Indian Patents
Title of Invention

COMPOUNDS MODULATING C-FMS AND/OR C-KIT ACTIVITY
Abstract Compounds active on the receptor protein tyrosine kinases c-kit and/or c-fms are provided herewith. Also provided herewith are compositions useful for treatment of c-kit mediated diseases or conditions and/or c-fms-mediated diseases or conditions, and methods for the use thereof.
Full Text COMPOUNDS MODULATING C-FMS AND/OR C-KIT ACTIVITY
AND USES THEREFOR
RELATED PATENT APPLICATIONS
[000l] This application claims priority to U.S. Provisional App. No. 60/860,749, entitled
"Compounds Modulating c-Fms and c-Kit Activity and Uses Therefor", filed November 22, 2006,
and is related to U.S. Patent App. No. 11/435,381, entitled "Compounds Modulating c-Kit and
c-Fms Activity and Uses Therefor", filed May 16, 2006, which claims the benefit of U.S.
• Provisional App. No. 60/682,063, entitled "Compounds Modulating c-Kit Activity and Uses
Therefor", filed May 17, 2005, U.S. Provisional App. No. 60/682,051, entitled "Compounds
Modulating c-Fms Activity and Uses Therefor", filed May 17, 2005, U.S. Provisional App. No.
60/682,042, entitled "Compounds Modulating c-Kit and c-Fms Activity and Uses Therefor", filed
May 17, 2005, U.S. Provisional App. No. 60/692,750, entitled "Compounds Modulating c-Kit and
c-Fms Activity and Uses Therefor", filed June 22, 2005, and U.S. Provisional App. No.
60/692,960, entitled "Compounds and Methods for Kinase Modulation, and Indications Therefor",
filed June 22, 2005, all of which are incorporated herein by reference in their entireties and for all
purposes.
FIELD OF THE INVENTION
[0002] This invention relates to ligands for c-fms and c-kit, and to methods for use thereof. The
information provided is intended solely to assist the understanding of the reader. None of the
information provided nor references cited is admitted to be prior art to the present invention. Each
of the references cited is incorporated herein in its entirety and for any purpose.
BACKGROUND OF THE INVENTION
[0003] C-fms and c-kit are both type III transmembrane receptor protein tyrosine kinases
(RPTKs) that regulate key signal transduction cascades that control cellular growth and
proliferation. Both receptors have similar structural features comprising five extracellular
immunoglobulin (IG) domains, a single transmembrane domain, and a split cytoplasmic kinase
domain separated by a kinase insert segment.


c-Fms
[00041 C-fms is a member of the family of genes originally isolated from the Susan McDonough
strain of feline sarcoma viruses. The cellular proto-oncogene FMS (c-fms, gellular feline
McDonough sarcoma) codes for the receptor for the macrophage colony-stimulating factor (M-
CSF). C-fms is crucial for the growth and differentiation of the monocyte-macrophage lineage,
and upon binding of M-CSF to the extracellular domain of c-fms, the receptor dimerizes and trans-
autophosphorylates cytoplasmic tyrosine residues.
[0005] M-CSF, first described by Robinson and co-workers (Blood. 1969, 33:396-9), is a
cytokine that controls the production, differentiation, and function of macrophages. M-CSF
stimulates differentiation of progenitor cells to mature monocytes, and prolongs the survival of
monocytes. Furthermore, M-CSF enhances cytotoxicity, superoxide production, phagocytosis,
chemotaxis, and secondary cytokine production of additional factors in monocytes and
macrophages. Examples of such additional factors include granulocyte colony stimulating factor
(G-CSF), interleukin-6 (IL-6), and interleukin-8 (IL-8). M-CSF stimulates hematopoiesis,
promotes differentiation and proliferation of osteoclast progenitor cells, and has profound effects
on lipid metabolism. Furthermore, M-CSF is important in pregnancy. Physiologically, large
amounts of M-CSF are produced in the placenta, and M-CSF is believed to play an essential role in
trophoblast differentiation (Motoyoshi, Int J Hematol. 1998,67:109-22). The elevated serum
levels of M-CSF in early pregnancy may participate in the immunologic mechanisms responsible
for the maintenance of the pregnancy (Flanagan & Lader, Curr Opin Hematol. 1998, 5:181-5).
(0006] Related to c-fms and c-kit are two platelet-derived growth factor receptors, alpha (i.e.,
pdgfra) and beta (pdgfrb) (PDGF). The gene coding for pdgfra is located on chromosome 4ql 1-
ql2 in the same region of chromosome 4 as the oncogene coding for c-kit. The genes coding for
pdgfra and c-fms appear to have evolved from a common ancestral gene by gene duplication,
inasmuch as these two genes are tandemly linked on chromosome 5. They are oriented head-to-
tail with the 5-prime exon of the c-fms gene located only 500 bp from the last 3-prime exon of the
gene coding for pdgfra. Most gastrointestinal stromal tumors (GIST) have activating mutations in
c-kit, and most patients with GISTs respond well to Gleevec, which inhibits c-kit. Heinrich et al.
(Science 2003, 299:708-10) have shown that approximately 35% of GISTs lacking c-kit mutations
have intragenic activation mutations in the gene encoding pdgfra, and that tumors expressing c-kit
or pdgfra are indistinguishable with respect to activation of downstream signaling intermediates
and cytogenetic changes associated with tumor progression. Thus, c-kit and pdgfra mutations
appear to be alternative and mutually exclusive oncogenic mechanisms in GISTs.

10007] Similarly, the observation that production of M-CSF, the major macrophage growth
factor, is increased in tissues during inflammation points out a role for c-fms in diseases, such as
for example inflammatory diseases. More particularly, because elevated levels of M-CSF are
found in the disease state, modulation of the activity of c-fms can ameliorate disease associated
with increased levels of M-CSF.
c-Kit
[0008] The Stem Cell Factor (SCF) receptor c-kit plays an important role in the development of
mclanocytes and mast, germ and hematopoietic cells. Stem Cell Factor (SCF) is a protein encoded
by the S1 locus, and has also been called "kit ligand" (KL) and mast cell growth factor (MGF),
based on the biological properties used to identify it (reviewed in Tsujimura, Pathol Int 1996,
46:933-938; Loveland, et al., J. Endocrinol 1997, 153:337-344; Vliagoftis, et al., Clin Immunol
1997, 100:435-440; Broudy, Blood 1997, 90:1345-1364; Pignon, Hermatol Cell Ther 1997,
39:114-116; and Lyman, et al., Blood 1998, 91:1101-1134.). Herein the abbreviation SCF refers
to the physiological ligand for c-kit.
[0009] SCF is synthesized as a transmembrane protein with a molecular weight of 220 or 248
Dalton, depending on alternative splicing of the mRNA to encode exon 6. The larger protein can
be proteolytically cleaved to form a soluble, glycosylated protein which noncovalently dimerizes.
Both the soluble and membrane-bound forms of SCF can bind to and activate c-kit. For example,
in the skin, SCF is predominantly expressed by fibroblasts, keratinocytes, and endothelial cells,
which modulate the activity of melanocytes and mast cells expressing c-kit. In bone, marrow
stromal cells express SCF and regulate hematopoiesis of c-kit expressing stem cells. In the
gastrointestinal tract, intestinal epithelial cells express SCF and affect the interstitial cells of Cajal
and intraepithelial lymphocytes. In the testis, sertoli cells and granulosa cells express SCF which
regulates spermatogenesis by interaction with c-kit on germ cells.
SUMMARY OF THE INVENTION
[0010] The present invention relates to compounds active on c-fms, c-kit, or both c-fms and c-
kit. In accordance with one aspect of the present invention, it has been discovered that in the
treatment of diseases amenable to treatment by an effective amount of a modulator of either c-fms
alone or c-kit alone, the efficacy of treatment can be enhanced if said compounds are dual
inhibitors of both c-fms and c-kit. In another aspect of the present invention, compounds active on
c-fms, c-kit, or both c-fms and c-kit are also active on one or more of TrkA, TrkB and HGK. In
particular, the invention provides compounds of Formula II, and all sub-generic formulae thereof

(e.g. Formula IIa, IIb, He, IIg and IIp), Fonnula III, or additional compounds as described in the
synthetic examples, as well as methods of using such compounds as described below. Thus, the
invention provides methods of using compounds that can be used therapeutically and/or
prophylactically involving modulation of c-fms, c-kit, or both c-fms and c-kit, or involving one or
more of TrkA, TrkB and HGK in addition to c-fms, c-kit, or both c-fms and c-kit.

in which ? indicates the attachment point of D to A2 of Formula II;
A2 is -CH2- or -C(O)-;
B is selected from the group consisting of hydrogen, -CN, -OR41. -SR41, -NHR41, -NR41R41,
-NR39C(O)R4\ -NR39S(O)jR41, -C(O)NRJV, -C(O)R41, -S(O)2NRMR41, -S(O)2R41,
halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower
alkyl is optionally substituted with one or more substituents selected from the group
consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro
substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl,
heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and

hetcroaryl as B, or as substituents of lower alkyl are optionally substituted with one or
more substituents selected from the group consisting of-OH, -NH2, -CN, -NO2,
-S(O)2NH2, -C(O)NH2, -OR", -SR42, -NHR42, -NR42R42, -NR3'C(O)R42, -NR39S(O)2R42.
-S(O)2R42, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;
M4 is -NR39CH2-, -NR39CHCR40)-, -NR39CH2CH2-, or -NR39C(O)-;
M5. M,o> and M)8 are selected from the group consisting of a bond, -NR3'-, -S-, -O-, -NR39CH2-,
-NR3'CH2CH2-, -NR^CHCR40)-, -SCH2-, -OCH2-, -C(O)NR39-, -S(O)2NR39-, -CH2NR3'-,
-CH(RW)NR39-, -NR39C(O)-, and -NR39S(O)2-;
M8 is selected from the group consisting of a bond, -CH2-, -CH2C(O)-, -S(O)2-, -S(O)3CHr,
-S(O)2CH(CH3)-, -S(O)2CH2CH2-, -S(O)2NR39-, -S(O)2NR39CH2-, -S(O)2NR39CH(CH3)-,
-S(O)2NR39CH2CH2-, -C(O)-, -C(O)CH2-, -C(O)CH(CH3)-, -C(O)CH2CH2-, -C(O)NR39-,
-C(O)NR39CH2-, -C(O)NR39CH(CH3)-, and -C(O)NR39CH2CH2-;
Q' is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more
substituents selected from the group consisting of-OR41, -SR41, -S(O)R41, -S(O)2R41,
-NHR41, -NR4IR41, -NR39C(O)R41, -NR3'S(O)2R41, halogen, lower alkyl, cycloalkyl,
heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with
one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro
substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-
alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein
cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as a substituent of Q'or as a substituent
of lower alkyl are optionally substituted with one or more substituents selected from the
group consisting of-OH, -NH2, -CN, -NO2, -S(O)2NH2) -C(O)NH2, -OR42, -SR42, -NHR42,
-NR42R42, -NR39C(O)R42, -NR39S(O)2R42. -S(O)2R42, halogen, lower alkyl, fluoro
substituted lower alkyl, and cycloalkylamino;
Q11, Q41. Q61. and Q141 are lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl,
wherein lower alkyl is optionally substituted with one or more fluoro, lower alkoxy, or
fluoro substituted lower alkoxy, and wherein cyclaolkyl, heterocycloalkyl, aryl or
heteroaryl are optionally substituted with one or more substituents selected from the group
consisting of-OR41, -SR41, -S(O)R41, -S(O)R41, -NHR41, -NR4IR4, -NR39C(O)R4-NR39S(O)2R41, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl,
wherein lower alkyl is optionally substituted with one or more substituents selected from
the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower
alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl,
heterocycloalkyl, aryl, and heteroaryl, and wherein cycloalkyl, heterocycloalkyl, aryl, and
heteroaryl as a substituent of Q11, Q41, Q61, or Q141, or as a substituent of lower alkyl are
optionally substituted with one or more substituents selected from the group consisting of


-OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR42, -SR42, -NHR42, -NR42R42,
-NR39C(O)R42, -NR39S(O)2R42, -S(O),R42, halogen, lower alkyl, fluoro substituted lower
alkyl, and cycloalkylamino;
Q12 is fluoro, chloro or -CF3;
Q13 and Q14 are independently hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted
lower alkyl;
Q22, Q24 Q52, and Q54 are independently selected from the group consisting of hydrogen,
halogen, lower alkyl, fluoro substituted lower alkyl, -NR44R44, -OR44, and -SR44, provided,
however, that at least one of Q22 and Q24 and at least one of Q52 and QS4 is hydrogen,
fluoro, chloro, lower alkyl or fluoro substituted lower alkyl;
Q74 and Q152 are hydrogen, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl,
-NR^R44,-OR44, or-SR44;
Q72 is hydrogen, lower alkyl or fluoro substituted lower alkyl;
R39 at each occurrence is independently hydrogen or lower alkyl;
R40 is lower alkyl or fluoro substituted lower alkyl;
R41 at each occurrence is independently selected from the group consisting of lower alkyl,
cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally
substituted with one or more substituents selected from the group consisting of fluoro,
lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower
alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and
heteroaryl, and wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R41 or as
substituents of lower alkyl are optionally substituted with one or more substituents
selected from the group consisting of-OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2,
-OR42, -SR42, -NHR42, -NR42R42, -NR39C(O)R42, -NR39S(O)2R42, -S(O)jR42, halogen, lower
alkyl, fluoro substituted lower alkyl, and cycloalkylamino;
R42 at each occurrence is independently selected from the group consisting of lower alkyl,
heterocycloalkyl and heteroaryl, wherein lower alkyl is optionally substituted with one or
more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro
substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-
alkylamino, di-alkylamino, and cycloalkylamino, and wherein heterocycloalkyl and
heteroaryl are optionally substituted with one or more substituents selected from the group
consisting of halogen, -CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy and
fluoro substituted lower alkoxy; and
each R44 is independently hydrogen, lower alkyl or fluoro substituted lower alkyl;



Q5 is hydrogen, -CN, -OR41, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, aryl or
heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more
substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted
lower alkyl, -NHR41, -NR41R41, and -OR41; and
A2, M4, Q12, Q13, Q14 and R41 are as defined for Formula II;

(00131 In one embodiment of compounds of Formula IIa, A2 is -CH2- and M4 is -NHCH2-. In
one embodiment A2 is -C(O)- and M4 is -NHCH2-. In one embodiment A2 is -C(O)- and M4 is
-NHC(O)-. In one embodiment A2 is -CH2- and M4 is -NHC(O)-,
[0014] In one embodiment of compounds of Formula Ila, A2 is -CH2-, M4 is -NHCH2-, Q5 is
-OR41, -CN, C1-3 alkyl, fluoro substituted C1-3 alkyl, fluoro, chloro, aryl or heteroaryl, wherein aryl
or heteroaryl are optionally substituted with one or more substituents selected from the group
consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41, -NR4IR41, -OR41 and
-S(O)2R41; and Q13 and Q14 are hydrogen.
|0015| In one embodiment of compounds of Formula Ila, A2 is -C(O)-, M, is -NHCH2-, Q5 is
-OR41, -CN, C1-3 alkyl, fluoro substituted C1-3 alkyl, fluoro, chloro, aryl or heteroaryl, wherein aryl
or heteroaryl are optionally substituted with one or more substituents selected from the group
consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41, -NR4IR41, -OR41 and
-SCO)2R41; and Q13 and Q14 are hydrogen.
[00161 In one embodiment of compounds of Formula Ila, A2 is -C(O)-, M4 is -NHC(O)-, Q5 is
-OR41, -CN, C1-3 alkyl, fluoro substituted C1-3 alkyl, fluoro, chloro, aryl or heteroaryl, wherein aryl
or heteroaryl are optionally substituted with one or more substituents selected from the group
consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41, -NR4IR41, -OR41 and
-S(O)2R41; and Q13 and Q14 are hydrogen.
[0017] In one embodiment of compounds of Formula Ila, A2 is -CH2-, M4 is -NHC(O}-, Q5 is
-OR41, -CN, C1-3 alkyl, fluoro substituted C1-3 alkyl, fluoro, chloro, aryl or heteroaryl, wherein aryl
or heteroaryl are optionally substituted with one or more substituents selected from the group
consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41, -NR4IR41, -OR41 and
-S(O)2R41; and Q13 and Q14 are hydrogen.

[0018] In one embodiment, further to any of the embodiments of Formula Ha above, R41 is R42 as
defined for Formula II.
[0019] In one embodiment, further to any of the embodiments of Formula Ha above, Q1' is
phenyl or pyridinyl, wherein phenyl or pyridinyl are substituted with 1 or 2 substituents selected
from the group consisting of fluoro, chloro, methyl, methoxy, trifluoromethyl, difluoromethoxy
and trifluoromethoxy; A2 is -CH2-; M4 is -NHCH2-; and Qs is -CN, fluoro, chloro, methyl,
trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, aryl or heteroaryl, wherein aryl or
heteroaryl are optionally substituted with one or more halogen, lower alkyl, fluoro substituted
lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy. In one embodiment, further to any
of the embodiments of Formula IIa above, Q" is phenyl mono substituted with chloro, preferably
at the 4-position; A2 is -CH2-; M4 is -NHCH2-; and Q5 is -CN, fluoro, chloro, methyl,
trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, aryl or heteroaryl, wherein aryl or
heteroaryl are optionally substituted with one or more halogen, lower alkyl, fluoro substituted
lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy. In one embodiment, further to any
of the embodiments of Formula Ila, Q1a is pyridin-3-yl monosubstituted with methyl, methoxy,
trifluoromethyl, difluoromethoxy or trifluoromethoxy, preferably at the 6-position; A2 is -CH2-; M4
is -NHCH2-; Q5 is -CN, fluoro, chloro, methyl, trifluoromethyl, methoxy, difluoromethoxy,
trifluoromethoxy, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one
or more halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted
lower alkoxy.
[0020] In one embodiment of compounds of Formula Ila, A2 is -CH2-; M4 is -NHCH2-; Qu is
phenyl or pyridinyl, wherein phenyl or pyridinyl are substituted with 1 or 2 substituents selected
from the group consisting of fluoro, chloro, methyl, methoxy, trifluoromethyl, difluoromethoxy
and trifluoromethoxy; Q5 is hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl,
difluoromethoxy, trifluoromethoxy, -CN, or 1-methyl-1 H-pyrazole-4-yl; Q13 is fluoro or chloro;
and Ql} and Q14 are hydrogen. In one embodiment, A2 is -CH2-; M4 is -NHCH2-; Q15 is phenyl
mono substituted with chloro, preferably at the 4-position; Q5 is hydrogen, chloro, methyl,
methoxy, or -CN; Q12 is fluoro or chloro; and Q13 and QM are hydrogen. In one embodiment, A: is
-CH2-; M4 is -NHCH2-; Q" is pyridin-3-yl monosubstituted with methyl, methoxy, trifluoromethyl,
difluoromethoxy or trifluoromethoxy, preferably at the 6-position; Q5 is hydrogen, chloro, methyl,
methoxy, -CN, or l-methyl-lH-pyrazole-4-yl; Q12 is fluoro or chloro; and Q13 and Q14 are
hydrogen.
[0021] In one embodiment of compounds of Formula Ila, the compound is selected from the
group consisting of:
9

(4-Chloro-benzyI)-[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-
amine (P-0132),
(4-Chloro-benzyl)-[6-chloro-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-ainine
(P-0161),
[6-Chloro-5-(IH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-
ylmethyO-amine (P-0174),
[6-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-
pyridin-3-ylmethyl)-amine (P-0176),
{6-Chloro-5-[5-(l-methyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl]-pyridin-2-yl}-
(6-trifluoromethyl-pyridin-3-ylmethyl)-amine (P-0179),
[5-(5-Chloro-lH-pyrTolo[2,3-b]pyridin-3-ylmcthyl)-6-fluoro-pyridin-2-yl]-(6-trifluoromethyl-
pyridin-3-ylmethyl)-amine (P-0186),
[6-Fluoro-5-(5-methoxy-lH-pyiTolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-{6-trifluoromethyl-
pyridin-3-ylmethyl)-amine (P-0187),
[6-Fluoro-5-(lH-pynt)lo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoroinethyl-pyridin-3-
ylmethyl)-amine (P-0188),
3-{2-Chloro-6-[(6-trifluoromethyl-pyridin-3-ylmethyl)-aniino]-pyridin-3-ylinethyl}-lH-
pyrTolo[2,3-b]pyridine-5-carbonitrile(P-0232),
[6-Chloro-5-(5-methyl-lH-pyrTolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-
pyridin-3-ylmethyl)-amine (P-0233),
[6-Chloro-5-(5-methyl-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-
pyridin-3-ylmethyl)-amine (P-0234),
[6-Fluoro-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-methoxy-pyTidJn-3-ylmethyl)-
araine (P-0378),
[5-(5-Chloro-lH-pyrrolof2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-methoxy-pyridin-3-
ylmethyl)-amine (P-0379),
(5-F[uoro-pyridin-3-ylmethyI)-[6-fluoro-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-
araine (P-O414),
3-{2-Fluoro-6-[(5-fluoro-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl}-lH-pyrrolo[2,3-
b]pyridine-5-carbonitrile (P-0415),
3-[6-(4-Chloro-benzylamino)-2-fluoro-pyridin-3-ylmethyl]-lH-pyiTolo[2,3-b]pyridine-5-
carbonilrile (P-0432), and
all salts, prodrugs, tautomers, and isomers thereof.
|0022] In one embodiment, a compound of Formula II has a structure according to the following
sub-generic structure, Formula lib,



all salts, prodrugs, tautomers, and isomers thereof,
wherein:
A3 is -CH2- or -C(O)-;
Q15 is hydrogen, -CN, -OR41, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl,
cycloalky], heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl
or heteroaryl are optionally substituted with one or more substituents selected from the
group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41,
-NR4lR4l,and-OR41;and
Ms, Q", Q22, Q24, and R41, are as defined for Formula II.
|0023] In one embodiment of compounds of Formula lib, Ms is -NR3'CH2-, -NR39CH(R40)-,
-NR"CH2CH2-, or -NR3'C(O)-; A3 is -CH2- or -C(O)-, preferably -CH2-; Q11 is cycloalkyl,
heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are
optionally substituted with one or more substituents selected from the group consisting of halogen,
lower alkyl, fluoro substituted lower alkyl. -NHR41, -NR4IR41, -OR41 and -S(O)jR41; Q13 is
hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro
substituted lower alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl,
heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents
selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41,
-NR4IR41, -OR41 and -S(O)2R41; and QH and Q24 are independently hydrogen, fluoro, chloro, lower
alkyl, or fluoro substituted lower alkyl, preferably hydrogen, fluoro, chloro, or -CF3, more
preferably both Q22 and Q24 are hydrogen; wherein R41 is as defined for Formula II.
[0024] In one embodiment, further to any of the embodiments of Formula IIb above, R41 is R42 as
defined for Formula II.
[002S| In one embodiment of compounds of Formula 11b, M5 is -NHCH2CH2-, -NHCH2-
-N(CH,)CH2-, or -NHCH(CH3)-, preferably -NHCH2-; A, is -CH2-; Q" is cycloalkyl,
heterocycloalkyl, phenyl or heteroaryl, wherein phenyl or heteroaryl arc optionally substituted
with 1 or 2 substituents selected from the group consisting of halogen, lower alkyl, fluoro

substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, di-alkylamino, and
heterocycloaJkyl; QIS is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl,
lower alkoxy, fluoro substituted lower alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl,
wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more
substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower
alkyl, lower alkoxy, and fluoro substituted lower alkoxy; and Q2J and Q2A are independently
hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl, preferably hydrogen,
fluoro, chloro, or -CF3, more preferably both Q22 and Q24 are hydrogen.
|0026] In one embodiment of compounds of Formula IIb, M4 is -NHCH3-; A3 is -CH2-; Q1' is
phenyl substituted with 1 or 2 substituents selected from the group consisting of fluoro, chloro,
methyl, fluoro substituted methyl, methoxy, and fluoro substituted methoxy; Q15 is hydrogen, -CN,
fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower
alkoxy, preferably hydrogen or chloro; and Q22 and Q24 are hydrogen.
[0027] In one embodiment of compounds of Formula lib, the compound is selected from the
group consisting of:
(4-Chloro-ben2yl)-[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine
(P-0260),
[5-(5-Chloro-lH-pyrTolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2,6-difluoro-ben2yl)-amine
(P-0261),
[5-(5-Chloro-lH-pyrroIo[2,3-b]pyridin-3-yImethyI).pyrimidin-2-yl]-(2-trifluoromethyl-benzy0-
amine (P-0262),
(2-Chloro-benzyl)-[5-(5-chloro-lH-pyrTolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine
(P-0263),
[5-(5-Chloro-lH-pyrrolo[2)3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-fluoro-ben2yl)-amine
(P-0264),
[5-(5-Chloro-lH-pyrrolo[2,3-bJpyridin-3-ylmethyl)-pyrimidin-2-yl]-(2,4-difluoro-ben2yI)-amine
(P-0265),
[5-(5-ChIoro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yI]-(4-trifluoromethyl-benzyl)-
amine (P-0266),
[5-(5-ChIoro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-ylH2,5-difluoro-benzyl)-amine
(P-0267),
[5-(5-Chloro-IH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidia-2-yl]-(3-trifluoromethyl-benzyl)-
amine (P-0268),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-fluoro-5-trifluoroinethyl-
12

benzyl)-amine (P-0289),
(2-Fluoro-5-trifluoromethyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-
amine (P-0291),
(2,5-Difluoro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyriinidin-2-yl]-amine(P-0292),
(2-Chloro-5-trifluoromethyl-benzyl)-[5-(lH-pyrTolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-
amine (P-0293),
(3-Fluoro-5-trifluoromethyl-benzyl)-[5-(lH-pyirolo[2,3-b]pyridin-3-ylmethyI)-pyrimidin-2-yl]-
amine (P-0294),
(3,5-Difluoro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine(P-0295),
(2-FIuoro-benzyl)-[5-( 1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (P-0300),
(2-Chloro-benzyl)-[5-(lH-pyrrolo[2,3-bJpyridin-3-yImethyI)-pyTimidin-2-yl]-aniine(P-0301),
[5-(lH-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyriniidin-2-yl]-(2-trifluoromcthyl-benzyl)-amine
(P-0302),
[5-(lH-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-ylJ-(2-trifluoromethoxy-benzyl)-amine
(P-0303),
(5-Chloro-2-fluoro-bcnzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-ainine
(P-0304),
(2,4-DichIoro-benzyI)-[5-(IH-pyiTolo[2,3-b]pyridin-3-ylniethyl)-pyrimidin-2-yl]-amine(P-030S),
(2)4-Difluoro-benzyl)-[5-(lH-pyrrolo[213-b]pyridin-3-ylmethyl)-pyriniidin-2-yl]-aminc(P-0306),
(4-Chloro-bcnzyl)-[5-(lH-pyrTolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (P-0307),
[5-(lH-Pyrrolo[2,3-b]pyridin-3-ylmethyI)-pyTimidin-2-yl]-(4-trifluoromethyl-benzyl)-amine
(P-0308),
(2-Fluoro-3-trifluoromethyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-
amine (P-0309),
(2,5-Dichloro-benzyl)-[5-(lH-pyiTolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine(P-0310),
(3-Chloro-2-fiuoro-bcnzyl)-[5-(IH-pyrroIo[2,3-b]pyridin-3-ylmethyl)-pyriiiiidin-2-yl]-atnine
(P-03I1),
(2-Difluoromethoxy-benzyl)-[5-(lH-pyiTolot2,3-b]pyridin-3-ylmethyl)-pyriinidin-2-yl]-amine
(P-0312),
(2,3-Dichloro-benzyl)-[5-( 1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (P-0313),
(4-Chloro-2-fluoro-benzyl)-[5-(lH-pyTrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine
(P-0314),
(5-FIuoro-2-trifluoromethyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-ylJ-
amine (P-0315),
(2-Chloro-4-fluoro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine
(P-0316),
13

(5-Chloro-2-methyl-benzyl)-[5-{lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine
(P-0317),
(5-Fluoro-2-mcthyI-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylniethyl)-pyriniidin-2-y]]-amine
(P-0318),
(2-Fluoro-4-trifluoromethyl-benzyl>[5-(lH-pyrrolo[2,3-b]pyridui-3-ylmethyl)-pyrimidin-2-yl]-
amine (P-0319),
(4-Fluoro-2-trifluoromethyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-
atninc (P-0320),
[5-(5-Chloro-lH-pyrroIo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-difluoromethoxy-benzyl)-
amine (P-0390),
[5-(5-ChJoro-lH-pyrroIo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(5-fluoro-2-trifluoromethyl-
benzylj-amine (P-0391),
(3-Chloro-2-fluoro-benzyl)-[5 -(5 -chloro-1 H-pyrrolo[2,3-b]pyridin-3-ylmethy])-pyriniidin -2 -yl] -
amine (P-0392),
[5-(S-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-fluoro-3-trifluoromethyl-
ben2yl)-amine (P-0393),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-fluoro-4-trifluoromethyl-
benzyl)-amine (P-0394),
f5-(5-Chloro-IH-pyiTolo[2,3-b]pyridin-3-ylmethyl)-pyriniidin-2-yl]-(2,3-difluoro-benzy])-amine
(P-0395),
(2-Chloro-4-fluoro-benzyl)-[5-(5-chloro-lH-pyTTolo[2,3-b]pyridin-3-ylmethyl)-pyriniidin-2-yl]-
aminc (P-0396),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl)-(2-trifluoromethoxy-benzy))-
amine (P-0402),
(2-Chloro-5-fluoro-benzyl)-[5-(lH-pyiTolo[2,3-b]pyridin-3-ylmethyl)-pyriniidin-2-yl]-aniine
(P-0407),
(2-Chioro-5-fluoro-benzyl)-[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-
amine (P-0408),
[5-(5-ChIoro-lH-pynrolot2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-pyridin-4-ylmcthyl-amine
(P-0416),
f5-(5-ChIoro-lH-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-pyriinidin-2-yl]-(2-pyiTolidin-l-yl-ethyl)-
amine (P-0417),
Benzyl-[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (P-0418),
Benzyl-[5-(5-chloro-IH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-inelhyl-ainine
(P-0419),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylinethyl)-pyrimidin-2-yl]-{4-trifluoromethoxy-benzyl)-


amine (P-0420),
(3-Chloro-benzyl)-[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine
(P-0421),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-pyridin-3-ylmethyl-amine
(P-0422),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-fluoro-benzyl)-amine
(P-0423),
(3-Chloro-benzyl)-[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-:pyriinidin-2-yl]-methyl-
amine (P-0424),
[5-(5-Chloro-lH-pyrTolo[2,3-b]pyridin-3-ylmcthyl)-pyrimidin-2-yl]-(3,5-difluoro-benzyl)-amine
(P-0425),
[5-{5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylinethyl)-pyrimidin-2-yl]-[l-(2-nuoro-phenyl)-ethyl]-
amine (P-0426),
[l-(4-Chloro-phenyl)-ethyl]-[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-
amine (P-0427),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-[(S)-l-(4-fluoro-phenyl)-
ethyl]-amine (P-0428),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(6-trifluoromethyl-pyridin-3-
ybnethyl)-amine (P-0429),
(2-Chloro-benzyl)-[5- amine (P-0430),
[5-(5-Chloro-lH-pyrTolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-methyl-benzyl)-amine
(P-0431),
[5-(5-Chloro-lH-pyrTolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-methoxy-benzyl)-ainine
(P-0433),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-morpholin-4-yl-ethyl)-
amine (P-0434),
[5-(5-Ch]oro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyL)-pyrimidin-2-yl]-cyclohexylmethyl-amine
(P-0435),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-pyridin-2-yImethyl-amine
(P-0436),
[2-(4-Chloro-phenyl)-ethyl]-[5- amine (P-0437),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-difluoromethoxy-benzyl)-
amine (P-0438),
[5-(5 -Chloro-1 H-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-pyrimidin-2-yl]-(4-methoxy-benzyl)-amine


(P-0439),
[5-(S-Chloro-lH-pyrrolot2,3-b]pyridin-3-ylmethyl)-pyriniidin-2-yl]-(4-inelhyl-benzyl)-amine
(P-0440),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-yhnethyl)-pyrimtdin-2-yI]-(2-methoxy-ethyl)-amJiie
(P-0441),
[5-(5-Chloro-lH-pyrrolot2,3-b]pyridin-3-ylmcthyl)-pyrimidin-2-yl]-(3-fluoro-benzyl)-ainine
(P-0442),
(3-Chloro-4-fluoro-benzyl)-[5-(5-chloro-lH-pyn-o]o[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-
amine (P-0443),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-{2-ethoxy-benzy0-amine
(P-0444),
[5-(5-Chloro-1 H-pyrrolo [2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-morpholin-4-yl-benzyl)-
amine (P-0445),
[5-{5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(3-difluoromethoxy-ben2yl)-
amine (P-0446),
(4-Chloro-3-fluoro-beti2yl)-[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-
araine (P-0447),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-[l-(3-fluoro-phenyl)-eihyI]-
amine (P-0448),
[5-(5-Chloro-lH-pyrTolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-dimethylamuio-benzyl)-
amine (P-0449), and
all salts, prodrugs, tautomers, and isomers thereof.
(0028) In one embodiment, a compound of Formula II has a structure according to the following
sub-generic structure. Formula He,

all salts, prodrugs, tautomers, and isomers thereof,
wherein:
A6 is -CH2- or -C(O)-;
M8 is -CHr, -CH2C(O)-, -C(O)NR39CH2-, -CfOJNR^CHCR40)-, or -C(O)NR3QCH2CH2-;

Q*s is hydrogen, -CN, -OR*1, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl,
cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl
or heteroaryl are optionally substituted with one or more substituents selected from the
group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41,
-NR41R41, and -OR41; and

[0029| In one embodiment of compounds of Formula lie, M8, is -C(O)NR39CH2-,
-C(O)NR3'CH(CH3)-, or -C(O)NR39(CH2)2-; A« is -CH2- or -C(O)-, preferably -CH2-; Q41 is aryl or
heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents
selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41,
-NR4IR41, -OR"1 and -S(O)2R41; Q45 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro
substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, cycloalkyl,
heterocycloalkyl, aryl or hcteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are
optionally substituted with one or more substituents selected from the group consisting of halogen,
lower alkyl, fluoro substituted lower alkyl, -NHR41, -NR41R41, -OR41 and -S(O)jR41; and Q52 and
Q94 are independently hydrogen, fluoro, chJoro, lower alkyl, or fluoro substituted lower alkyl,
preferably Q52 and Q54 are independently hydrogen, fluoro, chloro, methyl, or -CF3; wherein R41 is
as defined in Formula II.
[0030] In one embodiment, further to any of the embodiments of Formula lie above, R41 is R42 as
defined for Formula II.
|0031) In one embodiment of compounds of Formula He, M8, is -C(O)NHCH2-,
-C(O)NHCH(CH3)- or -C(O)NH(CH2)2-; A6 is -CH2- or -C(O)-, preferably -CH2-; Q41 is ary! or
heteroaryl, wherein ary] or heteroaryl are optionally substituted with 1 or 2 substituents selected
from the group consisting of fluoro, chloro, methyl, fluoro substituted methyl, methoxy, and fluoro
substituted methoxy; Q45 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower
alkyl, lower alkoxy, or fluoro substituted lower alkoxy, preferably hydrogen or chloro; and Q32 and

Q54 arc independently hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl,
preferably Q" and Qi4 arc methyl.
[0032] In one embodiment of compounds of Formula lie, the compound is selected from the
group consisting of:
3-(l-Benzyl-3,5-dimethyMH-pyrazol-4-ylmethyl)-lH-pyrrolot2,3-b]pyridineCP-0133),
2-[3,5-DimefhyI-4-( 1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazol-l -yl]-l -phenyl-ethanone
(P-0134),
3,5-Dimethyl-4-( 1 H-pyrroIof2,3-b]pyridin-3-ylmethyl)-pyrazole-l -carboxylic acid 4-methoxy-
benzylamide (P-0135),
3,5-Dimethyl-4-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyJ)-pyrazole-l-carboxylic acid 2-chloro-
benzylamide (P-0136),
3,5-Dimethyl-4-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-l -carboxylic acid 2-fluoro-
benzylamide (P-0137),
3-[3,5-Dimethyl-l-(5-trifluoromethyl-furan-2-ylmcthyl)-lH-pyrazol-4-ylmethyl]-lH-pyrrolo[2,3-
bjpyridine (P-0138),
3-[3,5-Dimethyl-l-(5-methyl-isoxazol-3-ylmethyl)-lH-pyrazol-4-ylinethyl]-lH-pyrrolo[2,3-
bjpyridine (P-0139),
3,5-Dimethyl-4-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-l -carboxylic acid 4-chloro-
benzylamide (P-0140),
3,5-Dimethyl-4-(lH-pyrrolo[2)3-b]pyridin-3-ylmethyl)-pyra2ole-l phenyl)-ethyl]-amide (P-0141),
3,S-Dimethyl-4-( 1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyra2ole-l -carboxylic acid 3-methoxy-
benzylamide (P-0142),
3-{3,5-Dimethyl-l-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-lH-pyrazol-4-
ylmethyl} -1 H-pyrrolo[2,3-b]pyridine (P-0143),
3-[3,5-Dimethyl-l-(4-methyl-2-phenyl-thiazol-5-ylmethyl)-lH-pyra2ol-4-ylmethyl]-lH-
pyrro]o[2,3-b]pyridine (P-0144),
3,5-Dimethyl-4-(l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-l -carboxylic acid 2-methoxy-
benzylamide (P-0145),
3,5-Dimethyl-4-( 1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1 -carboxylic acid [2-(2,4-
dichloro-phenyl)-ethyl]-amide(P-0146),
3,5-Dimethyl-4-( 1 H-pyrroIo[2,3-bJpyridin-3-ylmethyl)-pyrazole-1 -carboxylic acid [2-(4-fluoro-
phenyl)-ethyl]-amide (P-0147),
3,5-DimethyI-4-(l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyra2ole-1 -carboxylic acid [2-(2-fluoro-
phenyl)-ethyl]-amide (P-0148),


3,5-Dimethyl-4-( 1 H-pyrrolo[2,3-b]pyridin-3-ylniethyl)-pyrazole-1 -carboxylic acid ((S)-1 -phenyl-
ethyl)-amide (P-O149),
3,5-Dimethyl-4-( 1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-l -carboxylic acid 3-fluoro-
benzylamide (P-0150),
3,5-Dimethyl-4-(l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1 -carboxylic acid 4-fluoro-
benzylamide (P-0151),
3,5-Dimethyl-4-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-l-carboxylic acid 4-methyl-
benzylamide (P-0152),
3,5-Dimethyl-4-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-l-carboxylic acid 2-methyl-
benzylamide (P-0153),
4-(5-Chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-3,5-dimethyl-pyra2ole-l -carboxylic acid [2-(4-
fluoro-phenyl)-ethyl]-amide(P-0157),
4-{5-Chloro-1H-pyrroIo[2,3-b]pyridin-3-ylmethyl)-3,5-dimethyl-pyrazole-l-carboxylic acid 4-
fluoro-bcnzylamide (P-0158),
4-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-3,5-dimethyl-pyrazole-l-carboxylic acid 4-
chloro-benzylamide (P-0159),
4-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-3,5-dimethyl-pyrazole-l-carboxylic acid [(S)-
l-(4-fluoro-phenyl)-ethyl]-amide (P-0160), and
all salts, prodrugs, tautomers, and isomers thereof.
[0033] In one embodiment, a compound of Formula II has a structure according to the following
sub-generic structure, Formula Ilg,
72

all salts, prodrugs, tautomers, and isomers thereof,
wherein:
A, is -CH2-, or -C(O)-;
O65 is hydrogen, -CN, -OR41, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl,
cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl
or heteroaryl are optionally substituted with one or more substituents selected from the

group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41, •
-NR4lR4l,and-OR41;and
Mio, Q61, Q72, Q74, and R41 are as defined for Formula II.
[0034] In one embodiment of compounds of Formula Ilg, M!0 is -NRWCH2- or -NR39-(CH2)2-;
Ag is -CH2- or -C(O)-, preferably -CH2-; Q61 is aryl or heteroaryl, wherein aryl or heteroaryl are
optionally substituted with one or more substituents selected from the group consisting of halogen,
lower alkyl, fluoro substituted lower alkyl, -NHR41, -NR4IR41, -OR41 and -S(O)2R41; QM is
hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro
substituted lower alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl,
heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents
selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41,
-NR41R41, -OR41 and -S(O)jR41; and Q74 is hydrogen, fluoro, chloro, lower alkyl or fluoro
substituted lower alkyl, wherein R41 is as defined for Formula II.
[0035] In one embodiment, further to any of the embodiments of Formula Ilg above, R41 is R42 as
defined for Formula II.
[0036] In one embodiment of compounds of Formula Ilg, M|0 is -NHCH2-; As is -CH2-; Q61 is
phenyl optionally substituted with 1 or 2 substituents selected from the group consisting of fluoro,
chloro, methyl, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy; QM is hydrogen,
fluoro, -CN, or l-methyl-pyrazol-4-yl; Q72 is lower alkyl or fluoro substituted lower alkyl; and Q74
is hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl. In one embodiment, M10
is -NHCH2-; As is -CH2-; Q61 is 4-fluoro-phenyl; Q65 is hydrogen, chloro, -CN, or 1-methyl -
pyrazol-4-yl; Q72 is methyl or ethyl; and Q74 is hydrogen or chloro.
[0037] In one embodiment, the compound of Formula Ilg is selected from the group consisting
of:
[l-Ethyl-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-lH-pyrazol-3-yl]-(4-fluoro-ben2yl)-amine
(P-0165),
(4-Fluoro-benzyl)-[l-methyl-5-(lH-pyTrolo[2,3-b]pyridin-3-ylmethyl)-lH-pyrazol-3-yl]-amine
(P-0169),
[5-(5-Chloro-lH-pym>lo[2,3-b]pyridin-3-ylmethyl)-l-methyl-lH-pyrazol-3-yl]-(4-fluoro-benzyl)-
amine (P-0170),
(4-Fluoro-benzyl)-{ 1 -methyl-5-[5-(l -methyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-3-
ylmethyl]-1 H-pyrazol-3 -yl} -amine (P-0180),
(5-ChIoro-lH-pyrrolo[2,3-b]pyridin-3-yl)-[2-ethyl-5-(4-fluoro-benzylamino)-2H-pyrazol-3-yl]-


methanone (P-0184),
[5-(5-Chloro-l H-pynolo[2,3-b]pyridin-3-ylmcthyl)-l -ethyl-1 H-pyrazol-3-yl]-{4-fluoro-benzyl)-
. amine (P-0185),
3-[5-(4-Fluoro-bcnzylamino)-2-methyl-2H-pyrazol-3-ylmethyl]-lH-pyrrolo[2,3-b]pyridine-5-
carbonitrile(P-0191),
(3-Chloro-benzyl)-t5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylraethyl)-l-methyl-lH-pyrazol-3-yl]-
amine (P-0410),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-l-methyl-lH-pyrazol-3-yl]-{2,5-difluoro-
benzyl)-amine (P-0411),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylraethyl)-l-methyl-lH-pyrazol-3-yl]-(2-fluoro-benzyl)-
amine (P-0413), and
all salts, prodrugs, tautomers, and isomers thereof.
[0038] In one embodiment, a compound of Formula II has a structure according to the following
sub-generic structure, Formula Up,

all salts, prodrugs, tautomers, and isomers thereof,
wherein:
A16 is -CH2- or -C(O)-;
Ql4S is hydrogen, -CN, -OR41, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl,
cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl
or heteroaryl are optionally substituted with one or more substituents selected from the
group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR4',
-NR41R4l,and-OR41;
Q112 is hydrogen, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or
fluoro substituted lower alkoxy; and
M18, Ql41 and R41, are as defined for Formula II;


