-2346, P-2347, P-2350, P-2351, P-2352, P-2353,
P-2354, P-2355, P-2356, P-2357, P-2358, P-2359, P-2360, P-2361,
P-2363, P-2364, P-2366, P-2367, P-2368, P-2369, P-2370, P-2371,
P-2372, P-2373, P-2374, P-2375, P-2376, P-2377, P-2379, P-2382,
P-2383, P-2393, P-2394, P-2395, P-2396, P-2397, P-2398, P-2399,
P-2400, P-2402, P-2403, P-2404, P-2406, P-2407, P-2408, P-2409,
P-2412, P-2413, P-2414, P-2415, P-2416, P-2417, P-2418, P-2420,
P-2422, P-2425, P-2430, P-2431, P-2432, P-2434, P-2444, P-2445,
P-2447, P-2465, P-2481
TABLE-US-00023 TABLE 11c Compounds with activity toward kinase
B-Raf V600E with IC.sub.50 .ltoreq. 10 .mu.M. B-Raf P-2002, P-2003,
P-2004, P-2005, P-2006, P-2007, P-2008, P-2009, V600E P-2010,
P-2011, P-2014, P-2015, P-2016, P-2017, P-2018, P-2019, P-2020,
P-2021, P-2022, P-2023, P-2024, P-2025, P-2026, P-2027, P-2028,
P-2029, P-2030, P-2031, P-2032, P-2033, P-2034, P-2035, P-2036,
P-2037, P-2038, P-2039, P-2040, P-2041, P-2042, P-2043, P-2044,
P-2045, P-2046, P-2047, P-2050, P-2051, P-2052, P-2053, P-2054,
P-2055, P-2056, P-2057, P-2058, P-2059, P-2060, P-2061, P-2062,
P-2063, P-2064, P-2065, P-2066, P-2067, P-2068, P-2069, P-2070,
P-2071, P-2072, P-2073, P-2074, P-2075, P-2076, P-2077, P-2078,
P-2079, P-2080, P-2081, P-2082, P-2083, P-2084, P-2085, P-2086,
P-2087, P-2088, P-2089, P-2090, P-2091, P-2092, P-2093, P-2094,
P-2095, P-2096, P-2097, P-2098, P-2099, P-2100, P-2101, P-2102,
P-2103, P-2104, P-2105, P-2108, P-2110, P-2111, P-2120, P-2127,
P-2129, P-2130, P-2131, P-2132, P-2133, P-2134, P-2135, P-2136,
P-2139, P-2140, P-2147, P-2150, P-2151, P-2152, P-2153, P-2154,
P-2155, P-2156, P-2157, P-2158, P-2159, P-2160, P-2161, P-2162,
P-2164, P-2165, P-2166, P-2167, P-2168, P-2169, P-2170, P-2171,
P-2172, P-2173, P-2174, P-2175, P-2176, P-2177, P-2178, P-2179,
P-2180, P-2181, P-2182, P-2183, P-2184, P-2185, P-2186, P-2187,
P-2188, P-2189, P-2190, P-2191, P-2192, P-2193, P-2194, P-2195,
P-2196, P-2197, P-2198, P-2199, P-2200, P-2201, P-2203, P-2204,
P-2207, P-2208, P-2209, P-2210, P-2211, P-2212, P-2213, P-2214,
P-2215, P-2216, P-2217, P-2218, P-2219, P-2220, P-2222, P-2223,
P-2224, P-2225, P-2226, P-2227, P-2228, P-2229, P-2230, P-2231,
P-2232, P-2233, P-2234, P-2235, P-2236, P-2238, P-2239, P-2240,
P-2243, P-2244, P-2247, P-2248, P-2250, P-2255, P-2257, P-2258,
P-2259, P-2260, P-2261, P-2268, P-2269, P-2270, P-2271, P-2272,
P-2273, P-2274, P-2275, P-2276, P-2277, P-2278, P-2279, P-2280,
P-2281, P-2282, P-2283, P-2284, P-2285, P-2286, P-2287, P-2288,
P-2289, P-2290, P-2291, P-2292, P-2293, P-2294, P-2295, P-2296,
P-2297, P-2298, P-2299, P-2300, P-2301, P-2302, P-2303, P-2304,
P-2305, P-2306, P-2307, P-2308, P-2309, P-2310, P-2311, P-2312,