[0039| In one embodiment of compounds of Formula IIp, M18 is -NR39CH2- or -NR39-(CH2)2-;
A16 is -CH2- or -C(O)-, preferably -CH2-; Q141 is aryl or heteroaryl, wherein aryl or heteroaryl are
optionally substituted with one or more substituents selected from the group consisting of halogen,
lower alkyl, fluoro substituted lower alkyl, -NHR41, -NR41R41, -OR41 and -S(O)2R41; QI45 is
hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro
substituted lower alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl,
heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents
selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41,
-NR41R41, -OR41 and -S(O)2R41; and Q152 is hydrogen, fluoro, chloro, lower alkyl, or fluoro
substituted lower alkyl; wherein R41 is as defined for Formula II.
[0040] In one embodiment of compounds of Formula lip, Mn is -NH-CH2- or -NH-(CH2)2-,
preferably -NH-CH2-; A16 is -CHr or -C(O)-, preferably -CH2-; Q14' is aryl or heteroaryl, wherein
aryl or heteroaryl are optionally substituted with 1 or 2 substituents selected from the group
consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro
substituted lower alkoxy, and heterocycloalkyl; Q145 is hydrogen, -CN, fluoro, chloro, lower alkyl,
fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy, preferably
hydrogen, -CN, or chloro; and Q152 is hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted
lower alkyl, preferably hydrogen or chloro, more preferably chloro.
[0041] In one embodiment, the compound of Formula Di is selected from the group consisting of
[4-Chloro-5-(lH-pyiTolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-ben2yl)-amine
(P-0156),
[4-Ethyl-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyl)-amine(P-0162),
(4-Fluoro-benzyl)-[4-mcthyl-5-(lH-pyrrolo[2,3-b]pyridm-3-ylmethyl)-thiazol-2-yl]-amine
(P-0163),
[4-Chloro-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-pyridin-3-ylmethyl-amine
(P-0164),

[4-Chloro-5-(lH-pyrrolo[2.3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-pyridin-2-ylmethyl-amine
(P-0167),
[4-Chloro-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-pyridin-4-yImethyl-amine
(P-0168),
[4-Chloro-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-methyl-pyridin-2-ylmethyl)-
amine (P-0171),
[4-Chloro-5-(lH-pyirolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yI]-(l,5-dimcthyl-lH-pyrazol-3-
ylmethyl)-amine (P-0172),
^-Chloro-S-ClH-pyrroIop.S-blpyridin-S-ylmethyO-thiazol^-yll^e-trifluoromethyl-pyridin-S-
ylmethyl)-amine (P-0173),
[4-Chloro-5-(1 H-pyrrolo[2,3-b]pyridin-3-ylmeihyl)-thiazol-2-yl J-(2,5-dimethyl-2H-pyrazol-3-
ylmethyl)-amine(P-0175),
[2-(4-Fluoro-benzylamino)-thiazol-5-yl]-( 1 H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (P-0177),
{2-[(4-Chloro-ben2yl)-methyl-amino]-thtazoI-5-yl}-(lH-pyrrolo[2,3-b]pyridin-3-yl)-methanone
(P-0178),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-thiazol-2-ylmethyl-
amine (P-0189),
[4-ChIoro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-methoxy-pyridin-3-
ylmethyO-amine (P-0190),
Benzyl-[4-chloro-5-(5-chloro-lH-pyirolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-amine(P-0192),
[4-Chloro-5-(5-chloro-lH-pyjTolo[2,3-b]pyridin-3-yImethyl)-thiazol-2-yl]-{3-mcthoxy-benzyi)-
amine (P-0193),
(4-Chloro-benzyl)-[4-chloro-5-(5-chloro-lH-pyirolo[2)3-b]pyridin-3-ylmcthyl)-thiazol-2-yl]-
amine (P-0194),
[4-Chloro-5-(5-chloro-IH-pyrrolo[2,3-b]pyridin-3-ylraethyl)-thiazoI-2-yl]-(4-fluoro-benzyl)-
amine (P-0195),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2,4-dimethyl-thiazol-5-
ylmethy!)-amine (P-0196),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thia2ol-2-yl]-(2-ethyl-5-methyl-3H-
imidazol-4-ylmethyl)-amine (P-0197),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b)pyridin-3-ylmethyl)-thiazol-2-yl]-(2-ethyl-2H-pyrazol-3-
ylmethyl)-amine (P-0198),
[4-Chloro-5-(5-chloro-lH-pynolo[2,3-b]pyridin-3-ylmethyl)-thia2ol-2-yl]-(6-methoxy-pyridin-2-
ylmethyl)-aminc (P-0199),
[4-Chloro-5-(5-chloro-lH-pym)lot2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(3-fluoro-pyridin-4-
ylmethyO-amine (P-0200),
23

[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-nicthyl-thiazol-4-
ylmethyl)-amine (P-0201),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-methyl-thiazol-5-
ylmethyl)-amine (P-0202),
[4-Chloro-5-{5-chloro-lH-pyiTolo[2,3-b]pyridin-3-yImethyl)-thiazol-2-yl]-(5-chloro-pyridin-2-
ylmethyl)-amine (P-0203),
[4-Chloro-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2,4-dimethyI-thiazol-5-
ylmethyl)-amine (P-0204),
[4-Chloro-5-(lH-pyn-olo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-ethyl-5-methyl-3H-iniidazol-
4-ylmethyl)-amine (P-0205),
[4-Chloro-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-{5-fluoro-pyridin-2-ylmcthyl)-
amine (P-0206),
[4-Chloro-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(5-methoxy-pyridin-3-ylmethyl)-
amine (P-0207),
[4-Chloro-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4,5-dimethyl-thiophen-2-
ylmethyl)-amine (P-0208),
[4-Chloro-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2,5-dimethyl-thiophen-3-
ylmethyl)-amine (P-0209),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(5-fluoro-pyridin-3-
ylmethyl)-amine (P-0231),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-pyridin-3-ylmethyl-
amine (P-0236),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-pyridin-4-ylmethyl-
amine (P-0237),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(3-chloro-pyridin-4-
ylmethyl)-amine (P-0238),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(l-ethyl-lH-pyrazol-4-
ylmethyl)-amine (P-0239),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-{5-fluoro-pyridin-2-
ylmethy!)-amine (P-0240),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(5-mcthoxy-pyridin-3-
ylmethyl)-amine (P-0241),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-thiazol-2-yl]-(6-trifluoromethyl-
pyridin-3-ylmethyl)-aminc (P-0242),
[4-Chloro-5- benzyl)-amine (P-0243),
24

t4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-phenethyl-amine
(P-0244),
^-Chloro-S-CS-chloro-lH-pyrroloP^-blpyridin-S-ylmethyO-thiazol^-yll-fl^-difluoro-benzyl)-
amine (P-0245),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyrjdin-3-ylraethyl)-thiazol-2-yl]-(2-fluoro-ben2yl)-
amine (P-0246),
[4-Chloro-5-(5-chloro-lH-pyrroIo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-methoxy-pyridin-3-
ylmethyl)-amine (P-0247),
(2-Chloro-benzyl)-[4-chloro-5-(5-chloro-]H-pyrrolot2>3-b]pyridin-3-ylmethyl)-thia2ol-2-yl]-
amine (P-0248),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-methyl-benzyl)-
amine (P-0249),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyI)-thiazol-2-yl]-(2-chloro-4-fluoro-
benzyO-amine (P-0250),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(3-fluoro-pyridin-2-
ylmethyl)-amine (P-0251),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-morpholin-4-yl-
pyridin-2-ylmethyl)-amine (P-0252),
[4-Chloro-5-(5-chloro-lH-pyniOlo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(3,5-dichloro-pyridin-4-
y!methyl)-amine (P-0253),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylnnethyl)-thiazol-2-yl]-(2-trifluoromethyl-
benzyl>amine (P-0254),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-methyl-pyridin-2-
ylmethyl)-amine (P-0255),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyl)-amine
(P-0290), and
all salts, prodrugs, tautomers, and isomers thereof.

[0042] The compounds of Formula IH have the following structure:

all salts, prodrugs, tautomers, and isomers thereof,
wherein:
U is -CH2-, -CH2CH2-, -CH(R40)-, -C(O)- or -C(O)NH-;
R" is selected from the group consisting of hydrogen, -OR41, -CN, fluoro, chloro, lower alkyl,
fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein
cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more
substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted
lower alkyl, -NHR41, -NR4IR41, -OR41 and -S(O)2R";
RK is selected from the group consisting of hydrogen, C1-3 alkyl, fluoro substituted C2J alkyl,
OH, Cio alkoxy, and fluoro substituted C1-3 alkoxy;
R83 is heterocycloalkyl, heteroaryl, „. , .a which * indicates the
attachment point of Ru to L» of Formula III, wherein heterocycloalkyl or heteroaryl are
optionally substituted with one or more substituents selected from the group consisting of
halogen, lower alkyl, fluoro substituted lower alkyl, cycloalkylaraino, -NHR41, -NR4IR41,
-OR41 and -S(O)2R41;
R92, RM, R94, R95, and R96 are independently selected from the group consisting of hydrogen,
halogen, lower alkyl, fluoro substituted lower alkyl, cycloalkylamino, -NHS(O)2R41,
-NHC(O)R41, -NHR41, -NR41R41, -OR41 and -S(O)2R41; and
R40 and R4' are as defined for Formula II;



alkoxy, or fluoro substituted lower alkoxy; Rw is hydrogen; R" is n~ , wherein R92,
R'\ RM, R95, and R'6 are independently hydrogen, fluoro, chloro, lower alkyl, fluoro substituted
lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy, provided, however, that when R94 is
fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower
alkoxy, at least one of Rw, R9J, R95, and R9' is fluoro, chloro, lower alkyl, fluoro substituted lower
alkyl, lower alkoxy, or fluoro substituted lower alkoxy.
[0044J In one embodiment of compounds of Formula III, L4 is -CH2-, -CH2CH:-, -CH(CH,)- or
-C(O)-; R81 is hydrogen, fluoro, chloro, -CN, methyl, or methoxy, preferably hydrogen, chloro,
-CN, or methyl; R82 is hydrogen; R83 is , wherein R92, RM, RM, R95, and R" are
independently hydrogen, fluoro, chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy,
difluoromethoxy or trifluoromethoxy, preferably hydrogen, chloro, methyl, trifluoromethyl,
methoxy, ethoxy, or trifluoromethoxy, provided, however, that when R94 is fluoro, chloro, methyl,
ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy, at least one of Rw,
R", R95, and R96 is fluoro, chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy,
difluoromethoxy or trifluoromethoxy.

[004S] In one embodiment of compounds of Formula III, L4 is -CH:-; R81 is fluoro, chloro, -CN,
methyl, or methoxy, preferably chloro, -CN, or methyl; R82 is hydrogen; R83 is
wherein R94 is hydrogen and R92, R93, RM, and R96 are independently hydrogen, fluoro, chloro,
methyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy.
[0046] In one embodiment of compounds of Formula III, L4 is -CH2-, -CH3CH2-, -C(O)-, or
-CH(CH})-, preferably -CH2- or -C(O)-; R81 is hydrogen or flouro; R82 is hydrogen; R83 is
wherein R92 is fluoro, chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy,
difluoromethoxy, or trifluoromethoxy, preferably fluoro, chloro, methyl, or trifluoromethyl, and
RH, R94, R95, and R" are independently hydrogen, fluoro, chloro, methyl, trifluoromethyl,
methoxy, difluoromethoxy or trifluoromethoxy, preferably hydrogen or fluoro. In one
embodiment, L4 is -CH2-, -C(O)-, or -CH(CH3)-; R8' is hydrogen; R82 is hydrogen; R92 is fluoro,
chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy,
preferably fluoro, methyl, or trifluoromethyl; and R93, R94, R93, and R96 are hydrogen. In one
embodiment, L4 is -CH2-, -C(O)-, or -CH(CH3)-; R" is hydrogen; R82 is hydrogen; R9J is fluoro,
chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy,
preferably fluoro, methyl, or trifluoromethyl; R94, R95, and R96 are hydrogen; and R93 is fluoro,
chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy,
preferably fluoro, chloro, trifluoromethyl or methoxy, more preferably fluoro. In one embodiment,
L4 is -CH2-, -C(O)-, or -CH(CH3)-; R81 is hydrogen; R82 is hydrogen; R92 is fluoro, chloro, methyl,
ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy, preferably fluoro,
methyl, or trifluoromethyl; R93, R95, and R96 are hydrogen; and R94 is fluoro, chloro, methyl, ethyl,
trifluoromethyl, methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy, preferably fluoro, chloro,
methyl or trifluoromethyl, more preferably fluoro. In one embodiment, L4 is -CH2CH2- or -C(O)-;
R81 is hydrogen; R82 is hydrogen; R92, R95, and R94 are hydrogen; R93 is hydrogen, fluoro, chloro,
methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy, preferably
hydrogen, fluoro, chloro, methyl, trifluoromethyl, methoxy, or trifluoromethoxy, more preferably
fluoro, chloro, trifluoromethyl or methoxy; and R94 is hydrogen, fluoro, or chloro; provided,
however, that when L4 is -C(O)- and R93 is fluoro or chloro, R93 is not hydrogen. In one

embodiment, L4 is -CH2CH2-; R81 is hydrogen; R82 is hydrogen; R92, R94, R95, and R96 are
hydrogen; and R93 is hydrogen, fluoro, chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy,
difluoromethoxy, or trifluoromethoxy, preferably hydrogen or fluoro. In one embodiment, L, is
-C(O)-; R" is hydrogen; R82 is hydrogen; R92, R95, and R96 are hydrogen; R9J is fluoro, chloro,
methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy, preferably
fluoro, chloro, trifluoromethyl or methoxy; and R94 is hydrogen, fluoro, or chloro.
[0047] In one embodiment of compounds of Formula III, R83 is pyrrolidine, morpholine,
pyridine, pyrimidine, pyrazine, pyrazole, isoxazole, imidazol, or benzimidazole, wherein R83 is
optionally substituted with one or more substituents independently selected from the group
consisting of halogen, lower alkyl, fluoro substituted lower alkyl, cycloalkylamino, -NHR41,
-NR4IR41, -OR41 and -S(O)iR41, preferably wherein R83 is optionally substituted with 1 or 2
substituents independently selected from fluoro, chloro, lower alkyl, fluoro substituted lower alkyl,
lower alkoxy, fluoro substituted lower alkoxy, or cycloalkylamino, more preferably fluoro, chloro,
methyl, trifluoromethyl, methoxy or morpholine.
(0048) In one embodiment of compounds of Formula III, L4 is -CH2-, -CH2CH2-, -CH(CHj)- or
-C(O)-, preferably -CH2-, -CH2CH2-, or -C(O)-; R81 is hydrogen, fluoro, chloro, -CN, lower alkyl,
fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy, preferably
hydrogen, chloro, methyl or -CN; R82 is hydrogen; and R83 is pyrrolidine, morpholine, pyridine,
pyrimidine, pyrazine, pyrazole, isoxazole, imidazole, or benzimidazole, wherein R83 is optionally
substituted with 1 or 2 substituents independently selected from fluoro, chloro, lower alkyl, fluoro
substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, or cycloalkylamino,
preferably fluoro, chloro, methyl, trifluoromethyl, methoxy or morpholine.
[0049] In one embodiment of compounds of Formula III, the compound is selected from the
group consisting of:
Pyridin-3-ylmethyl-[5-( 1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-0094),
(5-Methyl-isoxazol-3-ylmethyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine
(P-0095),
(2-Pyrrolidin-l-yl-ethyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-0096),
[l-(4-Methanesulfonyl-phenyl)-ethyl]-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-
amine (P-0097),
(2-Morpholin-4-yl-ethyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(P-0099),
3,4-Dichloro-N-[5-(lH-pyrrolo[2,3-b]pyridin-3-yImethyl)-pyridin-2-yl]-benzamide(P-0100),
2-Chloro-4-fluoro-N-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide(P-0101),
2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [5-( 1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-


yl]-amide (P-0102),
Thiophenc-2-carboxyIic acid [5-(lH-pyiTolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amide
(P-0103),
2-Methoxy-N-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-isonicotinamide(P-0104),
N-[5-(lH-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-isonicotinamide{P-0105),
Pyrazine-2-carboxylic acid [5-(l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amide
(P-0106),
Pyridine-2-carboxylic acid [5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amide
(P-0107),
6-Methyl-N-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-nicotinamide(P-0108),
4-Fluoro-3-methyl-N-[5-(lH-pyrrolo[2>3-b]pyridin-3-ylniethyl)-pyridin-2-yl]-benzamide
(P-0109),
5-Methyl-pyrazine-2-carboxylic acid [5-{lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-
amide (P-0110),
S-Chloro-N-fS^lH-pyTrolop.S-blpyridin-B-ylmethyO-pyridin^-ylJ-benzamideCP-Olll),
4-Fluoro-N-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-pyridin-2-yl]-3-trifluoronicthyl-ben2amide
(P-0112),
N-[5-(lH-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-3-trifluoromethoxy-benzamide
(P-0113),
N-[5-(lH-Pyrrolo[2,3-b]pyridin-3-ylmcthyl)-pyridin-2-yl]-3-trifluoromethyl-benzamide(P-0114),
3-Chloro-4-fluoro-N-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide(P-0115),
3,4-Difluoro-N-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylinethyl)-pyridin-2-yl]-benzainide(P-0116),
2-Chloro-N-[5-(l H-pynt3lo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide (P-0117),
5-Fluoro-2-methyl-N-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide
(P-0118),
2-Fluoro-N-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamidc(P-0119),
3-Methoxy-N-[5-{lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamidc(P-0120),
3-Fluoro-N-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide(P-0121),
3-Methyl-N-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-bcnzamide(P-0122),
2-Chloro-N-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-isonicotinamide (P-0123),
((R)-l-Phenyl-ethyl)-[5-( 1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-012S),
(3-Morpholin-4-yl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2.yl]-amine
(P-0126),
[ I -(2-FIuoro-phenyl)-ethyl]-[5-(l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine
(P-0127),
[2-{3-Fluoro-phenyl)-ethyl]-[5-(lH-pyrTolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine


(P-0128),
(3-Chloro-benzyl)-[5-{ 1 H-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-pyridin-2-yl]-amine (P-0129),
(l-Methyl-lH-imidazol-4-ylmethyl)-[5-(lH-pyrrolo[2,3-b]pyridJn-3-ylmethyl)-pyridin-2-yl]-
amine (P-0130),
(l,5-Dimethyl-lH-pyrazoI-3-ylmethyl)-[5-(lH-pyirolo[2,3-b]pyridin-3-yImethyl)-pyridin-2-yl]-
amine (P-0131),
[5-(5-Chloro-IH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-
ylmethyl)-amine (P-0181),
t5-(lH-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yI]-(6-trifluoromethyI-pyridin-3-ylmethyl)-
amine (P-0182),
(3-Chloro-pyridin-4-ylmethyl)-[5-( 1 H-pyiTolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl] -amine
(P-0183),
(2-ChIoro-6-fluoro-benzyl)-[5-(lH-pyrTolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-aniine
(P-0210),
Phenethyl-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-ainine(P-0211),
(2,4-Difluoro-benzyl)-[S-( I H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-0212),
(2-Fluoro-benzyl)-[5-(lH-pyrTolo[2,3-b]pyridin-3-ylmethy])-pyridin-2-yl]-aniine(P-0213),
(3-Bromo-pyridin-4-ylmethyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine
(P-0214),
(2-Methoxy-pyridin-3-ylmethyl)-[5-(lH-pyrro]o[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine
(P-0215),
(2-Chloro-benzyl)-t5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylJ-amine(P-02l6),
(2-Methyl-benzyl)-[5-( 1 H-pynolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-0217),
(1 -Methyl-1 H-benzoimidazol-2-ylmethyl)-[5-(l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-
yl]-aminc(P-0218),
(6-Methoxy-pyridin-3-ylmethyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine
(P-0219),
(lH-Benzoinaidazol-2-ylmethyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine
(P-0220),
(2-Chloro-4-fluoro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine
(P-0221),
(5-Methoxy-pyridin-3-ylmethyl)-[5-(lH-pyiTolo[2,3-b]pyridin-3-ylniethyl)-pyridin-2-yl]-amine
(P-0222),
(3-Fluoro-pyridin-4-ylmethyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine
(P-0223),
(6-Methoxy-pyridin-2-ylmethyl)-[5-(lH-pyrrolo[2,3-bJpyridin-3-ylmethyl)-pyridin-2-yI]-ainine


(P-0224),
(4-Fluoro-2-trifluoromethyl-benzyl)-[5-( 1 H-pyrrolo[2,3-b]pyridin-3 -ylmethyl)-pyridin-2-yl]-
aminc (P-022S),
[5-(lH-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-trifluoromethyl-benzyl)-amine
(P-0226),
(3,5-Dichloro-pyridin-4-ylmethyl)-[5-(lH-pyrrolot2,3-b]pyridin-3-ylinethyl)-pyridin-2-yl]-aminc
(P-0227),
(6-Morpholin-4-yl-pyridin-2-ylmethyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-
amine (P-0228),
(3-Fluoro-pyridin-2-ylmethyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-yImethyl)-pyridin-2-yl]-amine
(P-0229),
(5-Fluoro-pyridin-3-ylmethyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-yImethyl)-pyridin-2-yl]-amine
(P-0230),
(3-Chloro-pyridin-4-ylmethyl)-[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-yimethyl)-pyridin-2-yl]-
amine (P-0235),
3-{6-[(3-Chloro-pyridin-4-ylmethyl)-amino]-pyridin-3-ylmethyl}-lH-pyrrolo[2,3-b]pyridine-5-
carbonitrile (P-0256),
3-[6-(4-Chloro-benzylamino)-pyridin-3-ylinethyl]-lH-pyjTolo[2,3-b]pyridine-5-carbonitrile
(P-0257),
Propane-1 -sulfonic acid (2,4-difluoro-3-{[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-
ylamino]-methyl}-phenyl)-amide (P-02S8),
Propane-l-sulfonicacid(3-{[5-(5-chloro-lH-pyiTolot2,3-b]pyridin-3-ylmethyl)-pyridin-2-
ylamino]-methyl}-2,4-difluoro-phenyl)-amide(P-0259),
3-[6-(4-Trifluoromethyl-benzylamino)-pyridin-3-ylmethyl]-lH-pyrroIo[2,3-b]pyridine-5-
carbonitrile (P-0269),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-yImethyl)-pyridin-2-yl]-(2-fluoro-benzyl)-amine
(P-0270),
3-[6-(2-Fluoro-benzylamino)-pyridin-3-yImethyl]-lH-pyrTolo[2,3-b]pyridinc-5-carbonitrile
(P-0271),
(2-Fluoro-benzyl)-[5-{5-methyl-lH-pyrrolo[2,3-b]pyridin-3-ylmethyI)-pyridin-2-yl]-ainine
(P-0272),
3-{6-[(6-Trifluoromethyl-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl}-lH-pyrrolo[2l3-
b]pyridine-5-carbonitrile (P-0273),
3-[6-(2-Trifluoromethyl-ben2ylamino)-pyridin-3-ylmethyl]-lH-pyrroIo[2,3-b]pyridine-5-
carbonitrile (P-0274),
[5-(5-Chloro-lH-pyrTolo[213-b]pyridin-3-ylmcthyl)-pyridin-2-yl]-(2-trifluoromethyl-benzyl)-


amine (P-0275),
[5-(5-Mcthyl-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-trifluororaethyl-benzyl)-
amine (P-0276),
3-[6-(2,6-Difluoro-benzylamino)-pyridin-3-ylmethyl]-lH-pyrrolo[2,3-b]pyridine-5-carbonitrile
(P-0277),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2,6-difluoro-benzyl)-amine
(P-0278),
(2-Chloro-benzyl)-[5-(5-methyl-lH-pyrroIot2,3-b]pyridin-3-ylmethyl)-pyridiii-2-yI]-amine
(P-0279),
(2-Chloro-benzyl)-[5-(5-chloro-lH-pynolo[2,3-b]pyridin-3-ylmcthyl)-pyridin-2-yl]-amine
(P-0280),
3-[6-(2-Chloro-benzylamino)-pyridin-3-ylmethyl]-lH-pyrrolo[2,3-b]pyridine-5-carboniuile
(P-0281),
(6-Methoxy-pyridin-3-yImethyl)-[5-{5-methyl-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-
yl]-amine (P-0282),
[5-(5-Chloro-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl] -(6-methoxy-pyridin-3-
ylraethyl)-amine (P-0283),
3-{6-[(6-Methoxy-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmcthyl}-lH-pyrrolo[2,3-b]pyridine-5-
carbonitrile (P-0284),
(2-Methoxy-pyridin-3-ylmethyl)-[5-{5-raethyl-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-
yl]-amine (P-0285),
[5-{5-Chloro-lH-pyiTolo[2,3-b]pyridin-3-ylinethyl)-pyridin-2-yl]-(2-methoxy-pyridin-3-
ylmethyD-amine (P-0286),
3-{6-[(2-Methoxy-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl}-lH-pyiTolo[2,3-b]pyridine-5-
carbonitrile (P-0287),
(2-Ethoxy-benzyI)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(P-0288),
(2,5-Difluoro-ben2yl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(P-0296),
(2,5-Difluoro-benzyl)-[5-(5-methyl-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine
(P-0297),
t5-(5-Chloro-lH-pyrrolot2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2,5-difluoro-benzyI)-aniinc
(P-0298),
3-[6-(2,5-Difluoro-benzylamino)-pyridin-3-ylmcthyl]-lH-pyrrolo[2,3-b]pyridine-5-carbonitrile
(P-0299),
3-[6-(2-Trifluoromethoxy-benzylamino)-pyridin-3-ylmethyl]-lH-pyiTolo[2,3-b]pyridine-5-
carbonitrile (P-0321),
[5-(lH-PyiTolo[213-b]pyridin-3-ylraethyl)-pyridin-2-yl]-(2-trifluoromethoxy-benzyl)-amine


(P-0322),
3-[6-(2-Ethoxy-benzylatnino)-pyridin-3-ylmcthyI]-lH-pyrrolo[2,3-b]pyridine-5-carbonitrile
(P-0323),
[S-(5-Chloro-lH-pyrrolo[2,3-blpyridin-3-ylmethyl)-pyridin-l-yl]-(5-fluoro-pyridinO-ylmethyl)-
ainine (P-0324),
[5-(5-Fluoro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-{2-trifluoromethyl-benzyl)-
amine (P-032S),
[5-(5-Methoxy-lH-pyrrolo[2,3-b]pyridin-3-yImethyl)-pyridin-2-yl]-(2-trifluoroniethyl-benzyl)-
amine (P-0326),
(2-Chloro-benzyl)-[5-(5-fluoro-lH-pyrrolo[2,3-b]pyridin-3-y[methyl)-pyridin-2-yl]-amine
(P-0327),
(2-Chloro-benzyl)-[5-{5-methoxy-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine
(P-0328),
(2,5-Difluoro-benzyl)-[5-(5-fluoro-lH-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-pyridin-2-yl]-aminc
(P-0329),
(2,5-Difluoro-benzyl)-[5-(5-methoxy-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine
(P-0330),
[5-(5-Fluoro-lH-pyrTolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-mcthoxy-pyridin-3-ylmethyl)-
amine (P-0331),
(6-Mcthoxy-pyridin-3-ylmethyl)-[5-(5-methoxy-lH-pyrTolot2,3-b]pyridin-3-ylmethyl)-pyridin-2-
yl]-aminc (P-0332),
(2,6-Difluoro-benzy])-[5-(5-fluoro-lH-pyrrolot2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine
(P-0333),
(2,6-Difluoro-benzyl)-[5-(5-methoxy-lH-pyrrolo[2,3-b]pyridin-3-yIniethyl)-pyridin-2-yI]-amine
(P-0334),
(2-Methoxy-benzyl)-[5-( 1 H-pyrrolo[2,3-b]pyridin-3 -ylmethyl)-pyridin-2-yl]-amine (P-0336),
3-[6-(2-Methoxy-benzylamino)-pyridin-3-ylmethyl]-lH-pyrrolo[2,3-b]pyridine-5-carbonitrile
(P-0337),
[5-(5-Chloro-lH-pyrroIo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-difluoromethoxy-benzyl)-
amine (P-0338),
3-[6-{2-Difluoromethoxy-benzylamino)-pyridin-3-ylmethyl]-lH-pyrrolo[2,3-b]pyridine-5-
carbonitrile (P-0339),
(2,6-Difluoro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-yImethy])-pyridin-2-yl]-amine(P-0340),
(2,6-Difluoro-benzyl)-[5-(5-methyl-lH-pyrrolo[2,3-b]pyridin-3-ylinethyl)-pyridin-2-yl]-amine
(P-0341),
(2,4-Dichloro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-y!]-amine(P-0342),


(3-Fluoro-benzyl)-[5-(lH-pytTolof2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(P-0343),
(2-Fluoro-4-trifluoromethyl-benzyl)-t5-{1H-pyirolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-
amine (P-0344),
(4-Chloro-2-fluoro-bcnzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-yIinethyl)-pyridin-2-yl]-amine
(P-0345),
(3-Fluoro-5-trifluoromethyl-benzyl)-t5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-
amine (P-0346),
(2-Morpholin-4-yl-pyridin-3-ylmethyl)-[5-(lH-pyrrolof2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-
amine (P-0347),
(4-Chloro-3-trifluoromethyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-
amine (P-0348),
(2-Chloro-5-trifluoromethyl-ben2yl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-
amine (P-0349), '
(2-Fluoro-5-trifluoromethyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-
amine (P-0350),
(2,3-Dichloro-benzyl)-[5- (2-Fluoro-3-methoxy-benzyl)-[5-{]H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine
(P-0352),
Dimethyl-(5-{[5-(lH-pyrrolot2,3-b]pyridin-3-yIniethyl)-pyridin-2-ylamino]-methyl}-pyrimidin-2-
yl)-amine (P-0353),
(3-Chloro-2-fluoro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-aminc
(P-0354),
(5-Fluoro-pyridin-2-ylmethyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-ainine
(P-0355),
(3,5-Difluoro-benzyl)-[5-( 1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-0356),
(2-Propoxy-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(P-0357),
(2-Morpholin-4-yl-benzyl)-[5-(lH-pyrTolo[2,3-b]pyridin-3-ylmethyI)-i)yridin-2-yl]-amine
(P-0358),
(2-Chloro-3-methoxy-benzyl)-[5-(lH-pyTrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine
(P-0359),
(2-Fluoro-6-trifluoromethyl-benzyl)-t5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-
amine (P-0360),
[2-(2-Morpholin-4-yl-ethoxy)-benzyl]-[5-(lH-pyTTolo[2)3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-
amine (P-0361),
(2,3-Difluoro-benzyl)-t5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-y]]-amineCP-0362),
(2-Chloro-3-trifiuoromethyl-benzyl)-[5-(lH-pytTolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-


amine (P-0363),
(2-Chloro-5-fluoro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine
(P-0364),
(2-Fluoro-3-trifluororaethyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-
amine (P-0365),
(5-FIuoro-2-methoxy-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine
(P-0366),
(2-Difluoromethoxy-benzyl)-[5-{lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine
(P-0367),
(2-Fluoro-4-mcthyl-ben2yl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylJ-amine
(P-0368),
[2-(3-Dimethylamino-propoxy)-benzyl]-[5-(lH-pyrTolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-
amine (P-0369),
(2,6-Dimethoxy-pyridin-3-ylmethyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-
amine (P-0370),
(2-Fluoro-5-methoxy-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine
(P-0371),
(4-Fluoro-2-methyl-benzyl)-[5-(lH-pynlolo[2,3-b]pyridin-3-ylmethy!)-pyridin-2-yl]-amine
(P-0372),
(3-Chloro-5-fluoro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine
(P-0373),
(6-Cyclopentyloxy-pyridin-3-ylmethyl)-[5-{lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-
amine (P-0374),
(5-Fluoro-2-trifluoromethyl-bcnzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-pyridin-2-yl]-
amine (P-0375),
[5-(lH-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-[2-(2,2,2-lrifluoro-ethoxy)-pyridin-3-
ylmethyl]-amine (P-0376),
Propanc-1 -sulfonic acid (2-fluoro-3-{[5-(l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-
ylamino]-methyl} -phenyl)-amide (P-0377),
(2,5-Dichloro-benzyl)-[5-( 1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-0380),
Pyrimidin-5-ylmethyl-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(P-0381),
(5-Ghloro-2-fluoro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yI]-amine
(P-0382),
(2-Ethyl-benzyl)-[5-(lH-pyrroIo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(P-0383),
2,2-Dimethyl-N-(3-{[5-(lH-pyrroIo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yIamino]-tnethyl}-
pyridin-2-yl)-propionamide (P-0384),


Methyl-(3-{[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamino]-methyl}-pyridin-2-yl)-
amine (P-0385),
Methyl-(5-{[5-(lH-pyn-olo[2,3-b]pyridin-3-ylmethyI)-pyridin-2-ylamino]-tnethyl}-pyrimidin-2-
yl)-amine (P-0386),
(2-Chloro-4-methanesulfonyi-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-pyridin-2-yl]-
amine (P-0387),
Possibly to be added (P-0388),
(5-Fluoro-2-methyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yI]-aminc
(P-0397),
Dimethyl-{3-{[5-(lH-pyrrolo[2,3-b]pyridin-3-yImethyl)-pyridin-2-ylamino]-methyl}-pyridin-2-
yl)-amine (P-0399),
(5-Chloro-pyridin-3-ylmethyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine
(P-0400),
(2-Methoxy-pyrimidin-5-ylmethyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine
(P-0401),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-[6-(2,2,2-trifluoro-ethoxy)-
pyridin-3-yImethyl]-amine(P-0409),
l-(3-Fluoro-phenyl)-3-[5-(lH-pyn-olo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-urea (P-0412), and
all salts, prodrugs, tautomers, and isomers thereof.
|0050] In one embodiment, a compound of the invention is:
(4-Chloro-benzyl)-[6-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridazin-3-yl]-aniine(P-0092),
(4-Morpholin-4-ylmethyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-yImethyl)-pyridin-2-yl]-amine
(P-0093),
(2-Methoxy-ethyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(P-0098),
[4-Chloro-l -ethyl-5-( 1 H-pyrrolo [2,3-b]pyridin-3-ylmethyl)-l H-pyrazol-3-y I] -[ 1 -(4-fluoro-
phenyl)-mcth-(E)-ylidene]-amine(P-0166),
((2,2-Difluoro-benzo[ 1,3]dioxoI-4-ylmethyl)-[5-( 1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-
yl]-amine (P-0398); or
any salts, prodrugs, tautomers, and isomers thereof.
|0051] In certain embodiments of the above compounds, compounds are excluded where N
(except where N is a heteroaryl ring atom), O, or S is bound to a carbon that is also bound to N
(except where N is a heteroaryl ring atom), O, or S, except where the carbon forms a double bond
with one of the heteroatoms, such as in an amide, carboxylic acid, and the like; or where N (except
where N is a heteroaryl ring atom), O, C(S), C(O), or S(O)n (n is 0-2) is bound to an alkene carbon


of an alkenyl group or bound to an alkyne carbon of an alkynyl group; accordingly, in certain
embodiments compounds which include linkages such as the following are excluded from the
present invention: -NR-CH2-NR-, -O-CH2-NR-, -S-CHj-NR-, -NR-CHj-O-, -O-CH2-0-,
-S-CHj-O-.-NR-CHj-S-, -O-CHj-S-, -S-CHj-S-, -NR-CH=CH-, -CH=CH-NR-, -NR-C sC-,
-C=C-NR-, -O-CH=CH-, -CH=CH-O-, -O-C*€-, -CsC-O-, -S(0)o.2-CH=CH-, -CH=CH-S(O)0.2-,
-StOJo-j-C =€-, -C sC-S(O),»-, -C(O)-CH=CH-, -CH=CH-C(O)-, -C ^-C(O)-, or -C(O)-C s€-,
-C(S)-CH=CH-, -CH=CH-C(S)-, -Cs€-C(S)-, or -C(S)-Cs€-.
(0052| In reference to compounds herein, specification of a compound or group of compounds
includes pharmaceutically acceptable salts of such compound(s), prodrug(s), and all stereoisomers,
unless clearly indicated to the contrary. In reference to compounds of Formula II, it is understood
that such reference includes compounds of Formulae Ha, lib, lie, Ilg and Up, and all sub-
embodiments thereof.
[0053] In another aspect, the invention provides methods for treating a c-kit-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 c-kit activity (e.g. kinase activity).
Invention methods involve administering to the subject suffering from or at risk of a c-kit-
mediated disease or condition an effective amount of a compound of Formula II or Formula III,
and all sub-embodiments thereof. In one embodiment, the c-kit mediated disease is selected from
the group consisting of malignancies, including, but not limited to, 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, but not limited to, asthma, rheumatoid arthritis, allergic rhinitis, multiple sclerosis,
inflammatory bowel syndrome, transplant rejection, and hypereosinophilia.
10054 J In a related aspect, compounds of Formula II or Formula III, and all sub-embodiments
thereof, can be used in the preparation of a medicament for the treatment of a c-kit-mediated
disease or condition selected from the group consisting of malignancies, including, but not limited
to, 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, but not limited to, asthma, rheumatoid arthritis, allergic
rhinitis, multiple sclerosis, inflammatory bowel syndrome, transplant rejection, and
hypereosinophilia.
[0055] In a further aspect, the invention provides methods for treating a c-fms-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 c-fms activity (e.g. kinase
activity). Invention methods involve administering to the subject suffering from or at risk of a c-
fms-mediated disease or condition an effective amount of compound of Formula II or Formula III,
and all sub-embodiments thereof. In one embodiment, the c-fms mediated disease is selected from
the group consisting of immune disorders, including, but not limited to, rheumatoid arthritis,
systemic lupus erythematosis (SLE), and transplant rejection; inflammatory diseases including, but
not limited to, osteoarthritis, inflammatory bowel syndrome, ulcerative colitis, Crohn's disease,
chronic obstructive pulmonary disease (COPD), emphysema, Kawasaki's Disease,
hemophagocytic syndrome (macrophage activation syndrome), multicentric reticulohistiocytosis,
and atherosclerosis; metabolic disorders, including, but not limited to, Type I diabetes, Type II
diabetes, insulin resistance, hyperglycemia, obesity, and lipolysis; disorders of bone structure,
mineralization and bone formation and resorption, including, but not limited to, osteoporosis,
increased risk of fracture, Paget's disease, hypercalcemia, infection-mediated osteolysis (e.g.
osteomyelitis), peri-prosthetic or wear-debris-mediated osteolysis, and metastasis of cancer to
bone; kidney and genitourinary diseases, including, but not limited to, endometriosis, nephritis
(e.g. glomerulonephritis, interstitial nephritis, Lupus nephritis), tubular necrosis, diabetes-
associated renal complications (e.g. diabetic nephropathy), and renal hypertrophy; disorders of the
central nervous system, including, but not limited to, multiple sclerosis, stroke, Alzheimer's
disease and Parkinson's disease; inflammatory and chronic pain, including, but not limited to, bone
pain; and cancers, including, but not limited to, multiple myeloma, acute myeloid leukemia
(AML), chronic myeloid leukemia (CML), prostate cancer, breast cancer, ovarian cancer,
melanoma, glioblastoma multiforme, metastasis of tumors to other tissues, and other chronic
myeloproliferative diseases such as myelofibrosis.
[0056] In a related aspect, compounds of Formula II or Formula III, and all sub-embodiments
thereof, can be used in the preparation of a medicament for the treatment of a c-fms-mediated
disease or condition selected from the group consisting of immune disorders, including, but not
limited to, rheumatoid arthritis, systemic lupus erythematosis (SLE), and transplant rejection;


inflammatory diseases including, but not limited to, osteoarthritis, inflammatory bowel syndrome,
ulcerative colitis, Crohn's disease, chronic obstructive pulmonary disease (COPD), emphysema,
Kawasaki's Disease, hemopnagocytic syndrome (macrophage activation syndrome), multicentric
reticulohistiocytosis, and atherosclerosis; metabolic disorders, including, but not limited to, Type I
diabetes, Type II diabetes, insulin resistance, hyperglycemia, obesity, and lipolysis; disorders of
bone structure, mineralization and bone formation and resorption, including, but not limited to,
osteoporosis, increased risk of fracture, Paget's disease, hypercalcemia, infection-mediated
osteolysis (e.g. osteomyelitis), peri-prosthetic or wear-debris-mediated osteolysis, and metastasis
of cancer to bone; kidney and genitourinary diseases, including, but not limited to, endometriosis,
nephritis (e.g. glomerulonephritis, interstitial nephritis, Lupus nephritis), tubular necrosis,
diabetes-associated renal complications (e.g. diabetic nephropathy), and renal hypertrophy;
disorders of the central nervous system, including, but not limited to, multiple sclerosis, stroke,
Alzheimer's disease and Parkinson's disease; inflammatory and chronic pain, including, but not
limited to, bone pain; and cancers, including, but not limited to, multiple myeloma, acute myeloid
leukemia (AML), chronic myeloid leukemia (CML), prostate cancer, breast cancer, ovarian cancer,
melanoma, giioblastoma multiforme, metastasis of rumors to other tissues, and other chronic
myeloproliferative diseases such as myelofibrosis.
[0057] In a further aspect, the invention provides methods for treating, 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 pels such as dogs and cats), a disease or condition mediated
by c-fms and c-kit, e.g., a disease or condition characterized by abnormal c-fms activity and c-kit
activity (e.g. kinase activity). Invention methods involve administering to the subject suffering
from or at risk of a disease or condition mediated by c-fms and c-kit an effective amount of
compound of Formula II or Formula III, and all sub-embodiments thereof. In one embodiment, the
condition mediated by c-fms and c-kit is selected from the group consisting of mast cell tumors,
small cell lung cancer, testicular cancer, gastrointestinal stromal tumors, giioblastoma,
astrocytoma, neuroblastoma, carcinomas of the female genital tract, sarcomas of neuroectodermal
origin, colorectal carcinoma, carcinoma in situ, Schwann cell neoplasia associated with
neurofibromatosis, acute myeloid leukemia, acute lymphocytic leukemia, chronic myelogcnous
leukemia, multiple myeloma, mastocytosis, melanoma, breast cancer, ovarian cancer, prostate
cancer, canine mast cell tumors, metastasis of cancer to bone or other tissues, chronic
myeloproliferative diseases such as myelofibrosis, renal hypertrophy, asthma, rheumatoid arthritis,
allergic rhinitis, multiple sclerosis, osteoarthritis, inflammatory bowel syndrome, transplant
rejection, systemic lupus erythematosis, ulcerative colitis, Crohn's disease, chronic obstructive
pulmonary disease, emphysema, Kawasaki's Disease, hemopnagocytic syndrome (macrophage


activation syndrome), multicentric reticulohistiocytosis, atherosclerosis, Type I diabetes, Type II
diabetes, insulin resistance, hyperglycemia, obesity, lipolysis, hypereosinophilia, osteoporosis,
increased risk of fracture, Paget's disease, hypercalcemia, infection-mediated osteolysis (e.g.
osteomyelitis), peri-prosthetic or wear-debris-mediated osteolysis, endometriosis,
glomerulonephritis, interstitial nephritis, Lupus nephritis, tubular necrosis, diabetic nephropathy,
stroke, Alzheimer's disease, Parkinson's disease, inflammatory pain, chronic pain, and bone pain.
[0058] In a related aspect, compounds of Formula II or Formula III, and all sub-embodiments
thereof, can be used in the preparation of a medicament for the treatment of a disease or condition
mediated by c-fms and c-kit selected from the group consisting of mast cell tumors, small cell lung
cancer, testicular cancer, gastrointestinal stromal tumors, 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 myeloid leukemia, acute lymphocytic leukemia, chronic myelogenous
leukemia, multiple myeloma, mastocytosis, melanoma, breast cancer, ovarian cancer, prostate
cancer, canine mast cell tumors, metastasis of cancer to bone or other tissues, chronic
myeloproliferative diseases such as myelofibrosis, renal hypertrophy, asthma, rheumatoid arthritis,
allergic rhinitis, multiple sclerosis, osteoarthritis, inflammatory bowel syndrome, transplant
rejection, systemic lupus erythematosis, ulcerative colitis, Crohn's disease, chronic obstructive
pulmonary disease, emphysema, Kawasaki's Disease, hemophagocytic syndrome (macrophage
activation syndrome), multicentric reticulohistiocytosis, atherosclerosis, Type I diabetes, Type II
diabetes, insulin resistance, hyperglycemia, obesity, lipolysis, hypereosinophilia, osteoporosis,
increased risk of fracture, Paget's disease, hypercalcemia, infection-mediated osteolysis (e.g.
osteomyelitis), peri-prosthetic or wear-debris-mediated osteolysis, endometriosis,
glomerulonephritis, interstitial nephritis, Lupus nephritis, tubular necrosis, diabetic nephropathy,
stroke, Alzheimer's disease, Parkinson's disease, inflammatory pain, chronic pain, and bone pain.
|0059] In particular embodiments, the compound has an ICSO of less than 100 nM, less than 50
nM, less than 20 nM, less than 10 nM, or less than 5 nM as determined in a generally accepted
kinase activity assay. In certain embodiments, the selectivity of the compound is such that the
compound is at least 2-fold, 5-fold, 10-fold, or 100-fold more active on c-kit than on Ret, PDGF,
or both Ret and PDGF. In certain embodiments, the selectivity of the compound is such that the
compound is at least 2-fold, 5-fold, 10-fold, or 100-fold more active on c-kit than on c-fms. In
certain embodiments, the selectivity of the compound is such that the compound is at least 2-fold,
5-fold, 10-fold, or 100-fold more active on c-fms than on c-kit. In certain embodiments, the

compound has in combination each pairing of activity (e.g. IC50) and/or selectivity as specified in
this paragraph.
[0060] In particular embodiments, the compound has an IC50 of less than 100 nM, less than 50
nM, less than 20 nM, less than 10 nM, or less than 5 nM as determined in a generally accepted
kinase activity assay for c-kit, c-fms, or both c-kit and c-fms kinasc activity. In certain
embodiments, the selectivity of the compound is such that the compound is at least 2-fold, S-fold,
10-fold, or 100-fold more active on c-kit, c-fms, or both c-kit and c-fms than on Ret, PDGF, or
both Ret and PDGF.
[0061] In particular embodiments, the compound has an IC30 of less than 100 nM, less than 50
nM, less than 20 nM, less than 10 nM, or less than 5 nM as determined in a generally accepted
kinase activity assay for c-kit, c-fms, or both c-kit and c-fms kinase activity, and further has an
IC50 of less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, or less than 5 nM as
determined in a generally accepted kinase activity assay for at least one of HGK, TrkA, or TrkB
kinase activity.
10062] An additional aspect of this invention relates to compositions that include a
therapeutically effective amount of a compound of Formula II or Formula III and all sub-
embodiments thereof and at least one pharmaceutically acceptable carrier, excipient, and/or
diluent, including combinations of any two or more compounds of Formula II or Formula III. The
composition can further include one or more different pharmacologically active compounds, which
can include one or more compounds of Formula II or Formula III.
[0063] In one aspect, the invention provides a method of treating a cancer by administering to
the subject an effective amount of a composition including a compound of Formula II or Formula
III, 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 aspect, 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, 7-ray, or
electron, proton, neutron, or a particle beam), hyperthermia heating (e.g. microwave, ultrasound,
radiofrequency ablation), Vaccine therapy (e.g. APP 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, and bone marrow and stem cell transplantation.
[0064] In one aspect, the invention provides a method of treating a cancer by administering to
the subject an effective amount of a composition including a compound of Formula II or Formula
III, in combination with one or more suitable chemotherapeutic agents. In one aspect, the one or
more suitable chemotherapeutic agents is selected from an alkylating agent, including, but not
limited to, adozelesin, altretamine, bizelesin, busulfan, carboplatin, carboquone, cannustine,
chlorambucil, cisplatin, cyclophosphamide, dacarbazine, estramustinc, fotemustine, hepsulfam,
ifosfamide, improsulfan, irofulven, lomustine, mechlorethamine, melphalan, oxaliplatin,
piposulfan, semustine, streptozocin, temozolomide, thiotepa, and treosulfan; an antibiotic,
including, but not limited to, bleomycin, dactinomycin, daunorubicin, doxorubicin, epimbicin,
idambicin, menogaril, milomycin, mitoxantrone, neocarzinostatin, pentostatin, and plicamycin; an
antimetabolite, including, but not limited to, azacitidine, capecitabine, cladribine, clofarabine,
cytarabine, decitabine, floxuridine, fludarabine, 5-fluorouracil, ftorafur, gemcitabine, hydroxyurea,
mercaptopurine, methotrexate, nelarabine, pemetrexed, raltitrexed, thioguanine, and trimetrexate;
an immunotherapy, including, but not limited to, alemtuzumab, bevacizumab, cetuximab,
galiximab, gemtuzumab, panitumumab, pertuzumab, rituximab, tositumomab, trastuzumab, and 90
Y ibritumomab tiuxetan; 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, paclitaxel and DHA-paclitaxel; a
retinoid, including, but not limited to, alitretinoin, bexarotene, fenretinide, isotretinoin, and
tretinoin; an alkaloid, including, but not limited to, etoposide, homoharringtonine, tenipostde,
vinblastine, vincristine, vindesine, 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, edotecarin,
exatecan, irinotecan (also active metabolite SN-38 (7-ethyl-10-hydroxy-camptothecin)), rubitecan,
topotecan, and 9-aminocamptothecin; a kinase inhibitor, including, but not limited to, erlotinib,
gefitinib, flavopiridol, imatinib mesylate, lapatinib, sorafenib, sunitinib malate, AEE-788, AG-
013736, AMG 706, AMN107, BMS-354825, 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-, and interleukin-2; and other chemotherapeutics, including, but not
limited to 3-AP (3-amino-2-carboxyaldehydc thiosemicarbazone), aminoglutethimide,
asparaginase, bryostatin-1, cilengitide, E7389, ixabepilone, procarbazine, sulindac, temsirolimus,


tipifamib. Preferably, the method of treating a cancer involves administering to the subject an
effective amount of a composition of Formula II, Formula III or Formula IV in combination with a
chemotherapeutic agent selected from 5-fluorouracil, carboplatin, dacarbazine, gefitinib,
oxaliplatin, paclitaxel, SN-38, temozolomide, vinblastine, bevacizumab, cetuximab, or erlotinib.
[0065] 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 a
compound of Formula II or Formula III, 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.
[0066| In a related aspect, the invention provides kits that include a composition as described
herein. In particular 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
c-kit- and/or c-fms-mediated disease or condition; the kit of the invention includes written
instructions on use and/or other indication that the composition is suitable or approved for
administration to a mammal, e.g., a human, for a c-kit- and/or c-fms-mediated disease or
condition; the composition is packaged in unit dose or single dose form, e.g., single dose pills,
capsules, or the like.
[0067] In another aspect, the present invention also provides a method for modulating c-kit or
c-fms activity by contacting c-kit or c-fms with an effective amount of a compound of Formula II
or Formula III and all sub-embodiments thereof active on c-kit and/or c-fms (such as compounds
developed using methods described herein). The compound is preferably provided at a level
sufficient to modulate the activity of the c-kit or c-fms by at least 10%, more preferably at least
20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or greater than 90%. In many embodiments, the
compound will be at a concentration of about 1 μM, 100 μM, or 1 mM, or in a range of 1-100 nM,
100-500 nM, 500-1000 nM, 1-100 μM, 100-500 μM, or 500-1000 μM. In particular embodiments,
the contacting is carried out in vitro.
[0068] Additional aspects and embodiments will be apparent from the following Detailed
Description and from the claims.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0069] As used herein the following definitions apply:
[0070] "Halo" and "halogen" refer to all halogens, that is, chloro (C1), fluoro (F), bromo (Br), or
iodo (I).
[0071) "Hydroxyl" and "hydroxy" refer to the group -OH.
[0072] "Thiol" refers to the group -SH.
[0073] "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 alkyl group is attached at any available point to produce 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. "Optionally substituted lower alkyl" denotes lower alkyl that is independently
substituted, with one or more, preferably 1, 2, 3,4 or 5, also 1, 2, or 3 substituents, attached at any
available atom to produce a stable compound. For example "fluoro substituted lower alkyl"
denotes a lower alkyl group substituted with one or more fluoro atoms, such as pcrfluoroalkyl,
where preferably the lower alkyl is substituted with 1,2, 3,4 or 5 fluoro atoms, also 1,2, or 3
fluoro atoms. While it is understood that substitutions are attached at any available atom to
produce a stable compound, when optionally substituted alkyl is an R group of a moiety such as -
OR, -NHR, -C(O)NHR, and the like, substitution of the alkyl R group is such that substitution of
the alkyl carbon bound to any -O-, -S-, or -N- of the moiety (except where -N- is a heteroaryl ring
atom) excludes substituents that would result in any -O-, -S-, or -N- of the substituent (except
where -N- is a heteroaryl ring atom) being bound to the alkyl carbon bound to any -O-, -S-, or -N-
of the moiety.
[0074] "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, with one or more, preferably 1,2, 3,4 or 5, also 1,2,
or 3 substituents, attached at any available atom to produce a stable compound.
[0075] "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
one of the ring carbons is 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, with one or more, preferably 1, 2, 3,4 or 5, also
1, 2, or 3 substituents, attached at any available atom to produce a stable compound.
[0076| "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, with one or more, preferably 1, 2, 3,4 or 5, also 1, 2, or 3
substituents, attached at any available atom to produce a stable compound.
[0077] "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
produced. Examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl,
pyrazinyl, quinaoxalyl, indolizinyl, benzo[b]thienyl, quinazolinyl, purinyl, indolyl, quinolinyl,
pyrimidinyl, pyrrolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl,
tetrazolyl, imidazolyl, triazinyl, furanyl, benzofuryl, and indolyl. "Nitrogen containing heteroaryl"
refers to heteroaryl wherein any heteroatoms are N. A "substituted heteroaryl" is a heteroaryl that
is independently substituted, with one or more, preferably 1, 2, 3, 4 or 5, also I, 2, or 3
substituents, attached at any available atom to produce a stable compound.
[0078] "Lower alkoxy" denotes the group -OR1, where Rr is lower alkyl. "Substituted lower
alkoxy" denotes lower alkoxy in which R1 is lower alkyl substituted with one or more substituents
as indicated herein attached at any available atom to produce 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. While it is understood that substitutions on


alkoxy are attached at any available atom to produce a stable compound, substitution of alkoxy is
such that -O-, -S-, or -N- (except where N is a heteroaryl ring atom), are not bound to the alkyl
carbon bound to the alkoxy -O-. Further, where alkoxy is described as a substituent of another
moiety, the alkoxy oxygen is not bound to a carbon atom that is bound to an -O-, -S-, or -N- of the
other moiety (except where N is a heteroaryl ring atom), or to an alkene or alkyne carbon of the
other moiety.
[0079] "Lower alkylthio" denotes the group -SR", where R" is lower alkyl. "Substituted lower
alkylthio" denotes lower alkylthio in which R" is lower alkyl substituted with one or more
substituents as indicated herein attached at any available atom to produce 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. While it is understood
that substitutions on alkylthio are attached at any available atom to produce a stable compound,
substitution of alkylthio is such that -O-, -S-, or -N- (except where N is a heteroaryl ring atom),
are not bound to the alkyl carbon bound to the alkylthio -S-. Further, where alkylthio is described
as a substituent of another moiety, the alkylthio sulfur is not bound to a carbon atom that is bound
to an -O-, -S-, or -N- of the other moiety (except where N is a heteroaryl ring atom), or to an
alkene or alkyne carbon of the other moiety.
[0080] "Mono-alkylamino" denotes the group -NHRbb where Rbb is lower alkyl. "Di-
alkylamino" denotes the group -NR^60, where R1* and RM are independently lower alkyl.
"Cycloalkylamino" denotes the group -NR^R™, where R*1 and R" 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
lower alkyl. Examples of 5-7 membered heterocycloalkyl include, but are not limited to,
piperidine, piperazine, 4-methylpiperazine, morpholine, and thiomorpholine. While it is
understood that when mono-alkylamino, di-alkylamino, or cycloalkylamino are substituents on
other moieties that are attached at any available atom to produce a stable compound, the nitrogen
of mono-alkylamino, di-alkylamino, or cycloalkylamino as substituents is not bound to a carbon
atom that is bound to an -O-, -S-, or -N- of the other moiety.
[0081] As used herein, the term c-kit-mediated disease or condition refers to a disease or
condition in which the biological function of c-kit affects the development and/or course of the
disease or condition, and/or in which modulation of c-kit alters the development, course, and/or
symptoms. For example, mutations in the c-kit gene such as the W42, Wv, and W41 mutations


reported by Herbst et al al (J. Biol. Chem., 1992,267: 13210-13216) confer severe, intermediate,
and mild phcnotypic characteristics, respectively. These mutations attenuate the intrinsic tyrosine
kinase activity of the receptor to different degrees and are models for the effect of modulation of
c-kit activity. A c-kit mediated disease or condition includes a disease or condition for which c-kit
inhibition provides a therapeutic benefit, e.g. wherein treatment with c-kit inhibitors, including
compounds described herein, provides a therapeutic benefit to the subject suffering from or at risk
of the disease or condition.
[0082] As used herein, the term c-fms-mediated disease or condition refers to a disease or
condition in which the biological function of c-fms affects the development and/or course of the
disease or condition, and/or in which modulation of c-fms alters the development, course, and/or
symptoms. For example, the Csflr/Csflr mutant mouse of Dai et al (Blood, 2002, 99: 111-120)
which lacks c-fms is an animal model for diseases or conditions wherein c-fms activity has been
abolished. A c-fms mediated disease or condition includes a disease or condition for which c-fms
inhibition provides a therapeutic benefit, e.g. wherein treatment with c-fms inhibitors, including
compounds described herein, provides a therapeutic benefit to the subject suffering from or at risk
of the disease or condition.
[0083] As used herein, the term "composition" refers to a formulation suitable for administration
to an intended animal subject for therapeutic purposes that contains at least one pharmaceutically
active compound and at least one pharmaceutically acceptable carrier or excipient.
[0084] 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.
[0085] In the present context, the terms "therapeutically effective" and "effective amount"
indicate 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.
|0086] 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
c-kit or c-fms. For example, an agonist or antagonist of a particular biomolecule modulates the
activity of that biomolecule, e.g., an enzyme.


[0087] The term "c-kit activity" refers to a biological activity of c-kit, particularly including
kinase activity. The term "c-fms activity" refers to a biological activity of c-fms, particularly
including kinase activity.
I. General
[0088] In one aspect, the present invention concerns compounds of Formula II, IIa, IIb, IIe, IIg,
IIp or III and all sub-embodiments thereof, that are inhibitors of c-kit, c-fms, or both c-kit and
c-fms, and the use of the compounds in treating diseases that are mediated by c-kit, c-fms, or both
c-kit and c-fms.
Exemplary Diseases Associated with c-Kit.
[0089] The compounds described herein are useful for treating disorders related to c-kit e.g.,
diseases related to unregulated kinase signal transduction, including cell proliferative disorders,
fibrotic disorders and metabolic disorders, among others. As described in more detail below and
in Lipson et al., U.S. 20040002534 (U.S. application 10/600, 868, filed June 23, 2003) which is
incorporated herein by reference in its entirety, cell proliferative disorders which can be treated by
the present invention include cancers, and mast cell proliferative disorders.
(0090] The presence of c-kit has also been associated with a number of different types of
cancers. In addition, the association between abnormalities in c-kit and disease are not restricted
to cancer. As such, c-kit has been associated with 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.
Exemplary diseases associated with c-fms
[0091] The presence of c-fms has been associated with a number of different types of diseases.
As such, c-fms has been associated with immune disorders, including, but not limited to,
rheumatoid arthritis, systemic lupus erythematosis (SLE), and transplant rejection; inflammatory
diseases including, but not limited to, inflammatory bowel syndrome, ulcerative colitis, Crohn's
disease, chronic obstructive pulmonary disease (COPD), emphysema, Kawasaki's Disease,
hemophagocytic syndrome (macrophage activation syndrome), multicentric reticulohistiocytosis,


and atherosclerosis; metabolic disorders, including, but not limited to, Type I diabetes. Type II
diabetes, insulin resistance, hyperglycemia, obesity, and lipolysis; disorders of bone structure,
mineralization and bone formation and resorption, including, but not limited to, osteoporosis,
increased risk of fracture, Paget's disease, hypercalcemia, infection-mediated osteolysis (e.g.,
osteomyelitis), peri-prosthetic or wear-debris-mediated osteolysis, and metastasis of cancer to
bone; kidney and genitourinary diseases, including, but not limited to, endometriosis, nephritis
(e.g. glomerulonephritis, interstitial nephritis, Lupus nephritis), tubular necrosis, diabetes-
associated renal complications (e.g. diapetic nephropathy), and renal hypertrophy; disorders of the
central nervous system, including, but not limited to, multiple sclerosis, stroke, Alzheimer's
disease and Parkinson's disease; inflammatory and chronic pain, including, but not limited to, bone
pain; and cancers, including, but not limited to, multiple myeloma, acute myeloid leukemia
(AML), chronic myeloid leukemia (CML), prostate cancer, breast cancer, ovarian cancer,
melanoma, glioblastoma multiforme, metastasis of tumors to other tissues, and other chronic
myeloproliferative diseases such as myelofibrosis.
Exemplary diseases associated with TrkA and TrkB
[0092] TrkA: Target kinase TrkA (i.e., neurotrophic tvrosine kinase. receptor, type 1) is a 140
kDatyrosine kinase encoded by chromosome Iq21-q22 (symbol: NTRK1). TrkA inhibitors may
be useful in treating pain (e.g. chronic pain, neuropathic pain), cancer (e.g. prostate cancer, lung
cancer, myeloid leukemia, pancreatic cancer), arthritis, allergic disorders (e.g. asthma), diabetic
retinopathy, macular degeneration and psoriasis.
(0093] TrkB: Target kinase TrkB (i.e., neurotrophic tvrosine kinase. receptor, type 2) is a 145
kDa tyrosine kinase encoded by chromosome 9q22.1 (symbol: NTRK2). TrkB inhibitors may be
useful in treating various cancers and their metastases (e.g. prostate cancer, lung cancer, Wilm's
tumors, neuroblastoma, and pancreatic cancer), and various neuropathies (e.g. stroke, multiple
sclerosis, transverse myelitis, and encephalitis).
Exemplary diseases associated with HGK
[0094] HGK: Target kinase HGK (i.e., Hematopoietic progenitor kinase/Gerninal center kinase-
like Kinase, aka mitogen-activated protein kinase kinase kinase kinase 4) is a 130 kDa
serine/threonine kinase encoded by chromosome 2ql 1.2-q12 (symbol: MAP4K4). HGK inhibitors
may be useful in treating metabolic indications, including re-sensitizing fat and muscle cells to
insulin, ameliorating the pathology in adipocytes, ameliorating the pathology in muscle cells, 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.
V. Organic Synthetic Techniques
[0095] A wide array of organic synthetic techniques exist in the art to meet the challenge of
constructing 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 suh 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.
VI. Alternative Compound Forms or Derivatives
[0096] Alternative forms or derivatives, such as (a) Isomers, Prodrugs, and Active Metabolites
(b) Tautomers, Stereoisomers, Regioisomers, and Solvated Forms (c) Prodrugs and Metabolites
(d) Pharmaceutically acceptable salts and (e) Polymorphic forms, are described, for example, in
US Patent Application Publication number US 2007/0032519, the disclosure of which is hereby
incorporated by reference in its entirety.
VII. Administration
[0097] 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.
In this context, the terms "subject," "animal subject," and the like refer to human and non-human
vertebrates, e.g. mammals, such as non-human primates, sports and commercial animals, e.g.,
equines, bovines, porcines, ovines, rodents, and pets, e.g., canines and felines. A description of
possible methods and routes of administration may be found, for example, in US Patent
Application Publication number US 2007/0032S19, the disclosure of which is hereby incorporated
by reference in its entirety.
EXAMPLES
[0098] A number of examples illustrative of the present invention are described below. In most
cases, alternative techniques could also be used. The examples are intended to be illustrative and
are not limiting or restrictive to the scope of the invention. Unless specifically noted to the
contrary, in cases where a compound number is not proceeded by a "P-" (e.g., "P-0001") in the
Examples section, compound naming and/or enumeration is not related to naming and/or
enumeration employed in other sections of this application. Similarly, structure and substituent


naming and enumeration within the Examples are independent of structure and substituent naming
and enumeration in above sections of this application unless clearly indicated otherwise.
[0099] In the following Examples, it is understood that the solvents and reagents used or
suggested are not limiting, and can be substituted appropriately with solvents and reagents known
to those of skill in the art. Reaction products may be isolated by means known in the art, such as
extraction with a suitable solvent, precipitation from a suitable solvent, chromatography using a
suitable solvent system, including silica gel column chromatography, HPLC, preparative TLC, and
the like. Exemplary methods for synthesis of compounds of the present invention may be found in
US Patent Application Publication number US 2007/0032519, the disclosure of which is hereby
incorporated by reference. The lH-pyrrolo[2,3-b]pyridine core of compounds described in the
examples may also be referred to as 7-azaindole in the examples.
Example 1: Synthesis of [5-(5-Bromo-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(4-
chloro-benzyl)-amine (P-0038)
|0100| [5-(5-Bromo-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(4-chloro-benzyl)-
amine P-0038 was synthesized in 5 steps from commercially available 2-Amino-S-bromopyridine
15 as shown in Scheme 19.
Scheme 19

Step 1- Synthesis of(5-Bromo-pyridin-2-yl)-(4-chloro-benzyl)-amine (41)
[0101] To 2-Amino-5-bromopyridine (15, 6.10 g, 0.0352 mol) in toluene (90.0 mL) were added
4-chlorobenzaldehyde (40, 5.00 g, 0.0356 mol), trifluoroacetic acid (8.0 mL, 0.10 mol) and
triethylsilane (16.5 mL, 0.103 mol). The reaction was heated to reflux for 48 hours. The reaction

was concentrated, poured into aqueous potassium carbonate and extracted with ethyl acetate. The
organic layer was washed with brine, dried over sodium sulfate and concentrated. The crude
residue was crystallized with ethyl acetate to give compound (41, 6.8 g, 65.4%).
Step 2 - Synthesis of6-(4-Chloro-benzylamino)-pyridine-3-carbaldehyde (42)
10102] To (5-Bromo-pyridin-2-yl)-(4-chloro-benzyl)-amine (41, 10.00 g, 0.03360 mol) in
tetrahydrofiiran (400.0 mL) under an atmosphere of nitrogen at -78 "C was added n-butyllithium
(17.5 mL, 2.00 M in cyclohexane). After 90 minutes, tert-butyllithium (42.00 mL, 1.70 M in
hexane) was added to the reaction. After 80 minutes, N.N-dimethylformamide (6.9 mL, 0.089
mol) was added to the reaction. The reaction mixture was stirred at -78 °C for 2 hours, then
allowed to warm to room temperature for 1 hour. The reaction mixture was poured into water and
extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate
and concentrated to give the crude compound, which was crystallized from /err-butoxyl methyl
ether to provide compound (42, 7.66 g, 92.2%).
Step 3 - Synthesis of(4-Chloro-benzyl)-(5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (43)
10103] To 6-(4-Chloro-benzylamino)-pyridine-3-carbaldehyde (42, 2.00 g, 8.11 mmol) in
dichloromethane (20.0 mL) were added triethylamine (1.70 mL, 12.2 mmol), di-tert-
butyldicarbonate (2.00 g, 9.16 mmol) and 4-dimethylaminopyridine (52.3 tng, 0.43 ramol). The
reaction was stirred at room temperature for 48 hours. The reaction was concentrated and purified
by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give compound
(43, 2.50 g, 89.3%).
Step 4 - Synthesis of{5-[(5-Bromo-lH-pyrrolo[2,3-b]pyridin-3'yl)-hydroxy-methyl]-pyridin-2-yl}-
(4-chloro-benzyl)-carbamic acid tert-butyl ester (45)
[0104] To 5-bromo-7-azaindole (44, 198.0 mg, 1.01 mmol) in methanol (30.0 mL, 0.741 mol)
were added (4-Chloro-benzyl)-(5-formyl-pyridin-2-yI)-carbamic acid tert-butyl ester (43, 355.0
mg, 1.02 mmol) and potassium hydroxide (80.0 mg, 1.42 mmol). The reaction was stirred at room
temperature 48 hours. The reaction mixture was poured into water and extracted with ethyl
acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and
purified by silica gel column chromatography eluting with 8% methanol in dichloromethane to
give compound (45, 200.0 mg, 36.8%).

Step 5 - Synthesis of[5-(5-Bromo-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(4-chloro-
benzyl)-amine (P-0038)
[01051 To {5-[(5-Bromo-lH-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-pyridin-2-yl}-(4-
chloro-benzyl)-carbamic acid tert-butyl ester (45,180.0 mg, 0.33 mmol) in acetonitrile (30.0 mL)
were added trifluoroacetic acid (2.0 mL, 0.026 mol) and triethylsilane (4.0 mL, 0.025 mol). The
reaction was heated to reflux for 4 hours. The reaction mixture was poured into water and
extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate,
concentrated and purified by silica gel column chromatography eluting with 10% methanol in
dichloromethane to give compound (P-0038,120 mg, 85.2%). MS(ESI)[M+H+f = 427.2,429.2.
|0106] Additional compounds were prepared following the protocol of Scheme 19, optionally
replacing 4-chlorobenzaldehyde 40 with an appropriate aldehyde in Step 1 and optionally
replacing 5-bromo-7-azaindole 44 with an appropriate azaindole in Step 4. The following
compounds were made following this procedure:
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-
ylmethyl)-amine (P-0181),
[5-(lH-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifhioromethyl-pyridin-3-ylmethyl)-
amine (P-0182),
3-[6-(4-Chloro-benzylamino)-pyridin-3-ylmethyl]-lH-pyrrolo[2,3-b]pyridine-5-carbonitrile
(P-0257),
3-[6-(4-Trifluoromethyl-benzylamino)-pyridin-3-ylmethyl]-lH-pyrrolo[2,3-b]pyridine-5-
carbonitrile (P-0269),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-fluoro-benzyl)-amine
(P-0270),
3-[6-(2-Fluoro-benzylamino)-pyridin-3-ylmethyl]-lH-pyrrolo[2,3-b]pyridine-5-carbonitrile
(P-0271),
(2-Fluoro-benzyl)-[5-(5-methyl-lH-pyrrolo[2,3-b]pyridin-3-ylmethyI)-pyridin-2-yl]-amine
(P-0272),
3-{6-[(6-Trifluoromethyl-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl}-lH-pyrrolo[2,3-
b]pyridine-5-carbonitrile (P-0273),
3-[6-(2-Trifluoromethyl-benzylaniino)-pyridin-3-ylmcthyl]-lH-pyrrolo[2,3-b]pyridine-5-
carbanitrile (P-0274),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-trifluoromethyl-benzyl)-
amine (P-0275),
[5-(5-Methyl-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-trifluoromethyl-benzyl)-


amine (P-0276),
3-[6-(2,6-Difluoro-benzylamino)-pyridin-3-ylmethyl]-lH-pyrrolo[2,3-b]pyridine-5-carbonitrile
(P-0277),
[5-(5-Chloro-lH-pyrroIo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl)-(2,6-difluoro-benzyl)-amine
(P-0278),
(2-Chloro-benzyl)-[5-(5-methyl-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-p>Tidin-2-yl]-amine
(P-0279).
(2-Chloro-benzyl)-[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-pyridin-2-yl]-amine
(P-0280),
3-[6-(2-Chloro-benzylamino)-pyridin-3-ylmethyl]-lH-pyrTolo[2,3-b]pyridine-5-carbonitrile
(P-0281),
(6-Methoxy-pyridin-3-ylmethyl)-[5-(5-methyl-lH-pyn-olo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-
yl]-amine (P-0282),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]- ylmethyl)-amine (P-0283),
3-{6-[(6-Methoxy-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl}-lH-pyrTolo[2,3-b]pyridine-5-
carbonitrile (P-0284),
(2-Methoxy-pyridin-3-ylmethyl)-t5-(5-methyl-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-
yl]-amine (P-0285),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethy!)-pyridin-2-yl]-(2-methoxy-pyridin-3-
ylmethyl)-amine (P-0286),
3-{6-t(2-Methoxy-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl}-lH-pyrrolo[2,3-b]pyridine-5-
carbonitrile (P-0287),
(2-Ethoxy-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(P-0288),
(2,5-Difluoro-bcnzyl)-[5-(lH-pyrrolot2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(P-0296),
(2,5-Difluoro-benzyl)-[5-(5-methyl-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine
(P-0297),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2,5-difluoro-benzyI)-araine
(P-0298),
3-[6-(2,5-Difluoro-benzylamino)-pyridin-3-ylmethylJ-lH-pyrrolo[2,3-b]pyridine-5-carbonitrile
(P-0299),
3-[6-(2-Trifluorotnetlioxy-benzylamino)-pyridin-3-ylnaethyl]-lH-pyrrolo[2,3-b]pyridine-5-
carbonitrile (P-0321),
[5-(lH-Pymjlo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-trifluoromethoxy-benzyl)-amine
(P-0322),
3-[6-(2-Ethoxy-benzylamino)-pyridin-3-ylmethyl]-lH-pyrrolo[2,3-b]pyridine-5-carbonitrile


(P-0323),
[5-(5-Fluoro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-trifluoromethyl-benzyl)-
amine (P-0325),
[5-(5-Methoxy-lH-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-pyridin-2-yl]-(2-trifluoromethyl-benzyl)-
amine (P-0326),
(2-Chloro-benzyl)-[5-(5-fluoro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-aniine
(P-0327),
(2-Chloro-bcnzyl)-[5-(5-methoxy-lH-pyrrolo[2,3-b]pyridin-3-ylmelhyl)-pyridin-2-yl]-amine
(P-0328),
(2,5-Difluoro-benzyl)-[5-(5-fluoro-lH-pyrrolo[2,3-b]pyridin-3-ylniethyl)-pyridin-2-yl]-aminc
(P-0329),
(2,5-Difluoro-benzyl)-[5-(5-methoxy-lH-pyrrolot2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine
(P-0330),
[5-(5-Fluoro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yI]-(6-methoxy-pyridin-3-ylmethyl)-
amine (P-0331),
(6-Methoxy-pyridin-3-ylmethyl)-[5-(5-methoxy-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-
yl]-amine (P-0332),
(2,6-Dinuoro-benzyl)-[5-(5-fluoro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-ainine
(P-0333),
(2,6-Difluoro-benzyl)-[5-(5-methoxy-lH-pynrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine
(P-0334),
(2-Methoxy-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(P-0336),
3-[6-(2-Methoxy-benzylamino)-pyridin-3-ylmethyl]-lH-pyrrolo[2,3-b]pyridine-5-carbonitrile
(P-0337),
(216-Difluoro-benzyl)-{5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(P-0340),
and
(2,6-Difluoro-benzyl)-[5-(5-methyl-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-ainine
(P-0341).
The following table indicates the aldehyde used in Step 1 in Column 3 and the azaindole used in
Step 4 in Column 2 to provide the compound of Column 4. Column 1 provides the compound
number and Column 5 the measured mass spectrometry result.











[0107] Additional compounds were prepared following the protocol of Scheme 19, Steps 4 and
5, replacing (4-Chloro-benzyl)-(5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester 43 with an
appropriate protected aldehyde and 5-bromo-7-azaindole 44 with an appropriate azaindole in Step
4. Aldehydes were prepared as described in Example 60. The following compounds were made
following this procedure:
3-{2-Chloro-6-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl}-lH-
pyrrolo[2,3-b]pyridine-5-carbonitrile(P-0232),
[6-Chloro-5-(5-methyl-lH-pyrrolo[2,3-b]pyridin-3-yhnethyl)-pyridin-2-yl]-(6-trifluoromethyl-
pyridin-3-ylmethyl)-amine (P-0233),




Example 2: Synthesis of l-triisopropylsilanyl-lH-pyrrolo[2,3-b]pyridine-3-carbaldchyde 47.
(0108] Compound 47 was synthesized in 2 steps from 7-azaindole 1 as described in Scheme 20.
Scheme 20

Step 1 - Preparation oflH-pyrrolo[2,3-b]pyridine-3-carbaldehyde (46):
[0109] To 1 H-Pyrrolo[2,3-b]pyridine (1,16.0 g, 135 mmol) in water (110 mL), were added
hexamethylenetetramine (26.0 g, 185 mmol), and acetic acid (55.0 mL, 967 mmol). The reaction
was refluxed for 12 hours. Water (329 mL) was added and the reaction was cooled to room
temperature. The reaction was filtrated and washed with water to give compound (46, 15.0 g,
76%). MS(ESI)[M+HT = 147.
Step 2 - Preparation of l-triisopropylsilanyl-lH-pyrrolo[2,3-b]pyridine-3-carbaldehyde (47):
|0110] To lH-Pyrrolo[2,3-b]pyridine-3-carbaldehyde (46, 4.05 g, 27.71 mmol) in
tetrahydrofuran (30.0 mL) were added sodium hydride (60% in mineral oil, 1.5 g, 38 mmol) and
triisopropylsilyl chloride (8.0 mL, 38 mmol) under an atmosphere of nitrogen. The reaction was
stirred for 2 hours at room temperature. The reaction was poured into water and extracted with
ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and
filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting
with 10 % ethyl acetate in hexane to give compound (47, 3.0 g, 36%). MS(ESI)[M+H"T = 303.
[01111 1 -(tert-Butyl-dimethyl-silanyl)-3-iodo-lH-pyrrolo[2,3-b]pyridine 66

was prepared following the protocol of Scheme 20 Step 2, substituting lH-Pyrrolo[2,3-b]pyridine-
3-carbaldehyde 46 with 3-iodo-lH-pyrrolo[2,3-b]pyridine and triisopropylsilyl chloride with tert-
Butyl-dimethyl-silyl chloride.

[0112} l-Benzenesulfonyl-lH-pyrrolo[2,3-b]pyridine-3-carbaldehyde 55

was prepared following the protocol of Scheme 20, substituting triisopropylsilyl chloride with
benzenesulfonyl chloride in Step 2.
Example 3: Synthesis of 5 substituted 7-azaindole intermediates
[0113] 5-(2-Morpholin-4-yl-ethoxy)-lH-pyrrolo[2,3-b]pyridine 79 was synthesized in 1 Step
from commercially available 5-bromo-azaindole as shown in Scheme 31.

Step 1 - 5-(2-Morpholin-4-yl-ethoxy)-lH-pyrrolo[2,3-b]pyridine (79):
[0114J To 4-morpholineethanol (30 mL, 0.2 mol) in N, N-dimethylformamide (30 mL) was
slowly added sodium hydride (7 g, 60% dispersion in mineral oil, 0.2 mol). After the solution
turned clear, a solution of S-bromo-7-azaindole (44, 1.0 g, 0.OOS1 mol) in N,N-dimethylformamide
(5 mL) and copper(I) bromide (1.4 g, 0.0098 mol) were added. The reaction mixture was stirred at
120 °C under nitrogen for 2 hours. The reaction mixture was concentrated and the residue was
dissolved in ethyl acetate and water. The organic layer was collected, washed with a solution of
ammonium chloride and ammonium hydroxide (4:1), brine, and dried over magnesium sulfate.
After removal of solvent, the residue was purified by silica gel column chromatography eluting
with ethyl acetate in hexane to provide the compound as an off-white solid (79, 0.62 g, 50%). MS
(ESI) [M+HT = 248.25.
[0115] Additional 5-substituted 7-azaindoles were prepared following the protocol of Scheme
31, replacing 4-morpholineethanol with either 2-diethylamino-ethanol, 3-diethylamino-propan-l-
ol, 2-piperidin-l-yl-ethanol, or 2-pyrrolidin-l-yl-ethanol to provide diethyl-[2-(lH-pyrrolo[2,3-

b]pyridin-5-yloxy)-ethyl]-amine, Diethyl-[3-(lH-pyrrolo[2,3-b]pyridin-5-yloxy)-propyl]-amine, 5-
(2-piperidin-1 -yl-ethoxy)-1 H-pyrrolo[2,3-b]pyridine, and 5-(2-pyrrolidin-1 -yl-ethoxy)-1H-
pyrrolo[2,3-b]pyridine, respectively.
Example 4: Synthesis of 3,5-Dimethyl-4-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-
l-carboxylic acid benzylamide P-0084
[0116] 3,5-Dimethyl-4-(l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-l-carboxylic acid
benzylamide P-0084 was synthesized in 6 steps from dimethyl-(lH-pyrrolo[2,3-b]pyridin-3-
ylmethyl)-amine 2 as shown in Scheme 158.

Step 1: Preparation of3-Dimethylaminomethyl-pyrrolo[2,i-b]pyridine-l-carboxylic acid tert-
butyl ester (511)
10117] To dimethyl-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-amine (2, 2.50 g, 14.3 mmol,) in
tetrahydroruran (200.0 mL) was added sodium hydride (0.685 g, 60% in mineral oil, 17.1 mmol).
After 10 minutes, dwert-butyldicarbonate (3.74 g, 17.1 mmol) was added to the reaction. The
reaction was stirred at room temperature overnight. The reaction was poured into water and
extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and
filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting
with 30% ethyl acetate in hexane to give as a white solid (511, 3.80 g, 96.7%).
Step 2: Preparation of3-Chloromethyl-pyrrolo[2,3-b]pyridine-l-carboxylic acid tert-butyl ester
(512)
[0118) To 3-dimethylaminomethyl-pyrrolo[2,3-b]pyridine-l-carboxylic acid tert-butyl ester
(511,2.60 g, 9.44 mmol) in toluene (50.00 mL) was added isopropyl chloroformate (11.3 mL, 1.0
M in toluene) under an atmosphere of nitrogen. The reaction was stirred at room temperature for 3


hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was
dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by
silica gel column chromatography ehiting with 20% ethyl acetate in hexane to give a white solid
(512, 2.0 g, 79.4%).
Step 3 - Preparation of3-(2-Acetyl-3-oxo-butyl)-pyrrolo[2,3-b]pyridine-l-carboxylic add ten-
butyl ester (513):
[0119] To acetylacetone (0.563 g, 5.62 mmol) in dimethyl sulfoxide (29.0 mL) was added
sodium hydride (0.225 g, 60% in mineral oil, 5.62 mmol). After 20 minutes, 3-chloromethyl-
pyrrolo[2,3-b]pyridine-l-carboxylic acid tert-butyl ester (512, 1.00 g, 3.75 mmol) was added to
the reaction. The reaction was stirred at room temperature for 2 hours. The reaction was poured
into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium
sulfate and filtered. The filtrate was concentrated and purified by silica gel column
chromatography eluting with 40% ethyl acetate in hexane to give a colorless oil (513, 0.59 g,
48.0%). MS (ESI) [M+HT= 331.4.
Step 4 - Preparation of3-(3,5-Dimethyl-lH-pyrazol-4-ylmethyl)-pyrrolo[2,3-b]pyridine-J-
carboxylic acid tert-butyl ester (514)
[0120] To 3-(2-acetyl-3-oxo-butyl)-pyrrolo[2,3-b]pyridine-l-carboxylic acid tert-butyl ester
(513, 1.20 g, 3.63 mmol) in methanol (15.0 mL), cooled to -20 °C under an atmosphere of
nitrogen, was added hydrazine (0.128 g, 4.00 mmol) in dichloromethane (6.0 mL). The reaction
was stirred for 2 hours. The reaction was concentrated to remove the solvents, and the residue was
poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous
sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column
chromatography eluting with 60% ethyl acetate in hexane to give a white solid (514, 1.0 g, 84.4%).
MS (ESI) [M+HT= 327.4.
Step 5 - Preparation of3-(l-Benzylcarbamoyl-3,5-dimethyl-lH-pyrazol-4-ylmethyl)-pyrrolo[2,3-
b]pyridine-l-carboxylic acid tert-butyl ester (515)
[0121J To 3-(3,5-dimethyl-lH-pyrazol-4-ylmethyl)-pyrrolo[2,3-b]pyridine-l-carboxylic acid
tert-butyl ester (514, 60.0 mg, 0.18 mmol) in dichloromethane (6.0 mL) were added 1,8-
diazabicyclo[5.4.0]undec-7-ene (0.033 mL, 0.220 mmol) and benzyl isocyanate (29.4 mg, 0.220
mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature for 2 hours.
The reaction was concentrated and purified by silica gel column chromatography eluting with 30%
ethyl acetate in hexane to give crude compound (515, approx. 50 mg) that was used in the next
step directly. MS (ESI) [M+H+]4 = 460.5.