P-2313, P-2314, P-2315, P-2316, P-2317, P-2318, P-2319, P-2320,
P-2321, P-2322, P-2323, P-2324, P-2325, P-2326, P-2327, P-2328,
P-2329, P-2330, P-2331, P-2332, P-2333, P-2334, P-2335, P-2336,
P-2337, P-2338, P-2339, P-2340, P-2341, P-2342, P-2343, P-2344,
P-2345, P-2346, P-2347, P-2348, P-2350, P-2351, P-2352, P-2353,
P-2354, P-2355, P-2356, P-2357, P-2358, P-2359, P-2360, P-2361,
P-2362, P-2363, P-2364, P-2365, P-2366, P-2367, P-2368, P-2369,
P-2370, P-2371, P-2372, P-2373, P-2374, P-2375, P-2376, P-2377,
P-2378, P-2379, P-2382, P-2383, P-2384, P-2385, P-2386, P-2387,
P-2388, P-2389, P-2390, P-2391, P-2392, P-2393, P-2394, P-2395,
P-2396, P-2397, P-2398, P-2399, P-2400, P-2401, P-2402, P-2403,
P-2404, P-2406, P-2407, P-2408, P-2409, P-2410, P-2411, P-2412,
P-2413, P-2414, P-2415, P-2416, P-2417, P-2418, P-2419, P-2420,
P-2421, P-2422, P-2423, P-2424, P-2425, P-2429, P-2430, P-2431,
P-2432, P-2433, P-2434, P-2435, P-2436, P-2437, P-2442, P-2444,
P-2445, P-2446, P-2447, P-2449, P-2450, P-2452, P-2453, P-2454,
P-2455, P-2456, P-2457, P-2464, P-2465, P-2466, P-2467, P-2468
TABLE-US-00024 TABLE 11d Compounds with activity toward kinase
C-Raf with IC.sub.50 .ltoreq. 10 .mu.M. C-Raf P-2001, P-2002,
P-2003, P-2004, P-2005, P-2006, P-2007, P-2008, P-2009, P-2010,
P-2011, P-2014, P-2015, P-2016, P-2017, P-2018, P-2019, P-2020,
P-2021, P-2022, P-2023, P-2024, P-2025, P-2026, P-2027, P-2028,
P-2029, P-2030, P-2031, P-2032, P-2033, P-2034, P-2035, P-2036,
P-2037, P-2038, P-2039, P-2040, P-2041, P-2042, P-2043, P-2044,
P-2045, P-2046, P-2047, P-2050, P-2051, P-2052, P-2053, P-2054,
P-2055, P-2056, P-2057, P-2058, P-2059, P-2060, P-2061, P-2062,
P-2063, P-2064, P-2065, P-2066, P-2067, P-2068, P-2069, P-2070,
P-2071, P-2072, P-2073, P-2074, P-2075, P-2076, P-2077, P-2078,
P-2079, P-2080, P-2081, P-2083, P-2084, P-2085, P-2086, P-2087,
P-2088, P-2089, P-2090, P-2092, P-2101, P-2105, P-2116, P-2117,
P-2119, P-2139, P-2140, P-2143, P-2147, P-2150, P-2151, P-2154,
P-2155, P-2162, P-2165, P-2166, P-2167, P-2168, P-2178, P-2179,
P-2182, P-2185, P-2193, P-2196, P-2199, P-2200, P-2201, P-2208,
P-2209, P-2210, P-2211, P-2213, P-2214, P-2215, P-2216, P-2217,
P-2218, P-2219, P-2220, P-2222, P-2223, P-2224, P-2225, P-2226,
P-2227, P-2228, P-2229, P-2230, P-2231, P-2232, P-2233, P-2234,
P-2235, P-2236, P-2238, P-2239, P-2240, P-2243, P-2244, P-2247,
P-2248, P-2250, P-2255, P-2257, P-2258, P-2259, P-2260, P-2261,
P-2272, P-2273, P-2274, P-2275, P-2276, P-2277, P-2278, P-2279,
P-2280, P-2281, P-2282, P-2283, P-2284, P-2285, P-2286, P-2287,
P-2288, P-2289, P-2290, P-2291, P-2292, P-2293, P-2294, P-2295,
P-2297, P-2303, P-2304, P-2305, P-2306, P-2307, P-2308, P-2310,
P-2311, P-2312, P-2313, P-2314, P-2317, P-2318, P-2319, P-2320,