Step 6 - 3.5-Dimeihyl-4-(lH-pyrrob[2,3-b]pyridin-3-ylmethyl)-pyrazole-I-carboxylic acid
benzylamide (P-0084)
[0122] To 3-( 1 -benzylcarbamoyl-3,5-dimethyl-l H-pyrazol-4-ylmethyl)-pyrrolo[2,3-b]pyridine-
1-carboxylic acid ten-butyl ester (515, 50.0 mg, 0.11 mmol) in dichloromethane (6.0 mL) was
added trifluoroacetic acid (0.20 mL, 2.6 mmol) under an atmosphere of nitrogen. The reaction was
stirred at room temperature for 20 minutes. The reaction was poured into aqueous potassium
carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium
sulfate and filtered. The filtrate was concentrated and purified by silica gel column
chromatography eluting with 30% ethyl acetate in hexane to give a white solid (P-0084, 11.0 mg,
28.1%). MS (ESI) [M+HY = 360.5.
|0123| 3-(3,5-Dimethyl-1 H-pyrazol-4-ylmethyl)-pyrrolo[2,3-b]pyridine P-0124
i
was prepared from 3-(3,5-Dimethyl-lH-pyrazol-4-ylmethyl)-pyrrolo[2,3-b]pyridine-l-carboxylic
acid tert-butyl ester (514, 15.0 mg, 0.046 mmol) by dissolving in dichloromethane (10.0 mL) to
which trifluoroacetic acid (0.10 mL, 1.3 mmol) was added. The reaction was stirred at room
temperature for 1 hour, then poured into aqueous potassium carbonate and extracted with ethyl
acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was
concentrated and washed with ethyl acetate in hexane to give an off-white solid (P-0124, 7.5 mg,
72.0%). MS (ESI) [M+H+]+ = 227.3.
[0124] Additional compounds were prepared following the protocol of Scheme 158, replacing
dimethyl-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-arnine 2 with (5-chloro-lH-pyrrolo[2,3-
b]pyridin-3-yImethyl)-dimethyl-amine (prepared as described in Example 10, Scheme 164,
isolated after step 1) in Step 1 and replacing benzyl isocyanate with an appropriate electrophile in
Step 5. The following compounds were made following this procedure:
4-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-3,5-dimethyl-pyrazole-l-carboxylic
acid [2-(4-fluoro-phenyl)-ethyl]-amide (P-0157),
4-(5-Chloro-lH-pytTolo[2,3-b]pyridin-3-ylmethyl)-3,5-dimethyl-pyrazoIe-I-carboxylic
acid 4-fluoro-benzylamide (P-0158),
4-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-3,5-dimethyl-pyrazole-l-carboxylic
acid 4-chloro-benzylamide (P-0159), and




Step 1 - Preparation of4-chloro-2-[(pyridin-4-ylmethyl)-amino]-thiazole-5-carbaldehyde (517):
[0127) To a solution of 4-(aminomethyl)pyridine (516, 1.16 mL, 11.5 mmol) and N,N-
diisopropylethylamine (3.8 mL, 22 mmol) in tetrahydrofuran (50 mL) was added 2,4-dichloro-
thiazole-5-carbaldehyde (93, 2.0 g, 11.0 mmol) in tetrahydrofuran (5 mL) at room temperature.
The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured
into ice water, extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. The
crude compound 4-chloro-2-[(pyridin-4-ylmethyl)-amino]-thiazole-5-carbaldehyde (517) was used
for the next step without purification.
Step 2 - Preparation of(4-chloro-5-formyl-thiazol-2-yl)-pyridin-4-ylmethyl-carbamic acid tert-
butyl ester (518):
[0128] A mixture of 4-chloro-2-[(pyridin-4-ylmethyl)-amino]-thiazole-5-carbaldehyde (517,
3.28 g, 11.0 mmol), di-tert-butyldicarbonate (4.0 g, 18 mol) and triethylamine (10 mL, 74 mmol)
in dichloromelhane (120 mL) was stirred at room temperature for 6 hours. The reaction mixture
was poured into ice water, extracted with ethyl acetate, washed with brine, and dried over sodium
sulfate. After removal of solvent, the residue was purified by silica gel column chromatography
eluting with ethyl acetate in hexanes to provide the desired compound as a yellow solid (518, 564
mg, 15%). MS (ESI) [M+HT= 354.1.
Step 3 - Preparation of{4-chloro-5-[hydroxy-(l-triisopropylsilanyl-lH-pyrrolo[2,3-b]pyridm-3-
yl)-methyl]-thiazol-2-yl}-pyridin-4-ylmethyl-carbamic acid tert-butyl ester (519):
|0129] To a solution of 3-iodo-l-triisopropylsilanyl-lH-pyrrolo[2,3-b]pyridine (96, 0.44 g, 1.1
mmol) in tetrahydrofuran (20 mL) at -20 °C, isopropylmagnesium chloride (2 M in
tetrahydrofuran, 0.6 mL, 1.2 mmol) was added drop wise. The reaction mixture was allowed to
warm to 0 °C in 10 minutes. The reaction mixture was then cooled to -40 "C. A solution of (4-

chloro-5-fonnyl-thiazol-2-yl)-pyridin-4-ylmethyl-carbamic acid tert-butyl ester (518, 0.26 g, 0.73
mmol) in tetrahydrofuran (4 mL) was added to the reaction mixture. The reaction mixture was
allowed to warm to -10 "C over 30 minutes. The reaction mixture was poured into ice water,
extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. After removal of
solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in
hexanes to provide the desired compound as a yellow solid (519, 397 mg, 86%). MS (ESI)
[M+HY = 628.3.
Step 4 - Preparation of[4-chloro-5-(lH-pyrrolo[2,3-b}pyridin-3-ylmethyl)-thiazol-2-yl]-pyridin-
4-ylmethyl-carbamic acid tert-butyl ester (520):
[0130] A mixture of {4-chloro-5-[hydroxy-(l-triisopropylsilanyMH-pyrrolo[2,3-b]pyridin-3-
yl)-methyl]-thiazol-2-yl}-pyridin-4-ylmethyl-carbamic acid tert-butyl ester (519,0.397 g, 0.57
mmol), triethylsilane (1.0 mL, 6.3 mmol), and trifluoroacetic acid (0.5 mL, 6 mmol) in acetonitrile
(10 mL) was stirred at 40 °C for 2 hours. The reaction mixture was poured into ice water,
extracted with ethyl acetate, washed with sodium bicarbonate, washed with brine, and dried over
sodium sulfate. After removal of solvent, the residue was purified by silica gel column
chromatography eluting with methanol in dichloromethane to provide the desired compound as a
yellow solid (520, 126 mg, 49%). MS (ESI) [M+H+]+= 456.2.
Step 5 - Preparation of[4-chloro-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-pyridin-
4-ylmethyl-amine (P-0168):
[0131] To a solution of [4-chloro-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-
pvridin-4-ylmethyl-carbamic acid tert-butyl ester (520, 126 mg, 0.000276 mol) in dichloromethane
(2 mL) was added hydrogen chloride (4 M in 1,4-dioxane, 2 mL). The reaction mixture was
stirred at room temperature overnight. The reaction mixture was poured into cold sodium
bicarbonate solution, extracted with ethyl acetate, washed with brine and dried over magnesium
sulfate. After removal of solvents, the residue was washed with ethyl acetate to provide the
desired compound as a light yellow solid (P-0168, 68.4 mg, 70%). MS (ESI) [M+HT = 356.2.
[0132] Additional compounds were prepared following the protocol of Scheme 159, replacing
4-(aminomethyl)pyridine 516 with an appropriate amine. The following compounds were made
following this procedure:
[4-Chloro-5-(lH-pyrrolo[2,3-A]pyridin-3-ylmethyl)-thiazol-2-yl]-pyridin-3-ylmethyl-amine
(P-0164),
t4-Chloro-5-(lH-pyrrolo[2,3-6]pyridin-3-ylmethyl)-thiazol-2-yl]-pyridin-2-ylmethyl-amine
(P-0167),
70

[4-ChIoro-5-(lH-pyrToIot2,3-iJpyridin-3-yImethyl)-thiazol-2-yl]-(6-methyl-pyridin-2-
ylmethyl)-amine (P-0171),
[4-Chloro-5-(lH-p>rrolo[2,3-fc]pyridin-3-ylmcthyl)-thiazol-2-yl]-(6-trifluoromethyl-pyridin-3-
ylmethyl)-amine (P-0173),
t4-Chloro-5-(lH-pyrrolo[2,3-fc]pyridin-3-ylmethyl)-thiazol-2-yl]-(l,5-dimethyl-lH-pyrazol-3-
ylmethyl)-amine (P-0172),
[4-Chloro-5-(lH-pyrrolo[2,3-A]pyridiii-3-ylmethyl)-thiazol-2-yl]-(2,5-dimethyl-2H-pyra2ol-3-
ylmethyl)-amine (P-0175), and
[4-Chloro-5-(lH-pyn-olo[2,3-A]pyridin-3-ylmethyl)-thia2ol-2-yl]-(4-fluoro-benzyl)-amine(P-
0156).
The following table indicates the amine (Column 2) used in Scheme 159 to provide the compounds
(Column 3). Column 1 provides the compound number and Column 4 the observed mass.


Example 6: Synthesis of I4-cthyl-5-(lH-pyrrolo(2,3-b]pyridin-3-ylmethyl)-tniazoI-2-yl|-(4-
f1uoro-benzyl)-amine P-0162 and (4-fluoro-benzyl)-[4-methyl-5-(lH-pyrrolo|2r3-b|pyridin-3-
ylmethyI)-thiazol-2-yl]-amine P-0162
[0133] [4-Ethyl-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyI)-amine
P-0162 was synthesized in 1 step from [4-chloro-5-(lH-pyrrolo[2, 3-b] pyridin-3-ylmethyI)-
thiazol-2-yl]-(4-fluoro-benzyl)-amine P-0156 as shown in Scheme 160.

Step 1 - Preparation of[4-ethyl-5-(}H-pyrrolo[2,3-b]pyridin~3-ylmethyl)-thiazol-2-yl]-(4-fluoro-
benzyl)-amine (P-0162):
(0134] Into a round bottom flask, under an atmosphere of nitrogen, [1 ,l'-bis(diphenyl phosphino)
ferrocene] dichloro palladium (II), complex with dichlororoethane (1:1), was placed with toluene
(15 mL, 140 mmol). [4-Chloro-5-(lH-pyrrolo[2,3-b] pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-
benzyl)-amine (P-0156,145 mg, 0.4 mmol) was added in 5 ml of toluene at room temperature.
The mixture was stirred for 10 minutes. To the stirring reaction, a solution of 3.13 M ethyl
magnesium bromide in ether (1.86 mL) was added dropwise at room temperature. The opaque
solution was heated to 60 "C. Tetrahydrofuran (10 mL) was added to the warm solution. The
mixture was heated to reflux for an additional two hours. After cooling to 0 "C, the reaction was
quenched with a solution of citric acid at pH 4-5 in ice-water and stirred to room temperature. The
mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate and brine.
The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under
reduced pressure. Purification with flash chromatography, eluting with a gradient of ethyl
acetate:hexanes (20:100), gave a yellow solid that was further washed with ethyl acetate to give P-
0162 (15 mg,10%) as an off-white solid. MS (ESI) [M+HT= 367.2.
|0135J (4-Fluoro-benzyl)-[4-methyl-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-
amineP-0163


was prepared using the protocol of Scheme 160, substituting the 3.13 M ethyl magnesium bromide
in ether solution with 1.4 M of methylmagnesium bromide in tetrahydrofuran. MS (ESI) [M+H*]*
= 353.2.
Example 7: Synthesis of (4-Chloro-benzyl)-(6-(lH-pyrrolo|2,3-b]pyridin-3-ylniethyl)-
pyridazin-3-yl]-amine P-0092
10136] (4-Chloro-benzyl)-[6-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyi)-pyridazin-3-yl]-amineP-
0092 was synthesized in 3 steps as shown in Scheme 161.

Step I - Synthesis af(6-bramo-pyridazin-3-yl)-(4-chloro-benzyl)-amine (522):
|0137] To 6-bromo-pyridazin-3-ylamine (521,0.85 g, 0.0049 mol) in acetonitrile (30.0 mL) were
added 4-chlorobenzaldehyde (40,0.82 g, 0.0058 mol), triethylsilane (4.0 mL, 0.025 mol) and
trifluoroacetic acid (2.0 mL, 0.026 mol). The reaction was heated to reflux for 4 hours, then
poured into water, and extracted with ethyl acetate. The organic layer was washed with brine,
dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and washed with
ethyl acetate to give a white solid (522, 1.0 g). MS (ESI) [M+HT= 298.3, 300.2.
Step 2 - Preparation of3-[6-(4-chloro-benzylamino)-pyridazin-3-ylmethyl]-pyrrolo[2,3-
bjpyridine-l-carboxylic acid tert-butyl ester (523):

[0138] To (6-bromo-pyridazin-3-yl)-(4-chloro-benzyl)-aniine (522, 0.560 g, 1.88 mmol) in
tetrahydrofuran (45.0 mL), under an atmosphere of nitrogen at -78 °C, was added n-butyllithium
(2.50 M in hexane, 0.760 mL) slowly. After 10 minutes, l,2-bis-(chloro-dimethyl-silanyl)-ethane
(0.201 g, 0.94 mmol) in tetrahydrofuran (5.0 mL) was added to the reaction. The reaction mixture
was allowed to stir at room temperature for 3 hours. The reaction was cooled to -78 °C, followed
by addition of 1.70 M of tert-butyllithium in hexane (1.20 mL) slowly. The reaction was stirred
for 20 minutes, followed by addition of a solution of CuCN.2LiCl (0.6 M in tetrahydrofuran, 3.00
mL) and 3-chloromethyl-pyrrolo[2,3-b]pyridine-l-carboxylic acid tert-butyl ester (512, 0.47 g, 1.8
mol) in tetrahydrofuran (10.0 mL). After 30 minutes, the reaction was allowed to warm to room
temperature for 10 minutes. The reaction was poured into water and extracted with ethyl acetate.
The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was treated
with trifluoroacetic acid (1.0 mL) dissolved in dichloromethane (10.0 mL) for 10 minutes. The
reaction was concentrated, poured into aqueous potassium carbonate and extracted with ethyl
acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was
concentrated and purified with silica gel column chromatography eluting with 60% ethyl acetate in
hexane to give the desired compound (523,0.10 g, 23.8%). MS (ESI) [M+H*]* = 450.1.
Step 3 - Preparation of(4-chloro-benzyl)-[6-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridazin-3-
ylj-amine (P-0092):
|0139] To 3'[6-(4-chloro-benzylamino)-pyridazin-3-ylmethyl]-pyrrolo[2,3-b]pyridine-1 -
carboxylic acid tert-butyl ester (523, 50.0 mg, 0.111 mmol) in dichloromethane (10.0 mL) was
added trifluoroacetic acid (0.30 mL, 0.0039 mol). The reaction was stirred at room temperature
overnight. The reaction was concentrated, poured into aqueous potassium carbonate and extracted
with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The
filtrate was concentrated and washed with ethyl acetate and hexane to give an off-white solid (P-
0092, 7.3 mg, 19.0%). MS (ESI) [M+HT = 350.1.
Example 8: Synthesis of |l-ethyl-5-(lH-pyrrolo|2,3-b]pyridin-3-ylmethyI)-lH-pyrazol-3-yl]-
(4-fluoro-benzyl)-amine P-0165
|0140] [l-Ethyl-5-(lH-pyrrolo[2,3-b]pyridin-3-yImethyl)-lH-pyrazol-3-yl]-(4-fluoro-bcnzyl)-
amine P-0165 was synthesized in 7 steps as shown in Scheme 162.


Step 1 - Preparation ofS-nitro-2H-pyrazole-3-carboxylic acid methyl ester (525):
[0141) To 5-nitro-2H-pyrazole-3-carboxylic acid (524, 10.0 g, 0.0637 mol) in methanol (100.0
mL) was added concentrated sulfuric acid (1.00 mL, 0.0180 mol). The reaction was stirred at
room temperature overnight. The reaction was poured into aqueous potassium carbonate and
extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and
filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting
with 20% ethyl acetate in hexane to give a white solid (525, 1.5 g, 13.8%).
Step 2 — Preparation of2-ethyl-5-nitro-2H-pyrazole-3-carboxylic acid methyl ester (526):
[0142J To 5-nitro-2H-pyrazole-3-carboxylic acid methyl ester (525, 2.50 g, 0.0146 mol) in N,N-
dimethylformamide (62.5 mL) were added iodoethane (1.2 mL, 0.016 mol) and potassium
carbonate (4.17 g, 0.0301 mol) under an atmosphere of nitrogen. The reaction was stirred at room
temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The
organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated
and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in
hexane to give a white solid (526, 1.3 g, 44.7%).
Step 3 - Preparation ofS-amino-2-ethyl-2H-pyrazole-3-carboxylic acid methyl ester (527):

[0143] To 2-ethyl-5-nitro-2H-pyrazole-3-carboxylic acid methyl ester (526,1.30 g, 6.53 mmol)
in methanol (60.0 mL) was added 20% Pd(OH)2/C (0.1 g). The reaction was stirred under an
atmosphere of hydrogen overnight. The reaction was filtered and concentrated to give a light
yellow solid (527, 1.0 g, 90.6%).
Step 4 - Preparation of2-ethyl-5-(4-fluoro-benzylamino)-2H-pyrazole-3-carboxylic acid methyl
ester (529):
[0144J To 5-amino-2-ethyl-2H-pyrazoIe-3-carboxylic acid methyl ester (527,1.00 g, 5.91 mmol)
in acetonitrile (27.5 mL) were added 4-fluorobenzaldehyde (528,0.660 mL, 6.26 mmol),
triethylsilane (4.77 mL, 0.0298 mol) and trifluoroacetic acid (2.38 mL, 0.0310 mol). The reaction
was stirred at 80 °C for 4 hours, then concentrated, poured into aqueous potassium carbonate, and
extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and
filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting
with 20% to 100% ethyl acetate in hexane to give a white solid (529, 1.00 g, 61%).
Step 5 - Preparation of2-ethyl-5-(4-fluoro-benzylamino)-2H-pyrazole-3-carbaldehyde (S30):
[0145] To 2-ethyl-5-(4-fluoro-benzylamino)-2H-pyrazole-3-carboxylic acid methyl ester (529,
1.00 g, 3.61 mol) in tetrahydroruran (70.0 mL) under an atmosphere of nitrogen at room
temperature, lithium tetrahydroaluminate (1.00 M of in tetrahydroruran, 10.00 mL) was slowly
added. The reaction was stirred at room temperature overnight, followed by slowly adding sodium
sulfate decahydrate (15.0 g). After 2 hours, the reaction was filtered, concentrated and purified
with silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a
yellow oil (530,0.16 g, 18%). MS (ESI) [M+H*]+= 248.2.
Step 6- Preparation ofl-ethyl-5-[methoxy-(lH-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-lH-pyrazol-
3-yl-(4-fluoro-benzyl)-amine (531):
[0146] To lH-Pyrrolo[2,3-b]pyridine (1, 54.0 mg, 0.46 mmol) in methanol (15.0 mL) were
added 2-ethyl-5-(4-fluoro-benzylarnino)-2H-pyrazole-3-carbaldehyde (530, 110.0 mg, 0.44 mmol)
and potassium hydroxide (0.60 g, 0.011 mol) under an atmosphere of nitrogen. The reaction was
stirred at room temperature overnight, then poured into water and extracted with ethyl acetate.
The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was
concentrated and purified by silica gel column chromatography eluting with 40% ethyl acetate in
hexane to give a white solid (531, 0.12 g, 71.1%). MS (ESI) [M-H*]- = 378.2.
Step 7 - Preparation of[l-ethyl-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-lH-pyrazol-3-yl]-(4-
fluoro-benzyl)-amine (P-0165):

I0147J Tol-ethyl-5-[methoxy-(lH-pyrrolo[2,3-b]pyridin-3.yl)-methyl]-lH-pyrazol-3-yl-(4-
fluoro-benzyl)-amine (531,0.12 g, 0.32 mmol) in acetonitrile (10.0 mL, 0.191 mol) were added
tricthylsilane (0.60 mL, 0.0038 mol) and trifluoroacetic acid (0.30 mL, 0.0039 mol). The reaction
was stirred at 80 °C for 2 hours. The reaction was poured into aqueous potassium carbonate and
extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and
filtered. The filtrate was concentrated and washed with ethyl acetate and hexane to give crude
compound. 'H NMR indicated that the reaction was incomplete. The crude compound was
dissolved in dichloromethane (15.0 mL), trifluoroacetic acid (0.30 mL) and triethylsilane (0.60
mL). The reaction was stirred at 43 °C for 72 hours. The reaction was concentrated, poured into
aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over
anhydrous sodium sulfate and filtered. The filtrate was concentrated and washed with ethyl
acetate and hexane to give an off-white solid (P-0165, 18.7 mg, 17%). MS (ESI) [M+HT =
350.3.
[0148] (4-Fluoro-benzyI)-[ 1 -methyl-5-( 1 H-pyrTolo[2,3-b]pyridin-3-ylmethyl> 1 H-pyrazol-3-yl]-
amine P-0169

was prepared using the protocol of Scheme 162, substituting iodoethane with iodomethanc in Step
2. MS (ESI) [M+HT = 336.3.
|0149] [5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-l-methyl-lH-pyrazol-3-yl]-(4-fluoro-
benzyl)-amine P-0170

was prepared using the protocol of Scheme 162, substituting iodoethane with iodomethane in step
2 and lH-pyrrolo[2,3-b]pvridine 1 with 5-chloro-lH-pyrrolo[2,3-b]pyridine in step 6. MS (ESI)
[M+HT = 370.3
10150) (4-Fluoro-benzyl)-{l-methyl-5-[5-(l-methyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-
3-ylmethyl]-1 H-pyrazol-3-yl} -amine P-0180


was prepared using the protocol of Scheme 162, substituting iodocthane with iodomethane in step
2 and 1 H-Pyrrolo[2,3-b]pyridine 1 with 5-(l -Methyl- lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridine
(prepared as described in Example 18, Scheme 172) in step 6. MS (ESI) [M+HT = 416.2.
[0151] 3-[5-(4-Fluoro-benzylamino)-2-methyl-2H-pyrazol-3-ylmethyl]-lH-pyrrolo[2,3-
b]pyridine-5-carbonitrile P-0191

was prepared using the protocol of Scheme 162, substituting lH-Pyrrolo[2,3-b]pyridine 1 with 1H-
Pyrrolo[2,3-b]pyridine-5-carbonitrile in Step 6. MS (ESI) [M+H+]+ = 361.5.
Example 9: Synthesis of [4-chloro-l-ethyl-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-lH-
pyrazol-3-yl]-[l-(4-fluoro-phenyl)-meth-(E)-yUdene]-ainine P-0166
[0152J [4-chloro-l-ethyl-5-(lH-pyrrolo[2,3-b]pyridin-3-ylinethyl)-lH-pyrazol-3-yl]-[l-(4-
fluoro-phenyl)-meth-(E)-ylidene]-amine P-0166 was synthesized in 1 step as shown in Scheme
163.

Step 1 - Preparation of[4-chloro-l-ethyl-5-(lH-pyrrolo[2.3-b]pyridin-3-ylmethyl)-lH-pyrazol-3-
yl]-[l-(4-fluoro-phenyl)-meth-(E)-ylidene]-amine (P-0166):
[0153J To[l-ethyl-5-(lH-pyn-olo[2,3-b]pyridin-3-ylmethyl)-lH-pyrazol-3-yl]-(4-fluoro-benzyl)-
amine (P-0165,10.1 mg, 0.0289 mmol, prepared as described in Example 8, Scheme 162) in
acetonitrile (8.0 mL) was added N-chloro-succinimide (4.18 mg, 0.0318 mmol). The reaction was
stirred at room temperature for 2 hours. The reaction was concentrated and purified by silica gel

column chromatography cluting with 20% to 100% ethyl acetate in hexane to give a white solid
(P-0166, 1.1 ing). MS (ESI) [M+HT]* = 382.1.
Example 10: Synthesis of 5-chloro-3-chloroinethyl-pyrrolo(2,3-b]pyridine-l-carboxyIic acid
tert-butyl ester
[0154] 5-chloro-3-chloromethyl-pyrrolo[2,3-b]pyridine-l -carboxylic acid tert-butyl ester was
synthesized in 3 steps as shown in Scheme 164.
Scheme 164
/ /
Step 1 - Preparation of(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-dimethyl-amine (533):
[0155] To 5-Chloro-lH-pyrrolo[2,3-b]pyridine (532, 8.00 g, 0.0524 mol) in isopropyl alcohol
(250.0 mL) were added dimethylamine hydrochloride (4.79 g, 0.0587 mol) and formaldehyde
(1.77 g, 0.0589 mol). The reaction was stirred at room temperature overnight, followed by
refluxing for 4 hours. The reaction was concentrated, poured into water, and extracted with ethyl
acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was
concentrated to give crude compound (533, 10.0 g, 91%), that was used directly in the next step.
Step 2 and 3 - Preparation of 5-chloro-3-chloromethyl-pyrrolo[2,3-b]pyridine-l-carboxylic acid
tert-butyl ester (535):
(0156) 5-Chloro-3-chloromethyl-pynolo[2,3-b]pyridine-l -carboxylic acid tert-butyl ester 535
was prepared following the protocol of Scheme 158 (Example 4) steps 1 and 2, substituting
dimethyl-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-amine 2 with (5-chloro-lH-pyrrolo[2,3-
b]pyridin-3-yImethyl)-dimethyl-amine 533 in step 1.
Example 11: Synthesis of (4-chloro-benzyl)-[5-(5-chloro-lH-pyrrolo[2^-b]p>Tidin-3-
ylmethyl)-6-nuoro-pyridin-2-yll-amincP-0132
[0157J (4-Chloro-benzyl)-[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-
yl]-amine P-0132 was synthesized in 3 steps as shown in Scheme 165.
Scheme 165


Step I - Preparation of(4-chloro-benzyl)-(6-fluoro-pyridin-2-yl)-amine (536):
[0158] To 2,6-difluoropyridine (58, 9.85 g, 0.0856 mol) in N-methylpyrroIidinone (50.0 mL)
were added p-chlorobenzylamine (61,10.5 mL, 8.63 mmol) and N,N-diisopropylethy]amine (30.0
mL, 0.172 mol). The reaction was stirred at 90 °C overnight. The reaction was poured into water
and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and
filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting
with 25% ethyl acetate in hexane, then washed with ethyl acetate/hexane to give a white solid
(536, 10 g, 50%).
Step 2 - Preparation of(5-bromo-6-Jluoro-pyridin-2-yl)-(4-chloro-benzyl)-amine (537):
[0159] To (4-chloro-benzyl)-(6-fluoro-pyridin-2-yl)-amine (536, 1.03 g, 4.35 mmol) in
acetonitrile (30.0 mL), under an atmosphere of nitrogen, N-bromosuccinimide (0.820 g, 4.61 mol)
was added slowly. After 2 hours, the reaction was poured into a solution of sodium thiosulfate and
extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated and
crytstallized with ethyl acetate and hexane to give a white solid (537, 1.10 g, 80.1 %).
Step 3 - Preparation of(4-chloro-benzyl)-[5-(5-chloro-IH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-
fluoro-pyridin-2-yl]-amine(P-0132):
[0160) To (5-bromo-6-fluoro-pyridin-2-yl)- tetrahydrofuran (90.0 mL), under an atmosphere of nitrogen at -78 °C, n-butyllithium (2.50 M in
hexane, 3.64 mL) was added slowly. After 60 minutes, l,2-bis-(chloro-dimethyl-silanyl)-ethane
(0.942 g, 4.38 mol) in tetrahydrofiiran (8.0 mL) was added to the reaction. The reaction mixture
was allowed to stir at room temperature for 2 hours. The reaction was cooled to -78 °C, followed
by addition of tert-butyllithium (1.70 M in hexane, 10.50 mL). The reaction was stirred for 30

minutes, followed by addition of 0.65 M of CuCN.2LiCl in tetrahydrofuran (14.0 mL). The
reaction was stirred at -35 °C for 10 minutes, followed by addition of 5-chloro-3-chloromethyl-
pyrrolo[2,3-b]pyridine-l-carboxylic acid tert-butyl ester (535, 1.70 g, 5.64 mol, prepared as
described in Example 10, Scheme 164) in tetrahydrofuran (10.0 mL). The reaction was allowed to
warm to room temperature for 1 hour and 2 N HC1 (30 mL) was added to the reaction mixture,
then stirred for 30 minutes. The reaction was poured into aqueous ammonia and extracted with
ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The Filtrate
was concentrated and purified with silica gel column chromatography eluting with 30% ethyl
acetate in hexane to give the desired compound (P-0132,0.75 g, 33.1%). MS (ESI) [M+H*]* =
401.1.
Example 12: Synthesis of 5-chloro-3-(2,6-difluoro-pyridin-3-yIniethy])-lH-pyrrolo[2,3-
b]pyridine P-0155
[0161) 5-Chloro-3-(2,6-difluoro-pyridin-3-ylmethyl)-lH-pyrrDlo[2,3-b]pyridine P-0155 was
synthesized in 1 step as shown in Scheme 166.
Scheme 166

Step 1 - Preparation of5-chloro-3-(2,6-di/Iuoro-pyridin-3-ylmethyl)-lH-pyrroIof2,3-b]pyridine
(P-0155):
[0162] To 2,6-Difluoropyridine (58, 3.40 g, 0.0295 mol) in telrahydrofuran (200.0 mL), under an
atmosphere of nitrogen at -78 °C, 2.50 M of n-butyllithium in hexane (12.0 mL) was added slowly.
After 60 minutes, CuCN.2LiCl (0.75 M in tetrahydrofuran, 40.0 mL) was added to the reaction
mixture. After 5 minutes, 5-chloro-3-chloromethyI-pyrrolot2,3-b]pyridine-l-carboxylic acid tert-
butyl ester (535,4.20 g, 0.0139 mol, prepared as described in Example 10, Scheme 164) in
tetrahydrofuran (20 mL) was added to the reaction. The reaction was stin-ed at -78 °C overnight,
then poured into water and ammonia (10 mL), and extracted with ethyl acetate. The organic layer
was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified
by silica gel column chromatography eluting with 15% ethyl acetate in hexane to give a white
solid (P-0155, 300 mg, 7.7%). MS (ESI) [M-H*]' = 278.1.

Example 13: Synthesis of 3-(2,6-difluoro-pyridin-3-ylmethyl)-lH-pyrrolo[2,3-b]p>ridine P-
01S4
[0163] 3-(2,6-difluoro-pyridin-3-ylmethyl)-lH-pyrro!o[2,3-b]pyridine P-0154 was synthesized
in 1 step as shown in Scheme 167.

Step 1 - Preparation of3-(2,6-difluoro-pyridin-3-ylmethyl)-lH-pyrrolo[2,3-b]pyridine (P-0154):
[0164] To 3-(2,6-difluoro-pyridin-3-ylniethyl)-pyrrolo[2,3-b]pyridine-l-carboxylic acid tert-
butyl ester (536, 0.35 g, 1.0 mmol, prepared as described in Example 10, Scheme 164, replacing 5-
chloro-lH-pyrrolo[2,3-b]pyridine532 with 1 H-pyrroIo[2,3-b]pyridine in step 1) in N-
methylpyrrolidinone (3.00 mL) were added p-chlorobenzylamine (0.20 mL, 1.6 mmol) and N,N-
diisopropylethylamine (0.30 mL, 0.0017 mol). The reaction was stirred at 50 °C for 72 hours. The
reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over
anhydrous sodium sulfate and filtered. The filtrate was concentrated and the crude intermediate
was dissolve in dichloromethane (15.0 mL) and trifluoroacetic acid (0.5 mL). The reaction was
stirred at room temperature for 2 hours, then concentrated, poured into aqueous potassium
carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium
sulfate and filtered. The filtrate was concentrated and purified by silica gel column
chromatography eluting with 35% ethyl acetate in hexane to give a white solid (P-0154,0.18 g,
72%). MS (ESI) [M+HT = 246.2.
Example 14: Synthesis of 5-((lH-pyrrolo[2,3-bIpyridin-3-yl)methyl)-N-(4-chlorobenzyl)-6-
cbloropyridin-2-amine P-0161
[0165] 5-(( 1 H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-N-(4-chlorobenzyl)-6-chloropyridin-2-amine
P-0161 was synthesized in 6 steps as shown in Scheme 168.
Scheme 168

o

Step 1 - Preparation of(4~chloro-benzyl)-(6-chloro-pyridin-2-yl)-amine (538):
[0166] To 6-chloro-pyridin-2-ylamine (537, 5.60 g, 0.0436 mol) in acetonitrile (300 mL) were
added 4-chlorobenzaldehyde (40, 6.7 g, 0.048 mol), trifluoroacetic acid (13 mL, 0.17 mol) and
triethylsilane (21 mL, 0.13 mol). The reaction was heated to reflux for 4 hours, then concentrated,
poured into water, extracted with ethyl acetate, and washed with sodium bicarbonate and brine.
The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The filtrate
was purified with silica gel column chromatography eluting with 20% to 100% ethyl acetate in
hexane to give a white solid (538, 6.5 g, 59%). MS (ESI) [M+HT = 255.1.
Step 2 - Preparation of(5-bromo-6-chloro-pyridin-2-yl)-(4-chloro-benzyl)-amine (539):
[0167J To (4-chloro-benzyI)-(6-chloro-pyridin-2-yl)-amine (538,4.00 g, 0.0158 mol) in
acetonitrile (66.7 mL, 1.28 mol) under an atmosphere of nitrogen, N-bromosuccinimide (2.81 g,
0.0158 mol) in acetonitrile (20 mL) was added slowly. The reaction was stirred at room
temperature overnight, then poured into water and extracted with ethyl acetate. The organic layer
was dried over sodium sulfate, concentrated and crystallized with ethyl acetate in hexane to give a
white solid (539, 2.60 g, 95.3%).
Step 3 - Preparation of2-chloro-6-(4-chloro-benzylamino)-pyridine-3-carbaldehyde (540):
[0168} T° (5-bromo-6-chloro-pyridin-2-yl)-(4-chloro-benzyl)-amine (539, 2.60 g, 7.83 mmol) in
tetrahydroruran (60.0 mL) under an atmosphere of nitrogen at -78 °C, isopropylmagnesium
chloride (2.00 M in tetrahydroruran, 4.20 mL) was added over 10 minutes. The reaction was
stirred at -78 °C for 20 minutes, then allowed to warm to room temperature for 10 minutes. The
reaction was cooled to -78 °C. tert-Butyllithium (1.70 M in hexane, 10.2 mL) was added to the
reaction over 10 minutes. After 40 minutes, N.N-dimethylformamide (1.80 mL, 0.0232 mol) was
added to the reaction. The reaction was stirred at -78 °C for 40 minutes, then allowed to warm to

room temperature for another 30 minutes. The reaction mixture was poured into water and
extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate,
concentrated and purified by silica gel column chromatography eluting with 35% to 100% ethyl
acetate in hexane to give a light yellow solid (540,1.0 g, 45.4%). MS (ESI) [M-FT]" = 279.0.
Step 4 - Preparation of(4-chloro-benzyl)-(6-chloro-5-formyl-pyridin-2-yl)-carbamic acid tert-
butyl ester (541):
[0169] To 2-chloro-6-(4-chloro-benzylamino)-pyridine-3-carbaldehyde (540, 0.40 g, 1.42 mmol)
in dichloromethane (10.0 mL) were added 4-dimethylaminopyridine (10.0 mg, 0.082 mmol), di-
tert-butyldicarbonate (0.693 g, 3.17 mmol) and triethylamine (0.50 mL, 0.0036 mol). The reaction
was stirred at room temperature overnight, then concentrated and purified by silica gel column
chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound
(541, 0.45 g, 83.0%).
Step 5 - Preparation of(4-chloro-benzyl)-6-chIoro-5-[hydroxy-(lH-pyrrolo[2.3-b]pyridin-3-yl)-
methylJ-pyridin-2-yl-carbamic acid tert-butyl ester (542):
[0170J To lH-Pyrrolo[2,3-b]pyridine (1, 465 mg, 3.93 mmol) in methanol (50 mL) were added
sodium hydroxide (0.630 g, 0.0157 mol) and (4-chloro-benzyl)-(6-chloro-5-formyl-pyridin-2-yl)-
carbamic acid tert-butyl ester (541, 1.5 g, 0.0039 mol). 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 sodium sulfate, concentrated and purified with silica gel column
chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound
(542, l.Og, 51%). MS (ESI) [M+HT= 499.1.
Step 6 - Preparation of5-((lH-pyrrolo[2,3-b]pyridin-3-yl)methyl)-N-(4-chlorobenzyl)-6-
chloropyridin-2-amine (P-0161):
|0171) To(4-chloro-benzyl)-6-chloro-5-[hydroxy-(lH-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-
pyridin-2-yl-carbamic acid tert-butyl ester (542, 1.00 g, 2.00 mmol) in acetonitrile (130.0 mL)
were added triethylsilane (11.5 mL, 0.0720 mol) and trifluoroacetic acid (5.5 mL, 0.071 mol). The
reaction was heated to reflux for 2 hours, then concentrated, poured into aqueous potassium
carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium
sulfate and filtered. The filtrate was concentrated and washed with ethyl acetate and hexane to
give a light yellow solid (P-0161, 480 mg, 62%). MS (ESI) [M+HT = 383.1, 385.1.
(0172] [6-Chloro-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-
pyridin-3-ylmethyl)-amine P-0174


was prepared following the protocol of Scheme 168, substituting 4-chloro-benzaldehyde 40 with
6-trifluoromethyl-pyridine-3-carbaldehyde in step 1. MS (ESI) [M+HT = 418.2.
[0173) [6-Chloro-5-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-
trifIuoromethyl-pyridin-3-ylmethyl)-amine P-0176

was prepared following the protocol of Scheme 168, substituting 4-chloro-benzaldehyde 40 with
6-trifluoromethyl-pyridine-3-carbaldehyde in step 1 and lH-Pyrrolo[2,3-b]pyridine 1 with 5-
chloro-lH-pyrrolo[2,3-b]pyridine in step 5. MS (ESI) [M+HT = 452.0.
[0174J {6-Chloro-5-[5-( 1 -methyl-1 H-pyrazol-4-yl)-1 H-pyrrolo[2,3-b]pyridin-3-yImethyl]-
pyridin-2-yl} -(6-trifluoromethyl-pyridin-3 -ylmethyl)-amine P-0179

was prepared following the protocol of Scheme 168, substituting 4-chloro-benzaldehyde 40 with
6-trifluoromethyl-pyridine-3-carbaldehyde in step 1 and lH-Pyrrolo[2,3-b]pyridine 1 with 5-(l-
Methyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridine (prepared as described in Example 18,
Scheme 172) in step 5. MS (ESI) [M+FfY = 498.0.
Example IS: Synthesis of (3-chloro-benzyl)-[5-(lH-pyrroloI2,3-bJpyridlii-3-ylmethyI)-
pyridin-2-yl]-amine P-0129
(0175] (3-Chloro-ben2yl)-t5-(lH-pyrrolot2,3-b]pyridin-3-ylmethyl)-pyridin-2-yI]-amine P-0129
was synthesized in 1 step as shown in Scheme 169.
Scheme 169


Step I - Preparation of(3-chloro-bemyl)-[S-(lH-pyrrolo[2,3-b]pyridm-3-ylmethyl)-pyridin-2-yl]-
amine (P-0129):
[01761 3-(6-bromo-pyridin-3-ylmethyl)-l-triisopropylsilanyl-lH-pyrrolo[2,3-b]pyridine (6a, 10
mg, 0.023 mmol) was combined with 3-chlorobenzyl amine (543, 13 mg, 0.093 mmol) in dioxane
(0.3 mL). Tris(dibenzylideneacetone)-dipalladium(0) (3 mg), 4,5-bis(diphenylphosphino)-9,9-
dimethylxanthene (Xantphos, 3 mg) and sodium terf-butoxide (15 mg) were added. The mixture
was heated at 100 °C overnight. Acetic acid (0.1 mL) was added and the solvents removed under
reduced pressure. The remaining residue was dissolved in DMSO and purified by reverse phase
HPLC on a YMC-Pack ODS-A C-18 column (50mm x 10mm ID), eluting with water with 0.1 %
trifluoroacetic acid and 5-40% acetonitrile with 0.1 % trifluoroacetic acid over 13 minutes at a flow
rate of 6 mL/minute to provide the desired compound P-0129. MS (ESI) [U+W]*= 349.1.
|0177] Additional compounds were prepared following the protocol of Scheme 169, replacing
3-chlorobenzyl amine 543 with an appropriate amine. The following compounds were made
following this procedure:
(4-Morpholin-4-ylmemyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-
amine (P-0093),
Pyridin-3-ylmethyl-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pvridin-2-yl]-amine(P-0094),
(5-Methyl-isoxazol-3-ylmethyl)-[5-(lH-pyrrolo[2,3-b]pyridui-3-ylmethyl)-pyridin-2-yl]-amine
(P-0095),
(2-Pyrrolidin-l-yl-ethyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pvridin-2-yl]-aminc(P-
0096),
[l-(4.Methanesulfonyl-phenyl)-ethyl]-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-
amine (P-0097),
(2-Metboxy-ethyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(P-0098),
(2-Morpholin-4-yl-ethyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(P-
0099),
((R)-l-Phenyl-ethyl)-t5-(lH-pyrrolo[2,3-b]pvridin-3-ylmethyl)-pyridin-2-yl]-amine(P-0125),
(3-Morpholin-4-yl-benzyl)-[5-( 1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-
0126),





[0180] 3-(6-Bromo-pyridin-3-yImethyl)-l-triisopropylsilanyl-lH-pyrrolo[2,3-b]pyridine (6a, 10
mg, 0.023 mmol) was combined with 3-chloro-benzamide (544,15 mg, 0.096 mmol) in dioxane
(0.4 mL). Tris(dibenzylideneacetone)-dipalladium(0) (3 mg), 4,5-bis(diphenylphosphino)-9,9-
dimethylxanthene (Xantphos, 3 mg), and sodium tert-butoxide (15 mg) were added. Cesium
carbonate (20 mg) was added and the mixture was heated at 100 °C overnight. Acetic acid (0.1
mL) was added and the solvents removed under reduced pressure. The remaining residue was
dissolved in DMSO (0.2 mL) and purified by reverse phase HPLC on a YMC-Pack ODS-A C-l 8
column (50mm x 10mm ID), eluting with water with 0.1 % trifluoroacetic acid and 5-40%
acetonitrile with 0.1 % trifluoroacetic acid over 13 minutes at a flow rate of 6 mL/minute to
provide the desired compound P-0111. MS (ESI) [M+H*]+= 363.1.
[0181] Additional compounds were prepared following the protocol of Scheme 170, replacing
3-chloro-benzamide 544 with an appropriate amide. The following compounds were made
following this procedure:
3,4-Dichloro-N-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide(P-0100),
2-Chloro-4-fluoro-N-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide(P-
0101),
2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [5-( 1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-
pyridin-2-yl]-amide (P-0102),
Thiophcnc-2-carboxylic acid [5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amide
(P-0103),
2-Methoxy-N-[5-(lH-pvrrolo[2,3-b]pyridb-3-ylmethyl)-pyridin-2-yl]-isonicotinamide(P-
0104),
N-[5-(lH-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-isonicotinamide(P-0105),
Pyrazine-2-carboxylic acid [5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amide (P-
0106),
Pyridine-2-carboxylic acid [5-(lH-pyrrolo[2,3-b]pyridin-3-yImethyl)-pyridin-2-yl]-amide (P-
0107),
6-Methyl-N-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-nicotinamide(P-0108),
4-Fluoro-3-methyl-N-[5-( 1 H-pvrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide (P-
0109),
S-Methyl-pyrazine-2-carboxylic acid [5-(l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-
amide(P-OllO),
4-Fluoro-N-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-3-trifluoromethyl-
bcnzamide(P-0112),

N-[5-(lH-Pyirolo[2,3-b]pyridin-3-yImethyl)-pyridin-2-yl]-3-trifluoromethoxy-benzamide(P-
0113),
N-[5-(lH-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-3-trifluoromethyl-benzamide(P-
0114),
3-Chloro-4-fluoro-N-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzainide(P-
0115),
3,4-Difluoro-N-[5-(l H-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-pyridin-2-yl]-bcnzamide (P-0116),
2-Chloro-N-[5-(lH-pyiTo!o[2)3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide(P-0117),
5-Fluoro-2-raethyl-N-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide(P-
0118),
2-Fluoro-N-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide(P-0119),
3-Methoxy-N-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide(P-0120),
3-FIuoro-N-[5-(lH-pynx)lo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide(P-0121),
3-Methyl-N-[5-(l H-pynolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-ben2amide (P-0122), and
2-Chloro-N-f5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-isoiiicotinainide(P-0123).
[0182] The following table indicates the amide (Column 2) used in Scheme 170 to provide the
compounds (Column 3). Column 1 provides the compound number and Column 4 the observed
mass.






Example 17: Synthesis of 3,5-dimethyl-4-(lH-pyrrolo[2^-b]pyridin-3-ylmethyl)-pyrazole-l-
carboxylic acid 4-methoxy-benzylamide P-0135
I0183J 3,5-Dimethyl-4.(lH-pyrTolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-l-carboxylic acid 4-
methoxy-benzylamide P-0135 was synthesized in 1 step as shown in Scheme 171.

Step I -Preparation of3,5-dimethyl-4-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazale-l-
carboxylic acid 4-methoxy-benzylamide (P-0135):
[0184] 3-(3,5-dimethyl-lH-pyrazol-4-ylmcthyI)-pyrrolo[2,3-b]pyridine-l-carboxylic acid tert-
butyl ester (514, 10 mg, 0.03 mmol) was dissolved in dichloromethane (0.S mL). 1,8-
Diazabicylo[5.4.0]unde-7-ene (6 mg, 0.04 mmol) was added. l-Jsocyanatomethyl-4-methoxy-
benzene (545,6.5 mg, 0.04 mmol) was added. The reaction was allowed to proceed at room
temperature for 30 minutes. Acetic acid (0.2 mL) was added to the rcaciton. The solvents were
removed under reduced pressure. The residue was dissolved in dimethyl sulfoxide (0.2 mL) and
purified by reverse phase HPLC on a Phenomenex column (50mm x 10mm ID), eluting with water
with 0.1 % trifluoroacetic acid and 20-100% acetonitrile with 0.1% trifluoroacetic acid over 16
minutes at a flow rate of 6mL/minute to provide the desired compound P-0135. MS (ESI)
[M+HT= 390.3.
[0185] Additional compounds were prepared following the protocol of Scheme 171, replacing
l-isocyanatomethyl-4-methoxy-benzene 545 with an appropriate isocyanate or bromide. The
following compounds were made following this procedure:
3-(1-Benzyl-3,5-dimethyl-lH-pyrazol-4-ylmethyl)-1H-pyrroIo[2,3-b]pyridine (P-0123),
2-[3,5-Dimethyl-4-( 1 H-pyrrolo[2,3-b]pyridin-3-yImethyl)-pyrazol-1 -yl]-1 -phenyl-ethanone
(P-0134),
3,5-Dimelhyl-4-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-l-carboxylic acid 2-chloro-
benzylamide (P-0136),

3,5-Dimethyl-4-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyra2ole-l-carboxylic acid 2-fluoro-
benzylamide (P-0137),
3-[3,5-Dimethyl-l -(5-trinuoromethyl-furan-2-ylmethyl)-l H-pyrazol-4-ylmethyl]-1H-
pyirolo[2,3-b]pyridine (P-0138),
3-[3,5-Dimethyl-l-(5-methyl-isoxazol-3-ylinethyl)-lH-pyrazol-4-ylniethyl]-lH-pyrTolo[2,3-
bjpyridine (P-0139),
3,5-Dimethyl-4-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-l-carboxylicacid4-chloro-
benzylamide (P-0140),
3,5-Dimethyl-4-(l H-pyrrolo[2,3-b]pyridin-3-ylmetb.yl)-pyrazole-l-carboxylic acid [2-(4-
ethoxy-phenyl)-ethyl]-amide (P-0141),
3,5-Dimethyl-4-(lH-pyrroIo[2,3-b]pyridin-3-ylmethyl)-pyrazole-l-carboxylic acid 3-methoxy-
benzylamide (P-0142),
3-{3,5-Dimethyl-l-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-lH-pyrazol-4-
ylmethyl}-lH-pyrrolo[2,3-b]pyridinc (P-0143),
3-[3,5-Dimethyl-]-(4-methyl-2-pheny!-thiazol-5-yIniethyl)-lH-pyrazol-4-ylmethyl]-lH-
pyrrolo[2,3-b]pyridine (P-0144),
3,5-Dimethyl-4-(l H-pyrrolo[2,3 -b]pyridin-3-ylracthyl)-pyrazole-1 -carboxylic acid 2-methoxy-
benzylamide (P-0145),
3,5-Dimethyl-4-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-l-carboxylicacid [2-(2,4-
dichloro-phenyl)-ethyl]-amide(P-0146),
3,5-Dimethyl-4-(lH-pyrTolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-l-carboxylicacid [2-(4-
fluoro-phenyl)-ethyl]-amide(P-0147),
3,5-Dimethyl-4-(lH-pyrroio[2,3-b]pyridin-3-ylmethyl)-pyrazole-l-carboxylicacid [2-(2-
fluoro-phcnyl)-ethyl]-amidc(P-0148),
3,5-Dimethyl-4-(lH-pymolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-l-carboxylic acid ((S)-l-
phenyl-ethyl)-amidc (P-0149),
3,5-Dimethyl-4-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1 -carboxylic acid 3-fluoro-
bcnzylamide (P-0150),
3,5-Dimethyl-4-(l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-l -carboxylic acid 4-fluoro-
benzylamide (P-0151),
3,5-Dimethyl-4-{lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-l-carboxylic acid 4-methyl-
benzylamide (P-0152), and
3,5-Dimethyl-4-(l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyra2ole-1 -carboxylic acid 2-methyl-
benzylamide (P-0153).






Example 18: Synthesis of 5-(l-methyHH-pyrazol-4-yI)-lH-pyrroloI2,3-b]pyridine 547.
[0187] 5-(l-Methyl-lH-pyrazol-4-yI)-lH-pynolo[2,3-b]pyridine 547 was synthesized in 1 step
from 5-bromo-lH-pvrTolo[2,3-b]pyridine 44 as shown in Scheme 172.

Step I - Preparation of5'(I-Methyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3~b]pyridine (547):
[0188] To 5-bromo-7-azaindole (44, 1.04 g, 5.28 mmol) in 1.00 M potassium carbonate in water
(15.8 mL) and tetrahydrofuran (50.0 mL) were added J-methyl-4-(4,4>5,5-tetramethyl-
[l,3,2]dioxaborolan-2-yl)-lH-pyrazole (546,1.65 g, 7.92 mmol),
Tetrakis(triphenylphosphine)palladium(0) (0.305 mg, 0.26 mmol) and tetra-n-butylammoniurn
iodide (0.20 g, 0.53 mmol). The reaction mixture was stirred at 70 °C overnight. The reaction
mixture was poured into water and the organic layer was washed with brine, dried over sodium
sulfate, and concentrated. The residue was purified with silica gel column chromatography eluting
with 25% ethyl acetate in hexane to provide a light yellow solid (547, 670 mg, 64.0%).
MS(ESI)[M+HT= 199.4.
Example 19: Synthesis of [2-(4-fluoro-benzylainino)-thiazol-5-yl)-(lH-pyrrolo|2,3-b]pyridin-
3-yl )-methanone P-0177.
|0189] [2-(4-Fluoro-benzylamino)-thiazol-5 -yl]-(l H-pyrrolo[2,3-b]pyridin-3-yl )-methanone P-
0177 was synthesized in 2 steps as shown in Scheme 173.


Step 1 - Preparation of(4-fluoro-benzyl)-[5-(lH-pyrrolo[2, 3-b]pyridine-3-carbonyl)-thiazol-2-
ylj-carbamic acid ten-butyl ester (549):
I0190J A mixture of {4-chIoro-5-[hydroxy-(l-triisopropylsiIanyl-lH-pyrrolo[2,3-b]pyridin-3-
yl)-methyl]-thiazol-2-yl}-pyridin-4-ylmethyl-carbamic acid tert-butyl ester (548,0.397 g, 0.57
mmol, prepared according to the protocol of Scheme 159, Example 5, replacing 4-
(aminomcthyl)pyridine 516 with 4-fluoro-benzylamine in step 1, isolated after step 3),
triethylsilane (1.0 mL, 6.3 mmol), and trifluoroacetic acid (0.5 mL, 6 mmol) in acetonitrile (10
mL) was stirred at 40 °C for 2 hours. The reaction mixture was poured into ice water, extracted
with ethyl acetate, washed with sodium bicarbonate and brine, and dried over sodium sulfate.
After removal of solvent, the residue was purified by silica gel column chromatography eluting
with methanol in dichloromethane to provide the desired compound as a yellow solid (549, 0.11 g,
9%). MS (ESI) [M-HT = 451.10.
Step 2 - Preparation of[2-(4-Jluoro-benzyIamino)-thiazol-5-yl]-(lH-pyrrolo[2,3-b]pyridin-3-yl)-
methanone (P-0177):
[0191) To a solution of (4-fluoro-benzyl)-[5-( 1 H-pyrrolo[2, 3-b]pyridine-3-carbonyl)-thiazol-2-
yrj-carbamic acid tert-butyl ester (549, 0.11 g, 0.2 mmol) in dichloromethane (2 mL) was added
hydrogen chloride (4 M in 1,4-dioxane, 2 mL). The reaction mixture was stirred at room
temperature overnight. The reaction mixture was poured into cold sodium bicarbonate solution,
extracted with ethyl acetate, washed with brine and dried over magnesium sulfate. After removal
of solvents, the residue was washed with ethyl acetate to provide the desired compound as a
yellow solid (P-0177, 9 mg, 10%). MS (ESI) [M+H+]+= 353.12.
Example 20: Synthesis of {2-I(4-chloro-benzyl)-methyl-amino]-thiazol-5-yI}-(lH-pyrrolo[2,3-
b]pyridin-3-yl)-methanonc P-0178.
10192] {2-[(4-Chloro-benzyl)-methyl-amino]-thiazol-5-yl}-(lH-pyrrolo[2,3-b]pyridin-3-yl)-
methanone P-0178 was synthesized in 3 steps as shown in Scheme 174.


Step 1 - Preparation of4-chloro-2-[(4-chloro-benzyl)-methy l-amino]-thiazole-5-carbaldehyde
(551):
[0193J To a solution of (4-chloro-benzyl)-methyl-amine (550, 2 g, 0.01 mol) and
N,N-diisopropylethylamine (4 mL, 0.03 mol) in tetrahydroftiran (50 mL) was added 2,4-dichloro-
thiazole-5-carbaldehyde (93, 3 g, 0.01 mmmol) in tetrahydrofiiran (20 mL) at room temperature.
The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured
into ice water, extracted with ethyl acetate, washed with brine, and dried over sodium sulfate.
After removal of solvent, the residue was collected by filtration and washed with hexanes to
provide the desired compound as a light-yellow solid (551, 3.6 g, 90%).
Step 2 - Preparation of {4-chloro-2-[(4-chloro-benzyl)-methyl-amino]-thiazol-5-yl}-
(l-triisopropylsilanyl-lH-pyrrolo[2,3-b]pyridin-3-yl)-methanol (552):
|0194] To a solution of 3-iodo-l-triisopropylsilanyl-lH-pyrrolo[2,3-b]pyridine (96, 0.82 g, 2.0
mmol) in tetrahydrofuran (5 mL) at -20 °C, isopropylmagnesium chloride (2 M in tetrahydrofuran,
1.1 mL, 2.2 mmol) was added dropwise. The reaction mixture was allowed to warm to 0 °C in 10
minutes. The reaction mixture was then cooled to -40 "C. To the reaction mixture was added a
solution of 4-chloro-2-[(4-chloro-benzyl)-methyl-amino]-thiazole-5-carbaldchyde (551, 0.41 g, 1.4
mmol) in tetrahydrofuran (10 mL). The reaction mixture was allowed to warm to -10 °C in 30
minutes. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed
with brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by
silica gel column chromatography eluting with ethyl acetate in hexanes to provide the desired
compound as a yellow solid (552,0.5 g, 60%). MS (ESI) [M+HT= 575.29.
Step 3 - Preparation qf{2-[(4-ckloro-benzyl)-methyl-amino]-lhiazol-S-yl}-(lH-pyrrolo[2.3-
b]pyridin-3-yl)-methanone (P-0178):

[01951 A mixture of {4-chloro-2-[(4-chloro-ben2yl)-methyl-amino]-thiazol-5-yl}-(l-
triisopropy]silanyl-lH-pyrro]o[2,3-bJpyridin-3-yl)-methanol (552, 1 g, 2 mmol), triethylsilane (2
mL, 12 mmol), and trifluoroacetic acid (1 mL, 13 mmol) in acctonitrile (10 mL) was stirred at 40
"C for 2 hours. The reaction mixture was poured into ice water, extracted with ethyl acetate,
washed with sodium bicarbonate and brine, and dried over sodium sulfate. After removal of
solvent, the residue was purified by silica gel column chromatography eluting with methanol in
dichloromelhane to provide the desired compound as a yellow solid (P-0178, 0.17 g, 30%). MS
(ESI) [M+HT= 383.09.
Example 21: Synthesis of aldehyde intermediates.
|0196| (3-Chloro-pyridin-4-ylmethyl)-(5-fonnyl-pyridin-2-yl)-carbamic acid tert-butyl ester 558
was synthesized in 4 steps from 6-amino-nicotinic acid methyl ester 553 as shown in Scheme 175.
Scheme 175

Step I - Synthesis of6-[(3-chloro-pyridin-4-ylmethyl)-amino]-nicotinic acid methyl ester (555):
101971 To 6-amino-nicotinic acid methyl ester (553,2.15 g, 0.014 mol) in acetonitrile (60.0 mL)
were added 3-chloro-pyridine-4-carbaldehyde (554, 2.00 g, 0.014 mol), triethylsilane (11.00 mL,
0.069 mol) and trifluoroacetic acid (5.00 mL, 0.065 mol). The reaction was stirred at 80 °C
overnight. The reaction was concentrated, poured into aqueous potassium carbonate, and extracted
with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The
filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to
100% ethyl acetate in hexane to give the desired compound (555, 1.5 g, 38.2%). MS (ESI)
[M+HT= 278.9.
Step 2 - Synthesis of6-[(3-Chloro-pyridin-4-ylmethyl)-amino]-pyridin-3-yl-methanol (556):
[0198J To 6-[(3-chloro-pyridin-4-ylmethyl)-amino]-nicotinic acid methyl ester (555, 1.00 g, 3.60
mmol) in tctrahydrofuran (120 mL) was added a solution of lithium tetrahydroaluminate (1.00 M
in tetrahydrofuran, 5.00 mL) under an atmosphere of nitrogen at room temperature. The reaction

was stirred at room temperature overnight, followed with addition of sodium sulfate decahydrate.
After 1 hour, the reaction mixture was filtered, concentrated, and purified with silica gel column
chromatography eluting with 2% to 20% methanol in dichloromethane to give the desired
compound as a white solid (556, 0.5 g, 56%). MS (ESI) [M+H*]' = 250.1.
Step 3 - Synthesis of6-[(3-chbro-pyridin-4-ylmethyl)-amino]-pyridine-3'Carbaldehyde (557):
[0199J To 6-[(3-chloro-pyridin-4-ylniethyl)-amino]-pvridin-3-yl-methanol (556, 0.50 g, 2.00
mmol) in tetrahydrofiiran (20.0 mL) was added Dess-Martin periodinane (1.02 g, 2.40 mmol). The
reaction was stirred at room temperature for 10 minutes, then poured into aqueous potassium
carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium
sulfate and filtered. The filtrate was concentrated to give crude compound (557,0.45 g, 91%) that
was used in the next step without further purification.
Step 4 - Synthesis of(3-chloro-pyridin-4-ylmethyl)-(5-formyl-pyridin-2-yl)-carbamic acid tert-
butyl ester (558):
(02001 To 6-[(3-chloro-pyridin-4-ylmethyl)-amino]-pyridine-3-carbaldehyde (557, 0.45 g, 1.80
mmol) in dichloromethane (20.0 mL) were added di-tert-butyldicarbonate (0.65 g, 3.00mmol),
4-dimethylaminopyridine (0.012 g, 0.010 mmol) and triethylamine (0.28 mL, 2.00 mmol). The
reaction was stirred at room temperature overnight, then concentrated and purified with silica gel
column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired
compound (558,250 mg, 40.0%).
[02011 (2-Difluoromethoxy-benzyl)-(5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester 559

was prepared following the protocol of Scheme 175, substituting 3-chloro-pyridine-4-carbaldehyde
554 with 2-difluoromethoxy-benzaldehyde in Step 1.
[02021 [2,6-Difluoro-3-(propane-1 -sulfonylamino)-benzyl]-(5-formyl-pyridin-2-yl)-carbamic
acid tert-butyl ester 560

was prepared following the protocol of Scheme 175, substituting 3-chloro-pyridine-4-carbaldehyde
554 with propane-1-sulfonic acid (2,4-difiuoro-3-formyl-phenyl)-amide in Step 1. MS (ESI)
[M+HY = 470.3.
[0203] (6-Fluoro-5-forinyl-pyridin-2-yl)-(6-trifluoromethyl-pyridin-3 -ylmethyl)-carbamic acid
tert-butyl ester 565 was synthesized in 4 steps from 2,6-Difluoro-nicotinic acid methyl ester 60 as
shown in Scheme 176.
Scheme 176

Step I - Synthesis of2-fluoro-6-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-nicotinic acid
methyl ester (562):
[0204] To 2,6-difluoro-nicotinic acid methyl ester (60, 1.82 g, 0.0105 mol) in N,N-
dimethylformamide (20.0 mL), under an atmosphere of nitrogen at -40 °C, C-(6-trifluoromethyl-
pyridin-3-yl)-methylamine (561, 1.00 g, 5.68 mmol) was added. The reaction was stirred at -40 °C,
then allowed to warm to room temperature for 2 hours. The reaction was poured into water and
extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and
filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting
with 35% to 100% ethyl acetate in hexane to give a white solid (562,1.40 g, 74.9). MS (ESI)
[M+HT-330.1.
Step 2 - Synthesis of2-fluoro-6-[(6-trifluoromelhyl-pyridin-3-ylmethyl)~amino]-pyridin-3-yl-
methanol (563):
[0205] To 2-fluoro-6-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-nicotinic acid methyl ester
(562, 1.40 g, 4.25 mmol) in tetrahydrofuran (100.0 mL) under an atmosphere of nitrogen at room
temperature, a solution of lithium tetrahydroaluminate (1.00 M in tetrahydrofuran, 10.0 mL) was
added slowly. The reaction was stirred at room temperature overnight, followed by addition of an
appropriate amount of sodium sulfate decahydrate. After 1 hour, the reaction mixture was filtered
and concentrated to give crude compound (563,1.2 g, 93.7%) that was used in the next step
without further purification.

Step 3 - Synthesis of2-fluoro-6-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-pyridine-3-
carbaldehyde (564):
[0206) To2-fluoro-6-[(6-trifluorotnethyI-pyridin-3-ylmethyl)-amino]-pyridin-3-yl-methanol
(563, 1.20 g, 3.98 tnmol) in dichloromethane (40.0 mL) was added Dess-Martin periodinane (1.86
g, 4.38 mmol). The reaction was stirred at room temperature for 10 minutes, then poured into
aqueous sodium thiosulfatc and potassium carbonate, and extracted with ethyl acetate. The organic
layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and
purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to
give the desired compound (564, 0.28 g, 23.5%).
Step 4 - Synthesis of(6-fluoro-5-formyl-pyridin-2-yl)-(6-trifluoromethyl-pyridin-3-ylmethyl)-
carbamic acid tert-butyl ester (565):
[0207] To2-fluoro-6-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-pyridine-3-carbaldehyde
(564,0.28 g, 0.94 mmol) in tetrahydrofuran (10.0 mL) were added di-tert-butyldicarbonate (0.245
g, 1.12 mmol) and 4-dimethylaminopyridine (0.050 g, 0.41 mmol). The reaction was stirred at
room temperature overnight, then concentrated and purified with silica gel column
chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound
(565, 0.22 g, 59%).
[0208] (6-Chloro-5-formyl-pyridin-2-yl)-(6-trifluoromethyl-pyridin-3-yImethyl)-carbamicacid
tert-butyl ester 570 was synthesized in 4 steps from 6-chloro-pyridin-2-ylamine 537 as shown in
Scheme 177.
Scheme 177

Step 1 - Synthesis of(6-chloro-pyridin-2-yl)-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine (567):
[0209] To 6-chIoro-pyridin-2-ylamine (537,0.760 g, 5.91 mmol) in acetonitrile (30.0 mL),
6-trifluoromethyl-pyridine-3-carbaldehyde (566, 1.06 g, 6.05 mmol), trifluoroacetic acid (3.00 mL,

0.0389 mol) and triethylsilane (6.00 mL, 0.0376 mol) were added. The reaction was heated to
reflux for 4 hours. The reaction was concentrated, poured into aqueous potassium carbonate, and
extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered
and concentrated and purified with silica gel column chromatography eluting with 20% to 100%
ethyl acetate in hexane to give a white solid (567, 1.60 g, 94.1%).
Step 2 - Synthesis of(5-bromo-6-chloro-pyridin-2-yl)-(6-trifluoromethyl-pyridin-3-ylmethyl)-
amine (568):
[0210| To (6-chloro-pyridin-2-yl)-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine (567,4.50 g,
0.0156 mol) in acetonitrile (120.0 mL) under an atmosphere of nitrogen, N-bromosuccinimide
(3.03 g, 0.0170 mol) in acetonitrile (SO mL) was added slowly. The reaction was stirred at room
temperature overnight, then poured into water, and extracted with ethyl acetate. The organic layer
was dried over sodium sulfate, concentrated and purified with silica gel column chromatography
eluting with 25% to 100% ethyl acetate in hexane to give a white solid (568,6.20 g, 80.2%).
Step 3 - Synthesis of2-chloro-6-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-pyridine-3-
carbaldehyde (569):
[0211] To (5-bromo-6-chloro-pyridin-2-yl)-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine (568,
4.60 g, 0.0125 mol) in tetrahydrofuran (60.0 mL) under an atmosphere of nitrogen at -78 °C,
isopropylmagnesium chloride (2.00 M in tetrahydrofuran, 6.44 mL) was added over 10 minutes.
The reaction was stirred at -78 CC for 20 minutes, and then allowed to warm to room temperature
for 10 minutes. The reaction was cooled to -78 °C, followed by adding tert-butyllithium (1.70 M in
hexane, 15.3 mL) over 10 minutes. After 40 minutes, N,N-dimethylformamide (1.23 mL, 0.0158
mol) was added and the reaction was stirred at -78 °C for 40 minutes, then allowed to warm to
room temperature for 30 minutes. The reaction mixture was poured into water and extracted with
ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated
and purified by silica gel column chromatography eluting with 35% to 100% ethyl acetate in
hexane to give a light yellow solid (569, 2.84 g, 71.7%).
Step 4 - Synthesis of(6-cMoro-5-formyl-pyridin-2-yl)-(6-trifluoramethyl-pyridin-3-ylmeikyl)-
carbamic acid tert-butyl ester (570)
[0212] To a solution of 2-chloro-6-[(6-trifluoromethyl-pyridin-3-ylrnethyl)-amino]-pyridine-3-
carbaldehyde (569, 0.545 g, 1.73 mmol) in tetrahydrofuran (10 mL), N,N-diisopropylcthylamine
(0.60 mL, 3.40 mmol), 4-dimethylaminopyridine (20 mg, 0.10 mmol), and a solution of di-tert-
butyldicarbonate (0.41 g, 0.0019 mol) were added. The reaction mixture was stirred at room
temperature overnight, then concentrated, poured into water, and extracted with ethyl acetate. The
organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by silica

gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired
compound (570, 0.60 g, 83.6%).
[0213| (5-Bromo-6-fluoro-pyridin-2-yl)-(2-chloro-benzyl)-amine 571

was prepared following the protocol of Steps 1 and 2 of Scheme 177, substituting 6-chloro-
pyridin-2-ylamine 537 and 6-trifluoromethyl-pyridine-3-carbaldehyde 566 with 6-fluoro-pyridin-
2-ylamine and 2-chloro-benzaldehyde, respectively in Step 1.
[0214] (6-Fluoro-5-formyl-pvridin-2-yl)-(6-methoxy-pyridin-3-ylmethyl)-carbamic acid tert-
butyl ester 572

r
was prepared following the protocol of Scheme 177, substituting 6-chloro-pyridin-2-ylamine 537
and 6-trifluoromethyl-pyridine-3-carbaldehyde 566 with 6-fluoro-pyridin-2-ylamine and 6-
methoxy-pyridine-3-carbaldehyde, respectively in Step 1.
[0215| (5-bromo-6-fluoro-pyridin-2-yl)-(5-fluoro-pyridin-3-ylmethyl)-carbamic acid tert-butyl
ester 631

r*
was prepared following the protocol of Scheme 177, substituting 6-chloro-pyridin-2-ylamine 537
and 6-trifluoromethyl-pyridine-3-carbaldehyde 566 with 6-fluoro-pyridin-2-ylamine and 5-fluoro-
pyridine-3-carbaldehydc, respectively in Step 1, without Step 3 (i.e. the product of Step 2 is
reacted according to Step 4).
[0216| (5-Bromo-6-fluoro-pyridin-2-yl)-(4-chloro-benzyl)-carbamic acid tert-butyl ester 637

i-

was prepared following the protocol of Scheme 177, substituting 6-chloro-pyridin-2-ylamine 537
and 6-trifluoromethyl-pyridine-3-carbaldehyde 566 with 6-fluoro-pyridin-2-ylamine and 5-chloro-
benzaldehyde, respectively in Step 1, without Step 3 (i.e. the product of Step 2 is reacted
according to Step 4).
Example 22: Synthesis of propane-1-sulfonic acid (2,4-difluoro-3-[5-(lH-pyrrolo[2,3-
b|pyridin-3-ylmethyl)-pyridin-2-ylaminoJ-methyl-phenyl)-amide P-0258
[0217J Propane-1-sulfonic acid (2,4-difluoro-3-[5-(l H-pvrrolo[2,3-bJpyridin-3-ylmethyl)-
pyridin-2-ylamino]-methyl-phenyl)-amide P-0258 was synthesized in 2 steps from 3-Iodo-l-
triisopropylsilanyl-lH-pyrrolo[2,3-b]pyridine 96 as shown in Scheme 178.
n P-U23S
Step 1 -Synthesis of[2,6-difluoro-3-(propane-l-sulfonylamino)-benzyl]-5-[hydroxy-(l-
triisopropylsilanyl-1H-pyrrolo[2,3-b]pyr idin-3-yl)-methyl]-pyridin-2-yl-carbamic acid ten-butyl
ester (574):
|0218J To a solution of 3-Iodo-l-triisopropylsilanyl-lH-pyjTolo[2,3-b]pyridine (96, 0.644 g, 1.61
mmol) in tctrahydrofuran (10.0 mL) at -40 °C under nitrogen, isopropylmagnesium chloride (2.0
M in tetrahydrofuran, 0.80 mL) was added slowly. The reaction was allowed to warm to 15 °C
over 100 minutes, then cooled to -40 °C, followed by adding [2,6-difluoro-3-(propane-l-
sulfonylamino)-benzyl]-(5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (560, 0.100 g, 0.21
mmol, prepared as described in Example 21, Scheme 175) in tetrahydrofuran (2.0 mL). The
reaction was allowed to warm to 5 °C over 2 hours, then poured into aqueous ammonium chloride,
and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and
filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting
with 20% to 100% ethyl acetate in hexane to give a yellow solid (574, 75 mg, 47%). MS (ESI)
[M+HT = 744.7.

Step 2 - Synthesis of Propane-1-sulfonic acid (2,4-difluoro-3-[5-(lH-pyrrolo[2,3-b]pyridin-3-
ylmethyl)-pyridin~2-ylamino]-methyl-phenyl)-amide (P-0258):
J0219) To [2,6-difluoro-3-(propane-l-sulfonylamino)-benzyl]-5-[hydroxy-(l-triisopropylsilanyI-
1 H-pyrrolo[2,3-b]pyr idin-3-yl)-methyl]-pyridin-2-yl-cart>amic acid tert-bulyl ester (574, 75.0 mg,
0.10 mmol) in acetonitrile (10.0 mL) were added triethylsilane (0.40 mL, 2.5 mmol) and
trifluoroacetic acid (0.20 mL, 2.6 mmol). The reaction was stirred at 80 °C for 4 hours. The
reaction was poured into aqueous potassium carbonate, and extracted with ethyl acetate. The
organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated
and purified by silica gel column chromatography eluting with 2% to 15% methanoi in
dichloromethane to give an off-white solid (P-0258, 29.3 mg, 61.6%). MS (ESI) [M+HY = 472.4.
[0220] Propane-1 -sulfonic acid (3-{[5-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-
2-ylarnino]-raethyl}-2,4-difluoro-phenyl)-amide (P-0259), [6-Fluoro-5-(l H-pyrrolo[2,3-b]pyridin-
3-ylmethyl)-pyridin-2-yl]-(6-methoxy-pyridin-3-ylmethyl)-amine(P-0378), and
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmelhyI)-6-fluoro-pyridin-2-yl]-(6-methoxy-pyridin-3-
ylmethyl)-amine (P-0379),
c

respectively, were prepared following the protocol of Scheme 178. P-0259 was prepared by
replacing 3-iodo-l-triisopropylsilanyl-lH-pyrrolo[2,3-b]pyridine 96 with 5-chloro-3-iodo-l-
triisopropylsilanyl-IH-pyrrolo[2,3-b]pyridine in Step 1 (MS [M+HT = 506.1). P-0378 was
prepared by replacing [2,6-difluoro-3-(propane-l-sulfonylamino)-benzyl]-(5-formyl-pyridin-2-yl)-
carbamic acid tert-butyl ester 560 with (6-Fluoro-5-fonnyl-pyridin-2-yl)-(6-methoxy-pyridin-3-
y!methy!)-carbamic acid tert-butyl ester 572 (prepared as described in Example 21, Scheme 177)
in Step 1 (MS [M+H+]+ - 364.1). P-0379 was prepared by replacing both azaindole 96 with 5-
chloro-3-iodo-l-triisopropylsilanyl-lH-pyrrolo[2,3-b]pyridine and aldehyde 560 with aldehyde
572 in Step 1 (MS [M+HT = 400.0).
Example 23: Synthesis of [6-fluoro-5-(5-niethoxy-lH-pyrroIo|2J3-b|pyridin-3-ylinethyl)-
pyridin-2-yl]-(6-trinuoromethyl-pyridin-3-ylmethyl)-amineP-0187
{0221] [6-Fluoro-5-(5-methoxy-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-
trifluoromethyl-pyridin-3-ylmethyl)-amine P-0187 was synthesized in 3 steps from
l-benzenesulfonyl-3-iodo-5-methoxy-lH-pyrrolo[2,3-b]pyridine 575 as shown in Scheme 179.


Step 1 - Synthesis of5-[(l-benzenesulfonyl-5-methoxy-lH-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-
methyl]-6-fluoro-pyridin-2-yl-(6-trifluoromethyl-pyridin-3-ylmethyl )-carbamic acid tert-butyl
ester (576):
|0222] To 1 -benzenesulfonyl-3-iodo-5-methoxy-l H-pyrrolo[2,3-b]pyridine (575,0.326 g,
0.000788 mol) in tetrahydrofuran (3.00 mL) at -45 °C under nitrogen, isopropylmagnesium
chloride (2.0 M in tetrahydrofuran, 0.380 mL) was added slowly. The reaction was allowed to
warm to -25 °C in 30 minutes, and then cooled to -45 °C followed by adding (6-fluoro-5-formyl-
pyridin-2-yl)-(6-trifluoromethyl-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (565, 80.0 mg,
0.20 mmol, prepared as described in Example 21, Scheme 176) in tetrahydrofuran (1.0 mL). The
reaction was allowed to warm to room temperature over 2 hours. The reaction was poured into
aqueous ammonium chloride, and extracted with ethyl acetate. The organic layer was dried over
anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel
column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired
compound (576, 0.080 g, 60%). MS (ESI) [M+H+]+ = 688.1.
Step 2 - Synthesis of[5-(l-Benzenesulfonyl-5-methoxy-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-
Jluoro-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine (577):
|0223] To5-[(l-benzenesulfonyl-5-methoxy-lH-pynolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-6-
fluoro-pyridin-2-yl-(6-trifl\ioromethyl-pyridin-3-ylmethyl )-carbamic acid tert-butyl ester (576,
0.100 g, 0.15 mmol) in acetonitrile (12.6 mL) were added triethylsilane (0.34 mL, 2.10 mmol) and
trifluoroacetic acid (0.17 mL, 2.20 mmol). The reaction was heated to 80 °C for 2 hours. The
reaction was poured into aqueous potassium carbonate, and extracted with ethyl acetate. The
organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated
to give the crude compound (577, 90 mg, 100%) that was used in the next step without further
purification.

Step 3 ~ Synthesis of[6-Fluoro-5-(S-methoxy-lH-pyrrolo[2.3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-
(6-trifluoromethyl-pyridin-3-ylmethyl)-amine (P-0187):
(0224) To [5-( 1 -benzenesulfonyl-5-methoxy-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-
pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine (577,0.08 g, 0.13 mmol) in
tetrahydrofuran (10.0 mL) was added tetrabutylammonium fluoride, trihydrate (0.110 g, 0.35
mmol). The reaction was stirred at room temperature overnight, then poured into water, and
extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and
filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting
with 20% to 100% ethyl acetate in hexane to give an off-white solid (P-0187, 8.1 mg, 10%). MS
(ESI) [M+HT = 431.9.
[0225J [6-Fluoro-5-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-
trifluoromethyl-pyridin-3-ylmethyl)-amine P-0186 and [6-Fluoro-5-(lH-pyrrolo[2,3-b]pyridin-3-
ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmelhyl)-amine P-0188,
-••- • --J----- ■ ~'j >
were prepared following the protocol of Scheme 179, substituting l-benzenesulfonyl-3-iodo-5-
methoxy-1 H-pyrrolo[2,3-b]pyridine575 with 1 -benzenesulfonyl-3-iodo-5-chloro-lH-pyrrolo[2,3-
bjpyridineor l-Benzenesulfonyl-3-iodo-lH-pyrrolo[2,3-b]pyridine, respectively, in Step 1. MS
(ESI) [M+H+]+ = 435.7 and 401.6, respectively.
Example 24: Synthesis of |6-(2-fluoro-benzylamino)-pyridin-3-yl]-(lH-pyrrolo|2r3-b]pyridin-
3-yl)-metbanone P-0403
(0226) Synthesis of [6-(2-fluoro-benzylamino)-pyridin-3-yl]-(lH-pyrrolo[2,3-b]pyridin-3-yl>-
methanone P-0403 was synthesized in 2 steps from 3-Iodo-l-triisopropylsilanyl-lH-pyrrolo[2,3-
b]pyridine 96 as shown in Scheme 180.


acid tert-butyl ester (580):
[0227] To 3-iodo-l-triisopropylsilanyl-lH-pyrrolo[2,3-b]pyridine (96,0.550 g, 1.37 mmol) in
tctrahydrofiiran (15.0 mL) at -40 °C under nitrogen, isopropylmagnesium chloride (2.0 M in
tetrahydrofuran, 0.65 mL) was added slowly. The reaction was allowed to warm to 5 °C over
70 minutes, then cooled to -40 °C, followed by adding (2-fluoro-benzyl)-(5-formyl-pyridin-2-yl)-
carbamic acid tert-butyl ester (579, prepared according to the protocol of Example 1, Scheme 19,
Steps 1-3, replacing 4-chlorobenzaldehyde 40 with 2-fluoro-benzaldehyde in Step 1) in
tetrahydrofuran (4.0 mL). The reaction was allowed to warm to room temperature over 1 hour,
then poured into aqueous ammonium chloride, and extracted with ethyl acetate. The organic layer
was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified
by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the
desired compound (580, 0.14 g, 26%). MS (ESI) [M+HT = 447.0.
Step 2 - Synthesis of[6-(2-Fluoro-benzylamino)-pyridin-3-yl]-(lH-pyrrolo[2,3-b]pyridin-3-yl)-
methanone (P-0403):
[0228] To (2-fluoro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-pyridin-2-yl]-carbamic
acid tert-butyl ester (580, 0.080 g, 0.18 mmol) in dichloromethane (3.0 mL) was added
trifluoroacetic acid (1.0 mL, 0.013 mol). The reaction was stirred at room temperature overnight,
then concentrated, poured into water, and extracted with ethyl acetate. The organic layer was dried
over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel
column chromatography eluting with 2% to 15 % methanol in dichloromethane to give the desired
compound (P-0403, 15.0 mg, 23.0%). MS (ESI) [M+HT = 347.5.
Example 25: Synthesis of (5-chloro-lH-pyrrolo[2r3-b]pyridin-3-yl)-[6-(2-fluoro-
benzylamino)-pyridin-3-yl]-methanone P-0404
[0229) (5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-yl)-[6-(2-fluoro-benzylamino)-pyridin-3-yl]-
methanone P-0404 was synthesized in 4 steps from l-benzenesulfonyl-5-chloro-3-iodo-lH-
pyrrolo[2,3-b]pyridine 581 as shown in Scheme 181.


Step 1 - Synthesis of5-[(l-benzenesulfonyl-5-chloro-lH-pyrroh[2,3-b]pyridm-3-yl)-hydroxy-
methyl]-pyridin-2-yl-(2-fluoro-benzyl)-carbamic acid tert-butyl ester (582)
|0230] To a solution of l-benzenesulfonyl-5-chloro-3-iodo-lH-pyrrolo[2,3-b]pyridine (581,
0.420 g, 1.00 mmol) in tetrahydrofiiran (15.0 mL) at -40 °C under nitrogen, isopropylmagnesium
chloride (2.0 M in tetrahydrofuran, 0.49 mL) was added slowly. The reaction was allowed to warm
to 5 °C over 70 minutes, then cooled to -40 °C, followed by adding (2-fluoro-benzyl)-(5-formyl-
pyridin-2-yl)-carbamic acid tert-butyl ester 579 in tetrahydrofuran (6.0 mL). The reaction was
allowed to warm to room temperature over 1 hour, then poured into aqueous ammonium chloride,
and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and
filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting
with 20% to 100% ethyl acetate in hexane to give the desired compound (582, 0.25 g, 41%). MS
(ESI) [M+HT = 623.1.
Step 2 - Synthesis of[5-(l-Benzenesulfonyl-S-chlaro-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-
pyridin-2-yl]-(2-fluoro-benzyl)-carbamic acid tert-butyl ester (583):
[02311 To5-[(l-benzenesulfonyl-5-chloro-lH-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-
pyridin-2-yl-(2-fIuoro-benzy!)-carbamic acid tert-butyl ester (582, 0.25 g, 0.40 mmol) in
dichloromethane (5.0 mL) was added Dess-Martin periodinane (0.20 g, 0.48 mmol). The reaction
was stirred at room temperature for 10 minutes, then poured into aqueous potassium carbonate,
and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and
filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting
with 20% to 100% ethyl acetate in hexane to give the desired compound (583, 0.060 g., 24%).
Step 3 - Synthesis of[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-pyridin-2-yl]-(2-jluoro-
benzyl)-carbamic acid tert-butyl ester (584):
|0232| To [5-( 1 -benzenesulfonyl-5-chloro-l H-pyrrolo[2)3-b]pyridine-3-carbonyl)-pyridin-2-ylj-

(2-fluoro-benzyl)-carbamic acid tert-butyl ester (583,60.0 mg, 0.097 mmol) in tetrahydrofuran
(1.0 mL) was added aqueous potassium carbonate (1.0 M, 1.0 mL). The reaction was irradiated
with microwave on 300 watts, 100"C for 10 minutes, then poured into water and extracted with
ethyl acetate. The organic layer was dried over anhydrous sodium sulfatc and filtered. The filtrate
was concentrated to give crude compound (584, 0.040 g, 64%) that was used in the next step
without further purification.
Step 4 - Synthesis of(S-Chloro-JH-pyrrol6[2,3-b]pyridin-3-yl)-[6-(2-fluoro-benzylamino)-
pyridin-3-yl]-methanone (P-0404):
[0233] To [5-(5-chloro-1 H-pymolo[2,3-b]pyridine-3-carbonyl)-pyridin-2-yl]-(2-fluoro-benzyl)-
carbamic acid tert-butyl ester (584,0.030 g, 0.062 mmol) in dichloromethane (1.0 mL) was added
trifluoroacetic acid (1.0 mL, 0.013 mol). The reaction was stirred at room temperature overnight,
then poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer
was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified
by silica gel column chromatography eluting with 2% to 15% methanol in dichloromethane to give
the desired compound (P-0404, 2.8 mg, 12%). MS (ESI) [M+HY = 381.0.
Example 26: Synthesis of (5-chloro-lH-pyrrolo(2,3-b|pyridin-3-yl)-6-[(6-methoxy-pyridin-3-
ylmethyl)-amino]-pyridin-3-yl-methanone P-0405
[0234] (5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-yl)-6-[(6-methoxy-pyridin-3-ylmethyl)-amino]-
pyridin-3-yl-methanone P-0405 was synthesized in 3 steps from 5-Chloro-1H-pyrroIo[2,3-
bjpyridine 532 as shown in Scheme 182.

Step 1 - Synthesis of5-[(5-chhro-lH-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-pyridin-2-yl-
(6-methoxy-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (586):
[0235] To 5-chloro-I H-pyrrolo[2,3-b]pyridine (532,0.092 g, 0.60 mmol) in methanol (15.0 mL)
were added (5-formyl-pyridin-2-yl)-(6-methoxy-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester

(585,0.240 g, 0.70 mmol, prepared according to the protocol of Example 1, Scheme 19, Steps 1-3,
replacing 4-chlorobenzaldehyde 40 with 6-methoxy-pyridine-3-carbaldehyde in Step 1) and
potassium hydroxide (1.2 g, 0.021 mol). The reaction was stirred at room temperature overnight,
then poured into water, and extracted with ethyl acetate. The organic layer was dried over
anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel
column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired
compound (586, 0.110 g, 37%).
Step 2 - Synthesis of[5-(5-chloro-lH-pyrrolo[2.3-b]pyridine-3-carbonyl)-pyridin-2-yl]-(6-
methoxy-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (587):
|0236) To 5-[(5-chloro-lH-pyrrolo[2,3-b]pyridra-3-yl)-hydroxy-methyl]-pyridin-2-yl-(6-
methoxy-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (586, 0.060 g, 0.12 mmol) in
dichloromethane (10.0 mL) was added Dess-Martin periodinane (0.062 g, 0.15 mmol). The
reaction was stirred at room temperature for 10 minutes. The reaction was concentrated and
purified with a silica gel column chromatography eluting with 20% to 100% ethyl acetate in
hexane to give the desired compound (587, 0.020 g, 33%).
Step 3 - Synthesis of(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-yl)-6-[(6-methoxy-pyridin-3-ylmethyl)-
aminoJ-pyridin-3-yl-methanone (P-0405):
[0237J To [5-(5-chloro-1 H-pyrrolo[2,3-b]pyridine-3-carbonyl)-pyridin-2-yl]-(6-methoxy-
pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (587, 0.020 g, 0.040 mmol) in dichloromethane
(2.0 mL) was added trifluoroacetic acid (0.30 mL, 0.0039 mol). The reaction was stirred at room
temperature for 2 hours, then poured into aqueous potassium carbonate, and extracted with ethyl
acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was
concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl
acetate in hexane to give the desired compound (P-0405, 5.5 mg, 34%). MS (ESI) [M+H*]* =
394.3.
(0238] {6-[(6-Methoxy-pyridin-3-ylmethyl)-amino]-pyridin-3-yl}-(lH-pyrrolot2,3-b]pyridin-3-
yl)-methanone P-0406
" H
was prepared following the protocol of Scheme 182, substituting 5-chloro-lH-pyrrolo[2,3-
bjpyridine 532 with 5-methoxy-lH-pyrrolo[2,3-b]pyridine in step 1. MS (ESI) [M+H++]+= 390.1.

Example 27: Synthesis of intermediate 5-(l-benzenesulfonyl-5-chloro-lH-pyrrolo|2,3-
b]pyridin-3-ylmethyl)-4-chloro-thiazol-2-ylaniine592
[0239] 5-(l-Benzenesulfonyl-5-chIoro-lH-pyrroIo[2,3-b]pyridin-3-ylmethyl)-4-chloro-thiaEol-
2-ylamine 592 was synthesized in 4 steps from 2-amino-4-chloro-thiazole-5-carbaldchyde 588 as
shown in Scheme 183.
Scheme 183

Step 1 - Synthesis of(4-chloro-5-formyl-thiazol-2-yl)-carbamic acid tert-butyl ester (589):
[0240] To 2-amino-4-chloro-thiazole-5-carbaldehyde (588, 5.00 g, 0.0308 mol) in
tetrahydrofiiran (122 mL) were added di-tert-butyldicarbonate (7.38 g, 0.0338 mol) and
4-dimethylaminopyridine (0.35 g, 0.0029 mol). The reaction was stirred at 58 °C for 2 hours, then
concentrated and purified with silica gel column chromatography eluting with 20% to 80% ethyl
acetate in hexane to give a yellow solid (589, 7.0 g, 87%).
Step 2 - Synthesis of 5-[(l' -benzenesulfonyl-5-chloro-l'H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-
methyl]-4-chloro-thiazol-2-yl-carbamic acid tert-butyl ester (590):
|0241] To a solution of l-benzenesuIfonyl-5-chloro-3-iodo-lH-pyrrolo[2,3-b]pyridine (581,
4.40 g, 10.5 mmol) in tetrahydrofiiran (30.0 mL) at -45 °C under nitrogen, a solution of
isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 5.4 mL) was added slowly over 10
minutes. The reaction was allowed to warm to -25 °C over 30 minutes. The reaction was cooled to
-65 °C, followed by adding the cold deprotonated (4-chloro-5-formyl-thiazol-2-yl)-carbamic acid
tert-butyl ester 589, which was prepared in situ by adding isopropylmagnesium chloride (2.0 M in
tetrahydrofuran, 5.0 mL) to (4-chloro-5-formyl-thiazol-2-yl)-carbamic acid tert-butyl ester (589,
2.51 g, 9.55 mmol) in tetrahydrofuran (23.0 mL) at -78 °C under an atmosphere of nitrogen. The
reaction was allowed to warm to room temperature in 2 hours, then poured into aqueous
ammonium chloride, and extracted with ethyl acetate. The organic layer was dried over anhydrous

sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column
chromatography eluting with 25%to 100% ethyl acetate in hexane to give the desired compound
(590, 3.70 g, 60.3%). MS (ESI) [M+HT = 554.2.
Step 3 - Synthesis of[5-(l-benzenesulfonyl-5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-
chloro-thiazol-2-ylJ-carbamic acid tert-butyl ester (591):
[0242] To 5-[(l-benzenesulfonyl-5-chloro-lH-pyrroIo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-4-
chloro-thiazol-2-yl-carbamic acid tert-butyl ester (590, 0.200 g, 0.32 mmol) in dichloromethane
(15.0 mL) were added triethylsilane (0.600 mL, 376 mmol) and trifluoroacetic acid (0.300 mL,
3.89 mmol). The reaction was stirred at room temperature for 3 hours, then concentrated, poured
into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried
over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel
column chromatography eluting with 25%to 100% ethyl acetate in hexane to give the desired
compound (591, 0.155 g, 88.7%). MS (ESI) [M+HT = 538.9.
Step 4 - Synthesis of5-(l-Benzenesulfonyl-5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-
chloro-thiazol-2-ylamine (592):
(0243{ To [5-( 1 -benzenesulfonyl-5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-chIoro-
thiazol-2-yl]-carbamic acid tert-butyl ester (591, 4.30 g, 7.97 mmol) in dichloromethane (70.0 mL)
was added a solution of hydrogen chloride (4.00 M in 1,4-dioxane, 42.0 mL). The reaction was
stirred at room temperature for 2 days, then concentrated, and titrated with ethyl ether and ethyl
acetate to give the desired compound (592, 2.60 g, 74.2%). MS (ESI) [M+H*]* = 439.0.
|0244] 5-(l-Benzenesulfonyl-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-chloro-thiazol-2-ylamine
593

was prepared following the protocol of Scheme 183, substituting l-benzenesulfonyl-5-ch!oro-3-
iodo-lH-pvm>lo[2,3-b]pyridinc581 with l-benzenesulfonyl-3-iodo-lH-pyrrolo[2,3-b]pyridine in
Step 2. MS (ESI) [M+H] = 404.4.