P-2321, P-2322, P-2323, P-2324, P-2327, P-2328, P-2329, P-2330,
P-2331, P-2332, P-2333, P-2335, P-2336, P-2337, P-2338, P-2339,
P-2340, P-2341, P-2342, P-2343, P-2346, P-2347, P-2350, P-2353,
P-2354, P-2355, P-2356, P-2357, P-2358, P-2359, P-2360, P-2361,
P-2362, P-2363, P-2364, P-2365, P-2366, P-2367, P-2368, P-2369,
P-2370, P-2371, P-2372, P-2373, P-2374, P-2375, P-2376, P-2377,
P-2379, P-2382, P-2383, P-2391, P-2392, P-2393, P-2394, P-2395,
P-2396, P-2397, P-2398, P-2399, P-2400, P-2401, P-2402, P-2403,
P-2404, P-2407, P-2408, P-2409, P-2410, P-2411, P-2412, P-2413,
P-2414, P-2415, P-2416, P-2417, P-2418, P-2420, P-2421, P-2422,
P-2424, P-2425, P-2430, P-2431, P-2432, P-2434, P-2444, P-2445,
P-2446, P-2447, P-2467, P-2481, P-2483
TABLE-US-00025 TABLE 11e Compounds with activity toward kinase Btk
with IC.sub.50 .ltoreq. 10 .mu.M. Btk P-2022, P-2041, P-2042,
P-2043, P-2044, P-2045, P-2051, P-2052, P-2053, P-2054, P-2079,
P-2080, P-2086, P-2087, P-2099, P-2100, P-2101, P-2102, P-2103,
P-2105, P-2114, P-2120, P-2129, P-2130, P-2131, P-2134, P-2136,
P-2138, P-2139, P-2140, P-2142, P-2144, P-2145, P-2147, P-2157,
P-2158, P-2159, P-2160, P-2161, P-2165, P-2168, P-2174, P-2176,
P-2177, P-2178, P-2184, P-2190, P-2194, P-2199, P-2214, P-2222,
P-2229, P-2235, P-2260, P-2270, P-2271, P-2286, P-2287, P-2295,
P-2299, P-2302, P-2308, P-2322, P-2323, P-2345, P-2350, P-2351,
P-2352, P-2371, P-2372, P-2379, P-2383, P-2394, P-2399, P-2400,
P-2401, P-2402, P-2410, P-2414, P-2420, P-2429, P-2431, P-2432,
P-2433, P-2434, P-2440, P-2444, P-2446, P-2447, P-2448, P-2449,
P-2454, P-2455, P-2456, P-2457, P-2460, P-2461, P-2462, P-2464,
P-2468, P-2469, P-2471
TABLE-US-00026 TABLE 11f Compounds with activity toward kinase Fms
with IC.sub.50 .ltoreq. 10 .mu.M. Fms P-2001, P-2002, P-2003,
P-2004, P-2005, P-2006, P-2007, P-2008, P-2010, P-2015, P-2017,
P-2018, P-2022, P-2042, P-2043, P-2044, P-2088, P-2099, P-2100,
P-2101, P-2102, P-2103, P-2104, P-2105, P-2106, P-2107, P-2108,
P-2110, P-2111, P-2112, P-2113, P-2114, P-2115, P-2116, P-2117,
P-2118, P-2120, P-2121, P-2122, P-2123, P-2124, P-2125, P-2127,
P-2128, P-2129, P-2130, P-2131, P-2132, P-2133, P-2134, P-2135,
P-2136, P-2137, P-2138, P-2139, P-2140, P-2141, P-2142, P-2143,
P-2144, P-2145, P-2148, P-2149, P-2151, P-2152, P-2153, P-2155,
P-2157, P-2158, P-2159, P-2161, P-2164, P-2165, P-2166, P-2167,
P-2168, P-2169, P-2170, P-2172, P-2174, P-2175, P-2176, P-2177,
P-2178, P-2179, P-2180, P-2181, P-2183, P-2184, P-2185, P-2187,
P-2190, P-2192, P-2193, P-2194, P-2198, P-2199, P-2200, P-2201,
P-2203, P-2204, P-2207, P-2211, P-2212, P-2213, P-2214, P-2215,
P-2216, P-2218, P-2221, P-2222, P-2224, P-2226, P-2228, P-2230,