Example 28: Synthesis of [4-Chloro-5^5-cbJoro-lH-pyrroIo[2,3-b]pyridin-3-ylnjethyI)-
thiazoI-2-yI]-(5>fluoro-pyridin-3-ylmethyl)-amineP-0231
[0245] [4-ChIoro-5-(5-chloro-lH-pyrroIo[2,3-b]pyridin-3-ylmethyJ)-thiazol-2-yl]-(5-fluoro-
pyridin-3-ylraethyI)-amine P-0231 was synthesized in 2 steps from 5-(l-benzenesulfonyl-5-chIoro-
lH-pyrroIo[2,3-b]pyridin-3-ylmethyl)-4-chloro-thiazoI-2-ylamine 592 as shown in Scheme 184.

Step I - Synthesis of[5-(l-benzenesulfonyl-5-chloro-lH-pyrrolo[2,3-b]pyridm-3-ylrnethyl)-4-
chloro~thiazol-2-yl]-(5'fluoro-pyridin-3-ylmethyl)-amine(595);
[0246] To5-(l-benzenesuIfonyl-5-chloro-lH-pyrroIo[2,3-b]pyridin-3-ylmethyl)-4-chloro-
thiazol-2-ylamine (592, 50.0 mg, 0.11 mmol, prepared as described in Example 27, Scheme 183)
in ethanol (1.60 mL) and acetic acid (0.08 mL) were added 5-fluoro-pyridLne-3-carbaldehyde (594,
43 mg, 0.34 mmol) and silica supported cyanoborohydride (1.21 mmol/g, 0.180 g). The reaction
was irradiated with microwave on 300 watts, 100°C for 7 minutes. The reaction was poured into
aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over
anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel
column chromalography eluting with 20% ethyl acetate in hexane to give the desired compound
(595, 0.030 g, 48%).
Step 2 - Synthesis of[4-chloro-5-(5-chloro-lH-pyrrolo[2.3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(5-
fluoro-pyridin-3-ylmethyl)-amine (P-0231):
[0247] To [5-( 1 -benzenesulfonyl-5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-chloro-
thiazol-2-yl]-(5-fluoro-pyridin-3-ylmethyl)-amine (595, 0.030 g, 0.055 mmol) in tetrahydrofuran
(6.0 mL) was added tetrabutylammonium fluoride, trihydrate (0.034 g, 0.11 mmol) under an
atmosphere of nitrogen. The reaction was stirred at room temperature for 3 hours, then poured into
water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate
and filtered. The filtrate was concentrated and purified by silica gel column chromatography
eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (P-0231, 1.5 mg,

6.7%). MS (ESI) [M+HY = 408.1.
Example 29: Synthesis of 5-(l-benzenesulfonyl-5-chloro-lH-pyrrolo[2,3-b]pyridin-3-
ylmethyl)-pyridin-2-ylaminc 599
|0248] 5-( 1 -Benzenesulfonyl-5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-pyridin-2-ylainine
599 was synthesized in 4 steps from 5-chloro-lH-pyrrolo[2,3-b]pyridine 532 as shown in Scheme
185.

Step 1 - Synthesis of 5-chloro-l H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (596):
[0249] To 5-chloro-l H-pyrrolo[2,3-b]pyridine (532, 10.0 g, 65.5 mmol) in acetic acid (28.3 mL)
were added hexamethylenetetramine (11.9 g, 85.2 mmol) and water (56.7 mL). The reaction was
refluxed overnight, followed by addition of 200 mL of water. After 30 minutes, the reaction was
filtered to recover the solid, then dried under air to give the desired compound (596, 7.0 g. 59%).
Step 2 - Synthesis of 1 -benzenesulfonyl-5-chloro-]H-pyrrolo[2,3-b]pyridine-3-carbaldehyde
(597):
[0250] To 5-chloro-lH-pyrrolo[2,3-b]pyridine-3-carbaldehyde (596, 3.60 g, 0.0199 mol) in
dichloromethane (100 mL) were added a solution of potassium hydroxide (9 M in water, 50 mL),
tetrabutylammonium hydrogen sulfate (400 mg, 0.001 mol) and benzenesulfonyl chloride (2.9 mL,
0.023 mol). The reaction was stirred at room temperature for 3 hours, then poured into water and
extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and
filtered. The filtrate was concentrated and washed with ethyl acetate to give a white solid (597, 2.3
g, 36.0%).
Step 3 - Synthesis of(6-amino-pyridin-3-yl)-(l-benzenesulfonyl-5-chloro-IH-pyrrolo[2.3-
b]pyridin-3-yl)-methanol (598):
[0251] To 2-amino-5-bromopyridine (15, 3.10 g, 17.9 mmol) in tetrahydrofuran (80.0 mL) under

an atmosphere of nitrogen at -78 °C, a solution n-butyllithium (2.50 M in hcxane, 7.10 mL) was
added slowly. After 30 minutes, l,2-bis-(chloro-dimethyl-silanyl)-ethane (3.90 g dissolved in
tetrahydrofuran 20.0 mL, 18.1 mmol) was added to the reaction mixture slowly, and then allowed
to warm to room temperature for 1 hour. The reaction was cooled to -78 °C followed by adding a
solution of n-butyllithium (2.50 M in Hexane, 7.10 mL). The reaction mixture was stirred at -78 °C
for 30 minutes, then allowed to warm to room temperature for 60 minutes. The reaction mixture
was cooled to -78 °C, followed by adding a solution of n-butyllithium (2.50 M in Hexane, 7.50
mL) slowly. After 60 minutes, l-benzenesulfbnyl-5-chloro-lH-pyrrolo[2,3-b]pyridine-3-
carbaldehyde (597, 1.90 g in 30 mL tetrahydrofiiran, 5.92 mmol) was added to the reaction
mixture. The reaction mixture was stirred at -78 °C for 2 hours, then allowed to warm to room
temperature for 1 hour. The reaction was poured into water and extracted with ethyl acetate. The
organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated
and purified by silica gel column chromatography eluting with 2% to 20% methanol in
dichloromethane to give the desired compound (598,1.25 g, 50.9%). MS (ESI) [M+H+]+ = 415.2.
Step 4 - Synthesis ofS-(l-benzenesulfonyl-5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-
2-ylamine (599):
[0252] To(6-amino-pyridin-3-yl)-(l-benzenesulfonyl-5-chloro-lH-pyrrolo[2,3-b]pyridin-3-yl)-
methanol (598, 1.00 g, 0.00241 mol) in dichloromethane (25.0 mL) were added triethylsilane (3.00
mL, 0.0188 mol) and trifluoroacetic acid (1.50 mL, 0.0195 mol). The reaction was stirred at room
temperature overnight, then concentrated, poured into aqueous potassium carbonate, and extracted
with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The
nitrate was concentrated and purified by silica gel column chromatography eluting with 20% to
100% ethyl acetate in hexane to give the desired compound (599, 0.70 g, 73%).
[0253] 5-(l-Benzenesulfonyl-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine600

was prepared following the protocol of Scheme 185, substituting 5-chloro-lH-pyrroIo[2,3-
bjpyridine 532 with lH-pyrrolo[2,3-b]pyridine in Step 1. MS (ESI) [M+FT]* = 365.2.
Example 30: Synthesis of [5-(5-chloro-lH-pyrrolo(2^-b]pyridin-3-ylinetbyI)-pyridin-2-yl]-(5-
fluoro-pyridin-3-ylmethyI)-amineP-0324

[0254] [5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(5-nuoro-pyridin-3-
ylmethyl)-amine P-0324 was synthesized in 2 steps from 5-(I-benzenesuIfonyl-5-chloro-IH-
py!Tolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yiamine 599 as shown in Scheme 186.

Step 1 - Synthesis of[5-(l-benzenesulfonyl-5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-
pyridin-2-yl]-(5-fluoro-pyridin-3-ylmethyl)-amine (601):
(0255] To 5-(l-benzenesulfonyl-5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-
ylaraine (599, 80.0 mg, 0.20 mmol, prepared as described in Example 29, Scheme 185) in ethanol
(2.0 mL) and acetic acid (0.10 mL, 0.0018 mol) were added 5-fluoro-pyridine-3-carbaldehyde
(594, 62.7 mg, 0.50 mmol) and sodium cyanoborohydridc on silica gel (1.200 mmol/g loading;
0.251 g, 0.30 mmol). The reaction was irradiated with microwave on 300 watts, 100 °C for 10
minutes. The reaction was poured into aqueous potassium carbonate and extracted with ethyl
acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was
concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl
acetate in hexane to give the desired compound (601, 0.060 g, 59%).
Step 2 - Synthesis of[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridiTi-2-yl]-(5-fluoro-
pyridin-3-ylmethyl)-amine (P-0324):
10256] To[5-(l-benzenesulfonyl-5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-
(5-fluoro-pyridin-3-ylmethyl)-amine (601, 0.060 g, 0.12 mmol) in tetrahydrofuran (10.0 mL) was
added tetrabutylammonium fluoride, trihydrate (0.11 g, 0.35 mmol). The reaction was stirred at
room temperature overnight, then poured into water and extracted with ethyl acetate. The organic
layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and
purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to
give the desired compound (P-0324, 13.5mg, 31%). MS (ESI) [M+HT = 368.0.
Example 31: Synthesis of (3-Chloro-pyridLa-4-ylmethyl)-[5-(lH-pyrrolo[2)3-b]pyridin-3-
ylmethyl)-pyridin-2-yl]-aminc P-0183

10257] (3-Chloro-pyridin-4-yImethyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-
amine P-0183 was synthesized in 2 steps from 5-(l-benzenesulfonyl-lH-pyrrolo[2,3-b]pyridin-3-
ylmethyl)-pyridin-2-ylamine 600 as shown in Scheme 187.

Step I - Synthesis of[5-(l-benzenesutfonyl-lH-pyrrolo[2,3-h]pyridin-3-ylmethyl)-pyridin-2-yl]-
(4-chloro-pyridin-3-ylmethyl)-amme (602):
[0258| To 5-(l-benzenesulfonyl-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine (600,
120.0 mg, 0.33 mmol, prepared as described in Example 29, Scheme 18S) in acetonitrile (10.0 mL)
were added 3-chloro-pyridine-4-carbaldehyde (554, 51.3 mg, 0.36 mmol), trifluoroacetic acid
(0.30 mL, 0.0039 mol) and triethylsilane (0.60 mL, 0.0038 mol). The reaction was heated to reflux
overnight, then poured into aqueous potassium carbonate and extracted with ethyl acetate. The
organic layer was dried over anhydrous sodium sulfale and filtered. The filtrate was concentrated
and purified by silica gel column chromatography eluting with 30% to 100% ethyl acetate in
hexane to give the desired compound (602, 80 mg, 49.6%). MS [M+HT= 490.2.
Step 2 - Synthesis of(3-chloro-pyridin-4-ylmethyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-
pyridin-2-yl]-amine (P-0183):
[0259] To [5-(l -benzenesulfonyl-1 H-pvrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(4-chloro-
pyridin-3-ylmethyl)-amine (602, 0.08 g, 0.16 mmol) in tetrahydrofuran (10.0 mL) was added
tetrabutylammonium fluoride, trihydrate (0.240 g, 0.76 mmol). The reaction was stirred at room
temperature overnight. The reaction was concentrated and purified by silica gel column
chromatography eluting with 20% to 100% ethyl acetate in hexane to give a yellow solid (P-0183,
4.0 mg, 7%). MS (ESI) [M+HT = 350.2.
Example 32: Synthesis of [5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-
|6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylmethyl]-amine P-0409
[0260] [5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(5-fluoro-pyridin-3-
ylmethyl)-amine P-0409 was synthesized in 2 steps from 5-(l-benzenesulfonyl-5-chloro-lH-
pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine 599 as shown in Scheme 188.


Step 1 - Synthesis of[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-[6-(2,2,2-
trifluoro-ethoxy)-pyridin-3-ylmethyl]-amine(P-0409):
[02611 To5-(l-benzenesulfonyl-5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylniethyI)-pyridin-2-
ylamine (599, 124.1 mg, 0.31 mmol, prepared as described in Example 29, Scheme 185) in
ethanoi (3.00 mL) and acetic acid (0.2 mL) were added 6-(2,2,2-trifluoro-ethoxy)-pyridine-3-
carbaldehyde (603, 164.0 mg, 0.80 mmol) and silica supported cyanoborohydride (1.21 mmol/g,
0.700 g). The reaction was irradiated with microwave on 300 watts, 100°C for 150 minutes. To the
reaction was added a solution of potassium hydroxide (9.0 M in water, 1.0 mL). The reaction was
irradiated with microwave on 300 watts, 100 °C for 10 minutes. The reaction was poured into
aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over
anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel
column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired
compound (P-0409, 10.6 mg, 7.6%). MS ESI) [M+HT = 448.4.
Example 33: Synthesis of l-(3-fluoro-phenyl)-3-[5-(lH-pyrrolo|2,3-b]pyridin-3-ylmethyl)-
pyridin-2-ylJ-urea P-0412
fO262J l-(3-Fluoro-pheny])-3-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-urea
P-0412 was synthesized in 2 steps from 5-(l-benzenesuIfonyl-lH-pyrrolo[2,3-b]pyridin-3-
ylmethyl)-pyridin-2-ylamine 600 as shown in Scheme 189.

Step 1 - Synthesis ofl-[5-(I-benzenesulfonyl-IH-pyrroh[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-
3-(3-fluoro-phenyl)-urea (60S):

I0263J To 5-(l -benzenesulfonyl-1 H-pym>lo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine (600,
1S0.0 mg, 0.41 mmol, prepared as described in Example 29, Scheme 185) in acetonitrile (12.5 mL)
were added 3-fluoro-isocyanato-benzenc (604, 61.6 mg, 0.45 mmol), 4-dimethylaminopyridine
(10.0 mg, 0.082 mmol) and triethylamine (0.25 mL, 0.0018 mol). The reaction mixture was heated
at 70 °C overnight, then poured into water, and extracted with ethyl acetate. The organic layer was
dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by
silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a
white solid (605, 0.100 g, 48.4%).
Step 2 - Synthesis ofI-(3-Fluoro-phenyl)-3-[5-(lH-pyrroh(2,3-b]pyridin-3-ylmethyl)-pyridin-2-
ylj-urea (P-0412):
[0264) To l-[5-(l-benzenesulfonyl-lH-pyrrolo[2,3-bJpyridin-3-ylmethyl)-pyridin-2-yl]-3-(3-
fluoro-phenyl)-urea (605,0.100 g, 0.20 mmol) in tetrahydrofuran (10.0 mL) was added
tetrabutylammonium fluoride, trihydrate (0.240 g, 0.76 mmol). The reaction was stirred at room
temperature for 5 hours, then poured into water, and extracted with ethyl acetate. The organic layer
was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified
by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a
white solid (P-0412, 17.9 mg, 24.8%). MS (ESI) [M+HT = 362.2.
Example 34: Synthesis of (2-cbloro-bcnzyI)-[6-f]uoro-5-(lH-pyrrolo|2,3-bjpyridin-3-
ylmethyI)-pyridin-2-yl]-ainineP-0335
[0265) (2-Chloro-benzyl)-[6-fluoro-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-
amine P-0335 was synthesized in 2 steps from (5-bromo-6-fluoro-pyridin-2-yl)-(2-chloro-benzyl)-
amine 571 as shown in Scheme 190.

Step I -Synthesis of{6-(2-chloro-benzylamino)-2-fIuoro-pyridin-3-yl]-(l-triisopropylsilanyt-!H'
pyrrolo[2,3-b]pyridin-3-yl)-methanol (606):
[0266] To (5-bromo-6-fluoro-pyridin-2-yl)-(2-chloro-benzyl)-amine (571, 0.635 g, 2.01 mmol,
prepared as described in Example 21, Scheme 177) in tetrahydrofuran (25.0 mL) under an

atmosphere of nitrogen at -78 °C, a solution of n-butyllithium (2.50 M in hexane, 0.80 mL) was
added slowly. After 20 minutes, tert-butyllithium (1.7 M in hexane, 2.40 mL) was added to the
reaction and after 30 minutes, l-triisopropylsilanyl-lH-pyrrolo[2,3-b]pyridine-3-carbaldehyde (47,
0.575 g, 1.90 mmol) in tetrahydrofuran (8.0 mL) was added to the reaction. The reaction mixture
was stirred at -78 °C for 60 minutes, then allowed to warm to room temperature for another 10
minutes. The reaction mixture was poured into aqueous ammonium chloride and extracted with
ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated
and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in
hexane to give the desired compound (606,0.180 g, 17.6%). MS (ESI) [M+H*]+= 539.2.
Step 2 - Synthesis of(2-chhro-benzyl)-[6-fluoro-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-
2-ylJ-amine (P-0335):
[0267] To [6-(2-chloro-benzylamino)-2-fluoro-pyridin-3-yl]-(l-triisopropylsilanyl-1H-
pyrrolo[2,3-b]pyridin-3-yl)-methanol (606, 180.0 mg, 0.33 mmol) in acetonitrile (15.0 mL) were
added triethylsilane (1.00 mL, 6.26 mmol) and trifluoroacetic acid (0.50 mL, 6.50 mmol). The
reaction was heated to reflux for 2 hours, then poured into aqueous potassium carbonate and
extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and
filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting
with 20% to 100% ethyl acetate in hexane to give a white solid (P-0335, 24.9 mg, 19.4%). MS
(ESI) [M+HT = 367.0.
Example 35: Synthesis of l-benzenesulfonyl-5-chloro-3-(2-raethanesulfonyl-pyriinidin-5-
ylmethyl)-lH-pyrrolo[2,3-b]pYridine610
[0268] 1 -Benzenesulfonyl-5-chloro-3-(2-methanesulfonyl-pyrimidin-5-yImethyl)-1H-
pyrrolo[2,3-b]pyridine 610 was synthesized in 3 steps from l-benzcnesulfonyl-5-chloro-3-iodo-
lH-pyiToIo[2,3-b]pyridine 581 as shown in Scheme 191.
Scheme 191


Step 1 - Synthesis of(l-benzenesulfonyl-5-chloro-lH-pyrrolo[2,3-b]pyridin-3-yl)-(2-
methylsulfany!-pyrimidin-5-yl)-methanol (608):
[0269] To a solution of l-Benzenesulfonyl-5-chloro-3-iodo-IH-pvrrolo[2,3-b]pyridine (581,
4.36 g, J0.4 mmol) in tetrahydrofiiran (100.0 mL) at -40 °C under nitrogen, isopropylmagnesium
chloride (2.0 M in tetrahydrofuran. 5.06 mL) was added slowly. The reaction was allowed to warm
to 5 °C over 60 minutes, then cooled to -40 °C, followed by adding 2-methylsulfanyl-pyrimidine-
5-carbaldehyde (607, 1.30 g, 8.43 mmol, dissolved in tetrahydrofuran 15.0 mL). The reaction was
allowed to warm to 10 °C over 2 hours. The reaction was poured into aqueous ammonium chloride
and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and
filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting
with 2% to 15% methanol in dichloromethane to give the desired compound (608, 3.00 g, 79.6%).
MS (ESI) [M+H+]+ = 447.2.
Step 2 - Synthesis of l-benzenesulfonyl-5-chloro-3-(2'methylsulfanyl-pyrimidin-5-ylmethyl)-lH-
pyrrolo[2,3-b]pyridine (609):
[0270] To(l-benzenesulfonyl-5-chloro-lH-pyrrolo[2,3-b]pyridin-3-yl)-(2-methylsulfanyl-
pyrimidin-5-yl)-methanol (608, 0.35 g, 0.78 mmol) in dichloromethane (15.0 mL) were added
triethylsilane (2.00 mL, 12.52 mmol) and trifhioroacetic acid (1.00 mL, 13.0 mmol). The reaction
was stirred at 35 °C overnight, then concentrated, poured into aqueous potassium carbonate, and
extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and
filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting
with 20% to 100% ethyl acetate in hexane to give the desired compound (609, 0.25 g, 74%). MS
(ESI) [M+UT = 430.9.
Step 3 - Synthesis ofl-benzenesulfonyl-5-chloro-3-(2-methanesulfonyl-pyrimidin-5-yImethyl)-lH-
pyrrolo[2,3-b]pyridine (610) and l-benzenesulfonyl-5-chloro-3-(2-methanesul/inyt-pyrimidin-5-
ylmethyl)-lH-pyrrolo[2,3-bJpyridine (611):
[0271] To l-benzenesulfonyl-5-chloro-3-(2-methylsulfanyl-pyrimidin-5-ylmethyl)-lH-
pyrrolo[2,3-b]pyridine (609, 0.500 g, 1.16 mmol) in dichloromethane (15.0 mL) was added meta-
chloroperoxybenzoic acid (max. 77%, 0.572 g, 2.55 mmol) at 0 °C. The reaction was stirred at 0
°C for 70 minutes, then poured into water and extracted with ethyl acetate. The organic layer was
dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by
silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the
desired compounds (610, 0.310 g, 57.7%), MS (ESI) [M+HY = 463.1; and (611, 0.200 g, 38.6%),
MS (ESI) [M+HT = 447.2.

[02721 1 -Benzenesulfony l-3-(2-methanesulfonyl-pyrimidin-5 -ylmethyl)-1 H-pyrrolo[2,3-
bjpyridine 612

was prepared following the protocol of Scheme 191, substituting 1 -benzenesulfonyl-5-chloro-3-
iodo-lH-pyrrolo[2,3-b]pyridine 581 with l-benzenesulfonyl-3-iodo-lH-pyrrolo[2,3-b]pyridine in
Step 1.
Example 36: Synthesis of (4-chloro-benzyI)-[5-(5-chloro-lH-pyrrolo{2,3-b]pyridin-3-
ylmethyl)-pyriinidin-2-yll-ainineP-0260
|0273] (4-Chloro-benzyl)-[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyriinidin-2-yl]-
amine P-0260 was synthesized in 2 steps from l-benzenesulfonyl-5-chloro-3-(2-methanesulfonyl-
pyrimidin-5-ylmethyl)-lH-pyrrolo[2,3-b]pyridine 610 as shown in Scheme 192.
Scheme 192

Step I — Synthesis of[5-(l-benzenesulfonyl-5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-
pyrimidin-2-yl]-(4-chloro-benzyl)-amine (613):
[0274] To 1 -benzenesulfonyl-5-chloro-3-(2-methanesulfonyl-pyrirnidin-5-ylmethyl)-l H-
pyrrolo[2,3-b]pyridine (610,0.060 g, 0.13 mmol, prepared as described in Example 35, Scheme
191) in N-methylpyrrolidinone (1.80 mL) was added p-chlorobenzylamine (61,0.20 g, 1.4 mmol).
The reaction was irradiated with microwave on 300 watts, 150 °C for 15 minutes, then poured into
water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate
and filtered. The filtrate was concentrated and purified by silica gel column chromatography
eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (613, 0.05 g,
74%). MS (ESI) [M+HT = 524.3.
Step 2 - Synthesis of(4-chloro-benzyl)-[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-
pyrimidin-2-ylj'-aminc (P-0260):
|0275] To [5-( 1 -benzenesulfonyl-5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-

yl]-(4-chloro-benzy])-amine (613,0.050 g, 0.095 mmol) in tetrahydrofuran (10.0 mL) was added
tetrabutylammonium fluoride, trihydrate (0.20 g, 0.63 mmol) under an atmosphere of nitrogen.
The reaction was stirred at room temperature overnight, then poured into water, and extracted with
ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate
was concentrated and washed with ethyl acetate in hexane to give an off-white solid (P-0260,16.9
mg, 46%). MS (ESI) [M+HT = 385.9.
[0276] Additional compounds were prepared following the protocol of Scheme 192, substituting
p-chlorobenzylamine 61 with a suitable amine in Step 1. The following compounds were prepared
following this protocol:
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2,6-difluoro-benzyl)-amine
(P-0261),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-trifluoromethyl-ben2yl)-
amine (P-0262),
(2-Chloro-benzyl)-[5-(5-chloro-lH-pyrrolo[2,3-b]pvridin-3-ylmethyl)-pyrimidin-2-yl]-amine
(P-0263),
[5-(5-Chloro-lH-pvrrolo[2,3-b]pyridin-3-ylmethyl)-pvrimidin-2-yl]-(2-fluoro-benzyl)-amine
(P-0264),
[5-(5-Chloro-lH-pyn-olo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2,4-difluoro-benzyl)-amine
(P-0265),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pvridin-3-ylmethyl)-pyrimidin-2-yl]-(4-trifluoromethyl-benzyl)-
amine (P-0266),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pvridin-3-ylmethyl)-pyrimidin-2-yl]-(2,5-difluoro-benzyl)-amine
(P-0267), and
[5-(5-Chloro-lH-pyrroIo[2,3-b]pvridin-3-ylmethyl)-pyrimidin-2-yl]-(3-trifluoromethyl-benzyl)-
amine (P-0268).
The following table indicates the amine (Column 2) used in Scheme 192 to provide the compounds
(Column 3). Column 1 provides the compound number and Column 4 the experimental mass
spectrometry result.




Step I -Synthesis of(2-fluoro-5-trifluoromethyl-berayl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-
ylmethyl)-pyrimidin-2-yl]-amine (P-0291):
(0278] To 1 -benzenesulfonyl-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-l H-pyirolo[2,3-
bjpyridine (612,0.080 g, 0.19 mmol, prepared as described in Example 35, Scheme 191) in N-
methylpyrrolidinone (1.00 mL) was added 2-fluoro-5-trifluoromethyl-benzylamine (614, 0.20 g,
1.0 mmol). The reaction was irradated with microwave on 300 watts, 150°C for IS minutes.
Potassium hydroxide in water (1.00 M, 2.00 mL) was added to the reaction. The reaction was
irradiated with microwave on 300 watts, 90°C for 10 minutes, then poured into water and extracted
with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The
filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to
100% ethyl acetate in hexane to give a white solid (P-0291, 37.4 mg, 50%). MS (ESI) [M+HT]' =
402.6.
(0279] Additional compounds were prepared following the protocol of Scheme 193, substituting
2-fluoro-5-trifluoromethyl-benzylamine 614 with a suitable arnine. The following compounds
were prepared following this protocol:
(2,5-Difluoro-ben2yl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine(P-0292),
(2-Chloro-5-trifluoromethyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-
amine (P-0293),
(3-Fluoro-5-trifluoromethyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-
amine (P-0294),
(3,5-Difluoro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine(P-0295),
(2-Fluoro-benzyl)-[5-( 1 H-pyrTolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (P-0300),
(2-Chloro-benzyl)-(5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine(P-0301),
[5-(lH-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-trifluoromethyl-benzyl)-amine
(P-0302),
[5-(lH-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-trifluoromethoxy-benzyl)-amine
(P-0303),
(5-Chloro-2-fluoro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine
(P-0304),
(2,4-Dichloro-ben2yl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine(P-0305),
(2,4-Difluoro-benzyl)-[5-( 1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (P-0306),
(4-Chloro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine(P-0307),
[5-(lH-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-trifluoromethyl-benzyl)-amine
(P-0308),
(2-Fluoro-3-trifluoromethyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-

amine (P-0309),
(2,5-Dichloro-ben2yl)-[5-(lH-pyrrolot2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-aminc(P-0310),
(3-Chloro-2-fluoro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine
(P-0311),
(2-Difluoromethoxy-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyriniidin-2-yl]-amine
(P-0312),
(2,3-DichIoro-benzyl)-[5-( 1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-ainine (P-0313),
(4-Chloro-2-fluoro-ben2yl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine
(P-0314),
(5-Fluoro-2-trifluoromethyl-benzyl)-[5-{lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-
amine (P-0315),
(2-Chloro-4-fluoro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine
(P-0316),
(5-Chloro-2-methyl-benzyI)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine
(P-0317),
(5-Fluoro-2-methyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridm-3-ylmethyl)-pyrimidin-2-yl]-amine
(P-0318),
(2-Fluoro-4-trifluoromethyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-
amine (P-0319),
(4-Fluoro-2-trifluoromethyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-
amine (P-0320), and
(2-Chloro-5-fluoro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyI)-pyrimidin-2-yl]-amine
(P-0407).
The following table indicates the amine (Column 2) used in Scheme 193 to provide the compounds
(Column 3). Column 1 provides the compound number and Column 4 the experimental mass







Example 38: Synthesis of [5-(5-Cb]oro-lH-pyrroIo[2,3-b]pyrfdin-3-ylmethyl)-pyriinidin-2-
yl]-(2-difluoromethoxy-benzyl)-amineP-0390
[0280] [5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-difluoromethoxy-
benzyl)-amine P-0390 was synthesized in 1 step from l-benzenesulfonyl-5-chloro-3-(2-
methanesulfonyl-pyrirnidin-5-ylmethyl)-lH-pyrrolo[2,3-b]pyridine 610 as shown in Scheme 194.

Step 1 -Synthesis of |5-(5-Chloro-lH-pyrroIo|2,3-bIpyridin-3-yImethyl)-pyrimidin-2-yI]-(2-
difluoromethoxy-benzyl)-amine (P-0390)
[0281] To 1 -benzenesulfonyl-5-chloro-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-l H-
pyrrolo[2,3-b]pyridine(610, 0.060 g, 0.13 mmol, prepared as described in Example 35, Scheme
191) in N-methylpyrrolidinone (1.40 mL) was added 2-difluoromethoxy-benzylamine (615, 0.200
g, 1.16 mmol). The reaction was irradiated with microwave on 300 watts, 150 °C for 15 minutes.
Potassium hydroxide in water (1.00 M, 2.00 mL) was added to the reaction. The reaction was
irradiated with microwave on 300 watts, 90 °C for 10 minutes, then poured into ethyl acetate and
water. The organic layer was concentrated and purified by silica gel column chromatography
eluting with 20% to 100% ethyl acetate in hexane to give a white solid (P-0390, 10.9 mg, 20%).
MS(ESI)[M+HT = 418.0.
[0282] Additional compounds were prepared following the protocol of Scheme 194, substituting
2-difluoromethoxy-benzylamine 615 with a suitable amine. The following compounds were
prepared following this protocol:
[5-(5-Chloro-lH-pyrroIo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-fluoro-5-trifluoromethyl-
benzyl)-amine (P-0289),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(5-fluoro-2-trifluoromethyl-
benzyl)-amine (P-0391),

(3-ChIoro-2-fluoro-ben2:yl)-[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-
amine (P-0392),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylnaethyl)-pyrimidin-2-yl]-(2-fluoro-3-trifluoromethyI-
benzyl)-amine (P-0393),
[5-(5-Chloro-lH-pyrrolo[213-b]pyridin-3-ylmethyI)-pyriinidin-2-yI]-(2-fluoro-4-trifluoromethyl-
benzyl)-amine (P-0394),
[5-{5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2,3-difluoro-ben2yl)-amine
(P-0395),
(2-Chloro-4-fluoro-benzyI)-[5-(5-chloro-lH-pyrroIot2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yI]-
amine (P-0396),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-trifluoromethoxy-bcnzyl)-
amine (P-0402),
(2-Chloro-5-fluoro-benzyl)-t5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-
amine (P-O408),
[5-{5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-yImethy])-pyriinidin-2-yl]-pyridin-4-y]methyl-amine
(P-0416),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-pyrrolidin-l-yl-ethyl)-
amine (P-0417),
Benzyl-[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine(P-0418),
Benzyl-[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-methyl-amine
(P-0419),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-trifluoromethoxy-benzyl)-
amine (P-0420),
(3-Chloro-benzyl)-[5-(5-chloro-IH-pyrrolo[2,3-b]pyridin-3-ylmethyI)-pyrimidin-2-yl]-amine
(P-0421),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-pyridin-3-ylmethyl-amine
(P-0422),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-yImethyl)-pyrimidin-2-yl]-(4-fluoro-benzyl)-amine
(P-0423),
(3-Chloro-benzyl)-[5-(5-chIoro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-methyl-
amine (P-0424),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(3,5-difluoro-benzyl)-aniine
(P-0425),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-[l-(2-fluoro-phenyl)-ethyl]-
amine (P-0426),
[l-(4-Chloro-phenyl)-ethyl]-[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-
111

amine (P-0427),
[5-(5-Chloro-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyI)-pyrimidin-2-yl]-[(S)-1 -(4-fluoro-phenyl)-
ethyl]-amine (P-0428),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-pyrimidin-2-y]]-(6-trifluoromethyI-pyridin-3-
ylmethyl)-amine (P-0429),
(2-Chloro-ben2yl)-[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-pyrimidin-2-yl]-methyl-
amine (P-0430),
[5-(5-Chloro-lH-pyrTOlo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-{2-methyl-benzyl)-aniine
(P-0431),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl>pyriinidin-2-yl]-(2-methoxy-benEyI)-amine
(P-0433),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-morpholin-4-yl-ethyl)-
amine (P-0434),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-cyclohcxylmcthyl-amine
(P-0435),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-pyridin-2-ylmethyl-ainine
(P-0436),
[2-(4-Chloro-phenyl)-ethyl]-[5-(5-chloro-IH-pyrrolo[2,3-b]pyridin-3-ylmethyI)-pyrimidin-2-yl]-
amine (P-0437),
t5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-yImethyl)-pyriniidin-2-yl]-(4-difluoromelhoxy-benzyl)-
amine (P-0438),
t5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-methoxy-benzyl)-amine
(P-0439),
[5-(5-Chloro-lH-pym)Io[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-{4-methyl-benzyI)-amine
(P-0440),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-methoxy-ethyl)-amine
(P-0441),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(3-fluoro-benzyl)-aminc
(P-0442),
(3-Chloro-4-fluoro-benzyl)-[5-(5-chloro-lH-pyrrolot2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-
amine (P-0443),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmelhyl)-pyrimidin-2-yl]-(2-ethoxy-benzyl)-amine
(P-0444),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethy])-pyrimidin-2-yl]-(4-morpholin-4-yl-benzyl>
amine (P-0445),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(3-difluoromethoxy-benzyl)-
134









Example 39: Synthesis of (2-chloro-6-nuoro-benzyl)-|5-(lH-pyrrolo[2,3-b]pyridin-3-
y lmetbyl)-pyridin-2-yl|-amine P-0210
[0283J (2-Chloro-6-nuoro-bcn2yl).[5-(lH-pyrrolo[2,3-bJpyridin-3-ylmethyl)-pyridin-2-ylJ-
amine P-0210 was synthesized in 2 steps from 5-(l-BenzenesulfonyMH-pyrrolo[2,3-b]pyridin-3-
ylmethyl)-pyridin-2-ylamine 600 as shown in Scheme 195.

Step I -Preparation of[5-(l-benzenesulfonyl-lH-pyrrolo[2,3-b]pyridin-3-ylmeihyl)-pyridin-2-
yl]-(2-chloro-6-fluoro-benzyl)-amine (617):
(02841 5-(l-Benzenesulfonyl-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine (600, 30
mg, 0.083 rnmol, prepared as described in Example 29, Scheme 185) was combined with 2-chloro-
6-fluoro-benzaldehyde (616, 26.2 mg, 0.165 mmol) in a 2 mL microwave reaction vial. The
mixture was dissolved in ethanolracetic acid (95:5, 0.6 mL). Silica supported cyanoborohydride
(1.0 mmol/g, 83 mg, 0.083 mmol) was added and the mixture was irradiated with microwave on
300 watts for 5 minutes at 100 °C. The silica was separated by centrifuging and the supernatant
solution was decanted. The silica residue was rinsed with ethanol (0.500 mL) and centrifuged. The
solvents were combined and removed under reduced pressure to give compound 617, which was
used in the next step without further purification.
Step 2 - Preparation of(2-chloro-6-fluoro-benzyl)-[5-(lH-pyrroto[2.3-b]pyridin-3-ylmethyl)-
pyridin-2-ylJ-amine (P-0210):
[0285] [5-(l-Benzenesulfonyl-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-chloro-6-
fluoro-benzyl)-amine 617 was combined with methanol:potassium hydroxide (1M) (1:1, 0.5 mL).
The mixture was heated at 80 °C for 2 hours. Acetic acid (0.1 mL) was added and the solvents
removed under reduced pressure. The remaining residue was dissolved in dimethylsulfoxide (0.4
mL) and purified by reverse phase HPLC on a Phenomenex column (50mm x 10mm ED) eluting
with 0.1 % trifluoroacetic acid in water and 20-100 % acetonitrile with 0.1% trifluoroacetic acid
over 16 minutes at a flow rate of 6 mL/minute to provide the desired compound P-0210. MS (ESI)
[M+HT= 367.1.

(0286] Additional compounds were prepared following the protocol of Scheme 195, replacing
2-chloro-6-fluoro-benzaldehyde 616 with an appropriate aldehyde in Step 1. The following
compounds were made following this procedure:
Phenethyl-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(P-0211),
(2,4-Difluoro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylniethyl)-pyridin-2-yl]-amine(P-0212),
(2-Fluoro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(P-0213),
(3-Bromo-pyridin-4-yImethyI)-[5-(IH-pyrrolo[2,3-bJpyridm-3-ylmethyl)-pyridin-2-yl]-amine(P-
0214),
(2-Methoxy-pyridin-3-ylmethyl)-[5-(lH-pyrrolot2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine
(P-0215),
(2-Chloro-benzyl)-[5-( 1 H-pyrrolo[2,3-b]pyridin-3-yImethyl)-pyridin-2-yl]-amine (P-0216),
(2-Methyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(P-0217),
(1 -Methyl-1 H-benzoimidazol-2-ylmethyl)-[5-( 1 H-pyrrolo[2,3-bJpyridin-3-ylmethyl)-pyridin-2-
yl]-amine(P-0218),
(6-Methoxy-pyridin-3-ylmethyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine
(P-0219),
(1 H-Benzoimidazol-2-ylmethyl)-[5-( 1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine
(P-0220),
(2-Chloro-4-fluoro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(P-
0221),
(5-Methoxy-pyridin-3-ylmethyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine
(P-0222),
(3-Fluoro-pyridin-4-ylmethyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-yImethyl)-pyridin-2-yl]-amine(P-
0223),
(6-Methoxy-pyridin-2-ylmethyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine
(P-0224),
(4-Fluoro-2-trifluoromethyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-
amine (P-0225),
[5-(lH-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-trifluoromethyl-benzyl)-amine
(P-0226),
(3,5-Dichloro-pyridin-4-ylmethyl)-[5-(lH-pyrrolo[213-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine
(P-0227),
(6-Morpholin-4-yl-pyridin-2-ylmethyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-
amine (P-0228),
(3-Fluoro-pyridin-2-ylmethyl)-[5-( 1 H-pyrrolo[2,3-b]pyridin-3-yImethyI)-pyridin-2-yl]-amine (P-
0229),

(5-Fluoro-pyridin-3-ylmethyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-aniine
(P-0230),
(2,4-Dichloro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(P-0342),
(3-Fluoro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(P-0343),
(2-Fluoro-4-trifluoromethyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-pyridin-2-yIJ-
amine (P-0344),
(4-ChIoro-2-fluoro-ben2yl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(P-
0345),
(3-Fluoro-5-trifluoromethyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-
amine (P-0346),
(2-Morpholin-4-yl-pyridin-3-ylmethyl)-[5-(lH-pyrroIo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-
amine (P-0347),
(4-Chloro-3-trifluoromethyl-benzyl)-[5-(lH-pyrroIo[2,3-bJpyridin-3-ylmethyI)-pyridin-2-yl]-
amine (P-0348),
(2-Chloro-5-trifluoromethyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-
amine (P-0349),
(2-Fluoro-5-trifluoromethyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmelhyl)-pyridin-2-yl]-
amine (P-0350),
(2,3-Dichloro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(P-0351),
(2-Fluoro-3-methoxy-benzyl)-[5-(lH-pyrTolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-
0352),
Dimethyl-(5-{[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamino]-methyl}-pyrimidin-2-
yl)-amine (P-0353),
(3-Chloro-2-fluoro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(P-
0354),
(5-Fluoro-pyridin-2-ylmethyl)-[5-(lH-pynrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(P-
0355),
(3(5-Difluoro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(P-0356),
(2-Propoxy-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-y)]-amine(P-0357),
(2-Morpholin-4-yl-benzyl)-[5-( 1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-
0358),
(2-Chloro-3-methoxy-benzyl)-[5-(lH-pynolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(P-
0359).
(2-Fluoro-6-trifluoromethyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylniethyl)-pyridin-2-yl]-
amine (P-0360),
[2-(2-Morpho]in-4-yl-ethoxy)-benzyl]-[5-(lH-pyrrolo[2,3-b]pyridin-3-yImethyl)-pyridin-2-yl]-

amine (P-0361),
(Z.S-Difluoro-benzyO-fS-ClH-pyrroJop.S-bJpyridinO-ylmcthyiJ-pyridin-Z-ylJ-amineCP-Ojei),
(2-Chloro-3-trifluoromethyl-ben2yl)-[5-(lH-pyiToJo[2,3-b]pyridin-3-y]methyl)-pyridin-2-yJ]-
amine (P-0363),
(2-Chloro-5-fluoro-benzyl)-[5-(lH-pyrrolo[2>3-b]pyridin-3-ylniethyl)-pyridin-2-yI]-amine(P-
0364),
(2-Fluoro-3-trifluoromethyl-ben2yl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yI]-
amine (P-0365),
(5-Fluoro-2-niethoxy-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(P-
0366),
(2-Difluoromethoxy-benzyl)-[5-( 1 H-pyirolo[2,3-b]pyridin-3-ylmethyI)-pyridin-2-yl]-amine (P-
0367),
(2-F]uoro-4-methyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyI)-pyridin-2-yl]-amine(P-
0368),
[2-(3-Dimethylamino-propoxy)-benzyl]-[5-(lH-pyrrolof2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-
amine (P-0369),
(2,6-Dimethoxy-pyridin-3-ylmethyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-
amine (P-0370),
(2-Fluoro-5-methoxy-benzyl)-[5-( 1 H-pyrT0lo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-
0371),
(4-Fluoro-2-methyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(P-
0372),
(3-Chloro-5-fluoro-benzyl)-[5-(]H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(P-
0373),
(6-Cyclopentyloxy-pyridin-3-yImethyl)-[5-(lH-pyrro]o[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-
amine (P-0374),
(5-Fluoro-2-trifluoromethyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yI]-
amine (P-0375),
[5-(lH-Pyrrolo[2,3-b)pyridin-3-ylmethyl)-pyridin-2-yJ]-[2-(2,2,2-trifluoro-ethoxy)-pyridin-3-
ylmethyl]-amine (P-0376),
Propane-1 -sulfonic acid (2-fluoro-3- {[5-(l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-
ylamino]-methyl}-phcnyl)-ainide(P-0377),
(2,5-Dichloro-benzyl)-[5-(lH-pyn-oIo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(P-0380)>
Pyrimidin-5-ylmethyl-[5-(lH-pyrrolo[2I3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(P-0381)1
(5-ChJoro-2-fluoro-benzyl)-[5-( 1 H-pyrrolot2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-
0382),

(2-Ethy]-benzyI)-[5-(lH-pyrro]o[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-aminc(P-0383),
2)2-Dimethyl-N-(3-{t5-(lH-pyrrolo[2,3-b]pyridin-3-ylmeihyl)-pyridin-2-ylamino]-methyl}-
pvridin-2-yl)-propionamide(P-0384),
Methyl-(3-{[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamino]-methyl}-pyridin-2-yl)-
aminc (P-0385),
Methyl-(5-{[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yIamino]-methyI}-pyrimidin-2-
yl)-amine (P-0386),
(2-Chloro-4-methanesulfonyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-pyridin-2-yl]-
amine (P-0387),
(5-Fluoro-2-methyl-benzyl)-(5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(P-
0397),
(2,2-Difluoro-benzo[l,3]dioxol-4-ylmethyI)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-
yl]-amine (P-0398),
Dimethyl-(3-{f5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamino]-methyl}-pyridin-2-
yl)-amine (P-0399),
(5-Chloro-pyridin-3-ylmethyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-pyridin-2-yl]-amuie(P-
0400), and
(2-Methoxy-pyrimidin-5-ylmethyl)-[5-(lH-pyrrolof2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine
(P-0401).
The following table indicates the aldehyde (Column 2) used in Step 1 of Scheme 195 to provide
the compounds (Column 3). Column 1 provides the compound number and Column 4 the















Example 40: Synthesis of I4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-bJpyridin-3-ylrnethyl)-
thiazol-2-ylJ-(6-methoxy-pyridin-3-ylrjiethyl)-ainine P-0190
[0287) [4-ChIoro-5-(5-chloro-lH-pyrro]o[2,3-b]pyridin-3-yIraethyl)-thiazoI-2-yl]-(6-methoxy-
pyridin-3-yImethyl)-amine P-0190 was synthesized in 2 steps from 5-(l-benzenesulfonyI-5-chloro-
lH-pyrroIo[2,3-b]pyridin-3-ylmethyl)-4-chloro-thiazol-2-ylamine592 as shown in Scheme 196.