P-2232, P-2233, P-2234, P-2235, P-2236, P-2239, P-2241, P-2242,
P-2260, P-2268, P-2270, P-2271, P-2273, P-2296, P-2297, P-2298,
P-2299, P-2300, P-2301, P-2302, P-2304, P-2322, P-2324, P-2326,
P-2331, P-2334, P-2339, P-2343, P-2344, P-2348, P-2350, P-2351,
P-2352, P-2371, P-2383, P-2390, P-2404, P-2406, P-2423, P-2425,
P-2429, P-2430, P-2431, P-2432, P-2433, P-2434, P-2435, P-2436,
P-2437, P-2438, P-2439, P-2440, P-2441, P-2442, P-2443, P-2444,
P-2445, P-2446, P-2447, P-2448, P-2449, P-2450, P-2451, P-2452,
P-2453, P-2454, P-2455, P-2456, P-2457, P-2458, P-2460, P-2461,
P-2464, P-2465, P-2468, P-2469, P-2471
TABLE-US-00027 TABLE 11g Compounds with activity toward kinase Kdr
with IC.sub.50 .ltoreq. 10 .mu.M. Kdr P-2001, P-2002, P-2003,
P-2004, P-2005, P-2006, P-2008, P-2009, P-2010, P-2011, P-2014,
P-2015, P-2016, P-2017, P-2018, P-2019, P-2020, P-2021, P-2022,
P-2023, P-2024, P-2025, P-2026, P-2027, P-2029, P-2030, P-2031,
P-2032, P-2033, P-2034, P-2036, P-2037, P-2038, P-2041, P-2042,
P-2043, P-2044, P-2051, P-2052, P-2054, P-2055, P-2058, P-2059,
P-2060, P-2061, P-2062, P-2064, P-2065, P-2066, P-2067, P-2070,
P-2075, P-2079, P-2080, P-2081, P-2082, P-2088, P-2089, P-2093,
P-2094, P-2095, P-2096, P-2097, P-2099, P-2100, P-2101, P-2102,
P-2103, P-2104, P-2105, P-2106, P-2107, P-2108, P-2109, P-2110,
P-2111, P-2113, P-2114, P-2115, P-2117, P-2118, P-2120, P-2121,
P-2122, P-2124, P-2125, P-2126, P-2127, P-2128, P-2129, P-2130,
P-2131, P-2132, P-2133, P-2134, P-2135, P-2136, P-2137, P-2138,
P-2139, P-2140, P-2141, P-2142, P-2143, P-2144, P-2145, P-2146,
P-2147, P-2148, P-2149, P-2150, P-2151, P-2152, P-2153, P-2154,
P-2155, P-2156, P-2157, P-2158, P-2159, P-2160, P-2161, P-2162,
P-2164, P-2165, P-2166, P-2167, P-2168, P-2169, P-2170, P-2171,
P-2172, P-2174, P-2175, P-2176, P-2177, P-2178, P-2179, P-2180,
P-2181, P-2182, P-2183, P-2184, P-2185, P-2186, P-2187, P-2188,
P-2189, P-2190, P-2191, P-2192, P-2193, P-2194, P-2195, P-2196,
P-2197, P-2199, P-2200, P-2201, P-2203, P-2204, P-2207, P-2208,
P-2209, P-2210, P-2211, P-2212, P-2213, P-2214, P-2215, P-2216,
P-2217, P-2218, P-2219, P-2220, P-2221, P-2222, P-2223, P-2224,
P-2225, P-2226, P-2227, P-2228, P-2229, P-2230, P-2231, P-2232,
P-2233, P-2234, P-2235, P-2236, P-2237, P-2238, P-2239, P-2240,
P-2241, P-2242, P-2243, P-2247, P-2248, P-2250, P-2255, P-2260,
P-2261, P-2268, P-2269, P-2270, P-2271, P-2272, P-2273, P-2274,
P-2275, P-2276, P-2277, P-2278, P-2279, P-2280, P-2281, P-2286,
P-2287, P-2288, P-2289, P-2290, P-2291, P-2292, P-2293, P-2294,
P-2295, P-2296, P-2298, P-2299, P-2300, P-2301, P-2302, P-2303,
P-2304, P-2305, P-2308, P-2309, P-2310, P-2311, P-2312, P-2313,
P-2315, P-2319, P-2320, P-2321, P-2322, P-2323, P-2324, P-2326,
P-2327, P-2328, P-2329, P-2331, P-2333, P-2334, P-2335, P-2337,
P-2338, P-2339, P-2343, P-2344, P-2345, P-2346, P-2347, P-2348,
P-2349, P-2350, P-2351, P-2352, P-2353, P-2354, P-2355, P-2356,
P-2357, P-2358, P-2359, P-2360, P-2362, P-2363, P-2364, P-2365,
P-2370, P-2371, P-2372, P-2373, P-2374, P-2375, P-2376, P-2377,
P-2378, P-2379, P-2382, P-2383, P-2384, P-2385, P-2386, P-2387,
P-2389, P-2390, P-2394, P-2398, P-2399, P-2400, P-2401, P-2403,
P-2404, P-2406, P-2408, P-2409, P-2417, P-2422, P-2423, P-2424,
P-2425, P-2430, P-2431, P-2432, P-2433, P-2434, P-2435, P-2436,
P-2437, P-2438, P-2439, P-2442, P-2443, P-2444, P-2445, P-2446,
P-2447, P-2448, P-2449, P-2450, P-2451, P-2452, P-2453, P-2454,
P-2455, P-2456, P-2457, P-2458, P-2459, P-2460, P-2461, P-2463,
P-2464, P-2465, P-2466, P-2468, P-2469, P-2470, P-2471, P-2481,
P-2483
TABLE-US-00028 TABLE 11h Compounds with activity toward kinase Kit
with IC.sub.50 .ltoreq. 10 .mu.M. Kit P-2001, P-2002, P-2003,
P-2004, P-2005, P-2006, P-2007, P-2008, P-2009, P-2010, P-2011,
P-2014, P-2015, P-2016, P-2017, P-2018, P-2019, P-2020, P-2021,
P-2022, P-2023, P-2024, P-2025, P-2026, P-2027, P-2029, P-2030,
P-2031, P-2032, P-2033, P-2034, P-2035, P-2036, P-2037, P-2038,
P-2039, P-2041, P-2042, P-2043, P-2044, P-2046, P-2047, P-2051,
P-2052, P-2054, P-2055, P-2058, P-2071, P-2088, P-2094, P-2099,
P-2100, P-2101, P-2102, P-2103, P-2104, P-2105, P-2106, P-2107,
P-2108, P-2109, P-2110, P-2111, P-2112, P-2113, P-2114, P-2115,
P-2116, P-2117, P-2118, P-2120, P-2121, P-2122, P-2123, P-2124,
P-2125, P-2126, P-2127, P-2128, P-2129, P-2130, P-2131, P-2132,
P-2133, P-2134, P-2135, P-2136, P-2138, P-2139, P-2140, P-2141,
P-2142, P-2144, P-2145, P-2147, P-2148, P-2149, P-2151, P-2152,
P-2153, P-2155, P-2157, P-2158, P-2159, P-2161, P-2164, P-2165,
P-2166, P-2167, P-2168, P-2169, P-2170, P-2172, P-2174, P-2175,
P-2176, P-2177, P-2178, P-2179, P-2180, P-2181, P-2182, P-2183,
P-2184, P-2185, P-2187, P-2190, P-2192, P-2193, P-2194, P-2195,
P-2199, P-2200, P-2201, P-2203, P-2204, P-2207, P-2209, P-2213,
P-2214, P-2215, P-2216, P-2218, P-2220, P-2221, P-2222, P-2223,
P-2224, P-2226, P-2228, P-2229, P-2230, P-2231, P-2232, P-2233,
P-2234, P-2235, P-2236, P-2238, P-2239, P-2240, P-2241, P-2242,
P-2260, P-2268, P-2270, P-2271, P-2272, P-2273, P-2274, P-2275,
P-2282, P-2288, P-2289, P-2290, P-2291, P-2293, P-2296, P-2297,
P-2298, P-2299, P-2300, P-2301, P-2302, P-2303, P-2304, P-2305,
P-2306, P-2307, P-2309, P-2310, P-2311, P-2314, P-2315, P-2317,
P-2318, P-2319, P-2322, P-2324, P-2325, P-2326, P-2327, P-2328,
P-2329, P-2331, P-2333, P-2334, P-2335, P-2338, P-2341, P-2343,
P-2344, P-2345, P-2347, P-2348, P-2350, P-2351, P-2352, P-2353,