Step I - Preparation of [5-(]-benzenesulfonyl-5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-
chloro-lhiazol-2-yl]-(6-methoxy-pyridin-3-ylmethyl)-amine (619):
|0288] S-Cl-Benzenesulfonyl-S-chloro-lH-pyrrolofZ^-bJpyridinO-ylmethylH-chloro-thiazoI-
2-ylamine (592, 30 mg, 0.083 mmol, prepared as described in Example 27, Scheme 183) was
combined with 6-methoxy-pyridine-3-carbaldehyde (618, 26.2 mg, 0.165 mmol) in a 2 mL
microwave reaction vial. The mixture was dissolved in ethanol: acetic acid (95:5, 0.6 mL). Silica
supported cyanoborohydride (1.0 mmol/g, 83 mg, 0.083 mmol) was added and the mixture was
irradiated with microwave on 300 watts for 5 minutes at 100 °C. The silica was separated by
cenlrifuging and the supernatant solution was decanted. The silica residue was rinsed with ethanol
(0.S00 mL) and centrifuged. The solvents were combined and removed under reduced pressure to
give the desired compound 619, which was used without further purification.
Step II- Preparation of[4-chIoro-5-(5-chloro-JH-pyrrolo[2.3-b]pyridin-3-ylmethyl)-thiazol-2-
yl]-(6-methoxy-pyridin-3-ylmethyl)-amine(P-0I90):

[0289) [5-(l-Benzenesulfonyl-lH-pyfTolo[2,3-b]pyridin-3-ylraethyl)-4-chloro-thiazol-2-yI]-(6-
methoxy-pyridin-3-ylmethyl)-amine 619 was combined with methanol: potassium hydroxide (1M)
(1:1,0-5 mL). The mixture was heated at 80 "C for 2 hours. Acetic acid (0.1 mL) was added and
the solvents removed under reduced pressure. The remaining residue was dissolved in
dimethylsulfoxide (0.4 mL) and purified by reverse phase HPLC on a Phenomenex column (50mm
x 10mm ID) eluting with 0.1 % triiluoroacetic acid in water and 20-100 % acetonitrile with 0.1%
trifluoroacetic acid over 16 minutes at a flow rate of 6 ml/minute to provide the desired compound
P-0190. MS (ESI) [M+HT= 419.9.
|0290] Additional compounds were prepared following the protocol of Scheme 196, replacing
6-methoxy-pyridine-3-carbaldehyde 618 with a suitable aldehyde in Step 1. The following
compounds were made following this procedure:
[4-Chloro-5-(5-chloro-lH-pyrroIo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-thiazol-2-ylrflethyl-
amine(P-0189),
Benzyl-[4-chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-amine(P-0192),
[4-Chloro-5-(5-chloro-IH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(3-methoxy-benzyl)-
amine (P-0193),
(4-Chloro-berjzyl)-[4-chloro-5-(5-chloro-lH-pyrrolof2,3-b]pyridin-3-ylmethyl)-thiazoI-2-yl]-
amine (P-0194),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thia2ol-2-yl]-(4-fluoro-benzyl)-
amine (P-0195),
t4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2,4-dimethyl-thiazol-5-
ylmethyO-amine (P-0196),
[4-Chloro-5-(5-chIoro-1 H-pyrrolo[2,3-b]pyridin-3 -ylmethyl)-thiazol-2-yl]-(2-ethyl-5-methyl-3H-
imidazol-4-ylmethyl)-amine (P-0197),
[4-Chloro-5-(5-chloro-lH-pyrTolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-ethyl-2H-pyrazol-3-
ylmethyl)-amine (P-0198),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-methoxy-pyridin-2-
ylmethyl)-amine (P-0199),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pvridin-3-ylinethyl)-thiazol-2-yl]-(3-fluoro-pyridin-4-
ylmethyO-amine (P-0200),
[4-Chloro-5-(5-chloro-lH-pyn-olo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-methyl-thiazol-4-
ylmethyl)-amine (P-0201),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-methyl-thiazol-5-
ylmethyl)-amine (P-0202),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(5-chloro-pyridin-2-

ylmethyl)-amine (P-0203),
H-Chloro-S-CS-chloro-lH-pyrrolop.S-bJpyridin-S-ylmethyO-thiazol^-ylJ-pyridinO-ylmethyl-
amine (P-0236),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-pyridin-4-ylmethyl-
amine (P-0237),
[4-ChIoro-5-(5-chloro-lH-pyrrolo[213-b]pyridin-3-ylmcthyl)-thiazoI-2-yl]-(3-chIoro-pyridin-4-
ylmethyl)-amine (P-0238),
[4-Chloro-5-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-( 1 -ethyl-1 H-pyrazol-4-
ylmethyl)-amine (P-0239),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(5-fluoro-pyridin-2-
ylmethylj-amine (P-0240),
[4-Chloro-5-(5-chloro-lH-pyrroIo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(5-methoxy-pyridin-3-
ylmethyl)-amine (P-0241),
[4-Chloro-5-(5-chloro-lH-pyrro!ot2,3-b]pyridin-3-ylinethyl)-thiazol-2-yJ]-(6-trifluoromethyl-
pyridin-3-ylmethyl)-amine(P-0242),
[4-Chloro-5-(5-chloro-lH-pyrroIo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-chloro-6-nuoro-
benzyl)-amine (P-0243),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-phenethyl-aminc
(P-0244),
[4-Chloro-5-(5-chloro-lH-pyrTolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2,4-difluoro-benzyl)-
amine (P-0245),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yI]-(2-fluoro-bcnzyl)-
amiue (P-0246),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyI)-thiazol-2-yl]-(2-methoxy-pyridin-3-
ylmethyl)-amine (P-0247),
(2-Chloro-benzyl)-[4-chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-
amine (P-0248),
[4-Chloro-5-(5-chloro-lH-pyrTolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-methyl-benzyl)-
amine (P-0249),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-bJpyridin-3-ylmethyl)-thiazol-2-yl]-(2-chloro-4-fluoro-
benzyl)-amine (P-0250),
[4-Chloro-5-(5-chloro-lH-pyfTolo[2,3-b]pyridin-3-yImethyl)-thiazol-2-yl]-(3-fluoro-pyridin-2-
ylmethyl)-amine (P-0251),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]p>Tidin-3-yImethyl)-thiazol-2-yl]-(6-morpholin-4-yl-
pyridin-2-ylmethyl)-amine(P-0252),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(3,5-dichloro-pyridin-4-

ylmethyl)-amine (P-0253),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylinethyl)-thia2ol-2-yl]-(2-trifluoromethyl-
benzyl)-amine (P-0254), and
[4-Ch)oro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-methyl-pyridin-2-
ylmethyl)-amine (P-0255).
The following table indicates the aldehyde (Column 2) used in Step 1 of Scheme 196 to provide
the compounds (Column 3). Column 1 provides the compound number and Column 4 the











Example 41: Synthesis of 5-|l-(lH-pyrrolo{2,3-b]pyridin-3-yl)-ethyl]-pyridin-2-yl-(4-
trifluoromethyl-benzyl)-aminc P-0388
[02921 5-[l-(lH-Pyrrolo[2,3-b]pyridin-3-yl)-ethyl]-pyridin-2-yl-(4-trifluororuethyl-benzyl)-
amine P-0388 was synthesized from (5-bromo-pyridin-2-yl)-(4-trifluoromethyl-benzyl)-amine 17
as shown in Scheme 197.

Step 1 - Preparation of l-[6-(4-trifluoromethyl-benzylamino)-pyridin-3-yl]-ethanone (620):
|0293] (5-Bromo-pyridin-2-yl)-(4-trifluoromethyl-benzyl)-amine (17, 3.00 g, 9.06 mmol) was
dissolved in tetrahydrofuran (80 mL). The reaction was cooled at -78 °C under an atmosphere of
argon. 2.5 M n-butyllithium in hexane (10.9 mL) was added. The reaction was stirred at -78 °C for
60 minutes. N-Methoxy-N-methylacetamide (1.93 mL, 18.1 mmol) was added to the reaction,
which was allowed to warm to room temperature. The reaction was poured into 1M ammonium
chloride and brine and extracted with ethyl acetate. The organic portions were dried with
anhydrous sodium sulfatc, filtered and the filtrate was adsorbed onto silica. The mixture was
purified by silica gel chromatography (ethyl acetate: hexanes) to provide the desired compound as
an oil that crystallized to a white solid (620,1.328 g, 50%), consistent with the compound structure
by 'H-NMR and MS(ESI): [M+HT=295.3.
Step 2 - Preparation of(5-acetyl-pyridin-2-yl)-(4-trifluoromethyl-benzyl)-carbamic acid tert-butyl
ester (621):
[0294] To l-[6-(4-trifluoromethyl-benzylamino)-pyridin-3-yl]-ethanone (620, 1.30 g, 4.42
mmol) in tetrahydrofuran (15.0 mL) were added di-tert-butyldicarbonate (1.10 g, 5.04 mmol), 4-
dimethylaminopyridine (0.0259 g, 0.21 mmol) and N,N-diisopropylethylamine (0.888 mL, 5.10
mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature for 3 days.

The mixture was extracted with ethyl acetate and saturated sodium bicabonate. The organic
portions were dried with anhydrous sodium sulfate, filtered and the filtrate was adsorbed onto
silica. The mixture was purified by silica gel chromatography (0-15% ethyl acetate:hexanes) to
provide the desired compound as an oil that solidified to a white solid (621, 1.29g, 74%),
consistent with the compound structure by 'H-NMR.
Step 3 - Preparation ofJ-[6-(4-trifluoromethyl-benzylamino)-pyridin-3-yl]-l-(l-
triisopropylsilanyl-1 H-pyrrolo[2,3-b]pyridin-3-yl)-ethanol (622):
|0295] 3-Iodo-l -triisopropylsilanyl-1 H-pyrrolo[2,3-b]pyridine (96,485.9 mg, 1.21 mmol) was
dissolved in tetrahydrofuran (8 mL) at -20 °C under an atmosphere of nitrogen. 2.0 M
isopropylmagnesium chloride in tetrahydrofuran (0.655 mL) was added. The reaction was stirred
at -20 °C for 1 hour. Into the reaction was added (5-acetyl-pyridin-2-yl)-(4-trifluoromethyl-
benzyl)-carbamic acid tert-butyl ester (621, 300.0 mg, 0.76 mmol) in tetrahydrofuran (6 mL) The
reaction was allowed to warm to room temperature overnight. The mixture was extracted with
ethyl acetate and saturated sodium bicabonate. The organic portions were dried with anhydrous
sodium sulfate, filtered and the filtrate was adsorbed onto silica. The mixture was purified by silica
gel chromatography on the (ethyl acetate.hexanes), to provide the desired compound as an oil
(622, 125 mg, 29%), consistent with the compound structure by ' H-NMR.
Step 4 - Preparation of5-[l-(lH-pyrrolo[2,3-b]pyridin-3-yl)-vinyl]-pyridin-2-yl-(4-
trifluoromethyl-benzyt)-amine (623):
[0296] l-[6-(4-Trifluoromethyl-benzylamino)-pyridin-3-yl]-l-(l-triisopropylsilanyl-1 H-
pyrro!o[2,3-b]pyridin-3-yl)-ethanol (622, 125.0 mg, 0.22 mmol) was dissolved in acetonitrile (11.7
mL) and trifluoroacetic acid (0.175 mL, 2.3 mmol) and triethylsilane (0.292 mL, 1.8 mmol) were
added. The reaction was heated to reflux overnight. The reaction was concentrated, then washed
with ethyl acetate and saturated sodium bicarbonate. The organic portions were dried with
anhydrous sodium sulfate, filtered and the filtrate was adsorbed onto silica. The mixture was
purified by silica gel chromatography (0-60% ethyl acetateihexanes) to provide the desired
compound (623,43 mg, 50%), consistent with the compound structure by 'H-NMR.
Step 5 - Preparation of5-[I-(lH-pyrrolo[2,3-b]pyridin-3-yl)-ethyl]-pyridin-2-yl-(4-
trifluoromethyl-benzyl)-amim(P-0388):
[0297] 5-[l -(1 H-Pyrrolo[2,3-b]pyridin-3-yl)-vinyl]-pyridin-2-yl-(4-trifluoromethyl-benzyl)-
amine (623, 0.043 g, 0.00011 mol) was dissolved in tetrahydrofuran (10 mL) and methanol (10
mL). The reaction was shaken under an atmosphere of hydrogen (30 psi) overnight. The reaction
was filtered through Celite and the filtrate adsorbed onto silica and purified by silica gel column
chromatography (ethyl acetate:hexanes) to provide the desired compound as a white solid (P-0388,

2.1 mg, 5%), consistent with compound structure by 'H-NMR and MS(ESI): [M+H+]+=397.6.
Example 42: Synthesis of [5-{5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-
(4-fIuoro-benzyl)-amine P-0290
[0298] [5-(5-Chloro-lH.pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyl)-amine
P-0290 was synthesized in four steps from (4-fluoro-benzyl)-(4-chloro-5-formyl-thiazol-2-yl)-
carbaraic acid tert-butyl ester 624 as shown in Scheme 198.
Scheme 198

Step I - Preparation of(4-/luoro-benzyl)-(4-chloro-5-formyl-thiazol-2-yt)-carbamic acid tert-butyl
ester (625):
[0299] To a solution of (4-fluoro-benzyl)-(4-chloro-5-formyl-thiazol-2-yl)-carbamic acid tert-
butyl ester (624,1 g, 2.70 mmol, prepared as described in Example 5, Scheme 159, Step 2, where
4-(aminomethyl)pyridine 516 is replaced with p-fluorobenzylamine, i.e. intermediate in preparing
compound P-01S6) in methanol (100 mL) was added Pd/C (100 mg, 50% water wet) and sodium
acetate (660 mg, 8.09 mmol) and the mixture was shaken under an atmosphere of hydrogen (50
psi) overnight observing ~50% conversion by LC/MS. The mixture was filtered over a bed of
Celite and the solvent was removed in vacuo and purified by silica gel chromatography (ethyl
acetate/heptane) to provide the desired compound as an off-white solid (450 mg, 50 %), consistent
with compound structure by 'H-NMR.
Step 2 - Preparation of {5-[(5-chloro-l -triisopropylsilanyl-l H-pyrrolo[2.3-bJpyridin-3-yl)-
hydroxy-methyl]-thiazol-2-yl}-(4-fluoro-benzyl)-carbamic acid tert-butyl ester (627):
[0300] To a solution of 5-chloro-3-iodo-1 -(triisopropyIsilyl)-1 H-pyrroLo[2,3-b]pyridine (626,
300 mg, 0.69 mmol) in tetrahydrofuran (10 mL) at -20 "C was added dropwise iso-propyl-

magnesium chloride (2M in tetrahydrofuran, 0.44 mL, 0.88 mmol). The reaction mixture was
allowed to warm to 0 °C over 10 minutes and then cooled to -40 °C. To this reaction mixture was
added a solution of (4-fluoro-benzyl)-(4-chloro-5-formyl-thia2ol-2-yl)-carbamic acid tert-butyl
ester (625, 211 mg, 0.63 mmol) in tetrahydrofuran (S mL). The reaction mixture was allowed to
warm to 0 CC over 30 minutes and then quenched with brine (50 mL). The mixture was transferred
to a separately funnel and the layers were separated. The organic layer was dried over sodium
sulfate and evaporated in vacuo to give the crude material which was purified by silica gel column
chromatography (0-30% ethyl acetate/heptane) to provide the desired compound as a foam (120
mg, 30%), consistent with structure by 'H-NMR.
Step 3 - Preparation of[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-
fluoro-benzyl)-carbamic acid tert-butyl ester (628):
[0301] To a solution of {5-[(5-chloro-l-triisopropylsilanyl-lH-pyrrolo[2,3-b]pyridin-3-yl)-
hydroxy-methyl]-thiazol-2-yl}-(4-fluoro-benzyl)-carbamic acid tert-butyl ester (627, 120 mg,
0.186 mmol) in acetonitrile (3 mL) was added trifluoroacetic acid (0.14 mL, 1.86 mmol) and
triethylsilane (0.30 mL, 1.86 mmol). The resulting mixture was stirred for 2 hours at 40 °C. The
solvent was then removed in vacuo and the residue was used directly in the next step.
Step 4: Preparation of [S-(5-chloro-lH-pyrrolo[2,3-bJpyridin-3-ylmethyIJ-thiazol-2-ylJ-(4-fluoro-
benzyl)-amine (P-0290):
[0302] To the solution of crude [5-(5-chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yI]-
(4-fluoro-benzyl)-carbamic acid tert-butyl ester (628,0.186 mmol theory) in dichloromethane (5
mL) at room temperature was added trifluoroacetic acid (1 mL) and the reaction was allowed to
stir overnight. The solvent was removed in vacuo and the residue taken up in ethyl acetate and
then washed with saturated aqueous potassium carbonate making sure basicity was reached. The
layers were separated and the aqueous layer was back-extracted with ethyl acetate. The combined
organic layers were dried over sodium sulfate and evaporated in vacuo to give the crude compound
which was purified by silica gel chromatography (0-10% methanol/ethyl acetate). The solvent was
removed in vacuo and the material was triturated with dichloromethane to give the desired
compound as an off-white solid (20 mg, 29 % over 2 steps) consistent with compound structure by
'H-NMR and MS(ESI): [M+H+]+=372.9.



was synthesized following the protocol of Scheme 198, replacing 5-chloro-3-iodo-l-
(triisopropylsilyl)-lH-pyrrolo[2,3-b]pyridine 626 with 3-iodo-l-triisopropylsilanyl-lH-
pyrrolo[2,3-b]pyridine 96, to provide the desired compound, consistent with structure by 1H-NMR
and MS(ESI): [M+H+]*=339.0.
Example 43: Synthesis of (5-chloro-lH-pyrroIo|2,3-b)pyrldin-3-yl)-[2-ethyl-5-(4-fluoro-
benzylamino)-2H-pyrazol-3-yl]-methanone P-0184
|0304] (5-Chloro-l H-pyrrolo[2,3-b]pyridin- 3-yI)-[2-ethyl-5-(4-fluoro-benzylamino)-2H-
pyrazol-3-yl]-raethanone P-0184 was synthesized from 5-chloro-lH-pyrrolo[2,3-b]pyridine 532 in
1 step as shown in Scheme 199.

Step 1 - Synthesis of(5-chloro-lH-pyrrolo[2,3-b]pyridin- 3-yl)-[2-ethyl-5-(4-Jluoro-benzylamino)-
2H-pyrazol-3-yl]-methanone (P-0184):
[0305] S-Chloro-lH-pyrrolo[2,3-b]pyridine (532,0.068 g, 0.44 mmol) was combined with
methanol (10 mL) and potassium hydroxide (0.16 g, 2.8 mmol). The mixture was stirred for SO
minutes, then 2-ethyl-5-(4-fluoro-benzylamino)-2H-pyrazole-3-carbaldehyde (530, 0.100 g, 0.40
mmol, prepared as described in Example 8, Scheme 162, Step 5) was added and the reaction was
stirred overnight at room temperature and then concentrated. Ethyl acetate was added and the
mixture was washed with sodium bicarbonate saturated solution and brine. After drying over
anhydrous sodium sulfate the solvent was removed under reduced pressure. Purification with silica
gel column chromatography eluting with a gradient of ethyl acetate (10-100%) in hexanes
provided the desired compound (0.0033 g. 2%). MS (ESI) [M+H+]+ = 398.1.

Example 44: Synthesis of [5-(S-chioro-lH-pyrroIo[2,3-b|pyridin-3-ylmetbyI)-l-ethyl-lH-
pyrazol-3-yl]-(4-fluoro-benzyl)-amine P-018S
[0306] tS-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyI)-l-cthyi-lH-pyrazol-3-yl]-(4-fluoro-
benzyl)-amine P-0185 was synthesized from 5-chloro-3-iodo-l-triisopropylsilanyI-lH-pyrrolo[2,3-
b]pyridine 629 in 2 steps as shown in Scheme 200.

Step 1 - Synthesis of(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-yl)-[2-ethyl-5-(4-fluoro-benzylamino)-
2H-pyrazoI-3-yl] -methanol (630):
[0307] 5-Chloro-3-iodo-l-triisopropylsilanyl-lH-pyrrolo[2,3-b]pyridine (629, 0.15 g, 0.34
mmol) was dissolved in tetrahydrofuran (3 mL, 40 mmol) and the solution was cooled to -20 °C. 2
M isopropylmagnesium chloride in tetrahydrofuran (200 μL) was added dropwise and the reaction
was stirred and allowed to warm to -5 °C. After the reaction was cooled to -20 °C, 2-ethyl-5-(4-
fluoro-benzylamino)-2H-pyrazole-3-carbaldehyde (530,0.043g, 0.17 mmol, prepared as described
in Example 8, Scheme 162, Step 5) in tetrahydrofuran (4 mL) was added to the mixture. The
reaction was stirred and allowed to warm to -5 °C, then concentrated, ethyl acetate was added and
the mixture was washed with sodium bicarbonate saturated solution and brine. After drying over
anhydrous sodium sulfate, the solvent was removed under reduced pressure. Purification with
silica gel column chromatography eluting with a gradient of ethyl acetate (5-80%) in hexanes gave
the desired compound (630, 0.038 g, 40%).
Step 2 - Synthesis of5-(5-chloro-lH-pyrrolo[2,3-b]pyrid in-3-ylmethyl)-l-ethyl-lH-pyra2ol-3 -yl]-
(4-fluoro-benzyl)-amine (P-0185):
[0308] (5-Chloro-l-triisopropylsilanyl-lH-pyrrolo[2,3-b]pyridin-3-yl)-[2-ethy l-5-(4-fluoro-
benzylamino)-2H-pyrazol-3-yl]-methanol (630,0.045 g, 0.081 mmol) was dissolved in acetonitrile
(5 mL) and triethylsilane (0.4 mL, 2.0 mmol) was added, followed by trifluoroacctic acid (0.2 mL,
2.0 mmol). The reaction was stirred at room temperature for 45 minutes, then stirred at 60 °C for
45 minutes. The solvent was removed under reduced pressure, ethyl acetate was added and the
organic was washed with sodium bicarbonate saturated solution and brine. After drying over
anhydrous sodium sulfate, the solvent was evaporated to dryness. Purification with silica gel

column chromatography eluting with a gradient of ethyl acetate (40-100%) in hexanes gave the
desired compound (P-0185,0.0068 g, 22%). MS (ESI) [M+HY= 384.1.
Example 45: Synthesis of 3-2-Fluoro-6-[(5-fluoro-pyridin-3-ylmethyl)-ainino]-pyridin-3-
ylmethyI-lH-pyrrolo[2,3-blpyridine-5-carbonItrile P-0415
|0309] 3 -2-Fluoro-6-[(5-fluoro-pyridin-3 -ylmethyl)-amino]-pyridin-3 -ylmethyl-1 H-pyrrolo[2,3-
b]pyridine-5-carbonitrile P-0415 was synthesized in 5 steps from lH-Pyrrolo[2,3-b]pyridine-5-
carbonitrile 632 as shown in Scheme 201.
Scheme 201

Step 1 - Synthesis of3-dimethylaminomethyl-lH-pyrrolo[2,3-b]pyridine-5-carbonitrile (633):
[0310] To lH-Pyrrolo[2,3-b]pyridine-5-carbonitrile (632, 3.00 g, 0.0210 mol) in isopropyl
alcohol (120 mL) were added dimethylamine hydrochloride (1.91 g, 0.023S mol) and
formaldehyde (0.708 g, 0.0236 mol). The reaction was heated to reflux overnight, then
concentrated, poured into water, and extracted with ethyl acetate. The organic layer was dried over
anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel
column chromatography eluting with 5% to 30% methanol in dichloromethane containing 0.3%
triethyl amine to give the desired compound (633, 2.0 g, 48%).
Step 2 - Synthesis of5-cyano-3-dimethylaminomethyl-pyrrolo[2.3-b]pyridine-l-carboxylic acid
tert-butyl ester (634):
[0311] To 3-dimethylaminomethyl-lH-pyrrolo[2,3-b]pyridine-5-carbonitrile (633, 2.0 g, 0.010
mol) in tetrahydrofuran (60.0 mL) were added di-tert-butyldicarbonate (2.62 g, 0.0120 mol),
4-dimethylaminopyridine (0.12 g, 0.0010 mol) and triethylamine (4.0 mL, 0.029 mol). The
reaction was stirred at 45 °C over a weekend, then concentrated, poured into aqueous potassium
carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium
sulfate and filtered. The filtrate was concentrated and purified by silica gel column
chromatography eluting with 2% to 30% methanol in dichloromethane in hexane to give the

desired compound (634,2.50 g, 83%).
Step 3 - Synthesis of 3-chIoromethyl-5-cyano-pyrrolo 2,3-bJpyridirte-l-carboxylic acid tert-bntyl
ester (635):
[0312] To 5-cyano-3-dimethylaminomethyl-pyrrolo[2,3-b]pyridine-l -carboxylic acid tert-butyl
ester (634, 2.60 g, 8.66 mmol) in toluene (60.0 mL) under an atmosphere of nitrogen was added
ethyl chloroformale (0.828 mL, 8.66 mmol). The reaction was stirred at room temperature for 3
hours, then poured into water and extracted with ethyl acetate. The organic layer was dried over
anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel
column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a white solid
(635, 400 mg, 16%).
Step 4 — Synthesis of [5-(5-cyano-lH'pyrralo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-(5-
fluoro-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (636):
|0313] To (5-bromo-6-fluoro-pyridin-2-yl)-(5-fluoro-pyridin-3-ylmethyl)-carbamic acid tert-
butyl ester (631, 0.600 g, 1.S0 mmol, prepared as described in Example 21) in tetrahydrofuran
(10.0 mL) at -25 °C under an atmosphere of nitrogen, was added a solution of
isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 0.730 mL). The reaction was allowed to
warm to 5 "C over 1 hour. The reaction was cooled to -35 °C, followed by addition of a solution of
CuCN.2LiCl (0.65 M in tetrahydrofuran, 2.4 mL). After 5 minutes, 3-chloromethyl-5-cyano-
pyrrolo[2,3-b]pyridine-l-carboxylic acid tert-butyl ester (635,0.086 g, 0.29 mmol) in
tetrahydrofuran (4.0 mL) was added to the reaction. The reaction was allowed to warm to room
temperature over 1 hour, then poured into a diluted ammonia solution, and extracted with ethyl
acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was
concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl
acetate in hexane to give the desired compound (636, 0.13 g, 92%). MS (ESI) [M+HT = 477.4.
Step 5 - Synthesis of3-2-fluoro-6-[(5-fluoro-pyridin-3-ylmethyl)-amino)-pyridin-3-ylmethyl'lH-
pyrrolo[2,3-b]pyridine-S-carbonitrile (P-0415):
|0314] To [5-(5-cyano-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)^-fluoro-pyridin-2-yl]-(5-fluoro-
pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (636, 0.130 g, 0.27 mmol) in dichloromethane
(10.0 mL) was added trifluoroacetic acid (1.00 mL, 0.0130 mol). The reaction was stirred at room
temperature overnight. The reaction was concentrated, poured into aqueous potassium carbonate,
and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and
filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting
with 25% to 100% ethyl acetate in hexane to give a white solid (P-0415, 85.6 mg, 83.4%). MS
(ESI) [M+HT = 377.0.

[0315] (5-Fluoro-pyridin-3-ylrnethyl)-[6-fluoro-5-(lH-pyrrolo[2,3-b]pyridin-3-yImethyl)-
pyridin-2-yl]-amine P-0414
was prepared following the protocol of Scheme 201, substituting lH-Pyrrolo[2,3-b]pyridine-5-
carbonitrile 632 with 1 H-Pyrrolo[2,3-b]pyridine in Step 1. MS (ESI) [M+H*]+ = 352.5.
[0316] 3-[6-(4-Chloro-benzylamino)-2-fluoro-pyridin-3-ylmethyl]-lH-pyrrolo[2,3-b]pyridinc-5-
caibonitrile P-0432

was prepared following the protocol of Scheme 201, replacing 5-bromo-6-fluoro-pyridin-2-yl)-(5-
fluorc~pyridin-3-ylmethyl)-carbamic acid tert-butyl ester 631 with (5-Bromo-6-fluoro-pyridin-2-
yl)-(4-chloro-benzyl)-carbamic acid tert-butyl ester 637 (prepared as described in Example 21) in
Step 4. MS (ESI) [M+HT = 391.9.
Example 46: Synthesis of (3-chloro-benzyl)-[5-(5-chloro-lH-pyrrolo [2,3-b] pyridin-3-
ylmethyl)-l-methyl-lH-pyrazol-3-yl|-amineP-0410
[0317] (3-Chloro-ben2yl)-[5-(5-chloro-lH-pyrrolo [2,3-b]pyridin-3-ylmethyl)-l - methyl-1 H-
pyrazol-3-yl]-amine P-0410 was synthesized in 11 steps from lH-pyrazole-3,5-dicarboxylic acid
monohydrate 638 as shown in Scheme 202.


Step 1 — Preparation of lH-pyrazole-3,5-dicarboxylic acid dimethyl ester (639):
|0318] lH-Pyrazole-3,5-dicarboxylic acid monohydrate (638, 21.1 g, 121.0 mmol) was
combined with methanol (350 mL) and hydrogen chloride (10 mL). The reaction was stirred at
reflux overnight and then concentrated. The resulting solid was washed with ethyl acetate and
hexanes and dried under reduced pressure. The obtained compound 639 was used without further
purification. MS (ESI) [M+HY= 185.0.
Step 2 - Preparation ofl-methyl-lH-pyrazole-3.5-dicarboxylic acid dimethyl ester (640):
[0319) 1H-Pyrazole-3,5-dicarboxylic acid dimethyl ester (639, 9.1 g, 49.0 mmol) was combined
with acetone (400 mL) and potassium carbonate (10.2 g, 74.1 mmol). The mixture was stirred for
40 minutes under an atmosphere of nitrogen. To the stirring suspension, methyl iodide (3.4 mL,
54.0 mmol) was added drop wise. The reaction was stirred at room temperature overnight and then
the solvent was evaporated under reduced pressure. The resulting solid was washed with water and
filtered. After toluene was added, the solvent was removed under reduced pressure. The resulting
compound 640 was used without further purification.
Step 3 - Preparation of 1-methyl-l H-pyrazole-3,5-dicarboxylic acid S-methyl ester (641):
(0320] l-Methyl-lH-pyrazole-3,5-dicarboxylic acid dimethyl ester (640, 3.7 g, 19.0 mmol) was
combined with 1,4-dioxane (20 mL) and water (60 mL). Concentrated sulfuric acid (1.0 mL) in 2
mL of water was added to the solution. After the reaction was stirred at reflux overnight, it was
cooled to room temperature and concentrated until precipitation began. The obtained mixture was
left standing overnight. The resulting solid was filtered and dried under reduced pressure. The

collected aqueous fractions were extracted with ethyl acetate. The organic portion was dried over
anhydrous sodium sulfate and concentrated. Additional solid was crystallized from ethyl acetate to
give the desired compound (641, 2.33 g, 68%). MS (ESI) [M+H*]*m 185.0, melting point 175 °C.
Step 4 - Preparation o/5-azidocarbonyl-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester
(642):
[0321] 1 -Methyl-1 H-pyrazole-3,5-dicarboxylic acid 5-methyl ester (641, 3.2 g, 17.0 mmol) was
combined with thionyl chloride (5 mL). The reaction was heated to reflux for 40 minutes and then
concentrated twice from toluene. The resulting solid was dried under reduced pressure overnight.
The product was dissolved into acetone (20 mL) and sodium azide (3.5 g, 54.0 mmol) was added
in water (10 mL) rapidly at once. The obtained solution was stirred for one minute and then poured
into ice-water (50mL). The precipitate was filtered and dried under reduced pressure. The final
compound was used without further purification (642,2.8 g, 77%).
Step 5 - Preparation of5-benzyloxycarbonylamino-2-melhyl-2H-pyrazole-3-carboxylic acid
methyl ester (643):
[0322] 5-Azidocarbonyl-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (642, 2.8 g, 13.0
mmol) was combined with toluene (35 mL) and benzyl alcohol (2.1 mL, 20.0 mmol). The reaction
was heated to reflux for 45 minutes and then the solvent was removed under reduced pressure. The
compound (643, 2.4 g, 62%) was washed with methanol and dried under vacuum. MS (ESI)
[M+HY = 290.3.
Step 6 - Preparation of5-amino-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (644):
[0323] 5-Benzyloxycarbonylamino-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (643,
2.2 g, 7.6 mmol) was combined with methanol (50 mL) and 10% palladium on carbon (500 mg).
The mixture was stirred under an atmosphere of hydrogen for three hours. The mixture was filtered
through Celite and the solvent was removed under reduced pressure to give the desired compound
(644, 1.2 g, 98%). (ESI) [M+H*]+= 156.1.
Step 7 - Preparation of5-(3-chloro-benzylamino)-2-methyl-2H-pyrazole-3-carboxylic acid methyl
ester (646):
|0324] 5-Amino-2-methy!-2H-pyrazole-3-carboxylic acid methyl ester (644, 1.3 g, 8.0 mmol)
was combined with 3-chlorobenzaldehydc (645, 0.95 mL, 8.4 mmol) and acetonitrile (40 mL).
Trifluoroacetic acid (3.2 mL, 42.0 mmol) was added followed by triethylsilane (6.7 mL, 42.0
mmol). The reaction was heated to reflux overnight and then concentrated. Ethyl acetate was
added and the solution was washed with IN potassium carbonate. The organic portion was dried
over anhydrous sodium sulfate, filtered and concentrated. The compound (646, 0.944 g, 42%) was


crystallized from a mixture of ethyl acetate: hexane.
Step 8 - Preparation of[5-(3-chloro-benzylamino)-2-methyl-2H-pyrazol-3-yl]-methanol (647):
[0325| 5-(3-Chloro-benzylamino)-2-melhyl-2 H-pyrazoIe-3-carboxylic acid methyl ester (646,
0.944 g, 3.37 mmol) was combined with tetrahydrofuran (20 mL) and the solution was cooled to
-40 °C. 1.0 M lithium tetrahydroaluminate in tetrahydrofuran (3.7 mL) was added and the reaction
was stirred for 45 min at -20 °C. 1.0 M lithium tetrahydroaluminate in tetrahydrofuran (3.7 mL)
was added at -40 °C and the reaction was stirred to 10°C. Sodium sulfate decahydrate was added
in small portions and the mixture was stirred for two hours at room temperature, then filtered
through Celite and concentrated. The resulting compound (647,0.821 g, 97%) was washed with a
mixture of ethyl acetate: hexanes and dried under reduced pressure.
Step 9 - Preparation of5-(3-chloro-benzylamino)-2-methyl-2H-pyrazole-3-carbaldehyde (648):
|0326] [5-(3-Chloro-benzylamino)-2-methyl-2H-pyrazol-3-yl]-methanol (647,0.821 g, 3.26
mmol) was combined with dichloromethane (70 mL) and manganese(TV) oxide (4 g). The reaction
was stirred at room temperature overnight under an atmosphere of nitrogen. The mixture was
filtered through Celite and concentrated. Purification by silica gel column chromatography eluting
with a gradient of ethyl acetate (10-100%) in hexane gave the desired aldehyde (648, 0.482 g,
60%).
Step 10- Preparation of[5-(3-chloro-benzylamino)-2-methyl-2H-pyrazol-3-yl]-(5-chloro-l-
triisopropylsUanyl-lH-pyrrolo[2,3-b]pyridin~3-yl)-methanol(649):
[0327] 5-Chloro-3-iodo-l-triisopropylsilanyl-lH-pyrrolo[2,3-b]pyridine (629, 0.19 g, 0.44
mmol) was dissolved in tetrahydrofuran (0.9 mL). The solution was cooled to -20 °C. 2M
isopropylmagnesium chloride in tetrahydrofuran (200 uL) was added dropwise to the mixture, then
stirred to -5 °C. After the reaction was cooled to -20 °C, 5-(3-chloro-benzylamino)-2-mcthyl-2 H-
pyrazole-3-carbaldehyde (648, 0.050 g, 0.20 mmol) in 2 mL of tetrahydrofuran was added at once
to the mixture. The reaction was stirred to 0 °C and then concentrated. Ethyl acetate was added and
the mixture was washed with sodium bicarbonate saturated solution and brine. The organic portion
was dried over anhydrous sodium sulfate and concentrated. Purification with silica gel column
chromatography eluting with a gradient of ethyl acetate (5-80%) in hexane gave the desired
compound (649,0.033 g, 30%). (ESI) [M+H*]+= 558.3, 560.9.
Step 11 -Preparation of(3-chloro-benzyl)-[5-(S-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-l-
methyl-IH-pyrazol-3-ylJ-amine (P-0410):
[0328] [5-(3-Chloro-benzylamino)-2-methyl-2H-pyrazol-3-yl]-(5-chloro-l-triisopropylsilanyl-
1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol (649, 0.033 g, 0.059 mmol) was combined with


dichloromethane (5 tnL, 0.08 mol) and triethylsilane (200 (iL, 1.0 mmol) was added, followed by
trifluoroacetic acid (100 uL, 1.0 mmol). The reaction was stirred at room temperature overnight
and then concentrated. Ethyl acetate was added and the organic portion was washed with 1 M
potassium carbonate, dried over anhydrous sodium sulfate and concentrated. Purification with
silica gel flash chromalography eluting with a gradient of methanol (2-20%) and dichloromethane
followed by washes with a mixture of ethyl acetate:hexane gave the desired compound (P-0410,
0.0039 g, 17%). (ESI) [M+H+]+= 387.30.
[03291 [5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-l-methyl-lH-pyrazol-3-yl)-(2,5-
difluoro-benzyl)-amine P-0411 and [5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylrnethyl)-l-methyl-
lH-pyrazol-3-yl]-(2-fluoro-benzyl)-amine P-0413,

were prepared following the protocol of Scheme 202, replacing 3-chlorobenzaldehyde 645 with
2,5-difluorobenzaldehyde and 2-fluorobenzaldehyde, respectively, in Step 7. (ESI) [M+H*]* =
389.95 (P-0411) and 370.20 (P-0413).
Example 47: Enzyme activity assays
[0330] Assays for the activity of c-Kit or c-Fms are known in the art, for example as described in
US Patent Application Publication number US 2007/0032519, the disclosure of which is hereby
incorporated by reference in its entirety. Similar assays may be used to assess the activity of
TrkA, TrkB, and HGK.
[0331] Additional cell based assays can be correlated to the Fms activity of compounds of the
invention. For example, the ability of osteoclast precursor cells (commercially available from
Lonza) to differentiate into mature osteoclasts, due to stimulation by M-CSF and RANKL, in the
presence of compounds, can be measured using a method analogous to that previously reported
(Hudson et al., Journal of Urology, 1947, 58:89-92), where the amount of acid phosphatase in the
supernatant (i.e. TRAP5b excreted by mature osteoclasts) is proportional to the number of mature
osteoclasts present. In another example, the ability of M-CSF-dependent murine macrophage cells
(BAC1.2F5) to proliferate in the presence of compounds can be measured by culturing cells as
previously described (Morgan et al., Journal of Cellular Physiology, 1987,130:420-427) and





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.
[0337] 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 provide additional compounds of
Formulae II or III and/or various methods of administration can be used. Thus, such additional
embodiments are within the scope of the present invention and the following claims.
[0338] 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. 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.
[0339] 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.
[0340] 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.
[0341] Thus, additional embodiments are within the scope of the invention and within the
following claims.