P-2354, P-2355, P-2356, P-2357, P-2358, P-2359, P-2360, P-2361,
P-2365, P-2366, P-2367, P-2369, P-2371, P-2372, P-2374, P-2375,
P-2379, P-2383, P-2384, P-2389, P-2390, P-2391, P-2392, P-2393,
P-2398, P-2400, P-2401, P-2406, P-2419, P-2430, P-2431, P-2432,
P-2433, P-2434, P-2435, P-2436, P-2438, P-2441, P-2443, P-2444,
P-2445, P-2446, P-2447, P-2448, P-2449, P-2450, P-2451, P-2452,
P-2453, P-2454, P-2455, P-2456, P-2457, P-2458, P-2459, P-2460,
P-2461, P-2464, P-2465, P-2466, P-2468, P-2471
TABLE-US-00029 TABLE 11i Compounds with activity toward kinase Src
with IC.sub.50 .ltoreq. 10 .mu.M. Src P-2001, P-2002, P-2003,
P-2004, P-2005, P-2006, P-2007, P-2009, P-2010, P-2011, P-2014,
P-2015, P-2016, P-2017, P-2018, P-2019, P-2020, P-2021, P-2022,
P-2023, P-2024, P-2025, P-2026, P-2027, P-2029, P-2030, P-2031,
P-2032, P-2033, P-2034, P-2036, P-2037, P-2038, P-2039, P-2040,
P-2041, P-2042, P-2043, P-2044, P-2045, P-2046, P-2047, P-2051,
P-2052, P-2053, P-2054, P-2055, P-2056, P-2057, P-2059, P-2060,
P-2061, P-2062, P-2063, P-2065, P-2067, P-2069, P-2070, P-2071,
P-2073, P-2074, P-2075, P-2076, P-2078, P-2079, P-2080, P-2087,
P-2100, P-2101, P-2102, P-2103, P-2104, P-2105, P-2137, P-2138,
P-2139, P-2140, P-2142, P-2144, P-2145, P-2147, P-2148, P-2149,
P-2150, P-2151, P-2153, P-2154, P-2155, P-2156, P-2157, P-2158,
P-2159, P-2161, P-2162, P-2164, P-2165, P-2166, P-2167, P-2168,
P-2169, P-2170, P-2171, P-2172, P-2174, P-2175, P-2176, P-2177,
P-2178, P-2179, P-2180, P-2181, P-2184, P-2185, P-2187, P-2190,
P-2191, P-2192, P-2193, P-2194, P-2195, P-2196, P-2204, P-2209,
P-2210, P-2211, P-2213, P-2214, P-2215, P-2216, P-2217, P-2219,
P-2220, P-2222, P-2223, P-2224, P-2225, P-2226, P-2228, P-2229,
P-2230, P-2231, P-2232, P-2233, P-2234, P-2235, P-2236, P-2237,
P-2238, P-2239, P-2240, P-2242, P-2260, P-2261, P-2268, P-2270,
P-2271, P-2272, P-2273, P-2275, P-2276, P-2277, P-2280, P-2284,
P-2286, P-2287, P-2290, P-2296, P-2298, P-2299, P-2300, P-2301,
P-2302, P-2303, P-2304, P-2305, P-2306, P-2308, P-2309, P-2310,
P-2311, P-2312, P-2313, P-2315, P-2316, P-2318, P-2319, P-2321,
P-2322, P-2323, P-2324, P-2325, P-2326, P-2327, P-2328, P-2329,
P-2330, P-2331, P-2332, P-2333, P-2334, P-2335, P-2336, P-2337,
P-2338, P-2339, P-2340, P-2341, P-2342, P-2343, P-2344, P-2345,
P-2346, P-2347, P-2350, P-2351, P-2352, P-2354, P-2355, P-2356,
P-2357, P-2358, P-2359, P-2360, P-2361, P-2364, P-2365, P-2367,
P-2368, P-2369, P-2371, P-2372, P-2373, P-2374, P-2375, P-2376,
P-2377, P-2378, P-2379, P-2382, P-2383, P-2384, P-2389, P-2390,
P-2391, P-2392, P-2393, P-2394, P-2396, P-2397, P-2398, P-2399,
P-2400, P-2401, P-2402, P-2408, P-2414, P-2429, P-2431, P-2432,