A2 is -CH2- or -C(O)-;
B is selected from the group consisting of hydrogen, -CN, -OR41, -SR4', -NHR41, -NR41R41,
-NR39C(O)R4', -NR3'S(O)2R41, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and
heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents
selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower
alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-
alkylamino, cycloalkyl, heterocycloalkyi, aryl, and heteroaryl, and wherein cycloalkyl,
heterocycloalkyl, aryl, and heteroaryl as B, or as substituents of lower alkyl are optionally
substituted with one or more substituents selected from the group consisting of-OH, -NH2>
-CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR4J, -SR4J, -NHR42, -NR4V2, -NR39C(O)R42,
-NRMS(O)2R42, -S(O)2R42, halogen, lower alkyl, fluoro substituted lower alkyl, and
cycloalkylamino;
M4 is -NR39CHr, -NR^CHCR40)-, -NRMCH2CH2-, or -NR39C(O)-;

M5. M10,andM18 are selected from the group consisting of a bond, -NR3*-, -S-, -O-, -NR3*CHZ-,
-NR39CH2CH2-, -NRMCH(R"°)-, -SCHr, -OCH2-, -C(O)NR39-, -S(O)2NR39-, -CHjNR39-,
-CH(R40)NR39-, -NR39C(O)-, and -NR39S(O)2-;
M8 is selected from the group consisting of a bond, -CH2-, -CH2C(O)-, -S(O)2-, -S(O)2CH2-,
-S(O)2CH(CH3)-, -S(O)2CH2CH2-, -S(O)2NRM-, -S(O)2NR39CH2-, -S(O)2NR39CH(CH3)-,
-S(O)JNRMCH2CHJ-, -C(O)-, -C(O)CH2-. -C(O)CH(CH3)-, -C(O)CH2CH2-, -C(O)NR39-,
-C(O)NR3*CH2-, -C(O)NR39CH(CH3)-, and -C(O)NR3'CH2CH2-;
Q' is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more
substituents selected from the group consisting of-OR41, -SR41, -S(O)R41, -S(O)2R41,
-NHR41, -NR4IR41, -NR39C(O)R41, -NR39S(O)2R41, halogen, lower alkyl, cycloalkyl,
heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with
one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro
substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-
alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein
cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as Q'or as a substituent of lower alkyl
are optionally substituted with one or more substituents selected from the group consisting
of-OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR42, -SR42, -NHR42, -NR42R42,
-NR39C(O)R43, -NR39S(O)2R42. -S(O)2R45, halogen, lower alkyl, fluoro substituted lower
alkyl, and cycloalkylamino;
Q". Q41. Q6'» and Q141 are lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl,
wherein lower alkyl is optionally substituted with one or more fluoro, lower alkoxy, or
fluoro substituted lower alkoxy, and wherein cyclaolkyl, heterocycloalkyl, aryl or
heteroaryl are optionally substituted with one or more substituents selected from the group
consisting of-OR41, -SR41, -S(O)R41, -S(O)jR41, -NHR41, -NR41R41, -NR39C(O)R41,
-NR39S(O)2R41, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl,
wherein lower alkyl is optionally substituted with one or more substituents selected from
the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower
alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl,
heterocycloalkyl, aryl, and heteroaryl, and wherein cycloalkyl, heterocycloalkyl, aryl, and
heteroaryl as a substituent of Q", Q41, Q61, or Q141, or as a substituent of lower alkyl are
optionally substituted with one or more substituents selected from the group consisting of
-OH, -NH2, -CN, -NOj, -S(O)2NH2l -C(O)NHj, -OR42, -SR42, -NHR42, -NR42R42,
-NR39C(O)R42, -NR39S(O)2R4Z, -S(O)2R42, halogen, lower alkyl, fluoro substituted lower
alkyl, and cycloalkylamino;
Q12 is fluoro, chloro or -CF3;

Q13 and QM are independently hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted
lower alkyl;
Q22, Q24, Q", and Q14 are independently selected from the group consisting of hydrogen,
halogen, lower alkyl, fluoro substituted lower alkyl, -NR^R44, -OR44, and -SR44, provided,
however, that at least one of Q22 and Q24 and at least one of Q52 and Q34 is hydrogen,
fluoro, chloro, lower alkyl or fluoro substituted lower alkyl;
Qu and Q1" are hydrogen, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl,
-NR^R44, -OR44, or-SR44;
Q72 is hydrogen, lower alkyl or fluoro substituted lower alkyl;
RJ9 at each occurrence is independently hydrogen or lower alkyl;
R40 is lower alkyl or fluoro substituted lower alkyl;
R41 at each occurrence is independently selected from the group consisting of lower alkyl,
cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally
substituted with one or more substituents selected from the group consisting of fluoro,
lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower
alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and
heteroaryl, and wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R4' or as
substituents of lower alkyl are are optionally substituted with one or more substituents
selected from the group consisting of-OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2,
-OR42, -SR42, -NHR42, -NR4:R42, -NR39C(O)R42, -NR39S(O)2R42, -S(O)2R42, halogen, lower
alkyl, fluoro substituted lower alkyl, and cycloalkylamino;
R42 at each occurrence is independently selected from the group consisting of lower alkyl,
heterocycloalkyl and heteroaryl, wherein lower alkyl is optionally substituted with one or
more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro
substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-
alkylamino, di-alkylamino, and cycloalkylamino, and wherein heterocycloalkyl and
heteroaryl are optionally substituted with one or more substituents selected from the group
consisting of halogen, -CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy and
fluoro substituted lower alkoxy; and
each R44 is independently hydrogen, lower alkyl or fluoro substituted lower alkyl;
provided, however, that the compound is not
LJ . l_l _


all salts, prodrugs, tautomers, and isomers thereof,
wherein:
Q1* is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more
substitucnts selected from the group consisting of halogen, lower alkyl, fluoro substituted
lower alkyl, -NHR41, -NR4IR"", and -OR41;
Qs is hydrogen, -CN, -OR41, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, aryl or
heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more
substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted
lower alkyl, -NHR41, -NR4IR41, and -OR41; and
A,, M4. Q12, Q13, Q14 and R41 are as defined for Claim 1.

3. The compound of Claim 2 selected from the group consisting of:
(4-Chloro-benzyl)-[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yI]-
amine,
(4-Chloro-benzyl)-[6-chloro-5-ClH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine,
[6-Chloro-5-(lH-pyrrolof2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-
ylmethyl)-amine,
[6-Chloro-5-(5-chloro-lH-pynolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-
pyridin-3-ylmethyl)-amine,
{6-Chloro-5-[5-( 1 -methyl-1 H-pyrazol-4-yl)-1 H-pyrrolo[2,3 -b]pyridin-3-ylmethyl] -pyridin-2-yl} -
(6-trifluoromethyl-pyridin-3-ylmethyl)-amine,
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridb-2-yl]-(6-trifluoromethyl-
pyridin-3-ylmethyl)-amine,
[6-Fluoro-5-(5-methoxy-lH-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-pyridin-2-yl]-(6-trifluoromethyl-
pyridin-3 -ylmethyl)-am ine,
[6-Fluoro-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-
ylmethyl)-amine,
3- {2-Chloro-6-[(6-trifluoromethyl-pyridin-3 -ylmethyl)-amino]-pyridin-3-ylmethyl} -1H-
pyrrolo[2,3-b]pyridine-5-carbonitrile,
[6-Chloro-5-(5-methyl-lH-pynrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-
pyridin-3-ylmethyl)-amine,
[6-Chloro-5-(5-methyl-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-
pyridin-3 -ylmethy l)-amine,
[6-Fluoro-5-(lH-pyn-olo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-methoxy-pyridin-3-ylmethyl)-
amine,
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-methoxy-pyridin-3-
ylmethyl)-amine,
(5-Fluoro-pyridin-3-yImethyl)-[6-fluoro-5-(lH-pyrrolo[2,3-b]pyridin-3-ylinethyl)-pyridin-2-yl]-
amine,
3- {2-Fluoro-6-[(5-fluoro-pyridin-3-ylmethyl)-arnino]-pyridin-3-yImethyl} -1 H-pyrrolo[2,3-
b]pyridine-5-carbonitrile,
3-[6-(4-Chloro-benzylamino)-2-fluoro-pyridin-3-ylmethyl]-lH-pyrrolo[2,3-b]pyridine-5-
carbonitrile; and
all salts, prodrugs, tautomers, and isomers thereof.

4. A compound of Claim 1 having the structure of Formula lib

all salts, prodrugs, tautomers, and isomers thereof,
wherein:
Aj is -CH2- or -C(O)-;
Qls is hydrogen, -CN, -OR41, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl,
cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl
or heteroaryl are optionally substituted with one or more substituents selected from the
group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41,
-NR4lR41,and-OR4l;and
M5, Q", Q22, Q24, and R41, are as defined for Formula II.
5. The compound of Claim 4 selected from the group consisting of:
(4-Chloro-benzyl)-[5-(5-chloro-lH-pyrroIo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine,
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2,6-difluoro-benzyl)-amine,
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-trifluoromethyl-benzyl)-
amine,
(2-Chloro-benzyl)-[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine,
[5-(5-ChIoro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-fluoro-ben2yl)-amine,
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-yImethyl)-pyrimidin-2-yl]-(2,4-difluoro-ben2yl)-amine,
[5-(5-Chloro-lH-pyrrolot213-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-trifluoromcthyl-benzyl)-
aminc,
[5-(5-ChIoro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2,5-difluoro-benzyI)-amine,
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(3-trifluoromethyl-benzyl)-
amine,
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yI]-(2-fluoro-5-trifluoromethyl-
benzyl)-amine,
(2-FIuoro-5-trJfIuoromethyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-
amine,
(2)5-Difluoro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine,
(2-Chloro-5-trifluoromethyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-

amine,
(3-Fluoro-5-trif]uoromethyl-benzyl)-[5-(lH-pynrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-
amine,
(3,5-Difluoro-ben2yl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine,
(2-Fluoro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyriniidin-2-yl]-amine,
(2-Chloro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine,
[5-(lH-PyrroIo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-trifluoromethyI-benzyl)-amine,
[5-(lH-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-trifluoromethoxy-ben2yl)-amine,
(5-Chloro-2-fluoro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-pyrimidin-2-yl]-ainine,
(2,4-Dichloro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine,
(2,4-Difluoro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyriinidin-2.yl]-amine,
(4-Chloro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine,
[5-(lH-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-{4-trifluoromethyl-ben2yl)-amine,
(2-Fluoro-3-trifluoromethyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-
amine,
(2,5-Dichloro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amme, (3-
Chloro-2-fluoro-benzyl)-t5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine,
(2-Difluoromethoxy-benzyl)-[5-(lH-pyrTolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-aminet
(2,3-Dichloro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine,
(4-Chloro-2-fluoro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine,
(5-Fluoro-2-trifluoromethyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridiji-3-ylmethyl)-pyrimidin-2-yl]-
amine,
(2-Chloro-4-fluoro-benzyl)-[5-(lH-pyrTolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine,
(5-Chloro-2-methyl-benzyl)-[5-(lH-pyrTolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine,
(5-Fluoro-2-mcthyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine,
(2-FIuoro-4-trifluoromethyl-benzyI)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-
amine,
(4-Fluoro-2-trifluoromethyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-
amine,
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-dinuoromethoxy-benzyl)-
amine,
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(5-fluoro-2-lrinuoromethyl-
benzyl)-amine,
(3-Chloro-2-fluoro-benzyl)-[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yI]-
amine,
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-y!]-(2-fluoro-3-trinuoromethyl-

benzyl)-amine,
[5-(5-Chloro-lH-pyn-olo[2,3-b]pyridiii-3-ylmethyl)-p>Timidin-2-yl]-(2-nuoro-4-trifluoromethyl-
benzyl)-amine,
[5-(5-Chloro-lH-pyrTolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yI]-(2,3-difluoro-benzyl)-amine,
(2-Chloro-4-fluoro-benzy!)-[S-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-yImethyl)-pyrimidin-2-yl]-
amine,
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-trifluoroniethoxy-ben2y0-
amine,
(2-Chloro-5-fluoro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-p>Tiniidin-2-yl]-amine,
(2-Chloro-5-fluoro-benzyl)-[5-(5-chloro-lH-pymolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-
amine,
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-pyridin-4-ylmethyl-amine,
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyI)-pyrimidin-2-yl]-(2-pyrrolidin-]-yl-ethyl)-
amine,
BenzyI-[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine,
Benzyl-[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-pyriniidin-2-yl]-methyl-amine,
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-y!methyl)-pyrimidin-2-ylJ-(4-trifluoromethoxy-benzyl)-
amine,
(3-Chloro-benzyl)-[5-(5-chloro-lH-pyirolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine,
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-pyridin-3-ylmethyl-ainine,
[5-(5-ChIoro-lH-pyrrolo[2,3-b]pyridin-3-y]methyl)-pyrimidin-2-yl]-(4-fluoro-benzyl)-amine,
(3-Chloro-benzyl)-[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-methyl-
amine,
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(3>5-difluoro-benzyl)-amine,
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-[l-(2-fluoro-phenyl)-ethyl]-
amine,
[ 1 -(4-Chloro-phenyl)-ethyl]-[5-(5-chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-
amine,
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-[(S)-l-{4-fluoro-phenyl)-
ethyl]-amine,
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(6-trifluoromethyl-pyridin-3-
ylmethyl)-amine,
(2-Chloro-benzyl)-[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrJmidin-2-yl]-methyl-
amine,
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-pyrimidin-2-yl]-(2-methyl-ben2yl)-amine,
[5-(5-Ch]oro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidia-2-yl]-(2-metlioxy-benzyl)-amine,

[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-morpholin-4-yl-ethyl)-
amine,
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylinethyI)-pyrimidin-2-yL]-cyclohexylmethyl-amine,
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylTnethyl)-pyrimidin-2-yl]-pyridin-2-ylmethyl-amine,
[2-(4-Chloro-phenyl)-eihyl]-[5-(5-chloro-lH-pyirolo[2,3-b]pyridin-3-ylmethyl)-pyriniidin-2-yl]-
amine,
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-difluoroniethoxy-benzyl)-
amine,
[5-(5-ChIoro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yI]-(4-methoxy-benzyl)-amine,
[5-(5-ChIoro-lH-pyirolo[2,3-b)pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-methyl-benzyl)-amine,
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-methoxy-ethyl)-amine,
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylniethyl)-pyrimidin-2-yl]-(3-fluoro-benzyl)-amine,
(3-Chloro-4-fluoro-benzyl)-[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-
amine,
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-ethoxy-benzyl)-amine>
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyI)-pyrimidin-2-yl]-(4-morpholin-4-yl-benzyl)-
amine,
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(3-difluoromethoxy-benzyl)-
amine,
(4-Chloro-3-nuoro-benzyl)-[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyI)-pyrimidin-2-yI]-
amine,
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyriinidin-2-yl]-[l-(3-fluoro-phenyl)-ethyl]-
amine,
(5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-dimethylamino-benzyl)-
amine; and
all salts, prodrugs, tautomers, and isomers thereof.
6. The compound of Claim 4 selected from the group consisting of:
(4-Chloro-benzyl)-[5-(5-chloro-lH-pyrrolo[2)3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine,
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-trifluoromethyl-benzyl)-
amine,
(2-Chloro-benzyl)-[5-(5-chloro-lH-pyrTolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine,
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-fluoro-benzyl)-amine,
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2,4-difluoro-benzyl)-amine,
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ybnethyl)-pyrimidin-2-yl]-(4-trifluoromethyl-benzyl)-
amine,

[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2,5-difluoro-benzy0-ainine,
[5-(5-Chloro-lH-pyrrolo[2,3-blpyridin-S-ylmethylJ-pyrimidin^-ylJ-CS-trifluoromethyl-benzyl)-
amine,
[5-(5-Chloro-lH-pyrrolot2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-fluoro-5-trifluoroniethyl-
benzyl)-amine,
[5-(lH-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-trifluoromethyl-benzyl)-amine; and
all salts, prodrugs, tautomers, and isomers thereof.
7. The compound of Claim 1 having the chemical structure of Formula He,

n
all salts, prodrugs, tautomers, and isomers thereof,
wherein:
A« is -CH2- or -C(O)-;
M8, is selected from the group consisting of -CH2-, -CH2C(O)-, -C(O)NR39CH2-,
-C(O)NR39CH(R40)-, and -C(O)NR39CH2CH2-;
Q4S is hydrogen, -CN, -OR41, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl,
cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl
or heteroaryl are optionally substituted with one or more substituents selected from the
group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR4',
-NR41R41, and-OR41; and
Q41, Q52, Q34, R39, R40, and R41 are as defined for Claim I.
8. The compound of Claim 7 selected from the group consisting of:
3-( 1 -Benzyl-3,5-dimethyl-1 H-pyrazol-4-ylmethyl)-1 H-pyrrolo[2,3-b]pyridine,
2-[3,5-Dimethyl-4-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyra2ol-l-yl]-l-phenyl-ethanone,
3,5-Dimethyl-4-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazolc-l -carboxylic acid 4-methoxy-
benzylamide,
3,5-Dimethyl-4-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-l -carboxylic acid 2-chloro-
benzylamide,
3,5-Dimethyl-4-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-l-carboxylic acid 2-fluoro-
benzylamide,
3-[3,5-Dimethyl-l-(5-trifluoromethyl-niran-2-ylmelhyl)-lH-pyra2ol-4-ylmethyl]-lH-pyrrolo[2,3-
•

bjpyridine,
3-[3,5-Dimethyl-l-(5-mcthyl-isoxazol-3-ylmethyl)-lH-pyra2»i-4-ylmethyl]-lH-pyrrolo[2,3-
bjpyridine,
3,5-Dimethyl-4-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-l-carboxylic acid 4-chloro-
benzylamide,
3,5-Dimethyl-4-(lH-pym)lo[2,3-b]pyridin-3-ylmethyl)-pyrazole-l-carboxylicacid [2-(4-methoxy-
phenyl)-ethyl]-amide,
3,5-Dimethyl-4-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-l-carboxylic acid 3-methoxy-
benzylamide,
3-{3,5-Dimethyl-l-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-lH-pyrazol-4-
ylmcthyl}-1 H-pyrrolo[2,3-b]pyridine,
3-(3,5-Dimethyl-l-(4-methyl-2-phenyl-thiazol-5-ylmethyl)-lH-pyrazol-4-ylmethyl]-lH-
pyrrolo[2,3-b]pyridine,
3,5-Dimethyl-4-(lH-pyrTolo[2,3-b]pyridin-3-ylraethyl)-pyra2ole-l-carboxylicacid 2-methoxy-
benzylamide,
3,5-Dimethyl-4-(lH-pym>lo[2,3-b]pyridin-3-ylmethyl)-pyrazole-l -carboxylic acid [2-(2,4-
dichloro-phenyl)-ethyl]-amide,
3,5-Dimcthyl-4-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-l-carboxylic acid [2-(4-fluoro-
phenyl)-ethyl]-amide,
3,5-Dimethyl-4-(I H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-l-carboxylic acid [2-(2-fluoro-
phenyl)-cthyl] - amide,
3,5-Dimethyl-4-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-p>Tazole-l-carboxylic acid ((S)-1-phenyl-
cthyl)-amide,
3,5-Diniethyl-4-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyra2ole-l-carboxylic acid 3-fluoro-
benzylamide,
3,5-Dimethyl-4-( 1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1 -carboxylic acid 4- fluoro-
benzylamide,
3,5-Dimelhyl-4-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-l-carboxylic acid 4-methyl-
benzylamide,
3,5-Dimethyl-4-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyra2ole-l-carboxylic acid 2-methyI-
benzylamide,
4-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-3,5-diinethyl-pyrazole-l-carboxylicacid [2-(4-
fluoro-phenyl)-ethyl]-amide,
4-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-3,5-dimethyl-pyrazole-l-carboxylicacid4-
fluoro-benzylamide,
4-(5-Chloro-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-3,5-dimelhyl-pyrazole-1 -carboxylic acid 4-

chloro-benzylamide,
4-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-3,5-diniethyl-pyrazole-l-carboxylic acid [(S)-
1 -(4-fluoro-phenyl)-ethyl]-amide; and
all salts, prodrugs, tautomers, or isomers thereof.
9. A compound of Claim 1 having the chemical structure of Formula Ilg,

all salts, prodrugs, tautomers, and isomers thereof,
wherein:
A8 is -CH2-, or -C(O)-;
Q65 is hydrogen, -CN, -OR41, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl,
cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl
or heteroaryl are optionally substituted with one or more substituents selected from the
group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41,
-NR4IR41, and -OR41; and
M,o> Q61, Q72, Q74, and R41 are as defined for Claim 1.
10. The compound of Claim 9 selected from the group consisting of:
[ 1 -Ethyl-5-(l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1 H-pyrazol-3-yl]-(4-fluoro-bcnzyl)-amine,
(4-Fluoro-benzyl)-[l-methyl-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-lH-pyrazol-3-yl]-amine,
[5-(5-Chloro-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-l -methyl-1 H-pyrazol-3-yl] -(4-fluoro-benzyl)-
amine,
(4-Fluoro-benzyl)- {1 -methyl-5 -[5-(l -methyl-1 H-pyrazol-4-yl)-1 H-pyrrolo[2,3-b]pyridin-3-
ylmethyl]-1 H-pyrazol-3-yl }-amine,
(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-yl)-[2-ethyl-5-(4-fluoro-bcnzylamino)-2H-pyrazol-3-yl]-
methanone,
[5-(5-Chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-l -ethyl-1 H-pyrazol-3-yl]-(4-fluoro-benzyl)-
amine,
3-[5-(4-Fluoro-benzylamino)-2-methyl-2H-pyrazol-3-ylmethyl]-lH-pyrrolo[2,3-b]pyridine-5-
carbonitrile,
(3-Chloro-benzyl)-[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-l-methyl-l H-pyrazol-3-yl]-

amine,
[5-{5-Chloro-1 H-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-1 -methyl-1 H-pyrazol-3-yI]-(2,5-difluoro-
benzyl)-amine,
[5-(5-Chloro-lH-pyrroIo[2,3-b]pyridin-3-ylmethyI)-l-methyl-lH-pyra2ol-3-yl]-(2-fluoro-benzyl)-
amine; and
all salts, prodrugs, tautomers, or isomers thereof.
11. The compound of Claim 9 is [5-(5-ChJoro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-
1 -methyl-1 H-pyrazol-3-yl]-(4-fluoro-benzyl)-amine, 3-[5-(4-Fluoro-benzyIamino)-2-methyl-2H-
pyrazol-3-ylmethyl]-lH-pyrrolo[2,3-b]pyridine-5-carbonitrile, or any salts, prodrugs, tautomers, or
isomers thereof.
12. A compound of Claim 1 having the chemical structure of Formula lip,

all salts, prodrugs, tautomers, and isomers thereof,
wherein:
A8 is -CH2-, or -C(O)-;
Q65 is hydrogen, -CN, -OR41, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl,
cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl
or heteroaryl are optionally substituted with one or more substituents selected from the
group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41,
-NR41R4l,and-OR4l;and
Mio, Q61, Q72, Q74, and R41 are as defined for Claim 1.
13. The compound of Claim 12 selected from the group consisting of:
[4-ChIoro-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyl)-amine,
[4-Ethyl-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyl)-amine,
(4-Fluoro-benzyl)-[4-methyl-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-amine,
[4-Chloro-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-p>Tidin-3-ylmethyl-amine,
[4-Chloro-5-(lH-pyrTolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-pyridin-2-ylmethyl-amine,
[4-Chloro-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-pyridin-4-ylmethyl-amine,
[4-Chloro-5-(]H-pyrrolo[2,3-b]pyridin-3-ylmethyI)-thiazol-2-yl]-(6-methyI-pyridin-2-ylmethyl)-

amine,
[4-Chloro-5-( 1 H-pyrrolo[2,3-b]pyridin-3-ylmethyI)-lhiazol-2-yl]-( 1,5-dimethyI-1 H-pyrazoI-3-
yltnethyl)-aminc,
[4-Chloro-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-trifluoromethyl-pyridin-3-
ylmethyl)-amine,
[4-ChIoro-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2,5-djmethyl-2H-pyrazol-3-
ylmethyl)-amine,
[2-(4-Fluoro-benzylamino)-thiazol-5-yI]-(lH-pyrrolo[2,3-b]pyridin-3-yl)-methanone,
{2-[(4-Chloro-ben2yl)-methyl-amino]-thiazol-5-yl}-(lH-pyirolo[2,3-b]pyridin-3-yl)-methanone,
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-thiazol-2-ylmethyl-
amine,
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-methoxy-pyridin-3-
ylmcthyl)-amine,
Benzyl-[4-chloro-5-(5-chloro-lH-pyrroIo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-amine,
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(3-inethoxy-ben2yl)-
amine,
(4-Chloro-benzyl)-[4-chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-
amine,
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyl)-
amine,
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2,4-dimethyl-thiazol-5-
ylmethyl)-amine,
[4-Chtoro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-ethyl-5-methyl-3H-
imidazol-4-ylmcthyl)-amine,
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylraethyl)-thiazol-2-yl]-(2-ethyl-2H-pyrazol-3-
ylmethyl)-amine,
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazo!-2-yl]-(6-methoxy-pyridin-2-
ylmethyl)-amine,
[4-Chloro-5-(5-chloro-lH-pyn-o!o[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(3-fluoro-pyridin-4-
ylmethyl)-amine,
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-methyl-thiazol-4-
ylmethyl)-amine,
[4-Chloro-5-(5-chloro-1 H-pyn-olo [2,3-b]pyridin-3-ylmethyl)-thiazol-2-yI]-(4-methyI-thiazol-5-
ylmethyl)-amine,
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-thiazol-2-yl]-(5-chloro-pyridin-2-
ylmethyl)-amine,
187

[4-Chloro-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2,4-dimethyl-thiazol-5-
ylmethy])-amine,
[4-Chloro-5-(lH-pyrroIo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-ethyl-5-methyl-3H-imidazol-
4-ylmethyl)-amine,
[4-Chloro-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(5-fluoro-pyridin-2-ylmcthyl)-
amine,
[4-Chloro-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(5-methoxy-pyridin-3-ylmethyl)-
amine,
[4-Chloro-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4,5-dimethyl-thiophen-2-
ylmethyl)-amine,
[4-Chloro-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazoI-2-yl]-(2,5-dimethyl-thiophen-3-
ylmethyl)-amine,
t4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(5-fluoro-pyridin-3-
ylmethyl)-amine,
[4-Chloro-5-(5-chloro-lH-pyn-olo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-pyridin-3-ylmethyl-
amine,
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thia2ol-2-yl]-pyridin-4-ylmethyl-
amine,
t4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(3-chloro-pyridin-4-
ylmethyl)-amine,
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(l-ethyl-lH-pyrazol-4-
ylmethyl)-amine,
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thia2ol-2-yl]-(5-fluoro-pyridin-2-
ylmethyl)-amine,
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thia2ol-2-yl]-(5-melhoxy-pyridin-3-
ylmethyl)-amine,
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-{6-trifluoromethyl-
pyridin-3-ylmethyl)-amine,
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-chloro-6-fluoro-
benzyl)-amine,
[4-Chloro-5-(5-chloro-lH-pyrrolot2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-phenethyl-ainine,
^-Chloro-S-CS-chloro-lH-pynrolop.S-bJpyridinO-ylmethyO-thiazol^-ylJ^^-difluoro-benzyl)-
amine,
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-fluoro-benzyl)-
amine,
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazo!-2-yl]-(2-methoxy-pyridin-3-
188

ylmethyl)-amine,
(2-Chloro-benzyl)-[4-chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylinethyl)-thiazol-2-yl]-
amine,
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-thiazol-2-yl]-(2-methyl-benzyl)-
amine,
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-chloro-4-fluoro-
benzyl)-amine,
t4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylinethyl)-thia2ol-2-yl]-(3-nuoro-pyridin-2-
ylmethyl)-amine,
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-lhiazol-2-yl]-(6-morpholin-4-yl-
pyridin-2-ylmethyl)-amine,
[4-Chloro-5-(5-chloro-lH-pyrro]o[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(3,5-dichloro-pyridin-4-
ylmethyl)-amine,
[4-Chloro-5-{5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thia2ol-2-yl]-(2-trifluoronicthyl-
benzyl)-amine,
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-methyl-pyridin-2-
ylmethyl)-amine,
[5-(5-Chloro-lH-pyrroIot2,3-b]pyridin-3-ylmcthyl)-thiazol-2-yl]-(4-fluoro-benzyl)-amine; and
all salts, pro drugs, tautomers, or isomers thereof.
14. The compound of Claim 12 selected from the group consisting of:
[4-Chloro-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyl)-amine,
[4-Chloro-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-trifluoromethyl-pyridin-3-
ylmethyl)-amine,
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridm-3-ylmethyl)-thiazol-2-yl]-(6-methoxy-pyridin-3-
ylmethyl)-amine,
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(3-methoxy-benzyl)-
amine,
(4-Chloro-bcnzyl)-[4-chloro-5-(5-chloro-lH-pynt>lo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-
amine,
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyI)-
amine,
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-methoxy-pyridin-2-
ylmethyl)-amine,
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(3-fluoro-pyridin-4-
ylmethyl)-amine,
189

[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-yImethyI)-thiazol-2-yl]-(2-raethyl-thiazol-4-
ylmethyl)-amine,
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(5-chloro-pyridin-2-
ylmethyl)-amine,
[4-Chloro-5-(lH-pyrTolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(5-fluoro-pyridin-2-yImethyI)-
amine,
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(5-fluoro-pyridin-3-
ylmethyl)-amine,
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazoI-2-yl]-pyridin-3-ylmethyl-
amine,
[4-Chloro-5-(5-chloro-lH-pyiToIo[2,3-b]pyridin-3-yImethyl)-thiazol-2-ylJ-pyridin-4-ylniethyl-
amine,
[4-Chloro-5-(5-chloro-lH-pyrTolo[2,3-b]pyridin-3-ylmethyl)-thiazoI-2-yl]-(3-chloro-pyridin-4-
ylmethyl)-amine,
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yI]-(l-ethyl-lH-pyra2o]-4-
ylmethyl)-amine,
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thia2»l-2-yl]-(5-fluoro-pyrtdin-2-
ylmethyl)-amine,
[4-Chloro-5-(5-chIoro-lH-pyrrolo[2,3-b]pyridin-3-yImethyl)-thiazol-2-yI]-(5-methoxy-pyridin-3-
ylmethyl)-amine,
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-trifluoromethyl-
pyridin-3-yImethyI)-amine,
[4-Chloro-5-(5-chIoro-lH-pyrrolo[2)3-b]pyridin-3-ylmethyl)-thiazol-2-yI]-phenethyl-amine,
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thia20l-2-yI]-(2,4-difluoro-benzyl)-
amine,
t4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-fluoro-bcnzyI)-
amine,
t4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazoI-2-yI]-(2-methoxy-pyridin-3-
ylmethyl)-amine,
(2-Chloro-benzyl)-[4-chIoro-5-(5-chloro-lH-pyrroIo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-
amine,
(4-ChIoro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyI)-thiazol-2-yl]-(2-methyI-benzyl)-
amine,
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-chloro-4-fluoro-
benzyl)-amine,
[4-Chloro-5-(5-chloro-lH-pyiToIo[2,3-b]pyridin-3-ylmethyl)-thiazoI-2-yl]-(6-morpholin-4-yl-


pyridin-2-yImethyl)-amine,
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-methyI-pyridin-2-
ylmethyl)-amine; and
all salts, prodrugs, tautomers, or isomers thereof.

H
all salts, prodrugs, tautomers, and isomers thereof,
wherein:
U is -CH2-, -CH2CH2-, -CHCR40)-, -C(O)- or -C(O)NH-;
R81 is selected from the group consisting of hydrogen, -OR41, -CN, fluoro, chloro, lower alkyl,
fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein
cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more
substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted
lower alkyl, -NHR4', -NR4IR41, -OR41 and -S(O)2R41;
R82 is selected from the group consisting of hydrogen, C1-3 alkyl, fluoro substituted C2-3 alkyl,
OH, C1-3 alkoxy, and fluoro substituted C1-3 alkoxy;

R83 is heterocycloalkyl, heteroaryl, c. , in which ? indicates the
attachment point of RH to L4 of Formula III, wherein heterocycloalkyl or heteroaryl are
optionally substituted with one or more substituents selected from the group consisting of
halogen, lower alkyl, fluoro substituted lower alkyl, cycloalkylamino, -NHR41, -NR41R41,
-OR41and-S(O)2R41;
R", R", R*\ R", and R96 are independently selected from the group consisting of hydrogen,
halogen, lower alkyl, fluoro substituted lower alkyl, cycloalkylamino, -NHS(O)2R41,
-NHC(O)R41, -NHR41, -NR41R41, -OR41 and -S(O)2R41;
R40 is selected from the group consisting of lower alkyl, and fluoro substituted lower alkyl;
R4> at each occurrence is independently selected from the group consisting of lower alkyl,
cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally
substituted with one or more substituents selected from the group consisting of fluoro.

lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower
alkylthio, raono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and
heteroaryl, and wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R41 or as
substituents of lower alkyl are are optionally substituted with one or more substituents
selected from the group consisting of-OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2,
-OR"2, -SR42, -NHR42, -NR42R42, -NR39C(O)R42, -NR39S(O)2R42, -S(O)2R42, halogen, lowe:
alkyl, fluoro substituted lower alkyl, and cycloalkylamino; and
R42 at each occurrence is independently selected from the group consisting of lower alkyl,
heterocycloalkyl and heteroaryl, wherein lower alkyl is optionally substituted with one or
more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro
substituted lower alkoxy, lower aikylthio, fluoro substituted lower alkylthio, mono-
alkylamino, di-alkylamino, and cycloalkylamino, and wherein heterocycloalkyl and
heteroaryl are optionally substituted with one or more substituents selected from the group
consisting of halogen, -CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy and
fluoro substituted lower alkoxy;



16. The compound of Claim IS selected from the group consisting of:
Pyridin-3-ylmcthyl-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridui-2-yl]-amine,
(2-Morpholin-4-yl-cthyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine,
2-Chloro-4-fluoro-N-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide>
2,5-Dimethyl-2H-pyrazole-3-carboxyIicacid[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-
yl]-amide,
5-Methyl-pyrazine-2-carboxylic acid [5-(l H-pyrrolo[2(3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-
amide,
3-Chloro-N-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide,
4-Fluoro-N-[5-( 1 H-pyrrolo[2,3-b]pyridin-3 -ylmethy!)-pyridin-2-yl]-3-trifluoromethyl-benzamide,
N-[5-(lH-Pyrrolo[2,3-b]pyridin-3-ylmcthyl)-pyridin-2-yl]-3-trifluoroinethyl-ben2amide,
3-Chloro-4-fluoro-N-[5-(lH-pyrrolo[2,3-b]pyridb-3-ylmethyl)-pyridin-2-yl]-benzamide,
3,4-Difluoro-N-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide,
3-Methoxy-N-[5-(lH-pyrTolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide,
((R)-1 -Phenyl-ethyl)-[5-( 1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine,
(3 -Morpholin-4-yl-benzyl)-[5-( 1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine,
[l-(2-Fluoro-phenyl)-ethyl]-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine,
[2-(3-Fluoro-phenyl)-ethyl]-[5-(lH-pyrrolo[2,3-b]pyridin-3-ytmethyI)-pyridin-2-yl]-amine,

(3-Chloro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridih-3-ylmethyl)-pyridin-2-yl]-amine,
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyTidin-2-yl]-(6-trifluoromcthyl-pyridin-3-
ylmcthyl)-amine,
[5-(lH-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-p>Tidin-2-yl]- amine,
(3-Chloro-pyridin-4-ylmethyl)-[5-(lH-pynolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine,
Phenethyl-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine,
(2,4-Difluoro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylniethyl)-pyridin-2-yl]-ainine,
(2-Fluoro-benzyl)-[5-(lH-pyrrolo[2)3-b]pyridin-3-ylmethyl)-pyridJn-2-yl]-amine,
(2-Methoxy-pyridin-3-ylmethyl)-[5-(lH-pyrroIo[2,3-b]pyridin-3-yImethyl)-pyridin-2-yI]-amine,
(2-Methyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-pyridin-2-yl]-amine,
(6-Methoxy-pyridin-3-ylmethyl)-[5-(IH-pyiToIo[2,3-bIpyridin-3-yImethyl)-pyridin-2-yIJ-an)ine,
(2-Chloro-4-fluoro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-arnine,
(5-Melhoxy-pyridin-3-ylmethyl)-[5-(IH-pyrroIo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine,
(3-Fluoro-pyridin-4-ylmethyl)-[5-(lH-pyrrolo[2,3-b]pyTidin-3-ylmethyl)-pyridin-2-yl]-amine,
(6-Methoxy-pyridin-2-ylmethyl)-[5-(lH-pyiToIo[2,3-b]pyridin-3-y!methyl)-pyridin-2-yl]-amine,
(4-Fluoro-2-trifluoromethyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-
amine,
[5-(lH-Pynolo[2,3-b]pyridin-3-ylmethyl)-pyridiij-2-yl]-(2-trifluoromethyl-benzyl)-amine,
(3,5-DichIoro-pyridin-4-ylmethyl)-[5-(lH-pyrroIo[2,3-b]pyridin-3-yIinethyI)-pyridin-2-yI]-amine,
(6-Morpholin-4-yl-pyridin-2-ylmethyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-
amine,
(5-Fluoro-pyridin-3-ylmethyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine,
(3-Chloro-pyridin-4-ylmethyl)-[5-(5-chloro-lH-pyirolo[2,3-b]pyridin-3-yImethyI)-pyridin-2-yl]-
amine,
3-{6-[(3-Chloro-pyridin-4-ylmethyl)-amino]-pyridin-3-ylmethy!}-IH-pyrrolo[2,3-b]pyridine-5-
carbonitrile,
3-[6-(4-Chloro-ben2ylamino)-pyridin-3-ylinethyl]-lH-pyrroIo[2,3-b]pyridine-5-carbonitrile,
3-[6-(4-Trifluoromethyl-benzylamino)-pyridin-3-ylmethyl]-lH-pyrrolo[2,3-b]pyridine-5-
carbonitrile,
t5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-fluoro-benzyl)-amine,
3-[6-(2-Fluoro-bcnzylamino)-pyridin-3-ylmethyl]-iH-pymjlo[2,3-b]pyridine-5-carbonitrile,
(2-Fluoro-benzyl)-[5-(5-methyl-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine,
3- {6-t(6-Trifluoromethyl-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl} -1 H-pyrrolo[2,3-
b]pyridine-5 -carbonitrile,
3-[6-(2-Trifluoromethyl-benzyIamino)-pyridin-3-ylmethyi]-IH-pyrrolo[2,3-b]pyridine-5-


carbonitrile,
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-y!methyl)-pyridin-2-yl]-(2-trifluorotnethyl-benzyl)-
amine,
[5-(5-Methyl-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-trifluororaethyl-benzyl)-
amine,
3-[6-(2,6-Difluoro-benzylamino)-pyridin-3-ylmethyl)-lH-pyrrolo[2,3-b]pyridine-S-carbonitril6,
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2)6-difluoro-ben2yl)-amine,
(2-Chloro-benzyl)-[5-(5-methyl-lH-pyrrolo[2,3-b]pyridin-3-ylmeUiyl)-pyridin-2-yl]-amine,
(2-Chloro-benzyl)-[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-aniine,
3-[6-(2-Chloro-ben2ylamino)-pyridin-3-ylmethyl]-lH-pyrrolo[2,3-b]pyridine-5-carbonitrile,
(6-Methoxy-pyridin-3-ylmethyl)-[5-(5-methyl-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-
yl]-amine,
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-methoxy-pyridin-3-
ylmethyl)-amine,
3-{6-[(6-Methoxy-pyridin-3-ylmethyl)-ainino]-pyridin-3-ylmethyl}-lH-pyrrolo[2,3-b]pyridine-5-
carbonitrile,
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-methoxy-pyridin-3-
ylraethyl)-ainine,
3-[6-(2-Trifluoromethoxy-benzylamino)-pyridin-3-ylmethyl]-lH-pyrrolo[2,3-b]pyridine-5-
carbonitrile,
3-[6-(2-Ethoxy-ben2ylamino)-pyridin-3-ylmethyl]-lH-pyrTolo[2,3-b]pyridine-5-carbonitrile; and
all salts, prodrugs, tautomers, or isomers thereof.
17. A composition comprising a pharmaceutically acceptable carrier and a compound
according to any of Claims 1-16.
18. A method for treating a subject suffering from or at risk of a c-kit and/or c-fms
mediated disease or condition, comprising administering to the subject an effective amount of a
compound of any of Claims 1-16.
19. The method of Claim 18, wherein the disease or condition is selected from the
group consisting of mast cell tumors, small cell lung cancer, testicular cancer, gastrointestinal
stromal tumors, 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 myeloid leukemia, acute lymphocytic
leukemia, chronic myelogenous leukemia, multiple myeloma, mastocytosis, melanoma, breast
cancer, ovarian cancer, prostate cancer, canine mast cell tumors, metastasis of cancer to bone or


other tissues, chronic myeloproliferative diseases such as myelofibrosis, renal hypertrophy,
asthma, rheumatoid arthritis, allergic rhinitis, multiple sclerosis, osteoarthritis, inflammatory bowel
syndrome, transplant rejection, systemic lupus erythematosis, ulcerative colitis, Crohn's disease,
chronic obstructive pulmonary disease, emphysema, Kawasaki's Disease, hemophagocytic
syndrome, multicentric reticulohistiocytosis, atherosclerosis, Type I diabetes, Type II diabetes,
insulin resistance, hyperglycemia, obesity, lipolysis, hypereosinophilia, osteoporosis, increased
risk of fracture, Paget's disease, hypercalcemia, osteomyelitis, peri-prosthetic or wcar-debris-
mediated osteolysis, endometriosis, glomerulonephritis, interstitial nephritis, Lupus nephritis,
tubular necrosis, diabetic nephropathy, stroke, Alzheimer's disease, Parkinson's disease,
inflammatory pain, chronic pain, and bone pain.
20. The method of Claims 19, wherein the compound is approved for administration
to a human.
21. A kit comprising a composition according to Claim 17.
22. The kit of Claim 21, wherein the composition is approved for a medical indication
selected from the group consisting of mast cell tumors, small cell lung cancer, testicular cancer,
gastrointestinal stromal tumors, 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 myeloid leukemia, acute
lymphocytic leukemia, chronic myelogenous leukemia, multiple myeloma, mastocytosis,
melanoma, breast cancer, ovarian cancer, prostate cancer, canine mast cell tumors, metastasis of
cancer to bone or other tissues, chronic myeloproliferative diseases such as myelofibrosis, renal
hypertrophy, asthma, rheumatoid arthritis, allergic rhinitis, multiple sclerosis, osteoarthritis,
inflammatory bowel syndrome, transplant rejection, systemic lupus erythematosis, ulcerative
colitis, Crohn's disease, chronic obstructive pulmonary disease, emphysema, Kawasaki's Disease,
hemophagocytic syndrome, multicentric reticulohistiocytosis, atherosclerosis, Type I diabetes,
Type II diabetes, insulin resistance, hyperglycemia, obesity, lipolysis, hypereosinophilia,
osteoporosis, increased risk of fracture, Paget's disease, hypercalcemia, osteomyelitis, peri-
prosthetic or wear-debris-mediated osteolysis, endometriosis, glomerulonephritis, interstitial
nephritis, Lupus nephritis, tubular necrosis, diabetic nephropathy, stroke, Alzheimer's disease,
Parkinson's disease, inflammatory pain, chronic pain, and bone pain.

Compounds active on the receptor protein tyrosine kinases c-kit and/or c-fms are provided herewith. Also provided herewith are compositions useful for treatment of c-kit mediated diseases or conditions and/or c-fms-mediated diseases or conditions, and methods for the use thereof.

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Patent Number 271905
Indian Patent Application Number 1879/KOLNP/2009
PG Journal Number 11/2016
Publication Date 11-Mar-2016
Grant Date 09-Mar-2016
Date of Filing 20-May-2009
Name of Patentee PLEXXIKON, INC.
Applicant Address 91 BOLIVAR DRIVE, SUITE A, BERKELEY, CA 94710
Inventors:
# Inventor's Name Inventor's Address
1 ARTIS, DEAN R. 50 ARLMONT DRIVE, KENSINGTON, CA 94707
2 WU, GUOXIAN 240 VENTURA AVENUE, PALO ALTO, CA 94306
3 ZHU, HONGYAO 91 BOLIVAR DRIVE, SUITE A, BERKELEY, CA 94710
4 NESPI, MARIKA 564 SAN LUIS ROAD, BERKELEY, CA 94707
5 ZHANG, CHAO 397 SPRINGFIELD PLAZA, MORAGA, CA 94556
6 IBRAHIM, PRABHA N. 3380 LUBICH DRIVE, MOUNTAIN VIEW, CA 94040
7 BREMER, RYAN 476 WELDON AVENUE, APT. 3, OAKLAND, CA 94610
8 ZHANG, JIAZHONG 888 FOSTER CITY BLVD., APT. Q4, FOSTER CITY, CA 94404
PCT International Classification Number C07D 471/04
PCT International Application Number PCT/US2007/085289
PCT International Filing date 2007-11-20
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/860,749 2006-11-22 U.S.A.