P-2433, P-2434, P-2444, P-2445, P-2446, P-2447, P-2448, P-2457,
P-2460, P-2465, P-2466, P-2481
TABLE-US-00030 TABLE 11j Compounds with activity toward kinase TEC
with IC.sub.50 .ltoreq. 10 .mu.M. TEC P-2003, P-2020, P-2021,
P-2022, P-2023, P-2024, P-2027, P-2029, P-2030, P-2031, P-2040,
P-2041, P-2042, P-2043, P-2044, P-2045, P-2046, P-2047, P-2051,
P-2052, P-2053, P-2054, P-2067, P-2070, P-2071, P-2072, P-2079,
P-2080, P-2087, P-2099, P-2105, P-2111, P-2118, P-2120, P-2129,
P-2130, P-2131, P-2132, P-2133, P-2134, P-2135, P-2136, P-2138,
P-2139, P-2140, P-2142, P-2144, P-2145, P-2161, P-2174, P-2177,
P-2198, P-2199, P-2207, P-2212, P-2214, P-2247, P-2248, P-2250,
P-2257, P-2260, P-2261, P-2271, P-2278, P-2282, P-2287, P-2292,
P-2299, P-2302, P-2306, P-2307, P-2308, P-2309, P-2310, P-2312,
P-2313, P-2322, P-2323, P-2330, P-2333, P-2342, P-2352, P-2353,
P-2354, P-2355, P-2356, P-2357, P-2358, P-2359, P-2361, P-2371,
P-2372, P-2373, P-2376, P-2377, P-2378, P-2379, P-2382, P-2383,
P-2394, P-2399, P-2400, P-2401, P-2402, P-2414, P-2417, P-2430,
P-2432, P-2434, P-2440, P-2441, P-2442, P-2443, P-2444, P-2445,
P-2446, P-2447, P-2448, P-2454, P-2455, P-2457, P-2460, P-2461,
P-2464, P-2467, P-2468, P-2471
TABLE-US-00031 TABLE 11k Compounds with activity toward kinase TrkA
with IC.sub.50 .ltoreq. 10 .mu.M. TrkA P-2060, P-2061, P-2105,
P-2168, P-2174, P-2176, P-2239, P-2240, P-2301, P-2302, P-2344,
P-2345, P-2407
TABLE-US-00032 TABLE 11m Compounds with activity toward kinase
MAP4K4 with IC.sub.50 .ltoreq. 10 .mu.M. MAP4K4 P-2002, P-2003,
P-2008, P-2009, P-2010, P-2011, P-2014, P-2015, P-2016, P-2017,
P-2018, P-2019, P-2021, P-2022, P-2023, P-2024, P-2025, P-2026,
P-2029, P-2030, P-2031, P-2033, P-2034, P-2036, P-2061, P-2062,
P-2063, P-2064, P-2065, P-2066, P-2067, P-2069, P-2070, P-2071,
P-2074, P-2075, P-2076, P-2099, P-2105, P-2137, P-2138, P-2139,
P-2140, P-2141, P-2142, P-2143, P-2144, P-2145, P-2146, P-2147,
P-2148, P-2149, P-2176, P-2182, P-2193, P-2199, P-2211, P-2214,
P-2215, P-2219, P-2220, P-2221, P-2222, P-2223, P-2224, P-2226,
P-2228, P-2229, P-2230, P-2231, P-2232, P-2233, P-2234, P-2235,
P-2236, P-2239, P-2240, P-2242, P-2244, P-2247, P-2269, P-2270,
P-2272, P-2274, P-2275, P-2276, P-2277, P-2278, P-2279, P-2288,
P-2289, P-2290, P-2291, P-2300, P-2301, P-2308, P-2309, P-2310,
P-2312, P-2315, P-2324, P-2327, P-2328, P-2329, P-2331, P-2335,
P-2337, P-2338, P-2339, P-2346, P-2347, P-2353, P-2354, P-2355,
P-2356, P-2357, P-2360, P-2362, P-2366, P-2367, P-2375, P-2382,
P-2383, P-2407, P-2408, P-2430, P-2432, P-2434, P-2443, P-2444,
P-2445, P-2446, P-2447, P-2448, P-2452, P-2453, P-2457, P-2458,
P-2459, P-2460, P-2461, P-2462, P-2464, P-2465, P-2466, P-2467
TABLE-US-00033 TABLE 11n Compounds with activity toward kinase Flt1
with IC.sub.50 .ltoreq. 10 .mu.M. Flt1 P-2099, P-2100, P-2105,
P-2150, P-2151, P-2162, P-2193, P-2196, P-2199, P-2200, P-2201,
P-2203, P-2210, P-2213, P-2214, P-2215, P-2216, P-2217, P-2218,
P-2299, P-2302, P-2404, P-2430, P-2432, P-2434, P-2457
TABLE-US-00034 TABLE 11o Compounds with activity toward kinase
PI3K.alpha. with IC.sub.50 .ltoreq. 10 .mu.M. PI3K.alpha. P-2040,
P-2041, P-2042, P-2043, P-2044, P-2045, P-2079, P-2080, P-2139,
P-2145, P-2147, P-2149, P-2170, P-2174, P-2188, P-2193, P-2214,
P-2220, P-2234, P-2286, P-2287, P-2295, P-2322, P-2323, P-2333,
P-2342, P-2371, P-2372, P-2373, P-2399, P-2401, P-2402, P-2407
TABLE-US-00035 TABLE 11p Compounds with activity toward kinase
PI3K.delta. with IC.sub.50 .ltoreq. 10 .mu.M. PI3K.delta. P-2170,
P-2188
TABLE-US-00036 TABLE 11q Compounds with activity toward kinase
PI3K.gamma. with IC.sub.50 .ltoreq. 10 .mu.M. PI3K.gamma. P-2188,
P-2220, P-2407
[2403] Additional examples of certain methods contemplated by the
present invention may be found in the following applications: U.S.
Patent Publ. No. 2006/058339, application Ser. No. 11/154,287; U.S.
Patent Publ. No. 2006/058340, application Ser. No. 11/154,988; U.S.
Prov. App. No. 60/682,076, filed May 17, 2005; U.S. Prov. App. No.
60/682,058, filed May 17, 2005; U.S. Prov. App. No. 60/682,063,
filed May 17, 2005; U.S. Prov. App. No. 60/682,051, filed May 17,
2005; U.S. Prov. App. No. 60/682,042, filed May 17, 2005; U.S.
Prov. App. No. 60/692,750, filed Jun. 22, 2005; and U.S. Prov. App.
No. 60/692,960, filed Jun. 22, 2005; U.S. Prov. App. No.
60/731,528, filed Oct. 28, 2005, U.S. patent application Ser. No.
11/435,381, filed May 16, 2006, and U.S. patent application Ser.
No. 11/473,347, filed Jun. 21, 2006, each of which are hereby
incorporated by reference herein in their entireties including all
specifications, figures, and tables, and for all purposes.
[2404] 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.
[2405] 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.
[2406] 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. For example, variations can be made to
crystallization or co-crystallization conditions for Ret and Ret
surrogate proteins and/or various kinase domain sequences can be
used. Thus, such additional embodiments are within the scope of the
present invention and the following claims.
[2407] 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.
[2408] 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.
[2409] 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.
[2410] Thus, additional embodiments are within the scope of the
invention and within the following claims.
* * * * *